Application of continuous positive airway pressure (CPAP) as the standard treatment for sleep apnea/hypopnea syndrome (SAHS) is a moot point. Studies on the effectiveness of this treatment have been challenged because of the lack of a suitable placebo. The recent description of a true placebo (sham CPAP) prompted us to conduct a randomized trial of CPAP or placebo to assess the effectiveness of CPAP in improving SAHS-related symptoms and daytime function in patients with moderate to severe SAHS. Forty-eight patients, stratified in four groups according to severity, were randomly allocated into two treatment groups (optimal and sham CPAP) for a 6-wk period. Of these, 45 completed follow-up (91% males; age: 54 +/- 10 yr; body mass index [BMI]: 32 +/- 6 kg/m(2); apnea-hypopnea index [AHI]: 54 +/- 19 events/h; and Epworth Sleepiness Scale [ESS]: 16 +/- 5). The ESS, a questionnaire on SAHS-related symptoms, Functional Outcomes Sleep Questionnaire (FOSQ), and the Short Form Health Survey (SF-36) were completed at inclusion and after treatment. After 10 d of washout, the placebo group was treated with optimal CPAP and reassessed before and after optimal CPAP. The group receiving optimal CPAP when compared with the group with sham CPAP showed considerably greater improvement in the relief of sleepiness (-9.5 versus -2.3, p < 0.001), other SAHS-related symptoms (-18.5 versus -4.5, p < 0.001), vigilance (+8.5 versus +3.4, p = 0.009), and general productivity (+4.0 versus +0.5, p = 0.04) FOSQ scales. Both groups used a similar number of hours for the optimal and the sham CPAP (4.3 versus 4.5, (p = NS). The patients initially treated with placebo CPAP improved significantly more when optimal CPAP was applied for ESS (-2.3 versus -6.7, p < 0.001) and other sleep apnea syndrome (SAS)-related symptoms (-4.5 versus -11.2, p = 0.02). Our study provides strong evidence of the effectiveness of CPAP treatment in improving symptoms and perceived health status in moderate to severe SAHS.

SummaryDNA methylation profiling of TAFs reveals global demethylation and a selective impact on the TGF-β pathway. Moreover, it suggests the fibrocyte origin of a fraction of TAFs, and identifies a novel prognostic biomarker in non-small cell lung cancer.

The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non-small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal-or tumor-like stiffnesses at different serum concentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues of matrix rigidity were driven by b1 integrin mechanosensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in b1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC-TAFs exhibited higher FAK (pY397), b1 expression, and ERK1/2 (pT202/Y204) than ADCTAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC-TAFs (>50%) compared with ADC-TAFs (10%-20%). In contrast, SCC-TAFs were largely serum desensitized, whereas ADC-TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC-TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or b1 integrin-dependent mechano regulation may be effective against SCC-TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC-TAFs.Implications: This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells.