Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial that was conducted in China, we randomly assigned 841 patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate) severity to receive a once-daily inhaled dose (18 µg) of tiotropium (419 patients) or matching placebo (422) for 2 years. The primary end point was the between-group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second (FEV1) before bronchodilator use. Secondary end points included the between-group difference in the change from baseline to 24 months in the FEV1 after bronchodilator use and the between-group difference in the annual decline in the FEV1 before and after bronchodilator use from day 30 to month 24. RESULTS: Of 841 patients who underwent randomization, 388 patients in the tiotropium group and 383 in the placebo group were included in the full analysis set. The FEV1 in patients who received tiotropium was higher than in those who received placebo throughout the trial (ranges of mean differences, 127 to 169 ml before bronchodilator use and 71 to 133 ml after bronchodilator use; P<0.001 for all comparisons). There was no significant amelioration of the mean (±SE) annual decline in the FEV1 before bronchodilator use: the decline was 38±6 ml per year in the tiotropium group and 53±6 ml per year in the placebo group (difference, 15 ml per year; 95% confidence interval [CI], -1 to 31; P=0.06). In contrast, the annual decline in the FEV1 after bronchodilator use was significantly less in the tiotropium group than in the placebo group (29±5 ml per year vs. 51±6 ml per year; difference, 22 ml per year [95% CI, 6 to 37]; P=0.006). The incidence of adverse events was generally similar in the two groups. CONCLUSIONS: Tiotropium resulted in a higher FEV1 than placebo at 24 months and ameliorated the annual decline in the FEV1 after bronchodilator use in patients with COPD of GOLD stage 1 or 2. (Funded by Boehringer Ingelheim and others; Tie-COPD ClinicalTrials.gov number, NCT01455129 .).

Sex-Determining Region Y-box 2 Promotes Growth of Lung Squamous Cell Carcinoma and Directly Targets Cyclin D1.

Sex-determining region Y-box 2 (SOX2) is an oncogene known to be amplified and overexpressed in various human malignancies, including lung squamous cell carcinoma (SCC). However, the role played by SOX2 in lung SCC development remains to be elucidated. We measured the levels of SOX2 and cyclin D1 mRNA and protein expression in lung SCC tissues and a lung SCC cell line, and found that both levels were dramatically upregulated in specimens of lung SCC tissue when compared with their expression levels in samples of adjacent nonneoplastic tissue. The lung SCC cell line also showed higher levels of SOX2 and cyclin D1 expression than a normal human bronchial epithelium cell line. After using RNA interference to knock down SOX2 expression in NCI-H520 lung SCC cells, their proliferation was reduced. Furthermore, overexpression of SOX2 promoted the proliferation of normal human bronchial epithelium cells. To further determine whether cyclin D1 was downstream target gene of SOX2, we measured the levels of cyclin D1 expression that occurred when SOX2 was knocked down or overexpressed. SOX2 knockdown significantly decreased the levels of cyclin D1 mRNA and protein expression, while SOX2 overexpression upregulated the levels of cyclin D1. We used bioinformatics data to identify potential cyclin D1 promoter binding sites for SOX2. Results of luciferase reporter assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation assays confirmed that cyclin D1 was a direct target of transcription factor SOX2 in human lung SCC cells.