Nuclear localization of the androgen receptor (AR) is necessary for its activation as a transcription factor. Defining the mechanisms regulating AR nuclear localization in androgen-sensitive cells and how these mechanisms are dysregulated in castration-resistant prostate cancer (CRPC) cells is fundamentally important and clinically relevant. According to the classical model of AR intracellular trafficking, androgens induce AR nuclear import and androgen withdrawal causes AR nuclear export. The present study has led to an updated model that AR could be imported in the absence of androgens, ubiquitinated, and degraded in the nucleus. Androgen withdrawal caused nuclear AR degradation, but not export. In comparison with their parental androgen-sensitive LNCaP prostate cancer cells, castration-resistant C4-2 cells exhibited reduced nuclear AR polyubiquitination and increased nuclear AR level. We previously identified 3-(4-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (CPPI) in a high-throughput screen for its inhibition of androgen-independent AR nuclear localization in CRPC cells. The current study shows that CPPI is a competitive AR antagonist capable of enhancing AR interaction with its E3 ligase MDM2 and degradation of AR in the nuclei of CRPC cells. Also, CPPI blocked androgen-independent AR nuclear import. Overall, these findings suggest the feasibility of targeting androgen-independent AR nuclear import and stabilization, two necessary steps leading to AR nuclear localization and activation in CRPC cells, with small molecule inhibitors.

Background: The Cox regression model is not sufficiently accurate to predict the survival prognosis of nasopharyngeal carcinoma (NPC) patients. It is impossible to calculate and rank the importance of impact factors due to the low predictive accuracy of the Cox regression model. So, we developed a system. Using the SEER (The Surveillance, Epidemiology, and End Results) database data on NPC patients, we proposed the use of random survival forest (RSF) and survival-support vector machine (SVM) from the machine learning methods to develop a survival prediction system specifically for NPC patients. This approach aimed to make up for the insufficiency of the Cox regression model. We also used the Cox regression model to validate the development of the nomogram and compared it with machine learning methods. Methods: A total of 1,683 NPC patients were extracted from the SEER database from January 2010 to December 2015. We used R language for modeling work, established the nomogram of survival prognosis of NPC patients by Cox regression model, ranked the correlation of influencing factors by RSF model VIMP (variable important) method, developed a survival prognosis system for NPC patients based on survival-SVM, and used C-index for model evaluation and performance comparison. Results: Although the Cox regression models can be developed to predict the prognosis of NPC patients, their accuracy was lower than that of machine learning methods. When we substituted the data for the Cox model, the C-index for the training set was only 0.740, and the C-index for the test set was 0.721. In contrast, the C index of the survival-SVM model was 0.785. The C-index of the RSF model was 0.729. The importance ranking of each variable could be obtained according to the VIMP method. Conclusions: The prediction results from the Cox model are not as good as those of the RSF method and survival-SVM based on the machine learning method. For the survival prognosis of NPC patients, the machine learning method can be considered for clinical application.

Skin aging is a complicated physiological process, and microRNA-mediated regulation has been shown to contribute to this process. Exosomes mediate intercellular communication through miRNAs, mRNAs and proteins, and participate in many physiological and pathological processes. Vascular endothelial cell-derived exosomes have been confirmed to be involved in the development of many diseases, however, their effects on skin aging have not been reported. In this study, senescent endothelial cells could regulate skin fibroblast functions and promote cell senescence through exosomal pathway. miR-767 was highly expressed in senescent vascular endothelial cells and their exosomes, and miR-767 is also upregulated in skin fibroblasts after treatment with exosomes derived from senescent vascular endothelial cells. In addition, transfection with miR-767 mimic promoted senescence of skin fibroblasts, while transfection with miR-767 inhibitor reversed the effect of D-galactose. Double luciferase analysis confirmed that TAB1 was a direct target gene of miR-767. Furthermore, miR-767 expression was increased and TAB1 expression was decreased in D-galactose induced aging mice. In mice that overexpressed miR-767, HE staining showed thinning of dermis and senescence appearance. In conclusion, senescent vascular endothelial cell-derived exosome mediated miR-767 regulates skin fibroblasts through the exosome pathway. Our study reveals the role of vascular endothelial cell-derived exosomes in aging in the skin microenvironment and contributes to the discovery of new targets for delaying senescence.