Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Toxic metal exposures have been associated with cardiovascular disease in adults and growing evidence suggests metal exposures also adversely affect cardiovascular phenotypes in childhood and adolescence. However, to our knowledge, the influence of perinatal metals exposure, particularly metal mixtures, in relation to cardiovascular-related outcomes have not been comprehensively reviewed. RECENT FINDINGS/RESULTS:We summarized 17 contemporary studies (2017-2021) that investigated the impact of perinatal metal exposures on measures of cardiovascular health in children. Accumulating evidence supports a potential adverse impact of perinatal Pb exposure on BP in children. Fewer recent studies have focused on perinatal As, Hg, and Cd; thus, the cardiovascular impacts of these metals are less clear. Studies of metal mixtures demonstrate that interactions between metals may be complex and have identified numerous understudied elements and essential metals, including Mo, Co, Ni, Se, Zn, and Mn, which may influence cardiovascular risk. A key question that remains is whether perinatal metals exposure influences cardiovascular health into adulthood. Comparisons across studies remain challenging due to several factors, including differences in the timing of exposure/outcome assessments and exposure biomarkers, as well as variability in exposure levels and mixture compositions across populations. Future studies longitudinally investigating trajectories of cardiovascular outcomes could help determine the influence of perinatal metals exposure on long-term effects of clinical relevance in later life and whether interventions, which reduce metals exposures during this key developmental window, could alter disease development.

The incidence of esophageal adenocarcinoma (EA) has drastically increased in the United States since 1970s for unclear reasons. We hypothesized that the widespread usage of antibiotics has increased the procarcinogenic potential of the orodigestive microbiota along the sequence of gastroesophageal reflux (GR), Barrett's esophagus (BE) and EA phenotypes. This case control study included normal controls (NC) and three disease phenotypes GR, BE and EA. Microbiota in the mouth, esophagus, and stomach, and rectum were analyzed using 16S rRNA gene sequencing. Overall, we discovered 44 significant pairwise differences in abundance of microbial taxa between the four phenotypes, with 12 differences in the mouth, 21 in the esophagus, two in the stomach, and nine in the rectum. Along the GR→BE→EA sequence, oral and esophageal microbiota were more diversified, the dominant genus Streptococcus was progressively depleted while six other genera Atopobium, Actinomyces, Veillonella, Ralstonia, Burkholderia and Lautropia progressively enriched. In NC, Streptococcus appeared to control populations of other genera in the foregut via numerous negative and positive connections, while in disease states, the rich network was markedly simplified. Inferred gene functional content showed a progressive enrichment through the stages of EA development in genes encoding antibiotic resistance, ligands of Toll-like and NOD-like receptors, nitrate-nitrite-nitric oxide pathway and acetaldehyde metabolism. The orodigestive microbiota is in a progressive dysbiotic state along the GR-BE-EA sequence. The increasing dysbiosis and antibiotic and procarcinogenic genes in the disease states warrants further study to define their roles in EA pathogenesis.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Recent studies have suggested that inter-eye differences (IEDs) in peripapillary retinal nerve fiber layer (pRNFL) or ganglion cell+inner plexiform (GCIPL) thickness by spectral-domain optical coherence tomography (SD-OCT) may identify people with a history of unilateral optic neuritis (ON). However, this requires further validation. Machine learning classification may be useful for validating thresholds for OCT IEDs and for examining added utility for visual function tests, such as low-contrast letter acuity (LCLA), in the diagnosis of people with multiple sclerosis (PwMS) and for unilateral ON history. METHODS:Participants were from 11 sites within the International Multiple Sclerosis Visual System (IMSVISUAL) consortium. pRNFL and GCIPL thicknesses were measured using SD-OCT. A composite score combining OCT and visual measures was compared individual measurements to determine the best model to distinguish PwMS from controls. These methods were also used to distinguish those with history of ON among PwMS. ROC curve analysis was performed on a training dataset (2/3 of cohort), then applied to a testing dataset (1/3 of cohort). Support vector machine (SVM) analysis was used to assess whether machine learning models improved diagnostic capability of OCT. RESULTS:Among 1,568 PwMS and 552 controls, variable selection models identified GCIPL IED, average GCIPL thickness (both eyes), and binocular 2.5% LCLA as most important for classifying PwMS vs. controls. This composite score performed best, with AUC=0.89 (95% CI 0.85, 0.93), sensitivity=81% and specificity=80%. The composite score ROC curve performed better than any of the individual measures from the model (p<0.0001). GCIPL IED remained the best single discriminator of unilateral ON history among PwMS (AUC=0.77, 95% CI 0.71,0.83, sensitivity=68%, specificity=77%). SVM analysis performed comparably to standard logistic regression models. CONCLUSIONS:A composite score combining visual structure and function improved the capacity of SD-OCT to distinguish PwMS from controls. GCIPL IED best distinguished those with history of unilateral ON. SVM performed as well as standard statistical models for these classifications. CLASSIFICATION OF EVIDENCE/METHODS:The study provides Class III evidence that SD-OCT accurately distinguishes multiple sclerosis from normal controls as compared to clinical criteria.

BACKGROUND:Neighborhood walkability (NW) has been linked to increased physical activity, which in turn is associated with lower concentrations of sex hormones and higher concentration of SHBG in women. However, no study has directly examined the association of NW with female sex hormone levels. OBJECTIVE:We conducted a cross-sectional study to evaluate the association between NW and circulating levels of sex hormones and SHBG in pre- and post-menopausal women. METHODS:We included 797 premenopausal and 618 postmenopausal women from the New York University Women's Health Study (NYUWHS) who were healthy controls in previous nested case-control studies in which sex hormones (androstenedione, testosterone, DHEAS, estradiol and estrone) and SHBG had been measured in serum at enrollment. Baseline residential addresses were geo-coded and the Built Environment and Health Neighborhood Walkability Index (BEH-NWI) was calculated. Generalized Estimating Equations were used to assess the association between BEH-NWI and sex hormone and SHBG concentrations adjusting for individual- and neighborhood-level factors. RESULTS:In premenopausal women, a one standard deviation (SD) increment in BEH-NWI was associated with a 3.5% (95% CI 0.9%-6.1%) lower DHEAS concentration. In postmenopausal women, a one SD increment in BEH-NWI was related to an 8.5% (95% CI 5.4%-11.5%) lower level of DHEAS, a 3.7% (95% CI 0.5%-6.8%) lower level of testosterone, a 1.8% (95% CI 0.5%-3.0%) lower level of estrone, and a 4.2% (95% CI 2.7%-5.7%) higher level of SHBG. However, the associations with respect to DHEAS and estrone became apparent only after adjusting for neighborhood-level variables. Sensitivity analyses using fixed effects meta-analysis and inverse probability weighting accounting for potential selection bias yielded similar results. CONCLUSION/CONCLUSIONS:Our findings suggest that NW is associated with lower concentrations of androgens and estrone, and increased SHBG, in postmenopausal women, and lower levels of DHEAS in premenopausal women.

BACKGROUND:This study was performed to investigate the association between body mass index (BMI) and gastric cancer (GC) in East and Southeast Asia where most of GC is non-cardia GC. METHODS:Based on 8,997 GC cases among the Asia Cohort Consortium participants from China, Japan, Korea, and Singapore (N=538,835), we assessed GC risk according to BMI by calculating hazard ratios (HRs) and 95% confidence intervals (CIs) using the Cox proportional hazard regression model. RESULTS:A U-shaped associations between BMI and GC risk were observed. GC risks in underweight group (<18.5 kg/m2) and in obesity group (≥27.5 kg/m2) were higher than reference BMI group (23-24.9 kg/m2) (HR=1.15, 95% CI 1.05-1.25 for underweight; HR=1.12, 95% CI 1.03-1.22 for obesity, respectively). The associations of underweight and obesity with GC risk were consistent in the analyses for non-cardia GC, intestinal type GC, and late onset GC. No significant association of underweight and obesity with the risk of cardia GC, diffuse type GC, and early onset GC was observed. Additionally, we found that the U-shaped association between BMI and GC risk remained in non-smokers, while only underweight was related to increased GC risk in smokers. CONCLUSIONS:BMI has a U-shaped association with GC risk in East and Southeast Asian population, especially for the non-cardia GC, intestinal type GC, and late onset GC. IMPACT/CONCLUSIONS:Future studies with consideration of anatomical location and histology of GC are needed to establish the association of underweight as well as obesity with GC risk.

BACKGROUND:The association between body mass index (BMI) and oesophageal cancer (OC) has been consistently negative among Asians, whereas different associations based on histological OC subtypes have been observed in Europeans and North Americans. We examined the association between BMI and OC mortality in the Asia Cohort Consortium. METHODS:We performed a pooled analysis to evaluate the association between BMI and OC mortality among 842 630 Asians from 18 cohort studies. Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS:A wide J-shaped association between BMI and overall OC mortality was observed. The OC mortality risk was increased for underweight (BMI <18.5 kg/m2: HR = 2.20, 95% CI 1.80-2.70) and extreme obesity (BMI ≥35 kg/m2: HR = 4.38, 95% CI 2.25-8.52) relative to the reference BMI (23-25 kg/m2). This association pattern was confirmed by several alternative analyses based on OC incidence and meta-analysis. A similar wide J-shaped association was observed in oesophageal squamous cell carcinoma (OSCC). Smoking and alcohol synergistically increased the OC mortality risk in underweight participants (HR = 6.96, 95% CI 4.54-10.67) relative to that in reference BMI participants not exposed to smoking and alcohol. CONCLUSION/CONCLUSIONS:Extreme obesity and being underweight were associated with an OC mortality risk among Asians. OC mortality and BMI formed a wide J-shaped association mirrored by OSCC mortality. Although the effect of BMI on OSCC and oesophageal adenocarcinoma mortality can be different in Asians, further research based on a large case-control study is recommended.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer with limited meaningful treatment options. NEPC lesions uniquely express delta-like ligand 3 (DLL3) on their cell surface. Taking advantage of DLL3 overexpression, we developed and evaluated lutetium-177 (¹⁷⁷Lu)-labeled DLL3-targeting antibody SC16 (¹⁷⁷Lu-DTPA-SC16) as a treatment for NEPC. SC16 was functionalized with DTPA-CHX-A" chelator and radiolabeled with ¹⁷⁷Lu to produce ¹⁷⁷Lu-DTPA-SC16. Specificity and selectivity of ¹⁷⁷Lu-DTPA-SC16 were evaluated in vitro and in vivo using NCI-H660 (NEPC, DLL3-positive) and DU145 (adenocarcinoma, DLL3-negative) cells and xenografts. Dose-dependent treatment efficacy and specificity of ¹⁷⁷Lu-DTPA-SC16 radionuclide therapy were evaluated in H660 and DU145 xenograft-bearing mice. Safety of the agent was assessed by monitoring hematologic parameters. ¹⁷⁷Lu-DTPA-SC16 showed high tumor uptake and specificity in H660 xenografts, with minimal uptake in DU145 xenografts. At all three tested doses of ¹⁷⁷Lu-DTPA-SC16 (4.63, 9.25, and 27.75 MBq/mouse), complete responses were observed in H660-bearing mice; 9.25 and 27.75 MBq/mouse doses were curative. Even the lowest tested dose proved curative in five (63%) of eight mice, and recurring tumors could be successfully re-treated at the same dose to achieve complete responses. In DU145 xenografts, ¹⁷⁷Lu-DTPA-SC16 therapy did not inhibit tumor growth. Platelets and hematocrit transiently dropped, reaching nadir at 2 to 3 wk. This was out of range only in the highest-dose cohort and quickly recovered to normal range by week 4. Weight loss was observed only in the highest-dose cohort. Therefore, our data demonstrate that ¹⁷⁷Lu-DTPA-SC16 is a potent and safe radioimmunotherapeutic agent for testing in humans with NEPC.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, with ∼80% of CVD-related deaths occurring in low- and middle-income countries. Growing evidence suggests that chronic arsenic exposure may contribute to CVD through its effect on endothelial function in adults. However, few studies have examined the influence of arsenic exposure on cardiovascular health in children and adolescents. To examine arsenic's relation to preclinical markers of endothelial dysfunction, we enrolled 200 adolescent children (ages 15-19 years; median 17) of adult participants in the Health Effects of Arsenic Longitudinal Study (HEALS), in Araihazar, Bangladesh. Participants' arsenic exposure was determined by recall of lifetime well usage for drinking water. As part of HEALS, wells were color-coded to indicate arsenic level (<10 μg/L, 10-50 μg/L, >50 μg/L). Endothelial function was measured by recording fingertip arterial pulsatile volume change and reactive hyperemia index (RHI) score, an independent CVD risk factor, was calculated from these measurements. In linear regression models adjusted for participant's sex, age, education, maternal education, land ownership and body weight, individuals who reported always drinking water from wells with >50 μg/L arsenic had a 11.75% lower level of RHI (95% CI: -21.26, -1.09, p = 0.03), as compared to participants who drank exclusively from wells with ≤50 μg/L arsenic. Sex-stratified analyses suggest that these associations were stronger in female participants. As compared to individuals who drank exclusively from wells with ≤50 μg/L arsenic, the use of wells with >50 μg/L arsenic was associated with 14.36% lower RHI (95% CI: -25.69, -1.29, p = 0.03) in females, as compared to 5.35% lower RHI (95% CI: -22.28, 15.37, p = 0.58) in males for the same comparison. Our results suggest that chronic arsenic exposure may be related to endothelial dysfunction in adolescents, especially among females. Further work is needed to confirm these findings and examine whether these changes may increase risk of later adverse cardiovascular health events.

BACKGROUND:Water arsenic (As) sources beyond a rural household's primary well may be a significant source for certain individuals, including schoolchildren and men working elsewhere. OBJECTIVE:To improve exposure assessment by estimating the fraction of drinking water that comes from wells other than the household's primary well in a densely populated area. METHODS:area of Araihazar upazila, Bangladesh, for 11,197 participants in the Health Effects of Arsenic Longitudinal Study (HEALS). We estimate the fraction of water that participants drink from different wells by imposing a long-term mass-balance constraint for both As and water. RESULTS:The mass-balance model suggest that, on average, HEALS participants obtain 60-75% of their drinking water from their primary household wells and 25-40% from other wells, in addition to water from food and cellular respiration. Because of this newly quantified contribution from other wells, As in drinking water rather than rice was identified as the largest source of As exposure at baseline for HEALS participants with a primary household well containing ≤50 µg/L As. SIGNIFICANCE/CONCLUSIONS:Dose-response relationships for As based on water As should take into account other wells. The mass-balance approach could be applied to study other toxicants.