The SMAC mimetic GDC-0152 is a direct ABCB1-ATPase activity modulator and BIRC5 expression suppressor in cancer cells.

Upregulation of the multidrug efflux pump ABCB1/MDR1 (P-gp) and the anti-apoptotic protein BIRC5/Survivin promotes multidrug resistance in various human cancers. GDC-0152 is a DIABLO/SMAC mimetic currently being tested in patients with solid tumors. However, it is still unclear whether GDC-0152 is therapeutically applicable for patients with ABCB1-overexpressing multidrug-resistant tumors, and the molecular mechanism of action of GDC-0152 in cancer cells is still incompletely understood. In this study, we found that the potency of GDC-0152 is unaffected by the expression of ABCB1 in cancer cells. Interestingly, through in silico and in vitro analysis, we discovered that GDC-0152 directly modulates the ABCB1-ATPase activity and inhibits ABCB1 multidrug efflux activity at sub-cytotoxic concentrations (i.e., 0.25×IC50 or less). Further investigation revealed that GDC-0152 also decreases BIRC5 expression, induces mitophagy, and lowers intracellular ATP levels in cancer cells at low cytotoxic concentrations (i.e., 0.5×IC50). Co-treatment with GDC-0152 restored the sensitivity to the known ABCB1 substrates, including paclitaxel, vincristine, and YM155 in ABCB1-expressing multidrug-resistant cancer cells, and it also restored the sensitivity to tamoxifen in BIRC5-overexpressing tamoxifen-resistant breast cancer cells in vitro. Moreover, co-treatment with GDC-0152 restored and potentiated the anticancer effects of paclitaxel in ABCB1 and BIRC5 co-expressing xenograft tumors in vivo. In conclusion, GDC-0152 has the potential for use in the management of cancer patients with ABCB1 and BIRC5-related drug resistance. The findings of our study provide essential information to physicians for designing a more patient-specific GDC-0152 clinical trial program in the future.

Predicting the Risk of Future Multiple Suicide Attempt among First-Time Suicide Attempters: Implications for Suicide Prevention Policy.

Suicide is listed in the top ten causes of death in Taiwan. Previous studies have pointed out that psychiatric patients having suicide attempts in their history are more likely to attempt suicide again than non-psychiatric patients. Therefore, how to predict the future multiple suicide attempts of psychiatric patients is an important issue of public health. Different from previous studies, we collect the psychiatric patients who have a suicide diagnosis in the National Health Insurance Research Database (NHIRD) as the study cohort. Study variables include psychiatric patients' characteristics, medical behavior characteristics, physician characteristics, and hospital characteristics. Three machine learning techniques, including decision tree (DT), support vector machine (SVM), and artificial neural network (ANN), are used to develop models for predicting the risk of future multiple suicide attempts. The Adaboost technique is further used to improve prediction performance in model development. The experimental results show that Adaboost+DT performs the best in predicting the behavior of multiple suicide attempts among psychiatric patients. The findings of this study can help clinical staffs to early identify high-risk patients and improve the effectiveness of suicide prevention.

Young-aged woman with invasive ductal carcinoma arising in atypical microglandular adenosis: a case report.

Microglandular adenosis (MGA) and atypical microglandular adenosis (AMGA) are extremely rare and unique forms of adenosis of the breast. Both forms of adenosis are strongly associated with carcinoma arising in microglandular adenosis (MGACA) and are recognised as precursor lesions of invasive breast carcinoma. Here we provide a clinical report of a young Taiwanese woman who was diagnosed with MGACA and AMGA by means of echo-guided core biopsy. The subsequent lumpectomy revealed a spectrum of lesions ranging from MGA and AMGA to ductal carcinoma in situ (DCIS) and invasive carcinoma. All of the above lesions have similar immunohistochemical results (expression of S-100 protein, the absence of oestrogen receptors, progesterone receptors and Her2/neu, and the lack of p63 and the smooth muscle myosin-heavy chain) with a rather different Ki-67 labelling proliferation index. This report is of practical interest because the diagnosis of AMGA and MGACA had already been made via needle biopsy.

Pneumothorax after central venous cannulation via the infraclavicular axillary vein--a case report.

It has ever been reported that central venous cannulation via the infraclavicular axillary vein (IAV) could cause pneumothorax. However, recently at our hospital, a 66-year-old female patient undergoing craniectomy for brain tumor sustained pneumothorax after cannulation of the IAV for intraoperate monitoring. The complication was not recognized until a postoperative chest X-ray had been taken. The departmental panel on morbidity reviewed the anatomy of the infraclavicular area to explore the possible causes of the incident. As to prevention of pneumothorax, we also bring forward some important points for discussion that have not been discoursed in previous reports.