Search

Background Pancreaticobiliary reflux (PBR) causes chronic inflammation of the gallbladder mucosa and changes in the bile components, which are known to promote gallstone formation. This study aimed to investigate the bile biochemistry changes in gallstone patients with PBR and provide new clues for research on the involvement of PBR in gallstone formation. Methods Patients undergoing surgery for gallstones between December 2020 and May 2021 were eligible for inclusion. The bile biochemistry (including amylase, lipase, triglyceride, cholesterol, free fatty acids [FFAs], alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [γ-GT]) of the included gallstone patients was analysed to determine correlations with PBR. Results In this study, 144 gallstone patients who underwent surgery were enrolled. Overall, 15.97 % of the patients had an increased bile amylase level, which was associated with older age and significantly higher bile levels of ALP, lipase, triglyceride, and FFAs. Positive correlations were observed between amylase and lipase, triglyceride, FFAs levels in the gallbladder bile. However, the bile levels of triglyceride, FFAs, and lipase were positively correlated with each other only in the PBR group and showed no significant correlation in the control (N) group. In addition, elevated bile FFAs levels were found to be an independent risk factor for gallbladder wall thickening. Conclusions In conclusion, PBR-induced increase in FFAs and triglyceride in the gallbladder bile is a cause of gallstone formation, and an increase in bile ALP suggests the presence of cholestasis in PBR.

Introduction: Occult pancreaticobiliary reflux (OPBR) causes chronic inflammation of the gallbladder and associated mucosal malignant changes, but its pathogenic mechanism remains unclear. Objective The aim of this study was to investigate the pathogenic mechanism in OPBR through untargeted metabolomic analysis of bile collected during surgery. Methods Patients undergoing surgery for gallstones between December 2020 and May 2021 were eligible for inclusion. There were 30 OPBR patients and 338 non-OPBR patients, and 30 non-OPBR patients were randomly selected as normal controls. Metabolomics analysis was performed based on bile samples from patients in the OPBR group. Results The principal component analysis by liquid chromatography-mass spectrometry revealed that 30 metabolites were significantly different between patients with OPBR compared to controls. Among these characteristic metabolites, palmitic acid and arachidonic acid are known to be involved in gallstone formation, methionine and lysophosphatidylcholine are known to be associated with carcinogenesis. Conclusions The present study suggested that an LC/MS-based metabolomic studies provide an efficient and promising method for identifying potential biomarkers of OPBR. The identified characteristic metabolites in the OPBR group were significantly different to the control group.

Utilizing genomic data to predict cancer prognosis was insufficient. Proteomics can improve our understanding of the etiology and progression of cancer and improve the assessment of cancer prognosis. And the Clinical Proteomic Tumor Analysis Consortium (CPTAC) has generated extensive proteomics data of the vast majority of tumors. Based on CPTAC, we can perform a proteomic pan-carcinoma analysis. We collected the proteomics data and clinical features of cancer patients from CPTAC. Then, we screened 69 differentially expressed proteins (DEPs) with R software in five cancers: hepatocellular carcinoma (HCC), children’s brain tumor tissue consortium (CBTTC), clear cell renal cell carcinoma (CCRC), lung adenocarcinoma (LUAD) and uterine corpus endometrial carcinoma (UCEC). GO and KEGG analysis were performed to clarify the function of these proteins. We also identified their interactions. The DEPs-based prognostic model for predicting over survival was identified by least absolute shrinkage and selection operator (LASSO)-Cox regression model in training cohort. Then, we used the time-dependent receiver operating characteristics analysis to evaluate the ability of the prognostic model to predict overall survival and validated it in validation cohort. The results showed that the DEPs-based prognostic model could accurately and effectively predict the survival rate of most cancers.

Magnetic sensors have been widely used for current measurements in diverse industries. In order to achieve a large current measurement without an iron core structure, magnetic sensors are often arranged to be a circular array for designing a new electronic current transformer (ECT). However, this ECT with a circular array of magnetic sensors usually suffers from tradeoffs between the number of sensors and the measurement accuracy. This paper visualizes this tradeoff and proposes a 3-D magnetic-field model to analyze the impact of the magnetic sensor circular array position on current measurements. We develop an analytical expression of the current measurement errors to estimate the minimum number of required magnetic sensors and point out the acceptable deviations of the ECT position under various accuracy classes. Based on the estimation results, we design a new circular array with eight magnetic sensors and build a three-phase current measurement system. The test results demonstrate the efficiency and the robustness of the designed class-1.0 ECT, which successfully maintains accuracy class 1.0 under various position deviations in balanced or unbalanced three-phase power delivery systems.

Background. Pancreatic cancer is one of the most malignant tumors of the digestive system, and its treatment has rarely progressed for the last two decades. Studies on m6A regulators for the past few years have seemingly provided a novel approach for malignant tumor therapy. m6A-related factors may be potential biomarkers and therapeutic targets. This research is focused on the gene characteristics and clinical values of m6A regulators in predicting prognosis in pancreatic cancer. Methods. In our study, we obtained gene expression profiles with copy number variation (CNV) data and clinical characteristic data of 186 patients with pancreatic cancer from The Cancer Genome Atlas (TCGA) portal. Then, we determined the alteration of m6a regulators and their correlation with clinicopathological features using the log-rank tests, Cox regression model, and chi-square test. Additionally, we validated the prognostic value of m6A regulators in the International Cancer Genome Consortium (ICGC). Results. The results suggested that pancreatic cancer patients with ALKBH5 CNV were associated with worse overall survival and disease-free survival than those with diploid genes. Additionally, upregulation of the writer gene ALKBH5 had a positive correlation with the activation of AKT pathways in the TCGA database. Conclusion. Our study not only demonstrated genetic characteristic changes of m6A-related genes in pancreatic cancer and found a strong relationship between the changes of ALKBH5 and poor prognosis but also provided a novel therapeutic target for pancreatic cancer therapy.

Background: Pancreatic cancer is one of the most malignant tumors of the digestive system and its treatment has rarely progressed for the last two decades. Studies on m6A regulators for the past few years have seemingly provided a novel approach for malignant tumor therapy. m6A-related factors may be potential biomarkers and therapeutic targets. This research is focused on the gene characteristics and clinical values of m6A regulators in predicting prognosis in pancreatic cancer. Methods: In our study, we obtained gene expression profiles with copy number variation (CNV) data and clinical characteristic data of 186 patients with pancreatic cancer from The Cancer Genome Atlas portal (TCGA). Then, we determined the alteration of m6a regulators and their correlation with clinicopathological features using the log-rank tests, Cox regression model, and chi-square test. Results: The results suggested that pancreatic cancer patients with ALKBH5 CNV were associated with worse overall survival and disease-free survival than those with diploid genes. Additionally, upregulation of the writer gene ALKBH5 had a positive correlation with the activation of AKT pathways. Conclusion: Our study not only demonstrated genetic characteristic changes of m6A-related genes in pancreatic cancer and found a strong relationship between the changes of ALKBH5 and poor prognosis but also provided a novel therapeutic target for pancreatic cancer therapy.

Background: Circadian clock genes have been reported to exhibit a regulatory effect on the carcinogenesis and progression of numerous cancers. Nevertheless, the specific relationship between hepatocellular carcinoma (HCC) and circadian rhythm associated genes still remain to be clarified. Therefore, we evaluate the prognosis function of circadian clock genes in HCC with the online datasets of The Cancer Genome Atlas (TCGA) and the international cancer genome consortium (ICGC). Methods: In our research, the RNA-seq of the selected core circadian genes in HCC patients and their relevant clinical data were acquired from the online TCGA database and the ICGC database. R software and cBioPortal website were performed. Results: As consequence, among the 22 typical circadian clock genes, 16 genes were statistically expressed between HCC and adjacent normal tissues. Accordingly, 11 clock genes with regression coefficients were used to constitute a new risk score formula, which was related to the prognosis in HCC. Moreover, the new nomogram, which consisting risk score and several clinical traits , could be applied for the purpose of accurate prediction of the OS time for the patients. Finally, we identified a novel nomogram related with OS in HCC patients with a comprehensive analysis of circadian clock genes and other clinical characteristics profiles. It was also the first time we systematically demonstrated the relationship between clock genes and the HCC prognosis, which would contribute to the treatment of HCC. Conclusions: The current study demonstrated the potential of circadian clock genes as clinically associated biomarkers for prognosis prediction in HCC, which may make a significant contribution to the further investigations of HCC progression.

Background: Utilizing genomic data to predict cancer prognosis was insufficient. Proteomics can improve our understanding of the etiology and progression of cancer and improve the assessment of cancer prognosis. Based on CPTAC (Clinical Proteomic Tumor Analysis Consortium) which has generated extensive proteomics data of the vast majority of tumors, we can perform a proteomic pan-carcinoma analysis.Methods: The proteomics data and clinical features of cancer patients were collected from CPTAC. We screened 69 differentially expressed proteins with R software. GO and KEGG analysis were performed to clarify the function of these proteins. The DEPs-based prognostic model was identified by least absolute shrinkage and selection operator (LASSO)-Cox regression model. The time-dependent receiver operating characteristics analysis was used to evaluate the ability of the prognostic model to predict overall survival.Results: A total of 69 differentially expressed proteins were screened in five different types of cancers: hepatocellular carcinoma (HCC), lung adenocarcinoma (LUAD), children's brain tumor tissue consortium (CBTTC), clear cell renal cell carcinoma (CCRC) and uterine corpus endometrial carcinoma (UCEC). Furthermore, the differentially expressed proteins were related to cell metabolism, cell proliferation and extracellular matrix. Then 24 DEPs-based classifiers for predicting OS was developed by LASSO-Cox regression model in training cohort, which was validated in validation cohort. Conclusions: In the present study, we identified DEPs-based survival-predictor model to predict most cancers. We are the first group to utilize proteomics to construct a pan-cancer prognosis model, which could accurately and effectively predict the survival rate of most cancers.

Aberrant glucose metabolism of diabetes mellitus or hyperglycemia stimulates pancreatic tumorigenesis and progression. Hyperglycemic environment can increase the ROS level of tumors, but the role of upregulation of ROS levels in pancreatic cancer (PC) still remains controversial. Here, the same as other reports, we demonstrate that high glucose promoted pancreatic cancer cell growth and resulted in an increase in the level of ROS. However, it is interesting that the phosphorylation of JNK was reduced. When treating PC cells with N-acetyl-L-cysteine (NAC), the intracellular ROS generation is repressed, but the expression of phosphorylation of JNK and c-Jun increased. Moreover, the JNK inhibitor SP600125 significantly promoted cell proliferation and suppressed cell apoptosis of pancreatic cancer cells under high glucose conditions. Collectively, high levels of ROS induced by high glucose conditions stimulated the proliferation of pancreatic cancer cells, and it may be achieved by inactivating the JNK pathway.

Dinglai Yu,1 Tingting Ye,1 Yukai Xiang,1 Zhehao Shi,1 Jie Zhang,1 Bin Lou,1 Fan Zhang,1 Bicheng Chen,1,2 Mengtao Zhou1 1Department of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China; 2Zhejiang Provincial Top Key Discipline in Surgery, Wenzhou Key Laboratory of Surgery, Wenzhou, Zhejiang Province, People’s Republic of China Abstract: Quercetin, a flavone, is multifaceted, having anti-oxidative, anti-inflammatory, and anticancer properties. In the present study, we explored the effects of quercetin on the epithelial–mesenchymal transition (EMT) and invasion of pancreatic cancer cells and the underlying mechanisms. We noted that quercetin exerted pronounced inhibitory effects in PANC-1 and PATU-8988 cells. Moreover, quercetin inhibited EMT and decreased the secretion of matrix metalloproteinase (MMP). Meanwhile, we determined the activity of STAT3 after quercetin treatment. STAT3 phosphorylation decreased following treatment with quercetin. We also used activating agent of STAT3, IL-6, to induce an increase in cell malignancy and to observe the effects of treatment with quercetin. As expected, the EMT and MMP secretion increased with activation of the STAT3 signaling pathway, and quercetin reversed IL-6-induced EMT, invasion, and migration. Therefore, our results demonstrate that quercetin triggers inhibition of EMT, invasion, and metastasis by blocking the STAT3 signaling pathway, and thus, quercetin merits further investigation. Keywords: quercetin, EMT, MMPs, STAT3, pancreatic cancer

Acute lung injury (ALI) is a critical event involved in the pathophysiological process of acute pancreatitis (AP). Many methods have been widely used for the treatment of AP-ALI, but few are useful during early inflammation. Lipoxin A4 (LXA4), a potent available anti-inflammatory and novel antioxidant mediator, has been extensively studied in AP-ALI, but its underlying mechanism as a protective mediator is not clear. This research was conducted to identify the possible targets and mechanisms involved in the anti-AP-ALI effect of LXA4. First, we confirmed that LXA4 strongly inhibited AP-ALI in mice. Next, using ELISA, PCR, and fluorescence detection to evaluate different parameters, LXA4 was shown to reduce the inflammatory cytokine production induced by AP and block reactive oxygen species (ROS) generation in vivo and in vitro. In addition, TNF-α treatment activated the nuclear factor E2-related factor 2 (Nrf2) signaling pathway and its downstream gene heme oxygenase-1 (HO-1) in human pulmonary microvascular endothelial cells (HPMECs), and LXA4 further promoted their expression. This study also provided evidence that LXA4 phosphorylates Ser40 and triggers its nuclear translocation to activate Nrf2. Moreover, when Nrf2-knockout (Nrf2-/-) mice and cells were used to further assess the effect of the Nrf2/HO-1 pathway, we found that Nrf2 expression knockdown partially eliminated the effect of LXA4 on the reductions in inflammatory factor levels while abrogating the inhibitory effect of LXA4 on the ROS generation stimulated by AP-ALI. Overall, LXA4 attenuated the resolution of AP-induced inflammation and ROS generation to mitigate ALI, perhaps by modulating the Nrf2/HO-1 pathway. These findings have laid a foundation for the treatment of AP-ALI.

Brusatol, a natural quassinoid isolated from a traditional Chinese herbal medicine known as Bruceae Fructus, has recently been reported to possess powerful cytotoxic effects against various cancer cell lines, highlighting its potential as an anti-cancer drug. However, the precise molecular mechanisms by which Brusatol exerts its anti-cancer effects remain poorly understood in hepatocellular carcinoma (HCC). In this study, we demonstrated that Brusatol inhibited cell viability, proliferation and induced apoptosis in liver cancer lines. Furthermore, Brusatol could activate autophagy in diverse liver cell lines, and the autophagy inhibitor chloroquine (CQ) reversed Brusatol-induced apoptosis in Bel7404 cells. In addition, we found that Brusatol inhibited PI3K/Akt/mTOR. Brusatol may also inhibit invasion, migration and the epithelial-mesenchymal transition (EMT). In a human liver xenograft tumor model in nude mice, immunohistochemistry showed that Brusatol significantly inhibited tumor invasion and proliferation. Taken together, these results revealed that Brusatol effectively inhibited proliferation and induced apoptosis in HCC through autophagy induction, probably via the PI3K/Akt/mTOR pathway, and inhibited tumor invasion and migration in vivo and in vitro. All above indicated that Brusatol is an encouraging anti-tumor drug candidate or a supplement to the current chemotherapeutic systematic plan.

Although gemcitabine is the standard chemotherapy treatment for advanced pancreatic cancer, its benefits are quite limited due to prevalent chemoresistance, and the mechanism underlying gemcitabine chemoresistance remains unclear. Currently, Nrf2 has been deemed as a significant contributor to gemcitabine chemoresistance in pancreatic cancer. Brusatol is a unique inhibitor of the Nrf2 pathway, and in previous studies, we determined that brusatol exhibits the effects of growth inhibition and proapoptosis in pancreatic cancer cells. Due to these data, we speculate that brusatol can reverse gemcitabine-induced Nrf2 activation and propose that it can enhance gemcitabine efficacy in treating pancreatic cancer. In this study, we first proved that brusatol can effectively inhibit the Nrf2 signalling pathway and increase ROS accumulation in pancreatic cancer cells. Next, we demonstrated that brusatol can abrogate gemcitabine-induced Nrf2 activation in pancreatic cancer cells. In addition, we discovered that brusatol potentiates gemcitabine-induced growth inhibition and apoptosis in human pancreatic cancer cells. In nude mice with PANC-1 xenografts, treatment with a combination of brusatol and gemcitabine considerably reduced in vivo tumour growth compared with control treatment or treatment with either brusatol or gemcitabine alone. Immunohistochemical staining also showed that Nrf2 expression levels were reduced in brusatol-treated xenograft tumour tissues. In summary, our results suggest that brusatol is capable of enhancing the antitumour effects of gemcitabine in both pancreatic cancer cells and PANC-1 xenografts via suppressing the Nrf2 pathway.

Dermokine (DMKN) was first identified in relation to skin lesion healing and skin carcinoma. Recently, its expression was associated with pancreatic cancer tumorigenesis, although its involvement remains poorly understood. Herein, we showed that DMKN loss of function in Patu-8988 and PANC-1 pancreatic cancer cell lines resulted in reduced phosphorylation of signal transducer and activator of transcription 3, and increased activation of ERK1/2 and AKT serine/threonine kinase. This decreased the proliferation ability of pancreatic ductal adenocarcinoma (PDAC) cells. In addition, DMKN knockdown decreased the invasion and migration of PDAC cells, partially reversed the epithelial-mesenchymal transition, retarded tumor growth in a xenograft animal model by decreasing the density of microvessels, and attenuated the distant metastasis of human PDAC in a mouse model. Taken together, these data suggested that DMKN could be a potential prognostic biomarker and therapeutic target in pancreatic cancer.