ABSTRACT
Etoposide (VP16) is a topoisomerase II inhibitor and has been used for the treatment of non-small cell lung cancer (NSCLC). Xeroderma pigmentosum complementation group C (XPC) protein is a DNA damage recognition factor in nucleotide excision repair and involved in regulating NSCLC cell proliferation and viability. Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. In this study, we report whether Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) enhanced etoposide-induced cytotoxicity in NSCLC cells through modulating the XPC expression. We found that etoposide increased XPC expression in an AKT activation manner in 2 squamous cell carcinoma H1703 and H520 cells. Knockdown of XPC using siRNA or inactivation of AKT by pharmacological inhibitor PI3K inhibitor (LY294002) enhanced the cytotoxic effects of etoposide. In contrast, enforced expression of XPC cDNA or AKT-CA (a constitutively active form of AKT) reduced the cytotoxicity and cell growth inhibition of etoposide. Hsp90 inhibitor 17-AAG enhanced cytotoxicity and cell growth inhibition of etoposide in NSCLC cells, which were associated with the downregulation of XPC expression and inactivation of AKT. Our findings suggested that the Hsp90 inhibition induced XPC downregulation involved in enhancing the etoposide-induced cytotoxicity in H1703 and H520 cells.
Subject(s)
Benzoquinones/pharmacology , Etoposide/pharmacology , Lactams, Macrocyclic/pharmacology , Xeroderma Pigmentosum/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chromones/pharmacology , Down-Regulation/drug effects , Drug Synergism , Humans , Morpholines/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , RNA, Small Interfering/pharmacologyABSTRACT
BACKGROUND: A brief but comprehensive TB elimination program began in a remote region of Taiwan in 1997 involving five contiguous villages (n=2308). METHODS: An aggressive intervention included tuberculin skin testing and treatment of latent TB infection. Normal program data was collected and later analyzed forming the basis of an operational research study. RESULTS: An initial 31% reduction in active TB cases (81 to 56 over 4 years) (p=0.033) was observed and persisted until the end of the 10-year follow-up period despite no further intervention. In the control population, no sustained reduction of TB was noted for the same period. CONCLUSIONS: Although encouraging, a more robust study is needed to reasonably attribute the persistence of this significantly lower TB rate to this brief intensive intervention.
Subject(s)
Antitubercular Agents/therapeutic use , Directly Observed Therapy , Tuberculosis/prevention & control , Follow-Up Studies , Humans , Latent Tuberculosis , Rural Population , Taiwan , Time Factors , Tuberculin Test , Tuberculosis/drug therapy , Tuberculosis/transmissionABSTRACT
This study used Medicare Part B claims and enrollment data to estimate the prevalence of macular disease in Kansas at county and area levels. Spatial analysis by aggregated county clusters was assessed with standardized prevalence ratios and 95% confidence intervals, and a thematic map was produced to illustrate geographic distribution. A total of 17888 unduplicated claims were identified among 335132 beneficiaries older than age 64 years. Compared with the state prevalence of 5.34%, the central agricultural area showed a disproportionately high macular disease prevalence.
