American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Sep 2019
Driver Mutations in Normal Airway Epithelium Elucidate Spatiotemporal Resolution of Lung Cancer.
Rationale: Uninvolved normal-appearing airway epithelium has been shown to exhibit specific mutations characteristic of nearby non-small cell lung cancers (NSCLCs). Yet, its somatic mutational landscape in patients with early-stage NSCLC is unknown. Objectives: To comprehensively survey the somatic mutational architecture of the normal airway epithelium in patients with early-stage NSCLC. ⋯ Integrative analysis of single-nucleotide variants and allelic imbalance events revealed driver genes with shared "two-hit" alterations in the airway field (e.g., TP53, KRAS, KEAP1, STK11, and CDKN2A) and those with single hits progressing to two in the NSCLCs (e.g., PIK3CA and NOTCH1). Conclusions: Tumor-adjacent and tumor-distant normal-appearing airway epithelia exhibit somatic driver alterations that undergo selection-driven clonal expansion in NSCLC. These events offer spatiotemporal insights into the development of NSCLC and, thus, potential targets for early treatment.
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Am. J. Respir. Crit. Care Med. · Sep 2019
Unique Effect of Aspirin Therapy on Biomarkers in Aspirin-exacerbated Respiratory Disease. A Prospective Trial.
Rationale: Daily high-dose aspirin therapy benefits many patients with aspirin-exacerbated respiratory disease but provides no benefit for aspirin-tolerant patients with asthma. Type 2 inflammation characterizes aspirin-exacerbated respiratory disease. Objectives: To determine whether high-dose aspirin therapy changes biomarkers of type 2 inflammation in aspirin-exacerbated respiratory disease. ⋯ Aspirin had no effect on platelet-leukocyte aggregates, platelet activation markers, or plasma cytokines in either group. Conclusions: High-dose aspirin therapy for 8 weeks paradoxically increases markers of type 2 inflammation in subjects with aspirin-exacerbated respiratory disease, despite reducing nasal symptoms. This effect of aspirin is unique to aspirin-exacerbated respiratory disease and not observed in subjects with aspirin-tolerant asthma.
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Am. J. Respir. Crit. Care Med. · Sep 2019
A Genetic Risk Score Associated with COPD Susceptibility and Lung Structure on Computed Tomography.
Rationale: Chronic obstructive pulmonary disease (COPD) has been associated with numerous genetic variants, yet the extent to which its genetic risk is mediated by variation in lung structure remains unknown. Objectives: To characterize associations between a genetic risk score (GRS) associated with COPD susceptibility and lung structure on computed tomography (CT). Methods: We analyzed data from MESA Lung (Multi-Ethnic Study of Atherosclerosis Lung Study), a U. ⋯ Lung structure (P < 0.0001), but not the GRS (P > 0.10), improved discrimination of moderate-to-severe COPD cases relative to clinical factors alone. Conclusions: A GRS associated with COPD susceptibility was associated with CT lung structure. Lung structure may be an important mediator of heritability and determinant of personalized COPD risk.
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Am. J. Respir. Crit. Care Med. · Sep 2019
Synergistic Association of House Endotoxin Exposure and Ambient Air Pollution with Asthma Outcomes.
Rationale: House endotoxin and ambient air pollution are risk factors for asthma; however, the effects of their coexposure on asthma are not well characterized. Objectives: To examine potential synergistic associations of coexposure to house dust endotoxin and ambient air pollutants with asthma outcomes. Methods: We analyzed data of 6,488 participants in the National Health and Nutrition Examination Survey 2005-2006. ⋯ A synergistic association was also found for coexposure to higher concentrations of endotoxin and NO2 in children (OR, 3.45; 95% CI, 1.65-7.18). Conclusions: Coexposure to elevated concentrations of residential endotoxin and ambient PM2.5 in all participants and NO2 in children is synergistically associated with increased emergency room visits for asthma. Therefore, decreasing exposure to both endotoxin and air pollution may help reduce asthma morbidity.