Recombinant fibroblast growth factor 4 ameliorates axonal regeneration and functional recovery in acute spinal cord injury through altering microglia/macrophage phenotype.

Neuroinflammation is one of the extensive secondary injury processes that aggravate metabolic and cellular dysfunction and tissue loss following spinal cord injury (SCI). Thus, an anti-inflammatory strategy is crucial for modulating structural and functional restoration during the stage of acute and chronic SCI. Recombinant fibroblast growth factor 4 (rFGF4) has eliminated its mitogenic activity and demonstrated a metabolic regulator for alleviating hyperglycemia in type 2 diabetes and liver injury in non-alcoholic steatohepatitis. However, it remains to be explored whether or not rFGF4 has a neuroprotective effect for restoring neurological disorders, such as SCI. Here, we identified that rFGF4 could polarize microglia/macrophages into the restorative M2 subtype, thus exerting an anti-inflammatory effect to promote neurological functional recovery and nerve fiber regeneration after SCI. Importantly, these effects by rFGF4 were related to triggering PI3K/AKT/GSK3ß and attenuating TLR4/NF-κB signaling axes. Conversely, gene silencing of the PI3K/AKT/GSK3ß signaling or pharmacological reactivation of the TLR4/NF-κB axis aggravated inflammatory reaction. Thus, our findings highlight rFGF4 as a potentially therapeutic regulator for repairing SCI, and its outstanding effect is associated with regulating macrophage/microglial polarization.

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.

Efficacy and Safety of Argon Plasma Coagulation for Hemorrhagic Chronic Radiation Proctopathy: A Systematic Review.

Hemorrhagic chronic radiation proctopathy (CRP) is a common complication after pelvic radiotherapy in patients with prostate or gynecological cancers. This systematic review was conducted to evaluate the efficacy and safety of argon plasma coagulation (APC) in treating hemorrhagic CRP. The databases of PubMed, Embase, and Cochrane Library were searched for related studies from inception to July 2017. Finally, 33 studies were identified with a total of 821 hemorrhagic CRP patients. After APC treatment, hemoglobin levels increased from 7.7-13.4 g/L to 11-14 g/L (including 15 studies). All (n = 33) studies reported an effective rate in rectal bleeding, among which five studies had a rate of 100%. Short-term complications were reported in 31 studies, while long-term complications in 33 studies and no complication in 11 studies. As for the severe complications, perforation was reported by 2 out of 33 studies, and the incidences were 3.3% (1/30) and 3.7% (1/27), respectively. As for APC setting, argon gas flow rate (median 1.5 L/min) and electric power (median 50 W) had no significant influence on complications and hemostasis. In conclusion, current literature indicated that APC therapy was an effective and safe strategy for hemorrhagic CRP, and large-scale prospective studies are needed to warrant our study.

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.

Integrated strategy of differentially expressed genes associated with ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is associated with both genetic and environmental factors; however, the underlying pathogenesis of UC remains unclear. The present study aimed to further explore 12 microarray datasets from patients with UC obtained from the Gene Expression Omnibus repository, for potential genetic pathogenesis of UC through a global bioinformatics view, which included identification of differentially expressed genes (DEGs), functional enrichments, protein­protein interactions, transcriptional and post­transcriptional regulation and drug­gene associations. This integrated analysis screened 233 DEGs that were compared between UC and normal control tissue samples; these included 173 upregulated and 60 downregulated DEGs. Subsequently, transcription factors, such as TATA­binding protein 1 (TBP1; hsa_TATAAA_V$TATA_01) and nuclear factor-κB (NF-κB; hsa_V$NFKAPPAB_01) and microRNAs (miRNAs; such as miR­516­3p and miR­23a) were revealed to be associated with 233 DEGs. Notably, further analysis indicated that these DEGs were enriched in certain diseases, including inflammation, fibrosis and immune system diseases, and were also associated with some drugs, including prednisone, collagenase and mycophenolate mofetil, which may provide choice for treatment of UC. In conclusion, this study may provide novel insights into discovering potential molecular targets involved in the pathogenesis and treatment of UC.

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.

Probiotics in Helicobacter pylori eradication therapy: Systematic review and network meta-analysis.

BACKGROUND: Several probiotics were effective in the eradication treatment for Helicobacter pylori (Hp), but their comparative efficacy was unknown. AIM: To compare the efficacy of different probiotics when supplemented in Hp eradication therapy. METHODS: A comprehensive search was conducted to identify all relevant studies in multiple databases and previous meta-analyses. Bayesian network meta-analysis was performed to combine direct and indirect evidence and estimate the relative effects. RESULTS: One hundred and forty studies (44 English and 96 Chinese) were identified with a total of 20,215 patients, and more than 10 probiotic strategies were supplemented in Hp eradication therapy. The rates of eradication and adverse events were 84.1 and 14.4% in probiotic group, while 70.5 and 30.1% in the control group. In general, supplementary probiotics were effective in improving the efficacy of Hp eradication and decreasing the incidence of adverse events, despite of few ineffective subtypes. In triple eradication therapy, there was no significant difference among the effective probiotics, and combined probiotics did not show a better efficacy and tolerance than single use. In triple therapy of 7 days and 14 days, Lactobacillus acidopilus was a slightly better choice, while Saccharomyces boulardii was more applicable for 10-day triple therapy. CONCLUSIONS: Compared to placebo, most probiotic strategies were effective when supplemented in Hp eradication therapy. In triple eradication therapy, no probiotic showed a superior efficacy to the others. Compared to single use, combined probiotics could not improve the efficacy or tolerance significantly.

Co-expression network analysis identified six hub genes in association with metastasis risk and prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a high incidence and mortality worldwide, and its carcinogenesis and progression are influenced by a complex network of gene interactions. A weighted gene co-expression network was constructed to identify gene modules associated with the clinical traits in HCC (n = 214). Among the 13 modules, high correlation was only found between the red module and metastasis risk (classified by the HCC metastasis gene signature) (R2 = -0.74). Moreover, in the red module, 34 network hub genes for metastasis risk were identified, six of which (ABAT, AGXT, ALDH6A1, CYP4A11, DAO and EHHADH) were also hub nodes in the protein-protein interaction network of the module genes. Thus, a total of six hub genes were identified. In validation, all hub genes showed a negative correlation with the four-stage HCC progression (P for trend < 0.05) in the test set. Furthermore, in the training set, HCC samples with any hub gene lowly expressed demonstrated a higher recurrence rate and poorer survival rate (hazard ratios with 95% confidence intervals > 1). RNA-sequencing data of 142 HCC samples showed consistent results in the prognosis. Gene set enrichment analysis (GSEA) demonstrated that in the samples with any hub gene highly expressed, a total of 24 functional gene sets were enriched, most of which focused on amino acid metabolism and oxidation. In conclusion, co-expression network analysis identified six hub genes in association with HCC metastasis risk and prognosis, which might improve the prognosis by influencing amino acid metabolism and oxidation.

Carbohydrate and protein intake and risk of ulcerative colitis: Systematic review and dose-response meta-analysis of epidemiological studies.

BACKGROUND & AIM: Dietary carbohydrate and protein intake is generally thought as risk factors for onset of ulcerative colitis (UC), while epidemiological data had been controversial. This study aimed to evaluate the role of carbohydrate and protein intake in the development of UC. METHODS: Comprehensive search in PubMed and Embase was conducted to identify all relevant studies, and the role of carbohydrate and protein intake in the development of UC was quantitatively assessed by dose-response meta-analysis. RESULTS: Nine studies (5 case-control and 4 prospective cohort) were identified with a total of 975 UC cases and 239352 controls. The summary relative risks (RR) for per 10 g increment/day were 1.005 (95%CI: 0.991-1.019, I2 = 31.5%, n = 5) for total carbohydrate intake, 1.001 (95%CI: 0.971-1.032, I2 = 0.0%, n = 7) for the subtype of fiber intake, 1.029 (95%CI: 0.962-1.101, I2 = 68.9%, n = 2) for the subtype of sugar intake, and 1.010 (95%CI: 0.975-1.047, I2 = 12.4%, n = 7) for total protein intake. Among sugar subtypes, only sucrose intake was found positively related with UC risk (RR for per 10 g increment/day: 1.098, 95%CI: 1.024-1.177, I2 = 0.0%, n = 3). No evidence of a non-linear dose-response association was found between the nutrient intake and UC risk, except for the subtype of sucrose (P for non-linear trend = 0.032). Subgroup analyses showed consistent results. CONCLUSIONS: This meta-analysis suggested a lack of association between dietary carbohydrate or protein intake and the risk of UC, except for the subtype of sucrose which played a significant role in the development of UC. Large-scale prospective designed studies are needed to confirm our findings.