LIGHT Amplification by NF-κB Contributes to TLR3 Signaling Pathway-Induced Acute Hepatitis.

LIGHT is a member of the TNF superfamily and a proinflammatory cytokine involved in liver pathogenesis. Many liver diseases involve activation of Toll-like receptor 3 (TLR3), which is activated by double-stranded RNA (dsRNA). However, the involvement of LIGHT in TLR3 implicated liver diseases is not clear. In this study, we investigated the role of LIGHT in TLR3 involved liver pathogenesis by using a mouse model of TLR3 agonist poly(I:C)-induced hepatitis. We found LIGHT expression at both protein and mRNA level in liver tissues is dramatically increased during the course of poly(I:C)-induced liver injury. This induction depends on NF-κB activation as pretreating the mice with a NF-κB inhibitor abrogates LIGHT upregulation. Importantly, blockade of the LIGHT signaling pathway with the recombinant LIGHT receptor HVEM protein ameliorates liver injury in poly(I:C)-induced hepatitis. Conclusions. These results indicate that LIGHT amplification by NF-κB plays a significant role in TLR3 involved hepatitis and points LIGHT to be a potential drug target for liver disease therapy.

Development and Validation of a Prognostic Nomogram for Colorectal Cancer Patients With Synchronous Peritoneal Metastasis.

PURPOSE: Synchronous peritoneal metastasis (S-PM) is considered a poor prognostic factor for colorectal cancer (CRC) and there is no nomogram to predict the survival of these patients. In this study, we aimed to use a multicenter data to identify the factors associated with S-PM of CRC to construct a nomogram for predicting the overall survival (OS) of these patients. METHODS: CRC patients with S-PM from two medical centers were enrolled between September 2007 and June 2017. Multivariate analysis was used to identify independent factors associated with OS for the nomogram to predict the 1-, 2-, and 3-year OS rates in the development group. The concordance index (C-index), calibration plot, relative operating characteristic (ROC) curve with area under the curve (AUC) were calculated to evaluate the performance of the nomogram in both the development and an external validation group. RESULTS: 277 CRC patients with S-PM in the development group and 68 patients in the validation group were eligible for this study. In multivariate analysis of development group, age, carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and chemotherapy were independent variables for OS, based on which the nomogram was built. The C-index of the nomogram in the development and validation group was 0.701 (95% Cl, 0.666-0.736) and 0.716 (95% Cl, 0.622-0.810); demonstrating good discriminative ability. The calibration plots showed satisfactory consistency between actual observation and nomogram-predicted OS probabilities in the development and external validation group. The nomogram showed good predictive accuracy for 1-, 2-, and 3-year OS rates in both groups with AUC >0.70. An online dynamic webserver was also developed for increasing the ease of the nomogram. CONCLUSIONS: We developed and validated a predictive nomogram with good discriminative and high accuracy to predict the OS in CRC patients with S-PM.

Survival outcome of palliative primary tumor resection for colorectal cancer patients with synchronous liver and/or lung metastases: A retrospective cohort study in the SEER database by propensity score matching analysis.

BACKGROUND: There is a great matter of controversies whether some of these synchronous metastatic colorectal cancer patients can benefit from palliative primary tumor resection (pPTR) and there is still no reported randomized control trial to address this issue. METHODS: Patients with microscopically proven metastatic colorectal cancer were identified within the SEER database (2010-2016). Patients were propensity matched 1:1 into pPTR and non-surgery groups and among the matched cohort, the univariable and multivariable Cox proportional hazards regression models were performed to identify predictors of survival. Median survival was calculated by using the Kaplan-Meier method. RESULTS: Of 21,405 colorectal cancer patients diagnosed with synchronous liver and/or lung metastases, 7386 were identified in the matched cohort. The median overall survival was 12.0 months, 22.0 months in the non-surgery, surgery groups, respectively (p < 0.001) and the corresponding median cancer-specific survival was 13.0 months, 22.0 months, respectively (p < 0.001). Multivariable Cox regression analysis demonstrated that surgery was independently associated with improved overall survival (hazard ratio, 0.531) as well as cancer-specific survival (hazard ratio, 0.516). In stratified analyses by primary site and patterns of distant metastases, those patients with pPTR had better prognosis. In addition, stratified analysis revealed that trimodality therapy was linked with the greatest therapeutic effect followed by addition of chemotherapy to pPTR. CONCLUSIONS: pPTR may offer some therapeutic benefits among carefully selected patients, and surgery-based multimodality therapy was associated with better survival.

Short- and long-term outcomes following laparoscopic vs open surgery for pathological T4 colorectal cancer: 10 years of experience in a single center.

AIM: To evaluate the short-term and long-term outcomes following laparoscopic vs open surgery for pathological T4 (pT4) colorectal cancer. METHODS: We retrospectively analyzed the short- and long-term outcomes of proven pT4 colorectal cancer patients who underwent complete resection by laparoscopic or open surgery from 2006 to 2015 at Guangdong General Hospital. RESULTS: A total of 211 pT4 colorectal cancer patients were included in this analysis, including 101 cases in the laparoscopy (LAP) group and 110 cases in the open surgery (OPEN) group [including 15 (12.9%) cases of conversion to open surgery]. Clinical information (age, gender, body mass index, comorbidities, American Society of Anesthesiologists score, etc.) did not differ between the two groups. In terms of blood loss, postoperative complications and rate of recovery, the LAP group performed significantly more favorably (P < 0.05). With regard to pT4a/b and combined organ resection, there were significantly more cases in the OPEN group (P < 0.05). The 3- and 5-year overall survival rates were 74.9% and 60.5%, respectively, for the LAP group and 62.4% and 46.5%, respectively, for the OPEN group (P = 0.060). The 3- and 5-year disease-free survival rates were 68.0% and 57.3%, respectively, for the LAP group and 55.8% and 39.8%, respectively, for the OPEN group (P = 0.053). Multivariate analysis showed that IIIB/IIIC stage, lymph node status, and CA19-9 were significant predictors of overall survival. PT4a/b, IIIC stage, histological subtypes, CA19-9, and adjuvant chemotherapy were independent factors affecting disease-free survival. CONCLUSION: Laparoscopy is safely used in the treatment of pT4 colorectal cancer while offering advantages of minimal invasiveness and faster recovery. Laparoscopy is able to achieve good oncologic outcomes similar to those of open surgery. We recommend that laparoscopy be carried out in experienced centers. It is still required to screen the appropriate cases for laparoscopic surgery, optimize the preoperative diagnosis process, and reduce the conversion rate. Multi-center, prospective, and large-sample studies are required to assess these issues.

The superiority of 256-slice spiral computed tomography angiography for preoperative evaluation of surrounding arteries in patients with gastric cancer.

OBJECTIVE: To evaluate the utilization of 256-slice spiral computed tomography (CT) angiography in preoperative assessment of perigastric vascular anatomy in patients with gastric cancer. METHODS: In this study, 80 gastric cancer patients were included. The medical procedure of 256-slice spiral CT angiography was performed on each of these patients consecutively. Thereafter, these patients were subjected to surgical treatment in our hospital. The techniques of volume rendering (VR) and maximum intensity projection (MIP) were used to image reconstruction of arteries around the stomach. RESULTS: Both VR and MIP were applied to reconstruct the images of perigastric arteries. The results indicated that VR imaging was inferior to MIP in determining the variant small artery anatomy around the greater curvature and fundus. The respective rates of imaging produced by VR and MIP for left gastroepiploic artery, short gastric artery, and posterior gastric artery, were 32.50% versus 100%, 16.25% versus 87.50%, and 3.75% versus 25.00%, respectively. According to Hiatt's classification, 75 out of 240 cases were abnormal types, among which we found Type II in 30 cases, Type III in 33 cases, Type IV in three cases, Type V in six cases, and Type VI in only three cases. There was no significant difference for total and every single variation type, between our group and Hiatt's group (P>0.05). CONCLUSION: The 256-slice spiral CT angiography can be regarded as an effective and accurate diagnostic modality for preoperative assessing anatomical arterial variations in gastric cancer; MIP was superior to VR at identifying variations of some small artery, whereas VR was better than MIP at showing anatomical arterial variations due to its three-dimensional effect.

Expression and prognostic value of glutamate dehydrogenase in extrahepatic cholangiocarcinoma patients.

Glutamate dehydrogenase (GDH) produces a precursor to glutathione, an important molecule in maintaining cellular redox balance and the cancerous characteristics of tumor cells through intracellular signaling pathways. However, the underlying molecular mechanisms linking glutamate dehydrogenase and extrahepatic cholangiocarcinoma have not been elucidated yet. Herein, we examined GDH expression levels and evaluated its potential correlations with prognosis. Meanwhile, the therapeutic value of GDH targeting the Smad pathways in extrahepatic cholangiocarcinoma was explored. Immunohistochemical studies revealed that GDH expression level was correlated to CD34 expression, cellular differentiation, the presence or absence of capsular and vascular invasion, lymph node metastasis, neural invasion and patient age. Kaplan-Meier survival analysis and COX proportional hazards models demonstrated that the prognosis was closely associated with GDH expression, CD34 positivity, nerve infiltration and cell differentiation. GDH silencing significantly reduced the proliferation, migratory potential and invasive capability. We also demonstrated that GDH promoted cell proliferation and metastasis potentially through Smad-mediated induction of TGF-ß signaling pathway. Therefore, GDH may be an important prognostic indicator and may provide a new target for novel treatments of extrahepatic cholangiocarcinoma.

Silencing MRP1-4 genes by RNA interference enhances sensitivity of human hepatoma cells to chemotherapy.

AIM: Besides surgical treatment, systematic chemotherapy plays a crucial role in HCC treatment, especially for patients with advanced HCC. However, none of the single-drug-treatment strategies have shown significant survival benefit due to a high incidence rate of chemoresistance. This study was designed to observe the effect of small interfering of RNA (SiRNA) targeting multidrug resistance-related protein 1-4 (MRP1, MRP2, MRP3, and MRP4) in modulating drug resistance of HepG2/ADM and SMMC7721/ADM cells. METHODS: HepG2/Adriamycin (ADM) and SMMC7721/ADM cell lines were developed by exposing parental cells to stepwise increasing concentrations of ADM. MTT assay was used to determine drug sensitivity and half inhibitory concentration (IC50) of drugs was calculated. Flow cytometry was employed to analyze cell cycle distribution. MRP1-4 mRNA expression levels were measured by quantitative real-time PCR (QRT-PCR). Expression of proteins was analyzed by Western blot. The growth curve was draw and the cell apoptosis was also observed. Animal experiment was used to compare the cell growth. RESULTS: MTT assay showed that the values of IC50 and RI of HepG2/ADM and SMMC7721/ADM decreased after siRNA treatment in HepG2/ADM cells and SMMC7721/ADM cells. QRT-PCR analysis demonstrated the MRP1-4 mRNA expression decreased significantly in HepG2/ADM cells and SMMC7721/ADM cells after siRNA transfection. In addition, compared with parental cells, MRP1-4 protein expressions apparently decreased in SMMC7721/ADM and HepG2/ADM cells. Flow cytometry showed significantly elevated apoptosis rate following MRP1-4 siRNA transfection. Animal experiment suggested that silencing MRP1-4 gene in vivo inhibited tumor growth. CONCLUSION: Inhibition of MRP1-4 by small interfering RNA enhanced and selectively restored sensitivity of hepatoma cells to drugs. MRP1-4 siRNA might represent a new therapeutic option for HCC.