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Strong D.R.,University of California at San Diego | Hartman S.J.,University of California at San Diego | Nodora J.,University of California at San Diego | Messer K.,University of California at San Diego | And 6 more authors.
Nicotine and Tobacco Research | Year: 2015

Objectives: The susceptibility to smoking index can be improved as it only identifies one third of future adult smokers. Adding curiosity to this index may increase the identification of future smokers and improve the identification of effective prevention messages. Methods: Analyses used data from the California Longitudinal Study of Smoking Transitions in Youth, for whom tobacco use behaviors, attitudes, and beliefs were assessed at 3 time points from age 12 through early adulthood. Logistic regressions were used to evaluate whether baseline curiosity about smoking was predictive of smoking during the 6-year follow-up period and whether curiosity about smoking provided evidence of incremental validity over existing measures of susceptibility to smoking. Results: Compared to those who were classified as definitely not curious about smoking, teens who were classified as probably not curious (ORadj = 1.90, 95% CI = 1.28-2.81) and those classified as definitely curious (ORadj = 2.38, 95% CI= 1.49-3.79) had an increase in the odds of becoming a young adult smoker. Adding curiosity to the original susceptibility to smoking index increased the sensitivity of the enhanced susceptibility index to 78.9% compared to 62.2% identified by the original susceptibility index. However, a loss of specificity meant there was no improvement in the positive predictive value. Conclusions: The enhanced susceptibility index significantly improves identification of teens at risk for becoming young adult smokers. Thus, this enhanced index is preferred for identifying and testing potentially effective prevention messages. © The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.


Nodora J.,University of California at San Diego | Hartman S.J.,University of California at San Diego | Strong D.R.,University of California at San Diego | Messer K.,University of California at San Diego | And 6 more authors.
Addictive Behaviors | Year: 2014

Purpose: To improve smoking prevention efforts, better methods for identifying at-risk youth are needed. The widely used measure of susceptibility to smoking identifies at-risk adolescents; however, it correctly identifies only about one third of future smokers. Adding curiosity about smoking to this susceptibility index may allow us to identify a greater proportion of future smokers while they are still pre-teens. Methods: We use longitudinal data from a recent national study on parenting to prevent problem behaviors. Only oldest children between 10 and 13. years of age were eligible. Participants were identified by RDD survey and followed for 6. years. All baseline never smokers with at least one follow-up assessment were included (n. = 878). The association of curiosity about smoking with future smoking behavior was assessed. Then, curiosity was added to form an enhanced susceptibility index and sensitivity, specificity and positive predictive value were calculated. Results: Among committed never smokers at baseline, those who were 'definitely not curious' were less likely to progress toward smoking than both those who were 'probably not curious' (ORadj=1.89; 95% CI=1.03-3.47) or 'probably/definitely curious' (ORadj=2.88; 95% CI=1.11-7.45). Incorporating curiosity into the susceptibility index increased the proportion identified as at-risk to smoke from 25.1% to 46.9%. The sensitivity (true positives) for this enhanced susceptibility index for both experimentation and established smoking increased from 37-40% to over 50%, although the positive predictive value did not improve. Conclusion: The addition of curiosity significantly improves the identification and classification of which adolescents will experiment with smoking or become established smokers. © 2014 Elsevier Ltd.


Behl M.,Kelly Government Solutions Inc. | Behl M.,U.S. National Institutes of Health | Rao D.,Integrated Laboratory Systems, Inc. | Aagaard K.,Baylor College of Medicine | And 9 more authors.
Environmental Health Perspectives | Year: 2013

Background: An emerging literature suggests that environmental chemicals may play a role in the development of childhood obesity and metabolic disorders, especially when exposure occurs early in life. Objective: Here we assess the association between these health outcomes and exposure to maternal smoking during pregnancy as part of a broader effort to develop a research agenda to better understand the role of environmental chemicals as potential risk factors for obesity and metabolic disorders. Methods: PubMed was searched up to 8 March 2012 for epidemiological and experimental animal studies related to maternal smoking or nicotine exposure during pregnancy and childhood obesity or metabolic disorders at any age. A total of 101 studies-83 in humans and 18 in animals-were identified as the primary literature. Discussion: Current epidemiological data support a positive association between maternal smoking and increased risk of obesity or overweight in ofspring. The data strongly suggest a causal relation, although the possibility that the association is attributable to unmeasured residual confounding cannot be completely ruled out. This conclusion is supported by findings from laboratory animals exposed to nicotine during development. Te existing literature on human exposures does not support an association between maternal smoking during pregnancy and type 1 diabetes in ofspring. Too few human studies have assessed outcomes related to type 2 diabetes or metabolic syndrome to reach conclusions based on patterns of findings. There may be a number of mechanistic pathways important for the development of aberrant metabolic outcomes following perinatal exposure to cigarette smoke, which remain largely unexplored. Conclusions: From a toxicological perspective, the linkages between maternal smoking during pregnancy and childhood overweight/obesity provide proof-of-concept of how early-life exposure to an environmental toxicant can be a risk factor for childhood obesity.


Davis M.,U.S. National Cancer Institute | Li J.,Kelly Government Solutions Inc. | Li J.,National Health Research Institute | Knight E.,U.S. National Cancer Institute | And 3 more authors.
Frontiers in Genetics | Year: 2015

Combinations of anticancer agents may have synergistic anti-tumor effects, but enhanced hematological toxicity often limit their clinical use. We examined whether "microarray profiles" could be used to compare early molecular responses following a single dose of agents administered individually with that of the agents administered in a combination. We compared the mRNA responses within bone marrow of Sprague-Dawley rats after a single 30 min treatment with topotecan at 4.7 mg/kg or oxaliplatin at 15 mg/kg alone to that of sequentially administered combination therapy or vehicle control for 1, 6, and 24 h. We also examined the histopathology of the bone marrow following all treatments. Drug-related histopathological lesions were limited to bone marrow hypocellularity for animals dosed with either agent alone or in combination. Lesions had an earlier onset and higher incidence for animals given topotecan alone or in combination with oxaliplatin. Severity increased from mild to moderate when topotecan was administered prior to oxaliplatin compared with administering oxaliplatin first. Notably, six patterns of co-expressed genes were detected at the 1 h time point that indicate regulatory expression of genes that are dependent on the order of the administration. These results suggest alterations in histone biology, chromatin remodeling, DNA repair, bone regeneration, and respiratory and oxidative phosphorylation are among the prominent pathways modulated in bone marrow from animals treated with an oxaliplatin/topotecan combination. These data also demonstrate the potential for early mRNA patterns derived from target organs of toxicity to inform toxicological risk and molecular mechanisms for agents given in combination. © 2015 Davis, Li, Knight, Eldridge, Daniels and Bushel.


Greytak S.R.,Kelly Government Solutions Inc. | Engel K.B.,Preferred Solutions Group | Bass B.P.,Kelly Government Solutions Inc. | Moore H.M.,U.S. National Cancer Institute
Cancer Research | Year: 2015

Formalin-fixed and paraffin-embedded (FFPE) tissue biospecimens are a valuable resource for molecular cancer research. Although much can be gained from their use, it remains unclear whether the genomic and expression profiles obtained from FFPE biospecimens accurately reflect the physiologic condition of the patient from which they were procured, or if such profiles are confounded by biologic effects from formalin fixation and processing. To assess the physiologic accuracy of genomic and expression data generated with FFPE specimens, we surveyed the literature for articles investigating genomic and expression endpoints in case-matched FFPE and fresh or frozen human biospecimens using the National Cancer Institute's Biospecimen Research Database (http://biospecimens.cancer.gov/brd). Results of the survey revealed that the level of concordance between differentially preserved biospecimens varied among analytical parameters and platforms but also among reports, genes/transcripts of interest, and tumor status. The identified analytical techniques and parameters that resulted in strong correlations between FFPE and frozen biospecimens may provide guidance when optimizing molecular protocols for FFPE use; however, discrepancies reported for similar assays also illustrate the importance of validating protocols optimized for use with FFPE specimens with a case-matched fresh or frozen cohort for each platform, gene or transcript, and FFPE processing regime. On the basis of evidence published to date, validation of analytical parameters with a properly handled frozen cohort is necessary to ensure a high degree of concordance and confidence in the results obtained with FFPE biospecimens. © 2015 American Association for Cancer Research.


PubMed | Kelly Government Solutions Inc., National Cancer Institute and Preferred Solutions Group
Type: Journal Article | Journal: Cancer research | Year: 2015

Formalin-fixed and paraffin-embedded (FFPE) tissue biospecimens are a valuable resource for molecular cancer research. Although much can be gained from their use, it remains unclear whether the genomic and expression profiles obtained from FFPE biospecimens accurately reflect the physiologic condition of the patient from which they were procured, or if such profiles are confounded by biologic effects from formalin fixation and processing. To assess the physiologic accuracy of genomic and expression data generated with FFPE specimens, we surveyed the literature for articles investigating genomic and expression endpoints in case-matched FFPE and fresh or frozen human biospecimens using the National Cancer Institutes Biospecimen Research Database (http://biospecimens.cancer.gov/brd). Results of the survey revealed that the level of concordance between differentially preserved biospecimens varied among analytical parameters and platforms but also among reports, genes/transcripts of interest, and tumor status. The identified analytical techniques and parameters that resulted in strong correlations between FFPE and frozen biospecimens may provide guidance when optimizing molecular protocols for FFPE use; however, discrepancies reported for similar assays also illustrate the importance of validating protocols optimized for use with FFPE specimens with a case-matched fresh or frozen cohort for each platform, gene or transcript, and FFPE processing regime. On the basis of evidence published to date, validation of analytical parameters with a properly handled frozen cohort is necessary to ensure a high degree of concordance and confidence in the results obtained with FFPE biospecimens.


PubMed | Eli Lilly and Company, Kelly Government Solutions Inc., National Institute of Environmental Health and Safety, Clinical Research Laboratories and 2 more.
Type: | Journal: BMC genomics | Year: 2016

MicroRNAs (miRNA) are ~19-25 nucleotide long RNA molecules that fine tune gene expression through the inhibition of translation or degradation of the mRNA through incorporation into the RNA induced silencing complex (RISC). MicroRNAs are stable in the serum and plasma, are detectable in a wide variety of body fluids, are conserved across veterinary species and humans and are expressed in a tissue specific manner. They can be detected at low concentrations in circulation in animals and humans, generating interest in the utilization of miRNAs as serum and/or plasma based biomarkers of tissue injury. MicroRNA tissue profiling in rodents has been published, but sample an insufficient number of organs of toxicologic interest using microarray or qPCR technologies for miRNA detection. Here we impart an improved rat microRNA body atlas consisting of 21 and 23 tissues of toxicologic interest from male and female Sprague Dawley rats respectively, using Illumina miRNA sequencing. Several of the authors created a dog miRNA body atlas and we collaborated to test miRNAs conserved in rat and dog pancreas in caerulein toxicity studies utilizing both species.A rich data set is presented that more robustly defines the tissue specificity and enrichment profiles of previously published and undiscovered rat miRNAs. We generated 1,927 sequences that mapped to mature miRNAs in rat, mouse and human from miRBase and discovered an additional 1,162 rat miRNAs as compared to the current number of rat miRNAs in miRBase version 21. Tissue specific and enriched miRNAs were identified and a subset of these miRNAs were validated by qPCR for tissue specificity or enrichment. As an example of the power of this approach, we have conducted rat and dog pancreas toxicity studies and examined the levels of some tissue specific and enriched miRNAs conserved between rat and dog in the serum of each species. The studies demonstrate that conserved tissue specific/enriched miRs-216a-5p, 375-3p, 148a-3p, 216b-5p and 141-3p are candidate biomarkers of pancreatic injury in the rat and dog.A microRNA body atlas for rat and dog was useful in identifying new candidate miRNA biomarkers of organ toxicity in 2 toxicologically relevant species.


Conway K.P.,U.S. National Institute on Drug Abuse | Vullo G.C.,U.S. National Institute on Drug Abuse | Vullo G.C.,Kelly Government Solutions Inc. | Nichter B.,National Health Research Institute | And 4 more authors.
Journal of Adolescent Health | Year: 2013

Purpose: The current study examines the prevalence and demographic correlates of self-reported substance use and identifies subgroups of polysubstance users among a cohort of United States 10th-grade students. Methods: A nationally representative school-based cohort of United States 10th-grade students completed the NEXT Generation Health Study baseline survey in spring 2010 (N = 2,524). Results: Past-year use of marijuana was most common among illicit drugs (26%), followed by misuse of medication (9%) and use of other illicit drugs (8%). During the past month, alcohol use was reported by more than one third (35%), binge drinking by 27%, and cigarette smoking by 19%. Results further show that substance use varied somewhat by demographic characteristics. Results from the latent class analysis of polysubstance use indicated a four-class solution as the best-fitting model; class 1 (59%) included the nonuser group; class 2 (23%) comprised the predominant alcohol user group; class 3 (11%) formed the predominant marijuana user group; and class 4 (8%) was characterized as the predominant polysubstance user group. Somatic and depressive symptoms varied significantly by class membership, with predominant polysubstance users reporting elevated levels of somatic and depressive symptoms. Conclusions: The findings from this national study of 10th-grade students indicate high rates of substance and polysubstance use. The high level of depressive and somatic symptoms among polysubstance users indicates the need for mental health screening and referral. © Published by Elsevier Inc. on behalf of Society for Adolescent Health and Medicine.


PubMed | National Health Research Institute, U.S. Environmental Protection Agency, Kelly Government Solutions Inc. and University of Louisville
Type: Journal Article | Journal: Neurotoxicology and teratology | Year: 2015

Due to their toxicity and persistence in the environment, brominated flame retardants (BFRs) are being phased out of commercial use, leading to the increased use of alternative chemicals such as the organophosphorus flame retardants (OPFRs). There is, however, limited information on the potential health effects of OPFRs. Due to the structural similarity of the OPFRs to organophosphorus insecticides, there is concern regarding developmental toxicity and neurotoxicity. In response, we evaluated a set of OPFRs (triphenyl phosphate [TPHP]), isopropylated phenyl phosphate [IPP], 2-ethylhexyl diphenyl phosphate [EHDP], tert-butylated phenyl diphenyl phosphate [BPDP], trimethyl phenyl phosphate [TMPP], isodecyl diphenyl phosphate [IDDP], (tris(1,3-dichloroisopropyl) phosphate [TDCIPP], and tris(2-chloroethyl)phosphate [TCEP]) in a battery of cell-based in vitro assays and alternative model organisms and compared the results to those obtained for two classical BFRs (3,3,5,5-tetrabromobisphenol A [TBBPA] and 2,24,4-brominated diphenyl ether [BDE-47]). The assays used evaluated the effects of chemicals on the differentiation of mouse embryonic stem cells, the proliferation and growth of human neural stem cells, rat neuronal growth and network activity, and development of nematode (Caenorhabditis elegans) and zebrafish (Danio rerio). All assays were performed in a concentration-response format, allowing for the determination of the point of departure (POD: the lowest concentration where a chemically-induced response exceeds background noise). The majority of OPFRs (8/9) were active in multiple assays in the range of 1-10 M, most of which had comparable activity to the BFRs TBBPA and BDE-47. TCEP was negative in all assays. The results indicate that the replacement OPFRs, with the exception of TCEP, showed comparable activity to the two BFRs in the assays tested. Based on these results, more comprehensive studies are warranted to further characterize the potential hazard of some of these OPFR compounds.


Camp K.M.,Kelly Government Solutions Inc. | Trujillo E.,U.S. National Institutes of Health
Journal of the Academy of Nutrition and Dietetics | Year: 2014

It is the position of the Academy of Nutrition and Dietetics that nutritional genomics provides insight into how diet and genotype interactions affect phenotype. The practical application of nutritional genomics for complex chronic disease is an emerging science and the use of nutrigenetic testing to provide dietary advice is not ready for routine dietetics practice. Registered dietitian nutritionists need basic competency in genetics as a foundation for understanding nutritional genomics; proficiency requires advanced knowledge and skills. Unlike single-gene defects in which a mutation in a single gene results in a specific disorder, most chronic diseases, such as cardiovascular disease, diabetes, and cancer are multigenetic and multifactorial and therefore genetic mutations are only partially predictive of disease risk. Family history, biochemical parameters, and the presence of risk factors in individuals are relevant tools for personalizing dietary interventions. Direct-to-consumer genetic testing is not closely regulated in the United States and may not be accompanied by access to health care practitioners. Applying nutritional genomics in clinical practice through the use of genetic testing requires that registered dietitian nutritionists understand, interpret, and communicate complex test results in which the actual risk of developing a disease may not be known. The practical application of nutritional genomics in dietetics practice will require an evidence-based approach to validate that personalized recommendations result in health benefits to individuals and do not cause harm. © 2014 Academy of Nutrition and Dietetics.

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