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Pancreatic adenocarcinoma (PAAD) as one of the most aggressive and lethal malignant tumors is correlated with increased morbidity and mortality. Tumorigenesis, growth, and metastasis are affected by various cytokines. Among them, CC chemokines can modulate the infiltration of immune cells and recruit cancer-associated immune cells, which play an important role in the inhibition of tumor immunity and affect the clinical outcome of cancer patients. However, the therapeutic potential and prognostic value of CC chemokines in PAAD have not yet been elucidated. To do this, we comprehensively explore and analyze large amounts of data on the basis of ONCOMINE database, GEPIA, LinkedOmics, cBioPortal, GeneMANIA, UALCAN, jvenn, DAVID 6.8, TRRUST, TIMER, and TISIDB. We found the transcriptional levels of CCL5/7/13/15/18/19/20 in PAAD tissues were remarkably increased, whereas the transcriptional level of CCL17 was decreased. CCL20 expression had significantly been correlated with the tumor stage of PAAD patients. High expressions of CCL5, CCL7, CCL13, CCL18, and CCL20 were notably correlated with the prognosis of patients. Moreover, patients with CCL18 and CCL19 alterations showed a poor prognosis in both overall survival (OS) and disease-specific survival (DSS), and patients with CCL5 and CCL15 alterations also presented a poor prognosis in OS. The functions of the aberrantly expressed CC chemokines were mainly correlated with the cytokine-cytokine receptor interaction, chemokine signaling pathway, inflammatory response, and immune response. Our study shows that the key transcription factors for CC chemokines are RELA and NF-κB1. We also discovered significant associations between the expression levels of CC chemokines and six infiltrating immune cells including CD8+ T cells, CD4+ T cells, B cells, macrophages, neutrophils, and dendritic cells. Taken together, our study indicated the interaction between CC chemokines and PAAD and clarified the value of CC chemokines as potential therapeutic targets as well as prognostic markers for PAAD.

Colon cancer is a common malignancy and its poor outcome mainly attributes to chemotherapy resistance. AMP-activated protein kinase (AMPK) is noted to mediate development of and chemotherapy resistance in colon cancer. This study aims to explore the mechanism regarding AMPK-mediated β-catenin degradation in chemotherapy resistance in colon cancer. β-catenin was upregulated in colon cancer tissues and cells, as it was positively correlated with the malignancy and poor prognosis, and chemotherapy resistance of colon cancer. As colon cancer cells were exposed to cisplatin and tamoxifen, functional experiment revealed that AMPK activated by its agonist metformin inhibited the proliferation and chemotherapy resistance of colon cancer cells by regulating β-catenin. Co-immunoprecipitation assay confirmed the interaction between β-catenin, E3 ubiquitin ligase Parkin and AMPK. Finally, we xenografted tumors in nude mice and validated the effects of AMPK and β-catenin on tumor growth and chemotherapy resistance in vivo. Parkin induced ubiquitination and degradation of β-catenin while AMPK downregulated β-catenin by elevating the phosphorylation of Parkin. Taken together, AMPK phosphorylates Parkin to promote the ubiquitination and degradation of β-catenin, thereby downregulating β-catenin, which inhibits the proliferation of colon cancer cells and reverses the chemotherapy resistance in colon cancer.

Nowadays, there are few studies in vivo to explore the effects of Human Cytomegalovirus (HCMV) single gene such as immediate early protein 2 (IE2) on the nervous system, let alone the mechanism that IE2 causes cognitive impairment. In this study, the Rosa26-LSL-IE2/Cre mouse was used to show the effects of IE2 on the cognitive ability and the GluNRs/CaMKIIα/CREB signaling pathway in the hippocampus. We divided the mice into experimental and control groups based on the results of PCR firstly. After that, the cognitive abilities of the two groups were compared through new object recognition (NOR) and Morris water maze (MWM) tests. The results of the behavioral tests showed that the cognitive ability of the experimental mice was lower than that of the control group. It is known that changes in the expression levels of N-methyl D-aspartate receptor 1, 2 A, and 2B (GluN1, GluN2A, GluN2B) affect synaptic plasticity and cause cognitive changes. Finally, we analyzed the expression levels of GluN1, GluN2A, GluN2B, and related signaling pathway molecules by qPCR and western blot. We found that the expression levels of the GluNRs/CaMKIIα/CREB signaling pathway were decreased in the experimental group. These results indicated that IE2 could affect the expression levels of GluNRs/CaMKIIα/CREB signaling pathway, which was closely related to the cognitive impairment of the experimental group. In summary, we used this novel mouse model to show that IE2 could cause cognitive impairment in the hippocampus, which might be related to the GluNRs/CaMKIIα/CREB signaling pathway. It is helpful to further understand the mechanism of the cognitive impairment induced by HCMV IE2.

This study aims to investigate effects of polymorphisms in key Th-17 immune response genes on the susceptibility to HBeAg-positive (HBeAg+) chronic hepatitis B (CHB) and response to PEG-IFNa-2α. A total of 139 patients with HBeAg+ CHB treated with PEG-IFNa-2α and 145 healthy controls were enrolled to explore the association between IL-17A, IL-17F, IL-21 and IL-23R polymorphisms and HBeAg+ CHB susceptibility, as well as treatment efficacies. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. IL-17A rs4711998 and IL-17F rs763780 may affect susceptibility to HBeAg+ CHB and response to PEG-IFNa-2α treatment. The T allele of IL-21 rs12508721 may lower HBeAg+ CHB susceptibility but enhance PEG-IFNa-2α response, and the GA genotype and the A allele of IL-23R rs11209026 may reduce the susceptibility to HBeAg+ CHB. Th17-related gene polymorphisms were linked to HBeAg+ CHB susceptibility, and rs4711998, rs763780 and rs12508721 were associated with sustained responses to PEG-IFNa-2α.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronically intestinal autoimmune disease, the pathological mechanisms of which are not very clear. Wild type p-53 induced phosphatase 1 (Wip1), a serine/threonine protein phosphatase, has been reported to negatively regulate the inflammation in sepsis. However, the role of Wip1 in IBD is not very clear. Therefore, colonic tissues and peripheral blood from patients with IBD and healthy controls were collected to analyzed mRNA and protein expression of Wip1 using the method of qPCR and immunohistochemistry. Immune cells of neutrophils, CD4+ T cells, CD8+ T cells, B cells, monocytes and intestinal epithelial cells were isolated to analyze Wip1 expression by means of qPCR. Expression of Wip 1 was analyzed after the cells were stimulated by various of cytokines. DSS-colitis model was induced on the wild type (WT) and Wip 1 knock out (Wip1-/-) mice, and cytokines expression were analyzed in intestinal lamina propria from WT and Wip1-/- mice. Neutrophil specific markers were examined in intestinal lamina propria from WT and Wip1-/- mice. Moreover, neutrophils were isolated from bone marrow of WT and Wip1-/- mice to examine neutrophil migration with or without inhibitors of signaling pathway in vitro. The expression of Wip 1 mRNA and protein were found to be significantly decreased in patients with active IBD compared with healthy controls. And Wip 1 was mainly expressed on neutrophils from peripheral blood and colonic tissues. Moreover, expression of Wip1 was significantly decreased on neutrophils after the stimulation of TNF-α and IFN-γ. Wip1-/- mice were more susceptible to DSS induced colitis compared to WT mice, and expressed more pro-inflammatory cytokines (e.g. TNF-α, IFN-γ, IL-17A, etc). Moreover, expression of neutrophil specific markers (e.g. Ly6G, CD11b, elastase, etc) was also increased in Wip1-/- mice. The migration of neutrophils from the bone marrow of Wip1 mice was marked increased, which was mediated by MAPK-P38 signaling pathway. Wip1 plays an importantly protective role in the pathogenesis of IBD. Therefore, Wip1 may be used a new targets in the treatment for IBD in the future.

Background: Gastric microbiome has been well characterized gastric cancer. Alterations associated with gastric cancer have been identified. However, little is known regarding the dysbiotic features in early gastric cancer. Methods: Gastric microbiome was assessed in early gastric cancer (n=30), advanced gastric cancer (n=30) and chronic gastritis (n=60). Random forest machine learning algorithm was used to identify signatures capable of predicting early gastric cancer. In addition, influence of Helicobacter pylori virulence and cancer-associated single nucleotide polymorphisms in PRKAA1, PTGER4, PSCA, MUC1 and UNC5CL on gastric microbiome was determined. Findings: There were significant differences in the microbial profile and composition between early and advanced gastric cancer, suggesting alterations associated with cancer progression. Compared with chronic gastritis, 32 bacteria genera were found to be enriched or depleted in early gastric cancer. Production of urease and synthesis of bacteria flagellum were decreased, while glycolysis of fructose and hydrolysis of glycosides were enhanced. The correlation network became simplified and fragmented. A microbial signature enclosing 24 bacteria was identified, which could distinguish early gastric cancer from chronic gastritis with an AUC value of 0.97. H. pylori had impacts on gastric microbiome. The minor allele of MUC1 SNP rs4072037 was associated with increased abundance of Ochrobactrum. Interpretation: Gastric microbiome showed distinct features in early gastric cancer. The identified microbial signature could be used as biomarkers for predicting early gastric cancer. Funding: National natural Science Foundation of China (31870777, 81602144). Declaration of Interest: The authors declare no conflicts of interest. Ethical Approval: This study was approved by the Research Ethnics Committee of Qingdao Municipal Hospital, China. Informed written consent was obtained from all participants.