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Search Results: 1 - 10 of 216567 matches for " Patricia L. Blount "
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Application of Biomarkers in Cancer Risk Management: Evaluation from Stochastic Clonal Evolutionary and Dynamic System Optimization Points of View
Xiaohong Li ,Patricia L. Blount,Thomas L. Vaughan,Brian J. Reid
PLOS Computational Biology , 2011, DOI: 10.1371/journal.pcbi.1001087
Abstract: Aside from primary prevention, early detection remains the most effective way to decrease mortality associated with the majority of solid cancers. Previous cancer screening models are largely based on classification of at-risk populations into three conceptually defined groups (normal, cancer without symptoms, and cancer with symptoms). Unfortunately, this approach has achieved limited successes in reducing cancer mortality. With advances in molecular biology and genomic technologies, many candidate somatic genetic and epigenetic “biomarkers” have been identified as potential predictors of cancer risk. However, none have yet been validated as robust predictors of progression to cancer or shown to reduce cancer mortality. In this Perspective, we first define the necessary and sufficient conditions for precise prediction of future cancer development and early cancer detection within a simple physical model framework. We then evaluate cancer risk prediction and early detection from a dynamic clonal evolution point of view, examining the implications of dynamic clonal evolution of biomarkers and the application of clonal evolution for cancer risk management in clinical practice. Finally, we propose a framework to guide future collaborative research between mathematical modelers and biomarker researchers to design studies to investigate and model dynamic clonal evolution. This approach will allow optimization of available resources for cancer control and intervention timing based on molecular biomarkers in predicting cancer among various risk subsets that dynamically evolve over time.
The Role of Tobacco, Alcohol, and Obesity in Neoplastic Progression to Esophageal Adenocarcinoma: A Prospective Study of Barrett's Esophagus
Sheetal Hardikar, Lynn Onstad, Patricia L. Blount, Robert D. Odze, Brian J. Reid, Thomas L. Vaughan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0052192
Abstract: Background Esophageal adenocarcinoma (EA) incidence in many developed countries has increased dramatically over four decades, while survival remains poor. Persons with Barrett's esophagus (BE), who experience substantially elevated EA risk, are typically followed in surveillance involving periodic endoscopy with biopsies, although few progress to EA. No medical, surgical or lifestyle interventions have been proven to safely lower EA risk. Design We investigated whether smoking, obesity or alcohol could predict progression to EA in a prospective cohort of 411 BE patients. Data were collected during personal interview. Adjusted hazard ratios (HR) were estimated using Cox regression. Results 39% had body mass index (BMI) over 30 and 64% had smoked cigarettes. Main analyses focused on those with at least 5 months of follow-up (33,635 person-months), in whom 45 developed EA. Risk increased by 3% per year of age (trend p-value 0.02), with approximate doubling of risk among males. EA risk increased with smoking pack-years (trend p-value 0.04) and duration (p-value 0.05). Compared to never-smokers, the HR for those in the highest pack-year tertile was 2.29 (95%CI 1.04–5.07). No association was found with alcohol or BMI, whereas a suggestion of increased risk was observed in those with higher waist-hip ratio, especially among males. Conclusion EA risk significantly increased with increasing age and cigarette exposure. Abdominal obesity, but not BMI, was associated with a modest increased risk. Continued follow-up of this and other cohorts is needed to precisely define these relationships so as to inform risk stratification and preventive interventions.
p16 Mutation Spectrum in the Premalignant Condition Barrett's Esophagus
Thomas G. Paulson, Patricia C. Galipeau, Lianjun Xu, Heather D. Kissel, Xiaohong Li, Patricia L. Blount, Carissa A. Sanchez, Robert D. Odze, Brian J. Reid
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003809
Abstract: Background Mutation, promoter hypermethylation and loss of heterozygosity involving the tumor suppressor gene p16 (CDKN2a/INK4a) have been detected in a wide variety of human cancers, but much less is known concerning the frequency and spectrum of p16 mutations in premalignant conditions. Methods and Findings We have determined the p16 mutation spectrum for a cohort of 304 patients with Barrett's esophagus, a premalignant condition that predisposes to the development of esophageal adenocarcinoma. Forty seven mutations were detected by sequencing of p16 exon 2 in 44 BE patients (14.5%) with a mutation spectrum consistent with that caused by oxidative damage and chronic inflammation. The percentage of patients with p16 mutations increased with increasing histologic grade. In addition, samples from 3 out of 19 patients (15.8%) who underwent esophagectomy were found to have mutations. Conclusions The results of this study suggest the environment of the esophagus in BE patients can both generate and select for clones with p16 mutations.
NSAIDs Modulate Clonal Evolution in Barrett's Esophagus
Rumen L. Kostadinov,Mary K. Kuhner,Xiaohong Li,Carissa A. Sanchez,Patricia C. Galipeau,Thomas G. Paulson,Cassandra L. Sather,Amitabh Srivastava,Robert D. Odze,Patricia L. Blount,Thomas L. Vaughan,Brian J. Reid,Carlo C. Maley
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003553
Abstract: Cancer is considered an outcome of decades-long clonal evolution fueled by acquisition of somatic genomic abnormalities (SGAs). Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce cancer risk, including risk of progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA). However, the cancer chemopreventive mechanisms of NSAIDs are not fully understood. We hypothesized that NSAIDs modulate clonal evolution by reducing SGA acquisition rate. We evaluated thirteen individuals with BE. Eleven had not used NSAIDs for 6.2±3.5 (mean±standard deviation) years and then began using NSAIDs for 5.6±2.7 years, whereas two had used NSAIDs for 3.3±1.4 years and then discontinued use for 7.9±0.7 years. 161 BE biopsies, collected at 5–8 time points over 6.4–19 years, were analyzed using 1Million-SNP arrays to detect SGAs. Even in the earliest biopsies there were many SGAs (284±246 in 10/13 and 1442±560 in 3/13 individuals) and in most individuals the number of SGAs changed little over time, with both increases and decreases in SGAs detected. The estimated SGA rate was 7.8 per genome per year (95% support interval [SI], 7.1–8.6) off-NSAIDs and 0.6 (95% SI 0.3–1.5) on-NSAIDs. Twelve individuals did not progress to EA. In ten we detected 279±86 SGAs affecting 53±30 Mb of the genome per biopsy per time point and in two we detected 1,463±375 SGAs affecting 180±100 Mb. In one individual who progressed to EA we detected a clone having 2,291±78 SGAs affecting 588±18 Mb of the genome at three time points in the last three of 11.4 years of follow-up. NSAIDs were associated with reduced rate of acquisition of SGAs in eleven of thirteen individuals. Barrett's cells maintained relative equilibrium level of SGAs over time with occasional punctuations by expansion of clones having massive amount of SGAs.
NSAIDs Modulate CDKN2A, TP53, and DNA Content Risk for Progression to Esophageal Adenocarcinoma
Patricia C Galipeau equal contributor ,Xiaohong Li equal contributor,Patricia L Blount,Carlo C Maley,Carissa A Sanchez,Robert D Odze,Kamran Ayub,Peter S Rabinovitch,Thomas L Vaughan,Brian J Reid
PLOS Medicine , 2007, DOI: 10.1371/journal.pmed.0040067
Abstract: Background Somatic genetic CDKN2A, TP53, and DNA content abnormalities are common in many human cancers and their precursors, including esophageal adenocarcinoma (EA) and Barrett's esophagus (BE), conditions for which aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as possible chemopreventive agents; however, little is known about the ability of a biomarker panel to predict progression to cancer nor how NSAID use may modulate progression. We aimed to evaluate somatic genetic abnormalities with NSAIDs as predictors of EA in a prospective cohort study of patients with BE. Methods and Findings Esophageal biopsies from 243 patients with BE were evaluated at baseline for TP53 and CDKN2A (p16) alterations, tetraploidy, and aneuploidy using sequencing; loss of heterozygosity (LOH); methylation-specific PCR; and flow cytometry. At 10 y, all abnormalities, except CDKN2A mutation and methylation, contributed to EA risk significantly by univariate analysis, ranging from 17p LOH (relative risk [RR] = 10.6; 95% confidence interval [CI] 5.2–21.3, p < 0.001) to 9p LOH (RR = 2.6; 95% CI 1.1–6.0, p = 0.03). A panel of abnormalities including 17p LOH, DNA content tetraploidy and aneuploidy, and 9p LOH was the best predictor of EA (RR = 38.7; 95% CI 10.8–138.5, p < 0.001). Patients with no baseline abnormality had a 12% 10-y cumulative EA incidence, whereas patients with 17p LOH, DNA content abnormalities, and 9p LOH had at least a 79.1% 10-y EA incidence. In patients with zero, one, two, or three baseline panel abnormalities, there was a significant trend toward EA risk reduction among NSAID users compared to nonusers (p = 0.01). The strongest protective effect was seen in participants with multiple genetic abnormalities, with NSAID nonusers having an observed 10-y EA risk of 79%, compared to 30% for NSAID users (p < 0.001). Conclusions A combination of 17p LOH, 9p LOH, and DNA content abnormalities provided better EA risk prediction than any single TP53, CDKN2A, or DNA content lesion alone. NSAIDs are associated with reduced EA risk, especially in patients with multiple high-risk molecular abnormalities.
Selenium, Selenoenzymes, Oxidative Stress and Risk of Neoplastic Progression from Barrett's Esophagus: Results from Biomarkers and Genetic Variants
Yumie Takata, Alan R. Kristal, Regina M. Santella, Irena B. King, David J. Duggan, Johanna W. Lampe, Margaret P. Rayman, Patricia L. Blount, Brian J. Reid, Thomas L. Vaughan, Ulrike Peters
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038612
Abstract: Clinical trials have suggested a protective effect of selenium supplementation on the risk of esophageal cancer, which may be mediated through the antioxidant activity of selenoenzymes. We investigated whether serum selenium concentrations, selenoenzyme activity, oxidative stress and genetic variation in selenoenzymes were associated with the risk of neoplastic progression to esophageal adenocarcinoma (EA) and two intermediate endpoints, aneuploidy and tetraploidy. In this prospective cohort study, during an average follow-up of 7.3 years, 47 EA cases, 41 aneuploidy cases and 51 tetraploidy cases accrued among 361 participants from the Seattle Barrett's Esophagus Research Study who were free of EA at the time of blood draw and had at least one follow-up visit. Development to EA was assessed histologically and aneuploidy and tetraploidy by DNA content flow cytometry. Serum selenium concentrations were measured using atomic absorption spectrometry, activity of glutathione peroxidase (GPX) 1 and GPX3 by substrate-specific coupled test procedures, selenoprotein P (SEPP1) concentrations and protein carbonyl content by ELISA method and malondialdehyde concentrations by HPLC. Genetic variants in GPX1-4 and SEPP1 were genotyped. Serum selenium was not associated with the risk of neoplastic progression to EA, aneuploidy or tetraploidy (P for trend = 0.25 to 0.85). SEPP1 concentrations were positively associated with the risk of EA [hazard ratio (HR) = 3.95, 95% confidence intervals (CI) = 1.42–10.97 comparing the third tertile with the first] and with aneuploidy (HR = 6.53, 95% CI = 1.31–32.58), but not selenoenzyme activity or oxidative stress markers. No genetic variants, overall, were associated with the risk of neoplastic progression to EA (global p = 0.12–0.69). Our results do not support a protective effect of selenium on risk of neoplastic progression to EA. Our study is the first to report positive associations of plasma SEPP1 concentrations with the risk of EA and aneuploidy, which warrants further investigation.
Application of Physiologically Based Pharmacokinetic Models in Chemical Risk Assessment
Moiz Mumtaz,Jeffrey Fisher,Benjamin Blount,Patricia Ruiz
Journal of Toxicology , 2012, DOI: 10.1155/2012/904603
Abstract: Post-exposure risk assessment of chemical and environmental stressors is a public health challenge. Linking exposure to health outcomes is a 4-step process: exposure assessment, hazard identification, dose response assessment, and risk characterization. This process is increasingly adopting “in silico” tools such as physiologically based pharmacokinetic (PBPK) models to fine-tune exposure assessments and determine internal doses in target organs/tissues. Many excellent PBPK models have been developed. But most, because of their scientific sophistication, have found limited field application—health assessors rarely use them. Over the years, government agencies, stakeholders/partners, and the scientific community have attempted to use these models or their underlying principles in combination with other practical procedures. During the past two decades, through cooperative agreements and contracts at several research and higher education institutions, ATSDR funded translational research has encouraged the use of various types of models. Such collaborative efforts have led to the development and use of transparent and user-friendly models. The “human PBPK model toolkit” is one such project. While not necessarily state of the art, this toolkit is sufficiently accurate for screening purposes. Highlighted in this paper are some selected examples of environmental and occupational exposure assessments of chemicals and their mixtures. 1. Background As industrial society inhabitants, we are exposed to hundreds of chemicals and to an increasing number of chemical combinations, as mixtures. Exposure to multiple chemicals simultaneously or sequentially is the rule rather than the exception [1]. Chemical risk assessments estimate public health consequences from exposure—specifically, exposure to environmental, occupational, or therapeutic chemicals. Most often, estimates of unintentional exposures are based on imprecise metrics of external (air, water, and soil) concentrations and default exposure factors. Chemical exposure assessment thus continues to challenge public health and environmental protection. Evaluation of human exposure data in the context of public health (i.e., the linking of exposures to health outcome through the establishment of the cause-effect relationship) is a complex process. To establish this relationship, several traditional programs have been used, including health surveillance and disease registries. Through these programs, researchers closely monitor chemical releases in the environment and conduct health studies. When exposed cohorts of
REACH: una herramienta para la prevención del riesgo químico.
E. Blount
Revista de Toxicología , 2005,
Tris(2-benzamidoethyl)ammonium tetrafluoroborate
Marcy L. Pilate,Henry Blount,Frank R. Fronczek,Md. Alamgir Hossain
Acta Crystallographica Section E , 2010, DOI: 10.1107/s1600536810024323
Abstract: In the title compound, C27H31N4O3+·BF4 , the central N atom is protonated. The three arms form a pocket and one amidic O atom accepts an intermolecular hydrogen bond with the protonated amine. The tetrafluoroborate anion is outside the cavity and is hydrogen bonded to one amide N atom. Adjacent organic cations are connected by a pair of N—H...O hydrogen bonds, forming a chain.
Volatility in High-Frequency Intensive Care Mortality Time Series: Application of Univariate and Multivariate GARCH Models  [PDF]
John L. Moran, Patricia J. Solomon
Open Journal of Applied Sciences (OJAppS) , 2017, DOI: 10.4236/ojapps.2017.78030
Abstract: Mortality time series display time-varying volatility. The utility of statistical estimators from the financial time-series paradigm, which account for this characteristic, has not been addressed for high-frequency mortality series. Using daily mean-mortality series of an exemplar intensive care unit (ICU) from the Australian and New Zealand Intensive Care Society adult patient database, joint estimation of a mean and conditional variance (volatility) model for a stationary series was undertaken via univariate autoregressive moving average (ARMA, lags (p, q)), GARCH (Generalised Autoregressive Conditional Heteroscedasticity, lags (p, q)). The temporal dynamics of the conditional variance and correlations of multiple provider series, from rural/ regional, metropolitan, tertiary and private ICUs, were estimated utilising multivariate GARCH models. For the stationary first differenced series, an asymmetric power GARCH model (lags (1, 1)) with t distribution (degrees-of- freedom, 11.6) and ARMA (7,0) for the mean-model, was the best-fitting. The four multivariate component series demonstrated varying trend mortality decline and persistent autocorrelation. Within each MGARCH series no model specification dominated. The conditional correlations were surprisingly low (<0.1) between tertiary series and substantial (0.4 - 0.6) between rural-regional and private series. The conditional-variances of both the univariate and multivariate series demonstrated a slow rate of time decline from periods of early volatility and volatility spikes.
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