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Sample records for adjusted cox model

  1. A note on calculating asymptotic confidence intervals for the adjusted risk difference and number needed to treat in the Cox regression model.

    PubMed

    Laubender, Ruediger P; Bender, Ralf

    2014-02-28

    Recently, Laubender and Bender (Stat. Med. 2010; 29: 851-859) applied the average risk difference (RD) approach to estimate adjusted RD and corresponding number needed to treat measures in the Cox proportional hazards model. We calculated standard errors and confidence intervals by using bootstrap techniques. In this paper, we develop asymptotic variance estimates of the adjusted RD measures and corresponding asymptotic confidence intervals within the counting process theory and evaluated them in a simulation study. We illustrate the use of the asymptotic confidence intervals by means of data of the Düsseldorf Obesity Mortality Study.

  2. Tree-augmented Cox proportional hazards models.

    PubMed

    Su, Xiaogang; Tsai, Chih-Ling

    2005-07-01

    We study a hybrid model that combines Cox proportional hazards regression with tree-structured modeling. The main idea is to use step functions, provided by a tree structure, to 'augment' Cox (1972) proportional hazards models. The proposed model not only provides a natural assessment of the adequacy of the Cox proportional hazards model but also improves its model fitting without loss of interpretability. Both simulations and an empirical example are provided to illustrate the use of the proposed method.

  3. Objective Bayesian model selection for Cox regression.

    PubMed

    Held, Leonhard; Gravestock, Isaac; Sabanés Bové, Daniel

    2016-12-20

    There is now a large literature on objective Bayesian model selection in the linear model based on the g-prior. The methodology has been recently extended to generalized linear models using test-based Bayes factors. In this paper, we show that test-based Bayes factors can also be applied to the Cox proportional hazards model. If the goal is to select a single model, then both the maximum a posteriori and the median probability model can be calculated. For clinical prediction of survival, we shrink the model-specific log hazard ratio estimates with subsequent calculation of the Breslow estimate of the cumulative baseline hazard function. A Bayesian model average can also be employed. We illustrate the proposed methodology with the analysis of survival data on primary biliary cirrhosis patients and the development of a clinical prediction model for future cardiovascular events based on data from the Second Manifestations of ARTerial disease (SMART) cohort study. Cross-validation is applied to compare the predictive performance with alternative model selection approaches based on Harrell's c-Index, the calibration slope and the integrated Brier score. Finally, a novel application of Bayesian variable selection to optimal conditional prediction via landmarking is described. Copyright © 2016 John Wiley & Sons, Ltd.

  4. Covariate analysis of survival data: a small-sample study of Cox's model

    SciTech Connect

    Johnson, M.E.; Tolley, H.D.; Bryson, M.C.; Goldman, A.S.

    1982-09-01

    Cox's proportional-hazards model is frequently used to adjust for covariate effects in survival-data analysis. The small-sample performances of the maximum partial likelihood estimators of the regression parameters in a two-covariate hazard function model are evaluated with respect to bias, variance, and power in hypothesis tests. Previous Monte Carlo work on the two-sample problem is reviewed.

  5. Prior event rate ratio adjustment for hidden confounding in observational studies of treatment effectiveness: a pairwise Cox likelihood approach.

    PubMed

    Lin, Nan Xuan; Henley, William Edward

    2016-12-10

    Observational studies provide a rich source of information for assessing effectiveness of treatment interventions in many situations where it is not ethical or practical to perform randomized controlled trials. However, such studies are prone to bias from hidden (unmeasured) confounding. A promising approach to identifying and reducing the impact of unmeasured confounding is prior event rate ratio (PERR) adjustment, a quasi-experimental analytic method proposed in the context of electronic medical record database studies. In this paper, we present a statistical framework for using a pairwise approach to PERR adjustment that removes bias inherent in the original PERR method. A flexible pairwise Cox likelihood function is derived and used to demonstrate the consistency of the simple and convenient alternative PERR (PERR-ALT) estimator. We show how to estimate standard errors and confidence intervals for treatment effect estimates based on the observed information and provide R code to illustrate how to implement the method. Assumptions required for the pairwise approach (as well as PERR) are clarified, and the consequences of model misspecification are explored. Our results confirm the need for researchers to consider carefully the suitability of the method in the context of each problem. Extensions of the pairwise likelihood to more complex designs involving time-varying covariates or more than two periods are considered. We illustrate the application of the method using data from a longitudinal cohort study of enzyme replacement therapy for lysosomal storage disorders. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

  6. Model Selection for Cox Models with Time-Varying Coefficients

    PubMed Central

    Yan, Jun; Huang, Jian

    2011-01-01

    Summary Cox models with time-varying coefficients offer great flexibility in capturing the temporal dynamics of covariate effects on right censored failure times. Since not all covariate coefficients are time-varying, model selection for such models presents an additional challenge, which is to distinguish covariates with time-varying coefficient from those with time-independent coefficient. We propose an adaptive group lasso method that not only selects important variables but also selects between time-independent and time-varying specifications of their presence in the model. Each covariate effect is partitioned into a time-independent part and a time-varying part, the latter of which is characterized by a group of coefficients of basis splines without intercept. Model selection and estimation are carried out through a fast, iterative group shooting algorithm. Our approach is shown to have good properties in a simulation study that mimics realistic situations with up to 20 variables. A real example illustrates the utility of the method. PMID:22506825

  7. Box-Cox Mixed Logit Model for Travel Behavior Analysis

    NASA Astrophysics Data System (ADS)

    Orro, Alfonso; Novales, Margarita; Benitez, Francisco G.

    2010-09-01

    To represent the behavior of travelers when they are deciding how they are going to get to their destination, discrete choice models, based on the random utility theory, have become one of the most widely used tools. The field in which these models were developed was halfway between econometrics and transport engineering, although the latter now constitutes one of their principal areas of application. In the transport field, they have mainly been applied to mode choice, but also to the selection of destination, route, and other important decisions such as the vehicle ownership. In usual practice, the most frequently employed discrete choice models implement a fixed coefficient utility function that is linear in the parameters. The principal aim of this paper is to present the viability of specifying utility functions with random coefficients that are nonlinear in the parameters, in applications of discrete choice models to transport. Nonlinear specifications in the parameters were present in discrete choice theory at its outset, although they have seldom been used in practice until recently. The specification of random coefficients, however, began with the probit and the hedonic models in the 1970s, and, after a period of apparent little practical interest, has burgeoned into a field of intense activity in recent years with the new generation of mixed logit models. In this communication, we present a Box-Cox mixed logit model, original of the authors. It includes the estimation of the Box-Cox exponents in addition to the parameters of the random coefficients distribution. Probability of choose an alternative is an integral that will be calculated by simulation. The estimation of the model is carried out by maximizing the simulated log-likelihood of a sample of observed individual choices between alternatives. The differences between the predictions yielded by models that are inconsistent with real behavior have been studied with simulation experiments.

  8. A simulation study of finite-sample properties of marginal structural Cox proportional hazards models.

    PubMed

    Westreich, Daniel; Cole, Stephen R; Schisterman, Enrique F; Platt, Robert W

    2012-08-30

    Motivated by a previously published study of HIV treatment, we simulated data subject to time-varying confounding affected by prior treatment to examine some finite-sample properties of marginal structural Cox proportional hazards models. We compared (a) unadjusted, (b) regression-adjusted, (c) unstabilized, and (d) stabilized marginal structural (inverse probability-of-treatment [IPT] weighted) model estimators of effect in terms of bias, standard error, root mean squared error (MSE), and 95% confidence limit coverage over a range of research scenarios, including relatively small sample sizes and 10 study assessments. In the base-case scenario resembling the motivating example, where the true hazard ratio was 0.5, both IPT-weighted analyses were unbiased, whereas crude and adjusted analyses showed substantial bias towards and across the null. Stabilized IPT-weighted analyses remained unbiased across a range of scenarios, including relatively small sample size; however, the standard error was generally smaller in crude and adjusted models. In many cases, unstabilized weighted analysis showed a substantial increase in standard error compared with other approaches. Root MSE was smallest in the IPT-weighted analyses for the base-case scenario. In situations where time-varying confounding affected by prior treatment was absent, IPT-weighted analyses were less precise and therefore had greater root MSE compared with adjusted analyses. The 95% confidence limit coverage was close to nominal for all stabilized IPT-weighted but poor in crude, adjusted, and unstabilized IPT-weighted analysis. Under realistic scenarios, marginal structural Cox proportional hazards models performed according to expectations based on large-sample theory and provided accurate estimates of the hazard ratio.

  9. Gaussian estimation for discretely observed Cox-Ingersoll-Ross model

    NASA Astrophysics Data System (ADS)

    Wei, Chao; Shu, Huisheng; Liu, Yurong

    2016-07-01

    This paper is concerned with the parameter estimation problem for Cox-Ingersoll-Ross model based on discrete observation. First, a new discretized process is built based on the Euler-Maruyama scheme. Then, the parameter estimators are obtained by employing the maximum likelihood method and the explicit expressions of the error of estimation are given. Subsequently, the consistency property of all parameter estimators are proved by applying the law of large numbers for martingales, Holder's inequality, B-D-G inequality and Cauchy-Schwarz inequality. Finally, a numerical simulation example for estimators and the absolute error between estimators and true values is presented to demonstrate the effectiveness of the estimation approach used in this paper.

  10. Sieve estimation of Cox models with latent structures.

    PubMed

    Cao, Yongxiu; Huang, Jian; Liu, Yanyan; Zhao, Xingqiu

    2016-12-01

    This article considers sieve estimation in the Cox model with an unknown regression structure based on right-censored data. We propose a semiparametric pursuit method to simultaneously identify and estimate linear and nonparametric covariate effects based on B-spline expansions through a penalized group selection method with concave penalties. We show that the estimators of the linear effects and the nonparametric component are consistent. Furthermore, we establish the asymptotic normality of the estimator of the linear effects. To compute the proposed estimators, we develop a modified blockwise majorization descent algorithm that is efficient and easy to implement. Simulation studies demonstrate that the proposed method performs well in finite sample situations. We also use the primary biliary cirrhosis data to illustrate its application.

  11. Analyzing Student Learning Outcomes: Usefulness of Logistic and Cox Regression Models. IR Applications, Volume 5

    ERIC Educational Resources Information Center

    Chen, Chau-Kuang

    2005-01-01

    Logistic and Cox regression methods are practical tools used to model the relationships between certain student learning outcomes and their relevant explanatory variables. The logistic regression model fits an S-shaped curve into a binary outcome with data points of zero and one. The Cox regression model allows investigators to study the duration…

  12. Cyclooxygenases (COX-1 and COX-2) for tissue engineering of articular cartilage--from a developmental model to first results of tissue and scaffold expression.

    PubMed

    Brochhausen, Christoph; Zehbe, Rolf; Gross, Ulrich; Libera, Jeanette; Schubert, Helmut; Nüsing, Rolf M; Klaus, Günter; Kirkpatrick, C James

    2008-01-01

    Tissue engineering of articular cartilage remains an ongoing challenge. Since tissue regeneration recapitulates ontogenetic processes the growth plate can be regarded as an innovative model to target suitable signalling molecules and growth factors for the tissue engineering of cartilage. In the present study we analysed the expression of cyclooxygenases (COX) in a short-term chondrocyte culture in gelatin-based scaffolds and in articular cartilage of rats and compared it with that in the growth plate. Our results demonstrate the strong cellular expression of COX-1 but only a focal weak expression of COX-2 in the seeded scaffolds. Articular cartilage of rats expresses homogeneously COX-1 and COX-2 with the exception of the apical cell layer. Our findings indicate a functional role of COX in the metabolism of articular chondrocytes. The expression of COX in articular cartilage and in the seeded scaffolds opens interesting perspectives to improve the proliferation and differentiation of chondrocytes in scaffold materials by addition of specific receptor ligands of the COX system.

  13. Increased COX-2 expression in epithelial and stromal cells of high mammographic density tissues and in a xenograft model of mammographic density.

    PubMed

    Chew, G L; Huo, C W; Huang, D; Hill, P; Cawson, J; Frazer, H; Hopper, J L; Haviv, I; Henderson, M A; Britt, K; Thompson, E W

    2015-08-01

    Mammographic density (MD) adjusted for age and body mass index is one of the strongest known risk factors for breast cancer. Given the high attributable risk of MD for breast cancer, chemoprevention with a safe and available agent that reduces MD and breast cancer risk would be beneficial. Cox-2 has been implicated in MD-related breast cancer risk, and was increased in stromal cells in high MD tissues in one study. Our study assessed differential Cox-2 expression in epithelial and stromal cells in paired samples of high and low MD human breast tissue, and in a validated xenograft biochamber model of MD. We also examined the effects of endocrine treatment upon Cox-2 expression in high and low MD tissues in the MD xenograft model. Paired high and low MD human breast tissue samples were immunostained for Cox-2, then assessed for differential expression and staining intensity in epithelial and stromal cells. High and low MD human breast tissues were separately maintained in biochambers in mice treated with Tamoxifen, oestrogen or placebo implants, then assessed for percentage Cox-2 staining in epithelial and stromal cells. Percentage Cox-2 staining was greater for both epithelial (p = 0.01) and stromal cells (p < 0.0001) of high compared with low MD breast tissues. In high MD biochamber tissues, percentage Cox-2 staining was greater in stromal cells of oestrogen-treated versus placebo-treated tissues (p = 0.05).

  14. Cox Proportional Hazards Models for Modeling the Time to Onset of Decompression Sickness in Hypobaric Environments

    NASA Technical Reports Server (NTRS)

    Thompson, Laura A.; Chhikara, Raj S.; Conkin, Johnny

    2003-01-01

    In this paper we fit Cox proportional hazards models to a subset of data from the Hypobaric Decompression Sickness Databank. The data bank contains records on the time to decompression sickness (DCS) and venous gas emboli (VGE) for over 130,000 person-exposures to high altitude in chamber tests. The subset we use contains 1,321 records, with 87% censoring, and has the most recent experimental tests on DCS made available from Johnson Space Center. We build on previous analyses of this data set by considering more expanded models and more detailed model assessments specific to the Cox model. Our model - which is stratified on the quartiles of the final ambient pressure at altitude - includes the final ambient pressure at altitude as a nonlinear continuous predictor, the computed tissue partial pressure of nitrogen at altitude, and whether exercise was done at altitude. We conduct various assessments of our model, many of which are recently developed in the statistical literature, and conclude where the model needs improvement. We consider the addition of frailties to the stratified Cox model, but found that no significant gain was attained above a model that does not include frailties. Finally, we validate some of the models that we fit.

  15. Modeling age-of-onset: Cox model with latent major gene effects

    SciTech Connect

    Li, H.; Thompson, E.A.

    1994-09-01

    Analysis of age-of-onset is a key factor in the segregation and linkage analysis of complex genetic traits, but is complicated by the censoring of unaffected individuals. Most previous work has used parametric distributional assumptions, but it is hard to characterize the distribution of age-of-onset by a single distribution. Other approaches discretize age-of-onset and use logistic regression to model incidence; this approach does not use the information fully. Frailty models have been used for age-of-oset in the biostatistics literature, but these models do not lend themselves to modeling the correlations due to genetic effects which segregate within a family. Here, we propose use of the Cox model with latent major gene effects; conditional on the major genotypes, Cox`s proportional hazards model is used for age-of-onset for each individual. This is a semiparametric model; we do not specify the baseline hazard function. Likelihood analysis of such models is restricted by the difficulty in evaluating of maximizing the likelihood, especially when data are available for some of the members of an extended pedigree. Markov chain Monte Carlo permits genotypic configurations to be realized from the posterior distributions given a current model and the observed data. Hence methods for likelihood analysis can be developed: Monte Carlo EM is used for estimation of the parameters and their variance-covariance matrix. Markers and observed covariates are easily incorporated into this analysis. We present the model, methods for likelihood analysis and the results of a simulation study. The results are comparable with those based on a Cox model with known genotypic dependence in a pedigree. An early-onset Alzheimer`s pedigree and some breast cancer pedigrees have been used as real data examples. Some possible extensions are also discussed.

  16. Comparing the effects of COX and non-COX-inhibiting NSAIDs on enhancement of apoptosis and inhibition of aberrant crypt foci formation in a rat colorectal cancer model.

    PubMed

    Martin, Jonathan E; Young, Graeme P; LE Leu, Richard K; Hu, Ying

    2013-09-01

    The protection against colorectal cancer (CRC) by non-steroidal anti-inflammatory drugs (NSAIDs) is in part dependent on inhibition of cyclooxygenase (COX). We compared the efficacy of the non-COX-inhibiting R-flurbiprofen (R-FB) with COX-inhibiting sulindac and racemic flurbiprofen (Rac-FB), and determined their effects on apoptosis, in an azoxymethane (AOM)-induced rat CRC model. In experiment 1, groups of rats were given a daily drug gavage (R-FB 30 mg/kg, Rac-FB 10 mg/kg and Sulindac 20 mg/kg) for one week, followed by AOM treatment and were sacrificed eight hours later, colons were examined for apoptosis and cell proliferation. In experiment 2, groups of rats were given two AOM treatments, followed by a daily drug gavage until they were sacrificed ten weeks later, and colons were examined for aberrant crypt foci (ACF) and prostaglandin E2 production. All drugs significantly enhanced apoptosis and inhibited ACF, irrespective of their COX-inhibiting potency (p<0.01), but sulindac was more potent in inhibition of large ACF, p<0.05. COX-inhibiting sulindac achieved the greatest protective effect. The greater safety profile of Rac-FB should provide an advantage for chemoprevention.

  17. High-dimensional Cox models: the choice of penalty as part of the model building process.

    PubMed

    Benner, Axel; Zucknick, Manuela; Hielscher, Thomas; Ittrich, Carina; Mansmann, Ulrich

    2010-02-01

    The Cox proportional hazards regression model is the most popular approach to model covariate information for survival times. In this context, the development of high-dimensional models where the number of covariates is much larger than the number of observations (p>n) is an ongoing challenge. A practicable approach is to use ridge penalized Cox regression in such situations. Beside focussing on finding the best prediction rule, one is often interested in determining a subset of covariates that are the most important ones for prognosis. This could be a gene set in the biostatistical analysis of microarray data. Covariate selection can then, for example, be done by L(1)-penalized Cox regression using the lasso (Tibshirani (1997). Statistics in Medicine 16, 385-395). Several approaches beyond the lasso, that incorporate covariate selection, have been developed in recent years. This includes modifications of the lasso as well as nonconvex variants such as smoothly clipped absolute deviation (SCAD) (Fan and Li (2001). Journal of the American Statistical Association 96, 1348-1360; Fan and Li (2002). The Annals of Statistics 30, 74-99). The purpose of this article is to implement them practically into the model building process when analyzing high-dimensional data with the Cox proportional hazards model. To evaluate penalized regression models beyond the lasso, we included SCAD variants and the adaptive lasso (Zou (2006). Journal of the American Statistical Association 101, 1418-1429). We compare them with "standard" applications such as ridge regression, the lasso, and the elastic net. Predictive accuracy, features of variable selection, and estimation bias will be studied to assess the practical use of these methods. We observed that the performance of SCAD and adaptive lasso is highly dependent on nontrivial preselection procedures. A practical solution to this problem does not yet exist. Since there is high risk of missing relevant covariates when using SCAD or

  18. Extension of a Cox proportional hazards cure model when cure information is partially known

    PubMed Central

    Wu, Yu; Lin, Yong; Lu, Shou-En; Li, Chin-Shang; Shih, Weichung Joe

    2014-01-01

    When there is evidence of long-term survivors, cure models are often used to model the survival curve. A cure model is a mixture model consisting of a cured fraction and an uncured fraction. Traditional cure models assume that the cured or uncured status in the censored set cannot be distinguished. But in many practices, some diagnostic procedures may provide partial information about the cured or uncured status relative to certain sensitivity and specificity. The traditional cure model does not take advantage of this additional information. Motivated by a clinical study on bone injury in pediatric patients, we propose a novel extension of a traditional Cox proportional hazards (PH) cure model that incorporates the additional information about the cured status. This extension can be applied when the latency part of the cure model is modeled by the Cox PH model. Extensive simulations demonstrated that the proposed extension provides more efficient and less biased estimations, and the higher efficiency and smaller bias is associated with higher sensitivity and specificity of diagnostic procedures. When the proposed extended Cox PH cure model was applied to the motivating example, there was a substantial improvement in the estimation. PMID:24511081

  19. JOINT STRUCTURE SELECTION AND ESTIMATION IN THE TIME-VARYING COEFFICIENT COX MODEL

    PubMed Central

    Xiao, Wei; Lu, Wenbin; Zhang, Hao Helen

    2016-01-01

    Time-varying coefficient Cox model has been widely studied and popularly used in survival data analysis due to its flexibility for modeling covariate effects. It is of great practical interest to accurately identify the structure of covariate effects in a time-varying coefficient Cox model, i.e. covariates with null effect, constant effect and truly time-varying effect, and estimate the corresponding regression coefficients. Combining the ideas of local polynomial smoothing and group nonnegative garrote, we develop a new penalization approach to achieve such goals. Our method is able to identify the underlying true model structure with probability tending to one and simultaneously estimate the time-varying coefficients consistently. The asymptotic normalities of the resulting estimators are also established. We demonstrate the performance of our method using simulations and an application to the primary biliary cirrhosis data. PMID:27540275

  20. Maximum Likelihood Inference for the Cox Regression Model with Applications to Missing Covariates.

    PubMed

    Chen, Ming-Hui; Ibrahim, Joseph G; Shao, Qi-Man

    2009-10-01

    In this paper, we carry out an in-depth theoretical investigation for existence of maximum likelihood estimates for the Cox model (Cox, 1972, 1975) both in the full data setting as well as in the presence of missing covariate data. The main motivation for this work arises from missing data problems, where models can easily become difficult to estimate with certain missing data configurations or large missing data fractions. We establish necessary and sufficient conditions for existence of the maximum partial likelihood estimate (MPLE) for completely observed data (i.e., no missing data) settings as well as sufficient conditions for existence of the maximum likelihood estimate (MLE) for survival data with missing covariates via a profile likelihood method. Several theorems are given to establish these conditions. A real dataset from a cancer clinical trial is presented to further illustrate the proposed methodology.

  1. Sample Size and Power for a Logrank Test and Cox Proportional Hazards Model with Multiple Groups and Strata, or a Quantitative Covariate with Multiple Strata

    PubMed Central

    Lachin, John M.

    2013-01-01

    Summary General expressions are described for the evaluation of sample size and power for the K group Mantel-logrank test or the Cox PH model score test. Under an exponential model, the method of Lachin and Foulkes [1] for the 2 group case is extended to the K ≥ 2 group case using the non-centrality parameter of the K – 1 df chi-square test. Similar results are also shown to apply to the K group score test in a Cox PH model. Lachin and Foulkes [1] employed a truncated exponential distribution to provide for a non-linear rate of enrollment. Expressions for the mean time of enrollment and the expected follow-up time in the presence of exponential losses-to-follow-up are presented. When used with the expression for the non-centrality parameter for the test, equations are derived for the evaluation of sample size and power under specific designs with R years of recruitment and T years total duration. Sample size and power are also described for a stratified-adjusted K group test and for the assessment of a group by stratum interaction. Similarly computations are described for a stratified-adjusted analysis of a quantitative covariate and a test of a stratum by covariate interaction in the Cox PH model. PMID:23670965

  2. Accounting for covariate measurement error in a Cox model analysis of recurrence of depression.

    PubMed

    Liu, K; Mazumdar, S; Stone, R A; Dew, M A; Houck, P R; Reynolds, C F

    2001-01-01

    When a covariate measured with error is used as a predictor in a survival analysis using the Cox model, the parameter estimate is usually biased. In clinical research, covariates measured without error such as treatment procedure or sex are often used in conjunction with a covariate measured with error. In a randomized clinical trial of two types of treatments, we account for the measurement error in the covariate, log-transformed total rapid eye movement (REM) activity counts, in a Cox model analysis of the time to recurrence of major depression in an elderly population. Regression calibration and two variants of a likelihood-based approach are used to account for measurement error. The likelihood-based approach is extended to account for the correlation between replicate measures of the covariate. Using the replicate data decreases the standard error of the parameter estimate for log(total REM) counts while maintaining the bias reduction of the estimate. We conclude that covariate measurement error and the correlation between replicates can affect results in a Cox model analysis and should be accounted for. In the depression data, these methods render comparable results that have less bias than the results when measurement error is ignored.

  3. A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-kappaB, COX-1, and COX-2.

    PubMed

    Yeoh, Ann S J; Gibson, Rachel J; Yeoh, Eric E K; Bowen, Joanne M; Stringer, Andrea M; Giam, Kar A; Keefe, Dorothy M K

    2007-08-01

    Radiation-induced mucositis is a common and serious side effect of radiotherapy. Molecular mechanisms of mucosal injury, however, are still poorly understood and extremely difficult to study in humans. A novel Dark Agouti rat model using fractionated radiotherapy to induce mucositis has been developed to investigate the occurrence of alimentary mucosal injury. Twenty-four Dark Agouti rats were randomly assigned to receive either fractionated radiotherapy or no radiotherapy. The irradiated rats received a fractionated course of abdominal radiotherapy at 45 Gy/18 fractions/6 weeks treating thrice weekly (i.e., at a radiation dose of 2.5 Gy per fraction). After each week of radiation, a group of irradiated rats was killed. Histomorphology and mucin distribution in the alimentary tract was investigated. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used to examine apoptosis in the colon and jejunum, and intestinal morphometry was used to assess villus length, crypt length, and mitotic crypt count. Immunohistochemistry of p53, nuclear factor-kappaB, cyclooxygenase (COX)-1, and COX-2 was also done. The fractionated radiotherapy course induced alimentary mucositis from week 1, with more severe injury seen in the small intestine. The hallmark appearance of apoptosis was present in the crypts of the small and large intestine. In the jejunum and colon, goblet cell disorganization and degeneration was obvious and crypt mitotic counts were severely depleted throughout the treatment. Expression of p53, nuclear factor-kappaB, COX-1, and COX-2 was increased in the irradiated intestinal sections. Fractionated radiation-induced alimentary mucositis has been effectively documented in the Dark Agouti rat for the first time. Further studies investigating the molecular mechanisms underlying radiation-induced mucositis are planned to ultimately achieve anti-mucotoxic-targeted therapies.

  4. Default risk modeling beyond the first-passage approximation: extended Black-Cox model.

    PubMed

    Katz, Yuri A; Shokhirev, Nikolai V

    2010-07-01

    We develop a generalization of the Black-Cox structural model of default risk. The extended model captures uncertainty related to firm's ability to avoid default even if company's liabilities momentarily exceeding its assets. Diffusion in a linear potential with the radiation boundary condition is used to mimic a company's default process. The exact solution of the corresponding Fokker-Planck equation allows for derivation of analytical expressions for the cumulative probability of default and the relevant hazard rate. Obtained closed formulas fit well the historical data on global corporate defaults and demonstrate the split behavior of credit spreads for bonds of companies in different categories of speculative-grade ratings with varying time to maturity. Introduction of the finite rate of default at the boundary improves valuation of credit risk for short time horizons, which is the key advantage of the proposed model. We also consider the influence of uncertainty in the initial distance to the default barrier on the outcome of the model and demonstrate that this additional source of incomplete information may be responsible for nonzero credit spreads for bonds with very short time to maturity.

  5. Default risk modeling beyond the first-passage approximation: Extended Black-Cox model

    NASA Astrophysics Data System (ADS)

    Katz, Yuri A.; Shokhirev, Nikolai V.

    2010-07-01

    We develop a generalization of the Black-Cox structural model of default risk. The extended model captures uncertainty related to firm’s ability to avoid default even if company’s liabilities momentarily exceeding its assets. Diffusion in a linear potential with the radiation boundary condition is used to mimic a company’s default process. The exact solution of the corresponding Fokker-Planck equation allows for derivation of analytical expressions for the cumulative probability of default and the relevant hazard rate. Obtained closed formulas fit well the historical data on global corporate defaults and demonstrate the split behavior of credit spreads for bonds of companies in different categories of speculative-grade ratings with varying time to maturity. Introduction of the finite rate of default at the boundary improves valuation of credit risk for short time horizons, which is the key advantage of the proposed model. We also consider the influence of uncertainty in the initial distance to the default barrier on the outcome of the model and demonstrate that this additional source of incomplete information may be responsible for nonzero credit spreads for bonds with very short time to maturity.

  6. DWCox: A density-weighted Cox model for outlier-robust prediction of prostate cancer survival

    PubMed Central

    Xiao, Jinfeng; Wang, Sheng; Shang, Jingbo; Lin, Henry; Xin, Doris; Ren, Xiang; Han, Jiawei; Peng, Jian

    2016-01-01

    Reliable predictions on the risk and survival time of prostate cancer patients based on their clinical records can help guide their treatment and provide hints about the disease mechanism. The Cox regression is currently a commonly accepted approach for such tasks in clinical applications. More complex methods, like ensemble approaches, have the potential of reaching better prediction accuracy at the cost of increased training difficulty and worse result interpretability. Better performance on a specific data set may also be obtained by extensive manual exploration in the data space, but such developed models are subject to overfitting and usually not directly applicable to a different data set. We propose DWCox, a density-weighted Cox model that has improved robustness against outliers and thus can provide more accurate predictions of prostate cancer survival. DWCox assigns weights to the training data according to their local kernel density in the feature space, and incorporates those weights into the partial likelihood function. A linear regression is then used to predict the actual survival times from the predicted risks. In the 2015 Prostate Cancer DREAM Challenge, DWCox obtained the best average ranking in prediction accuracy on the risk and survival time. The success of DWCox is remarkable given that it is one of the smallest and most interpretable models submitted to the challenge. In simulations, DWCox performed consistently better than a standard Cox model when the training data contained many sparsely distributed outliers. Although developed for prostate cancer patients, DWCox can be easily re-trained and applied to other survival analysis problems. DWCox is implemented in R and can be downloaded from https://github.com/JinfengXiao/DWCox. PMID:28299178

  7. [Clinical research XXII. From clinical judgment to Cox proportional hazards model].

    PubMed

    Pérez-Rodríguez, Marcela; Rivas-Ruiz, Rodolfo; Palacios-Cruz, Lino; Talavera, Juan O

    2014-01-01

    Survival analyses are commonly used to determine the time of an event (for example, death). However, they can be used also for other clinical outcomes on the condition that these are dichotomous, for example healing time. These analyses only consider the relationship of one variable. However, Cox proportional hazards model is a multivariate analysis of the survival analysis, in which other potentially confounding covariates of the effect of the main maneuver studied, such as age, gender or disease stage, are taken into account. This analysis can include both quantitative and qualitative variables in the model. The measure of association used is called hazard ratio (HR) or relative risk ratio, which is not the same as the relative risk or odds ratio (OR). The difference is that the HR refers to the possibility that one of the groups develops the event before it is compared with the other group. The proportional hazards multivariate model of Cox is the most widely used in medicine when the phenomenon is studied in two dimensions: time and event.

  8. Positional isomerism markedly affects the growth inhibition of colon cancer cells by NOSH-aspirin: COX inhibition and modeling.

    PubMed

    Vannini, Federica; Chattopadhyay, Mitali; Kodela, Ravinder; Rao, Praveen P N; Kashfi, Khosrow

    2015-12-01

    We recently reported the synthesis of NOSH-aspirin, a novel hybrid that releases both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e. ortho-NOSH-aspirin (o-NOSH-aspirin). In the present study, we compared the effects of the positional isomers of NOSH-ASA (o-NOSH-aspirin, m-NOSH-aspirin and p-NOSH-aspirin) to that of aspirin on growth of HT-29 and HCT 15 colon cancer cells, belonging to the same histological subtype, but with different expression of cyclooxygenase (COX) enzymes; HT-29 express both COX-1 and COX-2, whereas HCT 15 is COX-null. We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells. Since the parent compound aspirin, inhibits both COX-1 and COX-2, we also evaluated the effects of these compounds on COX-1 and COX-2 enzyme activities and also performed modeling of the interactions between the positional isomers of NOSH-aspirin and COX-1 and COX-2 enzymes. We observed that the three positional isomers of NOSH aspirin inhibited the growth of both colon cancer cell lines with IC50s in the nano-molar range. In particular in HT-29 cells the IC50s for growth inhibition were: o-NOSH-ASA, 0.04±0.011 µM; m-NOSH-ASA, 0.24±0.11 µM; p-NOSH-ASA, 0.46±0.17 µM; and in HCT 15 cells the IC50s for o-NOSH-ASA, m-NOSH-ASA, and p-NOSH-ASA were 0.062 ±0.006 µM, 0.092±0.004 µM, and 0.37±0.04 µM, respectively. The IC50 for aspirin in both cell lines was >5mM at 24h. The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis. All 3 positional isomers of NOSH-aspirin preferentially inhibited COX-1 over COX-2. These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential.

  9. A semiparametric copula method for Cox models with covariate measurement error.

    PubMed

    Kim, Sehee; Li, Yi; Spiegelman, Donna

    2016-01-01

    We consider measurement error problem in the Cox model, where the underlying association between the true exposure and its surrogate is unknown, but can be estimated from a validation study. Under this framework, one can accommodate general distributional structures for the error-prone covariates, not restricted to a linear additive measurement error model or Gaussian measurement error. The proposed copula-based approach enables us to fit flexible measurement error models, and to be applicable with an internal or external validation study. Large sample properties are derived and finite sample properties are investigated through extensive simulation studies. The methods are applied to a study of physical activity in relation to breast cancer mortality in the Nurses' Health Study.

  10. Vortex stretching and bottom torques in the Bryan-Cox ocean circulation model

    NASA Astrophysics Data System (ADS)

    Bell, Michael J.

    1999-10-01

    After 3 months of integration the barotropic stream functions in the 1° global versions of the Bryan-Cox ocean models [Bryan, 1969; Cox, 1984] run at the U.K. Meteorological Office have weaker recirculations to the north and south of the Gulf Stream than are believed to exist and than are obtained in some diagnostic models of comparable resolution. Diagnostics of the contributions to the rate of change of the vorticity of the vertically meaned and vertically integrated currents in the third month of a model integration are presented. Those for the vertically integrated current show that the main patterns of northward advection of planetary vorticity are accounted for by the bottom pressure torque and viscous torque; the contributions from the curl of the wind stress and nonlinear advection are comparatively small. Using this result, a new relationship is derived between the bottom pressure torque in the model and the vortex stretching at the top of the steps in the bathymetry. Diagnostic calculations of the contributions to the stream function driven by each of the torques suggest two alternative interpretations of the weakness of the northern recirculation gyre and the poor separation of the Gulf Stream at Cape Hatteras in the model. One is based on the difference between the vortex stretching and bottom pressure torque in the model, the other on the flow driven by the viscous torque on the fluid interior (i.e., on grid cells that are not adjacent to bathymetric steps). The main changes to the patterns of these diagnostics after 10 years of integration are summarized.

  11. Novel harmonic regularization approach for variable selection in Cox's proportional hazards model.

    PubMed

    Chu, Ge-Jin; Liang, Yong; Wang, Jia-Xuan

    2014-01-01

    Variable selection is an important issue in regression and a number of variable selection methods have been proposed involving nonconvex penalty functions. In this paper, we investigate a novel harmonic regularization method, which can approximate nonconvex Lq  (1/2 < q < 1) regularizations, to select key risk factors in the Cox's proportional hazards model using microarray gene expression data. The harmonic regularization method can be efficiently solved using our proposed direct path seeking approach, which can produce solutions that closely approximate those for the convex loss function and the nonconvex regularization. Simulation results based on the artificial datasets and four real microarray gene expression datasets, such as real diffuse large B-cell lymphoma (DCBCL), the lung cancer, and the AML datasets, show that the harmonic regularization method can be more accurate for variable selection than existing Lasso series methods.

  12. Sparse Estimation of Cox Proportional Hazards Models via Approximated Information Criteria

    PubMed Central

    Fan, Juanjuan; Zhang, Ying

    2016-01-01

    Summary We propose a new sparse estimation method for Cox (1972) proportional hazards models by optimizing an approximated information criterion. The main idea involves approximation of the ℓ0 norm with a continuous or smooth unit dent function. The proposed method bridges the best subset selection and regularisation by borrowing strength from both. It mimics the best subset selection using a penalised likelihood approach yet with no need of a tuning parameter. We further reformulate the problem with a reparameterisation step so that it reduces to one unconstrained nonconvex yet smooth programming problem, which can be solved efficiently as in computing the maximum partial likelihood estimator (MPLE). Furthermore, the reparameterisation tactic yields an additional advantage in terms of circumventing post-selection inference. The oracle property of the proposed method is established. Both simulated experiments and empirical examples are provided for assessment and illustration. PMID:26873398

  13. Interpretable inference on the mixed effect model with the Box-Cox transformation.

    PubMed

    Maruo, K; Yamaguchi, Y; Noma, H; Gosho, M

    2017-03-10

    We derived results for inference on parameters of the marginal model of the mixed effect model with the Box-Cox transformation based on the asymptotic theory approach. We also provided a robust variance estimator of the maximum likelihood estimator of the parameters of this model in consideration of the model misspecifications. Using these results, we developed an inference procedure for the difference of the model median between treatment groups at the specified occasion in the context of mixed effects models for repeated measures analysis for randomized clinical trials, which provided interpretable estimates of the treatment effect. From simulation studies, it was shown that our proposed method controlled type I error of the statistical test for the model median difference in almost all the situations and had moderate or high performance for power compared with the existing methods. We illustrated our method with cluster of differentiation 4 (CD4) data in an AIDS clinical trial, where the interpretability of the analysis results based on our proposed method is demonstrated. Copyright © 2017 John Wiley & Sons, Ltd.

  14. Diminished Neurogenic Femoral Artery Vasoconstrictor Response in a Zucker Obese Rat Model: Differential Regulation of NOS and COX Derivatives

    PubMed Central

    Martínez, Ana Cristina; Hernández, Medardo; Novella, Susana; Martínez, María Pilar; Pagán, Rosa María; Hermenegildo, Carlos; García-Sacristán, Albino; Prieto, Dolores; Benedito, Sara

    2014-01-01

    Objective Peripheral arterial disease is one of the macrovascular complications of type 2 diabetes mellitus. This study addresses femoral artery regulation in a prediabetic model of obese Zucker rats (OZR) by examining cross-talk between endothelial and neural factors. Methods and Results Arterial preparations from lean (LZR) and OZR were subjected to electrical field stimulation (EFS) on basal tone. Nitric oxide synthase (NOS) and cyclooxygenase (COX) isoform expression patterns were determined by immunohistochemical labelling and Western blotting. Results indicate significantly reduced noradrenergic contractions in preparations from OZR compared with those of LZR. Functional inhibition of endothelial NOS (eNOS) indicated a predominant role of this isoform in LZR and its modified activity in OZR. Neural (nNOS) and inducible NOS (iNOS) were activated and their expression was higher in femoral arteries from OZR. Neurotransmission modulated by large-conductance Ca2+-activated (BKCa) or voltage-dependent (KV) K+ channels did not seem compromised in the obese animals. Endothelial COX-1 and COX-2 were expressed in LZR and an additional adventitial location of COX-2 was also observed in OZR, explaining the higher COX-2 protein levels detected in this group. Prostanoids derived from both isoforms helped maintain vasoconstriction in LZR while in OZR only COX-2 was active. Superoxide anion inhibition reduced contractions in endothelium-intact arteries from OZR. Conclusions Endothelial dysfunction led to reduced neurogenic vasoconstriction in femoral arteries from OZR. In a setting of obesity, NO-dependent nNOS and iNOS dilation activity could be an alternative mechanism to offset COX-2- and reactive oxygen species-mediated vasoconstriction, along with impaired endothelial NO relaxation. PMID:25216050

  15. Combined survival analysis of cardiac patients by a Cox PH model and a Markov chain.

    PubMed

    Shauly, Michal; Rabinowitz, Gad; Gilutz, Harel; Parmet, Yisrael

    2011-10-01

    The control and treatment of dyslipidemia is a major public health challenge, particularly for patients with coronary heart diseases. In this paper we propose a framework for survival analysis of patients who had a major cardiac event, focusing on assessment of the effect of changing LDL-cholesterol level and statins consumption on survival. This framework includes a Cox PH model and a Markov chain, and combines their results into reinforced conclusions regarding the factors that affect survival time. We prospectively studied 2,277 cardiac patients, and the results show high congruence between the Markov model and the PH model; both evidence that diabetes, history of stroke, peripheral vascular disease and smoking significantly increase hazard rate and reduce survival time. On the other hand, statin consumption is correlated with a lower hazard rate and longer survival time in both models. The role of such a framework in understanding the therapeutic behavior of patients and implementing effective secondary and primary prevention of heart diseases is discussed here.

  16. A Modified Adaptive Lasso for Identifying Interactions in the Cox Model with the Heredity Constraint.

    PubMed

    Wang, Lu; Shen, Jincheng; Thall, Peter F

    2014-10-01

    In many biomedical studies, identifying effects of covariate interactions on survival is a major goal. Important examples are treatment-subgroup interactions in clinical trials, and gene-gene or gene-environment interactions in genomic studies. A common problem when implementing a variable selection algorithm in such settings is the requirement that the model must satisfy the strong heredity constraint, wherein an interaction may be included in the model only if the interaction's component variables are included as main effects. We propose a modified Lasso method for the Cox regression model that adaptively selects important single covariates and pairwise interactions while enforcing the strong heredity constraint. The proposed method is based on a modified log partial likelihood including two adaptively weighted penalties, one for main effects and one for interactions. A two-dimensional tuning parameter for the penalties is determined by generalized cross-validation. Asymptotic properties are established, including consistency and rate of convergence, and it is shown that the proposed selection procedure has oracle properties, given proper choice of regularization parameters. Simulations illustrate that the proposed method performs reliably across a range of different scenarios.

  17. A cross-classified and multiple membership Cox model applied to calf mortality data.

    PubMed

    Elghafghuf, Adel; Stryhn, Henrik; Waldner, Cheryl

    2014-07-01

    A cross-classified and multiple membership Cox model was applied to calf mortality data from Western Canada, where 23,409 calves from 174 herds were followed for up to 180 days after calving. The herds were cross-classified by 49 veterinary clinics and 9 ecological regions and in a multiple membership relation to the veterinary clinics, resulting in a 3-level cross-classified and multiple membership data structure. The model was formulated in a mixed-effects Poisson model framework with normally distributed random effects, and was fitted to the data by Bayesian Markov Chain Monte Carlo (MCMC) estimation. Important fixed effects included whether the calf was a twin, calf gender, assistance at calving, cow age, average temperature the first week after calving, the percentage of the herd that had already calved, whether calf shelters were provided, whether cow-calf pairs were moved to a nursery area, and whether any animals were purchased into the herd at or near the time of calving. The analysis demonstrated a greater variation among herds than among both ecological regions and veterinary clinics. Further, a simulation study for a setting similar to the real data gave evidence that the used approach provides valid estimates.

  18. Dynamics of HPV vaccination initiation in Flanders (Belgium) 2007-2009: a Cox regression model

    PubMed Central

    2011-01-01

    Background We investigated dynamic patterns and predictors of HPV vaccination initiation in Flanders (Belgium) by girls aged 12 to 18, between 2007 and 2009, the period immediately after the introduction of the HPV vaccines on the Belgian market. During this period the initiative for vaccination was taken by the girl, her family or the general practitioner/pediatrician/gynecologist. Methods We used a Cox regression model with time constant and time varying predictors to model hazard rates of HPV vaccination initiation. The sample existed of 117,151 female members of the National Alliance of Christian Mutualities, the largest sickness fund in Flanders. Results The study showed that the hazard of HPV vaccination initiation was higher (1) for older girls, (2) for girls with a more favorable socio-economic background, (3) under more generous reimbursement regimes (with this effect being more pronounced for girls with weak socioeconomic backgrounds), (4) for girls that were informed personally about the reimbursement rules. Conclusions When the initiative for HPV vaccination lies with the girls, their families or the physicians (no organized setting) the uptake of the vaccines is affected by both individual and organizational factors. PMID:21672202

  19. Fitting Cox Models with Doubly Censored Data Using Spline-Based Sieve Marginal Likelihood.

    PubMed

    Li, Zhiguo; Owzar, Kouros

    2016-06-01

    In some applications, the failure time of interest is the time from an originating event to a failure event, while both event times are interval censored. We propose fitting Cox proportional hazards models to this type of data using a spline-based sieve maximum marginal likelihood, where the time to the originating event is integrated out in the empirical likelihood function of the failure time of interest. This greatly reduces the complexity of the objective function compared with the fully semiparametric likelihood. The dependence of the time of interest on time to the originating event is induced by including the latter as a covariate in the proportional hazards model for the failure time of interest. The use of splines results in a higher rate of convergence of the estimator of the baseline hazard function compared with the usual nonparametric estimator. The computation of the estimator is facilitated by a multiple imputation approach. Asymptotic theory is established and a simulation study is conducted to assess its finite sample performance. It is also applied to analyzing a real data set on AIDS incubation time.

  20. Prediction of Mild Cognitive Impairment Conversion Using a Combination of Independent Component Analysis and the Cox Model

    PubMed Central

    Liu, Ke; Chen, Kewei; Yao, Li; Guo, Xiaojuan

    2017-01-01

    Mild cognitive impairment (MCI) represents a transitional stage from normal aging to Alzheimer’s disease (AD) and corresponds to a higher risk of developing AD. Thus, it is necessary to explore and predict the onset of AD in MCI stage. In this study, we propose a combination of independent component analysis (ICA) and the multivariate Cox proportional hazards regression model to investigate promising risk factors associated with MCI conversion among 126 MCI converters and 108 MCI non-converters from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Using structural magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) data, we extracted brain networks from AD and normal control groups via ICA and then constructed Cox models that included network-based neuroimaging factors for the MCI group. We carried out five separate Cox analyses and the two-modality neuroimaging Cox model identified three significant network-based risk factors with higher prediction performance (accuracy = 73.50%) than those in either single-modality model (accuracy = 68.80%). Additionally, the results of the comprehensive Cox model, including significant neuroimaging factors and clinical variables, demonstrated that MCI individuals with reduced gray matter volume in a temporal lobe-related network of structural MRI [hazard ratio (HR) = 8.29E-05 (95% confidence interval (CI), 5.10E- 07 ~ 0.013)], low glucose metabolism in the posterior default mode network based on FDG-PET [HR = 0.066 (95% CI, 4.63E-03 ~ 0.928)], positive apolipoprotein E ε4-status [HR = 1. 988 (95% CI, 1.531 ~ 2.581)], increased Alzheimer’s Disease Assessment Scale-Cognitive Subscale scores [HR = 1.100 (95% CI, 1.059 ~ 1.144)] and Sum of Boxes of Clinical Dementia Rating scores [HR = 1.622 (95% CI, 1.364 ~ 1.930)] were more likely to convert to AD within 36 months after baselines. These significant risk factors in such comprehensive Cox model had the best prediction

  1. Generating survival times to simulate Cox proportional hazards models with time-varying covariates.

    PubMed

    Austin, Peter C

    2012-12-20

    Simulations and Monte Carlo methods serve an important role in modern statistical research. They allow for an examination of the performance of statistical procedures in settings in which analytic and mathematical derivations may not be feasible. A key element in any statistical simulation is the existence of an appropriate data-generating process: one must be able to simulate data from a specified statistical model. We describe data-generating processes for the Cox proportional hazards model with time-varying covariates when event times follow an exponential, Weibull, or Gompertz distribution. We consider three types of time-varying covariates: first, a dichotomous time-varying covariate that can change at most once from untreated to treated (e.g., organ transplant); second, a continuous time-varying covariate such as cumulative exposure at a constant dose to radiation or to a pharmaceutical agent used for a chronic condition; third, a dichotomous time-varying covariate with a subject being able to move repeatedly between treatment states (e.g., current compliance or use of a medication). In each setting, we derive closed-form expressions that allow one to simulate survival times so that survival times are related to a vector of fixed or time-invariant covariates and to a single time-varying covariate. We illustrate the utility of our closed-form expressions for simulating event times by using Monte Carlo simulations to estimate the statistical power to detect as statistically significant the effect of different types of binary time-varying covariates. This is compared with the statistical power to detect as statistically significant a binary time-invariant covariate.

  2. Testing a theoretical model for examining the relationship between family adjustment and expatriates' work adjustment.

    PubMed

    Caligiuri, P M; Hyland, M M; Joshi, A; Bross, A S

    1998-08-01

    Based on theoretical perspectives from the work/family literature, this study tested a model for examining expatriate families' adjustment while on global assignments as an antecedent to expatriates' adjustment to working in a host country. Data were collected from 110 families that had been relocated for global assignments. Longitudinal data, assessing family characteristics before the assignment and cross-cultural adjustment approximately 6 months into the assignment, were coded. This study found that family characteristics (family support, family communication, family adaptability) were related to expatriates' adjustment to working in the host country. As hypothesized, the families' cross-cultural adjustment mediated the effect of family characteristics on expatriates' host-country work adjustment.

  3. Assessing the prediction accuracy of cure in the Cox proportional hazards cure model: an application to breast cancer data.

    PubMed

    Asano, Junichi; Hirakawa, Akihiro; Hamada, Chikuma

    2014-01-01

    A cure rate model is a survival model incorporating the cure rate with the assumption that the population contains both uncured and cured individuals. It is a powerful statistical tool for prognostic studies, especially in cancer. The cure rate is important for making treatment decisions in clinical practice. The proportional hazards (PH) cure model can predict the cure rate for each patient. This contains a logistic regression component for the cure rate and a Cox regression component to estimate the hazard for uncured patients. A measure for quantifying the predictive accuracy of the cure rate estimated by the Cox PH cure model is required, as there has been a lack of previous research in this area. We used the Cox PH cure model for the breast cancer data; however, the area under the receiver operating characteristic curve (AUC) could not be estimated because many patients were censored. In this study, we used imputation-based AUCs to assess the predictive accuracy of the cure rate from the PH cure model. We examined the precision of these AUCs using simulation studies. The results demonstrated that the imputation-based AUCs were estimable and their biases were negligibly small in many cases, although ordinary AUC could not be estimated. Additionally, we introduced the bias-correction method of imputation-based AUCs and found that the bias-corrected estimate successfully compensated the overestimation in the simulation studies. We also illustrated the estimation of the imputation-based AUCs using breast cancer data.

  4. Effect of flux adjustments on temperature variability in climate models

    NASA Astrophysics Data System (ADS)

    CMIP investigators; Duffy, P. B.; Bell, J.; Covey, C.; Sloan, L.

    2000-03-01

    It has been suggested that “flux adjustments” in climate models suppress simulated temperature variability. If true, this might invalidate the conclusion that at least some of observed temperature increases since 1860 are anthropogenic, since this conclusion is based in part on estimates of natural temperature variability derived from flux-adjusted models. We assess variability of surface air temperatures in 17 simulations of internal temperature variability submitted to the Coupled Model Intercomparison Project. By comparing variability in flux-adjusted vs. non-flux adjusted simulations, we find no evidence that flux adjustments suppress temperature variability in climate models; other, largely unknown, factors are much more important in determining simulated temperature variability. Therefore the conclusion that at least some of observed temperature increases are anthropogenic cannot be questioned on the grounds that it is based in part on results of flux-adjusted models. Also, reducing or eliminating flux adjustments would probably do little to improve simulations of temperature variability.

  5. Nepeta Dschuparensis Bornm Extract Moderates COX-2 and IL-1β Proteins in a Rat Model of Cerebral Ischemia

    PubMed Central

    Nia, Alireza Mousavi; Kalantaripour, Taj Pari; Basiri, Mohsen; Vafaee, Farzaneh; Asadi-Shekaari, Majid; Eslami, Azam; Zadeh, Fatemeh Darvish

    2017-01-01

    Background: Nepeta dschuparensis Bornm (NP) is used as a medicinal herb in Iran. In traditional medicine, this herb is extensively employed for curing ailments such as cardiovascular diseases. NP has antioxidant and anti-inflammatory properties. This project examined the effects of the NP extract on cyclooxygenase-2 (COX-2) and interleukin-1β (IL-1β) protein levels and its efficacy in neuroprotection in a cerebral ischemia-reperfusion model. Methods: Twenty-six male rats were randomly divided into 3 groups: 1) sham (n=6): no middle cerebral artery occlusion (MCAO) procedure, 2) control (n=10): MCAO procedure and treatment with normal saline, and 3) NP extract (n=10): MCAO procedure and treatment with the NP extract (20 mg/kg, i.p.) at the beginning of reperfusion. To examine the injury caused by cerebral ischemia, we measured motor coordination and the infarct area using the rotarod test and triphenyl tetrazolium chloride staining, respectively. IL-1β and COX-2 protein levels, as inflammatory markers, were measured by immunoblotting assay. The statistical analyses were performed using SPSS, version 16, and the data are expressed as means±SEMs. Statistical difference was evaluated using the one-way ANOVA, followed by the post hoc LSD test (P<0.01). Results: Treatment with the NP extract significantly diminished the infarct volume and alleviated the motor coordination disorder induced by cerebral ischemia. The NP extract administration significantly attenuated the increase in IL-1β and COX-2 protein levels too (P<0.01). Conclusion: The beneficial effects of the NP extract are related to its ability to decrease the levels of IL-1β and COX-2. PMID:28360444

  6. Survival analysis of clinical mastitis data using a nested frailty Cox model fit as a mixed-effects Poisson model.

    PubMed

    Elghafghuf, Adel; Dufour, Simon; Reyher, Kristen; Dohoo, Ian; Stryhn, Henrik

    2014-12-01

    Mastitis is a complex disease affecting dairy cows and is considered to be the most costly disease of dairy herds. The hazard of mastitis is a function of many factors, both managerial and environmental, making its control a difficult issue to milk producers. Observational studies of clinical mastitis (CM) often generate datasets with a number of characteristics which influence the analysis of those data: the outcome of interest may be the time to occurrence of a case of mastitis, predictors may change over time (time-dependent predictors), the effects of factors may change over time (time-dependent effects), there are usually multiple hierarchical levels, and datasets may be very large. Analysis of such data often requires expansion of the data into the counting-process format - leading to larger datasets - thus complicating the analysis and requiring excessive computing time. In this study, a nested frailty Cox model with time-dependent predictors and effects was applied to Canadian Bovine Mastitis Research Network data in which 10,831 lactations of 8035 cows from 69 herds were followed through lactation until the first occurrence of CM. The model was fit to the data as a Poisson model with nested normally distributed random effects at the cow and herd levels. Risk factors associated with the hazard of CM during the lactation were identified, such as parity, calving season, herd somatic cell score, pasture access, fore-stripping, and proportion of treated cases of CM in a herd. The analysis showed that most of the predictors had a strong effect early in lactation and also demonstrated substantial variation in the baseline hazard among cows and between herds. A small simulation study for a setting similar to the real data was conducted to evaluate the Poisson maximum likelihood estimation approach with both Gaussian quadrature method and Laplace approximation. Further, the performance of the two methods was compared with the performance of a widely used estimation

  7. Comparison between artificial neural network and Cox regression model in predicting the survival rate of gastric cancer patients.

    PubMed

    Zhu, Lucheng; Luo, Wenhua; Su, Meng; Wei, Hangping; Wei, Juan; Zhang, Xuebang; Zou, Changlin

    2013-09-01

    The aim of this study was to determine the prognostic factors and their significance in gastric cancer (GC) patients, using the artificial neural network (ANN) and Cox regression hazard (CPH) models. A retrospective analysis was undertaken, including 289 patients with GC who had undergone gastrectomy between 2006 and 2007. According to the CPH analysis, disease stage, peritoneal dissemination, radical surgery and body mass index (BMI) were selected as the significant variables. According to the ANN model, disease stage, radical surgery, serum CA19-9 levels, peritoneal dissemination and BMI were selected as the significant variables. The true prediction of the ANN was 85.3% and of the CPH model 81.9%. In conclusion, the present study demonstrated that the ANN model is a more powerful tool in determining the significant prognostic variables for GC patients, compared to the CPH model. Therefore, this model is recommended for determining the risk factors of such patients.

  8. Investigation factors affecting the first recurrence of coronary artery disease in patients undergone angioplasty using cox survival model

    PubMed Central

    Nasseryan, Javad; Hajizadeh, Ebrahim; Rasekhi, Aliakbar; Ahangar, Hassan

    2016-01-01

    Background: The incidence of restenosis in patients suffering from coronary artery disease after undergoing angioplasty is of paramount importance. Accordingly, this study aimed to investigate factors affecting the time of the first incidence of restenosis in patients undergone angioplasty in the city of Zanjan, Iran. Methods: This retrospective cohort study was conducted on 421 patients who referred to Ayatollah Musavi hospital in Zanjan for angioplasty during 2009 to 2012. The time of the incidence of restenosis after angioplasty constituted the dependent variable of the study. Independent variables of the study included signs of diabetes, hypertension, hyperlipidemia, kidney disease, carotid stenosis, lung disease, anemia, angina history, and MI. The Cox regression model with the significance level of 0.05 was deployed for the statistical analysis. Results: According to the Cox regression model, hazard ratio of the first incidence of restenosis in patients with hypertension and angina was 22.8% and 29.5% less than other patients, respectively. However, hazard ratio of the first incidence of restenosis was 7.4 times more in patients suffering from carotid stenosis than other patients (p<0.05). Conclusion: The results of this study revealed that as time goes on, the risk of the incidence of restenosis in angioplasty patients increases such that patients’ survival decreases dramatically after a year. To determine the role of effective factors on the incidence of restenosis, conducting a prospective interventional study is highly recommended. PMID:28210606

  9. COX-2 and Prostate Cancer Angiogenesis

    DTIC Science & Technology

    2002-03-01

    sphingomyelin to ceramide , a mediator of apopto- sis (Figure 1).10 The initial interest in COX-2 grew out of the In colon cancer, much of the focus has been...Sphingomyelin - Ceramide Arachidanic Acid \\\\ COX-1 / COX-2 Prostaglandin G2 Prostaglandin H2 Oxidation of Xenobiolics Prostaglandins Malordialdehyde FIGURE 1...variety of tissues in- corneal model, it was demonstrated that endothe- cluding skin , urinary bladder, gastric mucosa, lial cell COX-2 is essential for

  10. Effects of nimesulide, a selective COX-2 inhibitor, on cardiovascular function in 2 rat models of diabetes.

    PubMed

    Leung, Joanne Y T; Pang, Catherine C Y

    2014-07-01

    Cyclooxygenase-2 (COX-2) has been found to be activated in diabetes. We investigated whether nimesulide (selective COX-2 inhibitor) alters cardiovascular responses to adrenaline in 2 rat models of diabetes. Wistar rats (5-week old) were continuously fed a normal or high-fructose diet (60% of caloric intake). At week 2, half of the rats in each diet regimen were given streptozotocin (STZ) (60 mg/kg, intravenously). At week 6, cardiovascular effects of adrenaline (6 and 16 × 10 mol·kg·min, intravenously) were measured in 4 groups of thiobutabarbital-anesthetized rats (control, fructose, STZ, and fructose-streptozotocin [F-STZ]) before and after the injection of nimesulide (3 mg/kg, intravenously). Both the STZ and F-STZ groups exhibited hyperglycemia and significantly (P < 0.05) reduced left ventricular contractility, mean arterial pressure, arterial and venous resistance, and mean circulatory filling pressure (index of venous tone) responses to adrenaline, relative to the control and fructose groups. Nimesulide did not affect responses in the control and fructose groups but increased the venous and, to a less extent, arterial constriction to adrenaline in both the groups of diabetic rats. The cardiac contractile responses, however, were not altered after nimesulide treatment. The results show that nimesulide partially restored arterial and venous constriction to adrenaline in rats with STZ- and F-STZ-induced diabetes.

  11. Prediction of Early Breast Cancer Metastasis from DNA Microarray Data Using High-Dimensional Cox Regression Models

    PubMed Central

    Zemmour, Christophe; Bertucci, François; Finetti, Pascal; Chetrit, Bernard; Birnbaum, Daniel; Filleron, Thomas; Boher, Jean-Marie

    2015-01-01

    BACKGROUND DNA microarray studies identified gene expression signatures predictive of metastatic relapse in early breast cancer. Standard feature selection procedures applied to reduce the set of predictive genes did not take into account the correlation between genes. In this paper, we studied the performances of three high-dimensional regression methods – CoxBoost, LASSO (Least Absolute Shrinkage and Selection Operator), and Elastic net – to identify prognostic signatures in patients with early breast cancer. METHODS We analyzed three public retrospective datasets, including a total of 384 patients with axillary lymph node-negative breast cancer. The Amsterdam van’t Veer’s training set of 78 patients was used to determine the optimal gene sets and classifiers using sensitivity thresholds resulting in mis-classification of no more than 10% of the poor-prognosis group. To ensure the comparability between different methods, an automatic selection procedure was used to determine the number of genes included in each model. The van de Vijver’s and Desmedt’s datasets were used as validation sets to evaluate separately the prognostic performances of our classifiers. The results were compared to the original Amsterdam 70-gene classifier. RESULTS The automatic selection procedure reduced the number of predictive genes up to a minimum of six genes. In the two validation sets, the three models (Elastic net, LASSO, and CoxBoost) led to the definition of genomic classifiers predicting the 5-year metastatic status with similar performances, with respective 59, 56, and 54% accuracy, 83, 75, and 83% sensitivity, and 53, 52, and 48% specificity in the Desmedt’s dataset. In comparison, the Amsterdam 70-gene signature showed 45% accuracy, 97% sensitivity, and 34% specificity. The gene overlap and the classification concordance between the three classifiers were high. All the classifiers added significant prognostic information to that provided by the traditional

  12. Toward the understanding of the molecular basis for the inhibition of COX-1 and COX-2 by phenolic compounds present in Uruguayan propolis and grape pomace.

    PubMed

    Paulino, Margot; Alvareda, Elena; Iribarne, Federico; Miranda, Pablo; Espinosa, Victoria; Aguilera, Sara; Pardo, Helena

    2016-12-01

    Propolis and grape pomace have significant amounts of phenols which can take part in anti-inflammatory mechanisms. As the cyclooxygenases 1 and 2 (COX-1 and COX-2) are involved in said mechanisms, the possibility for a selective inhibition of COX-2 was analyzed in vitro and in silico. Propolis and grape pomace from Uruguayan species were collected, extracted in hydroalcoholic mixture and analyzed. Based on phenols previously identified, and taking as reference the crystallographic structures of COX-1 and COX-2 in complex with the commercial drug Celecoxib, a molecular docking procedure was devised to adjust 123 phenolic molecular models at the enzyme-binding sites. The most important results of this work are that the extracts have an overall inhibition activity very similar in COX-1 and COX-2, i.e. they do not possess selective inhibition activity for COX-2. Nevertheless, 10 compounds of the phenolic database turned out to be more selective and 94 phenols resulted with similar selectivity than Celecoxib, an outcome that accounts for the overall experimental inhibition measures. Binding site environment observations showed increased polarity in COX-2 as compared with COX-1, suggesting that polarity is the key for selectivity. Accordingly, the screening of molecular contacts pointed to the residues: Arg106, Gln178, Leu338, Ser339, Tyr341, Tyr371, Arg499, Ala502, Val509, and Ser516, which would explain, at the atomic level, the anti-inflammatory effect of the phenolic compounds. Among them, Gln178 and Arg499 appear to be essential for the selective inhibition of COX-2.

  13. Shape adjustment of cable mesh reflector antennas considering modeling uncertainties

    NASA Astrophysics Data System (ADS)

    Du, Jingli; Bao, Hong; Cui, Chuanzhen

    2014-04-01

    Cable mesh antennas are the most important implement to construct large space antennas nowadays. Reflector surface of cable mesh antennas has to be carefully adjusted to achieve required accuracy, which is an effective way to compensate manufacturing and assembly errors or other imperfections. In this paper shape adjustment of cable mesh antennas is addressed. The required displacement of the reflector surface is determined with respect to a modified paraboloid whose axial vertex offset is also considered as a variable. Then the adjustment problem is solved by minimizing the RMS error with respect to the desired paraboloid using minimal norm least squares method. To deal with the modeling uncertainties, the adjustment is achieved by solving a simple worst-case optimization problem instead of directly using the least squares method. A numerical example demonstrates the worst-case method is of good convergence and accuracy, and is robust to perturbations.

  14. Storm Water Management Model Climate Adjustment Tool (SWMM-CAT)

    EPA Science Inventory

    The US EPA’s newest tool, the Stormwater Management Model (SWMM) – Climate Adjustment Tool (CAT) is meant to help municipal stormwater utilities better address potential climate change impacts affecting their operations. SWMM, first released in 1971, models hydrology and hydrauli...

  15. A Comparison of Seven Cox Regression-Based Models to Account for Heterogeneity Across Multiple HIV Treatment Cohorts in Latin America and the Caribbean

    PubMed Central

    Giganti, Mark J.; Luz, Paula M.; Caro-Vega, Yanink; Cesar, Carina; Padgett, Denis; Koenig, Serena; Echevarria, Juan; McGowan, Catherine C.; Shepherd, Bryan E.

    2015-01-01

    Abstract Many studies of HIV/AIDS aggregate data from multiple cohorts to improve power and generalizability. There are several analysis approaches to account for cross-cohort heterogeneity; we assessed how different approaches can impact results from an HIV/AIDS study investigating predictors of mortality. Using data from 13,658 HIV-infected patients starting antiretroviral therapy from seven Latin American and Caribbean cohorts, we illustrate the assumptions of seven readily implementable approaches to account for across cohort heterogeneity with Cox proportional hazards models, and we compare hazard ratio estimates across approaches. As a sensitivity analysis, we modify cohort membership to generate specific heterogeneity conditions. Hazard ratio estimates varied slightly between the seven analysis approaches, but differences were not clinically meaningful. Adjusted hazard ratio estimates for the association between AIDS at treatment initiation and death varied from 2.00 to 2.20 across approaches that accounted for heterogeneity; the adjusted hazard ratio was estimated as 1.73 in analyses that ignored across cohort heterogeneity. In sensitivity analyses with more extreme heterogeneity, we noted a slightly greater distinction between approaches. Despite substantial heterogeneity between cohorts, the impact of the specific approach to account for heterogeneity was minimal in our case study. Our results suggest that it is important to account for across cohort heterogeneity in analyses, but that the specific technique for addressing heterogeneity may be less important. Because of their flexibility in accounting for cohort heterogeneity, we prefer stratification or meta-analysis methods, but we encourage investigators to consider their specific study conditions and objectives. PMID:25647087

  16. Bayesian inference for multivariate meta-analysis Box-Cox transformation models for individual patient data with applications to evaluation of cholesterol-lowering drugs.

    PubMed

    Kim, Sungduk; Chen, Ming-Hui; Ibrahim, Joseph G; Shah, Arvind K; Lin, Jianxin

    2013-10-15

    In this paper, we propose a class of Box-Cox transformation regression models with multidimensional random effects for analyzing multivariate responses for individual patient data in meta-analysis. Our modeling formulation uses a multivariate normal response meta-analysis model with multivariate random effects, in which each response is allowed to have its own Box-Cox transformation. Prior distributions are specified for the Box-Cox transformation parameters as well as the regression coefficients in this complex model, and the deviance information criterion is used to select the best transformation model. Because the model is quite complex, we develop a novel Monte Carlo Markov chain sampling scheme to sample from the joint posterior of the parameters. This model is motivated by a very rich dataset comprising 26 clinical trials involving cholesterol-lowering drugs where the goal is to jointly model the three-dimensional response consisting of low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG) (LDL-C, HDL-C, TG). Because the joint distribution of (LDL-C, HDL-C, TG) is not multivariate normal and in fact quite skewed, a Box-Cox transformation is needed to achieve normality. In the clinical literature, these three variables are usually analyzed univariately; however, a multivariate approach would be more appropriate because these variables are correlated with each other. We carry out a detailed analysis of these data by using the proposed methodology.

  17. Cytochrome aa3 of Rhodobacter sphaeroides as a model for mitochondrial cytochrome c oxidase. The coxII/coxIII operon codes for structural and assembly proteins homologous to those in yeast.

    PubMed

    Cao, J; Hosler, J; Shapleigh, J; Revzin, A; Ferguson-Miller, S

    1992-12-05

    The coxII/coxIII operon of Rhodobacter sphaeroides cytochrome c oxidase has been sequenced and characterized by insertional inactivation/complementation analysis. The organization of the genes in this locus (coxII.orf1.orf3.coxIII) is the same as that of the equivalent operon of Paracoccus denitrificans (ctaC.ctaB.ctaG.ctaE), but unlike that of other bacteria whose cytochrome oxidase genes have been characterized so far. The predicted amino acid sequence homology with eukaryotic oxidases is also higher for Rb. sphaeroides (and P. denitrificans) than for other bacterial versions of the enzyme. The inactivation of coxII results in loss of the characteristic cytochrome oxidase spectrum from membranes of the mutant strain. Full recovery requires introduction into the bacterium of the complete operon containing coxII.orf1.orf3.coxIII; partial complementation yielding a spectrally altered enzyme is achieved with a plasmid containing coxII or coxII.orf1.orf3. These results indicate that the peptides ORF1, ORF3, and COXIII are all required for assembly of native cytochrome c oxidase, suggesting an oxidase-specific assembly or chaperonin function for the ORFs in Rb. sphaeroides similar to that observed for the homologous gene products in yeast, COX10 and COX11.

  18. A Proportional Hazards Regression Model for the Sub-distribution with Covariates Adjusted Censoring Weight for Competing Risks Data

    PubMed Central

    HE, PENG; ERIKSSON, FRANK; SCHEIKE, THOMAS H.; ZHANG, MEI-JIE

    2015-01-01

    With competing risks data, one often needs to assess the treatment and covariate effects on the cumulative incidence function. Fine and Gray proposed a proportional hazards regression model for the subdistribution of a competing risk with the assumption that the censoring distribution and the covariates are independent. Covariate-dependent censoring sometimes occurs in medical studies. In this paper, we study the proportional hazards regression model for the subdistribution of a competing risk with proper adjustments for covariate-dependent censoring. We consider a covariate-adjusted weight function by fitting the Cox model for the censoring distribution and using the predictive probability for each individual. Our simulation study shows that the covariate-adjusted weight estimator is basically unbiased when the censoring time depends on the covariates, and the covariate-adjusted weight approach works well for the variance estimator as well. We illustrate our methods with bone marrow transplant data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Here cancer relapse and death in complete remission are two competing risks. PMID:27034534

  19. Adjustment in mothers of children with Asperger syndrome: an application of the double ABCX model of family adjustment.

    PubMed

    Pakenham, Kenneth I; Samios, Christina; Sofronoff, Kate

    2005-05-01

    The present study examined the applicability of the double ABCX model of family adjustment in explaining maternal adjustment to caring for a child diagnosed with Asperger syndrome. Forty-seven mothers completed questionnaires at a university clinic while their children were participating in an anxiety intervention. The children were aged between 10 and 12 years. Results of correlations showed that each of the model components was related to one or more domains of maternal adjustment in the direction predicted, with the exception of problem-focused coping. Hierarchical regression analyses demonstrated that, after controlling for the effects of relevant demographics, stressor severity, pile-up of demands and coping were related to adjustment. Findings indicate the utility of the double ABCX model in guiding research into parental adjustment when caring for a child with Asperger syndrome. Limitations of the study and clinical implications are discussed.

  20. Coercively Adjusted Auto Regression Model for Forecasting in Epilepsy EEG

    PubMed Central

    Kim, Sun-Hee; Faloutsos, Christos; Yang, Hyung-Jeong

    2013-01-01

    Recently, data with complex characteristics such as epilepsy electroencephalography (EEG) time series has emerged. Epilepsy EEG data has special characteristics including nonlinearity, nonnormality, and nonperiodicity. Therefore, it is important to find a suitable forecasting method that covers these special characteristics. In this paper, we propose a coercively adjusted autoregression (CA-AR) method that forecasts future values from a multivariable epilepsy EEG time series. We use the technique of random coefficients, which forcefully adjusts the coefficients with −1 and 1. The fractal dimension is used to determine the order of the CA-AR model. We applied the CA-AR method reflecting special characteristics of data to forecast the future value of epilepsy EEG data. Experimental results show that when compared to previous methods, the proposed method can forecast faster and accurately. PMID:23710252

  1. Pro-inflammatory Signaling in a 3D Organotypic Skin Model after Low LET Irradiation—NF-κB, COX-2 Activation, and Impact on Cell Differentiation

    PubMed Central

    Acheva, Anna; Schettino, Giuseppe; Prise, Kevin M.

    2017-01-01

    Nearly 85% of radiotherapy patients develop acute radiation dermatitis, which is an inflammatory reaction of the skin at the treatment field and in the surrounding area. The aims of this study were to unravel the mechanisms of radiation-induced inflammatory responses after localized irradiation in a human 3D organotypic skin culture model. This could provide possible inflammatory targets for reduction of skin side effects. 3D organotypic skin cultures were set up and locally irradiated with 225 kVp X-rays, using a combination of full exposure and partial shielding (50%) of the cultures. The secretion of pro-inflammatory cytokines, the phenotype, and the differentiation markers expression of the cultures were assessed up to 10 days postirradiation. The pro-inflammatory transcription factor nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (COX-2) pathways have been studied. The results showed fast activation of NF-κB, most likely triggered by DNA damage in the irradiated cells, followed by upregulation of p38 MAPK and COX-2 in the irradiated and surrounding, non-irradiated, areas of the 3D cultures. The application of the COX-2 inhibitor sc-236 was effective at reducing the COX-2 mRNA levels 4 h postirradiation. The same inhibitor also suppressed the PGE2 secretion significantly 72 h after the treatment. The expression of a pro-inflammatory phenotype and abnormal differentiation markers of the cultures were also reduced. However, the use of an NF-κB inhibitor (Bay 11-7085) did not have the predicted positive effect on the cultures phenotype postirradiation. Radiation-induced pro-inflammatory responses have been observed in the 3D skin model. The activated signaling pathways involved NF-κB transcription factor and its downstream target COX-2. Further experiments aiming to suppress the inflammatory response via specific inhibitors showed that COX-2 is a suitable target for reduction of the normal skin inflammatory responses at radiotherapy, while NF

  2. Pro-inflammatory Signaling in a 3D Organotypic Skin Model after Low LET Irradiation-NF-κB, COX-2 Activation, and Impact on Cell Differentiation.

    PubMed

    Acheva, Anna; Schettino, Giuseppe; Prise, Kevin M

    2017-01-01

    Nearly 85% of radiotherapy patients develop acute radiation dermatitis, which is an inflammatory reaction of the skin at the treatment field and in the surrounding area. The aims of this study were to unravel the mechanisms of radiation-induced inflammatory responses after localized irradiation in a human 3D organotypic skin culture model. This could provide possible inflammatory targets for reduction of skin side effects. 3D organotypic skin cultures were set up and locally irradiated with 225 kVp X-rays, using a combination of full exposure and partial shielding (50%) of the cultures. The secretion of pro-inflammatory cytokines, the phenotype, and the differentiation markers expression of the cultures were assessed up to 10 days postirradiation. The pro-inflammatory transcription factor nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (COX-2) pathways have been studied. The results showed fast activation of NF-κB, most likely triggered by DNA damage in the irradiated cells, followed by upregulation of p38 MAPK and COX-2 in the irradiated and surrounding, non-irradiated, areas of the 3D cultures. The application of the COX-2 inhibitor sc-236 was effective at reducing the COX-2 mRNA levels 4 h postirradiation. The same inhibitor also suppressed the PGE2 secretion significantly 72 h after the treatment. The expression of a pro-inflammatory phenotype and abnormal differentiation markers of the cultures were also reduced. However, the use of an NF-κB inhibitor (Bay 11-7085) did not have the predicted positive effect on the cultures phenotype postirradiation. Radiation-induced pro-inflammatory responses have been observed in the 3D skin model. The activated signaling pathways involved NF-κB transcription factor and its downstream target COX-2. Further experiments aiming to suppress the inflammatory response via specific inhibitors showed that COX-2 is a suitable target for reduction of the normal skin inflammatory responses at radiotherapy, while NF

  3. Integrated proteomics identified novel activation of dynein IC2-GR-COX-1 signaling in neurofibromatosis type I (NF1) disease model cells.

    PubMed

    Hirayama, Mio; Kobayashi, Daiki; Mizuguchi, Souhei; Morikawa, Takashi; Nagayama, Megumi; Midorikawa, Uichi; Wilson, Masayo M; Nambu, Akiko N; Yoshizawa, Akiyasu C; Kawano, Shin; Araki, Norie

    2013-05-01

    Neurofibromatosis type 1 (NF1) tumor suppressor gene product, neurofibromin, functions in part as a Ras-GAP, and though its loss is implicated in the neuronal abnormality of NF1 patients, its precise cellular function remains unclear. To study the molecular mechanism of NF1 pathogenesis, we prepared NF1 gene knockdown (KD) PC12 cells, as a NF1 disease model, and analyzed their molecular (gene and protein) expression profiles with a unique integrated proteomics approach, comprising iTRAQ, 2D-DIGE, and DNA microarrays, using an integrated protein and gene expression analysis chart (iPEACH). In NF1-KD PC12 cells showing abnormal neuronal differentiation after NGF treatment, of 3198 molecules quantitatively identified and listed in iPEACH, 97 molecules continuously up- or down-regulated over time were extracted. Pathway and network analysis further revealed overrepresentation of calcium signaling and transcriptional regulation by glucocorticoid receptor (GR) in the up-regulated protein set, whereas nerve system development was overrepresented in the down-regulated protein set. The novel up-regulated network we discovered, "dynein IC2-GR-COX-1 signaling," was then examined in NF1-KD cells. Validation studies confirmed that NF1 knockdown induces altered splicing and phosphorylation patterns of dynein IC2 isomers, up-regulation and accumulation of nuclear GR, and increased COX-1 expression in NGF-treated cells. Moreover, the neurite retraction phenotype observed in NF1-KD cells was significantly recovered by knockdown of the dynein IC2-C isoform and COX-1. In addition, dynein IC2 siRNA significantly inhibited nuclear translocation and accumulation of GR and up-regulation of COX-1 expression. These results suggest that dynein IC2 up-regulates GR nuclear translocation and accumulation, and subsequently causes increased COX-1 expression, in this NF1 disease model. Our integrated proteomics strategy, which combines multiple approaches, demonstrates that NF1-related neural

  4. Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells*

    PubMed Central

    Hirayama, Mio; Kobayashi, Daiki; Mizuguchi, Souhei; Morikawa, Takashi; Nagayama, Megumi; Midorikawa, Uichi; Wilson, Masayo M.; Nambu, Akiko N.; Yoshizawa, Akiyasu C.; Kawano, Shin; Araki, Norie

    2013-01-01

    Neurofibromatosis type 1 (NF1) tumor suppressor gene product, neurofibromin, functions in part as a Ras-GAP, and though its loss is implicated in the neuronal abnormality of NF1 patients, its precise cellular function remains unclear. To study the molecular mechanism of NF1 pathogenesis, we prepared NF1 gene knockdown (KD) PC12 cells, as a NF1 disease model, and analyzed their molecular (gene and protein) expression profiles with a unique integrated proteomics approach, comprising iTRAQ, 2D-DIGE, and DNA microarrays, using an integrated protein and gene expression analysis chart (iPEACH). In NF1-KD PC12 cells showing abnormal neuronal differentiation after NGF treatment, of 3198 molecules quantitatively identified and listed in iPEACH, 97 molecules continuously up- or down-regulated over time were extracted. Pathway and network analysis further revealed overrepresentation of calcium signaling and transcriptional regulation by glucocorticoid receptor (GR) in the up-regulated protein set, whereas nerve system development was overrepresented in the down-regulated protein set. The novel up-regulated network we discovered, “dynein IC2-GR-COX-1 signaling,” was then examined in NF1-KD cells. Validation studies confirmed that NF1 knockdown induces altered splicing and phosphorylation patterns of dynein IC2 isomers, up-regulation and accumulation of nuclear GR, and increased COX-1 expression in NGF-treated cells. Moreover, the neurite retraction phenotype observed in NF1-KD cells was significantly recovered by knockdown of the dynein IC2-C isoform and COX-1. In addition, dynein IC2 siRNA significantly inhibited nuclear translocation and accumulation of GR and up-regulation of COX-1 expression. These results suggest that dynein IC2 up-regulates GR nuclear translocation and accumulation, and subsequently causes increased COX-1 expression, in this NF1 disease model. Our integrated proteomics strategy, which combines multiple approaches, demonstrates that NF1-related neural

  5. A Controlled Trial of Chemoprevention Using COX-2 Inhibitors in an Avian Model of Spontaneous Ovarian Carcinogesis

    DTIC Science & Technology

    2006-03-01

    laying hen. The effect of varying doses of COX-2 inhibitor 4 on egg -laying activity as a surrogate marker for ovulatory frequency were also...personal communication: W. Berry) and the dramatic effect of decreased egg laying activity of Depo-Provera administered to similar laying hens (3...delivered to the hens. 5 hens were utilized per dose level for a total of 20 hens. The hens were monitored for egg laying activity as defined by

  6. Uncertainty estimation of a complex water quality model: The influence of Box-Cox transformation on Bayesian approaches and comparison with a non-Bayesian method

    NASA Astrophysics Data System (ADS)

    Freni, Gabriele; Mannina, Giorgio

    In urban drainage modelling, uncertainty analysis is of undoubted necessity. However, uncertainty analysis in urban water-quality modelling is still in its infancy and only few studies have been carried out. Therefore, several methodological aspects still need to be experienced and clarified especially regarding water quality modelling. The use of the Bayesian approach for uncertainty analysis has been stimulated by its rigorous theoretical framework and by the possibility of evaluating the impact of new knowledge on the modelling predictions. Nevertheless, the Bayesian approach relies on some restrictive hypotheses that are not present in less formal methods like the Generalised Likelihood Uncertainty Estimation (GLUE). One crucial point in the application of Bayesian method is the formulation of a likelihood function that is conditioned by the hypotheses made regarding model residuals. Statistical transformations, such as the use of Box-Cox equation, are generally used to ensure the homoscedasticity of residuals. However, this practice may affect the reliability of the analysis leading to a wrong uncertainty estimation. The present paper aims to explore the influence of the Box-Cox equation for environmental water quality models. To this end, five cases were considered one of which was the “real” residuals distributions (i.e. drawn from available data). The analysis was applied to the Nocella experimental catchment (Italy) which is an agricultural and semi-urbanised basin where two sewer systems, two wastewater treatment plants and a river reach were monitored during both dry and wet weather periods. The results show that the uncertainty estimation is greatly affected by residual transformation and a wrong assumption may also affect the evaluation of model uncertainty. The use of less formal methods always provide an overestimation of modelling uncertainty with respect to Bayesian method but such effect is reduced if a wrong assumption is made regarding the

  7. Optimising Golgi–Cox staining for use with perfusion-fixed brain tissue validated in the zQ175 mouse model of Huntington's disease

    PubMed Central

    Bayram-Weston, Zubeyde; Olsen, Elliott; Harrison, David J.; Dunnett, Stephen B.; Brooks, Simon P.

    2016-01-01

    Background The Golgi–Cox stain is an established method for characterising neuron cell morphology. The method highlights neurite processes of stained cells allowing the complexity of dendritic branching to be measured. New methods Conventional rapid Golgi and Golgi–Cox methods all require fresh impregnation in unfixed brain blocks. Here, we describe a modified method that gives high quality staining on brain tissue blocks perfusion-fixed with 4% paraformaldehyde (PFA) and post-fixed by immersion for 24 h. Results Tissue perfused with 4% PFA and post fixed for 24 h remained viable for the modified Golgi–Cox silver impregnation staining of mouse striatum from perfused wild type and zQ175. It was not found necessary to impregnate tissue blocks with Golgi solutions prior to sectioning, as post-sectioned tissues yielded equally good impregnation. Impregnation for 14 days resulted in optimal visualisation of striatal neuron and dendritic morphology. Although no modifications applied to the rapid Golgi method were reliable, the modified Golgi–Cox method yielded consistently reliable high-quality staining. Comparison with existing methods The current method used fixed tissues to reduce damage and preserve cell morphology. The revised method was found to be fast, reliable and cost effective without the need for expensive staining kits and could be performed in any neuroscience lab with limited specialist equipment. Conclusions The present study introduces a robust reproducible and inexpensive staining method for identifying neuronal morphological changes in the post fixed mouse brain, and is suitable for assessing changes in cell morphology in models of neurodegeneration and in response to experimental treatment. PMID:26459195

  8. Withania coagulans Extract Induces Cell Apoptosis and Inhibits COX-2 Expression in a Rat Model of Benign Prostatic Hyperplasia

    PubMed Central

    Sarbishegi, Maryam; Khajavi, Ozra; Arab, Mohammad Reza

    2016-01-01

    Background Phytotherapy is a popular treatment option in cases of benign prostatic hyperplasia (BPH), with many different herbal products being used for the treatment of this condition. Withania coagulans (WC) is an herbal medicine that has shown anti-tumoral, anti-inflammatory, and antioxidant effects. Objectives This study examined the effect of Withania coagulans extract (WCE) on prostatic cell apoptosis and cyclooxygenase-2 (COX-2) expression in cases of benign prostatic hyperplasia (BPH) in rats. Methods Forty Wistar rats were equally divided into five groups: control, sham, BPH, BPH + WCE, and BPH + CLX (celecoxib) as a positive control group. The induction of BPH was achieved via the subcutaneous injection of 3 mg/kg of testosterone propionate (TP) daily for 28 days. The animals received WCE, celecoxib, or distilled water by oral gavage accompanied by the TP injection. After four weeks, the prostate glands of the rats were weighed to measure the prostatic index (PI). The ventral lobes of the prostates were dissected and processed with paraffin blocks in order to study the number of mast cells. A TUNEL analysis was performed to evaluate the cell apoptosis, while the expression of COX-2 was examined using immunohistochemistry. Results BPH was obvious in the ventral lobe of the prostate, and the administration of WCE markedly decreased the PI and the number of mast cells (P < 0.001) in the BPH rats. Additionally, the WCE treatment induced prostatic cell apoptosis when compared to the BPH group. Furthermore, following the WCE treatment, the expression of COX-2 in the prostatic tissues was significantly decreased when compared to the BPH groups. Conclusions According to the results of this study, WCE was effective in the treatment of BPH in rats. It may therefore have beneficial effects in the treatment of patients with BPH. PMID:27878112

  9. Adjusting power for a baseline covariate in linear models

    PubMed Central

    Glueck, Deborah H.; Muller, Keith E.

    2009-01-01

    SUMMARY The analysis of covariance provides a common approach to adjusting for a baseline covariate in medical research. With Gaussian errors, adding random covariates does not change either the theory or the computations of general linear model data analysis. However, adding random covariates does change the theory and computation of power analysis. Many data analysts fail to fully account for this complication in planning a study. We present our results in five parts. (i) A review of published results helps document the importance of the problem and the limitations of available methods. (ii) A taxonomy for general linear multivariate models and hypotheses allows identifying a particular problem. (iii) We describe how random covariates introduce the need to consider quantiles and conditional values of power. (iv) We provide new exact and approximate methods for power analysis of a range of multivariate models with a Gaussian baseline covariate, for both small and large samples. The new results apply to the Hotelling-Lawley test and the four tests in the “univariate” approach to repeated measures (unadjusted, Huynh-Feldt, Geisser-Greenhouse, Box). The techniques allow rapid calculation and an interactive, graphical approach to sample size choice. (v) Calculating power for a clinical trial of a treatment for increasing bone density illustrates the new methods. We particularly recommend using quantile power with a new Satterthwaite-style approximation. PMID:12898543

  10. Adjusting the Adjusted X[superscript 2]/df Ratio Statistic for Dichotomous Item Response Theory Analyses: Does the Model Fit?

    ERIC Educational Resources Information Center

    Tay, Louis; Drasgow, Fritz

    2012-01-01

    Two Monte Carlo simulation studies investigated the effectiveness of the mean adjusted X[superscript 2]/df statistic proposed by Drasgow and colleagues and, because of problems with the method, a new approach for assessing the goodness of fit of an item response theory model was developed. It has been previously recommended that mean adjusted…

  11. Disaster Hits Home: A Model of Displaced Family Adjustment after Hurricane Katrina

    ERIC Educational Resources Information Center

    Peek, Lori; Morrissey, Bridget; Marlatt, Holly

    2011-01-01

    The authors explored individual and family adjustment processes among parents (n = 30) and children (n = 55) who were displaced to Colorado after Hurricane Katrina. Drawing on in-depth interviews with 23 families, this article offers an inductive model of displaced family adjustment. Four stages of family adjustment are presented in the model: (a)…

  12. Survival analysis of cervical cancer using stratified Cox regression

    NASA Astrophysics Data System (ADS)

    Purnami, S. W.; Inayati, K. D.; Sari, N. W. Wulan; Chosuvivatwong, V.; Sriplung, H.

    2016-04-01

    Cervical cancer is one of the mostly widely cancer cause of the women death in the world including Indonesia. Most cervical cancer patients come to the hospital already in an advanced stadium. As a result, the treatment of cervical cancer becomes more difficult and even can increase the death's risk. One of parameter that can be used to assess successfully of treatment is the probability of survival. This study raises the issue of cervical cancer survival patients at Dr. Soetomo Hospital using stratified Cox regression based on six factors such as age, stadium, treatment initiation, companion disease, complication, and anemia. Stratified Cox model is used because there is one independent variable that does not satisfy the proportional hazards assumption that is stadium. The results of the stratified Cox model show that the complication variable is significant factor which influent survival probability of cervical cancer patient. The obtained hazard ratio is 7.35. It means that cervical cancer patient who has complication is at risk of dying 7.35 times greater than patient who did not has complication. While the adjusted survival curves showed that stadium IV had the lowest probability of survival.

  13. COX-2 chronology

    PubMed Central

    Hawkey, C J

    2005-01-01

    The role of selective cyclooxygenase (COX)-2 inhibitors in medical practice has become controversial since evidence emerged that their use is associated with an increased risk of myocardial infarction. Selective COX-2 inhibitors were seen as successor to non-selective non-steroidal anti-inflammatory drugs, in turn successors to aspirin. The importance of pain relief means that such drugs have always attracted attention. The fact that they work through inhibition of cyclooxygenase, are widespread, and have multiple effects also means that adverse effects that were unanticipated (even though predictable) have always emerged. In this paper I therefore present an historical perspective so that the lessons of the past may be applied to the present. PMID:16227351

  14. Using Swiss Webster mice to model Fetal Alcohol Spectrum Disorders (FASD): An analysis of multilevel time-to-event data through mixed-effects Cox proportional hazards models.

    PubMed

    Chi, Peter; Aras, Radha; Martin, Katie; Favero, Carlita

    2016-05-15

    Fetal Alcohol Spectrum Disorders (FASD) collectively describes the constellation of effects resulting from human alcohol consumption during pregnancy. Even with public awareness, the incidence of FASD is estimated to be upwards of 5% in the general population and is becoming a global health problem. The physical, cognitive, and behavioral impairments of FASD are recapitulated in animal models. Recently rodent models utilizing voluntary drinking paradigms have been developed that accurately reflect moderate consumption, which makes up the majority of FASD cases. The range in severity of FASD characteristics reflects the frequency, dose, developmental timing, and individual susceptibility to alcohol exposure. As most rodent models of FASD use C57BL/6 mice, there is a need to expand the stocks of mice studied in order to more fully understand the complex neurobiology of this disorder. To that end, we allowed pregnant Swiss Webster mice to voluntarily drink ethanol via the drinking in the dark (DID) paradigm throughout their gestation period. Ethanol exposure did not alter gestational outcomes as determined by no significant differences in maternal weight gain, maternal liquid consumption, litter size, or pup weight at birth or weaning. Despite seemingly normal gestation, ethanol-exposed offspring exhibit significantly altered timing to achieve developmental milestones (surface righting, cliff aversion, and open field traversal), as analyzed through mixed-effects Cox proportional hazards models. These results confirm Swiss Webster mice as a viable option to study the incidence and causes of ethanol-induced neurobehavioral alterations during development. Future studies in our laboratory will investigate the brain regions and molecules responsible for these behavioral changes.

  15. QSAR and classification models of a novel series of COX-2 selective inhibitors: 1,5-diarylimidazoles based on support vector machines.

    PubMed

    Liu, H X; Zhang, R S; Yao, X J; Liu, M C; Hu, Z D; Fan, B T

    2004-06-01

    The support vector machine, which is a novel algorithm from the machine learning community, was used to develop quantitation and classification models which can be used as a potential screening mechanism for a novel series of COX-2 selective inhibitors. Each compound was represented by calculated structural descriptors that encode constitutional, topological, geometrical, electrostatic, and quantum-chemical features. The heuristic method was then used to search the descriptor space and select the descriptors responsible for activity. Quantitative modelling results in a nonlinear, seven-descriptor model based on SVMs with root mean-square errors of 0.107 and 0.136 for training and prediction sets, respectively. The best classification results are found using SVMs: the accuracy for training and test sets is 91.2% and 88.2%, respectively. This paper proposes a new and effective method for drug design and screening.

  16. Use of Cox's Cure Model to Establish Clinical Determinants of Long-Term Disease-Free Survival in Neoadjuvant-Chemotherapy-Treated Breast Cancer Patients without Pathologic Complete Response.

    PubMed

    Asano, Junichi; Hirakawa, Akihiro; Hamada, Chikuma; Yonemori, Kan; Hirata, Taizo; Shimizu, Chikako; Tamura, Kenji; Fujiwara, Yasuhiro

    2013-01-01

    In prognostic studies for breast cancer patients treated with neoadjuvant chemotherapy (NAC), the ordinary Cox proportional-hazards (PH) model has been often used to identify prognostic factors for disease-free survival (DFS). This model assumes that all patients eventually experience relapse or death. However, a subset of NAC-treated breast cancer patients never experience these events during long-term follow-up (>10 years) and may be considered clinically "cured." Clinical factors associated with cure have not been studied adequately. Because the ordinary Cox PH model cannot be used to identify such clinical factors, we used the Cox PH cure model, a recently developed statistical method. This model includes both a logistic regression component for the cure rate and a Cox regression component for the hazard for uncured patients. The purpose of this study was to identify the clinical factors associated with cure and the variables associated with the time to recurrence or death in NAC-treated breast cancer patients without a pathologic complete response, by using the Cox PH cure model. We found that hormone receptor status, clinical response, human epidermal growth factor receptor 2 status, histological grade, and the number of lymph node metastases were associated with cure.

  17. Cell Intrinsic Role of Cox-2 in Pancreatic Cancer Development

    PubMed Central

    Hill, Reginald; Li, Yunfeng; Tran, Linh M.; Dry, Sarah; Calvopina, Joseph Hargan; Garcia, Alejandro; Kim, Christine; Wang, Ying; Donahue, Timothy R.; Herschman, Harvey R.; Wu, Hong

    2012-01-01

    Cyclooxygenase-2 (COX-2) is upregulated in pancreatic ductal adenocarcinomas (PDAC). However, how COX-2 promotes PDAC development is unclear. While previous studies have evaluated the efficacy of COX-2 inhibition via the use of non steroidal anti-inflammatory drugs (NSAIDs) or the COX-2 inhibitor celecoxib in PDAC models, none have addressed the cell intrinsic vs. microenvironment roles of COX-2 in modulating PDAC initiation and progression. We tested the cell intrinsic role of COX-2 in PDAC progression, using both loss-of-function and gain-of-function approaches. Cox-2 deletion in Pdx1+ pancreatic progenitor cells significantly delays the development of PDAC in mice with K-ras activation and Pten haploinsufficiency. Conversely, COX-2 over-expression promotes early onset and progression of PDAC in the K-ras mouse model. Loss of PTEN function is a critical factor in determining lethal PDAC onset and overall survival. Mechanistically, COX-2 over-expression increases P-AKT levels in the precursor lesions of Pdx1+;K-rasG12D/+;Ptenlox/+ mice in the absence of Pten LOH. In contrast, Cox-2 deletion in the same setting diminishes P-AKT levels and delays cancer progression. These data suggest an important cell intrinsic role for COX-2 in tumor initiation and progression through activation of the PI3K/AKT pathway. PDAC that is independent of intrinsic COX-2 expression eventually develops with decreased FKBP5 and increased GRP78 expression, two alternate pathways leading to AKT activation. Together, these results support a cell intrinsic role for COX-2 in PDAC development and suggest that, while anti-COX-2 therapy may delay the development and progression of PDAC, mechanisms known to increase chemoresistance through AKT activation must also be overcome. PMID:22784710

  18. Women's Work Conditions and Marital Adjustment in Two-Earner Couples: A Structural Model.

    ERIC Educational Resources Information Center

    Sears, Heather A.; Galambos, Nancy L.

    1992-01-01

    Evaluated structural model of women's work conditions, women's stress, and marital adjustment using path analysis. Findings from 86 2-earner couples with adolescents indicated support for spillover model in which women's work stress and global stress mediated link between their work conditions and their perceptions of marital adjustment.…

  19. Examining Competing Models of the Associations among Peer Victimization, Adjustment Problems, and School Connectedness

    ERIC Educational Resources Information Center

    Loukas, Alexandra; Ripperger-Suhler, Ken G.; Herrera, Denise E.

    2012-01-01

    The present study tested two competing models to assess whether psychosocial adjustment problems mediate the associations between peer victimization and school connectedness one year later, or if peer victimization mediates the associations between psychosocial adjustment problems and school connectedness. Participants were 500 10- to 14-year-old…

  20. Parental Support, Coping Strategies, and Psychological Adjustment: An Integrative Model with Late Adolescents.

    ERIC Educational Resources Information Center

    Holahan, Charles J.; And Others

    1995-01-01

    An integrative predictive model was applied to responses of 241 college freshmen to examine interrelationships among parental support, adaptive coping strategies, and psychological adjustment. Social support from both parents and a nonconflictual parental relationship were positively associated with adolescents' psychological adjustment. (SLD)

  1. Tweaking Model Parameters: Manual Adjustment and Self Calibration

    NASA Astrophysics Data System (ADS)

    Schulz, B.; Tuffs, R. J.; Laureijs, R. J.; Lu, N.; Peschke, S. B.; Gabriel, C.; Khan, I.

    2002-12-01

    The reduction of P32 data is not always straight forward and the application of the transient model needs tight control by the user. This paper describes how to access the model parameters within the P32Tools software and how to work with the "Inspect signals per pixel" panel, in order to explore the parameter space and improve the model fit.

  2. Covariate-Adjusted Linear Mixed Effects Model with an Application to Longitudinal Data

    PubMed Central

    Nguyen, Danh V.; Şentürk, Damla; Carroll, Raymond J.

    2009-01-01

    Linear mixed effects (LME) models are useful for longitudinal data/repeated measurements. We propose a new class of covariate-adjusted LME models for longitudinal data that nonparametrically adjusts for a normalizing covariate. The proposed approach involves fitting a parametric LME model to the data after adjusting for the nonparametric effects of a baseline confounding covariate. In particular, the effect of the observable covariate on the response and predictors of the LME model is modeled nonparametrically via smooth unknown functions. In addition to covariate-adjusted estimation of fixed/population parameters and random effects, an estimation procedure for the variance components is also developed. Numerical properties of the proposed estimators are investigated with simulation studies. The consistency and convergence rates of the proposed estimators are also established. An application to a longitudinal data set on calcium absorption, accounting for baseline distortion from body mass index, illustrates the proposed methodology. PMID:19266053

  3. The relationship of values to adjustment in illness: a model for nursing practice.

    PubMed

    Harvey, R M

    1992-04-01

    This paper proposes a model of the relationship between values, in particular health value, and adjustment to illness. The importance of values as well as the need for value change are described in the literature related to adjustment to physical disability and chronic illness. An empirical model, however, that explains the relationship of values to adjustment or adaptation has not been found by this researcher. Balance theory and its application to the abstract and perceived cognitions of health value and health perception are described here to explain the relationship of values like health value to outcomes associated with adjustment or adaptation to illness. The proposed model is based on the balance theories of Heider, Festinger and Feather. Hypotheses based on the model were tested and supported in a study of 100 adults with visible and invisible chronic illness. Nursing interventions based on the model are described and suggestions for further research discussed.

  4. A New Climate Adjustment Tool: An update to EPA’s Storm Water Management Model

    EPA Science Inventory

    The US EPA’s newest tool, the Stormwater Management Model (SWMM) – Climate Adjustment Tool (CAT) is meant to help municipal stormwater utilities better address potential climate change impacts affecting their operations.

  5. The Moxie of Kathy Cox

    ERIC Educational Resources Information Center

    Johns, Stephanie

    2010-01-01

    Kathy Cox, the superintendent of schools for Georgia, believes "excellence is not an accident". She made a name for herself by winning $1 million proving she was smarter than a fifth-grader on a popular television show. This article presents a profile of Cox, her family, her role as school superintendent, and her accomplishments.…

  6. A Disequilibrium Adjustment Mechanism for CPE Macroeconometric Models: Initial Testing on SOVMOD.

    DTIC Science & Technology

    1979-02-01

    062 1H0 SRI INTERNATIONAL ARLINGTON VA STRATEGIC STUDIES CENTER F/ T 5/3 DISEQUILIBRIUM ADJUSTMENT MECHANISM FOR CPE MACROECOAI0AIETRIC -E (U) FEB...wC) u Approved for Review Distribution: 0 Richard B. Foster, Director Strategic Studies Center Approved for public release; distribution unlimited...describes work on the model aimed at facilitating the integration of a disequilibrium adjustment mechanism into the macroeconometric model. The

  7. Modeling of an Adjustable Beam Solid State Light Project

    NASA Technical Reports Server (NTRS)

    Clark, Toni

    2015-01-01

    This proposal is for the development of a computational model of a prototype variable beam light source using optical modeling software, Zemax Optics Studio. The variable beam light source would be designed to generate flood, spot, and directional beam patterns, while maintaining the same average power usage. The optical model would demonstrate the possibility of such a light source and its ability to address several issues: commonality of design, human task variability, and light source design process improvements. An adaptive lighting solution that utilizes the same electronics footprint and power constraints while addressing variability of lighting needed for the range of exploration tasks can save costs and allow for the development of common avionics for lighting controls.

  8. Spherical Model Integrating Academic Competence with Social Adjustment and Psychopathology.

    ERIC Educational Resources Information Center

    Schaefer, Earl S.; And Others

    This study replicates and elaborates a three-dimensional, spherical model that integrates research findings concerning social and emotional behavior, psychopathology, and academic competence. Kindergarten teachers completed an extensive set of rating scales on 100 children, including the Classroom Behavior Inventory and the Child Adaptive Behavior…

  9. Human COX20 cooperates with SCO1 and SCO2 to mature COX2 and promote the assembly of cytochrome c oxidase.

    PubMed

    Bourens, Myriam; Boulet, Aren; Leary, Scot C; Barrientos, Antoni

    2014-06-01

    Cytochrome c oxidase (CIV) deficiency is one of the most common respiratory chain defects in patients presenting with mitochondrial encephalocardiomyopathies. CIV biogenesis is complicated by the dual genetic origin of its structural subunits, and assembly of a functional holoenzyme complex requires a large number of nucleus-encoded assembly factors. In general, the functions of these assembly factors remain poorly understood, and mechanistic investigations of human CIV biogenesis have been limited by the availability of model cell lines. Here, we have used small interference RNA and transcription activator-like effector nucleases (TALENs) technology to create knockdown and knockout human cell lines, respectively, to study the function of the CIV assembly factor COX20 (FAM36A). These cell lines exhibit a severe, isolated CIV deficiency due to instability of COX2, a mitochondrion-encoded CIV subunit. Mitochondria lacking COX20 accumulate CIV subassemblies containing COX1 and COX4, similar to those detected in fibroblasts from patients carrying mutations in the COX2 copper chaperones SCO1 and SCO2. These results imply that in the absence of COX20, COX2 is inefficiently incorporated into early CIV subassemblies. Immunoprecipitation assays using a stable COX20 knockout cell line expressing functional COX20-FLAG allowed us to identify an interaction between COX20 and newly synthesized COX2. Additionally, we show that SCO1 and SCO2 act on COX20-bound COX2. We propose that COX20 acts as a chaperone in the early steps of COX2 maturation, stabilizing the newly synthesized protein and presenting COX2 to its metallochaperone module, which in turn facilitates the incorporation of mature COX2 into the CIV assembly line.

  10. Analysis of error-prone survival data under additive hazards models: measurement error effects and adjustments.

    PubMed

    Yan, Ying; Yi, Grace Y

    2016-07-01

    Covariate measurement error occurs commonly in survival analysis. Under the proportional hazards model, measurement error effects have been well studied, and various inference methods have been developed to correct for error effects under such a model. In contrast, error-contaminated survival data under the additive hazards model have received relatively less attention. In this paper, we investigate this problem by exploring measurement error effects on parameter estimation and the change of the hazard function. New insights of measurement error effects are revealed, as opposed to well-documented results for the Cox proportional hazards model. We propose a class of bias correction estimators that embraces certain existing estimators as special cases. In addition, we exploit the regression calibration method to reduce measurement error effects. Theoretical results for the developed methods are established, and numerical assessments are conducted to illustrate the finite sample performance of our methods.

  11. An evaluation of bias in propensity score-adjusted non-linear regression models.

    PubMed

    Wan, Fei; Mitra, Nandita

    2016-04-19

    Propensity score methods are commonly used to adjust for observed confounding when estimating the conditional treatment effect in observational studies. One popular method, covariate adjustment of the propensity score in a regression model, has been empirically shown to be biased in non-linear models. However, no compelling underlying theoretical reason has been presented. We propose a new framework to investigate bias and consistency of propensity score-adjusted treatment effects in non-linear models that uses a simple geometric approach to forge a link between the consistency of the propensity score estimator and the collapsibility of non-linear models. Under this framework, we demonstrate that adjustment of the propensity score in an outcome model results in the decomposition of observed covariates into the propensity score and a remainder term. Omission of this remainder term from a non-collapsible regression model leads to biased estimates of the conditional odds ratio and conditional hazard ratio, but not for the conditional rate ratio. We further show, via simulation studies, that the bias in these propensity score-adjusted estimators increases with larger treatment effect size, larger covariate effects, and increasing dissimilarity between the coefficients of the covariates in the treatment model versus the outcome model.

  12. Comparison of the Properties of Regression and Categorical Risk-Adjustment Models

    PubMed Central

    Averill, Richard F.; Muldoon, John H.; Hughes, John S.

    2016-01-01

    Clinical risk-adjustment, the ability to standardize the comparison of individuals with different health needs, is based upon 2 main alternative approaches: regression models and clinical categorical models. In this article, we examine the impact of the differences in the way these models are constructed on end user applications. PMID:26945302

  13. Using Wherry's Adjusted R Squared and Mallow's C (p) for Model Selection from All Possible Regressions.

    ERIC Educational Resources Information Center

    Olejnik, Stephen; Mills, Jamie; Keselman, Harvey

    2000-01-01

    Evaluated the use of Mallow's C(p) and Wherry's adjusted R squared (R. Wherry, 1931) statistics to select a final model from a pool of model solutions using computer generated data. Neither statistic identified the underlying regression model any better than, and usually less well than, the stepwise selection method, which itself was poor for…

  14. The development of a risk-adjusted capitation payment system: the Maryland Medicaid model.

    PubMed

    Weiner, J P; Tucker, A M; Collins, A M; Fakhraei, H; Lieberman, R; Abrams, C; Trapnell, G R; Folkemer, J G

    1998-10-01

    This article describes the risk-adjusted payment methodology employed by the Maryland Medicaid program to pay managed care organizations. It also presents an empirical simulation analysis using claims data from 230,000 Maryland Medicaid recipients. This simulation suggests that the new payment model will help adjust for adverse or favorable selection. The article is intended for a wide audience, including state and national policy makers concerned with the design of managed care Medicaid programs and actuaries, analysts, and researchers involved in the design and implementation of risk-adjusted capitation payment systems.

  15. Modeling and Control of the Redundant Parallel Adjustment Mechanism on a Deployable Antenna Panel

    PubMed Central

    Tian, Lili; Bao, Hong; Wang, Meng; Duan, Xuechao

    2016-01-01

    With the aim of developing multiple input and multiple output (MIMO) coupling systems with a redundant parallel adjustment mechanism on the deployable antenna panel, a structural control integrated design methodology is proposed in this paper. Firstly, the modal information from the finite element model of the structure of the antenna panel is extracted, and then the mathematical model is established with the Hamilton principle; Secondly, the discrete Linear Quadratic Regulator (LQR) controller is added to the model in order to control the actuators and adjust the shape of the panel. Finally, the engineering practicality of the modeling and control method based on finite element analysis simulation is verified. PMID:27706076

  16. Modeling and Control of the Redundant Parallel Adjustment Mechanism on a Deployable Antenna Panel.

    PubMed

    Tian, Lili; Bao, Hong; Wang, Meng; Duan, Xuechao

    2016-10-01

    With the aim of developing multiple input and multiple output (MIMO) coupling systems with a redundant parallel adjustment mechanism on the deployable antenna panel, a structural control integrated design methodology is proposed in this paper. Firstly, the modal information from the finite element model of the structure of the antenna panel is extracted, and then the mathematical model is established with the Hamilton principle; Secondly, the discrete Linear Quadratic Regulator (LQR) controller is added to the model in order to control the actuators and adjust the shape of the panel. Finally, the engineering practicality of the modeling and control method based on finite element analysis simulation is verified.

  17. Pulmonary cyclooxygenase-1 (COX-1) and COX-2 cellular expression and distribution after respiratory syncytial virus and parainfluenza virus infection.

    PubMed

    Radi, Zaher A; Meyerholz, David K; Ackermann, Mark R

    2010-02-01

    Prostaglandins (PGs) play an important role in pulmonary physiology and various pathophysiological processes following infection. The initial step in the biosynthesis of PGs is regulated by two distinct cyclooxygenase enzymes, cyclooxygenase-1 (COX-1) and COX-2. The goal of this study was to investigate the pulmonary cellular localization and distribution of COX-1 and COX-2 in a neonatal lamb model following respiratory syncytial virus (RSV) and parainfluenza virus 3 (PI3) infection, organisms that also cause significant respiratory disease in children. No significant differences were seen in pulmonary COX-1 expression at various microanatomical locations following RSV or PI3 infection compared to controls. In contrast, COX-2 was upregulated following RSV and PI3 infection. Strong expression was restricted to bronchial and bronchiolar epithelial cells and macrophages, while minimal expression was present in the same microanatomical locations in the uninfected lungs. Other microanatomical locations in both the controls and the infected lungs lacked expression. This work suggests that during RSV or PI3 infection: (1) COX-1 cellular expression is not altered, (2) COX-2 cellular expression is upregulated in airway bronchiolar and bronchial epithelial cells and macrophages, (3) respiratory epithelium along with macrophages are important microanatomical compartments regulating the host inflammatory response during viral infection, and (4) COX-2 may be a potential target for RSV and PI3 therapy.

  18. Valuation of Indonesian catastrophic earthquake bonds with generalized extreme value (GEV) distribution and Cox-Ingersoll-Ross (CIR) interest rate model

    NASA Astrophysics Data System (ADS)

    Gunardi, Setiawan, Ezra Putranda

    2015-12-01

    Indonesia is a country with high risk of earthquake, because of its position in the border of earth's tectonic plate. An earthquake could raise very high amount of damage, loss, and other economic impacts. So, Indonesia needs a mechanism for transferring the risk of earthquake from the government or the (reinsurance) company, as it could collect enough money for implementing the rehabilitation and reconstruction program. One of the mechanisms is by issuing catastrophe bond, `act-of-God bond', or simply CAT bond. A catastrophe bond issued by a special-purpose-vehicle (SPV) company, and then sold to the investor. The revenue from this transaction is joined with the money (premium) from the sponsor company and then invested in other product. If a catastrophe happened before the time-of-maturity, cash flow from the SPV to the investor will discounted or stopped, and the cash flow is paid to the sponsor company to compensate their loss because of this catastrophe event. When we consider the earthquake only, the amount of discounted cash flow could determine based on the earthquake's magnitude. A case study with Indonesian earthquake magnitude data show that the probability of maximum magnitude can model by generalized extreme value (GEV) distribution. In pricing this catastrophe bond, we assumed stochastic interest rate that following the Cox-Ingersoll-Ross (CIR) interest rate model. We develop formulas for pricing three types of catastrophe bond, namely zero coupon bonds, `coupon only at risk' bond, and `principal and coupon at risk' bond. Relationship between price of the catastrophe bond and CIR model's parameter, GEV's parameter, percentage of coupon, and discounted cash flow rule then explained via Monte Carlo simulation.

  19. On the hydrologic adjustment of climate-model projections: The potential pitfall of potential evapotranspiration

    USGS Publications Warehouse

    Milly, P.C.D.; Dunne, K.A.

    2011-01-01

    Hydrologic models often are applied to adjust projections of hydroclimatic change that come from climate models. Such adjustment includes climate-bias correction, spatial refinement ("downscaling"), and consideration of the roles of hydrologic processes that were neglected in the climate model. Described herein is a quantitative analysis of the effects of hydrologic adjustment on the projections of runoff change associated with projected twenty-first-century climate change. In a case study including three climate models and 10 river basins in the contiguous United States, the authors find that relative (i.e., fractional or percentage) runoff change computed with hydrologic adjustment more often than not was less positive (or, equivalently, more negative) than what was projected by the climate models. The dominant contributor to this decrease in runoff was a ubiquitous change in runoff (median 211%) caused by the hydrologic model's apparent amplification of the climate-model-implied growth in potential evapotranspiration. Analysis suggests that the hydrologic model, on the basis of the empirical, temperature-based modified Jensen-Haise formula, calculates a change in potential evapotranspiration that is typically 3 times the change implied by the climate models, which explicitly track surface energy budgets. In comparison with the amplification of potential evapotranspiration, central tendencies of other contributions from hydrologic adjustment (spatial refinement, climate-bias adjustment, and process refinement) were relatively small. The authors' findings highlight the need for caution when projecting changes in potential evapotranspiration for use in hydrologic models or drought indices to evaluate climatechange impacts on water. Copyright ?? 2011, Paper 15-001; 35,952 words, 3 Figures, 0 Animations, 1 Tables.

  20. On the Hydrologic Adjustment of Climate-Model Projections: The Potential Pitfall of Potential Evapotranspiration

    USGS Publications Warehouse

    Milly, Paul C.D.; Dunne, Krista A.

    2011-01-01

    Hydrologic models often are applied to adjust projections of hydroclimatic change that come from climate models. Such adjustment includes climate-bias correction, spatial refinement ("downscaling"), and consideration of the roles of hydrologic processes that were neglected in the climate model. Described herein is a quantitative analysis of the effects of hydrologic adjustment on the projections of runoff change associated with projected twenty-first-century climate change. In a case study including three climate models and 10 river basins in the contiguous United States, the authors find that relative (i.e., fractional or percentage) runoff change computed with hydrologic adjustment more often than not was less positive (or, equivalently, more negative) than what was projected by the climate models. The dominant contributor to this decrease in runoff was a ubiquitous change in runoff (median -11%) caused by the hydrologic model’s apparent amplification of the climate-model-implied growth in potential evapotranspiration. Analysis suggests that the hydrologic model, on the basis of the empirical, temperature-based modified Jensen–Haise formula, calculates a change in potential evapotranspiration that is typically 3 times the change implied by the climate models, which explicitly track surface energy budgets. In comparison with the amplification of potential evapotranspiration, central tendencies of other contributions from hydrologic adjustment (spatial refinement, climate-bias adjustment, and process refinement) were relatively small. The authors’ findings highlight the need for caution when projecting changes in potential evapotranspiration for use in hydrologic models or drought indices to evaluate climate-change impacts on water.

  1. Valuation of Indonesian catastrophic earthquake bonds with generalized extreme value (GEV) distribution and Cox-Ingersoll-Ross (CIR) interest rate model

    SciTech Connect

    Gunardi,; Setiawan, Ezra Putranda

    2015-12-22

    Indonesia is a country with high risk of earthquake, because of its position in the border of earth’s tectonic plate. An earthquake could raise very high amount of damage, loss, and other economic impacts. So, Indonesia needs a mechanism for transferring the risk of earthquake from the government or the (reinsurance) company, as it could collect enough money for implementing the rehabilitation and reconstruction program. One of the mechanisms is by issuing catastrophe bond, ‘act-of-God bond’, or simply CAT bond. A catastrophe bond issued by a special-purpose-vehicle (SPV) company, and then sold to the investor. The revenue from this transaction is joined with the money (premium) from the sponsor company and then invested in other product. If a catastrophe happened before the time-of-maturity, cash flow from the SPV to the investor will discounted or stopped, and the cash flow is paid to the sponsor company to compensate their loss because of this catastrophe event. When we consider the earthquake only, the amount of discounted cash flow could determine based on the earthquake’s magnitude. A case study with Indonesian earthquake magnitude data show that the probability of maximum magnitude can model by generalized extreme value (GEV) distribution. In pricing this catastrophe bond, we assumed stochastic interest rate that following the Cox-Ingersoll-Ross (CIR) interest rate model. We develop formulas for pricing three types of catastrophe bond, namely zero coupon bonds, ‘coupon only at risk’ bond, and ‘principal and coupon at risk’ bond. Relationship between price of the catastrophe bond and CIR model’s parameter, GEV’s parameter, percentage of coupon, and discounted cash flow rule then explained via Monte Carlo simulation.

  2. Survival analysis and Cox regression.

    PubMed

    Benítez-Parejo, N; Rodríguez del Águila, M M; Pérez-Vicente, S

    2011-01-01

    The data provided by clinical trials are often expressed in terms of survival. The analysis of survival comprises a series of statistical analytical techniques in which the measurements analysed represent the time elapsed between a given exposure and the outcome of a certain event. Despite the name of these techniques, the outcome in question does not necessarily have to be either survival or death, and may be healing versus no healing, relief versus pain, complication versus no complication, relapse versus no relapse, etc. The present article describes the analysis of survival from both a descriptive perspective, based on the Kaplan-Meier estimation method, and in terms of bivariate comparisons using the log-rank statistic. Likewise, a description is provided of the Cox regression models for the study of risk factors or covariables associated to the probability of survival. These models are defined in both simple and multiple forms, and a description is provided of how they are calculated and how the postulates for application are checked - accompanied by illustrating examples with the shareware application R.

  3. Cell-type-specific roles for COX-2 in UVB-induced skin cancer.

    PubMed

    Jiao, Jing; Mikulec, Carol; Ishikawa, Tomo-o; Magyar, Clara; Dumlao, Darren S; Dennis, Edward A; Fischer, Susan M; Herschman, Harvey

    2014-06-01

    In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2(flox/flox) mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2(flox/flox);K14Cre(+) mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2(flox/flox);K14Cre(+) papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2(flox/flox); LysMCre(+) myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer.

  4. Cell-type-specific roles for COX-2 in UVB-induced skin cancer

    PubMed Central

    Herschman, Harvey

    2014-01-01

    In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2 flox/flox mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2 flox/flox;K14Cre + mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2 flox/flox;K14Cre + papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2 flox/flox; LysMCre + myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer. PMID:24469308

  5. Assessment and indirect adjustment for confounding by smoking in cohort studies using relative hazards models.

    PubMed

    Richardson, David B; Laurier, Dominique; Schubauer-Berigan, Mary K; Tchetgen Tchetgen, Eric; Cole, Stephen R

    2014-11-01

    Workers' smoking histories are not measured in many occupational cohort studies. Here we discuss the use of negative control outcomes to detect and adjust for confounding in analyses that lack information on smoking. We clarify the assumptions necessary to detect confounding by smoking and the additional assumptions necessary to indirectly adjust for such bias. We illustrate these methods using data from 2 studies of radiation and lung cancer: the Colorado Plateau cohort study (1950-2005) of underground uranium miners (in which smoking was measured) and a French cohort study (1950-2004) of nuclear industry workers (in which smoking was unmeasured). A cause-specific relative hazards model is proposed for estimation of indirectly adjusted associations. Among the miners, the proposed method suggests no confounding by smoking of the association between radon and lung cancer--a conclusion supported by adjustment for measured smoking. Among the nuclear workers, the proposed method suggests substantial confounding by smoking of the association between radiation and lung cancer. Indirect adjustment for confounding by smoking resulted in an 18% decrease in the adjusted estimated hazard ratio, yet this cannot be verified because smoking was unmeasured. Assumptions underlying this method are described, and a cause-specific proportional hazards model that allows easy implementation using standard software is presented.

  6. A model of parental representations, second individuation, and psychological adjustment in late adolescence.

    PubMed

    Boles, S A

    1999-04-01

    This study examined the role that mental representations and the second individuation process play in adjustment during late adolescence. Participants between the ages of 18 and 22 were used to test a theoretical model exploring the various relationships among the following latent variables: Parental Representations, Psychological Differentiation, Psychological Dependence, Positive Adjustment, and Maladjustment. The results indicated that the quality of parental representations facilitates the second individuation process, which in turn facilitates psychological adjustment in late adolescence. Furthermore, the results indicated that the second individuation process mediates the influence that the quality of parental representations have on psychological adjustment in late adolescence. These findings are discussed in light of previous research in this area, and clinical implications and suggestions for future research are offered.

  7. Modeling Quality-Adjusted Life Expectancy Loss Resulting from Tobacco Use in the United States

    ERIC Educational Resources Information Center

    Kaplan, Robert M.; Anderson, John P.; Kaplan, Cameron M.

    2007-01-01

    Purpose: To describe the development of a model for estimating the effects of tobacco use upon Quality Adjusted Life Years (QALYs) and to estimate the impact of tobacco use on health outcomes for the United States (US) population using the model. Method: We obtained estimates of tobacco consumption from 6 years of the National Health Interview…

  8. A Model of Divorce Adjustment for Use in Family Service Agencies.

    ERIC Educational Resources Information Center

    Faust, Ruth Griffith

    1987-01-01

    Presents a combined educationally and therapeutically oriented model of treatment to (1) control and lessen disruptive experiences associated with divorce; (2) enable individuals to improve their skill in coping with adjustment reactions to divorce; and (3) modify the pressures and response of single parenthood. Describes the model's four-session…

  9. Targeted nano-delivery of novel omega-3 conjugate against hepatocellular carcinoma: Regulating COX-2/bcl-2 expression in an animal model.

    PubMed

    Khan, Azmat Ali; Alanazi, Amer M; Jabeen, Mumtaz; Hassan, Iftekhar; Bhat, Mashooq Ahmad

    2016-07-01

    The present approach enumerates the effectiveness of tuftsin tagged nano-liposome for the cytosolic transport of 2,6-di-isopropylphenol-linolenic acid conjugate against liver cancer in mice. Initially, the conjugate in its free form was examined for anticancer potential on HepG2 liver cancer cells. Induction of apoptosis and suppression of migration and adhesion of HepG2 cells confirmed the effectiveness of conjugate as an anticancer agent. After this, role of the conjugate entrapped in a nano-carrier was evaluated in animal model. The nano-formulation comprising of conjugate bearing tuftsin tagged liposome was firsly characterized and then its therapeutic effect was determined. The nano-formulation had 100-130nm size nanoparticles and showed sustained release of the conjugate in the surrounding milieu. The nano-formulation distinctly reduced the expression of COX-2, an important molecule that is vastly expressed in hepatocellular carcinoma. The utilization of in-house engineered nano-formulation was also successful in significantly up-regulating Bax and down-regulating bcl-2 gene expression eventually helping in better survival of treated mice. Histopathological analysis also revealed positive recovery of the general architecture and the violent death of cancer cells by apoptosis at tumor specific site. The site specific delivery of conjugate entrapped in tuftsin tagged liposomes was highly safe as well as efficaceous. Nano-formulation based approach showed a visible chemotherapeutic effect on liver cancer progression in experimental mice thereby making it a potential candidate for treatment of liver cancer in clinical settings.

  10. Early induction of cytokines/cytokine receptors and Cox2, and activation of NF-κB in 4-nitroquinoline 1-oxide-induced murine oral cancer model.

    PubMed

    Liu, Yu-Ching; Ho, Heng-Chien; Lee, Miau-Rong; Lai, Kuang-Chi; Yeh, Chung-Min; Lin, Yueh-Min; Ho, Tin-Yun; Hsiang, Chien-Yun; Chung, Jing-Gung

    2012-07-15

    The purpose of this study was to identify the genes induced early in murine oral carcinogenesis. Murine tongue tumors induced by the carcinogen, 4-nitroquinoline 1-oxide (4-NQO), and paired non-tumor tissues were subjected to microarray analysis. Hierarchical clustering of upregulated genes in the tumor tissues revealed an association of induced genes with inflammation. Cytokines/cytokine receptors induced early were subsequently identified, clearly indicating their involvement in oral carcinogenesis. Hierarchical clustering also showed that cytokine-mediated inflammation was possibly linked with Mapk6. Cox2 exhibited the greatest extent (9-18 fold) of induction in the microarray data, and its early induction was observed in a 2h painting experiment by RT-PCR. MetaCore analysis showed that overexpressed Cox2 may interact with p53 and transcriptionally inhibit expression of several downstream genes. A painting experiment in transgenic mice also demonstrated that NF-κB activates early independently of Cox2 induction. MetaCore analysis revealed the most striking metabolic alterations in tumor tissues, especially in lipid metabolism resulting from the reduction of Pparα and Rxrg. Reduced expression of Mapk12 was noted, and MetaCore analysis established its relationship with decreased efficiency of Pparα phosphorylation. In conclusion, in addition to cytokines/cytokine receptors, the early induction of Cox2 and NF-κB activation is involved in murine oral carcinogenesis.

  11. Early induction of cytokines/cytokine receptors and Cox2, and activation of NF-κB in 4-nitroquinoline 1-oxide-induced murine oral cancer model

    SciTech Connect

    Liu, Yu-Ching; Ho, Heng-Chien; Lee, Miau-Rong; Lai, Kuang-Chi; Yeh, Chung-Min; Lin, Yueh-Min; Ho, Tin-Yun; Hsiang, Chien-Yun; Chung, Jing-Gung

    2012-07-15

    The purpose of this study was to identify the genes induced early in murine oral carcinogenesis. Murine tongue tumors induced by the carcinogen, 4-nitroquinoline 1-oxide (4-NQO), and paired non-tumor tissues were subjected to microarray analysis. Hierarchical clustering of upregulated genes in the tumor tissues revealed an association of induced genes with inflammation. Cytokines/cytokine receptors induced early were subsequently identified, clearly indicating their involvement in oral carcinogenesis. Hierarchical clustering also showed that cytokine-mediated inflammation was possibly linked with Mapk6. Cox2 exhibited the greatest extent (9–18 fold) of induction in the microarray data, and its early induction was observed in a 2 h painting experiment by RT-PCR. MetaCore analysis showed that overexpressed Cox2 may interact with p53 and transcriptionally inhibit expression of several downstream genes. A painting experiment in transgenic mice also demonstrated that NF-κB activates early independently of Cox2 induction. MetaCore analysis revealed the most striking metabolic alterations in tumor tissues, especially in lipid metabolism resulting from the reduction of Pparα and Rxrg. Reduced expression of Mapk12 was noted, and MetaCore analysis established its relationship with decreased efficiency of Pparα phosphorylation. In conclusion, in addition to cytokines/cytokine receptors, the early induction of Cox2 and NF-κB activation is involved in murine oral carcinogenesis.

  12. Testing a developmental cascade model of adolescent substance use trajectories and young adult adjustment

    PubMed Central

    LYNNE-LANDSMAN, SARAH D.; BRADSHAW, CATHERINE P.; IALONGO, NICHOLAS S.

    2013-01-01

    Developmental models highlight the impact of early risk factors on both the onset and growth of substance use, yet few studies have systematically examined the indirect effects of risk factors across several domains, and at multiple developmental time points, on trajectories of substance use and adult adjustment outcomes (e.g., educational attainment, mental health problems, criminal behavior). The current study used data from a community epidemiologically defined sample of 678 urban, primarily African American youth, followed from first grade through young adulthood (age 21) to test a developmental cascade model of substance use and young adult adjustment outcomes. Drawing upon transactional developmental theories and using growth mixture modeling procedures, we found evidence for a developmental progression from behavioral risk to adjustment problems in the peer context, culminating in a high-risk trajectory of alcohol, cigarette, and marijuana use during adolescence. Substance use trajectory membership was associated with adjustment in adulthood. These findings highlight the developmental significance of early individual and interpersonal risk factors on subsequent risk for substance use and, in turn, young adult adjustment outcomes. PMID:20883591

  13. Contact angle adjustment in equation-of-state-based pseudopotential model

    NASA Astrophysics Data System (ADS)

    Hu, Anjie; Li, Longjian; Uddin, Rizwan; Liu, Dong

    2016-05-01

    The single component pseudopotential lattice Boltzmann model has been widely applied in multiphase simulation due to its simplicity and stability. In many studies, it has been claimed that this model can be stable for density ratios larger than 1000. However, the application of the model is still limited to small density ratios when the contact angle is considered. The reason is that the original contact angle adjustment method influences the stability of the model. Moreover, simulation results in the present work show that, by applying the original contact angle adjustment method, the density distribution near the wall is artificially changed, and the contact angle is dependent on the surface tension. Hence, it is very inconvenient to apply this method with a fixed contact angle, and the accuracy of the model cannot be guaranteed. To solve these problems, a contact angle adjustment method based on the geometry analysis is proposed and numerically compared with the original method. Simulation results show that, with our contact angle adjustment method, the stability of the model is highly improved when the density ratio is relatively large, and it is independent of the surface tension.

  14. Contact angle adjustment in equation-of-state-based pseudopotential model.

    PubMed

    Hu, Anjie; Li, Longjian; Uddin, Rizwan; Liu, Dong

    2016-05-01

    The single component pseudopotential lattice Boltzmann model has been widely applied in multiphase simulation due to its simplicity and stability. In many studies, it has been claimed that this model can be stable for density ratios larger than 1000. However, the application of the model is still limited to small density ratios when the contact angle is considered. The reason is that the original contact angle adjustment method influences the stability of the model. Moreover, simulation results in the present work show that, by applying the original contact angle adjustment method, the density distribution near the wall is artificially changed, and the contact angle is dependent on the surface tension. Hence, it is very inconvenient to apply this method with a fixed contact angle, and the accuracy of the model cannot be guaranteed. To solve these problems, a contact angle adjustment method based on the geometry analysis is proposed and numerically compared with the original method. Simulation results show that, with our contact angle adjustment method, the stability of the model is highly improved when the density ratio is relatively large, and it is independent of the surface tension.

  15. Analysis of Case-Parent Trios Using a Loglinear Model with Adjustment for Transmission Ratio Distortion

    PubMed Central

    Huang, Lam O.; Infante-Rivard, Claire; Labbe, Aurélie

    2016-01-01

    Transmission of the two parental alleles to offspring deviating from the Mendelian ratio is termed Transmission Ratio Distortion (TRD), occurs throughout gametic and embryonic development. TRD has been well-studied in animals, but remains largely unknown in humans. The Transmission Disequilibrium Test (TDT) was first proposed to test for association and linkage in case-trios (affected offspring and parents); adjusting for TRD using control-trios was recommended. However, the TDT does not provide risk parameter estimates for different genetic models. A loglinear model was later proposed to provide child and maternal relative risk (RR) estimates of disease, assuming Mendelian transmission. Results from our simulation study showed that case-trios RR estimates using this model are biased in the presence of TRD; power and Type 1 error are compromised. We propose an extended loglinear model adjusting for TRD. Under this extended model, RR estimates, power and Type 1 error are correctly restored. We applied this model to an intrauterine growth restriction dataset, and showed consistent results with a previous approach that adjusted for TRD using control-trios. Our findings suggested the need to adjust for TRD in avoiding spurious results. Documenting TRD in the population is therefore essential for the correct interpretation of genetic association studies. PMID:27630667

  16. Testing a Social Ecological Model for Relations between Political Violence and Child Adjustment in Northern Ireland

    PubMed Central

    Cummings, E. Mark; Merrilees, Christine E.; Schermerhorn, Alice C.; Goeke-Morey, Marcie C.; Shirlow, Peter; Cairns, Ed

    2013-01-01

    Relations between political violence and child adjustment are matters of international concern. Past research demonstrates the significance of community, family and child psychological processes in child adjustment, supporting study of inter-relations between multiple social ecological factors and child adjustment in contexts of political violence. Testing a social ecological model, 300 mothers and their children (M= 12.28 years, SD = 1.77) from Catholic and Protestant working class neighborhoods in Belfast, Northern Ireland completed measures of community discord, family relations, and children’s regulatory processes (i.e., emotional security) and outcomes. Historical political violence in neighborhoods based on objective records (i.e., politically motivated deaths) were related to family members’ reports of current sectarian and non-sectarian antisocial behavior. Interparental conflict and parental monitoring and children’s emotional security about both the community and family contributed to explanatory pathways for relations between sectarian antisocial behavior in communities and children’s adjustment problems. The discussion evaluates support for social ecological models for relations between political violence and child adjustment and its implications for understanding relations in other parts of the world. PMID:20423550

  17. Testing a social ecological model for relations between political violence and child adjustment in Northern Ireland.

    PubMed

    Cummings, E Mark; Merrilees, Christine E; Schermerhorn, Alice C; Goeke-Morey, Marcie C; Shirlow, Peter; Cairns, Ed

    2010-05-01

    Relations between political violence and child adjustment are matters of international concern. Past research demonstrates the significance of community, family, and child psychological processes in child adjustment, supporting study of interrelations between multiple social ecological factors and child adjustment in contexts of political violence. Testing a social ecological model, 300 mothers and their children (M = 12.28 years, SD = 1.77) from Catholic and Protestant working class neighborhoods in Belfast, Northern Ireland, completed measures of community discord, family relations, and children's regulatory processes (i.e., emotional security) and outcomes. Historical political violence in neighborhoods based on objective records (i.e., politically motivated deaths) were related to family members' reports of current sectarian antisocial behavior and nonsectarian antisocial behavior. Interparental conflict and parental monitoring and children's emotional security about both the community and family contributed to explanatory pathways for relations between sectarian antisocial behavior in communities and children's adjustment problems. The discussion evaluates support for social ecological models for relations between political violence and child adjustment and its implications for understanding relations in other parts of the world.

  18. Parametric estimation of quality adjusted lifetime (QAL) distribution in progressive illness--death model.

    PubMed

    Pradhan, Biswabrata; Dewanji, Anup

    2009-07-10

    In this work, we consider the parametric estimation of quality adjusted lifetime (QAL) distribution in progressive illness-death models. The main idea of this paper is to derive the theoretical distribution of QAL for the progressive illness-death models, under parametric models for the sojourn time distributions in different states, and then replace the model parameters by their estimates obtained by standard techniques of survival analysis. The method of estimation of the model parameters is also described. A data set of IBCSG Trial V has been analyzed for illustration. Extension to more general illness-death models is also discussed.

  19. Two Models of Caregiver Strain and Bereavement Adjustment: A Comparison of Husband and Daughter Caregivers of Breast Cancer Hospice Patients

    ERIC Educational Resources Information Center

    Bernard, Lori L.; Guarnaccia, Charles A.

    2003-01-01

    Purpose: Caregiver bereavement adjustment literature suggests opposite models of impact of role strain on bereavement adjustment after care-recipient death--a Complicated Grief Model and a Relief Model. This study tests these competing models for husband and adult-daughter caregivers of breast cancer hospice patients. Design and Methods: This…

  20. A Threshold Model of Social Support, Adjustment, and Distress after Breast Cancer Treatment

    ERIC Educational Resources Information Center

    Mallinckrodt, Brent; Armer, Jane M.; Heppner, P. Paul

    2012-01-01

    This study examined a threshold model that proposes that social support exhibits a curvilinear association with adjustment and distress, such that support in excess of a critical threshold level has decreasing incremental benefits. Women diagnosed with a first occurrence of breast cancer (N = 154) completed survey measures of perceived support…

  1. A Study of Perfectionism, Attachment, and College Student Adjustment: Testing Mediational Models.

    ERIC Educational Resources Information Center

    Hood, Camille A.; Kubal, Anne E.; Pfaller, Joan; Rice, Kenneth G.

    Mediational models predicting college students' adjustment were tested using regression analyses. Contemporary adult attachment theory was employed to explore the cognitive/affective mechanisms by which adult attachment and perfectionism affect various aspects of psychological functioning. Consistent with theoretical expectations, results…

  2. A Four-Part Model of Autonomy during Emerging Adulthood: Associations with Adjustment

    ERIC Educational Resources Information Center

    Lamborn, Susie D.; Groh, Kelly

    2009-01-01

    We found support for a four-part model of autonomy that links connectedness, separation, detachment, and agency to adjustment during emerging adulthood. Based on self-report surveys of 285 American college students, expected associations among the autonomy variables were found. In addition, agency, as measured by self-reliance, predicted lower…

  3. Towards an Integrated Conceptual Model of International Student Adjustment and Adaptation

    ERIC Educational Resources Information Center

    Schartner, Alina; Young, Tony Johnstone

    2016-01-01

    Despite a burgeoning body of empirical research on "the international student experience", the area remains under-theorized. The literature to date lacks a guiding conceptual model that captures the adjustment and adaptation trajectories of this unique, growing, and important sojourner group. In this paper, we therefore put forward a…

  4. Lineage-specific fragmentation and nuclear relocation of the mitochondrial cox2 gene in chlorophycean green algae (Chlorophyta).

    PubMed

    Rodríguez-Salinas, Elizabeth; Riveros-Rosas, Héctor; Li, Zhongkui; Fucíková, Karolina; Brand, Jerry J; Lewis, Louise A; González-Halphen, Diego

    2012-07-01

    In most eukaryotes the subunit 2 of cytochrome c oxidase (COX2) is encoded in intact mitochondrial genes. Some green algae, however, exhibit split cox2 genes (cox2a and cox2b) encoding two polypeptides (COX2A and COX2B) that form a heterodimeric COX2 subunit. Here, we analyzed the distribution of intact and split cox2 gene sequences in 39 phylogenetically diverse green algae in phylum Chlorophyta obtained from databases (28 sequences from 22 taxa) and from new cox2 data generated in this work (23 sequences from 18 taxa). Our results support previous observations based on a smaller number of taxa, indicating that algae in classes Prasinophyceae, Ulvophyceae, and Trebouxiophyceae contain orthodox, intact mitochondrial cox2 genes. In contrast, all of the algae in Chlorophyceae that we examined exhibited split cox2 genes, and could be separated into two groups: one that has a mitochondrion-localized cox2a gene and a nucleus-localized cox2b gene ("Scenedesmus-like"), and another that has both cox2a and cox2b genes in the nucleus ("Chlamydomonas-like"). The location of the split cox2a and cox2b genes was inferred using five different criteria: differences in amino acid sequences, codon usage (mitochondrial vs. nuclear), codon preference (third position frequencies), presence of nucleotide sequences encoding mitochondrial targeting sequences and presence of spliceosomal introns. Distinct green algae could be grouped according to the form of cox2 gene they contain: intact or fragmented, mitochondrion- or nucleus-localized, and intron-containing or intron-less. We present a model describing the events that led to mitochondrial cox2 gene fragmentation and the independent and sequential migration of cox2a and cox2b genes to the nucleus in chlorophycean green algae. We also suggest that the distribution of the different forms of the cox2 gene provides important insights into the phylogenetic relationships among major groups of Chlorophyceae.

  5. 10 km running performance predicted by a multiple linear regression model with allometrically adjusted variables

    PubMed Central

    Abad, Cesar C. C.; Barros, Ronaldo V.; Bertuzzi, Romulo; Gagliardi, João F. L.; Lima-Silva, Adriano E.; Lambert, Mike I.

    2016-01-01

    Abstract The aim of this study was to verify the power of VO2max, peak treadmill running velocity (PTV), and running economy (RE), unadjusted or allometrically adjusted, in predicting 10 km running performance. Eighteen male endurance runners performed: 1) an incremental test to exhaustion to determine VO2max and PTV; 2) a constant submaximal run at 12 km·h−1 on an outdoor track for RE determination; and 3) a 10 km running race. Unadjusted (VO2max, PTV and RE) and adjusted variables (VO2max0.72, PTV0.72 and RE0.60) were investigated through independent multiple regression models to predict 10 km running race time. There were no significant correlations between 10 km running time and either the adjusted or unadjusted VO2max. Significant correlations (p < 0.01) were found between 10 km running time and adjusted and unadjusted RE and PTV, providing models with effect size > 0.84 and power > 0.88. The allometrically adjusted predictive model was composed of PTV0.72 and RE0.60 and explained 83% of the variance in 10 km running time with a standard error of the estimate (SEE) of 1.5 min. The unadjusted model composed of a single PVT accounted for 72% of the variance in 10 km running time (SEE of 1.9 min). Both regression models provided powerful estimates of 10 km running time; however, the unadjusted PTV may provide an uncomplicated estimation. PMID:28149382

  6. Transgenic expression of cyclooxygenase-2 (COX2) causes premature aging phenotypes in mice

    PubMed Central

    Feng, Mingxiao; Field, Kevin; Chatzistamou, Ioulia; Shim, Minsub

    2016-01-01

    Cyclooxygenase (COX) is a key enzyme in the biosynthesis of prostanoids, lipid signaling molecules that regulate various physiological processes. COX2, one of the isoforms of COX, is highly inducible in response to a wide variety of cellular and environmental stresses. Increased COX2 expression is thought to play a role in the pathogenesis of many age-related diseases. COX2 expression is also reported to be increased in the tissues of aged humans and mice, which suggests the involvement of COX2 in the aging process. However, it is not clear whether the increased COX2 expression is causal to or a result of aging. We have now addressed this question by creating an inducible COX2 transgenic mouse model. Here we show that post-natal expression of COX2 led to a panel of aging-related phenotypes. The expression of p16, p53, and phospho-H2AX was increased in the tissues of COX2 transgenic mice. Additionally, adult mouse lung fibroblasts from COX2 transgenic mice exhibited increased expression of the senescence-associated β-galactosidase. Our study reveals that the increased COX2 expression has an impact on the aging process and suggests that modulation of COX2 and its downstream signaling may be an approach for intervention of age-related disorders. PMID:27750221

  7. Adjusted adaptive Lasso for covariate model-building in nonlinear mixed-effect pharmacokinetic models.

    PubMed

    Haem, Elham; Harling, Kajsa; Ayatollahi, Seyyed Mohammad Taghi; Zare, Najaf; Karlsson, Mats O

    2017-02-01

    One important aim in population pharmacokinetics (PK) and pharmacodynamics is identification and quantification of the relationships between the parameters and covariates. Lasso has been suggested as a technique for simultaneous estimation and covariate selection. In linear regression, it has been shown that Lasso possesses no oracle properties, which means it asymptotically performs as though the true underlying model was given in advance. Adaptive Lasso (ALasso) with appropriate initial weights is claimed to possess oracle properties; however, it can lead to poor predictive performance when there is multicollinearity between covariates. This simulation study implemented a new version of ALasso, called adjusted ALasso (AALasso), to take into account the ratio of the standard error of the maximum likelihood (ML) estimator to the ML coefficient as the initial weight in ALasso to deal with multicollinearity in non-linear mixed-effect models. The performance of AALasso was compared with that of ALasso and Lasso. PK data was simulated in four set-ups from a one-compartment bolus input model. Covariates were created by sampling from a multivariate standard normal distribution with no, low (0.2), moderate (0.5) or high (0.7) correlation. The true covariates influenced only clearance at different magnitudes. AALasso, ALasso and Lasso were compared in terms of mean absolute prediction error and error of the estimated covariate coefficient. The results show that AALasso performed better in small data sets, even in those in which a high correlation existed between covariates. This makes AALasso a promising method for covariate selection in nonlinear mixed-effect models.

  8. Improving the global applicability of the RUSLE model - adjustment of the topographical and rainfall erosivity factors

    NASA Astrophysics Data System (ADS)

    Naipal, V.; Reick, C.; Pongratz, J.; Van Oost, K.

    2015-09-01

    Large uncertainties exist in estimated rates and the extent of soil erosion by surface runoff on a global scale. This limits our understanding of the global impact that soil erosion might have on agriculture and climate. The Revised Universal Soil Loss Equation (RUSLE) model is, due to its simple structure and empirical basis, a frequently used tool in estimating average annual soil erosion rates at regional to global scales. However, large spatial-scale applications often rely on coarse data input, which is not compatible with the local scale on which the model is parameterized. Our study aims at providing the first steps in improving the global applicability of the RUSLE model in order to derive more accurate global soil erosion rates. We adjusted the topographical and rainfall erosivity factors of the RUSLE model and compared the resulting erosion rates to extensive empirical databases from the USA and Europe. By scaling the slope according to the fractal method to adjust the topographical factor, we managed to improve the topographical detail in a coarse resolution global digital elevation model. Applying the linear multiple regression method to adjust rainfall erosivity for various climate zones resulted in values that compared well to high resolution erosivity data for different regions. However, this method needs to be extended to tropical climates, for which erosivity is biased due to the lack of high resolution erosivity data. After applying the adjusted and the unadjusted versions of the RUSLE model on a global scale we find that the adjusted version shows a global higher mean erosion rate and more variability in the erosion rates. Comparison to empirical data sets of the USA and Europe shows that the adjusted RUSLE model is able to decrease the very high erosion rates in hilly regions that are observed in the unadjusted RUSLE model results. Although there are still some regional differences with the empirical databases, the results indicate that the

  9. Synthesis and evaluation of fluorobenzoylated di- and tripeptides as inhibitors of cyclooxygenase-2 (COX-2).

    PubMed

    Sharma, Sai Kiran; Al-Hourani, Baker Jawabrah; Wuest, Melinda; Mane, Jonathan Y; Tuszynski, Jack; Baracos, Vickie; Suresh, Mavanur; Wuest, Frank

    2012-04-01

    A series of fluorobenzoylated di- and tripeptides as potential leads for the development of molecular probes for imaging of COX-2 expression was prepared according to standard Fmoc-based solid-phase peptide synthesis. All peptides were assessed for their COX-2 inhibitory potency and selectivity profile in a fluorescence-based COX binding assay. Within the series of 15 peptides tested, cysteine-containing peptides numbered 7, 8, 11 and 12, respectively, were the most potent COX-2 inhibitors possessing IC(50) values ranging from 5 to 85 μM. Fluorobenzoylated tripeptides 7 and 8 displayed some COX-2 selectivity (COX-2 selectivity index 2.1 and 1.6), whereas fluorobenzoylated dipeptides 11 and 12 were shown not to be COX-2 selective. Fluorbenzoylated tripeptide FB-Phe-Cys-Ser-OH was further used in molecular modeling docking studies to determine the binding mode within the active site of the COX-2 enzyme.

  10. Adjusting lidar-derived digital terrain models in coastal marshes based on estimated aboveground biomass density

    SciTech Connect

    Medeiros, Stephen; Hagen, Scott; Weishampel, John; Angelo, James

    2015-03-25

    Digital elevation models (DEMs) derived from airborne lidar are traditionally unreliable in coastal salt marshes due to the inability of the laser to penetrate the dense grasses and reach the underlying soil. To that end, we present a novel processing methodology that uses ASTER Band 2 (visible red), an interferometric SAR (IfSAR) digital surface model, and lidar-derived canopy height to classify biomass density using both a three-class scheme (high, medium and low) and a two-class scheme (high and low). Elevation adjustments associated with these classes using both median and quartile approaches were applied to adjust lidar-derived elevation values closer to true bare earth elevation. The performance of the method was tested on 229 elevation points in the lower Apalachicola River Marsh. The two-class quartile-based adjusted DEM produced the best results, reducing the RMS error in elevation from 0.65 m to 0.40 m, a 38% improvement. The raw mean errors for the lidar DEM and the adjusted DEM were 0.61 ± 0.24 m and 0.32 ± 0.24 m, respectively, thereby reducing the high bias by approximately 49%.

  11. Adjusting lidar-derived digital terrain models in coastal marshes based on estimated aboveground biomass density

    DOE PAGES

    Medeiros, Stephen; Hagen, Scott; Weishampel, John; ...

    2015-03-25

    Digital elevation models (DEMs) derived from airborne lidar are traditionally unreliable in coastal salt marshes due to the inability of the laser to penetrate the dense grasses and reach the underlying soil. To that end, we present a novel processing methodology that uses ASTER Band 2 (visible red), an interferometric SAR (IfSAR) digital surface model, and lidar-derived canopy height to classify biomass density using both a three-class scheme (high, medium and low) and a two-class scheme (high and low). Elevation adjustments associated with these classes using both median and quartile approaches were applied to adjust lidar-derived elevation values closer tomore » true bare earth elevation. The performance of the method was tested on 229 elevation points in the lower Apalachicola River Marsh. The two-class quartile-based adjusted DEM produced the best results, reducing the RMS error in elevation from 0.65 m to 0.40 m, a 38% improvement. The raw mean errors for the lidar DEM and the adjusted DEM were 0.61 ± 0.24 m and 0.32 ± 0.24 m, respectively, thereby reducing the high bias by approximately 49%.« less

  12. An appraisal-based coping model of attachment and adjustment to arthritis.

    PubMed

    Sirois, Fuschia M; Gick, Mary L

    2016-05-01

    Guided by pain-related attachment models and coping theory, we used structural equation modeling to test an appraisal-based coping model of how insecure attachment was linked to arthritis adjustment in a sample of 365 people with arthritis. The structural equation modeling analyses revealed indirect and direct associations of anxious and avoidant attachment with greater appraisals of disease-related threat, less perceived social support to deal with this threat, and less coping efficacy. There was evidence of reappraisal processes for avoidant but not anxious attachment. Findings highlight the importance of considering attachment style when assessing how people cope with the daily challenges of arthritis.

  13. Mathematical modeling on experimental protocol of glucose adjustment for non-invasive blood glucose sensing

    NASA Astrophysics Data System (ADS)

    Jiang, Jingying; Min, Xiaolin; Zou, Da; Xu, Kexin

    2012-03-01

    Currently, blood glucose concentration levels from OGTT(Oral Glucose Tolerance Test) results are used to build PLS model in noninvasive blood glucose sensing by Near-Infrared(NIR) Spectroscopy. However, the univocal dynamic change trend of blood glucose concentration based on OGTT results is not various enough to provide comprehensive data to make PLS model robust and accurate. In this talk, with the final purpose of improving the stability and accuracy of the PLS model, we introduced an integrated minimal model(IMM) of glucose metabolism system. First, by adjusting parameters, which represent different metabolism characteristics and individual differences, comparatively ideal mediation programs to different groups of people, even individuals were customized. Second, with different glucose input types(oral method, intravenous injection, or intravenous drip), we got various changes of blood glucose concentration. And by studying the adjustment methods of blood glucose concentration, we would thus customize corresponding experimental protocols of glucose adjustment to different people for noninvasive blood glucose concentration and supply comprehensive data for PLS model.

  14. Modelling the rate of change in a longitudinal study with missing data, adjusting for contact attempts.

    PubMed

    Akacha, Mouna; Hutton, Jane L

    2011-05-10

    The Collaborative Ankle Support Trial (CAST) is a longitudinal trial of treatments for severe ankle sprains in which interest lies in the rate of improvement, the effectiveness of reminders and potentially informative missingness. A model is proposed for continuous longitudinal data with non-ignorable or informative missingness, taking into account the nature of attempts made to contact initial non-responders. The model combines a non-linear mixed model for the outcome model with logistic regression models for the reminder processes. A sensitivity analysis is used to contrast this model with the traditional selection model, where we adjust for missingness by modelling the missingness process. The conclusions that recovery is slower, and less satisfactory with age and more rapid with below knee cast than with a tubular bandage do not alter materially across all models investigated. The results also suggest that phone calls are most effective in retrieving questionnaires.

  15. Effect of structural modification of enol-carboxamide-type nonsteroidal antiinflammatory drugs on COX-2/COX-1 selectivity.

    PubMed

    Lazer, E S; Miao, C K; Cywin, C L; Sorcek, R; Wong, H C; Meng, Z; Potocki, I; Hoermann, M; Snow, R J; Tschantz, M A; Kelly, T A; McNeil, D W; Coutts, S J; Churchill, L; Graham, A G; David, E; Grob, P M; Engel, W; Meier, H; Trummlitz, G

    1997-03-14

    Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6- and 7-positions of the 4-oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothizines, benzothienothiazines, naphthothiazines, and 1,3- and 1,4-dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.

  16. Simultaneous confidence bands for Cox regression from semiparametric random censorship.

    PubMed

    Mondal, Shoubhik; Subramanian, Sundarraman

    2016-01-01

    Cox regression is combined with semiparametric random censorship models to construct simultaneous confidence bands (SCBs) for subject-specific survival curves. Simulation results are presented to compare the performance of the proposed SCBs with the SCBs that are based only on standard Cox. The new SCBs provide correct empirical coverage and are more informative. The proposed SCBs are illustrated with two real examples. An extension to handle missing censoring indicators is also outlined.

  17. A statistical test for the equality of differently adjusted incidence rate ratios.

    PubMed

    Hoffmann, Kurt; Pischon, Tobias; Schulz, Mandy; Schulze, Matthias B; Ray, Jennifer; Boeing, Heiner

    2008-03-01

    An incidence rate ratio (IRR) is a meaningful effect measure in epidemiology if it is adjusted for all important confounders. For evaluation of the impact of adjustment, adjusted IRRs should be compared with crude IRRs. The aim of this methodological study was to present a statistical approach for testing the equality of adjusted and crude IRRs and to derive a confidence interval for the ratio of the two IRRs. The method can be extended to compare two differently adjusted IRRs and, thus, to evaluate the effect of additional adjustment. The method runs immediately on existing software. To illustrate the application of this approach, the authors studied adjusted IRRs for two risk factors of type 2 diabetes using data from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study from 2005. The statistical method described may be helpful as an additional tool for analyzing epidemiologic cohort data and for interpreting results obtained from Cox regression models with adjustment for different covariates.

  18. The HHS-HCC Risk Adjustment Model for Individual and Small Group Markets under the Affordable Care Act

    PubMed Central

    Kautter, John; Pope, Gregory C; Ingber, Melvin; Freeman, Sara; Patterson, Lindsey; Cohen, Michael; Keenan, Patricia

    2014-01-01

    Beginning in 2014, individuals and small businesses are able to purchase private health insurance through competitive Marketplaces. The Affordable Care Act (ACA) provides for a program of risk adjustment in the individual and small group markets in 2014 as Marketplaces are implemented and new market reforms take effect. The purpose of risk adjustment is to lessen or eliminate the influence of risk selection on the premiums that plans charge. The risk adjustment methodology includes the risk adjustment model and the risk transfer formula. This article is the second of three in this issue of the Review that describe the Department of Health and Human Services (HHS) risk adjustment methodology and focuses on the risk adjustment model. In our first companion article, we discuss the key issues and choices in developing the methodology. In this article, we present the risk adjustment model, which is named the HHS-Hierarchical Condition Categories (HHS-HCC) risk adjustment model. We first summarize the HHS-HCC diagnostic classification, which is the key element of the risk adjustment model. Then the data and methods, results, and evaluation of the risk adjustment model are presented. Fifteen separate models are developed. For each age group (adult, child, and infant), a model is developed for each cost sharing level (platinum, gold, silver, and bronze metal levels, as well as catastrophic plans). Evaluation of the risk adjustment models shows good predictive accuracy, both for individuals and for groups. Lastly, this article provides examples of how the model output is used to calculate risk scores, which are an input into the risk transfer formula. Our third companion paper describes the risk transfer formula. PMID:25360387

  19. Lithium-ion Open Circuit Voltage (OCV) curve modelling and its ageing adjustment

    NASA Astrophysics Data System (ADS)

    Lavigne, L.; Sabatier, J.; Francisco, J. Mbala; Guillemard, F.; Noury, A.

    2016-08-01

    This paper is a contribution to lithium-ion batteries modelling taking into account aging effects. It first analyses the impact of aging on electrode stoichiometry and then on lithium-ion cell Open Circuit Voltage (OCV) curve. Through some hypotheses and an appropriate definition of the cell state of charge, it shows that each electrode equilibrium potential, but also the whole cell equilibrium potential can be modelled by a polynomial that requires only one adjustment parameter during aging. An adjustment algorithm, based on the idea that for two fixed OCVs, the state of charge between these two equilibrium states is unique for a given aging level, is then proposed. Its efficiency is evaluated on a battery pack constituted of four cells.

  20. Modelling goal adjustment in social relationships: Two experimental studies with children and adults.

    PubMed

    Thomsen, Tamara; Kappes, Cathleen; Schwerdt, Laura; Sander, Johanna; Poller, Charlotte

    2016-10-23

    In two experiments, we investigated observational learning in social relationships as one possible pathway to the development of goal adjustment processes. In the first experiment, 56 children (M = 9.29 years) observed their parent as a model; in the second, 50 adults (M = 32.27 years) observed their romantic partner. Subjects were randomly assigned to three groups: goal engagement (GE), goal disengagement (GD), or control group (CO) and were asked to solve (unsolvable) puzzles. Before trying to solve the puzzles by themselves, subjects observed the instructed model, who was told to continue with the same puzzle (GE) or to switch to the next puzzle (GD). Results show that children in the GE group switched significantly less than in the GD or CO group. There was no difference between the GD group and CO group. Adults in the GE group switched significantly less than in the GD or CO group, whereas subjects in the GD group switched significantly more often than the CO group. Statement of contribution What is already known on this subject? Previous research focused mainly on the functions of goal adjustment processes. It rarely considered processes and conditions that contribute to the development of goal engagement and goal disengagement. There are only two cross-sectional studies that directly investigate this topic. Previous research that claims observational learning as a pathway of learning emotion regulation or adjustment processes has (only) relied on correlational methods and, thus, do not allow any causal interpretations. Previous research, albeit claiming a life span focus, mostly investigated goal adjustment processes in one specific age group (mainly adults). There is no study that investigates the same processes in different age groups. What does this study add? In our two studies, we focus on the conditions of goal adjustment processes and sought to demonstrate one potential pathway of learning or changing the application of goal adjustment

  1. Army Physical Therapy Productivity According to the Performance Based Adjustment Model

    DTIC Science & Technology

    2008-05-02

    FTE) data from 34 military treatment facilities (MTFs). Results: Statistical process control identified extensive special cause variation in Army PT... Treatment Facility (MTF) efficiency with specialty specific productivity benchmarks established by the Performance Based Adjustment Model (PBAM...generates 1.2 RVUs and a 15-minute ultrasound treatment generates .21 RVUs of workload. See Appendix A for a list of commonly used physical therapy

  2. Stress and Personal Resource as Predictors of the Adjustment of Parents to Autistic Children: A Multivariate Model

    ERIC Educational Resources Information Center

    Siman-Tov, Ayelet; Kaniel, Shlomo

    2011-01-01

    The research validates a multivariate model that predicts parental adjustment to coping successfully with an autistic child. The model comprises four elements: parental stress, parental resources, parental adjustment and the child's autism symptoms. 176 parents of children aged between 6 to 16 diagnosed with PDD answered several questionnaires…

  3. Adjusting for unmeasured confounding due to either of two crossed factors with a logistic regression model.

    PubMed

    Li, Li; Brumback, Babette A; Weppelmann, Thomas A; Morris, J Glenn; Ali, Afsar

    2016-08-15

    Motivated by an investigation of the effect of surface water temperature on the presence of Vibrio cholerae in water samples collected from different fixed surface water monitoring sites in Haiti in different months, we investigated methods to adjust for unmeasured confounding due to either of the two crossed factors site and month. In the process, we extended previous methods that adjust for unmeasured confounding due to one nesting factor (such as site, which nests the water samples from different months) to the case of two crossed factors. First, we developed a conditional pseudolikelihood estimator that eliminates fixed effects for the levels of each of the crossed factors from the estimating equation. Using the theory of U-Statistics for independent but non-identically distributed vectors, we show that our estimator is consistent and asymptotically normal, but that its variance depends on the nuisance parameters and thus cannot be easily estimated. Consequently, we apply our estimator in conjunction with a permutation test, and we investigate use of the pigeonhole bootstrap and the jackknife for constructing confidence intervals. We also incorporate our estimator into a diagnostic test for a logistic mixed model with crossed random effects and no unmeasured confounding. For comparison, we investigate between-within models extended to two crossed factors. These generalized linear mixed models include covariate means for each level of each factor in order to adjust for the unmeasured confounding. We conduct simulation studies, and we apply the methods to the Haitian data. Copyright © 2016 John Wiley & Sons, Ltd.

  4. [Applying temporally-adjusted land use regression models to estimate ambient air pollution exposure during pregnancy].

    PubMed

    Zhang, Y J; Xue, F X; Bai, Z P

    2017-03-06

    The impact of maternal air pollution exposure on offspring health has received much attention. Precise and feasible exposure estimation is particularly important for clarifying exposure-response relationships and reducing heterogeneity among studies. Temporally-adjusted land use regression (LUR) models are exposure assessment methods developed in recent years that have the advantage of having high spatial-temporal resolution. Studies on the health effects of outdoor air pollution exposure during pregnancy have been increasingly carried out using this model. In China, research applying LUR models was done mostly at the model construction stage, and findings from related epidemiological studies were rarely reported. In this paper, the sources of heterogeneity and research progress of meta-analysis research on the associations between air pollution and adverse pregnancy outcomes were analyzed. The methods of the characteristics of temporally-adjusted LUR models were introduced. The current epidemiological studies on adverse pregnancy outcomes that applied this model were systematically summarized. Recommendations for the development and application of LUR models in China are presented. This will encourage the implementation of more valid exposure predictions during pregnancy in large-scale epidemiological studies on the health effects of air pollution in China.

  5. Using Green's Functions to initialize and adjust a global, eddying ocean biogeochemistry general circulation model

    NASA Astrophysics Data System (ADS)

    Brix, H.; Menemenlis, D.; Hill, C.; Dutkiewicz, S.; Jahn, O.; Wang, D.; Bowman, K.; Zhang, H.

    2015-11-01

    The NASA Carbon Monitoring System (CMS) Flux Project aims to attribute changes in the atmospheric accumulation of carbon dioxide to spatially resolved fluxes by utilizing the full suite of NASA data, models, and assimilation capabilities. For the oceanic part of this project, we introduce ECCO2-Darwin, a new ocean biogeochemistry general circulation model based on combining the following pre-existing components: (i) a full-depth, eddying, global-ocean configuration of the Massachusetts Institute of Technology general circulation model (MITgcm), (ii) an adjoint-method-based estimate of ocean circulation from the Estimating the Circulation and Climate of the Ocean, Phase II (ECCO2) project, (iii) the MIT ecosystem model "Darwin", and (iv) a marine carbon chemistry model. Air-sea gas exchange coefficients and initial conditions of dissolved inorganic carbon, alkalinity, and oxygen are adjusted using a Green's Functions approach in order to optimize modeled air-sea CO2 fluxes. Data constraints include observations of carbon dioxide partial pressure (pCO2) for 2009-2010, global air-sea CO2 flux estimates, and the seasonal cycle of the Takahashi et al. (2009) Atlas. The model sensitivity experiments (or Green's Functions) include simulations that start from different initial conditions as well as experiments that perturb air-sea gas exchange parameters and the ratio of particulate inorganic to organic carbon. The Green's Functions approach yields a linear combination of these sensitivity experiments that minimizes model-data differences. The resulting initial conditions and gas exchange coefficients are then used to integrate the ECCO2-Darwin model forward. Despite the small number (six) of control parameters, the adjusted simulation is significantly closer to the data constraints (37% cost function reduction, i.e., reduction in the model-data difference, relative to the baseline simulation) and to independent observations (e.g., alkalinity). The adjusted air-sea gas

  6. Adjusting exposure limits for long and short exposure periods using a physiological pharmacokinetic model.

    PubMed

    Andersen, M E; MacNaughton, M G; Clewell, H J; Paustenbach, D J

    1987-04-01

    The rationale for adjusting occupational exposure limits for unusual work schedules is to assure, as much as possible, that persons on these schedules are placed at no greater risk of injury or discomfort than persons who work a standard 8 hr/day, 40 hr/week. For most systemic toxicants, the risk index upon which the adjustments are made will be either peak blood concentration or integrated tissue dose, depending on what chemical's presumed mechanism of toxicity. Over the past ten years, at least four different models have been proposed for adjusting exposure limits for unusually short and long work schedules. This paper advocates use of a physiologically-based pharmacokinetic (PB-PK) model for determining adjustment factors for unusual exposure schedules, an approach that should be more accurate than those proposed previously. The PB-PK model requires data on the blood:air and tissue:blood partition coefficients, the rate of metabolism of the chemical, organ volumes, organ blood flows and ventilation rates in humans. Laboratory data on two industrially important chemicals--styrene and methylene chloride--were used to illustrate the PB-PK approach. At inhaled concentrations near their respective 8-hr Threshold Limit Value-Time-weighted averages (TLV-TWAs), both of these chemicals are primarily eliminated from the body by metabolism. For these two chemicals, the appropriate risk indexing parameters are integrated tissue dose or total amount of parent chemical metabolized. Since methylene chloride is metabolized to carbon monoxide, the maximum blood carboxyhemoglobin concentrations also might be useful as an index of risk for this chemical.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Interfacial free energy adjustable phase field crystal model for homogeneous nucleation.

    PubMed

    Guo, Can; Wang, Jincheng; Wang, Zhijun; Li, Junjie; Guo, Yaolin; Huang, Yunhao

    2016-05-18

    To describe the homogeneous nucleation process, an interfacial free energy adjustable phase-field crystal model (IPFC) was proposed by reconstructing the energy functional of the original phase field crystal (PFC) methodology. Compared with the original PFC model, the additional interface term in the IPFC model effectively can adjust the magnitude of the interfacial free energy, but does not affect the equilibrium phase diagram and the interfacial energy anisotropy. The IPFC model overcame the limitation that the interfacial free energy of the original PFC model is much less than the theoretical results. Using the IPFC model, we investigated some basic issues in homogeneous nucleation. From the viewpoint of simulation, we proceeded with an in situ observation of the process of cluster fluctuation and obtained quite similar snapshots to colloidal crystallization experiments. We also counted the size distribution of crystal-like clusters and the nucleation rate. Our simulations show that the size distribution is independent of the evolution time, and the nucleation rate remains constant after a period of relaxation, which are consistent with experimental observations. The linear relation between logarithmic nucleation rate and reciprocal driving force also conforms to the steady state nucleation theory.

  8. Parametric Adjustments to the Rankine Vortex Wind Model for Gulf of Mexico Hurricanes

    DTIC Science & Technology

    2012-11-01

    Gulf of Mexico hurricanes show considerable differences between the resulting wind speeds and data. The differences are used to guide the development of adjustment factors to improve the wind fields resulting from the Rankine Vortex model. The corrected model shows a significant improvement in the shape, size, and wind speed contours for 14 out of 17 hurricanes examined. The effect on wave fields resulting from the original and modified wind fields are on the order of 4 m, which is important for the estimation of extreme wave

  9. Adjustment of the k-ω SST turbulence model for prediction of airfoil characteristics near stall

    NASA Astrophysics Data System (ADS)

    Matyushenko, A. A.; Garbaruk, A. V.

    2016-11-01

    A version of k-ra SST turbulence model adjusted for flow around airfoils at high Reynolds numbers is presented. The modified version decreases eddy viscosity and significantly improves the accuracy of prediction of aerodynamic characteristics in a wide range of angles of attack. However, considered reduction of eddy viscosity destroys calibration of the model, which leads to decreasing accuracy of skin-friction coefficient prediction even for relatively simple wall-bounded turbulent flows. Therefore, the area of applicability of the suggested modification is limited to flows around airfoils.

  10. Asymptotically Normal and Efficient Estimation of Covariate-Adjusted Gaussian Graphical Model

    PubMed Central

    Chen, Mengjie; Ren, Zhao; Zhao, Hongyu; Zhou, Harrison

    2015-01-01

    A tuning-free procedure is proposed to estimate the covariate-adjusted Gaussian graphical model. For each finite subgraph, this estimator is asymptotically normal and efficient. As a consequence, a confidence interval can be obtained for each edge. The procedure enjoys easy implementation and efficient computation through parallel estimation on subgraphs or edges. We further apply the asymptotic normality result to perform support recovery through edge-wise adaptive thresholding. This support recovery procedure is called ANTAC, standing for Asymptotically Normal estimation with Thresholding after Adjusting Covariates. ANTAC outperforms other methodologies in the literature in a range of simulation studies. We apply ANTAC to identify gene-gene interactions using an eQTL dataset. Our result achieves better interpretability and accuracy in comparison with CAMPE. PMID:27499564

  11. Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia.

    PubMed

    Candelario-Jalil, Eduardo; González-Falcón, Armando; García-Cabrera, Michel; Alvarez, Dalia; Al-Dalain, Said; Martínez, Gregorio; León, Olga Sonia; Springer, Joe E

    2003-08-01

    We investigated the relative contribution of COX-1 and/or COX-2 to oxidative damage, prostaglandin E2 (PGE2) production and hippocampal CA1 neuronal loss in a model of 5 min transient global cerebral ischemia in gerbils. Our results revealed a biphasic and significant increase in PGE2 levels after 2 and 24-48 h of reperfusion. The late increase in PGE2 levels (24 h) was more potently reduced by the highly selective COX-2 inhibitor rofecoxib (20 mg/kg) relative to the COX-1 inhibitor valeryl salicylate (20 mg/kg). The delayed rise in COX catalytic activity preceded the onset of histopathological changes in the CA1 subfield of the hippocampus. Post-ischemia treatment with rofecoxib (starting 6 h after restoration of blood flow) significantly reduced measures of oxidative damage (glutathione depletion and lipid peroxidation) seen at 48 h after the initial ischemic episode, indicating that the late increase in COX-2 activity is involved in the delayed occurrence of oxidative damage in the hippocampus after global ischemia. Interestingly, either selective inhibition of COX-2 with rofecoxib or inhibition of COX-1 with valeryl salicylate significantly increased the number of healthy neurons in the hippocampal CA1 sector even when the treatment began 6 h after ischemia. These results provide the first evidence that both COX isoforms are involved in the progression of neuronal damage following global cerebral ischemia, and have important implications for the potential therapeutic use of COX inhibitors in cerebral ischemia.

  12. Remote Sensing-based Methodologies for Snow Model Adjustments in Operational Streamflow Prediction

    NASA Astrophysics Data System (ADS)

    Bender, S.; Miller, W. P.; Bernard, B.; Stokes, M.; Oaida, C. M.; Painter, T. H.

    2015-12-01

    Water management agencies rely on hydrologic forecasts issued by operational agencies such as NOAA's Colorado Basin River Forecast Center (CBRFC). The CBRFC has partnered with the Jet Propulsion Laboratory (JPL) under funding from NASA to incorporate research-oriented, remotely-sensed snow data into CBRFC operations and to improve the accuracy of CBRFC forecasts. The partnership has yielded valuable analysis of snow surface albedo as represented in JPL's MODIS Dust Radiative Forcing in Snow (MODDRFS) data, across the CBRFC's area of responsibility. When dust layers within a snowpack emerge, reducing the snow surface albedo, the snowmelt rate may accelerate. The CBRFC operational snow model (SNOW17) is a temperature-index model that lacks explicit representation of snowpack surface albedo. CBRFC forecasters monitor MODDRFS data for emerging dust layers and may manually adjust SNOW17 melt rates. A technique was needed for efficient and objective incorporation of the MODDRFS data into SNOW17. Initial development focused in Colorado, where dust-on-snow events frequently occur. CBRFC forecasters used retrospective JPL-CBRFC analysis and developed a quantitative relationship between MODDRFS data and mean areal temperature (MAT) data. The relationship was used to generate adjusted, MODDRFS-informed input for SNOW17. Impacts of the MODDRFS-SNOW17 MAT adjustment method on snowmelt-driven streamflow prediction varied spatially and with characteristics of the dust deposition events. The largest improvements occurred in southwestern Colorado, in years with intense dust deposition events. Application of the method in other regions of Colorado and in "low dust" years resulted in minimal impact. The MODDRFS-SNOW17 MAT technique will be implemented in CBRFC operations in late 2015, prior to spring 2016 runoff. Collaborative investigation of remote sensing-based adjustment methods for the CBRFC operational hydrologic forecasting environment will continue over the next several years.

  13. “A model of mother-child Adjustment in Arab Muslim Immigrants to the US”

    PubMed Central

    Hough, Edythe s; Templin, Thomas N; Kulwicki, Anahid; Ramaswamy, Vidya; Katz, Anne

    2009-01-01

    We examined the mother-child adjustment and child behavior problems in Arab Muslim immigrant families residing in the U.S.A. The sample of 635 mother-child dyads was comprised of mothers who emigrated from 1989 or later and had at least one early adolescent child between the ages of 11 to 15 years old who was also willing to participate. Arabic speaking research assistants collected the data from the mothers and children using established measures of maternal and child stressors, coping, and social support; maternal distress; parent-child relationship; and child behavior problems. A structural equation model (SEM) was specified a priori with 17 predicted pathways. With a few exceptions, the final SEM model was highly consistent with the proposed model and had a good fit to the data. The model accounted for 67% of the variance in child behavior problems. Child stressors, mother-child relationship, and maternal stressors were the causal variables that contributed the most to child behavior problems. The model also accounted for 27% of the variance in mother-child relationship. Child active coping, child gender, mother’s education, and maternal distress were all predictive of the mother-child relationship. Mother-child relationship also mediated the effects of maternal distress and child active coping on child behavior problems. These findings indicate that immigrant mothers contribute greatly to adolescent adjustment, both as a source of risk and protection. These findings also suggest that intervening with immigrant mothers to reduce their stress and strengthening the parent-child relationship are two important areas for promoting adolescent adjustment. PMID:19758737

  14. A spatial model of bird abundance as adjusted for detection probability

    USGS Publications Warehouse

    Gorresen, P.M.; Mcmillan, G.P.; Camp, R.J.; Pratt, T.K.

    2009-01-01

    Modeling the spatial distribution of animals can be complicated by spatial and temporal effects (i.e. spatial autocorrelation and trends in abundance over time) and other factors such as imperfect detection probabilities and observation-related nuisance variables. Recent advances in modeling have demonstrated various approaches that handle most of these factors but which require a degree of sampling effort (e.g. replication) not available to many field studies. We present a two-step approach that addresses these challenges to spatially model species abundance. Habitat, spatial and temporal variables were handled with a Bayesian approach which facilitated modeling hierarchically structured data. Predicted abundance was subsequently adjusted to account for imperfect detection and the area effectively sampled for each species. We provide examples of our modeling approach for two endemic Hawaiian nectarivorous honeycreepers: 'i'iwi Vestiaria coccinea and 'apapane Himatione sanguinea. ?? 2009 Ecography.

  15. Relationship of the Topological Distances and Activities between mPGES-1 and COX-2 versus COX-1: Implications of the Different Post-Translational Endoplasmic Reticulum Organizations of COX-1 and COX-2.

    PubMed

    Akasaka, Hironari; So, Shui-Ping; Ruan, Ke-He

    2015-06-16

    In vascular inflammation, prostaglandin E2 (PGE₂) is largely biosynthesized by microsomal PGE₂ synthase-1 (mPGES-1), competing with other downstream eicosanoid-synthesizing enzymes, such as PGIS, a synthase of a vascular protector prostacyclin (PGI₂), to isomerize the cyclooxygenase (COX)-2-derived prostaglandin H2 (PGH₂). In this study, we found that a majority of the product from the cells co-expressing human COX-2, mPGES-1, and PGIS was PGE₂. We hypothesize that the molecular and cellular mechanisms are related to the post-translational endoplasmic reticulum (ER) arrangement of those enzymes. A set of fusion enzymes, COX-2-linker [10 amino acids (aa)]-PGIS and COX-2-linker (22 amino acids)-PGIS, were created as "The Bioruler", in which the 10 and 22 amino acids are defined linkers with known helical structures and distances (14.4 and 30.8 Å, respectively). Our experiments have shown that the efficiency of PGI₂ biosynthesis was reduced when the separation distance increased from 10 to 22 amino acids. When COX-2-10aa-PGIS (with a 14.4 Å separation) was co-expressed with mPGES-1 on the ER membrane, a major product was PGE₂, but not PGI₂. However, expression of COX-2-10aa-PGIS and mPGES-1 on a separated ER with a distance of ≫30.8 Å reduced the level of PGE₂ production. These data indicated that the mPGES-1 is "complex-likely" colocalized with COX-2 within a distance of 14.4 Å. In addition, the cells co-expressing COX-1-10aa-PGIS and mPGES-1 produced PGI₂ mainly, but not PGE₂. This indicates that mPGES-1 is expressed much farther from COX-1. These findings have led to proposed models showing the different post-translational ER organization between COX-2 and COX-1 with respect to the topological arrangement of the mPGES-1 during vascular inflammation.

  16. Immunohistochemical and morphometric evaluation of COX-1 and COX-2 in the remodeled lung in idiopathic pulmonary fibrosis and systemic sclerosis* ,**

    PubMed Central

    Parra, Edwin Roger; Lin, Flavia; Martins, Vanessa; Rangel, Maristela Peres; Capelozzi, Vera Luiza

    2013-01-01

    OBJECTIVE: To study the expression of COX-1 and COX-2 in the remodeled lung in systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) patients, correlating that expression with patient survival. METHODS: We examined open lung biopsy specimens from 24 SSc patients and 30 IPF patients, using normal lung tissue as a control. The histological patterns included fibrotic nonspecific interstitial pneumonia (NSIP) in SSc patients and usual interstitial pneumonia (UIP) in IPF patients. We used immunohistochemistry and histomorphometry to evaluate the expression of COX-1 and COX-2 in alveolar septa, vessels, and bronchioles. We then correlated that expression with pulmonary function test results and evaluated its impact on patient survival. RESULTS: The expression of COX-1 and COX-2 in alveolar septa was significantly higher in IPF-UIP and SSc-NSIP lung tissue than in the control tissue. No difference was found between IPF-UIP and SSc-NSIP tissue regarding COX-1 and COX-2 expression. Multivariate analysis based on the Cox regression model showed that the factors associated with a low risk of death were younger age, high DLCO/alveolar volume, IPF, and high COX-1 expression in alveolar septa, whereas those associated with a high risk of death were advanced age, low DLCO/alveolar volume, SSc (with NSIP), and low COX-1 expression in alveolar septa. CONCLUSIONS: Our findings suggest that strategies aimed at preventing low COX-1 synthesis will have a greater impact on SSc, whereas those aimed at preventing high COX-2 synthesis will have a greater impact on IPF. However, prospective randomized clinical trials are needed in order to confirm that. PMID:24473763

  17. Dynamically adjustable foot-ground contact model to estimate ground reaction force during walking and running.

    PubMed

    Jung, Yihwan; Jung, Moonki; Ryu, Jiseon; Yoon, Sukhoon; Park, Sang-Kyoon; Koo, Seungbum

    2016-03-01

    Human dynamic models have been used to estimate joint kinetics during various activities. Kinetics estimation is in demand in sports and clinical applications where data on external forces, such as the ground reaction force (GRF), are not available. The purpose of this study was to estimate the GRF during gait by utilizing distance- and velocity-dependent force models between the foot and ground in an inverse-dynamics-based optimization. Ten males were tested as they walked at four different speeds on a force plate-embedded treadmill system. The full-GRF model whose foot-ground reaction elements were dynamically adjusted according to vertical displacement and anterior-posterior speed between the foot and ground was implemented in a full-body skeletal model. The model estimated the vertical and shear forces of the GRF from body kinematics. The shear-GRF model with dynamically adjustable shear reaction elements according to the input vertical force was also implemented in the foot of a full-body skeletal model. Shear forces of the GRF were estimated from body kinematics, vertical GRF, and center of pressure. The estimated full GRF had the lowest root mean square (RMS) errors at the slow walking speed (1.0m/s) with 4.2, 1.3, and 5.7% BW for anterior-posterior, medial-lateral, and vertical forces, respectively. The estimated shear forces were not significantly different between the full-GRF and shear-GRF models, but the RMS errors of the estimated knee joint kinetics were significantly lower for the shear-GRF model. Providing COP and vertical GRF with sensors, such as an insole-type pressure mat, can help estimate shear forces of the GRF and increase accuracy for estimation of joint kinetics.

  18. Glacial isostatic adjustment using GNSS permanent stations and GIA modelling tools

    NASA Astrophysics Data System (ADS)

    Kollo, Karin; Spada, Giorgio; Vermeer, Martin

    2013-04-01

    Glacial Isostatic Adjustment (GIA) affects the Earth's mantle in areas which were once ice covered and the process is still ongoing. In this contribution we focus on GIA processes in Fennoscandian and North American uplift regions. In this contribution we use horizontal and vertical uplift rates from Global Navigation Satellite System (GNSS) permanent stations. For Fennoscandia the BIFROST dataset (Lidberg, 2010) and North America the dataset from Sella, 2007 were used respectively. We perform GIA modelling with the SELEN program (Spada and Stocchi, 2007) and we vary ice model parameters in space in order to find ice model which suits best with uplift values obtained from GNSS time series analysis. In the GIA modelling, the ice models ICE-5G (Peltier, 2004) and the ice model denoted as ANU05 ((Fleming and Lambeck, 2004) and references therein) were used. As reference, the velocity field from GNSS permanent station time series was used for both target areas. Firstly the sensitivity to the harmonic degree was tested in order to reduce the computation time. In the test, nominal viscosity values and pre-defined lithosphere thicknesses models were used, varying maximum harmonic degree values. Main criteria for choosing the suitable harmonic degree was chi-square fit - if the error measure does not differ more than 10%, then one might use as well lower harmonic degree value. From this test, maximum harmonic degree of 72 was chosen to perform calculations, as the larger value did not significantly modify the results obtained, as well the computational time for observations was kept reasonable. Secondly the GIA computations were performed to find the model, which could fit with highest probability to the GNSS-based velocity field in the target areas. In order to find best fitting Earth viscosity parameters, different viscosity profiles for the Earth models were tested and their impact on horizontal and vertical velocity rates from GIA modelling was studied. For every

  19. Resolution of a Rank-Deficient Adjustment Model Via an Isomorphic Geometrical Setup with Tensor Structure.

    DTIC Science & Technology

    1987-03-01

    AFGL,-TR-87-0102 4. TITLE (ad Subtile) S . TYPE Of REPORT & ERIOD COVERED RESOLUTION OF A RANK-DEFICIENT ADJUSTMENT MODEL Final Report. VIA AN...transformation of multiple integrals. i IVnc’lass it i cd e- S CURITY C1 AIrIC ATIOIN O f THIS PAG P .𔃻 ’ FnI.f* d) TABLE OF CONTENTS Page ABSTRACT i...associated metric tensor is then given as g = krIs +jrs r ... + s + while the necessary associated metric tensor is -4 grs =ars jr s ’g = +jj 4 .... where

  20. Case-mix adjusted hospital mortality is a poor proxy for preventable mortality: a modelling study

    PubMed Central

    Girling, Alan J; Hofer, Timothy P; Wu, Jianhua; Chilton, Peter J; Nicholl, Jonathan P; Mohammed, Mohammed A; Lilford, Richard J

    2012-01-01

    Risk-adjustment schemes are used to monitor hospital performance, on the assumption that excess mortality not explained by case mix is largely attributable to suboptimal care. We have developed a model to estimate the proportion of the variation in standardised mortality ratios (SMRs) that can be accounted for by variation in preventable mortality. The model was populated with values from the literature to estimate a predictive value of the SMR in this context—specifically the proportion of those hospitals with SMRs among the highest 2.5% that fall among the worst 2.5% for preventable mortality. The extent to which SMRs reflect preventable mortality rates is highly sensitive to the proportion of deaths that are preventable. If 6% of hospital deaths are preventable (as suggested by the literature), the predictive value of the SMR can be no greater than 9%. This value could rise to 30%, if 15% of deaths are preventable. The model offers a ‘reality check’ for case mix adjustment schemes designed to isolate the preventable component of any outcome rate. PMID:23069860

  1. Cox1 mutation abrogates need for Cox23 in cytochrome c oxidase biogenesis

    PubMed Central

    Dela Cruz, Richard; Jeong, Mi-Young; Winge, Dennis R.

    2016-01-01

    Cox23 is a known conserved assembly factor for cytochrome c oxidase, although its role in cytochrome c oxidase (CcO) biogenesis remains unresolved. To gain additional insights into its role, we isolated spontaneous suppressors of the respiratory growth defect in cox23∆ yeast cells. We recovered independent colonies that propagated on glycerol/lactate medium for cox23∆ cells at 37°C. We mapped these mutations to the mitochondrial genome and specifically to COX1 yielding an I101F substitution. The I101F Cox1 allele is a gain-of-function mutation enabling yeast to respire in the absence of Cox23. CcO subunit steady-state levels were restored with the I101F Cox1 suppressor mutation and oxygen consumption and CcO activity were likewise restored. Cells harboring the mitochondrial genome encoding I101F Cox1 were used to delete genes for other CcO assembly factors to test the specificity of the Cox1 mutation as a suppressor of cox23∆ cells. The Cox1 mutant allele fails to support respiratory growth in yeast lacking Cox17, Cox19, Coa1, Coa2, Cox14 or Shy1, demonstrating its specific suppressor activity for cox23∆ cells.

  2. Allan Cox 1926”1987

    NASA Astrophysics Data System (ADS)

    Coe, Rob; Dalrymple, Brent

    More than 1000 friends, students, and colleagues from all over the country filled Stanford Memorial Chapel (Stanford, Calif.) on February 3, 1987, to join in “A Celebration of the Life of Allan Cox.” Allan died early on the morning of January 27 while bicycling, the sport he had come to love the most. Between pieces of his favorite music by Bach and Mozart, Stanford administrators and colleagues spoke in tribute of Allan's unique qualities as friend, scientist, teacher, and dean of the School of Earth Sciences. James Rosse, Vice President and Provost of Stanford University, struck a particularly resonant chord with his personal remarks: "Allan reached out to each person he knew with the warmth and attention that can only come from deep respect and affection for others. I never heard him speak ill of others, and I do not believe he was capable of doing anything that would harm another being. He cared too much to intrude where he was not wanted, but his curiosity about people and the loving care with which he approached them broke down reserve to create remarkable friendships. His enthusiasm and good humor made him a welcome guest in the hearts of the hundreds of students and colleagues who shared the opportunity of knowing Allan Cox as a person."

  3. Validation, replication, and sensitivity testing of Heckman-type selection models to adjust estimates of HIV prevalence.

    PubMed

    Clark, Samuel J; Houle, Brian

    2014-01-01

    A recent study using Heckman-type selection models to adjust for non-response in the Zambia 2007 Demographic and Health Survey (DHS) found a large correction in HIV prevalence for males. We aim to validate this finding, replicate the adjustment approach in other DHSs, apply the adjustment approach in an external empirical context, and assess the robustness of the technique to different adjustment approaches. We used 6 DHSs, and an HIV prevalence study from rural South Africa to validate and replicate the adjustment approach. We also developed an alternative, systematic model of selection processes and applied it to all surveys. We decomposed corrections from both approaches into rate change and age-structure change components. We are able to reproduce the adjustment approach for the 2007 Zambia DHS and derive results comparable with the original findings. We are able to replicate applying the approach in several other DHSs. The approach also yields reasonable adjustments for a survey in rural South Africa. The technique is relatively robust to how the adjustment approach is specified. The Heckman selection model is a useful tool for assessing the possibility and extent of selection bias in HIV prevalence estimates from sample surveys.

  4. Automatic parameter estimation of multicompartmental neuron models via minimization of trace error with control adjustment

    PubMed Central

    Goeritz, Marie L.; Marder, Eve

    2014-01-01

    We describe a new technique to fit conductance-based neuron models to intracellular voltage traces from isolated biological neurons. The biological neurons are recorded in current-clamp with pink (1/f) noise injected to perturb the activity of the neuron. The new algorithm finds a set of parameters that allows a multicompartmental model neuron to match the recorded voltage trace. Attempting to match a recorded voltage trace directly has a well-known problem: mismatch in the timing of action potentials between biological and model neuron is inevitable and results in poor phenomenological match between the model and data. Our approach avoids this by applying a weak control adjustment to the model to promote alignment during the fitting procedure. This approach is closely related to the control theoretic concept of a Luenberger observer. We tested this approach on synthetic data and on data recorded from an anterior gastric receptor neuron from the stomatogastric ganglion of the crab Cancer borealis. To test the flexibility of this approach, the synthetic data were constructed with conductance models that were different from the ones used in the fitting model. For both synthetic and biological data, the resultant models had good spike-timing accuracy. PMID:25008414

  5. Adjustment of automatic control systems of production facilities at coal processing plants using multivariant physico- mathematical models

    NASA Astrophysics Data System (ADS)

    Evtushenko, V. F.; Myshlyaev, L. P.; Makarov, G. V.; Ivushkin, K. A.; Burkova, E. V.

    2016-10-01

    The structure of multi-variant physical and mathematical models of control system is offered as well as its application for adjustment of automatic control system (ACS) of production facilities on the example of coal processing plant.

  6. COX-1 and COX-2 expression in feline oral squamous cell carcinoma.

    PubMed

    Hayes, A; Scase, T; Miller, J; Murphy, S; Sparkes, A; Adams, V

    2006-01-01

    This study demonstrated immunohistochemically the expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in feline oral squamous cell carcinoma (FOSCC), with primary polyclonal antibodies raised against human epitopes. COX-2 immunolabelling was intracytoplasmic and, in some neoplastic cells, perinuclear; it was demonstrated in a small proportion (< or = 1%) of neoplastic cells and its intensity was usually mild to moderate. In contrast, all neoplastic tissues showed extensive nuclear and cytoplasmic COX-1 immunolabelling. Cytoplasmic COX-1 immunolabelling was less intense than nuclear labelling in neoplastic tissue. In the adjacent histologically normal oral mucosa, COX-2 immunolabelling was absent. The cytoplasmic and nuclear intensity and distribution of COX-1 immunolabelling was significantly higher in neoplastic tissue than in adjacent normal oral mucosa. The results indicate that COX-1 and COX-2 are overexpressed in FOSCC, but the clinical and pathophysiological significance of this finding remains to be determined.

  7. COX-1 vs. COX-2 as a determinant of basal tone in the internal anal sphincter

    PubMed Central

    de Godoy, Márcio A. F.; Rattan, Neeru; Rattan, Satish

    2009-01-01

    Prostanoids, produced endogenously via cyclooxygenases (COXs), have been implicated in the sustained contraction of different smooth muscles. The two major types of COXs are COX-1 and COX-2. The COX subtype involved in the basal state of the internal anal sphincter (IAS) smooth muscle tone is not known. To identify the COX subtype, we examined the effect of COX-1- and COX-2-selective inhibitors, SC-560 and rofecoxib, respectively, on basal tone in the rat IAS. We also determined the effect of selective deletion of COX-1 and COX-2 genes (COX-1−/− and COX-2−/− mice) on basal tone in murine IAS. Our data show that SC-560 causes significantly more efficacious and potent concentration-dependent decreases in IAS tone than rofecoxib. In support of these data, significantly higher levels of COX-1 than COX-2 mRNA were found in the IAS. In addition, higher levels of COX-1 mRNA and protein were expressed in rat IAS than rectal smooth muscle. In wild-type mice, IAS tone was decreased 41.4 ± 3.4% (mean ± SE) by SC-560 (1 × 10−5 M) and 5.4 ± 2.2% by rofecoxib (P < 0.05, n = 5). Basal tone was 0.172 ± 0.021 mN//mg in the IAS from wild-type mice and significantly less (0.080 ± 0.015 mN/mg) in the IAS from COX-1−/− mice (P < 0.05, n = 5). However, basal tone in COX-2−/− mice was not significantly different from that in wild-type mice. We conclude that COX-1-related products contribute significantly to IAS tone. PMID:19056763

  8. Nonparametric randomization-based covariate adjustment for stratified analysis of time-to-event or dichotomous outcomes.

    PubMed

    Hussey, Michael A; Koch, Gary G; Preisser, John S; Saville, Benjamin R

    2016-01-01

    Time-to-event or dichotomous outcomes in randomized clinical trials often have analyses using the Cox proportional hazards model or conditional logistic regression, respectively, to obtain covariate-adjusted log hazard (or odds) ratios. Nonparametric Randomization-Based Analysis of Covariance (NPANCOVA) can be applied to unadjusted log hazard (or odds) ratios estimated from a model containing treatment as the only explanatory variable. These adjusted estimates are stratified population-averaged treatment effects and only require a valid randomization to the two treatment groups and avoid key modeling assumptions (e.g., proportional hazards in the case of a Cox model) for the adjustment variables. The methodology has application in the regulatory environment where such assumptions cannot be verified a priori. Application of the methodology is illustrated through three examples on real data from two randomized trials.

  9. Lower-order effects adjustment in quantitative traits model-based multifactor dimensionality reduction.

    PubMed

    Mahachie John, Jestinah M; Cattaert, Tom; Lishout, François Van; Gusareva, Elena S; Steen, Kristel Van

    2012-01-01

    Identifying gene-gene interactions or gene-environment interactions in studies of human complex diseases remains a big challenge in genetic epidemiology. An additional challenge, often forgotten, is to account for important lower-order genetic effects. These may hamper the identification of genuine epistasis. If lower-order genetic effects contribute to the genetic variance of a trait, identified statistical interactions may simply be due to a signal boost of these effects. In this study, we restrict attention to quantitative traits and bi-allelic SNPs as genetic markers. Moreover, our interaction study focuses on 2-way SNP-SNP interactions. Via simulations, we assess the performance of different corrective measures for lower-order genetic effects in Model-Based Multifactor Dimensionality Reduction epistasis detection, using additive and co-dominant coding schemes. Performance is evaluated in terms of power and familywise error rate. Our simulations indicate that empirical power estimates are reduced with correction of lower-order effects, likewise familywise error rates. Easy-to-use automatic SNP selection procedures, SNP selection based on "top" findings, or SNP selection based on p-value criterion for interesting main effects result in reduced power but also almost zero false positive rates. Always accounting for main effects in the SNP-SNP pair under investigation during Model-Based Multifactor Dimensionality Reduction analysis adequately controls false positive epistasis findings. This is particularly true when adopting a co-dominant corrective coding scheme. In conclusion, automatic search procedures to identify lower-order effects to correct for during epistasis screening should be avoided. The same is true for procedures that adjust for lower-order effects prior to Model-Based Multifactor Dimensionality Reduction and involve using residuals as the new trait. We advocate using "on-the-fly" lower-order effects adjusting when screening for SNP-SNP interactions

  10. A model of the western Laurentide Ice Sheet, using observations of glacial isostatic adjustment

    NASA Astrophysics Data System (ADS)

    Gowan, Evan J.; Tregoning, Paul; Purcell, Anthony; Montillet, Jean-Philippe; McClusky, Simon

    2016-05-01

    We present the results of a new numerical model of the late glacial western Laurentide Ice Sheet, constrained by observations of glacial isostatic adjustment (GIA), including relative sea level indicators, uplift rates from permanent GPS stations, contemporary differential lake level change, and postglacial tilt of glacial lake level indicators. The later two datasets have been underutilized in previous GIA based ice sheet reconstructions. The ice sheet model, called NAICE, is constructed using simple ice physics on the basis of changing margin location and basal shear stress conditions in order to produce ice volumes required to match GIA. The model matches the majority of the observations, while maintaining a relatively realistic ice sheet geometry. Our model has a peak volume at 18,000 yr BP, with a dome located just east of Great Slave Lake with peak thickness of 4000 m, and surface elevation of 3500 m. The modelled ice volume loss between 16,000 and 14,000 yr BP amounts to about 7.5 m of sea level equivalent, which is consistent with the hypothesis that a large portion of Meltwater Pulse 1A was sourced from this part of the ice sheet. The southern part of the ice sheet was thin and had a low elevation profile. This model provides an accurate representation of ice thickness and paleo-topography, and can be used to assess present day uplift and infer past climate.

  11. Procedures for adjusting regional regression models of urban-runoff quality using local data

    USGS Publications Warehouse

    Hoos, A.B.; Sisolak, J.K.

    1993-01-01

    Statistical operations termed model-adjustment procedures (MAP?s) can be used to incorporate local data into existing regression models to improve the prediction of urban-runoff quality. Each MAP is a form of regression analysis in which the local data base is used as a calibration data set. Regression coefficients are determined from the local data base, and the resulting `adjusted? regression models can then be used to predict storm-runoff quality at unmonitored sites. The response variable in the regression analyses is the observed load or mean concentration of a constituent in storm runoff for a single storm. The set of explanatory variables used in the regression analyses is different for each MAP, but always includes the predicted value of load or mean concentration from a regional regression model. The four MAP?s examined in this study were: single-factor regression against the regional model prediction, P, (termed MAP-lF-P), regression against P,, (termed MAP-R-P), regression against P, and additional local variables (termed MAP-R-P+nV), and a weighted combination of P, and a local-regression prediction (termed MAP-W). The procedures were tested by means of split-sample analysis, using data from three cities included in the Nationwide Urban Runoff Program: Denver, Colorado; Bellevue, Washington; and Knoxville, Tennessee. The MAP that provided the greatest predictive accuracy for the verification data set differed among the three test data bases and among model types (MAP-W for Denver and Knoxville, MAP-lF-P and MAP-R-P for Bellevue load models, and MAP-R-P+nV for Bellevue concentration models) and, in many cases, was not clearly indicated by the values of standard error of estimate for the calibration data set. A scheme to guide MAP selection, based on exploratory data analysis of the calibration data set, is presented and tested. The MAP?s were tested for sensitivity to the size of a calibration data set. As expected, predictive accuracy of all MAP?s for

  12. Race and Gender Influences on Adjustment in Early Adolescence: Investigation of an Integrative Model.

    ERIC Educational Resources Information Center

    DuBois, David L.; Burk-Braxton, Carol; Swenson, Lance P.; Tevendale, Heather D.; Hardesty, Jennifer L.

    2002-01-01

    Investigated the influence of racial and gender discrimination and difficulties on adolescent adjustment. Found that discrimination and hassles contribute to a general stress context which in turn influences emotional and behavioral problems in adjustment, while racial and gender identity positively affect self-esteem and thus adjustment. Revealed…

  13. Social Support and Psychological Adjustment Among Latinas With Arthritis: A Test of a Theoretical Model

    PubMed Central

    Abraído-Lanza, Ana F.

    2013-01-01

    Background Among people coping with chronic illness, tangible social support sometimes has unintended negative consequences on the recipient’s psychological health. Identity processes may help explain these effects. Individuals derive self-worth and a sense of competence by enacting social roles that are central to the self-concept. Purpose This study tested a model drawing from some of these theoretical propositions. The central hypothesis was that tangible support in fulfilling a highly valued role undermines self-esteem and a sense of self-efficacy, which, in turn, affect psychological adjustment Methods Structured interviews were conducted with 98 Latina women with arthritis who rated the homemaker identity as being of central importance to the self-concept. Results A path analysis indicated that, contrary to predictions, tangible housework support was related to less psychological distress. Emotional support predicted greater psychological well-being. These relationships were not mediated by self-esteem or self-efficacy. Qualitative data revealed that half of the sample expressed either ambivalent or negative feelings about receiving housework support Conclusions Results may reflect social and cultural norms concerning the types of support that are helpful and appropriate from specific support providers. Future research should consider the cultural meaning and normative context of the support transaction. This study contributes to scarce literatures on the mechanisms that mediate the relationship between social support and adjustment, as well as illness and psychosocial adaptation among Latina women with chronic illness. PMID:15184092

  14. Ku80 cooperates with CBP to promote COX-2 expression and tumor growth

    PubMed Central

    Qin, Yu; Xuan, Yang; Jia, Yunlu; Hu, Wenxian; Yu, Wendan; Dai, Meng; Li, Zhenglin; Yi, Canhui; Zhao, Shilei; Li, Mei; Du, Sha; Cheng, Wei; Xiao, Xiangsheng; Chen, Yiming; Wu, Taihua; Meng, Songshu; Yuan, Yuhui; Liu, Quentin; Huang, Wenlin; Guo, Wei; Wang, Shusen; Deng, Wuguo

    2015-01-01

    Cyclooxygenase-2 (COX-2) plays an important role in lung cancer development and progression. Using streptavidin-agarose pulldown and proteomics assay, we identified and validated Ku80, a dimer of Ku participating in the repair of broken DNA double strands, as a new binding protein of the COX-2 gene promoter. Overexpression of Ku80 up-regulated COX-2 promoter activation and COX-2 expression in lung cancer cells. Silencing of Ku80 by siRNA down-regulated COX-2 expression and inhibited tumor cell growth in vitro and in a xenograft mouse model. Ku80 knockdown suppressed phosphorylation of ERK, resulting in an inactivation of the MAPK pathway. Moreover, CBP, a transcription co-activator, interacted with and acetylated Ku80 to co-regulate the activation of COX-2 promoter. Overexpression of CBP increased Ku80 acetylation, thereby promoting COX-2 expression and cell growth. Suppression of CBP by a CBP-specific inhibitor or siRNA inhibited COX-2 expression as well as tumor cell growth. Tissue microarray immunohistochemical analysis of lung adenocarcinomas revealed a strong positive correlation between levels of Ku80 and COX-2 and clinicopathologic variables. Overexpression of Ku80 was associated with poor prognosis in patients with lung cancers. We conclude that Ku80 promotes COX-2 expression and tumor growth and is a potential therapeutic target in lung cancer. PMID:25797267

  15. Adjusting Satellite Rainfall Error in Mountainous Areas for Flood Modeling Applications

    NASA Astrophysics Data System (ADS)

    Zhang, X.; Anagnostou, E. N.; Astitha, M.; Vergara, H. J.; Gourley, J. J.; Hong, Y.

    2014-12-01

    This study aims to investigate the use of high-resolution Numerical Weather Prediction (NWP) for evaluating biases of satellite rainfall estimates of flood-inducing storms in mountainous areas and associated improvements in flood modeling. Satellite-retrieved precipitation has been considered as a feasible data source for global-scale flood modeling, given that satellite has the spatial coverage advantage over in situ (rain gauges and radar) observations particularly over mountainous areas. However, orographically induced heavy precipitation events tend to be underestimated and spatially smoothed by satellite products, which error propagates non-linearly in flood simulations.We apply a recently developed retrieval error and resolution effect correction method (Zhang et al. 2013*) on the NOAA Climate Prediction Center morphing technique (CMORPH) product based on NWP analysis (or forecasting in the case of real-time satellite products). The NWP rainfall is derived from the Weather Research and Forecasting Model (WRF) set up with high spatial resolution (1-2 km) and explicit treatment of precipitation microphysics.In this study we will show results on NWP-adjusted CMORPH rain rates based on tropical cyclones and a convective precipitation event measured during NASA's IPHEX experiment in the South Appalachian region. We will use hydrologic simulations over different basins in the region to evaluate propagation of bias correction in flood simulations. We show that the adjustment reduced the underestimation of high rain rates thus moderating the strong rainfall magnitude dependence of CMORPH rainfall bias, which results in significant improvement in flood peak simulations. Further study over Blue Nile Basin (western Ethiopia) will be investigated and included in the presentation. *Zhang, X. et al. 2013: Using NWP Simulations in Satellite Rainfall Estimation of Heavy Precipitation Events over Mountainous Areas. J. Hydrometeor, 14, 1844-1858.

  16. A data-driven model of present-day glacial isostatic adjustment in North America

    NASA Astrophysics Data System (ADS)

    Simon, Karen; Riva, Riccardo

    2016-04-01

    Geodetic measurements of gravity change and vertical land motion are incorporated into an a priori model of present-day glacial isostatic adjustment (GIA) via least-squares inversion. The result is an updated model of present-day GIA wherein the final predicted signal is informed by both observational data with realistic errors, and prior knowledge of GIA inferred from forward models. This method and other similar techniques have been implemented within a limited but growing number of GIA studies (e.g., Hill et al. 2010). The combination method allows calculation of the uncertainties of predicted GIA fields, and thus offers a significant advantage over predictions from purely forward GIA models. Here, we show the results of using the combination approach to predict present-day rates of GIA in North America through the incorporation of both GPS-measured vertical land motion rates and GRACE-measured gravity observations into the prior model. In order to assess the influence of each dataset on the final GIA prediction, the vertical motion and gravimetry datasets are incorporated into the model first independently (i.e., one dataset only), then simultaneously. Because the a priori GIA model and its associated covariance are developed by averaging predictions from a suite of forward models that varies aspects of the Earth rheology and ice sheet history, the final GIA model is not independent of forward model predictions. However, we determine the sensitivity of the final model result to the prior GIA model information by using different representations of the input model covariance. We show that when both datasets are incorporated into the inversion, the final model adequately predicts available observational constraints, minimizes the uncertainty associated with the forward modelled GIA inputs, and includes a realistic estimation of the formal error associated with the GIA process. Along parts of the North American coastline, improved predictions of the long-term (kyr

  17. The use of satellites in gravity field determination and model adjustment

    NASA Astrophysics Data System (ADS)

    Visser, Petrus Nicolaas Anna Maria

    1992-06-01

    Methods to improve gravity field models of the Earth with available data from satellite observations are proposed and discussed. In principle, all types of satellite observations mentioned give information of the satellite orbit perturbations and in conjunction the Earth's gravity field, because the satellite orbits are affected most by the Earth's gravity field. Therefore, two subjects are addressed: representation forms of the gravity field of the Earth and the theory of satellite orbit perturbations. An analytical orbit perturbation theory is presented and shown to be sufficiently accurate for describing satellite orbit perturbations if certain conditions are fulfilled. Gravity field adjustment experiments using the analytical orbit perturbation theory are discussed using real satellite observations. These observations consisted of Seasat laser range measurements and crossover differences, and of Geosat altimeter measurements and crossover differences. A look into the future, particularly relating to the ARISTOTELES (Applications and Research Involving Space Techniques for the Observation of the Earth's field from Low Earth Orbit Spacecraft) mission, is given.

  18. Positive Adjustment Among American Repatriated Prisoners of the Vietnam War: Modeling the Long-Term Effects of Captivity.

    PubMed

    King, Daniel W; King, Lynda A; Park, Crystal L; Lee, Lewina O; Kaiser, Anica Pless; Spiro, Avron; Moore, Jeffrey L; Kaloupek, Danny G; Keane, Terence M

    2015-11-01

    A longitudinal lifespan model of factors contributing to later-life positive adjustment was tested on 567 American repatriated prisoners from the Vietnam War. This model encompassed demographics at time of capture and attributes assessed after return to the U.S. (reports of torture and mental distress) and approximately 3 decades later (later-life stressors, perceived social support, positive appraisal of military experiences, and positive adjustment). Age and education at time of capture and physical torture were associated with repatriation mental distress, which directly predicted poorer adjustment 30 years later. Physical torture also had a salutary effect, enhancing later-life positive appraisals of military experiences. Later-life events were directly and indirectly (through concerns about retirement) associated with positive adjustment. Results suggest that the personal resources of older age and more education and early-life adverse experiences can have cascading effects over the lifespan to impact well-being in both positive and negative ways.

  19. Positive Adjustment Among American Repatriated Prisoners of the Vietnam War: Modeling the Long-Term Effects of Captivity

    PubMed Central

    King, Daniel W.; King, Lynda A.; Park, Crystal L.; Lee, Lewina O.; Kaiser, Anica Pless; Spiro, Avron; Moore, Jeffrey L.; Kaloupek, Danny G.; Keane, Terence M.

    2015-01-01

    A longitudinal lifespan model of factors contributing to later-life positive adjustment was tested on 567 American repatriated prisoners from the Vietnam War. This model encompassed demographics at time of capture and attributes assessed after return to the U.S. (reports of torture and mental distress) and approximately 3 decades later (later-life stressors, perceived social support, positive appraisal of military experiences, and positive adjustment). Age and education at time of capture and physical torture were associated with repatriation mental distress, which directly predicted poorer adjustment 30 years later. Physical torture also had a salutary effect, enhancing later-life positive appraisals of military experiences. Later-life events were directly and indirectly (through concerns about retirement) associated with positive adjustment. Results suggest that the personal resources of older age and more education and early-life adverse experiences can have cascading effects over the lifespan to impact well-being in both positive and negative ways. PMID:26693100

  20. Adjustment of regional climate model output for modeling the climatic mass balance of all glaciers on Svalbard.

    PubMed

    Möller, Marco; Obleitner, Friedrich; Reijmer, Carleen H; Pohjola, Veijo A; Głowacki, Piotr; Kohler, Jack

    2016-05-27

    Large-scale modeling of glacier mass balance relies often on the output from regional climate models (RCMs). However, the limited accuracy and spatial resolution of RCM output pose limitations on mass balance simulations at subregional or local scales. Moreover, RCM output is still rarely available over larger regions or for longer time periods. This study evaluates the extent to which it is possible to derive reliable region-wide glacier mass balance estimates, using coarse resolution (10 km) RCM output for model forcing. Our data cover the entire Svalbard archipelago over one decade. To calculate mass balance, we use an index-based model. Model parameters are not calibrated, but the RCM air temperature and precipitation fields are adjusted using in situ mass balance measurements as reference. We compare two different calibration methods: root mean square error minimization and regression optimization. The obtained air temperature shifts (+1.43°C versus +2.22°C) and precipitation scaling factors (1.23 versus 1.86) differ considerably between the two methods, which we attribute to inhomogeneities in the spatiotemporal distribution of the reference data. Our modeling suggests a mean annual climatic mass balance of -0.05 ± 0.40 m w.e. a(-1) for Svalbard over 2000-2011 and a mean equilibrium line altitude of 452 ± 200 m  above sea level. We find that the limited spatial resolution of the RCM forcing with respect to real surface topography and the usage of spatially homogeneous RCM output adjustments and mass balance model parameters are responsible for much of the modeling uncertainty. Sensitivity of the results to model parameter uncertainty is comparably small and of minor importance.

  1. Carvedilol Decrease IL-1β and TNF-α, Inhibits MMP-2, MMP-9, COX-2, and RANKL Expression, and Up-Regulates OPG in a Rat Model of Periodontitis

    PubMed Central

    de Araújo Júnior, Raimundo Fernandes; Souza, Tatiana Oliveira; de Medeiros, Caroline Addison Xavier; de Souza, Lélia Batista; Freitas, Maria de Lourdes; de Lucena, Hévio Freitas; do Socorro Costa Feitosa Alves, Maria; de Araújo, Aurigena Antunes

    2013-01-01

    Periodontal diseases are initiated primarily by Gram-negative, tooth-associated microbial biofilms that elicit a host response that causes osseous and soft tissue destruction. Carvedilol is a β-blocker used as a multifunctional neurohormonal antagonist that has been shown to act not only as an anti-oxidant but also as an anti-inflammatory drug. This study evaluated whether Carvedilol exerted a protective role against ligature-induced periodontitis in a rat model and defined how Carvedilol affected metalloproteinases and RANKL/RANK/OPG expression in the context of bone remodeling. Rats were randomly divided into 5 groups (n = 10/group): (1) non-ligated (NL), (2) ligature-only (LO), and (3) ligature plus Carvedilol (1, 5 or 10 mg/kg daily for 10 days). Periodontal tissue was analyzed for histopathlogy and using immunohistochemical analysis characterized the expression profiles of MMP-2, MMP-9, COX-2, and RANKL/RANK/OPG and determined the presence of IL-1β, IL-10 and TNF-α, myeloperoxidase (MPO), malonaldehyde (MDA) and, glutathione (GSH). MPO activity in the group with periodontal disease was significantly increased compared to the control group (p<0.05). Rats treated with 10 mg/kg Carvedilol presented with significantly reduced MPO and MDA concentrations (p<0.05) in addition to presenting with reduced levels of the pro-inflammatory cytokines IL-1 β and TNF-α (p<0.05). IL-10 levels in Carvedilol-treated rats remained unaltered. Immunohistochemical analysis demonstrated reduced expression of MMP-2, MMP-9, RANK, RANKL, COX-2, and OPG in rats treated with 10 mg/kg Carvedilol. This study demonstrated that Carvedilol affected bone formation/destruction and anti-inflammatory activity in a rat model of periodontitis. PMID:23843954

  2. Nonlinear relative-proportion-based route adjustment process for day-to-day traffic dynamics: modeling, equilibrium and stability analysis

    NASA Astrophysics Data System (ADS)

    Zhu, Wenlong; Ma, Shoufeng; Tian, Junfang; Li, Geng

    2016-11-01

    Travelers' route adjustment behaviors in a congested road traffic network are acknowledged as a dynamic game process between them. Existing Proportional-Switch Adjustment Process (PSAP) models have been extensively investigated to characterize travelers' route choice behaviors; PSAP has concise structure and intuitive behavior rule. Unfortunately most of which have some limitations, i.e., the flow over adjustment problem for the discrete PSAP model, the absolute cost differences route adjustment problem, etc. This paper proposes a relative-Proportion-based Route Adjustment Process (rePRAP) maintains the advantages of PSAP and overcomes these limitations. The rePRAP describes the situation that travelers on higher cost route switch to those with lower cost at the rate that is unilaterally depended on the relative cost differences between higher cost route and its alternatives. It is verified to be consistent with the principle of the rational behavior adjustment process. The equivalence among user equilibrium, stationary path flow pattern and stationary link flow pattern is established, which can be applied to judge whether a given network traffic flow has reached UE or not by detecting the stationary or non-stationary state of link flow pattern. The stability theorem is proved by the Lyapunov function approach. A simple example is tested to demonstrate the effectiveness of the rePRAP model.

  3. HNE as an inducer of COX-2.

    PubMed

    Uchida, Koji

    2017-02-09

    Cyclooxygenase-2 (COX-2), an inducible isoform responsible for high levels of prostaglandin (PG) production during inflammation and immune responses, mediate a variety of biological actions involved in vascular pathophysiology. COX-2 is induced by various stimuli, including proinflammatory cytokines, to result in PG synthesis associated with inflammation and carcinogenesis. 4-Hydroxy-2-nonenal (HNE) is one of a group of small molecules that can induce COX-2 expression. The mechanistic studies have revealed that the HNE-induced COX-2 expression results from the stabilization of COX-2 mRNA mediated by the p38 mitogen-activated protein kinase signaling pathway and uniquely requires a serum component, which is eventually identified to be modified low-density lipoproteins (LDLs), such as the oxidized form of LDLs. It has also been shown that HNE-induced COX-2 expression is mechanistically linked to the expression of transcription factor p53 and that the overexpression of COX-2 is associated with down-regulation of a proteasome subunit, leading to the enhanced accumulation of p53 and ubiquitinated proteins and to the enhanced sensitivity toward HNE. Thus, the overall mechanism and pathophysiological role of the COX-2 induction by HNE have become increasingly evident.

  4. A new glacial isostatic adjustment model of the Innuitian Ice Sheet, Arctic Canada

    NASA Astrophysics Data System (ADS)

    Simon, K. M.; James, T. S.; Dyke, A. S.

    2015-07-01

    A reconstruction of the Innuitian Ice Sheet (IIS) is developed that incorporates first-order constraints on its spatial extent and history as suggested by regional glacial geology studies. Glacial isostatic adjustment modelling of this ice sheet provides relative sea-level predictions that are in good agreement with measurements of post-glacial sea-level change at 18 locations. The results indicate peak thicknesses of the Innuitian Ice Sheet of approximately 1600 m, up to 400 m thicker than the minimum peak thicknesses estimated from glacial geology studies, but between approximately 1000 to 1500 m thinner than the peak thicknesses present in previous GIA models. The thickness history of the best-fit Innuitian Ice Sheet model developed here, termed SJD15, differs from the ICE-5G reconstruction and provides an improved fit to sea-level measurements from the lowland sector of the ice sheet. Both models provide a similar fit to relative sea-level measurements from the alpine sector. The vertical crustal motion predictions of the best-fit IIS model are in general agreement with limited GPS observations, after correction for a significant elastic crustal response to present-day ice mass change. The new model provides approximately 2.7 m equivalent contribution to global sea-level rise, an increase of +0.6 m compared to the Innuitian portion of ICE-5G. SJD15 is qualitatively more similar to the recent ICE-6G ice sheet reconstruction, which appears to also include more spatially extensive ice cover in the Innuitian region than ICE-5G.

  5. Development of a GIA (Glacial Isostatic Adjustment) - Fault Model of Greenland

    NASA Astrophysics Data System (ADS)

    Steffen, R.; Lund, B.

    2015-12-01

    The increase in sea level due to climate change is an intensely discussed phenomenon, while less attention is being paid to the change in earthquake activity that may accompany disappearing ice masses. The melting of the Greenland Ice Sheet, for example, induces changes in the crustal stress field, which could result in the activation of existing faults and the generation of destructive earthquakes. Such glacially induced earthquakes are known to have occurred in Fennoscandia 10,000 years ago. Within a new project ("Glacially induced earthquakes in Greenland", start in October 2015), we will analyse the potential for glacially induced earthquakes in Greenland due to the ongoing melting. The objectives include the development of a three-dimensional (3D) subsurface model of Greenland, which is based on geologic, geophysical and geodetic datasets, and which also fulfils the boundary conditions of glacial isostatic adjustment (GIA) modelling. Here we will present an overview of the project, including the most recently available datasets and the methodologies needed for model construction and the simulation of GIA induced earthquakes.

  6. Olmesartan decreased levels of IL-1β and TNF-α, down-regulated MMP-2, MMP-9, COX-2, RANK/RANKL and up-regulated SOCs-1 in an intestinal mucositis model.

    PubMed

    de Araújo, Raimundo Fernandes; Reinaldo, Maria Patrícia Oliveira da Silva; Brito, Gerly Anne de Castro; Cavalcanti, Pedro de França; Freire, Marco Aurélio; de Moura Freire, Marco Aurélio; de Medeiros, Caroline Addison Xavier; de Araújo, Aurigena Antunes

    2014-01-01

    Methotrexate (MTX) is a pro-oxidant compound that depletes dihydrofolate pools and is widely used in the treatment of leukaemia and other malignancies. The efficacy of methotrexate is often limited by mucositis and intestinal injury, which are major causes of morbidity in children and adults. The aim of this study was to evaluate the effect of olmesartan (OLM), an angiotensin II receptor antagonist, on an Intestinal Mucositis Model (IMM) induced by MTX in Wistar rats. IMM was induced via intraperitoneal (i.p.) administration of MTX (7 mg/kg) for three consecutive days. The animals were pre-treated with oral OLM at 0.5, 1 or 5 mg/kg or with vehicle 30 min prior to exposure to MTX. Small intestinal homogenates were assayed for levels of the IL-1β, IL-10 and TNF-α cytokines, malondialdehyde and myeloperoxidase activity. Additionally, immunohistochemical analyses of MMP-2, MMP-9, COX-2, RANK/RANKL and SOCS-1 and confocal microscopy analysis of SOCS-1 expression were performed. Treatment with MTX + OLM (5 mg/kg) resulted in a reduction of mucosal inflammatory infiltration, ulcerations, vasodilatation and haemorrhagic areas (p<0.05) as well as reduced concentrations of MPO (p<0.001) and the pro-inflammatory cytokines IL-1β (p<0.001) and TNF-a (p<0.01), and increase anti-inflammatory cytocine IL-10 (p<0.05). Additionally, the combined treatment reduced expression of MMP-2, MMP-9, COX-2, RANK and RANKL(p<0.05) and increased cytoplasmic expression of SOCS-1 (p<0.05). Our findings confirm the involvement of OLM in reducing the inflammatory response through increased immunosuppressive signalling in an IMM. We also suggest that the beneficial effect of olmesartan treatment is specifically exerted during the damage through blocking inflammatory cytocines.

  7. Case-mix adjustment of the National CAHPS benchmarking data 1.0: a violation of model assumptions?

    PubMed Central

    Elliott, M N; Swartz, R; Adams, J; Spritzer, K L; Hays, R D

    2001-01-01

    OBJECTIVE: To compare models for the case-mix adjustment of consumer reports and ratings of health care. DATA SOURCES: The study used the Consumer Assessment of Health Plans (CAHPS) survey 1.0 National CAHPS Benchmarking Database data from 54 commercial and 31 Medicaid health plans from across the United States: 19,541 adults (age > or = 18 years) in commercial plans and 8,813 adults in Medicaid plans responded regarding their own health care, and 9,871 Medicaid adults responded regarding the health care of their minor children. STUDY DESIGN: Four case-mix models (no adjustment; self-rated health and age; health, age, and education; and health, age, education, and plan interactions) were compared on 21 ratings and reports regarding health care for three populations (adults in commercial plans, adults in Medicaid plans, and children in Medicaid plans). The magnitude of case-mix adjustments, the effects of adjustments on plan rankings, and the homogeneity of these effects across plans were examined. DATA EXTRACTION: All ratings and reports were linearly transformed to a possible range of 0 to 100 for comparability. PRINCIPAL FINDINGS: Case-mix adjusters, especially self-rated health, have substantial effects, but these effects vary substantially from plan to plan, a violation of standard case-mix assumptions. CONCLUSION: Case-mix adjustment of CAHPS data needs to be re-examined, perhaps by using demographically stratified reporting or by developing better measures of response bias. PMID:11482589

  8. ESTIMATION OF EMISSION ADJUSTMENTS FROM THE APPLICATION OF FOUR-DIMENSIONAL DATA ASSIMILATION TO PHOTOCHEMICAL AIR QUALITY MODELING. (R826372)

    EPA Science Inventory

    Four-dimensional data assimilation applied to photochemical air quality modeling is used to suggest adjustments to the emissions inventory of the Atlanta, Georgia metropolitan area. In this approach, a three-dimensional air quality model, coupled with direct sensitivity analys...

  9. Adjusting multistate capture-recapture models for misclassification bias: manatee breeding proportions

    USGS Publications Warehouse

    Kendall, W.L.; Hines, J.E.; Nichols, J.D.

    2003-01-01

    Matrix population models are important tools for research and management of populations. Estimating the parameters of these models is an important step in applying them to real populations. Multistate capture-recapture methods have provided a useful means for estimating survival and parameters of transition between locations or life history states but have mostly relied on the assumption that the state occupied by each detected animal is known with certainty. Nevertheless, in some cases animals can be misclassified. Using multiple capture sessions within each period of interest, we developed a method that adjusts estimates of transition probabilities for bias due to misclassification. We applied this method to 10 years of sighting data for a population of Florida manatees (Trichechus manatus latirostris) in order to estimate the annual probability of transition from nonbreeding to breeding status. Some sighted females were unequivocally classified as breeders because they were clearly accompanied by a first-year calf. The remainder were classified, sometimes erroneously, as nonbreeders because an attendant first-year calf was not observed or was classified as more than one year old. We estimated a conditional breeding probability of 0.31 + 0.04 (estimate + 1 SE) when we ignored misclassification bias, and 0.61 + 0.09 when we accounted for misclassification.

  10. Enhancing multiple-point geostatistical modeling: 1. Graph theory and pattern adjustment

    NASA Astrophysics Data System (ADS)

    Tahmasebi, Pejman; Sahimi, Muhammad

    2016-03-01

    In recent years, higher-order geostatistical methods have been used for modeling of a wide variety of large-scale porous media, such as groundwater aquifers and oil reservoirs. Their popularity stems from their ability to account for qualitative data and the great flexibility that they offer for conditioning the models to hard (quantitative) data, which endow them with the capability for generating realistic realizations of porous formations with very complex channels, as well as features that are mainly a barrier to fluid flow. One group of such models consists of pattern-based methods that use a set of data points for generating stochastic realizations by which the large-scale structure and highly-connected features are reproduced accurately. The cross correlation-based simulation (CCSIM) algorithm, proposed previously by the authors, is a member of this group that has been shown to be capable of simulating multimillion cell models in a matter of a few CPU seconds. The method is, however, sensitive to pattern's specifications, such as boundaries and the number of replicates. In this paper the original CCSIM algorithm is reconsidered and two significant improvements are proposed for accurately reproducing large-scale patterns of heterogeneities in porous media. First, an effective boundary-correction method based on the graph theory is presented by which one identifies the optimal cutting path/surface for removing the patchiness and discontinuities in the realization of a porous medium. Next, a new pattern adjustment method is proposed that automatically transfers the features in a pattern to one that seamlessly matches the surrounding patterns. The original CCSIM algorithm is then combined with the two methods and is tested using various complex two- and three-dimensional examples. It should, however, be emphasized that the methods that we propose in this paper are applicable to other pattern-based geostatistical simulation methods.

  11. Adjustments of the TaD electron density reconstruction model with GNSS-TEC parameters for operational application purposes

    NASA Astrophysics Data System (ADS)

    Kutiev, Ivan; Marinov, Pencho; Fidanova, Stefka; Belehaki, Anna; Tsagouri, Ioanna

    2012-12-01

    Validation results on the latest version of TaD model (TaDv2) show realistic reconstruction of the electron density profiles (EDPs) with an average error of 3 TECU, similar to the error obtained from GNSS-TEC calculated paremeters. The work presented here has the aim to further improve the accuracy of the TaD topside reconstruction, adjusting the TEC parameter calculated from TaD model with the TEC parameter calculated by GNSS transmitting RINEX files provided by receivers co-located with the Digisondes. The performance of the new version is tested during a storm period demonstrating further improvements in respect to the previous version. Statistical comparison of modeled and observed TEC confirms the validity of the proposed adjustment. A significant benefit of the proposed upgrade is that it facilitates the real-time implementation of TaD. The model needs a reliable measure of the scale height at the peak height, which is supposed to be provided by Digisondes. Oftenly, the automatic scaling software fails to correctly calculate the scale height at the peak, Hm, due to interferences in the receiving signal. Consequently the model estimated topside scale height is wrongly calculated leading to unrealistic results for the modeled EDP. The proposed TEC adjustment forces the model to correctly reproduce the topside scale height, despite the inaccurate values of Hm. This adjustment is very important for the application of TaD in an operational environment.

  12. Immunohistochemical evaluation of COX-1 and COX-2 expression in keloid and hypertrophic scar.

    PubMed

    Abdou, Asmaa G; Maraee, Alaa H; Saif, Hala F Abd-Elsattar

    2014-04-01

    Both keloids (KLs) and hypertrophic scars (HSs) are considered as dermal fibroproliferative diseases that differ clinically and histopathologically. Although several factors have been postulated in the etiopathogenesis of these conditions, there has been growing evidence to suggest the role of COXs in the pathogenesis of abnormal wound healing because of the reduction of formation of KL and HS in patients using nonsteroidal anti-inflammatory drugs and a COX-2 inhibitor. The aim of the present work is to evaluate the pattern and localization of COX-1 and COX-2 expression in KL and HS compared with surgical scars. COX-1 and COX-2 were analyzed on skin biopsies of 30 patients who presented with KL (15) and HS (15) and 10 normal surgical scars (controls). Both COX-1 and COX-2 were expressed not only in dermal components (fibroblasts, inflammatory cells, and endothelial cells) but also in keratinocytes of the overlying epidermis in the different studied scar lesions. The percentage of COX-1 expression increased progressively from surgical scar (40%) to HS (53.3%) to KL (100%) with a statistically significant difference (P = 0.002). COX-2 was expressed in 100% of surgical scars, 73.3% of HS and 86.7% of KL with the absence of significant differences (P > 0.05). The significant difference in COX-1 expression between HS and KL may refer to the presence of different pathways for the emergence of these diseases. The expression of COX-2 in all scars (normal or abnormal) indicates its active role as an inflammatory mediator. Keratinocytes play an active role in induction of scarring by up-regulation of inflammatory mediators, such as COX-1 and COX-2.

  13. An assessment of the ICE6G_C(VM5a) glacial isostatic adjustment model

    NASA Astrophysics Data System (ADS)

    Purcell, A.; Tregoning, P.; Dehecq, A.

    2016-05-01

    The recent release of the next-generation global ice history model, ICE6G_C(VM5a), is likely to be of interest to a wide range of disciplines including oceanography (sea level studies), space gravity (mass balance studies), glaciology, and, of course, geodynamics (Earth rheology studies). In this paper we make an assessment of some aspects of the ICE6G_C(VM5a) model and show that the published present-day radial uplift rates are too high along the eastern side of the Antarctic Peninsula (by ˜8.6 mm/yr) and beneath the Ross Ice Shelf (by ˜5 mm/yr). Furthermore, the published spherical harmonic coefficients—which are meant to represent the dimensionless present-day changes due to glacial isostatic adjustment (GIA)—contain excessive power for degree ≥90, do not agree with physical expectations and do not represent accurately the ICE6G_C(VM5a) model. We show that the excessive power in the high-degree terms produces erroneous uplift rates when the empirical relationship of Purcell et al. (2011) is applied, but when correct Stokes coefficients are used, the empirical relationship produces excellent agreement with the fully rigorous computation of the radial velocity field, subject to the caveats first noted by Purcell et al. (2011). Using the Australian National University (ANU) groups CALSEA software package, we recompute the present-day GIA signal for the ice thickness history and Earth rheology used by Peltier et al. (2015) and provide dimensionless Stokes coefficients that can be used to correct satellite altimetry observations for GIA over oceans and by the space gravity community to separate GIA and present-day mass balance change signals. We denote the new data sets as ICE6G_ANU.

  14. Comparison of Two Foreign Body Retrieval Devices with Adjustable Loops in a Swine Model

    SciTech Connect

    Konya, Andras

    2006-12-15

    The purpose of the study was to compare two similar foreign body retrieval devices, the Texan{sup TM} (TX) and the Texan LONGhorn{sup TM} (TX-LG), in a swine model. Both devices feature a {<=}30-mm adjustable loop. Capture times and total procedure times for retrieving foreign bodies from the infrarenal aorta, inferior vena cava, and stomach were compared. All attempts with both devices (TX, n = 15; TX-LG, n = 14) were successful. Foreign bodies in the vasculature were captured quickly using both devices (mean {+-} SD, 88 {+-} 106 sec for TX vs 67 {+-} 42 sec for TX-LG) with no significant difference between them. The TX-LG, however, allowed significantly better capture times than the TX in the stomach (p = 0.022), Overall, capture times for the TX-LG were significantly better than for the TX (p = 0.029). There was no significant difference between the total procedure times in any anatomic region. TX-LG performed significantly better than the TX in the stomach and therefore overall. The better torque control and maneuverability of TX-LG resulted in better performance in large anatomic spaces.

  15. Sensitivity assessment, adjustment, and comparison of mathematical models describing the migration of pesticides in soil using lysimetric data

    NASA Astrophysics Data System (ADS)

    Shein, E. V.; Kokoreva, A. A.; Gorbatov, V. S.; Umarova, A. B.; Kolupaeva, V. N.; Perevertin, K. A.

    2009-07-01

    The water block of physically founded models of different levels (chromatographic PEARL models and dual-porosity MACRO models) was parameterized using laboratory experimental data and tested using the results of studying the water regime of loamy soddy-podzolic soil in large lysimeters of the Experimental Soil Station of Moscow State University. The models were adapted using a stepwise approach, which involved the sequential assessment and adjustment of each submodel. The models unadjusted for the water block underestimated the lysimeter flow and overestimated the soil water content. The theoretical necessity of the model adjustment was explained by the different scales of the experimental objects (soil samples) and simulated phenomenon (soil profile). The adjustment of the models by selecting the most sensitive hydrophysical parameters of the soils (the approximation parameters of the soil water retention curve (SWRC)) gave good agreement between the predicted moisture profiles and their actual values. In distinction from the PEARL model, the MARCO model reliably described the migration of a pesticide through the soil profile, which confirmed the necessity of physically founded models accounting for the separation of preferential flows in the pore space for the prediction, analysis, optimization, and management of modern agricultural technologies.

  16. An assessment of the ICE6G_C (VM5A) glacial isostatic adjustment model

    NASA Astrophysics Data System (ADS)

    Purcell, Anthony; Tregoning, Paul; Dehecq, Amaury

    2016-04-01

    The recent release of the next-generation global ice history model, ICE6G_C(VM5a) [Peltier et al., 2015, Argus et al. 2014] is likely to be of interest to a wide range of disciplines including oceanography (sea level studies), space gravity (mass balance studies), glaciology and, of course, geodynamics (Earth rheology studies). In this presentation I will assess some aspects of the ICE6G_C(VM5a) model and the accompanying published data sets. I will demonstrate that the published present-day radial uplift rates are too high along the eastern side of the Antarctic Peninsula (by ˜8.6 mm/yr) and beneath the Ross Ice Shelf (by ˜5 mm/yr). Further, the published spherical harmonic coefficients - which are meant to represent the dimensionless present-day changes due to glacial isostatic adjustment (GIA) - will be shown to contain excessive power for degree ≥ 90, to be physically implausible and to not represent accurately the ICE6G_C(VM5a) model. The excessive power in the high degree terms produces erroneous uplift rates when the empirical relationship of Purcell et al. [2011] is applied but, when correct Stokes' coefficients are used, the empirical relationship will be shown to produce excellent agreement with the fully rigorous computation of the radial velocity field, subject to the caveats first noted by Purcell et al. [2011]. Finally, a global radial velocity field for the present-day GIA signal, and corresponding Stoke's coefficients will be presented for the ICE6GC ice model history using the VM5a rheology model. These results have been obtained using the ANU group's CALSEA software package and can be used to correct satellite altimetry observations for GIA over oceans and by the space gravity community to separate GIA and present-day mass balance change signals without any of the shortcomings of the previously published data-sets. We denote the new data sets ICE6G_ANU.

  17. Log Gaussian Cox processes and spatially aggregated disease incidence data.

    PubMed

    Li, Ye; Brown, Patrick; Gesink, Dionne C; Rue, Håvard

    2012-10-01

    This article presents a methodology for modeling aggregated disease incidence data with the spatially continuous log-Gaussian Cox process. Statistical models for spatially aggregated disease incidence data usually assign the same relative risk to all individuals in the same reporting region (census areas or postal regions). A further assumption that the relative risks in two regions are independent given their neighbor's risks (the Markov assumption) makes the commonly used Besag-York-Mollié model computationally simple. The continuous model proposed here uses a data augmentation step to sample from the posterior distribution of the exact locations at each step of an Markov chain Monte Carlo algorithm, and models the exact locations with an log-Gaussian Cox process. A simulation study shows the log-Gaussian Cox process model consistently outperforming the Besag-York-Mollié model. The method is illustrated by making inference on the spatial distribution of syphilis risk in North Carolina. The effect of several known social risk factors are estimated, and areas with risk well in excess of that expected given these risk factors are identified.

  18. DaMoScope and its internet graphics for the visual control of adjusting mathematical models describing experimental data

    NASA Astrophysics Data System (ADS)

    Belousov, V. I.; Ezhela, V. V.; Kuyanov, Yu. V.; Tkachenko, N. P.

    2015-12-01

    The experience of using the dynamic atlas of the experimental data and mathematical models of their description in the problems of adjusting parametric models of observable values depending on kinematic variables is presented. The functional possibilities of an image of a large number of experimental data and the models describing them are shown by examples of data and models of observable values determined by the amplitudes of elastic scattering of hadrons. The Internet implementation of an interactive tool DaMoScope and its interface with the experimental data and codes of adjusted parametric models with the parameters of the best description of data are schematically shown. The DaMoScope codes are freely available.

  19. DaMoScope and its internet graphics for the visual control of adjusting mathematical models describing experimental data

    SciTech Connect

    Belousov, V. I.; Ezhela, V. V.; Kuyanov, Yu. V. Tkachenko, N. P.

    2015-12-15

    The experience of using the dynamic atlas of the experimental data and mathematical models of their description in the problems of adjusting parametric models of observable values depending on kinematic variables is presented. The functional possibilities of an image of a large number of experimental data and the models describing them are shown by examples of data and models of observable values determined by the amplitudes of elastic scattering of hadrons. The Internet implementation of an interactive tool DaMoScope and its interface with the experimental data and codes of adjusted parametric models with the parameters of the best description of data are schematically shown. The DaMoScope codes are freely available.

  20. Rejection, Feeling Bad, and Being Hurt: Using Multilevel Modeling to Clarify the Link between Peer Group Aggression and Adjustment

    ERIC Educational Resources Information Center

    Rulison, Kelly L.; Gest, Scott D.; Loken, Eric; Welsh, Janet A.

    2010-01-01

    The association between affiliating with aggressive peers and behavioral, social and psychological adjustment was examined. Students initially in 3rd, 4th, and 5th grade (N = 427) were followed biannually through 7th grade. Students' peer-nominated groups were identified. Multilevel modeling was used to examine the independent contributions of…

  1. Patterns of Children's Adrenocortical Reactivity to Interparental Conflict and Associations with Child Adjustment: A Growth Mixture Modeling Approach

    ERIC Educational Resources Information Center

    Koss, Kalsea J.; George, Melissa R. W.; Davies, Patrick T.; Cicchetti, Dante; Cummings, E. Mark; Sturge-Apple, Melissa L.

    2013-01-01

    Examining children's physiological functioning is an important direction for understanding the links between interparental conflict and child adjustment. Utilizing growth mixture modeling, the present study examined children's cortisol reactivity patterns in response to a marital dispute. Analyses revealed three different patterns of cortisol…

  2. Internal Working Models and Adjustment of Physically Abused Children: The Mediating Role of Self-Regulatory Abilities

    ERIC Educational Resources Information Center

    Hawkins, Amy L.; Haskett, Mary E.

    2014-01-01

    Background: Abused children's internal working models (IWM) of relationships are known to relate to their socioemotional adjustment, but mechanisms through which negative representations increase vulnerability to maladjustment have not been explored. We sought to expand the understanding of individual differences in IWM of abused children and…

  3. Adolescent Sibling Relationship Quality and Adjustment: Sibling Trustworthiness and Modeling, as Factors Directly and Indirectly Influencing These Associations

    ERIC Educational Resources Information Center

    Gamble, Wendy C.; Yu, Jeong Jin; Kuehn, Emily D.

    2011-01-01

    The main goal of this study was to examine the direct and moderating effects of trustworthiness and modeling on adolescent siblings' adjustment. Data were collected from 438 families including a mother, a younger sibling in fifth, sixth, or seventh grade (M = 11.6 years), and an older sibling (M = 14.3 years). Respondents completed Web-based…

  4. The Effectiveness of the Strength-Centered Career Adjustment Model for Dual-Career Women in Taiwan

    ERIC Educational Resources Information Center

    Wang, Yu-Chen; Tien, Hsiu-Lan Shelley

    2011-01-01

    The authors investigated the effectiveness of a Strength-Centered Career Adjustment Model for dual-career women (N = 28). Fourteen women in the experimental group received strength-centered career counseling for 6 to 8 sessions; the 14 women in the control group received test services in 1 to 2 sessions. All participants completed the Personal…

  5. Viscum album-Mediated COX-2 Inhibition Implicates Destabilization of COX-2 mRNA

    PubMed Central

    Saha, Chaitrali; Hegde, Pushpa; Friboulet, Alain; Bayry, Jagadeesh; Kaveri, Srinivas V.

    2015-01-01

    Extensive use of Viscum album (VA) preparations in the complementary therapy of cancer and in several other human pathologies has led to an increasing number of cellular and molecular approaches to explore the mechanisms of action of VA. We have recently demonstrated that, VA preparations exert a potent anti-inflammatory effect by selectively down-regulating the COX-2-mediated cytokine-induced secretion of prostaglandin E2 (PGE2), one of the important molecular signatures of inflammatory reactions. In this study, we observed a significant down-regulation of COX-2 protein expression in VA-treated A549 cells however COX-2 mRNA levels were unaltered. Therefore, we hypothesized that VA induces destabilisation of COX-2 mRNA, thereby depleting the available functional COX-2 mRNA for the protein synthesis and for the subsequent secretion of PGE2. To address this question, we analyzed the molecular degradation of COX-2 protein and its corresponding mRNA in A549 cell line. Using cyclohexamide pulse chase experiment, we demonstrate that, COX-2 protein degradation is not affected by the treatment with VA whereas experiments on transcriptional blockade with actinomycin D, revealed a marked reduction in the half life of COX-2 mRNA due to its rapid degradation in the cells treated with VA compared to that in IL-1β-stimulated cells. These results thus demonstrate that VA-mediated inhibition of PGE2 implicates destabilization of COX-2 mRNA. PMID:25664986

  6. COX-2 inhibitors: a novel strategy in the management of breast cancer.

    PubMed

    Regulski, Miłosz; Regulska, Katarzyna; Prukała, Wiesław; Piotrowska, Hanna; Stanisz, Beata; Murias, Marek

    2016-04-01

    Cyclooxygenase-2 (COX-2) inhibitors are common anti-inflammatory drugs with pleiotropic, endogenous actions that could be useful in the management of breast cancer. Here, we provide a complete understanding of the biochemistry of COX-2 and discuss the various molecular mechanisms behind its increased expression in breast cancer. We also analyze the possible mechanisms responsible for the anticancer effect of COX-2 inhibitors and provide an overview of the available preclinical and clinical data on the use of COX-2 inhibitors in breast cancer. Finally, we describe a mathematical model of the relation between the structure and biological potency of promising new COX-2 inhibitors (trans-stilbenes) using a 2D quantitative structure-activity relationship (QSAR) technique.

  7. Endomicroscopic Imaging of COX-2 Activity in Murine Sporadic and Colitis-Associated Colorectal Cancer

    PubMed Central

    Foersch, Sebastian; Neufert, Clemens; Neurath, Markus F.; Waldner, Maximilian J.

    2013-01-01

    Although several studies propose a chemopreventive effect of aspirin for colorectal cancer (CRC) development, the general use of aspirin cannot be recommended due to its adverse side effects. As the protective effect of aspirin has been associated with an increased expression of COX-2, molecular imaging of COX-2, for instance, during confocal endomicroscopy could enable the identification of patients who would possibly benefit from aspirin treatment. In this pilot trial, we used a COX-2-specific fluorescent probe for detection of colitis-associated and sporadic CRC in mice using confocal microscopy. Following the injection of the COX-2 probe into tumor-bearing APCmin mice or mice exposed to the AOM + DSS model of colitis-associated cancer, the tumor-specific upregulation of COX-2 could be validated with in vivo fluorescence imaging. Subsequent confocal imaging of tumor tissue showed an increased number of COX-2 expressing cells when compared to the normal mucosa of healthy controls. COX-2-expression was detectable with subcellular resolution in tumor cells and infiltrating stroma cells. These findings pose a proof of concept and suggest the use of CLE for the detection of COX-2 expression during colorectal cancer surveillance endoscopy. This could improve early detection and stratification of chemoprevention in patients with CRC. PMID:23401648

  8. Endomicroscopic Imaging of COX-2 Activity in Murine Sporadic and Colitis-Associated Colorectal Cancer.

    PubMed

    Foersch, Sebastian; Neufert, Clemens; Neurath, Markus F; Waldner, Maximilian J

    2013-01-01

    Although several studies propose a chemopreventive effect of aspirin for colorectal cancer (CRC) development, the general use of aspirin cannot be recommended due to its adverse side effects. As the protective effect of aspirin has been associated with an increased expression of COX-2, molecular imaging of COX-2, for instance, during confocal endomicroscopy could enable the identification of patients who would possibly benefit from aspirin treatment. In this pilot trial, we used a COX-2-specific fluorescent probe for detection of colitis-associated and sporadic CRC in mice using confocal microscopy. Following the injection of the COX-2 probe into tumor-bearing APCmin mice or mice exposed to the AOM + DSS model of colitis-associated cancer, the tumor-specific upregulation of COX-2 could be validated with in vivo fluorescence imaging. Subsequent confocal imaging of tumor tissue showed an increased number of COX-2 expressing cells when compared to the normal mucosa of healthy controls. COX-2-expression was detectable with subcellular resolution in tumor cells and infiltrating stroma cells. These findings pose a proof of concept and suggest the use of CLE for the detection of COX-2 expression during colorectal cancer surveillance endoscopy. This could improve early detection and stratification of chemoprevention in patients with CRC.

  9. The 2′-Trifluoromethyl Analogue of Indomethacin Is a Potent and Selective COX-2 Inhibitor

    PubMed Central

    2013-01-01

    Indomethacin is a potent, time-dependent, nonselective inhibitor of the cyclooxygenase enzymes (COX-1 and COX-2). Deletion of the 2′-methyl group of indomethacin produces a weak, reversible COX inhibitor, leading us to explore functionality at that position. Here, we report that substitution of the 2′-methyl group of indomethacin with trifluoromethyl produces CF3–indomethacin, a tight-binding inhibitor with kinetic properties similar to those of indomethacin and unexpected COX-2 selectivity (IC50 mCOX-2 = 267 nM; IC50 oCOX-1 > 100 μM). Studies with site-directed mutants reveal that COX-2 selectivity results from insertion of the CF3 group into a small hydrophobic pocket formed by Ala-527, Val-349, Ser-530, and Leu-531 and projection of the methoxy group toward a side pocket bordered by Val-523. CF3–indomethacin inhibited COX-2 activity in human head and neck squamous cell carcinoma cells and exhibited in vivo anti-inflammatory activity in the carrageenan-induced rat paw edema model with similar potency to that of indomethacin. PMID:23687559

  10. The 2'-Trifluoromethyl Analogue of Indomethacin Is a Potent and Selective COX-2 Inhibitor.

    PubMed

    Blobaum, Anna L; Uddin, Md Jashim; Felts, Andrew S; Crews, Brenda C; Rouzer, Carol A; Marnett, Lawrence J

    2013-05-09

    Indomethacin is a potent, time-dependent, nonselective inhibitor of the cyclooxygenase enzymes (COX-1 and COX-2). Deletion of the 2'-methyl group of indomethacin produces a weak, reversible COX inhibitor, leading us to explore functionality at that position. Here, we report that substitution of the 2'-methyl group of indomethacin with trifluoromethyl produces CF3-indomethacin, a tight-binding inhibitor with kinetic properties similar to those of indomethacin and unexpected COX-2 selectivity (IC50 mCOX-2 = 267 nM; IC50 oCOX-1 > 100 μM). Studies with site-directed mutants reveal that COX-2 selectivity results from insertion of the CF3 group into a small hydrophobic pocket formed by Ala-527, Val-349, Ser-530, and Leu-531 and projection of the methoxy group toward a side pocket bordered by Val-523. CF3-indomethacin inhibited COX-2 activity in human head and neck squamous cell carcinoma cells and exhibited in vivo anti-inflammatory activity in the carrageenan-induced rat paw edema model with similar potency to that of indomethacin.

  11. Data Assimilation and Adjusted Spherical Harmonic Model of VTEC Map over Thailand

    NASA Astrophysics Data System (ADS)

    Klinngam, Somjai; Maruyama, Takashi; Tsugawa, Takuya; Ishii, Mamoru; Supnithi, Pornchai; Chiablaem, Athiwat

    2016-07-01

    The global navigation satellite system (GNSS) and high frequency (HF) communication are vulnerable to the ionospheric irregularities, especially when the signal travels through the low-latitude region and around the magnetic equator known as equatorial ionization anomaly (EIA) region. In order to study the ionospheric effects to the communications performance in this region, the regional map of the observed total electron content (TEC) can show the characteristic and irregularities of the ionosphere. In this work, we develop the two-dimensional (2D) map of vertical TEC (VTEC) over Thailand using the adjusted spherical harmonic model (ASHM) and the data assimilation technique. We calculate the VTEC from the receiver independent exchange (RINEX) files recorded by the dual-frequency global positioning system (GPS) receivers on July 8th, 2012 (quiet day) at 12 stations around Thailand: 0° to 25°E and 95°N to 110°N. These stations are managed by Department of Public Works and Town & Country Planning (DPT), Thailand, and the South East Asia Low-latitude ionospheric Network (SEALION) project operated by National Institute of Information and Communications Technology (NICT), Japan, and King Mongkut's Institute of Technology Ladkrabang (KMITL). We compute the median observed VTEC (OBS-VTEC) in the grids with the spatial resolution of 2.5°x5° in latitude and longitude and time resolution of 2 hours. We assimilate the OBS-VTEC with the estimated VTEC from the International Reference Ionosphere model (IRI-VTEC) as well as the ionosphere map exchange (IONEX) files provided by the International GNSS Service (IGS-VTEC). The results show that the estimation of the 15-degree ASHM can be improved when both of IRI-VTEC and IGS-VTEC are weighted by the latitude-dependent factors before assimilating with the OBS-VTEC. However, the IRI-VTEC assimilation can improve the ASHM estimation more than the IGS-VTEC assimilation. Acknowledgment: This work is partially funded by the

  12. Effects of Ge Gen Decoction on PGE2 content and COX activity in the degenarated cervical intervertebral discs of rats.

    PubMed

    Jun, Zhou; Fang, Suping; Huo, Hairu; Qi, Yun; Guo, Shuying; Jiang, Tingliang; Shi, Qi

    2005-09-01

    After the rat model of cervical spondylosis was developed for 6 months, the PGE2 content and COX activity in the cervical intervertebral discs were determined respectively by radioimmunoassay and catalytic activity assay. The results indicated that the PGE2 content and COX activity in the model rat increased significantly, and that Ge Gen Decoction could down-regulate the PGE2 content and inhibit COX activity. This is possibly one of the mechanisms of Ge Gen Decoction for treating cervical spondylosis.

  13. Moment Reconstruction and Moment-Adjusted Imputation When Exposure is Generated by a Complex, Nonlinear Random Effects Modeling Process

    PubMed Central

    Potgieter, Cornelis J.; Wei, Rubin; Kipnis, Victor; Freedman, Laurence S.; Carroll, Raymond J.

    2016-01-01

    Summary For the classical, homoscedastic measurement error model, moment reconstruction (Freedman et al., 2004, 2008) and moment-adjusted imputation (Thomas et al., 2011) are appealing, computationally simple imputation-like methods for general model fitting. Like classical regression calibration, the idea is to replace the unobserved variable subject to measurement error with a proxy that can be used in a variety of analyses. Moment reconstruction and moment-adjusted imputation differ from regression calibration in that they attempt to match multiple features of the latent variable, and also to match some of the latent variable’s relationships with the response and additional covariates. In this note, we consider a problem where true exposure is generated by a complex, nonlinear random effects modeling process, and develop analogues of moment reconstruction and moment-adjusted imputation for this case. This general model includes classical measurement errors, Berkson measurement errors, mixtures of Berkson and classical errors and problems that are not measurement error problems, but also cases where the data generating process for true exposure is a complex, nonlinear random effects modeling process. The methods are illustrated using the National Institutes of Health-AARP Diet and Health Study where the latent variable is a dietary pattern score called the Healthy Eating Index - 2005. We also show how our general model includes methods used in radiation epidemiology as a special case. Simulations are used to illustrate the methods. PMID:27061196

  14. Divorce Stress and Adjustment Model: Locus of Control and Demographic Predictors.

    ERIC Educational Resources Information Center

    Barnet, Helen Smith

    This study depicts the divorce process over three time periods: predivorce decision phase, divorce proper, and postdivorce. Research has suggested that persons with a more internal locus of control experience less intense and shorter intervals of stress during the divorce proper and better postdivorce adjustment than do persons with a more…

  15. Social Adjustment and Academic Achievement: A Predictive Model for Students with Diverse Academic and Behavior Competencies

    ERIC Educational Resources Information Center

    Ray, Corey E.; Elliott, Stephen N.

    2006-01-01

    This study examined the hypothesized relationship between social adjustment, as measured by perceived social support, self-concept, and social skills, and performance on academic achievement tests. Participants included 27 teachers and 77 fourth- and eighth-grade students with diverse academic and behavior competencies. Teachers were asked to…

  16. Extending the Integrated Model of Retirement Adjustment: Incorporating Mastery and Retirement Planning

    ERIC Educational Resources Information Center

    Donaldson, Tarryn; Earl, Joanne K.; Muratore, Alexa M.

    2010-01-01

    Extending earlier research, this study explores individual (e.g. demographic and health characteristics), psychosocial (e.g. mastery and planning) and organizational factors (e.g. conditions of workforce exit) influencing retirement adjustment. Survey data were collected from 570 semi-retired and retired men and women aged 45 years and older.…

  17. A Key Challenge in Global HRM: Adding New Insights to Existing Expatriate Spouse Adjustment Models

    ERIC Educational Resources Information Center

    Gupta, Ritu; Banerjee, Pratyush; Gaur, Jighyasu

    2012-01-01

    This study is an attempt to strengthen the existing knowledge about factors affecting the adjustment process of the trailing expatriate spouse and the subsequent impact of any maladjustment or expatriate failure. We conducted a qualitative enquiry using grounded theory methodology with 26 Indian spouses who had to deal with their partner's…

  18. A Structural Equation Modeling Approach to the Study of Stress and Psychological Adjustment in Emerging Adults

    ERIC Educational Resources Information Center

    Asberg, Kia K.; Bowers, Clint; Renk, Kimberly; McKinney, Cliff

    2008-01-01

    Today's society puts constant demands on the time and resources of all individuals, with the resulting stress promoting a decline in psychological adjustment. Emerging adults are not exempt from this experience, with an alarming number reporting excessive levels of stress and stress-related problems. As a result, the present study addresses the…

  19. Towards an Integrated Model of Individual, Psychosocial, and Organizational Predictors of Retirement Adjustment

    ERIC Educational Resources Information Center

    Wong, Jessica Y.; Earl, Joanne K.

    2009-01-01

    This cross-sectional study examines three predictors of retirement adjustment: individual (demographic and health), psychosocial (work centrality), and organizational (conditions of workforce exit). It also examines the effect of work centrality on post-retirement activity levels. Survey data was collected from 394 retirees (aged 45-93 years).…

  20. Models of Cultural Adjustment for Child and Adolescent Migrants to Australia: Internal Process and Situational Factors

    ERIC Educational Resources Information Center

    Sonderegger, Robi; Barrett, Paula M.; Creed, Peter A.

    2004-01-01

    Building on previous cultural adjustment profile work by Sonderegger and Barrett (2004), the aim of this study was to propose an organised structure for a number of single risk factors that have been linked to acculturative-stress in young migrants. In recognising that divergent situational characteristics (e.g., school level, gender, residential…

  1. Verification and adjustment of regional regression models for urban storm-runoff quality using data collected in Little Rock, Arkansas

    USGS Publications Warehouse

    Barks, C.S.

    1995-01-01

    Storm-runoff water-quality data were used to verify and, when appropriate, adjust regional regression models previously developed to estimate urban storm- runoff loads and mean concentrations in Little Rock, Arkansas. Data collected at 5 representative sites during 22 storms from June 1992 through January 1994 compose the Little Rock data base. Comparison of observed values (0) of storm-runoff loads and mean concentrations to the predicted values (Pu) from the regional regression models for nine constituents (chemical oxygen demand, suspended solids, total nitrogen, total ammonia plus organic nitrogen as nitrogen, total phosphorus, dissolved phosphorus, total recoverable copper, total recoverable lead, and total recoverable zinc) shows large prediction errors ranging from 63 to several thousand percent. Prediction errors for six of the regional regression models are less than 100 percent, and can be considered reasonable for water-quality models. Differences between 0 and Pu are due to variability in the Little Rock data base and error in the regional models. Where applicable, a model adjustment procedure (termed MAP-R-P) based upon regression with 0 against Pu was applied to improve predictive accuracy. For 11 of the 18 regional water-quality models, 0 and Pu are significantly correlated, that is much of the variation in 0 is explained by the regional models. Five of these 11 regional models consistently overestimate O; therefore, MAP-R-P can be used to provide a better estimate. For the remaining seven regional models, 0 and Pu are not significanfly correlated, thus neither the unadjusted regional models nor the MAP-R-P is appropriate. A simple estimator, such as the mean of the observed values may be used if the regression models are not appropriate. Standard error of estimate of the adjusted models ranges from 48 to 130 percent. Calibration results may be biased due to the limited data set sizes in the Little Rock data base. The relatively large values of

  2. Design, synthesis, evaluation and molecular modelling studies of some novel 5,6-diphenyl-1,2,4-triazin-3(2H)-ones bearing five-member heterocyclic moieties as potential COX-2 inhibitors: A hybrid pharmacophore approach.

    PubMed

    Banerjee, Anupam G; Das, Nirupam; Shengule, Sushant A; Sharma, Piyoosh A; Srivastava, Radhey Shyam; Shrivastava, Sushant Kumar

    2016-12-01

    A series of novel hybrids comprising of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole tethered to 5,6-diphenyl-1,2,4-triazin-3(2H)-one were designed, synthesised and evaluated as COX-2 inhibitors for the treatment of inflammation. The synthesised hybrids were characterised using FT-IR, 1H NMR, 13C NMR, elemental (C,H,N) analyses and assessed for their anti-inflammatory potential by in vitro albumin denaturation assay. Compounds exhibiting activity comparable to indomethacin and celecoxib were further evaluated for in vivo anti-inflammatory activity. Oral administration of promising compounds 3c-3e and 4c-4e did not evoke significant gastric, hepatic and renal toxicity in rats. These potential compounds exhibited reduced malondialdehyde (MDA) content on the gastric mucosa suggesting their protective effects by inhibition of lipid peroxidation. Based on the outcome of in vitro COX assay, compounds 3c-3e and 4c-4e (IC50 0.60-1.11μM) elicited an interesting profile as competitive selective COX-2 inhibitors. Further, selected compounds 3e and 4c were found devoid of cardiotoxicity post evaluation on myocardial infarcted rats. The in silico binding mode of the potential compounds into the COX-2 active site through docking and molecular dynamics exemplified their consensual interaction and subsequent COX-2 inhibition with significant implications for structure-based drug design.

  3. AtCOX17, an Arabidopsis homolog of the yeast copper chaperone COX17.

    PubMed

    Balandin, Teresa; Castresana, Carmen

    2002-08-01

    We have identified a new plant gene, AtCOX17, encoding a protein that shares sequence similarity to COX17, a Cu-binding protein from yeast (Saccharomyces cerevisiae) and vertebrates that mediates the delivery of Cu to the mitochondria for the assembly of a functional cytochrome oxidase complex. The newly characterized Arabidopsis protein has six Cys residues at positions corresponding to those known to coordinate Cu binding in the yeast homolog. Moreover, we show that the Arabidopsis COX17 cDNA complements a COX17 mutant of yeast restoring the respiratory deficiency associated with that mutation. These two lines of evidence indicate that the plant protein identified here is a functional equivalent of yeast COX17 and might serve as a Cu delivery protein for the plant mitochondria. COX17 was identified by investigating the hypersensitive response-like necrotic response provoked in tobacco (Nicotiana tabacum) leaves after harpin inoculation. AtCOX17 expression was activated by high concentrations of Cu, bacterial inoculation, salicylic acid treatment, and treatments that generated NO and hydrogen peroxide. All of the conditions inducing COX17 are known to inhibit mitochondrial respiration and to produce an increase of reactive oxygen species, suggesting that gene induction occurs in response to stress situations that interfere with mitochondrial function.

  4. Targeting Estrogen-Induced COX-2 Activity in Lymphangioleiomyomatosis (LAM)

    DTIC Science & Technology

    2014-12-01

    Lymphangioleiomyomatosis (LAM), prostaglandin biosynthesis, cyclooxygenase-2 (COX-2), COX-2 inhibitors, xenograft tumors, bioluminescent imaging...Lymphangioleiomyomatosis (LAM), prostaglandin biosynthesis, cyclooxygenase-2 (COX-2), COX-2 inhibitors, xenograft tumors, bioluminescent imaging...TSC2- null cells. We found that aspirin treatment for three weeks decreased the intensity of bioluminescence , Page 5 of 8 and decreased the

  5. Dynamic Conceptual Model of Sediment Fluxes Underlying Numerical Modelling of Spatial and Temporal Variability and Adjustment to Environmental Change

    NASA Astrophysics Data System (ADS)

    Hooke, J.

    2015-12-01

    It is essential that a strong conceptual model underlies numerical modelling of basin fluxes and is inclusive of all factors and routeways through the system. Even under stable environmental conditions river fluxes in large basins vary spatially and temporally. Spatial variations arise due to location in the basin, relation to sources and connectivity, and due to morphology, boundary resistance and hydraulics of successive reaches. Temporal variations at a range of scales, from seasonal to decadal, occur within averaged 'stable' conditions, which produce changes in morphology and flux and subsequent feedback effects. Sediment flux in a reach can differ between similar peak magnitude events, depending on duration, season, connectivity and supply state, and existing morphology. Autogenic processes such as channel pattern and position changes, vegetation changes, and floodplain cyclicity also take place within the system. The major drivers of change at decadal-centennial timescales are assumed to be climate, land use cover and practices, and direct catchment and channel modification. Different parts of the system will have different trajectories of adjustment, depending on their location and spatial relation to connectivity within the system and on the reach morphological and resistance characteristics. These will govern the rate and extent of transmission of changes. The changes will also be influenced by the occurrence and sequence of flow events and their feedback effects, in relation to changing thresholds produced by the response to the environmental changes. It is essential that the underlying dynamics and inherent variability are recognised in numerical modelling and river management and that spatial sequencing of changes and their feedbacks are incorporated. The challenge is to produce quantifiable relations of the rate or propagation of changes through a basin given spatial variability of reach characteristics, under dynamic flow scenarios.

  6. How do attachment dimensions affect bereavement adjustment? A mediation model of continuing bonds.

    PubMed

    Yu, Wei; He, Li; Xu, Wei; Wang, Jianping; Prigerson, Holly G

    2016-04-30

    The current study aims to examine mechanisms underlying the impact of attachment dimensions on bereavement adjustment. Bereaved mainland Chinese participants (N=247) completed anonymous, retrospective, self-report surveys assessing attachment dimensions, continuing bonds (CB), grief symptoms and posttraumatic growth (PTG). Results demonstrated that attachment anxiety predicted grief symptoms via externalized CB and predicted PTG via internalized CB at the same time, whereas attachment avoidance positively predicted grief symptoms via externalized CB but negatively predicted PTG directly. Findings suggested that individuals with a high level of attachment anxiety could both suffer from grief and obtain posttraumatic growth after loss, but it depended on which kind of CB they used. By contrast, attachment avoidance was associated with a heightened risk of maladaptive bereavement adjustment. Future grief therapy may encourage the bereaved to establish CB with the deceased and gradually shift from externalized CB to internalized CB.

  7. Modeling and optimization of adjustable multifrequency axially polarized multilayer composite cylindrical transducer

    NASA Astrophysics Data System (ADS)

    Wang, Jianjun; Shi, Zhifei; Song, Gangbing

    2015-04-01

    A novel adjustable multifrequency axially polarized multilayer composite cylindrical transducer is developed in this paper. The transducer is composed of two parts: an actuator part and a sensor part. Each part is considered as a multilayer piezoelectric/elastic composite structure. The actuator part is utilized to actuate the transducer, while the senor part is used to adjust its dynamic characteristics through connecting to an external electric resistance. Based on the plane stress assumption, the radial vibration of this new kind of transducer is analyzed, and its input electric admittance is derived analytically. Comparisons with the earlier works are conducted to validate the theoretical solution. Furthermore, numerical analysis is performed to study the effects of the external electric resistance on the transducer’s dynamic characteristics, such as resonance and anti-resonance frequencies, as well as the corresponding electromechanical coupling factor. Numerical results show that the multifrequency cylindrical transducer can be designed through adjusting the external electric resistance and the ratio of piezoelectric layer numbers between the actuator part and the sensor part. In addition, the optimized transducer can be proposed at the matching electric resistance. The proposed cylindrical transducer plays an important role in designing the cymbal transducer, which can be used in underwater sound projectors and ultrasonic radiators.

  8. In vitro import and assembly of the nucleus-encoded mitochondrial subunit III of cytochrome c oxidase (Cox3).

    PubMed

    Vázquez-Acevedo, Miriam; Rubalcava-Gracia, Diana; González-Halphen, Diego

    2014-11-01

    The cox3 gene, encoding subunit III of cytochrome c oxidase (Cox3) is in mitochondrial genomes except in chlorophycean algae, where it is localized in the nucleus. Therefore, algae like Chlamydomonas reinhardtii, Polytomella sp. and Volvox carteri, synthesize the Cox3 polypeptide in the cytosol, import it into mitochondria, and integrate it into the cytochrome c oxidase complex. In this work, we followed the in vitro internalization of the Cox3 precursor by isolated, import-competent mitochondria of Polytomella sp. In this colorless alga, the precursor Cox3 protein is synthesized with a long, cleavable, N-terminal mitochondrial targeting sequence (MTS) of 98 residues. In an import time course, a transient Cox3 intermediate was identified, suggesting that the long MTS is processed more than once. The first processing step is sensitive to the metalo-protease inhibitor 1,10-ortophenantroline, suggesting that it is probably carried out by the matrix-located Mitochondrial Processing Protease. Cox3 is readily imported through an energy-dependent import pathway and integrated into the inner mitochondrial membrane, becoming resistant to carbonate extraction. Furthermore, the imported Cox3 protein was assembled into cytochrome c oxidase, as judged by the presence of a labeled band co-migrating with complex IV in Blue Native Electrophoresis. A model for the biogenesis of Cox3 in chlorophycean algae is proposed. This is the first time that the in vitro mitochondrial import of a cytosol-synthesized Cox3 subunit is described.

  9. The potential role of COX-2 in cancer stem cell-mediated canine mammary tumor initiation: an immunohistochemical study.

    PubMed

    Huang, Jian; Zhang, Di; Xie, Fuqiang; Lin, Degui

    2015-01-01

    Increasing evidence suggests that cancer stem cells (CSCs) are responsible for tumor initiation and maintenance. Additionally, it is becoming apparent that cyclooxygenase (COX) signaling is associated with canine mammary tumor development. The goals of the present study were to investigate COX-2 expression patterns and their effect on CSC-mediated tumor initiation in primary canine mammary tissues and tumorsphere models using immunohistochemistry. Patterns of COX-2, CD44, octamer-binding transcription factor (Oct)-3/4, and epidermal growth factor receptor (EGFR) expression were examined in malignant mammary tumor (MMT) samples and analyzed in terms of clinicopathological characteristics. COX-2 and Oct-3/4 expression was higher in MMTs compared to other histological samples with heterogeneous patterns. In MMTs, COX-2 expression correlated with tumor malignancy features. Significant associations between COX-2, CD44, and EGFR were observed in low-differentiated MMTs. Comparative analysis showed that the levels of COX-2, CD44, and Oct-3/4 expression varied significantly among TSs of three histological grades. Enhanced COX-2 staining was consistently observed in TSs. Similar levels of staining intensity were found for CD44 and Oct-3/4, but EGFR expression was weak. Our findings indicate the potential role of COX-2 in CSC-mediated tumor initiation, and suggest that COX-2 inhibition may help treat canine mammary tumors by targeting CSCs.

  10. NKG201xGIA - first results for a new model of glacial isostatic adjustment in Fennoscandia

    NASA Astrophysics Data System (ADS)

    Steffen, Holger; Barletta, Valentina; Kollo, Karin; Milne, Glenn A.; Nordman, Maaria; Olsson, Per-Anders; Simpson, Matthew J. R.; Tarasov, Lev; Ågren, Jonas

    2016-04-01

    Glacial isostatic adjustment (GIA) is a dominant process in northern Europe, which is observed with several geodetic and geophysical methods. The observed land uplift due to this process amounts to about 1 cm/year in the northern Gulf of Bothnia. GIA affects the establishment and maintenance of reliable geodetic and gravimetric reference networks in the Nordic countries. To support a high level of accuracy in the determination of position, adequate corrections have to be applied with dedicated models. Currently, there are efforts within a Nordic Geodetic Commission (NKG) activity towards a model of glacial isostatic adjustment for Fennoscandia. The new model, NKG201xGIA, to be developed in the near future will complement the forthcoming empirical NKG land uplift model, which will substitute the currently used empirical land uplift model NKG2005LU (Ågren & Svensson, 2007). Together, the models will be a reference for vertical and horizontal motion, gravity and geoid change and more. NKG201xGIA will also provide uncertainty estimates for each field. Following former investigations, the GIA model is based on a combination of an ice and an earth model. The selected reference ice model, GLAC, for Fennoscandia, the Barents/Kara seas and the British Isles is provided by Lev Tarasov and co-workers. Tests of different ice and earth models will be performed based on the expertise of each involved modeler. This includes studies on high resolution ice sheets, different rheologies, lateral variations in lithosphere and mantle viscosity and more. This will also be done in co-operation with scientists outside NKG who help in the development and testing of the model. References Ågren, J., Svensson, R. (2007): Postglacial Land Uplift Model and System Definition for the New Swedish Height System RH 2000. Reports in Geodesy and Geographical Information Systems Rapportserie, LMV-Rapport 4, Lantmäteriet, Gävle.

  11. The novel anti-inflammatory agent VA694, endowed with both NO-releasing and COX2-selective inhibiting properties, exhibits NO-mediated positive effects on blood pressure, coronary flow and endothelium in an experimental model of hypertension and endothelial dysfunction.

    PubMed

    Martelli, A; Testai, L; Anzini, M; Cappelli, A; Di Capua, A; Biava, M; Poce, G; Consalvi, S; Giordani, A; Caselli, G; Rovati, L; Ghelardini, C; Patrignani, P; Sautebin, L; Breschi, M C; Calderone, V

    2013-12-01

    Selective cyclooxygenase 2 (COX2) inhibitors (COXIBs) are effective anti-inflammatory and analgesic drugs with improved gastrointestinal (GI) safety compared to nonselective nonsteroidal anti-inflammatory drugs known as traditional (tNSAIDs). However, their use is associated with a cardiovascular (CV) hazard (i.e. increased incidence of thrombotic events and hypertension) due to the inhibition of COX2-dependent vascular prostacyclin. Aiming to design COX2-selective inhibitors with improved CV safety, new NO-releasing COXIBs (NO-COXIBs) have been developed. In these hybrid drugs, the NO-mediated CV effects are expected to compensate for the COXIB-mediated inhibition of prostacyclin. This study evaluates the potential CV beneficial effects of VA694, a promising NO-COXIB, the anti-inflammatory effects of which have been previously characterized in several in vitro and in vivo experimental models. When incubated in hepatic homogenate, VA694 acted as a slow NO-donor. Moreover, it caused NO-mediated relaxant effects in the vascular smooth muscle. The chronic oral administration of VA694 to young spontaneously hypertensive rats (SHRs) significantly slowed down the age-related development of hypertension and was associated with increased plasma levels of nitrates, stable end-metabolites of NO. Furthermore, a significant improvement of coronary flow and a significant reduction of endothelial dysfunction were observed in SHRs submitted to chronic administration of VA694. In conclusion, VA694 is a promising COX2-inhibiting hybrid drug, showing NO releasing properties which may mitigate the CV deleterious effects associated with the COX2-inhibition.

  12. Comparison of stopped Cox regression with direct methods such as pseudo-values and binomial regression.

    PubMed

    van Houwelingen, Hans C; Putter, Hein

    2015-04-01

    By far the most popular model to obtain survival predictions for individual patients is the Cox model. The Cox model does not make any assumptions on the underlying hazard, but it relies heavily on the proportional hazards assumption. The most common ways to circumvent this robustness problem are 1) to categorize patients based on their prognostic risk score and to base predictions on Kaplan-Meier curves for the risk categories, or 2) to include interactions with the covariates and suitable functions of time. Robust estimators of the t(0)-year survival probabilities can also be obtained from a "stopped Cox" regression model, in which all observations are administratively censored at t(0). Other recent approaches to solve this robustness problem, originally proposed in the context of competing risks, are pseudo-values and direct binomial regression, based on unbiased estimating equations. In this paper stopped Cox regression is compared with these direct approaches. This is done by means of a simulation study to assess the biases of the different approaches and an analysis of breast cancer data to get some feeling for the performance in practice. The tentative conclusion is that stopped Cox and direct models agree well if the follow-up is not too long. There are larger differences for long-term follow-up data. There stopped Cox might be more efficient, but less robust.

  13. Protective effects of levamisole, acetylsalicylic acid, and α-tocopherol against dioxin toxicity measured as the expression of AhR and COX-2 in a chicken embryo model.

    PubMed

    Gostomska-Pampuch, Kinga; Ostrowska, Alicja; Kuropka, Piotr; Dobrzyński, Maciej; Ziółkowski, Piotr; Kowalczyk, Artur; Łukaszewicz, Ewa; Gamian, Andrzej; Całkosiński, Ireneusz

    2017-04-01

    Polychlorinated dibenzo-p-dioxins and dibenzofurans (dioxins) are classed as persistent organic pollutants and have adverse effects on multiple functions within the body. Dioxins are known carcinogens, immunotoxins, and teratogens. Dioxins are transformed in vivo, and interactions between the products and the aryl hydrocarbon receptor (AhR) lead to the formation of proinflammatory and toxic metabolites. The aim of this study was to determine whether α-tocopherol (vitamin E), acetylsalicylic acid (ASA), and levamisole can decrease the amount of damage caused by dioxins. Fertile Hubbard Flex commercial line chicken eggs were injected with solutions containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or containing TCDD and the test compounds. The chicken embryos and organs were analyzed after 7 and 13 days. The levels at which AhR and cyclooxygenase-2 (COX-2) proteins (which are induced during inflammation) were expressed were evaluated by performing immunohistochemical analyses on embryos treated with TCDD alone or with TCDD and the test compounds. TCDD caused developmental disorders and increased AhR and COX-2 expression in the chicken embryo tissues. Vitamin E, levamisole, ASA, and ASA plus vitamin E inhibited AhR and COX-2 expression in embryos after 7 days and decreased AhR and COX-2 expression in embryos after 13 days. ASA, levamisole, and ASA plus vitamin E weakened the immune response and prevented multiple organ changes. Vitamin E was not fully protective against developmental changes in the embryos.

  14. What's the Risk? A Simple Approach for Estimating Adjusted Risk Measures from Nonlinear Models Including Logistic Regression

    PubMed Central

    Kleinman, Lawrence C; Norton, Edward C

    2009-01-01

    Objective To develop and validate a general method (called regression risk analysis) to estimate adjusted risk measures from logistic and other nonlinear multiple regression models. We show how to estimate standard errors for these estimates. These measures could supplant various approximations (e.g., adjusted odds ratio [AOR]) that may diverge, especially when outcomes are common. Study Design Regression risk analysis estimates were compared with internal standards as well as with Mantel–Haenszel estimates, Poisson and log-binomial regressions, and a widely used (but flawed) equation to calculate adjusted risk ratios (ARR) from AOR. Data Collection Data sets produced using Monte Carlo simulations. Principal Findings Regression risk analysis accurately estimates ARR and differences directly from multiple regression models, even when confounders are continuous, distributions are skewed, outcomes are common, and effect size is large. It is statistically sound and intuitive, and has properties favoring it over other methods in many cases. Conclusions Regression risk analysis should be the new standard for presenting findings from multiple regression analysis of dichotomous outcomes for cross-sectional, cohort, and population-based case–control studies, particularly when outcomes are common or effect size is large. PMID:18793213

  15. Chiropractic Adjustment

    MedlinePlus

    ... structural alignment and improve your body's physical function. Low back pain, neck pain and headache are the most common ... treated. Chiropractic adjustment can be effective in treating low back pain, although much of the research done shows only ...

  16. Adjustment disorder

    MedlinePlus

    ... from other people Skipped heartbeats and other physical complaints Trembling or twitching To have adjustment disorder, you ... ADAM Health Solutions. About MedlinePlus Site Map FAQs Customer Support Get email updates Subscribe to RSS Follow ...

  17. A limit-cycle model of leg movements in cross-country skiing and its adjustments with fatigue.

    PubMed

    Cignetti, F; Schena, F; Mottet, D; Rouard, A

    2010-08-01

    Using dynamical modeling tools, the aim of the study was to establish a minimal model reproducing leg movements in cross-country skiing, and to evaluate the eventual adjustments of this model with fatigue. The participants (N=8) skied on a treadmill at 90% of their maximal oxygen consumption, up to exhaustion, using the diagonal stride technique. Qualitative analysis of leg kinematics portrayed in phase planes, Hooke planes, and velocity profiles suggested the inclusion in the model of a linear stiffness and an asymmetric van der Pol-type nonlinear damping. Quantitative analysis revealed that this model reproduced the observed kinematics patterns of the leg with adequacy, accounting for 87% of the variance. A rising influence of the stiffness term and a dropping influence of the damping terms were also evidenced with fatigue. The meaning of these changes was discussed in the framework of motor control.

  18. Molecular Dynamics Simulations of Arachidonic Acid Complexes with COX-1 and COX-2

    PubMed Central

    Furse, Kristina E.; Pratt, Derek A.; Porter, Ned A.; Lybrand, Terry P.

    2008-01-01

    The cyclooxygenase (COX) enzymes are responsible for the committed step in prostaglandin biosynthesis, the generation of prostaglandin H2. As a result, these enzymes are pharmacologically important targets for non-steroidal anti-inflammatory drugs, such as aspirin and newer COX-2 selective inhibitors. The cyclooxygenases are functional homodimers, and each subunit contains both a cyclooxygenase and a peroxidase active site. These enzymes are quite interesting mechanistically, as the conversion of arachidonic acid to prostaglandin H2 requires two oxygenation and two cyclization reactions, resulting in the formation of five new chiral centers with nearly absolute regio- and stereochemical fidelity. We have used molecular dynamics (MD) simulations to investigate the equilibrium behavior of both COX-1 and COX-2 enzyme isoforms with bound arachidonate. These simulations were compared with reference simulations of arachidonate in solution to explore the effect of enzyme on substrate conformation and positioning in the active site. The simulations suggest that the substrate has greater conformational freedom in the COX-2 active site, consistent with the larger COX-2 active site volume observed in X-ray crystal structures. The simulations reveal different conformational behavior for arachidonate in each subunit over the course of extended equilibrium MD simulations. The simulations also provide detailed information for several protein channels that might be important for oxygen and water transport to or from active sites, or for intermediate trafficking between the cyclooxygenase and peroxidase active sites. The detailed comparisons for COX-1 versus COX-2 active site structural fluctuations may also provide useful information for design of new isozyme-selective inhibitors. PMID:16519514

  19. A local adjustment strategy for the initialization of dynamic causal modelling to infer effective connectivity in brain epileptic structures.

    PubMed

    Xiang, Wentao; Karfoul, Ahmad; Shu, Huazhong; Le Bouquin Jeannès, Régine

    2017-03-07

    This paper addresses the question of effective connectivity in the human cerebral cortex in the context of epilepsy. Among model based approaches to infer brain connectivity, spectral Dynamic Causal Modelling is a conventional technique for which we propose an alternative to estimate cross spectral density. The proposed strategy we investigated tackles the sub-estimation of the free energy using the well-known variational Expectation-Maximization algorithm highly sensitive to the initialization of the parameters vector by a permanent local adjustment of the initialization process. The performance of the proposed strategy in terms of effective connectivity identification is assessed using simulated data generated by a neuronal mass model (simulating unidirectional and bidirectional flows) and real epileptic intracerebral Electroencephalographic signals. Results show the efficiency of proposed approach compared to the conventional Dynamic Causal Modelling and the one wherein a deterministic annealing scheme is employed.

  20. The combined geodetic network adjusted on the reference ellipsoid - a comparison of three functional models for GNSS observations

    NASA Astrophysics Data System (ADS)

    Kadaj, Roman

    2016-12-01

    The adjustment problem of the so-called combined (hybrid, integrated) network created with GNSS vectors and terrestrial observations has been the subject of many theoretical and applied works. The network adjustment in various mathematical spaces was considered: in the Cartesian geocentric system on a reference ellipsoid and on a mapping plane. For practical reasons, it often takes a geodetic coordinate system associated with the reference ellipsoid. In this case, the Cartesian GNSS vectors are converted, for example, into geodesic parameters (azimuth and length) on the ellipsoid, but the simple form of converted pseudo-observations are the direct differences of the geodetic coordinates. Unfortunately, such an approach may be essentially distorted by a systematic error resulting from the position error of the GNSS vector, before its projection on the ellipsoid surface. In this paper, an analysis of the impact of this error on the determined measures of geometric ellipsoid elements, including the differences of geodetic coordinates or geodesic parameters is presented. Assuming that the adjustment of a combined network on the ellipsoid shows that the optimal functional approach in relation to the satellite observation, is to create the observational equations directly for the original GNSS Cartesian vector components, writing them directly as a function of the geodetic coordinates (in numerical applications, we use the linearized forms of observational equations with explicitly specified coefficients). While retaining the original character of the Cartesian vector, one avoids any systematic errors that may occur in the conversion of the original GNSS vectors to ellipsoid elements, for example the vector of the geodesic parameters. The problem is theoretically developed and numerically tested. An example of the adjustment of a subnet loaded from the database of reference stations of the ASG-EUPOS system was considered for the preferred functional model of the GNSS

  1. Golgi-Cox Staining Step by Step

    PubMed Central

    Zaqout, Sami; Kaindl, Angela M.

    2016-01-01

    Golgi staining remains a key method to study neuronal morphology in vivo. Since most protocols delineating modifications of the original staining method lack details on critical steps, establishing this method in a laboratory can be time-consuming and frustrating. Here, we describe the Golgi-Cox staining in such detail that should turn the staining into an easily feasible method for all scientists working in the neuroscience field. PMID:27065817

  2. Functional Polymorphisms in COX-2 Gene Are Correlated with the Risk of Oral Cancer

    PubMed Central

    Li, Dong; Hao, Shu-Hong; Sun, Yan; Hu, Chun-Mei; Ma, Zhi-Hua; Wang, Zhi Ming; Liu, Jie; Liu, Hong Bo; Ye, Ming; Zhang, Yu Fei; Yang, Dong Sheng; Shi, Guang

    2015-01-01

    Background. This meta-analysis investigated the association between functional COX-2 gene polymorphisms and the risk of oral cancer. Methods. Several electronic databases were searched for published studies using combinations of keywords related to COX-2 gene polymorphisms and oral cancer. After selection of relevant studies, following strict inclusion and exclusion criteria, data was performed using STATA 12.0 software. Results. We retrieved 83 studies from database search using specific search terms. After multiple rounds of selection and elimination, 7 studies were finally identified as suitable to be included in our present meta-analysis, based on their relevance and data integrity. These 7 studies contained a combined total of 2,296 oral cancer patients and 3,647 healthy controls. Our findings demonstrated that +837 T > C (rs5275) polymorphism in COX-2 showed statistically significant differences in gene frequencies in case and control groups in allele model and dominant model. Similar results were obtained with COX-2 gene polymorphism 765 G > C (rs20417). On the other hand, 1195 A > G (rs689466) polymorphism in COX-2 did not confer susceptibility to oral cancers. Conclusion. Based on our results, COX-2 gene polymorphisms, +837 T > C (rs5275) and −765G > C (rs20417), showed clear links with oral cancer susceptibility, and the 1195A > G (rs689466) polymorphism did not show such a correlation. PMID:25977924

  3. Testing Momentum Enhancement of Ribbon Fin Based Propulsion Using a Robotic Model With an Adjustable Body

    NASA Astrophysics Data System (ADS)

    English, Ian; Curet, Oscar

    2016-11-01

    Lighthill and Blake's 1990 momentum enhancement theory suggests there is a multiplicative propulsive effect linked to the ratio of body and fin heights in Gymnotiform and Balistiform swimmers, which propel themselves using multi-rayed undulating fins while keeping their bodies mostly rigid. Proof of such a momentum enhancement could have a profound effect on unmanned underwater vehicle design and shed light on the evolutionary advantage to body-fin ratios found in nature, shown as optimal for momentum enhancement in Lighthill and Blake's theory. A robotic ribbon fin with twelve independent fin rays, elastic fin membrane, and a body of adjustable height was developed specifically to experimentally test momentum enhancement. Thrust tests for various body heights were conducted in a recirculating flow tank at different flow speeds and fin flapping frequencies. When comparing thrust at different body heights, flow speeds, and frequencies to a 'no-body' thrust test case at each frequency and flow speed, data indicate there is no momentum enhancement factor due to the presence of a body on top of an undulating fin. This suggests that if there is a benefit to a specific ratio between body and fin height, it is not due to momentum enhancement.

  4. Mapping disability-adjusted life years: a Bayesian hierarchical model framework for burden of disease and injury assessment.

    PubMed

    MacNab, Ying C

    2007-11-20

    This paper presents a Bayesian disability-adjusted life year (DALY) methodology for spatial and spatiotemporal analyses of disease and/or injury burden. A Bayesian disease mapping model framework, which blends together spatial modelling, shared-component modelling (SCM), temporal modelling, ecological modelling, and non-linear modelling, is developed for small-area DALY estimation and inference. In particular, we develop a model framework that enables SCM as well as multivariate CAR modelling of non-fatal and fatal disease or injury rates and facilitates spline smoothing for non-linear modelling of temporal rate and risk trends. Using British Columbia (Canada) hospital admission-separation data and vital statistics mortality data on non-fatal and fatal road traffic injuries to male population age 20-39 for year 1991-2000 and for 84 local health areas and 16 health service delivery areas, spatial and spatiotemporal estimation and inference on years of life lost due to premature death, years lived with disability, and DALYs are presented. Fully Bayesian estimation and inference, with Markov chain Monte Carlo implementation, are illustrated. We present a methodological framework within which the DALY and the Bayesian disease mapping methodologies interface and intersect. Its development brings the relative importance of premature mortality and disability into the assessment of community health and health needs in order to provide reliable information and evidence for community-based public health surveillance and evaluation, disease and injury prevention, and resource provision.

  5. Co-expression of COX-2 and 5-LO in primary glioblastoma is associated with poor prognosis.

    PubMed

    Wang, Xingfu; Chen, Yupeng; Zhang, Sheng; Zhang, Lifeng; Liu, Xueyong; Zhang, Li; Li, Xiaoling; Chen, Dayang

    2015-11-01

    Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) are important factors in tumorigenesis and malignant progression; however, studies of their roles in glioblastoma have produced conflicting results. To define the frequencies of COX-2 and 5-LO expression and their correlation with clinicopathological features and prognosis, tumor tissues from 76 cases of newly diagnosed primary ordinary glioblastoma were examined for COX-2 and 5-LO expression by immunohistochemistry. The expression levels of COX-2 and 5-LO and the relationships between the co-expression of COX-2/5-LO and patient age and gender, edema index (EI), Karnofsky Performance Scale and overall survival (OS) were analyzed. COX-2 and 5-LO were expressed in 73.7 % (56/76) and 92.1 % (70/76) of the samples, respectively. Among the clinicopathological characteristics, only age (>60 years) exhibited a significant association with the high expression of COX-2. No statistically significant correlations were found in the 5-LO cohort. A significant positive correlation was revealed between the COX-2 and 5-LO scores (r = 0.374; p = 0.001). The elevated co-expression of COX-2 and 5-LO was observed primarily in the patients over the age of 60 years. Patients with a high expression of COX-2 had a significantly shorter OS (p < 0.01), whereas the immunoexpression of 5-LO was not associated with the OS of patients with glioblastoma. Survival analysis indicated that simultaneous high levels of COX-2 and 5-LO expression were significantly correlated with poor OS and, conversely, that a low/low expression pattern of these two proteins was significantly associated with better OS (p < 0.05). Moreover, the Cox multivariable proportional hazard model showed that a high expression of COX-2, high co-expression of COX-2 and 5-LO, and a high Ki-67 index were significant predictors of shorter OS in primary glioblastoma, independent of age, gender, EI, 5-LO expression and p53 status. The hazard ratios for OS were 2.347 (95 % CI 1

  6. Dynamic Modeling of Adjustable-Speed Pumped Storage Hydropower Plant: Preprint

    SciTech Connect

    Muljadi, E.; Singh, M.; Gevorgian, V.; Mohanpurkar, M.; Havsapian, R.; Koritarov, V.

    2015-04-06

    Hydropower is the largest producer of renewable energy in the U.S. More than 60% of the total renewable generation comes from hydropower. There is also approximately 22 GW of pumped storage hydropower (PSH). Conventional PSH uses a synchronous generator, and thus the rotational speed is constant at synchronous speed. This work details a hydrodynamic model and generator/power converter dynamic model. The optimization of the hydrodynamic model is executed by the hydro-turbine controller, and the electrical output real/reactive power is controlled by the power converter. All essential controllers to perform grid-interface functions and provide ancillary services are included in the model.

  7. The Analysis of Repeated Measurements with Mixed-Model Adjusted "F" Tests

    ERIC Educational Resources Information Center

    Kowalchuk, Rhonda K.; Keselman, H. J.; Algina, James; Wolfinger, Russell D.

    2004-01-01

    One approach to the analysis of repeated measures data allows researchers to model the covariance structure of their data rather than presume a certain structure, as is the case with conventional univariate and multivariate test statistics. This mixed-model approach, available through SAS PROC MIXED, was compared to a Welch-James type statistic.…

  8. The timing of the Black Sea flood event: Insights from modeling of glacial isostatic adjustment

    NASA Astrophysics Data System (ADS)

    Goldberg, Samuel L.; Lau, Harriet C. P.; Mitrovica, Jerry X.; Latychev, Konstantin

    2016-10-01

    We present a suite of gravitationally self-consistent predictions of sea-level change since Last Glacial Maximum (LGM) in the vicinity of the Bosphorus and Dardanelles straits that combine signals associated with glacial isostatic adjustment (GIA) and the flooding of the Black Sea. Our predictions are tuned to fit a relative sea level (RSL) record at the island of Samothrace in the north Aegean Sea and they include realistic 3-D variations in viscoelastic structure, including lateral variations in mantle viscosity and the elastic thickness of the lithosphere, as well as weak plate boundary zones. We demonstrate that 3-D Earth structure and the magnitude of the flood event (which depends on the pre-flood level of the lake) both have significant impact on the predicted RSL change at the location of the Bosphorus sill, and therefore on the inferred timing of the marine incursion. We summarize our results in a plot showing the predicted RSL change at the Bosphorus sill as a function of the timing of the flood event for different flood magnitudes up to 100 m. These results suggest, for example, that a flood event at 9 ka implies that the elevation of the sill was lowered through erosion by ∼14-21 m during, and after, the flood. In contrast, a flood event at 7 ka suggests erosion of ∼24-31 m at the sill since the flood. More generally, our results will be useful for future research aimed at constraining the details of this controversial, and widely debated geological event.

  9. The inflammatory effect of infection with Hymenolepis diminuta via the increased expression and activity of COX-1 and COX-2 in the rat jejunum and colon.

    PubMed

    Kosik-Bogacka, D I; Baranowska-Bosiacka, I; Kolasa-Wołosiuk, A; Lanocha-Arendarczyk, N; Gutowska, I; Korbecki, J; Namięta, H; Rotter, I

    2016-10-01

    The aim of this study was to determine whether Hymenolepis diminuta may affect the expression and activity of cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2), resulting in the altered levels of their main products - prostaglandins (PGE2) and thromboxane B2 (TXB2). The study used the same experimental model as in our previous studies in which we had observed changes in the transepithelial ion transport, tight junctions and in the indicators of oxidative stress, in both small and large intestines of rats infected with H. diminuta. In this paper, we investigated not only the site of immediate presence of the tapeworm (jejunum), but also a distant site (colon). Inflammation related to H. diminuta infection is associated with the increased expression and activation of cyclooxygenase (COX), enzyme responsible for the synthesis of PGE2 and TXB2, local hormones contributing to the enhanced inflammatory reaction in the jejunum and colon in the infected rats. The increased COX expression and activity is probably caused by the increased levels of free radicals and the weakening of the host's antioxidant defense induced by the presence of the parasite. Our immunohistochemical analysis showed that H. diminuta infection affected not only the intensity of the immunodetection of COX but also the enzyme protein localization within intestinal epithelial cells - from the entire cytoplasm to apical/basal regions of cells, or even to the nucleus.

  10. Modeling and simulation of M/M/c queuing pharmacy system with adjustable parameters

    NASA Astrophysics Data System (ADS)

    Rashida, A. R.; Fadzli, Mohammad; Ibrahim, Safwati; Goh, Siti Rohana

    2016-02-01

    This paper studies a discrete event simulation (DES) as a computer based modelling that imitates a real system of pharmacy unit. M/M/c queuing theo is used to model and analyse the characteristic of queuing system at the pharmacy unit of Hospital Tuanku Fauziah, Kangar in Perlis, Malaysia. The input of this model is based on statistical data collected for 20 working days in June 2014. Currently, patient waiting time of pharmacy unit is more than 15 minutes. The actual operation of the pharmacy unit is a mixed queuing server with M/M/2 queuing model where the pharmacist is referred as the server parameters. DES approach and ProModel simulation software is used to simulate the queuing model and to propose the improvement for queuing system at this pharmacy system. Waiting time for each server is analysed and found out that Counter 3 and 4 has the highest waiting time which is 16.98 and 16.73 minutes. Three scenarios; M/M/3, M/M/4 and M/M/5 are simulated and waiting time for actual queuing model and experimental queuing model are compared. The simulation results show that by adding the server (pharmacist), it will reduce patient waiting time to a reasonable improvement. Almost 50% average patient waiting time is reduced when one pharmacist is added to the counter. However, it is not necessary to fully utilize all counters because eventhough M/M/4 and M/M/5 produced more reduction in patient waiting time, but it is ineffective since Counter 5 is rarely used.

  11. Towards a universal barcode of oomycetes--a comparison of the cox1 and cox2 loci.

    PubMed

    Choi, Young-Joon; Beakes, Gordon; Glockling, Sally; Kruse, Julia; Nam, Bora; Nigrelli, Lisa; Ploch, Sebastian; Shin, Hyeon-Dong; Shivas, Roger G; Telle, Sabine; Voglmayr, Hermann; Thines, Marco

    2015-11-01

    Oomycetes are a diverse group of eukaryotes in terrestrial, limnic and marine habitats worldwide and include several devastating plant pathogens, for example Phytophthora infestans (potato late blight). The cytochrome c oxidase subunit 2 gene (cox2) has been widely used for identification, taxonomy and phylogeny of various oomycete groups. However, recently the cox1 gene was proposed as a DNA barcode marker instead, together with ITS rDNA. The cox1 locus has been used in some studies of Pythium and Phytophthora, but has rarely been used for other oomycetes, as amplification success of cox1 varies with different lineages and sample ages. To determine which out of cox1 or cox2 is best suited as a universal oomycete barcode, we compared these two genes in terms of (i) PCR efficiency for 31 representative genera, as well as for historic herbarium specimens, and (ii) sequence polymorphism, intra- and interspecific divergence. The primer sets for cox2 successfully amplified all oomycete genera tested, while cox1 failed to amplify three genera. In addition, cox2 exhibited higher PCR efficiency for historic herbarium specimens, providing easier access to barcoding-type material. Sequence data for several historic type specimens exist for cox2, but there are none for cox1. In addition, cox2 yielded higher species identification success, with higher interspecific and lower intraspecific divergences than cox1. Therefore, cox2 is suggested as a partner DNA barcode along with ITS rDNA instead of cox1. The cox2-1 spacer could be a useful marker below species level. Improved protocols and universal primers are presented for all genes to facilitate future barcoding efforts.

  12. Mitochondrial disease genes COA6, COX6B and SCO2 have overlapping roles in COX2 biogenesis

    PubMed Central

    Ghosh, Alok; Pratt, Anthony T.; Soma, Shivatheja; Theriault, Sarah G.; Griffin, Aaron T.; Trivedi, Prachi P.; Gohil, Vishal M.

    2016-01-01

    Biogenesis of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain, is a complex process facilitated by several assembly factors. Pathogenic mutations were recently reported in one such assembly factor, COA6, and our previous work linked Coa6 function to mitochondrial copper metabolism and expression of Cox2, a copper-containing subunit of CcO. However, the precise role of Coa6 in Cox2 biogenesis remained unknown. Here we show that yeast Coa6 is an orthologue of human COA6, and like Cox2, is regulated by copper availability, further implicating it in copper delivery to Cox2. In order to place Coa6 in the Cox2 copper delivery pathway, we performed a comprehensive genetic epistasis analysis in the yeast Saccharomyces cerevisiae and found that simultaneous deletion of Coa6 and Sco2, a mitochondrial copper metallochaperone, or Coa6 and Cox12/COX6B, a structural subunit of CcO, completely abrogates Cox2 biogenesis. Unlike Coa6 deficient cells, copper supplementation fails to rescue Cox2 levels of these double mutants. Overexpression of Cox12 or Sco proteins partially rescues the coa6Δ phenotype, suggesting their overlapping but non-redundant roles in copper delivery to Cox2. These genetic data are strongly corroborated by biochemical studies demonstrating physical interactions between Coa6, Cox2, Cox12 and Sco proteins. Furthermore, we show that patient mutations in Coa6 disrupt Coa6–Cox2 interaction, providing the biochemical basis for disease pathogenesis. Taken together, these results place COA6 in the copper delivery pathway to CcO and, surprisingly, link it to a previously unidentified function of CcO subunit Cox12 in Cox2 biogenesis. PMID:26669719

  13. COX-Independent Mechanisms of Cancer Chemoprevention by Anti-Inflammatory Drugs

    PubMed Central

    Gurpinar, Evrim; Grizzle, William E.; Piazza, Gary A.

    2013-01-01

    Epidemiological and clinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase (COX)-2 selective inhibitors, reduce the risk of developing cancer. Experimental studies in human cancer cell lines and rodent models of carcinogenesis support these observations by providing strong evidence for the antineoplastic properties of NSAIDs. The involvement of COX-2 in tumorigenesis and its overexpression in various cancer tissues suggest that inhibition of COX-2 is responsible for the chemopreventive efficacy of these agents. However, the precise mechanisms by which NSAIDs exert their antiproliferative effects are still a matter of debate. Numerous other studies have shown that NSAIDs can act through COX-independent mechanisms. This review provides a detailed description of the major COX-independent molecular targets of NSAIDs and discusses how these targets may be involved in their anticancer effects. Toxicities resulting from COX inhibition and the suppression of prostaglandin synthesis preclude the long-term use of NSAIDs for cancer chemoprevention. Furthermore, chemopreventive efficacy is incomplete and treatment often leads to the development of resistance. Identification of alternative NSAID targets and elucidation of the biochemical processes by which they inhibit tumor growth could lead to the development of safer and more efficacious drugs for cancer chemoprevention. PMID:23875171

  14. Reduced COX-2 Expression in Aged Mice Is Associated With Impaired Fracture Healing

    PubMed Central

    Naik, Amish A; Xie, Chao; Zuscik, Michael J; Kingsley, Paul; Schwarz, Edward M; Awad, Hani; Guldberg, Robert; Drissi, Hicham; Puzas, J Edward; Boyce, Brendan; Zhang, Xinping; O'Keefe, Regis J

    2009-01-01

    The cellular and molecular events responsible for reduced fracture healing with aging are unknown. Cyclooxygenase 2 (COX-2), the inducible regulator of prostaglandin E2 (PGE2) synthesis, is critical for normal bone repair. A femoral fracture repair model was used in mice at either 7–9 or 52–56 wk of age, and healing was evaluated by imaging, histology, and gene expression studies. Aging was associated with a decreased rate of chondrogenesis, decreased bone formation, reduced callus vascularization, delayed remodeling, and altered expression of genes involved in repair and remodeling. COX-2 expression in young mice peaked at 5 days, coinciding with the transition of mesenchymal progenitors to cartilage and the onset of expression of early cartilage markers. In situ hybridization and immunohistochemistry showed that COX-2 is expressed primarily in early cartilage precursors that co-express col-2. COX-2 expression was reduced by 75% and 65% in fractures from aged mice compared with young mice on days 5 and 7, respectively. Local administration of an EP4 agonist to the fracture repair site in aged mice enhanced the rate of chondrogenesis and bone formation to levels observed in young mice, suggesting that the expression of COX-2 during the early inflammatory phase of repair regulates critical subsequent events including chondrogenesis, bone formation, and remodeling. The findings suggest that COX-2/EP4 agonists may compensate for deficient molecular signals that result in the reduced fracture healing associated with aging. PMID:18847332

  15. Lifetime imaging of GFP at CoxVIIIa reports respiratory supercomplex assembly in live cells

    PubMed Central

    Rieger, Bettina; Shalaeva, Daria N.; Söhnel, Anna-Carina; Kohl, Wladislaw; Duwe, Patrick; Mulkidjanian, Armen Y.; Busch, Karin B.

    2017-01-01

    The assembly of respiratory complexes into macromolecular supercomplexes is currently a hot topic, especially in the context of newly available structural details. However, most work to date has been done with purified detergent-solubilized material and in situ confirmation is absent. We here set out to enable the recording of respiratory supercomplex formation in living cells. Fluorescent sensor proteins were placed at specific positions at cytochrome c oxidase suspected to either be at the surface of a CI1CIII2CIV1 supercomplex or buried within this supercomplex. In contrast to other loci, sensors at subunits CoxVIIIa and CoxVIIc reported a dense protein environment, as detected by significantly shortened fluorescence lifetimes. According to 3D modelling CoxVIIIa and CoxVIIc are buried in the CI1CIII2CIV1 supercomplex. Suppression of supercomplex scaffold proteins HIGD2A and CoxVIIa2l was accompanied by an increase in the lifetime of the CoxVIIIa-sensor in line with release of CIV from supercomplexes. Strikingly, our data provide strong evidence for defined stable supercomplex configuration in situ. PMID:28383048

  16. Adjusting particle-size distributions to account for aggregation in tephra-deposit model forecasts

    NASA Astrophysics Data System (ADS)

    Mastin, Larry G.; Van Eaton, Alexa R.; Durant, Adam J.

    2016-07-01

    Volcanic ash transport and dispersion (VATD) models are used to forecast tephra deposition during volcanic eruptions. Model accuracy is limited by the fact that fine-ash aggregates (clumps into clusters), thus altering patterns of deposition. In most models this is accounted for by ad hoc changes to model input, representing fine ash as aggregates with density ρagg, and a log-normal size distribution with median μagg and standard deviation σagg. Optimal values may vary between eruptions. To test the variance, we used the Ash3d tephra model to simulate four deposits: 18 May 1980 Mount St. Helens; 16-17 September 1992 Crater Peak (Mount Spurr); 17 June 1996 Ruapehu; and 23 March 2009 Mount Redoubt. In 192 simulations, we systematically varied μagg and σagg, holding ρagg constant at 600 kg m-3. We evaluated the fit using three indices that compare modeled versus measured (1) mass load at sample locations; (2) mass load versus distance along the dispersal axis; and (3) isomass area. For all deposits, under these inputs, the best-fit value of μagg ranged narrowly between ˜ 2.3 and 2.7φ (0.20-0.15 mm), despite large variations in erupted mass (0.25-50 Tg), plume height (8.5-25 km), mass fraction of fine ( < 0.063 mm) ash (3-59 %), atmospheric temperature, and water content between these eruptions. This close agreement suggests that aggregation may be treated as a discrete process that is insensitive to eruptive style or magnitude. This result offers the potential for a simple, computationally efficient parameterization scheme for use in operational model forecasts. Further research may indicate whether this narrow range also reflects physical constraints on processes in the evolving cloud.

  17. Adjusting for mortality effects in chronic toxicity testing: Mixture model approach

    SciTech Connect

    Wang, S.C.D.; Smith, E.P.

    2000-01-01

    Chronic toxicity tests, such as the Ceriodaphnia dubia 7-d test are typically analyzed using standard statistical methods such as analysis of variance or regression. Recent research has emphasized the use of Poisson regression or more generalized regression for the analysis of the fecundity data from these studies. A possible problem in using standard statistical techniques is that mortality may occur from toxicant effects as well as reduced fecundity. A mixture model that accounts for fecundity and mortality is proposed for the analysis of data arising from these studies. Inferences about key parameters in the model are discussed. A joint estimate of the inhibition concentration is proposed based on the model. Confidence interval estimations via the bootstrap method is discussed. An example is given for a study involving copper and mercury.

  18. Shaft adjuster

    DOEpatents

    Harry, H.H.

    1988-03-11

    Abstract and method for the adjustment and alignment of shafts in high power devices. A plurality of adjacent rotatable angled cylinders are positioned between a base and the shaft to be aligned which when rotated introduce an axial offset. The apparatus is electrically conductive and constructed of a structurally rigid material. The angled cylinders allow the shaft such as the center conductor in a pulse line machine to be offset in any desired alignment position within the range of the apparatus. 3 figs.

  19. Shaft adjuster

    DOEpatents

    Harry, Herbert H.

    1989-01-01

    Apparatus and method for the adjustment and alignment of shafts in high power devices. A plurality of adjacent rotatable angled cylinders are positioned between a base and the shaft to be aligned which when rotated introduce an axial offset. The apparatus is electrically conductive and constructed of a structurally rigid material. The angled cylinders allow the shaft such as the center conductor in a pulse line machine to be offset in any desired alignment position within the range of the apparatus.

  20. Citizens' Perceptions of Flood Hazard Adjustments: An Application of the Protective Action Decision Model

    ERIC Educational Resources Information Center

    Terpstra, Teun; Lindell, Michael K.

    2013-01-01

    Although research indicates that adoption of flood preparations among Europeans is low, only a few studies have attempted to explain citizens' preparedness behavior. This article applies the Protective Action Decision Model (PADM) to explain flood preparedness intentions in the Netherlands. Survey data ("N" = 1,115) showed that…

  1. Preserving Heterogeneity and Consistency in Hydrological Model Inversions by Adjusting Pedotransfer Functions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerical modeling is the dominant method for quantifying water flow and the transport of dissolved constituents in surface soils as well as the deeper vadose zone. While the fundamental laws that govern the mechanics of the flow processes in terms of Richards' and convection-dispersion equations a...

  2. Glacial isostatic adjustment associated with the Barents Sea ice sheet: A modelling inter-comparison

    NASA Astrophysics Data System (ADS)

    Auriac, A.; Whitehouse, P. L.; Bentley, M. J.; Patton, H.; Lloyd, J. M.; Hubbard, A.

    2016-09-01

    The 3D geometrical evolution of the Barents Sea Ice Sheet (BSIS), particularly during its late-glacial retreat phase, remains largely ambiguous due to the paucity of direct marine- and terrestrial-based evidence constraining its horizontal and vertical extent and chronology. One way of validating the numerous BSIS reconstructions previously proposed is to collate and apply them under a wide range of Earth models and to compare prognostic (isostatic) output through time with known relative sea-level (RSL) data. Here we compare six contrasting BSIS load scenarios via a spherical Earth system model and derive a best-fit, χ2 parameter using RSL data from the four main terrestrial regions within the domain: Svalbard, Franz Josef Land, Novaya Zemlya and northern Norway. Poor χ2 values allow two load scenarios to be dismissed, leaving four that agree well with RSL observations. The remaining four scenarios optimally fit the RSL data when combined with Earth models that have an upper mantle viscosity of 0.2-2 × 1021 Pa s, while there is less sensitivity to the lithosphere thickness (ranging from 71 to 120 km) and lower mantle viscosity (spanning 1-50 × 1021 Pa s). GPS observations are also compared with predictions of present-day uplift across the Barents Sea. Key locations where relative sea-level and GPS data would prove critical in constraining future ice-sheet modelling efforts are also identified.

  3. A Unified Model Exploring Parenting Practices as Mediators of Marital Conflict and Children's Adjustment

    ERIC Educational Resources Information Center

    Coln, Kristen L.; Jordan, Sara S.; Mercer, Sterett H.

    2013-01-01

    We examined positive and negative parenting practices and psychological control as mediators of the relations between constructive and destructive marital conflict and children's internalizing and externalizing problems in a unified model. Married mothers of 121 children between the ages of 6 and 12 completed questionnaires measuring marital…

  4. A Gender-Moderated Model of Family Relationships and Adolescent Adjustment

    ERIC Educational Resources Information Center

    Elizur, Yoel; Spivak, Amos; Ofran, Shlomit; Jacobs, Shira

    2007-01-01

    The objective of this study was to explain why adolescent girls with conduct problems (CP) are more at risk than boys to develop emotional distress (ED) in a sample composed of Israeli-born and immigrant youth from Ethiopia and the former Soviet Union (n = 305, ages 14-18). We tested a structural equation model and found a very good fit to the…

  5. Adjusting particle-size distributions to account for aggregation in tephra-deposit model forecasts

    USGS Publications Warehouse

    Mastin, Larry G.; Van Eaton, Alexa; Durant, A.J.

    2016-01-01

    Volcanic ash transport and dispersion (VATD) models are used to forecast tephra deposition during volcanic eruptions. Model accuracy is limited by the fact that fine-ash aggregates (clumps into clusters), thus altering patterns of deposition. In most models this is accounted for by ad hoc changes to model input, representing fine ash as aggregates with density ρagg, and a log-normal size distribution with median μagg and standard deviation σagg. Optimal values may vary between eruptions. To test the variance, we used the Ash3d tephra model to simulate four deposits: 18 May 1980 Mount St. Helens; 16–17 September 1992 Crater Peak (Mount Spurr); 17 June 1996 Ruapehu; and 23 March 2009 Mount Redoubt. In 192 simulations, we systematically varied μagg and σagg, holding ρagg constant at 600 kg m−3. We evaluated the fit using three indices that compare modeled versus measured (1) mass load at sample locations; (2) mass load versus distance along the dispersal axis; and (3) isomass area. For all deposits, under these inputs, the best-fit value of μagg ranged narrowly between  ∼  2.3 and 2.7φ (0.20–0.15 mm), despite large variations in erupted mass (0.25–50 Tg), plume height (8.5–25 km), mass fraction of fine ( <  0.063 mm) ash (3–59 %), atmospheric temperature, and water content between these eruptions. This close agreement suggests that aggregation may be treated as a discrete process that is insensitive to eruptive style or magnitude. This result offers the potential for a simple, computationally efficient parameterization scheme for use in operational model forecasts. Further research may indicate whether this narrow range also reflects physical constraints on processes in the evolving cloud.

  6. Dynamic gauge adjustment of high-resolution X-band radar data for convective rain storms: Model-based evaluation against measured combined sewer overflow

    NASA Astrophysics Data System (ADS)

    Borup, Morten; Grum, Morten; Linde, Jens Jørgen; Mikkelsen, Peter Steen

    2016-08-01

    Numerous studies have shown that radar rainfall estimates need to be adjusted against rain gauge measurements in order to be useful for hydrological modelling. In the current study we investigate if adjustment can improve radar rainfall estimates to the point where they can be used for modelling overflows from urban drainage systems, and we furthermore investigate the importance of the aggregation period of the adjustment scheme. This is done by continuously adjusting X-band radar data based on the previous 5-30 min of rain data recorded by multiple rain gauges and propagating the rainfall estimates through a hydraulic urban drainage model. The model is built entirely from physical data, without any calibration, to avoid bias towards any specific type of rainfall estimate. The performance is assessed by comparing measured and modelled water levels at a weir downstream of a highly impermeable, well defined, 64 ha urban catchment, for nine overflow generating rain events. The dynamically adjusted radar data perform best when the aggregation period is as small as 10-20 min, in which case it performs much better than static adjusted radar data and data from rain gauges situated 2-3 km away.

  7. Cyclooxygenase (COX)-1 and COX-2 both play an important role in the protection of the duodenal mucosa in cats.

    PubMed

    Satoh, Hiroshi; Amagase, Kikuko; Ebara, Satomi; Akiba, Yasutada; Takeuchi, Koji

    2013-01-01

    Although nonsteroidal anti-inflammatory drugs often cause ulcers in the duodenum in humans, the role of cyclooxygenase (COX) isoforms in the pathogenesis of duodenal ulcers has not been fully elucidated. We examined in cats the 1) ulcerogenic effects of selective COX-1 (SC-560, ketorolac) and COX-2 (celecoxib, meloxicam) inhibitors on the gastrointestinal mucosa, 2) effect of feeding and cimetidine on the expression of COX isoforms and prostaglandin E(2) (PGE(2)) level in the duodenum, and 3) localization of COX isoforms in the duodenum. COX inhibitors were administered after the morning meal in cats once daily for 3 days. Gastrointestinal lesions were examined on day 4. Localization and expression of COX isoforms (by immunohistochemistry, Western blot) and PGE(2) level (by enzyme immunoassay) were examined. Results were as follows. First, selective COX-1 or COX-2 inhibitors alone produced marked ulcers in the duodenum but did not cause obvious lesions in the small intestine. Coadministration of SC-560 and celecoxib produced marked lesions in the small intestine. Second, feeding increased both the expression of COX isoforms and PGE(2) level in the duodenum, and the effects were markedly inhibited by pretreatment with cimetidine. Third, COX-1 was localized in goblet and Brunner's gland cells, Meissner's and Auerbach's plexus, smooth muscle cells, and arterioles; and COX-2 was observed in capillaries, venules, and basal granulated cells. The expression of COX isoforms in the duodenum is up-regulated by feeding, and inhibition of either COX-1 or COX-2 causes ulcers in the duodenum, suggesting that both isoforms play an important role in the protection of the duodenal mucosa.

  8. Sensitivity of palaeotidal models of the northwest European shelf seas to glacial isostatic adjustment since the Last Glacial Maximum

    NASA Astrophysics Data System (ADS)

    Ward, Sophie L.; Neill, Simon P.; Scourse, James D.; Bradley, Sarah L.; Uehara, Katsuto

    2016-11-01

    The spatial and temporal distribution of relative sea-level change over the northwest European shelf seas has varied considerably since the Last Glacial Maximum, due to eustatic sea-level rise and a complex isostatic response to deglaciation of both near- and far-field ice sheets. Because of the complex pattern of relative sea level changes, the region is an ideal focus for modelling the impact of significant sea-level change on shelf sea tidal dynamics. Changes in tidal dynamics influence tidal range, the location of tidal mixing fronts, dissipation of tidal energy, shelf sea biogeochemistry and sediment transport pathways. Significant advancements in glacial isostatic adjustment (GIA) modelling of the region have been made in recent years, and earlier palaeotidal models of the northwest European shelf seas were developed using output from less well-constrained GIA models as input to generate palaeobathymetric grids. We use the most up-to-date and well-constrained GIA model for the region as palaeotopographic input for a new high resolution, three-dimensional tidal model (ROMS) of the northwest European shelf seas. With focus on model output for 1 ka time slices from the Last Glacial Maximum (taken as being 21 ka BP) to present day, we demonstrate that spatial and temporal changes in simulated tidal dynamics are very sensitive to relative sea-level distribution. The new high resolution palaeotidal model is considered a significant improvement on previous depth-averaged palaeotidal models, in particular where the outputs are to be used in sediment transport studies, where consideration of the near-bed stress is critical, and for constraining sea level index points.

  9. DNA compaction by the bacteriophage protein Cox studied on the single DNA molecule level using nanofluidic channels.

    PubMed

    Frykholm, Karolin; Berntsson, Ronnie Per-Arne; Claesson, Magnus; de Battice, Laura; Odegrip, Richard; Stenmark, Pål; Westerlund, Fredrik

    2016-09-06

    The Cox protein from bacteriophage P2 forms oligomeric filaments and it has been proposed that DNA can be wound up around these filaments, similar to how histones condense DNA. We here use fluorescence microscopy to study single DNA-Cox complexes in nanofluidic channels and compare how the Cox homologs from phages P2 and WΦ affect DNA. By measuring the extension of nanoconfined DNA in absence and presence of Cox we show that the protein compacts DNA and that the binding is highly cooperative, in agreement with the model of a Cox filament around which DNA is wrapped. Furthermore, comparing microscopy images for the wild-type P2 Cox protein and two mutants allows us to discriminate between compaction due to filament formation and compaction by monomeric Cox. P2 and WΦ Cox have similar effects on the physical properties of DNA and the subtle, but significant, differences in DNA binding are due to differences in binding affinity rather than binding mode. The presented work highlights the use of single DNA molecule studies to confirm structural predictions from X-ray crystallography. It also shows how a small protein by oligomerization can have great impact on the organization of DNA and thereby fulfill multiple regulatory functions.

  10. High expression levels of COX-2 and P300 are associated with unfavorable survival in laryngeal squamous cell carcinoma.

    PubMed

    Chen, Yan-Feng; Luo, Rong-Zhen; Li, Yong; Cui, Bo-Kang; Song, Ming; Yang, An-Kui; Chen, Wen-Kuan

    2013-03-01

    In order to provide a basis for clinical treatment decisions, we explored whether there was a correlation between the expression of COX-2 and P300 and clinical factors in a group of patients with laryngeal squamous cell carcinoma (LSCC). A retrospective analysis of clinicopathological data was conducted in 80 patients with LSCC who presented between January 1997 and December 1998. An immunohistochemistry tissue microarray was conducted of 80 surgically resected LSCC and 20 adjacent normal tissue specimens. Survival analysis and Kaplan-Meier curves were used to compare the effects of clinicopathological factors on survival. The Cox model was applied for multivariate analysis. The expression level of COX-2/P300 in LSCC tissues and adjacent normal tissues were 47.5/50.0 versus 0.0/15.0 %. The expression of COX-2 and P300 was correlated with higher T category, N category, clinical staging, histological grade and recurrence (P < 0.05). P300 expression was correlated with COX-2 expression (P < 0.05). Univariate survival analysis showed that P300, COX-2, N category, clinical staging and recurrence factors were closely correlated with unfavorable survival (P < 0.05). Multivariate analysis showed that COX-2 expression, histological grade and recurrence were independent prognostic factors for LSCC. High expression levels of COX-2 and P300 indicated poor survival outcomes for patients with LSCC.

  11. DNA compaction by the bacteriophage protein Cox studied on the single DNA molecule level using nanofluidic channels

    PubMed Central

    Frykholm, Karolin; Berntsson, Ronnie Per-Arne; Claesson, Magnus; de Battice, Laura; Odegrip, Richard; Stenmark, Pål; Westerlund, Fredrik

    2016-01-01

    The Cox protein from bacteriophage P2 forms oligomeric filaments and it has been proposed that DNA can be wound up around these filaments, similar to how histones condense DNA. We here use fluorescence microscopy to study single DNA–Cox complexes in nanofluidic channels and compare how the Cox homologs from phages P2 and WΦ affect DNA. By measuring the extension of nanoconfined DNA in absence and presence of Cox we show that the protein compacts DNA and that the binding is highly cooperative, in agreement with the model of a Cox filament around which DNA is wrapped. Furthermore, comparing microscopy images for the wild-type P2 Cox protein and two mutants allows us to discriminate between compaction due to filament formation and compaction by monomeric Cox. P2 and WΦ Cox have similar effects on the physical properties of DNA and the subtle, but significant, differences in DNA binding are due to differences in binding affinity rather than binding mode. The presented work highlights the use of single DNA molecule studies to confirm structural predictions from X-ray crystallography. It also shows how a small protein by oligomerization can have great impact on the organization of DNA and thereby fulfill multiple regulatory functions. PMID:27131370

  12. The Role of Coa2 in Hemylation of Yeast Cox1 Revealed by Its Genetic Interaction with Cox10 ▿

    PubMed Central

    Bestwick, Megan; Khalimonchuk, Oleh; Pierrel, Fabien; Winge, Dennis R.

    2010-01-01

    Saccharomyces cerevisiae cells lacking the cytochrome c oxidase (CcO) assembly factor Coa2 are impaired in Cox1 maturation and exhibit a rapid degradation of newly synthesized Cox1. The respiratory deficiency of coa2Δ cells is suppressed either by the presence of a mutant allele of the Cox10 farnesyl transferase involved in heme a biosynthesis or through impaired proteolysis by the disruption of the mitochondrial Oma1 protease. Cox10 with an N196K substitution functions as a robust gain-of-function suppressor of the respiratory deficiency of coa2Δ cells but lacks suppressor activity for two other CcO assembly mutant strains, the coa1Δ and shy1Δ mutants. The suppressor activity of N196K mutant Cox10 is dependent on its catalytic function and the presence of Cox15, the second enzyme involved in heme a biosynthesis. Varying the substitution at Asn196 reveals a correlation between the suppressor activity and the stabilization of the high-mass homo-oligomeric Cox10 complex. We postulate that the mutant Cox10 complex has enhanced efficiency in the addition of heme a to Cox1. Coa2 appears to impart stability to the oligomeric wild-type Cox10 complex involved in Cox1 hemylation. PMID:19841065

  13. Reconciling observed and modeled temperature and precipitation trends over Europe by adjusting for circulation variability

    NASA Astrophysics Data System (ADS)

    Saffioti, Claudio; Fischer, Erich M.; Scherrer, Simon C.; Knutti, Reto

    2016-08-01

    Europe experienced a pronounced winter cooling of about -0.37°C/decade in the period 1989-2012, in contrast to the strong warming simulated by the Coupled Model Intercomparison Project Phase 5 multimodel average during the same period. Even more pronounced discrepancies between observed and simulated short-term trends are found at the local scale, e.g., a strong winter cooling over Switzerland and a pronounced reduction in precipitation along the coast of Norway. We show that monthly sea level pressure variability accounts for much of the short-term variations of temperature over most of the domain and of precipitation in certain regions. Removing the effect of atmospheric circulation through a regression approach reconciles the observed temperature trends over Europe and Switzerland and the precipitation trend along the coast of Norway with the corresponding multimodel mean trends.

  14. SU-E-T-247: Multi-Leaf Collimator Model Adjustments Improve Small Field Dosimetry in VMAT Plans

    SciTech Connect

    Young, L; Yang, F

    2014-06-01

    Purpose: The Elekta beam modulator linac employs a 4-mm micro multileaf collimator (MLC) backed by a fixed jaw. Out-of-field dose discrepancies between treatment planning system (TPS) calculations and output water phantom measurements are caused by the 1-mm leaf gap required for all moving MLCs in a VMAT arc. In this study, MLC parameters are optimized to improve TPS out-of-field dose approximations. Methods: Static 2.4 cm square fields were created with a 1-mm leaf gap for MLCs that would normally park behind the jaw. Doses in the open field and leaf gap were measured with an A16 micro ion chamber and EDR2 film for comparison with corresponding point doses in the Pinnacle TPS. The MLC offset table and tip radius were adjusted until TPS point doses agreed with photon measurements. Improvements to the beam models were tested using static arcs consisting of square fields ranging from 1.6 to 14.0 cm, with 45° collimator rotation, and 1-mm leaf gap to replicate VMAT conditions. Gamma values for the 3-mm distance, 3% dose difference criteria were evaluated using standard QA procedures with a cylindrical detector array. Results: The best agreement in point doses within the leaf gap and open field was achieved by offsetting the default rounded leaf end table by 0.1 cm and adjusting the leaf tip radius to 13 cm. Improvements in TPS models for 6 and 10 MV photon beams were more significant for smaller field sizes 3.6 cm or less where the initial gamma factors progressively increased as field size decreased, i.e. for a 1.6cm field size, the Gamma increased from 56.1% to 98.8%. Conclusion: The MLC optimization techniques developed will achieve greater dosimetric accuracy in small field VMAT treatment plans for fixed jaw linear accelerators. Accurate predictions of dose to organs at risk may reduce adverse effects of radiotherapy.

  15. Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor

    PubMed Central

    Riendeau, D; Percival, M D; Boyce, S; Brideau, C; Charleson, S; Cromlish, W; Ethier, D; Evans, J; Falgueyret, J -P; Ford-Hutchinson, A W; Gordon, R; Greig, G; Gresser, M; Guay, J; Kargman, S; Léger, S; Mancini, J A; O'Neill, G; Ouellet, M; Rodger, I W; Thérien, M; Wang, Z; Webb, J K; Wong, E; Xu, L; Young, R N; Zamboni, R; Prasit, P; Chan, C -C

    1997-01-01

    to indomethacin (IC50=0.68±0.17 μM). In contrast, DFU was at least 500 times less potent (IC50>97 μM) than indomethacin at inhibiting coagulation-induced TXB2 production (COX-1) (IC50=0.19±0.02 μM).In a sensitive assay with U937 cell microsomes at a low arachidonic acid concentration (0.1 μM), DFU inhibited COX-1 with an IC50 value of 13±2 μM as compared to 20±1 nM for indomethacin. CGP 28238, etodolac and SC-58125 were about 10 times more potent inhibitors of COX-1 than DFU. The order of potency of various inhibitors was diclofenac>indomethacin∼naproxen>nimesulide∼ meloxicam∼piroxicam>NS-398∼SC-57666>SC-58125>CGP 28238∼etodolac>L-745,337>DFU.DFU inhibited dose-dependently both the carrageenan-induced rat paw oedema (ED50 of 1.1 mg kg−1 vs 2.0 mg kg−1 for indomethacin) and hyperalgesia (ED50 of 0.95 mg kg−1 vs 1.5 mg kg−1 for indomethacin). The compound was also effective at reversing LPS-induced pyrexia in rats (ED50=0.76 mg kg−1 vs 1.1 mg kg−1 for indomethacin).In a sensitive model in which 51Cr faecal excretion was used to assess the integrity of the gastrointestinal tract in rats, no significant effect was detected after oral administration of DFU (100 mg kg−1, b.i.d.) for 5 days, whereas chromium leakage was observed with lower doses of diclofenac (3 mg kg−1), meloxicam (3 mg kg−1) or etodolac (10–30 mg kg−1). A 5 day administration of DFU in squirrel monkeys (100 mg kg−1) did not affect chromium leakage in contrast to diclofenac (1 mg kg−1) or naproxen (5 mg kg−1).The results indicate that COX-1 inhibitory effects can be detected for all selective COX-2 inhibitors tested by use of a sensitive assay at low substrate concentration. The novel inhibitor DFU shows the lowest inhibitory potency against COX-1, a consistent high selectivity of inhibition of COX-2 over COX-1 (>300 fold) with enzyme, whole cell and whole blood assays, with no detectable loss

  16. Modeling neuroendocrine stress reactivity in salivary cortisol: adjusting for peak latency variability.

    PubMed

    Lopez-Duran, Nestor L; Mayer, Stefanie E; Abelson, James L

    2014-07-01

    In this report, we present growth curve modeling (GCM) with landmark registration as an alternative statistical approach for the analysis of time series cortisol data. This approach addresses an often-ignored but critical source of variability in salivary cortisol analyses: individual and group differences in the time latency of post-stress peak concentrations. It allows for the simultaneous examination of cortisol changes before and after the peak while controlling for timing differences, and thus provides additional information that can help elucidate group differences in the underlying biological processes (e.g., intensity of response, regulatory capacity). We tested whether GCM with landmark registration is more sensitive than traditional statistical approaches (e.g., repeated measures ANOVA--rANOVA) in identifying sex differences in salivary cortisol responses to a psychosocial stressor (Trier Social Stress Test--TSST) in healthy adults (mean age 23). We used plasma ACTH measures as our "standard" and show that the new approach confirms in salivary cortisol the ACTH finding that males had longer peak latencies, higher post-stress peaks but a more intense post-peak decline. This finding would have been missed if only saliva cortisol was available and only more traditional analytic methods were used. This new approach may provide neuroendocrine researchers with a highly sensitive complementary tool to examine the dynamics of the cortisol response in a way that reduces risk of false negative findings when blood samples are not feasible.

  17. Adjustable Stiffness, External Fixator for the Rat Femur Osteotomy and Segmental Bone Defect Models

    PubMed Central

    Glatt, Vaida; Matthys, Romano

    2014-01-01

    The mechanical environment around the healing of broken bone is very important as it determines the way the fracture will heal. Over the past decade there has been great clinical interest in improving bone healing by altering the mechanical environment through the fixation stability around the lesion. One constraint of preclinical animal research in this area is the lack of experimental control over the local mechanical environment within a large segmental defect as well as osteotomies as they heal. In this paper we report on the design and use of an external fixator to study the healing of large segmental bone defects or osteotomies. This device not only allows for controlled axial stiffness on the bone lesion as it heals, but it also enables the change of stiffness during the healing process in vivo. The conducted experiments have shown that the fixators were able to maintain a 5 mm femoral defect gap in rats in vivo during unrestricted cage activity for at least 8 weeks. Likewise, we observed no distortion or infections, including pin infections during the entire healing period. These results demonstrate that our newly developed external fixator was able to achieve reproducible and standardized stabilization, and the alteration of the mechanical environment of in vivo rat large bone defects and various size osteotomies. This confirms that the external fixation device is well suited for preclinical research investigations using a rat model in the field of bone regeneration and repair. PMID:25350129

  18. Inhibition of cyclooxygenase (COX)-2 affects endothelial progenitor cell proliferation

    SciTech Connect

    Colleselli, Daniela; Bijuklic, Klaudija; Mosheimer, Birgit A.; Kaehler, Christian M. . E-mail: C.M.Kaehler@uibk.ac.at

    2006-09-10

    Growing evidence indicates that inducible cyclooxygenase-2 (COX-2) is involved in the pathogenesis of inflammatory disorders and various types of cancer. Endothelial progenitor cells recruited from the bone marrow have been shown to be involved in the formation of new vessels in malignancies and discussed for being a key point in tumour progression and metastasis. However, until now, nothing is known about an interaction between COX and endothelial progenitor cells (EPC). Expression of COX-1 and COX-2 was detected by semiquantitative RT-PCR and Western blot. Proliferation kinetics, cell cycle distribution and rate of apoptosis were analysed by MTT test and FACS analysis. Further analyses revealed an implication of Akt phosphorylation and caspase-3 activation. Both COX-1 and COX-2 expression can be found in bone-marrow-derived endothelial progenitor cells in vitro. COX-2 inhibition leads to a significant reduction in proliferation of endothelial progenitor cells by an increase in apoptosis and cell cycle arrest. COX-2 inhibition leads further to an increased cleavage of caspase-3 protein and inversely to inhibition of Akt activation. Highly proliferating endothelial progenitor cells can be targeted by selective COX-2 inhibition in vitro. These results indicate that upcoming therapy strategies in cancer patients targeting COX-2 may be effective in inhibiting tumour vasculogenesis as well as angiogenic processes.

  19. Modeling grain size adjustments in the downstream reach following run-of-river development

    NASA Astrophysics Data System (ADS)

    Fuller, Theodore K.; Venditti, Jeremy G.; Nelson, Peter A.; Palen, Wendy J.

    2016-04-01

    Disruptions to sediment supply continuity caused by run-of-river (RoR) hydropower development have the potential to cause downstream changes in surface sediment grain size which can influence the productivity of salmon habitat. The most common approach to understanding the impacts of RoR hydropower is to study channel changes in the years following project development, but by then, any impacts are manifest and difficult to reverse. Here we use a more proactive approach, focused on predicting impacts in the project planning stage. We use a one-dimensional morphodynamic model to test the hypothesis that the greatest risk of geomorphic change and impact to salmon habitat from a temporary sediment supply disruption exists where predevelopment sediment supply is high and project design creates substantial sediment storage volume. We focus on the potential impacts in the reach downstream of a powerhouse for a range of development scenarios that are typical of projects developed in the Pacific Northwest and British Columbia. Results indicate that increases in the median bed surface size (D50) are minor if development occurs on low sediment supply streams (<1 mm for supply rates 1 × 10-5 m2 s-1 or lower), and substantial for development on high sediment supply streams (8-30 mm for supply rates between 5.5 × 10-4 and 1 × 10-3 m2 s-1). However, high sediment supply streams recover rapidly to the predevelopment surface D50 (˜1 year) if sediment supply can be reestablished.

  20. Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function.

    PubMed

    Katsube, Takayuki; Wajima, Toshihiro; Ishibashi, Toru; Arjona Ferreira, Juan Camilo; Echols, Roger

    2017-01-01

    Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. Since cefiderocol is excreted primarily via the kidneys, this study was conducted to develop a population pharmacokinetics (PK) model to determine dose adjustment based on renal function. Population PK models were developed based on data for cefiderocol concentrations in plasma, urine, and dialysate with a nonlinear mixed-effects model approach. Monte-Carlo simulations were conducted to calculate the probability of target attainment (PTA) of fraction of time during the dosing interval where the free drug concentration in plasma exceeds the MIC (Tf>MIC) for an MIC range of 0.25 to 16 μg/ml. For the simulations, dose regimens were selected to compare cefiderocol exposure among groups with different levels of renal function. The developed models well described the PK of cefiderocol for each renal function group. A dose of 2 g every 8 h with 3-h infusions provided >90% PTA for 75% Tf>MIC for an MIC of ≤4 μg/ml for patients with normal renal function, while a more frequent dose (every 6 h) could be used for patients with augmented renal function. A reduced dose and/or extended dosing interval was selected for patients with impaired renal function. A supplemental dose immediately after intermittent hemodialysis was proposed for patients requiring intermittent hemodialysis. The PK of cefiderocol could be adequately modeled, and the modeling-and-simulation approach suggested dose regimens based on renal function, ensuring drug exposure with adequate bactericidal effect.

  1. The performance of automated case-mix adjustment regression model building methods in a health outcome prediction setting.

    PubMed

    Jen, Min-Hua; Bottle, Alex; Kirkwood, Graham; Johnston, Ron; Aylin, Paul

    2011-09-01

    We have previously described a system for monitoring a number of healthcare outcomes using case-mix adjustment models. It is desirable to automate the model fitting process in such a system if monitoring covers a large number of outcome measures or subgroup analyses. Our aim was to compare the performance of three different variable selection strategies: "manual", "automated" backward elimination and re-categorisation, and including all variables at once, irrespective of their apparent importance, with automated re-categorisation. Logistic regression models for predicting in-hospital mortality and emergency readmission within 28 days were fitted to an administrative database for 78 diagnosis groups and 126 procedures from 1996 to 2006 for National Health Services hospital trusts in England. The performance of models was assessed with Receiver Operating Characteristic (ROC) c statistics, (measuring discrimination) and Brier score (assessing the average of the predictive accuracy). Overall, discrimination was similar for diagnoses and procedures and consistently better for mortality than for emergency readmission. Brier scores were generally low overall (showing higher accuracy) and were lower for procedures than diagnoses, with a few exceptions for emergency readmission within 28 days. Among the three variable selection strategies, the automated procedure had similar performance to the manual method in almost all cases except low-risk groups with few outcome events. For the rapid generation of multiple case-mix models we suggest applying automated modelling to reduce the time required, in particular when examining different outcomes of large numbers of procedures and diseases in routinely collected administrative health data.

  2. Data assimilation and driver estimation for the Global Ionosphere-Thermosphere Model using the Ensemble Adjustment Kalman Filter

    NASA Astrophysics Data System (ADS)

    Morozov, Alexey V.; Ridley, Aaron J.; Bernstein, Dennis S.; Collins, Nancy; Hoar, Timothy J.; Anderson, Jeffrey L.

    2013-11-01

    This paper proposes a differential inflation scheme and applies this technique to driver estimation for the Global Ionosphere-Thermosphere Model (GITM) using the Ensemble Adjustment Kalman Filter (EAKF), which is a part of the Data Assimilation Research Testbed (DART). Driver estimation using EAKF is first demonstrated on a linear example and then applied to GITM. The Challenging Minisatellite Payload (CHAMP) neutral mass density measurements are assimilated into a biased version of GITM, and the solar flux index, F10.7, is estimated. Although the estimate of F10.7 obtained using DART does not converge to the measured values, the converged values are shown to drive the GITM output close to CHAMP measurements. In order to prevent the ensemble spread from converging to zero, the state and driver estimates are inflated. In particular, the F10.7 estimate is inflated to have a constant variance. It is shown that EAKF with differential inflation reduces the model bias from 73% down to 7% along the CHAMP satellite path when compared to the biased GITM output obtained without using data assimilation. The Gravity Recovery and Climate Experiment (GRACE) density measurements are used to validate the data assimilation performance at locations different from measurement locations. It is shown that the bias at GRACE locations is decreased from 76% down to 52% as compared to not using data assimilation, showing that model estimation of the thermosphere is improved globally.

  3. Brain-targeted ACE2 overexpression attenuates neurogenic hypertension by inhibiting COX mediated inflammation

    PubMed Central

    Sriramula, Srinivas; Xia, Huijing; Xu, Ping; Lazartigues, Eric

    2014-01-01

    Overactivity of the renin angiotensin system (RAS), oxidative stress, and cyclooxygenases (COX) in the brain are implicated in the pathogenesis of hypertension. We previously reported that Angiotensin-Converting Enzyme 2 (ACE2) overexpression in the brain attenuates the development of DOCA-salt hypertension, a neurogenic hypertension model with enhanced brain RAS and sympathetic activity. To elucidate the mechanisms involved, we investigated whether oxidative stress, mitogen activated protein kinase signaling and cyclooxygenase (COX) activation in the brain are modulated by ACE2 in neurogenic hypertension. DOCA-salt hypertension significantly increased expression of Nox-2 (+61 ±5 %), Nox-4 (+50 ±13 %) and nitrotyrosine (+89 ±32 %) and reduced activity of the antioxidant enzymes, catalase (−29 ±4 %) and SOD (−31 ±7 %), indicating increased oxidative stress in the brain of non-transgenic mice. This increased oxidative stress was attenuated in transgenic mice overexpressing ACE2 in the brain. DOCA-salt-induced reduction of nNOS expression (−26 ±7 %) and phosphorylated eNOS/total eNOS (−30 ±3 %), and enhanced phosphorylation of Akt and ERK1/2 in the paraventricular nucleus (PVN), were reversed by ACE2 overexpression. In addition, ACE2 overexpression blunted the hypertension-mediated increase in gene and protein expression of COX-1 and COX-2 in the PVN. Furthermore, gene silencing of either COX-1 or COX-2 in the brain, reduced microglial activation and accompanied neuro-inflammation, ultimately attenuating DOCA-salt hypertension. Together, these data provide evidence that brain ACE2 overexpression reduces oxidative stress and COX-mediated neuro-inflammation, improves anti-oxidant and nitric oxide signaling, and thereby attenuates the development of neurogenic hypertension. PMID:25489058

  4. Convergent synthesis and evaluation of (18)F-labeled azulenic COX2 probes for cancer imaging.

    PubMed

    Nolting, Donald D; Nickels, Michael; Tantawy, Mohammed N; Yu, James Y H; Xie, Jingping; Peterson, Todd E; Crews, Brenda C; Marnett, Larry; Gore, John C; Pham, Wellington

    2012-01-01

    The overall objectives of this research are to (i) develop azulene-based positron emission tomography (PET) probes and (ii) image COX2 as a potential biomarker of breast cancer. Several lines of research have demonstrated that COX2 is overexpressed in breast cancer and that its presence correlates with poor prognoses. While other studies have reported that COX2 inhibition can be modulated and used beneficially as a chemopreventive strategy in cancer, no viable mechanism for achieving that approach has yet been developed. This shortfall could be circumvented through in vivo imaging of COX2 activity, particularly using sensitive imaging techniques such as PET. Toward that goal, our laboratory focuses on the development of novel (18)F-labled COX2 probes. We began the synthesis of the probes by transforming tropolone into a lactone, which was subjected to an [8 + 2] cycloaddition reaction to yield 2-methylazulene as the core ring of the probe. After exploring numerous synthetic routes, the final target molecule and precursor PET compounds were prepared successfully using convergent synthesis. Conventional (18)F labeling methods caused precursor decomposition, which prompted us to hypothesize that the acidic protons of the methylene moiety between the azulene and thiazole rings were readily abstracted by a strong base such as potassium carbonate. Ultimately, this caused the precursors to disintegrate. This observation was supported after successfully using an (18)F labeling strategy that employed a much milder phosphate buffer. The (18)F-labeled COX2 probe was tested in a breast cancer xenograft mouse model. The data obtained via successive whole-body PET/CT scans indicated probe accumulation and retention in the tumor. Overall, the probe was stable in vivo and no defluorination was observed. A biodistribution study and Western blot analysis corroborate with the imaging data. In conclusion, this novel COX2 PET probe was shown to be a promising agent for cancer imaging

  5. Convergent synthesis and evaluation of 18F-labeled azulenic COX2 probes for cancer imaging

    PubMed Central

    Nolting, Donald D.; Nickels, Michael; Tantawy, Mohammed N.; Yu, James Y. H.; Xie, Jingping; Peterson, Todd E.; Crews, Brenda C.; Marnett, Larry; Gore, John C.; Pham, Wellington

    2013-01-01

    The overall objectives of this research are to (i) develop azulene-based positron emission tomography (PET) probes and (ii) image COX2 as a potential biomarker of breast cancer. Several lines of research have demonstrated that COX2 is overexpressed in breast cancer and that its presence correlates with poor prognoses. While other studies have reported that COX2 inhibition can be modulated and used beneficially as a chemopreventive strategy in cancer, no viable mechanism for achieving that approach has yet been developed. This shortfall could be circumvented through in vivo imaging of COX2 activity, particularly using sensitive imaging techniques such as PET. Toward that goal, our laboratory focuses on the development of novel 18F-labled COX2 probes. We began the synthesis of the probes by transforming tropolone into a lactone, which was subjected to an [8 + 2] cycloaddition reaction to yield 2-methylazulene as the core ring of the probe. After exploring numerous synthetic routes, the final target molecule and precursor PET compounds were prepared successfully using convergent synthesis. Conventional 18F labeling methods caused precursor decomposition, which prompted us to hypothesize that the acidic protons of the methylene moiety between the azulene and thiazole rings were readily abstracted by a strong base such as potassium carbonate. Ultimately, this caused the precursors to disintegrate. This observation was supported after successfully using an 18F labeling strategy that employed a much milder phosphate buffer. The 18F-labeled COX2 probe was tested in a breast cancer xenograft mouse model. The data obtained via successive whole-body PET/CT scans indicated probe accumulation and retention in the tumor. Overall, the probe was stable in vivo and no defluorination was observed. A biodistribution study and Western blot analysis corroborate with the imaging data. In conclusion, this novel COX2 PET probe was shown to be a promising agent for cancer imaging and

  6. Advances in Antarctic Mantle and Crustal Physics and Implications for Ice Sheet Models and Isostatic Adjustment Measurements

    NASA Astrophysics Data System (ADS)

    Ivins, Erik; Adhikari, Surendra; Seroussi, Helene; Larour, Eric; Wiens, Douglas; Scheinert, Mirko; Csatho, Beata; James, Thomas; Nyblade, Andrew

    2015-04-01

    The problem of improving both solid Earth structure models and assembling an appropriate tectonic framework for Antarctica is challenging for many reasons. The vast ice sheet cover is just one item in a long list of difficult observational challenges faced by solid Earth scientists. The ice sheet has a unique potential for causing relatively rapid global sea-level rise over the next couple of hundred years. This potential provides great impetus for employing extraordinary efforts to improve our knowledge of the thermo-mechanical properties and of the mass and energy transport systems operating in the underlying solid Earth. In this presentation we discuss the role of seismic mapping of the mantle and crust, heat flux inferences, models and measurements as they affect the state of the ice sheet and the predictions of present-day and future solid Earth glacial isostatic adjustment, global and regional sea-level variability. To illustrate the sensitivity to solid Earth parameters for deriving a model temperature at the base of the ice sheet, Tb, we have computed the differences between two models to produce maps of δTb, the differential temperature to the melting point at the base of the ice sheet using the ISSM 3-D Stokes flow model. A 'cold' case (with surface crustal heat flux qGHF = 40 mW/m^2) is compared to a 'hot' geothermal flux case (qGHF = 60 mW/m^2). Differences of δ Tb = 6 - 10 °C are predicted between the two heat flux assumptions, and these have associated differences in predicted ice velocities of a factor of 1.8-3.6. We also explore the hypothesis of a mantle plume, and its potential compatibility or incompatibility with basal ice sheet conditions in West Antarctica.

  7. A Simple Experimentally Based Model Using Proprioceptive Regulation of Motor Primitives Captures Adjusted Trajectory Formation in Spinal Frogs

    PubMed Central

    Kargo, William J.; Ramakrishnan, Arun; Hart, Corey B.; Rome, Lawrence C.

    2010-01-01

    Spinal circuits may organize trajectories using pattern generators and synergies. In frogs, prior work supports fixed-duration pulses of fixed composition synergies, forming primitives. In wiping behaviors, spinal frogs adjust their motor activity according to the starting limb position and generate fairly straight and accurate isochronous trajectories across the workspace. To test whether a compact description using primitives modulated by proprioceptive feedback could reproduce such trajectory formation, we built a biomechanical model based on physiological data. We recorded from hindlimb muscle spindles to evaluate possible proprioceptive input. As movement was initiated, early skeletofusimotor activity enhanced many muscle spindles firing rates. Before movement began, a rapid estimate of the limb position from simple combinations of spindle rates was possible. Three primitives were used in the model with muscle compositions based on those observed in frogs. Our simulations showed that simple gain and phase shifts of primitives based on published feedback mechanisms could generate accurate isochronous trajectories and motor patterns that matched those observed. Although on-line feedback effects were omitted from the model after movement onset, our primitive-based model reproduced the wiping behavior across a range of starting positions. Without modifications from proprioceptive feedback, the model behaviors missed the target in a manner similar to that in deafferented frogs. These data show how early proprioception might be used to make a simple estimate initial limb state and to implicitly plan a movement using observed spinal motor primitives. Simulations showed that choice of synergy composition played a role in this simplicity. To generate froglike trajectories, a hip flexor synergy without sartorius required motor patterns with more proprioceptive knee flexor control than did patterns built with a more natural synergy including sartorius. Such synergy

  8. [COX-2 regulation of prostaglandins in synaptic signaling].

    PubMed

    Yang, Hong-Wei

    2009-10-01

    Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme converting arachidonic acid to prostaglandins (PGs), which is a key messenger in traumatic brain injury- and ischemia-induced neuronal damage and in neuroinflammation. COX-2 is implicated in the pathogeneses of neurodegenerative diseases. Growing evidence implies that the contribution of COX-2 to neuropathology is associated with its involvement in synaptic alteration. Elevation or inhibition of COX-2 has been shown to enhance or suppress excitatory glutamatergic neurotransmission and long-term potentiation (LTP). These events are mainly mediated via PGE2, the predominant reaction product of COX-2, and the PGE2 subtype 2 receptor (EP2). Thus, elucidation of COX-2 in synaptic signaling may provide a mechanistic basis for designing new drugs aimed at preventing, treating or alleviating neuroinflammation-associated neurological disorders.

  9. COX, LOX and platelet aggregation inhibitory properties of Lauraceae neolignans.

    PubMed

    Coy, Ericsson David; Cuca, Luis Enrique; Sefkow, Michael

    2009-12-15

    The anti-inflammatory potential of 26 neolignans (14 of the bicyclooctane-type and 12 of the benzofuran-type), isolated from three Lauraceae species (Pleurothyrium cinereum, Ocotea macrophylla and Nectandra amazonum), was evaluated in vitro through inhibition of COX-1, COX-2, 5-LOX and agonist-induced aggregation of rabbit platelets. Benzofuran neolignans were found to be selective COX-2 inhibitors, whereas bicyclooctane neolignans inhibit selectively the PAF-action as well as COX-1 and 5-LOX. The neolignan 9-nor-7,8-dehydro-isolicarin B 15 and cinerin C 7 were found to be the most potent COX-2 inhibitor and PAF-antagonist, respectively. Nectamazin C 10 exhibited dual 5-LOX/COX-2 inhibition.

  10. External Validation of a Case-Mix Adjustment Model for the Standardized Reporting of 30-Day Stroke Mortality Rates in China

    PubMed Central

    Yu, Ping; Pan, Yuesong; Wang, Yongjun; Wang, Xianwei; Liu, Liping; Ji, Ruijun; Meng, Xia; Jing, Jing; Tong, Xu; Guo, Li; Wang, Yilong

    2016-01-01

    Background and Purpose A case-mix adjustment model has been developed and externally validated, demonstrating promise. However, the model has not been thoroughly tested among populations in China. In our study, we evaluated the performance of the model in Chinese patients with acute stroke. Methods The case-mix adjustment model A includes items on age, presence of atrial fibrillation on admission, National Institutes of Health Stroke Severity Scale (NIHSS) score on admission, and stroke type. Model B is similar to Model A but includes only the consciousness component of the NIHSS score. Both model A and B were evaluated to predict 30-day mortality rates in 13,948 patients with acute stroke from the China National Stroke Registry. The discrimination of the models was quantified by c-statistic. Calibration was assessed using Pearson’s correlation coefficient. Results The c-statistic of model A in our external validation cohort was 0.80 (95% confidence interval, 0.79–0.82), and the c-statistic of model B was 0.82 (95% confidence interval, 0.81–0.84). Excellent calibration was reported in the two models with Pearson’s correlation coefficient (0.892 for model A, p<0.001; 0.927 for model B, p = 0.008). Conclusions The case-mix adjustment model could be used to effectively predict 30-day mortality rates in Chinese patients with acute stroke. PMID:27846282

  11. Applying the Transactional Stress and Coping Model to Sickle Cell Disorder and Insulin-Dependent Diabetes Mellitus: Identifying Psychosocial Variables Related to Adjustment and Intervention

    ERIC Educational Resources Information Center

    Hocking, Matthew C.; Lochman, John E.

    2005-01-01

    This review paper examines the literature on psychosocial factors associated with adjustment to sickle cell disease and insulin-dependent diabetes mellitus in children through the framework of the transactional stress and coping (TSC) model. The transactional stress and coping model views adaptation to a childhood chronic illness as mediated by…

  12. Vertical motions in Northern Victoria Land inferred from GPS: A comparison with a glacial isostatic adjustment model

    USGS Publications Warehouse

    Mancini, F.; Negusini, M.; Zanutta, A.; Capra, A.

    2007-01-01

    Following the densification of GPS permanent and episodic trackers in Antarctica, geodetic observations are playing an increasing role in geodynamics research and the study of the glacial isostatic adjustment (GIA). The improvement in geodetic measurements accuracy suggests their use in constraining GIA models. It is essential to have a deeper knowledge on the sensitivity of GPS data to motionsrelated to long-term ice mass changes and the present-day mass imbalance of the ice sheets. In order to investigate the geodynamic phenomena in Northern Victoria Land (NVL), GPS geodetic observations were made during the last decade within the VLNDEF (Victoria Land Network for Deformation control) project. The processed data provided a picture of the motions occurring in NVL with a high level of accuracy and depicts, for the whole period, a well defined pattern of vertical motion. The comparison between GPS-derived vertical displacementsand GIA is addressed, showing a good degree of agreement and highlighting the future use of geodetic GPS measurements as constraints in GIA models. In spite of this agreement, the sensitivity of GPS vertical rates to non-GIA vertical motions has to be carefully evaluated.

  13. COX2 Inhibition Reduces Aortic Valve Calcification In Vivo

    PubMed Central

    Wirrig, Elaine E.; Gomez, M. Victoria; Hinton, Robert B.; Yutzey, Katherine E.

    2016-01-01

    Objective Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality, which affects approximately 1% of the US population and is characterized by calcific nodule formation and stenosis of the valve. Klotho-deficient mice were used to study the molecular mechanisms of CAVD as they develop robust aortic valve (AoV) calcification. Through microarray analysis of AoV tissues from klotho-deficient and wild type mice, increased expression of the gene encoding cyclooxygenase 2/COX2 (Ptgs2) was found. COX2 activity contributes to bone differentiation and homeostasis, thus the contribution of COX2 activity to AoV calcification was assessed. Approach and Results In klotho-deficient mice, COX2 expression is increased throughout regions of valve calcification and is induced in the valvular interstitial cells (VICs) prior to calcification formation. Similarly, COX2 expression is increased in human diseased AoVs. Treatment of cultured porcine aortic VICs with osteogenic media induces bone marker gene expression and calcification in vitro, which is blocked by inhibition of COX2 activity. In vivo, genetic loss of function of COX2 cyclooxygenase activity partially rescues AoV calcification in klotho-deficient mice. Moreover, pharmacologic inhibition of COX2 activity in klotho-deficient mice via celecoxib-containing diet reduces AoV calcification and blocks osteogenic gene expression. Conclusions COX2 expression is upregulated in CAVD and its activity contributes to osteogenic gene induction and valve calcification in vitro and in vivo. PMID:25722432

  14. Parental Expressivity, Child Physiological and Behavioral Regulation, and Child Adjustment: Testing a Three-Path Mediation Model

    ERIC Educational Resources Information Center

    Liew, Jeffrey; Johnson, Audrea Y.; Smith, Tracy R.; Thoemmes, Felix

    2011-01-01

    Research Findings: Parental expressivity, child physiological regulation (indexed by respiratory sinus arrhythmia suppression), child behavioral regulation, and child adjustment outcomes were examined in 45 children (M age = 4.32 years, SD = 1.30) and their parents. With the exception of child adjustment (i.e., internalizing and externalizing…

  15. Models of Traumatic Experiences and Children's Psychological Adjustment: The Roles of Perceived Parenting and the Children's Own Resources and Activity.

    ERIC Educational Resources Information Center

    Punamaki, Raija-Leena; Qouta, Samir; El Sarraj, Eyad

    1997-01-01

    Used path analysis to examine relations between trauma, perceived parenting, resources, political activity, and adjustment in Palestinian 11- and 12-year olds. Found that the more trauma experienced, the more negative parenting the children experienced, the more political activity they showed, and the more they suffered from adjustment problems.…

  16. The Molecular Basis for Dual Fatty Acid Amide Hydrolase (FAAH)/Cyclooxygenase (COX) Inhibition.

    PubMed

    Palermo, Giulia; Favia, Angelo D; Convertino, Marino; De Vivo, Marco

    2016-06-20

    The design of multitarget-directed ligands is a promising strategy for discovering innovative drugs. Here, we report a mechanistic study that clarifies key aspects of the dual inhibition of the fatty acid amide hydrolase (FAAH) and the cyclooxygenase (COX) enzymes by a new multitarget-directed ligand named ARN2508 (2-[3-fluoro-4-[3-(hexylcarbamoyloxy)phenyl]phenyl]propanoic acid). This potent dual inhibitor combines, in a single scaffold, the pharmacophoric elements often needed to block FAAH and COX, that is, a carbamate moiety and the 2-arylpropionic acid functionality, respectively. Molecular modeling and molecular dynamics simulations suggest that ARN2508 uses a noncovalent mechanism of inhibition to block COXs, while inhibiting FAAH via the acetylation of the catalytic Ser241, in line with previous experimental evidence for covalent FAAH inhibition. This study proposes the molecular basis for the dual FAAH/COX inhibition by this novel hybrid scaffold, stimulating further experimental studies and offering new insights for the rational design of novel anti-inflammatory agents that simultaneously act on FAAH and COX.

  17. Isomeric methoxy analogs of nimesulide for development of brain cyclooxygense-2 (COX-2)-targeted imaging agents: Synthesis, in vitro COX-2-inhibitory potency, and cellular transport properties.

    PubMed

    Yamamoto, Yumi; Hisa, Takuya; Arai, Jun; Saito, Yohei; Yamamoto, Fumihiko; Mukai, Takahiro; Ohshima, Takashi; Maeda, Minoru; Ohkubo, Yasuhito

    2015-11-01

    Nimesulide analogs bearing a methoxy substituent either at the ortho-, meta- or para-position on the phenyl ring, were designed, synthesized, and evaluated for potential as radioligands for brain cyclooxygenase-2 (COX-2) imaging. The synthesis of nimesulide and regioisomeric methoxy analogs was based on the copper-mediated arylation of phenolic derivatives for the construction of diaryl ethers. These isomeric methoxy analogs displayed lipophilicity similar to that of nimesulide itself, as evidenced by their HPLC logP7.4 values. In vitro inhibition studies using a colorimetric COX (ovine) inhibitor-screening assay demonstrated that the para-methoxy substituted analog retains the inhibition ability and selectivity observed for parent nimesulide toward COX-2 enzyme, whereas the meta- and ortho-methoxy substituents detrimentally affected COX-2-inhibition activity, which was further supported by molecular docking studies. Bidirectional transport cellular studies using Caco-2 cell culture model in the presence of the P-glycoprotein (P-gp) inhibitor, verapamil, showed that P-gp did not have a significant effect on the efflux of the para-methoxy substituted analog. Further investigations using the radiolabeled form of the para-methoxy substituted analog is warranted for in vivo characterization.

  18. Antipsychotics and Mortality: Adjusting for Mortality Risk Scores to Address Confounding by Terminal Illness

    PubMed Central

    Park, Yoonyoung; Franklin, Jessica M.; Schneeweiss, Sebastian; Levin, Raisa; Crystal, Stephen; Gerhard, Tobias; Huybrechts, Krista F.

    2014-01-01

    OBJECTIVES Earlier studies have documented a greater mortality risk associated with conventional compared with atypical antipsychotics. Concern remains that the association is not causal, but due to residual confounding by differences in underlying health. To address this concern, we evaluated whether adjustment for prognostic indices specifically developed fornursing home (NH) populations affected the magnitude of the previously observed associations. DESIGN Cohort study SETTING A merged dataset of Medicaid, Medicare, the Minimum Data Set (MDS), the Online Survey Certification and Reporting system (OSCAR), and the National Death Index in the US for 2001-2005 PARTICIPANTS Dual eligible subjects ≥ 65 years who initiated antipsychotic treatment in a NH (n=75,445). MEASUREMENTS Three mortality risk scores (MRIS, MMRI-R, and ADEPT) were derived for each patient using baseline MDS data, and their performance was assessed using c-statistics and goodness-of-fit tests. The impact of adjusting for these indices in addition to propensity scores (PS) on the antipsychotic-mortality association was evaluated using Cox models with and without adjustment for risk scores. RESULTS Each risk score showed moderate discrimination for 6-month mortality with c-statistics ranging from 0.61 to 0.63. There was no evidence of lack of fit. Imbalances in risk scores between conventional and atypical antipsychotic users in the full cohort, suggesting potential confounding, were greatly reduced within PS deciles. Accounting for each score in the Cox model did not change the relative risk estimates: 2.24 with PS only adjustment vs. 2.20, 2.20, 2.22 after further adjustment for the three risk scores. CONCLUSION Although causality cannot be proven based on non-randomized studies, this study adds to the body of evidence rejecting alternative explanations for the increased mortality risk associated with conventional antipsychotics. PMID:25752911

  19. The heme a synthase Cox15 associates with cytochrome c oxidase assembly intermediates during Cox1 maturation.

    PubMed

    Bareth, Bettina; Dennerlein, Sven; Mick, David U; Nikolov, Miroslav; Urlaub, Henning; Rehling, Peter

    2013-10-01

    Cox1, the core subunit of the cytochrome c oxidase, receives two heme a cofactors during assembly of the 13-subunit enzyme complex. However, at which step of the assembly process and how heme is inserted into Cox1 have remained an enigma. Shy1, the yeast SURF1 homolog, has been implicated in heme transfer to Cox1, whereas the heme a synthase, Cox15, catalyzes the final step of heme a synthesis. Here we performed a comprehensive analysis of cytochrome c oxidase assembly intermediates containing Shy1. Our analyses suggest that Cox15 displays a role in cytochrome c oxidase assembly, which is independent of its functions as the heme a synthase. Cox15 forms protein complexes with Shy1 and also associates with Cox1-containing complexes independently of Shy1 function. These findings indicate that Shy1 does not serve as a mobile heme carrier between the heme a synthase and maturing Cox1 but rather cooperates with Cox15 for heme transfer and insertion in early assembly intermediates of cytochrome c oxidase.

  20. Characterization of the peroxide sensitivity of COX-deficient yeast strains reveals unexpected relationships between COX assembly proteins.

    PubMed

    Veniamin, Simona; Sawatzky, Luanne G; Banting, Graham S; Glerum, D Moira

    2011-10-15

    A number of distinct cuproproteins of the mitochondrial inner membrane are required for the assembly of cytochrome oxidase (COX), thought to function in a "bucket brigade" fashion to provide copper to the Cu(A) and Cu(B) sites. In yeast, the loss of two these proteins, Sco1p and Cox11p, leads to respiratory deficiency and a specific inability to survive exposure to hydrogen peroxide (H(2)O(2)). Using a quantitative assay, we have identified subtle differences in the peroxide-sensitive phenotypes between sco1 and cox11 mutant strains. Interestingly, the peroxide sensitivity of the sco1 null strain can be suppressed by overexpressing either SCO2 or COX11, although overexpression of neither SCO1 nor SCO2 can rescue the cox11 null strain. We also find that overexpression of either CTT1, encoding the cytosolic catalase T, or CTA1, encoding the mitochondrial matrix catalase, suppresses the peroxide sensitivity in both the sco1 and the cox11 null mutants. Direct measurement of peroxide metabolism shows that sco1 and cox11 null strains fail to degrade a significant amount of exogenously provided H(2)O(2). Taken together, our data demonstrate that although Cox11p and Sco1p play distinct roles in COX assembly, they seem to play overlapping or related roles in peroxide metabolism that require further investigation.

  1. Expression of cyclooxygenase-2 (COX-2) in pituitary tumours

    PubMed Central

    Sokołowski, Grzegorz; Bałdys-Waligórska, Agata; Trofimiuk, Małgorzata; Adamek, Dariusz; Hubalewska-Dydejczyk, Alicja; Gołkowski, Filip

    2012-01-01

    Summary Background Microvessel density in angiogenesis is regarded as a prognostic factor of tumour invasiveness, independent of cell proliferation. In recent studies of pituitary tumours, correlation between the expression of cyclooxygenase-2 (COX-2) and micro-vascularization density and microvessel surface density has been established. We studied the expression of COX-2 in different types of pituitary adenomas to determine the usefulness of COX-2 expression as a prognostic factor of tumour progression or recurrence in patients with hypophyseal tumours. Material/Methods We retrospectively studied a group of 60 patients of mean age 46.7±17.6 (range, 18 to 85) years who underwent pituitary tumour surgery. Expression of COX-2, as determined by immunohistochemistry, was analyzed in relation to histopathology features of tumour, clinical symptoms, MR imaging and post-operative recurrence/progression of disease. Results COX-2 was expressed in adenomas of 87% of patients, with a median index value of 57.5% [IQR=60.5]. Highest COX-2 expression was observed in hormonally inactive adenomas and gonadotropinomas and lowest in prolactinomas. We found no differences in COX-2 expression with respect to patient age, gender, tumour size, degree of tumour invasiveness, or whether tumours were immunopositive or immunonegative for pituitary hormones, nor have we found any relation between COX-2 expression and recurrence or progression of tumour size. Conclusions COX-2 does not appear to be a predictive factor for recurrence or progression of tumour size. Nevertheless, due to the observed relatively high expression of COX-2 in pituitary adenomas, further studies with COX-2 inhibitors are justified in these tumours. PMID:22460097

  2. Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling

    PubMed Central

    Dixon, Dan A.; Tolley, Neal D.; Bemis-Standoli, Kristi; Martinez, Mark L.; Weyrich, Andrew S.; Morrow, Jason D.; Prescott, Stephen M.; Zimmerman, Guy A.

    2006-01-01

    Tight regulation of COX-2 expression is a key feature controlling eicosanoid production in atherosclerosis and other inflammatory syndromes. Adhesive interactions between platelets and monocytes occur in these conditions and deliver specific signals that trigger inflammatory gene expression. Using a cellular model of monocyte signaling induced by activated human platelets, we identified the central posttranscriptional mechanisms that regulate timing and magnitude of COX-2 expression. Tethering of monocytes to platelets and to purified P-selectin, a key adhesion molecule displayed by activated platelets, induces NF-κB activation and COX-2 promoter activity. Nevertheless, COX-2 mRNA is rapidly degraded, leading to aborted protein synthesis. Time-dependent signaling of monocytes induces a second phase of transcript accumulation accompanied by COX-2 enzyme synthesis and eicosanoid production. Here, generation of IL-1β, a proinflammatory cytokine, promoted stabilization of COX-2 mRNA by silencing of the AU-rich mRNA decay element (ARE) in the 3′-untranslated region (3'UTR) of the mRNA. Consistent with observed mRNA stabilization, activated platelets or IL-1β treatment induced cytoplasmic accumulation and enhanced ARE binding of the mRNA stability factor HuR in monocytes. These findings demonstrate that activated platelets induce COX-2 synthesis in monocytes by combinatorial signaling to transcriptional and posttranscriptional checkpoints. These checkpoints may be altered in disease and therefore useful as targets for antiinflammatory intervention. PMID:16998585

  3. Structural and antiferromagnetic properties of Ba(Fe1-x-y Cox Rhy)2 As2 compounds

    NASA Astrophysics Data System (ADS)

    Kim, Min Gyu; Heitmann, T. W.; Mulcahy, S. R.; Bourret-Courchesne, E. D.; Birgeneau, R. J.

    We present a systematic investigation of the electrical, structural, and antiferromagnetic properties for the series of Ba(Fe1-x-y CoxRhy)2 As2 compounds with fixed x = 0.027 and 0 < y <0.035. We compare our results for the Co-Rh doped Ba(Fe1-x-y CoxRhy)2 As2 compounds with Ba(Fe 1-xCox)2 As2 compounds. We demonstrate that the electrical, structural, antiferromagnetic, and superconducting properties of the Co-Rh doped compounds are similar to the properties of the Co doped compounds. We find that the overall behaviors of Ba(Fe1-x-y CoxRhy)2 As2 and Ba(Fe1-x Cox)2 As2 compounds are very similar when the total number of the extra electrons per Fe/TM (TM = transition metal) site is considered, which is consistent with the rigid band model. Despite the similarity, we find that the details of the transitions are different in between Ba(Fe1-x-y CoxRhy)2 As2 and Ba(Fe1-x Cox)2 As2 compounds. The work at the Lawrence Berkeley National Laboratory was supported by the U.S. Department of Energy (DOE), Office of Basic Energy Sciences, Materials Sciences and Engineering Division, under Contract No. DE-AC02-05CH11231.

  4. First-Year Village: Experimenting with an African Model for First-Year Adjustment and Support in South Africa

    ERIC Educational Resources Information Center

    Speckman, McGlory

    2016-01-01

    Predicated on the principles of success and contextuality, this chapter shares an African perspective on a first-year adjustment programme, known as First-Year Village, including its potential and challenges in establishing it.

  5. Holocene sea-level changes along the North Carolina Coastline and their implications for glacial isostatic adjustment models

    USGS Publications Warehouse

    Horton, B.P.; Peltier, W.R.; Culver, S.J.; Drummond, R.; Engelhart, S.E.; Kemp, A.C.; Mallinson, D.; Thieler, E.R.; Riggs, S.R.; Ames, D.V.; Thomson, K.H.

    2009-01-01

    We have synthesized new and existing relative sea-level (RSL) data to produce a quality-controlled, spatially comprehensive database from the North Carolina coastline. The RSL database consists of 54 sea-level index points that are quantitatively related to an appropriate tide level and assigned an error estimate, and a further 33 limiting dates that confine the maximum and minimum elevations of RSL. The temporal distribution of the index points is very uneven with only five index points older than 4000 cal a BP, but the form of the Holocene sea-level trend is constrained by both terrestrial and marine limiting dates. The data illustrate RSL rapidly rising during the early and mid Holocene from an observed elevation of -35.7 ?? 1.1 m MSL at 11062-10576 cal a BP to -4.2 m ?? 0.4 m MSL at 4240-3592 cal a BP. We restricted comparisons between observations and predictions from the ICE-5G(VM2) with rotational feedback Glacial Isostatic Adjustment (GIA) model to the Late Holocene RSL (last 4000 cal a BP) because of the wealth of sea-level data during this time interval. The ICE-5G(VM2) model predicts significant spatial variations in RSL across North Carolina, thus we subdivided the observations into two regions. The model forecasts an increase in the rate of sea-level rise in Region 1 (Albemarle, Currituck, Roanoke, Croatan, and northern Pamlico sounds) compared to Region 2 (southern Pamlico, Core and Bogue sounds, and farther south to Wilmington). The observations show Late Holocene sea-level rising at 1.14 ?? 0.03 mm year-1 and 0.82 ?? 0.02 mm year-1 in Regions 1 and 2, respectively. The ICE-5G(VM2) predictions capture the general temporal trend of the observations, although there is an apparent misfit for index points older than 2000 cal a BP. It is presently unknown whether these misfits are caused by possible tectonic uplift associated with the mid-Carolina Platform High or a flaw in the GIA model. A comparison of local tide gauge data with the Late Holocene RSL

  6. A Test of the Family Stress Model on Toddler-Aged Children's Adjustment among Hurricane Katrina Impacted and Nonimpacted Low-Income Families

    ERIC Educational Resources Information Center

    Scaramella, Laura V.; Sohr-Preston, Sara L.; Callahan, Kristin L.; Mirabile, Scott P.

    2008-01-01

    Hurricane Katrina dramatically altered the level of social and environmental stressors for the residents of the New Orleans area. The Family Stress Model describes a process whereby felt financial strain undermines parents' mental health, the quality of family relationships, and child adjustment. Our study considered the extent to which the Family…

  7. Class climate moderates peer relations and emotional adjustment in children with an early history of anxious solitude: a Child X Environment model.

    PubMed

    Gazelle, Heidi

    2006-11-01

    Classroom emotional climate was hypothesized to moderate psychosocial adjustment in 1st grade for children with an early childhood history of anxious solitude. Participants were 1,364 children in the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and their mothers, child-care providers, and teachers. As anticipated, children with an early childhood history of anxious solitude were more rejected, poorly accepted (boys), and victimized (girls) by peers and demonstrated more depressive symptoms (girls) in 1st-grade classrooms with negative observed emotional climate. Results support a Child x Environment model of children's social and emotional adjustment.

  8. Adjustable Autonomy Testbed

    NASA Technical Reports Server (NTRS)

    Malin, Jane T.; Schrenkenghost, Debra K.

    2001-01-01

    The Adjustable Autonomy Testbed (AAT) is a simulation-based testbed located in the Intelligent Systems Laboratory in the Automation, Robotics and Simulation Division at NASA Johnson Space Center. The purpose of the testbed is to support evaluation and validation of prototypes of adjustable autonomous agent software for control and fault management for complex systems. The AA T project has developed prototype adjustable autonomous agent software and human interfaces for cooperative fault management. This software builds on current autonomous agent technology by altering the architecture, components and interfaces for effective teamwork between autonomous systems and human experts. Autonomous agents include a planner, flexible executive, low level control and deductive model-based fault isolation. Adjustable autonomy is intended to increase the flexibility and effectiveness of fault management with an autonomous system. The test domain for this work is control of advanced life support systems for habitats for planetary exploration. The CONFIG hybrid discrete event simulation environment provides flexible and dynamically reconfigurable models of the behavior of components and fluids in the life support systems. Both discrete event and continuous (discrete time) simulation are supported, and flows and pressures are computed globally. This provides fast dynamic simulations of interacting hardware systems in closed loops that can be reconfigured during operations scenarios, producing complex cascading effects of operations and failures. Current object-oriented model libraries support modeling of fluid systems, and models have been developed of physico-chemical and biological subsystems for processing advanced life support gases. In FY01, water recovery system models will be developed.

  9. Modeling of Turbulent Boundary Layer Surface Pressure Fluctuation Auto and Cross Spectra - Verification and Adjustments Based on TU-144LL Data

    NASA Technical Reports Server (NTRS)

    Rackl, Robert; Weston, Adam

    2005-01-01

    The literature on turbulent boundary layer pressure fluctuations provides several empirical models which were compared to the measured TU-144 data. The Efimtsov model showed the best agreement. Adjustments were made to improve its agreement further, consisting of the addition of a broad band peak in the mid frequencies, and a minor modification to the high frequency rolloff. The adjusted Efimtsov predicted and measured results are compared for both subsonic and supersonic flight conditions. Measurements in the forward and middle portions of the fuselage have better agreement with the model than those from the aft portion. For High Speed Civil Transport supersonic cruise, interior levels predicted by use of this model are expected to increase by 1-3 dB due to the adjustments to the Efimtsov model. The space-time cross-correlations and cross-spectra of the fluctuating surface pressure were also investigated. This analysis is an important ingredient in structural acoustic models of aircraft interior noise. Once again the measured data were compared to the predicted levels from the Efimtsov model.

  10. Antinociceptive Effects of Prim-O-Glucosylcimifugin in Inflammatory Nociception via Reducing Spinal COX-2.

    PubMed

    Wu, Liu-Qing; Li, Yu; Li, Yuan-Yan; Xu, Shi-Hao; Yang, Zong-Yong; Lin, Zheng; Li, Jun

    2016-07-01

    We measured anti-nociceptive activity of prim-o-glucosylcimifugin (POG), a molecule from Saposhnikovia divaricate (Turcz) Schischk. Anti-nociceptive or anti-inflammatory effects of POG on a formalin-induced tonic nociceptive response and a complete Freund's adjuvant (CFA) inoculation-induced rat arthritis pain model were studied. Single subcutaneous injections of POG produced potent anti-nociception in both models that was comparable to indomethacin analgesia. Anti-nociceptive activity of POG was dose-dependent, maximally reducing pain 56.6% with an ED50 of 1.6 mg. Rats given POG over time did not develop tolerance. POG also time-dependently reduced serum TNFα, IL-1β and IL-6 in arthritic rats and both POG and indomethacin reduced spinal prostaglandin E2 (PGE2). Like indomethacin which inhibits cyclooxygenase-2 (COX-2) activity, POG dose-dependently decreased spinal COX-2 content in arthritic rats. Additionally, POG, and its metabolite cimifugin, downregulated COX-2 expression in vitro. Thus, POG produced potent anti-nociception by downregulating spinal COX-2 expression.

  11. Adjustment of Measurements with Multiplicative Errors: Error Analysis, Estimates of the Variance of Unit Weight, and Effect on Volume Estimation from LiDAR-Type Digital Elevation Models

    PubMed Central

    Shi, Yun; Xu, Peiliang; Peng, Junhuan; Shi, Chuang; Liu, Jingnan

    2014-01-01

    Modern observation technology has verified that measurement errors can be proportional to the true values of measurements such as GPS, VLBI baselines and LiDAR. Observational models of this type are called multiplicative error models. This paper is to extend the work of Xu and Shimada published in 2000 on multiplicative error models to analytical error analysis of quantities of practical interest and estimates of the variance of unit weight. We analytically derive the variance-covariance matrices of the three least squares (LS) adjustments, the adjusted measurements and the corrections of measurements in multiplicative error models. For quality evaluation, we construct five estimators for the variance of unit weight in association of the three LS adjustment methods. Although LiDAR measurements are contaminated with multiplicative random errors, LiDAR-based digital elevation models (DEM) have been constructed as if they were of additive random errors. We will simulate a model landslide, which is assumed to be surveyed with LiDAR, and investigate the effect of LiDAR-type multiplicative error measurements on DEM construction and its effect on the estimate of landslide mass volume from the constructed DEM. PMID:24434880

  12. Adjustment of measurements with multiplicative errors: error analysis, estimates of the variance of unit weight, and effect on volume estimation from LiDAR-type digital elevation models.

    PubMed

    Shi, Yun; Xu, Peiliang; Peng, Junhuan; Shi, Chuang; Liu, Jingnan

    2014-01-10

    Modern observation technology has verified that measurement errors can be proportional to the true values of measurements such as GPS, VLBI baselines and LiDAR. Observational models of this type are called multiplicative error models. This paper is to extend the work of Xu and Shimada published in 2000 on multiplicative error models to analytical error analysis of quantities of practical interest and estimates of the variance of unit weight. We analytically derive the variance-covariance matrices of the three least squares (LS) adjustments, the adjusted measurements and the corrections of measurements in multiplicative error models. For quality evaluation, we construct five estimators for the variance of unit weight in association of the three LS adjustment methods. Although LiDAR measurements are contaminated with multiplicative random errors, LiDAR-based digital elevation models (DEM) have been constructed as if they were of additive random errors. We will simulate a model landslide, which is assumed to be surveyed with LiDAR, and investigate the effect of LiDAR-type multiplicative error measurements on DEM construction and its effect on the estimate of landslide mass volume from the constructed DEM.

  13. A test of the Family Stress Model on toddler-aged children's adjustment among Hurricane Katrina impacted and nonimpacted low-income families.

    PubMed

    Scaramella, Laura V; Sohr-Preston, Sara L; Callahan, Kristin L; Mirabile, Scott P

    2008-07-01

    Hurricane Katrina dramatically altered the level of social and environmental stressors for the residents of the New Orleans area. The Family Stress Model describes a process whereby felt financial strain undermines parents' mental health, the quality of family relationships, and child adjustment. Our study considered the extent to which the Family Stress Model explained toddler-aged adjustment among Hurricane Katrina affected and nonaffected families. Two groups of very low-income mothers and their 2-year-old children participated (pre-Katrina, n = 55; post-Katrina, n = 47). Consistent with the Family Stress Model, financial strain and neighborhood violence were associated with higher levels of mothers' depressed mood; depressed mood was linked to less parenting efficacy. Poor parenting efficacy was associated to more child internalizing and externalizing problems.

  14. Development and Validation of a Brief Version of the Dyadic Adjustment Scale With a Nonparametric Item Analysis Model

    ERIC Educational Resources Information Center

    Sabourin, Stephane; Valois, Pierre; Lussier, Yvan

    2005-01-01

    The main purpose of the current research was to develop an abbreviated form of the Dyadic Adjustment Scale (DAS) with nonparametric item response theory. The authors conducted 5 studies, with a total participation of 8,256 married or cohabiting individuals. Results showed that the item characteristic curves behaved in a monotonically increasing…

  15. Data for and adjusted regional regression models of volume and quality of urban storm-water runoff in Boise and Garden City, Idaho, 1993-94

    USGS Publications Warehouse

    Kjelstrom, L.C.

    1995-01-01

    Previously developed U.S. Geological Survey regional regression models of runoff and 11 chemical constituents were evaluated to assess their suitability for use in urban areas in Boise and Garden City. Data collected in the study area were used to develop adjusted regional models of storm-runoff volumes and mean concentrations and loads of chemical oxygen demand, dissolved and suspended solids, total nitrogen and total ammonia plus organic nitrogen as nitrogen, total and dissolved phosphorus, and total recoverable cadmium, copper, lead, and zinc. Explanatory variables used in these models were drainage area, impervious area, land-use information, and precipitation data. Mean annual runoff volume and loads at the five outfalls were estimated from 904 individual storms during 1976 through 1993. Two methods were used to compute individual storm loads. The first method used adjusted regional models of storm loads and the second used adjusted regional models for mean concentration and runoff volume. For large storms, the first method seemed to produce excessively high loads for some constituents and the second method provided more reliable results for all constituents except suspended solids. The first method provided more reliable results for large storms for suspended solids.

  16. Shortwave radiative forcing, rapid adjustment, and feedback to the surface by sulfate geoengineering: analysis of the Geoengineering Model Intercomparison Project G4 scenario

    NASA Astrophysics Data System (ADS)

    Kashimura, Hiroki; Abe, Manabu; Watanabe, Shingo; Sekiya, Takashi; Ji, Duoying; Moore, John C.; Cole, Jason N. S.; Kravitz, Ben

    2017-03-01

    This study evaluates the forcing, rapid adjustment, and feedback of net shortwave radiation at the surface in the G4 experiment of the Geoengineering Model Intercomparison Project by analysing outputs from six participating models. G4 involves injection of 5 Tg yr-1 of SO2, a sulfate aerosol precursor, into the lower stratosphere from year 2020 to 2069 against a background scenario of RCP4.5. A single-layer atmospheric model for shortwave radiative transfer is used to estimate the direct forcing of solar radiation management (SRM), and rapid adjustment and feedbacks from changes in the water vapour amount, cloud amount, and surface albedo (compared with RCP4.5). The analysis shows that the globally and temporally averaged SRM forcing ranges from -3.6 to -1.6 W m-2, depending on the model. The sum of the rapid adjustments and feedback effects due to changes in the water vapour and cloud amounts increase the downwelling shortwave radiation at the surface by approximately 0.4 to 1.5 W m-2 and hence weaken the effect of SRM by around 50 %. The surface albedo changes decrease the net shortwave radiation at the surface; it is locally strong (˜ -4 W m-2) in snow and sea ice melting regions, but minor for the global average. The analyses show that the results of the G4 experiment, which simulates sulfate geoengineering, include large inter-model variability both in the direct SRM forcing and the shortwave rapid adjustment from change in the cloud amount, and imply a high uncertainty in modelled processes of sulfate aerosols and clouds.

  17. Role of LKB1-CRTC1 on Glycosylated COX-2 and Response to COX-2 Inhibition in Lung Cancer

    PubMed Central

    Cao, Chunxia; Gao, Ruli; Zhang, Min; Amelio, Antonio L.; Fallahi, Mohammad; Chen, Zirong; Gu, Yumei; Hu, Chengbin; Welsh, Eric A.; Engel, Brienne E.; Haura, Eric B.; Cress, W. Douglas; Wu, Lizi; Zajac-Kaye, Maria

    2015-01-01

    Background: Cyclooxygenase-2 (COX-2) directs the synthesis of prostaglandins including PGE-2 linking inflammation with mitogenic signaling. COX-2 is also an anticancer target, however, treatment strategies have been limited by unreliable expression assays and by inconsistent tumor responses to COX-2 inhibition. Methods: We analyzed the TCGA and Director’s Challenge lung cancer datasets (n = 188) and also generated an LKB1-null lung cancer gene signature (n = 53) to search the Broad Institute/Connectivity-MAP (C-MAP) dataset. We performed ChIP analyses, real-time polymerase chain reaction, immunoblotting, and drug testing of tumor cell lines (n = 8) and primary lung adenocarcinoma surgical resections (n = 13). Results: We show that COX-2 is a target of the cAMP/CREB coactivator CRTC1 signaling pathway. In addition, we detected a correlation between LKB1 status, CRTC1 activation, and presence of glycosylated, but not inactive hypoglycosylated COX-2 in primary lung adenocarcinoma. A search of the C-MAP drug database discovered that all high-ranking drugs positively associated with the LKB1-null signature are known CRTC1 activators, including forskolin and six different PGE-2 analogues. Somatic LKB1 mutations are present in 20.0% of lung adenocarcinomas, and we observed growth inhibition with COX-2 inhibitors in LKB1-null lung cancer cells with activated CRTC1 as compared with LKB1-wildtype cells (NS-398, P = .002 and Niflumic acid, P = .006; two-tailed t test). Conclusion: CRTC1 activation is a key event that drives the LKB1-null mRNA signature in lung cancer. We also identified a positive feedback LKB1/CRTC1 signaling loop for COX-2/PGE2 regulation. These data suggest a role for LKB1 status and glycosylated COX-2 as specific biomarkers that provide a framework for selecting patients for COX-2 inhibition studies. PMID:25465874

  18. COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats.

    PubMed

    Muñoz, Mercedes; Sánchez, Ana; Pilar Martínez, María; Benedito, Sara; López-Oliva, Maria-Elvira; García-Sacristán, Albino; Hernández, Medardo; Prieto, Dolores

    2015-07-01

    Obesity is related to vascular dysfunction through inflammation and oxidative stress and it has been identified as a risk factor for chronic renal disease. In the present study, we assessed the specific relationships among reactive oxygen species (ROS), cyclooxygenase 2 (COX-2), and endothelial dysfunction in renal interlobar arteries from a genetic model of obesity/insulin resistance, the obese Zucker rats (OZR). Relaxations to acetylcholine (ACh) were significantly reduced in renal arteries from OZR compared to their counterpart, the lean Zucker rat (LZR), suggesting endothelial dysfunction. Blockade of COX with indomethacin and with the selective blocker of COX-2 restored the relaxations to ACh in obese rats. Selective blockade of the TXA2/PGH2 (TP) receptor enhanced ACh relaxations only in OZR, while inhibition of the prostacyclin (PGI2) receptor (IP) enhanced basal tone and inhibited ACh vasodilator responses only in LZR. Basal production of superoxide was increased in arteries of OZR and involved NADPH and xanthine oxidase activation and NOS uncoupling. Under conditions of NOS blockade, ACh induced vasoconstriction and increased ROS generation that were augmented in arteries from OZR and blunted by COX-2 inhibition and by the ROS scavenger tempol. Hydrogen peroxide (H2O2) evoked both endothelium- and vascular smooth muscle (VSM)-dependent contractions, as well as ROS generation that was reduced by COX-2 inhibition. In addition, COX-2 expression was enhanced in both VSM and endothelium of renal arteries from OZR. These results suggest that increased COX-2-dependent vasoconstriction contributes to renal endothelial dysfunction through enhanced (ROS) generation in obesity. COX-2 activity is in turn upregulated by ROS.

  19. Students Speak With Gary Cox, EPIC Project Manager

    NASA Video Gallery

    From NASA’s International Space Station Mission Control Center Gary Cox EPIC Project Manager, participates in a Digital Learning Network (DLN) event with students at South Effingham Middle School...

  20. 32. SCIENTISTS ALLAN COX (SEATED), RICHARD DOELL, AND BRENT DALRYMPLE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    32. SCIENTISTS ALLAN COX (SEATED), RICHARD DOELL, AND BRENT DALRYMPLE AT CONTROL PANEL, ABOUT 1965. - U.S. Geological Survey, Rock Magnetics Laboratory, 345 Middlefield Road, Menlo Park, San Mateo County, CA

  1. AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/β-catenin signaling pathway

    PubMed Central

    Zhang, Yiyun; Wang, Jianfeng; Wheat, Justin; Chen, Xi; Jin, Shan; Sadrzadeh, Hossein; Fathi, Amir T.; Peterson, Randall T.; Kung, Andrew L.

    2013-01-01

    Developing novel therapies that suppress self-renewal of leukemia stem cells may reduce the likelihood of relapses and extend long-term survival of patients with acute myelogenous leukemia (AML). AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Previously, using a zebrafish model of AE and a whole-organism chemical suppressor screen, we have discovered that AE induces specific hematopoietic phenotypes in embryonic zebrafish through a cyclooxygenase (COX)-2 and β-catenin–dependent pathway. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells. Inhibition of COX suppresses β-catenin activation and serial replating of AE+ mouse HSPCs. Genetic knockdown of β-catenin also abrogates the clonogenic growth of AE+ mouse HSPCs and human leukemia cells. In addition, treatment with nimesulide, a COX-2 selective inhibitor, dramatically suppresses xenograft tumor formation and inhibits in vivo progression of human leukemia cells. In summary, our data indicate an important role of a COX/β-catenin–dependent signaling pathway in tumor initiation, growth, and self-renewal, and in providing the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments. PMID:23645839

  2. AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/β-catenin signaling pathway.

    PubMed

    Zhang, Yiyun; Wang, Jianfeng; Wheat, Justin; Chen, Xi; Jin, Shan; Sadrzadeh, Hossein; Fathi, Amir T; Peterson, Randall T; Kung, Andrew L; Sweetser, David A; Yeh, Jing-Ruey Joanna

    2013-06-13

    Developing novel therapies that suppress self-renewal of leukemia stem cells may reduce the likelihood of relapses and extend long-term survival of patients with acute myelogenous leukemia (AML). AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Previously, using a zebrafish model of AE and a whole-organism chemical suppressor screen, we have discovered that AE induces specific hematopoietic phenotypes in embryonic zebrafish through a cyclooxygenase (COX)-2 and β-catenin-dependent pathway. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells. Inhibition of COX suppresses β-catenin activation and serial replating of AE(+) mouse HSPCs. Genetic knockdown of β-catenin also abrogates the clonogenic growth of AE(+) mouse HSPCs and human leukemia cells. In addition, treatment with nimesulide, a COX-2 selective inhibitor, dramatically suppresses xenograft tumor formation and inhibits in vivo progression of human leukemia cells. In summary, our data indicate an important role of a COX/β-catenin-dependent signaling pathway in tumor initiation, growth, and self-renewal, and in providing the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments.

  3. COX-2 expression is correlated with VEGF-C, lymphangiogenesis and lymph node metastasis in human cervical cancer.

    PubMed

    Liu, Huidong; Xiao, Jianbing; Yang, Yanmei; Liu, Yan; Ma, Ruijin; Li, Yuhang; Deng, Fengchun; Zhang, Yafang

    2011-09-01

    Lymphangiogenesis has been shown to promote lymph node metastasis in cancers, making it an important target in cancer therapy. Vascular endothelial growth factor (VEGF)-C is upregulated in various tumors/cancers and is one of the most potent growth factors for inducing lymphangiogenesis and promoting lymph node metastasis (LNM). Likewise, cyclooxygenase (COX)-2 plays major roles in carcinogenesis, tumor growth and metastasis via multiple mechanisms including inactivation of host antitumor immunity and promotion of tumor cell migration, tumor cell invasiveness and tumor-associated angiogenesis and lymphangiogenesis. We previously demonstrated an association between COX-2 and VEGF-C in an in vitro model of lung cancer. However, little is known about the regulation of VEGF-C by COX-2 in cervical cancer. In this study, we measured the COX-2 and VEGF-C expressions by immunohistochemistry in 23 LNM-positive and 20 LNM-negative cervical cancer specimens. We then examined the correlations among the expressions and the lymphatic microvessel density (LMVD) and ultrastructural changes to the lymphatic vessel walls by enzyme histochemical staining and electron microscopy. In addition, we used the HeLa cervical cancer cell line to explore the in vitro regulation of VEGF-C by COX-2 and its metabolite, PGE(2), using siRNA-mediated gene silencing and EP receptor blockade. The LNM-positive specimens exhibited significantly higher VEGF-C expression, COX-2 expression and LMVD than the LNM-negative specimens. Furthermore, there were strong correlations between the levels of COX-2 expression and the levels of VEGF-C expression and secretion and a significant positive association between the LMVD and LNM. siRNA-mediated knockdown of COX-2 expression inhibited VEGF-C mRNA expression while EP1 and EP4 receptor antagonists reduced the VEGF-C protein level and tyrosine phosphorylation of Src kinase. Moreover, inhibition of Src kinase with the tyrosine kinase inhibitor PP1 attenuated VEGF

  4. A Variant in COX-2 Gene Is Associated with Left Main Coronary Artery Disease and Clinical Outcomes of Coronary Artery Bypass Grafting

    PubMed Central

    Liu, Hanning; Sun, Cheng

    2017-01-01

    As a particular severe phenotype of coronary artery disease (CAD), left main coronary artery disease (LMCAD) is heritable. Genetic variants related to prostaglandin metabolism are associated with LMCAD. Cyclooxygenase-2 (COX-2), a key synthase in prostaglandin pathways, displays high density in atherosclerotic lesions and promotes early atherosclerosis in CAD progression. We hypothesized that genetic variants in COX-2 gene contribute to LMCAD phenotype susceptibility compared to more peripheral coronary artery disease (MPCAD). In this study, we genotyped COX-2 rs5275, rs5277, and rs689466 of 1544 CAD patients undergoing coronary artery bypass grafting (CABG) and found that rs5277 C allele carriage was associated with LMCAD (adjusted OR: 1.590; 95% CI: 1.103~2.291; p = 0.013). Furtherly, long-term follow-up data suggested that rs5277 C allele carriage increased risk of major adverse cardiac and cerebrovascular events (MACCE) in the whole cohort (adjusted HR: 1.561; 95% CI: 1.025~2.377; p = 0.038) and LMCAD subgroup (adjusted HR: 2.014; 95% CI: 1.036~3.913; p = 0.039) but not in MPCAD subgroup (adjusted HR: 1.375; 95% CI: 0.791~2.392; p = 0.259). In conclusion, we demonstrate that COX-2 rs5277 C allele increases the risk of left main coronary artery lesion and is also correlated with poor prognosis of LMCAD patients with CABG therapy. PMID:28194409

  5. The representation of a synoptic-scale weather system in a thermodynamically adjusted version of the ECHAM4 general circulation model

    NASA Astrophysics Data System (ADS)

    Bauer, H.-S.; Wulfmeyer, V.; Bengtsson, L.

    2008-04-01

    In this work, a strong cyclone event is simulated by the general circulation model (GCM) ECHAM4 for studying the representation of weather systems in a climate model. The system developed along the East Coast of the U.S.A. between the 12th and 14th of March 1993. The GCM simulation was started from climatological conditions and was continuously forced to the analyzed state by a thermodynamical adjustment based on the Newtonian relaxation technique (nudging). Relaxation terms for vorticity, divergence, temperature, and the logarithm of surface pressure were added at each model level and time step. The necessary forcing files were calculated from the ECMWF re-analysis (ERA15). No nudging terms were added for the components of the water cycle. Using this forcing, the model was able to reproduce the synoptic-scale features and its temporal development realistically after a spin-up period. This is true even for quantities that are not adjusted to the analysis (e.g., humidity). Detailed comparisons of the model simulations with available observations and the forcing ERA15 were performed for the cyclone case. Systematic errors were detected in the simulation of the thermodynamic state of the atmosphere, which can be traced back to deficiencies in model parametrizations. Differences in the representation of the surface fluxes lead to systematic deviations in near-surface temperature and wind fields. The general situation is very similar in both model representations. Errors were detected in the simulation of the convective boundary layer behind the cold front. The observed strong convective activity is missed both by the adjusted ECHAM4 simulation and ERA15. This is most likely caused by weaknesses in the cloud and convection schemes or by a too strong downdraft compensating the frontal lifting and suppressing the vertical transport of moisture from the boundary layer to higher levels. This work demonstrates for the investigated case the value of simulating single weather

  6. The effects of celecoxib, a COX-2 selective inhibitor, on acute inflammation induced in irradiated rats.

    PubMed

    Khayyal, M T; El-Ghazaly, Mona A; El-Hazek, R M; Nada, A S

    2009-10-01

    The potential value of selective and non-selective COX-2 inhibitors in preventing some of the biochemical changes induced by ionizing radiation was studied in rats exposed to carrageenan-induced paw edema and 6-day-old air pouch models. The animals were exposed to different exposure levels of gamma-radiation, namely either to single doses of 2 and 7.5 Gy or a fractionated dose level of 7.5 Gy delivered as 0.5 Gy twice weekly for 7.5 weeks. The inflammatory response produced by carrageenan in irradiated rats was markedly higher than that induced in non-irradiated animals, and depended on the extent of irradiation. Celecoxib, a selective COX-2 inhibitor, in doses of 3, 5, 10, and 15 mg/kg was effective in reducing paw edema in irradiated and non-irradiated rats in a dose-dependent manner as well as diclofenac (3 mg/kg), a non-selective COX inhibitor. Irradiation of animals before the induction of the air pouch by an acute dose of 2 Gy led to a significant increase in leukocytic count, as well as in the level of interleukin-6 (IL-6), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), LTB(4), PGE(2) (as an index of COX-2 activity), TXB(2) (as an index of COX-1 activity), and the plasma level of MDA. This increase in level of these parameters was more marked than that observed in the non-irradiated animals subjected to the inflammagen. The blood GSH level was not affected by the dose of irradiation used, whereas superoxide dismutase (SOD) activity was suppressed. In many respects, celecoxib (5 mg/kg) was as potent as diclofenac in decreasing the elevated levels of IL-6, IL-1beta, TNF-alpha, LTB(4), PGE(2), but lacked any significant effect on TXB(2) level. Since it is mostly selective for COX-2 with a rare effect on COX-1 enzyme, both drugs at the selected dose levels showed no effect on level of MDA, GSH, and SOD activity.

  7. Formulation of distortion error for the line-of-sight (LOS) vector adjustment model and its role in restitution of SPOT imagery

    NASA Astrophysics Data System (ADS)

    Jung, Hyung-Sup; Won, Joong-Sun

    A recently developed line-of-sight (LOS) vector adjustment model is an effective geopositioning method for pushbroom images. A requirement for this method is that a predicted orbit be close to a true orbit. Although the method has proven very effective for SPOT 5, which has an accurate orbital control system, it was an open question whether or not the method could be effective for a satellite system with poor orbital accuracy. In this paper, a distortion error is defined and formulated as a common criterion for testing orbital requirements of a pushbroom system from the perspective of the LOS vector adjustment model. Using the distortion error, it is shown that a satellite system, even with poor locational accuracy comparable to SPOT 3-4, meets the orbital requirements as long as the maximum topographic height in the landscape is less than 4 km against the height level of the control points. A test was performed using three SPOT images and only five ground control points (GCPs). Results indicated that the root mean squared errors (RMSEs) of horizontal residual errors calculated from 30 check points were less than 10 m. The achieved accuracy of three-dimensional object-point determination was 6 m in the X-dimension and 7 m in both Y- and Z-dimensions. The conclusion can be drawn that the orbital requirements of this method can accommodate most space-borne systems, and therefore the LOS vector adjustment model is effective for SPOT and comparable pushbroom imagery.

  8. Design and synthesis of benzimidazole analogs endowed with oxadiazole as selective COX-2 inhibitor.

    PubMed

    Rathore, Ankita; Rahman, Mujeeb Ur; Siddiqui, Anees Ahamad; Ali, Abuzer; Shaharyar, Mohammad

    2014-12-01

    New molecules of benzimidazole endowed with oxadiazole were designed and synthesized from 2-(2-((pyrimidin-2-ylthio)methyl)-1H-benzo[d]imidazol-1-yl)acetohydrazide as 1-((5-substituted alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl)-2-((pyrimidin-2-ylthio)methyl)-1H-benzimidazoles (5a-r) with the aim to acquire selective cyclooxygenase (COX-2) inhibitor activity. The synthesized compounds were screened by in vitro cyclooxygenase assays to determine COX-1 and COX-2 inhibitory potency and the results showed that they had good-to-remarkable activity with an IC50 range of 11.6-56.1 µM. The most active compounds were further screened for their in vivo anti-inflammatory activity by using the carrageenan-induced rat paw edema model. In vitro anticancer activities of the hybrid compounds were assessed by the National Cancer Institute (NCI), USA, against 60 human cell lines, and the results showed a good spectrum. Compound 5l exhibited significant COX-2 inhibition with an IC50 value of 8.2 µM and a percent protection of 68.4%. Compound 5b evinced moderate cytotoxicity toward the UO-31 cell line of renal cancer. A docking study was performed using Maestro 9.0, to provide the binding mode into the binding sites of the cyclooxygenase enzyme. Hopefully, in the future, compound 5l could serve as a lead compound for developing new COX-2 inhibitors.

  9. Analysis models for variables associated with breastfeeding duration.

    PubMed

    dos S Neto, Edson Theodoro; Zandonade, Eliana; Emmerich, Adauto Oliveira

    2013-09-01

    OBJECTIVE To analyze the factors associated with breastfeeding duration by two statistical models. METHODS A population-based cohort study was conducted with 86 mothers and newborns from two areas primary covered by the National Health System, with high rates of infant mortality in Vitória, Espírito Santo, Brazil. During 30 months, 67 (78%) children and mothers were visited seven times at home by trained interviewers, who filled out survey forms. Data on food and sucking habits, socioeconomic and maternal characteristics were collected. Variables were analyzed by Cox regression models, considering duration of breastfeeding as the dependent variable, and logistic regression (dependent variables, was the presence of a breastfeeding child in different post-natal ages). RESULTS In the logistic regression model, the pacifier sucking (adjusted Odds Ratio: 3.4; 95%CI 1.2-9.55) and bottle feeding (adjusted Odds Ratio: 4.4; 95%CI 1.6-12.1) increased the chance of weaning a child before one year of age. Variables associated to breastfeeding duration in the Cox regression model were: pacifier sucking (adjusted Hazard Ratio 2.0; 95%CI 1.2-3.3) and bottle feeding (adjusted Hazard Ratio 2.0; 95%CI 1.2-3.5). However, protective factors (maternal age and family income) differed between both models. CONCLUSIONS Risk and protective factors associated with cessation of breastfeeding may be analyzed by different models of statistical regression. Cox Regression Models are adequate to analyze such factors in longitudinal studies.

  10. Multiple recent horizontal transfers of the cox1 intron in Solanaceae and extended co-conversion of flanking exons

    PubMed Central

    2011-01-01

    of extended co-conversion suggests that other cox1 conversions may be longer than realized but obscured by the exceptional conservation of plant mitochondrial sequences. Our findings provide further support for the rampant-transfer model of cox1 intron evolution and recommend the Solanaceae as a model system for the experimental analysis of cox1 intron transfer in plants. PMID:21943226

  11. Salt supplementation ameliorates developmental kidney defects in COX-2-/- mice.

    PubMed

    Slattery, Patrick; Frölich, Stefanie; Goren, Itamar; Nüsing, Rolf Michael

    2017-03-08

    Deficiency of cyclooxygenase-2 (COX-2) activity in the early postnatal time course causes impairment of kidney development leading to kidney insufficiency. We hypothesize that impaired NaCl reabsorption during the first days of life is a substantial cause for nephrogenic defects observed in COX-2-/- mice and that salt supplementation corrects these defects. Daily injections of 0.8 mg/g/d NaCl for the first 10 days after birth ameliorated impaired kidney development in COX-2-/- pups resulting in an increase in glomerular size and reduction of immature superficial glomeruli. However, impaired renal subcortical growth was not corrected. Increasing renal tubular flow by volume load or injections of KCl did not relieve the renal histomorphological damage. Administration of torsemide and spironolacton also affected nephrogenesis resulting in diminished glomeruli and cortical thinning. Treatment of COX-2-/- pups with NaCl/DOCA caused a stronger mitigation of glomerular size and also induced a slight but significant growth of cortical tissue mass. After birth renal mRNA expression of NHE3, NKCC2, ROMK, NCCT, ENaC, and Na+/K+-ATPase increased relative to day P2 in wild type mice. However, in COX-2-/- mice a significantly lower expression was observed for NCCT, while DOCA/NaCl treatment significantly increased NHE3 and ROMK expression. Regarding long-term effects of postnatal NaCl/DOCA injections improved kidney function with normalization of pathologically enhanced creatinine and urea plasma levels and albumin excretion was observed. In summary we present evidence that a salt supplementation during the COX-2 dependent time frame of nephrogenesis partly reverses renal morphological defects in COX-2-/- mice and improves kidney function.

  12. Increasing shape modelling accuracy by adjusting for subject positioning: an application to the analysis of radiographic proximal femur symmetry using data from the Osteoarthritis Initiative.

    PubMed

    Lindner, C; Wallis, G A; Cootes, T F

    2014-04-01

    In total hip arthroplasty, the shape of the contra-lateral femur frequently serves as a template for preoperative planning. Previous research on contra-lateral femoral symmetry has been based on conventional hip geometric measurements (which reduce shape to a series of linear measurements) and did not take the effect of subject positioning on radiographic femur shape into account. The aim of this study was to analyse proximal femur symmetry based on statistical shape models (SSMs) which quantify global femoral shape while also adjusting for differences in subject positioning during image acquisition. We applied our recently developed fully automatic shape model matching (FASMM) system to automatically segment the proximal femur from AP pelvic radiographs to generate SSMs of the proximal femurs of 1258 Caucasian females (mean age: 61.3 SD=9.0). We used a combined SSM (capturing the left and right femurs) to identify and adjust for shape variation attributable to subject positioning as well as a single SSM (including all femurs as left femurs) to analyse proximal femur symmetry. We also calculated conventional hip geometric measurements (head diameter, neck width, shaft width and neck-shaft angle) using the output of the FASMM system. The combined SSM revealed two modes that were clearly attributable to subject positioning. The average difference (mean point-to-curve distance) between left and right femur shape was 1.0mm before and 0.8mm after adjusting for these two modes. The automatic calculation of conventional hip geometric measurements after adjustment gave an average absolute percent asymmetry of within 3.1% and an average absolute difference of within 1.1mm or 2.9° for all measurements. We conclude that (i) for Caucasian females the global shape of the right and left proximal femurs is symmetric without isolated locations of asymmetry; (ii) a combined left-right SSM can be used to adjust for radiographic shape variation due to subject positioning; and (iii

  13. Allan V. Cox: AGU President 1978”1980

    NASA Astrophysics Data System (ADS)

    Richman, Barbara T.

    When Allan V. Cox was presented AGU's John Adam Fleming Medal in 1969, John Verhoogen described Cox's work as “characterized by painstaking care, proper attention to and use of statistics, and great insight.” Those same thoughts were echoed on February 3, 1987, during the memorial service for Cox, who died in a bicycling accident on January 27. The Stanford Memorial Church was crowded with colleagues, students, and friends.The Fleming Medal was presented to Cox in recognition of his studies on the fluctuation of the geomagnetic field. These studies helped to confirm theories of continental drift and seafloor spreading. The medal is awarded annually by AGU for original research and technical leadership in geomagnetism, atmospheric electricity, aeronomy, and related sciences. In addition to the Fleming Medal, Cox received the Antarctic Service Medal in 1970, the Vetlesen Prize in 1971, and the Arthur L. Day Prize of the National Academy of Sciences in 1984. He was a Fellow of AGU and a member of the National Academy of Sciences.

  14. Physiological COX-2 expression in breast epithelium associates with COX-2 levels in ductal carcinoma in situ and invasive breast cancer in young women.

    PubMed

    Fornetti, Jaime; Jindal, Sonali; Middleton, Kara A; Borges, Virginia F; Schedin, Pepper

    2014-04-01

    Cyclooxygenase-2 (COX-2) overexpression is implicated in increased risk and poorer outcomes in breast cancer in young women. We investigated COX-2 regulation in normal premenopausal breast tissue and its relationship to malignancy in young women. Quantitative COX-2 immunohistochemistry was performed on adjacent normal and breast cancer tissues from 96 premenopausal women with known clinical reproductive histories, and on rat mammary glands with distinct ovarian hormone exposures. COX-2 expression in the normal breast epithelium varied more than 40-fold between women and was associated with COX-2 expression levels in ductal carcinoma in situ and invasive cancer. Normal breast COX-2 expression was independent of known breast cancer prognostic indicators, including tumor stage and clinical subtype, indicating that factors regulating physiological COX-2 expression may be the primary drivers of COX-2 expression in breast cancer. Ovarian hormones, particularly at pregnancy levels, were identified as modulators of COX-2 in normal mammary epithelium. However, serial breast biopsy analysis in nonpregnant premenopausal women suggested relatively stable baseline levels of COX-2 expression, which persisted independent of menstrual cycling. These data provide impetus to investigate how baseline COX-2 expression is regulated in premenopausal breast tissue because COX-2 levels in normal breast epithelium may prove to be an indicator of breast cancer risk in young women, and predict the chemopreventive and therapeutic efficacy of COX-2 inhibitors in this population.

  15. Experiments to Determine Whether Recursive Partitioning (CART) or an Artificial Neural Network Overcomes Theoretical Limitations of Cox Proportional Hazards Regression

    NASA Technical Reports Server (NTRS)

    Kattan, Michael W.; Hess, Kenneth R.; Kattan, Michael W.

    1998-01-01

    New computationally intensive tools for medical survival analyses include recursive partitioning (also called CART) and artificial neural networks. A challenge that remains is to better understand the behavior of these techniques in effort to know when they will be effective tools. Theoretically they may overcome limitations of the traditional multivariable survival technique, the Cox proportional hazards regression model. Experiments were designed to test whether the new tools would, in practice, overcome these limitations. Two datasets in which theory suggests CART and the neural network should outperform the Cox model were selected. The first was a published leukemia dataset manipulated to have a strong interaction that CART should detect. The second was a published cirrhosis dataset with pronounced nonlinear effects that a neural network should fit. Repeated sampling of 50 training and testing subsets was applied to each technique. The concordance index C was calculated as a measure of predictive accuracy by each technique on the testing dataset. In the interaction dataset, CART outperformed Cox (P less than 0.05) with a C improvement of 0.1 (95% Cl, 0.08 to 0.12). In the nonlinear dataset, the neural network outperformed the Cox model (P less than 0.05), but by a very slight amount (0.015). As predicted by theory, CART and the neural network were able to overcome limitations of the Cox model. Experiments like these are important to increase our understanding of when one of these new techniques will outperform the standard Cox model. Further research is necessary to predict which technique will do best a priori and to assess the magnitude of superiority.

  16. Ribosome-Associated Mba1 Escorts Cox2 from Insertion Machinery to Maturing Assembly Intermediates

    PubMed Central

    Lorenzi, Isotta; Oeljeklaus, Silke; Ronsör, Christin; Bareth, Bettina; Warscheid, Bettina; Dennerlein, Sven

    2016-01-01

    The three conserved core subunits of the cytochrome c oxidase are encoded by mitochondria in close to all eukaryotes. The Cox2 subunit spans the inner membrane twice, exposing the N and C termini to the intermembrane space. For this, the N terminus is exported cotranslationally by Oxa1 and subsequently undergoes proteolytic maturation in Saccharomyces cerevisiae. Little is known about the translocation of the C terminus, but Cox18 has been identified to be a critical protein in this process. Here we find that the scaffold protein Cox20, which promotes processing of Cox2, is in complex with the ribosome receptor Mba1 and translating mitochondrial ribosomes in a Cox2-dependent manner. The Mba1-Cox20 complex accumulates when export of the C terminus of Cox2 is blocked by the loss of the Cox18 protein. While Cox20 engages with Cox18, Mba1 is no longer present at this stage. Our analyses indicate that Cox20 associates with nascent Cox2 and Mba1 to promote Cox2 maturation cotranslationally. We suggest that Mba1 stabilizes the Cox20-ribosome complex and supports the handover of Cox2 to the Cox18 tail export machinery. PMID:27550809

  17. COX-2 gene expression is correlated with cognitive function in recurrent depressive disorder.

    PubMed

    Gałecki, Piotr; Talarowska, Monika; Bobińska, Kinga; Szemraj, Janusz

    2014-02-28

    Cyclooxygenase-2(COX-2) may be a key inflammatory enzyme involved in recurrent depressive disorder(rDD). In rDD group, COX-2 expression were higher and significant correlations occurred between COX-2 expression and cognitive functions. In controls there was no significant association between analysed variables. Thus, the COX-2 enzyme may be important for cognitive functioning in rDD.

  18. Seizure following the Use of the COX-2 Inhibitor Etoricoxib

    PubMed Central

    Arnao, Valentina; Riolo, Marianna; Fierro, Brigida

    2017-01-01

    We describe a case of epileptic seizures occurring after the use of a COX-2 inhibitor. A 61-year-old man was admitted to our department because of a generalized tonic-clonic seizure. EEG showed generalized slowdown of the activity. Neuroimaging and blood samples studies did not evidence alterations, but a careful pharmacological history revealed that the patient had taken the COX-2 inhibitor etoricoxib to treat lumbago few days before the onset of clinical symptoms. No seizures were reported after etoricoxib discontinuation and an EEG resulted to be normal two months after this. Conclusion. Knowing the pharmacological history of a patient is important for understanding the clinical presentation and selecting appropriate treatment. This is, to the best of our knowledge, the first reported case of generalized seizures associated with the use of COX-2 inhibitors. PMID:28210513

  19. Synthesis and biological evaluation of 3,4-diphenyl-1,2,5-oxadiazole-2-oxides and 3,4-diphenyl-1,2,5-oxadiazoles as potential hybrid COX-2 inhibitor/nitric oxide donor agents.

    PubMed

    Velázquez, Carlos; Rao, P N Praveen; McDonald, Robert; Knaus, Edward E

    2005-04-15

    A group of 3,4-diphenyl-1,2,5-oxadiazole-2-oxides (3,4-diphenylfuroxans) and the corresponding N-desoxy 3,4-diphenyl-1,2,5-oxadiazoles (3,4-diphenylfurazans) analogs, were synthesized for in vitro evaluation as hybrid cyclooxygenase (COX) inhibitor/nitric oxide donor agents. Reaction of 1-[4-(methylsulfonyl)phenyl]-2-phenylethene with an aqueous sodium nitrite solution in acetic acid afforded a mixture (3:1 ratio) of the inseparable 4-[4-(methylsulfonyl)phenyl]-3-phenyl-1,2,5-oxadiazole-2-oxide (13a) and 3-[4-(methylsulfonyl)phenyl]-4-phenyl-1,2,5-oxadiazole-2-oxide (13b) regioisomers. A group of related regioisomers possessing either a p-aminosulfonylphenyl (16) or a p-azidosulfonylphenyl (17), moiety were obtained by chlorosulfonation of the unsubstituted 3,4-diphenylfuroxan (10) and subsequent reaction with either ammonium hydroxide or sodium azide, respectively. The methanesulfonyl regioisomers 13a,b [COX-1 IC50=11.6 microM; COX-2 IC50=0.12 microM; COX-2 selectivity index (SI)=97] and aminosulfonyl regioisomers 16 (COX-1 IC50=9.8 microM; COX-2 IC50=0.78 microM; COX-2 SI=12), like the reference drug celecoxib (COX-1 IC50=33.1 microM; COX-2 IC50=0.07 microM; COX-2 SI=472), were potent in vitro COX-2 inhibitors with a good COX-2 selectivity index. Release of nitric oxide (NO) from the 3,4-diphenylfuroxan compounds (10, 13a,b, 16, 17) was thiol-dependent since the % NO released was higher upon incubation in the presence of l-cysteine (0.57-3.18%) compared to that in phosphate buffer solution at pH7.4 (0.06-0.15%). Molecular modeling (docking) studies show that the methanesulfonyl (MeSO2) COX-2 pharmacophore present in regioisomers 13a,b is positioned in the vicinity of the COX-2 secondary pocket. The in vitro NO release data, COX-1/COX-2 inhibition and COX-2 SI structure-activity relationships acquired, and molecular modeling docking studies suggest that the 1,2,5-oxadiazole-2-oxide (furoxan) ring possesses beneficial features that should be present in a suitable

  20. Relationship between efficiency and clinical effectiveness indicators in an adjusted model of resource consumption: a cross-sectional study

    PubMed Central

    2013-01-01

    Background Adjusted clinical groups (ACG®) have been widely used to adjust resource distribution; however, the relationship with effectiveness has been questioned. The purpose of the study was to measure the relationship between efficiency assessed by ACG® and a clinical effectiveness indicator in adults attended in Primary Health Care Centres (PHCs). Methods Research design: cross-sectional study. Subjects: 196, 593 patients aged >14 years in 13 PHCs in Catalonia (Spain). Measures: Age, sex, PHC, basic care team (BCT), visits, episodes (diagnoses), and total direct costs of PHC care and co-morbidity as measured by ACG® indicators: Efficiency indices for costs, visits, and episodes (costs EI, visits EI, episodes EI); a complexity or risk index (RI); and effectiveness measured by a general synthetic index (SI). The relationship between EI, RI, and SI in each PHC and BCT was measured by multiple correlation coefficients (r). Results In total, 56 of the 106 defined ACG® were present in the study population, with five corresponding to 44.5% of the patients, 11 to 68.0% of patients, and 30 present in less than 0.5% of the sample. The RI in each PHC ranged from 0.9 to 1.1. Costs, visits, and episodes had similar trends for efficiency in six PHCs. There was moderate correlation between costs EI and visits EI (r = 0.59). SI correlation with episodes EI and costs EI was moderate (r = 0.48 and r = −0.34, respectively) and was r = −0.14 for visits EI. Correlation between RI and SI was r = 0.29. Conclusions The Efficiency and Effectiveness ACG® indicators permit a comparison of primary care processes between PHCs. Acceptable correlation exists between effectiveness and indicators of efficiency in episodes and costs. PMID:24139144

  1. Molecular Dynamics Simulations of Arachidonic Acid-Derived Pentadienyl Radical Intermediate Complexes with COX-1 and COX-2

    PubMed Central

    Furse, Kristina E.; Pratt, Derek A.; Schneider, Claus; Brash, Alan R.; Porter, Ned A.; Lybrand, Terry P.

    2008-01-01

    The two cyclooxygenase enzymes, COX-1 and COX-2, are responsible for the committed step in prostaglandin biosynthesis, and are the targets of the non-steroidal anti-inflammatory drugs aspirin, ibuprofen and the COX-2 selective inhibitors, Celebrex™, Vioxx™ and Bextra™. The enzymes are remarkable in that they catalyze two dioxygenations and two cyclizations of the native substrate, arachidonic acid, with near absolute regio- and stereoselectivity. Several theories have been advanced to explain the nature of enzymatic control over this series of reactions, including suggestions of steric shielding and oxygen channeling. As proposed here, selective radical trapping and spin localization in the substrate-derived pentadienyl radical intermediate can also be envisioned. Herein we describe the results of explicit, 10 ns molecular dynamics simulations of both COX-1 and COX-2 with the substrate-derived pentadienyl radical intermediate bound in the active site. The enzymes’ influence on the conformation of the pentadienyl radical was investigated, along with the accessible space above and below the radical plane, and the width of several channels to the active site that could function as access routes for molecular oxygen. Additional simulations demonstrated the extent of molecular oxygen mobility within the active site. The results suggest that spin localization is unlikely to play a role in enzymatic control of this reaction. Instead, a combination of oxygen channeling, steric shielding and selective radical trapping appears to be responsible. This work adds a dynamic perspective to the strong foundation of static structural data available for these enzymes. PMID:16519515

  2. Development of a computational framework to adjust the pre-impact spine posture of a whole-body model based on cadaver tests data.

    PubMed

    Poulard, David; Subit, Damien; Donlon, John-Paul; Kent, Richard W

    2015-02-26

    A method was developed to adjust the posture of a human numerical model to match the pre-impact posture of a human subject. The method involves pulling cables to prescribe the position and orientation of the head, spine and pelvis during a simulation. Six postured models matching the pre-impact posture measured on subjects tested in previous studies were created from a human numerical model. Posture scalars were measured on pre- and after applying the method to evaluate its efficiency. The lateral leaning angle θL defined between T1 and the pelvis in the coronal plane was found to be significantly improved after application with an average difference of 0.1±0.1° with the PMHS (4.6±2.7° before application). This method will be applied in further studies to analyze independently the contribution of pre-impact posture on impact response using human numerical models.

  3. Assessing model uncertainty using hexavalent chromium and ...

    EPA Pesticide Factsheets

    Introduction: The National Research Council recommended quantitative evaluation of uncertainty in effect estimates for risk assessment. This analysis considers uncertainty across model forms and model parameterizations with hexavalent chromium [Cr(VI)] and lung cancer mortality as an example. The objective of this analysis is to characterize model uncertainty by evaluating the variance in estimates across several epidemiologic analyses.Methods: This analysis compared 7 publications analyzing two different chromate production sites in Ohio and Maryland. The Ohio cohort consisted of 482 workers employed from 1940-72, while the Maryland site employed 2,357 workers from 1950-74. Cox and Poisson models were the only model forms considered by study authors to assess the effect of Cr(VI) on lung cancer mortality. All models adjusted for smoking and included a 5-year exposure lag, however other latency periods and model covariates such as age and race were considered. Published effect estimates were standardized to the same units and normalized by their variances to produce a standardized metric to compare variability in estimates across and within model forms. A total of 7 similarly parameterized analyses were considered across model forms, and 23 analyses with alternative parameterizations were considered within model form (14 Cox; 9 Poisson). Results: Across Cox and Poisson model forms, adjusted cumulative exposure coefficients for 7 similar analyses ranged from 2.47

  4. Novel COX-2 Inhibitor for Breast Cancer Therapy

    DTIC Science & Technology

    2005-07-01

    exothermic, chloroacetic acid (18.14 g, 192 mmol) was added portion wise, and the reaction mixture was re- fluxed for 5 h. This mixture was then poured into...arachadonic acid to prostaglandins (PGs) (Vane and Botting, 1998). Recent studies have shown that high levels of COX-2 are expressed in a large percentage...7.5 0 µM 3 µM 5 µM 8 µM Celebrex A Arachidonic acid (µM) Figure 9: Effect of substrate concentrations on the inactivation of COX-2 by Celebrex (A

  5. Multifocal Fixed Drug Eruption with COX-2 Inhibitor-Celecoxib

    PubMed Central

    Chugh, Shikha; Sarkar, Rashmi; Garg, Vijay K; Singh, Avninder; Keisham, Chitralekha

    2013-01-01

    Cyclooxygenase-2 (COX-2) inhibitors are rapidly becoming the first choice nonsteroidal anti-inflammatory drugs (NSAIDs) for various rheumatological and other painful conditions. However, they might not be as safe or free of side effects as they are considered to be. These COX-2inhibitors may cause a variety of dermatological and systemic side effects of which we should be aware to avoid their indiscriminate use. We hereby report a case of multifocal fixed drug eruption (FDE) with celecoxib which has not yet been reported in Indian settings. PMID:23716804

  6. Multifocal Fixed Drug Eruption with COX-2 Inhibitor-Celecoxib.

    PubMed

    Chugh, Shikha; Sarkar, Rashmi; Garg, Vijay K; Singh, Avninder; Keisham, Chitralekha

    2013-03-01

    Cyclooxygenase-2 (COX-2) inhibitors are rapidly becoming the first choice nonsteroidal anti-inflammatory drugs (NSAIDs) for various rheumatological and other painful conditions. However, they might not be as safe or free of side effects as they are considered to be. These COX-2inhibitors may cause a variety of dermatological and systemic side effects of which we should be aware to avoid their indiscriminate use. We hereby report a case of multifocal fixed drug eruption (FDE) with celecoxib which has not yet been reported in Indian settings.

  7. Controlling Time-Dependent Confounding by Health Status and Frailty: Restriction Versus Statistical Adjustment.

    PubMed

    McGrath, Leah J; Ellis, Alan R; Brookhart, M Alan

    2015-07-01

    Nonexperimental studies of preventive interventions are often biased because of the healthy-user effect and, in frail populations, because of confounding by functional status. Bias is evident when estimating influenza vaccine effectiveness, even after adjustment for claims-based indicators of illness. We explored bias reduction methods while estimating vaccine effectiveness in a cohort of adult hemodialysis patients. Using the United States Renal Data System and linked data from a commercial dialysis provider, we estimated vaccine effectiveness using a Cox proportional hazards marginal structural model of all-cause mortality before and during 3 influenza seasons in 2005/2006 through 2007/2008. To improve confounding control, we added frailty indicators to the model, measured time-varying confounders at different time intervals, and restricted the sample in multiple ways. Crude and baseline-adjusted marginal structural models remained strongly biased. Restricting to a healthier population removed some unmeasured confounding; however, this reduced the sample size, resulting in wide confidence intervals. We estimated an influenza vaccine effectiveness of 9% (hazard ratio = 0.91, 95% confidence interval: 0.72, 1.15) when bias was minimized through cohort restriction. In this study, the healthy-user bias could not be controlled through statistical adjustment; however, sample restriction reduced much of the bias.

  8. Redox-regulated dynamic interplay between Cox19 and the copper-binding protein Cox11 in the intermembrane space of mitochondria facilitates biogenesis of cytochrome c oxidase

    PubMed Central

    Bode, Manuela; Woellhaf, Michael W.; Bohnert, Maria; van der Laan, Martin; Sommer, Frederik; Jung, Martin; Zimmermann, Richard; Schroda, Michael; Herrmann, Johannes M.

    2015-01-01

    Members of the twin Cx9C protein family constitute the largest group of proteins in the intermembrane space (IMS) of mitochondria. Despite their conserved nature and their essential role in the biogenesis of the respiratory chain, the molecular function of twin Cx9C proteins is largely unknown. We performed a SILAC-based quantitative proteomic analysis to identify interaction partners of the conserved twin Cx9C protein Cox19. We found that Cox19 interacts in a dynamic manner with Cox11, a copper transfer protein that facilitates metalation of the Cu(B) center of subunit 1 of cytochrome c oxidase. The interaction with Cox11 is critical for the stable accumulation of Cox19 in mitochondria. Cox19 consists of a helical hairpin structure that forms a hydrophobic surface characterized by two highly conserved tyrosine-leucine dipeptides. These residues are essential for Cox19 function and its specific binding to a cysteine-containing sequence in Cox11. Our observations suggest that an oxidative modification of this cysteine residue of Cox11 stimulates Cox19 binding, pointing to a redox-regulated interplay of Cox19 and Cox11 that is critical for copper transfer in the IMS and thus for biogenesis of cytochrome c oxidase. PMID:25926683

  9. An age adjustment of very young children of India, 1981 and reappraisal of fertility and mortality rates--A model approach.

    PubMed

    Mukhopadhyay, B K

    1986-01-01

    Several approaches were made by actuaries and demographers to correct and smooth the Indian age distribution with special emphasis on population in age group 0-4 at different points of time. The present analysis conceives the life table stationary population (using the West Model) as 'reference standard'. 2 parameters were estimated from a regression equation using the proportion of population in age groups 5-14 and 60-plus as independent variables and that in 0-4 as the dependent variable. The corrected census proportions in age group 0-4 obtained from the regression model under certain assumptions for the 14 major states and India seem to be consistent and to have slightly lower values than those of the 1971 adjusted data. Moreover, unadjusted and adjusted proportions in 5-14 and 60 plus do not show any significant difference between the predicted values. Using the corrected population aged 0-4 years, the average annual birth and death rates during the 5 year period preceeding the 1981 census have been estimated for those 14 states and India as well. The estimated birth rates so obtained were further adjusted using an appropriate factor from the West Model and Indian life table survival ratios. The final estimates seem to be consistent, except for a few, and to have slightly higher values than those of earlier estimates. As the present analysis is based on a 5% sample and confined to only 14 states, it is proposed to study the same for all the states and India in greater detail using full count data on age distribution and actul life tables as and when available.

  10. Validation of the internalization of the Model Minority Myth Measure (IM-4) and its link to academic performance and psychological adjustment among Asian American adolescents.

    PubMed

    Yoo, Hyung Chol; Miller, Matthew J; Yip, Pansy

    2015-04-01

    There is limited research examining psychological correlates of a uniquely racialized experience of the model minority stereotype faced by Asian Americans. The present study examined the factor structure and fit of the only published measure of the internalization of the model minority myth, the Internalization of the Model Minority Myth Measure (IM-4; Yoo et al., 2010), with a sample of 155 Asian American high school adolescents. We also examined the link between internalization of the model minority myth types (i.e., myth associated with achievement and myth associated with unrestricted mobility) and psychological adjustment (i.e., affective distress, somatic distress, performance difficulty, academic expectations stress), and the potential moderating effect of academic performance (cumulative grade point average). Results suggested the 2-factor model of the IM-4 had an acceptable fit to the data and supported the factor structure using confirmatory factor analyses. Internalizing the model minority myth of achievement related positively to academic expectations stress; however, internalizing the model minority myth of unrestricted mobility related negatively to academic expectations stress, both controlling for gender and academic performance. Finally, academic performance moderated the model minority myth associated with unrestricted mobility and affective distress link and the model minority myth associated with achievement and performance difficulty link. These findings highlight the complex ways in which the model minority myth relates to psychological outcomes.

  11. COX-1 and COX-2 inhibition in horse blood by phenylbutazone, flunixin, carprofen and meloxicam: an in vitro analysis.

    PubMed

    Beretta, C; Garavaglia, G; Cavalli, M

    2005-10-01

    We report on the inhibitory activity of the NSAIDs meloxicam, carprofen, phenylbutazone and flunixin, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and carprofen are more selective inhibitors of COX-2 than phenylbutazone and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and flunixin (+29.7%) had greater COX-2 selectivity than at IC50, and meloxicam (-41.2%) and carprofen (-12.9%) had lower COX-2 selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level.

  12. Effects of β-glucosidase hydrolyzed products of harpagide and harpagoside on cyclooxygenase-2 (COX-2) in vitro.

    PubMed

    Zhang, Liuqiang; Feng, Li; Jia, Qi; Xu, Jinwen; Wang, Rui; Wang, Zhengtao; Wu, Yingchun; Li, Yiming

    2011-08-15

    Harpagide (1) and harpagoside (2) are two iridoid glycosides existing in many medicinal plants. Although they are believed to be the main bioactive compounds related to the anti-inflammatory efficacy of these plants, the mechanisms of their anti-inflammatory activities remain unclear. The results of our present study showed that 1 and 2 had no effects on inhibitions of cyclooxygenase (COX)-1/2 enzyme activity, tumor necrosis factor-α (TNF-α) release, and nitric oxide (NO) production in vitro. However, the hydrolyzed products of 1 and 2 with β-glucosidase treatment showed a significant inhibitory effect on COX-2 activity at 2.5-100 μM in a concentration-dependent manner. Our further study revealed that the hydrolyzed 2 product was structurally the same as the hydrolyzed 1 product (H-harpagide (3)). The structure of 3 was 2-(formylmethyl)-2,3,5-trihydroxy-5-methylcyclopentane carbaldehyde, with a backbone similar to prostaglandins and COX-2 inhibitors such as celecoxib. All of them have a pentatomic ring with two adjacent side chains. The result of molecular modeling and docking study showed that 3 could bind to the COX-2 active domain well through hydrophobic and hydrogen-bonding interactions, whereas 1 and 2 could not, implying that the hydrolysis of the glycosidic bond of 1 and 2 is a pre-requisite step for their COX-2 inhibitory activity.

  13. Downregulation of HOTAIR Expression Mediated Anti-Metastatic Effect of Artesunate on Cervical Cancer by Inhibiting COX-2 Expression

    PubMed Central

    Zhang, Lixin; Qian, Hua; Sha, Min; Luan, Zhengyun; Lin, Mei; Yuan, Donglan; Li, Xiaokang; Huang, Junxing; Ye, Lihua

    2016-01-01

    Artesunate (ART) has anti-cancer activities for a variety of solid tumors. The aim of this study was to investigate the anti-metastatic effect of ART on cervical cancer cells. In vivo anti-metastatic effect of ART was investigated in mice with the lung metastasis model by the subcutaneous injection of ART. The interaction of HOTAIR and COX-2 was measured by RNA immunoprecipitation and RNA pull-down assay. The effect of ART on metastasis of CaSki and Hela cells was evaluated by invasion and migration assay. We found that ART inhibited cervical cancer metastasis and HOTAIR expression. HOTAIR overexpression partially abolished the anti-metastatic effect of ART on cervical cancer cells. In addition, HOTAIR can interact with COX-2 to positively regulate COX-2 expression and catalytic activity. Finally, overexpression of COX-2 reversed the effect of HOTAIR knockdown on Hela cell migration and invasion. Taken together, our data revealed that ART may elicit anti-metastatic effect against cervical cancer by inhibition of HOTAIR expression, which resulted in the decrease of COX-2 expression. PMID:27736969

  14. Hemorrhage-Adjusted Iron Requirements, Hematinics and Hepcidin Define Hereditary Hemorrhagic Telangiectasia as a Model of Hemorrhagic Iron Deficiency

    PubMed Central

    Finnamore, Helen; Le Couteur, James; Hickson, Mary; Busbridge, Mark; Whelan, Kevin; Shovlin, Claire L.

    2013-01-01

    Background Iron deficiency anemia remains a major global health problem. Higher iron demands provide the potential for a targeted preventative approach before anemia develops. The primary study objective was to develop and validate a metric that stratifies recommended dietary iron intake to compensate for patient-specific non-menstrual hemorrhagic losses. The secondary objective was to examine whether iron deficiency can be attributed to under-replacement of epistaxis (nosebleed) hemorrhagic iron losses in hereditary hemorrhagic telangiectasia (HHT). Methodology/Principal Findings The hemorrhage adjusted iron requirement (HAIR) sums the recommended dietary allowance, and iron required to replace additional quantified hemorrhagic losses, based on the pre-menopausal increment to compensate for menstrual losses (formula provided). In a study population of 50 HHT patients completing concurrent dietary and nosebleed questionnaires, 43/50 (86%) met their recommended dietary allowance, but only 10/50 (20%) met their HAIR. Higher HAIR was a powerful predictor of lower hemoglobin (p = 0.009), lower mean corpuscular hemoglobin content (p<0.001), lower log-transformed serum iron (p = 0.009), and higher log-transformed red cell distribution width (p<0.001). There was no evidence of generalised abnormalities in iron handling Ferritin and ferritin2 explained 60% of the hepcidin variance (p<0.001), and the mean hepcidinferritin ratio was similar to reported controls. Iron supplement use increased the proportion of individuals meeting their HAIR, and blunted associations between HAIR and hematinic indices. Once adjusted for supplement use however, reciprocal relationships between HAIR and hemoglobin/serum iron persisted. Of 568 individuals using iron tablets, most reported problems completing the course. For patients with hereditary hemorrhagic telangiectasia, persistent anemia was reported three-times more frequently if iron tablets caused diarrhea or needed to be stopped

  15. Using an Adjusted Serfling Regression Model to Improve the Early Warning at the Arrival of Peak Timing of Influenza in Beijing

    PubMed Central

    Wang, Xiaoli; Wu, Shuangsheng; MacIntyre, C. Raina; Zhang, Hongbin; Shi, Weixian; Peng, Xiaomin; Duan, Wei; Yang, Peng; Zhang, Yi; Wang, Quanyi

    2015-01-01

    Serfling-type periodic regression models have been widely used to identify and analyse epidemic of influenza. In these approaches, the baseline is traditionally determined using cleaned historical non-epidemic data. However, we found that the previous exclusion of epidemic seasons was empirical, since year-year variations in the seasonal pattern of activity had been ignored. Therefore, excluding fixed ‘epidemic’ months did not seem reasonable. We made some adjustments in the rule of epidemic-period removal to avoid potentially subjective definition of the start and end of epidemic periods. We fitted the baseline iteratively. Firstly, we established a Serfling regression model based on the actual observations without any removals. After that, instead of manually excluding a predefined ‘epidemic’ period (the traditional method), we excluded observations which exceeded a calculated boundary. We then established Serfling regression once more using the cleaned data and excluded observations which exceeded a calculated boundary. We repeated this process until the R2 value stopped to increase. In addition, the definitions of the onset of influenza epidemic were heterogeneous, which might make it impossible to accurately evaluate the performance of alternative approaches. We then used this modified model to detect the peak timing of influenza instead of the onset of epidemic and compared this model with traditional Serfling models using observed weekly case counts of influenza-like illness (ILIs), in terms of sensitivity, specificity and lead time. A better performance was observed. In summary, we provide an adjusted Serfling model which may have improved performance over traditional models in early warning at arrival of peak timing of influenza. PMID:25756205

  16. Chicken model for studying dietary antioxidants reveals that apple (Cox's Orange)/broccoli (Brassica oleracea L. var. italica) stabilizes erythrocytes and reduces oxidation of insoluble muscle proteins and lipids in cooked liver.

    PubMed

    Young, Jette F; Steffensen, Charlotte L; Nielsen, Jacob H; Jensen, Søren K; Stagsted, Jan

    2002-08-28

    A chicken model for studying the effects of antioxidants in the diet on oxidative status was set up. Chickens fed a semi-synthetic diet low in antioxidants showed a remarkable decrease in erythrocyte stability toward H(2)O(2) or 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH), but increases in catalase activity in liver, carbonyls in insoluble muscle proteins, and enhanced lipid oxidation in heat-treated liver samples compared to that of conventionally fed chickens. Thus, this chicken model proved to be more susceptible to oxidative changes than conventionally fed chickens, reflecting a low antioxidative defense. Supplementing this low antioxidant diet with 10% apple/broccoli mixture counteracted these changes, except for activity of catalase in the liver and AAPH-induced lysis of erythrocytes. Supplementation with 10% sweet corn only reduced the carbonyl content in insoluble proteins. However, neither low antioxidant diet nor vegetable supplements affected selected antioxidative enzymes or oxidative stability of lipids in heat-treated muscle tissue.

  17. COX-2 FROM THE INJURY MILIEU IS CRITICAL FOR THE INITIATION OF PERIOSTEAL PROGENITOR CELL MEDIATED BONE HEALING

    PubMed Central

    Xie, Chao; Ming, Xue; Wang, Qun; Schwarz, Edward M.; Guldberg, Robert E.; O’Keefe, Regis J.; Zhang, Xinping

    2009-01-01

    Although a critical role of COX-2 in bone repair has been established, the mechanism involved remains unclear. During early inflammatory phase of bone healing, COX-2 is produced by the surrounding inflammatory cells as well as bone/cartilage progenitors. Based on the temporal and spatial expression of COX-2 during the early phase of fracture healing, we hypothesize that COX-2 from both sources is critical for progenitor cell activation, proliferation and differentiation. To directly test this we utilized a murine femoral grafting model, in which live segmental grafts from the same strains were transplanted and donor versus host cell involvement in healing was assessed. Specifically, fresh femur cortical bone grafts of 4-mm in length from COX-2-/- (KO) mice were transplanted into wild type (WT) mice with the same sized segmental defect in femurs. Similarly, grafts from WT were transplanted into the defects in KO mice. As controls, transplantations between wild types, and transplantations between KO were also performed. Histologic analyses showed that WT-to-WT transplantation resulted in normal endochondral bone healing as evidenced by markedly induction of neovascularization and periosteal bone formation on donor graft. In contrast, transplantation of KO graft into KO host led to 96 % reduction of bone formation and near elimination of donor cell-initiated periosteal bone formation. Similarly, transplantation of WT graft into a KO host resulted in 87% reduction of bone formation (n=8, p>0.05), indicating that KO host impaired WT donor progenitor cell expansion and differentiation. When a KO graft was transplanted into WT host, KO donor periosteal cell-initiated endochondral bone formation was restored. Histomorphometric analyses demonstrated 10-fold increase in bone formation and 3-fold increase in cartilage formation compared to KO-to-KO transplantation (n=8, p<0.05), suggesting that COX-2 deficient donor cells were capable to differentiate and form bone when

  18. Slope adjustment of runoff curve number (CN) using Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) Global Digital Elevation Model (GDEM) for Kuantan River Basin

    NASA Astrophysics Data System (ADS)

    Akbari, Abolghasem

    2015-10-01

    The Natural Resources Conservation Service Curve Number (NRCS-CN) method is widely used for predicting direct runoff from rainfall. It employs the hydrologic soil groups and landuse information along with period soil moisture conditions to derive NRCS-CN. This method has been well documented and available in popular rainfall-runoff models such as HEC-HMS, SWAT, SWMM and many more. The Sharply-Williams and Hank methods was used to adjust CN values provided in standard table of TR-55. The Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) Global Digital Elevation Model (GDEM) is used to derive slope map with spatial resolution of 30 m for Kuantan River Basin (KRB). The two investigated method stretches the conventional CN domain to the lower values. The study shows a successful application of remote sensing data and GIS tools in hydrological studies. The result of this work can be used for rainfall-runoff simulation and flood modeling in KRB.

  19. The carboxyl-terminal end of Cox1 is required for feedback assembly regulation of Cox1 synthesis in Saccharomyces cerevisiae mitochondria.

    PubMed

    Shingú-Vázquez, Miguel; Camacho-Villasana, Yolanda; Sandoval-Romero, Luisa; Butler, Christine A; Fox, Thomas D; Pérez-Martínez, Xochitl

    2010-11-05

    Synthesis of the largest cytochrome c oxidase (CcO) subunit, Cox1, on yeast mitochondrial ribosomes is coupled to assembly of CcO. The translational activator Mss51 is sequestered in early assembly intermediate complexes by an interaction with Cox14 that depends on the presence of newly synthesized Cox1. If CcO assembly is prevented, the level of Mss51 available for translational activation is reduced. We deleted the C-terminal 11 or 15 residues of Cox1 by site-directed mutagenesis of mtDNA. Although these deletions did not prevent respiratory growth of yeast, they eliminated the assembly-feedback control of Cox1 synthesis. Furthermore, these deletions reduced the strength of the Mss51-Cox14 interaction as detected by co-immunoprecipitation, confirming the importance of the Cox1 C-terminal residues for Mss51 sequestration. We surveyed a panel of mutations that block CcO assembly for the strength of their effect on Cox1 synthesis, both by pulse labeling and expression of the ARG8(m) reporter fused to COX1. Deletion of the nuclear gene encoding Cox6, one of the first subunits to be added to assembling CcO, caused the most severe reduction in Cox1 synthesis. Deletion of the C-terminal 15 amino acids of Cox1 increased Cox1 synthesis in the presence of each of these mutations, except pet54. Our data suggest a novel activity of Pet54 required for normal synthesis of Cox1 that is independent of the Cox1 C-terminal end.

  20. COX7A1 — EDRN Public Portal

    Cancer.gov

    COX7A1, cytochrome c oxidase subunit VIIa polypeptide 1 (muscle), is one of the polypeptide chains of cytochrome c oxidase, the terminal component of the mitochondrial respiratory chain. This polypeptide is present only in muscle tissues. Other polypeptides of subunit VIIa are present in both muscle and nonmuscle tissues, and are encoded by different genes.

  1. Model-based estimates of the effects of efavirenz on bedaquiline pharmacokinetics and suggested dose adjustments for patients coinfected with HIV and tuberculosis.

    PubMed

    Svensson, Elin M; Aweeka, Francesca; Park, Jeong-Gun; Marzan, Florence; Dooley, Kelly E; Karlsson, Mats O

    2013-06-01

    Safe, effective concomitant treatment regimens for tuberculosis (TB) and HIV infection are urgently needed. Bedaquiline (BDQ) is a promising new anti-TB drug, and efavirenz (EFV) is a commonly used antiretroviral. Due to EFV's induction of cytochrome P450 3A4, the metabolic enzyme responsible for BDQ biotransformation, the drugs are expected to interact. Based on data from a phase I, single-dose pharmacokinetic study, a nonlinear mixed-effects model characterizing BDQ pharmacokinetics and interaction with multiple-dose EFV was developed. BDQ pharmacokinetics were best described by a 3-compartment disposition model with absorption through a dynamic transit compartment model. Metabolites M2 and M3 were described by 2-compartment models with clearance of BDQ and M2, respectively, as input. Impact of induction was described as an instantaneous change in clearance 1 week after initialization of EFV treatment and estimated for all compounds. The model predicts average steady-state concentrations of BDQ and M2 to be reduced by 52% (relative standard error [RSE], 3.7%) with chronic coadministration. A range of models with alternative structural assumptions regarding onset of induction effect and fraction metabolized resulted in similar estimates of the typical reduction and did not offer a markedly better fit to data. Simulations to investigate alternative regimens mitigating the estimated interaction effect were performed. The results suggest that simple adjustments of the standard regimen during EFV coadministration can prevent reduced exposure to BDQ without increasing exposures to M2. However, exposure to M3 would increase. Evaluation in clinical trials of adjusted regimens is necessary to ensure appropriate dosing for HIV-infected TB patients on an EFV-based regimen.

  2. Apigenin inhibits COX-2, PGE2, and EP1 and also initiates terminal differentiation in the epidermis of tumor bearing mice.

    PubMed

    Kiraly, Alex J; Soliman, Eman; Jenkins, Audrey; Van Dross, Rukiyah T

    2016-01-01

    Non-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States. NMSC overexpresses cyclooxygenase-2 (COX-2). COX-2 synthesizes prostaglandins such as PGE2 which promote proliferation and tumorigenesis by engaging G-protein-coupled prostaglandin E receptors (EP). Apigenin is a bioflavonoid that blocks mouse skin tumorigenesis induced by the chemical carcinogens, 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the effect of apigenin on the COX-2 pathway has not been examined in the DMBA/TPA skin tumor model. In the present study, apigenin decreased tumor multiplicity and incidence in DMBA/TPA-treated SKH-1 mice. Analysis of the non-tumor epidermis revealed that apigenin reduced COX-2, PGE2, EP1, and EP2 synthesis and also increased terminal differentiation. In contrast, apigenin did not inhibit the COX-2 pathway or promote terminal differentiation in the tumors. Since fewer tumors developed in apigenin-treated animals which contained reduced epidermal COX-2 levels, our data suggest that apigenin may avert skin tumor development by blocking COX-2.

  3. A class frequency mixture model that adjusts for site-specific amino acid frequencies and improves inference of protein phylogeny

    PubMed Central

    2008-01-01

    Background Widely used substitution models for proteins, such as the Jones-Taylor-Thornton (JTT) or Whelan and Goldman (WAG) models, are based on empirical amino acid interchange matrices estimated from databases of protein alignments that incorporate the average amino acid frequencies of the data set under examination (e.g JTT + F). Variation in the evolutionary process between sites is typically modelled by a rates-across-sites distribution such as the gamma (Γ) distribution. However, sites in proteins also vary in the kinds of amino acid interchanges that are favoured, a feature that is ignored by standard empirical substitution matrices. Here we examine the degree to which the pattern of evolution at sites differs from that expected based on empirical amino acid substitution models and evaluate the impact of these deviations on phylogenetic estimation. Results We analyzed 21 large protein alignments with two statistical tests designed to detect deviation of site-specific amino acid distributions from data simulated under the standard empirical substitution model: JTT+ F + Γ. We found that the number of states at a given site is, on average, smaller and the frequencies of these states are less uniform than expected based on a JTT + F + Γ substitution model. With a four-taxon example, we show that phylogenetic estimation under the JTT + F + Γ model is seriously biased by a long-branch attraction artefact if the data are simulated under a model utilizing the observed site-specific amino acid frequencies from an alignment. Principal components analyses indicate the existence of at least four major site-specific frequency classes in these 21 protein alignments. Using a mixture model with these four separate classes of site-specific state frequencies plus a fifth class of global frequencies (the JTT + cF + Γ model), significant improvements in model fit for real data sets can be achieved. This simple mixture model also reduces the long-branch attraction problem

  4. Synthesis and evaluation of benzimidazole derivatives as selective COX-2 inhibitors.

    PubMed

    Rathore, Ankita; Mujeeb-Ur-Rahman; Siddiqui, Anees A; Ali, Abuzer; Yar, Mohammad Shahar

    2015-01-01

    A new series of 1-{(5-substituted-alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl}-2-(piperidin-1-ylmethyl)-1Hbenzimidazoles (5a-5r) was synthesized and screened for their inhibitory activity against COX (1 and 2). In vivo antiinflammatory activity of potent compounds was done by carrageenan-induced rat paw edema model. In vitro anticancer activity of synthesized compounds was also performed at the National Cancer Institute (NCI) against NCI 60 cell lines panel. Out of the 18 compounds screened, 5h, 5i, 5j and 5l were found to be potent COX-2 inhibitors in the range of IC50 0.06-0.81 μM. In vivo anti-inflammatory screening results revealed that the compounds 5h and 5j manifested profound percent protection of 72.8 and 75.0%, respectively. Compound 5f exhibited moderate cytotoxicity with 58.79% growth inhibition against SNB-75 (CNS Cancer) cell lines and moderate activity against COX-2 (IC50 = 8.0 μM).

  5. Food Polyphenols Fail to Cause a Biologically Relevant Reduction of COX-2 Activity.

    PubMed

    Willenberg, Ina; Meschede, Anna K; Gueler, Faikah; Jang, Mi-Sun; Shushakova, Nelli; Schebb, Nils Helge

    2015-01-01

    Epidemiologic studies show a correlation between the dietary intake of food polyphenols and beneficial health effects. Several in vitro studies indicate that the anti-inflammatory potential of polyphenols is, at least in part, mediated by a modulation of the enzymes of the arachidonic acid cascade, such as the prostaglandin forming cyclooxygenases (COXs). Evidence that this mode of action can be transferred to the situation in vivo is scarce. This study characterized effects of a subset of polyphenols on COX-2 expression and activity in vitro and compared the potency with known drugs. Next, the in vivo relevance of the observed in vitro effects was tested. Enzyme assays and incubations of polyphenols with the cancer cell line HCA-7 and lipopolysaccharide (LPS) stimulated primary monocytes support the hypothesis that polyphenols can effect COX-2 expression and activity in vitro. The effects were most pronounced in the monocyte assay for wogonin, apigenin, resveratrol and genistein with IC50 values of 1.5 μM, 2.6 μM, 2.8 μM and 7.4 μM. However, these values are 100- to 1000-fold higher in comparison to those of the known pharmaceuticals celecoxib, indomethacin and dexamethasone. In an animal model of LPS induced sepsis, pretreatment with polyphenols (i. p. 100 mg/kg bw) did not result in decreased plasma or tissue prostaglandin levels, whereas the positive control celecoxib effectively attenuated LPS induced prostaglandin formation. These data suggest that despite the moderate potency in vitro, an effect of polyphenols on COX-2 during acute inflammation is unlikely, even if a high dose of polyphenols is ingested.

  6. Multivariate Models of Parent-Late Adolescent Gender Dyads: The Importance of Parenting Processes in Predicting Adjustment

    ERIC Educational Resources Information Center

    McKinney, Cliff; Renk, Kimberly

    2008-01-01

    Although parent-adolescent interactions have been examined, relevant variables have not been integrated into a multivariate model. As a result, this study examined a multivariate model of parent-late adolescent gender dyads in an attempt to capture important predictors in late adolescents' important and unique transition to adulthood. The sample…

  7. Adjusting for Unequal Variances when Comparing Means in One-Way and Two-Way Fixed Effects ANOVA Models.

    ERIC Educational Resources Information Center

    Wilcox, Rand R.

    1989-01-01

    Two methods of handling unequal variances in the two-way fixed effects analysis of variance (ANOVA) model are described. One is based on an improved Wilcox (1988) method for the one-way model, and the other is an extension of G. S. James' (1951) second order method. (TJH)

  8. Influence of intraocular pressure on geometrical properties of a linear model of the eyeball: Effect of optical self-adjustment

    NASA Astrophysics Data System (ADS)

    Asejczyk-Widlicka, M.; Srodka, D. W.; Kasprzak, H.; Iskander, D. R.

    In general, visual acuity does not change with variations in intraocular pressure. Experiments in vitro as well as our clinical findings lead us to hypothesise that the eyeball could possess certain mechanical properties enabling it to automatically produce a sharp image on the retina despite variations in intraocular pressure. Previously reported simple biomechanical models of the eye did not confirm this hypothesis. Here, we propose a generalised mechanical model of the eyeball in which we include an appropriate limbus ring that mimics the ciliary body and the iris. The Finite Element Method is used to model the eyeball and to test its behaviour. A set of geometrical and material parameters has been determined for the model so that the postulated function of the eye is preserved. Numerical simulations have confirmed the hypothesis. The anatomically justified inclusion of the limbus ring in the proposed model of the eyeball makes it more realistic than those previously reported.

  9. Risk-adjusted capitation based on the Diagnostic Cost Group Model: an empirical evaluation with health survey information.

    PubMed Central

    Lamers, L M

    1999-01-01

    OBJECTIVE: To evaluate the predictive accuracy of the Diagnostic Cost Group (DCG) model using health survey information. DATA SOURCES/STUDY SETTING: Longitudinal data collected for a sample of members of a Dutch sickness fund. In the Netherlands the sickness funds provide compulsory health insurance coverage for the 60 percent of the population in the lowest income brackets. STUDY DESIGN: A demographic model and DCG capitation models are estimated by means of ordinary least squares, with an individual's annual healthcare expenditures in 1994 as the dependent variable. For subgroups based on health survey information, costs predicted by the models are compared with actual costs. Using stepwise regression procedures a subset of relevant survey variables that could improve the predictive accuracy of the three-year DCG model was identified. Capitation models were extended with these variables. DATA COLLECTION/EXTRACTION METHODS: For the empirical analysis, panel data of sickness fund members were used that contained demographic information, annual healthcare expenditures, and diagnostic information from hospitalizations for each member. In 1993, a mailed health survey was conducted among a random sample of 15,000 persons in the panel data set, with a 70 percent response rate. PRINCIPAL FINDINGS: The predictive accuracy of the demographic model improves when it is extended with diagnostic information from prior hospitalizations (DCGs). A subset of survey variables further improves the predictive accuracy of the DCG capitation models. The predictable profits and losses based on survey information for the DCG models are smaller than for the demographic model. Most persons with predictable losses based on health survey information were not hospitalized in the preceding year. CONCLUSIONS: The use of diagnostic information from prior hospitalizations is a promising option for improving the demographic capitation payment formula. This study suggests that diagnostic

  10. Automated docking and molecular dynamics simulations of nimesulide in the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 (COX-2)

    NASA Astrophysics Data System (ADS)

    García-Nieto, Raquel; Pérez, Carlos; Gago, Federico

    2000-02-01

    Molecular models of the complex between the selective COX-2 inhibitor nimesulide and the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 have been built using a combination of homology modelling, conformational searching and automated docking techniques. The stability of the resulting complexes has been assessed by molecular dynamics simulations and interaction energy decomposition. It is found that nimesulide exploits the extra space made available by the replacement at position 523 of an isoleucine residue in COX-1 by a valine in COX-2 and establishes electrostatic interactions with both Arg-106 and Arg-499 (Arg-120 and Arg-513 in PGHS-1 numbering). Two alternate binding modes are proposed which are compatible with the pharmacological profile of this agent as a COX-2 selective inhibitor.

  11. Antiinflammatory 2-benzyl-4-sulfonyl-4H-isoquinoline-1,3-diones: novel inhibitors of COX-2.

    PubMed

    Lazer, E S; Sorcek, R; Cywin, C L; Thome, D; Possanza, G J; Graham, A G; Churchill, L

    1998-05-19

    A series of 2-benzyl-4-sulfonyl-4H-isoquinoline-1,3-diones was prepared. Members of this series are potent and selective inhibitors of cyclooxygenase-2 (COX-2) in both microsomal and cellular assays. Two representatives demonstrated activity in the carrageenan-induced paw edema model in rats upon oral administration.

  12. Targeting inhibition of COX-2: a review of patents, 2002-2006.

    PubMed

    da Cunha, Elaine F F; Ramalho, Teodorico C; Josa, Daniela; Caetano, Melissa S; de Souza, Thaís C S

    2007-06-01

    The main COX inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs exert anti-inflammatory and analgesic effects through the inhibition of prostaglandin synthesis by blocking COX activity. Currently two COX isoenzymes are known, COX-1 and COX-2. Prostaglandins influenced by COX-1 maintain the integrity of the gastric mucosa. On the other hand, prostaglandins influenced by COX-2 mediate the inflammatory process. The common anti-inflammatory drugs (like aspirin, ibuprofen, and naproxen) all act by blocking the action of both the COX-1 and COX-2 enzymes. The COX-2 inhibitors represent a new class of drugs that do not affect COX-1, but selectively block COX-2. This selective action provides the benefits of reducing inflammation without irritating the stomach. This review will focus on the most recent developments published in the field, paying particular attention to promising COX-2 inhibitors, their chemistry and biological evaluation, and to new chemical and pharmaceutical processes. Moreover, we will discuss recent patents of structural analogs of the COX-2 inhibitors celecoxib and valdecoxib, and novel potential pyridazine, triazole, indole, thione derivatives as a future target for the treatment of inflammation, pain and other diseases.

  13. Adjustment of Sonar and Laser Acquisition Data for Building the 3D Reference Model of a Canal Tunnel.

    PubMed

    Moisan, Emmanuel; Charbonnier, Pierre; Foucher, Philippe; Grussenmeyer, Pierre; Guillemin, Samuel; Koehl, Mathieu

    2015-12-11

    In this paper, we focus on the construction of a full 3D model of a canal tunnel by combining terrestrial laser (for its above-water part) and sonar (for its underwater part) scans collected from static acquisitions. The modeling of such a structure is challenging because the sonar device is used in a narrow environment that induces many artifacts. Moreover, the location and the orientation of the sonar device are unknown. In our approach, sonar data are first simultaneously denoised and meshed. Then, above- and under-water point clouds are co-registered to generate directly the full 3D model of the canal tunnel. Faced with the lack of overlap between both models, we introduce a robust algorithm that relies on geometrical entities and partially-immersed targets, which are visible in both the laser and sonar point clouds. A full 3D model, visually promising, of the entrance of a canal tunnel is obtained. The analysis of the method raises several improvement directions that will help with obtaining more accurate models, in a more automated way, in the limits of the involved technology.

  14. Adjustment of Sonar and Laser Acquisition Data for Building the 3D Reference Model of a Canal Tunnel †

    PubMed Central

    Moisan, Emmanuel; Charbonnier, Pierre; Foucher, Philippe; Grussenmeyer, Pierre; Guillemin, Samuel; Koehl, Mathieu

    2015-01-01

    In this paper, we focus on the construction of a full 3D model of a canal tunnel by combining terrestrial laser (for its above-water part) and sonar (for its underwater part) scans collected from static acquisitions. The modeling of such a structure is challenging because the sonar device is used in a narrow environment that induces many artifacts. Moreover, the location and the orientation of the sonar device are unknown. In our approach, sonar data are first simultaneously denoised and meshed. Then, above- and under-water point clouds are co-registered to generate directly the full 3D model of the canal tunnel. Faced with the lack of overlap between both models, we introduce a robust algorithm that relies on geometrical entities and partially-immersed targets, which are visible in both the laser and sonar point clouds. A full 3D model, visually promising, of the entrance of a canal tunnel is obtained. The analysis of the method raises several improvement directions that will help with obtaining more accurate models, in a more automated way, in the limits of the involved technology. PMID:26690444

  15. Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma.

    PubMed

    Maroni, Paola; Matteucci, Emanuela; Luzzati, Alessandro; Perrucchini, Giuseppe; Bendinelli, Paola; Desiderio, Maria Alfonsina

    2011-09-01

    The aim of this article is to identify nuclear co-localization of COX-2 and HIF-1α in human-bone metastasis of breast cancer, index of transcriptionally activated cells and functional for gene expression. In particular, we verified whether hypoxia exerted a direct role on metastasis-gene expression or through COX-2 signaling, due to the relevance for clinical implications to individuate molecular targets for diagnosis and therapy. The experiments were performed in vitro with two metastatic clones, 1833 and MDA-231BO, and the parental MDA-MB231 cells, in vivo (1833-xenograft model), and in human-bone metastasis specimens. In 1833 cells in vitro, COX-2 signaling pathway was critical for nuclear HIF-1α-protein expression/translocation, mechanisms determining HIF-1 activity and gene expression. The data were corroborated by immunohistochemistry in human-bone metastasis specimens. COX-2 and HIF-1α showed wide co-localization in the nucleus, indicative of COX-2-nuclear import in transcriptionally activated metastatic cells and consistent with COX-2-HIF-1α functional interaction. A network of microenvironmental signals controlled COX-2 induction and HIF-1 activation downstream. In fact, hypoxia through HGF and TGF-β1 autoregulatory loops triggered a specific array of transcription factors responsible for COX-2 transactivation. The novelty was that HGF and TGF-β1 biological signals were produced by hypoxic metastatic cells and, therefore, the microenvironment seemed to be modified by metastatic-cell engraftment in the bone. In agreement, HIF-1α expression in bone marrow supportive cells occurred in metastasis-bearing animals. Altogether, the data supported the pre-metastatic-niche theory. Our observations might be useful to design therapies against bone metastasis, by affecting the phenotype changes of metastatic cells occurring at the secondary growth site through COX-2-HIF-1 interaction.

  16. Rescue of Impaired Fracture Healing in COX-2−/− Mice via Activation of Prostaglandin E2 Receptor Subtype 4

    PubMed Central

    Xie, Chao; Liang, Bojian; Xue, Ming; Lin, Angela S.P.; Loiselle, Alayna; Schwarz, Edward M.; Guldberg, Robert E.; O'Keefe, Regis J.; Zhang, Xinping

    2009-01-01

    Although the essential role of cyclooxygenase (COX)-2 in fracture healing is known, the targeted genes and molecular pathways remain unclear. Using prostaglandin E2 receptor (EP)2 and EP4 agonists, we examined the effects of EP receptor activation in compensation for the lack of COX-2 during fracture healing. In a fracture-healing model, COX-2−/− mice showed delayed initiation and impaired endochondral bone repair, accompanied by a severe angiogenesis deficiency. The EP4 agonist markedly improved the impaired healing in COX-2−/− mice, as evidenced by restoration of bony callus formation on day 14, a near complete reversal of bone formation, and an approximately 70% improvement of angiogenesis in the COX-2−/− callus. In comparison, the EP2 agonist only marginally enhanced bone formation in COX-2−/− mice. To determine the differential roles of EP2 and EP4 receptors on COX-2-mediated fracture repair, the effects of selective EP agonists on chondrogenesis were examined in E11.5 long-term limb bud micromass cultures. Only the EP4 agonist significantly increased cartilage nodule formation similar to that observed during prostaglandin E2 treatment. The prostaglandin E2/EP4 agonist also stimulated MMP-9 expression in bone marrow stromal cell cultures. The EP4 agonist further restored the reduction of MMP-9 expression in the COX-2−/− fracture callus. Taken together, our studies demonstrate that EP2 and EP4 have differential functions during endochondral bone repair. Activation of EP4, but not EP2 rescued impaired bone fracture healing in COX-2−/− mice. PMID:19628768

  17. Aggravation of Alzheimer's disease due to the COX-2-mediated reciprocal regulation of IL-1β and Aβ between glial and neuron cells.

    PubMed

    Wang, Pu; Guan, Pei-Pei; Wang, Tao; Yu, Xin; Guo, Jian-Jun; Wang, Zhan-You

    2014-08-01

    Alzheimer's disease (AD) is the most common form of dementia and displays the characteristics of chronic neurodegenerative disorders; amyloid plaques (AP) that contain amyloid β-protein (Aβ) accumulate in AD, which is also characterized by tau phosphorylation. Epidemiological evidence has demonstrated that long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) markedly reduces the risk of AD by inhibiting the expression of cyclooxygenase 2 (COX-2). Although the levels of COX-2 and its metabolic product prostaglandin (PG)E2 are elevated in the brain of AD patients, the mechanisms for the development of AD remain unknown. Using human- or mouse-derived glioblastoma and neuroblastoma cell lines as model systems, we delineated the signaling pathways by which COX-2 mediates the reciprocal regulation of interleukin-1β (IL-1β) and Aβ between glial and neuron cells. In glioblastoma cells, COX-2 regulates the synthesis of IL-1β in a PGE2 -dependent manner. Moreover, COX-2-derived PGE2 signals the activation of the PI3-K/AKT and PKA/CREB pathways via cyclic AMP; these pathways transactivate the NF-κB p65 subunit via phosphorylation at Ser 536 and Ser 276, leading to IL-1β synthesis. The secretion of IL-1β from glioblastoma cells in turn stimulates the expression of COX-2 in human or mouse neuroblastoma cells. Similar regulatory mechanisms were found for the COX-2 regulation of BACE-1 expression in neuroblastoma cells. More importantly, Aβ deposition mediated the inflammatory response of glial cells via inducing the expression of COX-2 in glioblastoma cells. These findings not only provide new insights into the mechanisms of COX-2-induced AD but also initially define the therapeutic targets of AD.

  18. A glacial isostatic adjustment model for the central and northern Laurentide Ice Sheet based on relative sea level and GPS measurements

    NASA Astrophysics Data System (ADS)

    Simon, K. M.; James, T. S.; Henton, J. A.; Dyke, A. S.

    2016-06-01

    The thickness and equivalent global sea level contribution of an improved model of the central and northern Laurentide Ice Sheet is constrained by 24 relative sea level histories and 18 present-day GPS-measured vertical land motion rates. The final model, termed Laur16, is derived from the ICE-5G model by holding the timing history constant and iteratively adjusting the thickness history, in four regions of northern Canada. In the final model, the last glacial maximum (LGM) thickness of the Laurentide Ice Sheet west of Hudson Bay was ˜3.4-3.6 km. Conversely, east of Hudson Bay, peak ice thicknesses reached ˜4 km. The ice model thicknesses inferred for these two regions represent, respectively, a ˜30 per cent decrease and an average ˜20-25 per cent increase to the load thickness relative to the ICE-5G reconstruction, which is generally consistent with other recent studies that have focussed on Laurentide Ice Sheet history. The final model also features peak ice thicknesses of 1.2-1.3 km in the Baffin Island region, a modest reduction relative to ICE-5G and unchanged thicknesses for a region in the central Canadian Arctic Archipelago west of Baffin Island. Vertical land motion predictions of the final model fit observed crustal uplift rates well, after an adjustment is made for the elastic crustal response to present-day ice mass changes of regional ice cover. The new Laur16 model provides more than a factor of two improvement of the fit to the RSL data (χ2 measure of misfit) and a factor of nine improvement to the fit of the GPS data (mean squared error measure of fit), compared to the ICE-5G starting model. Laur16 also fits the regional RSL data better by a factor of two and gives a slightly better fit to GPS uplift rates than the recent ICE-6G model. The volume history of the Laur16 reconstruction corresponds to an up to 8 m reduction in global sea level equivalent compared to ICE-5G at LGM.

  19. Factor demand in Swedish manufacturing industry with special reference to the demand for energy. Instantaneous adjustment models; some results

    NASA Astrophysics Data System (ADS)

    Sjoeholm, K. R.

    1981-02-01

    The dual approach to the theory of production is used to estimate factor demand functions of the Swedish manufacturing industry. Two approximations of the cost function, the translog and the generalized Leontief models, are used. The price elasticities of the factor demand do not seem to depend on the choice of model. This is at least true as to the sign pattern and as to the inputs capital, labor, total energy and other materials. Total energy is separated into solid fuels, gasoline, fuel oil, electricity and a residual. Fuel oil and electricity are found to be substitutes by both models. Capital and energy are shown to be substitutes. This implies that Swedish industry will save more energy if the capital cost can be reduced. Both models are, in the best versions, able to detect an inappropriate variable. The assumption of perfect competition on the product market, is shown to be inadequate by both models. When this assumption is relaxed, the normal substitution pattern among the inputs is resumed.

  20. A note on the empirical likelihood confidence band for hazards ratio with covariate adjustment.

    PubMed

    Zhu, Shihong; Yang, Yifan; Zhou, Mai

    2015-09-01

    In medical studies comparing two treatments in the presence of censored data, the stratified Cox model is an important tool that has the ability to flexibly handle non-proportional hazards while allowing parsimonious covariate adjustment. In order to capture the cumulative treatment effect, the ratio of the treatment specific cumulative baseline hazards is often used as a measure of the treatment effect. Pointwise and simultaneous confidence bands associated with the estimated ratio provide a global picture of how the treatment effect evolves over time. Recently, Dong and Matthews (2012, Biometrics 68, 408-418) proposed to construct a pointwise confidence interval for the ratio using a plug-in type empirical likelihood approach. However, their result on the limiting distribution of the empirical likelihood ratio is generally incorrect and the resulting confidence interval is asymptotically undercovering. In this article, we derive the correct limiting distribution for the likelihood ratio statistic. We also present simulation studies to demonstrate the effectiveness of our approach.

  1. Constitutively expressed COX-2 in osteoblasts positively regulates Akt signal transduction via suppression of PTEN activity.

    PubMed

    Li, Ching-Ju; Chang, Je-Ken; Wang, Gwo-Jaw; Ho, Mei-Ling

    2011-02-01

    Cyclooxygenase-2 (COX-2) is thought to be an inducible enzyme, but increasing reports indicate that COX-2 is constitutively expressed in several organs. The status of COX-2 expression in bone and its physiological role remains undefined. Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, which commonly suppress COX-2 activity, were reported to suppress osteoblast proliferation via Akt/FOXO3a/p27(Kip1) signaling, suggesting that COX-2 may be the key factor of the suppressive effects of NSAIDs on proliferation. Although Akt activation correlates with PTEN deficiency and cell viability, the role of COX-2 on PTEN/Akt regulation remains unclear. In this study, we hypothesized that COX-2 may be constitutively expressed in osteoblasts and regulate PTEN/Akt-related proliferation. We examined the localization and co-expression of COX-2 and p-Akt in normal mouse femurs and in cultured mouse (mOBs) and human osteoblasts (hOBs). Our results showed that osteoblasts adjacent to the trabeculae, periosteum and endosteum in mouse femurs constitutively expressed COX-2, while COX-2 co-expressed with p-Akt in osteoblasts sitting adjacent to trabeculae in vivo, and in mOBs and hOBs in vitro. We further used COX-2 siRNA to test the role of COX-2 in Akt signaling in hOBs; COX-2 silencing significantly inhibited PTEN phosphorylation, enhanced PTEN activity, and suppressed p-Akt level and proliferation. However, replenishment of the COX-2 enzymatic product, PGE2, failed to reverse COX-2-dependent Akt phosphorylation. Furthermore, transfection with recombinant human COX-2 (rhCOX-2) significantly reversed COX-2 siRNA-suppressed PTEN phosphorylation, but this effect was reduced when the enzymatic activity of rhCOX-2 was blocked. This finding indicated that the effect of COX-2 on PTEN/Akt signaling is not related to PGE2 but still dependent on COX-2 enzymatic activity. Conversely, COX-1 silencing did not affect PTEN/Akt signaling. Our findings provide

  2. Family, Neighborhood, and Peer Characteristics as Predictors of Child Adjustment: A Longitudinal Analysis of Additive and Mediation Models

    PubMed Central

    2008-01-01

    The purpose of this study was to test direct, additive, and mediation models involving family, neighborhood, and peer factors in relation to emerging antisocial behavior and social skills. Neighborhood danger, maternal depressive symptoms, and supportive parenting were assessed in early childhood. Peer group acceptance was measured in middle childhood, and data on antisocial behavior and social skills were collected when boys were 11 and 12 years old. Results were consistent with an additive effects model of child antisocial behavior. In contrast, peer relationships were stronger predictors of social skills than were family factors. Support for mediation was found in models involving neighborhood danger and supportive parenting. However, only peer group acceptance predicted change in antisocial and prosocial behavior. Implications for family and peer relations as socialization contexts are discussed. PMID:20161200

  3. Hyperalgesia and Persistent Pain after Breast Cancer Surgery: A Prospective Randomized Controlled Trial with Perioperative COX-2 Inhibition

    PubMed Central

    van Helmond, Noud; Steegers, Monique A.; Filippini-de Moor, Gertie P.; Vissers, Kris C.; Wilder-Smith, Oliver H.

    2016-01-01

    Background Persistent pain is a challenging clinical problem after breast cancer treatment. After surgery, inflammatory pain and nociceptive input from nerve injury induce central sensitization which may play a role in the genesis of persistent pain. Using quantitative sensory testing, we tested the hypothesis that adding COX-2 inhibition to standard treatment reduces hyperalgesia after breast cancer surgery. A secondary hypothesis was that patients developing persistent pain would exhibit more postoperative hyperalgesia. Methods 138 women scheduled for lumpectomy/mastectomy under general anesthesia with paravertebral block were randomized to COX-2 inhibition (2x40mg parecoxib on day of surgery, thereafter 2x200mg celecoxib/day until day five) or placebo. Preoperatively and 1, 5, 15 days and 1, 3, 6, 12 months postoperatively, we determined electric and pressure pain tolerance thresholds in dermatomes C6/T4/L1 and a 100mm VAS score for pain. We calculated the sum of pain tolerance thresholds and analyzed change in these versus preoperatively using mixed models analysis with factor medication. To assess hyperalgesia in persistent pain patients we performed an additional analysis on patients reporting VAS>30 at 12 months. Results 48 COX-2 inhibition and 46 placebo patients were analyzed in a modified intention to treat analysis. Contrary to our primary hypothesis, change in the sum of tolerance thresholds in the COX-2 inhibition group was not different versus placebo. COX-2 inhibition had an effect on pain on movement at postoperative day 5 (p<0.01). Consistent with our secondary hypothesis, change in sum of pressure pain tolerance thresholds in 11 patients that developed persistent pain was negative versus patients without pain (p<0.01) from day 5 to 1 year postoperatively. Conclusions Perioperative COX-2 inhibition has limited value in preventing sensitization and persistent pain after breast cancer surgery. Central sensitization may play a role in the genesis of

  4. Pharmacophore Elucidation and Molecular Docking Studies on 5-Phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic Acid Derivatives as COX-2 Inhibitors

    PubMed Central

    Lindner, Marc; Sippl, Wolfgang; Radwan, Awwad A.

    2010-01-01

    A set of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives (16–32) showing anti-inflammatory activity was analyzed using a three-dimensional qualitative structure-selectivity relationship (3D QSSR) method. The CatalystHipHop approach was used to generate a pharmacophore model for cyclooxygenase-2 (COX-2) inhibitors based on a training set of 15 active inhibitors (1–15). The degree of fitting of the test set compounds (16–32) to the generated hypothetical model revealed a qualitative measure of the more or less selective COX-2 inhibition of these compounds. The results indicate that most derivatives (16, 18, 20–25, and 30–32) are able to effectively satisfy the proposed pharmacophore geometry using energy accessible conformers (Econf < 20 kcal/mol). In addition, the triazole derivatives (16–32) were docked into COX-1 and COX-2 X-ray structures, using the program GOLD. Based on the docking results it is suggested that several of these novel triazole derivatives are active COX inhibitors with a significant preference for COX-2. In principle, this work presents an interesting, comprehensive approach to theoretically predict the mode of action of compounds that showed anti-inflammatory activity in an in vivo model. PMID:21179343

  5. A hidden Markov model to identify and adjust for selection bias: an example involving mixed migration strategies

    PubMed Central

    Fieberg, John R; Conn, Paul B

    2014-01-01

    An important assumption in observational studies is that sampled individuals are representative of some larger study population. Yet, this assumption is often unrealistic. Notable examples include online public-opinion polls, publication biases associated with statistically significant results, and in ecology, telemetry studies with significant habitat-induced probabilities of missed locations. This problem can be overcome by modeling selection probabilities simultaneously with other predictor–response relationships or by weighting observations by inverse selection probabilities. We illustrate the problem and a solution when modeling mixed migration strategies of northern white-tailed deer (Odocoileus virginianus). Captures occur on winter yards where deer migrate in response to changing environmental conditions. Yet, not all deer migrate in all years, and captures during mild years are more likely to target deer that migrate every year (i.e., obligate migrators). Characterizing deer as conditional or obligate migrators is also challenging unless deer are observed for many years and under a variety of winter conditions. We developed a hidden Markov model where the probability of capture depends on each individual's migration strategy (conditional versus obligate migrator), a partially latent variable that depends on winter severity in the year of capture. In a 15-year study, involving 168 white-tailed deer, the estimated probability of migrating for conditional migrators increased nonlinearly with an index of winter severity. We estimated a higher proportion of obligates in the study cohort than in the population, except during a span of 3 years surrounding back-to-back severe winters. These results support the hypothesis that selection biases occur as a result of capturing deer on winter yards, with the magnitude of bias depending on the severity of winter weather. Hidden Markov models offer an attractive framework for addressing selection biases due to their

  6. Political violence and child adjustment in Northern Ireland: Testing pathways in a social-ecological model including single-and two-parent families.

    PubMed

    Cummings, E Mark; Schermerhorn, Alice C; Merrilees, Christine E; Goeke-Morey, Marcie C; Shirlow, Peter; Cairns, Ed

    2010-07-01

    Moving beyond simply documenting that political violence negatively impacts children, we tested a social-ecological hypothesis for relations between political violence and child outcomes. Participants were 700 mother-child (M = 12.1 years, SD = 1.8) dyads from 18 working-class, socially deprived areas in Belfast, Northern Ireland, including single- and two-parent families. Sectarian community violence was associated with elevated family conflict and children's reduced security about multiple aspects of their social environment (i.e., family, parent-child relations, and community), with links to child adjustment problems and reductions in prosocial behavior. By comparison, and consistent with expectations, links with negative family processes, child regulatory problems, and child outcomes were less consistent for nonsectarian community violence. Support was found for a social-ecological model for relations between political violence and child outcomes among both single- and two-parent families, with evidence that emotional security and adjustment problems were more negatively affected in single-parent families. The implications for understanding social ecologies of political violence and children's functioning are discussed.

  7. The CoxD protein, a novel AAA+ ATPase involved in metal cluster assembly: hydrolysis of nucleotide-triphosphates and oligomerization.

    PubMed

    Maisel, Tobias; Joseph, Stephanie; Mielke, Thorsten; Bürger, Jörg; Schwarzinger, Stephan; Meyer, Ortwin

    2012-01-01

    CoxD of the α-proteobacterium Oligotropha carboxidovorans is a membrane protein which is involved in the posttranslational biosynthesis of the [CuSMoO₂] cluster in the active site of the enzyme CO dehydrogenase. The bacteria synthesize CoxD only in the presence of CO. Recombinant CoxD produced in E. coli K38 pGP1-2/pETMW2 appeared in inclusion bodies from where it was solubilized by urea and refolded by stepwise dilution. Circular dichroism spectroscopy revealed the presence of secondary structural elements in refolded CoxD. CoxD is a P-loop ATPase of the AAA-protein family. Refolded CoxD catalyzed the hydrolysis of MgATP yielding MgADP and inorganic phosphate at a 1∶1∶1 molar ratio. The reaction was inhibited by the slow hydrolysable MgATP-γ-S. GTPase activity of CoxD did not exceed 2% of the ATPase activity. Employing different methods (non linear regression, Hanes and Woolf, Lineweaver-Burk), preparations of CoxD revealed a mean K(M) value of 0.69±0.14 mM ATP and an apparent V(max) value of 19.3±2.3 nmol ATP hydrolyzed min⁻¹ mg⁻¹. Sucrose density gradient centrifugation and gel filtration showed that refolded CoxD can exist in various multimeric states (2-mer, 4-mer or 6-mer), preferentially as hexamer or dimer. Within weeks the hexamer dissociates into the dimer, a process which can be reversed by MgATP or MgATP-γ-S within hours. Only the hexamers and the dimers exhibited MgATPase activity. Transmission electron microscopy of negatively stained CoxD preparations revealed distinct particles within a size range of 10-16 nm, which further corroborates the oligomeric organization. The 3D structure of CoxD was modeled with the 3D structure of BchI from Rhodobacter capsulatus as template. It has the key elements of an AAA+ domain in the same arrangement and at same positions as in BchI and displays the characteristic inserts of the PS-II-insert clade. Possible functions of CoxD in [CuSMoO₂] cluster assembly are discussed.

  8. The CoxD Protein, a Novel AAA+ ATPase Involved in Metal Cluster Assembly: Hydrolysis of Nucleotide-Triphosphates and Oligomerization

    PubMed Central

    Maisel, Tobias; Joseph, Stephanie; Mielke, Thorsten; Bürger, Jörg; Schwarzinger, Stephan; Meyer, Ortwin

    2012-01-01

    CoxD of the α-proteobacterium Oligotropha carboxidovorans is a membrane protein which is involved in the posttranslational biosynthesis of the [CuSMoO2] cluster in the active site of the enzyme CO dehydrogenase. The bacteria synthesize CoxD only in the presence of CO. Recombinant CoxD produced in E. coli K38 pGP1-2/pETMW2 appeared in inclusion bodies from where it was solubilized by urea and refolded by stepwise dilution. Circular dichroism spectroscopy revealed the presence of secondary structural elements in refolded CoxD. CoxD is a P-loop ATPase of the AAA-protein family. Refolded CoxD catalyzed the hydrolysis of MgATP yielding MgADP and inorganic phosphate at a 1∶1∶1 molar ratio. The reaction was inhibited by the slow hydrolysable MgATP-γ-S. GTPase activity of CoxD did not exceed 2% of the ATPase activity. Employing different methods (non linear regression, Hanes and Woolf, Lineweaver-Burk), preparations of CoxD revealed a mean KM value of 0.69±0.14 mM ATP and an apparent Vmax value of 19.3±2.3 nmol ATP hydrolyzed min−1 mg−1. Sucrose density gradient centrifugation and gel filtration showed that refolded CoxD can exist in various multimeric states (2-mer, 4-mer or 6-mer), preferentially as hexamer or dimer. Within weeks the hexamer dissociates into the dimer, a process which can be reversed by MgATP or MgATP-γ-S within hours. Only the hexamers and the dimers exhibited MgATPase activity. Transmission electron microscopy of negatively stained CoxD preparations revealed distinct particles within a size range of 10–16 nm, which further corroborates the oligomeric organization. The 3D structure of CoxD was modeled with the 3D structure of BchI from Rhodobacter capsulatus as template. It has the key elements of an AAA+ domain in the same arrangement and at same positions as in BchI and displays the characteristic inserts of the PS-II-insert clade. Possible functions of CoxD in [CuSMoO2] cluster assembly are discussed. PMID:23077613

  9. The Arabidopsis COX11 Homolog is Essential for Cytochrome c Oxidase Activity.

    PubMed

    Radin, Ivan; Mansilla, Natanael; Rödel, Gerhard; Steinebrunner, Iris

    2015-01-01

    Members of the ubiquitous COX11 (cytochrome c oxidase 11) protein family are involved in copper delivery to the COX complex. In this work, we characterize the Arabidopsis thaliana COX11 homolog (encoded by locus At1g02410). Western blot analyses and confocal microscopy identified Arabidopsis COX11 as an integral mitochondrial protein. Despite sharing high sequence and structural similarities, the Arabidopsis COX11 is not able to functionally replace the Saccharomyces cerevisiae COX11 homolog. Nevertheless, further analysis confirmed the hypothesis that Arabidopsis COX11 is essential for COX activity. Disturbance of COX11 expression through knockdown (KD) or overexpression (OE) affected COX activity. In KD lines, the activity was reduced by ~50%, resulting in root growth inhibition, smaller rosettes and leaf curling. In OE lines, the reduction was less pronounced (~80% of the wild type), still resulting in root growth inhibition. Additionally, pollen germination was impaired in COX11 KD and OE plants. This effect on pollen germination can only partially be attributed to COX deficiency and may indicate a possible auxiliary role of COX11 in ROS metabolism. In agreement with its role in energy production, the COX11 promoter is highly active in cells and tissues with high-energy demand for example shoot and root meristems, or vascular tissues of source and sink organs. In COX11 KD lines, the expression of the plasma-membrane copper transporter COPT2 and of several copper chaperones was altered, indicative of a retrograde signaling pathway pertinent to copper homeostasis. Based on our data, we postulate that COX11 is a mitochondrial chaperone, which plays an important role for plant growth and pollen germination as an essential COX complex assembly factor.

  10. The Arabidopsis COX11 Homolog is Essential for Cytochrome c Oxidase Activity

    PubMed Central

    Radin, Ivan; Mansilla, Natanael; Rödel, Gerhard; Steinebrunner, Iris

    2015-01-01

    Members of the ubiquitous COX11 (cytochrome c oxidase 11) protein family are involved in copper delivery to the COX complex. In this work, we characterize the Arabidopsis thaliana COX11 homolog (encoded by locus At1g02410). Western blot analyses and confocal microscopy identified Arabidopsis COX11 as an integral mitochondrial protein. Despite sharing high sequence and structural similarities, the Arabidopsis COX11 is not able to functionally replace the Saccharomyces cerevisiae COX11 homolog. Nevertheless, further analysis confirmed the hypothesis that Arabidopsis COX11 is essential for COX activity. Disturbance of COX11 expression through knockdown (KD) or overexpression (OE) affected COX activity. In KD lines, the activity was reduced by ~50%, resulting in root growth inhibition, smaller rosettes and leaf curling. In OE lines, the reduction was less pronounced (~80% of the wild type), still resulting in root growth inhibition. Additionally, pollen germination was impaired in COX11 KD and OE plants. This effect on pollen germination can only partially be attributed to COX deficiency and may indicate a possible auxiliary role of COX11 in ROS metabolism. In agreement with its role in energy production, the COX11 promoter is highly active in cells and tissues with high-energy demand for example shoot and root meristems, or vascular tissues of source and sink organs. In COX11 KD lines, the expression of the plasma-membrane copper transporter COPT2 and of several copper chaperones was altered, indicative of a retrograde signaling pathway pertinent to copper homeostasis. Based on our data, we postulate that COX11 is a mitochondrial chaperone, which plays an important role for plant growth and pollen germination as an essential COX complex assembly factor. PMID:26734017

  11. Modelling the influence of Lake Agassiz on Glacial Isostatic Adjustment and deglaciation of the Laurentide ice sheet

    NASA Astrophysics Data System (ADS)

    Berends, Tijn; van de Wal, Roderik; de Boer, Bas; Bradley, Sarah

    2016-04-01

    ANICE is a 3-D ice-sheet-shelf model, which simulates ice dynamics on the continental scale. It uses a combination of the SIA and SSA approximations and here it is forced with benthic δ18O records using an inverse routine. It is coupled to SELEN, a model, which solves the gravitationally self-consistent sea-level equation and the solid earth deformation of a spherically symmetrical rotating Maxwell visco-elastic earth, accounting for all major GIA effects. The coupled ANICE-SELEN model thus captures ice-sea-level feedbacks and can be used to accurately simulate variations in local relative sea-level over geological time scales. In this study it is used to investigate the mass loss of the Laurentide ice-sheet during the last deglaciation, accounting in particular for the presence of the proglacial Lake Agassiz by way of its GIA effects and its effect on the ice sheet itself. We show that the mass of the water can have a significant effect on local relative sea-level through the same mechanisms as the ice-sheet - by perturbing the geoid and by deforming the solid earth. In addition we show that calving of the ice-shelf onto the lake could have had a strong influence on the behaviour of the deglaciation. In particular, when allowing lake calving, the ice-sheet retreats rapidly over the deepening bed of Hudson Bay during the deglaciation, resulting in a narrow ice dam over Hudson Strait. This dam collapses around 8.2 Kyr causing a global sea level rise of approximately 1 meter - an observation that agrees well with field data (for example, LaJeunesse and St. Onge, 2008). Without lake calving the model predicts a drainage towards the Arctic ocean in the North.

  12. Effect of isolated fractions of Harpagophytum procumbens D.C. (devil's claw) on COX-1, COX-2 activity and nitric oxide production on whole-blood assay.

    PubMed

    Anauate, Maria Cecilia; Torres, Luce Maria; de Mello, Suzana Beatriz Veríssimo

    2010-09-01

    The present study evaluates the effect of isolated fractions of Harpagophytum procumbens (devil's claw) on cyclooxygenase (COX-1 and COX-2) activities and NO production using a whole blood assay. The activity of COX-1 was quantified as platelet thromboxane B(2) production in blood clotting and COX-2 as prostaglandin E(2) production in LPS-stimulated whole blood. Total NO(2) (-)/NO(3) (-) concentration was determined by Griess reaction in LPS stimulated blood. Assays were performed by incubation of isolated fractions obtained by flash chromatography monitored with HPLC, TLC and identified by (1)HNMR, containing different amounts of harpagoside with blood from healthy donors. Indomethacin and etoricoxib were the positive controls of COX-1 and COX-2 Inhibition. Data shows that fraction containing the highest concentration of harpagoside inhibited indistinctively COX-1 and COX-2 (37.2 and 29.5% respectively) activity and greatly inhibited NO production (66%). In contrast the fraction including iridoid pool increased COX-2 and did not alter NO and COX-1 activities. The fraction containing cinnamic acid was able to reduce only NO production (67%). Our results demonstrated that the harpagoside fraction is the main responsible for the effect of devils claw on these enzyme activities. However, other components from devil's claw crude extract could antagonize or increase the synthesis of inflammatory mediators.

  13. Structure Based Library Design (SBLD) for new 1,4-dihydropyrimidine scaffold as simultaneous COX-1/COX-2 and 5-LOX inhibitors.

    PubMed

    Lokwani, Deepak; Azad, Rajaram; Sarkate, Aniket; Reddanna, Pallu; Shinde, Devanand

    2015-08-01

    The various scaffolds containing 1,4-dihydropyrimidine ring were designed by considering the environment of the active site of COX-1/COX-2 and 5-LOX enzymes. The structure-based library design approach, including the focused library design (Virtual Combinatorial Library Design) and virtual screening was used to select the 1,4-dihydropyrimidine scaffold for simultaneous inhibition of both enzyme pathways (COX-1/COX-2 and 5-LOX). The virtual library on each 1,4-dihydropyrimidine scaffold was enumerated in two alternative ways. In first way, the chemical reagents at R groups were filtered by docking of scaffold with single position substitution, that is, only at R1, or R2, or R3, … Rn on COX-2 enzyme using Glide XP docking mode. The structures that do not dock well were removed and the library was enumerated with filtered chemical reagents. In second alternative way, the single position docking stage was bypassed, and the entire library was enumerated using all chemical reagents by docking on the COX-2 enzyme. The entire library of approximately 15,629 compounds obtained from both ways after screening for drug like properties, were further screened for their binding affinity against COX-1 and 5-LOX enzymes using Virtual Screening Workflow. Finally, 142 hits were obtained and divided into two groups based on their binding affinity for COX-1/COX-2 and for both enzyme pathways (COX-1/COX-2 and 5-LOX). The ten molecules were selected, synthesized and evaluated for their COX-1, COX-2 and 5-LOX inhibiting activity.

  14. EGF receptor and COX-1/COX-2 enzyme proteins as related to corresponding mRNAs in human per-operative biopsies of colorectal cancer

    PubMed Central

    2013-01-01

    Background Cyclooxygenase (COX) and epidermal growth factor receptor (EGFR) activities promote progression of colorectal cancer. Combined treatment against these targets has not been more effective than single treatments alone. Therefore, our aim was to analyze relationships between COX and EGFR in peroperative colorectal tumor biopsies. Method Tumor and colon mucosa tissue were collected at primary intended curative operations in patients according to well-recognized statistical distributions of tumor stages in colorectal cancer. COX-1, COX-2 and EGFR content in tumor and colon mucosa tissue were quantified by western blot and Q-PCR. Results COX-2 protein appeared as two bands, one at 66 kDa in almost all tumor and mucosa samples and one at 74 kDa in 73% of the tumors and in 23% of the mucosa samples. Tumor COX-2 mRNA was not different from the content in mucosa samples, while COX-2 protein was increased in tumor tissue (p < 0.0003). A correlation between 74 kDa COX-2 protein and COX-2 mRNA occurred in tumor tissue, with significantly increasing COX-2 mRNA across tumor stages. EGFR mRNA content was lower in tumor tissue (p < 0.0001), while EGFR protein was similar in tumor and mucosa samples. COX-2 and EGFR proteins showed a positive correlation in mucosa, while a negative correlation occurred in tumor tissue. Tumor tissue with high COX-2 74 kDa protein lacked EGFR protein. Conclusion Our present results are compatible with the theory that COX-2 and EGFR signalling pathways are inversely related in colorectal cancer tissue. This may explain why combinatorial clinical treatments have been less rewarding. PMID:24171795

  15. Molecular docking studies of withanolides against Cox-2 enzyme.

    PubMed

    Prabhakaran, Yogeswaran; Dinakaran, Sathis Kumar; Macharala, Sravan Prasad; Ghosh, Somsubhra; Karanam, Sridevi Ranjitha; Kanthasamy, Naveena; Avasarala, Harani

    2012-07-01

    Withaniasomnifera (Ashwaganda) belonging to the family solanaceae is the subject of our present study. Withanoloides which are the major chemical constituents have been proved of interest because of their structural variations in the hybrids of different races. Docking is the process which brings the two structures together. In the present study we focus the extensive use of tool and graphical software for the identification of the binding energy of selected Withanolides like Withaferin -A, Withanolide-D from Withaniasomnifera and to screen the phytoconstituents that will dock/bind to the active sites of COX-2 enzyme. The relief from the symptoms of inflammation and pain can be by the Pharmacological inhibition of COX which involves the prediction of potential ligand for the treatment of inflammation. The energy value of docking between the target and the phytoconstituents under investigation and comparison with Diclofenac sodium was taken into consideration for coming into conclusion regarding the best pose and the binding ability.

  16. Trauma, comorbidity, and mortality following diagnoses of severe stress and adjustment disorders: a nationwide cohort study.

    PubMed

    Gradus, Jaimie L; Antonsen, Sussie; Svensson, Elisabeth; Lash, Timothy L; Resick, Patricia A; Hansen, Jens Georg

    2015-09-01

    Longitudinal outcomes following stress or trauma diagnoses are receiving attention, yet population-based studies are few. The aims of the present cohort study were to examine the cumulative incidence of traumatic events and psychiatric diagnoses following diagnoses of severe stress and adjustment disorders categorized using International Classification of Diseases, Tenth Revision, codes and to examine associations of these diagnoses with all-cause mortality and suicide. Data came from a longitudinal cohort of all Danes who received a diagnosis of reaction to severe stress or adjustment disorders (International Classification of Diseases, Tenth Revision, code F43.x) between 1995 and 2011, and they were compared with data from a general-population cohort. Cumulative incidence curves were plotted to examine traumatic experiences and psychiatric diagnoses during the study period. A Cox proportional hazards regression model was used to examine the associations of the disorders with mortality and suicide. Participants with stress diagnoses had a higher incidence of traumatic events and psychiatric diagnoses than did the comparison group. Each disorder was associated with a higher rate of all-cause mortality than that seen in the comparison cohort, and strong associations with suicide were found after adjustment. This study provides a comprehensive assessment of the associations of stress disorders with a variety of outcomes, and we found that stress diagnoses may have long-lasting and potentially severe consequences.

  17. [New studies of COX-inhibitors, yet issues remain].

    PubMed

    Wollheim, Frank A

    2003-09-18

    Advantages and risks related to the use of selective COX-2 inhibitors when treating arthritis are currently being scrutinized by authorities and public. The discussion tends towards exaggerated claims for or against their usefulness. The issue of cardiovascular safety is still not finally settled. In an experimental study using patients with severe coronary disease, administration of celecoxib resulted in improved endothelial function together with reduced CRP levels. Gastrointestinal tolerance was studied in patients who had recently recovered from peptic ulcer bleeding. In this group of high risk patients, celecoxib was as safe as combined therapy using omeprazol and diclofenac when given for 6 months. However, both COX inhibitors caused hypertension and adverse renal effects. The second generation of selective inhibitors is being launched. Etoricoxib--related to rofecoxib--was shown to be as potent as indomethacin in the treatment of acute gout, but it caused fewer adverse reactions. In general, however, any advantage of second generation as compared to first generation COX-2 inhibitors remains to be proven. The Swedish Council on Technology Assessment in Health Care, in its "SBU Alert", has published an appraisal of celecoxib and rofecoxib, in which the need for further long-term safety studies is emphasized.

  18. COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia

    PubMed Central

    Farooqui, M; Li, Y; Rogers, T; Poonawala, T; Griffin, R J; Song, C W; Gupta, K

    2007-01-01

    Morphine and its congener opioids are the main therapy for severe pain in cancer. However, chronic morphine treatment stimulates angiogenesis and tumour growth in mice. We examined if celecoxib (a cyclooxygenase-2 (COX-2) inhibitor) prevents morphine-induced tumour growth without compromising analgesia. The effect of chronic treatment with celecoxib (by gavage) and/or morphine (subcutaneously), or PBS on tumour prostaglandin E2 (PGE2), COX-2, angiogenesis, tumour growth, metastasis, pain behaviour and survival was determined in a highly invasive SCK breast cancer model in A/J mice. Two weeks of chronic morphine treatment at clinically relevant doses stimulates COX-2 and PGE2 (4.5-fold compared to vehicle alone) and angiogenesis in breast tumours in mice. This is accompanied by increased tumour weight (∼35%) and increased metastasis and reduced survival. Co-administration of celecoxib prevents these morphine-induced effects. In addition, morphine and celecoxib together provided better analgesia than either agent alone. Celecoxib prevents morphine-induced stimulation of COX-2, PGE2, angiogenesis, tumour growth, metastasis and mortality without compromising analgesia in a murine breast cancer model. In fact, the combination provided significantly better analgesia than with morphine or celecoxib alone. Clinical trials of this combination for analgesia in chronic and severe pain in cancer are warranted. PMID:17971769

  19. The common sense model of self-regulation and psychological adjustment to predictive genetic testing: a prospective study.

    PubMed

    van Oostrom, Iris; Meijers-Heijboer, Hanne; Duivenvoorden, Hugo J; Bröcker-Vriends, Annette H J T; van Asperen, Christi J; Sijmons, Rolf H; Seynaeve, Caroline; Van Gool, Arthur R; Klijn, Jan G M; Tibben, Aad

    2007-12-01

    This prospective study explored the contribution of illness representations and coping to cancer-related distress in unaffected individuals undergoing predictive genetic testing for an identified mutation in BRCA1/2 (BReast CAncer) or an HNPCC (Hereditary Nonpolyposis Colorectal Cancer)-related gene, based on the common sense model of self-regulation. Coping with hereditary cancer (UCL), illness representations (IPQ-R) and risk perception were assessed in 235 unaffected applicants for genetic testing before test result disclosure. Hereditary cancer distress (IES) and cancer worry (CWS) were assessed before, 2 weeks after and 6 months after result disclosure. Timeline (r = 0.30), consequences (r = 0.25), illness coherence (r = 0.21) and risk perception (r = 0.20) were significantly correlated to passive coping. Passive coping predicted hereditary cancer distress and cancer worry from pre-test (beta = 0.46 and 0.42, respectively) up to 6 months after result disclosure (beta = 0.32 and 0.19, respectively). Illness coherence predicted hereditary cancer distress up to 6 months after result disclosure (beta = 0.24), too. The self-regulatory model may be useful to predict the cognitive and emotional reactions to genetic cancer susceptibility testing. Identifying unhelpful representations and cognitive restructuring may be appropriate interventions to help distressed individuals undergoing genetic susceptibility testing for a BRCA1/2 or a HNPCC-related mutation.

  20. siRNA-mediated knock-down of COX-2 in melanocytes suppresses melanogenesis.

    PubMed

    Kim, Ji Y; Shin, Jae Y; Kim, Miri R; Hann, Seung-Kyung; Oh, Sang H

    2012-06-01

    Cyclooxygenase-2 (COX-2) is an enzyme induced in response to multiple mitogenic and inflammatory stimuli, including UV light. UV-induced COX-2 expression induces production of prostaglandin E2 (PGE2) in keratinocytes, which mediates inflammation and cell proliferation. Until recently, studies regarding COX-2 and PGE2 in the skin have focused on keratinocytes and skin cancer and the effect of PGs produced by keratinocytes on melanocytes. However, the effects of COX-2 itself or COX-2 inhibitors on melanogenesis are not well known. Therefore, to establish the role of COX-2 in melanogenesis, we investigated the effects of knock-down of COX-2 in melanocytes on melanin production and the expression of melanogenic molecules through silencing of COX-2 expression with COX-2 short interfering RNA (siRNA). COX-2 knock-down in melanocytes decreased the expressions of tyrosinase, TRP-1, TRP-2, gp100 and MITF and also reduced tyrosinase enzyme activity. Furthermore, COX-2 siRNA-transfected melanocytes showed markedly reduced alpha-melanocyte stimulating hormone (α-MSH)-induced melanin production. In addition, α-MSH-induced COX-2 expression in both scrambled siRNA-transfected and COX-2 siRNA-transfected melanocytes was greater than α-MSH-untreated cells. Our results suggest that COX-2 might be a candidate target for the development of anti-melanogenic agents and α-MSH-induced pigmentation could be closely associated with COX-2 expression. COX-2 inhibitors might therefore be of particular use in whitening cosmetics for hyperpigmentation disorders such as melasma, postinflammatory hyperpigmentation and solar lentigo.

  1. Expression of gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX-1, COX-2) in some benign salivary gland tumors.

    PubMed

    Lipari, L; Mauro, A; Gallina, S; Tortorici, S; Buscemi, M; Tete, S; Gerbino, A

    2012-01-01

    Salivary gland tumors, most of which are rare benign tumors, represent a histologically heterogenous group with the greatest diversity of morphological and cellular features. The aim of this study is to analyse the expression and possible interactions between gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX-1, COX-2) in some benign salivary gland tumors. We investigated the expression of gelatinases and cyclooxigenases in control salivary gland, Pleomorphic adenoma and Warthin's tumor through immunohistochemistry and Reverse Transcription - Polymerase Chain Reaction (PCR). We identified the expression of both classes of enzyme in normal samples and in the two types of pathological samples without any quantitative differences. From the present data no significant differences emerge in the expression of these enzymes among the different pathologies examined. Nevertheless, due to the small number of samples included in this study, general statements regarding correlation between the degree of severity of the tumoral pathology and the quantitative expression of these potential tumoral markers can not be made.

  2. COX-2 inhibitors from stem bark of Bauhinia rufescens Lam. (Fabaceae)

    PubMed Central

    Muhammad, Aminu; Sirat, Hasnah Mohd

    2013-01-01

    Chemical investigation of the stem bark of Bauhinia rufescens resulted in the isolation of a new cyanoglucoside and menisdaurin from methanol extract and oxepin from petroleum ether extract. The isolated compounds were tested for their anti-inflammatory potentials based on the cyclooxygenase-2 enzyme (COX-2) model. Cyanoglucoside exhibited the highest activity among the compounds with an inhibition activity of 49.34 % at 100 µM (IC50 0.46 µM) compared to the positive control, indomethacin (79.20 %, IC50 0.24 µM). PMID:26600739

  3. Holocene sea-level changes along the North Carolina Coastline and their implications for glacial isostatic adjustment models

    NASA Astrophysics Data System (ADS)

    Horton, B. P.; Peltier, W. R.; Culver, S. J.; Drummond, R.; Engelhart, S. E.; Kemp, A. C.; Mallinson, D.; Thieler, E. R.; Riggs, S. R.; Ames, D. V.

    2008-12-01

    We have synthesized new and existing relative sea-level (RSL) data to produce a quality-controlled, spatially comprehensive database of Holocene RSL changes from the North Carolina coastline. The RSL database consists of 51 sea-level index points that are quantitatively related to an appropriate tide level and assigned an error estimate, and a further 41 data points that provide limits on the maximum and minimum elevation of RSL. The data illustrate RSL rapidly rising during the early and middle Holocene from an observed elevation of -35.7 +/- 1.1 m MSL at 11062 - 10576 cal a BP to -4.2 m +/- 0.4 m MSL at 4240 - 3592 cal a BP. We subdivided the late Holocene RSL observations (last 4000 cal a BP) into two regions and compared these with predictions from the ICE-5G(VM2) GIA model. The observational data are explicable when rotational feedback is included in the ICE-5G(VM2) model. Rotational feedback is predicted to increase the rate of sea-level rise in Region 1 (Albemarle, Currituck, Roanoke, Croatan, and northern Pamlico sounds) compared to Region 2 (southern Pamlico, Core and Bogue sounds, and farther south to Wilmington). The observations show late Holocene sea-level rising at 1.14 +/- 0.03 mm yr-1 and 0.82 +/- 0.02 mm yr-1 in Regions 1 and 2, respectively. The ICE-5G(VM2) predictions capture the general temporal trend of the observations, although there is an apparent misfit for index points older than 2000 cal a BP. A comparison of local tide gauge data with the late-Holocene RSL trends from Regions 1 and 2 support the spatial variation in RSL across North Carolina, and imply an additional increase of mean sea-level of greater than 2 mm yr-1 during the latter half of the 20th century; this is in general agreement with historical tide gauge and satellite altimetry data.

  4. Altered arachidonic acid metabolism via COX-1 and COX-2 contributes to the endothelial dysfunction of penile arteries from obese Zucker rats

    PubMed Central

    Sánchez, A; Contreras, C; Villalba, N; Martínez, P; Martínez, AC; Bríones, A; Salaíces, M; García-Sacristán, A; Hernández, M; Prieto, D

    2010-01-01

    Background and purpose: The aim of the current study was to investigate the role of arachidonic acid (AA) metabolism via cyclooxygenase (COX) in the endothelial dysfunction of penile arteries from pre-diabetic, obese Zucker rats (OZR). Experimental approach: Penile arteries from OZR and from lean Zucker rats (LZR) were mounted in microvascular myographs to assess vascular function and COX expression was determined by immunohistochemistry. Key results: Acetylcholine (ACh) and AA elicited relaxations that were impaired in arteries from OZR. Inhibition of both COX-1 and COX-2 reduced the relaxant effects of ACh and AA in LZR but not in OZR. Inhibitors of COX-1 and of the TXA2/PGH2 (TP) receptor enhanced the relaxations induced by AA in both LZR and OZR, whereas COX-2 inhibition enhanced these responses only in OZR. TP receptor blockade did not restore ACh relaxant responses in arteries from OZR. Inhibition of COX-1 increased basal tension in OZR and this contraction was blunted by TP receptor blockade. The vasoconstrictor responses to noradrenaline were augmented by indomethacin and by COX-2 inhibition in LZR but not in OZR. Immunohistochemical staining showed that both COX-1 and COX-2 are expressed in the endothelium of penile arteries from both LZR and OZR. Conclusions and implications: Vasoactive prostanoids were formed via constitutively active COX-1 and COX-2 pathways in normal rat penile arteries. Under conditions of insulin resistance, the release and/or effects of vasodilator prostanoids were impaired, contributing to the blunted endothelium-dependent vasodilatation and to the enhanced vasoconstriction. PMID:20082610

  5. COX-2-dependent stabilization of survivin in non-small cell lung cancer.

    PubMed

    Krysan, Kostyantyn; Merchant, Farrukh H; Zhu, Li; Dohadwala, Mariam; Luo, Jie; Lin, Ying; Heuze-Vourc'h, Nathalie; Põld, Mehis; Seligson, David; Chia, David; Goodglick, Lee; Wang, Hejing; Strieter, Robert; Sharma, Sherven; Dubinett, Steven

    2004-01-01

    Elevated tumor cyclooxygenase 2 (COX-2) expression is associated with increased angiogenesis, tumor invasion and promotion of tumor cell resistance to apoptosis. The mechanism(s) by which COX-2 exerts its cytoprotective effects are not completely understood but may be due to an imbalance of pro- and anti-apoptotic gene expression. To analyze COX-2-dependent gene expression and apoptosis, we created cell lines constitutively expressing COX-2 cDNA in sense and antisense orientations. Whereas COX-2 sense cells have significantly heightened resistance to radiation and drug-induced apoptosis, COX-2 antisense cells are highly sensitive to apoptosis induction. We found that the expression of the anti-apoptotic protein survivin correlated positively with COX-2 expression. A COX-2-dependent modulation of survivin ubiquitination led to its stabilization in COX-2 overexpressing cells, and this effect was replicated by exogenous PGE2 treatment of parental tumor cells. In contrast to previous studies in other cell types, in nonsmall cell lung cancer cells survivin was expressed in a cell cycle-independent manner. When established in SCID mice in vivo, COX-2 antisense-derived tumors had significantly decreased survivin levels while COX-2 sense-derived tumors demonstrated elevated levels compared with controls. In accord with these findings, survivin and COX-2 were frequently upregulated and co-expressed in human lung cancers in situ.

  6. Enhancing Global Land Surface Hydrology Estimates from the NASA MERRA Reanalysis Using Precipitation Observations and Model Parameter Adjustments

    NASA Technical Reports Server (NTRS)

    Reichle, Rolf; Koster, Randal; DeLannoy, Gabrielle; Forman, Barton; Liu, Qing; Mahanama, Sarith; Toure, Ally

    2011-01-01

    The Modern-Era Retrospective analysis for Research and Applications (MERRA) is a state-of-the-art reanalysis that provides. in addition to atmospheric fields. global estimates of soil moisture, latent heat flux. snow. and runoff for J 979-present. This study introduces a supplemental and improved set of land surface hydrological fields ('MERRA-Land') generated by replaying a revised version of the land component of the MERRA system. Specifically. the MERRA-Land estimates benefit from corrections to the precipitation forcing with the Global Precipitation Climatology Project pentad product (version 2.1) and from revised parameters in the rainfall interception model, changes that effectively correct for known limitations in the MERRA land surface meteorological forcings. The skill (defined as the correlation coefficient of the anomaly time series) in land surface hydrological fields from MERRA and MERRA-Land is assessed here against observations and compared to the skill of the state-of-the-art ERA-Interim reanalysis. MERRA-Land and ERA-Interim root zone soil moisture skills (against in situ observations at 85 US stations) are comparable and significantly greater than that of MERRA. Throughout the northern hemisphere, MERRA and MERRA-Land agree reasonably well with in situ snow depth measurements (from 583 stations) and with snow water equivalent from an independent analysis. Runoff skill (against naturalized stream flow observations from 15 basins in the western US) of MERRA and MERRA-Land is typically higher than that of ERA-Interim. With a few exceptions. the MERRA-Land data appear more accurate than the original MERRA estimates and are thus recommended for those interested in using '\\-tERRA output for land surface hydrological studies.

  7. Impact of COX2 genotype, ER status and body constitution on risk of early events in different treatment groups of breast cancer patients.

    PubMed

    Markkula, Andrea; Simonsson, Maria; Rosendahl, Ann H; Gaber, Alexander; Ingvar, Christian; Rose, Carsten; Jernström, Helena

    2014-10-15

    The COX2 rs5277 (306G>C) polymorphism has been associated with inflammation-associated cancers. In breast cancer, tumor COX-2 expression has been associated with increased estrogen levels in estrogen receptor (ER)-positive and activated Akt-pathway in ER-negative tumors. Our study investigated the impact of COX2 genotypes on early breast cancer events and treatment response in relation to tumor ER status and body constitution. In Sweden, between 2002 and 2008, 634 primary breast cancer patients, aged 25-99 years, were included. Disease-free survival was assessed for 570 rs5277-genotyped patients. Body measurements and questionnaires were obtained preoperatively. Clinical data, patient- and tumor-characteristics were obtained from questionnaires, patients' charts, population registries and pathology reports. Minor allele(C) frequency was 16.1%. Genotype was not linked to COX-2 tumor expression. Median follow-up was 5.1 years. G/G genotype was not associated with early events in patients with ER-positive tumors, adjusted HR 0.77 (0.46-1.29), but conferred an over 4-fold increased risk in patients with ER-negative tumors, adjusted HR 4.41 (1.21-16.02)(p(interaction) = 0.015). Chemotherapy-treated G/G-carriers with a breast volume ≥ 850 ml had an increased risk of early events irrespective of ER status, adjusted HR 8.99 (1.14-70.89). Endocrine-treated C-allele carriers with ER-positive tumors and a breast volume ≥ 850 ml had increased risk of early events, adjusted HR 2.30 (1.12-4.75). COX2 genotype, body constitution and ER status had a combined effect on the risk of early events and treatment response. The high risk for early events in certain subgroups of patients suggests that COX2 genotype in combination with body measurements may identify patients in need of more personalized treatment.

  8. Land-use influences the distribution and activity of high affinity CO-oxidizing bacteria associated to type I-coxL genotype in soil

    PubMed Central

    Quiza, Liliana; Lalonde, Isabelle; Guertin, Claude; Constant, Philippe

    2014-01-01

    Soil carboxydovore bacteria are the biological sink of atmospheric carbon monoxide (CO). The initial oxidation of CO is catalyzed by a CO-dehydrogenase (CODH), and the gene coxL encodes the large subunit of the enzyme. Only a few carboxydovore isolates were shown to oxidize atmospheric CO and little is known about the potential impact of global change on the ecophysiology of this functional group. The main objective of this study was to assess the impact of land-use and soil properties on coxL gene diversity and identify molecular indicators for the soil uptake of atmospheric CO. Soil samples were collected in three neighboring sites encompassing different land-use types, namely deciduous forest, larch plantation and maize field. CO uptake activity was related to total carbon and nitrogen content in soil, with the highest activity observed in deciduous forest. An extensive coxL database was assembled to optimize a PCR detection assay targeting sequences belonging to functional type I-CODH and hypothetical type II-CODH. Fully replicated coxL gene libraries unveiled a unique molecular signature in deciduous forest soil, with enrichment of type I sequences. Genetic profiles of larch and maize monocultures were not statistically different and showed higher level of coxL gene richness than deciduous forest. Soil water content and CO uptake activity explained 38% of the variation of coxL gene profiles in a canonical ordination analysis, leading to the identification of sequences belonging to the δ-Proteobacteria cluster as indicator for high affinity CO uptake activity. Enrichment of type I and δ-Proteobacteria coxL sequences in deciduous forest were confirmed by qPCR in an independent soil survey. CO uptake activity in model carboxydovore bacteria suggested that a significant fraction of detected putative high affinity CO oxidizers were active in soil. Land-use was a driving force separating coxL diversity in deciduous forest from monocultures. PMID:24971077

  9. Does Cox analysis of a randomized survival study yield a causal treatment effect?

    PubMed

    Aalen, Odd O; Cook, Richard J; Røysland, Kjetil

    2015-10-01

    Statistical methods for survival analysis play a central role in the assessment of treatment effects in randomized clinical trials in cardiovascular disease, cancer, and many other fields. The most common approach to analysis involves fitting a Cox regression model including a treatment indicator, and basing inference on the large sample properties of the regression coefficient estimator. Despite the fact that treatment assignment is randomized, the hazard ratio is not a quantity which admits a causal interpretation in the case of unmodelled heterogeneity. This problem arises because the risk sets beyond the first event time are comprised of the subset of individuals who have not previously failed. The balance in the distribution of potential confounders between treatment arms is lost by this implicit conditioning, whether or not censoring is present. Thus while the Cox model may be used as a basis for valid tests of the null hypotheses of no treatment effect if robust variance estimates are used, modeling frameworks more compatible with causal reasoning may be preferrable in general for estimation.

  10. The Role of COX-2 in the Inflammatory and Fibrotic Response in the Lung Following Exposure to Multi-Walled Carbon Nanotubes

    NASA Astrophysics Data System (ADS)

    Sayers, Brian C.

    Exposure to multiwalled carbon nanotubes (MWCNT) has been demonstrated to exacerbate airway inflammation and fibrosis in allergen-challenged mouse model. These data have led to concern that individuals with asthma could represent a susceptible population to adverse health effects following exposure to MWCNT, and possibly other engineered nanoparticles. Asthma pathogenesis is caused by the interaction of a complex genetic predisposition and environmental exposures. Because chronic airway inflammation is common to all asthma phenotypes, it is logical to investigate genes that are involved in inflammatory pathways in order to understand the genetic basis of asthma. The metabolism of arachidonic acid by cyclooxygenase (COX) enzymes is the rate-determining step in the synthesis of prostanoids, which are biologically active lipids that are important modulators of inflammation. Based on the role of COX enzymes in inflammatory pathways, we sought to investigate how COX enzymes are involved in the inflammatory response following MWCNT exposure in asthmatic airways. We report that MWCNT significantly exacerbated allergen-induced airway inflammation and mucus cell metaplasia in COX-2 deficient mice compared to wild type mice. In addition, MWCNTs significantly enhanced allergen-induced cytokines involved in Th2 (IL-13, IL-5), Th1 (CXCL10), and Th17 (IL-17A) inflammatory responses in COX-2 deficient mice but not in WT mice. We conclude that exacerbation of allergen-induced airway inflammation and mucus cell metaplasia by MWCNTs is enhanced by deficiency in COX-2 and associated with activation of a mixed Th1/Th2/Th17 immune response. Based on our observation that COX-2 deficient mice developed a mixed Th immune response following MWCNT exposure, we sought to evaluate how cytokines associated with different Th immune responses alter COX expression following MWCNT exposure. For this study, a mouse macrophage cell line (RAW264.7) was used because MWCNT were largely sequestered

  11. An optimization model for regional air pollutants mitigation based on the economic structure adjustment and multiple measures: A case study in Urumqi city, China.

    PubMed

    Sun, Xiaowei; Li, Wei; Xie, Yulei; Huang, Guohe; Dong, Changjuan; Yin, Jianguang

    2016-11-01

    A model based on economic structure adjustment and pollutants mitigation was proposed and applied in Urumqi. Best-worst case analysis and scenarios analysis were performed in the model to guarantee the parameters accuracy, and to analyze the effect of changes of emission reduction styles. Results indicated that pollutant-mitigations of electric power industry, iron and steel industry, and traffic relied mainly on technological transformation measures, engineering transformation measures and structure emission reduction measures, respectively; Pollutant-mitigations of cement industry relied mainly on structure emission reduction measures and technological transformation measures; Pollutant-mitigations of thermal industry relied mainly on the four mitigation measures. They also indicated that structure emission reduction was a better measure for pollutants mitigation of Urumqi. Iron and steel industry contributed greatly in SO2, NOx and PM (particulate matters) emission reduction and should be given special attention in pollutants emission reduction. In addition, the scales of iron and steel industry should be reduced with the decrease of SO2 mitigation amounts. The scales of traffic and electric power industry should be reduced with the decrease of NOx mitigation amounts, and the scales of cement industry and iron and steel industry should be reduced with the decrease of PM mitigation amounts. The study can provide references of pollutants mitigation schemes to decision-makers for regional economic and environmental development in the 12th Five-Year Plan on National Economic and Social Development of Urumqi.

  12. Scenario analysis of carbon emissions' anti-driving effect on Qingdao's energy structure adjustment with an optimization model, Part II: Energy system planning and management.

    PubMed

    Wu, C B; Huang, G H; Liu, Z P; Zhen, J L; Yin, J G

    2017-03-01

    In this study, an inexact multistage stochastic mixed-integer programming (IMSMP) method was developed for supporting regional-scale energy system planning (EPS) associated with multiple uncertainties presented as discrete intervals, probability distributions and their combinations. An IMSMP-based energy system planning (IMSMP-ESP) model was formulated for Qingdao to demonstrate its applicability. Solutions which can provide optimal patterns of energy resources generation, conversion, transmission, allocation and facility capacity expansion schemes have been obtained. The results can help local decision makers generate cost-effective energy system management schemes and gain a comprehensive tradeoff between economic objectives and environmental requirements. Moreover, taking the CO2 emissions scenarios mentioned in Part I into consideration, the anti-driving effect of carbon emissions on energy structure adjustment was studied based on the developed model and scenario analysis. Several suggestions can be concluded from the results: (a) to ensure the smooth realization of low-carbon and sustainable development, appropriate price control and fiscal subsidy on high-cost energy resources should be considered by the decision-makers; (b) compared with coal, natural gas utilization should be strongly encouraged in order to insure that Qingdao could reach the carbon discharges peak value in 2020; (c) to guarantee Qingdao's power supply security in the future, the construction of new power plants should be emphasised instead of enhancing the transmission capacity of grid infrastructure.

  13. Cox process representation and inference for stochastic reaction-diffusion processes.

    PubMed

    Schnoerr, David; Grima, Ramon; Sanguinetti, Guido

    2016-05-25

    Complex behaviour in many systems arises from the stochastic interactions of spatially distributed particles or agents. Stochastic reaction-diffusion processes are widely used to model such behaviour in disciplines ranging from biology to the social sciences, yet they are notoriously difficult to simulate and calibrate to observational data. Here we use ideas from statistical physics and machine learning to provide a solution to the inverse problem of learning a stochastic reaction-diffusion process from data. Our solution relies on a non-trivial connection between stochastic reaction-diffusion processes and spatio-temporal Cox processes, a well-studied class of models from computational statistics. This connection leads to an efficient and flexible algorithm for parameter inference and model selection. Our approach shows excellent accuracy on numeric and real data examples from systems biology and epidemiology. Our work provides both insights into spatio-temporal stochastic systems, and a practical solution to a long-standing problem in computational modelling.

  14. Cox process representation and inference for stochastic reaction-diffusion processes

    NASA Astrophysics Data System (ADS)

    Schnoerr, David; Grima, Ramon; Sanguinetti, Guido

    2016-05-01

    Complex behaviour in many systems arises from the stochastic interactions of spatially distributed particles or agents. Stochastic reaction-diffusion processes are widely used to model such behaviour in disciplines ranging from biology to the social sciences, yet they are notoriously difficult to simulate and calibrate to observational data. Here we use ideas from statistical physics and machine learning to provide a solution to the inverse problem of learning a stochastic reaction-diffusion process from data. Our solution relies on a non-trivial connection between stochastic reaction-diffusion processes and spatio-temporal Cox processes, a well-studied class of models from computational statistics. This connection leads to an efficient and flexible algorithm for parameter inference and model selection. Our approach shows excellent accuracy on numeric and real data examples from systems biology and epidemiology. Our work provides both insights into spatio-temporal stochastic systems, and a practical solution to a long-standing problem in computational modelling.

  15. Cox26 is a novel stoichiometric subunit of the yeast cytochrome c oxidase.

    PubMed

    Levchenko, Maria; Wuttke, Jan-Moritz; Römpler, Katharina; Schmidt, Bernhard; Neifer, Klaus; Juris, Lisa; Wissel, Mirjam; Rehling, Peter; Deckers, Markus

    2016-07-01

    The cytochrome c oxidase (COX) is the terminal enzyme of the respiratory chain. The complex accepts electrons from cytochrome c and passes them onto molecular oxygen. This process contributes to energy capture in the form of a membrane potential across the inner membrane. The enzyme complex assembles in a stepwise process from the three mitochondria-encoded core subunits Cox1, Cox2 and Cox3, which associate with nuclear-encoded subunits and cofactors. In the yeast Saccharomyces cerevisiae, the cytochrome c oxidase associates with the bc1-complex into supercomplexes, allowing efficient energy transduction. Here we report on Cox26 as a protein found in respiratory chain supercomplexes containing cytochrome c oxidase. Our analyses reveal Cox26 as a novel stoichiometric structural subunit of the cytochrome c oxidase. A loss of Cox26 affects cytochrome c oxidase activity and respirasome organization.

  16. Lithosphere and upper-mantle structure of the southern Baltic Sea estimated from modelling relative sea-level data with glacial isostatic adjustment

    NASA Astrophysics Data System (ADS)

    Steffen, H.; Kaufmann, G.; Lampe, R.

    2014-06-01

    thickness as determined with ICE-5G does not agree with the lithosphere models. Hence, more investigations have to be undertaken to sufficiently determine structures such as the Ringkøbing-Fyn High as seen with seismics with the help of glacial isostatic adjustment modelling.

  17. Anti-inflammatory effects and gastrointestinal safety of NNU-hdpa, a novel dual COX/5-LOX inhibitor.

    PubMed

    Xu, Guang-Lin; Liu, Fei; Ao, Gui-Zhen; He, Shu-Ying; Ju, Min; Zhao, Yue; Xue, Ting

    2009-06-02

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a risk of serious adverse events. Now, the development of dual inhibitors of cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) has become a hot area in searching for safer NSAIDs. NNU-hdpa, 2-(4-hydroxylphenyl)-3-(3,5-dihydroxylphenyl) propenoic acid, a newly synthesized compound, is expected to have COX/5-LOX dual inhibition with an improved gastrointestinal profile. In this study, NNU-hdpa was subjected to in vitro and in vivo experiment protocols. In vitro COX/5-LOX inhibition assays showed that NNU-hdpa exhibits a dual inhibitory activity against the COX and 5-LOX enzymes. Anti-inflammatory activity in vivo was evaluated using two animal edema model tests. Pretreatment with NNU-hdpa (p.o.) dose-dependently inhibited the xylene-induced ear edema in mice and carrageenan-induced paw edema in rats respectively. In gastric lesion test, NNU-hdpa was gastric-sparing in that it elicited markedly fewer stomach lesions as compared to the stomach lesions caused by aspirin in rats. In further studies, NNU-hdpa was found to significantly inhibit the productions of PGE(2) and LTB(4) in LPS-challenged RAW 264.7, which is parallel to its prevention of the nuclear translocation of the NF-kappaB p50 and p65 subunits. These data indicate that NNU-hdpa comprises a novel class of dual inhibitors of COX and 5-LOX having therapeutic potential with an enhanced gastric safety profile.

  18. Remotely Adjustable Hydraulic Pump

    NASA Technical Reports Server (NTRS)

    Kouns, H. H.; Gardner, L. D.

    1987-01-01

    Outlet pressure adjusted to match varying loads. Electrohydraulic servo has positioned sleeve in leftmost position, adjusting outlet pressure to maximum value. Sleeve in equilibrium position, with control land covering control port. For lowest pressure setting, sleeve shifted toward right by increased pressure on sleeve shoulder from servovalve. Pump used in aircraft and robots, where hydraulic actuators repeatedly turned on and off, changing pump load frequently and over wide range.

  19. Adjustable Pitot Probe

    NASA Technical Reports Server (NTRS)

    Ashby, George C., Jr.; Robbins, W. Eugene; Horsley, Lewis A.

    1991-01-01

    Probe readily positionable in core of uniform flow in hypersonic wind tunnel. Formed of pair of mating cylindrical housings: transducer housing and pitot-tube housing. Pitot tube supported by adjustable wedge fairing attached to top of pitot-tube housing with semicircular foot. Probe adjusted both radially and circumferentially. In addition, pressure-sensing transducer cooled internally by water or other cooling fluid passing through annulus of cooling system.

  20. Weighted triangulation adjustment

    USGS Publications Warehouse

    Anderson, Walter L.

    1969-01-01

    The variation of coordinates method is employed to perform a weighted least squares adjustment of horizontal survey networks. Geodetic coordinates are required for each fixed and adjustable station. A preliminary inverse geodetic position computation is made for each observed line. Weights associated with each observed equation for direction, azimuth, and distance are applied in the formation of the normal equations in-the least squares adjustment. The number of normal equations that may be solved is twice the number of new stations and less than 150. When the normal equations are solved, shifts are produced at adjustable stations. Previously computed correction factors are applied to the shifts and a most probable geodetic position is found for each adjustable station. Pinal azimuths and distances are computed. These may be written onto magnetic tape for subsequent computation of state plane or grid coordinates. Input consists of punch cards containing project identification, program options, and position and observation information. Results listed include preliminary and final positions, residuals, observation equations, solution of the normal equations showing magnitudes of shifts, and a plot of each adjusted and fixed station. During processing, data sets containing irrecoverable errors are rejected and the type of error is listed. The computer resumes processing of additional data sets.. Other conditions cause warning-errors to be issued, and processing continues with the current data set.

  1. CERAMIC: Case-Control Association Testing in Samples with Related Individuals, Based on Retrospective Mixed Model Analysis with Adjustment for Covariates

    PubMed Central

    Zhong, Sheng; McPeek, Mary Sara

    2016-01-01

    We consider the problem of genetic association testing of a binary trait in a sample that contains related individuals, where we adjust for relevant covariates and allow for missing data. We propose CERAMIC, an estimating equation approach that can be viewed as a hybrid of logistic regression and linear mixed-effects model (LMM) approaches. CERAMIC extends the recently proposed CARAT method to allow samples with related individuals and to incorporate partially missing data. In simulations, we show that CERAMIC outperforms existing LMM and generalized LMM approaches, maintaining high power and correct type 1 error across a wider range of scenarios. CERAMIC results in a particularly large power increase over existing methods when the sample includes related individuals with some missing data (e.g., when some individuals with phenotype and covariate information have missing genotype), because CERAMIC is able to make use of the relationship information to incorporate partially missing data in the analysis while correcting for dependence. Because CERAMIC is based on a retrospective analysis, it is robust to misspecification of the phenotype model, resulting in better control of type 1 error and higher power than that of prospective methods, such as GMMAT, when the phenotype model is misspecified. CERAMIC is computationally efficient for genomewide analysis in samples of related individuals of almost any configuration, including small families, unrelated individuals and even large, complex pedigrees. We apply CERAMIC to data on type 2 diabetes (T2D) from the Framingham Heart Study. In a genome scan, 9 of the 10 smallest CERAMIC p-values occur in or near either known T2D susceptibility loci or plausible candidates, verifying that CERAMIC is able to home in on the important loci in a genome scan. PMID:27695091

  2. Overexpression of farnesoid X receptor in small airways contributes to epithelial to mesenchymal transition and COX-2 expression in chronic obstructive pulmonary disease

    PubMed Central

    Chen, Bi; You, Wen-Jie; Xue, Shan; Qin, Hui; Zhao, Xu-Ji; Zhang, Miao; Liu, Xue-Qing; Zhu, Shu-Yang

    2016-01-01

    Background Epithelial-mesenchymal transition (EMT) and cyclooxygenase-2 (COX-2) contribute to airway remodelling and inflammation in chronic obstructive pulmonary disease (COPD). Recent data suggest that the farnesoid X receptor (FXR), a nuclear receptor traditionally considered as bile acid-activated receptor, is also expressed in non-classical bile acids target tissues with novel functions beyond regulating bile acid homeostasis. This study aimed to investigate the potential role of FXR in the development of COPD, as well as factors that affect FXR expression. Methods Expression of FXR, EMT biomarkers and COX-2 was examined by immunohistochemistry in lung tissues from non-smokers, smokers, and smokers with COPD. The role of FXR in TGF-β1-induced EMT and COX-2 expression in human bronchial epithelial (HBE) cells was evaluated in vitro. Factors regulating FXR expression were assessed in cultured HBE cells and a cigarette smoke-induced rat model of COPD. Results Expression of FXR, EMT markers and COX-2 was significantly elevated in small airway epithelium of COPD patients compared with controls. The staining scores of FXR in small airway epithelium were negatively related with FEV1% of predicted of smokers without and with COPD. FXR agonist GW4064 remarkably enhanced and FXR antagonist Z-Guggulsterone significantly inhibited EMT changes in TGF-β1-treated HBE cells. Both chenodeoxycholic acid (CDCA) and GW4064 increased COX-2 expression in HBE cells, whereas Z-Guggulsterone dramatically restrained CDCA-induced COX-2 expression. Finally, FXR expression is induced by IL-4 and IL-13 in HBE cells, as well as by cigarette smoke exposure in a rat model of COPD. Conclusions Overexpression of FXR in small airway may contribute to airway remodelling and inflammation in COPD by regulating EMT and COX-2 expression. PMID:28066584

  3. Expected Power-Utility Maximization Under Incomplete Information and with Cox-Process Observations

    SciTech Connect

    Fujimoto, Kazufumi; Nagai, Hideo; Runggaldier, Wolfgang J.

    2013-02-15

    We consider the problem of maximization of expected terminal power utility (risk sensitive criterion). The underlying market model is a regime-switching diffusion model where the regime is determined by an unobservable factor process forming a finite state Markov process. The main novelty is due to the fact that prices are observed and the portfolio is rebalanced only at random times corresponding to a Cox process where the intensity is driven by the unobserved Markovian factor process as well. This leads to a more realistic modeling for many practical situations, like in markets with liquidity restrictions; on the other hand it considerably complicates the problem to the point that traditional methodologies cannot be directly applied. The approach presented here is specific to the power-utility. For log-utilities a different approach is presented in Fujimoto et al. (Preprint, 2012).

  4. Targeting COX-2 expression by natural compounds: a promising alternative strategy to synthetic COX-2 inhibitors for cancer chemoprevention and therapy.

    PubMed

    Cerella, Claudia; Sobolewski, Cyril; Dicato, Mario; Diederich, Marc

    2010-12-15

    Cyclooxygenase (COX)-2 is a pro-inflammatory immediate early response protein, chronically up-regulated in many pathological conditions. In autoimmune diseases, it is responsible for degenerative effects whereas in cancer, it correlates with poor prognosis. A constitutive expression of COX-2 is triggered since the earliest steps of carcinogenesis. Consequently, strategies aimed at inhibiting COX-2 enzymatic activity have been clinically applied for the treatment of autoimmune disorders; in addition, the same approaches are currently investigated for anti-cancer purposes. However, COX-2 protein inhibitors (i.e., NSAIDs and COXIBs) are not amenable to prolonged administration since they may cause severe side effects, and efforts are underway to identify alternative approaches for chemoprevention/therapy. COX-2 expression is a multi-step process, highly regulated at transcriptional and post-transcriptional levels. Defects in the modulation of one or both of these steps may be found in pathological conditions. Targeting COX-2 expression may therefore represent a promising strategy, by which the same preventive and therapeutic benefits may be gained while avoiding the severe side effects of COX-2 enzymatic inhibition. Naturally occurring compounds derived from plants/organisms represent a huge source of biologically active molecules, that remains largely unexplored. Derived from plants/organisms used in traditional forms of medicine or as dietary supplements, these compounds have been experimentally investigated for their anti-inflammatory and anti-cancer potential. In this review, we will analyze how natural compounds may modulate the multistep regulation of COX-2 gene expression and discuss their potential as a new generation of COX-2 targeting agents alternative to the synthetic COX-2 inhibitors.

  5. iNOS signaling interacts with COX-2 pathway in colonic fibroblasts.

    PubMed

    Zhu, Yingting; Zhu, Min; Lance, Peter

    2012-10-01

    COX-2 and iNOS are two major inflammatory mediators implicated in colorectal inflammation and cancer. Previously, the role of colorectal fibroblasts involved in regulation of COX-2 and iNOS expression was largely ignored. In addition, the combined interaction of COX-2 and iNOS signalings and their significance in the progression of colorectal inflammation and cancer within the fibroblasts have received little investigation. To address those issues, we investigated the role of colonic fibroblasts in the regulation of COX-2 and iNOS gene expression, and explored possible mechanisms of interaction between COX-2 and iNOS signalings using a colonic CCD-18Co fibroblast line and LPS, a potential stimulator of COX-2 and iNOS. Our results clearly demonstrated that LPS activated COX-2 gene expression and enhanced PGE(2) production, stimulated iNOS gene expression and promoted NO production in the fibroblasts. Interestingly, activation of COX-2 signaling by LPS was not involved in activation of iNOS signaling, while activation of iNOS signaling by LPS contributed in part to activation of COX-2 signaling. Further analysis indicated that PKC plays a major role in the activation and interaction of COX-2 and iNOS signalings induced by LPS in the fibroblasts.

  6. Sharp variation in coercivity and magnetic interactions in patterned CoxNi1-x nanoarrays

    NASA Astrophysics Data System (ADS)

    Yang, Chao-Yao; Wang, Liang-Wei; Chen, Po-An; Lin, Hong-Ji; Lai, Chih-Huang; Tseng, Yuan-Chieh

    2013-08-01

    We present a study concerning the unexpectedly large coercivity increase and associated magneto-structural properties of CoxNi1-x patterned arrays. An increase in x led to an face-center-cubic (FCC)→hexagonal-close-packed (HCP) transition in CoxNi1-x arrays, accompanied by a 6-fold increase in coercivity and strong 3d exchange interactions probed by x-ray magnetic circular dichroism. Sum-rule analysis revealed that orbital moment involved very little in the variable coercivity and magnetic anisotropy; this is distinct from other nanostructures displaying variable coercivity. The sharp rise in coercivity can be attributed to the geometrical confinement of the arrays, causing the microstructure of the nano-clusters to switch magnetization reversal mechanism from fanning to coherent with increasing x, based on the chain-of-spheres model. First-order-reversal curves revealed that the FCC and HCP arrays comprised both soft and hard ferromagnetic components; however, the soft component of the FCC was much more pronounced, leading to differences in reversibility. This type of nanostructure provides a sharp control of magnetic hardness that could be tailored in related technologies.

  7. Usefulness of selective COX-2 inhibitors as therapeutic agents against canine mammary tumors.

    PubMed

    Saito, Teruyoshi; Tamura, Dai; Asano, Ryuji

    2014-04-01

    Cyclooxygenase-2 (COX-2) is a key enzyme for converting arachidonic acids to prostanoids, which are known to be induced during inflammation and cancer initiation. Previously, it has been reported that COX inhibitors, such as aspirin, reduce the incidence of human colorectal cancer; therefore, it is widely believed that COX-2 is a potential therapeutic and chemoprevention target for several types of human cancer. However, whether selective COX-2 inhibitors have antitumor effects against canine mammary tumor cells remains unclear. In the present study, to elucidate the antitumor effect of selective COX-2 inhibitors against canine mammary tumors, we investigated the antitumor effects of meloxicam, etodolac and celecoxib using COX-2-expressing canine mammary tumor (CF33) cells. We analyzed the effects of selective COX-2 inhibitors on COX-2 protein expression levels in CF33 cells. Celecoxib (100 µM) was found to induce downregulation of COX-2 protein expression. We examined the effect of selective COX-2 inhibitors on CF33 cell proliferation. All the selective COX-2 inhibitors suppressed CF33 cell growth. Specifically, etodolac and celecoxib inhibited cell proliferation via a decrease in S-phase cells and an increase in G0/G1 arrest. We examined the apoptotic effect of selective COX-2 inhibitors on CF33 cells. Our data suggested that etodolac and celecoxib induced apoptosis in CF33 cells. In particular, celecoxib led to apoptosis mediated by the activation of the mitochondrial apoptosis pathway, including the upregulation of BAX expression, downregulation of Bcl-2 expression and activation of caspase-3/7. Furthermore, celecoxib increased the percentages of cells in both early apoptosis and late apoptosis. Our results revealed that celecoxib induced apoptosis and cell cycle arrest in CF33 cells. The data suggested that celecoxib is the most viable candidate as a therapeutic agent for the treatment of canine mammary tumors. Furthermore, our findings provide the first

  8. Prognostic relevance of cyclooxygenase-2 (COX-2) expression in Chinese patients with prostate cancer.

    PubMed

    Bin, Wu; He, Wang; Feng, Zhang; Xiangdong, Lu; Yong, Chen; Lele, Kou; Hongbin, Zhang; Honglin, Guo

    2011-02-01

    Cyclooxygenase-2 (COX-2), an inducible isoform of cyclooxygenase, has been reported to be correlated with tumorigenesis, tumor progression and metastasis. The present study was designed to investigate the clinicopathological and prognostic significance of COX-2 in Chinese patients with prostate cancer. Firstly, RT-PCR and Western blot assays were performed to detect the expression of COX-2 mRNA and protein in prostate cancer cell lines and 20 tissue samples (tumor or corresponding non-tumor). Next, immunohistochemistry was performed to detect the expression of COX-2 protein in 88 prostate cancer tissue samples. Finally, the correlation between COX-2 expression and clinicopathological factors and patient survival was evaluated. We found that the expression levels of COX-2 mRNA and protein showed significant difference among four prostate cancer cell lines. Moreover, the levels of COX-2 mRNA and protein were significantly higher in prostate cancer tissues than in corresponding non-tumor tissues. COX-2 staining was positive in the cytoplasm of prostate cancer cells. High-COX-2 expression was correlated with the Gleason score (P=0.009), tumor stage (P=0.012), and lymph-node status (P=0.036). Furthermore, patients with high-COX-2 expression showed lower disease-free (P=0.014) and overall survival (P=0.047) rates than those with low-COX-2 expression. Univariate and multivariate analyses suggested that the status of COX-2 protein expression was an independent prognostic indicator for patients' survival. Taken together, higher COX-2 protein expression might provide an independent prognostic marker for Chinese patients with prostate cancer who have undergone surgery.

  9. Dexamethasone damages the rat stomach but not small intestine during inhibition of COX-1.

    PubMed

    Yokota, Aya; Taniguchi, Masaki; Takahira, Yuka; Tanaka, Akiko; Takeuchi, Koji

    2007-06-01

    We previously reported that inhibition of both COX-1 and COX-2 is required for the gastrointestinal ulcerogenic properties of nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of COX-1 up-regulates COX-2 expression, and the prostaglandins (PGs) produced by COX-2 help to maintain the mucosal integrity during inhibition of COX-1. In the present study we investigated whether dexamethasone damages rat gastrointestinal mucosa during inhibition of COX-1 and further developed the idea that COX-2 expression is a key event in the ulcerogenic actions of NSAIDs. Dexamethasone was given p.o. in the absence or presence of SC-560 (a selective COX-1 inhibitor), and the stomach or intestine was examined 8 or 24 hr later, respectively. Neither dexamethasone nor SC-560 alone damaged the gastrointestinal mucosa. In the presence of SC-560, however, dexamethasone damaged the stomach but not small intestine. SC-560 decreased PGE(2) levels in both tissues, with a gradual recovery accompanying the up-regulation of COX-2 expression, and both the recovery of PGE(2) levels and the expression of COX-2 were inhibited by dexamethasone. In the animals treated with SC-560, iNOS expression was up-regulated in the intestinal but not the gastric mucosa, and this response was also inhibited by dexamethasone. These results suggest a risk from steroid therapy in the stomach when COX-2 expression is up-regulated. Dexamethasone does not provoke damage in the intestine, despite inhibiting the up-regulation of COX-2 expression under conditions of PG deficiency; at least one of the reasons is that this agent prevents the expression of iNOS, a major factor in the pathogenesis of intestinal lesions.

  10. COX-2 mRNA expression in esophageal squamous cell carcinoma (ESCC) and effect by NSAID.

    PubMed

    Liu, X; Li, P; Zhang, S-T; You, H; Jia, J-D; Yu, Z-L

    2008-01-01

    To investigate cyclooxygenase-2 (COX-2) mRNA expression in human esophageal squamous cell carcinoma and the effect of a non-steroidal anti-inflammatory drug (NSAID) on it, in order to explore the mechanism of COX-2 in esophageal squamous cell carcinoma (ESCC) carcinogenesis and the ability of NSAID to prevent or treat ESCC. Frozen specimens of human ESCC and adjacent normal esophageal squamous epithelium pairs (n = 22) were examined for COX-2 mRNA expression by reverse-transcription polymerase chain reaction (RT-PCR). After incubation with aspirin (a non-selective COX inhibitor) or Nimesulide (a selective COX-2 inhibitor), the proliferation status of two human esophageal squamous cancer cell lines, EC-9706 and EC-109, was quantified by 3-(4,5-dimethyl-thiazol-2yl)-2,5-diphenyltetrazolium bromide assay. The expression of COX-2 mRNA in these cells was detected by RT-PCR. COX-2 mRNA was expressed in 12 of 22 (54.5%) ESCC tissue samples, but it was undetectable in all the specimens of adjacent normal esophageal squamous epithelium COX-2 mRNA expression. Both aspirin (5-20 mmol/L) and Nimesulide (0.1-0.8 mmol/L) inhibited EC-9706 cell line proliferation and suppressed its COX-2 mRNA expression dose-dependently. However, only aspirin (5-20 mmol/L) could inhibit proliferation in the EC-109 cell line and suppress COX-2 mRNA expression. Nimesulide (0.1-0.8 mmol/L) could neither inhibit EC-109 cell growth nor suppress COX-2 mRNA expression. COX-2 mRNA expression is a frequent phenomenon in human ESCC tissue samples and plays an important role in the carcinogenesis of ESCC. NSAID may be useful in the chemoprevention and therapy of human ESCC and its effects are likely to be mediated by modulating COX-2 activity.

  11. Recirculating valve lash adjuster

    SciTech Connect

    Stoody, R.R.

    1987-02-24

    This patent describes an internal combustion engine with a valve assembly of the type including overhead valves supported by a cylinder head for opening and closing movements in a substantially vertical direction and a rotatable overhead camshaft thereabove lubricated by engine oil pumped by an engine oil pump. A hydraulic lash adjuster with an internal reservoir therein is solely supplied with run-off lubricating oil from the camshaft which oil is pumped into the internal reservoir of the lash adjuster by self-pumping operation of the lash adjuster produced by lateral forces thereon by the rotative operation of the camshaft comprising: a housing of the lash adjuster including an axially extending bore therethrough with a lower wall means of the housing closing the lower end thereof; a first plunger member being closely slidably received in the bore of the housing and having wall means defining a fluid filled power chamber with the lower wall means of the housing; and a second plunger member of the lash adjuster having a portion being loosely slidably received and extending into the bore of the housing for reciprocation therein. Another portion extends upwardly from the housing to operatively receive alternating side-to-side force inputs from operation of the camshaft.

  12. Loss of two introns from the Magnolia tripetala mitochondrial cox2 gene implicates horizontal gene transfer and gene conversion as a novel mechanism of intron loss.

    PubMed

    Hepburn, Nancy J; Schmidt, Derek W; Mower, Jeffrey P

    2012-10-01

    Intron loss is often thought to occur through retroprocessing, which is the reverse transcription and genomic integration of a spliced transcript. In plant mitochondria, several unambiguous examples of retroprocessing are supported by the parallel loss of an intron and numerous adjacent RNA edit sites, but in most cases, the evidence for intron loss via retroprocessing is weak or lacking entirely. To evaluate mechanisms of intron loss, we designed a polymerase chain reaction (PCR)-based assay to detect recent intron losses from the mitochondrial cox2 gene within genus Magnolia, which was previously suggested to have variability in cox2 intron content. Our assay showed that all 22 examined species have a cox2 gene with two introns. However, one species, Magnolia tripetala, contains an additional cox2 gene that lacks both introns. Quantitative PCR showed that both M. tripetala cox2 genes are present in the mitochondrial genome. Although the intronless gene has lost several ancestral RNA edit sites, their distribution is inconsistent with retroprocessing models. Instead, phylogenetic and gene conversion analyses indicate that the intronless gene was horizontally acquired from a eudicot and then underwent gene conversion with the native intron-containing gene. The models are presented to summarize the roles of horizontal gene transfer and gene conversion as a novel mechanism of intron loss.

  13. Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer.

    PubMed

    Wilson, Andrew J; Fadare, Oluwole; Beeghly-Fadiel, Alicia; Son, Deok-Soo; Liu, Qi; Zhao, Shilin; Saskowski, Jeanette; Uddin, Md Jashim; Daniel, Cristina; Crews, Brenda; Lehmann, Brian D; Pietenpol, Jennifer A; Crispens, Marta A; Marnett, Lawrence J; Khabele, Dineo

    2015-08-28

    Cyclooxygenase-1 (COX-1) is implicated in ovarian cancer. However, patterns of COX expression and function have been unclear and controversial. In this report, patterns of COX-1 and COX-2 gene expression were obtained from RNA-seq data through The Cancer Genome Atlas. Our analysis revealed markedly higher COX-1 mRNA expression than COX-2 in high-grade serous ovarian cancers (HGSOC) and higher COX-1 expression in HGSOC tumors than 10 other tumor types. High expression of COX-1 in HGSOC tumors was confirmed in an independent tissue microarray. In contrast, lower or similar expression of COX-1 compared to COX-2 was observed in endometrioid, mucinous and clear cell tumors. Stable COX-1 knockdown in HGSOC-representative OVCAR-3 ovarian cancer cells reduced gene expression in multiple pro-tumorigenic pathways. Functional cell viability, clonogenicity, and migration/invasion assays were consistent with transcriptomic changes. These effects were reversed by stable over-expression of COX-1 in SKOV-3 cells. Our results demonstrate a distinct pattern of COX-1 over-expression in HGSOC tumors and strong association of COX-1 with multiple pro-tumorigenic pathways in ovarian cancer cells. These findings provide additional insight into the role of COX-1 in human ovarian cancer and support further development of methods to selectively target COX-1 in the management of HGSOC tumors.

  14. Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer

    PubMed Central

    Wilson, Andrew J.; Fadare, Oluwole; Beeghly-Fadiel, Alicia; Son, Deok-Soo; Liu, Qi; Zhao, Shilin; Saskowski, Jeanette; Uddin, Md. Jashim; Daniel, Cristina; Crews, Brenda; Lehmann, Brian D.; Pietenpol, Jennifer A.; Crispens, Marta A.; Marnett, Lawrence J.; Khabele, Dineo

    2015-01-01

    Cyclooxygenase-1 (COX-1) is implicated in ovarian cancer. However, patterns of COX expression and function have been unclear and controversial. In this report, patterns of COX-1 and COX-2 gene expression were obtained from RNA-seq data through The Cancer Genome Atlas. Our analysis revealed markedly higher COX-1 mRNA expression than COX-2 in high-grade serous ovarian cancers (HGSOC) and higher COX-1 expression in HGSOC tumors than 10 other tumor types. High expression of COX-1 in HGSOC tumors was confirmed in an independent tissue microarray. In contrast, lower or similar expression of COX-1 compared to COX-2 was observed in endometrioid, mucinous and clear cell tumors. Stable COX-1 knockdown in HGSOC-representative OVCAR-3 ovarian cancer cells reduced gene expression in multiple pro-tumorigenic pathways. Functional cell viability, clonogenicity, and migration/invasion assays were consistent with transcriptomic changes. These effects were reversed by stable over-expression of COX-1 in SKOV-3 cells. Our results demonstrate a distinct pattern of COX-1 over-expression in HGSOC tumors and strong association of COX-1 with multiple pro-tumorigenic pathways in ovarian cancer cells. These findings provide additional insight into the role of COX-1 in human ovarian cancer and support further development of methods to selectively target COX-1 in the management of HGSOC tumors. PMID:25972361

  15. In Polytomella sp. mitochondria, biogenesis of the heterodimeric COX2 subunit of cytochrome c oxidase requires two different import pathways.

    PubMed

    Jiménez-Suárez, Alejandra; Vázquez-Acevedo, Miriam; Rojas-Hernández, Andrés; Funes, Soledad; Uribe-Carvajal, Salvador; González-Halphen, Diego

    2012-05-01

    In the vast majority of eukaryotic organisms, the mitochondrial cox2 gene encodes subunit II of cytochrome c oxidase (COX2). However, in some lineages including legumes and chlorophycean algae, the cox2 gene migrated to the nucleus. Furthermore, in chlorophycean algae, this gene was split in two different units. Thereby the COX2 subunit is encoded by two independent nuclear genes, cox2a and cox2b, and mitochondria have to import the cytosol-synthesized COX2A and COX2B subunits and assemble them into the cytochrome c oxidase complex. In the chlorophycean algae Chlamydomonas reinhardtii and Polytomella sp., the COX2A precursor exhibits a long (130-140 residues), cleavable mitochondrial targeting sequence (MTS). In contrast, COX2B lacks an MTS, suggesting that mitochondria use different mechanisms to import each subunit. Here, we explored the in vitro import processes of both, the Polytomella sp. COX2A precursor and the COX2B protein. We used isolated, import-competent mitochondria from this colorless alga. Our results suggest that COX2B is imported directly into the intermembrane space, while COX2A seems to follow an energy-dependent import pathway, through which it finally integrates into the inner mitochondrial membrane. In addition, the MTS of the COX2A precursor is eliminated. This is the first time that the in vitro import of split COX2 subunits into mitochondria has been achieved.

  16. MicroRNA-26a/-26b-COX-2-MIP-2 Loop Regulates Allergic Inflammation and Allergic Inflammation-promoted Enhanced Tumorigenic and Metastatic Potential of Cancer Cells.

    PubMed

    Kwon, Yoojung; Kim, Youngmi; Eom, Sangkyung; Kim, Misun; Park, Deokbum; Kim, Hyuna; Noh, Kyeonga; Lee, Hansoo; Lee, Yun Sil; Choe, Jongseon; Kim, Young Myeong; Jeoung, Dooil

    2015-05-29

    Cyclooxgenase-2 (COX-2) knock-out mouse experiments showed that COX-2 was necessary for in vivo allergic inflammation, such as passive cutaneous anaphylaxis, passive systemic anaphylaxis, and triphasic cutaneous allergic reaction. TargetScan analysis predicted COX-2 as a target of miR-26a and miR-26b. miR-26a/-26b decreased luciferase activity associated with COX-2-3'-UTR. miR-26a/-26b exerted negative effects on the features of in vitro and in vivo allergic inflammation by targeting COX-2. ChIP assays showed the binding of HDAC3 and SNAIL, but not COX-2, to the promoter sequences of miR-26a and miR-26b. Cytokine array analysis showed that the induction of chemokines, such as MIP-2, in the mouse passive systemic anaphylaxis model occurred in a COX-2-dependent manner. ChIP assays showed the binding of HDAC3 and COX-2 to the promoter sequences of MIP-2. In vitro and in vivo allergic inflammation was accompanied by the increased expression of MIP-2. miR-26a/-26b negatively regulated the expression of MIP-2. Allergic inflammation enhanced the tumorigenic and metastatic potential of cancer cells and induced positive feedback involving cancer cells and stromal cells, such as mast cells, macrophages, and endothelial cells. miR-26a mimic and miR-26b mimic negatively regulated the positive feedback between cancer cells and stromal cells and the positive feedback among stromal cells. miR-26a/-26b negatively regulated the enhanced tumorigenic potential by allergic inflammation. COX-2 was necessary for the enhanced metastatic potential of cancer cells by allergic inflammation. Taken together, our results indicate that the miR26a/-26b-COX-2-MIP-2 loop regulates allergic inflammation and the feedback relationship between allergic inflammation and the enhanced tumorigenic and metastatic potential.

  17. Clinical features, survival times and COX-1 and COX-2 expression in cats with transitional cell carcinoma of the urinary bladder treated with meloxicam.

    PubMed

    Bommer, Nicholas X; Hayes, Alison M; Scase, Timothy J; Gunn-Moore, Danièlle A

    2012-08-01

    Records of 11 cats with transitional cell carcinoma of the urinary bladder, which had been treated with meloxicam, were reviewed for signalment, duration of clinical signs prior to diagnosis, results of diagnostic imaging, whether or not concurrent surgery was performed and survival. Immunohistochemical expression of cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2) was assessed in the tumours of seven cats. Tumour location varied greatly. The cats had a mean age of 13 years. Three cats had a previous diagnosis of feline idiopathic cystitis of up to 2008 days duration. Ten of the cats showed clinical improvement (reduction of haematuria and/or dysuria), with a mean survival time (MST) of 311 days (range 10-1064); 1-year survival of 50%. All seven bladders assessed for COX staining were COX-1 positive and five were COX-2 positive. The MST for the COX-2-positive cats was 123 days, the MST for the COX-2-negative cases was 375 days.

  18. Capping risk adjustment?

    PubMed

    Eugster, Patrick; Sennhauser, Michèle; Zweifel, Peter

    2010-07-01

    When premiums are community-rated, risk adjustment (RA) serves to mitigate competitive insurers' incentive to select favorable risks. However, unless fully prospective, it also undermines their incentives for efficiency. By capping its volume, one may try to counteract this tendency, exposing insurers to some financial risk. This in term runs counter the quest to refine the RA formula, which would increase RA volume. Specifically, the adjuster, "Hospitalization or living in a nursing home during the previous year" will be added in Switzerland starting 2012. This paper investigates how to minimize the opportunity cost of capping RA in terms of increased incentives for risk selection.

  19. COX-2 inhibitors: a story of greed, deception and death.

    PubMed

    Halpern, Georges M

    2005-01-01

    In 1999, drug manufacturers introduced a class of NSAIDs called COX-2 inhibitors or coxibs. The drugs were avidly promoted directly to the consumers and became bestsellers from the start. Arthritis sufferers were eager to take medications that eased joint pain with less risk of causing gastrointestinal pain, bleeding and other side-effects. In the year after their introduction, doctors wrote over 100 million prescriptions for celecoxib (Celebrex) and rofecoxib (Vioxx). Celebrex is the sixth best-selling drug, with sales of more than US$ 4 billion since its debut in 1999. Vioxx had sales of US$ 2.6 billion in 2001. However, the coxibs increase the risk of heart attacks and strokes, and their price, in the USA, is obscene. The manufacturers faced a possibly complicit, toothless and bloodless FDA, and used every maneuvering to fleece the patients. We must now reflect on attitudes that we thought only belong to the tobacco industry. Fortunately, safe and active alternatives exist.

  20. COX-2 over-expression correlates with VEGF and tumour angiogenesis in canine mammary cancer.

    PubMed

    Queiroga, Felisbina L; Pires, Isabel; Parente, Margarida; Gregório, Hugo; Lopes, Carlos S

    2011-07-01

    This study was designed to investigate the possible roles of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in canine mammary cancer angiogenesis. Immunohistochemistry was performed on 70 tumours (28 benign and 42 malignant) in order to detect COX-2 and VEGF expression. Microvessel density (MVD) was determined by CD31 immunolabelling to assess tumour angiogenesis. There was a significantly higher expression of COX-2 (P<0.001), VEGF (P<0.001) and MVD (P<0.001) in malignant compared to benign tumours. In the malignant group, the MVD of COX-2 positive tumours was significantly higher than that of COX-2 negative tumours (P=0.026). A similar association was observed for VEGF (P<0.001) positive tumours. The results from this study suggested that over-expression of COX-2 and VEGF may contribute to increased angiogenesis and aggression in malignant tumours.

  1. Regulation of COX-2 expression by miR-146a in lung cancer cells.

    PubMed

    Cornett, Ashley L; Lutz, Carol S

    2014-09-01

    Prostaglandins are a class of molecules that mediate cellular inflammatory responses and control cell growth. The oxidative conversion of arachidonic acid to prostaglandin H2 is carried out by two isozymes of cyclooxygenase, COX-1 and COX-2. COX-1 is constitutively expressed, while COX-2 can be transiently induced by external stimuli, such as pro-inflammatory cytokines. Interestingly, COX-2 is overexpressed in numerous cancers, including lung cancer. MicroRNAs (miRNAs) are small RNA molecules that function to regulate gene expression. Previous studies have implicated an important role for miRNAs in human cancer. We demonstrate here that miR-146a expression levels are significantly lower in lung cancer cells as compared with normal lung cells. Conversely, lung cancer cells have higher levels of COX-2 protein and mRNA expression. Introduction of miR-146a can specifically ablate COX-2 protein and the biological activity of COX-2 as measured by prostaglandin production. The regulation of COX-2 by miR-146a is mediated through a single miRNA-binding site present in the 3' UTR. Therefore, we propose that decreased miR-146a expression contributes to the up-regulation and overexpression of COX-2 in lung cancer cells. Since potential miRNA-mediated regulation is a functional consequence of alternative polyadenylation site choice, understanding the molecular mechanisms that regulate COX-2 mRNA alternative polyadenylation and miRNA targeting will give us key insights into how COX-2 expression is involved in the development of a metastatic condition.

  2. The effect of adjusting model inputs to achieve mass balance on time-dynamic simulations in a food-web model of Lake Huron

    USGS Publications Warehouse

    Langseth, Brian J.; Jones, Michael L.; Riley, Stephen C.

    2014-01-01

    Ecopath with Ecosim (EwE) is a widely used modeling tool in fishery research and management. Ecopath requires a mass-balanced snapshot of a food web at a particular point in time, which Ecosim then uses to simulate changes in biomass over time. Initial inputs to Ecopath, including estimates for biomasses, production to biomass ratios, consumption to biomass ratios, and diets, rarely produce mass balance, and thus ad hoc changes to inputs are required to balance the model. There has been little previous research of whether ad hoc changes to achieve mass balance affect Ecosim simulations. We constructed an EwE model for the offshore community of Lake Huron, and balanced the model using four contrasting but realistic methods. The four balancing methods were based on two contrasting approaches; in the first approach, production of unbalanced groups was increased by increasing either biomass or the production to biomass ratio, while in the second approach, consumption of predators on unbalanced groups was decreased by decreasing either biomass or the consumption to biomass ratio. We compared six simulation scenarios based on three alternative assumptions about the extent to which mortality rates of prey can change in response to changes in predator biomass (i.e., vulnerabilities) under perturbations to either fishing mortality or environmental production. Changes in simulated biomass values over time were used in a principal components analysis to assess the comparative effect of balancing method, vulnerabilities, and perturbation types. Vulnerabilities explained the most variation in biomass, followed by the type of perturbation. Choice of balancing method explained little of the overall variation in biomass. Under scenarios where changes in predator biomass caused large changes in mortality rates of prey (i.e., high vulnerabilities), variation in biomass was greater than when changes in predator biomass caused only small changes in mortality rates of prey (i.e., low

  3. Using a Glacial Isostatic Adjustment model to investigate the contribution of the Antarctic and Greenland Ice sheet to the Last Interglacial Sea Level.

    NASA Astrophysics Data System (ADS)

    Bradley, Sarah; Hindmarsh, Richard C. A.

    2014-05-01

    Eustatic Sea Level during the Last interglacial (LIG) is likely to have been 4- 6 m higher than present day, with the observed relative sea level (RSL) at numerous far-field sites even higher [Dutton and Lambeck, 2012]. It has been suggested to generate this higher than present day sea level requires a retreat of both the Antarctic (AIS) and Greenland (GIS) Ice sheets beyond the present day extent, but the exact contribution of these two global ice sheets has yet to be resolved. By combing a Glacial Isostatic Adjustment (GIA) model with a suite of LIG ice-loading histories we will address a number of outstanding issues (i) What was the contribution of the AIS and GIS to ESL, (ii) Was the AIS or the GIS smaller during the LIG than the present interglacial? (iii) Can we generate the observed higher LIG RSL at a range of far-field sites? The suite of AIS and GIS ice-loading histories is constrained using the most recent near-field evidence, LIG stable isotope ice core data [Dahl-Jensen et al., 2013; Masson-Delmotte et al., 2011] and the output from ice sheet and climate models [Helsen et al., 2013; Pollard and DeConto, 2009; Stone et al., 2013]. Comparing the predicted RSL to a recent database of observed LIG far-field sea level [Dutton and Lambeck, 2012] allows for an assessment of the plausibility of the suite of ice loading histories. With this study, we aim to provide insight into the LIG history of the AIS and GIS. Dahl-Jensen, D., et al. (2013), Eemian interglacial reconstructed from a Greenland folded ice core, Nature, 493(7433), 489-494. Dutton, A., and K. Lambeck (2012), Ice Volume and Sea Level During the Last Interglacial, Science, 337(6091), 216-219. Helsen, M. M., W. J. van de Berg, R. S. W. van de Wal, M. R. van den Broeke, and J. Oerlemans (2013), Coupled regional climate-ice-sheet simulation shows limited Greenland ice loss during the Eemian, Clim Past, 9(4), 1773-1788. Masson-Delmotte, V., et al. (2011), A comparison of the present and last

  4. Psychological Adjustment and Homosexuality.

    ERIC Educational Resources Information Center

    Gonsiorek, John C.

    In this paper, the diverse literature bearing on the topic of homosexuality and psychological adjustment is critically reviewed and synthesized. The first chapter discusses the most crucial methodological issue in this area, the problem of sampling. The kinds of samples used to date are critically examined, and some suggestions for improved…

  5. Self Adjusting Sunglasses

    NASA Technical Reports Server (NTRS)

    1986-01-01

    Corning Glass Works' Serengeti Driver sunglasses are unique in that their lenses self-adjust and filter light while suppressing glare. They eliminate more than 99% of the ultraviolet rays in sunlight. The frames are based on the NASA Anthropometric Source Book.

  6. Self adjusting inclinometer

    DOEpatents

    Hunter, Steven L.

    2002-01-01

    An inclinometer utilizing synchronous demodulation for high resolution and electronic offset adjustment provides a wide dynamic range without any moving components. A device encompassing a tiltmeter and accompanying electronic circuitry provides quasi-leveled tilt sensors that detect highly resolved tilt change without signal saturation.

  7. Significance of Cox-2 expression in rectal cancers with or without preoperative radiotherapy

    SciTech Connect

    Pachkoria, Ketevan; Zhang Hong; Adell, Gunnar; Jarlsfelt, Ingvar; Sun Xiaofeng . E-mail: xiao-feng.sun@ibk.liu.se

    2005-11-01

    Purpose: Radiotherapy has reduced local recurrence of rectal cancers, but the result is not satisfactory. Further biologic factors are needed to identify patients for more effective radiotherapy. Our aims were to investigate the relationship of cyclooxygenase-2 (Cox-2) expression to radiotherapy, and clinicopathologic/biologic variables in rectal cancers with or without radiotherapy. Methods and Materials: Cox-2 expression was immunohistochemically examined in distal normal mucosa (n = 28), in adjacent normal mucosa (n = 107), in primary cancer (n = 138), lymph node metastasis (n = 30), and biopsy (n = 85). The patients participated in a rectal cancer trial of preoperative radiotherapy. Results: Cox-2 expression was increased in primary tumor compared with normal mucosa (p < 0.0001), but there was no significant change between primary tumor and metastasis. Cox-2 positivity was or tended to be related to more p53 and Ki-67 expression, and less apoptosis (p {<=} 0.05). In Cox-2-negative cases of either biopsy (p = 0.01) or surgical samples (p = 0.02), radiotherapy was related to less frequency of local recurrence, but this was not the case in Cox-2-positive cases. Conclusion: Cox-2 expression seemed to be an early event involved in rectal cancer development. Radiotherapy might reduce a rate of local recurrence in the patients with Cox-2 weakly stained tumors, but not in those with Cox-2 strongly stained tumors.

  8. Structural insight into DNA binding and oligomerization of the multifunctional Cox protein of bacteriophage P2.

    PubMed

    Berntsson, Ronnie P-A; Odegrip, Richard; Sehlén, Wilhelmina; Skaar, Karin; Svensson, Linda M; Massad, Tariq; Högbom, Martin; Haggård-Ljungquist, Elisabeth; Stenmark, Pål

    2014-02-01

    The Cox protein from bacteriophage P2 is a small multifunctional DNA-binding protein. It is involved in site-specific recombination leading to P2 prophage excision and functions as a transcriptional repressor of the P2 Pc promoter. Furthermore, it transcriptionally activates the unrelated, defective prophage P4 that depends on phage P2 late gene products for lytic growth. In this article, we have investigated the structural determinants to understand how P2 Cox performs these different functions. We have solved the structure of P2 Cox to 2.4 Å resolution. Interestingly, P2 Cox crystallized in a continuous oligomeric spiral with its DNA-binding helix and wing positioned outwards. The extended C-terminal part of P2 Cox is largely responsible for the oligomerization in the structure. The spacing between the repeating DNA-binding elements along the helical P2 Cox filament is consistent with DNA binding along the filament. Functional analyses of alanine mutants in P2 Cox argue for the importance of key residues for protein function. We here present the first structure from the Cox protein family and, together with previous biochemical observations, propose that P2 Cox achieves its various functions by specific binding of DNA while wrapping the DNA around its helical oligomer.

  9. Alteration of femoral bone morphology and density in COX-2-/- mice.

    PubMed

    Robertson, Galen; Xie, Chao; Chen, Di; Awad, Hani; Schwarz, Edward M; O'Keefe, Regis J; Guldberg, Robert E; Zhang, Xinping

    2006-10-01

    A role of COX-2 in pathological bone destruction and fracture repair has been established; however, few studies have been conducted to examine the involvement of COX-2 in maintaining bone mineral density and bone micro-architecture. In this study, we examined bone morphology in multiple trabecular and cortical regions within the distal and diaphyseal femur of 4-month-old wild-type and COX-2-/- mice using micro-computed tomography. Our results demonstrated that while COX-2-/- female mice had normal bone geometry and trabecular microarchitecture at 4 months of age, the male knockout mice displayed reduced bone volume fraction within the distal femoral metaphysis. Furthermore, male COX-2-/- mice had a significant reduction in cortical bone mineral density within the central cortical diaphysis and distal epiphysis and metaphysis. Consistent with the observed reduction in cortical mineral density, biomechanical testing via 4-point-bending showed that male COX-2-/- mice had a significant increase in postyield deformation, indicating a ductile bone phenotype in male COX-2-/- mice. In conclusion, our study suggests that genetic ablation of COX-2 may have a sex-related effect on cortical bone homeostasis and COX-2 plays a role in maintaining normal bone micro-architecture and density in mice.

  10. Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships

    PubMed Central

    Zarghi, Afshin; Arfaei, Sara

    2011-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the bioconversion of arachidonic acid to inflammatory prostaglandins (PGs). Their use is associated with the side effects such as gastrointestinal and renal toxicity. The therapeutic anti-inflammatory action of NSAIDs is produced by the inhibition of COX-2, while the undesired side effects arise from inhibition of COX-1 activity. Thus, it was though that more selective COX-2 inhibitors would have reduced side effects. Based upon a number of selective COX-2 inhibitors (rofecoxib, celecoxib, valdecoxibetc.) were developed as safer NSAIDs with improved gastric safety profile. However, the recent market removal of some COXIBs such as rofecoxib due to its adverse cardiovascular side effects clearly encourages the researchers to explore and evaluate alternative templates with COX-2 inhibitory activity. Recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Parkinson and Alzheimer’s diseases still continues to attract investigations on the development of COX-2 inhibitors. This review highlights the various structural classes of selective COX-2 inhibitors with special emphasis on their structure-activity relationships. PMID:24250402

  11. Alteration of femoral bone morphology and density in COX-2−/− mice

    PubMed Central

    Robertson, Galen; Xie, Chao; Chen, Di; Awad, Hani; Schwarz, Edward M.; O’Keefe, Regis J.; Guldberg, Robert E.; Zhang, Xinping

    2009-01-01

    A role of COX-2 in pathological bone destruction and fracture repair has been established; however, few studies have been conducted to examine the involvement of COX-2 in maintaining bone mineral density and bone micro-architecture. In this study, we examined bone morphology in multiple trabecular and cortical regions within the distal and diaphyseal femur of 4-month-old wild-type and COX-2−/− mice using micro-computed tomography. Our results demonstrated that while COX-2−/− female mice had normal bone geometry and trabecular microarchitecture at 4 months of age, the male knockout mice displayed reduced bone volume fraction within the distal femoral metaphysis. Furthermore, male COX-2−/− mice had a significant reduction in cortical bone mineral density within the central cortical diaphysis and distal epiphysis and metaphysis. Consistent with the observed reduction in cortical mineral density, biomechanical testing via 4-point-bending showed that male COX-2−/− mice had a significant increase in postyield deformation, indicating a ductile bone phenotype in male COX-2−/− mice. In conclusion, our study suggests that genetic ablation of COX-2 may have a sex-related effect on cortical bone homeostasis and COX-2 plays a role in maintaining normal bone micro-architecture and density in mice. PMID:16731065

  12. COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells.

    PubMed

    Ramer, Robert; Heinemann, Katharina; Merkord, Jutta; Rohde, Helga; Salamon, Achim; Linnebacher, Michael; Hinz, Burkhard

    2013-01-01

    The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-γ in cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-γ mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD(2) and 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) caused a translocation of PPAR-γ to the nucleus and induced a PPAR-γ-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-γ in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-γ and a subsequent nuclear translocation of PPAR-γ by COX-2-dependent PGs.

  13. Maternal socialization goals, parenting styles, and social-emotional adjustment among Chinese and European American young adults: testing a mediation model.

    PubMed

    Li, Yan; Costanzo, Philip R; Putallaz, Martha

    2010-01-01

    The authors compared the associations among perceived maternal socialization goals (self-development, filial piety, and collectivism), perceived maternal parenting styles (authoritative, authoritarian, and training), and the social-emotional adjustment (self-esteem, academic self-efficacy, and depression) between Chinese and European American young adults. The mediation processes in which socialization goals relate to young adults' adjustment outcomes through parenting styles were examined. Results showed that European American participants perceived higher maternal self-development socialization goals, whereas Chinese participants perceived higher maternal collectivism socialization goals as well as more authoritarian parenting. Cross-cultural similarities were found in the associations between perceived maternal authoritative parenting and socioemotional adjustment (e.g., higher self-esteem and higher academic self-efficacy) across the two cultural groups. However, perceived maternal authoritarian and training parenting styles were found only to be related to Chinese participants' adjustment (e.g., higher academic self-efficacy and lower depression). The mediation analyses showed that authoritative parenting significantly mediated the positive associations between the self-development and collectivism goal and socioemotional adjustment for both cultural groups. Additionally, training parenting significantly mediated the positive association between the filial piety goal and young adults' academic self-efficacy for the Chinese group only. Findings of this study highlight the importance of examining parental socialization goals in cross-cultural parenting research.

  14. Analysis models for variables associated with breastfeeding duration

    PubMed Central

    dos S., Edson Theodoro; Zandonade, Eliana; Emmerich, Adauto Oliveira

    2013-01-01

    OBJECTIVE To analyze the factors associated with breastfeeding duration by two statistical models. METHODS A population-based cohort study was conducted with 86 mothers and newborns from two areas primary covered by the National Health System, with high rates of infant mortality in Vitória, Espírito Santo, Brazil. During 30 months, 67 (78%) children and mothers were visited seven times at home by trained interviewers, who filled out survey forms. Data on food and sucking habits, socioeconomic and maternal characteristics were collected. Variables were analyzed by Cox regression models, considering duration of breastfeeding as the dependent variable, and logistic regression (dependent variables, was the presence of a breastfeeding child in different post-natal ages). RESULTS In the logistic regression model, the pacifier sucking (adjusted Odds Ratio: 3.4; 95%CI 1.2-9.55) and bottle feeding (adjusted Odds Ratio: 4.4; 95%CI 1.6-12.1) increased the chance of weaning a child before one year of age. Variables associated to breastfeeding duration in the Cox regression model were: pacifier sucking (adjusted Hazard Ratio 2.0; 95%CI 1.2-3.3) and bottle feeding (adjusted Hazard Ratio 2.0; 95%CI 1.2-3.5). However, protective factors (maternal age and family income) differed between both models. CONCLUSIONS Risk and protective factors associated with cessation of breastfeeding may be analyzed by different models of statistical regression. Cox Regression Models are adequate to analyze such factors in longitudinal studies. PMID:24142312

  15. Dual functions of Mss51 couple synthesis of Cox1 to assembly of cytochrome c oxidase in Saccharomyces cerevisiae mitochondria.

    PubMed

    Perez-Martinez, Xochitl; Butler, Christine A; Shingu-Vazquez, Miguel; Fox, Thomas D

    2009-10-01

    Functional interactions of the translational activator Mss51 with both the mitochondrially encoded COX1 mRNA 5'-untranslated region and with newly synthesized unassembled Cox1 protein suggest that it has a key role in coupling Cox1 synthesis with assembly of cytochrome c oxidase. Mss51 is present at levels that are near rate limiting for expression of a reporter gene inserted at COX1 in mitochondrial DNA, and a substantial fraction of Mss51 is associated with Cox1 protein in assembly intermediates. Thus, sequestration of Mss51 in assembly intermediates could limit Cox1 synthesis in wild type, and account for the reduced Cox1 synthesis caused by most yeast mutations that block assembly. Mss51 does not stably interact with newly synthesized Cox1 in a mutant lacking Cox14, suggesting that the failure of nuclear cox14 mutants to decrease Cox1 synthesis, despite their inability to assemble cytochrome c oxidase, is due to a failure to sequester Mss51. The physical interaction between Mss51 and Cox14 is dependent upon Cox1 synthesis, indicating dynamic assembly of early cytochrome c oxidase intermediates nucleated by Cox1. Regulation of COX1 mRNA translation by Mss51 seems to be an example of a homeostatic mechanism in which a positive effector of gene expression interacts with the product it regulates in a posttranslational assembly process.

  16. Burden of Six Healthcare-Associated Infections on European Population Health: Estimating Incidence-Based Disability-Adjusted Life Years through a Population Prevalence-Based Modelling Study

    PubMed Central

    Eckmanns, Tim; Abu Sin, Muna; Ducomble, Tanja; Harder, Thomas; Sixtensson, Madlen; Velasco, Edward; Weiß, Bettina; Kramarz, Piotr; Monnet, Dominique L.; Kretzschmar, Mirjam E.; Suetens, Carl

    2016-01-01

    Background Estimating the burden of healthcare-associated infections (HAIs) compared to other communicable diseases is an ongoing challenge given the need for good quality data on the incidence of these infections and the involved comorbidities. Based on the methodology of the Burden of Communicable Diseases in Europe (BCoDE) project and 2011–2012 data from the European Centre for Disease Prevention and Control (ECDC) point prevalence survey (PPS) of HAIs and antimicrobial use in European acute care hospitals, we estimated the burden of six common HAIs. Methods and Findings The included HAIs were healthcare-associated pneumonia (HAP), healthcare-associated urinary tract infection (HA UTI), surgical site infection (SSI), healthcare-associated Clostridium difficile infection (HA CDI), healthcare-associated neonatal sepsis, and healthcare-associated primary bloodstream infection (HA primary BSI). The burden of these HAIs was measured in disability-adjusted life years (DALYs). Evidence relating to the disease progression pathway of each type of HAI was collected through systematic literature reviews, in order to estimate the risks attributable to HAIs. For each of the six HAIs, gender and age group prevalence from the ECDC PPS was converted into incidence rates by applying the Rhame and Sudderth formula. We adjusted for reduced life expectancy within the hospital population using three severity groups based on McCabe score data from the ECDC PPS. We estimated that 2,609,911 new cases of HAI occur every year in the European Union and European Economic Area (EU/EEA). The cumulative burden of the six HAIs was estimated at 501 DALYs per 100,000 general population each year in EU/EEA. HAP and HA primary BSI were associated with the highest burden and represented more than 60% of the total burden, with 169 and 145 DALYs per 100,000 total population, respectively. HA UTI, SSI, HA CDI, and HA primary BSI ranked as the third to sixth syndromes in terms of burden of disease

  17. Network Meta-Analysis Comparing Relatively Selective COX-2 Inhibitors Versus Coxibs for the Prevention of NSAID-Induced Gastrointestinal Injury

    PubMed Central

    Yang, Man; Wang, Hong-Tao; Zhao, Miao; Meng, Wen-Bo; Ou, Jin-Qing; He, Jun-Hui; Zou, Bing; Lei, Ping-Guang

    2015-01-01

    Abstract Currently 2 difference classes of cyclooxygenase (COX)-2 inhibitors, coxibs and relatively selective COX-2 inhibitors, are available for patients requiring nonsteroidal anti-inflammatory drug (NSAID) therapy; their gastroprotective effect is hardly directly compared. The aim of this study was to compare the gastroprotective effect of relatively selective COX-2 inhibitors with coxibs. MEDLINE, EMBASE, and the Cochrane Library (from their inception to March 2015) were searched for potential eligible studies. We included randomized controlled trials comparing coxibs (celecoxib, etoricoxib, parecoxib, and lumiracoxib), relatively selective COX-2 inhibitors (nabumetone, meloxicam, and etodolac), and nonselective NSAIDs with a study duration ≥4 weeks. Comparative effectiveness and safety data were pooled by Bayesian network meta-analysis. The primary outcomes were ulcer complications and symptomatic ulcer. Summary effect-size was calculated as risk ratio (RR), together with the 95% confidence interval (CI). This study included 36 trials with a total of 112,351 participants. Network meta-analyses indicated no significant difference between relatively selective COX-2 inhibitors and coxibs regarding ulcer complications (RR, 1.38; 95% CI, 0.47–3.27), symptomatic ulcer (RR, 1.02; 95% CI, 0.09–3.92), and endoscopic ulcer (RR, 1.18; 95% CI, 0.37–2.96). Network meta-analyses adjusting potential influential factors (age, sex, previous ulcer disease, and follow-up time), and sensitivity analyses did not reveal any major change to the main results. Network meta-analyses suggested that relatively selective COX-2 inhibitors and coxibs were associated with comparable incidences of total adverse events (AEs) (RR, 1.09; 95% CI, 0.93–1.31), gastrointestinal AEs (RR, 1.04; 95% CI, 0.87–1.25), total withdrawals (RR, 1.00; 95% CI, 0.74–1.33), and gastrointestinal AE-related withdrawals (RR, 1.02; 95% CI, 0.57–1.74). Relatively selective COX-2 inhibitors appear to be

  18. Examining Non-Linear Associations between Accelerometer-Measured Physical Activity, Sedentary Behavior, and All-Cause Mortality Using Segmented Cox Regression

    PubMed Central

    Lee, Paul H.

    2016-01-01

    Healthy adults are advised to perform at least 150 min of moderate-intensity physical activity weekly, but this advice is based on studies using self-reports of questionable validity. This study examined the dose-response relationship of accelerometer-measured physical activity and sedentary behaviors on all-cause mortality using segmented Cox regression to empirically determine the break-points of the dose-response relationship. Data from 7006 adult participants aged 18 or above in the National Health and Nutrition Examination Survey waves 2003–2004 and 2005–2006 were included in the analysis and linked with death certificate data using a probabilistic matching approach in the National Death Index through December 31, 2011. Physical activity and sedentary behavior were measured using ActiGraph model 7164 accelerometer over the right hip for 7 consecutive days. Each minute with accelerometer count <100; 1952–5724; and ≥5725 were classified as sedentary, moderate-intensity physical activity, and vigorous-intensity physical activity, respectively. Segmented Cox regression was used to estimate the hazard ratio (HR) of time spent in sedentary behaviors, moderate-intensity physical activity, and vigorous-intensity physical activity and all-cause mortality, adjusted for demographic characteristics, health behaviors, and health conditions. Data were analyzed in 2016. During 47,119 person-year of follow-up, 608 deaths occurred. Each additional hour per day of sedentary behaviors was associated with a HR of 1.15 (95% CI 1.01, 1.31) among participants who spend at least 10.9 h per day on sedentary behaviors, and each additional minute per day spent on moderate-intensity physical activity was associated with a HR of 0.94 (95% CI 0.91, 0.96) among participants with daily moderate-intensity physical activity ≤14.1 min. Associations of moderate physical activity and sedentary behaviors on all-cause mortality were independent of each other. To conclude, evidence from

  19. Genomic, Lipidomic and Metabolomic Analysis of Cyclooxygenase-null Cells: Eicosanoid Storm, Cross Talk, and Compensation by COX-1.

    PubMed

    Islam, Abul B M M K; Dave, Mandar; Amin, Sonia; Jensen, Roderick V; Amin, Ashok R

    2016-04-01

    The constitutively-expressed cyclooxygenase 1 (COX-1) and the inducible COX-2 are both involved in the conversion of arachidonic acid (AA) to prostaglandins (PGs). However, the functional roles of COX-1 at the cellular level remain unclear. We hypothesized that by comparing differential gene expression and eicosanoid metabolism in lung fibroblasts from wild-type (WT) mice and COX-2(-/-) or COX-1(-/-) mice may help address the functional roles of COX-1 in inflammation and other cellular functions. Compared to WT, the number of specifically-induced transcripts were altered descendingly as follows: COX-2(-/-)>COX-1(-/-)>WT+IL-1β. COX-1(-/-) or COX-2(-/-) cells shared about 50% of the induced transcripts with WT cells treated with IL-1β, respectively. An interactive "anti-inflammatory, proinflammatory, and redox-activated" signature in the protein-protein interactome map was observed in COX-2(-/-) cells. The augmented COX-1 mRNA (in COX-2(-/-) cells) was associated with the upregulation of mRNAs for glutathione S-transferase (GST), superoxide dismutase (SOD), NAD(P)H dehydrogenase quinone 1 (NQO1), aryl hydrocarbon receptor (AhR), peroxiredoxin, phospholipase, prostacyclin synthase, and prostaglandin E synthase, resulting in a significant increase in the levels of PGE2, PGD2, leukotriene B4 (LTB4), PGF1α, thromboxane B2 (TXB2), and PGF2α. The COX-1 plays a dominant role in shifting AA toward the LTB4 pathway and anti-inflammatory activities. Compared to WT, the upregulated COX-1 mRNA in COX-2(-/-) cells generated an "eicosanoid storm". The genomic characteristics of COX-2(-/-) is similar to that of proinflammatory cells as observed in IL-1β induced WT cells. COX-1(-/-) and COX-2(-/-) cells exhibited compensation of various eicosanoids at the genomic and metabolic levels.

  20. Allelic variation in the canine Cox-2 promoter causes hypermethylation of the canine Cox-2 promoter in clinical cases of renal dysplasia

    PubMed Central

    2014-01-01

    Background Novel allelic variants in the promoter of the canine cyclooxygenase-2 (Cox-2) gene are associated with renal dysplasia (RD). These variants consist of either deletions of putative SP1 transcription factor-binding sites or insertions of tandem repeats of SP1-binding sites located in the CpG island just upstream of the ATG translation initiation site. The canine Cox-2 gene was studied because Cox-2-deficient mice have renal abnormalities and a pathology that is strikingly similar to RD in dogs. Findings The allelic variants were associated with hypermethylation of the Cox-2 promoter only in clinical cases of RD. The wild-type allele was never methylated, even in clinical cases that were heterozygous for a mutant allele. In cases that were biopsy-negative, the promoter remained unmethylated, regardless of the genotype. Methylated DNA was found in DNA from various adult tissues of dogs with clinical RD. Conclusions The mechanism of action of the allelic variation in the canine Cox-2 promoter most likely involves variation in the extent of epigenetic downregulation of this gene. This epigenetic downregulation must have occurred early in development because methylated Cox-2 promoter DNA sequences are found in various adult tissues. PMID:24708682

  1. Metformin inhibits castration-induced EMT in prostate cancer by repressing COX2/PGE2/STAT3 axis.

    PubMed

    Tong, Dali; Liu, Qiuli; Liu, Gaolei; Xu, Jing; Lan, Weihua; Jiang, Yao; Xiao, Hualiang; Zhang, Dianzheng; Jiang, Jun

    2017-03-28

    Castration is the standard therapeutic treatment for advanced prostate cancer but with limited benefit due to the profound relapse and metastasis. Activation of inflammatory signaling pathway and initiation of epithelial-mesenchymal transition (EMT) are closely related to drug resistance, tumor relapseas well as metastasis. In this study, we demonstrated that metformin is capable of inhibiting prostate cancer cell migration and invasion by repressing EMT evidenced by downregulating the mesenchymal markers N-cadherin, Vimentin, and Twist and upregulating the epithelium E-cadherin. These effects have also been observed in our animal model as well as prostate cancer patients. In addition, we showed the effects of metformin on the expression of genes involved in EMT through repressing the levels of COX2, PGE2 and phosphorylated STAT3. Furthermore, inactivating COX2 abolishes metformin's regulatory effects and exogenously administered PGE2 is capable of enhancing STAT3 phosphorylation and expression of EMT biomarker. We propose that metformin represses prostate cancer EMT and metastasis through targeting the COX2/PGE2/STAT3 axis. These findings suggest that metformin by itself or in combination with other anticancer drugs could be used as an anti-metastasis therapy.

  2. Precision adjustable stage

    DOEpatents

    Cutburth, Ronald W.; Silva, Leonard L.

    1988-01-01

    An improved mounting stage of the type used for the detection of laser beams is disclosed. A stage center block is mounted on each of two opposite sides by a pair of spaced ball bearing tracks which provide stability as well as simplicity. The use of the spaced ball bearing pairs in conjunction with an adjustment screw which also provides support eliminates extraneous stabilization components and permits maximization of the area of the center block laser transmission hole.

  3. TLR4 signaling promotes a COX-2/PGE2/STAT3 positive feedback loop in hepatocellular carcinoma (HCC) cells.

    PubMed

    Lin, Ang; Wang, Guan; Zhao, Huajun; Zhang, Yuyi; Han, Qiuju; Zhang, Cai; Tian, Zhigang; Zhang, Jian

    2016-02-01

    Toll-like receptors (TLRs) can be expressed by tumor cells, and each TLR exhibits different biological functions. Evidences showed the activation of some certain TLRs could promote tumor progression. One of which TLR4 has been found to promote hepatocellular carcinoma (HCC) cells proliferation, but the detailed mechanism is still unknown. In the present study, we verified that TLR4 was functionally expressed on HCC cells, and TLR4 agonist lipopolysaccharide (LPS) could stimulate the proliferation and clone formation of HCC cells. Most importantly, we found a COX-2/PGE2/STAT3 positive feedback loop exists in HCC cells, which could be provoked by TLR4 activation. Consistently, the expression of TLR4, COX-2 and p-STAT3(Y705) was positively correlated with each other in liver tumor tissues from patients with primary HCC. Further investigation demonstrated this loop played a dominant role in TLR4-induced HCC cell proliferation and multidrug resistance (MDR) to chemotherapy. Inhibition of TLR4 or COX-2/PGE2/STAT3 loop would attenuate LPS-induced inflammation and proliferation of HCC cells, and enhance the sensitivity of HCC cells to chemotherapeutics in vitro. By using a primary HCC model, we observed COX-2/PGE2/STAT3 loop was significantly blocked in TLR4(-/-) mice compared to wild type mice, and there was no obvious tumorgenesis sign in TLR4(-/-) mice. Therefore, these findings provided the precise molecular mechanism of TLR4 signaling pathway involved in HCC progress, and suggested that TLR4 may be a promising target for HCC treatment.

  4. Survival of patients with nonseminomatous germ cell cancer: a review of the IGCC classification by Cox regression and recursive partitioning.

    PubMed

    van Dijk, M R; Steyerberg, E W; Stenning, S P; Dusseldorp, E; Habbema, J D F

    2004-