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Background Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. In the phase 3 LIBERTY ASTHMA QUEST trial (NCT02414854) in patients with uncontrolled, moderate-to-severe asthma, add-on dupilumab 200 mg or 300 mg every 2 weeks reduced exacerbations and improved forced expiratory volume in 1 s (FEV1) and quality of life over 52 weeks. This analysis evaluates dupilimab's effect on lung function in the overall population, and subgroups with baseline elevated type 2 inflammatory biomarkers. Methods Patients were randomised to 52 weeks of subcutaneous dupilumab 200 mg every 2 weeks, 300 mg every 2 weeks, or matched-volume placebos. Lung function outcomes were analysed in the overall population, in patients with ≥150 eosinophils·µL−1, ≥300 eosinophils·µL−1, ≥25 ppb fractional exhaled nitric oxide (FeNO), and both ≥150 eosinophils·µL−1 and ≥25 ppb FeNO, at baseline. Results Dupilumab treatment (200 mg and 300 mg every 2 weeks) resulted in significant improvements versus placebo after 52 weeks in pre-bronchodilator FEV1 (0.20 and 0.13 L, respectively, versus placebo) and post-bronchodilator FEV1 (0.19 and 0.13 L, respectively), forced vital capacity (FVC) (0.20 and 0.14 L, respectively), forced expiratory flow (0.19 and 0.13 L·s−1, respectively) and pre-bronchodilator FEV1/FVC ratio (1.75% and 1.61%, respectively) in the overall population (p, Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation, improving lung function outcomes in patients with uncontrolled, moderate-to-severe asthma http://bit.ly/2OhKMpi

Chronic obstructive pulmonary disease (COPD) can cause extrapulmonary injury such as diaphragm dysfunction. Oxidative stress is one of the main factors causing diaphragm dysfunction in COPD. Exercise plays a positive role in the prevention and treatment of diaphragm dysfunction in COPD, and the changes in diaphragm structure and function induced by exercise are closely related to the regulation of oxidative stress. Therefore, on the basis of the review of oxidative stress and the changes in diaphragm structure and function in COPD, this article analyzed the effects of exercise on oxidative stress and diaphragm dysfunction in COPD and explored the possible mechanism by which exercise improves oxidative stress. Studies have found that diaphragm dysfunction in COPD includes the decline of muscle strength, endurance, and activity. Oxidative stress mainly affects the structure and function of the diaphragm in COPD through protein oxidation, protease activation and calcium sensitivity reduction. The effects of exercise on oxidative stress level and diaphragm dysfunction may differ depending on the intensity, duration, and style of exercise. The mechanism of exercise on oxidative stress in the diaphragm of COPD may include improving antioxidant capacity, reducing oxidase activity and improving mitochondrial function.

Introduction Dupilumab, a fully human anti-IL-4Rα monoclonal antibody, inhibits signaling of both interleukin (IL)-4 and IL-13, which are key drivers of type 2-mediated inflammation. Dupilumab is approved in the EU, USA, and other countries for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. Following positive phase 2 results in asthma, the phase 3 Liberty Asthma QUEST trial was initiated to provide further evidence for dupilumab efficacy and safety in patients with uncontrolled, moderate-to-severe asthma. Methods Liberty Asthma QUEST is a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (NCT02414854) in patients with persistent asthma who are receiving continuous treatment with inhaled corticosteroids (ICS) plus one or two other asthma controller medicines. A total of 1902 patients (aged ≥ 12 years) were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on therapy with subcutaneously administered dupilumab 200 or 300 mg every 2 weeks or matched placebo. The study consisted of a 4 ± 1-week screening period, 52-week randomized treatment period, and 12-week post-treatment follow-up period. All patients continued to receive their prescribed ICS plus up to two additional controller medications. The primary efficacy endpoints were annualized rate of severe exacerbation events during the 52-week treatment period and absolute change from baseline in pre-bronchodilator FEV1 at week 12. Conclusion Uncontrolled asthma patients with persistent symptoms represent a population of significant unmet need, for whom new treatments are required. Patients with severe asthma are at high risk of asthma exacerbations, and face an accelerated decline in lung function and impaired quality of life. QUEST examines the efficacy of dupilumab in this at-risk patient population; it is the largest placebo-controlled study in uncontrolled, moderate-to-severe asthma with a biologic agent to date, and the only phase 3 study of a biologic therapy of asthma that enrolled patients irrespective of baseline type 2 inflammatory biomarker levels. Funding Sanofi and Regeneron Pharmaceuticals, Inc. Clinical Trials.gov Identifier NCT02414854.

Background: Dupilumab (DPL), a fully human anti-IL-4Rα mAb that inhibits IL-4/IL-13, is approved for treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. In a phase 3 study (NCT02414854), asthma patients (pts) aged ≥12 years, with no minimum baseline (BL) eosinophil requirement, uncontrolled with medium-to-high-dose ICS, plus 1 or 2 controllers received DPL 200/300mg or placebo (PBO) every 2 weeks for 52 weeks. DPL reduced severe exacerbations, improved FEV1 and quality of life measures, and was generally well tolerated. Aim: Assess DPL effect on 22-item Sino-Nasal Outcome Test (SNOT-22) scores, a CRS disease-specific health-related quality of life (HRQoL) outcome, in asthma pts with CRS/NP. Methods: 382/1902 pts reported CRS/NP medical history. Outcome was change from BL in DPL vs PBO in SNOT-22 scores at Weeks 12, 24, and 52. Results: DPL improved SNOT-22 scores by Week 12, and over the 52-week treatment period (Table). SNOT-22 scores in the DPL-treated pts exceeded the minimal clinically important difference (≥8.9) at all time points compared to BL, and vs PBO at Week 52. The most common AE, with higher rates in 200/300mg DPL vs PBO, was injection-site reactions (21%/24% vs 6%/14%). Conclusion: Dupilumab significantly improved CRS/NP-specific symptoms and HRQoL in asthma pts with comorbid CRS/NP, and was generally well tolerated.

Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with uncontrolled asthma.We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV1) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV1 in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed.The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P

Polycyclic aromatic hydrocarbons (PAH) are a class of chemicals common in the environment. Certain PAH are carcinogenic, although the degree to which genetic variation influences susceptibility to carcinogenic PAH remains unclear. Also unknown is the influence of genetic variation on the procarcinogenic effect of in utero exposures to PAH. Benzo[a]pyrene (B[a]P) is a well-studied PAH that is classified as a probable human carcinogen. Within our New York City-based cohort, we explored interactions between maternal exposure to airborne PAH during pregnancy and maternal and newborn haplotypes (and in one case, a single-nucleotide polymorphism) in key B[a]P metabolism genes on B[a]P-DNA adducts in paired cord blood samples. The study subjects included non-smoking African-American (n = 132) and Dominican (n = 235) women with available data on maternal PAH exposure, paired cord adducts and genetic data who resided in the Washington Heights, Central Harlem and South Bronx neighborhoods of New York City. We selected seven maternal and newborn genes related to B[a]P metabolism, detoxification and repair for our analyses: CYP1A1, CYP1A2, CYP1B1, GSTM3, GSTT2, NQO1 and XRCC1. We found significant interactions between maternal PAH exposure and haplotype on cord B[a]P-DNA adducts in the following genes: maternal CYP1B1, XRCC1 and GSTM3, and newborn CYP1A2 and XRCC1 in African-Americans; and maternal XRCC1 and newborn NQO1 in Dominicans. These novel findings highlight differences in maternal and newborn genetic contributions to B[a]P-DNA adduct formation, as well as ethnic differences in gene-environment interactions, and have the potential to identify at-risk subpopulations who are susceptible to the carcinogenic potential of B[a]P.

Introduction: In a pivotal phase 2b trial (NCT01854047), adult patients (pts) with uncontrolled persistent asthma using ICS+LABA were randomized to 24 weeks (wks) of add-on therapy with dupilumab (DPL; an anti-IL-4Rα antibody), 200 or 300 mg every 2 weeks (q2w) or q4w, or placebo (PBO). DPL significantly reduced the rate of severe exacerbation when administered q2w. Most common adverse events (DPL vs PBO) were upper respiratory tract infections (12−15% vs 18%) and injection site erythema (8−22% vs 8%). We aimed to evaluate whether DPL, a dual antagonist of both IL-4 and IL-13, reduced severe exacerbations irrespective of baseline levels of serum periostin (PN; a biomarker of IL-13 activity). Methods: PN was assayed by ELISA (Shino-Test, Tokyo). Annualized rates of severe exacerbation in the 24-wk treatment period are given for “PN-high” and “PN-low” subgroups (≥ and Results: PN levels decreased on DPL vs PBO. Both DPL q2w regimens significantly reduced the rates of severe exacerbation in both PN-high and PN-low subgroups vs PBO. On PBO, the rate of exacerbation was 2-fold higher in PN-high vs PN-low pts. Conclusions : Dupilumab treatment, 200 and 300 mg q2w, reduces serum PN and the risk of severe exacerbation in both the more-frequently exacerbating PN-high and less-frequently exacerbating PN-low asthma pts.

Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist, irrespective of baseline eosinophil count.We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged ≥18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per μL assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16.769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per μL, the greatest increases (200 mg every 2 weeks, p=0·0008; 300 mg every 2 weeks, p=0·0063) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0·39 L [SE 0·05]; mean difference 0·21 [95% CI 0·06-0·36; p=0·0063]) and in the 200 mg group (mean change 0·43 L [SE 0·05]; mean difference 0·26 [0·11-0·40; p=0·0008]) compared with placebo (0·18 L [SE 0·05]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per μL subgroup (overall population: 200 mg every 2 weeks, p0·0001; 300 mg every 2 weeks, p0·0001;300 eosinophils per μL: 200 mg every 2 weeks, p=0·0034; 300 mg every 2 weeks, p=0·0086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70-70·5%), the subgroup with at least 300 eosinophils per μL (71·2-80·7%), and the subgroup with fewer than 300 eosinophils per μL (59·9-67·6%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33-41% vs 35%) and injection-site reactions (13-26% vs 13%).Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting β2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone.Sanofi-Genzyme and Regeneron Pharmaceuticals.

Background: Airborne polycyclic aromatic hydrocarbons (PAH) are widespread urban pollutants that can bind to DNA to form PAH–DNA adducts. Prenatal PAH exposure measured by personal monitoring has been linked to cognitive deficits in childhood in a prospective study conducted by the Columbia Center for Children’s Environmental Health. Objectives: We measured PAH–DNA and other bulky aromatic adducts in umbilical cord white blood cells using the 32P-postlabeling assay to determine the association between this molecular dosimeter and behavioral/attention problems in childhood. Methods: Children born to nonsmoking African-American and Dominican women residing in New York City (NYC) were followed from in utero to 7–8 years of age. At two time points before 8 years of age (mean ages, 4.8 years and 7 years), child behavior was assessed using the Child Behavior Checklist (CBCL). To estimate and test the association between adducts and behavioral outcomes, both CBCL continuous raw scores and dichotomized T-scores were analyzed. Results: Higher cord adducts were associated with higher symptom scores of Anxious/Depressed at 4.8 years and Attention Problems at 4.8 and 7 years, and with Diagnostic and Statistical Manual of Mental Disorders, 4th edition–oriented Anxiety Problems at 4.8 years. Conclusions: These results suggest that PAH exposure, measured by DNA adducts, may adversely affect child behavior, potentially affecting school performance.

Background Exposure to traffic-related air pollutants, including polycyclic aromatic hydrocarbons (PAHs), can induce asthma. However, the effects of early repeated PAH exposure over time on different asthma phenotypes have not been examined. Objective To assess associations between repeated PAH exposure, measured from prenatal personal and residential indoor monitors in children's homes, and asthma in an inner-city cohort. Methods Prenatal exposure was assessed by personal air monitoring during 48 hours and exposure at 5 to 6 years of age by 2-week residential monitoring in the Columbia Center for Children's Environmental Health cohort. PAH was dichotomized into pyrene (representative semivolatile PAH) and the sum of 8 nonvolatile PAHs. High exposure to each was defined as measures above the median at both repeated time points. Asthma and wheeze were determined by validated questionnaires at ages 5 to 6 years. Children with specific IgE levels greater than 0.35 IU/mL to any of 5 indoor allergens were considered seroatopic. Results Among all 354 children, repeated high exposure to pyrene was associated with asthma (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.13-3.20). Among 242 nonatopic children, but not those sensitized to indoor allergens (n = 87) or with elevated total IgE levels (n = 171), high pyrene levels were associated positively with asthma (OR, 2.89; 95% CI, 1.77-5.69), asthma medication use (OR, 2.28; 95% CI, 1.13-4.59), and emergency department visits for asthma (OR, 2.43; 95% CI, 1.20-4.91). Associations between the levels of the 8 nonvolatile PAHs and asthma were not observed, even when stratifying by seroatopy. Conclusion Nonatopic children may be more susceptible to the respiratory consequences of early pyrene exposures.

Background: Polycyclic aromatic hydrocarbons (PAHs) are a class of chemicals common in the environment. Major sources of PAHs include fossil fuel combustion and cigarette smoking. Certain PAHs are carcinogenic, though the degree to which genetic variation influences susceptibility to PAH exposure remains unclear. Benzo(a)pyrene (BaP) is a well-studied PAH that is classified as a probable human carcinogen. Here, we evaluated haplotype frequency in genes related to PAH metabolism and detoxification, and explored the interactions between PAH exposure and haplotype on BaP-DNA adducts, an established cancer risk marker, in umbilical cord white blood cells (WBCs). Methods: Maternal and umbilical cord blood were collected at delivery from participants in a longitudinal cohort study of African American (AA) and Dominican (D) mothers and newborns in New York City. WBC DNA was isolated from cord blood, and genetic polymorphisms and BaP-DNA cord adducts were then measured in 516 mothers and 323 newborns. Maternal PAH exposure was measured during pregnancy with a personal air exposure monitor. A total of 18 genes, selected for biologic relevance, were analyzed for SNPs. For this study, a subset of 7 maternal and newborn genes related to PAH metabolism, detoxification and repair were selected for haplotype analyses: CYP1A1, CYP1A2, CYP1B1, GSTM, GSTT, NQO1 and XRCC. Haplotype × PAH interactions on logarithmic-transformed BaP-DNA adduct levels were explored. Results: Notable differences in haplotype frequency were observed between AAs and Ds and between mothers and newborns. We observed a number of significant interactions between high PAH exposure and polymorphic haplotypes in both mothers and newborns on BaP-DNA adducts in cord blood. To give one example, the haplotype CACGCG of CYP1B1 in AA mothers had a frequency of 10.4%, versus 0.3% in D mothers (p Discussion: It is biologically plausible that an individual's ability to metabolically activate and detoxify BaP and repair DNA damage plays a role in susceptibility to DNA adduct formation following prenatal PAH exposure. Ultimately, this susceptibility could correlate with future risk of cancer development. We have identified haplotype patterns that differ between ethnic groups and also between mothers and newborns. We also observed several haplotype × PAH exposure interactions on cord BaP-DNA adducts, supporting the hypothesis that genetic variability can contribute to susceptibility and potential cancer risk from prenatal PAH exposures. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2753. doi:10.1158/1538-7445.AM2011-2753

L8 Prenatal and Postnatal Exposure to Polycyclic Aromatic Hydrocarbons and Asthma: Effect of Atopy at Ages 5-6 yrs in an Urban Birth Cohort K. Jung, S. Hsu, K. Moors, K. Bernabe, B. Yan, S. N. Chillrud, R. Whyatt, M. Perzanowski, L. Hoepner, I. Goldstein, B. Zhang, D. Camann, P. L. Kinney, F. P. Perera, R. L. Miller; Columbia University, New York, NY, Lamont-Doherty Earth Observatory, Palisades, NY, Mailman School of Public Health, New York, NY, Southwest Research Institute, San Antonio, TX, Division of Pulmonary, New York, NY. RATIONALE: Research suggests that exposure to traffic-related air pollutants may induce or trigger asthma. However, the combined effects of prenatal and early postnatal individual exposure to polycyclic aromatic hydrocarbons (PAHs) on respiratory outcomes have not been examined. We hypothesized that exposure to PAHs, and pyrene specifically, would be differentially associated with asthma among atopic and non-atopic children. METHODS: Prenatal PAH exposure was assessed by personal air monitoring over 48-hrs and postnatal PAH exposure by two-week residential indoor monitoring between ages 5/6 in the Columbia Center for Children’s Environmental Health birth cohort. PAH was dichotomized into +8PAHnonvolatile (MW 228-278) and pyrene. High PAH exposure group was defined as high-prenatal (upper 50%) and high-postnatal (upper 50%) exposure and compared to the rest of groups (Low-low, low-high, and high-low). Asthma was defined by validated questionnaires. Children with any indoor allergen specific IgE >_ 0.35 IU/ml were considered atopic. RESULTS: Among non-atopic children (n 5 152), a positive association between high pyrene levels and current asthma (OR 3.01, p5 0.017, 95% CI[1.2-7.5]) and emergency room visits (OR 2.50, p5 0.038, 95%CI[1.055.9]) was obtained in logistic regression analyses. Also among non-atopic children, an inverse association was found between high +8PAHnonvolatile exposure and current asthma (OR 0.31, p 5 0.033, 95%CI[0.11-0.91]) and wheeze (OR 0.24, p5 0.005, 95%CI[0.09-0.67]). Among atopic children (n 5 62), no significant associations were found between pyrene or +8PAHnonvolatile exposure and asthma-related symptoms. CONCLUSIONS: Among non-atopic children, high prenatal and postnatal exposure to pyrene was associated with greater odds of asthma-related symptoms, whereas combined prenatal and postnatal S8PAHnonvolatile exposure was associated with lower odds of asthma-related symptoms.