High expression of death-associated protein 5 promotes glucose metabolism in gastric cancer cells and correlates with poor survival outcomes / 南方医科大学学报

OBJECTIVE@#To investigate the prognostic value of death-associated protein 5 (DAP5) in gastric cancer (GC) and its regulatory effect on aerobic glycolysis in GC cells.@*METHODS@#We analyzed DAP5 expression levels in GC and adjacent tissues and its association with survival outcomes of GC patients using public databases. We collected paired samples of GC and adjacent tissues from 102 patients undergoing radical resection of GC in our hospital from June, 2012 to July, 2017, and analyzed the correlation of DAP5 expression level detected immunohistochemically with the clinicopathological parameters of the patients. Cox regression analysis, Kaplan-Meier analysis, and ROC curves were used to explore the independent risk factors and the predictive value of DAP5 expression for 5-year survival of the patients. In the cell experiments, we observed the changes in aerobic glycolysis in MGC-803 cells following lentivirus-mediated DAP5 knockdown or overexpression by measuring glucose uptake and cellular lactate level and using qRT-PCR and Western blotting.@*RESULTS@#Analysis using the public databases showed that DAP5 was highly expressed in GC and correlated with tumor progression and poor survival outcomes of the patients (P < 0.05). In the clinical samples, DAP5 expression was significantly higher in GC than in the adjacent tissues (3.19±0.60 vs 1.00±0.12; t=36.863, P < 0.01), and a high expression of DAP5 was associated with a reduced 5-year survival rate of the patients (17.6% vs 72.5%; χ2=29.921, P < 0.05). A high DAP5 expression, T3-4, N2-3, and CEA≥5 ng/mL were identified as independent risk factors affecting 5-year survival outcomes of GC (P < 0.05), for which DAP5 expression showed a prediction sensitivity, specificity and accuracy of 73.2%, 80.4% and 79.0%, respectively. In MGC-803 cells, DAP5 knockdown significantly reduced glucose uptake, lactate level and the expressions of GLUT1, HK2 and LDHA, and DAP5 overexpression produced the opposite effects (P < 0.05).@*CONCLUSION@#A high expression of DAP5 in GC, which enhances cellular aerobic glycolysis to promote cancer progression, is correlated with a poor survival outcome and may serve as a biomarker for evaluating long-term prognosis of GC patients.

FJX1 overexpression is associated with poor prognosis and promotes gastric cancer proliferation via the PI3K/AKT signaling pathway / 南方医科大学学报

OBJECTIVE@#To investigate the expression of four-jointed box kinase 1 (FJX1) in gastric cancer (GC), its correlation with survival outcomes of the patients, and its role in GC progression.@*METHODS@#The expression level of FJX1 in GC tissues and normal gastric mucosal tissues and its correlation with the survival outcomes of GC patients were analyzed using TCGA and GEO database GC cohort. Immunohistochemistry was used to detect FJX1 expression level in clinical specimens of GC tissue, and its correlations with the patients' clinicopathological parameters and prognosis were analyzed. Bioinformatic analysis was performed to identify the potential pathways of FJX1 in GC. The effects of FJX1 overexpression or FJX1 silencing on GC cell proliferation and expressions of proliferation-related proteins, PI3K, AKT, p-PI3K, and p-AKT were evaluated using CCK-8 assay and Western blotting. The effect of FJX1 overexpression on GC cell tumorigenicity was evaluated in nude mice.@*RESULTS@#GC tissues showed significantly higher expressions of FJX1 mRNA and protein compared with normal gastric mucosa tissues (P < 0.05). The high expression of FJX1 was associated with poor prognosis of GC patients (P < 0.05) and served as an independent risk factor for poor survival outcomes in GC (P < 0.05). FJX1 was expressed mainly in the cytoplasm of GC cells in positive correlation with Ki67 expression (R=0.34, P < 0.05), and was correlated with CA199 levels, depth of tumor infiltration and lymph node metastasis of GC (P < 0.05). In the cell experiment, FJX1 level was shown to regulate the expressions of Ki67 and PCNA and GC cell proliferation (P < 0.05). Gene set enrichment analysis indicated that the PI3K/AKT pathway potentially mediated the effect of FJX1, which regulated the expressions of PI3K and AKT and their phosphorylated proteins. In nude mice, FJX1 overexpression in GC cells significantly promoted the growth of the transplanted tumors (P < 0.05).@*CONCLUSION@#FJX1 is highly expressed in GC tissues and is correlated with poor prognosis of GC patients. FJX1 overexpression promotes GC cell proliferation through the PI3K/AKT signaling pathway, and may serve as a potential prognostic biomarker and therapeutic target for GC.

Pachymic acid protects against Crohn's disease-like intestinal barrier injury and colitis in miceby suppressingintestinal epithelial cell apoptosis via inhibiting PI3K/AKT signaling / 南方医科大学学报

OBJECTIVE@#To investigate the effect of pachymic acid (PA) against TNBS-induced Crohn's disease (CD)-like colitis in mice and explore the possible mechanism.@*METHODS@#Twenty-four C57BL/6J mice were randomized equally into control group, TNBS-induced colitis model group and PA treatment group. PA treatment was administered via intraperitoneal injection at the daily dose of 5 mg/kg for 7 days, and the mice in the control and model groups were treated with saline. After the treatments, the mice were euthanized for examination of the disease activity index (DAI) of colitis, body weight changes, colon length, intestinal inflammation, intestinal barrier function and apoptosis of intestinal epithelial cells, and the expressions of TNF-α, IL-6 and IL-1β in the colonic mucosa were detected using ELISA. The possible treatment targets of PA in CD were predicted by network pharmacology. String platform and Cytoscape 3.7.2 software were used to construct the protein-protein interaction (PPI) network. David database was used to analyze the GO function and KEGG pathway; The phosphorylation of PI3K/AKT in the colonic mucosal was detected with Western blotting.@*RESULTS@#PA significantly alleviated colitis in TNBS-treated mice as shown by improvements in the DAI, body weight loss, colon length, and histological inflammation score and lowered levels of TNF-α, IL-6 and IL-1β. PA treatment also significantly improved FITC-dextran permeability, serum I-FABP level and colonic transepithelial electrical resistance, and inhibited apoptosis of the intestinal epithelial cells in TNBS-treated mice. A total of 248 intersection targets were identified between PA and CD, and the core targets included EGFR, HRAS, SRC, MMP9, STAT3, AKT1, CASP3, ALB, HSP90AA1 and HIF1A. GO and KEGG analysis showed that PA negatively regulated apoptosis in close relation with PI3K/AKT signaling. Molecular docking showed that PA had a strong binding ability with AKT1, ALB, EGFR, HSP90AA1, SRC and STAT3. In TNBS-treated mice, PA significantly decreased p-PI3K and p-AKT expressions in the colonic mucosa.@*CONCLUSION@#PA ameliorates TNBS-induced intestinal barrier injury in mice by antagonizing apoptosis of intestinal epithelial cells possibly by inhibiting PI3K/AKT signaling.

Analysis on prognosis and influencing factors of postoperative low anterior resection syndrome for rectal cancer patients undergoing laparoscopic anus-preserving radical resection / 中华胃肠外科杂志

Objective@#To investigate the prognosis and influencing factors of postoperative low anterior resection syndrome (LARS) for rectal cancer patients undergoing laparoscopic sphincter-preserving radical resection.@*Methods@#A retrospective case-control study was used in this study. Clinical data of 268 rectal cancer patients undergoing laparoscopic sphincter-preserving radical resection at Department of Gastrointestinal Surgery of The First Affiliated Hospital of Bengbu Medical College from January 2016 to January 2018 were retrospectively collected. Inclusion criteria: (1) operation procedure was total mesorectal excision (TME) and sphincter-preserving radical resection; (2) rectal cancer was confirmed by postoperative pathology; (3) age of patient was ≥ 18 years old. Exclusion criteria: (1) patient who had history of pelvic surgery and pelvic fractures, which would affect the anorectal function; (2) patient who had history of preoperative chronic constipation and irritable bowel syndrome, which would affect defecation; (3) patient who developed postoperative complications, such as anastomotic leakage, which would affect defecation function; (4) patient who received long-term use of drugs, which would affect the function of gastrointestinal tract or anus; (5) patient suffered from mental illness, who was unable to communicate properly; (6) patient who was lack of clinical data or had incomplete clinical data. Patients were followed up at 3, 6 and 12 months postoperatively, and LARS was diagnosed and graded according to the LARS score scale. The LARS score ranged from 0 to 42 points, and 0 to 20 was difined as no LARS, 21 to 29 was mild LARS, and 30 to 42 was severe LARS. LARS score >20 points at any time point was defined as postoperative LARS. Severe LARS transferring into mild LARS and mild LARS transferring into no LARS was defined as symptom improvement. Incidence and outcomes of LARS were evaluated. The factors associated with LARS outcomes were analyzed using χ2 test and logistic regression model.@*Results@#A total of 268 patients were enrolled. The incidence of LARS was 42.9% (115/268), 32.5% (87/268) and 20.1% (54/268) at 3, 6, and 12 months postoperatively respectively, and no new case of LARS was found after 3 months postoperatively. The incidence of mild LARS was 25.7% (69/268), 17.2% (46/268) and 8.6% (23/268) at 3, 6, and 12 months postoperatively respectively, and mild LARS incidence at 6 months was significantly lower than that at 3 months (χ2=5.857, P=0.016), and was significantly higher than that at 12 months (χ2=8.799, P=0.003). The incidence of severe LARS was 17.2% (46/268), 15.3% (41/268) and 11.6% (31/268) at 3, 6, and 12 months postoperatively respectively, without significant difference among 3 time points (all P>0.05). The improvement rate within one year after surgery in patients with mild LARS diagnosed at 3 months was significantly higher than that in patients with severe LARS (88.4% vs. 32.6%, χ2=38.340, P<0.001). Univariate analysis showed that female, distance from anastomosis to anal verge < 5 cm and tumor diameter ≥ 5 cm were associated with unsatisfied LARS outcomes (all P<0.05). Logistic regression analysis showed that distance from anastomosis to anal verge <5 cm was an independent risk factor for LARS outcome (OR=3.589, 95% CI: 1.163 to 2.198, P<0.001).@*Conclusions@#The incidence of LARS after laparoscopic sphincter-preserving radical resection decreases with time. The improvement rate within postoperative 1-year of severe LARS is lower than that of mild LARS. Low anastomotic position may lead to impaired improvement of LARS.

Protective effect of procyanidin B2 on intestinal barrier and against enteritis in a mouse model of trinitrobenzene sulphonic acid-induced colitis / 南方医科大学学报

OBJECTIVE@#To investigate the protective effect of procyanidin B2 (PCB2) on the intestinal barrier and against enteritis in mice with trinitrobenzene sulphonic acid (TNBS)-induced colitis and explore the possible mechanism.@*METHODS@#A mouse model of TNBS-induced colitis was established in male Balb/c mice aged 6-8 weeks. The successfully established mouse models were randomly divided into PCB2 treatment group (=10) and model group (=10) and were treated with daily intragastric administration of PCB2 (100 mg/kg, 0.2 mL) and 0.2 mL normal saline, respectively. After 4 weeks, the disease symptoms, intestinal inflammation, intestinal mucosal cell barrier function and the changes in PI3K/AKT signaling were evaluated using HE staining, immunofluorescence assay and Western blotting.@*RESULTS@#The disease activity index of the mice was significantly lower and the mean body weight was significantly greater in PCB2 group than in the model group in the 3rd and 4th weeks of intervention ( < 0.05). The levels of colonic inflammation and intestinal mucosal inflammatory mediators IL-1β and TNF-α were significantly lower while IL-10 was significantly higher in PCB2 group than in the model group ( < 0.05). Compared with those in the model group, the mice in PCB2 treatment group showed a significantly lower positive rate of bacterial translocation in the mesenteric lymph nodes and a lower thiocyanate-dextran permeability of the intestinal mucosa ( < 0.05). Western blotting showed that PCB2 treatment significantly increased the expressions of claudin-1 and ZO-1 ( < 0.05) and significantly lowered the expression levels of p-PI3K and p-AKT in the intestinal mucosa as compared with those in the model group ( < 0.05).@*CONCLUSIONS@#PCB2 suppresses intestinal inflammation and protects intestinal mucosal functions and structural integrity by inhibiting intestinal PI3K/AKT signaling pathway, suggesting the potential of PCB2 as a new drug for Crohn's disease.

Association of adenylate cyclase-associated protein 2 expression with histopathology and long-term prognosis of gastric cancer / 南方医科大学学报

OBJECTIVE@#To explore association of the expression levels of adenylate cyclase-associated protein 2 (CAP2) in gastric cancer tissues with the histopathology and long-term prognosis of the malignancy.@*METHODS@#This study was conducted among a total of 105 patients with gastric cancer undergoing radical gastrectomy in our hospital between January, 2010 and October, 2013. Immunohistochemistry was used to quantitatively assess the expression of CAP2 in gastric cancer tissues and the adjacent tissues. Based on the median relative expression level of CAP2 of 3.5, the patients were divided into low CAP2 expression group (=52) and high CAP2 expression group (=53). The Cox regression model was used to analyze the effect of CAP2 expression on the 5-year survival rate of the patients, and ROC curve analysis was used to assess the predictive value of CAP2 expression for the patients' long-term survival.@*RESULTS@#Immunohistochemical analysis showed that the expression levels of CAP2 ( < 0.01) and Ki67 ( < 0.01) were significantly higher in gastric cancer tissues than in the adjacent tissues, and the expression level of CAP2 was positively correlated with Ki67 ( < 0.01), peripheral blood CEA ( < 0.01) and CA19-9 ( < 0.01). The percentages of patients with CEA≥5 μg/L, CA19-9≥37 kU/L, pathological grade of G3-G4, T stage of 3-4, and N stage of 2-3 were significantly higher in patients with high CAP2 expression than in those with low CAP2 expression ( < 0.05). Kaplan- Meier survival analysis showed that the 5-year survival rate was significantly lower in patients with a high CAP2 expression ( < 0.01). A high expression level of CAP2, CEA≥5μg/L, CA19-9≥37 and pathological grades G3-G4 were all independent risk factors for shortened 5-year survival after radical gastrectomy ( < 0.01). With the relative expression level of 3.45 as the cut-off value, the sensitivity of CAP2 was 70.15% for predicting death 5 years after the surgery, with a specificity of 71.05% and an area under the curve of 0.779 ( < 0.01).@*CONCLUSIONS@#CAP2 is highly expressed in gastric cancer tissues in close relation with the tumor progression. CAP2 is an independent risk factor for 5-year survival rate after radical gastrectomy for gastric cancer and can be of clinical value in prognostic evaluation of the patients.

Effect of intraoperative fluorouracil implant combined with raltitrexed regional chemotherapy in advanced gastric cancer surgery / 中国医师进修杂志

Objective To investigate the clinical efficacy of intraoperative fluorouracil implant combined with raltitrexed chemotherapy in advanced gastric cancer. Methods The clinical data of patients with advanced gastric cancer from November 2013 to November 2014 were retrospectively analyzed. The patients were divided into 2 groups according to intraoperative treatment method. Sixty-two cases (observation group) received intraoperative fluorouracil implant combined with raltitrexed regional chemotherapy, and 54 cases (control group) were not given the intraoperative chemotherapy drugs. The postoperative ventilation time, incidence of complications, peripheral blood white blood cell and platelets 1st, 3rd, 5th and 7th day after operation, cumulative recurrence rate and cumulative survival rate 3 years after operation were compared between 2 groups. Results There were no significant differences in postoperative ventilation time and incidence of complications between 2 groups (P > 0.05). The white blood cell 1st and 3rd day after operation in observation group was significantly lower than that in control group: (5.21 ± 1.03)×109/L vs. (6.52 ± 1.08)×109/L and (5.29 ± 1.11)×109/L vs. (6.37 ± 1.06)×109/L, the platelet 1st, 3rd and 5th day after operation in observation group was significantly lower than that in control group: (172.64 ± 31.48) × 109/L vs. (188.34 ± 30.05) × 109/L, (175.81 ± 31.77) × 109/L vs. (190.36 ± 31.12) ×109/L and (178.46 ± 32.04) ×109/L vs. (191.18 ± 31.29) ×109/L, and there were statistical differences (P＜0.05); but the white blood cell and platelets in 2 groups were in the normal range at all time points. The 3-year cumulative recurrence rate in the observation group was significantly lower than that in control group: 75.8% (47/62) vs. 83.3% (45/54), the 3-year cumulative survival rate was significantly higher than that in control group: 71.0% (44/62) vs. 51.9% (28/54), and there were statistical differences (P＜0.05). Further analysis of patients with recurrent 3 years after operation, the incidence of local recurrence and extensive peritoneal metastasis in observation group was significantly lower than that in control group: 40.4% (19/47) vs. 68.9% (31/45), and there was statistical difference (P＜0.01). Conclusions It is a safe and effective treatment for intraoperative fluorouracil implant combined with raltitrexed regional chemotherapy to inhibit local recurrence and peritoneal metastasis in patients with advanced gastric cancer.

Risk Factors for Postoperative Intra-abdominal Septic Complications in Crohn ’s Disease / 胃肠病学

Background:As postoperative intra-abdominal septic complications( IASCs)in Crohn’s disease( CD)are difficult to manage,it is of great importance to prevent this condition in CD patients after surgery. Till now,there are no large sample studies on risk factors for postoperative IASCs in CD in China. Aims:To determine the risk factors for postoperative IASCs in CD for guiding the formulation of preventive strategies. Methods:This retrospective study was based on a computerized database of CD patients who had undergone surgery for CD complications between 1999 and 2014 at Nanjing General Hospital of Nanjing Military Command,PLA. Patients were divided into IASCs group and non-IASCs group. Thirty potential variables were selected,and both univariate and multivariate( Logistic regression)analyses were performed to identify the risk factors for IASCs after surgery. Results:Seven hundred and sixteen operations were reviewed,and IASCs occurred in 41 cases(5. 7%). By univariate and multivariate analyses,IASCs were significantly associated with one stage anastomosis(OR=1. 656,95% CI:1261-3. 279),preoperative low albumin level( 10 mg/L)(OR=8. 641,95% CI:3. 376-16. 364),preoperative steroids use ≥3 months(OR=3. 785,95% CI:1. 237-4. 671)and presence of intra-abdominal abscess or infection at the time of surgery(OR=1. 784,95% CI:1. 155-3. 826). However,enterostomy(OR =0. 125,95% CI:0. 062-0. 561)and preoperative enteral nutrition ≥ 1 month( OR =0. 147,95% CI:0. 078-0. 781 ) were found to be the independent protective factors. Conclusions:Malnutrition,active CD and preoperative long-term steroids use increase the risk of postoperative IASCs in CD. Patients with these risk factors should not receive immediate surgery. If surgery is inevitable, enterostomy instead of resection and anastomosis should be the first choice. Preoperative enteral nutrition is helpful for reducing the occurrence of IASCs after surgery.