Chinese Consensus Report on Family-Based Helicobacter pylori Infection Control and Management (2021 Edition).

OBJECTIVE: Helicobacter pylori infection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-based H. pylori infection control and management to reduce the related disease burden. METHODS: Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. RESULTS: Experts discussed and modified the original 23 statements on family-based H. pylori infection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1) H. pylori infection and transmission among family members, (2) prevention and management of H. pylori infection in children and elderly people within households, and (3) strategies for prevention and management of H. pylori infection for family members. In addition to the 'test-and-treat' and 'screen-and-treat' strategies, this consensus also introduced a novel third 'family-based H. pylori infection control and management' strategy to prevent its intrafamilial transmission and development of related diseases. CONCLUSION: H. pylori is transmissible from person to person, and among family members. A family-based H. pylori prevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

Development and Validation of the Asia-Pacific Proximal Colon Neoplasia Risk Score.

BACKGROUND & AIMS: Patients found to be at high risk of advanced proximal neoplasia (APN) after flexible sigmoidoscopy screening should be considered for colonoscopy examination. We developed and validated a scoring system to identify persons at risk for APN. METHODS: We collected data from 7954 asymptomatic subjects (age, 50-75 y) who received screening colonoscopy examinations at 14 sites in Asia. We randomly assigned 5303 subjects to the derivation cohort and the remaining 2651 to the validation cohort. We collected data from the derivation cohort on age, sex, family history of colorectal cancer, smoking, drinking, body mass index, medical conditions, and use of nonsteroidal anti-inflammatory drugs or aspirin. Associations between the colonoscopic findings of APN and each risk factor were examined using the Pearson χ2 test, and we assigned each participant a risk score (0-15), with scores of 0 to 3 as average risk and scores of 4 or higher as high risk. The scoring system was tested in the validation cohort. We used the Cochran-Armitage test of trend to compare the prevalence of APN among subjects in each group. RESULTS: In the validation cohort, 79.5% of patients were classified as average risk and 20.5% were classified as high risk. The prevalence of APN in the average-risk group was 1.9% and in the high-risk group was 9.4% (adjusted relative risk, 5.08; 95% CI, 3.38-7.62; P < .001). The score included age (61-70 y, 3; ≥70 y, 4), smoking habits (current/past, 2), family history of colorectal cancer (present in a first-degree relative, 2), and the presence of neoplasia in the distal colorectum (nonadvanced adenoma 5-9 mm, 2; advanced neoplasia, 7). The c-statistic of the score was 0.74 (95% CI, 0.68-0.79), and for distal findings alone was 0.67 (95% CI, 0.60-0.74). The Hosmer-Lemeshow goodness-of-fit test statistic was greater than 0.05, indicating the reliability of the validation set. The number needed to refer was 11 (95% CI, 10-13), and the number needed to screen was 15 (95% CI, 12-17). CONCLUSIONS: We developed and validated a scoring system to identify persons at risk for APN. Screening participants who undergo flexible sigmoidoscopy screening with a score of 4 points or higher should undergo colonoscopy evaluation.

Prophylactic angiographic embolisation after endoscopic control of bleeding to high-risk peptic ulcers: a randomised controlled trial.

OBJECTIVES: In the management of patients with bleeding peptic ulcers, recurrent bleeding is associated with high mortality. We investigated if added angiographic embolisation after endoscopic haemostasis to high-risk ulcers could reduce recurrent bleeding. DESIGN: After endoscopic haemostasis to their bleeding gastroduodenal ulcers, we randomised patients with at least one of these criteria (ulcers≥20 mm in size, spurting bleeding, hypotensive shock or haemoglobin<9 g/dL) to receive added angiographic embolisation or standard treatment. Our primary endpoint was recurrent bleeding within 30 days. RESULTS: Between January 2010 and July 2014, 241 patients were randomised (added angiographic embolisation n=118, standard treatment n=123); 22 of 118 patients (18.6%) randomised to angiography did not receive embolisation. In an intention-to-treat analysis, 12 (10.2%) in the embolisation and 14 (11.4%) in the standard treatment group reached the primary endpoint (HR 1.14, 95% CI 0.53 to 2.46; p=0.745). The rate of reinterventions (13 vs 17; p=0.510) and deaths (3 vs 5, p=0.519) were similar. In a per-protocol analysis, 6 of 96 (6.2%) rebled after embolisation compared with 14 of 123 (11.4%) in the standard treatment group (HR 1.89, 95% CI 0.73 to 4.92; p=0.192). None of 96 patients died after embolisation compared with 5 (4.1%) deaths in the standard treatment group (p=0.108). In a posthoc analysis, embolisation reduced recurrent bleeding only in patients with ulcers≥15 mm in size (2 (4.5%) vs 12 (23.1%); p=0.027). CONCLUSIONS: After endoscopic haemostasis, added embolisation does not reduce recurrent bleeding. TRIAL REGISTRATION NUMBER: NCT01142180.

Asia-Pacific working group consensus on non-variceal upper gastrointestinal bleeding: an update 2018.

Non-variceal upper gastrointestinal bleeding remains an important emergency condition, leading to significant morbidity and mortality. As endoscopic therapy is the 'gold standard' of management, treatment of these patients can be considered in three stages: pre-endoscopic treatment, endoscopic haemostasis and post-endoscopic management. Since publication of the Asia-Pacific consensus on non-variceal upper gastrointestinal bleeding (NVUGIB) 7 years ago, there have been significant advancements in the clinical management of patients in all three stages. These include pre-endoscopy risk stratification scores, blood and platelet transfusion, use of proton pump inhibitors; during endoscopy new haemostasis techniques (haemostatic powder spray and over-the-scope clips); and post-endoscopy management by second-look endoscopy and medication strategies. Emerging techniques, including capsule endoscopy and Doppler endoscopic probe in assessing adequacy of endoscopic therapy, and the pre-emptive use of angiographic embolisation, are attracting new attention. An emerging problem is the increasing use of dual antiplatelet agents and direct oral anticoagulants in patients with cardiac and cerebrovascular diseases. Guidelines on the discontinuation and then resumption of these agents in patients presenting with NVUGIB are very much needed. The Asia-Pacific Working Group examined recent evidence and recommends practical management guidelines in this updated consensus statement.

FOXM1 promotes proliferation in human hepatocellular carcinoma cells by transcriptional activation of CCNB1.

The transcription factor Forkhead box protein M1 (FOXM1) plays critical roles in cancer development and progression, including human hepatocellular carcinoma (HCC). However, the regulatory role and underlying mechanisms of FOXM1 is still limited. Here, we found that the high level expression of FOXM1 and CCNB1 is closely associated with poor prognosis in HCC patients. And FOXM1 and CCNB1 were overexpressed concomitantly in liver tumor tissues. Knockdown of FOXM1 significantly inhibited the expression levels of CCNB1 in HCC cell lines at both the mRNA and protein levels. Mechanistic studies revealed that FOXM1 binds directly to the promoter region of CCNB1 and regulates the expression levels of the CCNB1 gene in the transcriptional level. Furthermore, the loss of functional and rescue experiments showed that CCNB1 is essential for FOXM1-driven proliferation in HCC cells. In the present study, our results partially explained the dysregulated expression of FOXM1 play an important role in proliferation of human hepatocellular carcinoma cells via transcriptional activation of CCNB1 expression. And it also highlights a FOXM1/CCNB1 axis could be a potential target for the treatment of HCCs.

A Risk-Scoring System Combined With a Fecal Immunochemical Test Is Effective in Screening High-Risk Subjects for Early Colonoscopy to Detect Advanced Colorectal Neoplasms.

BACKGROUND & AIMS: Age, sex, smoking, and family history are risk factors for colorectal cancer in Asia. The Asia-Pacific Colorectal Screening (APCS) scoring system was developed to identify subjects with a high risk for advanced neoplasm (AN). We tested an algorithm that combined APCS scores with fecal immunochemical test (FIT) in colorectal cancer screening. METHODS: We performed a multicenter prospective study, enrolling asymptomatic individuals older than 40 years old in 12 Asia-Pacific regions from December 2011 to December 2013. APCS scores were calculated for each individual (0-1 = low risk [LR], 2-3 = medium risk [MR], and 4-7 = high risk [HR] for AN). LR and MR subjects were offered FIT and referred for early colonoscopies if FIT results were positive. HR subjects were offered colonoscopies. The proportions of subjects with ANs were determined for each group based on colonoscopy findings; odd ratios for LR and MR subjects were calculated compared to LR individuals. We calculated the sensitivity of the APCS-FIT algorithm in identifying subjects with AN. RESULTS: A total of 5657 subjects were recruited: 646 subjects (11.4%) were considered LR, 3243 subjects (57.3%) were considered MR, and 1768 subjects (31.3%) were considered HR for AN. The proportions of individuals with an AN in these groups were 1.5%, 5.1%, and 10.9%, respectively. Compared with LR group, MR and HR subjects had a 3.4-fold increase and a 7.8-fold increase in risk for AN, respectively. A total of 70.6% subjects with AN (95% confidence interval: 65.6%-75.1%) and 95.1% subjects with invasive cancers (95% confidence interval: 82.2%-99.2%) were correctly instructed to undergo early colonoscopy examination. CONCLUSIONS: The APCS scoring system, which is based on age, sex, family history, and smoking, is a useful tool for determining risk for colorectal cancer and advanced adenoma in asymptomatic subjects. Use of the APCS score-based algorithm in triaging subjects for FIT or colonoscopy can substantially reduce colonoscopy workload.

POU2F2-oriented network promotes human gastric cancer metastasis.

BACKGROUND AND AIMS: Aberrant upregulation of POU2F2 expression has been discovered in metastatic gastric cancer (GC). However, the mechanisms underlying the aberrant upregulation and the potential functions of POU2F2 remain uncertain. DESIGN: The role and mechanism of POU2F2 in GC metastasis were investigated in gastric epithelial cells, GC cell lines and an experimental metastasis animal model by gain of function and loss of function. Upstream and downstream targets of POU2F2 were selected by bioinformatics and identified by luciferase reporter assay, electrophoretic mobility shift assay and chromatin immunoprecipitation PCR. The influence of miR-218 on its putative target genes (POU2F2, ROBO1 and IKK-ß) and GC metastasis was further explored via in vitro and in vivo approaches. RESULTS: Increased POU2F2 expression was detected in metastatic GC cell lines and patient samples. POU2F2 was induced by the activation of nuclear factor (NF)-κB and, in turn, regulated ROBO1 transcription, thus functionally contributing to GC metastasis. Finally, miR-218 was found to suppress GC metastasis by simultaneously mediating multiple molecules in the POU2F2-oriented network. CONCLUSIONS: This study demonstrated that NF-κB and the SLIT2/ROBO1 interaction network with POU2F2 as the central part may exert critical effects on tumour metastasis. Blocking the activation of the POU2F2-oriented metastasis network using miR-218 precursors exemplified a promising approach that sheds light on new strategies for GC treatment.

Risk of Colorectal Neoplasia in Individuals With Self-Reported Family History: A Prospective Colonoscopy Study from 16 Asia-Pacific Regions.

OBJECTIVES: We tested the hypothesis that the risk of colorectal cancer (CRC), advanced colorectal neoplasia (ACN), and colorectal adenoma among screening participants with different first-degree relatives (FDRs) affected by CRC was similar. METHODS: A multi-center, prospective colonoscopy study involving 16 Asia-Pacific regions was performed from 2008 to 2015. Consecutive self-referred CRC screening participants aged 40-70 years were recruited, and each subject received one direct optical colonoscopy. The prevalence of CRC, ACN, and colorectal adenoma was compared among subjects with different FDRs affected using Pearson's χ2 tests. Binary logistic regression analyses were performed to evaluate the risk of these lesions, controlling for recognized risk factors including age, gender, smoking habits, alcohol drinking, body mass index, and the presence of diabetes mellitus. RESULTS: Among 11,797 asymptomatic subjects, the prevalence of CRC was 0.6% (none: 0.6%; siblings: 1.1%; mother: 0.5%; father: 1.2%; ≥2 members: 3.1%, P<0.001), that of ACN was 6.5% (none: 6.1%; siblings: 8.3%; mother: 7.7%; father: 8.7%; ≥2 members: 9.3%, P<0.001), and that of colorectal adenoma was 29.3% (none: 28.6%; siblings: 33.5%; mother: 31.8%; father: 31.1%; ≥2 members: 38.1%, P<0.001). In multivariate regression analyses, subjects with at least one FDR affected were significantly more likely to have CRC (adjusted odds ratio (AOR)=2.02-7.89), ACN (AOR=1.55-2.06), and colorectal adenoma (AOR=1.31-1.92) than those without a family history. The risk of CRC (AOR=0.90, 95% confidence interval (CI) 0.34-2.35, P=0.830), ACN (AOR=1.07, 95% CI 0.75-1.52, P=0.714), and colorectal adenoma (AOR=0.96, 95% CI 0.78-1.19, P=0.718) in subjects with either parent affected was similar to that of subjects with their siblings affected. CONCLUSIONS: The risk of colorectal neoplasia was similar among subjects with different FDRs affected. These findings do not support the need to discriminate proband identity in screening participants with affected FDRs when their risks of colorectal neoplasia were estimated.

Polymorphisms in the vitamin D receptor gene and risk of primary biliary cirrhosis: a meta-analysis.

BACKGROUND AND AIM: Primary biliary cirrhosis (PBC) is a chronic and progressive cholestatic autoimmune liver disease. Although many studies have evaluated the association between many functional polymorphisms in the vitamin D receptor (VDR) gene and PBC risk, debates still exist. Our aim is to evaluate the association between VDR gene polymorphisms, including TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232), and the risk of PBC by a systematic review. METHODS: We searched literatures in PubMed, SCOPUS, and EMBASE until July 2013. We calculated pooled odds ratios (OR) and 95% confidence intervals (CIs) using a fixed effects model or a random effects model for the risk to PBC associated with different VDR gene polymorphisms. And the heterogeneity assumption decided the effect model. RESULTS: A total of six relevant studies, with 1322 PBC cases and 2264 controls, were included in this meta-analysis. The results indicated that TaqI (rs731236) polymorphism was significantly associated with PBC risk (for T vs t OR = 0.75, 95% CI 0.63, 0.89, Pz = 0.001; TT + Tt vs tt OR = 0.62, 95% CI 0.44, 0.86, Pz = 0.005; OR = 0.74, 95% CI 0.58, 0.94, Pz = 0.016 for recessive model), while ApaI (rs7975232) or BsmI (rs1544410) polymorphism did not. CONCLUSION: Based on current evidences from published studies, the cumulative effect of TaqI polymorphism in VDR was significantly associated with PBC. Larger studies with mixed ethnicity subjects and stratified by clinical and sub clinical characteristics are needed to validate our findings.

Geographic differences in psychological symptoms, sleep quality, and quality of life in patients with inflammatory bowel disease: A multicenter study in China.

OBJECTIVE: We aimed to explore the geographic differences in psychological symptoms, sleep quality, and quality of life (QoL) among adult patients with inflammatory bowel disease (IBD). METHODS: A unified questionnaire was developed to collect data on psychological status and QoL of IBD patients from 42 hospitals across 22 provinces, municipalities, and autonomous regions in China's mainland from September 2021 to May 2022. RESULTS: A total of 2478 patients with IBD were surveyed. The proportions of patients with anxiety (28.5% vs 23.1%), depression (32.3% vs 27.8%), and poor QoL (44.8% vs 32.2%) were significantly higher in patients from the northern region compared to the southern region (all P < 0.05). In the western region, the proportions of patients with anxiety (31.9% vs 23.0%), depression (37.7% vs 26.7%), sleep disturbances (64.5% vs 58.5%), and poor QoL (44.9% vs 34.8%) were significantly higher than in the eastern and central regions (all P < 0.01). Patients from inland regions had significantly higher rates of anxiety (27.1% vs 23.3%), depression (32.5% vs 26.0%), sleep disturbance (62.0% vs 57.7%), and poor QoL (43.5% vs 29.9%) compared to those from coastal regions (all P < 0.05). In economically underdeveloped areas, the proportions of patients with depression (33.1% vs 28.5%) and poor QoL (52.0% vs 32.4%) were significantly higher than in economically (relatively) developed areas (both P < 0.05). CONCLUSION: There are significant geographic differences in psychological symptoms, sleep quality, and QoL among Chinese patients with IBD, which might provide valuable insights for global IBD research and clinical practice.

Increased expression of FOXQ1 is a prognostic marker for patients with gastric cancer.

Altered expression of forkhead box Q1 (FOXQ1) is observed in various types of human cancers. However, the clinical significance of FOXQ1 expression in gastric cancer (GC) remains largely unknown. The present study aims to explore the clinicopathological significance and prognostic value of FOXQ1 in GC. FOXQ1 messenger RNA (mRNA) and protein expression were determined by quantitative real-time reverse transcriptase-polymerase chain reaction and Western blot in 20 pairs of fresh frozen GC tissues and corresponding noncancerous tissues. Additionally, FOXQ1 expression was analyzed by immunohistochemistry in 158 clinicopathologically characterized GC cases. The correlation of FOXQ1 expression with patients' survival rate was assessed by Kaplan-Meier and Cox regression. Our results showed that the expression levels of FOXQ1 mRNA and protein in GC tissues were both significantly higher than those in non-cancerous tissues. Our results showed that the high expression of FOXQ1 in GC was related to tumor size (P = 0.026), histological grade (P = 0.021), lymph node involvement (P = 0.002), and tumor-node-metastasis stage (P = 0.028). Kaplan-Meier survival analysis showed that a high expression level of FOXQ1 resulted in a significantly poor prognosis of GC patients. Furthermore, Cox multivariates analysis indicated that FOXQ1 expression level was an independent prognostic factor for the overall survival rate of GC patients. In conclusion, overexpression of FOXQ1 is closely related to progression of GC and might be regarded as an independent predictor of poor prognosis for GC.

Incidence and disease-related risk factors for cerebrovascular accidents in patients with inflammatory bowel diseases: A systematic review and meta-analysis.

OBJECTIVES: Risk of cerebrovascular accidents (CVAs) in patients with inflammatory bowel disease (IBD) remains inconclusive. In this systematic review and meta-analysis, we aimed to estimate the incidence of and identify the risk factors for CVA in patients with IBD. METHODS: PubMed, EMBASE and Web of Science were searched for articles published up to January 13, 2023 to identify those reported the incidence of CVA in IBD patients, along with the total person-years or related data to calculate it. The main outcomes were the incidence of and risk factors for CVA in IBD. RESULTS: Based on the analysis of 10 studies, the pooled incidence of CVA in IBD patients was 2.74 per 1000 person-years (95% confidence interval [CI] 1.83-4.10 person-years; I2 = 99.2%), which was higher than that in the general population (incidence rate ratio [IRR] 1.21, 95% CI 1.09-1.34, P = 0.0002; I2 = 84.8%). Risk factors for CVA in IBD patients were age (significance in different definitions), ulcerative colitis (IRR 1.214, 95% CI 1.000-1.474, P = 0.0499; I2 = 81.9%), disease flares (IRR 1.699, 95% CI 1.359-2.122, P < 0.0001; I2 = 28.7%) and chronic activity (IRR 2.202, 95% CI 1.378-3.519, P = 0.0010; I2 = 83.0%). CONCLUSIONS: The risk of CVA modestly increased in IBD patients. Both the traditional and IBD-related risk factors should be managed to prevent CVA in these patients. Since the effects of risk factors were derived from pooled results of only 2-3 studies, further research is needed to confirm our results.

Consensus for criteria of running a pediatric inflammatory bowel disease center using a modified Delphi approach.

BACKGROUND: Good quality of care for inflammatory bowel disease (IBD) depends on high-standard management and facility in the IBD center. Yet, there are no clear measures or criteria for evaluating pediatric IBD (PIBD) center in China. The aim of this study was to develop a comprehensive set of quality indicators (QIs) for evaluating PIBD center in China. METHODS: A modified Delphi consensus-based approach was used to identify a set of QIs of structure, process, and outcomes for defining the criteria. The process included an exhaustive search using complementary approaches to identify potential QIs, and two web-based voting rounds to select the QIs defining the criteria for PIBD center. RESULTS: A total of 101 QIs (35 structures, 48 processes and 18 outcomes) were included in this consensus. Structure QIs focused on the composition of multidisciplinary team, facilities and services that PIBD center should provide. Process QIs highlight core requirements in diagnosing, evaluating, treating PIBD, and disease follow-up. Outcome QIs mainly included criteria evaluating effectiveness of various interventions in PIBD centers. CONCLUSION: The present Delphi consensus developed a set of main QIs that may be useful for managing a PIBD center. Video Abstract.

Knowledge of, attitudes toward, and barriers to participation of colorectal cancer screening tests in the Asia-Pacific region: a multicenter study.

BACKGROUND: The rapid increase in the incidence of colorectal cancer (CRC) in the Asia-Pacific region in the past decade has resulted in recommendations to implement mass CRC screening programs. However, the knowledge of screening and population screening behaviors between countries is largely lacking. OBJECTIVE: This multicenter, international study investigated the association of screening test participation with knowledge of, attitudes toward, and barriers to CRC and screening tests in different cultural and sociopolitical contexts. METHODS: Person-to-person interviews by using a standardized survey instrument were conducted with subjects from 14 Asia-Pacific countries/regions to assess the prevailing screening participation rates, knowledge of and attitudes toward and barriers to CRC and screening tests, intent to participate, and cues to action. Independent predictors of the primary endpoint, screening participation was determined from subanalyses performed for high-, medium-, and low-participation countries. RESULTS: A total of 7915 subjects (49% male, 37.8% aged 50 years and older) were recruited. Of the respondents aged 50 years and older, 809 (27%) had undergone previous CRC testing; the Philippines (69%), Australia (48%), and Japan (38%) had the highest participation rates, whereas India (1.5%), Malaysia (3%), Indonesia (3%), Pakistan (7.5%), and Brunei (13.7%) had the lowest rates. Physician recommendation and knowledge of screening tests were significant predictors of CRC test uptake. In countries with low-test participation, lower perceived access barriers and higher perceived severity were independent predictors of participation. Respondents from low-participation countries had the least knowledge of symptoms, risk factors, and tests and reported the lowest physician recommendation rates. "Intent to undergo screening" and "perceived need for screening" was positively correlated in most countries; however, this was offset by financial and access barriers. LIMITATIONS: Ethnic heterogeneity may exist in each country that was not addressed. In addition, the participation tests and physician recommendation recalls were self-reported. CONCLUSIONS: In the Asia-Pacific region, considerable differences were evident in the participation of CRC tests, physician recommendations, and knowledge of, attitudes toward, and barriers to CRC screening. Physician recommendation was the uniform predictor of screening behavior in all countries. Before implementing mass screening programs, improving awareness of CRC and promoting the physicians' role are necessary to increase the screening participation rates.

Digestive cancer management in Asia: position statements: a report on GI Oncology Summit in 2011.

BACKGROUND AND AIM: With the rising incidence of digestive cancers in the Asia Pacific region and the advancement in diagnosis, management and palliation in these conditions, the clinical burden on oncologists is ever increasing. This Summit meeting was called to discuss the optimal management of digestive cancers and the role of Gastroenterologists. METHOD: Experts from Asia Pacific countries in the fields of medical, oncologic, surgical and endoscopic management of cancers in the esophagus, stomach, colon/rectum and the liver reviewed the literature and their practice. 18 position statements were drafted, debated and voted. RESULTS: It was agreed that the burden on GI cancer is increasing. More research will be warranted on chemotherapy, chemoprevention, cost-effectiveness of treatment and nutrition. Cancer management guidelines should be developed in this region when more clinical data are available. In order to improve care to patients, a multi-disciplinary team coordinated by a "cancer therapist" is proposed. This cancer therapist can be a gastroenterologist, a surgeon or any related discipline who have acquired core competence training. This training should include an attachment in a center-of-excellence in cancer management for no less than 12 months. CONCLUSION: The management of GI cancer should be an integrated multi-disciplinary approach and training for GI cancer therapists should be provided for.

RUNX3 directly interacts with intracellular domain of Notch1 and suppresses Notch signaling in hepatocellular carcinoma cells.

RUNX3 takes a strong suppressive effect in many tumors including hepatocellular carcinoma (HCC). HES-1, a downstream target of Notch signaling, is shown to be decreased in human HCC cell line SMMC7721 with RUNX3 gene transfection. Since Notch signaling is oncogenic in HCC, RUNX3 might exert its inhibitory effect in HCC partly through the suppression on Notch signaling. To investigate the possible mechanism of the down-regulation of HES-1 by RUNX3, we performed Western blot and reporter assay and found that RUNX3 suppressed intracellular domain of Notch1 (ICN1)-mediated transactivation of Notch signaling while it did not alter the expression of ICN1 and recombination signal binding protein-J kappa (RBP-J) in SMMC7721 cells. Besides, confocal microscopy, co-immunoprecipitation and GST pull-down assays showed that RUNX3 could co-localize with ICN1 and RBP-J, forming a complex with these two molecules in nucleus of SMMC7721 cells by its direct interaction with ICN1. Furthermore, RUNX3 was recruited to RBP-J recognition motif of HES-1 promoter, which was identified by chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA). Taken together, these findings indicate that RUNX3 suppresses Notch signaling in HCC SMMC7721 cells by its interaction with ICN1 and thus recruitment to the RBP-J recognition motif of downstream genes of Notch signaling.

[Early hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: the risk factors and long-time survival].

OBJECTIVE: To identify the risk factors of early post-TIPS hepatic encephalopathy (HE) and the long-time survival of patients with or without early post-TIPS HE. METHODS: Consecutive cirrhotic patients who underwent TIPS for variceal rebleeding or refractory ascites in our center from January 2003 to December 2008 were included in this study. More than 60 clinical characteristics were enrolled in univariate analysis and logistic regression analysis to define the risk factors of HE in 3 months after TIPS procedure (early post-TIPS HE). The long-time survival of patients with or without early post-TIPS HE was compared by Cox regression with several covariates. RESULTS: According to our inclusion criteria, 190 patients were included. The median follow-up was 30.5 months. Lower serum concentration of fibrinogen and higher Child-Pugh score were the independent risk factors for suffering early post-TIPS HE. Patients without early post-TIPS HE after TIPS showed better prognosis than those with early post-TIPS HE after TIPS (P = 0.044). CONCLUSION: Patients with lower serum fibrinogen and higher Child-Pugh score before TIPS might be more probably attacked by early post-TIPS HE which indicated worse long-term survival.

Potent inhibition of human gastric cancer by HER2-directed induction of apoptosis with anti-HER2 antibody and caspase-3 fusion protein.

BACKGROUND AND AIMS: HER2, an oncogene, has been found to be over-expressed in 10-40% of human gastric carcinomas. The aims of this study were to investigate if a fusion protein consisting of anti-HER2 sFv and constitutively active caspase-3 was capable of inducing apoptosis in HER2-expressing human gastric cancer cells and blocking the growth of human gastric cancer xenografts in nude mice. METHODS: NIH3T3 cells stably transduced with the pcDNA3.1-HER-PE-CP3 recombinant plasmid containing a secretion signal, a single-chain anti-HER2 monoclonal antibody fragment, a Pseudomonas exotoxin A translocation domain and a constitutively active caspase-3 molecule were used to induce apoptosis in human gastric cancer cells both in vitro and in vivo. Immunofluorescence staining and western blotting were used to examine the expression of the recombinant protein HER-PE-CP3. Apoptosis was determined by flow cytometry and TUNEL assay. RESULTS: Co-cultivation of HER-PE-CP3/ NIH3T3 with human gastric cancer cells led to internalisation of HER-PE-CP3 and apoptosis in HER2-expressing human gastric cancer cells but not in HER2-negative cancer cells. Inoculation of HER-PE-CP3/NIH3T3 in nude mice resulted in potent inhibition of human gastric cancer xenografts and much prolonged survival time of the tumour-bearing mice compared with the control. Significantly more apoptotic cells were detected in xenografts in mice receiving HER-PE-CP3/NIH3T3 than in control mice. CONCLUSIONS: The HER-PE-CP3 chimeric molecule could induce selective apoptosis and potent growth inhibition of HER2-positive human gastric cancer cells and might represent a novel HER2-directed treatment option for human gastric cancer.

Association of Serum Immunoglobulins Levels With Specific Disease Phenotypes of Crohn's Disease: A Multicenter Analysis in China.

Background and Aim: Serum immunoglobulins were reported to be associated with clinical characteristics of inflammatory bowel disease. However, whether a difference exists in the serum immunoglobulins levels in patients with Crohn's disease (CD) with different disease location and behavior phenotypes remains unclear. Therefore, this study aimed to explore the associations of serum immunoglobulins levels with specific CD phenotypes. Methods: Patients with CD having recorded serum immunoglobulins levels were recruited through multicenter collaborative efforts. The associations between serum immunoglobulins levels and distinct phenotypes of CD were evaluated using multiple logistic regression models. Results: A total of 608 patients with CD were included in the study. Elevated (above the upper limit of normal) serum immunoglobulin G (IgG), IgA, IgM, and IgG4 were identified in 24.5, 17.4, 2.1, and 8.2% of patients, respectively. Elevated serum IgG4 levels negatively correlated with complicated disease behavior [odds ratio (OR) 0.49, 95% confidence interval (CI) 0.26-0.92]. Elevated serum IgG was linked to isolated ileal disease with an OR of 0.37 (95% CI 0.23-0.61). The ORs of isolated ileal disease progressively reduced across increasing quartiles of IgG (P for trend < 0.001). The adjusted ORs of isolated ileal disease for increasing quartiles of IgM were 1.82 (1.07-3.1), 1.92 (1.14-3.24), 1.17 (0.69-1.98), and 1 (P for trend = 0.008). Besides, serum IgA and IgG levels significantly correlated with several disease activity indices. Conclusions: These results suggested that certain serum immunoglobulins were associated with specific disease phenotypes of CD. Further investigations to account for the associations are warranted.