Background: The development of gallbladder disease (GBD) is related to bile acid (BA) metabolism, and the rate of BA circulation increases the risk of biliary cancer. However, it is unclear whether patterns of circulating bile acids (BAs) change in patients with benign GBDs such as gallbladder stones and polyps. Herein, we compared and characterised plasma BA profiles in patients with cholecystolithiasis and non-neoplastic polyps with healthy controls, and explored relationships between plasma BA profiles, demographics, and laboratory test indices. Methods: A total of 330 subjects (13 healthy controls, 292 cholecystolithiasis and 25 non-neoplastic polyps) were recruited and plasma BA profiles including 14 metabolites from patients with pathologically confirmed cholecystolithiasis and non-neoplastic polyps were compared with controls. BAs were quantitated by liquid chromatography and mass spectrometry, and statistical and regression analyses of demographics and laboratory test indices were performed. Results: Females displayed a higher burden of GBD than males (63.36% cholecystolithiasis, 60% non-neoplastic polyps). Cholecystolithiasis and non-neoplastic polyps were associated with increased plasma total secondary BAs, while levels of primary BAs were lower than in healthy controls. Plasma ursodeoxycholic acid (UDCA), tauroursodeoxycholic acid (TUDCA), glycyurdeoxycholic acid (GUDCA), taurochenodeoxycholic acid (TCDCA) and glycochenodeoxycholic acid (GCDCA) were decreased significantly in GBDs, and ursodeoxycholic acid (UDCA) was negatively correlated with white blood cell count and neutrophil percentage. Conclusions: Secondary BA levels were higher in patients with cholecystolithiasis and non-neoplastic polyps. White blood cell count and percentage of neutrophil in peripheral blood were negatively correlated with UDCA, indicating an anti-inflammation effect of UDCA.

Objective: To develop and validate an MRI-radiomics nomogram for the prognosis of pancreatic ductal adenocarcinoma (PDAC).Background: “Radiomics” enables the investigation of huge amounts of radiological features in parallel by extracting high-throughput imaging data. MRI provides better tissue contrast with no ionizing radiation for PDAC.Methods: There were 78 PDAC patients enrolled in this study. In total, there were 386 radiomics features extracted from MRI scan, which were screened by the least absolute shrinkage and selection operator algorithm to develop a risk score. Cox multivariate regression analysis was applied to develop the radiomics-based nomogram. The performance was assessed by discrimination and calibration.Results: The radiomics-based risk-score was significantly associated with PDAC overall survival (OS) (P < 0.05). With respect to survival prediction, integrating the risk score, clinical data and TNM information into the nomogram exhibited better performance than the TNM staging system, radiomics model and clinical model. In addition, the nomogram showed fine discrimination and calibration.Conclusions: The radiomics nomogram incorporating the radiomics data, clinical data and TNM information exhibited precise survival prediction for PDAC, which may help accelerate personalized precision treatment.Clinical trial registration: clinicaltrials.gov, identifier NCT05313854.

Gallbladder cancer (GBC) is an extremely lethal malignancy with aggressive behaviors, including liver or distant metastasis; however, the underlying mechanisms driving the metastasis of GBC remain poorly understood. In this study, it is found that DNA methyltransferase DNMT3A is highly expressed in GBC tumor tissues compared to matched adjacent normal tissues. Clinicopathological analysis shows that DNMT3A is positively correlated with liver metastasis and poor overall survival outcomes in patients with GBC. Functional analysis confirms that DNMT3A promotes the metastasis of GBC cells in a manner dependent on its DNA methyltransferase activity. Mechanistically, DNMT3A interacts with and is recruited by YAP/TAZ to recognize and access the CpG island within the CDH1 promoter and generates hypermethylation of the CDH1 promoter, which leads to transcriptional silencing of CDH1 and accelerated epithelial‐to‐mesenchymal transition. Using tissue microarrays, the association between the expression of DNMT3A, YAP/TAZ, and CDH1 is confirmed, which affects the metastatic ability of GBC. These results reveal a novel mechanism through which DNMT3A recruitment by YAP/TAZ guides DNA methylation to drive GBC metastasis and provide insights into the treatment of GBC metastasis by targeting the functional connection between DNMT3A and YAP/TAZ.

The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) model, its Portsmouth (P-POSSUM) modification and the Estimation of physiologic ability and surgical stress (E-PASS) are three surgical risk scoring systems used extensively to predict postoperative morbidity and mortality in general surgery. The aim was to undertake the first study of the predictive value of these models in patients undergoing surgical treatment of hilar cholangiocarcinoma. A retrospective analysis was performed on data collected prospectively over a 10-year interval from January 2003 to December 2012. The morbidity and mortality risks were calculated using the POSSUM, P-POSSUM and E-PASS equations. One hundred patients underwent surgical treatment of hilar cholangiocarcinoma. Complications were seen in 52 of 100 patients (52.0%). There were 10 postoperative in-hospital deaths (10.0%). Of 31 preoperative and intraoperative variables studied, operative type (P = 0.000), preoperative serum albumin (P = 0.003) and aspartate aminotransferase (P = 0.029) were found to be factors multivariate associated with postoperative complications. Intraoperative blood loss (P = 0.015), Bismuth-Corlette classification (P = 0.033) and preoperative hemoglobin (P = 0.041) were independent factors multivariate associated with in-hospital death. The POSSUM system predicted morbidity risk effectively with no significant lack of fit (P = 0.488) and an area under the ROC curve (AUC) of 0.843. POSSUM, P-POSSUM and E-PASS scores showed no significant lack of fit in calculating the mortality risk (P >0.05) and all yielded an AUC value exceeding 0.8. POSSUM had significantly more accuracy in predicting morbidity after major and major plus operations (O:E (observed/expected) ratio 0.98 and AUC 0.901) than after minor and moderate operations (O:E ratio 1.13 and AUC 0.759). POSSUM, P-POSSUM and E-PASS scores effectively predict morbidity and mortality in surgical treatment of hilar cholangiocarcinoma. However, improvements are still needed in the future because none of these scoring systems yielded an AUC value exceeding 0.9 for operations with all different levels of severity. Only POSSUM had more accuracy in predicting postoperative morbidity after operations with higher severity. This study was undertaken after obtaining approval from the ethics committee of School of Medicine, Shanghai Jiao Tong University with a trial registration number of http://www.stcsm.gov.cn/ .

Background: Gallbladder cancer (GBC) is known for its high malignancy and multidrug resistance. Previously, we uncovered that impaired integrity and stability of the elongator complex leads to GBC chemotherapy resistance, but whether its restoration can be an efficient therapeutic strategy for GBC remains unknown. Methods: RT-qPCR, MS-qPCR and ChIP-qPCR were used to evaluate the direct association between ELP5 transcription and DNA methylation in tumour and non-tumour tissues of GBC. EMSA, chromatin accessibility assays, and luciferase assays were utilized to analysis the DNA methylation in interfering PAX5-DNA interactions. The functional experiments in vitro and in vivo were performed to investigate the effects of DNA demethylating agent decitabine (DAC) on the transcription activation of elongator complex and the enhanced sensitivity of gemcitabine in GBC cells. Tissue microarray contains GBC tumour tissues was used to evaluate the association between the expression of ELP5, DNMT3A and PAX5. Results: We demonstrated that transcriptional repression of ELP5 in GBC was highly correlated with hypermethylation of the promoter. Mechanistically, epigenetic analysis revealed that DNA methyltransferase DNMT3A-catalysed hypermethylation blocked transcription factor PAX5 activation of ELP5 by disrupting PAX5-DNA interaction, resulting in repressed ELP5 transcription. Pharmacologically, the DNA demethylating agent DAC eliminated the hypermethylated CpG dinucleotides in the ELP5 promoter and then facilitated PAX5 binding and reactivated ELP5 transcription, leading to the enhanced function of the elongator complex. To target this mechanism, we employed a sequential combination therapy of DAC and gemcitabine to sensitize GBC cells to gemcitabine-therapy through epigenetic activation of the elongator complex. Conclusions: Our findings suggest that ELP5 expression in GBC is controlled by DNA methylation-sensitive induction of PAX5. The sequential combination therapy of DAC and gemcitabine could be an efficient therapeutic strategy to overcome chemotherapy resistance in GBC.