Faculty Bibliography

BACKGROUND AND AIMS/OBJECTIVE:Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disorder that may complicate conditions such as obstructive airway disease. Our group has identified predictive biomarkers of GERD in particulate exposed first responders with obstructive airway disease. In addition, GERD diagnosis and treatment is costly and invasive. In light of these clinical concerns, we aimed to systematically review studies identifying noninvasive, multiOmic, and multicompartmental biomarkers of GERD. METHODS:A systematic review of PubMed and Embase was performed using keywords focusing on reflux disease and biomarkers and registered with PROSPERO. We included original human studies in English, articles focusing on noninvasive biomarkers of GERD published after December 31, 2009. GERD subtypes (non-erosive reflux disease and erosive esophagitis) and related conditions (Barrett's Esophagus [BE] and Esophageal Adenocarcinoma). Predictive measures were synthesized and risk of bias assessed (Newcastle-Ottawa Scale). RESULTS:0.94 (95% confidence interval; 0.85-1.00). CONCLUSION/CONCLUSIONS:Prior studies identified significant multiOmic, multicompartmental noninvasive biomarker risks for GERD and BE. However, studies have a high risk of bias and the reliability and accuracy of the biomarkers identified are greatly limited, which further highlights the need to discover and validate clinically relevant noninvasive biomarkers of GERD.

The use of electronic-cigarettes (e-cigs) has increased substantially in recent years, particularly among the younger generations. Liquid nicotine is the main component of e-cigs. Previous studies have shown that mice exposed to e-cig aerosols developed lung adenocarcinoma and bladder hyperplasia. These findings implicated a potential role for e-cig aerosols and nicotine in cancer development, although the underlying mechanisms are not fully understood. Here we report that exposure to liquid nicotine or nicotine aerosol generated from e-cig induces downregulation of Stem-loop binding protein (SLBP) and polyadenylation of canonical histone mRNAs in human bronchial epithelial cells and in mice lungs. Canonical histone mRNAs typically do not end in a poly(A) tail and the acquisition of such a tail via depletion of SLBP has been shown to causes chromosome instability. We show that nicotine-induced SLBP depletion is reversed by an inhibitor of α7-nicotinic acetylcholine receptors (α7-nAChR) or siRNA specific for α7-nAChR, indicating a nAChR-dependent reduction of SLBP by nicotine. Moreover, PI3K/AKT pathway is activated by nicotine exposure and CK2 and probably CDK1, two kinases well known for their function for SLBP phosphorylation and degradation, are shown to be involved, α7-nAChR-dependently, in nicotine-induced SLBP depletion. Importantly, nicotine-induced anchorage-independent cell growth is attenuated by inhibition of α7-nAChR and is rescued by overexpression of SLBP. We propose that the SLBP depletion and polyadenylation of canonical histone mRNAs via activation of α7-nAChR and a series of downstream signal transduction pathways, are critical for nicotine-induced cell transformation and potential carcinogenesis.

BACKGROUND:PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification. OBJECTIVES/OBJECTIVE:The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort. METHODS:Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death. RESULTS:A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH. CONCLUSIONS:PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification. (Pulmonary Vascular Disease Phenomics Program PVDOMICS [PVDOMICS]; NCT02980887).

The destruction of the World Trade Center (WTC) on September 11, 2001 (9/11) released large amounts of toxic dusts and fumes into the air that exposed many community members who lived and/or worked in the local area. Many community members, defined as WTC survivors by the federal government, developed lower respiratory symptoms (LRS). We previously reported the persistence of these symptoms in patients with normal spirometry despite treatment with inhaled corticosteroids and/or long-acting bronchodilators. This report expands upon our study of this group with the goal to identify molecular markers associated with exposure and heterogeneity in WTC survivors with LRS using a selected plasma biomarker approach. Samples from WTC survivors with LRS (n = 73, WTCS) and samples from healthy control participants of the NYU Bellevue Asthma Registry (NYUBAR, n = 55) were compared. WTCS provided information regarding WTC dust exposure intensity. Hierarchical clustering of the linear biomarker data identified two clusters within WTCS and two clusters within NYUBAR controls. Comparison of the WTCS clusters showed that one cluster had significantly increased levels of circulating matrix metalloproteinases (MMP1, 2, 3, 8, 12, 13), soluble inflammatory receptors (receptor for advanced glycation end-products-RAGE, Interleukin-1 receptor antagonist (IL-1RA), suppression of tumorigenicity (ST)2, triggering receptor expressed on myeloid cells (TREM)1, IL-6Ra, tumor necrosis factor (TNF)RI, TNFRII), and chemokines (IL-8, CC chemokine ligand- CCL17). Furthermore, this WTCS cluster was associated with WTC exposure variables, ash at work, and the participant category workers; but not with the exposure variable WTC dust cloud at 9/11. A comparison of WTC exposure categorial variables identified that chemokines (CCL17, CCL11), circulating receptors (RAGE, TREM1), MMPs (MMP3, MMP12), and vascular markers (Angiogenin, vascular cell adhesion molecule-VCAM1) significantly increased in the more exposed groups. Circulating biomarkers of remodeling and inflammation identified clusters within WTCS and were associated with WTC exposure.