Reciprocal negative feedback regulation of ATF6α and PTEN promotes prostate cancer progression.

Phosphatase and tensin homolog (PTEN) loss tightly correlates with prostate cancer (PCa) progression and metastasis. Inactivation of PTEN leads to abnormal activation of PI3K/AKT pathway. However, results from clinical trials with AKT inhibitors in PCa have been largely disappointing. Identification of novel regulators of PTEN in PTEN-dysfunctional PCa is urgently needed. Here we demonstrated that the expression level of PTEN is inversely correlated with the signature score of unfolded protein response (UPR) in PCa. Importantly, PTEN suppresses the activity of ATF6α, via interacting to de-phosphorylate ATF6α and consequently inhibiting its nuclear translocation. Conversely, ATF6α promotes the ubiquitination and degradation of PTEN by inducing CHIP expression. Thus, ATF6α and PTEN forms a negative feedback loop during PCa progression. Combination of ATF6α inhibitor with AKT inhibitor suppresses tumor cell proliferation and xenograft growth. Importantly, this study highlighted ATF6α as a therapeutic vulnerability in PTEN dysfunctional PCa.

Margin-Based Deep Learning Networks for Human Activity Recognition.

Human activity recognition (HAR) is a popular and challenging research topic, driven by a variety of applications. More recently, with significant progress in the development of deep learning networks for classification tasks, many researchers have made use of such models to recognise human activities in a sensor-based manner, which have achieved good performance. However, sensor-based HAR still faces challenges; in particular, recognising similar activities that only have a different sequentiality and similarly classifying activities with large inter-personal variability. This means that some human activities have large intra-class scatter and small inter-class separation. To deal with this problem, we introduce a margin mechanism to enhance the discriminative power of deep learning networks. We modified four kinds of common neural networks with our margin mechanism to test the effectiveness of our proposed method. The experimental results demonstrate that the margin-based models outperform the unmodified models on the OPPORTUNITY, UniMiB-SHAR, and PAMAP2 datasets. We also extend our research to the problem of open-set human activity recognition and evaluate the proposed method's performance in recognising new human activities.

Inhibition of hexokinases holds potential as treatment strategy for rheumatoid arthritis.

INTRODUCTION: Abnormal glycolytic metabolism contributes to joint inflammation and destruction in rheumatoid arthritis (RA). We examine the expression and function of hexokinases in RA and evaluate the potential of their specific inhibitor for clinical treatment. METHODS: Detection of HKs was assessed in synovial tissue by immunohistology and Western blot. SiRNA and a specific hexokinases inhibitor, lonidamine (LND), were used to evaluate the role of hexokinase-I/II (HK-I/II). Pro-inflammatory and glycolysis factors, cell viability, and apoptosis were assessed by ELISA, RT-qPCR, MTS, and flow cytometry. The clinical effects of LND on type II collagen-induced arthritis (CIA) in DBA-/1 mouse model was evaluated by scoring their clinical responses, synovitis, and cartilage destructions, and ELISA was employed to analyze the concentrations of antibody in the serum of CIA model. RESULTS: HK-I/II expression and their activities increased in the synovium of RA compared with osteoarthritis (OA). Silencing HK-I/II (siHK-I/II) or LND treatment decreased the production of pro-inflammatory factors, such as IL-6, IL-8, CXCL9, CXCL10, and CXCL11, and cell viability, but induced cell apoptosis of RASFs. The expression of TNF-α and IL-1ß of macrophage in response to LPS stimulation were depressed as well after treatment with siHK-I/II or LND. Furthermore, leucocyte infiltration co-cultured with RASFs was also suppressed after inhibiting the expression or activity of HK-I/II. These anti-inflammatory effects overlapped with their anti-glycolytic activities. Treatment with LND in mice with CIA decreased the production of antibodies against IgG1, IgG2a, and IgG2b and consequently attenuated joint inflammation and destruction. CONCLUSIONS: HK-I/II contribute to shape the inflammatory phenotype of RASFs and macrophages. LND may be a potential drug in treating patients with RA.