Wallace K.B.,University of Minnesota |
Kissling G.E.,Biostatistics Branch |
Melnick R.L.,NIEHS |
Melnick R.L.,Ron Melnick Consulting LLC |
Toxicology Letters | Year: 2013
Perfluorinated alkyl acids (PFAAs) represent a broad class of commercial products designed primarily for the coatings industry. However, detection of residues globally in a variety of species led to the discontinuation of production in the U.S. Although PFAAs cause activation of the PPARα and CAR nuclear receptors, interference with mitochondrial bioenergetics has been implicated as an alternative mechanism of cytotoxicity. Although the mechanisms by which the eight carbon chain PFAAs interfere with mitochondrial bioenergetics are fairly well described, the activities of the more highly substituted or shorter chain PFAAs are far less well characterized. The current investigation was designed to explore structure-activity relationships by which PFAAs interfere with mitochondrial respiration in vitro. Freshly isolated rat liver mitochondria were incubated with one of 16 different PFAAs, including perfluorinated carboxylic, acetic, and sulfonic acids, sulfonamides and sulfamido acetates, and alcohols. The effect on mitochondrial respiration was measured at five concentrations and dose-response curves were generated to describe the effects on state 3 and 4 respiration and respiratory control. With the exception of PFOS, all PFAAs at sufficiently high concentrations (>20. μM) stimulated state 4 and inhibited state 3 respiration. Stimulation of state 4 respiration was most pronounced for the carboxylic acids and the sulfonamides, which supports prior evidence that the perfluorinated carboxylic and acetic acids induce the mitochondrial permeability transition, whereas the sulfonamides are protonophoric uncouplers of oxidative phosphorylation. In both cases, potency increased with increasing carbon number, with a prominent inflection point between the six and eight carbon congeners. The results provide a foundation for classifying PFAAs according to specific modes of mitochondrial activity and, in combination with toxicokinetic considerations, establishing structure-activity-based boundaries for initial estimates of risk for noncancer endpoints for PFAAs for which minimal in vivo toxicity testing currently exists. © 2013 The Authors.
Shiels M.S.,U.S. National Cancer Institute |
Pfeiffer R.M.,Biostatistics Branch |
Hildesheim A.,U.S. National Cancer Institute |
Engels E.A.,U.S. National Cancer Institute |
And 8 more authors.
Journal of the National Cancer Institute | Year: 2013
BackgroundDespite growing recognition of an etiologic role for inflammation in lung carcinogenesis, few prospective epidemiologic studies have comprehensively investigated the association of circulating inflammation markers with lung cancer.MethodsWe conducted a nested case-control study (n = 526 lung cancer patients and n = 592 control subjects) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Control subjects were matched to lung cancer case patients on age, sex, follow-up time (median = 2.9 years), randomization year, and smoking (pack-years and time since quitting). Serum levels of 77 inflammation markers were measured using a Luminex bead-based assay. Conditional logistic regression and weighted Cox models were used to estimate odds ratios (ORs) and cumulative risks, respectively.ResultsOf 68 evaluable markers, 11 were statistically significantly associated with lung cancer risk (Ptrend across marker categories <. 05), including acute-phase proteins (C-reactive protein [CRP], serum amyloid A [SAA]), proinflammatory cytokines (soluble tumor necrosis factor receptor 2 [sTNFRII]), anti-inflammatory cytokines (interleukin 1 receptor antagonist [IL-1RA]), lymphoid differentiation cytokines (interleukin 7 [IL-7]), growth factors (transforming growth factor alpha [TGF-A]), and chemokines (epithelial neutrophil-activating peptide 78 [ENA 78/CXCL5], monokine induced by gamma interferon [MIG/CXCL9], B cell-attracting chemokine 1 [BCA-1/CXCL13], thymus activation regulated chemokine [TARC/CCL17], macrophage-derived chemokine [MDC/CCL22]). Elevated marker levels were associated with increased lung cancer risk, with odds ratios comparing the highest vs the lowest group ranging from 1.47 (IL-7) to 2.27 (CRP). For IL-1RA, elevated levels were associated with decreased lung cancer risk (OR = 0.71; 95% confidence interval = 0.51 to 1.00). Associations did not differ by smoking, lung cancer histology, or latency. A cross-validated inflammation score using four independent markers (CRP, BCA-1/CXCL13, MDC/CCL22, and IL-1RA) provided good separation in 10-year lung cancer cumulative risks among former smokers (quartile [Q] 1 = 1.1% vs Q4 = 3.1%) and current smokers (Q1 = 2.3% vs Q4 = 7.9%) even after adjustment for smoking.ConclusionsSome circulating inflammation marker levels are associated with prospective lung cancer risk. © 2013 Published by Oxford University Press 2013.
Dunton G.F.,University of Southern California |
Berrigan D.,Applied Research Program |
Ballard-Barbash R.,Applied Research Program |
Perna F.M.,Applied Research Program |
And 2 more authors.
American Journal of Preventive Medicine | Year: 2010
Background: Studies examining environmental influences on adolescent physical activity largely measure the presence and availability of social resources and built environment facilities. Unfortunately, this research approach provides limited information about adolescents' social company during exercise or the extent to which adolescents actually use physical settings for physical activity. Purpose: The current study used data from the nationally representative American Time Use Survey (20032006) to describe demographic and temporal patterns in the social and physical contexts of physical activity among adolescents. Methods: The sample consisted of high school students (aged 1518 years) reporting at least one bout of sports or exercise (N=867). During the interview, participants reported where (e.g., outdoors, home, work) and with whom (e.g., alone, family, friends) each bout occurred. Sample-weighted multinomial logistic regression analyses compared the proportion of bouts occurring in each environment by age, gender, family income, season, weekend/weekday, and time of day, controlling for race/ethnicity. Data were analyzed in 2009. Results: Girls were more likely to exercise with family (22% vs 16%), and less likely to exercise with friends/acquaintances/others (47% vs 52%) and outdoors (18% vs 24%) than boys. Compared with those aged 15 years, a larger proportion of exercise bouts among those aged 18 years occurred alone (23% vs 18%); and a smaller proportion occurred at home (14% vs 20%), at someone else's house (5% vs 12%), and at school (14% vs 27%) (p's<0.001). Conclusions: Information about the social and physical contexts of adolescents' sports and exercise can help guide the selection of future environmental targets for investigation and intervention. © 2010 American Journal of Preventive Medicine.
Vlachos A.,Cohen Childrens Medical Center |
Vlachos A.,Feinstein Institute for Medical Research |
Rosenberg P.S.,Biostatistics Branch |
Atsidaftos E.,Cohen Childrens Medical Center |
And 4 more authors.
Blood | Year: 2012
Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by red cell aplasia and congenital anomalies. A predisposition to cancer has been suggested but not quantified by case reports. The DBA Registry of North America (DBAR) is the largest established DBA patient cohort, with prospective follow-up since 1991. This report presents the first quantitative assessment of cancer incidence in DBA. Among 608 patients with 9458 person-years of follow-up, 15 solid tumors, 2 acute my-eloid leukemias, and 2 cases of myelodys-plastic syndrome were diagnosed at a median age of 41 years in patients who had not received a bone marrow transplant. Cancer incidence in DBA was significantly elevated. The observed-to-expected ratio for all cancers combined was 5.4 (P < .05); significant observed-to-expected ratios were 287 for myelodys-plastic syndrome, 28 for acute myeloid leukemia, 36 for colon carcinoma, 33 for osteogenic sarcoma, and 12 for female genital cancers. The median survival was 56 years, and the cumulative incidence of solid tumor/leukemia was approximately 20% by age 46 years. As in Fanconi anemia and dyskeratosis congenita, DBA is both an inherited bone marrow failure syndrome and a cancer predisposition syndrome; cancer risks appear lower in DBA than in Fanconi anemia or dyskerato-sis congenita. This trial was registered at www.clinicaltrials.gov as #NCT00106015. © 2011 by The American Society of Hematology.
Matsuno R.K.,Biostatistics Branch |
Matsuno R.K.,U.S. National Cancer Institute |
Matsuno R.K.,Johns Hopkins University |
Costantino J.P.,University of Pittsburgh |
And 8 more authors.
Journal of the National Cancer Institute | Year: 2011
Background The Breast Cancer Risk Assessment Tool (BCRAT) of the National Cancer Institute is widely used for estimating absolute risk of invasive breast cancer. However, the absolute risk estimates for Asian and Pacific Islander American (APA) women are based on data from white women. We developed a model for projecting absolute invasive breast cancer risk in APA women and compared its projections to those from BCRAT. Methods Data from 589 women with breast cancer (case patients) and 952 women without breast cancer (control subjects) in the Asian American Breast Cancer Study were used to compute relative and attributable risks based on the age at menarche, number of affected mothers, sisters, and daughters, and number of previous benign biopsies. Absolute risks were obtained by combining this information with ethnicity-specific data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program and with US ethnicity-specific mortality data to create the Asian American Breast Cancer Study model (AABCS model). Independent data from APA women in the Women's Health Initiative (WHI) were used to check the calibration and discriminatory accuracy of the AABCS model. Results The AABCS model estimated absolute risk separately for Chinese, Japanese, Filipino, Hawaiian, Other Pacific Islander, and Other Asian women. Relative and attributable risks for APA women were comparable to those in BCRAT, but the AABCS model usually estimated lower-risk projections than BCRAT in Chinese and Filipino, but not in Hawaiian women, and not in every age and ethnic subgroup. The AABCS model underestimated absolute risk by 17% (95% confidence interval = 1% to 38%) in independent data from WHI, but APA women in the WHI had incidence rates approximately 18% higher than those estimated from the SEER program. Conclusions The AABCS model was calibrated to ethnicity-specific incidence rates from the SEER program for projecting absolute invasive breast cancer risk and is preferable to BCRAT for counseling APA women. © 2011 The Author.
Li R.,National Health Research Institute |
Mav D.,SRA International, Inc. |
Grimm S.A.,National Health Research Institute |
Jothi R.,Biostatistics Branch |
And 2 more authors.
Epigenetics | Year: 2014
Epigenetic regulation of gene expression is fundamental for cell type-specific gene expression. However, integrated comparative transcriptomic and epigenomic analyses in various adult primary differentiated cells remain underrepresented. We generated promoter landscapes of DNA methylation and three important histone methylation marks (H3K4me3, H3K9me2, and H3K27me3) in two primary cell types (B lymphocytes and liver) from adult mice. In line with previous studies, we also observed distinct H3K4me3 patterns at promoters dictated by CpG content in differentiated primary cells. We further explored the distribution of initiating RNA polymerase II and elongating RNA polymerase II across genes within different promoter classes, suggesting different rate-limiting steps at CpG-rich vs. CpG-poor genes. Examination of differentially expressed genes revealed that regulation of tissue-specific genes is closely related to gene function regardless of promoter type. Although repressive chromatin marks displayed differential preference to promoters based on CpG content, we observed fine-tuning of the pattern of association of these marks with specific promoter types in a cell type-specific manner. The distribution of H3K9me2 and H3K27me3, relative to CpG content, differed substantially between the two cell types. Cell-type specific accumulation of repressive chromatin marks was also observed at silent genes in both cell types, suggesting that differentiated primary cells may exhibit cell-type specificity in the distribution of repressive chromatin marks. Epigenetic regulation of gene expression and the association of specific histone marks with promoter sequence classes are fine-tuned in a cell type-specific manner. This unexpected finding underscores the value of extensive study of epigenetic marks across cell and tissue types. © 2014 Landes Bioscience.
Moore A.B.,National Health Research Institute |
Yu L.,National Health Research Institute |
Swartz C.D.,Integrated Laboratory Systems Incorporated |
Zheng X.,National Health Research Institute |
And 6 more authors.
Cell Communication and Signaling | Year: 2010
Background: Uterine leiomyomas (fibroids) are benign smooth muscle tumors that often contain an excessive extracellular matrix (ECM). In the present study, we investigated the interactions between human uterine leiomyoma (UtLM) cells and uterine leiomyoma-derived fibroblasts (FB), and their importance in cell growth and ECM protein production using a coculture system. Results: We found enhanced cell proliferation, and elevated levels of ECM collagen type I and insulin-like growth factor-binding protein-3 after coculturing. There was also increased secretion of vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor-2, and platelet derived growth factor A and B in the media of UtLM cells cocultured with FB. Protein arrays revealed increased phosphorylated receptor tyrosine kinases (RTKs) of the above growth factor ligands, and immunoblots showed elevated levels of the RTK downstream effector, phospho-mitogen activated protein kinase 44/42 in cocultured UtLM cells. There was also increased secretion of transforming growth factor-beta 1 and 3, and immunoprecipitated transforming growth factor-beta receptor I from cocultured UtLM cells showed elevated phosphoserine expression. The downstream effectors phospho-small mothers against decapentaplegic -2 and -3 protein (SMAD) levels were also increased in cocultured UtLM cells. However, none of the above effects were seen in normal myometrial cells cocultured with FB. The soluble factors released by tumor-derived fibroblasts and/or UtLM cells, and activation of the growth factor receptors and their pathways stimulated the proliferation of UtLM cells and enhanced the production of ECM proteins. Conclusions: These data support the importance of interactions between fibroid tumor cells and ECM fibroblasts in vivo, and the role of growth factors, and ECM proteins in the pathogenesis of uterine fibroids. © 2010 Moore et al; licensee BioMed Central Ltd.
Beard J.D.,Brigham Young University |
Umbach D.M.,Biostatistics Branch |
Hoppin J.A.,U.S. National Institutes of Health |
Richards M.,Westat |
And 4 more authors.
Environmental Health Perspectives | Year: 2011
Background: An association may exist between pesticide exposure and suicide. Objective: We sought to evaluate the existence of an association between pesticide use and suicide using data from the Agricultural Health Study (AHS), a prospective cohort study of licensed pesticide applicators and their spouses in Iowa and North Carolina. Methods: Via linkage to state mortality files and the National Death Index, we identified 110 suicides occurring between enrollment in the AHS (from 1993 to 1997) and 31 May 2009, among 81,998 cohort members contributing 1,092,943 person-years of follow-up. The average length of follow-up was 13.3 years. AHS participants provided data on pesticide use and potential confounders via self-administered questionnaires at enrollment. We evaluated several measures of pesticide use: use of any pesticide, ever use of 50 specific pesticides, cumulative lifetime days of use and intensity-adjusted cumulative lifetime days of use of 22 specific pesticides, and ever use of 10 functional and chemical classes of pesticides. We used Cox proportional hazards regression models to estimate adjusted hazard ratios and 95% confidence intervals. Results: After adjusting for age at enrollment, sex, number of children in family, frequency of alcohol consumption during the past 12 months, and smoking status, we found no association between prior pesticide use and suicide in applicators and their spouses. Results were the same for applicators and spouses together or for applicators alone and were consistent across several measures of pesticide use. Conclusions: Our findings do not support an association between moderate pesticide use and suicide.
Lowe J.M.,National Institute of Environmental science |
Menendez D.,National Institute of Environmental science |
Bushel P.R.,Biostatistics Branch |
Shatz M.,National Institute of Environmental science |
And 5 more authors.
Cancer Research | Year: 2014
Macrophages are sentinel immune cells that survey the tissue microenvironment, releasing cytokines in response to both exogenous insults and endogenous events such as tumorigenesis. Macrophages mediate tumor surveillance and therapy-induced tumor regression; however, tumor-Associated macrophages (TAM) and their products may also promote tumor progression. Whereas NF-κB is prominent in macrophage-initiated inflammatory responses, little is known about the role of p53 in macrophage responses to environmental challenge, including chemotherapy or in TAMs. Here, we report that NF-κB and p53, which generally have opposing effects in cancer cells, coregulate induction of proinflammatory genes in primary human monocytes and macrophages. Using Nutlin-3 as a tool, we demonstrate that p53 and NF-κB rapidly and highly induce interleukin (IL)-6 by binding to its promoter. Transcriptome analysis revealed global p53/NF-κB co-regulation of immune response genes, including several chemokines, which effectively induced human neutrophil migration. In addition, we show that p53, activated by tumor cell paracrine factors, induces high basal levels of macrophage IL-6 in a TAM model system [tumor-conditioned macrophages (TCM)]. Compared with normal macrophages, TCMs exhibited higher p53 levels, enhanced p53 binding to the IL-6 promoter, and reduced IL-6 levels upon p53 inhibition. Taken together, we describe a mechanism by which human macrophages integrate signals through p53 and NF-κB to drive proinflammatory cytokine induction. Our results implicate a novel role for macrophage p53 in conditioning the tumor microenvironment and suggest a potential mechanism by which p53-Activating chemotherapeutics, acting upon p53-sufficient macrophages and precursor monocytes, may indirectly impact tumors lacking functional p53. © 2014 American Association for Cancer Research.
Laughon S.K.,U.S. National Institutes of Health |
McLain A.C.,Biostatistics Branch |
Sundaram R.,Biostatistics Branch |
Catov J.M.,Gynecology and Reproductive Services |
And 2 more authors.
Gynecologic and Obstetric Investigation | Year: 2014
Background/Aims: We sought to investigate the association between preconception serum lipids and their daily rate of change in relation to length of gestation. Methods: In a cohort of 70 women, 61 (87%) became pregnant, resulting in 48 (69%) live births. Serum lipid measurements (in milligrams per deciliter) included total cholesterol, free cholesterol, triglycerides and phospholipids at preconception, upon human chorionic gonadotropin-confirmed pregnancy and following pregnancy loss (<14 weeks) or post partum. Pregnancy outcome (loss, preterm and term delivery) and gestational length were modeled relative to daily rate of change in lipids using multinomial regression and Cox proportional hazards models, respectively, adjusting for body mass index and smoking. Results: A rate of triglyceride change below the median was associated with an increased risk for pregnancy loss compared with term birth (adjusted odds ratio: 9.02; 95% CI: 1.62-50.30). A rate of triglyceride change of ≤0.01 mg/dl per day versus above the median was associated with a trend for increased risk of pregnancy loss or preterm (<37 weeks) birth (adjusted hazard ratio: 1.77; 95% CI: 0.94-3.33). Conclusion: A low rate of triglyceride change during early pregnancy may be a signal of risk of pregnancy loss or preterm birth. Lipids offer promise for identifying pregnancies at risk for adverse outcomes. Copyright © 2013 S. Karger AG, Basel.