Androgen receptor-mediated growth suppression and apoptosis of human prostate epithelial cells

Androgen receptor (AR) signaling is crucial to the development, growth, and homeostasis of the prostate gland, and its dysregulation mediates common prostate pathologies, including benign and malignant forms of neoplasia. Prostate cancer is the second most prevalent cancer and the sixth leading cause of cancer mortality in men. The mechanisms whereby AR regulates growth suppression and survival/death of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells are not well understood, though they are central to prostate growth, homeostasis, and neoplasia. We hypothesized that in normal adult prostate, AR signaling may serve homeostatic roles in the regulation of cell cycle progression and programmed cell death such that it restrains the growth of healthy epithelial cells and accelerates the turnover of damaged epithelial cells. To test this hypothesis, we examined the growth/apoptosis response of human prostate epithelial cell lines (HPr-1AR, RWPE-AR and PC3-Lenti-AR) under optimized or stressed conditions, identified androgen-responsive genes that restrain cell cycle progression or mediate programmed cell death, and defined mechanisms whereby AR regulates their expression. Here, we report the mechanisms of AR-mediated growth suppression and AR-sensitized apoptotic cell death in these prostate epithelial cell lines. Under optimized culture conditions, AR signaling inhibits the proliferation of HPr-1AR and PC3-Lenti-AR cells, but does not induce cell death. AR-mediated growth suppression is dependent on the inhibition of cyclin D-CDK4/6 complexes through transcriptional repression of the CDK4 and CDK6 genes and transcriptional activation of the CDKN1A/p21 gene. Further, AR inhibits cyclin D2 transcription and destabilizes cyclin D1 mRNA in HPr-1AR cells. The decreased expression and activity of cyclin D-CDK4/6 complexes lead to a prolonged G0/G1 interval and, therefore, restrains cell cycle progression and proliferation of HPr-1AR and PC3-Lenti-AR. Under stressed culture conditions, AR signaling sensitizes HPr-1AR and RWPE-AR cells to apoptotic cell death. Co-treatment of these cells with androgen and a cell stress agent, such as staurosporine (STS) or TNFα, synergistically increases apoptotic cell death in comparison to treatment with cell stress agent alone. The synergy between androgen and stress inducer is dependent on AR and transcription and involves the activation of the intrinsic mitochondrial apoptotic pathway. Expression analyses reveal that pro-apoptotic genes (BCL2L11/BIM, BOK and AIFM2) are androgen-induced, whereas pro-survival genes (BCL2L1/BCL-XL and MCL1) are androgen-repressed. Hence, we propose that the net effect of these AR-mediated expression changes shifts the balance of BCL2-family proteins in a manner that sensitizes mitochondria to apoptotic signaling and thus renders HPr-1AR more vulnerable to cell stress agents. These studies provide novel insights into the homeostatic roles of AR in the regulation of prostate epithelial cell proliferation and turnover

Simvastatin suppresses cerebral aneurysm in rats through suppression of release of pro-inflammatory cytokines

Purpose: To investigate the protective effect of simvastatin (SA) against onset of cerebral aneurysmmediated inflammatory cytokine release and subsequent inflammation and degradation of the extracellular matrix of smooth muscle cells.Methods: Cerebral aneurysm was induced in male Wistar rats using elastase injection, and aneurysm growth was monitored for one month following SA treatment. Inhibition of aneurysm growth was determined along with the expression levels of chemokines and pro-inflammatory cytokines, including TNF-α, IL-8, IL-1β, IL-17, IL-6, macrophage chemoattractant protein-1 (MCP-1), and matrix metalloproteinases 2 and 9, using enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR).Results: Aneurysm size decreased in rats treated with SA, relative to values obtained for control rats (p < 0.05). The corresponding expressions of inflammatory cytokines and chemokines were also reduced following pre-treatment with SA (p < 0.05). The results indicate a reduction in the aneurysm area in rats pre-treated with SA, when compared to the untreated animals (p < 0.05).Conclusion: SA treatment inhibits the progression of cerebral aneurysms via its protective effect against inflammation, indicating its potential for use in the prevention and treatment of cerebralaneurysms

HGCN-GJS: Hierarchical Graph Convolutional Network with Groupwise Joint Sampling for Trajectory Prediction

Accurate pedestrian trajectory prediction is of great importance for downstream tasks such as autonomous driving and mobile robot navigation. Fully investigating the social interactions within the crowd is crucial for accurate pedestrian trajectory prediction. However, most existing methods do not capture group level interactions well, focusing only on pairwise interactions and neglecting group-wise interactions. In this work, we propose a hierarchical graph convolutional network, HGCN-GJS, for trajectory prediction which well leverages group level interactions within the crowd. Furthermore, we introduce a novel joint sampling scheme for modeling the joint distribution of multiple pedestrians in the future trajectories. Based on the group information, this scheme associates the trajectory of one person with the trajectory of other people in the group, but maintains the independence of the trajectories of outsiders. We demonstrate the performance of our network on several trajectory prediction datasets, achieving state-of-the-art results on all datasets considered.Comment: 8 pages, 5 figures, in submission to conferenc