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Background: Diesel engine exhaust (DEE) is classified as a Group 1 human carcinogen by the International Agency for Research on Cancer because of its carcinogenicity to the lung. However, the underlying molecular mechanisms of DEE carcinogenicity are not well understood. Methods: We previously conducted a cross-sectional molecular epidemiology study of diesel engine factory workers exposed to a wide range of DEE and unexposed comparable controls. Here, we carried out a pilot study of a representative subgroup of 19 exposed workers (total n = 54) and 19 unexposed controls (total n = 55). We measured serum level of 1238 targeted proteins using the SOMAScan assay (SOMALogic, Boulder, CA), which measures protein involved in a wide range of biological processes. We used linear regression to identify proteins associated with DEE (permutation p-value Results: Occupational exposure to DEE was significantly associated with altered levels of 22 serum proteins. Of these, 13 proteins (CXCL11, HAPLN1, FLT4, CD40LG, PES1, IGHE.IGK..IGL, TNFSF9, PGD, NAGK, CCL25, CCL4L1, PDXK, and PLA2G1B) showed a significant exposure-response relationship with EC (p-trend Conclusion: Results from our pilot study suggest that DEE exposure is associated with alteration of multiple proteins in the serum, which play a role in inflammation and immune regulation. Analysis of a larger sample size will be needed to confirm our findings. Citation Format: Mohammad L. Rahman, Yufei Dai, Roel Vermeulen, Wei Hu, Bryan Bassig, Eduard Drizik, Sean Corbett, Dianzhi Ren, Huawei Duan, Yong Niu, Jun Xu, Wei Fu, Kees Meliefste, Baosen Zhou, Xiaohui Zhang, Jufang Yang, Hanqiao Liu, Meng Ye, Gang Liu, Xiaowei Jia, Tao Meng, Ping Bin, Avrum Spira, Marc E. Lenburg, Debra Silverman, Nathaniel Rothman, Yuxin Zheng, Qing Lan. Proteomic analysis of serum in workers exposed to diesel engine exhaust [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 856.

523 Background: The Oncotype-DX recurrence score (RS) allows providers to identify hormone receptor positive and HER2-negative breast cancer (BC) patients that may benefit from adjuvant chemotherapy (AC). The TAILORx Trial showed no benefit of AC among patients with RS of 11-25, except for patients younger than 50 years. There are, however, limited studies examining any benefit of AC among those with RS of 26-30. We sought to examine the effect of AC on BC-specific survival among these patients utilizing a national database. Methods: We queried the Surveillance, Epidemiology, and End Results database for newly diagnosed female BC patients between 2010-2015. We included patients with T1-T3, hormone receptor positive, HER2-negative, and lymph node-negative BC with RS of 26-30. Patients with tumors 5 mm or less and with incomplete records were excluded. Cox Proportional-Hazards Model was done to examine the effect of AC on BC-specific survival. A sub-group analysis was performed for patients younger than 50 years to examine the effect of AC on BC-specific survival. Results: We included 2,982 patients, of whom 1,686 (56.5%) received AC. Administration of AC was associated with lower age (56.5 [9.2] vs 61.8 [9.7], p < 0.001), Grade III&IV (39.7% vs 30.2%, p < 0.001), married or patients with partners (66.5% vs 61.5%, p < 0.001), and T stage > 1 (31.3% vs 26.8%, p = 0.03). AC was not associated with insurance status, race, and histology. Overall 5-year BC-specific survival was 97.3% (96.2-98.3%). After adjustment through cox regression, AC was found to not have an effect on survival (HR: 0.54 [0.27-1.10], p = 0.09). There were 579 (19.4%) patients that were younger than 50 years, and AC did not have an effect on survival among these patients (HR: 0.44 [0.08-2.44], p = 0.35). Similarly, among the 2,403 (80.6%) patients aged 50 or older, AC did not have an effect on survival (HR: 0.49 [0.22-1.11], p = 0.09). Conclusions: In this retrospective analysis, administration of AC was associated with lower age, higher grade, marital status, and T stage. AC did not affect BC-specific survival among patients with a RS of 26-30. Subgroup analysis did not show any benefit of AC among patients younger than 50 years or among those 50 or older. Further prospective randomized trials are warranted to identify sub-groups that may potentially benefit from AC.

Background: Diesel engine exhaust (DEE) exposure causes lung cancer, but the molecular mechanisms by which this occurs are not well understood. Objectives: To assess transcriptomic alterations in nasal epithelium of DEE-exposed factory workers to better understand the cellular and molecular effects of DEE. Methods: Nasal epithelial brushings were obtained from 41 diesel engine factory workers exposed to relatively high levels of DEE (17.2–105.4 μg/m3), and 38 unexposed workers from factories without DEE exposure. mRNA was profiled for gene expression using Affymetrix microarrays. Linear modeling was used to identify differentially expressed genes associated with DEE exposure and interaction effects with current smoking status. Pathway enrichment among differentially expressed genes was assessed using EnrichR. Gene Set Enrichment Analysis (GSEA) was used to compare gene expression patterns between datasets. Results: 225 genes had expression associated with DEE exposure after adjusting for smoking status (FDR q

Little evidence is available regarding the physiological effects of exposure to electronic cigarette (ECIG) aerosol. We sought to determine the molecular impact of ECIG aerosol exposure in human bronchial epithelial cells (HBECs). Gene-expression profiling was conducted in primary grown at air liquid interface and exposed to 1 of 4 different ECIG aerosols, traditional tobacco cigarette (TCIG) smoke, or clean air. Findings were validated experimentally with quantitative polymerase chain reaction and a reactive oxygen species immunoassay. Using gene set enrichment analysis, signatures of in vitro ECIG exposure were compared with those generated from bronchial epithelial brushings of current TCIG smokers and former TCIG smokers currently using ECIGs. We found 546 genes differentially expressed across the ECIG, TCIG, and air-exposed groups of HBECs (ANOVA; FDR q 1.5). A subset of these changes were shared between TCIG- and ECIG-exposed HBECs. ECIG exposure induced genes involved in oxidative and xenobiotic stress pathways and increased a marker of reactive oxygen species production in a dose-dependent manner. ECIG exposure decreased expression of genes involved in cilia assembly and movement. Furthermore, gene-expression differences observed in vitro were concordant with differences observed in airway epithelium collected from ECIG users (q

Rationale: Recent epidemiological studies show that Diesel Engine Exhaust (DEE) exposure is associated with lung cancer, however the mechanism by which this occurs is not well understood. The goal of this study was to assess the transcriptomic alterations in the nasal epithelium of DEE exposed workers from factories where diesel engines are utilized. Methods: Nasal epithelium brushings were obtained from 41 subjects who work in a factory with DEE exposure, and 38 comparable control subjects who work in factories without any DEE exposure. The median Elemental Carbon (EC) levels of exposed individuals was 60.7μg/m3, with a range of 17.2-105.4 μg/m3, respectively. RNA was isolated from nasal epithelial cells, and profiled for gene expression using Affymetrix microarrays. Linear modeling was used to detect differential expression between DEE exposure and controls. Pathway enrichment in differentially expressed genes was assessed using GO Biological Process and KEGG terms via EnrichR. Results: We found 234 genes that were differentially expressed between samples derived from DEE exposed participants versus controls at FDR q < 0.25. Within this set of genes, we observed a higher expression of genes involved in oxidative stress response, as well as cell proliferation, cellular transcription, and regulation of apoptosis. In addition, we found that genes involved in ion transport, such as CFTR, were expressed at lower levels in DEE exposed samples. Conclusions: Chronic DEE exposure associates with changes in the airway transcriptome, with increased stress response as a major effect of DEE exposure. The transcriptomic alterations we identified may help provide insight into the underlying mechanisms of DEE carcinogenicity. Citation Format: Eduard I. Drizik, Sean Corbett, Roel Vermeulen, Yufei Dai, Wei Hu, Marc Lenburg, Dianzhi Ren, Huawei Duan, Yong Niu, Jun Xu, Wei Fu, Kees Meliefste, Baosen Zhou, JuFang Yang, Meng Ye, Xiaowei Jia, Tao Meng, Ping Bin, Yuxin Zheng, Debra Silverman, Nathaniel Rothman, Avrum Spira, Qing Lan. Impact of diesel engine exhaust exposure on the airway transcriptome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4256. doi:10.1158/1538-7445.AM2017-4256

Smoking is a significant risk factor for lung cancer, the leading cause of cancer-related deaths worldwide. Although microRNAs are regulators of many airway gene-expression changes induced by smoking, their role in modulating changes associated with lung cancer in these cells remains unknown. Here, we use next-generation sequencing of small RNAs in the airway to identify microRNA 4423 (miR-4423) as a primate-specific microRNA associated with lung cancer and expressed primarily in mucociliary epithelium. The endogenous expression of miR-4423 increases as bronchial epithelial cells undergo differentiation into mucociliary epithelium in vitro, and its overexpression during this process causes an increase in the number of ciliated cells. Furthermore, expression of miR-4423 is reduced in most lung tumors and in cytologically normal epithelium of the mainstem bronchus of smokers with lung cancer. In addition, ectopic expression of miR-4423 in a subset of lung cancer cell lines reduces their anchorage-independent growth and significantly decreases the size of the tumors formed in a mouse xenograft model. Consistent with these phenotypes, overexpression of miR-4423 induces a differentiated-like pattern of airway epithelium gene expression and reverses the expression of many genes that are altered in lung cancer. Together, our results indicate that miR-4423 is a regulator of airway epithelium differentiation and that the abrogation of its function contributes to lung carcinogenesis.

Electronic cigarettes (ECIGs) are an emerging alternative tobacco product thought by some to potentially be safer than traditional tobacco cigarettes (TCIGs). Despite the increasing prevalence of ECIG use, few studies have evaluated the potential physiological effects of ECIG exposure. In this study we aimed to determine the global gene expression effects of ECIG exposure on bronchial epithelium in vitro. Human bronchial epithelial cells (HBECs) grown at Air Liquid Interface (ALI) were exposed to TCIG smoke and ECIG vapor derived from tobacco or menthol flavored products with and without nicotine. We identified a number of gene expression alterations that were induced by both ECIG and TCIG exposure as well as a novel set of changes uniquely induced by ECIG exposure. ECIG exposure induced the expression of genes involved in oxidative and xenobiotic stress pathways and increased the production of reactive oxygen species, similar to, but generally lower in magnitude than, the effects of TCIGs. Furthermore, TCIG and ECIG exposure both decreased the expression of genes involved in cilia assembly and movement, suggesting that the integrity of the bronchial epithelium is concordantly impaired by both exposures. We additionally identified a number of ECIG-specific cell cycle and cell division pathway changes. Finally, we observed that ECIG-induced changes were dependent on both flavor and nicotine content. Together, these results indicate that ECIG vapor can induce cellular stress and molecular alterations within airway epithelium that share similarities with the effects of TCIG smoke. Based on these findings, further studies are warranted to determine whether ECIG use will lead to similar deleterious health outcomes as those caused by TCIGs. Citation Format: Elizabeth Moses, Teresa Wang, George R. Jackson, Sean Corbett, Eduard Drizik, Daniel Brooks, George O’Connor, Catalina Perdomo, Steven Dubinett, Patrick Hayden, Marc E. Lenburg, Avrum Spira. Molecular impact of in vitro exposure to electronic cigarette vapor in human bronchial epithelium. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4502.

BackgroundSeveral Chlamydia pneumoniae (Cp) biomarkers have been associated with asthma but Cp-specific IgE (Cp IgE) has not been investigated extensively. Our objective was to investigate Cp IgE in community adult asthma patients.Methods(1) Prevalence of Cp IgE (measured by immunoblotting) and Cp DNA (by polymerase chain reaction) in peripheral blood, and biomarker associations with asthma severity. (2) Case-control studies of Cp IgE association with asthma using healthy blood donor (study 1) and non-asthmatic clinic patient (study 2) controls.ResultsOf 66 asthma subjects (mean age 40.9 years, range 5-75, 59% male, 45% ever-smokers) 33 (50%) were Cp IgE positive and 16 (24%) were Cp DNA positive (P = 0.001 for association of Cp IgE and DNA). Cp IgE was detected in 21% of mild intermittent asthma v 79% of severe persistent asthma (test for trend over severity categories, P = 0.002). Cp IgE detection was significantly (P = 0.001) associated with asthma when compared to healthy blood donor controls but not when compared to clinic controls.ConclusionsHalf of this sample of community asthma patients had detectable IgE against C. pneumoniae. Cp IgE was strongly and positively associated with asthma severity and with asthma when healthy blood donor controls were used. These results support the inclusion of Cp IgE as a biomarker in future studies of infectious contributions to asthma pathogenesis.