The combined effect of non-alcoholic fatty liver disease and metabolic syndrome on colorectal carcinoma mortality: a retrospective in Chinese females.

BACKGROUND: This research aimed to investigate whether metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD) had both individual and synergistic effects on the prognosis for female colorectal carcinoma (CRC) patients. METHODS: The relationship between CRC prognosis and NAFLD as well as MetS was evaluated in 764 female participants. Based on the NAFLD level, patients were divided into significant NAFLD (SNAFLD), "moderate" and "severe" level, and non-SNAFLD, "non" and "mild" level. All the patients were categorized into four subgroups according to the status of SNAFLD and MetS and then a comparison of CRC prognosis among those four groups was performed. RESULTS: NAFLD, SNAFLD, and MetS were independent factors for CRC-specific mortality with the adjustment of age and other confounders. The hazard ratio (HR) of CRC-specific mortality in MetS (+) SNAFLD (+) group was significantly higher than that in other three groups. Relative excess risk of interaction (RERI) was 2.203 with 95% CI ranged from 0.197 to 4.210, attributable proportion (AP) was 0.444 with range from 0.222 to 0.667, and synergy index (SI) of 2.256 with 95% CI from 1.252 to 4.065, indicating SNAFLD and MetS had a significant synergic effect on CRC-specific mortality. CONCLUSIONS: SNAFLD and MetS are independent risk factors for CRC-specific mortality in females. Moreover, those two diseases have a synergistic effect on promoting CRC-specific mortality.

HK2 promotes migration and invasion of intrahepatic cholangiocarcinoma via enhancing cancer stem-like cells' resistance to anoikis.

Cancer stem-like cells (CSLCs) and anoikis resistance play crucial roles in the metastasis of cancers. However, it remains unclear whether CSLCs are related to anoikis resistance in intrahepatic cholangiocarcinoma (ICC). Here we identified a group of stemness-related anoikis genes (SRAGs) via bioinformatic analysis of public data. Accordingly, a novel anoikis-related classification was established and it divided ICC into C1 and C2 type. Different type ICC displayed distinct prognosis, molecular as well immune characteristics. Furthermore, we found one key SRAGs via several machine learning algorithms. HK2 was up-regulated in tumor-repopulating cells (TRCs) of ICC, a kind of CSLCs with a potent resistance to anoikis. Its up-regulation may be caused by the activation of MTORC1 signaling in ICC-TRCs. And inhibition of HK2 significantly increased anoikis and decreased migration as well invasion in ICC-TRCs. Our studies provide an insight into the molecular mechanism underlying the resistance of ICC-TRCs to anoikis and enhance the evidences for targeting HK2 in ICC.

NF-κB-Related Metabolic Gene Signature Predicts the Prognosis and Immunotherapy Response in Gastric Cancer.

BACKGROUND: Sufficient evidence indicated the crucial role of NF-κB family played in gastric cancer (GC). The novel discovery that NF-κB could regulate cancer metabolism and immune evasion greatly increased its attraction in cancer research. However, the correlation among NF-κB, metabolism, and cancer immunity in GC still requires further improvement. METHODS: TCGA, hTFtarget, and MSigDB databases were employed to identify NF-κB-related metabolic genes (NFMGs). Based on NFMGs, we used consensus clustering to divide GC patients into two subtypes. GSVA was employed to analyze the enriched pathway. ESTIMATE, CIBERSORT, ssGSEA, and MCPcounter algorithms were applied to evaluate immune infiltration in GC. The tumor immune dysfunction and exclusion (TIDE) algorithm was used to predict patients' response to immunotherapy. We also established a NFMG-related risk score by using the LASSO regression model and assessed its efficacy in TCGA and GSE62254 datasets. RESULTS: We used 27 NFMGs to conduct an unsupervised clustering on GC samples and classified them into two clusters. Cluster 1 was characterized by high active metabolism, tumor mutant burden, and microsatellite instability, while cluster 2 was featured with high immune infiltration. Compared to cluster 2, cluster 1 had a better prognosis and higher response to immunotherapy. In addition, we constructed a 12-NFMG (ADCY3, AHCY, CHDH, GUCY1A2, ITPA, MTHFD2, NRP1, POLA1, POLR1A, POLR3A, POLR3K, and SRM) risk score. Followed analysis indicated that this risk score acted as an effectively prognostic factor in GC. CONCLUSION: Our data suggested that GC subtypes classified by NFMGs may effectively guide prognosis and immunotherapy. Further study of these NFMGs will deepen our understanding of NF-κB-mediated cancer metabolism and immunity.

Evaluation of the risk factors for severe complications and surgery of intestinal foreign bodies in adults: a single-center experience with 180 cases.

Background: Foreign bodies (FBs) lodged in the intestine or causing intestinal complications are uncommon in clinical practice but may pose diagnostic difficulties and prove life-threatening. This study aimed to evaluate the risk factors for severe complications and surgery to aid clinicians in the diagnosis and management of intestinal FBs. Methods: We performed a retrospective analysis of patients in whom FBs were lodged in the intestine or caused complications from 2010 to 2020 in the First Affiliated Hospital of Wenzhou Medical University (Zhejiang, China). The characteristics of the patients and FBs, symptoms, imaging findings, diagnostics, treatment strategies, and clinical outcomes were analysed. Furthermore, the risk factors for complications and surgery were investigated. Results: In total, 180 patients were included in our study. Most patients (76.1%) were unable to provide a history of ingestion. Bezoars were the most common FBs (35.6%). The FBs were mainly located in the duodenum (32.8%) and the ileum (27.8%). Surgical removal of FBs was successful in 89 (49.4%) patients and endoscopic removal in 54 (30.0%) patients. Eleven with perforations were treated conservatively. FBs located in the jejunum or ileum were more likely to cause severe complications than those located in the duodenum. FBs located in the jejunum, ileum, or sigmoid colon were more likely to undergo surgery, and severe complications were an independent risk factor for surgery. Conclusion: Intestinal FBs, often localized in angulation, are likely to be misdiagnosed because most patients do not provide a history of FB ingestion. Surgery and endoscopic therapy are the most commonly used treatment modalities. Surgery is not mandatory in clinically stable patients with small and contained perforations. FBs located in the jejunum or ileum are risk factors for both complications and surgery.

Prediction of severe acute pancreatitis using classification and regression tree analysis.

BACKGROUND: The available prognostic scoring systems for acute pancreatitis have limitations that restrict their clinical value. AIMS: To develop a decision model based on classification and regression tree (CART) analysis for the prediction of severe acute pancreatitis (SAP). METHODS: A total of 420 patients with acute pancreatitis were enrolled. Study participants were randomly assigned to the training sample and test sample in a 2:1 ratio. First, univariate analysis and logistic regression analysis were used to identify predictors associated with SAP in the training sample. Then, CART analysis was carried out to develop a simple tree model for the prediction of SAP. A receiver operating characteristic (ROC) curve was constructed in order to assess the performance of the model. The prediction model was then applied to the test sample. RESULTS: Four variables (systemic inflammatory response syndrome [SIRS], pleural effusion, serum calcium, and blood urea nitrogen [BUN]) were identified as important predictors of SAP by logistic regression analysis. A tree model (which consisted of pleural effusion, serum calcium, and BUN) that was developed by CART analysis was able to early identify among cohorts at high (79.03%) and low (7.80%) risk of developing SAP. The area under the ROC curve of the tree model was higher than that of the APACHE II score (0.84 vs. 0.68; P < 0.001). The predicted accuracy of the tree model was validated in the test sample with an area under the ROC curve of 0.86. CONCLUSIONS: A decision tree model that consists of pleural effusion, serum calcium, and BUN may be useful for the prediction of SAP.

Endoscopic sphincterotomy plus endoprostheses in the treatment of large or multiple common bile duct stones.

BACKGROUND AND AIM: Little information is available on the outcomes of endoscopic sphincterotomy plus biliary stent placement without stone extraction as primary therapy at initial endoscopic retrograde cholangiopancreatography (ERCP) in the treatment of large or multiple common bile duct (CBD) stones. The aim of the present study was to study the effect of biliary stents and sphincterotomy as primary therapy for patients with choledocholithiasis. METHODS: Patients with large (≥20 mm) or multiple (≥3) CBD stones were retrospectively studied. The patients underwent endoscopic sphincterotomy and placement of plastic stents in the bile duct without stone extraction at the initial ERCP. Three or more months later, a second ERCP was carried out and stone removal was attempted. Differences in stone size and the largest CBD diameter before and after stenting were compared. Stone clearance and complications were also evaluated. RESULTS: 52 patients were enrolled. After a median of 124 days of biliary plastic stent placement the mean maximal stone diameter decreased from 16.6 mm to 10.0 mm (P < 0.01). The mean CBD diameter also decreased from 15.3 mm to 11.5 mm (P < 0.01). The total stone clearance at second ERCP was 94.2%, only 5.7% of which needed mechanical lithotripsy. COMPLICATIONS: pancreatitis in one (1.9%) at initial ERCP, cholangitis in two (3.8%) after 52 days and 84 days of placement of stent. No complications were recorded at second ERCP. CONCLUSIONS: Biliary plastic stents plus endoscopic sphincterotomy without stone extraction as primary therapy at initial ERCP is a safe and effective method in the management of large or multiple CBD stones.

Water exchange versus air insufflation for colonoscopy: A meta-analysis.

BACKGROUND/AIMS: To compare water exchange (WE) method with conventional air insufflation (AI) method for colonoscopy, evaluating the technical quality, screening efficacy, and patients' acceptance. MATERIALS AND METHODS: Electronic databases were systematically searched for randomized controlled trials comparing WE colonoscopy with AI colonoscopy. The pooled data of procedure-associated and patient-related outcomes were assessed, using the weighted mean difference (WMD) with 95% confidence interval (CI) for continuous variables and relative risk (RR) with 95% CI for dichotomous variables, respectively. RESULTS: A total of 13 studies involving 7056 patients were included. The cecum intubation rate was similar between WE and AI methods (RR = 1.01, 95% CI = 0.99-1.02,P = 0.37); however, a significantly longer cecum intubation time was shown in WE group (WMD = 1.56, 95% CI = 0.75-2.37,P = 0.002). Compared with AI, WE was associated with a higher risk of adenoma detection rate (ADR) (RR = 1.28, 95% CI = 1.18-1.38,P < 0.00001) and polyp detection rate (PDR) (RR = 1.30, 95% CI = 1.21-1.39,P < 0.00001). Patients in WE group experienced significantly less maximum pain score (WMD = -1.99, 95% CI = -2.68 to -1.30,P < 0.00001) and less requested on-demand sedation (RR = 0.58, 95% CI = 0.44-0.77,P = 0.0002). Likewise, they also experienced less abdominal compression (RR = 0.62, 95% CI = 0.51-0.74,P < 0.00001) and reposition (RR = 0.74, 95% CI = 0.63-0.86,P = 0.0001). Moreover, patients' willingness to repeat colonoscopy was significantly greater for WE (RR = 1.14, 95% CI = 1.07-1.21,P < 0.0001). CONCLUSION: This meta-analysis confirmed that WE method could significantly increase ADR/PDR and improve patients' acceptance of colonoscopy, while reducing the degree of pain and minimize the need for on-demand sedation and adjunct maneuvers, despite requiring more cecal intubation time.

Fibrinogen-like protein 2 prothrombinase may contribute to the progression of inflammatory bowel disease by mediating immune coagulation.

Inflammation and coagulation are interdependent processes that enable each process to activate and propagate the other in inflammatory bowel disease (IBD). Thus, we investigated the role of a novel immune coagulant, fibrinogen-like protein 2 prothrombinase (FGL2), in patients and mice with IBD. 83 IBD patients and 40 normal controls were enrolled, and trinitro-benzene-sulfonic acid (TNBS)-induced colitis mice were used. Expression of FGL2 in the intestine was detected by immunohistochemistry. Using serial sections, staining was performed to detect tumor necrosis factor α (TNF-α) expression, and to demonstrate co-localization of FGL2 with macrophages and fibrin. Correlations between FGL2 expression with some common laboratory parameters were examined. FGL2 was seen primarily in inflammatory infiltrating cells, mainly macrophages, and microvascular vessels and had a strong co-localization with fibrin deposition. IBD patients and mice had increased expression of FGL2 compared with controls. Furthermore, FGL2 expression was correlated with intestinal and plasmatic TNF-α expression, mean platelet volume (MPV), platelet count (PLT), platelet-crit (PCT), and fibrinogen. Our data indicate that FGL2 may mediate immune coagulation in IBD patients. It may be considered as a novel molecule that contributes to the onset and development of IBD.

The C825T Polymorphism of the G-Protein ß3 Gene as a Risk Factor for Functional Dyspepsia: A Meta-Analysis.

Background. Functional dyspepsia (FD) is a functional upper gastrointestinal disorder with significant morbidity and medical costs. Previous studies investigated the association of G-protein ß3 (GNB3) genetic polymorphisms with FD but with inconsistent results. Therefore, we performed a meta-analysis to derive a precise estimation of the relationship between GNB3 polymorphisms and FD. Methods. We searched different databases including PubMed, EMBASE, CNKI, and the Ovid Library to gather eligible studies on GNB3 polymorphisms and FD. The association was assessed by the odds ratio (OR) with 95% confidence intervals (CI). Results. We identified 12 studies with 1109 cases and 2853 controls for the analysis. We found no associations of GNB3 C825T polymorphism with FD in the overall population (T versus C, OR = 1.06, 95% CI: 0.96-1.18, P = 0.26; TT versus CC + CT, OR = 1.16, 95% CI: 0.97-1.39, P = 0.11; TT + CT versus CC, OR = 1.01, 95% CI: 0.77-1.31, P = 0.96; TT versus CC, OR = 1.15, 95% CI: 0.93-1.44, P = 0.20). Subgroup analyses by genotyping method indicated that the magnitude of association was strengthened for additive model (OR = 1.15, 95% CI: 1.07-2.24, P = 0.02). Sensitivity analysis did not reveal significant associations under all models. Conclusions. This meta-analysis demonstrates that GNB3 C825T polymorphism may not be a risk factor for FD.

The addition of S-1 to gemcitabine-based chemotherapy improves survival with increased toxicity for patients with advanced pancreatic cancer: combined meta-analysis of efficacy and safety profile.

PURPOSE: To investigate the efficiency and safety profile of the addition of S-1 to gemcitabine (GEM)-based chemotherapy for advanced pancreatic cancer (APC). METHODS: Computerized search was undertaken to identify randomized controlled trials of S-1 plus GEM versus GEM monotherapy in APC patients. The outcomes included overall survival (OS), progression-free survival (PFS), response rate, and toxicities. RESULTS: Five studies with 917 patients were included. Overall, there was a significant difference between the two regimens in terms of OS (HR=0.83, 95%CI=0.72-0.96, P=0.01), PFS (HR=0.64, 95%CI=0.56-0.74, P<0.0001), and overall response rate (ORR; RR=2.36, 95%CI=1.73-3.22, P<0.00001). Occurrence of grade 3/4 hematological toxicities (neutropenia, thrombocytopenia) and non-hematological toxicities (diarrhea, nausea/vomit, rush, stomatitis/mucositis) were significantly higher with GEM/S-1 treatment. CONCLUSIONS: This meta-analysis indicated a significant survival benefit with increased toxicity when S-1 was combined with GEM. GEM/S-1 might be an option of first-line chemotherapy for APC patients, at least in Asia.

The role of NF-kappaB in hepatocellular carcinoma cell.

OBJECTIVE: To evaluate the role of nuclear factor-kappa B (NF-kappaB) and inhibitory kappaB alpha (IkappaBalpha) in hepatocellular cacinoma (HCC) SMMC7721 cells, the consequence of NF-kappaB inhibition in SMMC7721 cells transfected with mutated IkappaBalpha (mIkappaBalpha) plasmid and the effect of stable inhibition of NF-kappaB activity in combination with Doxorubicin. METHODS: Western blot was used to determine the expression of NF-kappaB and IkappaBalpha in SMMC7721 cells and normal liver cells. Nuclear protein was used to evaluate the binding of the (32)P-labeled tandem kappaB sequence using electrophoretic mobility shift assay and the expression of NF-kappaB using Western blot between SMMC7721 cells transfected with mIkappaBalpha plasmid (SMMC7721-MT) and control cells. Furthermore, cell viability was plotted between SMMC7721-MT and control cells. The binding of kappaB sequence and cell viability between SMMC7721-MT and control cells at different concentrations of Doxorubicin were also investigated. RESULTS: Western blot analysis for nuclear extract showed more P50 (NF-kappaB1) and P65 (RelA) expression in SMMC7721 cells compared with normal liver cells. The expression of cytosolic IkappaBalpha protein in SMMC7721 cells was less than that in normal cells. SMMC7721-MT cells inhibited NF-kappaB nuclear translocation at 0, 24, 48 and 96 hours. Furthermore, NF-kappaB cannot be detected in the nuclear protein of SMMC7721-MT cells by Western blot. By calculating cell viability, the proliferation of SMMC7721-MT cells was shown to be suppressed more significantly than that of control cells. NF-kappaB in untransfected cells was activated by Doxorubicin in a dose-dependent manner, but that in SMMC7721-MT cells was not induced at low concentrations of Doxorubicin. Compared with untransfected cells, the viability of SMMC7721-MT cells was significantly suppressed at the same concentration of Doxorubicin (P < 0.01). CONCLUSIONS: The present study demonstrates that upregulation of NF-kappaB and downregulation of inhibitory kappa B (IkappaBalpha) in SMMC7721 cells are related with the growth of hepatocellular cacinoma cells. Stable expression of mIkappaBalpha in SMMC7721-MT cells can inhibit NF-kappaB nuclear translocation and suppress cell growth. Furthermore, stable inhibition of NF-kappaB activity in combination with Doxorubicin can significantly inhibit cell proliferation in SMMC7721-MT cells. Thus, modulation of NF-kappaB may represent an improvement in the efficacy of HCC therapies and be worthy of further research and investigation.

[Nuclear factor kappa B activity and cell viability of SMMC-7721 inhibited by mutated inhibitor kappa B alpha].

OBJECTIVE: To investigate the inhibition consequence of NF-kappaB activity and cell viability by transfecting mutated inhibitor kappa B alpha (mI(kappa)B(alpha)) into liver cancer cell line of SMMC-7721 cells. METHODS: The nucleic proteins of SMMC-7721 cells transfected with mI(kappa)B(alpha) plasmid and cells with empty pcDNA3 vector were used to determine not only the binding of the 32P-labelled kappaB probes by EMSA, but also the expression of NF-kappaB by western blot. Cell viability was also analyzed. RESULTS: NF-kappaB nuclear translocation was inhibited remarkably in SMMC-7721 cells transfected with mI(kappa)B(alpha) at 0, 24, 48 and 96 hours. Furthermore, NF-kappaB was not detected in the nucleic protein of mI(kappa)B(alpha) -transfected cells at the same intended time by western blot. Compared with that of control cells, the growth of SMMC-7721 cells transfected with mI(kappa)B(alpha) was suppressed evidently, especially on the second day, the cpm values of mI(kappa)B(alpha) -transfected cells, pcDNA3-transfected cells, and control cells were 5,092.63+/-541.41, 7,851.87+/-72.76, and 8,240.8+/-603.26 respectively (t = 14.29, P<0.01; t = 10.99, P<0.01). CONCLUSION: Stable expression of mI(kappa)B(alpha) in SMMC-7721 cells transfected with mI(kappa)B(alpha) plasmid inhibits NF-kappaB nuclear translocation, then suppresses the cell growth.

Bilateral stenting methods for hilar biliary obstructions.

OBJECTIVE: There is no consensus regarding the most appropriate methods (i.e., the side-by-side versus the stent-in-stent technique) for placing bilateral stents for malignant hilar biliary obstructions. We aimed to perform a quantitative review of the published data regarding the clinical efficacy of the side-by-side and stent-in-stent bilateral drainage techniques for hilar biliary obstructions. METHODS: A comprehensive search of several databases was conducted and a fixed-effects or random-effects model was used to pool the data from all of the study end-points. RESULTS: Four clinical trials were identified. A comparison of the side-by-side and stent-in-stent groups revealed no significant differences with respect to the rates of successful placement, successful drainage, early complications, late complications and stent occlusions. There were also no significant inter-group differences in stent patency and patient survival and no publication bias was observed. CONCLUSIONS: The performance of the side-by-side technique appears to be similar to that of the stent-in-stent technique for bilateral drainage in patients with malignant hilar biliary obstructions.