Faculty Bibliography

Abstract Rationale: Metabolic syndrome, inflammatory and vascular injury markers measured in serum after World Trade Center (WTC) exposures predict abnormal FEV1. We hypothesized that elevated LPA levels predict FEV1 < LLN. Methods: Nested case-control study of WTC-exposed firefighters. Cases had FEV1 < LLN. Controls derived from the baseline cohort. Demographics, pulmonary function, serum lipids, LPA and ApoA1 were measured. Results: LPA and ApoA1 levels were higher in cases than controls and predictive of case status. LPA increased the odds by 13% while ApoA1 increased the odds by 29% of an FEV1 < LLN in a multivariable model. Conclusions: Elevated LPA and ApoA1 are predictive of a significantly increased risk of developing an FEV1 < LLN.

RATIONALE: After 9/11/2001, most FDNY workers had persistent lung function decline but some exposed workers recovered. We hypothesized that the protease/anti-protease balance in serum soon after exposure predicts subsequent recovery. METHOD: S: We performed a nested case-control study measuring biomarkers in serum drawn before 3/2002 and subsequent forced expiratory volume at one second (FEV1) on repeat spirometry before 3/2008. Serum was assayed for matrix metalloproteinases (MMP-1,2,3,7,8,9,12 and 13) and tissue inhibitors of metalloproteinases (TIMP-1,2,3,4). The representative sub-cohort defined analyte distribution and a concentration above 75th percentile defined elevated biomarker expression. Having an FEV1 one standard deviation above the mean defined resistance to airway injury. Logistic regression was adjusted for pre-9/11 FEV1, BMI, age and exposure intensity modeled the association between elevated biomarker expression and above average FEV1. RESULTS:: FEV1 in cases and controls declined 10% of after 9/11/2001. Cases subsequently returned to 99% of their pre-exposure FEV1 while decline persisted in controls. Elevated TIMP-1 and MMP-2 increased the odds of resistance by 5.4 and 4.2 fold while elevated MMP-1 decreased it by 0.27 fold. CONCLUSIONS:: Resistant cases displayed healing, returning to 99% of pre-exposure values. High TIMP-1 and MMP-2 predict healing. MMP/TIMP balance reflects independent pathways to airway injury and repair after WTC exposure.

Squamous cell carcinoma (SQ) of the lung causes approximately 400,000 deaths per year worldwide, and no specifically targeted treatments yet exist. We used the SOMAscan proteomic platform (which measures 1129 proteins with a median limit of detection of 40 fM and 5% CV) in a broad-based analysis of serum and tissue samples to gain insight into the distinctive drivers of SQ malignant growth. We discovered unique SQ markers and pathways that show early expression of invasion and metastasis signals. Strong SQ signals were revealed. Our multi-center serum study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smoker and benign pulmonary nodule controls resulted in the discovery of 60 lung cancer biomarkers and the development of a 7-marker diagnostic panel. This panel was validated in two independent cohorts. The AUC for detection of SQ carcinoma was 0.93 in training and 0.89 in the Univ. of Heidelberg validation set (56 SQ cases/27 benign nodule controls). Performance was confirmed with an AUC of 0.87 in an independent validation cohort assembled by the EDRN (25 SQ cases/20 benign nodules/52 smoker controls). This non-invasive test could be used as an adjunct to CT to detect rapidly growing SQ tumors that are disproportionately missed as interval cancers in CT screening studies. In addition, we analyzed 68 NSCLC tumor and matched non-tumor tissue lysates. This study consisted of 49 adenocarcinoma (AD) and 19 SQ tumors, 88% of which were Stage I or II. Proteomic comparisons of tumor/non-tumor or AD/SQ tissue samples performed using the Mann-Whitney test identified 79 tumor markers. Differences between tumor and non-tumor tissue were dominated by inflammatory, apoptotic and cell proliferation proteins. Just as we observed in the serum studies, the most common pattern was an increasing difference in protein levels from non tumor to AD to SQ. Of note, 24% of the proteins were only markers in SQ. These SQ-only markers are enriched for angiogenesis, cell proliferation and cell adhesion f!