GluR2 can Drive Neuroinflammation and Cognitive Impairments Following Peripherally Repeated Lipopolysaccharide Exposures.

Neuroinflammation is being increasingly recognized as a vital factor in the development of various neurological and neuropsychiatric diseases. Lipopolysaccharides (LPS), an outer membrane component of gram-negative bacteria, can trigger innate immune responses, resulting in neuroinflammation and subsequent cognitive deficits. The expression of glutamate receptors (GluRs) on glial cells can induce glial activation. Therefore, we hypothesized that repeated LPS exposure can increase GluR levels, promoting microglial activation and ultimately affecting synaptic plasticity and cognitive function. In this study, C57/BL6 mice were repeatedly exposed to LPS to construct a neuroinflammation animal model. The levels of GluRs, inflammatory cytokines, ionized calcium-binding adaptor molecule 1, postsynaptic density protein 95, synaptophysin 38, NMDA receptor 2 A, and NMDA receptor 2B (GluN2B) were measured in the hippocampi. Furthermore, dendritic spine density in the CA1 hippocampal region was determined. Repeated LPS exposure induced cognitive impairments and microglial activation and increased GluR1 and GluR2 levels. This was accompanied by a significant decrease in GluN2B expression and dendritic spine density in the hippocampi. However, CFM-2, an α-amino-3- hydroxy-5-methyl-4-isoxazolepropionate receptor antagonist, reversed these anomalies. Furthermore, minocycline, a microglial inhibitor, reversed these anomalies and downregulated GluR2 but not GluR1 expression. In summary, we demonstrated that GluR2 plays an essential role in microglia-induced neuroinflammation, resulting in synaptic plasticity and cognitive impairment induced by repeated exposure to LPS.

A radiomics-based interpretable model to predict the pathological grade of pancreatic neuroendocrine tumors.

OBJECTIVES: To develop a computed tomography (CT) radiomics-based interpretable machine learning (ML) model to predict the pathological grade of pancreatic neuroendocrine tumors (pNETs) in a non-invasive manner. METHODS: Patients with pNETs who underwent contrast-enhanced abdominal CT between 2010 and 2022 were included in this retrospective study. Radiomics features were extracted, and five radiomics-based ML models, namely logistic regression (LR), random forest (RF), support vector machine (SVM), XGBoost, and GaussianNB, were developed. The performance of these models was evaluated using a time-independent testing set, and metrics such as sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC) were calculated. The accuracy of the radiomics model was compared to that of needle biopsy. The Shapley Additive Explanation (SHAP) tool and the correlation between radiomics and biological features were employed to explore the interpretability of the model. RESULTS: A total of 122 patients (mean age: 50 ± 14 years; 53 male) were included in the training set, whereas 100 patients (mean age: 48 ± 13 years; 50 male) were included in the testing set. The AUCs for LR, SVM, RF, XGBoost, and GaussianNB were 0.758, 0.742, 0.779, 0.744, and 0.745, respectively, with corresponding accuracies of 73.0%, 70.0%, 77.0%, 71.9%, and 72.9%. The SHAP tool identified two features of the venous phase as the most significant, which showed significant differences among the Ki-67 index or mitotic count subgroups (p < 0.001). CONCLUSIONS: An interpretable radiomics-based RF model can effectively differentiate between G1 and G2/3 of pNETs, demonstrating favorable interpretability. CLINICAL RELEVANCE STATEMENT: The radiomics-based interpretable model developed in this study has significant clinical relevance as it offers a non-invasive method for assessing the pathological grade of pancreatic neuroendocrine tumors and holds promise as an important complementary tool to traditional tissue biopsy. KEY POINTS: • A radiomics-based interpretable model was developed to predict the pathological grade of pNETs and compared with preoperative needle biopsy in terms of accuracy. • The model, based on CT radiomics, demonstrated favorable interpretability. • The radiomics model holds potential as a valuable complementary technique to preoperative needle biopsy; however, it should not be considered a replacement for biopsy.

Robotic-Assisted Versus Open Hemi-Hepatectomy: A Propensity Score Analysis.

INTRODUCTION: The robotic-assisted surgical system has been widely used in hepatectomy. However, the effectiveness and feasibility of robotic-assisted hemi-hepatectomy (RH) has not been well-documented. METHODS: Patients who underwent RH or open hemi-hepatectomy (OH) performed by a single surgeon at our hospital between January 2010 and August 2023 were included in this study. A stabilized inverse probability of treatment weighting adjusted analysis was performed. RESULTS: Of the 163 consecutive patients identified, 60 underwent RH, and 103 underwent OH. After stabilized inverse probability of treatment weighting adjustment, RH demonstrated less blood loss than OH. In subgroup analyses, robotic-assisted left hemi-hepatectomy was associated with a shorter postoperative stay, a lower postoperative complication rate, and less blood loss compared with open left hemi-hepatectomy. While robotic-assisted right hemi-hepatectomy (RRH) was associated with less blood loss and a lower intraoperative blood transfusion rate, but a longer operation time compared with open right hemi-hepatectomy. CONCLUSIONS: RH is a safe and effective technique. In addition to less blood loss, robotic-assisted left hemi-hepatectomy had advantages in postoperative complications and postoperative stay, while RRH had advantages in intraoperative blood transfusions. However, operation time was longer for RRH than for open right hemi-hepatectomy.

Imatinib facilitates gemcitabine sensitivity by targeting epigenetically activated PDGFC signaling in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally highly expressed in gemcitabine-resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway. The PDGFR inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect on the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine-resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.

HMGB1 mediates synaptic loss and cognitive impairment in an animal model of sepsis-associated encephalopathy.

BACKGROUND: Microglial activation-mediated neuroinflammation is one of the essential pathogenic mechanisms of sepsis-associated encephalopathy (SAE). Mounting evidence suggests that high mobility group box-1 protein (HMGB1) plays a pivotal role in neuroinflammation and SAE, yet the mechanism by which HMGB1 induces cognitive impairment in SAE remains unclear. Therefore, this study aimed to investigate the mechanism of HMGB1 underlying cognitive impairment in SAE. METHODS: An SAE model was established by cecal ligation and puncture (CLP); animals in the sham group underwent cecum exposure alone without ligation and perforation. Mice in the inflachromene (ICM) group were continuously injected with ICM intraperitoneally at a daily dose of 10 mg/kg for 9 days starting 1 h before the CLP operation. The open field, novel object recognition, and Y maze tests were performed on days 14-18 after surgery to assess locomotor activity and cognitive function. HMGB1 secretion, the state of microglia, and neuronal activity were measured by immunofluorescence. Golgi staining was performed to detect changes in neuronal morphology and dendritic spine density. In vitro electrophysiology was performed to detect changes in long-term potentiation (LTP) in the CA1 of the hippocampus. In vivo electrophysiology was performed to detect the changes in neural oscillation of the hippocampus. RESULTS: CLP-induced cognitive impairment was accompanied by increased HMGB1 secretion and microglial activation. The phagocytic capacity of microglia was enhanced, resulting in aberrant pruning of excitatory synapses in the hippocampus. The loss of excitatory synapses reduced neuronal activity, impaired LTP, and decreased theta oscillation in the hippocampus. Inhibiting HMGB1 secretion by ICM treatment reversed these changes. CONCLUSIONS: HMGB1 induces microglial activation, aberrant synaptic pruning, and neuron dysfunction in an animal model of SAE, leading to cognitive impairment. These results suggest that HMGB1 might be a target for SAE treatment.

Renin-angiotensin system inhibitors improve the survival of cholangiocarcinoma: a propensity score-matched cohort study.

BACKGROUND: Hypertension is a risk factor for cholangiocarcinoma (CCA). The effect of anti-hypertensive drugs on the prognosis of CCA is not clear. METHODS: This is a retrospective study of 102 patients (56.9% males, median age 66 years) diagnosed with CCA and hypertension concurrently and received radical surgery (R0), with a median follow-up of 36.7 months. Kaplan-Meier analysis, Cox regressions, and propensity score (PS) matching were applied for statistical analysis. RESULTS: Results of multivariable cox analysis showed that renin-angiotensin system inhibitors (RASis) usage was a protective factor for progression-free survival (PFS) (hazard ratio [HR] = 0.55, 95% confidence interval [95% CI]: 0.32-0.96) and overall survival (OS) (HR = 0.40, 95% CI: 0.20-0.79), respectively. Calcium channel blockers, diuretics, and ß-blockers didn't show significant associations. The association of RASis usage and PFS and OS was derived by PS matching, with a cohort of 28 RASis users and 56 RASis non-users. The median PFS and OS of RASis users (PFS, 17.6 months (9.2-34.4); OS, 24.8 months (16.5-42.3)) were longer than RASis non-users (PFS, 10.5 months (4.1-24.1); OS, 14.6 months (10.6-28.4)). The 1 year, 2 years, and 3 years' survival rates of RASis users (89.1%, 77.0%, and 65.5%) were higher than RASis non-users (70.9%, 54.0%, and 40.0%). CONCLUSIONS: RASis usage improves the survival of patients with CCA and hypertension concurrently.

Learning curve of robotic-assisted splenic vessel-preserving spleen-preserving distal pancreatectomy by one single surgeon: a retrospective cohort study.

AIM: Splenic vessel-preserving spleen-preserving distal pancreatectomy (SVP-SPDP) has a lower risk of splenic infarction than the splenicvessel-sacrificing SPDP, but it is more technically demanding. Learning curve of robotic-assisted SVP-SPDP (RSVP-SPDP) remains unreported. This study sought to analyze the perioperative outcomes and learning curve of RSVP-SPDP by one single surgeon. METHODS: Seventy-four patients who were intended to receive RSVP-SPDP at the First Affiliated Hospital of Sun Yat-sen University between May 2015 and January 2023 were included. The learning curve were retrospectively analyzed by using cumulative sum (CUSUM) analyses. RESULTS: Sixty-two patients underwent RSVP-SPDP (spleen preservation rate: 83.8%). According to CUSUM curve, the operation time (median, 318 vs. 220 min; P < 0.001) and intraoperative blood loss (median, 50 vs. 50 mL; P = 0.012) was improved significantly after 16 cases. Blood transfusion rate (12.5% vs. 3.4%; P = 0.202), postoperative major morbidity rate (6.3% vs. 3.4%; P = 0.524), and postoperative length-of-stay (median, 10 vs. 8 days; P = 0.120) improved after 16 cases but did not reach statistical difference. None of the patients had splenic infarction or abscess postoperatively. CONCLUSION: RSVP-SPDP was a safe and feasible approach for selected patients after learning curve. The improvement of operation time and intraoperative blood loss was achieved after 16 cases.

Pancreatic ductal adenocarcinoma cells regulated the gemcitabine-resistance function of CAFs by LINC00460.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with extremely poor prognosis. Gemcitabine resistance is a major challenge in the treatment of PDAC. Here, we showed that LINC00460 was associated with the response to gemcitabine both in PDAC patients and PDAC-PDX. After knocking down LINC00460 in PDAC tumor cells, results of RNA sequencing followed by gene ontology analysis indicated that LINC00460 influenced the activity of growth factors and modified the extracellular matrix. FISH showed that LINC00460 is mostly located in the cytoplasm. Results of RNA pull-down, LC-MS/MS, RIP, and immunoblotting confirmed that LINC00460 could directly bind to PDAP1. Furthermore, we demonstrated that LINC00460 mediated the cellular communication of PDAC tumor cells and CAFs by PDAP1/PDGFA/PDGFR signaling pathway and regulated the gemcitabine-resistance function of CAFs, which could be reversed by treatment with a PDGFR inhibitor (crenolanib). PDAC-PDX tumors with lower expression of LINC00460 showed a better response to gemcitabine plus crenolanib treatment. Our finding supported the application of LINC00460 in precision medicine that uses gemcitabine plus crenolanib to treat PDAC with low expression of LINC00460.

Bifunctional Sensors Based on Phosphomolybdates for Detection of Inorganic Hexavalent Chromium and Organic Tetracycline.

Exploring effective sensors for detecting possible hazards in a water system are greatly significant. This work proposed a strategy for stable and effective bifunctional sensors via incorporating hourglass-type phosphomolybdates into metal-organic fragments to construct a high-dimensional framework. Two hourglass-type phosphomolybdate-based electrochemical sensors toward heavy metal ion Cr(VI) and tetracycline (TC) detection were designed with the formula [CoII2(H2O)4NaI2][CoII(Hbpe)][NaI(bpe)1.5]{CoII[PV4MoV6O31H6]2}·9H2O (1) and [CoII(H2O)4NaI3][CoII(Hbpe)][CoII(bpe)]{CoII[PV4MoV6O31H6]2}·9H2O (2) [bpe = 1,2-di(4-pyridyl)ethylene]. Structural analysis showed that hybrids 1 and 2 possess three-dimensional POM-supported network features with favorable stability and exhibit reversible redox properties. Experiments found that this kind of hybrids as efficient sensors have excellent electrochemical performance toward Cr(VI) detection with high sensitivities of 0.111 µA·µM-1 for 1 and 0.141 µA·µM-1 for 2, fast response time of 1 s, and low detection limits of 30 nM for 1 and 27 nM for 2, which far meet the standard of WHO for drinking water. Moreover, hybrids 1-2 also exhibit fast responses to TC detection with sensitivities of 0.0073 and 0.022 µA·mM-1 and detection limits of 0.426 and 0.084 mM. This work offers a novel strategy for the purposeful design of efficient POM-based electrochemical sensors for accurate determination of contaminants in a practical water system.

Development and validation of nomogram to predict lymph node metastasis preoperatively in patients with pancreatic neuroendocrine tumor.

BACKGROUND: Routine lymphadenectomy in pancreatic neuroendocrine tumors (pNETs) is debated. There lacks accurate model to predict lymph node metastasis (LNM) preoperatively in pNETs. Therefore, this study aimed at developing a nomogram in predicting LNM in pNETs preoperatively. METHODS: Patients undergoing surgery from Surveillance, Epidemiology, and End Results (SEER) database (design cohort, n = 2742) and First Affiliated Hospital of Sun Yat-sen University (validation cohort, n = 136) were enrolled. Nomogram was developed based on risk factors determined by logistic regression analyses. The performance of nomogram was evaluated by area under receiver operating characteristics curve (AUC), calibration curve, and decision curve analysis. RESULTS: In design cohort, 915 of 2742 patients had LNM. Tumor in the pancreatic head, T stage, and tumor size were significantly associated with LNM (all p < 0.05). Prediction of nomogram was accurate with AUC of 0.776 in design cohort and 0.622 in validation cohort. The nomogram showed good agreement between prediction and observation in the design and validation cohort. Based on nomogram-predicted risk, patients with higher risk of LNM had worse overall survival over patients with lower risk of LNM (log-rank p < 0.001). CONCLUSIONS: The novel nomogram could accurately predict LNM in pNET preoperatively. For patients with high risk of LNM, lymphadenectomy was recommended.

Development and Validation of a New Nomogram for Predicting Clinically Relevant Postoperative Pancreatic Fistula After Pancreatoduodenectomy.

BACKGROUND: There lacks an ideal model for accurately predicting clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD). This study aimed at developing a nomogram with high accuracy in predicting CR-POPF after PD. METHODS: A total of 1182 patients undergoing PD in the First Affiliated Hospital of Sun Yat-sen University (FAHSYSU, n = 762) and Fudan University Shanghai Cancer Center (FUSCC, n = 420) between January 2010 and May 2018 were enrolled. The patients from FAHSYSU were assigned as testing cohort, and those from FUSCC were used as external validation cohort. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors for CR-POPF. Nomogram was developed on the basis of significant predictors. The performance of nomogram was evaluated by area under receiver operating characteristic (ROC) curve (AUC), calibration curve, and decision curve analysis. RESULTS: In testing cohort, 87 out of 762 patients developed CR-POPF. Three predictors were significantly associated with CR-POPF, including body mass index ≥24.0 kg/m2, pancreatic duct diameter <3 mm, and drainage fluid amylase on postoperative day 1 ≥2484 units/L (all p ≤ 0.001). Prediction of nomogram was accurate with AUC of 0.934 (95% confidence interval [CI]: 0.914-0.950) in testing cohort and 0.744 (95% CI: 0.699-0.785) in external validation cohort. The predictive accuracy of nomogram was better than that of previously proposed fistula risk scores both in testing and external validation cohort (all p < 0.05). CONCLUSIONS: The novel nomogram based on three easily available parameters could accurately predict CR-POPF after PD. It would have high clinical value due to its accuracy and convenience.

Evaluating the adequacy of nodal status in node-negative gallbladder cancer with T1b-T2 stages: use of nodal staging score.

BACKGROUND: The study aimed at establishing a nodal staging score (NSS) to quantify the likelihood that pathologic node-negative gallbladder cancer (GBC) patients are indeed free of lymph node (LN) metastasis. METHODS: Clinicopathological data of 1374 GBC patients with T1b-T2 stages were collected from the Surveillance, Epidemiology and End Result database (design cohort [DC], n = 1289) and the First Affiliated Hospital of Sun Yat-sen University (validation cohort [VC], n = 85). NSS was derived from the count of examined LNs (ELNs) and T stage by using a beta-binomial model, and represented the probability that a node-negative patient is correctly staged. The prognostic value of NSS in node-negative GBC was evaluated by survival analysis. RESULTS: The probability of missing a nodal disease in node-negative GBC patients with T1b-T2 stages (pT1bN0 and pT2N0) decreased as the number of ELNs increased. NSS increased as the number of ELNs increased. For pT1bN0 and pT2N0 patients, examination of 5 and 27 lymph nodes could ensure an NSS of 90.0%, respectively. Multivariate analysis revealed that NSS was an independent predictor for overall survival in pT1bN0 and pT2N0 GBC patients (DC, HR:0.53, 95%CI: 0.42-0.66, p < 0.001; VC, HR: 0.33, 95%CI: 0.14-0.76, p = 0.009). CONCLUSION: NSS could evaluate the adequacy of nodal staging and predict the prognosis in pT1bN0 and pT2N0 GBC patients, and hence was helpful to guide their treatment strategies.

Development and validation of a nomogram for predicting overall survival of node-negative ampullary carcinoma.

BACKGROUND: The accuracy of the current staging system for predicting the overall survival (OS) of patients with ampullary carcinoma (AC) is still unsatisfactory, especially in node-negative (N0) patients. We aimed at establishing a nomogram to accurately predict OS in N0 AC. METHODS: This study enrolled 697 N0 AC patients from the Surveillance, Epidemiology, and End Results database (design cohort [DC], n = 697) and the First Affiliated Hospital of Sun Yat-sen University (validation cohort [VC], n = 112), who underwent surgical resection. The nomogram was established by using prognostic factors determined by univariate and multivariate regression analyses. RESULTS: The nomogram for OS was developed by using four independent prognostic factors, including age, grade, T stage, and a number of examined lymph nodes. The C-index of a nomogram for OS in DC and VC was 0.665 and 0.731, respectively. Calibration curves showed good consistency of the nomogram. The nomogram had a better accuracy in predicting OS compared with conventional staging system (P < .05). On the basis of nomogram-predicted scores, the patients were stratified into groups with different risk. The OS of low-risk patients was significantly longer than high-risk ones (P ≤ .010). CONCLUSIONS: The nomogram could be used to predict the OS of N0 AC. It could help guide further treatment in clinical practice.

Impact of enhanced recovery after surgery protocol on pancreaticoduodenectomy: a meta-analysis of non-randomized and randomized controlled trials.

BACKGROUND: Enhanced recovery after surgery (ERAS) has been widely applied in many surgical specialties. However, with respect to the impact of ERAS on pancreaticoduodenectomy (PD), there still exist some controversies. METHODS: Literature search was performed in PubMed, Web of Science and the Cochrane Library from January, 1990 to July, 2019. A meta-analysis was performed using fixed-effects or random-effects models. RESULTS: Twenty-two studies containing 4147 patients were identified. The entire pooled data showed that ERAS significantly reduced overall and minor morbidity (RR: 0.80, 95% CI: 0.72-0.88, p < 0.001; RR: 0.78, 95% CI: 0.69-0.88, p < 0.001, respectively), but didn't affect major morbidity (RR: 0.97, 95% CI: 0.84-1.13, p = 0.72). ERAS markedly reduced the incidences of delayed gastric emptying (DGE) (RR: 0.69, 95% CI: 0.55-0.88, p = 0.002), incisional infection (RR: 0.75, 95% CI: 0.60-0.94, p = 0.01) and intra-abdominal infection (RR: 0.79, 95% CI: 0.63-1.00, p = 0.05), but didn't influence clinically-relevant postoperative pancreatic fistula (CR-POPF) (RR: 0.86, 95% CI: 0.73-1.01, p = 0.07). Shorter length of stay (LOS) (WMD: -5.07, 95% CI: -6.71 to -3.43, p < 0.001) was noted in ERAS group, without increasing 30-day readmission (RR: 1.03, 95% CI: 0.86-1.24, p = 0.71) and mortality (RR: 0.70, 95% CI: 0.41-1.21, p = 0.20). CONCLUSION: ERAS significantly reduced overall and minor morbidity, incidences of DGE, incisional and intra-abdominal infections, and shortened LOS in PD, without increasing 30-day readmission and mortality. However, more large-scale randomized controlled trials are still needed to confirm the findings.

EYA4 inhibits hepatocellular carcinoma by repressing MYCBP by dephosphorylating ß-catenin at Ser552.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the fourth leading cause of cancer-related death worldwide. Our previous study showed that EYA4 functioned by suppressing growth of HCC tumor cells, but its molecular mechanism is still not elucidated. Based on the results of gene microassay, EYA4 was inversely correlated with MYCBP and was verified in human HCC tissues by immunohistochemistry and western blot. Overexpressed and KO EYA4 in human HCC cell lines confirmed the negative correlation between EYA4 and MYCBP by qRT-PCR and western blot. Transfected siRNA of MYCBP in EYA4 overexpressed cells and overexpressed MYCBP in EYA4 KO cells could efficiently rescue the proliferation and G2/M arrest effects of EYA4 on HCC cells. Mechanistically, armed with serine/threonine-specific protein phosphatase activity, EYA4 reduced nuclear translocation of ß-catenin by dephosphorylating ß-catenin at Ser552, thereby suppressing the transcription of MYCBP which was induced by ß-catenin/LEF1 binding to the promoter of MYCBP. Clinically, HCC patients with highly expressed EYA4 and poorly expressed MYCBP had significantly longer disease-free survival and overall survival than HCC patients with poorly expressed EYA4 and highly expressed MYCBP. In conclusion, EYA4 suppressed HCC tumor cell growth by repressing MYCBP by dephosphorylating ß-catenin S552. EYA4 combined with MYCBP could be potential prognostic biomarkers in HCC.

Establishment of a Nomogram by Integrating Molecular Markers and Tumor-Node-Metastasis Staging System for Predicting the Prognosis of Hepatocellular Carcinoma.

AIMS: This study aimed to develop a valuable nomogram by integrating molecular markers and tumor-node-metastasis (TNM) staging system for predicting the long-term outcome of patients with hepatocellular carcinoma (HCC). METHODS: The gene expression profiles of HCC patients undergoing liver resection were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. One hundred and ninety-nine patients from TCGA and 94 patients from GEO were selected to be part of the training cohort and validation cohort respectively. Univariate and multivariate cox analyses were performed to identify genes with independent prognostic values for overall survival (OS) of HCC patients in training cohort. Risk score was calculated based on the coefficients and Z-score of 3 genes for each patient. The nomogram was developed based on the risk score and TNM staging system. Discrimination and predictive accuracy of the nomogram were measured by using the concordance index (C-index) and calibration curve. The efficacy of the nomogram was tested in the external validation cohort. RESULTS: Univariate and multivariate cox analyses revealed that EXT2 (p = 0.035, hazard ratio 13.412), ETV5 (p = 0.010, hazard ratio 4.325), and CHODL (p < 0.001, hazard ratio 6.286) were independent prognostic factors and chosen for further nomogram establishment. The C-index of the nomogram for predicting the OS in the training cohort was superior to that of the TNM staging system (0.77 vs. 0.64, p < 0.01). The calibration curve of predicted 1-, 3-, and 5-year OS showed satisfactory accuracy. The external validation cohort showed good performance of comprehensive nomogram as well. CONCLUSION: The novel nomogram by integrating the molecular markers and TNM staging system has better performance in predicting long-term prognosis in HCC patients than the TNM staging system alone.

Prognostic significance of neutrophil/prealbumin ratio for intrahepatic cholangiocarcinoma undergoing curative resection.

BACKGROUND: This study aimed to clarify the prognostic significance of neutrophil/prealbumin ratio index (NPRI) for overall survival (OS) and recurrence free survival (RFS) of ICC after curative surgery. METHODS: Two-hundred and seventy-six ICC patients who underwent curative resection from December 2006 to April 2017 were recruited and analyzed retrospectively. The correlations between clinicopathological features and NPRI were analyzed. OS and RFS were calculated using Kaplan-Meier curve, and cox univariate and multivariate analyses were used to identify the prognostic factors. RESULTS: The optimal cut-off value of NPRI determined by ROC curve was 1.74 and the patients were divided into high-value and low-value groups. High-value NPRI was associated with higher risk of postoperative complications (p = 0.035) and longer hospitalization (p = 0.004).Univariate and multivariate cox analyses demonstrated that NPRI was an independent predictor for OS (p = 0.015) and RFS (p = 0.004) in ICC after curative resection. Furthermore, NPRI was also a significant predictor for OS and RFS in different subgroups of ICC, including CA19-9<35U/mL, single tumor, no vascular invasion, no local invasion and AJCC stages I + II. CONCLUSIONS: NPRI was an independent prognostic predictor for ICC after curative resection. It would have high clinical values due to its convenience.

BTG2 Is Down-Regulated and Inhibits Cancer Stem Cell-Like Features of Side Population Cells in Hepatocellular Carcinoma.

BACKGROUND: Our previous study found that B cell translocation gene 2 (BTG2) was hyper-methylated and down-regulated in side population (SP) cells of hepatocellular carcinoma (HCC) cell line. However, its clinical significances and biological impacts on HCC SP cells remained unclear. AIMS: To investigate the prognostic value of BTG2 gene in HCC and its influences on cancer stem cells (CSCs)-like traits of HCC cell line SP cells. METHODS: BTG2 expression in human HCC and adjacent non-cancerous tissues was detected by immunohistochemical staining and quantitative real-time PCR, and also obtained from GEO and TCGA data. Its prognostic values were assessed. Its biological influences on HCC cell line SP cells were evaluated using cell viability, cell cycle, plate clone-forming assay, and chemoresistance in vitro and tumorigenicity in vivo. RESULTS: BTG2 expression was significantly suppressed in human HCC compared to adjacent non-cancerous tissues. BTG2 expression was correlated with TNM stage, tumor size and vascular invasion. Lower expression of BTG2 was associated with poorer overall survival and disease-free survival. In vitro, overexpression of BTG2 substantially suppressed cell proliferation and accumulation of HCC cell line SP cells in G0/G1 phase. Colony formation ability was markedly suppressed by BTG2 overexpression. Moreover, sensitivity of HCC cell line SP cells to 5-fluorouracil was substantially increased by overexpression of BTG2. Furthermore, tumorigenicity of HCC cell line SP cells transfected with BTG2 plasmids was significantly reduced in vivo. CONCLUSIONS: BTG2 gene could regulate the CSC-like traits of HCC cell line SP cells, and it represented as a molecular prognostic marker for HCC.

Hepatoprotective effect of ulinastatin in a rat model of major hepatectomy after obstructive jaundice.

BACKGROUND: To date, major hepatectomy with obstructive jaundice is still a highly risky and difficult surgery because of the high rate of complications. An excessive inflammatory response may be the primary hindrance to postoperative recovery of liver function. AIMS: Recent research has demonstrated that ulinastatin blocks the release of inflammatory factors and prevents the cytokine cascade reaction. This study was conducted to investigate the effect of ulinastatin on major hepatectomy after obstructive jaundice and to explore the potential mechanisms of this effect. METHODS: Male Sprague-Dawley rats were divided into three groups: sham, control and treated groups. In the control and treated groups, obstructive jaundice was induced, and a 70 % major hepatectomy was performed with implementation of ulinastatin treatment in the treated group but not the control group. The rats were sacrificed after hepatectomy on day 1, day 3, day 5 and day 7. The survival time, liver function, inflammatory cytokine expression and the indices of proliferation activities were examined. Kupffer cells were isolated, and the mRNA and protein levels of CD14 and NF-κB P65 in the Kupffer cells were determined. RESULTS: Compared to the control group, the survival rates, postoperative liver function, and the indices of proliferation activities were better in the treated group; in the treated group serum TNF-α and IL-6 levels were lower whereas serum IL-10 levels were higher. The expression of CD14 and NF-κB P65 in Kupffer cells at both the mRNA and protein levels was significantly higher in the control group than in the treated group. CONCLUSIONS: Ulinastatin has a protective effect in major hepatectomy with obstructive jaundice by inhibiting Kupffer cell activation and modulating the hepatic cytokine response.

DNA methylation profiling identifies EYA4 gene as a prognostic molecular marker in hepatocellular carcinoma.

BACKGROUND: DNA hypermethylation plays important roles in carcinogenesis by silencing key genes. This study aims to identify pivotal genes in hepatocellular carcinoma (HCC) by DNA methylation microarray and to assess their prognostic values. MATERIALS AND METHODS: DNA methylation microarray was performed in 45 pairs of HCC and adjacent nontumorous tissues and six normal liver tissues to identify hypermethylated genes in HCC. Potential prognosis-related genes were selected among hypermethylated genes by analyzing influences of methylation levels on disease-free survival (DFS) and overall survival (OS) in 45 patients. Their prognostic values were validated in 154 patients with HCC (including the initial 45 patients) to determine the independent prognostic gene. RESULTS: Altogether, 54 CpG islands in 44 genes were hypermethylated in HCC compared with liver tissues. Among them, methylation levels of ERG and HOXA11 were inversely associated with DFS (both P < 0.050), and methylation levels of EYA4 were inversely related to DFS and OS (both P < 0.050). EYA4 expression was inversely related to tumor size (P < 0.050). Lower EYA4 expression and larger tumor size were independent predictors of both shorter DFS and OS, and higher Barcelona Clinic Liver Cancer (BCLC) staging was an independent predictor of shorter OS (all P < 0.050). CONCLUSIONS: EYA4 functions as a prognostic molecular marker in HCC. Its aberrant hypermethylation and subsequent down-regulation may promote tumor progression.