[Effects of Angelicae Sinensis Radix on cAMP/Epac signaling pathway in the treatment of chronically infected cough mice with Yin deficiency syndrome].

OBJECTIVE: To investigate the effects of Angelicae Sinensis Radix (ASR) on cyclic adenosine monophosphate (cAMP) /exchange protein activated by cAMP (Epac) signaling pathway in the treatment of chronically infected cough mice with Yin deficiency syndrome. METHODS: Mice were randomly divided into blank control group, model control group, positive control group and ASR group (n=8). The chronic cough mouse model of hyperreactive and infected airway with Yin deficiency syndrome was established with fumigation (once a day, 30 days in total), lipopolysaccharide nasal drip (every 3 days 10 µl, 10 times in total), intragastric administration of thyroid gland (120 mg/kg, once a day, a total of 15 days) and inhalation of ammonia (3 min / time × 10 times). On the basis of observing eating and drinking water, body weight and autonomic activities, the effects of ASR on metabolic level, autonomous activities, antitussive effect, cell factor in bronchoalveolar lavage fluid (BALF) brain tissue 5-HT and lung tissue related active factors(SP, PGP9.5, cAMP, Epac1) were detected. RESULTS: ASR could significantly restrain cough, alleviate the pathological changes of bronchioles, reduce the contents of IL-4, IL-13, TNF-α in BALF and the levels of SP, PGP9.5, cAMP and Epac1 in lung tissues, increase the content of 5-HT in brain tissue (P＜0.05, 0.01). CONCLUSION: ASR has some effects on restraining cough and one of its mechanisms is to down-regulate cAMP/Epac signaling pathway, to alleviate airway neurogenic inflammation and reduce sensitivity of cough neural pathway.

[Effects of Butylphthalide on airway mucus hypersecretion, IL-13 and TNF-α in asthmatic mice].

Objective: To investigate the effects of Butylphthalide (NBP) on airway mucus hypersecretion, interleukin-13 (IL-13) and tumor necrosis factor-α (TNF-α) in asthmatic mice. Methods: The mice were randomly divided into control group, asthma group, DEX group and high, medium and low doses of NBP (100, 50, 25 mg/kg) groups (n=12). Ovalbumin (OVA) injection was sensitized on the 1st, 8th, and 15th day of the experiment, and OVA was inhaled on the 22nd day to stimulate for 5 weeks to replicate the asthma model, and 20 mg/kg of NBP was given for intervention before the challenge. Finally, the asthma behavior, the secretion of goblet cells and Mucin 5ac (Muc5ac)were observed, and meanwhile the viscosity of bronchoalveolar lavage fluid (BALF) and the levels of Muc5ac, IL-13 and TNF-α in BALF were measured by ELISA. Results: Compared with the control group, the degree of sneezing, nose scratching and asthma, the proliferation of airway epithelial goblet cells and secretion of Muc5ac in the asthma group were increased significantly (P＜0.01), meanwhile, the viscosity of BALF and the contents of Muc5ac, IL-13 and TNF-α were also increased significantly (P＜0.01). Compared with the asthma group, the above behavioral scores of asthma were decreased significantly (P＜0.01) after the intervention of 25, 50 and 100 mg/kg NBP, as well as the proliferation of airway epithelial goblet cells, secretion of Muc5ac, the viscosity of BALF and the contents of Muc5ac, IL-13 and TNF-α were significantly lower than those of the asthma group (P＜0.05, 0.01). Conclusion: NBP has the effect of anti-asthma by inhibiting mucus hypersecretion, and one of its mechanisms is to alleviate the abnormal expressions of IL-13 and TNF-α.

Establishment and validation of a nomogram to predict the risk of ovarian metastasis in gastric cancer: Based on a large cohort.

BACKGROUND: Ovarian metastasis is a special type of distant metastasis unique to female patients with gastric cancer. The pathogenesis of ovarian metastasis is incompletely understood, and the treatment options are controversial. Few studies have predicted the risk of ovarian metastasis. It is not clear which type of gastric cancer is more likely to metastasize to the ovary. A prediction model based on risk factors is needed to improve the rate of detection and diagnosis. AIM: To analyze risk factors of ovarian metastasis in female patients with gastric cancer and establish a nomogram to predict the probability of occurrence based on different clinicopathological features. METHODS: A retrospective cohort of 1696 female patients with gastric cancer between January 2006 and December 2017 were included in a single center, and patients with distant metastasis other than ovary and peritoneum metastasis were excluded. Potential risk factors for ovarian metastasis were analyzed using univariate and multivariable logistic regression. Independent risk factors were chosen to construct a nomogram which received internal validation. RESULTS: Ovarian metastasis occurred in 83 of 1696 female patients. Univariate analysis showed that age, Lauren type, whether the primary lesion contained signet-ring cells, vascular tumor emboli, T stage, N stage, the expression of estrogen receptor, the expression of progesterone receptor, serum carbohydrate antigen 125 and the neutrophil-to-lymphocyte ratio were risk factors for ovarian metastasis of gastric cancer (all P < 0.05). Multivariate analysis showed that age ≤ 50 years, Lauren typing of non-intestinal, gastric cancer lesions containing signet-ring cell components, N stage > N2, positive expression of estrogen receptor, serum carbohydrate antigen 125 > 35 U/mL, and a neutrophil-to-lymphocyte ratio > 2.16 were independent risk factors (all P < 0.05). The independent risk factors were constructed into a nomogram model using R language software. The consistency index after continuous correction was 0.840 [95% confidence interval: (0.774-0.906)]. After the internal self-sampling (Bootstrap) test, the calibration curve of the model was obtained with an average absolute error of 0.007. The receiver operating characteristic curve of the obtained model was drawn. The area under the curve was 0.867, the maximal Youden index was 0.613, the corresponding sensitivity was 0.794, and the specificity was 0.819. CONCLUSION: The nomogram model performed well in the prediction of ovarian metastasis. Attention should be paid to the possibility of ovarian metastasis in high-risk populations during re-examination, to ensure early detection and treatment.

Preoperative albumin levels predict prolonged postoperative ileus in gastrointestinal surgery.

BACKGROUND: Prolonged postoperative ileus (PPOI) is a prolonged state of "pathological" gastrointestinal (GI) tract dysmotility. There are relatively few studies examining the influence of preoperative nutritional status on the development of PPOI in patients who underwent GI surgery. The association between preoperative albumin and PPOI has not been fully studied. We hypothesized that preoperative albumin may be an independent indicator of PPOI. AIM: To analyze the role of preoperative albumin in predicting PPOI and to establish a nomogram for clinical risk evaluation. METHODS: Patients were drawn from a prospective hospital registry database of GI surgery. A total of 311 patients diagnosed with gastric or colorectal cancer between June 2016 and March 2017 were included. Potential predictors of PPOI were analyzed by univariate and multivariable logistic regression analyses, and a nomogram for quantifying the presence of PPOI was developed and internally validated. RESULTS: The overall PPOI rate was 21.54%. Advanced tumor stage and postoperative opioid analgesic administration were associated with PPOI. Preoperative albumin was an independent predictor of PPOI, and an optimal cutoff value of 39.15 was statistically calculated. After adjusting multiple variables, per unit or per SD increase in albumin resulted in a significant decrease in the incidence of PPOI of 8% (OR = 0.92, 95%CI: 0.85-1.00, P = 0.046) or 27% (OR = 0.73, 95%CI: 0.54-0.99, P = 0.046), respectively. Patients with a high level of preoperative albumin (≥ 39.15) tended to experience PPOI compared to those with low levels (< 39.15) (OR = 0.43, 95%CI: 0.24-0.78, P = 0.006). A nomogram for predicting PPOI was developed [area under the curve (AUC) = 0.741] and internally validated by bootstrap resampling (AUC = 0.725, 95%CI: 0.663-0.799). CONCLUSION: Preoperative albumin is an independent predictive factor of PPOI in patients who underwent GI surgery. The nomogram provided a model to screen for early indications in the clinical setting.

Nomogram to predict prolonged postoperative ileus after gastrectomy in gastric cancer.

BACKGROUND: Prolonged postoperative ileus (PPOI) is one of the common complications in gastric cancer patients who underwent gastrectomy. Evidence on the predictors of PPOI after gastrectomy is limited and few prediction models of nomogram are used to estimate the risk of PPOI. We hypothesized that a predictive nomogram can be used for clinical risk estimation of PPOI in gastric cancer patients. AIM: To investigate the risk factors for PPOI and establish a nomogram for clinical risk estimation. METHODS: Between June 2016 and March 2017, the data of 162 patients with gastrectomy were obtained from a prospective and observational registry database. Clinical data of patients who fulfilled the criteria were obtained. Univariate and multivariable logistic regression models were performed to detect the relationship between variables and PPOI. A nomogram for PPOI was developed and verified by bootstrap resampling. The calibration curve was employed to detect the concentricity between the model probability curve and ideal curve. The clinical usefulness of our model was evaluated using the net benefit curve. RESULTS: This study analyzed 14 potential variables of PPOI in 162 gastric cancer patients who underwent gastrectomy. The incidence of PPOI was 19.75% in patients with gastrectomy. Age older than 60 years, open surgery, advanced stage (III-IV), and postoperative use of opioid analgesic were independent risk factors for PPOI. We developed a simple and easy-to-use prediction nomogram of PPOI after gastrectomy. This nomogram had an excellent diagnostic performance [area under the curve (AUC) = 0.836, sensitivity = 84.4%, and specificity = 75.4%]. This nomogram was further validated by bootstrapping for 500 repetitions. The AUC of the bootstrap model was 0.832 (95%CI: 0.741-0.924). This model showed a good fitting and calibration and positive net benefits in decision curve analysis. CONCLUSION: We have developed a prediction nomogram of PPOI for gastric cancer. This novel nomogram might serve as an essential early warning sign of PPOI in gastric cancer patients.

[Corrigendum] Increased expression of Lgr5 is associated with chemotherapy resistance in human gastric cancer.

An interested reader drew to the attention of the Journal that the western blot featured in Fig. 3B of the above paper also appeared as Fig. 3D in the following publication, featuring many of the same authors: Xi HQ, Cai AZ, Wu XS et al: Leucine­rich repeat­containing G­protein­coupled receptor 5 is associated with invasion, metastasis, and could be a potential therapeutic target in human gastric cancer. Br J Cancer 110: 2011­2020, 2014. After having consulted the authors about this matter, they conceded that there was a data sharing violation here, and that the image should not have been reproduced in the above article without having received the prior permission of the British Journal of Cancer. This permission has now been sought after and obtained, and Fig. 3 is reproduced opposite, now including the appropriate credit for the original source of Fig. 3B. The authors apologize to the Editors of the British Journal of Cancer and Oncology Reports, and to the readership for any inconvenience caused. [the original article was published in Oncology Reports 32: 181­188, 2014; DOI: 10.3892/or.2014.3204].

Comparison between laparoscopic and open surgery for large gastrointestinal stromal tumors: A meta-analysis.

AIM: To investigate whether laparoscopic surgery is as safe and feasible as open resection for patients with larger gastrointestinal stromal tumors (GISTs) (≥ 5 cm). METHODS: A systematic search of PubMed, EMBASE, Web of Science and the Cochrane Library database was performed. Relevant studies of laparoscopic and open surgery for GISTs of > 5 cm published before December 2016 were identified from these databases. The quality of the studies was assessed by the Newcastle-Ottawa Quality Assessment Scale. The tumor size, operation time, blood loss, postoperative hospital stay, complication rate, and disease-free survival rate were assessed. The software Stata (version 12.0) was used for the meta-analysis. RESULTS: Five clinical trials comprising 209 patients with GISTs of similar larger sizes were evaluated. The pooled analysis of 100 patients in the laparoscopic resection group and 109 patients in the open resection group demonstrated that laparoscopic surgery was significantly associated with a shorter postoperative hospital stay (P < 0.001) and less blood loss (P = 0.002). Moreover, there were no statistically significant differences in the operation time (P = 0.38), postoperative complication rate (P = 0.88), or disease-free survival rate (P = 0.20) between two groups. CONCLUSION: Our findings revealed that for patients with large GISTs of comparable sizes, laparoscopic surgery did not significantly influence the operation factors or clinical outcomes compared with open surgery. This suggests that laparoscopic resection is as acceptable as open surgery for treatment of large gastric GISTs.

RNAi-mediated inhibition of Lgr5 leads to decreased angiogenesis in gastric cancer.

Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) is a novel gastric cancer marker. However, it is unclear whether it can play roles in tumor angiogenesis. In this study, we aim to investigate the role of Lgr5 on gastric cancer angiogenesis. Lgr5, VEGF expression levels and microvessel density (MVD) were detected in tumor tissue. Then, Lgr5 mRNA was downregulated by small interference RNA technique. Western blotting and real-time quantitative PCR (qRT-PCR) were performed to detect the expression of Lgr5 and VEGF protein and mRNA in Lgr5 siRNA-transfected gastric cancer cells. The effect of silencing Lgr5 on angiogenesis was examined by assessing human umbilical vein endothelia cell (HUVEC) capillary tube formation. The results indicated that Lgr5 expression was upregulated in gastric cancer and positively correlated with VEGF (r=0.305, P=0.001) and MVD (r=0.312, P=0.001). Silencing of Lgr5 expression resulted in suppression of VEGF mRNA and protein (all P=0.001). Moreover, when HUVECs were stimulated with conditioned medium from Lgr5 siRNA-transfected gastric cancer cells, tube formation was significantly decreased (2.51 ± 0.19 mm/mm2) compared with the treatment with regular cell culture medium (DMEM) (7.34 ± 0.30 mm/mm2) or medium from control siRNA-transfected cells (7.18 ± 0.33 mm/mm2) (all P=0.001). In conclusion, Lgr5 plays important roles in angiogenesis. Lgr5-specific siRNA could be designed into an effective therapeutic agent to inhibit gastric cancer angiogenesis.

Expression and clinicopathologic significance of TUFM and p53 for the normal-adenoma-carcinoma sequence in colorectal epithelia.

BACKGROUND: Evidence indicates that most cases of colorectal carcinoma (CRC) develop from adenoma. A previous study demonstrated that mitochondrial Tu translation elongation factor (TUFM) might serve as an independent prognostic factor for colorectal cancer. However, the expression and function of TUFM in the normal-adenoma-cancer sequence have not been reported. In this study, we investigated the clinicopathologic significance of TUFM and p53 expression for the normal-adenoma-carcinoma sequence in colorectal epithelia and evaluated the roles of TUFM during the progression of colorectal tumors. METHODS: Paraffin-embedded specimens from 261 colorectal normal mucosa samples, 157 adenomas, and 104 early carcinomas were analyzed for TUFM and p53 expression by immunohistochemistry. RESULTS: Expression of TUFM and p53 was significantly increased during the colorectal normal-adenoma-carcinoma sequence (all P < 0.05). The expression of TUFM and p53 was associated with histologic type of adenomas (P = 0.028; P = 0.001) and grade of dysplasia (all P = 0.001). Expression of TUFM was positively correlated with that of p53 (r = 0.319, P = 0.001). CONCLUSIONS: Upregulated TUFM expression may play an important role in the transformation from colorectal normal mucosa to carcinoma through adenoma. Combined immunohistochemical detection of TUFM and p53 may be useful for evaluating the biological behavior of colorectal adenoma.

Comparison of Therapeutic Efficacy between Gastrectomy with Transarterial Chemoembolization Plus Systemic Chemotherapy and Systemic Chemotherapy Alone in Gastric Cancer with Synchronous Liver Metastasis.

BACKGROUND: Systemic chemotherapy (SC) is the recommended treatment for gastric cancer with liver metastasis. However, the improvement in survival has been disappointing. The aim of this study was to compare the therapeutic efficacy of gastrectomy with transarterial chemoembolization plus SC (GTC) and SC alone for gastric cancer with synchronous liver metastasis. METHODS: From January 2008 to December 2013, 107 gastric cancer patients with synchronous liver metastasis attending the four participating centers were enrolled in this multicenter, ambispective, controlled cohort study. Patients who underwent GTC (n = 32) were compared with controls who were received SC alone (n = 75). The primary endpoints of the study were overall survival (OS) and progression-free survival (PFS). The secondary endpoints were response rate to treatment and treatment-related adverse effects. RESULTS: The median OS was 14.0 months (95% confidence interval [CI ]: 13.1-14.9 months) in the GTC treatment group and 8.0 months (95% CI : 6.6-9.4 months) in SC group, this difference being statistically significant (P < 0.001). The median PFS was significantly longer in the GTC than in the SC group (5 months, 95% CI : 2.2-7.8 months vs. 3 months, 95% CI : 2.3-3.4 months, respectively) (P < 0.001). The rate of response to treatment was significantly better in the GTC than the SC group (59.4% vs. 37.4%, respectively) (P = 0.035). According to multivariate analysis, OS in patients receiving combination treatment was significantly correlated with the size (P = 0.037) and extent of liver metastases (P < 0.001). PFS was also correlated with the extent of liver metastases (P = 0.003). CONCLUSIONS: GTC is more effective than SC alone in patients with gastric cancer with synchronous liver metastasis. GTC therapy prolongs the survival of selected gastric cancer patients with synchronous liver metastasis.

Prognostic role of miR-200c in various malignancies: a systematic review and meta-analysis.

MiR-200c expression is dysregulated in various malignancies and may predict the survival of patients with cancer, although the results of different studies conflict. Therefore, we conducted a meta-analysis to resolve this discrepancy. We queried the PubMed and Embase using multiple search strategies. Data were extracted from studies comparing overall survival and progression-free survival in patients with cancer with high and low levels of miR-200c expression. Fixed and random models were used where appropriate. A combined hazards ratio (HR) was calculated to estimate the association of high levels of miR-200c with survival. We selected 16 studies of 1485 participants for our final meta-analysis. Upregulated expression of miR-200c predicted significantly worse overall survival in patients with cancer (HR 1.51; 95% confidence interval [CI] 1.06-2.16, P = 0.023). Subgroup analysis indicated that high levels of miR-200c was associated with decreased survival of Caucasians and patients with gynecological tumors with pooled HR values of 1.82 (95% CI 1.27-2.26, P = 0.01) and 3.23 (95% CI 1.11-9.38, P = 0.032), respectively. Because of the absence of apparent heterogeneity, the combined HRs were 1.69 (95% CI 1.24-2.30, P = 0.001) for squamous cell carcinoma and 1.91 (95% CI 1.40-2.59, P < 0.001) for samples from peripheral blood. Increased expression of miR-200c significantly associated with shorter progression-free survival of patients with cancer (HR 2.37; 95% CI 1.47-3.81, P < 0.001). Our meta-analysis indicates that the level of miR-200c expression predicted survival of patients with cancer, particularly for Caucasians and patients with gynecological cancer. Increased expression of miR-200c predicted shorter survival of patients with squamous cell carcinomas. Our findings indicate that monitoring the levels of miR-200c in blood may be useful for following tumor progression as well as patients' prognosis.

Hemolysis-free plasma miR-214 as novel biomarker of gastric cancer and is correlated with distant metastasis.

Circulating miRNAs gains popularity for its potential ability to serve as biomarkers of cancer. The aim of present study was to evaluate the usefulness of plasma miR-214 as novel biomarkers for gastric cancer (GC) detection. Attempts were made to address several pitfalls in sample processing and study design in previous studies. We conducted a two-step analysis: (1) in pilot study comprising of 30 patients and 30 controls, levels of miR-214 were significantly higher in primary GC tissues than normal tissues (P = 0.0215). Plasma miR-214 was significantly higher in patients with GC than in controls (P < 0.0001). (2) In test of larger cohort, there was significantly decreasing tendency of plasma miR-214 from patients before, 14 days and 1 month after surgical resection (P < 0.0001). There were significantly higher levels of miR-214 in 80 GC patients than in 70 controls (P < 0.0001). Receiver operating characteristics (ROC) curves yielded area under the curve (AUC) value of 0.845. Moreover, high plasma miR-214 had significant correlation with distant metastasis (P = 0.038). Thus, our data suggest that plasma miR-214 was novel hemolysis-free markers of gastric cancer.

Increased expression of Lgr5 is associated with chemotherapy resistance in human gastric cancer.

Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5), a marker of adult stem cells and cancer stem cells, plays important roles in tumor progression. Furthermore, Lgr5 also contributes to chemoradiotherapy resistance. However, the function of Lgr5 in the prediction of preoperative chemotherapy efficacy has not been reported. We evaluated the potential of Lgr5 in predicting tumor response and overall survival in advanced gastric cancer treated with preoperative chemotherapy. The association between Lgr5 and chemotherapy resistance was also investigated in gastric cancer cell lines. Hematoxylin and eosin staining and immunohistochemical analysis of Lgr5 expression were performed in 68 cases of gastric cancer treated with preoperative chemotherapy. Lgr5 expression was specifically silenced in the AGS gastric cancer cell lines by RNA interference. Levels of Lgr5 mRNA and protein in cell lines were detected by quantitative reverse transcription-polymerase chain reaction or western blotting. Cell viability was evaluated by an MTT assay. Cell apoptosis was assessed by Annexin V-FITC/propidium iodide dual staining analysis. We found that Lgr5 expression was significantly associated with tumor regression grade after preoperative chemotherapy. The rate of positive Lgr5 expression was significantly higher in patients with poor tumor regression compared with those exhibiting tumor regression (P=0.001). Lgr5-positive patients had a significantly shorter survival time than Lgr5-negative patients (P=0.001). Inhibition of Lgr5 expression with small interfering RNA increased the sensitivity of AGS gastric cancer cells to chemotherapy. Our findings suggest that Lgr5 expression may be implicated in the chemoresistance of gastric cancer cells and is a potential novel biomarker for predicting response to chemotherapy and prognosis in gastric cancer patients, and may also represent a potential new therapeutic target for cancer therapy.