Limited information is available about epigenetic mechanisms by which cigarette smoke enhances the initiation and progression of lung cancer. To examine this issue, A549 and Calu-6 lung cancer cells were cultured in normal media with or without tobacco smoke condensate (TSC) under clinically relevant exposure conditions. Ten-day TSC exposure dramatically increased the tumorigenicity of lung cancer cells in nude mice. Microarray and quantitative reverse transcription-PCR (RT-PCR) experiments revealed that this phenomenon coincided with diminished expression of Dickkopf-1 (Dkk-1). Western blot, chromatin immunoprecipitation, methylationspecific PCR, and pyrosequencing experiments showed that repression of Dkk-1 coincided with decreased H4K16Ac, increased H3K27me3, and recruitment of SirT1, EZH2, SUZ12, and Bmi1 without DNA hypermethylation within the Dkk-1 promoter despite prolonged TSC exposures. Removal of TSC from culture media resulted in loss of promoterassociated polycomb repressor complexes and reexpression of Dkk-1. siRNA-mediated knockdown of EZH2 and SirT1 partially abrogated TSC-mediated inhibition of Dkk-1 expression. Western blot and quantitative RT-PCR array experiments showed that TSC exposure as well as knockdown of Dkk-1 activated Wnt signaling and significantly up-regulated Wnt5a in lung cancer cells. Knockdown of Dkk-1 recapitulated the dramatic protumorigenic effects of TSC exposure in Calu-6 cells. Despite the transient nature of Dkk-1 repression following TSC exposure in vitro, Dkk-1 remained silenced in tumor xenografts derived from TSC-treated Calu-6 cells. Collectively, these data provide evidence that cigarette smoke directly engages polycomb machinery to activate a signaling network implicated in maintenance of cancer stem cells.
Novel transcriptional regulatory mechanisms involving Aurora kinase and survivin appear to contribute to cytotoxicity mediated by HDAC inhibitors in lung cancer cells.
Unlike penetrating abdominal injuries where the decision to operate is relatively straight forward, those combat casualties that sustain blunt abdominal trauma offer more of a diagnostic and clinical challenge. For unstable patients with a positive focused abdominal sonography in trauma or diagnostic peritoneal lavage, exploratory laparotomy should be undertaken immediately. All grade IV-V splenic injuries should undergo splenectomy, patients undergoing attempted splenic salvage should be monitored in the Role 3 facility and embolization of such splenic injuries may be considered if available. Patients who fail non-operative management of the spleen require splenectomy at the Role 3 prior to aeromedical evacuation. Overwhelming post-splenectomy infection is a serious disease that can progress from a mild flu-like illness to fulminant sepsis in a short period of time. Although relatively rare, it has a high mortality rate with delayed or inadequate treatment. All splenectomized patients and those deemed to be functionally asplenic should be vaccinated within 14 days from splenectomy and prior to aeromedical evacuation.
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