Faculty Bibliography

First responders (FR) exposed to the World Trade Center (WTC) Ground Zero air over the first week after the 9/11 disaster have an increased heart disease incidence compared to unexposed FR and the general population. To test if WTC dusts were causative agents, rats were exposed to WTC dusts (under isoflurane [ISO] anesthesia) 2 h/day on 2 consecutive days; controls received air/ISO or air only. Hearts were collected 1, 30, 240, and 360 d post-exposure, left ventricle total RNA was extracted, and transcription profiles were obtained. The data showed that differentially expressed genes (DEG) for WTC vs. ISO rats did not reach any significance with a false discovery rate (FDR) < 0.05 at days 1, 30, and 240, indicating that the dusts did not impart effects beyond any from ISO. However, at day 360, 14 DEG with a low FDR were identified, reflecting potential long-term effects from WTC dust alone, and the majority of these DEG have been implicated as having an impact on heart functions. Furthermore, the functional gene set enrichment analysis (GSEA) data at day 360 showed that WTC dust could potentially impact the myocardial energy metabolism via PPAR signaling and heart valve development. This is the first study showing that WTC dust could significantly affect some genes that are associated with the heart/CV system, in the long term. Even > 20 years after the 9/11 disaster, this has potentially important implications for those FR exposed repeatedly at Ground Zero over the first week after the buildings collapsed.

Some observational studies suggested that heart failure (HF) is associated with increased risk of late-onset Alzheimer's disease (AD). On the other hand, a recently published Two-Sample Mendelian Randomization (2SMR) study was reported as inconclusive but the estimated odds ratios (ORs) were less than one indicating a potential causal association between genetically predicted HF and lowered risk of AD. Both HF and AD are quite common among elderly persons and frequently occur together resulting in a series of severe medical challenges and increased financial burden on healthcare. It is of great medical and financial interest to further investigate the statistical significance of the potential causal associations between genetically predicted HF and lowered risk of AD using large independent cohorts. To fill this important knowledge gap, the present study used the 2SMR method based on summary data from a recently published large genome-wide association study (GWAS) for AD on subjects with European ancestry. The 2SMR analysis provided statistically significant evidence of an association with ORs less than one between genetically predicted HF and late-onset AD (Inverse Variance Weighted, OR = 0.752, p = 0.004; MR Egger, OR = 0.546, p = 0.100; Weighted Median, OR = 0.757, p = 0.014). Further investigations of the significant associations between HF and late-onset AD, including specific genes related to the potential protective effect of HF-related medications on cognitive decline, are warranted.

Alzheimer's disease is the most common cause of dementia and the only illness among the top 10 causes of death for which there is no disease-modifying therapy. The failure rate of clinical trials is very high, in part due to the premature translation of successful results in transgenic mouse models to patients. Extensive evidence suggests that dysregulation of innate immunity and microglia/macrophages plays a key role in Alzheimer's disease pathogenesis. Activated resident microglia and peripheral macrophages can display protective or detrimental phenotypes depending on the stimulus and environment. Toll-like receptors (TLRs) are a family of innate immune regulators known to play an important role in governing the phenotypic status of microglia. We have shown in multiple transgenic Alzheimer's disease mouse models that harnessing innate immunity via TLR9 agonist CpG oligodeoxynucleotides (ODNs) modulates age-related defects associated with immune cells and safely reduces amyloid plaques, oligomeric amyloid-β, tau pathology, and cerebral amyloid angiopathy (CAA) while promoting cognitive benefits. In the current study we have used a non-human primate model of sporadic Alzheimer's disease pathology that develops extensive CAA-elderly squirrel monkeys. The major complications in current immunotherapeutic trials for Alzheimer's disease are amyloid-related imaging abnormalities, which are linked to the presence and extent of CAA; hence, the prominence of CAA in elderly squirrel monkeys makes them a valuable model for studying the safety of the CpG ODN-based concept of immunomodulation. We demonstrate that long-term use of Class B CpG ODN 2006 induces a favourable degree of innate immunity stimulation without producing excessive or sustained inflammation, resulting in efficient amelioration of both CAA and tau Alzheimer's disease-related pathologies in association with behavioural improvements and in the absence of microhaemorrhages in aged elderly squirrel monkeys. CpG ODN 2006 has been well established in numerous human trials for a variety of diseases. The present evidence together with our earlier, extensive preclinical research, validates the beneficial therapeutic outcomes and safety of this innovative immunomodulatory approach, increasing the likelihood of CpG ODN therapeutic efficacy in future clinical trials.

The destruction of World Trade Center on 11 September 2001 exposed local community members to a complex mixture of known carcinogens and potentially carcinogenic substances. To date, breast cancer has not been characterized in detail in the WTC-exposed civilian populations. The cancer characteristics of breast cancer patients were derived from the newly developed Pan-Cancer Database at the WTC Environmental Health Center (WTC EHC). We used the Surveillance, Epidemiology, and End Results (SEER) Program breast cancer data as a reference source. Between May 2002 and 31 December 2019, 2840 persons were diagnosed with any type of cancer at the WTC EHC, including 601 patients with a primary breast cancer diagnosis (592 women and 9 men). There was a higher proportion of grade 3 (poorly differentiated) tumors (34%) among the WTC EHC female breast cancers compared to that of the SEER-18 data (25%). Compared to that of the SEER data, female breast cancers in the WTC EHC had a lower proportion of luminal A (88% and 65%, respectively), higher proportion of luminal B (13% and 15%, respectively), and HER-2-enriched (5.5% and 7%, respectively) subtypes. These findings suggest considerable differences in the breast cancer characteristics and distribution of breast cancer intrinsic subtypes in the WTC-exposed civilian population compared to that of the general population. This is important because of the known effect of molecular subtypes on breast cancer prognosis.

A diagnosis of late stage melanoma is associated with significant mortality. From a public health perspective, knowledge of geographic disparities in late-stage diagnoses can inform efforts to facilitate the diagnosis of earlier stage, highly curable melanomas. We conducted a county-level analysis of melanoma in New York State to identify communities that may benefit from pilot health interventions to reduce the burden of late stage melanoma. From 1995 to 2016, late-stage melanoma incidence increased from 1.5 to 2.8 cases/100,000 in NY State. We found statistically significant associations between decreased county-level health system access (including physician density and resident educational status), and increased county incidence and proportion of late-stage disease among diagnosed cases (p<0.001 for both). Increased county-level socioeconomic status (SES), (including measures of resident wealth and medical insurance status), was positively associated with greater late-stage incidence (p<0.001). However, decreased county-level SES was positively associated with a greater proportion of late-stage disease among cases at diagnosis (p=0.009). Counties with reduced access to physician services and lower SES may be suitable for pilot interventions promoting recognition and diagnosis of early stage melanomas to reduce late stage diagnoses and associated mortality.

Introduction: Exertional respiratory symptoms are prominent in patients with environmental lung injury following inhalation of World Trade Center dust. Baseline pulmonary function testing in these patients is frequently normal, leaving symptoms unexplained. Although small airway dysfunction has been identified at rest, its role in producing exertional symptoms is unclear. In this study exercise evaluation with assessment of airway function was employed to uncover mechanisms for exertional dyspnea.
Method(s): 27 subjects were studied: 20 with unexplained dyspnea (normal spirometry) and 6 asymptomatic controls. Baseline pulmonary function testing was conducted along with respiratory oscillometry to assess small airway function. An incremental exercise protocol was performed that included a focused evaluation of airway function: (1) examination of tidal flow vs. volume curves during exercise to assess for dynamic hyperinflation and expiratory flow limitation; and (2) airway reactivity post-exercise using spirometry and oscillometry. Baseline: By design spirometry values were within normal limits in all subjects. Symptomatic individuals tended to have greater mean R5, R20, R5-20, and AX at baseline compared with asymptomatic controls (R5: 4.80+/-1.79 vs. 3.66+/-1.06; R20: 3.52+/-1.12 vs. 2.98+/-0.68; R5-20: 1.28+/-1.02 vs. 0.70+/-0.53; AX: 13.44+/-10.74 vs. 5.48+/-5.21). Exercise: Dyspnea was reproduced with exercise in symptomatic subjects (mean Borg dyspnea score 1.38+/-1.48 at baseline, 4.20+/-2.28 at peak exercise). Asymptomatic controls did not report significant dyspnea (mean Borg dyspnea score 0 at baseline, 1.60+/-1.14 at peak exercise). Expiratory flow limitation during exercise was noted in 13/20 symptomatic subjects compared with 0 controls. Post Exercise: Bronchial hyper-reactivity was evident in post-exercise spirometry (>10% decline in FEV1) in 3/20 symptomatic subjects vs. 1/6 controls; the fall in FEV1 was predominantly attributable to a fall in FVC, consistent with small airway dysfunction. An additional six symptomatic subjects demonstrated isolated small airway hyper-reactivity that was only revealed on oscillometry.
Conclusion(s): In patients with unexplained dyspnea and normal spirometry, symptoms were reproduced during exercise. Focused airway assessment uncovered small airway dysfunction both during and following exercise that contributed to the development of dyspnea

With recent advancement in cancer screening and treatment, many patients with cancers are identified at early stage and clinically cured. Importantly, uncured patients should be treated timely before the cancer progresses to advanced stages for which therapeutic options are rather limited. It is also crucial to identify uncured subjects among patients with early-stage cancers for clinical trials to develop effective adjuvant therapies. Thus, it is of interest to develop statistical predictive models with as high accuracy as possible in predicting the latent cure status. The receiver operating characteristic curve (ROC) and the area under the ROC curve (AUC) are among the most widely used statistical metrics for assessing predictive accuracy or discriminatory power for a dichotomous outcome (cured/uncured). Yet the conventional AUC cannot be directly used due to incompletely observed cure status. In this article, we proposed new estimates of the ROC curve and its AUC for predicting latent cure status in Cox proportional hazards (PH) cure models and transformation cure models. We developed explicit formulas to estimate sensitivity, specificity, the ROC and its AUC without requiring to know the patient cure status. We also developed EM type estimates to approximate sensitivity, specificity, ROC and AUC conditional on observed data. Numerical studies were used to assess their finite-sample performance of the proposed methods. Both methods are consistent and have similar efficiency as shown in our numerical studies. A melanoma dataset was used to demonstrate the utility of the proposed estimates of the ROC curve for the latent cure status. We also have developed an [Formula: see text] package called [Formula: see text] to efficiently compute the proposed estimates.