Construction of a Metabolism-Related Long Non-Coding RNAs-Based Risk Score Model of Hepatocellular Carcinoma for Prognosis and Personalized Treatment Prediction.

Background: Long non-coding RNAs (lncRNAs) play a key regulatory role in tumor metabolism. Although hepatocellular carcinoma (HCC) is a metabolic disease, there have been few systematic reports on the association between lncRNA expression and metabolism in HCC. Results: In this study, we screened 557 metabolism-related lncRNAs in HCC. A risk score model based on 13 metabolism-related lncRNA pairs was constructed to predict the outcome and drug response in HCC. The risk score model presented a better prediction of the outcomes than that with common clinicopathological characteristics, such as tumor stage, grade, and status and aneuploidy score in both training and testing cohorts. In addition, patients in the high-risk group exhibited higher responses to gemcitabine and epothilone, whereas those in the low-risk group were more sensitive to metformin and nilotinib. Conclusion: The metabolism-related lncRNAs-based risk score model and the other findings of this study may be helpful for HCC prognosis and personalized treatment prediction.

Dioscin ameliorates inflammatory bowel disease by up-regulating miR-125a-5p to regulate macrophage polarization.

PURPOSE: Dioscin has been proven to have anti-cancer, anti-inflammatory, and anti-infection roles. However, the role of Dioscin in inflammatory bowel disease (IBD) and its related mechanisms is unclear and needs further study. METHODS: The colitis model in mice was established. After Dioscin (20, 40, or 80 mg/kg) treatment, the colon length was measured by a ruler. Histopathology, inflammatory cytokines, gut permeability, tight junction proteins, macrophage infiltration, macrophage polarization, and miR-125a-5p level were detected by hematoxylin-eosin staining, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction (qRT-PCR), FITC-dextran, Western blot, and flow cytometry. In vitro experiments, after RAW264.7 cells induced by lipopolysaccharide (LPS)/interleukin-4 (IL-4), were treated with Dioscin and miR-125a-5p inhibitor, miR-125a-5p level, cell vitality, inflammatory cytokines, and M1/M2 marker genes were measured by qRT-PCR and MTT assay. RESULTS: Dioscin (20, 40, or 80 mg/kg) relieved DSS-triggered colitis and restrained the serum and colon of pro-inflammatory cytokines expression. Meanwhile, different concentrations' Dioscin weakened M1 macrophage polarization but facilitated tight junction protein expressions, M2 macrophage polarization, and miR-125a-5p level in colitic mice. Moreover, miR-125a-5p inhibitor reversed the modulation of Dioscin on miR-125a-5p expression, cell vitality, and inflammatory cytokines in lipopolysaccharide (LPS)-induced RAW264.7 cells. We further discovered that Dioscin restrained M1 marker gene (CD16) expression while intensifying M2 marker genes (CD206 and Arginase-1) expressions in vitro, which was reversed by miR-125a-5p inhibitor. CONCLUSION: Dioscin modulated macrophage polarization by increasing miR-125a-5p, thereby improving the intestinal epithelial barrier function and reducing IBD.

Piperlongumine potentiates the antitumor efficacy of oxaliplatin through ROS induction in gastric cancer cells.

PURPOSE: Oxaliplatin is one of the most commonly used chemotherapeutic agents in the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Therefore, there is a pressing need to develop novel therapies to potentiate the efficacy and reduce the toxicity of oxaliplatin. Piperlongumine (PL), an alkaloid isolated from Piper longum L., has recently been identified as a potent agent against cancer cells in vitro and in vivo. In the present study, we investigated whether PL can potentiate the antitumor effect of oxaliplatin in gastric cancer cells. METHODS: Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells or tumor tissues was determined using an endpoint insulin reduction assay. Western blotting was used to analyze the expression levels of the indicated proteins. Nude mice xenograft models were used to test the effects of PL and oxaliplatin combinations on gastric cancer cell growth in vivo. RESULTS: We found that PL significantly enhanced oxaliplatin-induced growth inhibition in both gastric and colon cancer cells. Moreover, we found that PL potentiated the antitumor effect of oxaliplatin by inhibiting TrxR1 activity. PL combined with oxaliplatin markedly suppressed the activity of TrxR1, resulting in the accumulation of ROS and, thereby, DNA damage induction and p38 and JNK signaling pathway activation. Pretreatment with antioxidant N-acetyl-L-cysteine (NAC) significantly abrogated the combined treatment-induced ROS generation, DNA damage and apoptosis. Importantly, we found that activation of the p38 and JNK signaling pathways prompted by PL and oxaliplatin was also reversed by NAC pretreatment. In vivo, we found that PL combined with oxaliplatin significantly suppressed tumor growth in a gastric cancer xenograft model, and effectively reduced the activity of TrxR1 in tumor tissues. Remarkably, we found that PL attenuated body weight loss evoked by oxaliplatin treatment. CONCLUSIONS: Our data support a synergistic effect of PL and oxaliplatin and suggest that application of its combination may be more effective for the treatment of gastric cancer than oxaliplatin alone.

Comparison of three lymph node staging schemes for predicting the outcome in patients with small bowel adenocarcinoma: A population-based cohort and international multicentre cohort study.

BACKGROUND: The prognostic roles of three common lymph node staging schemes, number of positive lymph nodes (pN), lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS) in small bowel adenocarcinoma (SBA) are unclear. We assessed their prognostic ability in SBA. METHODS: A total of 2128 patients diagnosed with SBA between 1988 and 2010 from the Surveillance, Epidemiology, and End Results (SEER) database and 186 patients from 15 hospitals in France and China were identified. We evaluated the prognostic ability of the schemes in both continuous and stratified patterns using R2, Harrell's C, and time-dependent receiver operating characteristic curve analyses. FINDINGS: For continuous pattern, the LODDS had a better capacity of discrimination and higher accuracy of prognosis than pN and LNR. Similarly, the stratified LODDS classification had a better performance of discrimination and higher accuracy of prognosis than the pN and LNR classification. The multivariable model using the LODDS classification also showed superiorly predictive accuracy and discriminatory capacity to those of the 7th and, 8th TNM node and LNR classification. These results were fully validated in an independent international multicentre cohort. INTERPRETATION: The LODDS scheme showed a better prognostic performance than the LNR or pN schemes in patients with SBA regardless of continuous or stratified pattern. The LODDS scheme could serve as an auxiliary to lymph node staging systems in future revisions of the American Joint Committee on Cancer (AJCC) manual. FUND: This work was funded by the Zhejiang Province Natural Science Fund of China.

Long non-coding antisense RNA GAS6-AS1 supports gastric cancer progression via increasing GAS6 expression.

OBJECTIVE: As one broader class of non-coding RNAs (lncRNAs), non-coding antisense (AS) transcripts are functionally characterized to play pivotal roles in various pathophysiological processes, including tumor biology. METHODS: In this study, the exact biological functions and regulation mechanisms of GAS6-AS1 in gastric cancer (GC) was examined. RESULTS: The expression of GAS6-AS1 was markedly upregulated in GC tissues and is associated with advanced stage (III + IV) of GC patients. Gain-of-function and loss-of-function experiments showed that GAS6-AS1 promoted cell proliferation, migration, invasion ability in vitro and xenograft tumor growth in vivo by promoting entry into S-phase. The mechanistic investigations showed that GAS6-AS1 can control the expression of its cognate sense gene GAS6 at the transcriptional or translational levels by forming a RNA-RNA duplex, consequently inducing an increase of AXL level and driveling AXL signaling pathway activation. CONCLUSIONS: Taken together, our studies indicate that GAS6-AS1 significantly driving the aggressive phenotype in GC through activating its cognate sense gene GAS6, and provides a more complete understanding of GAS6-AS1 as a potential therapeutic target for GC.

Long noncoding RNA FEZF1-AS1 indicates a poor prognosis of gastric cancer and promotes tumorigenesis via activation of Wnt signaling pathway.

Long non-coding RNAs (lncRNAs) have been demonstrated that it plays very important role in development and progression of carcinomas. LncRNA FEZF1 antisense RNA 1 (FEZF1-AS1) has been proved to be implicated in tumor initiation and progression of various cancers, recently. Nevertheless, the biological function and clinical significance of lncRNA FEZF1-AS1 in gastric cancer (GC) are not clear enough. Here, we concentrated on the association of FEZF1-AS1 expression and clinicopathological factors in GC tissues and cells. Moreover, we explored the potential regulatory mechanisms. The results showed that lncRNA FEZF1-AS1 was observably upregulated in human GC tissues and GC cell lines, compared with the adjacent non-tumor tissues and human gastric epithelial cell line (GES-1). Moreover, high expression of lncRNA FEZF1-AS1 was significantly associated with later stage and higher grade. Furthermore, Kaplan-Meier survival analysis was conducted, indicating that lncRNA FEZF1-AS1 may be an independent prognostic factor in GC. Additionally, the area under the receiver operating characteristic (ROC) curve of lncRNA FEZF1-AS1 exhibited its diagnostic value in GC. Notably, whenever the lncRNA FEZF1-AS1 was silenced, the proliferation of GC cells were significantly inhibited and the cell cycle was arrested at a G0/G1 stage in GC cells. Furthermore, downregulation of lncRNA FEZF1-AS1 could suppress the activation of the Wnt/ß-catenin signaling pathway. Conclusively, our findings indicated that lncRNA FEZF1-AS1 could be considered as a novel biomarker for the treatment of GC.

Human cytomegalovirus detection in gastric cancer and its possible association with lymphatic metastasis.

Increasing evidence suggests that human cytomegalovirus (HCMV) is associated with many human malignancies. However, its prevalence in gastric cancer (GC) and clinical association remain unknown. HCMV IgG and IgM antibodies in the sera of 80 GC patients and 80 healthy controls were detected using a microparticle enzyme immunoassay. The prevalence of HCMV UL47, UL55, UL56, and UL77 genes among 102 GC tumor tissues and adjacent normal specimens was measured by polymerase chain reaction (PCR) or nested PCR. Quantitative real-time PCR (Q-PCR) was used to determine viral load. Virus localization in neoplastic tissues was determined by immunohistochemistry. No significant difference of HCMV IgG and IgM seropositivity was found between GC patients and the healthy group. However, the overall HCMV DNA positivity rate was significantly higher in GC cancerous tissue compared with in paired normal tissue (P<0.01). HCMV infection was mainly localized in the tumorous epithelium. Q-PCR in HCMV-positive specimens indicated that the viral copy number was notably higher in GC tissues than in adjacent normal specimens (P<0.001). Clinical statistical analysis indicated that HCMV load in GC tumor tissue was positively associated with lymphatic metastasis (P=0.043), the area under the receiver operating characteristic (ROC) curve was 0.6638. Our data clearly provide the prevalence of HCMV in GC patients. We conclude that HCMV infection in malignant tissues might be associated with carcinogenesis or progression of GC and possibly relates to lymphatic metastasis.

Ginsenoside Rb1 protects the intestinal mucosal barrier following peritoneal air exposure.

Ginsenoside Rb1 (GRb1), which is one of the main ingredients derived from Panax ginseng, has been widely used to treat various gastrointestinal disorders. The present study aimed to determine whether GRb1 was able to prevent intestinal mucosal barrier damage in rats following peritoneal air exposure for 3 h. GRb1 (5, 10, and 20 mg/kg) was orally administrated via gavage four times prior to and following surgery. Blood and terminal ileum were sampled 24 h following surgery. Levels of serum D-lactate (D-LA) were detected using an enzyme-linked immunosorbent assay kit. Intestinal permeability was assessed by determining the intestinal clearance of fluorescein isothiocyanate-dextran (FD4). Activity of intestinal myeloperoxidase was measured to assess intestinal inflammation, and intestinal histopathology was assessed by light microscopy. The results showed that GRb1 reduced the level of serum D-LA, intestinal clearance of FD4, and the activity of intestinal myeloperoxidase. Intestinal edema and inflammation were also ameliorated by GRb1, and the Chiu's scores employed for assessing intestinal mucosal damage were also reduced in the GRb1-treated peritoneal air exposure group. In addition, GRb1 induced a significant difference at 10 and 20 mg/kg, indicating a dose-dependent effect. The results of the present study suggest that GRb1 may be able to protect the intestinal mucosal barrier against damage induced by peritoneal air exposure, which may be associated with its anti-inflammatory action.

Diagnosis and surgical treatment of intrahepatic hepatolithiasis associated cholangiocarcinoma.

Liver malignancy is known to be associated with hepatolithiasis. The present report summarises the results and our experience for management of 23 patients with intrahepatic hepatolithiasis associated cholangiocarcinoma (IHHCC). The correct diagnosis rates of US (ultrasonography), CT (computed tomography), and MRCP (magnetic resonance cholangiopancreatography) were 82.6% (19/23), 95.7% (22/23), and 91.7% (11/12), respectively. Carbohydrate antigen 19-9 (CA 19-9) was helpful in the diagnosis of IHHCC. All 23 patients with IHHCC underwent laparotomy. The surgical procedure consisted hepatectomy with a bile duct exploration in 16 patients (69.6%), a hepatectomy and drainage procedure such as sphincteroplasty and choledo-jejunostomy in three patients (13.0%), a bile duct exploration with biopsy in two patients (8.7%), and simple laparotomy and biopsy in two patients (8.7%). All the IHHCC patients who underwent a palliative procedure or laparotomy died within 1 year, and the overall cumulative survival rates at 1, 3, and 5 years were 43.8% (10/23), 13.0% (3/23), and 4.3% (1/23), respectively, and those patients who underwent curative resection were 88.9% (8/9), 33.3% (3/9), and 11.1% (1/9), respectively, which significantly longer than those (20.0%, 2/10; 0.0%, 0/10; and 0.0%, 0/10) patients who underwent palliative resection, respectively (p < 0.05). A suspicion of malignancy is necessary when managing patients with long-term hepatolithiasis. Hepatic resection with postoperative treatment is the treatment of choice for cholangiocarcinoma when it is resectable.

Indications and surgical treatment of chronic pancreatitis.

BACKGROUND: Some patients with chronic pancreatitis (CP) may require surgery mainly because of intractable pain, suspicion of malignancy, or complications related to CP. This study aimed to analyze the efficacy of surgical treatment for patients with CP in terms of pain relief, control of local complications, and pancreatic endocrine/exocrine function. METHODS: Twenty-six patients with CP were treated surgically at our hospital from June 1985 to November 2005. The clinical data of these patients were analyzed retrospectively. RESULTS: The follow-up time ranged from 8 to 130 months with a median of 60.6 months. No patients were lost to follow-up. All patients had improvement of clinical symptoms such as abdominal pain, steatorrhea and weight loss, to some degree, especially pain relief in patients with good dilation and high pressure of the main pancreatic duct. The endocrine and exocrine functions were not alleviated in all patients, otherwise the impaired glucose tolerance was improved in 8 (30.8%), 15 (57.7%) maintained the same body weight, one (3.8%) had an acute attack of CP, and 2 (7.7%) developed pancreatic carcinoma in the 16th and 28th month postoperatively and died within 3 years after operation for CP. The 1-, 3-, 5-year pain-free rates of CP patients were 96.2% (25/26), 88.5% (23/26) and 84.6% (22/26), respectively. CONCLUSIONS: In selected patients with CP, surgical treatment is a safe procedure and can effectively relieve pain and control local complications; also, it is helpful to improve the quality of life for patients with pancreatitis, and to control the development of this disease.