Co-expression network analysis identified CDH11 in association with progression and prognosis in gastric cancer.

BACKGROUND AND AIMS: Gastric cancer (GC) is one of the most common cancers worldwide, and its pathogenesis is related to a complex network of gene interactions. The aims of our study were to find hub genes associated with the progression and prognosis of GC and illustrate the underlying mechanisms. METHODS: Weighted gene co-expression network analysis (WGCNA) was conducted using the microarray dataset and clinical data of GC patients from Gene Expression Omnibus (GEO) database to identify significant gene modules and hub genes associated with TNM stage in GC. Functional enrichment analysis and protein-protein interaction network analysis were performed using the significant module genes. We regarded the common hub genes in the co-expression network and protein-protein interaction (PPI) network as "real" hub genes for further analysis. Hub gene was validated in another independent dataset and The Cancer Genome Atlas (TCGA) dataset. RESULTS: In the significant purple module (R 2=0.35), a total of 12 network hub genes were identified, among which six were also hub nodes in the PPI network of the module genes. Functional annotation revealed that the genes in the purple module focused on the biological processes of system development, biological adhesion, extracellular structure organization and metabolic process. In terms of validation, CDH11 had a higher correlation with the TNM stage than other hub genes and was strongly correlated with biological adhesion based on GO functional enrichment analysis. Data obtained from the Gene Expression Profiling Interactive Analysis (GEPIA) showed that CDH11 expression had a strong positive correlation with GC stages (P<0.0001). In the testing set and Oncomine dataset, CDH11 was highly expressed in GC tissues (P<0.0001). Survival analysis indicated that samples with a high CDH11 expression showed a poor prognosis. Cox regression analysis demonstrated an independent predictor of CDH11 expression in GC prognosis (HR=1.482, 95% CI: 1.015-2.164). Furthermore, gene set enrichment analysis (GSEA) demonstrated that multiple tumor-related pathways, especially focal adhesion, were enriched in CDH11 highly expressed samples. CONCLUSION: CDH11 was identified and validated in association with progression and prognosis in GC, probably by regulating biological adhesion and focal adhesion-related pathways.

A novel gene-pair signature for relapse-free survival prediction in colon cancer.

BACKGROUND: Colon cancer (CC) patients with early relapse usually have a poor prognosis. In this study, we aimed to identify a novel signature to improve the prediction of relapse-free survival (RFS) in CC. METHODS: Four microarray datasets were merged into a training set (n=1,045), and one RNA-sequencing dataset was used as a validation set (n=384). In the training set, microarray meta-analysis screened out 596 common RFS-related genes across datasets, which were used to construct 177,310 gene pairs. Then, the LASSO penalized generalized linear model identified 16 RFS-related gene pairs, and a risk score was calculated for each sample according to the model coefficients. RESULTS: The risk score demonstrated a good ability in predicting RFS (area under the curve [AUC] at 5 years: 0.724; concordance index [C-index]: 0.642, 95% CI: 0.615-0.669). High-risk patients showed a poorer prognosis than low-risk patients (HR: 3.519, 95% CI: 2.870-4.314). Subgroup analysis reached consistent results when considering multiple confounders. In the validation set, the risk score had a similar performance (AUC at 5 years: 0.697; C-index: 0.696, 95% CI: 0.627-0.766; HR: 2.926, 95% CI: 1.892-4.527). When compared with a 13-gene signature, a 15-gene signature, and TNM stage, the score showed a better performance (P<0.0001; P=0.0004; P=0.0125), especially for the patients with a longer follow-up (R2=0.988, P<0.0001). When the follow-up was >5 years (n=314), the score demonstrated an excellent performance (C-index: 0.869, 95% CI: 0.816-0.922; HR: 13.55, 95% CI: 7.409-24.78). CONCLUSION: Our study identified a novel gene-pair signature for prediction of RFS in CC.

WGCNA Reveals Key Roles of IL8 and MMP-9 in Progression of Involvement Area in Colon of Patients with Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic inflammatory disease and its involvement area in colon is influenced by a complex network of gene interactions. We analyzed the weighted gene co-expression networks in microarray dataset from colonic mucosa of patients with UC and identified one gene co-expression module that was highly associated with the progression of involved area in UC colon (Pearson coefficient=0.81, P<0.0001). In total, 523 hub genes in this module were found to be involved in immune system process after enrichment analysis in Gene Ontology. By the STRING and Cytoscape analysis, we observed that interleukin-8 (IL-8) and matrix metalloproteinase-9 (MMP-9) were centered in the network of hub genes. We then detected the expression of IL-8 and MMP-9 in mucosa from left-sided colon of patients using quantitative PCR and immunofluorescence assay respectively. Both quantitative PCR and immunofluorescence assay revealed the expression levels of IL-8 and MMP-9 were significantly different among the healthy controls, left-sided colitis group and pancolitis group (P<0.05). IL-8 and MMP-9 were detected with an enhanced expression in pancolitis as compared with leftsided colitis and healthy controls, respectively (P<0.05). This study demonstrates that immune system process is indispensable in the progression of disease in colon, and identifies that IL-8 and MMP-9 play potential critical roles for the progression.

ITGBL1 promotes migration, invasion and predicts a poor prognosis in colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies worldwide; its progression and prognosis are associated with oncogenes. The present study aimed to identify differentially expressed genes (DEGs) and explore the role and potential mechanism of integrin subunit ß like 1 (ITGBL1) in CRC. The microarray dataset GSE41258 was used to screen DEGs involved in CRC. Survival analysis was performed to predict the prognosis of CRC patients. To validate ITGBL1 expression, immunohistochemistry, quantitative real-time PCR and western blotting were performed in CRC tissues and cells. Subsequently, the effects of ITGBL1 were evaluated through colony formation, cell proliferation, migration and invasion assays. Finally, we took advantage of Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) to explore potential function and mechanism of ITGBL1 in CRC. In our study, 182 primary CRC tissues and 54 normal colon tissues were contained in GSE41258 dataset. A total of 318 DEGs were screened, among which ITGBL1 was found to be significantly up-regulated in CRC, and its high expression was associated with shortened survival of CRC patients. Moreover, knockdown of ITGBL1 promoted CRC cell proliferation, migration and invasion. Finally, GO analysis revealed that ITGBL1 was associated with cell adhesion. GSEA indicated that ITGBL1 was enriched in ECM receptor interaction and focal adhesion. In conclusion, a novel oncogene ITGBL1 was identified and demonstrated to be associated with the progression and prognosis of CRC, which might be a potential therapeutic target and prognostic biomarker for CRC patients.

Profiles of differentially expressed genes and overexpression of NEBL indicates a positive prognosis in patients with colorectal cancer.

The present study aimed to identify differentially expressed genes (DEGs) in colorectal cancer (CRC) and provide novel prognostic biomarkers for CRC. The microarray dataset GSE41258 was used to screen DEGs of CRC. Subsequently, a protein­protein interaction network of DEGs and Gene Ontology analysis were performed to identify hub genes and associated biological processes. Nebulette (NEBL) and complement C1q like 1 (C1QL1) were validated using reverse transcription­quantitative polymerase chain reaction in patients with CRC. Survival analysis was performed for the two hub genes. GSE41258 dataset included 182 CRC samples and 54 normal tissues. A total of 759 DEGs, including 279 upregulated and 480 downregulated were screened between both groups. NEBL and C1QL1 were identified as the two hub genes and upregulated genes involved in various biological processes, including 'regulation of biological quality' and 'response to stimulus', respectively. Additionally, the overexpression of NEBL and C1QL1 in experimental validation was consistent with the aforementioned bioinformatics analysis results. Survival analysis suggested that overexpressed NEBL in patients with CRC was associated with a positive prognosis for overall survival. In conclusion, CRC was associated with a large group of DEGs. From the upregulated genes, overexpressed NEBL in patients CRC indicated a positive prognosis for overall survival and may be used as a prognostic biomarker for patients with CRC.

Diagnostic Value of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Crohn's Disease.

The aim of this study is to investigate the diagnostic efficacy of neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-monocyte ratio (NMR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) in patients with Crohn's disease (CD) and non-CD controls. These ratios were all derived from complete blood counts. Two hundred and six participants including CD inpatients and non-CD controls were retrospectively enrolled. We found statistically higher NLR and PLR and lower LMR in CD patients than in non-CD controls (all P < 0.01). However, NMR was not different between the two groups (P = 0.18). In addition, NLR, PLR, and LMR were associated with CRP and ESR. Optimal cutoffs for NLR and PLR were 2.72 (sensitivity: 68.3%, specificity: 75.9%, and overall accuracy: 70.1%) and 132.88 (sensitivity: 76.7%, specificity: 84.8%, and overall accuracy: 80.8%), respectively. In conclusion, the NLR and PLR might be effective, readily available, and low-cost biomarkers for differentiating CD patients from non-CD controls.

Efficacy and safety of probiotic-supplemented triple therapy for eradication of Helicobacter pylori in children: a systematic review and network meta-analysis.

AIM: The aim of this study was to identify the best probiotic supplementation in triple therapy for pediatric population with Helicobacter pylori infection. METHODS: Eligible trials were identified by comprehensive searches. Relative risks with 95% confidence intervals and relative ranks with P scores were assessed. RESULTS: Twenty-nine trials (3122 participants) involving 17 probiotic regimens were identified. Compared with placebo, probiotic-supplemented triple therapy significantly increased H. pylori eradication rates (relative ratio (RR) 1.19, 95% CI 1.13-1.25) and reduced the incidence of total side effects (RR 0.49, 95% CI 0.38-0.65). Furthermore, to supplemented triple therapy, Lactobacillus casei was identified the best for H. pylori eradication rates (P score = 0.84), and multi-strain of Lactobacillus acidophilus and Lactobacillus rhamnosus for total side effects (P score = 0.93). As for the subtypes of side effects, multi-strain of Bifidobacterium infantis, Bifidobacterium longum, L. acidophilus, L. casei, Lactobacillus plantarum, Lactobacillus reuteri, L. rhamnosus, Lactobacillus salivarius, Lactobacillus sporogenes, and Streptococcus thermophilus was the best to reduce the incidence of diarrhea; multi-strain of Bacillus mesentericus, Clostridium butyricum, and Streptococcus faecalis for loss of appetite; multi-strain of B. longum, Lactobacillus bulgaricus, and S. thermophilus for constipation; multi-strain of Bifidobacterium bifidum, B. infantis, L. acidophilus, L. bulgaricus, L. casei, L. reuteri, and Streptococcus for taste disturbance; Saccharomyces boulardii for bloating; and multi-strain of Bifidobacterium breve, B. infantis, L. acidophilus, L. bulgaricus, L. casei, L. rhamnosus, and S. thermophilus for nausea/vomiting. CONCLUSIONS: Probiotics are recommended to supplement triple therapy in pediatrics, and the effectiveness of triple therapy is associated with specific probiotic supplementation.

Efficacy and safety of autologous hematopoietic stem cell therapy for refractory Crohn's disease: A systematic review and meta-analysis.

BACKGROUND: Autologous hematopoietic stem cell transplantation (HSCT) has been proposed for patients with refractory Crohn's disease (CD), but it is associated with mortality and adverse events; the balance between risks and benefits becomes significantly important in the therapy. The aim of the study was to assess the efficacy and safety of autologous HSCT therapy for refractory CD. METHODS: We conducted a comprehensive search of PubMed, Embase, the Cochrane library, and Web of Science from inception to February 2017. The pooled estimate rates for efficacy and safety of refractory CD was performed by meta-analysis and reported according to the standard Cochrane guidelines and the PRISMA statement. RESULTS: Four prospective uncontrolled cohort studies, 4 prospective case series, and 1 randomized controlled trial (RCT) were included. Autologous HSCT had a high rate of clinical and endoscopic remission in refractory CD [79.4%, 95% confidence interval (95% CI): 0.550-0.924; 81.9%, 95% CI: 0.603-0.931, respectively]. In the case of safety, it had a relatively high incidence rate of transplant-related mortality (6.4%, 95% CI: 0.028-0.140). A significant association was observed between autologous HSCT and the incidence of febrile neutropenia (83.2%, 95% CI: 0.632-0.934). About 18.5% (95% CI: 0.061-0.442) of patients with refractory CD reached clinical remission at mobilization phase. Besides, 82.1% (95% CI: 0.692-0.903) and 54.1% (95% CI: 0.261-0.797) patients with refractory CD could achieve immunosuppressive-free and steroid-free remission for at least 12 months after the therapy. CONCLUSION: Autologous HSCT could be a complicated treatment with relatively high mortality and significantly high efficacy for refractory CD, which should be used with caution. However, more RCTs of larger samples using refined and standardized protocols and longer period of follow-up time are needed to further assess the outcomes of autologous HSCT therapy.