Suicide attempts and death among heroin-involved women seeking methadone treatment in Taiwan.

BACKGROUND: The present study aims to profile the hazard fluctuation of suicide attempts and deaths among heroin-involved women seeking methadone maintenance treatment (MMT) and to investigate sociodemographic and clinical factors predicting the time to have suicidal behaviors. METHODS: We identified a retrospective cohort comprising 2780 women receiving methadone treatment in the period of 2012-2016. Healthcare records were obtained from Taiwan's National Health Insurance Research Database, and suicide deaths were ascertained from the national death register. Competing risk survival analyses were used to estimate the risk of suicide attempts and deaths within one year and three years of MMT enrollment. RESULTS: A total of 1.2 % of MMT-treated women ever visited hospital for suicide attempt, and 0.5 % died by confirmed suicide. The risk of treated suicide attempt reached its peak at the end of the 8th month after methadone initiation, whereas the risk of confirmed suicide death was relatively stable during the first one and a half years. A history of treated depressive disorders appears to be the strongest risk predictor for treated suicide attempts (Adjusted Hazard Ratio [aHR] = 3.45; 95 % CI = 1.66-7.19) and confirmed suicide death (aHR = 3.47; 95 % CI = 1.20-10.0). Retaining in methadone treatment may significantly lower the hazard of probable suicide death by 52 %. CONCLUSIONS: Women with heroin use disorders should receive careful attention for suicide risk at intake assessment and over the course of treatment and recovery. Preventive strategies should target unmet clinical and social needs and evaluate gender-specific barriers for treatment engagement.

Statin inhibits large hepatitis delta antigen-Smad3 -twist-mediated epithelial-to-mesenchymal transition and hepatitis D virus secretion.

BACKGROUND: Hepatitis D virus (HDV) infection may induce fulminant hepatitis in chronic hepatitis B patients (CHB) or rapid progression of CHB to cirrhosis or hepatocellular carcinoma. There is no effective treatment for HDV infection. HDV encodes small delta antigens (S-HDAg) and large delta antigens (L-HDAg). S-HDAg is essential for HDV replication. Prenylated L-HDAg plays a key role in HDV assembly. Previous studies indicate that L-HDAg transactivates transforming growth factor beta (TGF-ß) and induces epithelial-mesenchymal transition (EMT), possibly leading to liver fibrosis. However, the mechanism is unclear. METHODS: The mechanisms of the activation of Twist promoter by L-HDAg were investigated by luciferase reporter assay, chromatin immunoprecipitation, and co-immunoprecipitation analysis. ELISA and Western blotting were used to analyze L-HDAg prenylation, TGF-ß secretion, expression of EMT markers, and to evaluate efficacy of statins for HDV treatment. RESULTS: We found that L-HDAg activated Twist expression, TGF-ß expression and consequently induced EMT, based on its interaction with Smad3 on Twist promoter. The treatment of statin, a prenylation inhibitor, resulted in reduction of Twist promoter activity, TGF-ß expression, and EMT, and reduces the release of HDV virions into the culture medium. CONCLUSIONS: We demonstrate that L-HDAg activates EMT via Twist and TGF-ß activation. Treatment with statins suppressed Twist expression, and TGF-ß secretion, leading to downregulation of EMT. Our findings clarify the mechanism of HDV-induced EMT, and provide a basis for possible novel therapeutic strategies against HDV infection.

Interaction of glycosphingolipids GD3 and GD2 with growth factor receptors maintains breast cancer stem cell phenotype.

Many studies have suggested that disialogangliosides, GD2 and GD3, are involved in the development of various tumor types. However, the functional relationships between ganglioside expression and cancer development or aggressiveness are not fully described. GD3 is upregulated in approximately half of all invasive ductal breast carcinoma cases, and enhanced expression of GD3 synthase (GD3S, alpha-N-acetylneuraminide alpha-2,8-sialyltransferase) in estrogen receptor-negative breast tumors, was shown to correlate with reduced overall patient survival. We previously found that GD2 and GD3, together with their common upstream glycosyltransferases, GD3S and GD2/GM2 synthase, maintain a stem cell phenotype in breast cancer stem cells (CSCs). In the current study, we demonstrate that GD3S alone can sustain CSC properties and also promote malignant cancer properties. Using MALDI-MS and flow cytometry, we found that breast cancer cell lines, of various subtypes with or without ectopic GD3S-expression, exhibited distinct GD2/GD3 expression profiles. Furthermore, we found that GD3 was associated with EGFR and activated EGFR signaling in both breast CSCs and breast cancer cell lines. In addition, GD3S knockdown enhanced cytotoxicity of the EGFR-inhibitor gefitinib in resistant MDA-MB468 cells, both in vitro and in vivo. Based on this evidence, we propose that GD3S contributes to gefitinib-resistance in EGFR-positive breast cancer cells and may be an effective therapeutic target in drug-resistant breast cancers.