Lei Duan

Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway has been considered a novel therapeutic strategy to treat human cancers with constitutively active STAT3. In this study, we report the identification of niclosamide, an FDA-approved anthelmintic drug, as a new small-molecule inhibitor of the STAT3 signaling pathway. This compound potently inhibited the activation and transcriptional function of STAT3 and consequently induced cell growth inhibition, apoptosis, and cell cycle arrest of cancer cells with constitutively active STAT3. Our study provides a new promising lead compound with a salicylic amide scaffold for the development of STAT3 pathway inhibitors as novel molecularly targeted anticancer drugs.

Ligand-induced down-regulation controls the signaling potency of the epidermal growth factor receptor (EGFR/ErbB1). Overexpression studies have identified Cbl-mediated ubiquitinylation of EGFR as a mechanism of ligand-induced EGFR down-regulation. However, the role of endogenous Cbl in EGFR down-regulation and the precise step in the endocytic pathway regulated by Cbl remain unclear. Using Cbl-/- mouse embryonic fibroblast cell lines, we demonstrate that endogenous Cbl is essential for ligand-induced ubiquitinylation and efficient degradation of EGFR. Further analyses using Chinese hamster ovary cells with a temperature-sensitive defect in ubiquitinylation confirm a crucial role of the ubiquitin machinery in Cbl-mediated EGFR degradation. However, internalization into early endosomes did not require Cbl function or an intact ubiquitin pathway. Confocal immunolocalization studies indicated that Cbl-dependent ubiquitinylation plays a critical role at the early endosome to late endosome/lysosome sorting step of EGFR down-regulation. These findings establish Cbl as the major endogenous ubiquitin ligase responsible for EGFR degradation, and show that the critical role of Cbl-mediated ubiquitinylation is at the level of endosomal sorting, rather than at the level of internalization.

OBJECTIVE: To evaluate disparities in substance abuse treatment completion between and within racial and ethnic groups in publicly funded treatment in Los Angeles County, California. DATA SOURCE: The Los Angeles County Participant Reporting System with multicross-sectional annual data (2006-2009) for adult participants (n = 16,637) who received treatment from publicly funded programs (n = 276) for the first time. STUDY DESIGN: Retrospective analyses of county discharge and admission data. Hierarchical linear regressions models were used to test the hypotheses. DATA COLLECTION: Client data were collected during personal interviews at admission and discharge for most participants. PRINCIPAL FINDINGS: African Americans and Latinos reported lower odds of completing treatment compared with Whites. Within-group analysis revealed significant heterogeneity within racial and ethnic groups, highlighting primary drug problem, days of drug use before admission, and homelessness as significant factors affecting treatment completion. Service factors, such as referral by the criminal justice system, enabled completion among Latinos and Whites only. CONCLUSIONS: These findings have implications for reducing health disparities among members of racial and ethnic minorities by identifying individual and service factors associated with treatment adherence, particularly for first-time clients.