Thymulin has been shown to present anti-inflammatory and anti-fibrotic properties in experimental lung diseases. We hypothesized that a biologically active thymulin analog gene, methionine serum thymus factor, delivered by highly compacted DNA nanoparticles composed of single molecule of plasmid DNA compacted with block copolymers of poly-l-lysine and polyethylene glycol (CK30PEG) that have been found safe in a human phase I clinical trial, may prevent lung inflammation and remodeling in a mouse model of allergic asthma. Thymulin plasmids were detected in the lungs of ovalbumin-challenged asthmatic mice up to 27 days after administration of DNA nanoparticles carrying thymulin plasmids. A single dose of DNA nanoparticles carrying thymulin plasmids prevented lung inflammation, collagen deposition and smooth muscle hypertrophy in the lungs of a murine model of ovalbumin-challenged allergic asthma, leading to improved lung mechanics. In the present model of chronic allergic asthma, highly compacted DNA nanoparticles using thymulin analog gene modulated the inflammatory and remodeling processes improving lung mechanics.

Aim: To show additional prognostic information about the mutational profile and new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification of adenocarcinoma (ADC) in patients without epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatments. Methods: In human lung ADC patients (n = 125), including 24 lepidic, 67 acinar, 23 papillary, and 11 solid predominant subtypes, EGFR and KRAS were sequenced, and anaplastic lymphoma kinase (ALK) rearrangements were screened using fluorescence in situ hybridization (FISH). Results:EGFR was mutated in 21.6% of patients with 19.57% showing a mean expression. The most frequent EGFR mutation was a deletion in exon 19, followed by an L858R amino acid substitution in exon 21. KRAS was mutated in 26.4% of patients with 50% displaying mean expression. ALK rearrangement was detected in 6 patients (4.8%). Predominant acinar ADC was strongly associated with EGFR and KRAS mutation. Clinical stage, lymph node metastases, and EGFR mutation in exon 18 showed a significant difference in disease-free and overall survival, but only a trend significance for EGFR and KRAS mutations. Multivariate analysis revealed that men aged >71 years, with a history of smoking (<72 packs/year), clinical stage I/II, and acinar histologic subtype presented better survival than women aged ≤71 years, with a history of smoking (>72 packs/year), and having a predominant solid ADC and EGFR mutation in exon 18. Conclusions: These results indicate that the mutational profile and new IASLC/ATS/ERS classification provide additional prognostic information about lung ADC.

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Context.— Identification of gene mutations that are indicative of epithelial-mesenchymal transition and a noninflammatory immune phenotype may be important for predicting response to immune checkpoint inhibitors. Objective.— To evaluate the utility of multiplex immunofluorescence for immune profiling and to determine the relationships among tumor immune checkpoint and epithelial-mesenchymal transition genomic profiles and the clinical outcomes of patients with nonmetastatic non–small cell lung cancer. Design.— Tissue microarrays containing 164 primary tumor specimens from patients with stages I to IIIA non–small cell lung carcinoma were examined by multiplex immunofluorescence and image analysis to determine the expression of programmed death ligand-1 (PD-L1) on malignant cells, CD68+ macrophages, and cells expressing the immune markers CD3, CD8, CD57, CD45RO, FOXP3, PD-1, and CD20. Immune phenotype data were tested for correlations with clinicopathologic characteristics, somatic and germline genetic variants, and outcome. Results.— A high percentage of PD-L1+ malignant cells was associated with clinicopathologic characteristics, and high density of CD3+PD-1+ T cells was associated with metastasis, suggesting that these phenotypes may be clinically useful to identify patients who will likely benefit from immunotherapy. We also found that ZEB2 mutations were a proxy for immunologic ignorance and immune tolerance microenvironments and may predict response to checkpoint inhibitors. A multivariate Cox regression model predicted a lower risk of death for patients with a high density of CD3+CD45RO+ memory T cells, carriers of allele G of CTLA4 variant rs231775, and those whose tumors do not have ZEB2 mutations. Conclusions.— Genetic variants in epithelial-mesenchymal transition and immune checkpoint genes are associated with immune cell profiles and may predict patient outcomes and response to immune checkpoint blockade.