Inkyu Han

Selective Inhibition of HER2-Positive Breast Cancer Cells by the HIV Protease Inhibitor Nelfinavir

BACKGROUND Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is highly aggressive and has higher risk of recurrence than HER2-negative cancer. With few treatment options available, new drug targets specific for HER2-positive breast cancer are needed. METHODS We conducted a pharmacological profiling of seven genotypically distinct breast cancer cell lines using a subset of inhibitors of breast cancer cells from a screen of the Johns Hopkins Drug Library. To identify molecular targets of nelfinavir, identified in the screen as a selective inhibitor of HER2-positive cells, we conducted a genome-wide screen of a haploinsufficiency yeast mutant collection. We evaluated antitumor activity of nelfinavir with xenografts in athymic nude mouse models (n = 4-6 per group) of human breast cancer and repeated mixed-effects regression analysis. All statistical tests were two-sided. RESULTS Pharmacological profiling showed that nelfinavir, an anti-HIV drug, selectively inhibited the growth of HER2-positive breast cancer cells in vitro. A genome-wide screening of haploinsufficiency yeast mutants revealed that nelfinavir inhibited heat shock protein 90 (HSP90) function. Further characterization using proteolytic footprinting experiments indicated that nelfinavir inhibited HSP90 in breast cancer cells through a novel mechanism. In vivo, nelfinavir selectively inhibited the growth of HER2-positive breast cancer cells (tumor volume index of HCC1954 cells on day 29, vehicle vs nelfinavir, mean = 14.42 vs 5.16, difference = 9.25, 95% confidence interval [CI] = 5.93 to 12.56, P < .001; tumor volume index of BT474 cells on day 26, vehicle vs nelfinavir, mean = 2.21 vs 0.90, difference = 1.31, 95% CI = 0.83 to 1.78, P < .001). Moreover, nelfinavir inhibited the growth of trastuzumab- and/or lapatinib-resistant, HER2-positive breast cancer cells in vitro at clinically achievable concentrations. CONCLUSION Nelfinavir was found to be a new class of HSP90 inhibitor and can be brought to HER2-breast cancer treatment trials with the same dosage regimen as that used among HIV patients.

Hazardous chemicals in synthetic turf materials and their bioaccessibility in digestive fluids.

Many synthetic turf fields consist of not only artificial grass but also rubber granules that are used as infill. The public concerns about toxic chemicals possibly contained in either artificial (polyethylene) grass fibers or rubber granules have been escalating but are based on very limited information available to date. The aim of this research was to obtain data that will help assess potential health risks associated with chemical exposure. In this small-scale study, we collected seven samples of rubber granules and one sample of artificial grass fiber from synthetic turf fields at different ages of the fields. We analyzed these samples to determine the contents (maximum concentrations) of polycyclic aromatic hydrocarbons (PAHs) and several metals (Zn, Cr, As, Cd, and Pb). We also analyzed these samples to determine their bioaccessible fractions of PAHs and metals in synthetic digestive fluids including saliva, gastric fluid, and intestinal fluid through a laboratory simulation technique. Our findings include: (1) rubber granules often, especially when the synthetic turf fields were newer, contained PAHs at levels above health-based soil standards. The levels of PAHs generally appear to decline as the field ages. However, the decay trend may be complicated by adding new rubber granules to compensate for the loss of the material. (2) PAHs contained in rubber granules had zero or near-zero bioaccessibility in the synthetic digestive fluids. (3) The zinc contents were found to far exceed the soil limit. (4) Except one sample with a moderate lead content of 53 p.p.m., the other samples had relatively low concentrations of lead (3.12–5.76 p.p.m.), according to soil standards. However, 24.7–44.2% of the lead in the rubber granules was bioaccessible in the synthetic gastric fluid. (5) The artificial grass fiber sample showed a chromium content of 3.93 p.p.m., and 34.6% and 54.0% bioaccessibility of lead in the synthetic gastric and intestinal fluids, respectively.

Autism spectrum disorder prevalence and proximity to industrial facilities releasing arsenic, lead or mercury

Prenatal and perinatal exposures to air pollutants have been shown to adversely affect birth outcomes in offspring and may contribute to prevalence of autism spectrum disorder (ASD). For this ecologic study, we evaluated the association between ASD prevalence, at the census tract level, and proximity of tract centroids to the closest industrial facilities releasing arsenic, lead or mercury during the 1990s. We used 2000 to 2008 surveillance data from five sites of the Autism and Developmental Disabilities Monitoring (ADDM) network and 2000 census data to estimate prevalence. Multi-level negative binomial regression models were used to test associations between ASD prevalence and proximity to industrial facilities in existence from 1991 to 1999 according to the US Environmental Protection Agency Toxics Release Inventory (USEPA-TRI). Data for 2489 census tracts showed that after adjustment for demographic and socio-economic area-based characteristics, ASD prevalence was higher in census tracts located in the closest 10th percentile compared of distance to those in the furthest 50th percentile (adjusted RR=1.27, 95% CI: (1.00, 1.61), P=0.049). The findings observed in this study are suggestive of the association between urban residential proximity to industrial facilities emitting air pollutants and higher ASD prevalence.

Assessment of heterogeneity of metal composition of fine particulate matter collected from eight U.S. counties using principal component analysis

The main objectives of this study are to (1) characterize chemical constituents of particulate matter (PM) and (2) compare overall differences in PM collected from eight U.S. counties. This project was undertaken as a part of a larger research program conducted by the Johns Hopkins Particulate Matter Research Center (JHPMRC). The goal of the JHPMRC is to explore the relationship between health effects and exposure to ambient PM of differing composition. The JHPMRC collected weekly filter-based ambient fine particle samples from eight U.S. counties between January 2008 and January 2010. Each sampling effort consisted of a 5–6-week sampling period. Filters were analyzed for 25 metals using inductively coupled plasma mass spectrometry (ICP-MS). Overall compositional differences were ranked by principal component analysis (PCA). The results showed that weekly concentrations of each element varied 3–40 times between the eight counties. PCA showed that the first five principal components explained 85% of the total variance. The authors found significant overall compositional differences in PM as the average of standardized principal component scores differed between the counties. These findings demonstrate PCA is a useful tool to identify the differences in PM compositional mixtures by county. These differences will be helpful for epidemiological and toxicological studies to help explain why health risks associated with PM exposure are different in locations with similar mass concentrations of PM. Implications: Previous studies have demonstrated associations between health effects and particulate matter (PM) using a single component or a combination of few components. Other studies have shown constituents of PM can vary greatly by location and that these differences may explain why the health effects associated with PM exposure are different by location. However, a single or a combination of a few components cannot represent PM as a whole. To address the need for evaluating PM as a complex mixture, the authors demonstrated the utility of principal component analysis to assess heterogeneity of PM.

1-Hydroxypyrene concentrations in first morning voids and 24-h composite urine: intra- and inter-individual comparisons

Urinary 1-hydroxypyrene (1-OHP) has been suggested as an exposure biomarker for polycyclic aromatic hydrocarbons (PAHs). However, it remains unknown whether a first morning urine sample can be used to reflect average exposure. In this paper, we examine intra-individual differences and inter-individual associations between first morning voids and 24-h composite urine samples. The analysis was performed using data collected from 100 adults who had a wide range of PAH exposure due to differences in their occupation, e.g., coke oven workers vs. non-coke oven workers. For each subject, all the urine voids within each of two 24-h measurement periods were collected. Results showed a significant (40% to 62%) intra-individual difference between first morning voids and 24-h urinary 1-OHP concentrations (in ng/ml urine). Creatinine adjustments of 1-OHP concentrations (in μmol/mol urinary creatinine) reduced the intra-individual difference by approximately 10%. Across all the subjects, a high overall correlation (r=0.76) was observed between first morning and 24-h average 1-OHP concentrations. Work environment and sampling season were found to significantly affect the relationship between first morning and 24-h 1-OHP concentrations. An increase of 1 ng/ml of first morning urinary 1-OHP predicted an increase of 0.5 and 0.25 ng/ml of 24-h urinary 1-OHP for coke oven workers and non-coke oven workers, respectively. Data collected in a winter season showed a higher correlation between first morning and 24-h concentrations than data collected in a fall season. Creatinine adjustments did not significantly improve overall correlations between first morning void and 24-h measurements, but increased total variances for 24-h urines explained by first morning urines in coke workers.

Feasibility of using low-cost portable particle monitors for measurement of fine and coarse particulate matter in urban ambient air

ABSTRACT Exposure to ambient particulate matter (PM) is known as a significant risk factor for mortality and morbidity due to cardiorespiratory causes. Owing to increased interest in assessing personal and community exposures to PM, we evaluated the feasibility of employing a low-cost portable direct-reading instrument for measurement of ambient air PM exposure. A Dylos DC 1700 PM sensor was collocated with a Grimm 11-R in an urban residential area of Houston Texas. The 1-min averages of particle number concentrations for sizes between 0.5 and 2.5 µm (small size) and sizes larger than 2.5 µm (large size) from a DC 1700 were compared with the 1-min averages of PM2.5 (aerodynamic size less than 2.5 µm) and coarse PM (aerodynamic size between 2.5 and 10 µm) concentrations from a Grimm 11-R. We used a linear regression equation to convert DC 1700 number concentrations to mass concentrations, utilizing measurements from the Grimm 11-R. The estimated average DC 1700 PM2.5 concentration (13.2 ± 13.7 µg/m3) was similar to the average measured Grimm 11-R PM2.5 concentration (11.3 ± 15.1 µg/m3). The overall correlation (r2) for PM2.5 between the DC 1700 and Grimm 11-R was 0.778. The estimated average coarse PM concentration from the DC 1700 (5.6 ± 12.1 µg/m3) was also similar to that measured with the Grimm 11-R (4.8 ± 16.5 µg/m3) with an r2 of 0.481. The effects of relative humidity and particle size on the association between the DC 1700 and the Grimm 11-R results were also examined. The calculated PM mass concentrations from the DC 1700 were close to those measured with the Grimm 11-R when relative humidity was less than 60% for both PM2.5 and coarse PM. Particle size distribution was more important for the association of coarse PM between the DC 1700 and Grimm 11-R than it was for PM2.5. Implications: The performance of a low-cost particulate matter (PM) sensor was evaluated in an urban residential area. Both PM2.5 and coarse PM (PM10-2.5) mass concentrations were estimated using a DC1700 PM sensor. The calculated PM mass concentrations from the number concentrations of DC 1700 were close to those measured with the Grimm 11-R when relative humidity was less than 60% for both PM2.5 and coarse PM. Particle size distribution was more important for the association of coarse PM between the DC 1700 and Grimm 11-R than it was for PM2.5.

Depression Prevalence and Exposure to Organophosphate Esters in Aircraft Maintenance Workers.

INTRODUCTION Previous studies found that aircraft maintenance workers may be exposed to organophosphates in hydraulic fluid and engine oil. Studies have also illustrated a link between long-term low-level organophosphate pesticide exposure and depression. METHODS A questionnaire containing the Patient Health Questionnaire 8 depression screener was e-mailed to 52,080 aircraft maintenance workers (with N = 4801 complete responses) in a cross-sectional study to determine prevalence and severity of depression and descriptions of their occupational exposures. RESULTS There was no significant difference between reported depression prevalence and severity in similar exposure groups in which aircraft maintenance workers were exposed or may have been exposed to organophosphate esters compared to similar exposure groups in which they were not exposed. However, a dichotomous measure of the prevalence of depression was significantly associated with self-reported exposure levels from low (OR: 1.21) to moderate (OR: 1.68) to high exposure (OR: 2.70) and with each exposure route including contact (OR: 1.68), inhalation (OR: 2.52), and ingestion (OR: 2.55). A self-reported four-level measure of depression severity was also associated with a self-reported four-level measure of exposure. DISCUSSION Based on self-reported exposures and outcomes, an association is observed between organophosphate exposure and depression; however, we cannot assume that the associations we observed are causal because some workers may have been more likely to report exposure to organophosphate esters and also more likely to report depression. Future studies should consider using a larger sample size, better methods for characterizing crew chief exposures, and bioassays to measure dose rather than exposure. Hardos JE, Whitehead LW, Han I, Ott DK, Waller DK. Depression prevalence and exposure to organophosphate esters in aircraft maintenance workers. Aerosp Med Hum Perform. 2016; 87(8):712-717.

A Mixed-Methods Study to Examine the Role of Psychosocial Stress and Air Pollution on Hypertension in Mexican-Origin Hispanics

PurposeIndependent and combined effects of air pollution and psychosocial stressors on hypertension, a risk factor for cardiovascular disease, among Hispanics are not well studied.MethodsWe administered a pilot-tested questionnaire on individual- and neighborhood-level psychosocial stressors, developed with community input, to nearly 2500 individuals from the MD Anderson Cancer Center cohort of Mexican-Americans. We used data from local air quality monitors to estimate individual exposures to ozone (O3) and fine particulate matter (PM2.5) for the 12-month period preceding enrollment using inverse distance interpolation. We applied logistic regression models to examine relationships between exposures to psychosocial stressors and air pollution with prevalent hypertension and used stratified analyses to examine the interacting effects of these two exposures on hypertension.ResultsThere was a positive association between prevalent hypertension and a high frequency of feeling anxious or depressed (prevalence odds ratio (POR) = 1.36, 95% CI [1.06–1.75]) and experiencing aches and pains (POR = 1.29, 95% CI [1.01–1.64]). The odds of having hypertension were also elevated among those worrying about their own health (POR = 1.65, 95% CI [1.30–2.06]) or about not having enough money (POR = 1.27, 95% CI [1.01–1.6]). We observed an inverse association between O3 and hypertension. There was no interaction between psychosocial stressors and O3 on hypertension.ConclusionOur findings add to the evidence of a positive association between individual and family stressors on hypertension among Hispanics and other racial/ethnic groups. Contrary to previous studies reporting positive associations, our results suggest that long-term exposure to O3 may be inversely related to prevalent hypertension.

Effects of train and truck traffic on noise levels in urban communities

The objective of this study was to measure noise pollution in urban communities near industrial facilities in Houston, Texas and to evaluate the impact of train and truck (e.g., 18-wheeler) traffic associated with industrial activities on noise pollution. In this pilot study, we monitored noise levels as A-weighted decibels (dBA) using a sound level meter in two communities adjacent to industrial facilities for 11 days between 9 a.m. and 1 p.m. Our preliminary results showed that average noise levels in residential communities were 58.4±5.9 dBA without any trains or trucks passing by as compared to noise levels of 65.6±7.0 dBA and 64.1±7.1 dBA with train or truck traffic. Railroad and roadway traffic resulted in increases in background noise levels of 8.6% or 3.6%, respectively. Compared to background noise levels, railroad traffic significantly increased low ( 1000 Hz) whereas truck traffic significantly increased only low and medium frequencies. Add...

Accessing Disadvantaged Pregnant Women in Houston, Texas, and Characterizing Biomarkers of Metal Exposure: A Feasibility Study

Communities of color or low socioeconomic status are disproportionately affected by metal exposure given spatial variability of the ambient levels of these contaminants. Despite this, there is little research characterizing metal concentrations in blood among disadvantaged populations in the U.S., especially among pregnant women who are particularly vulnerable and difficult to access. Thus, we conducted a pilot study among disadvantaged pregnant women in Houston, Texas to assess willingness to participate in key activities of an epidemiologic study and characterize exposures to 16 metals. Thirty-one women attending a Medicaid-serving prenatal clinic were included in this pilot study and completed an interviewer-administered questionnaire. We obtained and measured metal compounds in whole blood samples for 22 of these women during third-trimester prenatal visits. Median whole blood concentrations of Ni, As, Cd, and Pb were 27, 1.4, 0.6, and 6.3 µg/L, respectively. Most women were willing to participate in critical aspects of a research study, including wearing a personal air-sampling badge for 2–3 days (87.1%), receiving ultrasounds (83.9%), and providing blood draws (64.5%). Despite the small sample, our results provide evidence of women’s metal exposure and their willingness to participate in future research studies to elucidate exposure pathways and explore related health effects experienced among this population of disadvantaged pregnant women.