Dora Il’yasova

Effects of Aerobic Training on Oxidative Status in Postsurgical Non-Small Cell Lung Cancer Patients: A Pilot Study

BACKGROUND Oxidative stress is postulated to contribute to the initiation, promotion, and progression of non-small cell lung cancer (NSCLC). We investigated the effects of supervised, moderate-intensity aerobic training on urinary markers of oxidative status in patients with postsurgical NSCLC. PATIENTS AND METHODS Sixteen patients with histologically confirmed stage I-IIIB NSCLC were recruited. Exercise training consisted of aerobic cycle ergometry sessions at 60 to ≥70% of baseline peak workload 20-45 min·d(-1), 3 d·wk(-1)for 14 weeks. Oxidative status was assessed via four urinary F(2)-isoprostanes isomers: iPF (2-alpha)-III, 2,3-dinor-iPF(2 alpha)-III, iPF (2-alpha)-VI, and 8,12-iso-iPF(2 alpha)-VI using liquid chromatography with tandem mass spectrometry detection. Peak oxygen consumption (VO2peak) was assessed using a maximal, incremental, cardiopulmonary exercise test with expired gas analysis. RESULTS A composite index of all four F2-isoprostanes isomers increased from baseline to post-intervention by 32% (p = 0.08). Concerning individual isomers, iPF (2-alpha)-III increased by 0.09 (+55%; p = .010), iPF (2-alpha)-VI by 0.81 (+29%; p = 0.04), and 8,12-iso-iPF(2 alpha)-VI by 0.59 (+28%; p = 0.07) from baseline to postintervention. There was no change in 2,3-dinor-iPF(2 alpha)-III levels. VO2peak increased 1.1 mL·kg·(-1) min(-1) (p = 0.14) and peak workload increased 10 Watts (p < .001). Change in VO2peak was not associated with change in markers of oxidative status. CONCLUSIONS Aerobic training was associated with significant increases in urinary measures of oxidative status in postsurgical NSCLC. The clinical implications of these findings are currently unknown. Further studies are required to elucidate the complex relationship between aerobic training, oxidative stress, tumor biology, and response to cytotoxic agents in mouse and human models of cancer.

Quantification of the oxidative damage biomarker 2,3-dinor-8-isoprostaglandin-F2α in human urine using liquid chromatography–tandem mass spectrometry

F(2)-isoprostanes are useful biomarkers of oxidative status in humans. We developed an ultraperformance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify 2,3-dinor-8-iso prostaglandin F(2alpha), a urinary metabolite of 8-iso-prostaglandin F(2alpha.) Urine was purified by solid-phase extraction and analyzed by UPLC-MS/MS with negative-ion electrospray ionization. The method was robust with a mean inaccuracy of 9%, interday and intraday imprecision of 7.5% or lower, and a lower limit of quantification of 0.5 microg/L, equivalent to 0.04 pmol injected onto the column. An analysis time of 6 min was shorter than previously published methods and amenable to large studies.

Distinctions in Breast Tumor Recurrence Patterns Post-Therapy among Racially Distinct Populations

Background Clinical studies have revealed a higher risk of breast tumor recurrence in African-American (AA) patients compared to European-American (EA) patients, contributing to the alarming inequality in clinical outcomes among the ethnic groups. However, distinctions in recurrence patterns upon receiving hormone, radiation, and/or chemotherapy between the races remain poorly characterized. Methods We compared patterns and rates (per 1000 cancer patients per 1 year) of recurrence following each form of treatment between AA (n = 1850) and EA breast cancer patients (n = 7931) from a cohort of patients (n = 10504) treated between 2005–2015 at Northside Hospital in Atlanta, GA. Results Among patients who received any combination of adjuvant therapy, AA displayed higher overall rates of recurrence than EA (p = 0.015; HR: 1.699; CI: 1.108–2.606). Furthermore, recurrence rates were higher in AA than EA among stage I (p = 0.031; HR: 1.736; CI: 1.052–2.864) and T1 classified patients (p = 0.003; HR: 2.009; CI: 1.263–3.197). Interestingly, among patients who received neoadjuvant chemotherapy, AA displayed higher rates of local recurrence than EA (p = 0.024; HR: 7.134; CI: 1.295–39.313). Conclusion Our analysis revealed higher incidence rates of recurrence in AA compared to EA among patients that received any combination of adjuvant therapy. Moreover, our data demonstrates an increased risk of tumor recurrence in AA than EA among patients diagnosed with minimally invasive disease. This is the first clinical study to suggest that neoadjuvant chemotherapy improves breast cancer recurrence rates and patterns in AA.

Cord Blood Cells for Developmental Toxicology and Environmental Health.

The Tox21 program initiated a shift in toxicology toward in vitro testing with a focus on the biological mechanisms responsible for toxicological response. We discuss the applications of these initiatives to developmental toxicology. Specifically, we briefly review current approaches that are widely used in developmental toxicology to demonstrate the gap in relevance to human populations. An important aspect of human relevance is the wide variability of cellular responses to toxicants. We discuss how this gap can be addressed by using cells isolated from umbilical cord blood, an entirely non-invasive source of fetal/newborn cells. Extension of toxicological testing to collections of human fetal/newborn cells would be useful for better understanding the effect of toxicants on fetal development in human populations. By presenting this perspective, we aim to initiate a discussion about the use of cord blood donor-specific cells to capture the variability of cellular toxicological responses during this vulnerable stage of human development.

Early Age-related Macular Degeneration with Cardiovascular and Renal Comorbidities: An Analysis of the National Health and Nutrition Examination Survey, 2005–2008

ABSTRACT Purpose: A cross sectional study was designed to examine the relationship of early age-related macular degeneration (AMD) with comorbidities of cardiovascular and renal conditions in the representative population using National Health and Nutrition Examination Survey (NHANES), 2005–2008. Methods: Participants (≥40 years) who underwent retinal photography were included. Early AMD was defined by the retinal digital images. The comorbidities were self-reported stroke and heart disease (HD), including angina pectoris (AP), coronary heart disease (CHD), congestive heart failure (CHF), and myocardial infarction (MI). Chronic kidney disease (CKD) was determined based on self-report, estimation of glomerular filtration rate (GFR), or the level of urine albumin. Results: The age-adjusted odds ratio (OR) and 95% CI for having early AMD for persons with the selected conditions were: 2.6 (1.9, 3.6) for any type of HD. When the conditions were considered separately, ORs (95% CIs) were: 2.0 (1.2, 3.4) for AP; 2.5 (1.6, 3.8) for CHD; 2.4 (1.6, 3.6) for MI; 2.3 (1.3, 3.9) for CHF; 3.3 (2.2, 5.0) for stroke; and 2.4 (1.8, 3.2) for CKD. Covariable-adjusted ORs (AOR) were attenuated for all examined conditions, but remained statistically significant. Having any single condition (AOR [95%CI]: 2.7 [1.5, 4.8]) was significantly associated with early AMD, as was having ≥ 2 conditions (AOR [95%CI]: 5.2 [3.0, 9.0]). The strongest association was between early AMD and the combination of HD and stroke (AOR [95% CI]: 6.3 [2.9, 13.8]). Conclusion: Cardiovascular and renal comorbidities are associated with early AMD in a representative sample of the US general population.

Application of mutagen sensitivity assay in a glioma case-control study

Graphical abstract

Sex-specific gene and pathway modeling of inherited glioma risk

Background To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10-6 and in the validation set when P < 0.001 in 2 of 3 algorithms. Results Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. Conclusions These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

Impact of atopy on risk of glioma: a Mendelian randomisation study

BackgroundAn inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.MethodsTwo-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis.ResultsUnder IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93–1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94–0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91–1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92–1.02, P = 0.194).ConclusionsOur investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions.

Abstract 3446: Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of glioma: Results from the Glioma International Case Control Study

Background: Numerous epidemiologic studies have examined the association between aspirin (ASA), non-steroid anti-inflammatory drugs (NSAIDs) and the development of glioma, but the results have been inconsistent. The goal of this study was to evaluate the relationship between the intake of these drugs and glioma risk in a large, international case-control study. Methods: Between 2010 and 2015, the Glioma International Case-Control Study (GICC) recruited newly diagnosed glioma cases and matched controls in 14 different sites across five countries. Each subject was interviewed using a standardized questionnaire to obtain NSAIDs and ASA use. We examined the associations between ever use (at least > 6 months), duration of drug use and glioma histology. Ever use data on 4533 glioma cases and 4171 controls was combined using maximum likelihood estimation/restricted maximum likelihood meta-analysis methods. Furthermore, based on a priori hypotheses, we performed subgroup analyses based on gender and glioma histological grades. Results: Use of ASA for > 6 months was associated with a 33% lower glioma risk compared to those who never took it (adjusted Meta-OR 0.67, 95% CI 0.54-0.83). Duration of intake showed a significant trend test (p 6 months was not associated with glioma risk (adjusted meta-OR 0.87, 95% CI 0.71-1.07). However, NSAIDs use was protective for women (adjusted meta-OR 0.72, 95% CI 0.55-0.93) in subgroup analyses but not for men (adjusted meta-OR 1.03; 95% CI 0.86-1.23). The interaction between gender, NSAIDs and glioma risk was significant (p-value 0.0076).. Sensitivity analyses excluding those who took ASA or NSAIDs within the past 12 months for headache, and the removal of proxy respondents did not change our results. Conclusion: ASA was associated with a significant protective effect for glioma, but NSAIDs were only associated with reduced glioma risk in women. Given the possibility of recall bias in case-control studies of brain tumors, we may verify dosage and duration of drug intake in those countries with electronic pharmacy records within the GICC. Citation Format: Rose K. Lai, Renke Zhou, E. Susan Amirian, Christoffer Johansen, Michael E. Scheurer, Georgina N. Armstrong, Ching C. Lau, Elizabeth B. Claus, Jill S. Barnholtz-Sloan, Dora Il’yasova, Joellen Schildkraut, Francis Ali-Osman, Siegal Sadetzki, Richard Houlston, Robert B. Jenkins, Daniel Lachance, Sara H. Olson, Jonine L. Bernstein, Ryan T. Merrell, Margaret R. Wrensch, Faith G. Davis, Sanjay Shete, Christopher I. Amos, Beatrice S. Melin, Melissa Bondy. Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of glioma: Results from the Glioma International Case Control Study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3446.