A pan-cancer analysis for the oncogenic role of cyclin-dependent kinase inhibitor 1B in human cancers.

BACKGROUND: Human health and life are threatened by cancer with high morbidity and mortality worldwide. In many experiments, CDKN1B level is associated with cancer risk, Nevertheless, no pan-cancer analysis has been conducted on CDKN1B in human cancers. METHODS: With the help of bioinformatics, a pan-cancer analysis was conducted on the expression levels of CDKN1B in cancer tissues and adjacent tissues from the TCGA, CPTAC and GEO databases. The CDKN1B expression levels in tumor patients was further validated using immunohistochemistry (IHC) and quantitative real-time PCR. RESULTS: In the study, we first investigated the cancer-related roles of CDKN1B's in 40 tumors with malignancy. The CDKN1B gene encodes the p27Kip1 protein, which can block the production cyclin-dependent kinase (CDK), which is obviously related to the function and survival of cancer cells and alters the prognosis of cancer patients. Furthermore, CDKN1B function requires both protein processing and RNA metabolism. Additionally, the elevated expression of the CDKN1B gene and protein was validated in several cancer tissues from the patients. CONCLUSIONS: These results showed that the levels of CDKN1B were considerably different in a number of cancer tissues, offering a potential future target for cancer therapy.

Upregulation of Long Noncoding RNA MALAT1 in Colorectal Cancer Promotes Radioresistance and Aggressive Malignance.

Background: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a conserved transcript with 8000 nt, is highly associated with malignancy of numerous cancer types. However, the function of MALAT1 plays in regulating the response to radiotherapy in colorectal cancer (CRC) remains unclear. Thus, the object of this study is to investigate the functions of MALAT1 in CRC radioresistance. Methods: First, the expression of MALAT1 in colon adenocarcinoma (COAD) was analyzed through the Cancer Genome Atlas (TCGA) database. Then, we detected the expression level of MALAT1 in tumor tissues and CRC cell lines and analyzed the relevance of MALAT1 and clinicopathological parameters. In the end, the effect of silencing MALAT1 on the radiosensitivity of CRC cells was investigated, and its potential mechanism was preliminarily illustrated. Results: The analysis of TCGA data showed that MALAT1 was closely related to the type of tumor, and high expression of MALAT1 was remarkably relevant to poor outcome. MALAT1 was highly expressed in CRC tissues and cell lines and related to tumor stages. Knockdown of MALAT1 could significantly suppress colony survival, proliferation, and migration and increase apoptosis, G2/M phase arrest, and formation of gamma-H2AX foci in HCT116, whether in combination with X-rays or not. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis demonstrated that the regulated proteins were principally enriched in the glycosaminoglycan degradation pathway after silencing MALAT1. Conclusion: Our results implied that MALAT1 was highly expressed in CRC and associated with tumor stage and prognosis. Silencing MALAT1 can increase HCT116 cell radiosensitivity, which may be potentially influenced by glycosaminoglycan degradation pathway.

THUMPD3-AS1 facilitates cell growth and aggressiveness by the miR-218-5p/SKAP1 axis in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a malignant cancer with a high mortality. Accumulating studies have revealed that mRNAs involved in ceRNA (competing endogenous RNA) network are implicated in the tumorigenesis and development of CRC. Here, we aimed to elucidate the ceRNA network involving Src kinase associated phosphoprotein 1 (SKAP1) in the biological characteristics of CRC. METHODS: Expression levels of genes in colon adenocarcinoma (COAD) samples and prognosis of COAD patients were predicted using publicly available online tool. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clony formation and Transwell assays were conducted to test the biological functions of SKAP1 and THUMPD3 antisense RNA 1 (THUMPD3-AS1) in CRC cells. Western blot was used to measure the protein levels of SKAP1. Gene expression in CRC cells was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The interaction between miR-218-5p and THUMPD3-AS1 (or SKAP1) was verified by RNA pulldown and luciferase reporter assays. RESULTS: SKAP1 was upregulated in COAD tissues and CRC cells and it reflected a poor prognosis in patients with COAD. SKAP1 knockdown inhibited CRC (HT-29 and HCT-116) cell proliferation, migration and invasion. Mechanistically, THUMPD3-AS1 acted as a ceRNA to sponge miR-218-5p and subsequently upregulated SKAP1 expression in CRC cells. SKAP1 overexpression reversed the suppressive effect of THUMPD3-AS1 knockdown on proliferation, migration and invision of CRC cells. CONCLUSIONS: THUMPD3-AS1 promotes CRC cell growth and aggressiveness by regulating the miR-218-5p/SKAP1 axis.

Integrated bioinformatics identifies the dysregulation induced by aberrant gene methylation in colorectal carcinoma.

Colorectal carcinoma (CRC) is one of the most common cancers, and is associated with a poor clinical outcome. The key genes and potential prognostic markers in colorectal carcinoma remain to be identified and explored for clinical application. DNA expression/methylation profiles were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed/methylated genes (DEGs and DEMs). A total of 255 genes and 372 genes were identified as being up-regulated and down-regulated, respectively, in GSE113513, GSE81558, and GSE89076. There were a total of 3350 hypermethylated genes and 443 hypomethylated genes identified in GSE48684. Twenty genes were found to be hypermethylated as well as down-regulated, and a functional enrichment analysis revealed that these genes were mainly involved in cancer-related pathways. Among these 20 genes, GPM6A, HAND2 and C2orf40 were related to poor outcomes in cancer patients based on a survival analysis. Concurrent decreases of GPM6A, HAND2 and C2orf40 protein expression were observed in highly-differentiated colorectal carcinoma tissues, and higher expression levels were found in undifferentiated or minimally-differentiated colorectal carcinoma tissues. In conclusion, 20 genes were found to be downregulated and hypermethylated in CRC, among which GPM6A, HAND2 and C2orf40 were explored for their potential prognostic value.

Gastrodin induces lysosomal biogenesis and autophagy to prevent the formation of foam cells via AMPK-FoxO1-TFEB signalling axis.

Abnormal accumulation of lipids and massive deposition of foam cells is a primary event in the pathogenesis of atherosclerosis. Recent studies have demonstrated that autophagy and lysosomal function of atherosclerotic macrophages are impaired, which exacerbates the accumulation of lipid in macrophages and formation of foam cells. Gastrodin, a major active component of Gastrodia elata Bl., has exerted a protective effect on nervous system, but the effect of gastrodin on atherosclerotic vascular disease remains unknown. We aimed to evaluate the effect of gastrodin on autophagy and lysosomal function of foam cells and explored the mechanism underlying gastrodin's effect on the formation of foam cells. In an in vitro foam cell model constructed by incubating macrophages with oxygenized low-density lipoproteins (ox-LDL), our results showed that lysosomal function and autophagy of foam cells were compromised. Gastrodin restored lysosomal function and autophagic activity via the induction of lysosomal biogenesis and autophagy. The restoration of lysosomal function and autophagic activity enhanced cholesterol efflux from macrophages, therefore, reducing lipid accumulation and preventing formation of foam cells. AMP-activated protein kinase (AMPK) was activated by gastrodin to promote phosphorylation and nuclear translocation of forkhead box O1 (FoxO1), subsequently resulting in increased transcription factor EB (TFEB) expression. TFEB was activated by gastrodin to promote lysosomal biogenesis and autophagy. Our study revealed that the effect of gastrodin on foam cell formation and that induction of lysosomal biogenesis and autophagy of foam cells through AMPK-FoxO1-TFEB signalling axis may be a novel therapeutic target of atherosclerosis.

The Anti-Tumor Activity of Afatinib in Pancreatic Ductal Adenocarcinoma Cells.

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is the most common form of pancreatic cancer and leading causes of pancreatic cancer death because of most PDAC patients with advanced unresectable disease at that time, which is remarkably resistant to all forms of chemotherapy and radiotherapy. OBJECTIVE: PDAC increases the social and patient's family burden. However, the PDAC pathogenesis is not identified. We are trying to uncover the underlying mechanism in the future. METHODS: In our research, the drug-resistant cell line was successfully induced in the vitro by progressive concentrations of Afatinib, which we named it as BxPC3-AR. RESULTS: It has been observed that the effect of autophagy was on the resistance of BxPC3-AR to Afatinib. CONCLUSION: It has been confirmed that autophagy plays a certain role in BxPC3-AR resistance to Afatinib. Our findings provide a new perspective on the role of autophagy in pancreatic ductal adenocarcinoma.

Ginsenoside Rb1 attenuates cardiomyocyte apoptosis induced by myocardial ischemia reperfusion injury through mTOR signal pathway.

OBJECTIVE: Ginsenoside Rb1 (GRb1) is known to play an effective protection on myocardial infarction, yet its therapeutic mechanism on myocardial ischemia/reperfusion (I/R) injury has remained obscure. Here we sought to investigate the protective mechanism of GRb1 preconditioning on myocardial I/R injury in rats. METHODS AND RESULTS: We report here that GRb1 preconditioning could improve myocardial I/R injury induced-cardiac functions including LVDP, -dp/dt min and + dp/dt max; however, the heart rate (HR) was maintained at a level comparable to the I/R group. Additionally, in I/R injury group given GRb1 preconditioning, release of myocardial enzymes (CK-MB and Trop l) and CtsB was decreased. Moreover, GRb1 decreased the expression of apoptotic related proteins e.g. cleaved-caspase 3; however, the ratio of Bcl-2/Bax related to anti-apoptosis was decreased. The study was extended by injecting rapamycin intraperitoneally before GRb1 pretreatment. Thus, mTOR pathway was significantly upregulated after GRb1 pretreatment when compared with I/R. Remarkably, the anti-apoptosis protection of GRb1 pretreatment was attenuated by rapamycin. Furthermore, GRb1 effectively reduced the infarct size thus supporting its role in anti-myocardial I/R injury. CONCLUSIONS: It is concluded that GRb1 preconditioning can ameliorate myocardial I/R injury as manifested by the improvement of cardiac function indices; moreover, release of myocardial enzymes, namely, CK-MB, Trop l and CtsB was reduced. More importantly, we have shown that the protective effect of GRb1 against I/R injury induced cardiomyocyte apoptosis is associated with the activation of mTOR signal pathway as evident by the use of rapamycin.

Cystatin C improves blood-brain barrier integrity after ischemic brain injury in mice.

Cystatin C, a well-established biomarker of renal function, has been associated with a protective effect against stroke. However, the potential neuroprotective mechanism of cystatin C in ischemic brain injury remains unclear. Our study hypothesized that cystatin C can ameliorate blood-brain barrier (BBB) disruption by up-regulating caveolin-1 expression, thereby improving neurological outcomes in cerebral ischemic injury. Western blotting, immunohistochemistry, immunofluorescence staining, and immunoprecipitation were performed to investigate target proteins. Evans Blue and gelatin zymography were used to examine the effect of cystatin C on BBB disruption. Plasmid and small interfering RNA transfection was used to observe alterations in caveolin-1 and occludin expression induced by changes in cystatin C expression. Intriguingly, our study showed that the expression of both cystatin C and caveolin-1 was increased in middle cerebral artery occlusion-injured mice, and pretreatment with exogenous cystatin C significantly increased caveolin-1 expression, reduced Evans Blue leakage in the injured brain region, and decreased the enzymatic activity of matrix metallopeptidase-9. Meanwhile, our study also showed that the over-expression of cystatin C greatly enhanced caveolin-1 expression, which later increased occludin expression in oxygen-glucose deprivation-exposed brain microvascular endothelial cells. The knockdown of cystatin C induced the opposite outcomes. These experimental results indicate a positive role for cystatin C in the regulation of caveolin-1 and occludin expression in cerebral ischemic injury. Taken together, these data unveil a new mechanism of the regulation of caveolin-1 expression by cystatin C in the maintenance of BBB integrity after ischemic brain injury and provide new clues for the identification of potential therapeutic strategies for stroke.

[Comparative study of clinical efficacy between video-assisted anal fistula treatment and traditional fistula resection plus seton in treatment of complex anal fistula].

OBJECTIVE: To explore the efficacy of video-assisted anal fistula treatment (VAAFT) in treatment of complex anal fistula. METHODS: Clinical data of 87 patients with complex anal fistula undergoing operation at Department of General Surgery, the Second Affiliated Hospital of Suzhou University from September 2015 to December 2016 were collected to conduct a cohort study. The operative procedure depended on economic conditions and patient preference. Patients were divided into VAAFT group (42 cases) and traditional fistula resection plus seton (FRS) group (45 cases). The procedure of FRS was to completely remove the fistula along external wall, the inner opening and surrounding scar tissues, then, the inner opening was closed with absorbable suture. For deeper and more complex fistula, the above procedure should be combined with seton. Based on the concept of endoscopic minimally invasive surgery, VAAFT could deal with the fistula and inner opening under direct vision. The brief steps were as follows: insertion of the anal fistula scope through external opening into the fistula; continuous injection of glycine-mannitol solution to expand and clean the foul fistula; electrocoagulation of all lesions; clearance of burnt tissues from the lumen with endoscopic brush and forceps; injection of medical fibrin glue through the inner opening; closing the inner opening by suture. Intraoperative and postoperative indices were compared between two groups. RESULTS: VAAFT group included 33 males and 9 females with mean age of (37.4±13.5) years, mean BMI of (24.3±3.2) kg/m2, and mean disease course of (4.8±3.9) months. Of 42 cases, 5 had preoperative diabetes mellitus, 31 were high fistula and 11 were low fistula. FRS group included 32 males and 13 females with mean age of (42.1±15.6) years, mean BMI of (24.8±3.7) kg/m2, and mean disease course of (5.7±3.6) months. Of 45 cases, 4 had preoperative diabetes mellitus, 37 were high fistula and 8 were low fistula. There were no significant differences in baseline data between two groups(all P>0.05). Compared with FRS group, VAAFT group had significantly shorter operative time [(44.6±10.5) minutes vs. (57.4±12.3) minutes, t=5.203, P=0.000], lower incidence of postoperative bleeding (14.3% vs. 33.3%,χ²=4.304, P=0.038), less pain (Visual Analogue Scale,VAS) (2.9±1.8 vs. 7.3±1.2, t=13.500, P=0.000), faster pain relief [(1.0±0.8) days vs. (4.5±1.2) days, t=15.890, P=0.000] and shorter hospital stay [(4.1±3.5) days vs.(7.5±2.3) days, t=5.389, P=0.000]. However, there were no significant differences between two groups in urinary retention rate, first postoperative fecal time and postoperative infection rate(all P>0.05). All patients were followed up for more than 6 months, FRS group had significantly higher incidence of anal incontinence than VAAFT group (20.0% vs. 2.4%, Fisher P=0.015). However, no significant difference in recurrence rate was found between VAAFT and FRS group(7.1% vs. 15.6%, Fisher P=0.317). CONCLUSIONS: Compared to traditional FRS treatment, VAAFT possesses some advantages in less injury, less pain, faster recovery, and lower postoperative anal incontinence rate. Thus, VAAFT is a superior operative choice in treatment of patients with complex anal fistula.

Prophylactic Mesh Application during Colostomy to Prevent Parastomal Hernia: A Meta-Analysis.

Background. Parastomal hernia is a common complication after stoma formation, especially in permanent colostomy. The present meta-analysis aimed to evaluate the effectiveness of prophylactic mesh application during permanent colostomy for preventing parastomal hernia. Methods. Randomized controlled trials comparing outcomes in patients who underwent colostomy with or without prophylactic mesh application were identified from PubMed, EMBASE, Science Citation Index, and the Cochrane Libraries. Results. This meta-analysis included 8 randomized controlled trials with 522 participants. Our pooled results showed that prophylactic mesh application (mesh group) reduced the incidence of clinically detected parastomal hernia (risk ratio [RR]: 0.22; 95% confidence interval [CI]: 0.13-0.38; P < 0.00001), radiologically detected parastomal hernia (RR: 0.62; 95% CI: 0.47-0.82; P = 0.0008), and surgical repair for herniation (RR: 0.34; 95% CI: 0.14-0.83; P = 0.02) when compared with conventional permanent colostomy formation (control group). The incidence of complications, including wound infection, peristomal infection, mesh infection, stomal necrosis and stenosis, stoma site pain, and fistula, was not higher in the mesh group than in the control group. Conclusions. Our meta-analysis demonstrated that prophylactic mesh application at the time of primary colostomy formation is a promising method for the prevention of parastomal herniation.

Wound-edge protection devices in gastrointestinal surgery: a meta-analysis.

BACKGROUND: The role of wound-edge protection devices (WEPDs) in wound infection prevention is still controversial. The aim of this meta-analysis was to assess the protective efficiency of WEPDs in gastrointestinal surgery in a pooled analysis of randomized controlled trials. MATERIALS AND METHODS: A variety of sources were searched for randomized controlled trials evaluating the protective efficiency of WEPDs in gastrointestinal surgery. Subgroup analysis and meta-regressions were conducted to investigate the possible influence of the type of WEPD on the size of intervention effect. This review was conducted in accordance with a prespecified protocol based on the guidance of the Cochrane Handbook and Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. RESULTS: Sixteen studies with 3663 patients were included. The WEPDs usage led to a significant decrease in surgical wound infection (risk ratio [RR] = 0.64; 95% confidence interval [CI]: 0.46-0.87; P = 0.005; I2 = 63%), with the dual-ring design usage yielding a more significant reduction in surgical wound infection (RR = 0.24; 95% CI: 0.11-0.50; P = 0.0002; I2 = 29%), whereas the single-ring design usage yielding a nonsignificant result (RR = 0.78; 95% CI: 0.58-1.04; P = 0.09; I2 = 53%). CONCLUSIONS: Double-ring WEPD, but not single-ring design, reduces wound infection rate significantly in gastrointestinal surgery. Therefore, the use of single-ring WEPD should be reconsidered.

Laparoscopic permanent sigmoid stoma creation through the extraperitoneal route versus transperitoneal route. A meta-analysis of stoma-related complications.

OBJECTIVES: To compare laparoscopic extraperitoneal colostomy with transperitoneal colostomy for construction of a permanent stoma by measuring the incidence of parastomal hernia, and other postoperative complications related to colostomy. METHODS: The meta-analysis was carried out in the General Surgery Department of the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China in 2014. A literature search of Medline, EMBASE, Cochrane database, and the Chinese Biomedical Literature Database (CBM) from the years 1990 to 2014 was performed. The literature searches were carried out using medical subject headings and free-text words: extraperitoneal colostomy, transperitoneal colostomy, laparoscopic extraperitoneal colostomy, rectal cancer,  laparoscopic abdominoperineal resection, parastomal hernia, permanent stoma, and colostomy-related complications. Two different reviewers carried out the search and evaluated studies independently. RESULTS: One randomized controlled trial and 6 retrospective studies were included. A total of 378 patients (209 extraperitoneal colostomy and 169 transperitoneal colostomy) were identified. Our analysis showed that there was a significantly lower rate of parastomal hernia (odds ratio 0.10; 95% confidence interval 0.03-0.29, p<0.0001) in the extraperitoneal colostomy group. However, the other stoma-related complications were not significantly different between the 2 groups. CONCLUSION: Colostomy construction via the extraperitoneal route using a laparoscopic approach can largely reduce the incidence of parastomal hernia. Laparoscopic permanent sigmoid stoma creation through the extraperitoneal route should be the first choice after laparoscopic abdominoperineal resection. 

Proximal gastrectomy versus total gastrectomy for proximal gastric carcinoma. A meta-analysis on postoperative complications, 5-year survival, and recurrence rate.

OBJECTIVE: To compare proximal gastrectomy (PG) with total gastrectomy (TG) for proximal gastric carcinoma, through the 5-year survival rate, recurrence rate, postoperative complications, and long-term life quality. METHODS: The meta-analysis was carried out in the General Surgery Department of the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China. We searched Medline, EMBASE, and the Cochrane Library from June to November 2012. The literature searches were carried out using medical subject headings and free-text word: `proximal gastrectomy` `total gastrectomy` `partial gastrectomy` `stomach neoplasms` and `gastric cancer`. Two different reviewers carried out the search and evaluated studies independently. RESULTS: Two randomized controlled trials and 9 retrospective studies were included. A total of 1364 patients were included in our study. Our analysis showed that there is no statistically significant difference in 5-year survival rate between PG and TG (60.9% versus 64.4%). But, the recurrence is higher in the PG group than the TG (38.7% versus 24.4%). The anastomotic stenosis rate is also higher in the PG than the TG (27.4% versus 7.4%). CONCLUSION: Proximal gastrectomy is an option for upper third gastric cancer in terms of safety. However, it is associated with high risk of reflux symptoms and anastomotic stenosis. Therefore, TG should be the first choice for proximal gastric cancer to prevent reflux symptoms.

Blockade of NF-κB nuclear translocation results in the inhibition of the invasiveness of human gastric cancer cells.

The aim of the present study was to investigate the effect of the nuclear factor-κB (NF-κB) p65 inhibitor, SN50, on the invasiveness and mechanisms of SGC7901 human gastric carcinoma cell xenografts in nude mice. Nude mice were randomly divided into model control and SN50 treatment groups. On days 5, 10 and 15 following treatment, the tumor samples were observed and a selection of parameters were recorded, including the level of tumor growth inhibition, the pathological changes in the tumor specimens, the expression levels of matrix metalloproteinase-9 (MMP-9), proliferating cell nuclear antigen (PCNA), tissue inhibitor of metalloproteinases type-1 (TIMP-1) and vascular endothelial growth factor (VEGF) and the apoptosis indices in the tumor samples. The results demonstrated that treating the tumor with SN50 for 5, 10 and 15 days inhibited carcinoma growth in comparison with the control group. Hematoxylin and eosin (HE) staining indicated that the level of inhibition increased progressively, in correlation with apoptosis. The expression of the MMP-9, PCNA and VEGF proteins was observed to be downregulated, while that of the TIMP-1 protein was shown to be upregulated, using immunohistochemical staining. In conclusion, the NF-κB p65 inhibitor, SN50, inhibited the invasiveness of the gastric cancer cells by downregulating the protein expression of MMP-9, PCNA and VEGF and upregulating the protein expression of TIMP-1. It was further suggested that SN50 may be a molecular target of anti-invasion therapy for gastric cancer, and that the inhibition of the NF-κB p65 signaling pathway may be considered as a potential strategy for treating gastric cancer.

Fistula plug versus conventional surgical treatment for anal fistulas. A system review and meta-analysis.

OBJECTIVE: To evaluate the recurrence and fecal incontinence of anal fistula plug versus conventional surgical treatment for anal fistulas. METHODS: This meta-analysis was carried out in the General Surgery Department of the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China. We searched the Medline, EMBASE, and Cochrane Library from June 2011 to April 2012. The literature searches were carried out using medical subject headings and free-text word: anal fistula, fibrin adhesive, fibrin sealant, and fistula plug. RESULTS: Two randomized controlled trials and 3 retrospective controlled studies were included. A total of 428 patients were included in our study. The recurrence rate was higher in those patients who accept fistula plug treatment (62.1% versus 47%) (p=0.004). CONCLUSION: Anal fistula plug has a moderate probability of success with little risk of incontinence, but the recurrence rate is significantly higher than the conventional surgical treatment. This treatment is minimally invasive, repeatable, and sphincter-sparing. This meta-analysis failed to find a statistically significant difference in incontinence rate between conservative treatment and conventional surgical treatment.