Search

Background and aimsPancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis.MethodsThe Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism.ResultsGABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression.ConclusionsOverexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.

The change of 2-［18F］-A-85380 in chronic ischemia rats with cognitive dysfunction was evaluated by Micro-PET. Chronic cerebral ischemia rat model was made by bilateral common carotid artery ligation. Four weeks later, Morris water experiments were performed to check cognitive dysfunction. After intravenous injection of 37 MBq 2-［18F］-A-85380, the normal isoflurane-anesthetized rat underwent Micro-PET scan. The brain scanning was performed for 10 minutes at 30, 60, 120, 180, 240 minutes after injection. Select the thalamus, frontal cortex, cerebellum as region of interesting for quantitative analysis. The chronic ischemia rats underwent Micro-PET scan for 10 minutes at 120 minutes. SUVave thalamus/SUVave cerebellum, SUVave frontal cortex/SUVave cerebellum were calculated. Four weeks after the surgical procedure, Morris water maze was used to assess working memory tasks with two groups of rats. The escape latency of the chronic ischemia group and the normal group at the fifth day was (24.16±27.18) s , (9.44±5.48) s, respectively. The chronic ischemia group compared with the normal group, the difference was statistically significant. The ischemic group in learning to find the platform slower than the normal rats. At the sixth day, the chronic ischemia rats by looking for the original platform quadrant after removed the platform, was slower than the normal group in Morris space exploration experiments. The chronic ischemia group was (2.60±1.67) times, the normal group was (6.20±2.95) times, the difference was statistically significant. By the Micro-PET scanning, the thalamus could be distinguished markedly during 120 minutes to 240 minutes, especially at 120 minutes. At 120 minutes, SUVave thalamus/SUVave cerebellum, SUVave frontal cortex/SUVave cerebellum of the chronic ischemia cognitive dysfunction rats was 1.27±0.02, 1.07±0.03, respectively. The SUVave thalamus/SUVave cerebellum, SUVave frontal cortex/SUVave cerebellum of the nomal group was 1.62±0.06 and 1.34±0.28, respectively. The difference was statistically significant. 2-［18F］-A-85380 is suitable for nAChRs imaging. The suitable time for rats Micro-PET imaging in vivo was 120~240 minutes, especially at 120 minutes.The quantitative analysis of nAChRs in different brain regions of rats was performed in vivo, which is very useful for detecting the changes of variety receptors in chronic ischemia cognitive dysfunction rats, meanwhile lay the foundation for investigating chronic ischemia cognitive dysfunction rats in various stages or evaluating the efficacy of treatment in chronic ischemia cognitive dysfunction rats.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis.The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism.GABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce CaOverexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.

Selective ensemble learning is a learning algorithm, trains a number of based classifier and selects some of them to ensemble. Through the selective ensemble, the algorithm would be more effective than each single one and better than the algorithm that select all the based classifier, and the algorithm would have effective generalization ability. In this paper, we apply a multi-lever selective ensemble learning algorithm, named. Test results show that has better learning results and generalization ability.

This paper makes a quite deep research on the related theories and technologies of OGSA (Open Grid Services Architecture), Web service, etc. a new model of system integration, which constructs a dynamic linking integration mechanism with good flexibility by using the service-oriented system and cross platform property of Web service. The model can improve the efficiency of Web service and the cooperation between Web services, Simulation experiments show that the model in a dynamic, service-oriented environment is feasible and effective.