Cytokine-induced killer cell/dendritic cell combined with cytokine-induced killer cell immunotherapy for treating advanced gastrointestinal cancer.

BACKGROUND: This study aimed to investigate the efficacy and safety of cytokine-induced killer (CIK)/dendritic cell combined with CIK (DC-CIK) cell therapy in advanced gastrointestinal cancer (GIC). METHODS: The PubMed, Cochrane library, and Embase were searched to conduct a meta-analysis of clinical controlled trials to evaluate the efficacy and safety of CIK/DC-CIK cell therapy in advanced GIC. The pooled risk ratios (RRs) or weighted mean difference (WMD) with 95% confidence intervals (95% CIs) were calculated. RESULTS: A total of nine studies with 1113 patients were identified. The overall survival (RR = 1.84, 95% CI = 1.41-2.40, Pheterogeneity = 0.654, I2 = 0%), progression-free survival (RR = 1.99, 95% CI = 1.52-2.60, Pheterogeneity = 0.727, I2 = 0%), and quality of life (WMD = 16.09, 95% CI = 1.66-30.52, Pheterogeneity < 0.001, I2 = 98.8%) were significantly improved in patients who received chemotherapy combined with CIK/DC-CIK cells, and no severe adverse events were reported. CONCLUSION: This meta-analysis suggested that the combination of CIK/DC-CIK immunotherapy and chemotherapy was safe and applicable for patients with advanced GIC. It is a feasible choice to prolong survival and improve quality of life.

Association Between Helicobacter pylori Infection and Risk of Periodontal Diseases in Han Chinese: A Case-Control Study.

BACKGROUND: This study was performed to test the association between Helicobacter pylori (HP) and periodontal disease (PD). MATERIAL/METHODS: This was a case-control study in a comprehensive hospital, including all patients with newly diagnosed PD between 2012 and 2014 as cases and all patients without PD as controls, thorough periodontal examinations. Those who tested positive for HP were examined by means of polymerase chain reaction. Single and multivariate logistic regression was used to analyze the data using SPSS 19.0 software. RESULTS: This case-control study included 212 Han Chinese non-smoking adults. The results indicated that HP-positive status significantly increased the risk of PD (2.63 times higher (odds ratio [OR]=2.63; 95% confidence interval [CI]=1.48-4.67). After adjustment for age, sex, level of education, physical exercise, body mass index, and history of alcohol and diabetes mellitus, this association remained significantly (OR=2.82, 95% CI=1.55-5.13). CONCLUSIONS: PD might be associated with HP infection in adults and HP infection may be a significant and independent risk factor for PD.

Fibronectin Overexpression Modulates Formation of Macrophage Foam Cells by Activating SREBP2 Involved in Endoplasmic Reticulum Stress.

AIMS: To explore the explicit role of fibronectin (FN) isforms in atherosclerotic lesions and the underlying mechanisms. METHODS AND RESULTS: Inducible stable expression was performed, and similar results were observed between EDA+FN (FN containing EDA domain) and EDA-FN (FN devoid of EDA domain). FN isforms could trigger endoplasmic reticulum (ER) stress, thereby leading to lipid accumulation in cultured Raw264.7 cells. FN isforms-induced gene expression and lipid accumulation were inhibited by a chemical chaperone 4-phenyl butyric acid (PBA) or by overexpression of the ER chaperone, GRP78/BiP, demonstrating a direct role of ER stress in activation of cholesterol/triglyceride biosynthesis. Moreover, activation of the sterol regulatory element binding protein-2 (SREBP2) was found to be downstream of ER stress, and this activation was affirmed to account for the intracellular accumulation of cholesterol using RNAi technique. CONCLUSION: our study suggests that enhanced FN in lesions facilitates foam cell formation due to dysregulation of the endogenous sterol response pathway by activation of ER stress, and confirms that EDA+FN has no more pro-atherogenic role than EDA-FN in triggering ER stress.

The interplay between GRP78 expression and Akt activation in human colon cancer cells under celecoxib treatment.

It has been reported previously that celecoxib shows antitumor effects in many types of cancers. Here, we detected its effects on DLD-1 and SW480 (two human colon cancer cell lines) and investigated the dynamic relationship between the 78-kDa glucose-regulatory protein (GRP78) and the phosphoinositide 3-kinase (PI3K)/Akt pathway. Gene expression was detected by real-time PCR and western blot analysis; the cytotoxicity was determined by the MTT assay and flow cytometry. First, the results showed that celecoxib induced cytotoxicity in a dose-dependent and time-dependent manner. Furthermore, we found the celecoxib-triggered unfolded protein response and the bidirectional regulation of Akt activation in both cell lines. Inhibiting the Akt activation by the PI3K inhibitor LY294002 markedly enhanced GRP78 expression. Besides, silencing the GRP78 expression regulated Akt activation in a time-dependent manner and increased the induction of the C/EBP homologous protein (CHOP) as well as considerably promoted celecoxib-induced apoptosis. In conclusion, these findings provide evidence that under the celecoxib treatment, GRP78 plays a protective role by modulating Akt activation and abrogating CHOP expression. However, Akt activation can provide a feedback loop to inhibit GRP78 expression. These studies can lead to novel therapeutic strategies for human colon cancer.

miR-152 suppresses gastric cancer cell proliferation and motility by targeting CD151.

We aimed to study the post-translational regulation of CD151 by the microRNA miR-152. CD151 is highly expressed in gastric cancer (GC) and has been shown to accelerate GC by enhancing invasion and metastasis; however, its regulation is still unclear. Our results showed decreased expression of miR-152 in GC tissue samples and cell lines. In addition, miR-152 complementation significantly inhibits both the proliferation and motility of GC cells. CD151 was found to be a target of miR-152, and overexpression of CD151 attenuated the suppressive effect of miR-152. Our findings highlight an essential role of miR-152 in the regulation of proliferation and motility of GC cells and suggest a potential application of miR-152 in GC treatment.

Machine learning based peri-surgical risk calculator for abdominal related emergency general surgery: a multicenter retrospective study.

BACKGROUND: Currently, there is a lack of ideal risk prediction tools in the field of emergency general surgery (EGS). The American Association for the Surgery of Trauma recommends developing risk assessment tools specifically for EGS-related diseases. In this study, we sought to utilize machine learning (ML) algorithms to explore and develop a web-based calculator for predicting five perioperative risk events of eight common operations in EGS. METHOD: This study focused on patients with EGS and utilized electronic medical record systems to obtain data retrospectively from five centers in China. Five ML algorithms, including Random Forest (RF), Support Vector Machine, Naive Bayes, XGBoost, and Logistic Regression, were employed to construct predictive models for postoperative mortality, pneumonia, surgical site infection, thrombosis, and mechanical ventilation >48 h. The optimal models for each outcome event were determined based on metrics, including the value of the Area Under the Curve, F1 score, and sensitivity. A comparative analysis was conducted between the optimal models and Emergency Surgery Score (ESS), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and American Society of Anesthesiologists (ASA) classification. A web-based calculator was developed to determine corresponding risk probabilities. RESULT: Based on 10 993 patients with EGS, we determined the optimal RF model. The RF model also exhibited strong predictive performance compared with the ESS, APACHE II score, and ASA classification. Using this optimal model, the authors developed an online calculator with a questionnaire-guided interactive interface, catering to both the preoperative and postoperative application scenarios. CONCLUSIONS: The authors successfully developed an ML-based calculator for predicting the risk of postoperative adverse events in patients with EGS. This calculator accurately predicted the occurrence risk of five outcome events, providing quantified risk probabilities for clinical diagnosis and treatment.

ARF triggers cell G1 arrest by a P53 independent ERK pathway.

In this study, in order to investigate the p53-independent function of p14ARF, we established p14ARF-inducible clones in the p53-deficient HCT cell line using the doxycycline-inducible expression system. A strong cell growth inhibition and G1/S arrest were observed after doxycycline induction in p53-/-HCT cells, and the cells also exhibited an obvious decrease of DNA synthesis. We further examined if the MEK/ERK pathway is involved in the G1 arrest induced by p14ARF in p53-/-HCT cells. The results indicate that ERK1/2 and p21 were activated upon p14ARF induction. Totally, the functional roles of ERK and p21 for ARF in p53-independent tumor suppression were demonstrated.

Construction of a gut microbiota-gene-pathway network to reveal the molecular mechanisms underlying right- and left-sided colorectal cancer.

Aiming to reveal the molecular mechanisms involved in right- and left-sided colorectal cancer (CRC) development, CRC gene expression data and a microorganism atlas were downloaded from The Cancer Genome Atlas and The Cancer Microbiome Atlas, respectively. The R package was used to screen differentially expressed genes (DEGs) between right- and left-sided CRC samples and identify those related to prognosis, a correlation analysis was performed between DEGs and prognosis-related microbiota, and an interaction network was created using Cytoscape. Finally, a taxon set enrichment analysis of the microbiota was performed and a gene-genus-pathway network was constructed after GO and KEGG analyses. In total, nine out of 1557 identified DEGs had a significant correlation with prognosis, whereas three out of 211 bacterial genera (Fusobacterium, Bacteroides and Parabacteroides) showed a significant correlation with prognosis. DEGs were mainly enriched in the PPAR pathway and vitamin metabolic and transport processes. According to a taxon set enrichment analysis, the microbes in the integrated network were significantly abundant in 28 host-intrinsic, two host-extrinsic and one environment taxon sets. This study provides new insights for understanding the molecular mechanisms of left- and right-CRC.

Anticancer effects and underlying mechanism of Colchicine on human gastric cancer cell lines in vitro and in vivo.

The present study investigated the effects of Colchicine on gastric carcinoma (GC) cells and explored its possible mechanisms underlying such effects. The results of MTT and colony formation assays showed that Colchicine (2, 5, and 10 ng/ml) markedly inhibited the proliferation of AGS and NCI-N87 cells in a dose-dependent manner. It also led to a reduction in cell migration in both GC cells as determined by Transwell migration assay. Mover, data form Hoechst 33342 staining and flow cytometry assay indicated that Colchicine (2, 5, and 10 ng/ml) promoted the apoptosis of NCI-N87 cells. In addition, the release of cytochrome c, the activation of bax, and the inhibition of bcl-2 were observed in NCI-N87 cells treated with Colchicine. Furthermore, the in vivo experiment further confirmed that Colchicine administration remarkably suppressed the tumor growth in nude mice via induction of apoptosis at 0.05 and 0.1 mg/kg. In addition, no visible toxicity was observed in liver and renal tissue of mice. This finding suggests that Colchicine-induced apoptosis is associated with caspase-3-mediated mitochondrial apoptotic pathways.

Preoperative Neutrophil Lymphocyte Ratio and Platelet Lymphocyte Ratio Cannot Predict Lymph Node Metastasis and Prognosis in Patients with Early Gastric Cancer: a Single Institution Investigation in China.

In the present study, we aimed at exploring the applied value of preoperative neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in the prediction of lymph node metastasis (LNM) and prognosis in patients with early gastric cancer (EGC). We retrospectively analyzed a total of248 consecutive patients who underwent curative gastrectomy to be identified T1 stage gastric adenocarcinoma between January 1, 2010 and May 1, 2016 in a single institution. According to median preoperative NLR and PLR value, we divided the patients into four groups: high NLR >1.73 and low NLR <1.73, high PLR >117.78 and low PLR <117.78. Furthermore, to evaluate the relationship between preoperative NLR and PLR values, we categorized patients according to cutoff preoperative NLR-PLR score of 2 [high NLR (>1.73) and high PLR (>117.78)], 1 [either high NLR or high PLR], and 0 [neither high NLR nor high PLR], Statistical analyses were conducted using SPSS 20.0 software. The results showed that the preoperative NLR or PLR values, lower or higher, could not predict the LNM in patients with EGC (both P=0.544>0.05). The invasive depth of tumor was significantly correlated with LNM of EGC (P0.001). Kaplan-Meier plots illustrated that preoperative NLR and PLR values were not associated with overall survival (OS) in patients with EGC. It was concluded that the preoperative NLR and PLR may be the predictors for LNM and prognosis in patients with advanced gastric cancer; nevertheless, they cannot predict LNM and prognosis in patients with EGC.

Detecting the polymorphisms of paraoxonase (PON) cluster in Chinese Han population based on a rapid method.

BACKGROUND: An increased risk of coronary heart disease has been shown to be associated with polymorphisms in PON1 gene in different populations. Polymorphisms in PON2 gene have been associated with the level of plasma lipoproteins and glucose and are thought to play a role in atherosclerosis. METHODS: To detect PONs polymorphisms more rapidly and reliably, we modified and improved the method established by Motti et al. We redesigned the primer for amplifying the common polymorphism at position 311 of PON2, which produced more reliable and efficient amplification. RESULTS: A second common polymorphism at codon 148 was also detected by our new method, as were the 2 polymorphisms in the PON1 gene. The new method allowed identification of 4 polymorphisms (PON1-192, PON1-55, PON2-148 and PON2-311) simultaneously. The PONs genotypes of 82 healthy persons were identified by this method. The allelic frequencies were: PON1-192: Q 46.3%, R 53.7%; PON1-55: L 95.1%, M 4.9%; PON2-148: A 85.4%, G 14.6%; PON2-311: S 77.4%, and C 22.6%, respectively. CONCLUSION: This method represents a simple, economical and time-saving technique to simultaneously detect 4 polymorphisms in the PON cluster. It provides a useful application to enable further study of the relationship between PON1 and PON2 and their role in atherosclerosis.

Celecoxib induces apoptosis but up-regulates VEGF via endoplasmic reticulum stress in human colorectal cancer in vitro and in vivo.

PURPOSE: In our previous study, we found that celecoxib, a kind of COX-2 inhibitor, led to cell apoptosis while up-regulating the expression of vascular endothelial growth factor (VEGF) in colorectal cancer HCT116 cells (COX-2 deficient), and endoplasmic reticulum (ER) stress was involved in the mechanism. Thus, we would like to explore whether these results are universal for other colorectal cancer cells, especially for COX-2-expressing ones, and whether the results in vitro and in vivo are matched. METHODS: HT29 cells (COX-2 expressing) were treated with celecoxib under different conditions to evaluate cell apoptosis, VEGF expression and the activation of ER stress. HT29 and HCT116 xenograft tumor models were established to evaluate anti-tumor effects and verify the experiment results we obtained in vitro. RESULTS: Celecoxib (≥60 µM) up-regulated the expression of ER stress markers (GRP78 and CHOP) and induced cell apoptosis accompanying with a correlated increased expression of VEGF in HT29 cells. Celecoxib-induced gene expression and cell apoptosis were inhibited by an ER stress inhibitor, PBA. In xenograft models, celecoxib treatment inhibited tumor growth with increased GRP78 and VEGF, which was consistent with the results in vitro. CONCLUSIONS: Celecoxib, both in vitro and in vivo, induced apoptosis of colorectal cancer cells but increased the VEGF levels at the same time in a COX-2-independent manner, namely by activating ER stress. The increased VEGF would impair the effect of celecoxib and bring drug resistant; hence, the optimal schedule of the combination of celecoxib with anti-VEGF drugs needs to be explored.

Lymph node mapping with carbon nanoparticles and the risk factors of lymph node metastasis in gastric cancer.

The study aimed to examine the applicability of carbon nanoparticles as a tracer for lymph node mapping and the related factors of lymph node and No.8p subgroup metastasis in patients with gastric cancer. Clinical data of 50 patients with gastric cancer, who had not received treatment preoperatively and underwent gastrectomy in Department of Gastrointestinal Surgery, Wuhan Union Hospital, between October 2014 and August 2015, were retrospectively analyzed. These patients were found to have no distant metastasis preoperatively. Thirty-five out of 50 patients were subjected to lymphatic mapping technique using carbon nanoparticles as the tracer, and the rest 15 cases did not experience the lymphatic mapping and served as controls. The sensitivity, specificity, false positive rate and false negative rate were calculated according to the number of lymph nodes, and the staining and metastasis condition of lymph nodes. The diagnostic value of carbon nanoparticles on metastatic lymph nodes was evaluated. The relationship between the metastasis of lymph nodes or subgroup No.8p lymph nodes and clinicopathologic features was analyzed by χ2-test or Fisher's exact test. All patients underwent D2 surgery (lymph node dissection including all the group 1 and group 2 nodes) plus the dissection of the subgroup No.8p lymph nodes. It was found that the average number of harvested lymph nodes in lymphatic mapping technique group (45.7±14.5) was greater than that in control group (39.2±11.7), but the difference was not significantly different (P=0.138>0.05). The success rate, the accuracy, sensitivity, specificity and false negative rate was 97%, 57%, 28%, 62% and 72% respectively. The metastasis of lymph nodes was correlated to the depth of cancer invasion (T stage) (P=0.004<0.05), and the metastasis of No.8p lymph nodes was correlated to the extent of lymph node involvement (N stage) (P=0.007<0.05). Six cases had lymph node metastasis in subgroup No.8p, and their TNM stages and clinical stages were as follows: T1N2M0 IIA, T3N3M0 IIIB, T4aN3M0 IIIC, T4aN3M0 IIIC, T4aN3M0 IIIC, and T4bN3M0 IIIC. In conclusion, our study indicated that carbon nanoparticles failed to show good selectivity for metastatic lymph nodes; the result of lymphatic mapping does not achieve a satisfactory performance; the incidence of lymph node metastasis may increase, accompanying with the increase of the depth of cancer invasion; No.8p lymph node metastasis tends to occur for gastric carcinoma patients with the extent of lymph node metastasis over N2 stage.

[Analysis of the relationship between stoma position and postoperative effects of procedure for prolapse and hemorrhoids in the treatment of hemorrhoids].

OBJECTIVE: To explore the relationship between stoma position and postoperative effects of procedure for prolapse and hemorrhoids (PPH) in the treatment of hemorrhoids. METHODS: Four hundred and one hemorrhoid patients were treated with circular stapler. II hemorrhoids, 45 cases; III-IV hemorrhoids, 356 cases. The position of stoma located 1 cm up dentate line, 219 cases; 1-2 cm up dentate line, 87 cases; 2-3 cm up dentate line, 60 cases; 3-4 cm up dentate line, 25 cases; > 4 cm up dentate line, 10 cases. The patients were followed from one week to two years postoperatively. RESULTS: Postoperative effects and procidentia rates have significant association with the position of stoma. If the distance between position of stoma and dentate line is < or = 2 cm, the postoperative procidentia rate was 1.1%, lower than that of the distance > or = 4 cm. CONCLUSIONS: The complication and procidentia rate of PPH is associated with the stoma position. The stoma position should be no more than 2 cm to dentate line.

Celecoxib induces cell apoptosis coupled with up-regulation of the expression of VEGF by a mechanism involving ER stress in human colorectal cancer cells.

Increasing evidence suggests that celecoxib, a COX-2 inhibitor with potent anticancer activity exerts its effects not only through COX-2, but also through COX-2-independent mechanisms. In the present study, we hypothesized that endoplasmic reticulum stress (ERS) is involved in the up-regulation of VEGF expression induced by celecoxib in colorectal cancer HCT116 cells and that ERS is a major mechanism by which celecoxib triggers tumor cell death in a COX-2-independent manner. HCT116 cells, which do not express COX-2, were cultured in the absence or presence of celecoxib. VEGF expression was detected by quantitative real-time RT-PCR and western blotting. ERS triggered by celecoxib was determined by expression of ER chaperones and other markers. PBA (an inhibitor of ERS) and GRP78 overexpression were both used to prevent ERS. Cell apoptosis was evaluated by TUNEL assay and fluorescence activated cell sorting. In HCT116 cells, celecoxib increased VEGF production with time-course and dose-response curves similar to those observed for the increase of the ER chaperone, GRP78. CHOP, a marker of ERS involved in apoptosis, was also increased by celecoxib. Moreover, celecoxib promoted cell apoptosis. Both apoptosis and up-regulation of VEGF were prevented by protecting cells from ERS. Celecoxib induces cell apoptosis and up-regulation of VEGF in HCT116 cells via activation of the ERS response. Further studies are necessary to evaluate whether the combination of celecoxib with anti-VEGF agents is a promising therapeutic modality for cancer.

[Effect of the width of excisional mucosa stoma ring on postoperative results of procedure for prolapse and hemorrhoids method].

OBJECTIVE: To explore the effect of the width of excisional mucosal stoma ring on postoperative results of procedure for prolapse and hemorrhoids (PPH) in the treatment of hemorrhoids. METHODS: Four hundred and eighty hemorrhoid patients were treated with circular stapler. Whether excisional mucosa stoma ring was regular or not, and its width were recorded. After follow-up from one month to 24 months,the outcomes were compared. RESULTS: The mean age of the patients was (46.6+/- 5.1) years. Regular mucosa stoma ring was excited in 303 cases,while irregular ring in 177 cases. Hemorrhoids prolapse occurred in 18 cases of the patients with irregular mucosal ring excited, while only 8 cases of the patients with regular ring excited (P< 0.01). There was significant difference in the incidence of hemorrhoids prolapse between the different groups according to different width of excisional mucosal stoma ring (P< 0.01), and the patients with postoperative hemorrhoids prolapse was lest with the width of excisional mucosal stoma ring more than 3 cm. CONCLUSIONS: The width of excisional mucosal stoma ring is one of the effecting factors of surgical outcomes. It is effective to excite mucosal stoma ring more than 2 cm,and most effective to excite mucosal stoma ring more than 3 cm.

[Association between RET proto-oncogene polymorphisms and Hirschsprung disease in Chinese Han population of Hubei district].

OBJECTIVE: To establish the genetic background of exon2, exon13, exon11 and exon15 polymorphisms of RET proto-oncogene and study the possible involvement of RET proto-oncogene in the etiology of Hirschsprung disease (HD) in Chinese Han population surrounding Province HuBei. METHODS: The genotype and allele frequencies of RET proto-oncogene polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLPS) in 94 HD patients and 122 control subjects. RESULTS: The genotype and allele frequencies of exon2 were AA 0.17, AG 0.72, GG 0.11, A 0.53, G 0.47 in control, and AA 0.61, AG 0.35, GG 0.04, A 0.78, G 0.22 in HD, and those of exon13 were GG 0.30, GT 0.52, TT 0.18, G 0.56, T 0.44 in control, and GG 0.49, GT 0.36, TT 0.15, G 0.67, T 0.33 in HD. There were significant differences in the two polymorphisms above between HD and control. The genotype and allele frequencies of exon11 were AA 0.05, AG 0.16, GG 0.79, A 0.13, G 0.87 in control and AA 0.02, AG 0.14, GG 0.84, A 0.09, G 0.91 in HD, the differences were not found between these two groups about this site. Exon15 were all of CC genotype in spite of control or HD. CONCLUSIONS: These data provide evidences for the contributions of exon2 and exon13 polymorphisms of RET proto-oncogene to susceptibility to HD in Chinese Han population surrounding province.