Targeted Tissue and Cell-Free Tumor DNA Sequencing of Advanced Lung Squamous-Cell Carcinoma Reveals Clinically Significant Prevalence of Actionable Alterations

Background

Major guidelines do not recommend routine molecular profiling of lung squamous-cell carcinoma (LUSC) because the prevalence of actionable alterations is thought to be low. Increased utilization of next-generation sequencing (NGS), particularly with cell-free circulating tumor DNA, facilitates reevaluation of this premise.

Does Question Wording Predict Support for the Affordable Care Act? An Analysis of Polling During the Implementation Period, 2010–2016

The Patient Protection and Affordable Care Act (ACA) continues to be the subject of fierce political debate in the United States. Drawing on issue framing theory, together with research on wording effects in survey responding, we tested how common differences in the wording of ACA surveys relate to apparent public support for the law. We report on a content analysis of N = 376 U.S. national opinion surveys fielded during a more than six-year period, beginning 23 March 2010 (when President Obama signed the bill into law) and ending 8 November 2016 (Election Day), and use ordinary least squares (OLS) regression models to predict public support for the law as a function of variation in question wording. We coded questions gauging general sentiment toward the law for differences in issue labeling (e.g., Obamacare, Affordable Care Act), whether or not they referenced particular political entities (e.g., President Obama, Congress) or segments of the public (e.g., You, Your Family), various opinion metrics (e.g., Support, Favor), and different response options (e.g., Repeal, Expand) which we used to model aggregate levels of support. The results revealed several key differences in question wording—for example, generic references to the Healthcare Law were employed much more frequently than Obamacare or Affordable Care Act—a number of which reliably predicted aggregate levels of public support. The discussion considers possible explanations for these patterns and reiterates the value of attending to questionnaire design features when interpreting survey data about politically contentious health policy issues.     

Molecular composition of the alveolar lining fluid in the aging lung

As we age, there is an increased risk for the development of pulmonary diseases, including infections, but few studies have considered changes in lung surfactant and components of the innate immune system as contributing factors to the increased susceptibility of the elderly to succumb to infections. We and others have demonstrated that human alveolar lining fluid (ALF) components, such as surfactant protein (SP)-A, SP-D, complement protein C3, and alveolar hydrolases, play a significant innate immune role in controlling microbial infections. However, there is a lack of information regarding the effect of increasing age on the level and function of ALF components in the lung. Here we addressed this gap in knowledge by determining the levels of ALF components in the aging lung that are important in controlling infection. Our findings demonstrate that pro-inflammatory cytokines, surfactant proteins and lipids, and complement components are significantly altered in the aged lung in both mice and humans. Further, we show that the aging lung is a relatively oxidized environment. Our study provides new information on how the pulmonary environment in old age can potentially modify mucosal immune responses, thereby impacting pulmonary infections and other pulmonary diseases in the elderly population.     

Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition

Epithelial to mesenchymal transition (EMT) is a key process in embryonic development and has been associated with cancer metastasis and drug resistance. For example, in EGFR mutated non-small cell lung cancers (NSCLC), EMT has been associated with acquired resistance to the EGFR inhibitor erlotinib. Moreover, “EGFR-addicted” cancer cell lines induced to undergo EMT become erlotinib-resistant in vitro. To identify potential therapeutic vulnerabilities specifically within these mesenchymal, erlotinib-resistant cells, we performed a small molecule screen of ~200 established anti-cancer agents using the EGFR mutant NSCLC HCC827 cell line and a corresponding mesenchymal derivative line. The mesenchymal cells were more resistant to most tested agents; however, a small number of agents showed selective growth inhibitory activity against the mesenchymal cells, with the most potent being the Abl/Src inhibitor, dasatinib. Analysis of the tyrosine phospho-proteome revealed several Src/FAK pathway kinases that were differentially phosphorylated in the mesenchymal cells, and RNAi depletion of the core Src/FAK pathway components in these mesenchymal cells caused apoptosis. These findings reveal a novel role for Src/FAK pathway kinases in drug resistance and identify dasatinib as a potential therapeutic for treatment of erlotinib resistance associated with EMT.