Transcriptome analysis of potential candidate genes and molecular pathways in colitis-associated colorectal cancer of Mkp-1-deficient mice.

BACKGROUND: The nuclear phosphatase mitogen-activate protein kinase phosphatase-1 (MKP-1) is a key negative regulator of the innate immune response through the regulation of the biosynthesis of proinflammatory cytokines. In colorectal cancer (CRC), which is induced mainly by chronic inflammation, Mkp-1 overexpression was found in addition to disturbances in Mkp-1 functions, which may play a role in cancer development in different types of tumors. However, the potential molecular mechanisms by which Mkp-1 influences CRC development is not clear. Here, we performed global gene expression profiling of Mkp-1 KO mice using RNA sequencing (RNA-seq) to explore the role of Mkp-1 in CRC progression using transcriptome analysis. METHODS: Azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models were used to examine the most dramatic molecular and signaling changes that occur during different phases of CRC development in wild-type mice and Mkp-1 KO mice. Comprehensive bioinformatics analyses were used to elucidate the molecular processes regulated by Mkp-1. Differentially expressed genes (DEGs) were identified and functionally analyzed by Gene Ontology (GO), Kyoto Enrichment of Genes and Genomes (KEGG). Then, protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape software. RESULTS: Persistent DEGs were different in adenoma and carcinoma stage (238 & 251, respectively) and in WT and MKp-1 KO mice (221& 196, respectively). Mkp-1 KO modulated key molecular processes typically activated in cancer, in particular, cell adhesion, ion transport, extracellular matrix organization, response to drug, response to hypoxia, and response to toxic substance. It was obvious that these pathways are closely associated with cancer development and metastasis. From the PPI network analyses, nine hub genes associated with CRC were identified. CONCLUSION: These findings suggest that MKp-1 and its hub genes may play a critical role in cancer development, prognosis, and determining treatment outcomes. We provide clues to build a potential link between Mkp-1 and colitis-associated tumorigenesis and identify areas requiring further investigation.

Identification of novel Nrf2 target genes as prognostic biomarkers in colitis-associated colorectal cancer in Nrf2-deficient mice.

AIMS: Colorectal cancer (CRC) is the third most common cancer worldwide. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of many cytoprotective genes, plays a protective role in carcinogenesis. Recent studies have identified a specific gene-expression signature regulated by the Nrf2 pathway in lung adenocarcinoma and head-and-neck squamous cell cancer. However, the roles of Nrf2 in the development of colitis-associated colorectal cancer (CACC) have not been well characterized. Nrf2 target genes as prognostic biomarkers in CACC remain to be explored. Thus, this work aimed to identify the molecular changes that occur during mouse CACC progression to facilitate the development of diagnostic and prognostic biomarkers. MAIN METHODS: The CACC model was established using azoxymethane (AOM) with dextran sulfate sodium salt (DSS) in BALB/c mice for 3 weeks to induce colitis-associated adenoma (CAA, early stage) and for 9 weeks to induce colitis-associated carcinoma (CAC, late stage). Using RNA-sequencing and bioinformatics analyses we examined the mRNA expression profiles of 6 groups: wild-type control (WT-C), WT-CAA, WT-CAC, Nrf2 knockout control (Nrf2KO-C), Nrf2KO-CAA, and Nrf2KO-CAC. KEY FINDINGS: In the AOM/DSS model of colitis-associated tumorigenesis, Nrf2-/- mice showed a phenotype similar to WT mice, but with significantly more tumors and a much higher percentage of adenocarcinomas. We identified 47 novel Nrf2 genes via gene expression profiling of tumor samples. Survival analysis showed that 23 of these genes were biomarkers of a poor prognosis in colon cancer patients. SIGNIFICANCE: Nrf2 target genes deserve exploration as prognostic and therapeutic targets for CRC.

AKR1B10 expression predicts response of gastric cancer to neoadjuvant chemotherapy.

Effective methods for predicting tumor response to preoperative chemotherapy are required. Aldo-ketoreductase family 1 member B10 (AKR1B10) is predominantly expressed in the gastrointestinal tract and serves an important function in cancer development and progression. The present study investigated whether AKR1B10 expression may predict the therapeutic response of locally advanced gastric cancer. A total of 53 patients with gastric cancer underwent neoadjuvant chemotherapy followed by surgery between January 2006 and December 2015. The protein expression level of AKR1B10 was determined in paraffin-embedded biopsy specimens using immunohistochemistry. Western blotting confirmed that the AKR1B10 protein is primarily localized to the cytoplasm. χ2 and Fisher's exact tests were used to determine the association of AKR1B10 with a number of clinic opathological features. Univariate and multivariate analyses were used to identify the prognostic factors. Survival rates were compared using Kaplan-Meier curves with a log-rank test. The positive rate of AKR1B10 protein expression was 58.5%, whereas 41.5% samples exhibited negative expression. The frequency of AKR1B10-positive gastric cancer samples was increased in patients with lymph node metastasis and decreased in those exhibiting tumor regression. The 5-years overall survival rate for the AKR1B10-positive group was significantly poorer than that for the AKR1B10-negative group. AKR1B10 expression was associated with lymph node metastasis and a poorer prognosis, along with a poor response to neoadjuvant chemotherapy suggesting that AKR1B10 may be a potential predictor for the therapeutic response of locally-advanced gastric cancer.

Risk Factors and Nomogram for Common Bile Duct Stricture in Chronic Pancreatitis: A Cohort of 2153 Patients.

GOALS: To identify the risk factors and develop nomograms for common bile duct (CBD) stricture in chronic pancreatitis (CP) patients. BACKGROUND: CBD stricture is a common complication in CP and has a variable clinical presentation ranging from asymptomatic to overt jaundice and cholangitis. STUDY: Patients with CP admitted to Changhai Hospital (Shanghai, China) from January 2000 to December 2013 were enrolled. Cumulative rates of CBD stricture after onset and diagnosis of CP were calculated. Patients were randomly assigned, in a 2:1 ratio, to the training and validation cohort. On the basis of the training cohort, risk factors for CBD stricture and symptomatic CBD stricture were identified through Cox proportional hazards regression model, and nomograms was developed, respectively. Internal and external validations were performed based on the training and validation cohort, respectively. RESULTS: With a total of 2153 patients, the median duration of follow-up was 7.0 years. CBD strictures were detected in 340 (15.8%) patients, whereas 159 of them were symptomatic. Male gender, age at onset of CP, smoking, body mass index, and morphology of main pancreatic duct were identified risk factors for CBD stricture development. Age at onset of CP, body mass index, and type of pain were identified risk factors for symptomatic CBD stricture development. Both nomograms achieved good concordance indexes with well-fitted calibration curves. CONCLUSIONS: The nomogram achieved an individualized prediction of symptomatic CBD stricture development in CP patients. It may help the early diagnosis and intervention of symptomatic CBD stricture and reduce the rates of severe adverse events.

Spatial Distribution of Pancreatic Stones in Chronic Pancreatitis.

OBJECTIVES: The aim of this study was to establish a standard to describe the spatial distribution of pancreatic stones in chronic pancreatitis (CP). METHODS: Two hundred forty-seven CP patients with pancreatic stones from June to December 2012 were enrolled. Two-dimensional images from coronal projection of 3-dimensional computed tomography images of pancreatic stones were gained. The number (n) of all stones and the geometric standard deviation (σ) of distances between the centroid of all stones and the centroids of every stone that represented the spatial distribution nonuniformity were calculated by Stone Reconstruction and Identification Programming System. RESULTS: The mean value of n and σ were 13.6 and 22.5; n > 13.6 and σ > 22.5 were determined as "multistones" and "nonuniform," respectively. Compared with alcoholic CP, idiopathic CP was less prone to multistones (odds ratio [OR], 0.310) and more prone to nonuniform (OR, 3.247). Pancreatic pseudocyst (OR, 2.211) in CP course was a risk factor of multistones, whereas diabetes mellitus in first-/second-/third-degree relatives (OR, 0.382) was a protective factor. Age at diagnosis of pancreatic stones (OR, 1.022) was a risk factor of nonuniformity. CONCLUSIONS: Compared with idiopathic CP, alcoholic CP patients were prone to more pancreatic stones that distribute more uniformly.

Extracorporeal Shock Wave Lithotripsy for Chronic Pancreatitis Patients With Stones After Pancreatic Surgery.

OBJECTIVES: The objective of this study was to evaluate the safety and efficacy of pancreatic extracorporeal shock wave lithotripsy (P-ESWL) in chronic pancreatitis (CP) patients with pancreatic stones after previous pancreatic surgery. METHODS: This is a single-center study prospectively conducted in pained CP patients undergoing P-ESWL. Patients with a pancreatic surgery history (PSH) were included in the PSH group, and patients without a PSH during the same period were assigned to the control group. The primary outcomes included complications associated with P-ESWL and pain relief. Secondary outcomes included stone clearance and improved quality-of-life scores. RESULTS: From March 2011 to October 2014, P-ESWLs were performed on 1017 patients (50 in the PSH group, 967 in the control group). No significant difference was observed in the frequency of occurrence of P-ESWL complications between the PSH group and control group (14.0% vs 13.2%, P = 0.877). At follow-up (2.6 years; range, 1.0-4.5 years), pain relief was achieved in 36 patients (75.0%), and 37 patients (77.1%) experienced complete stone clearance. No significant differences were observed between these patients and the matched controls. CONCLUSIONS: For CP patients who develop painful stones after pancreatic surgery, P-ESWL safely achieves significant pain relief and stone clearance, preventing the need for a repeat surgery.

Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients.

BACKGROUND: Risk of pancreatic cancer may increase in chronic pancreatitis patients. AIMS: This study aimed to identify the incidence of and risk factors for pancreatic cancer in chronic pancreatitis patients. METHODS: Chronic pancreatitis patients admitted to our center from January 2000 to December 2013 were enrolled. Cumulative rates of pancreatic cancer and survival rates were calculated. The standardized incidence ratio was calculated based on the pancreatic cancer incidence in general population of China. Risk factors for pancreatic cancer were identified. RESULTS: In a total of 1656 patients, the median follow-up duration was 8.0 years. Pancreatic cancer was detected in 21 patients (1.3%). The expected number of cases of pancreatic cancer was 1.039, yielding a standardized incidence ratio of 20.22. The standardized incidence ratios for patients with a >60 pack-year smoking history were much higher (145.82). Two risk factors for pancreatic cancer were identified: age at the onset of chronic pancreatitis (hazard ratio, 1.05) and a >60 pack-year smoking history (hazard ratio, 11.83). CONCLUSION: The risk of pancreatic cancer is markedly increased in chronic pancreatitis patients compared with the general population, especially in patients with an older age at onset and a >60 pack-year smoking history. The high-risk populations were suggested to be followed up closely.

Extracorporeal shock wave lithotripsy is safe and effective for pediatric patients with chronic pancreatitis.

Background and aims Pancreatic extracorporeal shock wave lithotripsy (P-ESWL) is recommended as the first-line treatment for pancreatic stones. However, how well P-ESWL performs in pediatric patients remains unclear. We aimed to evaluate the safety and efficacy of P-ESWL for pediatric patients with chronic pancreatitis. Methods This prospective observational study was conducted in patients with painful chronic pancreatitis who underwent P-ESWL. Patients aged under 18 years were included in the pediatric group; patients aged over 18 years who underwent P-ESWL in the same period were assigned to the control group. For investigation of long-term follow-up, the pediatric group were matched with patients from the control group in a 1:1 ratio. The primary outcomes were P-ESWL complications and pain relief. The secondary outcomes included: stone clearance, physical and mental health, quality of life score, and growth and developmental state. Results From March 2011 to March 2015, P-ESWL was performed in 1135 patients (72 in the pediatric group, 1063 in the control group). No significant differences were observed in the occurrence of P-ESWL complications between the two groups (11.1 % vs. 12.8 %; P = 0.68). Among the 67 pediatric patients (93.1 %) who underwent follow-up for 3.0 years (range 1.3 - 5.2), complete pain relief was achieved in 52 patients (52 /67; 77.6 %); this value was not significantly different from that of the matched controls (55 /69; 79.7 %; P = 0.94). Conclusions P-ESWL is safe and effective for pediatric patients with chronic pancreatitis. It can promote significant pain relief and stone clearance, and can benefit growth and development.

Risk factors and nomogram for pancreatic pseudocysts in chronic pancreatitis: A cohort of 1998 patients.

BACKGROUND AND AIM: Pancreatic pseudocyst is a common complication of chronic pancreatitis. The identification of risk factors and development of a nomogram for pancreatic pseudocysts in chronic pancreatitis patients may contribute to the early diagnosis and intervention of pancreatic pseudocysts. METHODS: Patients with chronic pancreatitis admitted to our center from January 2000 to December 2013 were enrolled. Cumulative rates of pancreatic pseudocysts after the onset of chronic pancreatitis and after the diagnosis of chronic pancreatitis were calculated. Patients were randomly assigned, in a 2:1 ratio, to the training and validation cohort. Based on the training cohort, risk factors were identified through Cox proportional hazards regression model, and nomogram was developed. Internal and external validations were performed based on the training and validation cohort, respectively. RESULTS: With a total of 1998 patients, pancreatic pseudocysts were detected in 228 (11.41%) patients. Age at the onset of chronic pancreatitis, smoking, and severe acute pancreatitis were identified risk factors for pancreatic pseudocysts development while steatorrhea and pancreatic stones were protective factors. Incorporating these five factors, the nomogram achieved good concordance indexes of 0.735 and 0.628 in the training and validation cohorts, respectively, with well-fitted calibration curves. CONCLUSION: The nomogram achieved an individualized prediction of pancreatic pseudocysts development in chronic pancreatitis. It may help the early diagnosis and management of pancreatic pseudocysts.

Risk Factors for Diabetes Mellitus in Chronic Pancreatitis: A Cohort of 2,011 Patients.

Diabetes mellitus (DM) is a common complication of chronic pancreatitis (CP) and increases the mortality. The identification of risk factors for DM development may contribute to the early detection and potential risk reduction of DM in patients with CP.Patients with CP admitted to Changhai Hospital (Shanghai, China) from January 2000 to December 2013 were enrolled. Cumulative rates of DM after the onset of CP were calculated by Kaplan-Meier method. Risk factors for DM development after the diagnosis of CP were identified by Cox proportional hazards regression model.A total of 2011 patients with CP were enrolled. During follow-up (median duration, 22.0 years), 564 patients developed DM. Cumulative rates of DM 20 and 50 years after the onset of CP were 45.8% (95% confidence interval [CI], 41.8%-50.0%) and 90.0% (95% CI, 75.4%-97.7%), respectively. Five risk factors for DM development after the diagnosis of CP were identified: male sex (hazard ratio [HR], 1.51; 95% CI, 1.08-2.11), alcohol abuse (HR, 2.00; 95% CI, 1.43-2.79), steatorrhea (HR, 1.46; 95% CI, 1.01-2.11), biliary stricture (HR, 2.25; 95% CI, 1.43-3.52), and distal pancreatectomy (HR, 3.41; 95% CI, 1.80-6.44).In conclusion, the risk of developing DM in patients with CP is not only influenced by the development of biliary stricture and steatorrhea indicating disease progression, and inherent nature of study subjects such as male sex, but also by modifiable factors including alcohol abuse and distal pancreatectomy.

Risk Factors for Steatorrhea in Chronic Pancreatitis: A Cohort of 2,153 Patients.

This study aimed to investigate the occurrence of and determine the risk factors for steatorrhea in chronic pancreatitis (CP). It was based on analysis of both retrospectively and prospectively acquired database for CP patients admitted to our center from January 2000 to December 2013. Demographic data, course of disease, medical history, and follow-up evaluations of patients were documented in detail. Cumulative rate of steatorrhea was calculated by using the Kaplan-Meier method. For risk factor analysis, multivariate analysis by Cox proportional hazards regression model was performed. A total of 2,153 CP patients were included with a mean follow-up duration of 9.3 years. Approximately 14% (291/2,153) of CP patients presented with steatorrhea at diagnosis of CP. Cumulative rates of steatorrhea at 1, 5, 10, and 20 years after diagnosis of CP were 4.27% (95% CI: 3.42%-5.34%), 12.53% (95% CI: 10.74%-14.59%), 20.44% (95% CI: 17.37%-23.98%) and 30.82% (95% CI: 20.20%-45.21%), respectively. Male gender (HR = 1.771, p = 0.004), diabetes (HR = 1.923, p < .001), alcohol abuse (HR = 1.503, p = 0.025) and pancreaticoduodenectomy (HR = 2.901, p < 0.001) were independent risk factors for steatorrhea while CP in adolescents (HR = 0.433, p = 0.009) was a protective factor. In conclusion, male gender, adult, diabetes, alcohol abuse and pancreaticoduodenectomy lead to increased risk of steatorrhea in CP patients.

Extracorporeal shock wave lithotripsy is a safe and effective treatment for pancreatic stones coexisting with pancreatic pseudocysts.

BACKGROUND AND AIMS: We aimed to investigate outcomes of pancreatic extracorporeal shock wave lithotripsy (P-ESWL) for the removal of large pancreatic stones coexisting with pancreatic pseudocysts (PPCs) in chronic pancreatitis (CP). METHODS: This is a prospective study performed in CP patients with at least 1 stone (≥5 mm). Patients were divided into the PPC group (stones coexisting with PPCs) or the control group (stones alone). Patients were initially subjected to successive P-ESWL treatments, followed by ERCP. Primary outcomes were P-ESWL adverse events, and secondary outcomes were stone clearance, long-term pain relief, improved quality-of-life scores, and PPC regression. RESULTS: A total of 849 patients (59 in the PPC group and 790 in the control group) was subjected to P-ESWL between March 2011 and October 2013. Occurrences of P-ESWL adverse events were similar between the PPC group and the control group (11.86% vs 12.41%, P = .940). After the treatment of initial P-ESWL combined with ERCP, the complete, partial, and nonclearance of stones occurred in 67.24%, 20.69%, and 12.07%, respectively, of patients in PPC group, with no significant difference from the control group (complete, partial, and nonclearance: 83.17%, 10.40%, and 11.39%, respectively; P = .106). Fifty-five of 59 patients (93.22%) with PPCs were followed for a median period of 21.9 months (range, 12.0-45.1). PPCs disappeared in 56.36% (31/55) and 76.36% (42/55) of patients after 3 months and 1 year of follow-up visits, respectively. Moreover, complete and partial pain relief were achieved in 63.64% (35/55) and 25.45% (14/55) of patients, respectively. The scores for quality of life (P < .001), physical health (P < .001), and weight loss (P < .001) improved. CONCLUSIONS: In our multispecialty tertiary center, initial P-ESWL followed by ERCP was safe in patients with coexisting pancreatic stones and PPCs and effective for stone clearance, main pancreatic duct drainage, and pain relief.

Risk factors for complications of pancreatic extracorporeal shock wave lithotripsy.

BACKGROUND AND STUDY AIMS: Extracorporeal shock wave lithotripsy is recommended as treatment for stones in chronic pancreatitis. The aim of this study was to investigate the risk factors for complications of pancreatic extracorporeal shock wave lithotripsy (P-ESWL). PATIENTS AND METHODS: Patients with painful chronic pancreatitis and pancreatic stones (> 5 mm diameter) who were treated with P-ESWL between March 2011 and June 2013 were prospectively included. Adverse events after P-ESWL were classified as complications and transient adverse events, depending on severity. The major complications of P-ESWL included post-ESWL pancreatitis, bleeding, infection, steinstrasse, and perforation. Multivariate analyses based on univariate analysis were performed to detect risk factors of overall and moderate-to-severe complications. RESULTS: A total of 634 patients underwent 1470 P-ESWL procedures. The overall complication rate was 6.7 % of all procedures. Complications occurred in 62 patients (9.8 %) after the first ESWL procedure. The risk factors for complications were pancreas divisum (odds ratio [OR] 1.28) and the interval between diagnosis of chronic pancreatitis and P-ESWL (OR 1.28). Protective factors were male sex (OR 0.50), diabetes (OR 0.45), and steatorrhea (OR 0.43). Male sex, the only identified predictor for moderate-to-severe complications, was a protective factor (OR 0.19). For the second P-ESWL procedure, complications occurred in 22/409 patients (5.4 %). Complication and asymptomatic hyperamylasemia after the first ESWL session were significantly associated with higher risk for complications after the second ESWL session (P < 0.05). CONCLUSIONS: Patient-related factors were important in determining a high risk of P-ESWL complications when no procedure-related factors were identified. Patients suffering from complications after the first ESWL session were also likely to experience complications in subsequent P-ESWL sessions.

Scientific publications in respiratory journals from Chinese authors in various parts of North Asia: a 10-year survey of literature.

OBJECTIVES: Respiratory disease remains one of the leading causes of morbidity and mortality in China. However, little is known about the research status of respirology in three major regions of China-Mainland (ML), Hong Kong (HK) and Taiwan (TW). A 10-year survey of literature was conducted to compare the three regions' outputs in the research of respirology. DESIGN: A bibliometric study. SETTING: China. PARTICIPANTS AND OUTCOME MEASURES: A literature search in PubMed database, updated as of September 2012, led to the identification of the related articles from 2000 to 2009. The number of total articles, randomised controlled trials, case reports, meta-analysis, impact factors (IF), citations and articles published in top general medicine journals was collected for quantity and quality comparisons. RESULTS: 2208 articles were collected, 814 from ML, 909 from TW and 485 from HK. The total number of articles from the three regions has increased significantly from 2000 to 2009. The number of articles published per year from ML has exceeded that from HK in 2005 and TW in 2008. The accumulated IF of articles from TW (3192.417) was much higher than that from ML (2409.956) and HK (1898.312). HK got the highest average IF of respirology articles and the majority of articles were published in top general medicine journals. CONCLUSIONS: The total number of published articles from the three major regions of China has increased notably from 2000 to 2009. The annual number of publications by ML researchers exceeded those from TW and HK. However, the quality of articles from TW and HK is better than that from ML.