Associations between antenatal maternal asthma status and placental DNA methylation.

INTRODUCTION: Maternal asthma in pregnancy is associated with adverse perinatal and child health outcomes; however, mechanisms are poorly understood. METHODS: The PRogramming of Intergenerational Stress Mechanisms (PRISM) prospective pregnancy cohort characterized asthma history during pregnancy via questionnaires and quantified placental DNAm using the Illumina Infinium HumanMethylation450 BeadChip. We performed epigenome-wide association analyses (n = 223) to estimate associations between maternal active or inactive asthma, as compared to never asthma, and placental differentially methylated positions (DMPs) and differentially variable positions (DVPs). Models adjusted for maternal pre-pregnancy body mass index, smoking status, parity, age and education level and child sex. P-values were FDR-adjusted. RESULTS: One hundred and fifty-nine (71.3%) pregnant women reported no history of asthma (never asthma), 15 (6.7%) reported inactive, and 49 (22%) reported active antenatal asthma. Women predominantly self-identified as Black/Hispanic Black [88 (39.5%)] and Hispanic/non-Black [42 (18.8%)]. We identified 10 probes at FDR<0.05 and 4 probes at FDR<0.10 characterized by higher variability in maternal active asthma compared to never asthma mapping to GPX3, LHPP, PECAM1, ATAD3C, and ARHGEF4 and 2 probes characterized by lower variation mapping to CHMP4A and C5orf24. Amongst women with inactive asthma, we identified 52 probes, 41 at FDR<0.05 and an additional 11 at FDR <0.10, with higher variability compared to never asthma; BMP4, LHPP, PHYHIPL, and ZSCAN23 were associated with multiple DVPs. No associations were observed with DMPs. DISCUSSION: We observed alterations in placental DNAm in women with antenatal asthma, as compared to women without a history of asthma. Further research is needed to understand the impact on fetal development.

An antibody Fc engineered for conditional antibody-dependent cellular cytotoxicity at the low tumor microenvironment pH.

Despite the exquisite specificity and high affinity of antibody-based cancer therapies, treatment side effects can occur since the tumor-associated antigens targeted are also present on healthy cells. However, the low pH of the tumor microenvironment provides an opportunity to develop conditionally active antibodies with enhanced tumor specificity. Here, we engineered the human IgG1 Fc domain to enhance pH-selective binding to the receptor FcγRIIIa and subsequent antibody-dependent cellular cytotoxicity (ADCC). We displayed the Fc domain on the surface of mammalian cells and generated a site-directed library by altering Fc residues at the Fc-FcγRIIIa interface to support interactions with positively charged histidine residues. We then used a competitive staining and flow cytometric selection strategy to isolate Fc variants exhibiting reduced FcγRIIIa affinities at neutral pH, but physiological affinities at the tumor-typical pH 6.5. We demonstrate that antibodies composed of Fab arms binding the breast cell epithelial marker Her2 and the lead Fc variant, termed acid-Fc, exhibited an ∼2-fold pH-selectivity for FcγRIIIa binding based on the ratio of equilibrium dissociation constants Kd,7.4/Kd,6.5, due to a faster dissociation rate at pH 7.4. Finally, in vitro ADCC assays with human FcγRIIIa-positive natural killer and Her2-positive target cells demonstrated similar activities for anti-Her2 antibodies bearing the wild-type or acid-Fc at pH 6.5, but nearly 20-fold reduced ADCC for acid-Fc at pH 7.4, based on EC50 ratios. This work shows the promise of mammalian cell display for Fc engineering and the feasibility of pH-selective Fc activation to provide a second dimension of selective tumor cell targeting.

Prenatal particulate air pollution and newborn telomere length: Effect modification by maternal antioxidant intakes and infant sex.

BACKGROUND: Evidence links gestational exposure to particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) with changes in leukocyte telomere length in cord blood with some studies showing sex-specific effects. PM2.5 exposure in utero increases oxidative stress, which can impact telomere biology. Thus, maternal antioxidant intakes may also modify the particulate air pollution effects. METHODS: We examined associations among prenatal PM2.5 exposure and newborn relative leukocyte telomere length (rLTL), and the modifying effects of maternal antioxidant intake and infant sex. We estimated daily PM2.5 exposures over gestation using a validated spatiotemporally resolved satellite-based model. Maternal dietary and supplemental antioxidant intakes over the prior three months were ascertained during the second trimester using the modified Block98 food frequency questionnaire; high and low antioxidant intakes were categorized based on a median split. We employed Bayesian distributed lag interaction models (BDLIMs) to identify both sensitive windows of exposure and cumulative effect estimates for prenatal PM2.5 exposure on newborn rLTL, and to examine effect modification by maternal antioxidant intakes. A 3-way interaction between PM2.5, maternal antioxidant intake and infant sex was also explored. RESULTS: For the main effect of PM2.5, BDLIMs identified a sensitive window at 12-20 weeks gestation for the association between increased prenatal PM2.5 exposure and shorter newborn rLTL and a cumulative effect of PM2.5 over gestation on newborn telomere length [cumulative effect estimate (CEE) = -0.29 (95% CI -0.49 to -0.10) per 1µg/m3 increase in PM2.5]. In models examining maternal antioxidant intake effects, BDLIMs found that children born to mothers reporting low antioxidant intakes were most vulnerable [CEE of low maternal antioxidant intake = -0.31 (95% CI -0.55 to -0.06) vs high maternal antioxidant intake = -0.07 (95% CI -0.34 to 0.17) per 1µg/m3 increase in PM2.5]. In exploratory models examining effect modification by both maternal antioxidant intakes and infant sex, the cumulative effect remained significant only in boys whose mothers reported low antioxidant intakes [CEE = -0.38 (95% CI -0.80 to -0.004)]; no sensitive windows were identified in any group. CONCLUSIONS: Prenatal PM2.5 exposure in mid-gestation was associated with reduced infant telomere length. Higher maternal antioxidant intakes mitigated these effects.

Detection and follow-up of chronic obstructive pulmonary disease (COPD) and risk factors in the Southern Cone of Latin America: the pulmonary risk in South America (PRISA) study.

BACKGROUND: The World Health Organization has estimated that by 2030, chronic obstructive pulmonary disease will be the third leading cause of death worldwide. Most knowledge of chronic obstructive pulmonary disease is based on studies performed in Europe or North America and little is known about the prevalence, patient characteristics and change in lung function over time in patients in developing countries, such as those of Latin America. This lack of knowledge is in sharp contrast to the high levels of tobacco consumption and exposure to biomass fuels exhibited in Latin America, both major risk factors for the development of chronic obstructive pulmonary disease. Studies have also demonstrated that most Latin American physicians frequently do not follow international chronic obstructive pulmonary disease diagnostic and treatment guidelines. The PRISA Study will expand the current knowledge regarding chronic obstructive pulmonary disease and risk factors in Argentina, Chile and Uruguay to inform policy makers and health professionals on the best policies and practices to address this condition. METHODS/DESIGN: PRISA is an observational, prospective cohort study with at least four years of follow-up. In the first year, PRISA has employed a randomized three-staged stratified cluster sampling strategy to identify 6,000 subjects from Marcos Paz and Bariloche, Argentina, Temuco, Chile, and Canelones, Uruguay. Information, such as comorbidities, socioeconomic status and tobacco and biomass exposure, will be collected and spirometry, anthropometric measurements, blood sampling and electrocardiogram will be performed. In year four, subjects will have repeat measurements taken. DISCUSSION: There is no longitudinal data on chronic obstructive pulmonary disease incidence and risk factors in the southern cone of Latin America, therefore this population-based prospective cohort study will fill knowledge gaps in the prevalence and incidence of chronic obstructive pulmonary disease, patient characteristics and changes in lung function over time as well as quality of life and health care resource utilization. Information gathered during the PRISA Study will inform public health interventions and prevention practices to reduce risk of COPD in the region.