Science.gov

Sample records for univariate cox regression

  1. Calibration transfer employing univariate correction and robust regression.

    PubMed

    Galvão, Roberto Kawakami Harrop; Soares, Sófacles Figueredo Carreiro; Martins, Marcelo Nascimento; Pimentel, Maria Fernanda; Araújo, Mário César Ugulino

    2015-03-15

    This paper proposes a new method for calibration transfer, which was specifically designed to work with isolated variables, rather than the full spectrum or spectral windows. For this purpose, a univariate procedure is initially employed to correct the spectral measurements of the secondary instrument, given a set of transfer samples. A robust regression technique is then used to obtain a model with low sensitivity with respect to the univariate correction residuals. The proposed method is employed in two case studies involving near infrared spectrometric determination of specific mass, research octane number and naphthenes in gasoline, and moisture and oil in corn. In both cases, better calibration transfer results were obtained in comparison with piecewise direct standardization (PDS). The proposed method should be of a particular value for use with application-targeted instruments that monitor only a small set of spectral variables. PMID:25732421

  2. Adaptive regression splines in the Cox model.

    PubMed

    LeBlanc, M; Crowley, J

    1999-03-01

    We develop a method for constructing adaptive regression spline models for the exploration of survival data. The method combines Cox's (1972, Journal of the Royal Statistical Society, Series B 34, 187-200) regression model with a weighted least-squares version of the multivariate adaptive regressi on spline (MARS) technique of Friedman (1991, Annals of Statistics 19, 1-141) to adaptively select the knots and covariates. The new technique can automatically fit models with terms that represent nonlinear effects and interactions among covariates. Applications based on simulated data and data from a clinical trial for myeloma are presented. Results from the myeloma application identified several important prognostic variables, including a possible nonmonotone relationship with survival in one laboratory variable. Results are compared to those from the adaptive hazard regression (HARE) method of Kooperberg, Stone, and Truong (1995, Journal of the American Statistical Association 90, 78-94). PMID:11318156

  3. 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. PMID:25691289

  4. 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.

  5. Robust Regression Analysis of Copy Number Variation Data based on a Univariate Score

    PubMed Central

    Satten, Glen A.; Allen, Andrew S.; Ikeda, Morna; Mulle, Jennifer G.; Warren, Stephen T.

    2014-01-01

    Motivation The discovery that copy number variants (CNVs) are widespread in the human genome has motivated development of numerous algorithms that attempt to detect CNVs from intensity data. However, all approaches are plagued by high false discovery rates. Further, because CNVs are characterized by two dimensions (length and intensity) it is unclear how to order called CNVs to prioritize experimental validation. Results We developed a univariate score that correlates with the likelihood that a CNV is true. This score can be used to order CNV calls in such a way that calls having larger scores are more likely to overlap a true CNV. We developed cnv.beast, a computationally efficient algorithm for calling CNVs that uses robust backward elimination regression to keep CNV calls with scores that exceed a user-defined threshold. Using an independent dataset that was measured using a different platform, we validated our score and showed that our approach performed better than six other currently-available methods. Availability cnv.beast is available at http://www.duke.edu/~asallen/Software.html. PMID:24516529

  6. 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…

  7. Factors Associated with Methadone Treatment Duration: A Cox Regression Analysis

    PubMed Central

    Peng, Ching-Yi; Chao, En; Lee, Tony Szu-Hsien

    2015-01-01

    This study examined retention rates and associated predictors of methadone maintenance treatment (MMT) duration among 128 newly admitted patients in Taiwan. A semi-structured questionnaire was used to obtain demographic and drug use history. Daily records of methadone taken and test results for HIV, HCV, and morphine toxicology were taken from a computerized medical registry. Cox regression analyses were performed to examine factors associated with MMT duration. MMT retention rates were 80.5%, 68.8%, 53.9%, and 41.4% for 3, 6, 12, and 18 months, respectively. Excluding 38 patients incarcerated during the study period, retention rates were 81.1%, 73.3%, 61.1%, and 48.9% for 3 months, 6 months, 12 months, and 18 months, respectively. No participant seroconverted to HIV and 1 died during the 18-months follow-up. Results showed that being female, imprisonment, a longer distance from house to clinic, having a lower methadone dose after 30 days, being HCV positive, and in the New Taipei city program predicted early patient dropout. The findings suggest favorable MMT outcomes of HIV seroincidence and mortality. Results indicate that the need to minimize travel distance and to provide programs that meet women’s requirements justify expansion of MMT clinics in Taiwan. PMID:25875531

  8. Regression Is a Univariate General Linear Model Subsuming Other Parametric Methods as Special Cases.

    ERIC Educational Resources Information Center

    Vidal, Sherry

    Although the concept of the general linear model (GLM) has existed since the 1960s, other univariate analyses such as the t-test and the analysis of variance models have remained popular. The GLM produces an equation that minimizes the mean differences of independent variables as they are related to a dependent variable. From a computer printout…

  9. Understanding cow evaluations in univariate and multivariate animal and random regression models.

    PubMed

    Mrode, R; Coffey, M

    2008-02-01

    The relationship between cow evaluations from a 305-d lactation yield animal model [i.e., lactation model (LM)] and a random regression model (RRM) were studied using the first-lactation milk yield of 2,477,807 Holstein heifers. In the LM analysis, 2 values of heritability were used, 0.35 (LM1-H) or 0.57 (LM2-H), the latter being equal to that used in the random regression model for the analysis of the Holstein test-day records (RRM-H). The relative weights on parent average (PA) and yield deviations (YD) were computed and studied to understand factors contributing to reranking of cows' predicted transmitting abilities (PTA) from the various models. The degree of relatedness and inbreeding were calculated for the top 2,000 cows from the various models. Analyses of Jersey milk yield in the first 3 parities was implemented using 305-d lactation yield multivariate animal (MLM-J) and random regression models (MRRM-J). The ability of both models using only first-parity yield records to predict evaluations in second and third parities when records for these later parities were excluded was studied in a sample of cows. The correlations of cow PTA between LM1-H or LM2-H and RRM-H were 0.91 and 0.92, respectively, in the Holstein data. The data sets used were identical in this case for all models in terms of number of cows and yield records. The correlations were slightly lower at 0.89, 0.87, and 0.88 for parities 1, 2, and 3 in the Jersey analyses, where the data sets were not identical. The relative weights on PA and YD were 0.28 (0.11) and 0.72 (0.89), respectively, from the LM2-H (RRM-H). The RRM-H placed more emphasis on YD and therefore on Mendelian sampling deviations. Thus, the top 2,000 cows from the RRM-H were less related and inbred. The average additive genetic relationship was 22% greater in the LM2-H and average inbreeding coefficients were 0.68 and 0.43% for the LM2-H and RRM-H, respectively. When records were initially available in the first parity, the MRRM-J predicted PTA in parities 2 and 3 with about 2 to 7% greater accuracy compared with the MLM-J. PMID:18218767

  10. Mortality Prediction in ICUs Using A Novel Time-Slicing Cox Regression Method

    PubMed Central

    Wang, Yuan; Chen, Wenlin; Heard, Kevin; Kollef, Marin H.; Bailey, Thomas C.; Cui, Zhicheng; He, Yujie; Lu, Chenyang; Chen, Yixin

    2015-01-01

    Over the last few decades, machine learning and data mining have been increasingly used for clinical prediction in ICUs. However, there is still a huge gap in making full use of the time-series data generated from ICUs. Aiming at filling this gap, we propose a novel approach entitled Time Slicing Cox regression (TS-Cox), which extends the classical Cox regression into a classification method on multi-dimensional time-series. Unlike traditional classifiers such as logistic regression and support vector machines, our model not only incorporates the discriminative features derived from the time-series, but also naturally exploits the temporal orders of these features based on a Cox-like function. Empirical evaluation on MIMIC-II database demonstrates the efficacy of the TS-Cox model. Our TS-Cox model outperforms all other baseline models by a good margin in terms of AUC_PR, sensitivity and PPV, which indicates that TS-Cox may be a promising tool for mortality prediction in ICUs. PMID:26958269

  11. NETWORK-REGULARIZED HIGH-DIMENSIONAL COX REGRESSION FOR ANALYSIS OF GENOMIC DATA

    PubMed Central

    Sun, Hokeun; Lin, Wei; Feng, Rui; Li, Hongzhe

    2015-01-01

    We consider estimation and variable selection in high-dimensional Cox regression when a prior knowledge of the relationships among the covariates, described by a network or graph, is available. A limitation of the existing methodology for survival analysis with high-dimensional genomic data is that a wealth of structural information about many biological processes, such as regulatory networks and pathways, has often been ignored. In order to incorporate such prior network information into the analysis of genomic data, we propose a network-based regularization method for high-dimensional Cox regression; it uses an ?1-penalty to induce sparsity of the regression coefficients and a quadratic Laplacian penalty to encourage smoothness between the coefficients of neighboring variables on a given network. The proposed method is implemented by an efficient coordinate descent algorithm. In the setting where the dimensionality p can grow exponentially fast with the sample size n, we establish model selection consistency and estimation bounds for the proposed estimators. The theoretical results provide insights into the gain from taking into account the network structural information. Extensive simulation studies indicate that our method outperforms Lasso and elastic net in terms of variable selection accuracy and stability. We apply our method to a breast cancer gene expression study and identify several biologically plausible subnetworks and pathways that are associated with breast cancer distant metastasis. PMID:26316678

  12. A global goodness-of-fit statistic for Cox regression models.

    PubMed

    Parzen, M; Lipsitz, S R

    1999-06-01

    In this paper, a global goodness-of-fit test statistic for a Cox regression model, which has an approximate chi-squared distribution when the model has been correctly specified, is proposed. Our goodness-of-fit statistic is global and has power to detect if interactions or higher order powers of covariates in the model are needed. The proposed statistic is similar to the Hosmer and Lemeshow (1980, Communications in Statistics A10, 1043-1069) goodness-of-fit statistic for binary data as well as Schoenfeld's (1980, Biometrika 67, 145-153) statistic for the Cox model. The methods are illustrated using data from a Mayo Clinic trial in primary billiary cirrhosis of the liver (Fleming and Harrington, 1991, Counting Processes and Survival Analysis), in which the outcome is the time until liver transplantation or death. The are 17 possible covariates. Two Cox proportional hazards models are fit to the data, and the proposed goodness-of-fit statistic is applied to the fitted models. PMID:11318217

  13. Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

    PubMed Central

    2014-01-01

    Background Recent global genomic analyses identified 69 gene sets and 12 core signaling pathways genetically altered in pancreatic cancer, which is a highly malignant disease. A comprehensive understanding of the genetic signatures and signaling pathways that are directly correlated to pancreatic cancer survival will help cancer researchers to develop effective multi-gene targeted, personalized therapies for the pancreatic cancer patients at different stages. A previous work that applied a LASSO penalized regression method, which only considered individual genetic effects, identified 12 genes associated with pancreatic cancer survival. Results In this work, we integrate pathway information into pancreatic cancer survival analysis. We introduce and apply a doubly regularized Cox regression model to identify both genes and signaling pathways related to pancreatic cancer survival. Conclusions Four signaling pathways, including Ion transport, immune phagocytosis, TGFβ (spermatogenesis), regulation of DNA-dependent transcription pathways, and 15 genes within the four pathways are identified and verified to be directly correlated to pancreatic cancer survival. Our findings can help cancer researchers design new strategies for the early detection and diagnosis of pancreatic cancer. PMID:24565114

  14. A comparison between univariate probabilistic and multivariate (logistic regression) methods for landslide susceptibility analysis: the example of the Febbraro valley (Northern Alps, Italy)

    NASA Astrophysics Data System (ADS)

    Rossi, M.; Apuani, T.; Felletti, F.

    2009-04-01

    The aim of this paper is to compare the results of two statistical methods for landslide susceptibility analysis: 1) univariate probabilistic method based on landslide susceptibility index, 2) multivariate method (logistic regression). The study area is the Febbraro valley, located in the central Italian Alps, where different types of metamorphic rocks croup out. On the eastern part of the studied basin a quaternary cover represented by colluvial and secondarily, by glacial deposits, is dominant. In this study 110 earth flows, mainly located toward NE portion of the catchment, were analyzed. They involve only the colluvial deposits and their extension mainly ranges from 36 to 3173 m2. Both statistical methods require to establish a spatial database, in which each landslide is described by several parameters that can be assigned using a main scarp central point of landslide. The spatial database is constructed using a Geographical Information System (GIS). Each landslide is described by several parameters corresponding to the value of main scarp central point of the landslide. Based on bibliographic review a total of 15 predisposing factors were utilized. The width of the intervals, in which the maps of the predisposing factors have to be reclassified, has been defined assuming constant intervals to: elevation (100 m), slope (5 °), solar radiation (0.1 MJ/cm2/year), profile curvature (1.2 1/m), tangential curvature (2.2 1/m), drainage density (0.5), lineament density (0.00126). For the other parameters have been used the results of the probability-probability plots analysis and the statistical indexes of landslides site. In particular slope length (0 ÷ 2, 2 ÷ 5, 5 ÷ 10, 10 ÷ 20, 20 ÷ 35, 35 ÷ 260), accumulation flow (0 ÷ 1, 1 ÷ 2, 2 ÷ 5, 5 ÷ 12, 12 ÷ 60, 60 ÷27265), Topographic Wetness Index 0 ÷ 0.74, 0.74 ÷ 1.94, 1.94 ÷ 2.62, 2.62 ÷ 3.48, 3.48 ÷ 6,00, 6.00 ÷ 9.44), Stream Power Index (0 ÷ 0.64, 0.64 ÷ 1.28, 1.28 ÷ 1.81, 1.81 ÷ 4.20, 4.20 ÷ 9.40). Geological map and land use map were also used, considering geological and land use properties as categorical variables. Appling the univariate probabilistic method the Landslide Susceptibility Index (LSI) is defined as the sum of the ratio Ra/Rb calculated for each predisposing factor, where Ra is the ratio between number of pixel of class and the total number of pixel of the study area, and Rb is the ratio between number of landslides respect to the pixel number of the interval area. From the analysis of the Ra/Rb ratio the relationship between landslide occurrence and predisposing factors were defined. Then the equation of LSI was used in GIS to trace the landslide susceptibility maps. The multivariate method for landslide susceptibility analysis, based on logistic regression, was performed starting from the density maps of the predisposing factors, calculated with the intervals defined above using the equation Rb/Rbtot, where Rbtot is a sum of all Rb values. Using stepwise forward algorithms the logistic regression was performed in two successive steps: first a univariate logistic regression is used to choose the most significant predisposing factors, then the multivariate logistic regression can be performed. The univariate regression highlighted the importance of the following factors: elevation, accumulation flow, drainage density, lineament density, geology and land use. When the multivariate regression was applied the number of controlling factors was reduced neglecting the geological properties. The resulting final susceptibility equation is: P = 1 / (1 + exp-(6.46-22.34*elevation-5.33*accumulation flow-7.99* drainage density-4.47*lineament density-17.31*land use)) and using this equation the susceptibility maps were obtained. To easy compare the results of the two methodologies, the susceptibility maps were reclassified in five susceptibility intervals (very high, high, moderate, low and very low) using natural breaks. Then the maps were validated using two cumulative distribution curves, one related to the landslides (number of landslides in each susceptibility class) and one to the basin (number of pixel covering each class). Comparing the curves for each method, it results that the two approaches (univariate and multivariate) are appropriate, providing acceptable results. In both maps the distribution of high susceptibility condition is mainly localized on the left slope of the catchment in agreement with the field evidences. The comparison between the methods was obtained by subtraction of the two maps. This operation shows that about 40% of the basin is classified by the same class of susceptibility. In general the univariate probabilistic method tends to overestimate the areal extension of the high susceptibility class with respect to the maps obtained by the logistic regression method.

  15. [Application of SAS macro to evaluated multiplicative and additive interaction in logistic and Cox regression in clinical practices].

    PubMed

    Nie, Z Q; Ou, Y Q; Zhuang, J; Qu, Y J; Mai, J Z; Chen, J M; Liu, X Q

    2016-05-10

    Conditional logistic regression analysis and unconditional logistic regression analysis are commonly used in case control study, but Cox proportional hazard model is often used in survival data analysis. Most literature only refer to main effect model, however, generalized linear model differs from general linear model, and the interaction was composed of multiplicative interaction and additive interaction. The former is only statistical significant, but the latter has biological significance. In this paper, macros was written by using SAS 9.4 and the contrast ratio, attributable proportion due to interaction and synergy index were calculated while calculating the items of logistic and Cox regression interactions, and the confidence intervals of Wald, delta and profile likelihood were used to evaluate additive interaction for the reference in big data analysis in clinical epidemiology and in analysis of genetic multiplicative and additive interactions. PMID:27188374

  16. A new method to analyse the pace of child development: Cox regression validated by a bootstrap resampling procedure

    PubMed Central

    2010-01-01

    Background Various perinatal factors influencing neuromotor development are known from cross sectional studies. Factors influencing the age at which distinct abilities are acquired are uncertain. We hypothesized that the Cox regression model might identify these factors. Methods Neonates treated at Aachen University Hospital in 2000/2001 were identified retrospectively (n = 796). Outcome data, based on a structured interview, were available from 466 children, as were perinatal data. Factors possibly related to outcome were identified by bootstrap selection and then included into a multivariate Cox regression model. To evaluate if the parental assessment might change with the time elapsed since birth we studied five age cohorts of 163 normally developed children. Results Birth weight, gestational age, congenital cardiac disease and periventricular leukomalacia were related to outcome in the multivariate analysis (p < 0.05). Analysis of the control cohorts revealed that the parents' assessment of the ability of bladder control is modified by the time elapsed since birth. Conclusions Combined application of the bootstrap resampling procedure and multivariate Cox regression analysis effectively identifies perinatal factors influencing the age at which distinct abilities are acquired. These were similar as known from previous cross sectional studies. Retrospective data acquistion may lead to a bias because the parental memories change with time. This recommends applying this statistical approach in larger prospective trials. PMID:20205739

  17. 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.

  18. High-dimensional, massive sample-size Cox proportional hazards regression for survival analysis

    PubMed Central

    Mittal, Sushil; Madigan, David; Burd, Randall S.; Suchard, Marc A.

    2014-01-01

    Survival analysis endures as an old, yet active research field with applications that spread across many domains. Continuing improvements in data acquisition techniques pose constant challenges in applying existing survival analysis methods to these emerging data sets. In this paper, we present tools for fitting regularized Cox survival analysis models on high-dimensional, massive sample-size (HDMSS) data using a variant of the cyclic coordinate descent optimization technique tailored for the sparsity that HDMSS data often present. Experiments on two real data examples demonstrate that efficient analyses of HDMSS data using these tools result in improved predictive performance and calibration. PMID:24096388

  19. Gene identification and survival prediction with Lp Cox regression and novel similarity measure.

    PubMed

    Liu, Zhenqiu; Jiang, Feng

    2009-01-01

    In this paper, Cox's proportional hazards model with Lp penalty method is developed for simultaneous gene selection and survival prediction. Lp penalty shrinks coefficients and produces some coefficients that are exactly zero, and therefore can be used to identify survival related downstream genes. We also define a novel similarity measure to hunt the regulatory genes that their gene expression changes may be low but they are highly correlated with the selected genes. Experimental results with gene expression data demonstrate that the proposed procedures can be used for identifying important gene clusters that are related to time to death due to cancer and for building parsimonious model for predicting the survival of future patients. PMID:20052904

  20. The Covariance Adjustment Approaches for Combining Incomparable Cox Regressions Caused by Unbalanced Covariates Adjustment: A Multivariate Meta-Analysis Study

    PubMed Central

    Dehesh, Tania; Zare, Najaf; Ayatollahi, Seyyed Mohammad Taghi

    2015-01-01

    Background. Univariate meta-analysis (UM) procedure, as a technique that provides a single overall result, has become increasingly popular. Neglecting the existence of other concomitant covariates in the models leads to loss of treatment efficiency. Our aim was proposing four new approximation approaches for the covariance matrix of the coefficients, which is not readily available for the multivariate generalized least square (MGLS) method as a multivariate meta-analysis approach. Methods. We evaluated the efficiency of four new approaches including zero correlation (ZC), common correlation (CC), estimated correlation (EC), and multivariate multilevel correlation (MMC) on the estimation bias, mean square error (MSE), and 95% probability coverage of the confidence interval (CI) in the synthesis of Cox proportional hazard models coefficients in a simulation study. Result. Comparing the results of the simulation study on the MSE, bias, and CI of the estimated coefficients indicated that MMC approach was the most accurate procedure compared to EC, CC, and ZC procedures. The precision ranking of the four approaches according to all above settings was MMC ≥ EC ≥ CC ≥ ZC. Conclusion. This study highlights advantages of MGLS meta-analysis on UM approach. The results suggested the use of MMC procedure to overcome the lack of information for having a complete covariance matrix of the coefficients. PMID:26413142

  1. 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 prognostic factors and showed a very high overlap with respect to gene ontologies (GOs) associated with genes overexpressed in the predicted poor-prognosis vs. good-prognosis classes and centred on cell proliferation. Interestingly, all classifiers reported high sensitivity to predict the 4-year status of metastatic disease. CONCLUSIONS High-dimensional regression methods are attractive in prognostic studies because finding a small subset of genes may facilitate the transfer to the clinic, and also because they strengthen the robustness of the model by limiting the selection of false-positive predictive genes. With only six genes, the CoxBoost classifier predicted the 4-year status of metastatic disease with 93% sensitivity. Selecting a few genes related to ontologies other than cell proliferation might further improve the overall sensitivity performance. PMID:25983547

  2. Evaluation of the efficiency of continuous wavelet transform as processing and preprocessing algorithm for resolution of overlapped signals in univariate and multivariate regression analyses; an application to ternary and quaternary mixtures.

    PubMed

    Hegazy, Maha A; Lotfy, Hayam M; Mowaka, Shereen; Mohamed, Ekram Hany

    2016-07-01

    Wavelets have been adapted for a vast number of signal-processing applications due to the amount of information that can be extracted from a signal. In this work, a comparative study on the efficiency of continuous wavelet transform (CWT) as a signal processing tool in univariate regression and a pre-processing tool in multivariate analysis using partial least square (CWT-PLS) was conducted. These were applied to complex spectral signals of ternary and quaternary mixtures. CWT-PLS method succeeded in the simultaneous determination of a quaternary mixture of drotaverine (DRO), caffeine (CAF), paracetamol (PAR) and p-aminophenol (PAP, the major impurity of paracetamol). While, the univariate CWT failed to simultaneously determine the quaternary mixture components and was able to determine only PAR and PAP, the ternary mixtures of DRO, CAF, and PAR and CAF, PAR, and PAP. During the calculations of CWT, different wavelet families were tested. The univariate CWT method was validated according to the ICH guidelines. While for the development of the CWT-PLS model a calibration set was prepared by means of an orthogonal experimental design and their absorption spectra were recorded and processed by CWT. The CWT-PLS model was constructed by regression between the wavelet coefficients and concentration matrices and validation was performed by both cross validation and external validation sets. Both methods were successfully applied for determination of the studied drugs in pharmaceutical formulations. PMID:27070527

  3. Five Years Survival of Patients After Liver Transplantation and Its Effective Factors by Neural Network and Cox Poroportional Hazard Regression Models

    PubMed Central

    Khosravi, Bahareh; Pourahmad, Saeedeh; Bahreini, Amin; Nikeghbalian, Saman; Mehrdad, Goli

    2015-01-01

    Background: Transplantation is the only treatment for patients with liver failure. Since the therapy imposes high expenses to the patients and community, identification of effective factors on survival of such patients after transplantation is valuable. Objectives: The current study attempted to model the survival of patients (two years old and above) after liver transplantation using neural network and Cox Proportional Hazards (Cox PH) regression models. The event is defined as death due to complications of liver transplantation. Patients and Methods: In a historical cohort study, the clinical findings of 1168 patients who underwent liver transplant surgery (from March 2008 to march 2013) at Shiraz Namazee Hospital Organ Transplantation Center, Shiraz, Southern Iran, were used. To model the one to five years survival of such patients, Cox PH regression model accompanied by three layers feed forward artificial neural network (ANN) method were applied on data separately and their prediction accuracy was compared using the area under the receiver operating characteristic curve (ROC). Furthermore, Kaplan-Meier method was used to estimate the survival probabilities in different years. Results: The estimated survival probability of one to five years for the patients were 91%, 89%, 85%, 84%, and 83%, respectively. The areas under the ROC were 86.4% and 80.7% for ANN and Cox PH models, respectively. In addition, the accuracy of prediction rate for ANN and Cox PH methods was equally 92.73%. Conclusions: The present study detected more accurate results for ANN method compared to those of Cox PH model to analyze the survival of patients with liver transplantation. Furthermore, the order of effective factors in patients’ survival after transplantation was clinically more acceptable. The large dataset with a few missing data was the advantage of this study, the fact which makes the results more reliable. PMID:26500682

  4. Novel spectrophotometric determination of chloramphenicol and dexamethasone in the presence of non labeled interfering substances using univariate methods and multivariate regression model updating

    NASA Astrophysics Data System (ADS)

    Hegazy, Maha A.; Lotfy, Hayam M.; Rezk, Mamdouh R.; Omran, Yasmin Rostom

    2015-04-01

    Smart and novel spectrophotometric and chemometric methods have been developed and validated for the simultaneous determination of a binary mixture of chloramphenicol (CPL) and dexamethasone sodium phosphate (DSP) in presence of interfering substances without prior separation. The first method depends upon derivative subtraction coupled with constant multiplication. The second one is ratio difference method at optimum wavelengths which were selected after applying derivative transformation method via multiplying by a decoding spectrum in order to cancel the contribution of non labeled interfering substances. The third method relies on partial least squares with regression model updating. They are so simple that they do not require any preliminary separation steps. Accuracy, precision and linearity ranges of these methods were determined. Moreover, specificity was assessed by analyzing synthetic mixtures of both drugs. The proposed methods were successfully applied for analysis of both drugs in their pharmaceutical formulation. The obtained results have been statistically compared to that of an official spectrophotometric method to give a conclusion that there is no significant difference between the proposed methods and the official ones with respect to accuracy and precision.

  5. Novel spectrophotometric determination of chloramphenicol and dexamethasone in the presence of non labeled interfering substances using univariate methods and multivariate regression model updating.

    PubMed

    Hegazy, Maha A; Lotfy, Hayam M; Rezk, Mamdouh R; Omran, Yasmin Rostom

    2015-04-01

    Smart and novel spectrophotometric and chemometric methods have been developed and validated for the simultaneous determination of a binary mixture of chloramphenicol (CPL) and dexamethasone sodium phosphate (DSP) in presence of interfering substances without prior separation. The first method depends upon derivative subtraction coupled with constant multiplication. The second one is ratio difference method at optimum wavelengths which were selected after applying derivative transformation method via multiplying by a decoding spectrum in order to cancel the contribution of non labeled interfering substances. The third method relies on partial least squares with regression model updating. They are so simple that they do not require any preliminary separation steps. Accuracy, precision and linearity ranges of these methods were determined. Moreover, specificity was assessed by analyzing synthetic mixtures of both drugs. The proposed methods were successfully applied for analysis of both drugs in their pharmaceutical formulation. The obtained results have been statistically compared to that of an official spectrophotometric method to give a conclusion that there is no significant difference between the proposed methods and the official ones with respect to accuracy and precision. PMID:25659506

  6. Univariate Probability Distributions

    ERIC Educational Resources Information Center

    Leemis, Lawrence M.; Luckett, Daniel J.; Powell, Austin G.; Vermeer, Peter E.

    2012-01-01

    We describe a web-based interactive graphic that can be used as a resource in introductory classes in mathematical statistics. This interactive graphic presents 76 common univariate distributions and gives details on (a) various features of the distribution such as the functional form of the probability density function and cumulative distribution…

  7. Factors determining disease duration in Alzheimer's disease: a postmortem study of 103 cases using the Kaplan-Meier estimator and Cox regression.

    PubMed

    Armstrong, R A

    2014-01-01

    Factors associated with duration of dementia in a consecutive series of 103 Alzheimer's disease (AD) cases were studied using the Kaplan-Meier estimator and Cox regression analysis (proportional hazard model). Mean disease duration was 7.1 years (range: 6 weeks-30 years, standard deviation = 5.18); 25% of cases died within four years, 50% within 6.9 years, and 75% within 10 years. Familial AD cases (FAD) had a longer duration than sporadic cases (SAD), especially cases linked to presenilin (PSEN) genes. No significant differences in duration were associated with age, sex, or apolipoprotein E (Apo E) genotype. Duration was reduced in cases with arterial hypertension. Cox regression analysis suggested longer duration was associated with an earlier disease onset and increased senile plaque (SP) and neurofibrillary tangle (NFT) pathology in the orbital gyrus (OrG), CA1 sector of the hippocampus, and nucleus basalis of Meynert (NBM). The data suggest shorter disease duration in SAD and in cases with hypertensive comorbidity. In addition, degree of neuropathology did not influence survival, but spread of SP/NFT pathology into the frontal lobe, hippocampus, and basal forebrain was associated with longer disease duration. PMID:24579083

  8. Assessing outcomes of large-scale public health interventions in the absence of baseline data using a mixture of Cox and binomial regressions

    PubMed Central

    2014-01-01

    Background Large-scale public health interventions with rapid scale-up are increasingly being implemented worldwide. Such implementation allows for a large target population to be reached in a short period of time. But when the time comes to investigate the effectiveness of these interventions, the rapid scale-up creates several methodological challenges, such as the lack of baseline data and the absence of control groups. One example of such an intervention is Avahan, the India HIV/AIDS initiative of the Bill & Melinda Gates Foundation. One question of interest is the effect of Avahan on condom use by female sex workers with their clients. By retrospectively reconstructing condom use and sex work history from survey data, it is possible to estimate how condom use rates evolve over time. However formal inference about how this rate changes at a given point in calendar time remains challenging. Methods We propose a new statistical procedure based on a mixture of binomial regression and Cox regression. We compare this new method to an existing approach based on generalized estimating equations through simulations and application to Indian data. Results Both methods are unbiased, but the proposed method is more powerful than the existing method, especially when initial condom use is high. When applied to the Indian data, the new method mostly agrees with the existing method, but seems to have corrected some implausible results of the latter in a few districts. We also show how the new method can be used to analyze the data of all districts combined. Conclusions The use of both methods can be recommended for exploratory data analysis. However for formal statistical inference, the new method has better power. PMID:24397563

  9. Reweighting estimators for Cox regression with missing covariate data: Analysis of insulin resistance and risk of stroke in the Northern Manhattan Study

    PubMed Central

    Xu, Qiang; Paik, Myunghee Cho; Rundek, Tatjana; Elkind, Mitchell S. V.; Sacco, Ralph L.

    2015-01-01

    Incomplete covariates often obscure analysis results from a Cox regression. In an analysis of the Northern Manhattan Study (NOMAS) to determine the influence of insulin resistance on the incidence of stroke in non-diabetic individuals, insulin level is unknown for 34.1% of the subjects. The available data suggest that the missingness mechanism depends on outcome variables, which may generate biases in estimating the parameters of interest if only using the complete observations. This article aimed to introduce practical strategies to analyze the NOMAS data and present sensitivity analyses by using the reweighting method in standard statistical packages. When the data set structure is in counting process style, the reweighting estimates can be obtained by built-in procedures with variance estimated by the jackknife method. Simulation results indicate that the jackknife variance estimate provides reasonable coverage probability in moderate sample sizes. We subsequently conducted sensitivity analyses for the NOMAS data, showing that the risk estimates are robust to a variety of missingness mechanisms. At the end of this article, we present the core SAS and R programs used in the analysis. PMID:21965165

  10. Univariate time series forecasting algorithm validation

    NASA Astrophysics Data System (ADS)

    Ismail, Suzilah; Zakaria, Rohaiza; Muda, Tuan Zalizam Tuan

    2014-12-01

    Forecasting is a complex process which requires expert tacit knowledge in producing accurate forecast values. This complexity contributes to the gaps between end users and expert. Automating this process by using algorithm can act as a bridge between them. Algorithm is a well-defined rule for solving a problem. In this study a univariate time series forecasting algorithm was developed in JAVA and validated using SPSS and Excel. Two set of simulated data (yearly and non-yearly); several univariate forecasting techniques (i.e. Moving Average, Decomposition, Exponential Smoothing, Time Series Regressions and ARIMA) and recent forecasting process (such as data partition, several error measures, recursive evaluation and etc.) were employed. Successfully, the results of the algorithm tally with the results of SPSS and Excel. This algorithm will not just benefit forecaster but also end users that lacking in depth knowledge of forecasting process.

  11. Survival prediction based on compound covariate under Cox proportional hazard models.

    PubMed

    Emura, Takeshi; Chen, Yi-Hau; Chen, Hsuan-Yu

    2012-01-01

    Survival prediction from a large number of covariates is a current focus of statistical and medical research. In this paper, we study a methodology known as the compound covariate prediction performed under univariate Cox proportional hazard models. We demonstrate via simulations and real data analysis that the compound covariate method generally competes well with ridge regression and Lasso methods, both already well-studied methods for predicting survival outcomes with a large number of covariates. Furthermore, we develop a refinement of the compound covariate method by incorporating likelihood information from multivariate Cox models. The new proposal is an adaptive method that borrows information contained in both the univariate and multivariate Cox regression estimators. We show that the new proposal has a theoretical justification from a statistical large sample theory and is naturally interpreted as a shrinkage-type estimator, a popular class of estimators in statistical literature. Two datasets, the primary biliary cirrhosis of the liver data and the non-small-cell lung cancer data, are used for illustration. The proposed method is implemented in R package "compound.Cox" available in CRAN at http://cran.r-project.org/. PMID:23112827

  12. Survival Prediction Based on Compound Covariate under Cox Proportional Hazard Models

    PubMed Central

    Emura, Takeshi; Chen, Yi-Hau; Chen, Hsuan-Yu

    2012-01-01

    Survival prediction from a large number of covariates is a current focus of statistical and medical research. In this paper, we study a methodology known as the compound covariate prediction performed under univariate Cox proportional hazard models. We demonstrate via simulations and real data analysis that the compound covariate method generally competes well with ridge regression and Lasso methods, both already well-studied methods for predicting survival outcomes with a large number of covariates. Furthermore, we develop a refinement of the compound covariate method by incorporating likelihood information from multivariate Cox models. The new proposal is an adaptive method that borrows information contained in both the univariate and multivariate Cox regression estimators. We show that the new proposal has a theoretical justification from a statistical large sample theory and is naturally interpreted as a shrinkage-type estimator, a popular class of estimators in statistical literature. Two datasets, the primary biliary cirrhosis of the liver data and the non-small-cell lung cancer data, are used for illustration. The proposed method is implemented in R package “compound.Cox” available in CRAN at http://cran.r-project.org/. PMID:23112827

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

    PubMed

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

    2015-05-01

    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

  14. Univariate and Multivariate Tests: ANOVA versus MANOVA.

    ERIC Educational Resources Information Center

    Harwell, Michael R.

    1988-01-01

    Multivariate and univariate analysis of variance methods (MANOVA and ANOVA, respectively) are compared for their relative value in educational research. The favoritism shown multivariate techniques is questioned. Criteria for the selection of the appropriate technique are outlined. The relationships among research hypotheses, statistical

  15. Portable EDXRF for quantification of metals in soils: Univariate calibration versus multivariate calibration

    NASA Astrophysics Data System (ADS)

    Novacoski, Ezequiel J.; dos Santos, Felipe R.; Melquiades, Fábio L.

    2013-05-01

    The objective of this study was to use the EDXRF spectra to perform a multivariate calibration via partial least square (PLS) regression for Mn, Ni, Cu, Zn, Sr, Rb, Y, Zr and Nb, in soil samples and compare with univariate calibration method. The advantage of multivariate calibration is that it is not necessary to determine the net peak areas.

  16. Identifying Prognostic SNPs in Clinical Cohorts: Complementing Univariate Analyses by Resampling and Multivariable Modeling

    PubMed Central

    Hieke, Stefanie; Benner, Axel; Schlenk, Richard F.; Schumacher, Martin; Bullinger, Lars; Binder, Harald

    2016-01-01

    Clinical cohorts with time-to-event endpoints are increasingly characterized by measurements of a number of single nucleotide polymorphisms that is by a magnitude larger than the number of measurements typically considered at the gene level. At the same time, the size of clinical cohorts often is still limited, calling for novel analysis strategies for identifying potentially prognostic SNPs that can help to better characterize disease processes. We propose such a strategy, drawing on univariate testing ideas from epidemiological case-controls studies on the one hand, and multivariable regression techniques as developed for gene expression data on the other hand. In particular, we focus on stable selection of a small set of SNPs and corresponding genes for subsequent validation. For univariate analysis, a permutation-based approach is proposed to test at the gene level. We use regularized multivariable regression models for considering all SNPs simultaneously and selecting a small set of potentially important prognostic SNPs. Stability is judged according to resampling inclusion frequencies for both the univariate and the multivariable approach. The overall strategy is illustrated with data from a cohort of acute myeloid leukemia patients and explored in a simulation study. The multivariable approach is seen to automatically focus on a smaller set of SNPs compared to the univariate approach, roughly in line with blocks of correlated SNPs. This more targeted extraction of SNPs results in more stable selection at the SNP as well as at the gene level. Thus, the multivariable regression approach with resampling provides a perspective in the proposed analysis strategy for SNP data in clinical cohorts highlighting what can be added by regularized regression techniques compared to univariate analyses. PMID:27159447

  17. Dennis Cox, USGS Volunteer

    Dennis Cox, a volunteer with the USGS Menlo Park Campus, helps visitors pan for gold at the 2009 Open House in Menlo Park. The 2012 Open House, to be held May 19-20, will include gold panning among its many activities. ...

  18. Validated univariate and multivariate spectrophotometric methods for the determination of pharmaceuticals mixture in complex wastewater

    NASA Astrophysics Data System (ADS)

    Riad, Safaa M.; Salem, Hesham; Elbalkiny, Heba T.; Khattab, Fatma I.

    2015-04-01

    Five, accurate, precise, and sensitive univariate and multivariate spectrophotometric methods were developed for the simultaneous determination of a ternary mixture containing Trimethoprim (TMP), Sulphamethoxazole (SMZ) and Oxytetracycline (OTC) in waste water samples collected from different cites either production wastewater or livestock wastewater after their solid phase extraction using OASIS HLB cartridges. In univariate methods OTC was determined at its λmax 355.7 nm (0D), while (TMP) and (SMZ) were determined by three different univariate methods. Method (A) is based on successive spectrophotometric resolution technique (SSRT). The technique starts with the ratio subtraction method followed by ratio difference method for determination of TMP and SMZ. Method (B) is successive derivative ratio technique (SDR). Method (C) is mean centering of the ratio spectra (MCR). The developed multivariate methods are principle component regression (PCR) and partial least squares (PLS). The specificity of the developed methods is investigated by analyzing laboratory prepared mixtures containing different ratios of the three drugs. The obtained results are statistically compared with those obtained by the official methods, showing no significant difference with respect to accuracy and precision at p = 0.05.

  19. Evaluating Univariate, Bivariate, and Multivariate Normality Using Graphical Procedures.

    ERIC Educational Resources Information Center

    Burdenski, Thomas K., Jr.

    This paper reviews graphical and nongraphical procedures for evaluating multivariate normality by guiding the reader through univariate and bivariate procedures that are necessary, but insufficient, indications of a multivariate normal distribution. A data set using three dependent variables for two groups provided by D. George and P. Mallery…

  20. Univariate Analysis of Multivariate Outcomes in Educational Psychology.

    ERIC Educational Resources Information Center

    Hubble, L. M.

    1984-01-01

    The author examined the prevalence of multiple operational definitions of outcome constructs and an estimate of the incidence of Type I error rates when univariate procedures were applied to multiple variables in educational psychology. Multiple operational definitions of constructs were advocated and wider use of multivariate analysis was…

  1. Univariate Analysis of Multivariate Outcomes in Educational Psychology.

    ERIC Educational Resources Information Center

    Hubble, L. M.

    1984-01-01

    The author examined the prevalence of multiple operational definitions of outcome constructs and an estimate of the incidence of Type I error rates when univariate procedures were applied to multiple variables in educational psychology. Multiple operational definitions of constructs were advocated and wider use of multivariate analysis was

  2. Univariate and Bivariate Loglinear Models for Discrete Test Score Distributions.

    ERIC Educational Resources Information Center

    Holland, Paul W.; Thayer, Dorothy T.

    2000-01-01

    Applied the theory of exponential families of distributions to the problem of fitting the univariate histograms and discrete bivariate frequency distributions that often arise in the analysis of test scores. Considers efficient computation of the maximum likelihood estimates of the parameters using Newton's Method and computationally efficient…

  3. Univariable Optimal Discriminant Analysis: One-Tailed Hypotheses.

    ERIC Educational Resources Information Center

    Soltysik, Robert C.; Yarnold, Paul R.

    1994-01-01

    This article describes the theoretical distribution of optima arising from two-category univariable optimal discriminant analysis (UniODA) of continuous random data for a one-tailed (directional) hypothesis. Directional UniODA is illustrated through an investigation of the relationship between depression and brain monoamine turnover. (SLD)

  4. Maximum Likelihood and Minimum Distance Applied to Univariate Mixture Distributions.

    ERIC Educational Resources Information Center

    Wang, Yuh-Yin Wu; Schafer, William D.

    This Monte-Carlo study compared modified Newton (NW), expectation-maximization algorithm (EM), and minimum Cramer-von Mises distance (MD), used to estimate parameters of univariate mixtures of two components. Data sets were fixed at size 160 and manipulated by mean separation, variance ratio, component proportion, and non-normality. Results…

  5. Comparison of Univariate and Multivariate Models of ¹³C SSNMR and XRPD Techniques for Quantification of Nimodipine Polymorphs.

    PubMed

    Rahman, Ziyaur; Mohammad, Adil; Siddiqui, Akhtar; Khan, Mansoor A

    2015-12-01

    The focus of the present investigation was to explore the use of solid-state nuclear magnetic resonance ((13)C ssNMR) and X-ray powder diffraction (XRPD) for quantification of nimodipine polymorphs (form I and form II) crystallized in a cosolvent formulation. The cosolvent formulation composed of polyethylene glycol 400, glycerin, water, and 2.5% drug, and was stored at 5°C for the drug crystallization. The (13)C ssNMR and XRPD data of the sample matrices containing varying percentages of nimodipine form I and form II were collected. Univariate and multivariate models were developed using the data. Least square method was used for the univariate model generation. Partial least square and principle component regressions were used for the multivariate models development. The univariate models of the (13)C ssNMR were better than the XRPD as indicated by statistical parameters such as correlation coefficient, R (2), root mean square error, and standard error. On the other hand, the XRPD multivariate models were better than the (13)C ssNMR as indicated by precision and accuracy parameters. Similar values were predicted by the univariate and multivariate models for independent samples. In conclusion, the univariate and multivariate models of (13)C ssNMR and XRPD can be used to quantitate nimodipine polymorphs. PMID:25956485

  6. 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. Although she

  7. Quantile Regression with Censored Data

    ERIC Educational Resources Information Center

    Lin, Guixian

    2009-01-01

    The Cox proportional hazards model and the accelerated failure time model are frequently used in survival data analysis. They are powerful, yet have limitation due to their model assumptions. Quantile regression offers a semiparametric approach to model data with possible heterogeneity. It is particularly powerful for censored responses, where the…

  8. 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

  9. Parallel Univariate Real Root Isolation on Multicore Processors

    NASA Astrophysics Data System (ADS)

    Chen, Changbo; Maza, Marc Moreno; Xie, Yuzhen

    2011-11-01

    We present parallel algorithms with optimal cache complexity for the kernel routine of many real root isolation algorithms, namely, Taylor shift, targeting multicore processors. We then report an efficient multithreaded implementation for isolating the real roots of univariate polynomials based on the parallel Taylor shift algorithms. For processing some well-known benchmark examples with sufficiently large size, our software tool reaches linear speedup on a 8-core machine. In addition, we show that our software is able to fully utilize the many cores and the memory space of a 32-core machine to tackle large problems that are out of reach for a desktop implementation.

  10. Forecasting electricity usage using univariate time series models

    NASA Astrophysics Data System (ADS)

    Hock-Eam, Lim; Chee-Yin, Yip

    2014-12-01

    Electricity is one of the important energy sources. A sufficient supply of electricity is vital to support a country's development and growth. Due to the changing of socio-economic characteristics, increasing competition and deregulation of electricity supply industry, the electricity demand forecasting is even more important than before. It is imperative to evaluate and compare the predictive performance of various forecasting methods. This will provide further insights on the weakness and strengths of each method. In literature, there are mixed evidences on the best forecasting methods of electricity demand. This paper aims to compare the predictive performance of univariate time series models for forecasting the electricity demand using a monthly data of maximum electricity load in Malaysia from January 2003 to December 2013. Results reveal that the Box-Jenkins method produces the best out-of-sample predictive performance. On the other hand, Holt-Winters exponential smoothing method is a good forecasting method for in-sample predictive performance.

  11. Dynamic treatment of invariant and univariant reactions in metamorphic systems

    SciTech Connect

    Lasaga, A.C.; Luettge, A.; Rye, D.M.; Bolton, E.W.

    2000-03-01

    A simple model is presented that incorporates the essential dynamics of metamorphic processes leading to reactions along univariant curves and up to and beyond the invariant point. The model includes both heat flow by conduction and convection as well as fluid flow in and out of a representative volume. Overall mineral reactions can then take place within this rock volume in response to internal and external factors. The paper derives a simple back-of-the-envelope expression for the steady state reached by the system. The steady state composition of the fluid and the steady state temperature are then compared with the composition and temperature predicted by the assumption of thermodynamic equilibrium. Expressions for the amount of fluid passing through the system based on the kinetic model are compared with previous calculations of the mass of fluid added to the system using the equilibrium assumptions. The approach to this steady state is also analyzed and an analytical solution is obtained for the time evolution up to the steady state. Both the steady state and the time evolution solution are then applied to an understanding of the dynamics involved in obtaining T-X-t paths in nature. The results of the kinetic approach lead to major revisions in many of the previously held concepts used in petrologic fluid flow models. These include the expected reaction pathway, the role of metastable reactions, the calculation of fluid flux, the role of the invariant point, and the interpretation of mineral textures and modal abundances of minerals.

  12. Prognostic models in coronary artery disease: Cox and network approaches.

    PubMed

    Mora, Antonio; Sicari, Rosa; Cortigiani, Lauro; Carpeggiani, Clara; Picano, Eugenio; Capobianco, Enrico

    2015-02-01

    Predictive assessment of the risk of developing cardiovascular diseases is usually provided by computational approaches centred on Cox models. The complex interdependence structure underlying clinical data patterns can limit the performance of Cox analysis and complicate the interpretation of results, thus calling for complementary and integrative methods. Prognostic models are proposed for studying the risk associated with patients with known or suspected coronary artery disease (CAD) undergoing vasodilator stress echocardiography, an established technique for CAD detection and prognostication. In order to complement standard Cox models, network inference is considered a possible solution to quantify the complex relationships between heterogeneous data categories. In particular, a mutual information network is designed to explore the paths linking patient-associated variables to endpoint events, to reveal prognostic factors and to identify the best possible predictors of death. Data from a prospective, multicentre, observational study are available from a previous study, based on 4313 patients (2532 men; 64±11 years) with known (n=1547) or suspected (n=2766) CAD, who underwent high-dose dipyridamole (0.84 mg kg(-1) over 6 min) stress echocardiography with coronary flow reserve (CFR) evaluation of left anterior descending (LAD) artery by Doppler. The overall mortality was the only endpoint analysed by Cox models. The estimated connectivity between clinical variables assigns a complementary value to the proposed network approach in relation to the established Cox model, for instance revealing connectivity paths. Depending on the use of multiple metrics, the constraints of regression analysis in measuring the association strength among clinical variables can be relaxed, and identification of communities and prognostic paths can be provided. On the basis of evidence from various model comparisons, we show in this CAD study that there may be characteristic factors involved in prognostic stratification whose complexity suggests an exploration beyond the analysis provided by the still fundamental Cox approach. PMID:26064595

  13. Prognostic models in coronary artery disease: Cox and network approaches

    PubMed Central

    Mora, Antonio; Sicari, Rosa; Cortigiani, Lauro; Carpeggiani, Clara; Picano, Eugenio; Capobianco, Enrico

    2015-01-01

    Predictive assessment of the risk of developing cardiovascular diseases is usually provided by computational approaches centred on Cox models. The complex interdependence structure underlying clinical data patterns can limit the performance of Cox analysis and complicate the interpretation of results, thus calling for complementary and integrative methods. Prognostic models are proposed for studying the risk associated with patients with known or suspected coronary artery disease (CAD) undergoing vasodilator stress echocardiography, an established technique for CAD detection and prognostication. In order to complement standard Cox models, network inference is considered a possible solution to quantify the complex relationships between heterogeneous data categories. In particular, a mutual information network is designed to explore the paths linking patient-associated variables to endpoint events, to reveal prognostic factors and to identify the best possible predictors of death. Data from a prospective, multicentre, observational study are available from a previous study, based on 4313 patients (2532 men; 64±11 years) with known (n=1547) or suspected (n=2766) CAD, who underwent high-dose dipyridamole (0.84 mg kg−1 over 6 min) stress echocardiography with coronary flow reserve (CFR) evaluation of left anterior descending (LAD) artery by Doppler. The overall mortality was the only endpoint analysed by Cox models. The estimated connectivity between clinical variables assigns a complementary value to the proposed network approach in relation to the established Cox model, for instance revealing connectivity paths. Depending on the use of multiple metrics, the constraints of regression analysis in measuring the association strength among clinical variables can be relaxed, and identification of communities and prognostic paths can be provided. On the basis of evidence from various model comparisons, we show in this CAD study that there may be characteristic factors involved in prognostic stratification whose complexity suggests an exploration beyond the analysis provided by the still fundamental Cox approach. PMID:26064595

  14. 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."

  15. 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. PMID:16952367

  16. Autistic Regression

    ERIC Educational Resources Information Center

    Matson, Johnny L.; Kozlowski, Alison M.

    2010-01-01

    Autistic regression is one of the many mysteries in the developmental course of autism and pervasive developmental disorders not otherwise specified (PDD-NOS). Various definitions of this phenomenon have been used, further clouding the study of the topic. Despite this problem, some efforts at establishing prevalence have been made. The purpose of…

  17. Analyzing Repeated Measures Designs Using Univariate and Multivariate Methods: A Primer.

    ERIC Educational Resources Information Center

    Tanguma, Jesus

    Similarities and differences in the univariate and multivariate analysis of repeated measures designs are discussed, using a hypothetical data set studying the effects of practice on the algebra performance of four students to illustrate both methods. When data are analyzed through the univariate approach and the homogeneity assumption is…

  18. Bootstrapping to Test for Nonzero Population Correlation Coefficients Using Univariate Sampling

    ERIC Educational Resources Information Center

    Beasley, William Howard; DeShea, Lise; Toothaker, Larry E.; Mendoza, Jorge L.; Bard, David E.; Rodgers, Joseph Lee

    2007-01-01

    This article proposes 2 new approaches to test a nonzero population correlation ([rho]): the hypothesis-imposed univariate sampling bootstrap (HI) and the observed-imposed univariate sampling bootstrap (OI). The authors simulated correlated populations with various combinations of normal and skewed variates. With [alpha[subscript "set"

  19. Robust Regression.

    PubMed

    Huang, Dong; Cabral, Ricardo; De la Torre, Fernando

    2016-02-01

    Discriminative methods (e.g., kernel regression, SVM) have been extensively used to solve problems such as object recognition, image alignment and pose estimation from images. These methods typically map image features ( X) to continuous (e.g., pose) or discrete (e.g., object category) values. A major drawback of existing discriminative methods is that samples are directly projected onto a subspace and hence fail to account for outliers common in realistic training sets due to occlusion, specular reflections or noise. It is important to notice that existing discriminative approaches assume the input variables X to be noise free. Thus, discriminative methods experience significant performance degradation when gross outliers are present. Despite its obvious importance, the problem of robust discriminative learning has been relatively unexplored in computer vision. This paper develops the theory of robust regression (RR) and presents an effective convex approach that uses recent advances on rank minimization. The framework applies to a variety of problems in computer vision including robust linear discriminant analysis, regression with missing data, and multi-label classification. Several synthetic and real examples with applications to head pose estimation from images, image and video classification and facial attribute classification with missing data are used to illustrate the benefits of RR. PMID:26761740

  20. COX-2 verexpression in pretreatment biopsies predicts response of rectal cancers to neoadjuvant radiochemotherapy

    SciTech Connect

    Smith, Fraser M.; Reynolds, John V. . E-mail: reynoldsjv@stjames.ie; Kay, Elaine W.; Crotty, Paul; Murphy, James O.; Hollywood, Donal; Gaffney, Eoin F.; Stephens, Richard B.; Kennedy, M. John

    2006-02-01

    Purpose: To determine the utility of COX-2 expression as a response predictor for patients with rectal cancer who are undergoing neoadjuvant radiochemotherapy (RCT). Methods and Materials: Pretreatment biopsies (PTB) from 49 patients who underwent RCT were included. COX-2 and proliferation in PTB were assessed by immunohistochemistry (IHC) and apoptosis was detected by TUNEL stain. Response to treatment was assessed by a 5-point tumor-regression grade (TRG) based on the ratio of residual tumor to fibrosis. Results: Good response (TRG 1 + 2), moderate response (TRG 3), and poor response (TRG 4 + 5) were seen in 21 patients (42%), 11 patients (22%), and 17 patients (34%), respectively. Patients with COX-2 overexpression in PTB were more likely to demonstrate moderate or poor response (TRG 3 + 4) to treatment than were those with normal COX-2 expression (p = 0.026, chi-square test). Similarly, poor response was more likely if patients had low levels of spontaneous apoptosis in PTBs (p = 0.0007, chi-square test). Conclusions: COX-2 overexpression and reduced apoptosis in PTB can predict poor response of rectal cancer to RCT. As COX-2 inhibitors are commercially available, their administration to patients who overexpress COX-2 warrants assessment in clinical trials in an attempt to increase overall response rates.

  1. Observational Studies: Matching or Regression?

    PubMed

    Brazauskas, Ruta; Logan, Brent R

    2016-03-01

    In observational studies with an aim of assessing treatment effect or comparing groups of patients, several approaches could be used. Often, baseline characteristics of patients may be imbalanced between groups, and adjustments are needed to account for this. It can be accomplished either via appropriate regression modeling or, alternatively, by conducting a matched pairs study. The latter is often chosen because it makes groups appear to be comparable. In this article we considered these 2 options in terms of their ability to detect a treatment effect in time-to-event studies. Our investigation shows that a Cox regression model applied to the entire cohort is often a more powerful tool in detecting treatment effect as compared with a matched study. Real data from a hematopoietic cell transplantation study is used as an example. PMID:26712591

  2. Cyclooxygenase (COX) Inhibitors and the Newborn Kidney

    PubMed Central

    Smith, Francine G.; Wade, Andrew W.; Lewis, Megan L.; Qi, Wei

    2012-01-01

    This review summarizes our current understanding of the role of cyclo-oxygenase inhibitors (COXI) in influencing the structural development as well as the function of the developing kidney. COXI administered either during pregnancy or after birth can influence kidney development including nephronogenesis, and can decrease renal perfusion and ultrafiltration potentially leading to acute kidney injury in the newborn period. To date, which COX isoform (COX-1 or COX-2) plays a more important role in during fetal development and influences kidney function early in life is not known, though evidence points to a predominant role for COX-2. Clinical implications of the use of COXI in pregnancy and in the newborn infant are also evaluated herein, with specific reference to the potential effects of COXI on nephronogenesis as well as newborn kidney function. PMID:24281306

  3. Viscum album-mediated COX-2 inhibition implicates destabilization of COX-2 mRNA.

    PubMed

    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

  4. Analysis of the correlation between P53 and Cox-2 expression and prognosis in esophageal cancer

    PubMed Central

    CHEN, JUN; WU, FANG; PEI, HONG-LEI; GU, WEN-DONG; NING, ZHONG-HUA; SHAO, YING-JIE; HUANG, JIN

    2015-01-01

    The present study aimed to explore the importance of P53 and Cox-2 protein expression in esophageal cancer and assess their influence on prognosis. The expression of P53 and Cox-2 was assessed in esophageal cancer samples from 195 patients subjected to radical surgery at Changzhou First People's Hospital (Changzhou, China) between May 2010 and December 2011. Expression of P53 and Cox-2 proteins were detected in 60.5% (118/195) and 69.7% (136/195) of the samples, respectively, and were co-expressed in 43.1% (84/195) of the samples. A correlation was identified between P53 expression and overall survival (OS) (P=0.0351) as well as disease-free survival (DFS) (P=0.0307). In addition, the co-expression of P53 and Cox-2 also correlated with OS (P=0.0040) and DFS (P=0.0042). P53 expression (P=0.023), TNM staging (P<0.001) and P53/Cox-2 co-expression (P=0.009) were identified as independent factors affecting OS in patients with esophageal cancer via a Cox multivariate regression model analysis. A similar analysis also identified P53 expression (P=0.020), TNM staging (P<0.001) and P53/Cox-2 co-expression (P=0.008) as independent prognostic factors influencing DFS in these patients. Binary logistic regression analysis demonstrated a correlation between P53 expression (P=0.012), TNM staging (P<0.001), tumor differentiation level (P=0.023) and P53/Cox-2 co-expression (P=0.021), and local recurrence or distant esophageal cancer metastasis. The results of the present study indicate that P53 and Cox-2 proteins may act synergistically in the development of esophageal cancer, and the assessment of P53/Cox-2 co-expression status in esophageal cancer biopsies may become an important diagnostic criterion to evaluate the prognosis of patients with esophageal cancer. PMID:26622818

  5. Mss51p and Cox14p jointly regulate mitochondrial Cox1p expression in Saccharomyces cerevisiae.

    PubMed

    Barrientos, Antoni; Zambrano, Andrea; Tzagoloff, Alexander

    2004-09-01

    Mutations in SURF1, the human homologue of yeast SHY1, are responsible for Leigh's syndrome, a neuropathy associated with cytochrome oxidase (COX) deficiency. Previous studies of the yeast model of this disease showed that mutant forms of Mss51p, a translational activator of COX1 mRNA, partially rescue the COX deficiency of shy1 mutants by restoring normal synthesis of the mitochondrially encoded Cox1p subunit of COX. Here we present evidence showing that Cox1p synthesis is reduced in most COX mutants but is restored to that of wild type by the same mss51 mutation that suppresses shy1 mutants. An important exception is a null mutation in COX14, which by itself or in combination with other COX mutations does not affect Cox1p synthesis. Cox14p and Mss51p are shown to interact with newly synthesized Cox1p and with each other. We propose that the interaction of Mss51p and Cox14p with Cox1p to form a transient Cox14p-Cox1p-Mss51p complex functions to downregulate Cox1p synthesis. The release of Mss51p from the complex occurs at a downstream step in the assembly pathway, probably catalyzed by Shy1p. PMID:15306853

  6. A counterexample to theorems of Cox and Fine

    SciTech Connect

    Halpern, J.Y.

    1996-12-31

    Cox`s well-known theorem justifying the use of probability is shown not to hold in finite domains. The counterexample also suggests that Cox`s assumptions are insufficient to prove the result even in infinite domains. The same counterexample is used to disprove a result of Fine on comparative conditional probability.

  7. Regression: A Bibliography.

    ERIC Educational Resources Information Center

    Pedrini, D. T.; Pedrini, Bonnie C.

    Regression, another mechanism studied by Sigmund Freud, has had much research, e.g., hypnotic regression, frustration regression, schizophrenic regression, and infra-human-animal regression (often directly related to fixation). Many investigators worked with hypnotic age regression, which has a long history, going back to Russian reflexologists.…

  8. Regression: A Bibliography.

    ERIC Educational Resources Information Center

    Pedrini, D. T.; Pedrini, Bonnie C.

    Regression, another mechanism studied by Sigmund Freud, has had much research, e.g., hypnotic regression, frustration regression, schizophrenic regression, and infra-human-animal regression (often directly related to fixation). Many investigators worked with hypnotic age regression, which has a long history, going back to Russian reflexologists.

  9. Suppression mechanisms of COX assembly defects in yeast and human: Insights into the COX assembly process

    PubMed Central

    Barrientos, Antoni; Gouget, Karine; Horn, Darryl; Soto, Ileana C.; Fontanesi, Flavia

    2008-01-01

    Eukaryotic cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. COX is a multimeric enzyme formed by subunits of dual genetic origin whose assembly is intricate and highly regulated. In addition to the structural subunits, a large number of accessory factors are required to build the holoenzyme. The function of these factors is required in all stages of the assembly process. They are relevant to human health because devastating human disorders have been associated with mutations in nuclear genes encoding conserved COX assembly factors. The study of yeast strains and human cell lines from patients carrying mutations in structural subunits and COX assembly factors has been invaluable to attain the current state of knowledge, even if still fragmentary, of the COX assembly process. After the identification of the genes involved, the isolation and characterization of genetic and metabolic suppressors of COX assembly defects, reviewed here, have become a profitable strategy to gain insight into their functions and the pathways in which they operate. Additionally, they have the potential to provide useful information for devising therapeutic approaches to combat human disorders associated with COX deficiency. PMID:18522805

  10. Weighted scores method for regression models with dependent data.

    PubMed

    Nikoloulopoulos, Aristidis K; Joe, Harry; Chaganty, N Rao

    2011-10-01

    There are copula-based statistical models in the literature for regression with dependent data such as clustered and longitudinal overdispersed counts, for which parameter estimation and inference are straightforward. For situations where the main interest is in the regression and other univariate parameters and not the dependence, we propose a "weighted scores method", which is based on weighting score functions of the univariate margins. The weight matrices are obtained initially fitting a discretized multivariate normal distribution, which admits a wide range of dependence. The general methodology is applied to negative binomial regression models. Asymptotic and small-sample efficiency calculations show that our method is robust and nearly as efficient as maximum likelihood for fully specified copula models. An illustrative example is given to show the use of our weighted scores method to analyze utilization of health care based on family characteristics. PMID:21436109

  11. Effects of the estrous cycle, pregnancy and interferon tau on expression of cyclooxygenase two (COX-2) in ovine endometrium.

    PubMed

    Kim, Seokwoon; Choi, Youngsok; Spencer, Thomas E; Bazer, Fuller W

    2003-08-20

    In sheep, the uterus produces luteolytic pulses of prostaglandin F2alpha (PGF) on Days 15 to 16 of estrous cycle to regress the corpus luteum (CL). These PGF pulses are produced by the endometrial lumenal epithelium (LE) and superficial ductal glandular epithelium (sGE) in response to binding of pituitary and/or luteal oxytocin to oxytocin receptors (OTR) and liberation of arachidonic acid, the precursor of PGF. Cyclooxygenase-one (COX-1) and COX-2 are rate-limiting enzymes in PGF synthesis, and COX-2 is the major form expressed in ovine endometrium. During pregnancy recognition, interferon tau (IFNtau), produced by the conceptus trophectoderm, acts in a paracrine manner to suppress development of the endometrial epithelial luteolytic mechanism by inhibiting transcription of estrogen receptor alpha (ERalpha) (directly) and OTR (indirectly) genes. Conflicting studies indicate that IFNtau increases, decreases or has no effect on COX-2 expression in bovine and ovine endometrial cells. In Study One, COX-2 mRNA and protein were detected solely in endometrial LE and sGE of both cyclic and pregnant ewes. During the estrous cycle, COX-2 expression increased from Days 10 to 12 and then decreased to Day 16. During early pregnancy, COX-2 expression increased from Days 10 to 12 and remained higher than in cyclic ewes. In Study Two, intrauterine infusion of recombinant ovine IFNtau in cyclic ewes from Days 11 to 16 post-estrus did not affect COX-2 expression in the endometrial epithelium. These results clearly indicate that IFNtau has no effect on expression of the COX-2 gene in the ovine endometrium. Therefore, antiluteolytic effects of IFNtau are to inhibit ERalpha and OTR gene transcription, thereby preventing endometrial production of luteolytic pulses of PGF. Indeed, expression of COX-2 in the endometrial epithelia as well as conceptus is likely to have a beneficial regulatory role in implantation and development of the conceptus. PMID:12956885

  12. Epileptic Seizure Prediction based on Ratio and Differential Linear Univariate Features

    PubMed Central

    Rasekhi, Jalil; Mollaei, Mohammad Reza Karami; Bandarabadi, Mojtaba; Teixeira, César A.; Dourado, António

    2015-01-01

    Bivariate features, obtained from multichannel electroencephalogram recordings, quantify the relation between different brain regions. Studies based on bivariate features have shown optimistic results for tackling epileptic seizure prediction problem in patients suffering from refractory epilepsy. A new bivariate approach using univariate features is proposed here. Differences and ratios of 22 linear univariate features were calculated using pairwise combination of 6 electroencephalograms channels, to create 330 differential, and 330 relative features. The feature subsets were classified using support vector machines separately, as one of the two classes of preictal and nonpreictal. Furthermore, minimum Redundancy Maximum Relevance feature reduction method is employed to improve the predictions and reduce the number of false alarms. The studies were carried out on features obtained from 10 patients. For reduced subset of 30 features and using differential approach, the seizures were on average predicted in 60.9% of the cases (28 out of 46 in 737.9 h of test data), with a low false prediction rate of 0.11 h−1. Results of bivariate approaches were compared with those achieved from original linear univariate features, extracted from 6 channels. The advantage of proposed bivariate features is the smaller number of false predictions in comparison to the original 22 univariate features. In addition, reduction in feature dimension could provide a less complex and the more cost-effective algorithm. Results indicate that applying machine learning methods on a multidimensional feature space resulting from relative/differential pairwise combination of 22 univariate features could predict seizure onsets with high performance. PMID:25709936

  13. Anandamide and decidual remodelling: COX-2 oxidative metabolism as a key regulator.

    PubMed

    Almada, M; Piscitelli, F; Fonseca, B M; Di Marzo, V; Correia-da-Silva, G; Teixeira, N

    2015-11-01

    Recently, endocannabinoids have emerged as signalling mediators in reproduction. It is widely accepted that anandamide (AEA) levels must be tightly regulated, and that a disturbance in AEA levels may impact decidual stability and regression. We have previously characterized the endocannabinoid machinery in rat decidual tissue and reported the pro-apoptotic action of AEA on rat decidual cells. Cyclooxygenase-2 (COX-2) is an inducible enzyme that plays a crucial role in early pregnancy, and is also a key modulator in the crosstalk between endocannabinoids and prostaglandins. On the other hand, AEA-oxidative metabolism by COX-2 is not merely a mean to inactivate its action, but it yields the formation of a new class of mediators, named prostaglandin-ethanolamides, or prostamides. In this study we found that AEA-induced apoptosis in decidual cells involves COX-2 metabolic pathway. AEA induced COX-2 expression through p38 MAPK, resulting in the formation of prostamide E2 (PME2). Our findings also suggest that AEA-induced effect is associated with NF-kB activation. Finally, we describe the involvement of PME2 in the induction of the intrinsic apoptotic pathway in rat decidual cells. Altogether, our findings highlight the role of COX-2 as a gatekeeper in the uterine environment and clarify the impact of the deregulation of AEA levels on the decidual remodelling process. PMID:26335727

  14. Is COX-2 inhibition a panacea for cancer prevention?

    PubMed

    Vainio, H

    2001-12-01

    The epidemiologic evidence and rodent studies suggest strongly that nonselective inhibitors of cyclooxygenase (COX) enzymes such as aspirin, inhibiting both COX-1 and COX-2 isoforms, reduce the incidence of and mortality from intestinal tumors. Genetically manipulated animals show that both Cox-1 and Cox-2 disruptions decrease the tumor yield, both in genetically predisposed and in carcinogen-treated mice. The mechanisms by which COX-1 and COX-2 deficiency decrease tumorigenesis are still unknown. Cox-2 overexpression increased the tumor yield in mammary glands of the multiparous, but not virginal female transgenic mice using the murine mammary tumor virus promoter. The Cox-2 protein was strongly induced during pregnancy and lactation. These data suggest that Cox-2 overexpression may be an important target for cancer chemoprevention. This finding was supported by the observed cancer-preventive effects of the COX-2-specific inhibitors in humans and in rodents. However, based on the available data, we cannot totally attribute the cancer preventive effects of nonsteroidal antiinflammatory drugs (NSAIDs) to COX-2 alone-even COX-1 may have an important role in cancer prevention as suggested by the Cox-1-deficient Min mice. It is likely that COX-1 plays a more important role in NSAID-induced toxicity in humans, such as in gastric ulcer formation-but inhibition of COX-2 may not be without toxic manifestations either, as suggested by the poor survival of the Cox-2-nulled mice. Combinations of COX-2 inhibitors with other agents that target other pathways in carcinogenesis may be a more efficacious and a less toxic strategy in cancer chemoprevention. PMID:11745453

  15. An approach to the estimation of growth standards: the univariate case.

    PubMed

    Fryer, J G; Karlberg, J; Hayes, M

    1989-01-01

    This paper shows how reference values can be determined when the underlying characteristic (say, weight) follows a distribution that is not too distant from the Gaussian. Application of the normalizing Box-Cox power transformation is the basis of our approach. This transformation is monotonic and hence invertible, so offering the choice of two scales of measurement on which to work--the original and the Gaussian. Modified versions of the procedure are provided allowing use of the basic transformation in the presence of certain deficiencies in the data, principally measurement error and misclassification. It is shown that application of Box-Cox to a cohort at several points in time can be quite revealing. When the data are already symmetrical the Box-Cox transformation has no effect: in this case the John-Draper modulus transformation and modifications of it are shown to be helpful. All of this is illustrated by using data from the Swedish Longitudinal Growth Study. PMID:2801103

  16. 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

  17. The predictive value of histological tumor regression grading (TRG) for therapeutic evaluation in locally advanced esophageal carcinoma treated with neoadjuvant chemotherapy

    PubMed Central

    Guo, Kang; Cai, Ling; Zhang, Yu; Zhu, Jian-Fei; Rong, Tie-Hua; Lin, Peng; Hao, Chong-Li; Wang, Wu-Ping; Li, Zhe; Zhang, Lan-Jun

    2012-01-01

    Response criteria remain controversial in therapeutic evaluation for locally advanced esophageal carcinoma treated with neoadjuvant chemotherapy. We aimed to identify the predictive value of tumor regression grading (TRG) in tumor response and prognosis. Fifty-two patients who underwent neoadjuvant chemotherapy followed by esophagectomy and radical 2-field lymphadenectomy between June 2007 and June 2011 were included in this study. All tissue specimens were reassessed according to the TRG scale. Potential prognostic factors, including clinicopathologic factors, were evaluated. Survival curves were generated by using the Kaplan-Meier method and compared with the log-rank test. Prognostic factors were determined with multivariate analysis by using the Cox regression model. Our results showed that of 52 cases, 43 (83%) were squamous cell carcinoma and 9 (17%) were adenocarcinoma. TRG was correlated with pathologic T (P = 0.006) and N (P < 0.001) categories. Median overall survival for the entire cohort was 33 months. The 1- and 2-year overall survival rates were 71% and 44%, respectively. Univariate survival analysis results showed that favorable prognostic factors were histological subtype (P = 0.003), pathologic T category (P = 0.026), pathologic N category (P < 0.001), and TRG G0 (P = 0.041). Multivariate analyses identified pathologic N category (P < 0.001) as a significant independent prognostic parameter. Our results indicate that histomorphologic TRG can be considered as an alternative option to predict the therapeutic efficacy and prognostic factor for patients with locally advanced esophageal carcinoma treated by neoadjuvant chemotherapy. PMID:22572013

  18. Statistical methods for astronomical data with upper limits. I - Univariate distributions

    NASA Technical Reports Server (NTRS)

    Feigelson, E. D.; Nelson, P. I.

    1985-01-01

    The statistical treatment of univariate censored data is discussed. A heuristic derivation of the Kaplan-Meier maximum-likelihood estimator from first principles is presented which results in an expression amenable to analytic error analysis. Methods for comparing two or more censored samples are given along with simple computational examples, stressing the fact that most astronomical problems involve upper limits while the standard mathematical methods require lower limits. The application of univariate survival analysis to six data sets in the recent astrophysical literature is described, and various aspects of the use of survival analysis in astronomy, such as the limitations of various two-sample tests and the role of parametric modelling, are discussed.

  19. 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

  20. Golgi-Cox Staining Step by Step.

    PubMed

    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

  1. Gene-Based Association Analysis for Censored Traits Via Fixed Effect Functional Regressions.

    PubMed

    Fan, Ruzong; Wang, Yifan; Yan, Qi; Ding, Ying; Weeks, Daniel E; Lu, Zhaohui; Ren, Haobo; Cook, Richard J; Xiong, Momiao; Swaroop, Anand; Chew, Emily Y; Chen, Wei

    2016-02-01

    Genetic studies of survival outcomes have been proposed and conducted recently, but statistical methods for identifying genetic variants that affect disease progression are rarely developed. Motivated by our ongoing real studies, here we develop Cox proportional hazard models using functional regression (FR) to perform gene-based association analysis of survival traits while adjusting for covariates. The proposed Cox models are fixed effect models where the genetic effects of multiple genetic variants are assumed to be fixed. We introduce likelihood ratio test (LRT) statistics to test for associations between the survival traits and multiple genetic variants in a genetic region. Extensive simulation studies demonstrate that the proposed Cox RF LRT statistics have well-controlled type I error rates. To evaluate power, we compare the Cox FR LRT with the previously developed burden test (BT) in a Cox model and sequence kernel association test (SKAT), which is based on mixed effect Cox models. The Cox FR LRT statistics have higher power than or similar power as Cox SKAT LRT except when 50%/50% causal variants had negative/positive effects and all causal variants are rare. In addition, the Cox FR LRT statistics have higher power than Cox BT LRT. The models and related test statistics can be useful in the whole genome and whole exome association studies. An age-related macular degeneration dataset was analyzed as an example. PMID:26782979

  2. On one-step worst-case optimal trisection in univariate bi-objective Lipschitz optimization

    NASA Astrophysics Data System (ADS)

    Žilinskas, Antanas; Gimbutienė, Gražina

    2016-06-01

    The bi-objective Lipschitz optimization with univariate objectives is considered. The concept of the tolerance of the lower Lipschitz bound over an interval is generalized to arbitrary subintervals of the search region. The one-step worst-case optimality of trisecting an interval with respect to the resulting tolerance is established. The theoretical investigation supports the previous usage of trisection in other algorithms. The trisection-based algorithm is introduced. Some numerical examples illustrating the performance of the algorithm are provided.

  3. Univariate time series modeling and an application to future claims amount in SOCSO's invalidity pension scheme

    NASA Astrophysics Data System (ADS)

    Chek, Mohd Zaki Awang; Ahmad, Abu Bakar; Ridzwan, Ahmad Nur Azam Ahmad; Jelas, Imran Md.; Jamal, Nur Faezah; Ismail, Isma Liana; Zulkifli, Faiz; Noor, Syamsul Ikram Mohd

    2012-09-01

    The main objective of this study is to forecast the future claims amount of Invalidity Pension Scheme (IPS). All data were derived from SOCSO annual reports from year 1972 - 2010. These claims consist of all claims amount from 7 benefits offered by SOCSO such as Invalidity Pension, Invalidity Grant, Survivors Pension, Constant Attendance Allowance, Rehabilitation, Funeral and Education. Prediction of future claims of Invalidity Pension Scheme will be made using Univariate Forecasting Models to predict the future claims among workforce in Malaysia.

  4. Treatment effect heterogeneity for univariate subgroups in clinical trials: Shrinkage, standardization, or else.

    PubMed

    Varadhan, Ravi; Wang, Sue-Jane

    2016-01-01

    Treatment effect heterogeneity is a well-recognized phenomenon in randomized controlled clinical trials. In this paper, we discuss subgroup analyses with prespecified subgroups of clinical or biological importance. We explore various alternatives to the naive (the traditional univariate) subgroup analyses to address the issues of multiplicity and confounding. Specifically, we consider a model-based Bayesian shrinkage (Bayes-DS) and a nonparametric, empirical Bayes shrinkage approach (Emp-Bayes) to temper the optimism of traditional univariate subgroup analyses; a standardization approach (standardization) that accounts for correlation between baseline covariates; and a model-based maximum likelihood estimation (MLE) approach. The Bayes-DS and Emp-Bayes methods model the variation in subgroup-specific treatment effect rather than testing the null hypothesis of no difference between subgroups. The standardization approach addresses the issue of confounding in subgroup analyses. The MLE approach is considered only for comparison in simulation studies as the "truth" since the data were generated from the same model. Using the characteristics of a hypothetical large outcome trial, we perform simulation studies and articulate the utilities and potential limitations of these estimators. Simulation results indicate that Bayes-DS and Emp-Bayes can protect against optimism present in the nave approach. Due to its simplicity, the nave approach should be the reference for reporting univariate subgroup-specific treatment effect estimates from exploratory subgroup analyses. Standardization, although it tends to have a larger variance, is suggested when it is important to address the confounding of univariate subgroup effects due to correlation between baseline covariates. The Bayes-DS approach is available as an R package (DSBayes). PMID:26485117

  5. Mss51p promotes mitochondrial Cox1p synthesis and interacts with newly synthesized Cox1p.

    PubMed

    Perez-Martinez, Xochitl; Broadley, Sarah A; Fox, Thomas D

    2003-11-01

    The post-transcriptional role of Mss51p in mitochondrial gene expression is of great interest since MSS51 mutations suppress the respiratory defect caused by shy1 mutations. SHY1 is a Saccharomyces cerevisiae homolog of human SURF1, which when mutated causes a cytochrome oxidase assembly defect. We found that MSS51 is required for expression of the mitochondrial reporter gene ARG8(m) when it is inserted at the COX1 locus, but not when it is at COX2 or COX3. Unlike the COX1 mRNA-specific translational activator PET309, MSS51 has at least two targets in COX1 mRNA. MSS51 acts in the untranslated regions of the COX1 mRNA, since it was required to synthesize Arg8p when ARG8(m) completely replaced the COX1 codons. MSS51 also acts on a target specified by the COX1 coding region, since it was required to translate either COX1 or COX1:: ARG8(m) coding sequences from an ectopic COX2 locus. Mss51p was found to interact physically with newly synthesized Cox1p, suggesting that it could coordinate Cox1p synthesis with insertion into the inner membrane or cytochrome oxidase assembly. PMID:14592991

  6. 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. PMID:25728598

  7. Altered expression of COX-1, COX-2, and mPGES in rats with nephrogenic and central diabetes insipidus.

    PubMed

    Kotnik, Primoz; Nielsen, Jakob; Kwon, Tae-Hwan; Krzisnik, Ciril; Frøkiaer, Jørgen; Nielsen, Søren

    2005-05-01

    Prostaglandins have an important role in renal salt and water reabsorption. PGE2 is the main kidney prostaglandin and is thought to be mainly produced in the kidney inner medulla (IM). There are indications that PGE2 synthesis in nephrogenic (NDI) and central (CDI) diabetes insipidus is altered. We hypothesize that the expression of the major PGE2 synthesis enzymes cyclooxygenases 1 and 2 (COX-1, COX-2) and membrane-associated PGE2 synthase (mPGES) is altered in the kidneys of rats with NDI and CDI. Wistar rats treated with lithium for 4 wk were used as the NDI model. One-half of the NDI model rats were additionally dehydrated for 48 h. Brattleboro (BB) rats that lack endogenous antidiuretic hormone were used as the CDI model. Expression and localization of COX-1, COX-2, and mPGES in IM, inner stripe of outer medulla (ISOM), and cortex were determined by immunoblotting and immunohistochemistry. In lithium-induced NDI, expression of COX-1, COX-2, and mPGES was markedly decreased in IM. In ISOM and cortex, COX-1 expression was marginally reduced and mPGES expression was unaltered. COX-2 expression was undetected in ISOM and marginally increased in cortex. Consistent with this, the density of COX-2-expressing cells in macula densa was significantly increased, indicating differential regulation of COX-2 in IM and cortex. Dehydration of NDI rats resulted in a marked increase in COX-2 immunolabeling in IM interstitial cells, and there was no significant change in COX-1 and mPGES expression in any kidney zone. Treatment of DDAVP in BB rats for 6 days resulted in a markedly increased expression of COX-1, COX-2, and mPGES in IM. In the cortex, there were no changes in the expression of COX-1 and mPGES, whereas COX-2 expression was decreased. These results identify markedly reduced expression of COX-1, COX-2, and mPGES in IM in lithium-induced NDI. Furthermore, there were major changes in the expression of COX-1, COX-2, and mPGES in rats with CDI. PMID:15644490

  8. Apoptotic effects of two COX-2 inhibitors on breast adenocarcinoma cells through COX-2 independent pathway.

    PubMed

    Norouzi, Mahnaz; Norouzi, Shaghayegh; Amini, Mohsen; Amanzadeh, Amir; Irian, Saeed; Salimi, Mona

    2015-01-01

    Recently, much effort has been directed toward the search for compounds that influence apoptosis and to understand their mechanisms of action. Cyclooxygenase (COX)-2 inhibitors may induce apoptosis through the COX-2-independent mechanism via a mitochondrial pathway. In view of the reported antiproliferative activities of two COX-2 inhibitor derivatives (1, 2) in breast cancer cells (MCF-7), the present study was undertaken to evaluate the potential of these compounds to induce apoptosis and unravel the associated mechanisms. The apoptotic activities of the two compounds were assessed using flow cytometry, fluorescence microscope, and Western blot analysis. Compounds 1 and 2-treated MCF-7 cells revealed the apoptotic cell death, as confirmed by the changes in nuclear morphology and the increased annexin-V/PI staining. Elevation of Bax to Bcl-2 ratio and activation of caspase-3 were found to be associated with the initiation of apoptosis induced by compound 1. Further investigation showed that compounds 1 and 2 inhibited NF-κB, FHC, and ERK activation, while no dramatic change was revealed in c-Myc and EGR-1 levels. Our data suggest that induction of apoptosis by compounds 1 and 2 is not associated with COX-2 expression and occurs through the NF-κB pathway, which sequentially inhibits P-ERK and FHC expression. PMID:25142612

  9. 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.

  10. Measurements on Melting Pressure, Metastable Solid Phases, and Molar Volume of Univariant Saturated Helium Mixture

    NASA Astrophysics Data System (ADS)

    Rysti, J.; Manninen, M. S.; Tuoriniemi, J.

    2014-06-01

    A concentration-saturated helium mixture at the melting pressure consists of two liquid phases and one or two solid phases. The equilibrium system is univariant, whose properties depend uniquely on temperature. Four coexisting phases can exist on singular points, which are called quadruple points. As a univariant system, the melting pressure could be used as a thermometric standard. It would provide some advantages compared to the current reference, namely pure He, especially at the lowest temperatures below 1 mK. We have extended the melting pressure measurements of the concentration-saturated helium mixture from 10 to 460 mK. The density of the dilute liquid phase was also recorded. The effect of the equilibrium crystal structure changing from hcp to bcc was clearly seen at mK at the melting pressure MPa. We observed the existence of metastable solid phases around this point. No evidence was found for the presence of another, disputed, quadruple point at around 400 mK. The experimental results agree well with our previous calculations at low temperatures, but deviate above 200 mK.

  11. Nonlinear reconstruction of single-molecule free-energy surfaces from univariate time series

    NASA Astrophysics Data System (ADS)

    Wang, Jiang; Ferguson, Andrew L.

    2016-03-01

    The stable conformations and dynamical fluctuations of polymers and macromolecules are governed by the underlying single-molecule free energy surface. By integrating ideas from dynamical systems theory with nonlinear manifold learning, we have recovered single-molecule free energy surfaces from univariate time series in a single coarse-grained system observable. Using Takens' Delay Embedding Theorem, we expand the univariate time series into a high dimensional space in which the dynamics are equivalent to those of the molecular motions in real space. We then apply the diffusion map nonlinear manifold learning algorithm to extract a low-dimensional representation of the free energy surface that is diffeomorphic to that computed from a complete knowledge of all system degrees of freedom. We validate our approach in molecular dynamics simulations of a C24H50 n -alkane chain to demonstrate that the two-dimensional free energy surface extracted from the atomistic simulation trajectory is - subject to spatial and temporal symmetries - geometrically and topologically equivalent to that recovered from a knowledge of only the head-to-tail distance of the chain. Our approach lays the foundations to extract empirical single-molecule free energy surfaces directly from experimental measurements.

  12. Automatic procedures for river reach delineation: Univariate and multivariate approaches in a fluvial context

    NASA Astrophysics Data System (ADS)

    Martínez-Fernández, V.; Solana-Gutiérrez, J.; González del Tánago, M.; García de Jalón, D.

    2016-01-01

    Segmenting the continuum of rivers into homogeneous reaches is an important issue in river research and management. Automatic procedures provide significance, objectivity, and repeatability. Although univariate techniques are frequently used to identify river reaches, multivariate approaches offer a more integrative context. Three nonparametric methods (multi-response permutation procedures (MRPP) with an advance in the significance level estimation, the Pettitt and Mann-Kendall tests) are applied for segmenting the river based on three geomorphic variables (valley width, active channel width, and channel slope) systematically measured in a GIS environment. The cited techniques have been applied to the Curueño River (NW Spain) to illustrate the methods, we analyse reach distribution along the river longitudinal profile. The methods successfully characterize the evident transitions along fluvial systems and also others less noticeable. The three methods provide more reaches according to valley width and less reaches according to channel slope (18.0 and 3.7 reaches on average, respectively). In contrast to the Mann-Kendall test, MRPP and Pettitt tests provide more stable segmentations when significance level varies. However, the Pettitt test provides irregular segmentations for regular patterns. The MRPP both univariate and multivariate applications enables a wider scope for the segmentation issue, which is useful in diverse aspects of fluvial domain.

  13. A Formally-Verified Decision Procedure for Univariate Polynomial Computation Based on Sturm's Theorem

    NASA Technical Reports Server (NTRS)

    Narkawicz, Anthony J.; Munoz, Cesar A.

    2014-01-01

    Sturm's Theorem is a well-known result in real algebraic geometry that provides a function that computes the number of roots of a univariate polynomial in a semiopen interval. This paper presents a formalization of this theorem in the PVS theorem prover, as well as a decision procedure that checks whether a polynomial is always positive, nonnegative, nonzero, negative, or nonpositive on any input interval. The soundness and completeness of the decision procedure is proven in PVS. The procedure and its correctness properties enable the implementation of a PVS strategy for automatically proving existential and universal univariate polynomial inequalities. Since the decision procedure is formally verified in PVS, the soundness of the strategy depends solely on the internal logic of PVS rather than on an external oracle. The procedure itself uses a combination of Sturm's Theorem, an interval bisection procedure, and the fact that a polynomial with exactly one root in a bounded interval is always nonnegative on that interval if and only if it is nonnegative at both endpoints.

  14. Unitary Response Regression Models

    ERIC Educational Resources Information Center

    Lipovetsky, S.

    2007-01-01

    The dependent variable in a regular linear regression is a numerical variable, and in a logistic regression it is a binary or categorical variable. In these models the dependent variable has varying values. However, there are problems yielding an identity output of a constant value which can also be modelled in a linear or logistic regression with…

  15. NCCS Regression Test Harness

    Energy Science and Technology Software Center (ESTSC)

    2015-09-09

    The NCCS Regression Test Harness is a software package that provides a framework to perform regression and acceptance testing on NCCS High Performance Computers. The package is written in Python and has only the dependency of a Subversion repository to store the regression tests.

  16. Binding Energy Calculation of Patchouli Alcohol Isomer Cyclooxygenase Complexes Suggested as COX-1/COX-2 Selective Inhibitor

    PubMed Central

    Mahdi, Chanif; Nurdiana, Nurdiana; Kikuchi, Takheshi; Fatchiyah, Fatchiyah

    2014-01-01

    To understand the structural features that dictate the selectivity of the two isoforms of the prostaglandin H2 synthase (PGHS/COX), the three-dimensional (3D) structure of COX-1/COX-2 was assessed by means of binding energy calculation of virtual molecular dynamic with using ligand alpha-Patchouli alcohol isomers. Molecular interaction studies with COX-1 and COX-2 were done using the molecular docking tools by Hex 8.0. Interactions were further visualized by using Discovery Studio Client 3.5 software tool. The binding energy of molecular interaction was calculated by AMBER12 and Virtual Molecular Dynamic 1.9.1 software. The analysis of the alpha-Patchouli alcohol isomer compounds showed that all alpha-Patchouli alcohol isomers were suggested as inhibitor of COX-1 and COX-2. Collectively, the scoring binding energy calculation (with PBSA Model Solvent) of alpha-Patchouli alcohol isomer compounds (CID442384, CID6432585, CID3080622, CID10955174, and CID56928117) was suggested as candidate for a selective COX-1 inhibitor and CID521903 as nonselective COX-1/COX-2. PMID:25484897

  17. 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. PMID:19880317

  18. Dynamics of intracranial electroencephalographic recordings from epilepsy patients using univariate and bivariate recurrence networks

    NASA Astrophysics Data System (ADS)

    Subramaniyam, Narayan Puthanmadam; Hyttinen, Jari

    2015-02-01

    Recently Andrezejak et al. combined the randomness and nonlinear independence test with iterative amplitude adjusted Fourier transform (iAAFT) surrogates to distinguish between the dynamics of seizure-free intracranial electroencephalographic (EEG) signals recorded from epileptogenic (focal) and nonepileptogenic (nonfocal) brain areas of epileptic patients. However, stationarity is a part of the null hypothesis for iAAFT surrogates and thus nonstationarity can violate the null hypothesis. In this work we first propose the application of the randomness and nonlinear independence test based on recurrence network measures to distinguish between the dynamics of focal and nonfocal EEG signals. Furthermore, we combine these tests with both iAAFT and truncated Fourier transform (TFT) surrogate methods, which also preserves the nonstationarity of the original data in the surrogates along with its linear structure. Our results indicate that focal EEG signals exhibit an increased degree of structural complexity and interdependency compared to nonfocal EEG signals. In general, we find higher rejections for randomness and nonlinear independence tests for focal EEG signals compared to nonfocal EEG signals. In particular, the univariate recurrence network measures, the average clustering coefficient C and assortativity R , and the bivariate recurrence network measure, the average cross-clustering coefficient Ccross, can successfully distinguish between the focal and nonfocal EEG signals, even when the analysis is restricted to nonstationary signals, irrespective of the type of surrogates used. On the other hand, we find that the univariate recurrence network measures, the average path length L , and the average betweenness centrality BC fail to distinguish between the focal and nonfocal EEG signals when iAAFT surrogates are used. However, these two measures can distinguish between focal and nonfocal EEG signals when TFT surrogates are used for nonstationary signals. We also report an improvement in the performance of nonlinear prediction error N and nonlinear interdependence measure L used by Andrezejak et al., when TFT surrogates are used for nonstationary EEG signals. We also find that the outcome of the nonlinear independence test based on the average cross-clustering coefficient Ccross is independent of the outcome of the randomness test based on the average clustering coefficient C . Thus, the univariate and bivariate recurrence network measures provide independent information regarding the dynamics of the focal and nonfocal EEG signals. In conclusion, recurrence network analysis combined with nonstationary surrogates can be applied to derive reliable biomarkers to distinguish between epileptogenic and nonepileptogenic brain areas using EEG signals.

  19. Trend and forecasting rate of cancer deaths at a public university hospital using univariate modeling

    NASA Astrophysics Data System (ADS)

    Ismail, A.; Hassan, Noor I.

    2013-09-01

    Cancer is one of the principal causes of death in Malaysia. This study was performed to determine the pattern of rate of cancer deaths at a public hospital in Malaysia over an 11 year period from year 2001 to 2011, to determine the best fitted model of forecasting the rate of cancer deaths using Univariate Modeling and to forecast the rates for the next two years (2012 to 2013). The medical records of the death of patients with cancer admitted at this Hospital over 11 year's period were reviewed, with a total of 663 cases. The cancers were classified according to 10th Revision International Classification of Diseases (ICD-10). Data collected include socio-demographic background of patients such as registration number, age, gender, ethnicity, ward and diagnosis. Data entry and analysis was accomplished using SPSS 19.0 and Minitab 16.0. The five Univariate Models used were Naïve with Trend Model, Average Percent Change Model (ACPM), Single Exponential Smoothing, Double Exponential Smoothing and Holt's Method. The overall 11 years rate of cancer deaths showed that at this hospital, Malay patients have the highest percentage (88.10%) compared to other ethnic groups with males (51.30%) higher than females. Lung and breast cancer have the most number of cancer deaths among gender. About 29.60% of the patients who died due to cancer were aged 61 years old and above. The best Univariate Model used for forecasting the rate of cancer deaths is Single Exponential Smoothing Technique with alpha of 0.10. The forecast for the rate of cancer deaths shows a horizontally or flat value. The forecasted mortality trend remains at 6.84% from January 2012 to December 2013. All the government and private sectors and non-governmental organizations need to highlight issues on cancer especially lung and breast cancers to the public through campaigns using mass media, media electronics, posters and pamphlets in the attempt to decrease the rate of cancer deaths in Malaysia.

  20. Cox-2 inhibitors and the risk of cardiovascular thrombotic events.

    PubMed

    Khan, M; Fraser, A

    2012-04-01

    In 1971, Vane showed that the analgesic action of traditional NSAIDs relies on inhibition of the cyclo-oxygenase (COX) enzyme, which in turn results in reduced synthesis of proalgesic prostaglandins. Two decades later COX was shown to exist as two distinct isoforms. The constitutive isoform COX-1, supports the beneficial homeostatic functions whereas the inducible isoform, COX-2 becomes up regulated by inflammatory mediators and its products cause many of the symptoms of inflammatory diseases such as rheumatoid and osteoarthritis. Despite the benefits of NSAIDs for acute and chronic pain one of the most clinically significant and well characterized adverse effect is on GI mucosa. The search for NSAIDs with less gastrointestinal toxicity led to the introduction of the selective cyclo-oxygenase-2 (COX-2) inhibitors. The COX-2 selective (COX-1 sparing) inhibitors are associated with reduced GI mucosal damage as demonstrated in several trials. In light of the overwhelming and sometimes contradictory information for patients and physicians regarding the safety of COX-2 agents this article will summarize the available evidence regarding cardiovascular (CV) safety data and contemporary recommendations for prescribing of COX-2-selective NSAIDs. PMID:22708229

  1. COX-2 signaling and cancer: new players in old arena.

    PubMed

    Misra, Shashank; Sharma, Kulbhushan

    2014-03-01

    Cancer is a leading cause of death worldwide. The expression of COX-2 and prostaglandins has not only been associated with various types of cancer but is also directly proportional to their aggressiveness including metastasis. Thus, inhibition of COX-2 activity has been one of the preferred targets for cancer reduction. Broad spectrum inhibition of all forms of COX (using NSAIDs) is associated with various side effects ranging from gastric ulceration to renal problems. Even specific COX-2 inhibitors (COXIBs) are associated with side effects like myocardial infarction. Alternative strategies including siRNA technology are also not very victorious due to their off-target associated problems. Thus, there is an urgent need for the development of strategies where COX-2 activity may be reduced without inducing any side effects. One of the approaches for designing novel inhibitors may be to target various molecules downstream of COX-2. In this review, we have tried to cover the basic biology of COX-2 and its association with different types of cancer. Various generations of COX-2 inhibitors have been covered with their merits and demerits. Possible exploitation of novel targets like EP receptors, mPGES and various other downstream molecules which can be utilized for a better COX-2 signaling inhibition and thus efficient cancer reduction with minimal side effects has been discussed. PMID:24467618

  2. Univariate and multivariate characterization of heavy fuel oil weathering and biodegradation in soil.

    PubMed

    Lamberts, Rasmus F; Johnsen, Anders R; Andersen, Ole; Christensen, Jan H

    2008-11-01

    Polycyclic aromatic compounds (PACs) of petrogenic origin are widespread contaminants of the environment. We investigated the weathering and biodegradation of fuel oil PACs in microcosms that contained natural soil or natural soil primed by adding bioremediated soil to a 2% concentration. In the primed soil, lag-phases were shorter, and biodegradation was more pronounced. To describe PAC degradation, changes in the relative distribution of PACs and changes in isomer ratios, that are specific for biodegradation, were determined by univariate and multivariate techniques. A multivariate approach based on normalized areas or isomer ratios, in combination with principal component analysis, provided the most detailed description of weathering and biodegradation. In particular, the sequence of degradation of PACs was more transparent when using the multivariate approach. We also identified new diagnostic ratios of dimethylphenanthrenes for use in the study of moderately and severely biodegraded samples. PMID:18395952

  3. Spatiotemporal Linear Mixed Effects Modeling for the Mass-univariate Analysis of Longitudinal Neuroimage Data

    PubMed Central

    Bernal-Rusiel, Jorge L.; Reuter, Martin; Greve, Douglas N.; Fischl, Bruce; Sabuncu, Mert R.

    2013-01-01

    We present an extension of the Linear Mixed Effects (LME) modeling approach to be applied to the mass-univariate analysis of longitudinal neuroimaging (LNI) data. The proposed method, called spatiotemporal LME or ST-LME, builds on the flexible LME framework and exploits the spatial structure in image data. We instantiated ST-LME for the analysis of cortical surface measurements (e.g. thickness) computed by FreeSurfer, a widely-used brain Magnetic Resonance Image (MRI) analysis software package. We validate the proposed ST-LME method and provide a quantitative and objective empirical comparison with two popular alternative methods, using two brain MRI datasets obtained from the Alzheimer’s disease neuroimaging initiative (ADNI) and Open Access Series of Imaging Studies (OASIS). Our experiments revealed that ST-LME offers a dramatic gain in statistical power and repeatability of findings, while providing good control of the false positive rate. PMID:23702413

  4. Towards a More General Type of Univariate Constrained Interpolation with Fractal Splines

    NASA Astrophysics Data System (ADS)

    Chand, A. K. B.; Viswanathan, P.; Reddy, K. M.

    2015-09-01

    Recently, in [Electron. Trans. Numer. Anal. 41 (2014) 420-442] authors introduced a new class of rational cubic fractal interpolation functions with linear denominators via fractal perturbation of traditional nonrecursive rational cubic splines and investigated their basic shape preserving properties. The main goal of the current paper is to embark on univariate constrained fractal interpolation that is more general than what was considered so far. To this end, we propose some strategies for selecting the parameters of the rational fractal spline so that the interpolating curves lie strictly above or below a prescribed linear or a quadratic spline function. Approximation property of the proposed rational cubic fractal spine is broached by using the Peano kernel theorem as an interlude. The paper also provides an illustration of background theory, veined by examples.

  5. Autistic epileptiform regression.

    PubMed

    Canitano, Roberto; Zappella, Michele

    2006-01-01

    Autistic regression is a well known condition that occurs in one third of children with pervasive developmental disorders, who, after normal development in the first year of life, undergo a global regression during the second year that encompasses language, social skills and play. In a portion of these subjects, epileptiform abnormalities are present with or without seizures, resembling, in some respects, other epileptiform regressions of language and behaviour such as Landau-Kleffner syndrome. In these cases, for a more accurate definition of the clinical entity, the term autistic epileptifom regression has been suggested. As in other epileptic syndromes with regression, the relationships between EEG abnormalities, language and behaviour, in autism, are still unclear. We describe two cases of autistic epileptiform regression selected from a larger group of children with autistic spectrum disorders, with the aim of discussing the clinical features of the condition, the therapeutic approach and the outcome. PMID:16796825

  6. Cycloheximide rapidly inhibits cortical COX activity and COX-dependent pial arteriolar dilation in piglets.

    PubMed

    Domoki, F; Perciaccante, J V; Veltkamp, R; Robins, G; Bari, F; Louis, T M; Busija, D W

    1999-09-01

    We have previously shown that cycloheximide (CHX) preserved neuronal function after global cerebral ischemia in piglets, in a manner similar to indomethacin. To elucidate the mechanism of this protection, we tested the hypothesis that CHX would inhibit cyclooxygenase (COX) activity in the piglet cerebral cortex and vasculature. Pial arteriolar responses to hypercapnia, arterial hypotension, and sodium nitroprusside (SNP) were determined before and 20 min after treatment with CHX (0.3-1 mg/kg iv) using a closed cranial window and intravital microscopy. We also determined baseline and arachidonic acid (AA)-stimulated cortical PGF(2alpha) and 6-keto-PGF(1alpha) production before and 20-60 min after CHX (1 mg/kg iv) treatment, using ELISA kits. CHX did not affect baseline diameters (approximately 100 microm) but significantly decreased arteriolar dilation to COX-dependent stimuli, such as hypercapnia and hypotension, but not to COX-independent SNP. In the 1 mg/kg CHX-treated group, increases in vascular diameters were reduced from 22 +/- 2 to 10 +/- 2%, from 49 +/- 5 to 31 +/- 3% (means +/- SE, 5 and 10% CO2, respectively, n = 8), from 12 +/- 3 to 3 +/- 1%, and from 26 +/- 5 to 6 +/- 2% ( approximately 25 and 40% decreases in blood pressure, respectively, n = 6). CHX also inhibited conversion of exogenous AA to both PGF(2alpha) and 6-keto-PGF(1alpha); for example, 20 min after CHX treatment 10 microg/ml AA-stimulated PGF(2alpha) concentrations in the artificial cerebrospinal fluid decreased from 14.28 +/- 3.04 to 5.90 +/- 1.26 ng/ml (n = 9). Thus CHX rapidly decreases COX activity in the piglet cerebral cortex. This result may explain in part the preservation of neuronal function of CHX in cerebral ischemia. PMID:10484435

  7. 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. PMID:23979592

  8. Optimizing the Classification Performance of Logistic Regression and Fisher's Discriminant Analyses.

    ERIC Educational Resources Information Center

    Yarnold, Paul R.; And Others

    1994-01-01

    A methodology is proposed to optimize the training classification performance of any suboptimal model. The method, referred to as univariate optimal discriminant analysis (UniODA), is illustrated through application to a two-group logistic regression analysis with 12 empirical examples. Maximizing percentage accuracy in classification is…

  9. Morse-Smale Regression

    PubMed Central

    Gerber, Samuel; Rübel, Oliver; Bremer, Peer-Timo; Pascucci, Valerio; Whitaker, Ross T.

    2012-01-01

    This paper introduces a novel partition-based regression approach that incorporates topological information. Partition-based regression typically introduce a quality-of-fit-driven decomposition of the domain. The emphasis in this work is on a topologically meaningful segmentation. Thus, the proposed regression approach is based on a segmentation induced by a discrete approximation of the Morse-Smale complex. This yields a segmentation with partitions corresponding to regions of the function with a single minimum and maximum that are often well approximated by a linear model. This approach yields regression models that are amenable to interpretation and have good predictive capacity. Typically, regression estimates are quantified by their geometrical accuracy. For the proposed regression, an important aspect is the quality of the segmentation itself. Thus, this paper introduces a new criterion that measures the topological accuracy of the estimate. The topological accuracy provides a complementary measure to the classical geometrical error measures and is very sensitive to over-fitting. The Morse-Smale regression is compared to state-of-the-art approaches in terms of geometry and topology and yields comparable or improved fits in many cases. Finally, a detailed study on climate-simulation data demonstrates the application of the Morse-Smale regression. Supplementary materials are available online and contain an implementation of the proposed approach in the R package msr, an analysis and simulations on the stability of the Morse-Smale complex approximation and additional tables for the climate-simulation study. PMID:23687424

  10. Improved Regression Calibration

    ERIC Educational Resources Information Center

    Skrondal, Anders; Kuha, Jouni

    2012-01-01

    The likelihood for generalized linear models with covariate measurement error cannot in general be expressed in closed form, which makes maximum likelihood estimation taxing. A popular alternative is regression calibration which is computationally efficient at the cost of inconsistent estimation. We propose an improved regression calibration…

  11. A consistent framework for Horton regression statistics that leads to a modified Hack's law

    USGS Publications Warehouse

    Furey, P.R.; Troutman, B.M.

    2008-01-01

    A statistical framework is introduced that resolves important problems with the interpretation and use of traditional Horton regression statistics. The framework is based on a univariate regression model that leads to an alternative expression for Horton ratio, connects Horton regression statistics to distributional simple scaling, and improves the accuracy in estimating Horton plot parameters. The model is used to examine data for drainage area A and mainstream length L from two groups of basins located in different physiographic settings. Results show that confidence intervals for the Horton plot regression statistics are quite wide. Nonetheless, an analysis of covariance shows that regression intercepts, but not regression slopes, can be used to distinguish between basin groups. The univariate model is generalized to include n > 1 dependent variables. For the case where the dependent variables represent ln A and ln L, the generalized model performs somewhat better at distinguishing between basin groups than two separate univariate models. The generalized model leads to a modification of Hack's law where L depends on both A and Strahler order ??. Data show that ?? plays a statistically significant role in the modified Hack's law expression. ?? 2008 Elsevier B.V.

  12. Resveratrol Directly Targets COX-2 to Inhibit Carcinogenesis

    PubMed Central

    Zykova, Tatyana A.; Zhu, Feng; Zhai, Xiuhong; Ma, Wei-ya; Ermakova, Svetlana P.; Lee, Ki Won; Bode, Ann M.; Dong, Zigang

    2008-01-01

    Targeted molecular cancer therapies can potentially deliver treatment directly to a specific protein or gene to optimize efficacy and reduce adverse side effects often associated with traditional chemotherapy. Key oncoprotein and oncogene targets are rapidly being identified based on their expression, pathogenesis and clinical outcome. One such protein target is cyclooxygenase-2 (COX-2), which is highly expressed in various cancers. Research findings suggest that resveratrol (3,5,4'-trihydroxy-trans-stilbene) demonstrates non-selective COX-2 inhibition. We report herein that resveratrol (RSVL) directly binds with COX-2 and this binding is absolutely required for RSVL's inhibition of the ability of human colon adenocarcinoma HT-29 cells to form colonies in soft agar. Binding of COX-2 with RSVL was compared with two RSVL analogues, 3,3’,4’,5’5’-pentahydroxy-trans-stilbene (RSVL-2) or 3,4’,5-trimethoxy-trans-stilbene (RSVL-3). The results indicated that COX-2 binds with RSVL-2 more strongly than with RSVL, but does not bind with RSVL-3. RSVL or RSVL-2, but not RSVL-3, inhibited COX-2-mediated PGE2 production in vitro and ex vivo. HT-29 human colon adenocarcinoma cells express high levels of COX-2 and either RSVL or RSVL-2, but not RSVL-3, suppressed anchorage independent growth of these cells in soft agar. RSVL or RSVL-2 (not RSVL-3) suppressed growth of COX-2+/+ cells by 60 or 80%, respectively. Notably, cells deficient in COX-2 were unresponsive to RSVL or RSVL-2. These data suggest that the anticancer effects of RSVL or RSLV-2 might be mediated directly through COX-2. PMID:18381589

  13. Analysis of meteorological droughts for the Saskatchewan River Basin using univariate and bivariate approaches

    NASA Astrophysics Data System (ADS)

    Masud, M. B.; Khaliq, M. N.; Wheater, H. S.

    2015-03-01

    This study is focused on the Saskatchewan River Basin (SRB) that spans southern parts of Alberta, Saskatchewan and Manitoba, the three Prairie Provinces of Canada, where most of the country's agricultural activities are concentrated. The SRB is confronted with immense water-related challenges and is now one of the ten GEWEX (Global Energy and Water Exchanges) Regional Hydroclimate Projects in the world. In the past, various multi-year droughts have been observed in this part of Canada that impacted agriculture, energy and socio-economic sectors. Therefore, proper understanding of the spatial and temporal characteristics of historical droughts is important for many water resources planning and management related activities across the basin. In the study, observed gridded data of daily precipitation and temperature and conventional univariate and copula-based bivariate frequency analyses are used to characterize drought events in terms of drought severity and duration on the basis of two drought indices, the Standardized Precipitation Index (SPI) and the Standardized Precipitation Evapotranspiration Index (SPEI). Within the framework of univariate and bivariate analyses, drought risk indicators are developed and mapped across the SRB to delineate the most vulnerable parts of the basin. Based on the results obtained, southern parts of the SRB (i.e., western part of the South Saskatchewan River, Seven Persons Creek and Bigstick Lake watersheds) are associated with a higher drought risk, while moderate risk is noted for the North Saskatchewan River (except its eastern parts), Red Deer River, Oldman River, Bow River, Sounding Creek, Carrot River and Battle River watersheds. Lower drought risk is found for the areas surrounding the Saskatchewan-Manitoba border (particularly, the Saskatchewan River watershed). It is also found that the areas characterized with higher drought severity are also associated with higher drought duration. A comparison of SPI- and SPEI-based analyses suggests only little effect of considering temperature, in the form of evapotranspiration, on identifying drought vulnerable areas. It is expected that the findings of the study will be helpful in the management and efficient utilization of the water resources of this important river basin in Canada.

  14. Applications of multivariate modeling to neuroimaging group analysis: a comprehensive alternative to univariate general linear model.

    PubMed

    Chen, Gang; Adleman, Nancy E; Saad, Ziad S; Leibenluft, Ellen; Cox, Robert W

    2014-10-01

    All neuroimaging packages can handle group analysis with t-tests or general linear modeling (GLM). However, they are quite hamstrung when there are multiple within-subject factors or when quantitative covariates are involved in the presence of a within-subject factor. In addition, sphericity is typically assumed for the variance-covariance structure when there are more than two levels in a within-subject factor. To overcome such limitations in the traditional AN(C)OVA and GLM, we adopt a multivariate modeling (MVM) approach to analyzing neuroimaging data at the group level with the following advantages: a) there is no limit on the number of factors as long as sample sizes are deemed appropriate; b) quantitative covariates can be analyzed together with within-subject factors; c) when a within-subject factor is involved, three testing methodologies are provided: traditional univariate testing (UVT) with sphericity assumption (UVT-UC) and with correction when the assumption is violated (UVT-SC), and within-subject multivariate testing (MVT-WS); d) to correct for sphericity violation at the voxel level, we propose a hybrid testing (HT) approach that achieves equal or higher power via combining traditional sphericity correction methods (Greenhouse-Geisser and Huynh-Feldt) with MVT-WS. To validate the MVM methodology, we performed simulations to assess the controllability for false positives and power achievement. A real FMRI dataset was analyzed to demonstrate the capability of the MVM approach. The methodology has been implemented into an open source program 3dMVM in AFNI, and all the statistical tests can be performed through symbolic coding with variable names instead of the tedious process of dummy coding. Our data indicates that the severity of sphericity violation varies substantially across brain regions. The differences among various modeling methodologies were addressed through direct comparisons between the MVM approach and some of the GLM implementations in the field, and the following two issues were raised: a) the improper formulation of test statistics in some univariate GLM implementations when a within-subject factor is involved in a data structure with two or more factors, and b) the unjustified presumption of uniform sphericity violation and the practice of estimating the variance-covariance structure through pooling across brain regions. PMID:24954281

  15. Boosted Beta Regression

    PubMed Central

    Schmid, Matthias; Wickler, Florian; Maloney, Kelly O.; Mitchell, Richard; Fenske, Nora; Mayr, Andreas

    2013-01-01

    Regression analysis with a bounded outcome is a common problem in applied statistics. Typical examples include regression models for percentage outcomes and the analysis of ratings that are measured on a bounded scale. In this paper, we consider beta regression, which is a generalization of logit models to situations where the response is continuous on the interval (0,1). Consequently, beta regression is a convenient tool for analyzing percentage responses. The classical approach to fit a beta regression model is to use maximum likelihood estimation with subsequent AIC-based variable selection. As an alternative to this established - yet unstable - approach, we propose a new estimation technique called boosted beta regression. With boosted beta regression estimation and variable selection can be carried out simultaneously in a highly efficient way. Additionally, both the mean and the variance of a percentage response can be modeled using flexible nonlinear covariate effects. As a consequence, the new method accounts for common problems such as overdispersion and non-binomial variance structures. PMID:23626706

  16. THE COX-MAZE IV PROCEDURE: PREDICTORS OF LATE RECURRENCE

    PubMed Central

    Damiano, Ralph J.; Schwartz, Forrest H.; Bailey, Marci S.; Maniar, Hersh S.; Munfakh, Nabil A.; Moon, Marc R.; Schuessler, Richard B.

    2010-01-01

    Objectives The Cox-Maze III procedure(CMP) achieved high cure rates and became the surgical gold standard for the treatment of atrial fibrillation(AF). Due to its invasiveness, a more simplified ablation-assisted procedure(CMP-IV) has been performed at our institution since January, 2002. The study examined multiple preoperative and perioperative variables to determine predictors of late recurrence. Methods Data were collected prospectively on 282 patients who underwent the CMP-IV from January 2002 through December 2009. Forty-two percent of patients had paroxysmal and 58% had either persistent or long-standing persistent AF. All patients were available for follow-up. Follow-up included ECGs in all patients. Since 2006, 24 hour holter monitoring was obtained in 94% of patients at 3, 6 and 12 months. Data were analyzed by logistic regression analysis at 12 months with 13 preoperative and perioperative variables used as co-variants. Results Sixty-six percent of patients had a concomitant procedure. Following an ablation-assisted CMP, the freedom from AF was 89%, 93%, and 89% at 3, 6, and 12 months, respectively. The freedom from both AF and antiarrhythmic drugs was 63%, 79%, and 78% at 3, 6, and 12 months. The risk factors for AF recurrence at one year were enlarged left atrial(LA) diameter(p=0.027), failure to isolate the entire posterior left atrium(p=0.022), and early atrial tachyarrhythmias (ATAs)(p=0.010). Conclusions The CMP-IV has a high success rate at one year, even with improved follow-up and stricter definitions of failure. In patients with large LA, there may be a need for more extensive size reduction or expanded lesion sets. PMID:21168019

  17. Univariate and default standard unit biases in estimation of body weight and caloric content.

    PubMed

    Geier, Andrew B; Rozin, Paul

    2009-06-01

    College students estimated the weight of adult women from either photographs or a live presentation by a set of models and estimated the calories in 1 of 2 actual meals. The 2 meals had the same items, but 1 had larger portion sizes than the other. The results suggest: (a) Judgments are biased toward transforming the example in question to the size and/or properties of a "standard" unit. For estimates of body weight, students assigned weights assuming a standard height, even though height information was provided in the photographs or directly present with live models. (b) There is an inclination to focus on 1 aspect or dimension of the stimulus (e.g., for female figures, their width, for meals the identity of the components as opposed to their size) and either devalue or completely ignore another parameter critical for accurate judgment (height, for the case of body weight estimations). That is, students defaulted to a normative unit size and thus treated the stimulus as a representative, categorical, and unvarying example, and focused on only 1 dimension (univariate bias) in making judgments. (PsycINFO Database Record (c) 2009 APA, all rights reserved). PMID:19586254

  18. Visual classification of very fine-grained sediments: Evaluation through univariate and multivariate statistics

    USGS Publications Warehouse

    Hohn, M. Ed; Nuhfer, E.B.; Vinopal, R.J.; Klanderman, D.S.

    1980-01-01

    Classifying very fine-grained rocks through fabric elements provides information about depositional environments, but is subject to the biases of visual taxonomy. To evaluate the statistical significance of an empirical classification of very fine-grained rocks, samples from Devonian shales in four cored wells in West Virginia and Virginia were measured for 15 variables: quartz, illite, pyrite and expandable clays determined by X-ray diffraction; total sulfur, organic content, inorganic carbon, matrix density, bulk density, porosity, silt, as well as density, sonic travel time, resistivity, and ??-ray response measured from well logs. The four lithologic types comprised: (1) sharply banded shale, (2) thinly laminated shale, (3) lenticularly laminated shale, and (4) nonbanded shale. Univariate and multivariate analyses of variance showed that the lithologic classification reflects significant differences for the variables measured, difference that can be detected independently of stratigraphic effects. Little-known statistical methods found useful in this work included: the multivariate analysis of variance with more than one effect, simultaneous plotting of samples and variables on canonical variates, and the use of parametric ANOVA and MANOVA on ranked data. ?? 1980 Plenum Publishing Corporation.

  19. Stress assessment based on EEG univariate features and functional connectivity measures.

    PubMed

    Alonso, J F; Romero, S; Ballester, M R; Antonijoan, R M; Maanas, M A

    2015-07-01

    The biological response to stress originates in the brain but involves different biochemical and physiological effects. Many common clinical methods to assess stress are based on the presence of specific hormones and on features extracted from different signals, including electrocardiogram, blood pressure, skin temperature, or galvanic skin response. The aim of this paper was to assess stress using EEG-based variables obtained from univariate analysis and functional connectivity evaluation. Two different stressors, the Stroop test and sleep deprivation, were applied to 30 volunteers to find common EEG patterns related to stress effects. Results showed a decrease of the high alpha power (11 to 12?Hz), an increase in the high beta band (23 to 36?Hz, considered a busy brain indicator), and a decrease in the approximate entropy. Moreover, connectivity showed that the high beta coherence and the interhemispheric nonlinear couplings, measured by the cross mutual information function, increased significantly for both stressors, suggesting that useful stress indexes may be obtained from EEG-based features. PMID:26015439

  20. Inference for correlated effect sizes using multiple univariate meta-analyses.

    PubMed

    Chen, Yong; Cai, Yi; Hong, Chuan; Jackson, Dan

    2016-04-30

    Multivariate meta-analysis, which involves jointly analyzing multiple and correlated outcomes from separate studies, has received a great deal of attention. One reason to prefer the multivariate approach is its ability to account for the dependence between multiple estimates from the same study. However, nearly all the existing methods for analyzing multivariate meta-analytic data require the knowledge of the within-study correlations, which are usually unavailable in practice. We propose a simple non-iterative method that can be used for the analysis of multivariate meta-analysis datasets, that has no convergence problems, and does not require the use of within-study correlations. Our approach uses standard univariate methods for the marginal effects but also provides valid joint inference for multiple parameters. The proposed method can directly handle missing outcomes under missing completely at random assumption. Simulation studies show that the proposed method provides unbiased estimates, well-estimated standard errors, and confidence intervals with good coverage probability. Furthermore, the proposed method is found to maintain high relative efficiency compared with conventional multivariate meta-analyses where the within-study correlations are known. We illustrate the proposed method through two real meta-analyses where functions of the estimated effects are of interest. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID:26537017

  1. 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.

  2. Recurrent and/or metastatic head and neck squamous cell carcinoma: a clinical, univariate and multivariate analysis of response and survival with cisplatin-based chemotherapy.

    PubMed

    Recondo, G; Armand, J P; Tellez-Bernal, E; Domenge, C; Belehradek, M; De Vathaire, F; Wibault, P; Richard, J M; Cvitkovic, E

    1991-05-01

    One hundred two patients with recurrent and/or metastatic head and neck squamous cell cancer were entered into four consecutive phase II trials, all cisplatinum (C-DDP, 100 mg/m2/cycle)-based. The two combinations tried were C-DDP, bleomycin, and fluorouracil (CFB) on 54 patients, and cisplatinum and vindesin in 36 patients (CV). The CFB combination was given with C-DDP by continuous infusion over 96 hours (23 patients) or on day 1 (31 patients). The CV regimen was also given in two different schedules, with VDS at 3 mg/m2/g weekly (12 patients) or by a 96-hour continuous infusion (0.6 to 1.0 mg/m2/d) in 24 patients. The following variables: sex, age, performance status, previous therapy, local recurrence, length of disease-free interval (DFI), distant metastases, weight loss, primary site, histological differentiation, type of chemotherapy, previous chemotherapy, evaluable/measurable disease, erythrosedimentation rate, and their relation with response to chemotherapy (WHO) and survival were submitted to both univariate and multivariate analysis (Cox). Overall response rate (RR:CR + PR) was 25 (28%) of 90. In the CFB protocols, RR was 12 (22%) of 54 vs. 13 (38%) of 36 (P = 0.15, NS) in the CV combination group. For the four different combinations the RR was CFB C-DDPci 7 (30%) of 23, CFB C-DDP 1 hour 5 (16%) of 31, CV VDS weekly 2 (17%) of 12, CV VDSci 11 (45%) of 24. The patient populations were very different, with the latest combination consisting of metastatic patients exclusively. Univariate analysis of multiple variables showed age less than 60 years, PS:0 or 1, no previous therapy, absence of local relapse, metastatic disease, long DFI, and that measurable disease was significant for the probability of response. Median survival was 7 months for the 90 evaluated patients, 5 months for nonresponders, and 9 months for responders (P = 0.01). In the univariate analysis, significant factors for survival were PS:0 or 1, a weight loss below 10%, long DFI, response to chemotherapy, erythrosedimentation rate (ESR) of less than 30 mm/1st hr, presence of bone metastasis, and the number of metastases. Multivariate analysis shows PS, the absence of local relapse, and disease-free interval as significant prognostic factors for response. Multivariate analysis factors of significance for survival were PS, weight loss, and response to chemotherapy. The analysis of the clinical pattern showed an evolution in RR from 3 (8%) of 36 on previously irradiated local recurrent disease to 8 (73%) of 11 in previously untreated patients with metastatic disease at presentation.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:1709437

  3. Bayesian isotonic density regression

    PubMed Central

    Wang, Lianming; Dunson, David B.

    2011-01-01

    Density regression models allow the conditional distribution of the response given predictors to change flexibly over the predictor space. Such models are much more flexible than nonparametric mean regression models with nonparametric residual distributions, and are well supported in many applications. A rich variety of Bayesian methods have been proposed for density regression, but it is not clear whether such priors have full support so that any true data-generating model can be accurately approximated. This article develops a new class of density regression models that incorporate stochastic-ordering constraints which are natural when a response tends to increase or decrease monotonely with a predictor. Theory is developed showing large support. Methods are developed for hypothesis testing, with posterior computation relying on a simple Gibbs sampler. Frequentist properties are illustrated in a simulation study, and an epidemiology application is considered. PMID:22822259

  4. 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. PMID:9083488

  5. Univariate analysis to examine predictors of response to leukocytapheresis in ulcerative colitis patients.

    PubMed

    Nagayama, Koji; Takedatsu, Hidetoshi; Mitsuyama, Keiichi; Yamasaki, Hiroshi; Kuwaki, Kotaro; Yoshioka, Shinichiro; Kobayashi, Teppei; Yamauchi, Ryosuke; Kakuma, Tatsuyuki; Sata, Michio

    2014-06-01

    Leukocytapheresis (LCAP) is reportedly effective for the treatment of active ulcerative colitis (UC) and is a therapeutic option for steroid-dependent or steroid-resistant patients with UC. However, a consensus regarding the use of LCAP for UC patients has not yet been established. Therefore, we analyzed patients' records to identify predictors of response to LCAP therapy and subsequent recurrence. Between October 2001 and March 2011, we recruited 41 patients who had been diagnosed as having UC and had received LCAP therapy. Patients diagnosed with moderate to severe UC with left-side or total colitis and received LCAP therapy for the first time were enrolled. We retrospectively performed a univariate analysis using the patients' medical records to identify factors affecting the therapeutic effect of LCAP. Body mass index exceeding 18.5 kg/m(2) was found to influence the therapeutic effect of LCAP. Male sex was correlated with a rapid response to LCAP treatment and the maintenance of remission. UC patients experiencing their first attack or had an elevated C-reactive protein level prior to LCAP therapy exhibited a relatively long remission period. In the "after LCAP therapy" group, a low Rachmilewitz endoscopic score, low erythrocyte sedimentation rate, or high white blood cell count was associated with a long remission period. Our results suggest that LCAP should be performed for the treatment of early-onset UC. LCAP can be expected to induce a long remission period, enabling mucosal healing, although the factors that affected the remission period did not influence the therapeutic effect and responsiveness. PMID:24965290

  6. Univariate and multivariate methods for chemical mapping of cervical cancer cells

    NASA Astrophysics Data System (ADS)

    Duraipandian, Shiyamala; Zheng, Wei; Huang, Zhiwei

    2012-01-01

    Visualization of cells and subcellular organelles are currently carried out using available microscopy methods such as cryoelectron microscopy, and fluorescence microscopy. These methods require external labeling using fluorescent dyes and extensive sample preparations to access the subcellular structures. However, Raman micro-spectroscopy provides a non-invasive, label-free method for imaging the cells with chemical specificity at sub-micrometer spatial resolutions. The scope of this paper is to image the biochemical/molecular distributions in cells associated with cancerous changes. Raman map data sets were acquired from the human cervical carcinoma cell lines (HeLa) after fixation under 785 nm excitation wavelength. The individual spectrum was recorded by raster-scanning the laser beam over the sample with 1μm step size and 10s exposure time. Images revealing nucleic acids, lipids and proteins (phenylalanine, amide I) were reconstructed using univariate methods. In near future, the small pixel to pixel variations will also be imaged using different multivariate methods (PCA, clustering (HCA, K-means, FCM)) to determine the main cellular constitutions. The hyper-spectral image of cell was reconstructed utilizing the spectral contrast at different pixels of the cell (due to the variation in the biochemical distribution) without using fluorescent dyes. Normal cervical squamous cells will also be imaged in order to differentiate normal and cancer cells of cervix using the biochemical changes in different grades of cancer. Based on the information obtained from the pseudo-color maps, constructed from the hyper-spectral cubes, the primary cellular constituents of normal and cervical cancer cells were identified.

  7. Female children with autism spectrum disorder: an insight from mass-univariate and pattern classification analyses.

    PubMed

    Calderoni, Sara; Retico, Alessandra; Biagi, Laura; Tancredi, Raffaella; Muratori, Filippo; Tosetti, Michela

    2012-01-16

    Several studies on structural MRI in children with autism spectrum disorders (ASD) have mainly focused on samples prevailingly consisting of males. Sex differences in brain structure are observable since infancy and therefore caution is required in transferring to females the results obtained for males. The neuroanatomical phenotype of female children with ASD (ASDf) represents indeed a neglected area of research. In this study, we investigated for the first time the anatomic brain structures of a sample entirely composed of ASDf (n=38; 2-7 years of age; mean=53 months; SD=18) with respect to 38 female age and non verbal IQ matched controls, using both mass-univariate and pattern classification approaches. The whole brain volumes of each group were compared using voxel-based morphometry (VBM) with diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL) procedure, allowing us to build a study-specific template. Significantly more gray matter (GM) was found in the left superior frontal gyrus (SFG) in ASDf subjects compared to controls. The GM segments obtained in the VBM-DARTEL preprocessing are also classified with a support vector machine (SVM), using the leave-pair-out cross-validation protocol. Then, the recursive feature elimination (SVM-RFE) approach allows for the identification of the most discriminating voxels in the GM segments and these prove extremely consistent with the SFG region identified by the VBM analysis. Furthermore, the SVM-RFE map obtained with the most discriminating set of voxels corresponding to the maximum Area Under the Receiver Operating Characteristic Curve (AUC(max)=0.80) highlighted a more complex circuitry of increased cortical volume in ASDf, involving bilaterally the SFG and the right temporo-parietal junction (TPJ). The SFG and TPJ abnormalities may be relevant to the pathophysiology of ASDf, since these structures participate in some core atypical features of autism. PMID:21896334

  8. Pleiotropic locus for emotion recognition and amygdala volume identified using univariate and bivariate linkage

    PubMed Central

    Knowles, Emma E. M.; McKay, D. Reese; Kent, Jack W.; Sprooten, Emma; Carless, Melanie A.; Curran, Joanne E.; de Almeida, Marcio A. A.; Dyer, Thomas D.; Gring, Harald H. H.; Olvera, Rene; Duggirala, Ravi; Fox, Peter; Almasy, Laura; Blangero, John; Glahn, David. C.

    2014-01-01

    The role of the amygdala in emotion recognition is well established and separately each trait has been shown to be highly heritable, but the potential role of common genetic influences on both traits has not been explored. Here we present an investigation of the pleiotropic influences of amygdala and emotion recognition in a sample of randomly selected, extended pedigrees (N = 858). Using a combination of univariate and bivariate linkage we found a pleiotropic region for amygdala and emotion recognition on 4q26 (LOD = 4.34). Association analysis conducted in the region underlying the bivariate linkage peak revealed a variant meeting the corrected significance level (pBonferroni = 5.0110?05) within an intron of PDE5A (rs2622497, ?2 =16.67, p = 4.410?05) as being jointly influential on both traits. PDE5A has been implicated previously in recognition-memory deficits and is expressed in subcortical structures that are thought to underlie memory ability including the amygdala. The present paper extends our understanding of the shared etiology between amygdala and emotion recognition by showing that the overlap between the two traits is due, at least in part, to common genetic influences. Moreover, the present paper identifies a pleiotropic locus for the two traits and an associated variant, which localizes the genetic signal even more precisely. These results, when taken in the context of previous research, highlight the potential utility of PDE5-inhibitors for ameliorating emotion-recognition deficits in populations including, but not exclusively, those individuals suffering from mental or neurodegenerative illness. PMID:25322361

  9. 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

  10. Univariate and Multivariate Omnibus Hypothesis Tests Selected to Control Type I Error Rates When Population Variances Are Not Necessarily Equal.

    ERIC Educational Resources Information Center

    Coombs, William T.; And Others

    1996-01-01

    Methods to compare population means in the univariate case and population mean vectors in the multivariate case are presented in terms of hypotheses tested by various procedures. Tests relevant to each hypothesis are described and compared in terms of maximizing power while controlling Type I error rates over the widest variety of conditions. (SLD)

  11. Regression versus No Regression in the Autistic Disorder: Developmental Trajectories

    ERIC Educational Resources Information Center

    Bernabei, P.; Cerquiglini, A.; Cortesi, F.; D' Ardia, C.

    2007-01-01

    Developmental regression is a complex phenomenon which occurs in 20-49% of the autistic population. Aim of the study was to assess possible differences in the development of regressed and non-regressed autistic preschoolers. We longitudinally studied 40 autistic children (18 regressed, 22 non-regressed) aged 2-6 years. The following developmental…

  12. 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

  13. 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. PMID:25988363

  14. [Clinical pharmacology of the selective COX-2 inhibitors].

    PubMed

    Burian, M; Geisslinger, G

    2003-12-01

    The discovery of two isoforms of cyclooxygenases (COX-1 and COX-2) has provided a new insight into the involvement of prostaglandins in the clinical effectiveness and gastrointestinal toxicity of NSAIDs. Currently, there are four selective COX-2 inhibitors available in Germany: celecoxib, rofecoxib, valdecoxib and parecoxib. Orally administered rofecoxib, celecoxib and valdecoxib have been approved for the relief of symptoms of osteoarthritis and rheumatoid arthritis. Parecoxib, the first selective COX-2 inhibitor for parenteral administration, has been approved for the short-term treatment of post-operative pain. The clinical efficacy of the marketed COX-2 inhibitors has been proved in large phase III clinical trials in comparison to both placebo and classical NSAIDs (e.g. diclofenac, naproxen). The incidence of gastrointestinal complications was significantly lower than that with the non-selective NSAIDs. However, the clinical relevance of these effects was, at least in some populations of patients (e.g. patients on low dose aspirin), not as high as initially expected. While not replacing less expensive classical NSAIDs, selective COX-2 inhibitors provide a marked enrichment of the spectrum of anti-inflammatory and analgesic therapeutics. PMID:14655004

  15. Practical Session: Logistic Regression

    NASA Astrophysics Data System (ADS)

    Clausel, M.; Grégoire, G.

    2014-12-01

    An exercise is proposed to illustrate the logistic regression. One investigates the different risk factors in the apparition of coronary heart disease. It has been proposed in Chapter 5 of the book of D.G. Kleinbaum and M. Klein, "Logistic Regression", Statistics for Biology and Health, Springer Science Business Media, LLC (2010) and also by D. Chessel and A.B. Dufour in Lyon 1 (see Sect. 6 of http://pbil.univ-lyon1.fr/R/pdf/tdr341.pdf). This example is based on data given in the file evans.txt coming from http://www.sph.emory.edu/dkleinb/logreg3.htm#data.

  16. Molecular dynamics simulations of arachidonic acid complexes with COX-1 and COX-2: insights into equilibrium behavior.

    PubMed

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

    2006-03-14

    The cyclooxygenase (COX) enzymes are responsible for the committed step in prostaglandin biosynthesis, the generation of prostaglandin H(2). As a result, these enzymes are pharmacologically important targets for nonsteroidal antiinflammatory 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 H(2) 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

  17. Mechanisms of neuroblastoma regression

    PubMed Central

    Brodeur, Garrett M.; Bagatell, Rochelle

    2014-01-01

    Recent genomic and biological studies of neuroblastoma have shed light on the dramatic heterogeneity in the clinical behaviour of this disease, which spans from spontaneous regression or differentiation in some patients, to relentless disease progression in others, despite intensive multimodality therapy. This evidence also suggests several possible mechanisms to explain the phenomena of spontaneous regression in neuroblastomas, including neurotrophin deprivation, humoral or cellular immunity, loss of telomerase activity and alterations in epigenetic regulation. A better understanding of the mechanisms of spontaneous regression might help to identify optimal therapeutic approaches for patients with these tumours. Currently, the most druggable mechanism is the delayed activation of developmentally programmed cell death regulated by the tropomyosin receptor kinase A pathway. Indeed, targeted therapy aimed at inhibiting neurotrophin receptors might be used in lieu of conventional chemotherapy or radiation in infants with biologically favourable tumours that require treatment. Alternative approaches consist of breaking immune tolerance to tumour antigens or activating neurotrophin receptor pathways to induce neuronal differentiation. These approaches are likely to be most effective against biologically favourable tumours, but they might also provide insights into treatment of biologically unfavourable tumours. We describe the different mechanisms of spontaneous neuroblastoma regression and the consequent therapeutic approaches. PMID:25331179

  18. Explorations in Statistics: Regression

    ERIC Educational Resources Information Center

    Curran-Everett, Douglas

    2011-01-01

    Learning about statistics is a lot like learning about science: the learning is more meaningful if you can actively explore. This seventh installment of "Explorations in Statistics" explores regression, a technique that estimates the nature of the relationship between two things for which we may only surmise a mechanistic or predictive connection.…

  19. Modern Regression Discontinuity Analysis

    ERIC Educational Resources Information Center

    Bloom, Howard S.

    2012-01-01

    This article provides a detailed discussion of the theory and practice of modern regression discontinuity (RD) analysis for estimating the effects of interventions or treatments. Part 1 briefly chronicles the history of RD analysis and summarizes its past applications. Part 2 explains how in theory an RD analysis can identify an average effect of…

  20. Explorations in Statistics: Regression

    ERIC Educational Resources Information Center

    Curran-Everett, Douglas

    2011-01-01

    Learning about statistics is a lot like learning about science: the learning is more meaningful if you can actively explore. This seventh installment of "Explorations in Statistics" explores regression, a technique that estimates the nature of the relationship between two things for which we may only surmise a mechanistic or predictive connection.

  1. Bayesian ARTMAP for regression.

    PubMed

    Sasu, L M; Andonie, R

    2013-10-01

    Bayesian ARTMAP (BA) is a recently introduced neural architecture which uses a combination of Fuzzy ARTMAP competitive learning and Bayesian learning. Training is generally performed online, in a single-epoch. During training, BA creates input data clusters as Gaussian categories, and also infers the conditional probabilities between input patterns and categories, and between categories and classes. During prediction, BA uses Bayesian posterior probability estimation. So far, BA was used only for classification. The goal of this paper is to analyze the efficiency of BA for regression problems. Our contributions are: (i) we generalize the BA algorithm using the clustering functionality of both ART modules, and name it BA for Regression (BAR); (ii) we prove that BAR is a universal approximator with the best approximation property. In other words, BAR approximates arbitrarily well any continuous function (universal approximation) and, for every given continuous function, there is one in the set of BAR approximators situated at minimum distance (best approximation); (iii) we experimentally compare the online trained BAR with several neural models, on the following standard regression benchmarks: CPU Computer Hardware, Boston Housing, Wisconsin Breast Cancer, and Communities and Crime. Our results show that BAR is an appropriate tool for regression tasks, both for theoretical and practical reasons. PMID:23665468

  2. CORRELATION AND REGRESSION

    EPA Science Inventory

    Webcast entitled Statistical Tools for Making Sense of Data, by the National Nutrient Criteria Support Center, N-STEPS (Nutrients-Scientific Technical Exchange Partnership. The section "Correlation and Regression" provides an overview of these two techniques in the context of nut...

  3. Partial covariate adjusted regression

    PubMed Central

    Şentürk, Damla; Nguyen, Danh V.

    2008-01-01

    Covariate adjusted regression (CAR) is a recently proposed adjustment method for regression analysis where both the response and predictors are not directly observed (Şentürk and Müller, 2005). The available data has been distorted by unknown functions of an observable confounding covariate. CAR provides consistent estimators for the coefficients of the regression between the variables of interest, adjusted for the confounder. We develop a broader class of partial covariate adjusted regression (PCAR) models to accommodate both distorted and undistorted (adjusted/unadjusted) predictors. The PCAR model allows for unadjusted predictors, such as age, gender and demographic variables, which are common in the analysis of biomedical and epidemiological data. The available estimation and inference procedures for CAR are shown to be invalid for the proposed PCAR model. We propose new estimators and develop new inference tools for the more general PCAR setting. In particular, we establish the asymptotic normality of the proposed estimators and propose consistent estimators of their asymptotic variances. Finite sample properties of the proposed estimators are investigated using simulation studies and the method is also illustrated with a Pima Indians diabetes data set. PMID:20126296

  4. Modern Regression Discontinuity Analysis

    ERIC Educational Resources Information Center

    Bloom, Howard S.

    2012-01-01

    This article provides a detailed discussion of the theory and practice of modern regression discontinuity (RD) analysis for estimating the effects of interventions or treatments. Part 1 briefly chronicles the history of RD analysis and summarizes its past applications. Part 2 explains how in theory an RD analysis can identify an average effect of

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

    PubMed Central

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

    2014-01-01

    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. PMID:24403053

  6. 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. PMID:25044997

  7. Evaluating the efficiency of spectral resolution of univariate methods manipulating ratio spectra and comparing to multivariate methods: An application to ternary mixture in common cold preparation

    NASA Astrophysics Data System (ADS)

    Moustafa, Azza Aziz; Salem, Hesham; Hegazy, Maha; Ali, Omnia

    2015-02-01

    Simple, accurate, and selective methods have been developed and validated for simultaneous determination of a ternary mixture of Chlorpheniramine maleate (CPM), Pseudoephedrine HCl (PSE) and Ibuprofen (IBF), in tablet dosage form. Four univariate methods manipulating ratio spectra were applied, method A is the double divisor-ratio difference spectrophotometric method (DD-RD). Method B is double divisor-derivative ratio spectrophotometric method (DD-RD). Method C is derivative ratio spectrum-zero crossing method (DRZC), while method D is mean centering of ratio spectra (MCR). Two multivariate methods were also developed and validated, methods E and F are Principal Component Regression (PCR) and Partial Least Squares (PLSs). The proposed methods have the advantage of simultaneous determination of the mentioned drugs without prior separation steps. They were successfully applied to laboratory-prepared mixtures and to commercial pharmaceutical preparation without any interference from additives. The proposed methods were validated according to the ICH guidelines. The obtained results were statistically compared with the official methods where no significant difference was observed regarding both accuracy and precision.

  8. Evaluating the efficiency of spectral resolution of univariate methods manipulating ratio spectra and comparing to multivariate methods: an application to ternary mixture in common cold preparation.

    PubMed

    Moustafa, Azza Aziz; Salem, Hesham; Hegazy, Maha; Ali, Omnia

    2015-02-25

    Simple, accurate, and selective methods have been developed and validated for simultaneous determination of a ternary mixture of Chlorpheniramine maleate (CPM), Pseudoephedrine HCl (PSE) and Ibuprofen (IBF), in tablet dosage form. Four univariate methods manipulating ratio spectra were applied, method A is the double divisor-ratio difference spectrophotometric method (DD-RD). Method B is double divisor-derivative ratio spectrophotometric method (DD-RD). Method C is derivative ratio spectrum-zero crossing method (DRZC), while method D is mean centering of ratio spectra (MCR). Two multivariate methods were also developed and validated, methods E and F are Principal Component Regression (PCR) and Partial Least Squares (PLSs). The proposed methods have the advantage of simultaneous determination of the mentioned drugs without prior separation steps. They were successfully applied to laboratory-prepared mixtures and to commercial pharmaceutical preparation without any interference from additives. The proposed methods were validated according to the ICH guidelines. The obtained results were statistically compared with the official methods where no significant difference was observed regarding both accuracy and precision. PMID:25306132

  9. Ridge Regression: A Regression Procedure for Analyzing Correlated Independent Variables.

    ERIC Educational Resources Information Center

    Rakow, Ernest A.

    Ridge regression is presented as an analytic technique to be used when predictor variables in a multiple linear regression situation are highly correlated, a situation which may result in unstable regression coefficients and difficulties in interpretation. Ridge regression avoids the problem of selection of variables that may occur in stepwise…

  10. A comparative study between nonlinear regression and artificial neural network approaches for modelling wild oat (Avena fatua) field emergence

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Non-linear regression techniques are used widely to fit weed field emergence patterns to soil microclimatic indices using S-type functions. Artificial neural networks present interesting and alternative features for such modeling purposes. In this work, a univariate hydrothermal-time based Weibull m...

  11. Fast Censored Linear Regression

    PubMed Central

    HUANG, YIJIAN

    2013-01-01

    Weighted log-rank estimating function has become a standard estimation method for the censored linear regression model, or the accelerated failure time model. Well established statistically, the estimator defined as a consistent root has, however, rather poor computational properties because the estimating function is neither continuous nor, in general, monotone. We propose a computationally efficient estimator through an asymptotics-guided Newton algorithm, in which censored quantile regression methods are tailored to yield an initial consistent estimate and a consistent derivative estimate of the limiting estimating function. We also develop fast interval estimation with a new proposal for sandwich variance estimation. The proposed estimator is asymptotically equivalent to the consistent root estimator and barely distinguishable in samples of practical size. However, computation time is typically reduced by two to three orders of magnitude for point estimation alone. Illustrations with clinical applications are provided. PMID:24347802

  12. [Atypical tumor regression].

    PubMed

    Heitplatz, B; Müller, K-M

    2013-11-01

    A 67-year-old man presented with a poorly differentiated squamous cell carcinoma of the esophagus diagnosed by biopsy. After neoadjuvant radiochemotherapy the gastroesophagectomy specimen showed diffuse polymorphic and anuclear cell residues ranging from 35 µm to 46 µm in size. Immunohistochemically, PanCK and AE1-3 revealed a positive staining while CD68 and MIB1 showed a negative staining. The retrospective anamnesis revealed that the patient had chronic polyarthritis as underlying illness, for which reason he had been taking humira and methotrexate, a cytostatic drug, for many years. Therefore, the development of the tumor might have been enhanced by these drugs. Electron microscopic analysis confirmed that the avital akaryote cell residues represented a special type of tumor regression. Complete tumor regression level IV without vital rest tumor tissue based on Baldus et al. was diagnosed. PMID:24154755

  13. Performance of univariate forecasting on seasonal diseases: the case of tuberculosis.

    PubMed

    Permanasari, Adhistya Erna; Rambli, Dayang Rohaya Awang; Dominic, P Dhanapal Durai

    2011-01-01

    The annual disease incident worldwide is desirable to be predicted for taking appropriate policy to prevent disease outbreak. This chapter considers the performance of different forecasting method to predict the future number of disease incidence, especially for seasonal disease. Six forecasting methods, namely linear regression, moving average, decomposition, Holt-Winter's, ARIMA, and artificial neural network (ANN), were used for disease forecasting on tuberculosis monthly data. The model derived met the requirement of time series with seasonality pattern and downward trend. The forecasting performance was compared using similar error measure in the base of the last 5 years forecast result. The findings indicate that ARIMA model was the most appropriate model since it obtained the less relatively error than the other model. PMID:21431557

  14. On computing standard errors for marginal structural Cox models.

    PubMed

    Ali, R Ayesha; Ali, M Adnan; Wei, Zhe

    2014-01-01

    In recent decades, marginal structural models have gained popularity for proper adjustment of time-dependent confounders in longitudinal studies through time-dependent weighting. When the marginal model is a Cox model, using current standard statistical software packages was thought to be problematic because they were not developed to compute standard errors in the presence of time-dependent weights. We address this practical modelling issue by extending the standard calculations for Cox models with case weights to time-dependent weights and show that the coxph procedure in R can readily compute asymptotic robust standard errors. Through a simulation study, we show that the robust standard errors are rather conservative, though corresponding confidence intervals have good coverage. A second contribution of this paper is to introduce a Cox score bootstrap procedure to compute the standard errors. We show that this method is efficient and tends to outperform the non-parametric bootstrap in small samples. PMID:23595535

  15. RNA editing intermediates of cox2 transcripts in maize mitochondria.

    PubMed Central

    Yang, A J; Mulligan, R M

    1991-01-01

    Eighteen cytidines are changed to uridines in the coding sequence of transcripts for cytochrome c oxidase subunit 2 (cox2) in maize mitochondria. The temporal relationship of editing and splicing was examined in cox2 transcripts by sequence analysis of spliced and unspliced cDNAs. Cloned cDNAs of unspliced cox2 transcripts ranged from clones with no edited nucleotides to completely edited forms, while spliced cDNAs were nearly completely edited. Incompletely edited transcripts in the nascent pool of unspliced transcripts represent intermediates of the editing process. These results indicate that editing proceeds without a strong directional bias and suggest that RNA editing is a posttranscriptional process. Images PMID:1712908

  16. Orthogonal Regression: A Teaching Perspective

    ERIC Educational Resources Information Center

    Carr, James R.

    2012-01-01

    A well-known approach to linear least squares regression is that which involves minimizing the sum of squared orthogonal projections of data points onto the best fit line. This form of regression is known as orthogonal regression, and the linear model that it yields is known as the major axis. A similar method, reduced major axis regression, is…

  17. Orthogonal Regression: A Teaching Perspective

    ERIC Educational Resources Information Center

    Carr, James R.

    2012-01-01

    A well-known approach to linear least squares regression is that which involves minimizing the sum of squared orthogonal projections of data points onto the best fit line. This form of regression is known as orthogonal regression, and the linear model that it yields is known as the major axis. A similar method, reduced major axis regression, is

  18. 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

  19. Regression Models: A Brief Introduction

    NASA Astrophysics Data System (ADS)

    Grégoire, G.

    2014-12-01

    This brief introduction, without pretension, aims to give some help to non-specialists of statistics to find their way in regression models. What are the basic notions of a regression? A regression model can be linear, generalized linear, nonlinear. Statisticians speak also of parametric, semiparametric, nonparametric regression models. We hope that what is behind these terms will be made clearer after the reading of chapters devoted to simple linear regression, multiple linear regression, logistic regression, survival data and regression, kernel methods... But it can be interesting to have a global view, before reading these chapters, on a rather wide range of regression methods, and to have a first sight on what type of question a particular regression model is answering and what can be expected from such a model on the ground of modelling the data we have in hand.

  20. 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

  1. 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

    Bode, Manuela; Woellhaf, Michael W; Bohnert, Maria; van der Laan, Martin; Sommer, Frederik; Jung, Martin; Zimmermann, Richard; Schroda, Michael; Herrmann, Johannes M

    2015-07-01

    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

  2. Nonidentical twins: Comparison of frequentist and Bayesian lasso for Cox models.

    PubMed

    Zucknick, Manuela; Saadati, Maral; Benner, Axel

    2015-11-01

    One important task in translational cancer research is the search for new prognostic biomarkers to improve survival prognosis for patients. The use of high-throughput technologies allows simultaneous measurement of genome-wide gene expression or other genomic data for all patients in a clinical trial. Penalized likelihood methods such as lasso regression can be applied to such high-dimensional data, where the number of (genomic) covariables is usually much larger than the sample size. There is a connection between the lasso and the Bayesian regression model with independent Laplace priors on the regression parameters, and understanding this connection has been useful for understanding the properties of lasso estimates in linear models (e.g. Park and Casella, 2008). In this paper, we study the lasso in the frequentist and Bayesian frameworks in the context of Cox models. For the Bayesian lasso we extend the approach by Lee et al. (2011). In particular, we impose the lasso penalty only on the genome features, but not on relevant clinical covariates, to allow the mandatory inclusion of important established factors. We investigate the models in high- and low-dimensional simulation settings and in an application to chronic lymphocytic leukemia. PMID:26417963

  3. Multiple Use One-Sided Hypotheses Testing in Univariate Linear Calibration

    NASA Technical Reports Server (NTRS)

    Krishnamoorthy, K.; Kulkarni, Pandurang M.; Mathew, Thomas

    1996-01-01

    Consider a normally distributed response variable, related to an explanatory variable through the simple linear regression model. Data obtained on the response variable, corresponding to known values of the explanatory variable (i.e., calibration data), are to be used for testing hypotheses concerning unknown values of the explanatory variable. We consider the problem of testing an unlimited sequence of one sided hypotheses concerning the explanatory variable, using the corresponding sequence of values of the response variable and the same set of calibration data. This is the situation of multiple use of the calibration data. The tests derived in this context are characterized by two types of uncertainties: one uncertainty associated with the sequence of values of the response variable, and a second uncertainty associated with the calibration data. We derive tests based on a condition that incorporates both of these uncertainties. The solution has practical applications in the decision limit problem. We illustrate our results using an example dealing with the estimation of blood alcohol concentration based on breath estimates of the alcohol concentration. In the example, the problem is to test if the unknown blood alcohol concentration of an individual exceeds a threshold that is safe for driving.

  4. SPReM: Sparse Projection Regression Model For High-dimensional Linear Regression *

    PubMed Central

    Sun, Qiang; Zhu, Hongtu; Liu, Yufeng; Ibrahim, Joseph G.

    2014-01-01

    The aim of this paper is to develop a sparse projection regression modeling (SPReM) framework to perform multivariate regression modeling with a large number of responses and a multivariate covariate of interest. We propose two novel heritability ratios to simultaneously perform dimension reduction, response selection, estimation, and testing, while explicitly accounting for correlations among multivariate responses. Our SPReM is devised to specifically address the low statistical power issue of many standard statistical approaches, such as the Hotelling’s T2 test statistic or a mass univariate analysis, for high-dimensional data. We formulate the estimation problem of SPREM as a novel sparse unit rank projection (SURP) problem and propose a fast optimization algorithm for SURP. Furthermore, we extend SURP to the sparse multi-rank projection (SMURP) by adopting a sequential SURP approximation. Theoretically, we have systematically investigated the convergence properties of SURP and the convergence rate of SURP estimates. Our simulation results and real data analysis have shown that SPReM out-performs other state-of-the-art methods. PMID:26527844

  5. Regression in organizational leadership.

    PubMed

    Kernberg, O F

    1979-02-01

    The choice of good leaders is a major task for all organizations. Inforamtion regarding the prospective administrator's personality should complement questions regarding his previous experience, his general conceptual skills, his technical knowledge, and the specific skills in the area for which he is being selected. The growing psychoanalytic knowledge about the crucial importance of internal, in contrast to external, object relations, and about the mutual relationships of regression in individuals and in groups, constitutes an important practical tool for the selection of leaders. PMID:760132

  6. Steganalysis using logistic regression

    NASA Astrophysics Data System (ADS)

    Lubenko, Ivans; Ker, Andrew D.

    2011-02-01

    We advocate Logistic Regression (LR) as an alternative to the Support Vector Machine (SVM) classifiers commonly used in steganalysis. LR offers more information than traditional SVM methods - it estimates class probabilities as well as providing a simple classification - and can be adapted more easily and efficiently for multiclass problems. Like SVM, LR can be kernelised for nonlinear classification, and it shows comparable classification accuracy to SVM methods. This work is a case study, comparing accuracy and speed of SVM and LR classifiers in detection of LSB Matching and other related spatial-domain image steganography, through the state-of-art 686-dimensional SPAM feature set, in three image sets.

  7. Empirical Bayes logistic regression.

    PubMed

    Strimenopoulou, Foteini; Brown, Philip J

    2008-01-01

    We construct a diagnostic predictor for patient disease status based on a single data set of mass spectra of serum samples together with the binary case-control response. The model is logistic regression with Bernoulli log-likelihood augmented either by quadratic ridge or absolute L1 penalties. For ridge penalization using the singular value decomposition we reduce the number of variables for maximization to the rank of the design matrix. With log-likelihood loss, 10-fold cross-validatory choice is employed to specify the penalization hyperparameter. Predictive ability is judged on a set-aside subset of the data. PMID:18312223

  8. Novel Harmonic Regularization Approach for Variable Selection in Cox's Proportional Hazards Model

    PubMed Central

    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. PMID:25506389

  9. Sulindac induced regression of colorectal adenomas in familial adenomatous polyposis: evaluation of predictive factors.

    PubMed Central

    Giardiello, F M; Offerhaus, J A; Tersmette, A C; Hylind, L M; Krush, A J; Brensinger, J D; Booker, S V; Hamilton, S R

    1996-01-01

    BACKGROUND--Sulindac, a non-steroidal anti-inflammatory drug, causes regression of colorectal adenomas in patients with familial adenomatous polyposis (FAP) but the response is variable. Specific clinical factors predictive of sulindac induced regression have not been studied. METHODS--22 patients with FAP were given sulindac 150 mg orally twice a day. Polyp number and size were determined before treatment and at three months. The relation of nine clinical factors to polyp regression (per cent of baseline polyp number after treatment) was evaluated by univariate and multivariate analysis. RESULTS--After three months of sulindac, polyp number had decreased to 45 per cent of baseline and polyp size to 50 per cent of baseline (p < 0.001 and p < 0.01, respectively). Univariate analysis showed greater polyp regression in older patients (p = 0.004), those with previous colectomy and ileorectal anastomosis (p = 0.001), and patients without identifiable mutation of the APC gene responsible for FAP (p = 0.05). With multivariate regression analysis, response to sulindac treatment was associated with previous subtotal colectomy. CONCLUSIONS--Sulindac treatment seems effective in producing regression of colorectal adenomas of FAP patients with previous subtotal colectomy regardless of baseline polyp number and size. Changed sulindac metabolism, reduced area of the target mucosa, or changed epithelial characteristics after ileorectal anastomosis may explain these findings. PMID:8707091

  10. HIF-1?/COX-2 expression and mouse brain capillary remodeling during prolonged moderate hypoxia and subsequent re-oxygenation

    PubMed Central

    Benderro, Girriso F.; LaManna, Joseph C.

    2014-01-01

    Dynamic microvascular remodeling maintains an optimal continuous supply of oxygen and nutrients to the brain to account for prolonged environmental variations. The objective of this study was to determine the relative time course of capillary regression during re-oxygenation after exposure to prolonged moderate hypoxia and expression of the primary signaling factors involved in the process. Four-month old male C57BL/6 mice were housed and maintained in a hypobaric chamber at 290 torr (0.4 ATM) for 21 days and allowed to recover at normoxia (room air) for up to 21 days. The mice were either decapitated or perfused in-situ and brain samples collected were either homogenized for Western blot analysis or fixed and embedded in paraffin for immunohistochemistry. Hypoxia inducible factor-1? (HIF-1?), vascular endothelial growth factor (VEGF) and erythropoietin (EPO) expression were increased during hypoxic exposure and diminished during subsequent re-oxygenation. However, cyclooxygenase-2 (COX-2) and angiopoietin-2 (Ang-2) were both elevated during hypoxia as well as subsequent re-oxygenation. Significantly increased capillary density at the end of the 3rd week of hypoxia regressed back toward normoxic baseline as the duration of re-oxygenation continued. In conclusion, elevated COX-2 and Ang-2 expression during hypoxia where angiogenesis occurs and re-oxygenation, when microvessels regress, identifies these proteins as vascular remodeling molecules crucial for angioplasticity. PMID:24796880

  11. HIF-1?/COX-2 expression and mouse brain capillary remodeling during prolonged moderate hypoxia and subsequent re-oxygenation.

    PubMed

    Benderro, Girriso F; LaManna, Joseph C

    2014-06-20

    Dynamic microvascular remodeling maintains an optimal continuous supply of oxygen and nutrients to the brain to account for prolonged environmental variations. The objective of this study was to determine the relative time course of capillary regression during re-oxygenation after exposure to prolonged moderate hypoxia and expression of the primary signaling factors involved in the process. Four-month old male C57BL/6 mice were housed and maintained in a hypobaric chamber at 290 Torr (0.4 atm) for 21 days and allowed to recover at normoxia (room air) for up to 21 days. The mice were either decapitated or perfused in-situ and brain samples collected were either homogenized for Western blot analysis or fixed and embedded in paraffin for immunohistochemistry. Hypoxia inducible factor-1? (HIF-1?), vascular endothelial growth factor (VEGF) and erythropoietin (EPO) expression were increased during hypoxic exposure and diminished during subsequent re-oxygenation. However, cyclooxygenase-2 (COX-2) and angiopoietin-2 (Ang-2) were both elevated during hypoxia as well as subsequent re-oxygenation. Significantly increased capillary density at the end of the 3rd week of hypoxia regressed back toward normoxic baseline as the duration of re-oxygenation continued. In conclusion, elevated COX-2 and Ang-2 expression during hypoxia where angiogenesis occurs and re-oxygenation, when micro-vessels regress, identifies these proteins as vascular remodeling molecules crucial for angioplasticity. PMID:24796880

  12. A Novel Function of Pet54 in Regulation of Cox1 Synthesis in Saccharomyces cerevisiae Mitochondria.

    PubMed

    Mayorga, Juan Pablo; Camacho-Villasana, Yolanda; Shingú-Vázquez, Miguel; García-Villegas, Rodolfo; Zamudio-Ochoa, Angélica; García-Guerrero, Aldo E; Hernández, Greco; Pérez-Martínez, Xochitl

    2016-04-22

    Cytochrome c oxidase assembly requires the synthesis of the mitochondria-encoded core subunits, Cox1, Cox2, and Cox3. In yeast, Pet54 protein is required to activate translation of the COX3 mRNA and to process the aI5β intron on the COX1 transcript. Here we report a third, novel function of Pet54 on Cox1 synthesis. We observed that Pet54 is necessary to achieve an efficient Cox1 synthesis. Translation of the COX1 mRNA is coupled to the assembly of cytochrome c oxidase by a mechanism that involves Mss51. This protein activates translation of the COX1 mRNA by acting on the COX1 5'-UTR, and, in addition, it interacts with the newly synthesized Cox1 protein in high molecular weight complexes that include the factors Coa3 and Cox14. Deletion of Pet54 decreased Cox1 synthesis, and, in contrast to what is commonly observed for other assembly mutants, double deletion of cox14 or coa3 did not recover Cox1 synthesis. Our results show that Pet54 is a positive regulator of Cox1 synthesis that renders Mss51 competent as a translational activator of the COX1 mRNA and that this role is independent of the assembly feedback regulatory loop of Cox1 synthesis. Pet54 may play a role in Mss51 hemylation/conformational change necessary for translational activity. Moreover, Pet54 physically interacts with the COX1 mRNA, and this binding was independent of the presence of Mss51. PMID:26929411

  13. On nonsingular potentials of Cox-Thompson inversion scheme

    SciTech Connect

    Palmai, Tamas; Apagyi, Barnabas

    2010-02-15

    We establish a condition for obtaining nonsingular potentials using the Cox-Thompson inverse scattering method with one phase shift. The anomalous singularities of the potentials are avoided by maintaining unique solutions of the underlying Regge-Newton integral equation for the transformation kernel. As a by-product, new inequality sequences of zeros of Bessel functions are discovered.

  14. On nonsingular potentials of Cox-Thompson inversion scheme

    NASA Astrophysics Data System (ADS)

    Pálmai, Tamás; Apagyi, Barnabás

    2010-02-01

    We establish a condition for obtaining nonsingular potentials using the Cox-Thompson inverse scattering method with one phase shift. The anomalous singularities of the potentials are avoided by maintaining unique solutions of the underlying Regge-Newton integral equation for the transformation kernel. As a by-product, new inequality sequences of zeros of Bessel functions are discovered.

  15. Molecular Docking of Bioactive Compounds Against BRCA and COX Proteins.

    PubMed

    2016-01-01

    The focus of molecular docking is to computationally simulate the molecular recognition process. A binding interaction between a small molecule ligand and protein may result in activation or inhibition of the protein. The docking method using BRCA1 or BRCA2 genes and COX proteins is carefully texted in this chapter to check docking of the best inhibitor molecule. PMID:26939289

  16. Cox Models Survival Analysis Based on Breast Cancer Treatments

    PubMed Central

    Abadi, Alireza; Yavari, Parvin; Dehghani-Arani, Monireh; Alavi-Majd, Hamid; Ghasemi, Erfan; Amanpour, Farzaneh; Bajdik, Chris

    2014-01-01

    Background The aim of this study is to evaluate the association between different treatments and survival time of breast cancer patients using either standard Cox model or stratified Cox model. Methods The study was conducted on 15830 women diagnosed with breast cancer in British Columbia, Canada. They were divided into eight groups according to patients ages and stage of disease Either Coxs PH model or stratified Cox model was fitted to each group according to the PH assumption and tested using Schoenfeld residuals. Results The data show that in the group of patients under age 50 years old and over age 50 with stage I cancer, the highest hazard was related to radiotherapy (HR= 3.15, CI: 1.85-5.35) and chemotherapy (HR= 3, CI: 2.29- 3.93) respectively. For both groups of patients with stage II cancer, the highest risk was related to radiotherapy (HR=3.02, CI: 2.26-4.03) (HR=2.16, CI:1.85-2.52). For both groups of patients with stage III cancer, the highest risk was for surgery (HR=0.49, CI: 0.33-0.73), (HR=0.45, CI: 0.36-0.57). For patients of age 50 years or less with stage IV cancer, none of the treatments were statistically significant. In group of patients over age 50 years old with stage IV cancer, the highest hazard was related to surgery (HR=0.64, CI: 0.53-0.78). Conclusion The results of this study show that for patients with stage I and II breast cancer, radiotherapy and chemotherapy had the highest hazard; for patients with stage III and IV breast cancer, the highest hazard was associated with treatment surgery. PMID:25250162

  17. 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. PMID:19075973

  18. Hierarchical Regression without Phantom Factors.

    ERIC Educational Resources Information Center

    Bentler, Peter M.; Satorra, Albert

    2000-01-01

    Shows that phantom factors are unnecessary to achieve the objectives of a hierarchical regression and gives a direct approach to computing hierarchical or fixed-order regressions that is equivalent to that proposed by P. de Jong (1999).(SLD)

  19. LIRA: LInear Regression in Astronomy

    NASA Astrophysics Data System (ADS)

    Sereno, Mauro

    2016-02-01

    LIRA (LInear Regression in Astronomy) performs Bayesian linear regression that accounts for heteroscedastic errors in both the independent and the dependent variables, intrinsic scatters (in both variables), time evolution of slopes, normalization and scatters, Malmquist and Eddington bias, and break of linearity. The posterior distribution of the regression parameters is sampled with a Gibbs method exploiting the JAGS (ascl:1209.002) library.

  20. The issue of multiple univariate comparisons in the context of neuroelectric brain mapping: an application in a neuromarketing experiment.

    PubMed

    Vecchiato, G; De Vico Fallani, F; Astolfi, L; Toppi, J; Cincotti, F; Mattia, D; Salinari, S; Babiloni, F

    2010-08-30

    This paper presents some considerations about the use of adequate statistical techniques in the framework of the neuroelectromagnetic brain mapping. With the use of advanced EEG/MEG recording setup involving hundred of sensors, the issue of the protection against the type I errors that could occur during the execution of hundred of univariate statistical tests, has gained interest. In the present experiment, we investigated the EEG signals from a mannequin acting as an experimental subject. Data have been collected while performing a neuromarketing experiment and analyzed with state of the art computational tools adopted in specialized literature. Results showed that electric data from the mannequin's head presents statistical significant differences in power spectra during the visualization of a commercial advertising when compared to the power spectra gathered during a documentary, when no adjustments were made on the alpha level of the multiple univariate tests performed. The use of the Bonferroni or Bonferroni-Holm adjustments returned correctly no differences between the signals gathered from the mannequin in the two experimental conditions. An partial sample of recently published literature on different neuroscience journals suggested that at least the 30% of the papers do not use statistical protection for the type I errors. While the occurrence of type I errors could be easily managed with appropriate statistical techniques, the use of such techniques is still not so largely adopted in the literature. PMID:20637802

  1. 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

  2. Multinomial logistic regression ensembles.

    PubMed

    Lee, Kyewon; Ahn, Hongshik; Moon, Hojin; Kodell, Ralph L; Chen, James J

    2013-05-01

    This article proposes a method for multiclass classification problems using ensembles of multinomial logistic regression models. A multinomial logit model is used as a base classifier in ensembles from random partitions of predictors. The multinomial logit model can be applied to each mutually exclusive subset of the feature space without variable selection. By combining multiple models the proposed method can handle a huge database without a constraint needed for analyzing high-dimensional data, and the random partition can improve the prediction accuracy by reducing the correlation among base classifiers. The proposed method is implemented using R, and the performance including overall prediction accuracy, sensitivity, and specificity for each category is evaluated on two real data sets and simulation data sets. To investigate the quality of prediction in terms of sensitivity and specificity, the area under the receiver operating characteristic (ROC) curve (AUC) is also examined. The performance of the proposed model is compared to a single multinomial logit model and it shows a substantial improvement in overall prediction accuracy. The proposed method is also compared with other classification methods such as the random forest, support vector machines, and random multinomial logit model. PMID:23611203

  3. Penalized Functional Regression

    PubMed Central

    Goldsmith, Jeff; Bobb, Jennifer; Crainiceanu, Ciprian M.; Caffo, Brian; Reich, Daniel

    2011-01-01

    We develop fast fitting methods for generalized functional linear models. The functional predictor is projected onto a large number of smooth eigenvectors and the coefficient function is estimated using penalized spline regression; confidence intervals based on the mixed model framework are obtained. Our method can be applied to many functional data designs including functions measured with and without error, sparsely or densely sampled. The methods also extend to the case of multiple functional predictors or functional predictors with a natural multilevel structure. The approach can be implemented using standard mixed effects software and is computationally fast. The methodology is motivated by a study of white-matter demyelination via diffusion tensor imaging (DTI). The aim of this study is to analyze differences between various cerebral white-matter tract property measurements of multiple sclerosis (MS) patients and controls. While the statistical developments proposed here were motivated by the DTI study, the methodology is designed and presented in generality and is applicable to many other areas of scientific research. An online appendix provides R implementations of all simulations. PMID:22368438

  4. Risk Factors of Graft Survival After Diagnosis of Post-kidney Transplant Malignancy: Using Cox Proportional Hazard Model

    PubMed Central

    Rahimi Foroushani, Abbas; Salesi, Mahmoud; Rostami, Zohreh; Mehrazmay, Ali Reza; Mohammadi, Jamile; Einollahi, Behzad; Eshraghian, Mohammad Reza

    2015-01-01

    Background: All recipients of kidney transplantation, especially those with posttransplant malignancy, are at risk of long-term graft failure. Objectives: The purpose of our study was to evaluate the risk factors associated with graft survival after diagnosis of malignancy. Patients and Methods: To reach this purpose, we conducted a historical cohort study in Iran and 266 cases with posttransplant malignancy were followed up from diagnosis of malignancy until long-term graft loss or the date of last visit. These patients were taken as a census from 16 Transplant Centers in Iran during 22 years follow-up period since October 1984 to December 2008. A Cox proportional hazards model was performed to determine the important independent predictors of graft survival after malignancy. Results: At the end of the study, long-term graft failure was seen in 27 (10.2%) cases. One-year and 2-year graft survival after diagnosis of cancer were 93.6% and 91.7%, respectively. The univariate analysis showed that the incidence of chronic graft loss was significantly higher in male patients with solid cancers, withdrawal of immunosuppressant regimen, no response to treatment, and tumor metastasis. In continuation, the Cox model indicated that the significant risk factors associated with graft survival were type of cancer (P < 0.0001), response to treatment (P < 0.0001, HR = 0.14, 95% CI: 0.06 - 0.32), metastasis (P < 0.0001, HR = 5.68, 95% CI: 2.24 - 14.42), and treatment modality (P = 0.0001). Conclusions: By controlling the modifiable risk factors and modality of treatment in our study, physicians can reach more effective treatment. PMID:26734477

  5. Cox rings, semigroups and automorphisms of affine algebraic varieties

    SciTech Connect

    Arzhantsev, Ivan V; Gaifullin, Sergei A

    2010-02-28

    We study the Cox realization of an affine variety, that is, a canonical representation of a normal affine variety with finitely generated divisor class group as a quotient of a factorially graded affine variety by an action of the Neron-Severi quasitorus. The realization is described explicitly for the quotient space of a linear action of a finite group. A universal property of this realization is proved, and some results in the divisor theory of an abstract semigroup emerging in this context are given. We show that each automorphism of an affine variety can be lifted to an automorphism of the Cox ring normalizing the grading. It follows that the automorphism group of an affine toric variety of dimension {>=}2 without nonconstant invertible regular functions has infinite dimension. We obtain a wild automorphism of the three-dimensional quadratic cone that rises to the Anick automorphism of the polynomial algebra in four variables. Bibliography: 22 titles.

  6. COX inhibitors directly alter gene expression: role in cancer prevention?

    PubMed Central

    Wang, Xingya; Baek, Seung Joon; Eling, Thomas

    2016-01-01

    Inflammation is an important contributor to the development and progression of human cancers. Inflammatory lipid metabolites, prostaglandins, formed from arachidonic acid by prostaglandin H synthases commonly called cyclooxygenases (COXs) bind to specific receptors that activate signaling pathways driving the development and progression of tumors. Inhibitors of prostaglandin formation, COX inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs) are well documented as agents that inhibit tumor growth and with long-term use prevent tumor development. NSAIDs also alter gene expression independent of COX inhibition and these changes in gene expression also appear to contribute to the anti-tumorigenic activity of these drugs. Many NSAIDs, as illustrated by sulindac sulfide, alter gene expressions by altering the expression or phosphorylation status of the transcription factors specificity protein 1 and early growth response-1 with the balance between these two events resulting in increases or decreases in specific target genes. In this review, we have summarized and discussed the various genes altered by this mechanism after NSAID treatment and how these changes in expression relate to the anti-tumorigenic activity. A major focus of the review is on NSAID-activated gene (NAG-1) or growth differentiation factor 15. This unique member of the TGF-? superfamily is highly induced by NSAIDs and numerous drugs and chemicals with anti-tumorigenic activities. Investigations with a transgenic mouse expressing the human NAG-1 suggest it acts to suppress tumor development in several mouse models of cancer. The biochemistry and biology of NAG-1 were discussed as potential contributor to cancer prevention by COX inhibitors. PMID:22020924

  7. Association Between COX-2 Polymorphisms and Lung Cancer Risk

    PubMed Central

    Wang, Weiwei; Fan, Xinyun; Zhang, Yong; Yang, Yi; Yang, Siyuan; Li, Gaofeng

    2015-01-01

    Background Multiple relevant risk factors for lung cancer have been reported in different populations, but results of previous studies were not consistent. Therefore, a meta-analysis is necessary to summarize these outcomes and reach a relatively comprehensive conclusion. Material/Methods STATA 12.0 software was used for all statistical of the relationship between COX-2 polymorphisms and lung cancer risk. Inter-study heterogeneity was examined with the Q statistic (significance level at P<0.1). The publication bias among studies in the meta-analysis was analyzed with Begg’s funnel plot and Egger’s test. Hardy-Weinberg equilibrium was tested in all controls of the studies. Results COX-2 rs20417 polymorphism had a significant association with reduced risk of lung cancer under homozygous and recessive models, and similar results were observed in white and population-based subgroups under 2 and 3 contrasts, respectively. Additionally, rs2066826 polymorphism manifested a strong correlation with increased risk of lung cancer under 5 genetic models. Conclusions In COX-2 gene, rs20417 may have a certain relationship with reduced risk of lung cancer, while rs2066826 may increase the risk of lung cancer. PMID:26624903

  8. COX-2 in cancer: Gordian knot or Achilles heel?

    PubMed Central

    Stasinopoulos, Ioannis; Shah, Tariq; Penet, Marie-France; Krishnamachary, Balaji; Bhujwalla, Zaver M.

    2013-01-01

    The networks of blood and lymphatic vessels and of the extracellular matrix and their cellular and structural components, that are collectively termed the tumor microenvironment, are frequently co-opted and shaped by cancer cells to survive, invade, and form distant metastasis. With an enviable capacity to adapt to continually changing environments, cancer represents the epitome of functional chaos, a stark contrast to the hierarchical and organized differentiation processes that dictate the development and life of biological organisms. The consequences of changing landscapes such as hypoxia and acidic extracellular pH in and around tumors create a cascade of changes in multiple pathways and networks that become apparent only several years later as recurrence and metastasis. These molecular and phenotypic changes, several of which are mediated by COX-2, approach the complexities of a Gordian Knot. We review evidence from our studies and from literature suggesting that cyclooxygenase-2 (COX-2) biology presents a nodal point in cancer biology and an Achilles heel of COX-2-dependent tumors. PMID:23579438

  9. Association Between COX-2 Polymorphisms and Lung Cancer Risk.

    PubMed

    Wang, Weiwei; Fan, Xinyun; Zhang, Yong; Yang, Yi; Yang, Siyuan; Li, Gaofeng

    2015-01-01

    BACKGROUND Multiple relevant risk factors for lung cancer have been reported in different populations, but results of previous studies were not consistent. Therefore, a meta-analysis is necessary to summarize these outcomes and reach a relatively comprehensive conclusion. MATERIAL AND METHODS STATA 12.0 software was used for all statistical of the relationship between COX-2 polymorphisms and lung cancer risk. Inter-study heterogeneity was examined with the Q statistic (significance level at P<0.1). The publication bias among studies in the meta-analysis was analyzed with Begg's funnel plot and Egger's test. Hardy-Weinberg equilibrium was tested in all controls of the studies. RESULTS COX-2 rs20417 polymorphism had a significant association with reduced risk of lung cancer under homozygous and recessive models, and similar results were observed in white and population-based subgroups under 2 and 3 contrasts, respectively. Additionally, rs2066826 polymorphism manifested a strong correlation with increased risk of lung cancer under 5 genetic models. CONCLUSIONS In COX-2 gene, rs20417 may have a certain relationship with reduced risk of lung cancer, while rs2066826 may increase the risk of lung cancer. PMID:26624903

  10. Limitations to benzene cancer risk assessment by Cox and Ricci

    SciTech Connect

    Crump, K.; Allen, B.; Clewell, H. )

    1993-04-01

    Cox and Ricci estimated human cancer risks from exposure to benzene by applying the linearized multi-stage model (LMS) to data on tumor responses in male mice. The unique feature of their analysis was their use of internal measures of dose estimated using a physiologically based pharmokinetic (PBPK) model. It is the authors' opinion that the inclusion of all squamous cell carcinomas in the Cox and Ricci experiment was not the most appropriate animal tumor category for the analysis. In addition, the authors' feel that to develop a dose-response curve for humans, it is reasonable to model a tumor that is more closely related to the observed human cancer endpoint, which is leukemia. To determine how robust the risk estimates made by Cox and Ricci were to different animal endpoints, in this work their methods were applied to two additional endpoints in mice: malignant lymphoma and alveolar/bronchial carcinoma. The methodology produced a good statistical fit to both sets of data.

  11. COX-2 gene expression in colon cancer tissue related to regulating factors and promoter methylation status

    PubMed Central

    2011-01-01

    Background Increased cyclooxygenase activity promotes progression of colorectal cancer, but the mechanisms behind COX-2 induction remain elusive. This study was therefore aimed to define external cell signaling and transcription factors relating to high COX-2 expression in colon cancer tissue. Method Tumor and normal colon tissue were collected at primary curative operation in 48 unselected patients. COX-2 expression in tumor and normal colon tissue was quantified including microarray analyses on tumor mRNA accounting for high and low tumor COX-2 expression. Cross hybridization was performed between tumor and normal colon tissue. Methylation status of up-stream COX-2 promoter region was evaluated. Results Tumors with high COX-2 expression displayed large differences in gene expression compared to normal colon. Numerous genes with altered expression appeared in tumors of high COX-2 expression compared to tumors of low COX-2. COX-2 expression in normal colon was increased in patients with tumors of high COX-2 compared to normal colon from patients with tumors of low COX-2. IL1β, IL6 and iNOS transcripts were up-regulated among external cell signaling factors; nine transcription factors (ATF3, C/EBP, c-Fos, Fos-B, JDP2, JunB, c-Maf, NF-κB, TCF4) showed increased expression and 5 (AP-2, CBP, Elk-1, p53, PEA3) were decreased in tumors with high COX-2. The promoter region of COX-2 gene did not show consistent methylation in tumor or normal colon tissue. Conclusions Transcription and external cell signaling factors are altered as covariates to COX-2 expression in colon cancer tissue, but DNA methylation of the COX-2 promoter region was not a significant factor behind COX-2 expression in tumor and normal colon tissue. PMID:21668942

  12. Supercomplex-associated Cox26 protein binds to cytochrome c oxidase.

    PubMed

    Strecker, Valentina; Kadeer, Zibirnisa; Heidler, Juliana; Cruciat, Cristina-Maria; Angerer, Heike; Giese, Heiko; Pfeiffer, Kathy; Stuart, Rosemary A; Wittig, Ilka

    2016-07-01

    Here we identified a hydrophobic 6.4kDa protein, Cox26, as a novel component of yeast mitochondrial supercomplex comprising respiratory complexes III and IV. Multi-dimensional native and denaturing electrophoretic techniques were used to identify proteins interacting with Cox26. The majority of the Cox26 protein was found non-covalently bound to the complex IV moiety of the III-IV supercomplexes. A population of Cox26 was observed to exist in a disulfide bond partnership with the Cox2 subunit of complex IV. No pronounced growth phenotype for Cox26 deficiency was observed, indicating that Cox26 may not play a critical role in the COX enzymology, and we speculate that Cox26 may serve to regulate or support the Cox2 protein. Respiratory supercomplexes are assembled in the absence of the Cox26 protein, however their pattern slightly differs to the wild type III-IV supercomplex appearance. The catalytic activities of complexes III and IV were observed to be normal and respiration was comparable to wild type as long as cells were cultivated under normal growth conditions. Stress conditions, such as elevated temperatures resulted in mild decrease of respiration in non-fermentative media when the Cox26 protein was absent. PMID:27091403

  13. Mutation analysis of COX18 in 29 patients with isolated cytochrome c oxidase deficiency.

    PubMed

    Sacconi, Sabrina; Salviati, Leonardo; Trevisson, Eva

    2009-07-01

    Isolated cytochrome c oxidase (COX) deficiency (MIM#220110) is a relatively common biochemical finding in pediatric patients with mitochondrial disorder. It has been associated with different clinical phenotypes ranging from isolated myopathy to severe multisystem disorder. It is a genetically heterogeneous trait, and the most frequent genetic defects affect SURF1 and SCO2, two genes required for COX assembly. However, a significant proportion of patients lacks mutation in these genes and in other known genes that require COX biogenesis. COX18 is a novel COX assembly gene required for membrane insertion of the C-terminal portion of COX subunit II. We have studied 29 pediatric patients with isolated COX deficiency in the skeletal muscle associated with different clinical phenotypes. Mutations in SURF1, SCO2, SCO1, COX10, COX15 and in mitochondrial DNA, had been ruled out earlier. The COX18 gene was analyzed using a PCR-single-stranded conformation polymorphism (PCR-SSCP) protocol, and in 15 patients, the analysis was repeated by direct sequencing. No pathogenic mutations were detected in our cohort of patients indicating that COX18 mutations may be very rare or associated with other phenotypes than isolated COX deficiency in infancy. PMID:19373256

  14. Linear regression in astronomy. II

    NASA Astrophysics Data System (ADS)

    Feigelson, Eric D.; Babu, Gutti J.

    1992-09-01

    A wide variety of least-squares linear regression procedures used in observational astronomy, particularly investigations of the cosmic distance scale, are presented and discussed. The classes of linear models considered are (1) unweighted regression lines, with bootstrap and jackknife resampling; (2) regression solutions when measurement error, in one or both variables, dominates the scatter; (3) methods to apply a calibration line to new data; (4) truncated regression models, which apply to flux-limited data sets; and (5) censored regression models, which apply when nondetections are present. For the calibration problem we develop two new procedures: a formula for the intercept offset between two parallel data sets, which propagates slope errors from one regression to the other; and a generalization of the Working-Hotelling confidence bands to nonstandard least-squares lines. They can provide improved error analysis for Faber-Jackson, Tully-Fisher, and similar cosmic distance scale relations.

  15. Retargeted Least Squares Regression Algorithm.

    PubMed

    Zhang, Xu-Yao; Wang, Lingfeng; Xiang, Shiming; Liu, Cheng-Lin

    2015-09-01

    This brief presents a framework of retargeted least squares regression (ReLSR) for multicategory classification. The core idea is to directly learn the regression targets from data other than using the traditional zero-one matrix as regression targets. The learned target matrix can guarantee a large margin constraint for the requirement of correct classification for each data point. Compared with the traditional least squares regression (LSR) and a recently proposed discriminative LSR models, ReLSR is much more accurate in measuring the classification error of the regression model. Furthermore, ReLSR is a single and compact model, hence there is no need to train two-class (binary) machines that are independent of each other. The convex optimization problem of ReLSR is solved elegantly and efficiently with an alternating procedure including regression and retargeting as substeps. The experimental evaluation over a range of databases identifies the validity of our method. PMID:25474813

  16. Quantile regression for climate data

    NASA Astrophysics Data System (ADS)

    Marasinghe, Dilhani Shalika

    Quantile regression is a developing statistical tool which is used to explain the relationship between response and predictor variables. This thesis describes two examples of climatology using quantile regression.Our main goal is to estimate derivatives of a conditional mean and/or conditional quantile function. We introduce a method to handle autocorrelation in the framework of quantile regression and used it with the temperature data. Also we explain some properties of the tornado data which is non-normally distributed. Even though quantile regression provides a more comprehensive view, when talking about residuals with the normality and the constant variance assumption, we would prefer least square regression for our temperature analysis. When dealing with the non-normality and non constant variance assumption, quantile regression is a better candidate for the estimation of the derivative.

  17. Error bounds in cascading regressions

    USGS Publications Warehouse

    Karlinger, M.R.; Troutman, B.M.

    1985-01-01

    Cascading regressions is a technique for predicting a value of a dependent variable when no paired measurements exist to perform a standard regression analysis. Biases in coefficients of a cascaded-regression line as well as error variance of points about the line are functions of the correlation coefficient between dependent and independent variables. Although this correlation cannot be computed because of the lack of paired data, bounds can be placed on errors through the required properties of the correlation coefficient. The potential meansquared error of a cascaded-regression prediction can be large, as illustrated through an example using geomorphologic data. ?? 1985 Plenum Publishing Corporation.

  18. Evaluating Differential Effects Using Regression Interactions and Regression Mixture Models

    ERIC Educational Resources Information Center

    Van Horn, M. Lee; Jaki, Thomas; Masyn, Katherine; Howe, George; Feaster, Daniel J.; Lamont, Andrea E.; George, Melissa R. W.; Kim, Minjung

    2015-01-01

    Research increasingly emphasizes understanding differential effects. This article focuses on understanding regression mixture models, which are relatively new statistical methods for assessing differential effects by comparing results to using an interactive term in linear regression. The research questions which each model answers, their…

  19. Evaluating Differential Effects Using Regression Interactions and Regression Mixture Models

    ERIC Educational Resources Information Center

    Van Horn, M. Lee; Jaki, Thomas; Masyn, Katherine; Howe, George; Feaster, Daniel J.; Lamont, Andrea E.; George, Melissa R. W.; Kim, Minjung

    2015-01-01

    Research increasingly emphasizes understanding differential effects. This article focuses on understanding regression mixture models, which are relatively new statistical methods for assessing differential effects by comparing results to using an interactive term in linear regression. The research questions which each model answers, their

  20. A General Semiparametric Hazards Regression Model: Efficient Estimation and Structure Selection

    PubMed Central

    Tong, Xingwei; Zhu, Liang; Leng, Chenlei; Leisenring, Wendy; Robison, Leslie L.

    2014-01-01

    We consider a general semiparametric hazards regression model that encompasses Coxs proportional hazards model and the accelerated failure time model for survival analysis. To overcome the nonexistence of the maximum likelihood, we derive a kernel-smoothed profile likelihood function, and prove that the resulting estimates of the regression parameters are consistent and achieve semiparametric efficiency. In addition, we develop penalized structure selection techniques to determine which covariates constitute the accelerate failure time model and which covariates constitute the proportional hazards model. The proposed method is able to estimate the model structure consistently and model parameters efficiently. Furthermore, variance estimation is straightforward. The proposed estimation performs well in simulation studies and is applied to the analysis of a real data set. Copyright PMID:23824784

  1. The Role of Prostaglandins and COX-Enzymes in Chondrogenic Differentiation of ATDC5 Progenitor Cells

    PubMed Central

    Caron, Marjolein M. J.; Emans, Pieter J.; Sanen, Kathleen; Surtel, Don A. M.; Cremers, Andy; Ophelders, Daan; van Rhijn, Lodewijk W.; Welting, Tim J. M.

    2016-01-01

    Objectives NSAIDs are used to relieve pain and decrease inflammation by inhibition of cyclooxygenase (COX)-catalyzed prostaglandin (PG) synthesis. PGs are fatty acid mediators involved in cartilage homeostasis, however the action of their synthesizing COX-enzymes in cartilage differentiation is not well understood. In this study we hypothesized that COX-1 and COX-2 have differential roles in chondrogenic differentiation. Methods ATDC5 cells were differentiated in the presence of COX-1 (SC-560, Mofezolac) or COX-2 (NS398, Celecoxib) specific inhibitors. Specificity of the NSAIDs and inhibition of specific prostaglandin levels were determined by EIA. Prostaglandins were added during the differentiation process. Chondrogenic outcome was determined by gene- and protein expression analyses. Results Inhibition of COX-1 prevented Col2a1 and Col10a1 expression. Inhibition of COX-2 resulted in decreased Col10a1 expression, while Col2a1 remained unaffected. To explain this difference expression patterns of both COX-enzymes as well as specific prostaglandin concentrations were determined. Both COX-enzymes are upregulated during late chondrogenic differentiation, whereas only COX-2 is briefly expressed also early in differentiation. PGD2 and PGE2 followed the COX-2 expression pattern, whereas PGF2α and TXA2 levels remained low. Furthermore, COX inhibition resulted in decreased levels of all tested PGs, except for PGD2 and PGF2α in the COX-1 inhibited condition. Addition of PGE2 and PGF2α resulted in increased expression of chondrogenic markers, whereas TXA2 increased expression of hypertrophic markers. Conclusions Our findings point towards a differential role for COX-enzymes and PG-production in chondrogenic differentiation of ATDC5 cells. Ongoing research is focusing on further elucidating the functional partition of cyclooxygenases and specific prostaglandin production. PMID:27050768

  2. Logistic Regression: Concept and Application

    ERIC Educational Resources Information Center

    Cokluk, Omay

    2010-01-01

    The main focus of logistic regression analysis is classification of individuals in different groups. The aim of the present study is to explain basic concepts and processes of binary logistic regression analysis intended to determine the combination of independent variables which best explain the membership in certain groups called dichotomous…

  3. Precision Efficacy Analysis for Regression.

    ERIC Educational Resources Information Center

    Brooks, Gordon P.

    When multiple linear regression is used to develop a prediction model, sample size must be large enough to ensure stable coefficients. If the derivation sample size is inadequate, the model may not predict well for future subjects. The precision efficacy analysis for regression (PEAR) method uses a cross- validity approach to select sample sizes…

  4. Purification, characterization, and localization of yeast Cox17p, a mitochondrial copper shuttle.

    PubMed

    Beers, J; Glerum, D M; Tzagoloff, A

    1997-12-26

    Cox17p was previously shown to be essential for the expression of cytochrome oxidase in Saccharomyces cerevisiae. In the present study COX17 has been placed under the control of the GAL10 promoter in an autonomously replicating plasmid. A yeast transformant harboring the high copy construct was used to purify Cox17p to homogeneity. Purified Cox17p contains 0.2-0.3 mol of copper per mol of protein. The molar copper content is increased to 1.8 after incubation of Cox17p in the presence of a 6-fold molar excess of cuprous chloride under reduced conditions. An antibody against Cox17p was obtained by immunization of rabbits with a carboxyl-terminal peptide coupled to bovine serum albumin. The antiserum detects Cox17p in both the mitochondrial and soluble protein fractions of wild type yeast and of the transformant overexpressing Cox17p. Exposure of intact mitochondria to hypotonic conditions causes most of Cox17p to be released as a soluble protein indicating that the mitochondrial fraction of Cox17p is localized in the intermembrane space. These results are consistent with the previously proposed function of Cox17p, namely in providing cytoplasmic copper for mitochondrial utilization. PMID:9407107

  5. COX-2 inhibition in schizophrenia and major depression.

    PubMed

    Müller, Norbert; Schwarz, Markus J

    2008-01-01

    In schizophrenia and depression, opposite patterns of type-1 - type-2 immune response seem to be associated with differences in the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and in the tryptophan - kynurenine metabolism resulting in increased production of kynurenic acid in schizophrenia and decreased production of kynurenic acid in depression. These differences are associated with an imbalance in the glutamatergic neurotransmission, which may contribute to an overweight of N-methyl-D-aspartate (NMDA) agonism in depression and of NMDA antagonism in schizophrenia. The differential activation of microglia cells and astrocytes may be an additional mechanism contributing to this imbalance. The immunological imbalance results both in schizophrenia and in depression in an increased Prostaglandin E(2) (PGE(2)) production and probably also in an increased Cyclo-oxygenase-2 (COX-2) expression. Although there is strong evidence for the view, that the interactions of the immune system, IDO, the serotonergic system, and the glutamatergic neurotransmission play a key role in schizophrenia and in depression, several gaps, e.g. the roles of genetics, disease course, sex, different psychopathological states, etc. have to be bridged by intense further research. There are already hints that anti-inflammatory therapy may have beneficial effects in schizophrenia and major depression. COX-2 inhibititors have been tested in animal models of depression and in preliminary clinical trials, the latter showing favourable effects compared to placebo, both, in schizophrenia and in major depression. The effects of COX-2 inhibition in the central nervous system (CNS) as well as the different components of the inflammatory system, the kynurenine-metabolism and the glutamatergic neurotransmission, however, still need careful further validation including clinical studies with sufficient sample size. PMID:18537668

  6. 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. PMID:27083394

  7. Electron paramagnetic resonance in Zn1-xCoxO

    NASA Astrophysics Data System (ADS)

    Acosta-Humánez, F.; Cogollo Pitalúa, R.; Almanza, O.

    2013-03-01

    In this paper is reported the Electron Paramagnetic Resonance (EPR) studies in Zn1-xCoxO powder, with 0.01≤x≤0.05, at many temperatures (105-250 K). These samples were synthesized by the sol-gel method (citrate route). Results suggest that the ferromagnetism behavior of the materials is governed by ferromagnetic coupling among cobalt ions. For cobalt concentration higher than 3% were obtained mean size particle higher than 25 nm, measured by X-ray diffraction, and for this were also observed shallow free radical.

  8. Room temperature ferromagnetic (Fe₁-xCox)₃BO₅ nanorods.

    PubMed

    He, Shuli; Zhang, Hongwang; Xing, Hui; Li, Kai; Cui, Hongfei; Yang, Chenguang; Sun, Shouheng; Zeng, Hao

    2014-07-01

    Cobalt-doped ferroferriborate ((Fe1-xCox)3BO5) nanorods (NRs) are synthesized by a one-pot high-temperature organic-solution-phase method. The aspect ratios of the NRs are tuned by the heating rate. These NRs form via anisotropic growth along twin boundaries of the multiply twinned nuclei. Magnetic properties are dramatically modified by Co substitutional doping, changing from antiferromagnetic order at low temperatures to ferromagnetic above room temperature, with a greatly enhanced magnetic ordering temperature. These anisotropic ferromagnetic NRs with a high ordering temperature may provide a new platform for understanding nanomagnetism and for magnetic applications. PMID:24905634

  9. COX-2 overexpression in resected pancreatic head adenocarcinomas correlates with favourable prognosis

    PubMed Central

    2014-01-01

    Background Overexpression of cyclooxygenase-2 (COX-2) has been implicated in oncogenesis and progression of adenocarcinomas of the pancreatic head. The data on the prognostic importance of COX expression in these tumours is inconsistent and conflicting. We evaluated how COX-2 overexpression affected overall postoperative survival in pancreatic head adenocarcinomas. Methods The study included 230 consecutive pancreatoduodenectomies for pancreatic cancer (PC, n = 92), ampullary cancer (AC, n = 62) and distal bile duct cancer (DBC, n = 76). COX-2 expression was assessed by immunohistochemistry. Associations between COX-2 expression and histopathologic variables including degree of differentiation, histopathologic type of differentiation (pancreatobiliary vs. intestinal) and lymph node ratio (LNR) were evaluated. Unadjusted and adjusted survival analysis was performed. Results COX-2 staining was positive in 71% of PC, 77% in AC and 72% in DBC. Irrespective of tumour origin, overall patient survival was more favourable in patients with COX-2 positive tumours than COX-2 negative (p = 0.043 in PC, p = 0.011 in AC, p = 0.06 in DBC). In tumours of pancreatobiliary type of histopathological differentiation, COX-2 expression did not significantly affect overall patient survival. In AC with intestinal differentiation COX-2 expression significantly predicted favourable survival (p = 0.003). In PC, COX-2 expression was significantly associated with high degree of differentiation (p = 0.002). COX-2 and LNR independently predicted good prognosis in a multivariate model. Conclusions COX-2 is overexpressed in pancreatic cancer, ampullary cancer and distal bile duct cancer and confers a survival benefit in all three cancer types. In pancreatic cancer, COX-2 overexpression is significantly associated with the degree of differentiation and independently predicts a favourable prognosis. PMID:24950702

  10. What Do Differences Between Multi-voxel and Univariate Analysis Mean? How Subject-, Voxel-, and Trial-level Variance Impact fMRI Analysis

    PubMed Central

    Davis, Tyler; LaRocque, Karen F.; Mumford, Jeanette; Norman, Kenneth A.; Wagner, Anthony D.; Poldrack, Russell A.

    2014-01-01

    Multi-voxel pattern analysis (MVPA) has led to major changes in how fMRI data are analyzed and interpreted. Many studies now report both MVPA results and results from standard univariate voxel-wise analysis, often with the goal of drawing different conclusions from each. Because MVPA results can be sensitive to latent multidimensional representations and processes whereas univariate voxel-wise analysis cannot, one conclusion that is often drawn when MVPA and univariate results differ is that the activation patterns underlying MVPA results contain a multidimensional code. In the current study, we conducted simulations to formally test this assumption. Our findings reveal that MVPA tests are sensitive to the magnitude of voxel-level variability in the effect of a condition within subjects, even when the same linear relationship is coded in all voxels. We also find that MVPA is insensitive to subject-level variability in mean activation across an ROI, which is the primary variance component of interest in many standard univariate tests. Together, these results illustrate that differences between MVPA and univariate tests do not afford conclusions about the nature or dimensionality of the neural code. Instead, targeted tests of the informational content and/or dimensionality of activation patterns are critical for drawing strong conclusions about the representational codes that are indicated by significant MVPA results. PMID:24768930

  11. Development of COX inhibitors in cancer prevention and therapy.

    PubMed

    Umar, Asad; Viner, Jaye L; Anderson, William F; Hawk, Ernest T

    2003-08-01

    On the strength of in vitro, in vivo, observational, and clinical data, nonsteroidal antiinflammatory drugs (NSAIDs)-also referred to as COX inhibitors-have emerged as lead compounds for cancer prevention, and possible adjuncts to cancer therapy. Thus far, the routine use of NSAIDs for these indications is limited, largely owing to toxicity concerns, the paucity of efficacy data for any specific target organ, and uncertainties with regard to the most appropriate regimen (i.e., the best agent, formulation, dose, route of administration, and duration). Strategies to address these concerns primarily aim to improve the therapeutic index (i.e., benefit:risk ratio) of COX inhibitors by 1) minimizing systemic exposures whenever feasible, 2) achieving greater mechanistic specificity, 3) coadministering agents that provide prophylaxis against common toxicities, and 4) coadministering other effective anticancer agents. Clinical trials testing most of these strategies have been completed or are under way. The National Cancer Institute has a substantial research portfolio dedicated to the identification, testing, and development of NSAIDs as preventive and therapeutic anticancer agents. Discovering how to apply NSAIDs in persons with-or at risk for-cancer, although challenging, has the potential for considerable clinical and public health benefits. PMID:12902856

  12. COX-2 active agents in the chemoprevention of colorectal cancer.

    PubMed

    Kraus, Sarah; Naumov, Inna; Arber, Nadir

    2013-01-01

    Chemopreventive strategies for colorectal cancer (CRC) have been extensively studied to prevent the recurrence of adenomas and/or delay their development in the gastrointestinal tract. The non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors have been proven as promising and the most attractive candidates for CRC clinical chemoprevention. The preventive efficacy of these agents is supported by a large number of animal and epidemiological studies which have clearly demonstrated that NSAID consumption prevents adenoma formation and decreases the incidence of, and mortality from CRC. On the basis of these studies, aspirin chemoprevention may be effective in preventing CRC within the general population, while aspirin and celecoxib may be effective in preventing adenomas in patients after polypectomy. Nevertheless, the consumption of NSAID and COX-2 inhibitors is not toxic free. Well-known serious adverse events to the gastrointestinal, renal and cardiovascular systems have been reported. These reports have led to some promising studies related to the use of lower doses and in combination with other chemopreventive agents and shown efficacy. In the intriguing jigsaw puzzle of cancer prevention, we now have a definite positive answer for the basic question "if", but several other parts of the equation-proper patient selection, the ultimate drug, optimal dosage and duration are still missing. PMID:22893201

  13. Specific NF-kappaB blockade selectively inhibits tumour necrosis factor-alpha-induced COX-2 but not constitutive COX-1 gene expression in HT-29 cells.

    PubMed Central

    Jobin, C; Morteau, O; Han, D S; Balfour Sartor, R

    1998-01-01

    Cyclo-oxygenase (COX) is the key regulatory enzyme of the prostaglandin/eicosanoid pathway. While COX-1 is mostly constitutively expressed, the COX-2 isoform is inducible by proinflammatory cytokines. We used an adenoviral vector containing an NF-kappaB super-repressor (Ad5IkappaB) to investigate the role of NF-kappaB in tumour necrosis factor-alpha (TNF-alpha)-mediated COX-2 gene expression in a colonic epithelial cell line. COX-1 mRNA and protein were constitutively expressed in uninfected, control Ad5LacZ- or Ad5IkappaB-infected HT-29 cells with no apparent change following TNF-alpha exposure. COX-2 mRNA and protein expression was undetectable in unstimulated cells but was strongly up-regulated after TNF-alpha stimulation in uninfected and Ad5LacZ-infected HT-29 cells. This induction was prevented in Ad5IkappaB cells. TNF-alpha increased prostaglandin E2 production by 20-fold in Ad5LacZ-infected HT-29 cells compared with uninfected cells and was significantly inhibited in Ad5IkappaB-infected cells in agreement with the COX-2 mRNA findings. We conclude that NF-kappaB activation is critical in mediating COX-2, but not COX-1 gene expression in HT-29 cells. Selective inhibition of COX-2 expression with the NF-kappaB super-repressor may be useful in distinguishing the role of inducible versus constitutive prostaglandins in intestinal function and provides greater specificity than pharmacological inhibitors. Images Figure 1 Figure 2 Figure 3 PMID:9893042

  14. Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.

    PubMed

    Antonicka, Hana; Leary, Scot C; Guercin, Guy-Hellen; Agar, Jeffrey N; Horvath, Rita; Kennaway, Nancy G; Harding, Cary O; Jaksch, Michaela; Shoubridge, Eric A

    2003-10-15

    Deficiencies in the activity of cytochrome c oxidase (COX) are an important cause of autosomal recessive respiratory chain disorders. Patients with isolated COX deficiency are clinically and genetically heterogeneous, and mutations in several different assembly factors have been found to cause specific clinical phenotypes. Two of the most common clinical presentations, Leigh Syndrome and hypertrophic cardiomyopathy, have so far only been associated with mutations in SURF1 or SCO2 and COX15, respectively. Here we show that expression of COX10 from a retroviral vector complements the COX deficiency in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy. A partial rescue was also obtained following microcell-mediated transfer of mouse chromosomes into patient fibroblasts. COX10 functions in the first step of the mitochondrial heme A biosynthetic pathway, catalyzing the conversion of protoheme (heme B) to heme O via the farnesylation of a vinyl group at position C2. Heme A content was reduced in mitochondria from patient muscle and fibroblasts in proportion to the reduction in COX enzyme activity and the amount of fully assembled enzyme. Mutation analysis of COX10 identified four different missense alleles, predicting amino acid substitutions at evolutionarily conserved residues. A topological model places these residues in regions of the protein shown to have important catalytic functions by mutation analysis of a prokaryotic ortholog. Mutations in COX10 have previously been reported in a single family with tubulopathy and leukodystrophy. This study shows that mutations in this gene can cause nearly the full range of clinical phenotypes associated with early onset isolated COX deficiency. PMID:12928484

  15. Practical Session: Simple Linear Regression

    NASA Astrophysics Data System (ADS)

    Clausel, M.; Grégoire, G.

    2014-12-01

    Two exercises are proposed to illustrate the simple linear regression. The first one is based on the famous Galton's data set on heredity. We use the lm R command and get coefficients estimates, standard error of the error, R2, residuals …In the second example, devoted to data related to the vapor tension of mercury, we fit a simple linear regression, predict values, and anticipate on multiple linear regression. This pratical session is an excerpt from practical exercises proposed by A. Dalalyan at EPNC (see Exercises 1 and 2 of http://certis.enpc.fr/~dalalyan/Download/TP_ENPC_4.pdf).

  16. Comparison of imputation methods for handling missing covariate data when fitting a Cox proportional hazards model: a resampling study

    PubMed Central

    2010-01-01

    Background The appropriate handling of missing covariate data in prognostic modelling studies is yet to be conclusively determined. A resampling study was performed to investigate the effects of different missing data methods on the performance of a prognostic model. Methods Observed data for 1000 cases were sampled with replacement from a large complete dataset of 7507 patients to obtain 500 replications. Five levels of missingness (ranging from 5% to 75%) were imposed on three covariates using a missing at random (MAR) mechanism. Five missing data methods were applied; a) complete case analysis (CC) b) single imputation using regression switching with predictive mean matching (SI), c) multiple imputation using regression switching imputation, d) multiple imputation using regression switching with predictive mean matching (MICE-PMM) and e) multiple imputation using flexible additive imputation models. A Cox proportional hazards model was fitted to each dataset and estimates for the regression coefficients and model performance measures obtained. Results CC produced biased regression coefficient estimates and inflated standard errors (SEs) with 25% or more missingness. The underestimated SE after SI resulted in poor coverage with 25% or more missingness. Of the MI approaches investigated, MI using MICE-PMM produced the least biased estimates and better model performance measures. However, this MI approach still produced biased regression coefficient estimates with 75% missingness. Conclusions Very few differences were seen between the results from all missing data approaches with 5% missingness. However, performing MI using MICE-PMM may be the preferred missing data approach for handling between 10% and 50% MAR missingness. PMID:21194416

  17. Neural Univariate Activity and Multivariate Pattern in the Posterior Superior Temporal Sulcus Differentially Encode Facial Expression and Identity.

    PubMed

    Yang, Zetian; Zhen, Zonglei; Huang, Lijie; Kong, Xiang-Zhen; Wang, Xu; Song, Yiying; Liu, Jia

    2016-01-01

    Faces contain a variety of information such as one's identity and expression. One prevailing model suggests a functional division of labor in processing faces that different aspects of facial information are processed in anatomically separated and functionally encapsulated brain regions. Here, we demonstrate that facial identity and expression can be processed in the same region, yet with different neural coding strategies. To this end, we employed functional magnetic resonance imaging to examine two types of coding schemes, namely univariate activity and multivariate pattern, in the posterior superior temporal cortex (pSTS) - a face-selective region that is traditionally viewed as being specialized for processing facial expression. With the individual difference approach, we found that participants with higher overall face selectivity in the right pSTS were better at differentiating facial expressions measured outside of the scanner. In contrast, individuals whose spatial pattern for faces in the right pSTS was less similar to that for objects were more accurate in identifying previously presented faces. The double dissociation of behavioral relevance between overall neural activity and spatial neural pattern suggests that the functional-division-of-labor model on face processing is over-simplified, and that coding strategies shall be incorporated in a revised model. PMID:26997104

  18. Neural Univariate Activity and Multivariate Pattern in the Posterior Superior Temporal Sulcus Differentially Encode Facial Expression and Identity

    PubMed Central

    Yang, Zetian; Zhen, Zonglei; Huang, Lijie; Kong, Xiang-zhen; Wang, Xu; Song, Yiying; Liu, Jia

    2016-01-01

    Faces contain a variety of information such as one’s identity and expression. One prevailing model suggests a functional division of labor in processing faces that different aspects of facial information are processed in anatomically separated and functionally encapsulated brain regions. Here, we demonstrate that facial identity and expression can be processed in the same region, yet with different neural coding strategies. To this end, we employed functional magnetic resonance imaging to examine two types of coding schemes, namely univariate activity and multivariate pattern, in the posterior superior temporal cortex (pSTS) - a face-selective region that is traditionally viewed as being specialized for processing facial expression. With the individual difference approach, we found that participants with higher overall face selectivity in the right pSTS were better at differentiating facial expressions measured outside of the scanner. In contrast, individuals whose spatial pattern for faces in the right pSTS was less similar to that for objects were more accurate in identifying previously presented faces. The double dissociation of behavioral relevance between overall neural activity and spatial neural pattern suggests that the functional-division-of-labor model on face processing is over-simplified, and that coding strategies shall be incorporated in a revised model. PMID:26997104

  19. 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

  20. Mechanisms underlying the cardiovascular effects of COX-inhibition: benefits and risks.

    PubMed

    Martínez-González, José; Badimon, Lina

    2007-01-01

    Selective inhibitors of cyclooxygenase-2 (COX-2) were designed to minimize gastrointestinal complications of traditional non-steroidal anti-inflammatory drugs (NSAIDs) attributed to the suppression of COX-1-derived prostanoids. Selective COX-2 inhibitors (coxibs) are effective anti-inflammatory and analgesic drugs. However, recently it has become apparent that some coxibs increase the risk of serious cardiovascular events, including myocardial infarction and stroke. This has led to the withdrawal of rofecoxib from markets and has raised the concern about an inherent atherothrombotic risk of this class of drugs. This question should be carefully analyzed in the light of the current knowledge on COX-2 functions in the cardiovascular system. COX-2 is regarded as an inducible enzyme involved in the pathophysiology of inflammation and pain. In the cardiovascular system, COX-2 has also been associated with pro-inflammatory/pro-atherogenic stages, due to its up-regulation in monocyte-derived macrophages present in atherosclerotic lesions. However, experimental and clinical studies suggest that COX-2 is "constitutively" expressed in some tissues, among them in the vascular endothelium, where COX-2-derived prostanoids, especially prostacyclin (PGI(2)), contribute in the maintenance of vascular homeostasis and integrity. This review provides an updated overview on the functions of COX-2 in the cardiovascular system addressing key issues that could help to understand why chronic COX-2 inhibition may have undesirable effects in patients at cardiovascular risk. PMID:17691994

  1. Stretch-induced myoblast proliferation is dependent on the COX2 pathway

    SciTech Connect

    Otis, Jeffrey S.; Burkholder, Thomas J.; Pavlath, Grace K. . E-mail: gpavlat@emory.edu

    2005-11-01

    Skeletal muscle increases in size due to weight bearing loads or passive stretch. This growth response is dependent in part upon myoblast proliferation. Although skeletal muscles are responsive to mechanical forces, the effect on myoblast proliferation remains unknown. To investigate the effects of mechanical stretch on myoblast proliferation, primary myoblasts isolated from Balb/c mice were subjected to 25% cyclical uniaxial stretch for 5 h at 0.5 Hz. Stretch stimulated myoblast proliferation by 32% and increased cell number by 41% 24 and 48 h after stretch, respectively. COX2 mRNA increased 3.5-fold immediately poststretch. Prostaglandin E2 and F{sub 2{alpha}} increased 2.4- and 1.6-fold 6 h after stretch, respectively. Because COX2 has been implicated in regulating muscle growth and regeneration, we hypothesized that stretched myoblasts may proliferate via a COX2-dependent mechanism. We employed two different models to disrupt COX2 activity: (1) treatment with a COX2-selective drug, and (2) transgenic mice null for COX2. Treating myoblasts with a COX2-specific inhibitor blocked stretch-induced proliferation. Likewise, stretched COX2{sup -/-} myoblasts failed to proliferate compared to controls. However, supplementing stretched, COX2{sup -/-} myoblasts with prostaglandin E2 or fluprostenol increased proliferation. These data suggest that the COX2 pathway is critical for myoblast proliferation in response to stretch.

  2. The cytochrome c oxidase biogenesis factor AtCOX17 modulates stress responses in Arabidopsis.

    PubMed

    Garcia, Lucila; Welchen, Elina; Gey, Uta; Arce, Agustín L; Steinebrunner, Iris; Gonzalez, Daniel H

    2016-03-01

    COX17 is a soluble protein from the mitochondrial intermembrane space that participates in the transfer of copper for cytochrome c oxidase (COX) assembly in eukaryotic organisms. In this work, we studied the function of both Arabidopsis thaliana AtCOX17 genes using plants with altered expression levels of these genes. Silencing of AtCOX17-1 in a cox17-2 knockout background generates plants with smaller rosettes and decreased expression of genes involved in the response of plants to different stress conditions, including several genes that are induced by mitochondrial dysfunctions. Silencing of either of the AtCOX17 genes does not affect plant development or COX activity but causes a decrease in the response of genes to salt stress. In addition, these plants contain higher reactive oxygen and lipid peroxidation levels after irrigation with high NaCl concentrations and are less sensitive to abscisic acid. In agreement with a role of AtCOX17 in stress and abscisic acid responses, both AtCOX17 genes are induced by several stress conditions, abscisic acid and mutation of the transcription factor ABI4. The results indicate that AtCOX17 is required for optimal expression of a group of stress-responsive genes, probably as a component of signalling pathways that link stress conditions to gene expression responses. PMID:26436309

  3. Time-Warped Geodesic Regression

    PubMed Central

    Hong, Yi; Singh, Nikhil; Kwitt, Roland; Niethammer, Marc

    2016-01-01

    We consider geodesic regression with parametric time-warps. This allows, for example, to capture saturation effects as typically observed during brain development or degeneration. While highly-flexible models to analyze time-varying image and shape data based on generalizations of splines and polynomials have been proposed recently, they come at the cost of substantially more complex inference. Our focus in this paper is therefore to keep the model and its inference as simple as possible while allowing to capture expected biological variation. We demonstrate that by augmenting geodesic regression with parametric time-warp functions, we can achieve comparable flexibility to more complex models while retaining model simplicity. In addition, the time-warp parameters provide useful information of underlying anatomical changes as demonstrated for the analysis of corpora callosa and rat calvariae. We exemplify our strategy for shape regression on the Grassmann manifold, but note that the method is generally applicable for time-warped geodesic regression. PMID:25485368

  4. Abstract Expression Grammar Symbolic Regression

    NASA Astrophysics Data System (ADS)

    Korns, Michael F.

    This chapter examines the use of Abstract Expression Grammars to perform the entire Symbolic Regression process without the use of Genetic Programming per se. The techniques explored produce a symbolic regression engine which has absolutely no bloat, which allows total user control of the search space and output formulas, which is faster, and more accurate than the engines produced in our previous papers using Genetic Programming. The genome is an all vector structure with four chromosomes plus additional epigenetic and constraint vectors, allowing total user control of the search space and the final output formulas. A combination of specialized compiler techniques, genetic algorithms, particle swarm, aged layered populations, plus discrete and continuous differential evolution are used to produce an improved symbolic regression sytem. Nine base test cases, from the literature, are used to test the improvement in speed and accuracy. The improved results indicate that these techniques move us a big step closer toward future industrial strength symbolic regression systems.

  5. Multiple Regression and Its Discontents

    ERIC Educational Resources Information Center

    Snell, Joel C.; Marsh, Mitchell

    2012-01-01

    Multiple regression is part of a larger statistical strategy originated by Gauss. The authors raise questions about the theory and suggest some changes that would make room for Mandelbrot and Serendipity.

  6. Basis Selection for Wavelet Regression

    NASA Technical Reports Server (NTRS)

    Wheeler, Kevin R.; Lau, Sonie (Technical Monitor)

    1998-01-01

    A wavelet basis selection procedure is presented for wavelet regression. Both the basis and the threshold are selected using cross-validation. The method includes the capability of incorporating prior knowledge on the smoothness (or shape of the basis functions) into the basis selection procedure. The results of the method are demonstrated on sampled functions widely used in the wavelet regression literature. The results of the method are contrasted with other published methods.

  7. Regression Discontinuity Designs in Epidemiology

    PubMed Central

    Moscoe, Ellen; Mutevedzi, Portia; Newell, Marie-Louise; Brnighausen, Till

    2014-01-01

    When patients receive an intervention based on whether they score below or above some threshold value on a continuously measured random variable, the intervention will be randomly assigned for patients close to the threshold. The regression discontinuity design exploits this fact to estimate causal treatment effects. In spite of its recent proliferation in economics, the regression discontinuity design has not been widely adopted in epidemiology. We describe regression discontinuity, its implementation, and the assumptions required for causal inference. We show that regression discontinuity is generalizable to the survival and nonlinear models that are mainstays of epidemiologic analysis. We then present an application of regression discontinuity to the much-debated epidemiologic question of when to start HIV patients on antiretroviral therapy. Using data from a large South African cohort (20072011), we estimate the causal effect of early versus deferred treatment eligibility on mortality. Patients whose first CD4 count was just below the 200 cells/?L CD4 count threshold had a 35% lower hazard of death (hazard ratio = 0.65 [95% confidence interval = 0.450.94]) than patients presenting with CD4 counts just above the threshold. We close by discussing the strengths and limitations of regression discontinuity designs for epidemiology. PMID:25061922

  8. 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

  9. 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. PMID:25071299

  10. p50-associated COX-2 extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-κB complexes

    PubMed Central

    Krawczyk, Michal; Emerson, Beverly M

    2014-01-01

    Deregulated expression of COX-2 has been causally linked to development, progression, and outcome of several types of human cancer. We describe a novel fundamental level of transcriptional control of COX-2 expression. Using primary human mammary epithelial cells and monocyte/macrophage cell lines, we show that the chromatin boundary/insulator factor CTCF establishes an open chromatin domain and induces expression of a long non-coding RNA within the upstream promoter region of COX-2. Upon induction of COX-2 expression, the lncRNA associates with p50, a repressive subunit of NF-κB, and occludes it from the COX-2 promoter, potentially facilitating interaction with activation-competent NF-κB p65/p50 dimers. This enables recruitment of the p300 histone acetyltransferase, a domain-wide increase in histone acetylation and assembly of RNA Polymerase II initiation complexes. Our findings reveal an unexpected mechanism of gene control by lncRNA-mediated repressor occlusion and identify the COX-2-lncRNA, PACER, as a new potential target for COX-2-modulation in inflammation and cancer. DOI: http://dx.doi.org/10.7554/eLife.01776.001 PMID:24843008

  11. (R)-Profens Are Substrate-Selective Inhibitors of Endocannabinoid Oxygenation by COX-2

    PubMed Central

    Duggan, Kelsey C.; Hermanson, Daniel J.; Musee, Joel; Prusakiewicz, Jeffery J.; Scheib, Jami L.; Carter, Bruce D.; Banerjee, Surajit; Oates, J.A.; Marnett, Lawrence J.

    2012-01-01

    Cyclooxygenase-2 (COX-2) catalyzes the oxygenation of arachidonic acid and the endocannabinoids, 2-arachidonoylglycerol and arachidonoylethanolamide. Evaluation of a series of COX-2 inhibitors revealed that many weak, competitive inhibitors of arachidonic acid oxygenation are potent inhibitors of endocannabinoid oxygenation. (R)-Enantiomers of ibuprofen, naproxen, and flurbiprofen, which are considered to be inactive as COX-2 inhibitors, are potent “substrate-selective inhibitors” of endocannabinoid oxygenation. Crystal structures of the COX-2-(R)-naproxen and COX-2-(R)-flurbiprofen complexes verified this unexpected binding and defined the orientation of the (R)-enantiomers relative to (S)-enantiomers. (R)-Profens selectively inhibited endocannabinoid oxygenation by lipopolysaccharide-stimulated dorsal root ganglion cells. Substrate-selective inhibition provides novel tools for investigating the role of COX-2 in endocannabinoid oxygenation and a possible explanation for the ability of (R)-profens to maintain endocannabinoid tone in models of neuropathic pain. PMID:22053353

  12. The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic infiltration and COX-2 expression and survival in patients with transitional cell carcinoma of the urinary bladder

    PubMed Central

    Hilmy, M; Campbell, R; Bartlett, J M S; McNicol, A-M; Underwood, M A; McMillan, D C

    2006-01-01

    The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic infiltration, and COX-2 expression and survival was examined in patients with transitional cell carcinoma of the urinary bladder (n=103). Sixty-one patients had superficial disease and 42 patients had invasive disease. Cancer-specific survival was shorter in those patients with invasive compared with superficial bladder cancer (P<0.001). On univariate analysis, stratified by stage, increased Ki-67 labelling index (P<0.05), increased COX-2 expression (P<0.05), C-reactive protein (P<0.05) and adjuvant therapy (P<0.01) were associated with poorer cancer-specific survival. On multivariate analysis of these significant factors, stratified by stage, only C-reactive protein (HR 2.89, 95% CI 1.42–5.91, P=0.004) and adjuvant therapy (HR 0.29, 95% CI 0.14–0.62, P=0.001) were independently associated with poorer cancer-specific survival. These results would suggest that tumour-based factors such as grade, COX-2 expression or T-lymphocytic infiltration are subordinate to systemic factors such as C-reactive protein in determining survival in patients with transitional cell carcinoma of the urinary bladder. PMID:17024120

  13. 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.

  14. Synaptic and extrasynaptic NMDA receptors differentially modulate neuronal COX-2 function, lipid peroxidation, and neuroprotection

    PubMed Central

    Stark, David T.; Bazan, Nicolas G.

    2011-01-01

    Stimulation of synaptic NMDA receptors (NMDARs) induces neuroprotection, while extrasynaptic NMDARs promote excitotoxic cell death. Neuronal expression of cyclooxygenase-2 (COX-2) is enhanced by synaptic NMDARs, and although this enzyme mediates neuronal functions, COX-2 is also regarded as a key modulator of neuroinflammation and is thought to exacerbate excitotoxicity via overproduction of prostaglandins. This raises an apparent paradox: synaptic NMDARs are pro-survival yet are essential for robust neuronal COX-2 expression. We hypothesized that stimulation of extrasynaptic NMDARs converts COX-2 signaling from a physiological to a potentially pathological process. We combined HPLC-ESI-MS/MS-based mediator lipidomics and unbiased image analysis in mouse dissociated and organotypic cortical cultures to uncover that synaptic and extrasynaptic NMDARs differentially modulate neuronal COX-2 expression and activity. We show that synaptic NMDARs enhance neuronal COX-2 expression, while sustained synaptic stimulation limits COX-2 activity by suppressing cellular levels of the primary COX-2 substrate, arachidonic acid (AA). In contrast, extrasynaptic NMDARs suppress COX-2 expression while activating phospholipase A2 (PLA2), which enhances AA levels by hydrolysis of membrane phospholipids. Thus, sequential activation of synaptic then extrasynaptic NMDARs maximizes COX-2-dependent prostaglandin synthesis. We also show that excitotoxic events only drive induction of COX-2 expression through abnormal synaptic network excitability. Finally, we show that non-enzymatic lipid peroxidation of arachidonic and other polyunsaturated fatty acids is a function of network activity history. A new paradigm emerges from our results suggesting that pathological COX-2 signaling associated with models of stroke, epilepsy, and neurodegeneration requires specific spatio-temporal NMDAR stimulation. PMID:21957234

  15. Corticosteroids induce COX-2 expression in cardiomyocytes: role of glucocorticoid receptor and C/EBP-β

    PubMed Central

    Sun, Haipeng; Sheveleva, Elena; Xu, Beibei; Inoue, Hiroyasu; Bowden, Tim G.; Chen, Qin M.

    2008-01-01

    Psychological stress increases the level of glucocorticoids in the circulating system. We found that dexamethasone administration in adult mice elevates the expression of COX-2 in the myocardium. With isolated neonatal cardiomyocytes, corticosterone (CT) at physiologically relevant doses (0.01–1 μM) induces the expression of COX-2 gene. The induction first appeared at 4 h and remained for at least 24 h with 1 μM CT treatment. This response is likely cardiomyocyte cell type specific since CT did not induce COX-2 expression in cardiac fibroblasts and glucocorticoids are known to suppress the expression of COX-2 in lymphocytes and several organs. Corticosteroids, but not estrogen or progesterone, induce COX-2 expression. The glucocorticoid receptor (GR) antagonist mifepristone (MF) prevented CT from inducing COX-2 gene, suggesting a GR-dependent induction in cardiomyocytes. COX-2 gene promoter deletion and mutation studies indicate a role of CCAAT/enhancer binding protein-β (C/EBP-β) in CT-induced COX-2 gene expression. Chromatin immunoprecipitation assays revealed that CT caused the binding of both GR and C/EBP-β to COX-2 promoter, while MF pretreatment blocked such binding. Coimmunoprecipitation experiments demonstrated that CT treatment induced the interaction of GR with C/EBP-β. Small interfering RNA against C/EBP-β prevented CT from activating COX-2 promoter or elevating COX-2 protein. Our data suggest that the interaction between GR and C/EBP-β contributes to elevated COX-2 gene transcription by CT in cardiomyocytes. PMID:18650268

  16. Aromatic hydrocarbons in the atmospheric environment - Part II: univariate and multivariate analysis and case studies of indoor concentrations

    NASA Astrophysics Data System (ADS)

    Ilgen, Elke; Levsen, Karsten; Angerer, Jürgen; Schneider, Peter; Heinrich, Joachim; Wichmann, H.-Erich

    The concentrations of the aromatic hydrocarbons benzene, toluene, ethylbenzene and the isomeric xylenes (BTEX) have been determined in the indoor air of 115 private non-smoker homes (˜380 individual rooms) situated in areas with an extreme traffic situation, i.e. in city streets (street canyons) with high traffic density and in rural areas with hardly any traffic at all. The influence of the traffic on the indoor concentration was apparent in the high traffic area. In order to identify other factors influencing the BTEX concentrations, the data and additional questionnaires were analyzed by univariate and multivariate analysis. The analysis was supplemented by some case studies. It is shown that meteorology (the seasons), the type of room (e.g. living room versus bedroom), the ventilation and, in particular, garages in the house strongly influence the indoor concentration of BTEX. Thus, the indoor BTEX level is significantly higher in winter than in summer. Moreover, garages with a connecting door to the living quarters lead to high indoor concentrations of aromatic hydrocarbons in these rooms. In addition, the storage of solvents and hobby materials, and also the presence of smoking guests increase the BTEX level. If rooms are directly heated by coal or wood, the BTEX level is higher compared to the use of gas heating. Surprisingly, no correlation was found between the building materials used and the BTEX level. Case studies were carried out for two homes with an integrated garage (and a connecting door to the living rooms) and for seven homes where redecoration work was carried out during sampling. In both instances, a pronounced increase was observed in the BTEX concentration.

  17. Molecular docking analysis of known flavonoids as duel COX-2 inhibitors in the context of cancer

    PubMed Central

    Dash, Raju; Uddin, Mir Muhammad Nasir; Hosen, S.M. Zahid; Rahim, Zahed Bin; Dinar, Abu Mansur; Kabir, Mohammad Shah Hafez; Sultan, Ramiz Ahmed; Islam, Ashekul; Hossain, Md Kamrul

    2015-01-01

    Cyclooxygenase-2 (COX-2) catalyzed synthesis of prostaglandin E2 and it associates with tumor growth, infiltration, and metastasis in preclinical experiments. Known inhibitors against COX-2 exhibit toxicity. Therefore, it is of interest to screen natural compounds like flavanoids against COX-2. Molecular docking using 12 known flavanoids against COX-2 by FlexX and of ArgusLab were performed. All compounds showed a favourable binding energy of >-10 KJ/mol in FlexX and > -8 kcal/mol in ArgusLab. However, this data requires in vitro and in vivo verification for further consideration. PMID:26770028

  18. Chapter 2: Mechanistic Aspects of COX-2 Expression in Colorectal Neoplasia

    PubMed Central

    Dixon, Dan A.; Blanco, Fernando F.; Bruno, Annalisa; Patrignani, Paola

    2012-01-01

    The cyclooxygenase-2 (COX-2) enzyme catalyzes the rate-limiting step of prostaglandin formation in pathogenic states and a large amount of evidence has demonstrated constitutive COX-2 expression to be a contributing factor promoting colorectal cancer (CRC). Various genetic, epigenetic, and inflammatory pathways have been identified to be involved in the etiology and development of CRC. Alteration in these pathways can influence COX-2 expression at multiple stages of colon carcinogenesis allowing for elevated prostanoid biosynthesis to occur in the tumor microenvironment. In normal cells, COX-2 expression levels are potently regulated at the post-transcriptional level through various RNA sequence elements present within the mRNA 3′-untranslated region(3′UTR). A conserved AU-rich element(ARE) functions to target COX-2 mRNA for rapid decay and translational inhibition through association with various RNA-binding proteins to influence the fate of COX-2 mRNA. Specific microRNAs bind regions within the COX-2 3′UTR and control COX-2 expression. In this chapter, we discuss novel insights in the mechanisms of altered posttranscriptional regulation of COX-2 in CRC and how this knowledge may be used to develop novel strategies for cancer prevention and treatment. PMID:22893198

  19. 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

  20. 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.

  1. 5-methoxyindole metabolites of L-tryptophan: control of COX-2 expression, inflammation and tumorigenesis

    PubMed Central

    2014-01-01

    Cyclooxygenase-2(COX-2) overexpression promotes inflammation and tumorigenesis. COX-2 expression in response to diverse stimuli is tightly controlled to avoid persistent overexpression. 5-methoxyindole metabolites of L-tryptophan represent a new class of compounds that control COX-2 expression at the transcriptional level. Two of the metabolites, the newly discovered 5-methoxytryptophan (5-MTP, also known as cytoguardin) and N-acetyl 5-methoxytryptamine (melatonin) are the focus of this review. 5-MTP is produced by mesenchymal cells such as fibroblasts via 5-hydroxytryptophan (5-HTP). It inhibits COX-2 transcriptional activation induced by diverse proinflammatory and mitogenic factors. Cancer cells are deficient in cytoguardin production which contributes to COX-2 overexpression. Fibroblast-generated 5-MTP is capable of restoring the control of COX-2 overexpression in cancer cells. 5-MTP blocks cancer cell migration and invasion in vitro and inhibits tumor growth and cancer metastasis in a xenograft model. Melatonin possesses similar COX-2 suppressing and anti-cancer properties albeit at supra-pharmacological concentrations. By contrast, 5-hydroxyindole metabolites of L-tryptophan such as 5-hydroxytryptamine (serotonin), 5-hydroxytryptophol and other serotonin catabolites do not control COX-2 expression. 5-hydroxytryptophan inhibits COX-2 expression through conversion to 5-MTP. The physiological relevance of 5-MTP as an endogenous regulator of inflammation and cancer metastasis remains to be investigated. On the other hand, 5-methoxyindole metabolites of tryptophan are valuable lead compounds for development of new anti-inflammatory drugs and cancer chemoprevention. PMID:24589238

  2. A Varying-Coefficient Cox Model for the Effect of Age at a Marker Event on Age at Menopause

    PubMed Central

    Nan, Bin; Lin, Xihong; Lisabeth, Lynda D.; Harlow, Siobán D.

    2005-01-01

    Summary It is of recent interest in reproductive health research to investigate the validity of a marker event for the onset of menopausal transition and to estimate age at menopause using age at the marker event. We propose a varying-coefficient Cox model to investigate the association between age at a marker event, defined as a specific bleeding pattern change, and age at menopause, where both events are subject to censoring and their association varies with age at the marker event. Estimation proceeds using the regression spline method. The proposed method is applied to the Tremin Trust data to evaluate the association between age at onset of the 60-day menstrual cycle and age at menopause. The performance of the proposed method is evaluated using a simulation study. PMID:16011707

  3. Regressing Eruptive Disseminated Spitz Nevi.

    PubMed

    Bhoyrul, Bevin; Tang, Diana Y L; Carling, Edward E; Harikumar, Chidambara; Newton-Bishop, Julia; Carmichael, Andrew J

    2015-01-01

    The eruptive disseminated form of Spitz nevi (EDSN) is the rarest variant, is cosmetically disabling, and has a poorly documented natural history. We report the case of a 4-year-old boy with more than 100 Spitz nevi that have significantly regressed 8 years after onset. There is no satisfactory treatment for EDSN. There have been no reports of supervening malignancy. Our case illustrates the possibility of regression of EDSN, corroborating long-term observation as a safe and acceptable management option. PMID:25968096

  4. Spontaneous regression of neonatal fibrosarcoma.

    PubMed Central

    Madden, N. P.; Spicer, R. D.; Allibone, E. B.; Lewis, I. J.

    1992-01-01

    We report a case of fibrosarcoma, which presented in a two week old boy. Excision was not performed because it would have required mutilating surgery. The tumour regressed and was impalpable by 7 months of age. The patient is tumour free at 4 years of age. This is the first reported case of spontaneous regression of a fibrosarcoma. The literature is reviewed. We conclude that the chances of metastasis are low, tumours are likely to respond to chemotherapy, and mutilating surgery is not appropriate initial treatment for infantile fibrosarcomas. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:1503930

  5. Pathophysiology of motility dysfunction in bowel obstruction: role of stretch-induced COX-2

    PubMed Central

    Lin, You-Min; Powell, Don W.; Sarna, Sushil K.

    2011-01-01

    In gastrointestinal conditions such as bowel obstruction, pseudo-obstruction, and idiopathic megacolon, the lumen of affected bowel segments is distended and its motility function impaired. Our hypothesis is that mechanical stretch of the distended segments alters gene expression of cyclooxygenase-2 (COX-2), which impairs motility function. Partial obstruction was induced with a silicon band in the distal colon of rats for up to 7 days, and wild-type and COX-2 gene-deficient mice for 4 days. Mechanical stretch was mimicked in vitro in colonic circular muscle strips and in primary culture of colonic circular smooth muscle cells (SMC) with a Flexercell system. The rat colonic circular muscle contractility was significantly decreased in the distended segment oral to obstruction, but not in the aboral segment. This change started as early as day 1 and persisted for at least 7 days after obstruction. The expression of COX-2 mRNA and protein increased dramatically also in the oral, but not aboral, segment. The upregulation of COX-2 expression started at 12 h and the effect persisted for 7 days. At 24 h after obstruction, the COX-2 mRNA level in the oral segment increased 26-fold compared with controls. This was not accompanied by any significant increase of myeloperoxidase or inflammatory cytokines. Immunohistochemical studies showed that COX-2 was selectively induced in the colonic SMC. In vitro stretch of colonic muscle strips or cultured SMC drastically induced COX-2 expression. Incubation of circular muscle strips from obstructed segment with COX-2 inhibitor NS-398 restored the contractility. The impairment of muscle contractility in obstructed colon was attenuated in the COX-2 gene-deficient mice. In conclusion, mechanical stretch in obstruction induces marked expression of COX-2 in the colonic SMC, and stretch-induced COX-2 plays a critical role in the suppression of smooth muscle contractility in bowel obstruction. PMID:21051526

  6. Peripheral inflammatory hyperalgesia depends on the COX increase in the dorsal root ganglion

    PubMed Central

    Araldi, Dionéia; Ferrari, Luiz Fernando; Lotufo, Celina Monteiro; Vieira, André Schwambach; Athié, Maria Carolina Pedro; Figueiredo, Jozi Godoy; Duarte, Djane Braz; Tambeli, Claudia Herrera; Ferreira, Sérgio Henrique; Parada, Carlos Amilcar

    2013-01-01

    It is well established that dorsal root ganglion (DRG) cells synthesize prostaglandin. However, the role that prostaglandin plays in the inflammatory hyperalgesia of peripheral tissue has not been established. Recently, we have successfully established a technique to inject drugs (3 μL) directly into the L5-DRG of rats, allowing in vivo identification of the role that DRG cell-derived COX-1 and COX-2 play in the development of inflammatory hyperalgesia of peripheral tissue. IL-1β (0.5 pg) or carrageenan (100 ng) was administered in the L5-peripheral field of rat hindpaw and mechanical hyperalgesia was evaluated after 3 h. Administration of a nonselective COX inhibitor (indomethacin), selective COX-1 (valeryl salicylate), or selective COX-2 (SC-236) inhibitors into the L5-DRG prevented the hyperalgesia induced by IL-1β. Similarly, oligodeoxynucleotide-antisense against COX-1 or COX-2, but not oligodeoxynucleotide-mismatch, decreased their respective expressions in the L5-DRG and prevented the hyperalgesia induced by IL-1β in the hindpaw. Immunofluorescence analysis demonstrated that the amount of COX-1 and COX-2, constitutively expressed in TRPV-1+ cells of the DRG, significantly increased after carrageenan or IL-1β administration. In addition, indomethacin administered into the L5-DRG prevented the increase of PKCε expression in DRG membrane cells induced by carrageenan. Finally, the administration of EP1/EP2 (7.5 ng) or EP4 (10 µg) receptor antagonists into L5-DRG prevented the hyperalgesia induced by IL-1β in the hindpaw. In conclusion, the results of this study suggest that the inflammatory hyperalgesia in peripheral tissue depends on activation of COX-1 and COX-2 in C-fibers, which contribute to the induction and maintenance of sensitization of primary sensory neurons. PMID:23401543

  7. Reversible Suppression of Cyclooxygenase 2 (COX-2) Expression In Vivo by Inducible RNA Interference

    PubMed Central

    Zaiss, Anne K.; Zuber, Johannes; Chu, Chun; Machado, Hidevaldo B.; Jiao, Jing; Catapang, Arthur B.; Ishikawa, Tomo-o; Gil, Jose S.; Lowe, Scott W.; Herschman, Harvey R.

    2014-01-01

    Prostaglandin-endoperoxide synthase 2 (PTGS2), also known as cyclooxygenase 2 (COX-2), plays a critical role in many normal physiological functions and modulates a variety of pathological conditions. The ability to turn endogenous COX-2 on and off in a reversible fashion, at specific times and in specific cell types, would be a powerful tool in determining its role in many contexts. To achieve this goal, we took advantage of a recently developed RNA interference system in mice. An shRNA targeting the Cox2 mRNA 3′untranslated region was inserted into a microRNA expression cassette, under the control of a tetracycline response element (TRE) promoter. Transgenic mice containing the COX-2-shRNA were crossed with mice encoding a CAG promoter-driven reverse tetracycline transactivator, which activates the TRE promoter in the presence of tetracycline/doxycycline. To facilitate testing the system, we generated a knockin reporter mouse in which the firefly luciferase gene replaces the Cox2 coding region. Cox2 promoter activation in cultured cells from triple transgenic mice containing the luciferase allele, the shRNA and the transactivator transgene resulted in robust luciferase and COX-2 expression that was reversibly down-regulated by doxycycline administration. In vivo, using a skin inflammation-model, both luciferase and COX-2 expression were inhibited over 80% in mice that received doxycycline in their diet, leading to a significant reduction of infiltrating leukocytes. In summary, using inducible RNA interference to target COX-2 expression, we demonstrate potent, reversible Cox2 gene silencing in vivo. This system should provide a valuable tool to analyze cell type-specific roles for COX-2. PMID:24988319

  8. Improving Your Data Transformations: Applying the Box-Cox Transformation

    ERIC Educational Resources Information Center

    Osborne, Jason W.

    2010-01-01

    Many of us in the social sciences deal with data that do not conform to assumptions of normality and/or homoscedasticity/homogeneity of variance. Some research has shown that parametric tests (e.g., multiple regression, ANOVA) can be robust to modest violations of these assumptions. Yet the reality is that almost all analyses (even nonparametric…

  9. Cactus: An Introduction to Regression

    ERIC Educational Resources Information Center

    Hyde, Hartley

    2008-01-01

    When the author first used "VisiCalc," the author thought it a very useful tool when he had the formulas. But how could he design a spreadsheet if there was no known formula for the quantities he was trying to predict? A few months later, the author relates he learned to use multiple linear regression software and suddenly it all clicked into…

  10. Fungible Weights in Multiple Regression

    ERIC Educational Resources Information Center

    Waller, Niels G.

    2008-01-01

    Every set of alternate weights (i.e., nonleast squares weights) in a multiple regression analysis with three or more predictors is associated with an infinite class of weights. All members of a given class can be deemed "fungible" because they yield identical "SSE" (sum of squared errors) and R[superscript 2] values. Equations for generating…

  11. Regression Models of Atlas Appearance

    PubMed Central

    Rohlfing, Torsten; Sullivan, Edith V.; Pfefferbaum, Adolf

    2010-01-01

    Models of object appearance based on principal components analysis provide powerful and versatile tools in computer vision and medical image analysis. A major shortcoming is that they rely entirely on the training data to extract principal modes of appearance variation and ignore underlying variables (e.g., subject age, gender). This paper introduces an appearance modeling framework based instead on generalized multi-linear regression. The training of regression appearance models is controlled by independent variables. This makes it straightforward to create model instances for specific values of these variables, which is akin to model interpolation. We demonstrate the new framework by creating an appearance model of the human brain from MR images of 36 subjects. Instances of the model created for different ages are compared with average shape atlases created from age-matched sub-populations. Relative tissue volumes vs. age in models are also compared with tissue volumes vs. subject age in the original images. In both experiments, we found excellent agreement between the regression models and the comparison data. We conclude that regression appearance models are a promising new technique for image analysis, with one potential application being the representation of a continuum of mutually consistent, age-specific atlases of the human brain. PMID:19694260

  12. Correlation Weights in Multiple Regression

    ERIC Educational Resources Information Center

    Waller, Niels G.; Jones, Jeff A.

    2010-01-01

    A general theory on the use of correlation weights in linear prediction has yet to be proposed. In this paper we take initial steps in developing such a theory by describing the conditions under which correlation weights perform well in population regression models. Using OLS weights as a comparison, we define cases in which the two weighting…

  13. Logistic Regression with Random Coefficients.

    ERIC Educational Resources Information Center

    Longford, Nicholas T.

    An approximation to the likelihood for the generalized linear models with random coefficients is derived and is the basis for an approximate Fisher scoring algorithm. The method is illustrated on the logistic regression model for one-way classification, but it has an extension to the class of generalized linear models and to more complex data…

  14. Weighting Regressions by Propensity Scores

    ERIC Educational Resources Information Center

    Freedman, David A.; Berk, Richard A.

    2008-01-01

    Regressions can be weighted by propensity scores in order to reduce bias. However, weighting is likely to increase random error in the estimates, and to bias the estimated standard errors downward, even when selection mechanisms are well understood. Moreover, in some cases, weighting will increase the bias in estimated causal parameters. If…

  15. Clinical use and pharmacological properties of selective COX-2 inhibitors.

    PubMed

    Shi, Shaojun; Klotz, Ulrich

    2008-03-01

    Selective COX-2 inhibitors (coxibs) are approved for the relief of acute pain and symptoms of chronic inflammatory conditions such as osteoarthritis (OA) and rheumatoid arthritis (RA). They have similar pharmacological properties but a slightly improved gastrointestinal (GI) safety profile if compared to traditional nonsteroidal anti-inflammatory drugs (tNSAIDs). However, long-term use of coxibs can be associated with an increased risk for cardiovascular (CV) adverse events (AEs). For this reason, two coxibs were withdrawn from the market. Currently celecoxib, etoricoxib, and lumiracoxib are used. These three coxibs differ in their chemical structure and selectivity for COX-2, which might explain some of their pharmacological features. Following oral administration, the less lipophilic celecoxib has a lower bioavailability (20-40%) than the other two coxibs (74-100%). All are eliminated by hepatic metabolism involving mainly CYP2C9 (celecoxib, lumiracoxib) and CYP3A4 (etoricoxib). Elimination half-life varies from 5 to 8 h (lumiracoxib), 11 to 16 h (celecoxib) and 19 to 32 h (etoricoxib). In patients with liver disease, plasma levels of celecoxib and etoricoxib are increased about two-fold. Clinical efficacies of the coxibs are comparable to tNSAIDs. There is an ongoing discussion about whether the slightly better GI tolerability (which is lost if acetylsalicylic acid is coadministered) of the coxibs is offset by their elevated risks for CV AEs (also seen with tNSAIDs other than naproxen), which apparently increase with dose and duration of exposure. In addition, the higher costs for coxibs (if compared to tNSAIDs, even when a "gastroprotective" proton pump inhibitor is coadministered) should be taken into consideration, if a coxib will be selected for certain patients with a high risk for GI complications. For such treatment, the lowest effective dose should be used for a limited time. Monitoring of kidney function and blood pressure appears advisable. It is hoped that further controlled studies can better define the therapeutic place of the coxibs. PMID:17999057

  16. Hierarchical Adaptive Regression Kernels for Regression with Functional Predictors

    PubMed Central

    Woodard, Dawn B.; Crainiceanu, Ciprian; Ruppert, David

    2013-01-01

    We propose a new method for regression using a parsimonious and scientifically interpretable representation of functional predictors. Our approach is designed for data that exhibit features such as spikes, dips, and plateaus whose frequency, location, size, and shape varies stochastically across subjects. We propose Bayesian inference of the joint functional and exposure models, and give a method for efficient computation. We contrast our approach with existing state-of-the-art methods for regression with functional predictors, and show that our method is more effective and efficient for data that include features occurring at varying locations. We apply our methodology to a large and complex dataset from the Sleep Heart Health Study, to quantify the association between sleep characteristics and health outcomes. Software and technical appendices are provided in online supplemental materials. PMID:24293988

  17. Glutathione selectively modulates the binding of platinum drugs to human copper chaperone Cox17.

    PubMed

    Zhao, Linhong; Wang, Zhen; Wu, Han; Xi, Zhaoyong; Liu, Yangzhong

    2015-12-01

    The copper chaperone Cox17 (cytochrome c oxidase copper chaperone) has been shown to facilitate the delivery of cisplatin to mitochondria, which contributes to the overall cytotoxicity of the drug [Zhao et al. (2014) Chem. Commun. 50: , 2667-2669]. Kinetic data indicate that Cox17 has reactivity similar to glutathione (GSH), the most abundant thiol-rich molecule in the cytoplasm. In the present study, we found that GSH significantly modulates the reaction of platinum complexes with Cox17. GSH enhances the reactivity of three anti-cancer drugs (cisplatin, carboplatin and oxaliplatin) to Cox17, but suppresses the reaction of transplatin. Surprisingly, the pre-formed cisplatin-GSH adducts are highly reactive to Cox17; over 90% platinum transfers from GSH to Cox17. On the other hand, transplatin-GSH adducts are inert to Cox17. These different effects are consistent with the drug activity of these platinum complexes. In addition, GSH attenuates the protein aggregation of Cox17 induced by platination. These results indicate that the platinum-protein interactions could be substantially influenced by the cellular environment. PMID:26399480

  18. Interaction of the renin angiotensin and cox systems in the kidney.

    PubMed

    Quadri, Syed S; Culver, Silas A; Li, Caixia; Siragy, Helmy M

    2016-01-01

    Cyclooxygenase-2 (COX-2) plays an important role in mediating actions of the renin-angiotensin system (RAS). This review sheds light on the recent developments regarding the complex interactions between components of RAS and COX-2; and their implications on renal function and disease. COX-2 is believed to counter regulate the effects of RAS activation and therefore counter balance the vasoconstriction effect of Ang II. In kidney, under normal conditions, these systems are essential for maintaining a balance between vasodilation and vasoconstriction. However, recent studies suggested a pivotal role for this interplay in pathology. COX-2 increases the renin release and Ang II formation leading to increase in blood pressure. COX-2 is also associated with diabetic nephropathy, where its upregulation in the kidney contributes to glomerular injury and albuminuria. Selective inhibition of COX-2 retards the progression of renal injury. COX-2 also mediates the pathologic effects of the (Pro)renin receptor (PRR) in the kidney. In summary, this review discusses the interaction between the RAS and COX-2 in health and disease. PMID:27100703

  19. Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer

    PubMed Central

    Jiang, Hong-Lin; Li, Liang-Dong; Hu, Xin; Xu, Xiao-En; Jin, Wei

    2015-01-01

    COX5B, a peripheral subunit of the cytochrome c oxidase complex, has previously been reported to maintain the stability of this complex. However, its functions and mechanisms involved in breast cancer progression remain unclear. Here, by performing SILAC assays in breast cancer cell models and detecting COX5B expression in tissues, we found that COX5B expression was elevated in breast cancer. Down-regulation of COX5B in breast cancer cell lines can suppress cell proliferation and induced cell senescence which was accompanied by elevating production of IL-8 and other cytokines. Interestingly, conditioned medium from COX5B knockdown cells could promote breast cancer cell migration. Mechanistic studies reveal that COX5B silence induces an increase in production of ROS, depolarization of MMP and a decrease in ATP. What's more, silence of COX5B leads to metabolic disorders, such as increased glucose uptake and decreased lactate secretion. Collectively, our study shows that loss of COX5B induces mitochondrial dysfunction and subsequently leads to cell growth suppression and cell senescence. Cytokines such as IL-8 secreted by senescent cells may in turn alter the microenvironment which could enhance cell migration. These findings may provide a novel paradigm for the treatment which combined anti-cancer drugs with particular cytokine inhibitors such as IL-8 blockers. PMID:26506233

  20. Human mitochondrial COX1 assembly into cytochrome c oxidase at a glance.

    PubMed

    Dennerlein, Sven; Rehling, Peter

    2015-03-01

    Mitochondria provide the main portion of cellular energy in form of ATP produced by the F1Fo ATP synthase, which uses the electrochemical gradient, generated by the mitochondrial respiratory chain (MRC). In human mitochondria, the MRC is composed of four multisubunit enzyme complexes, with the cytochrome c oxidase (COX, also known as complex IV) as the terminal enzyme. COX comprises 14 structural subunits, of nuclear or mitochondrial origin. Hence, mitochondria are faced with the predicament of organizing and controlling COX assembly with subunits that are synthesized by different translation machineries and that reach the inner membrane by alternative transport routes. An increasing number of COX assembly factors have been identified in recent years. Interestingly, mutations in several of these factors have been associated with human disorders leading to COX deficiency. Recently, studies have provided mechanistic insights into crosstalk between assembly intermediates, import processes and the synthesis of COX subunits in mitochondria, thus linking conceptually separated functions. This Cell Science at a Glance article and the accompanying poster will focus on COX assembly and discuss recent discoveries in the field, the molecular functions of known factors, as well as new players and control mechanisms. Furthermore, these findings will be discussed in the context of human COX-related disorders. PMID:25663696

  1. Bayesian dynamic regression models for interval censored survival data with application to children dental health.

    PubMed

    Wang, Xiaojing; Chen, Ming-Hui; Yan, Jun

    2013-07-01

    Cox models with time-varying coefficients offer great flexibility in capturing the temporal dynamics of covariate effects on event times, which could be hidden from a Cox proportional hazards model. Methodology development for varying coefficient Cox models, however, has been largely limited to right censored data; only limited work on interval censored data has been done. In most existing methods for varying coefficient models, analysts need to specify which covariate coefficients are time-varying and which are not at the time of fitting. We propose a dynamic Cox regression model for interval censored data in a Bayesian framework, where the coefficient curves are piecewise constant but the number of pieces and the jump points are covariate specific and estimated from the data. The model automatically determines the extent to which the temporal dynamics is needed for each covariate, resulting in smoother and more stable curve estimates. The posterior computation is carried out via an efficient reversible jump Markov chain Monte Carlo algorithm. Inference of each coefficient is based on an average of models with different number of pieces and jump points. A simulation study with three covariates, each with a coefficient of different degree in temporal dynamics, confirmed that the dynamic model is preferred to the existing time-varying model in terms of model comparison criteria through conditional predictive ordinate. When applied to a dental health data of children with age between 7 and 12 years, the dynamic model reveals that the relative risk of emergence of permanent tooth 24 between children with and without an infected primary predecessor is the highest at around age 7.5, and that it gradually reduces to one after age 11. These findings were not seen from the existing studies with Cox proportional hazards models. PMID:23389549

  2. Regression Verification Using Impact Summaries

    NASA Technical Reports Server (NTRS)

    Backes, John; Person, Suzette J.; Rungta, Neha; Thachuk, Oksana

    2013-01-01

    Regression verification techniques are used to prove equivalence of syntactically similar programs. Checking equivalence of large programs, however, can be computationally expensive. Existing regression verification techniques rely on abstraction and decomposition techniques to reduce the computational effort of checking equivalence of the entire program. These techniques are sound but not complete. In this work, we propose a novel approach to improve scalability of regression verification by classifying the program behaviors generated during symbolic execution as either impacted or unimpacted. Our technique uses a combination of static analysis and symbolic execution to generate summaries of impacted program behaviors. The impact summaries are then checked for equivalence using an o-the-shelf decision procedure. We prove that our approach is both sound and complete for sequential programs, with respect to the depth bound of symbolic execution. Our evaluation on a set of sequential C artifacts shows that reducing the size of the summaries can help reduce the cost of software equivalence checking. Various reduction, abstraction, and compositional techniques have been developed to help scale software verification techniques to industrial-sized systems. Although such techniques have greatly increased the size and complexity of systems that can be checked, analysis of large software systems remains costly. Regression analysis techniques, e.g., regression testing [16], regression model checking [22], and regression verification [19], restrict the scope of the analysis by leveraging the differences between program versions. These techniques are based on the idea that if code is checked early in development, then subsequent versions can be checked against a prior (checked) version, leveraging the results of the previous analysis to reduce analysis cost of the current version. Regression verification addresses the problem of proving equivalence of closely related program versions [19]. These techniques compare two programs with a large degree of syntactic similarity to prove that portions of one program version are equivalent to the other. Regression verification can be used for guaranteeing backward compatibility, and for showing behavioral equivalence in programs with syntactic differences, e.g., when a program is refactored to improve its performance, maintainability, or readability. Existing regression verification techniques leverage similarities between program versions by using abstraction and decomposition techniques to improve scalability of the analysis [10, 12, 19]. The abstractions and decomposition in the these techniques, e.g., summaries of unchanged code [12] or semantically equivalent methods [19], compute an over-approximation of the program behaviors. The equivalence checking results of these techniques are sound but not complete-they may characterize programs as not functionally equivalent when, in fact, they are equivalent. In this work we describe a novel approach that leverages the impact of the differences between two programs for scaling regression verification. We partition program behaviors of each version into (a) behaviors impacted by the changes and (b) behaviors not impacted (unimpacted) by the changes. Only the impacted program behaviors are used during equivalence checking. We then prove that checking equivalence of the impacted program behaviors is equivalent to checking equivalence of all program behaviors for a given depth bound. In this work we use symbolic execution to generate the program behaviors and leverage control- and data-dependence information to facilitate the partitioning of program behaviors. The impacted program behaviors are termed as impact summaries. The dependence analyses that facilitate the generation of the impact summaries, we believe, could be used in conjunction with other abstraction and decomposition based approaches, [10, 12], as a complementary reduction technique. An evaluation of our regression verification technique shows that our approach is capable of leveraging similarities between program versions to reduce the size of the queries and the time required to check for logical equivalence. The main contributions of this work are: - A regression verification technique to generate impact summaries that can be checked for functional equivalence using an off-the-shelf decision procedure. - A proof that our approach is sound and complete with respect to the depth bound of symbolic execution. - An implementation of our technique using the LLVMcompiler infrastructure, the klee Symbolic Virtual Machine [4], and a variety of Satisfiability Modulo Theory (SMT) solvers, e.g., STP [7] and Z3 [6]. - An empirical evaluation on a set of C artifacts which shows that the use of impact summaries can reduce the cost of regression verification.

  3. 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. PMID:16354394

  4. Statistical methods for astronomical data with upper limits. II - Correlation and regression

    NASA Technical Reports Server (NTRS)

    Isobe, T.; Feigelson, E. D.; Nelson, P. I.

    1986-01-01

    Statistical methods for calculating correlations and regressions in bivariate censored data where the dependent variable can have upper or lower limits are presented. Cox's regression and the generalization of Kendall's rank correlation coefficient provide significant levels of correlations, and the EM algorithm, under the assumption of normally distributed errors, and its nonparametric analog using the Kaplan-Meier estimator, give estimates for the slope of a regression line. Monte Carlo simulations demonstrate that survival analysis is reliable in determining correlations between luminosities at different bands. Survival analysis is applied to CO emission in infrared galaxies, X-ray emission in radio galaxies, H-alpha emission in cooling cluster cores, and radio emission in Seyfert galaxies.

  5. 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. PMID:26723915

  6. Reactive oxygen species induce Cox-2 expression via TAK1 activation in synovial fibroblast cells

    PubMed Central

    Onodera, Yuta; Teramura, Takeshi; Takehara, Toshiyuki; Shigi, Kanae; Fukuda, Kanji

    2015-01-01

    Oxidative stress within the arthritis joint has been indicated to be involved in generating mediators for tissue degeneration and inflammation. COX-2 is a mediator in inflammatory action, pain and some catabolic reactions in inflamed tissues. Here, we demonstrated a direct relationship between oxidative stress and Cox-2 expression in the bovine synovial fibroblasts. Furthermore, we elucidated a novel mechanism, in which oxidative stress induced phosphorylation of MAPKs and NF-κB through TAK1 activation and resulted in increased Cox-2 and prostaglandin E2 expression. Finally, we demonstrated that ROS-induced Cox-2 expression was inhibited by supplementation of an antioxidant such as N-acetyl cysteamine and hyaluronic acid in vitro and in vivo. From these results, we conclude that oxidative stress is an important factor for generation of Cox-2 in synovial fibroblasts and thus its neutralization may be an effective strategy in palliative therapy for chronic joint diseases. PMID:26110105

  7. Identification of COX inhibitors in the hexane extract of Japanese horse chestnut (Aesculus turbinata) seeds.

    PubMed

    Sato, Itaru; Kofujita, Hisayoshi; Tsuda, Shuji

    2007-07-01

    Japanese horse chestnut (Aesculus turbinata) seed extract inhibits the activity of cyclooxygenase (COX), but its active constituents have not been identified. In the present study, COX inhibitors were isolated from the hexane extract of this seed by means of 4 steps of liquid chromatography and were identified by gas chromatography/mass spectrometry and nuclear magnetic resonance. The COX inhibitors in the extract of Japanese horse chestnut seeds were identified as linoleic acid, linolenic acid, and oleic acid. Their efficacies were in the following order: linolenic acid = linoleic acid > oleic acid. These active constituents are C18 unsaturated fatty acids; stearic acid, a C18 saturated fatty acid, had no activity. Linolenic acid and linoleic acid had high selectivity toward COX-2 (selectivity index = 10), whereas oleic acid had no selectivity. Considering the efficacy and yield of each fatty acid, linoleic acid may be the principal COX inhibitor in this seed. PMID:17675801

  8. Regression Analysis and 2-Group Discriminant Analysis

    ERIC Educational Resources Information Center

    Huberty, Carl J.

    1972-01-01

    It is shown that in the special case of just two criterion groups the predictor variables may be equivalently ordered (with respect to contribution to prediction or discrimination) by the univariate F-ratios and by estimates of the predictor versus the linear discriminant function correlations. (Author)

  9. Structural and Electronic Factors Influencing the Selective Inhibition of COX-2.

    PubMed

    Aksakal, Fatma; Shvets, Natali; Khairullina, Veronika; Dimoglo, Anatholy

    2016-01-01

    Structural and electronic factors influencing the inhibition of cyclooxygenase-1 and -2 (COX-1/COX-2) were studied by means of Electronic-Topological Method combined with Neural Networks (ETM-NN), molecular docking and Density Functional Theory (DFT). A series of structurally diverse compounds containing 209 molecules were classified in accordance with their inhibiting properties, as selectively inhibiting and non-selectively inhibiting COX-2 receptor agents (110 and 99 molecules, correspondingly). The results obtained from the ETM-NN calculations gave us possibility of selecting those pharmacophoric molecular fragments, which allow for the search of new selective inhibitors of COX-2 with high probability of realization. The final selection of pharmacophores and anti-pharmacophores found was taken as a basis for a system designed for the COX-2 inhibitory activity prediction. Analysis of the electron density distribution showed that more effective binding with COX-2 receptor was observed for selective inhibitors. To make an assessment of these interactions, calculations of stabilization energies were carried out for the ligand-receptor complexes. From the results of the docking and from the analysis of electronic structures of active sites of enzymes, some peculiarities of ligand-receptor binding and its influence on the selectivity of the COX-2 relative to COX-1 inhibition were elucidated. 95% of compounds were recognized correctly, as the most active ones, by the system of prediction designed. Thus, the system being the result of the study is capable of predicting the selective inhibitory activity of COX-2 successfully. As a consequence, it can be used both for computer screening and synthesis of potent inhibitors of COX-2 with molecular skeletons that may vary considerably. PMID:26471968

  10. Nonparametric Mixture of Regression Models

    PubMed Central

    Huang, Mian; Li, Runze; Wang, Shaoli

    2013-01-01

    Motivated by an analysis of US house price index data, we propose nonparametric finite mixture of regression models. We study the identifiability issue of the proposed models, and develop an estimation procedure by employing kernel regression. We further systematically study the sampling properties of the proposed estimators, and establish their asymptotic normality. A modified EM algorithm is proposed to carry out the estimation procedure. We show that our algorithm preserves the ascent property of the EM algorithm in an asymptotic sense. Monte Carlo simulations are conducted to examine the finite sample performance of the proposed estimation procedure. An empirical analysis of the US house price index data is illustrated for the proposed methodology. PMID:24363475

  11. A univariate analysis of variance design for multiple-choice feeding-preference experiments: A hypothetical example with fruit-eating birds

    NASA Astrophysics Data System (ADS)

    Larrinaga, Asier R.

    2010-01-01

    I consider statistical problems in the analysis of multiple-choice food-preference experiments, and propose a univariate analysis of variance design for experiments of this type. I present an example experimental design, for a hypothetical comparison of fruit colour preferences between two frugivorous bird species. In each fictitious trial, four trays each containing a known weight of artificial fruits (red, blue, black, or green) are introduced into the cage, while four equivalent trays are left outside the cage, to control for tray weight loss due to other factors (notably desiccation). The proposed univariate approach allows data from such designs to be analysed with adequate power and no major violations of statistical assumptions. Nevertheless, there is no single "best" approach for experiments of this type: the best analysis in each case will depend on the particular aims and nature of the experiments.

  12. On identification in Bayesian disease mapping and ecological-spatial regression models.

    PubMed

    MacNab, Ying C

    2014-04-01

    We discuss identification of structural characteristics of the underlying relative risks ensemble for posterior relative risks inference within Bayesian generalized linear mixed model framework for small-area disease mapping and ecological-spatial regression. We revisit conditionally specified and locally characterized Gaussian Markov random field risks ensemble priors in univariate disease mapping and communicate insight into Gaussian Markov random field variance-covariance characteristics for representing disease risks variability and spatial risks interactions and for structural identification with respect to risks ensemble prior choices. Illustrative examples of identification in Bayesian disease mapping and ecological-spatial regression models are presented for Bayesian hierarchical generalized linear mixed Poisson models and zero-inflated Poisson models. PMID:22573502

  13. Assessment of brown trout habitat suitability in the Jucar River Basin (SPAIN): comparison of data-driven approaches with fuzzy-logic models and univariate suitability curves.

    PubMed

    Muñoz-Mas, Rafael; Martínez-Capel, Francisco; Schneider, Matthias; Mouton, Ans M

    2012-12-01

    The implementation of the Water Framework Directive implies the determination of an environmental flow (E-flow) in each running water body. In Spain, many of the minimum flow assessments were determined with the physical habitat simulation system based on univariate habitat suitability curves. Multivariate habitat suitability models, widely applied in habitat assessment, are potentially more accurate than univariate suitability models. This article analyses the microhabitat selection by medium-sized (10-20 cm) brown trout (Salmo trutta fario) in three streams of the Jucar River Basin District (eastern Iberian Peninsula). The data were collected with an equal effort sampling approach. Univariate habitat suitability curves were built with a data-driven process for depth, mean velocity and substrate classes; three types of data-driven fuzzy models were generated with the FISH software: two models of presence-absence and a model of abundance. FISH applies a hill-climbing algorithm to optimize the fuzzy rules. A hydraulic model was calibrated with the tool River-2D in a segment of the Cabriel River (Jucar River Basin). The fuzzy-logic models and three methods to produce a suitability index from the three univariate curves were applied to evaluate the river habitat in the tool CASiMiR©. The comparison of results was based on the spatial arrangement of habitat suitability and the curves of weighted usable area versus discharge. The differences were relevant in different aspects, e.g. in the estimated minimum environmental flow according to the Spanish legal norm for hydrological planning. This work demonstrates the impact of the model's selection on the habitat suitability modelling and the assessment of environmental flows, based on an objective data-driven procedure; the conclusions are important for the water management in the Jucar River Basin and other river systems in Europe, where the environmental flows are a keystone for the achievement of the goals established in the European Water Framework Directive. PMID:22909786

  14. Cytochrome c oxidase subassemblies in fibroblast cultures from patients carrying mutations in COX10, SCO1, or SURF1.

    PubMed

    Williams, Siôn L; Valnot, Isabelle; Rustin, Pierre; Taanman, Jan-Willem

    2004-02-27

    Cytochrome c oxidase contains two redox-active copper centers (Cu(A) and Cu(B)) and two redox-active heme A moieties. Assembly of the enzyme relies on several assembly factors in addition to the constituent subunits and prosthetic groups. We studied fibroblast cultures from patients carrying mutations in the assembly factors COX10, SCO1, or SURF1. COX10 is involved in heme A biosynthesis. SCO1 is required for formation of the Cu(A) center. The function of SURF1 is unknown. Immunoblot analysis of native gels demonstrated severely decreased levels of holoenzyme in the patient cultures compared with controls. In addition, the blots revealed the presence of five subassemblies: three subassemblies involving the core subunit MTCO1 but apparently no other subunits; a subassembly containing subunits MTCO1, COX4, and COX5A; and a subassembly containing at least subunits MTCO1, MTCO2, MTCO3, COX4, and COX5A. As some of the subassemblies correspond to known assembly intermediates of human cytochrome c oxidase, we think that these subassemblies are probably assembly intermediates that accumulate in patient cells. The MTCO1.COX4.COX5A subassembly was not detected in COX10-deficient cells, which suggests that heme A incorporation into MTCO1 occurs prior to association of MTCO1 with COX4 and COX5A. SCO1-deficient cells contained accumulated levels of the MTCO1.COX4.COX5A subassembly, suggesting that MTCO2 associates with the MTCO1.COX4.COX5A subassembly after the Cu(A) center of MTCO2 is formed. Assembly in SURF1-deficient cells appears to stall at the same stage as in SCO1-deficient cells, pointing to a role for SURF1 in promoting the association of MTCO2 with the MTCO1.COX4.COX5A subassembly. PMID:14607829

  15. Comparative study between univariate spectrophotometry and multivariate calibration as analytical tools for simultaneous quantitation of Moexipril and Hydrochlorothiazide

    NASA Astrophysics Data System (ADS)

    Tawakkol, Shereen M.; Farouk, M.; Elaziz, Omar Abd; Hemdan, A.; Shehata, Mostafa A.

    2014-12-01

    Three simple, accurate, reproducible, and selective methods have been developed and subsequently validated for the simultaneous determination of Moexipril (MOX) and Hydrochlorothiazide (HCTZ) in pharmaceutical dosage form. The first method is the new extended ratio subtraction method (EXRSM) coupled to ratio subtraction method (RSM) for determination of both drugs in commercial dosage form. The second and third methods are multivariate calibration which include Principal Component Regression (PCR) and Partial Least Squares (PLSs). A detailed validation of the methods was performed following the ICH guidelines and the standard curves were found to be linear in the range of 10-60 and 2-30 for MOX and HCTZ in EXRSM method, respectively, with well accepted mean correlation coefficient for each analyte. The intra-day and inter-day precision and accuracy results were well within the acceptable limits.

  16. Etoricoxib: new drug. Avoid using cox-2 inhibitors for pain.

    PubMed

    2007-12-01

    (1) Paracetamol is the first-choice analgesic for joint pain. Nonsteroidal antiinflammatory drugs (NSAIDs), especially ibuprofen, are second-line options. Cox-2 inhibitors are no more effective than traditional NSAIDs and have no tangible advantages in terms of gastrointestinal tolerability. In contrast, they expose patients to an increased risk of cardiovascular adverse effects. (2) Etoricoxib is marketed in some European countries to relieve symptoms of osteoarthritis, rheumatoid arthritis, and gout attacks. (3) Many clinical trials have tested etoricoxib in these indications, as well as in ankylosing spondylitis, low back pain, and various types of acute pain. Etoricoxib was no more effective than other NSAIDs such as ibuprofen, naproxen or diclofenac in these situations. (4) Comparative trials showed a higher overall mortality rate with etoricoxib than with naproxen. A combined analysis of long-term comparative trials including 5441 patients, mainly versus naproxen, showed that etoricoxib does not reduce the risk of perforation, ulcer or severe gastrointestinal haemorrhage. Similarly, it does not reduce the risk of mild gastrointestinal events in at-risk patients: those with a history of gastrointestinal disorders, aspirin use, etc. (5) Three trials including a total of 34 701 patients (MEDAL programme) compared cardiovascular thrombotic events associated with etoricoxib and diclofenac. Overall, the cardiovascular risks appear to be similar but the thrombotic risk may be slightly higher with diclofenac than with other conventional NSAIDs. (6) Etoricoxib provoked arterial hypertension, oedema and heart failure during clinical trials. Serious skin reactions were reported both during clinical trials and after marketing, but their precise incidence is not known. Etoricoxib is partly metabolised by the cytochrome P450 isoenzyme CYP 3A4 and increases the bioavailability of ethinylestradiol. (7) When a NSAID is considered, drugs with which we have the most experience should be chosen, such as ibuprofen, and used at the lowest acceptable dose regimen (daily dose and length of treatment). Etoricoxib should be avoided. PMID:18084859

  17. Human airway smooth muscle cells secrete amphiregulin via bradykinin/COX-2/PGE2, inducing COX-2, CXCL8, and VEGF expression in airway epithelial cells

    PubMed Central

    Knox, Alan J.

    2015-01-01

    Human airway smooth muscle cells (HASMC) contribute to asthma pathophysiology through an increased smooth muscle mass and elevated cytokine/chemokine output. Little is known about how HASMC and the airway epithelium interact to regulate chronic airway inflammation and remodeling. Amphiregulin is a member of the family of epidermal growth factor receptor (EGFR) agonists with cell growth and proinflammatory roles and increased expression in the lungs of asthma patients. Here we show that bradykinin (BK) stimulation of HASMC increases amphiregulin secretion in a mechanism dependent on BK-induced COX-2 expression, increased PGE2 output, and the stimulation of HASMC EP2 and EP4 receptors. Conditioned medium from BK treated HASMC induced CXCL8, VEGF, and COX-2 mRNA and protein accumulation in airway epithelial cells, which were blocked by anti-amphiregulin antibodies and amphiregulin siRNA, suggesting a paracrine effect of HASMC-derived amphiregulin on airway epithelial cells. Consistent with this, recombinant amphiregulin induced CXCL8, VEGF, and COX-2 in airway epithelial cells. Finally, we found that conditioned media from amphiregulin-stimulated airway epithelial cells induced amphiregulin expression in HASMC and that this was dependent on airway epithelial cell COX-2 activity. Our study provides evidence of a dynamic axis of interaction between HASMC and epithelial cells that amplifies CXCL8, VEGF, COX-2, and amphiregulin production. PMID:26047642

  18. Molecular dynamics simulations of arachidonic acid-derived pentadienyl radical intermediate complexes with COX-1 and COX-2: insights into oxygenation regio- and stereoselectivity.

    PubMed

    Furse, Kristina E; Pratt, Derek A; Schneider, Claus; Brash, Alan R; Porter, Ned A; Lybrand, Terry P

    2006-03-14

    The two cyclooxygenase enzymes, COX-1 and COX-2, are responsible for the committed step in prostaglandin biosynthesis and are the targets of the nonsteroidal antiinflammatory drugs aspirin and 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

  19. Carvacrol, a component of thyme oil, activates PPAR? and ? and suppresses COX-2 expression[S

    PubMed Central

    Hotta, Mariko; Nakata, Rieko; Katsukawa, Michiko; Hori, Kazuyuki; Takahashi, Saori; Inoue, Hiroyasu

    2010-01-01

    Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin biosynthesis, plays a key role in inflammation and circulatory homeostasis. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors belonging to the nuclear receptor superfamily and are involved in the control of COX-2 expression, and vice versa. Here, we show that COX-2 promoter activity was suppressed by essential oils derived from thyme, clove, rose, eucalyptus, fennel, and bergamot in cell-based transfection assays using bovine arterial endothelial cells. Moreover, from thyme oil, we identified carvacrol as a major component of the suppressor of COX-2 expression and an activator of PPAR? and ?. PPAR?-dependent suppression of COX-2 promoter activity was observed in response to carvacrol treatment. In human macrophage-like U937 cells, carvacrol suppressed lipopolysaccharide-induced COX-2 mRNA and protein expression, suggesting that carvacrol regulates COX-2 expression through its agonistic effect on PPAR?. These results may be important in understanding the antiinflammatory and antilifestyle-related disease properties of carvacrol. PMID:19578162

  20. Selective COX-2 inhibitors and gastrointestinal mucosal injury: pharmacological and therapeutic considerations.

    PubMed

    Dajani, E Z; Agrawal, N M

    2000-01-01

    It is well recognized that nonsteroidal antiinflammatory drugs (NSAIDs) induce gastrointestinal (GI) ulcerations, perforation and bleeding, which clearly limit their therapeutic value. The recent introduction of NSAIDs with selective cyclooxygenase-2 (COX-2) inhibitory effect is a major pharmacologic milestone in therapeutics. Selective COX-2 inhibitors exhibit considerable dissociation between their antiinflammatory/analgesic action and their GI toxicity. However, from a therapeutic consideration, there are still several unresolved and confusing issues with these drugs such as: the pharmacologic classification of the COX-2 selectivity; therapeutic value as antirheumatic/analgesic drugs; potential toxicity in patients at risk for the development of ulcer-related complications or patients with inflammatory bowel disease and potential renal toxicity. Although existing clinical efficacy studies with celecoxib and rofecoxib, two selective COX-2 inhibitors, were associated with considerably lower ulcerogenic rates when compared with nonselective NSAIDs, there are no long term outcome studies with these drugs similar to the MUCOSA trial performed with misoprostol. Furthermore, the selectivity of COX-2 inhibitors appears to be specific to the stomach and duodenum but not the kidney. While awaiting additional long term studies with selective COX-2 inhibitors, we recommend instituting prophylactic therapy with misoprostol in patients at risk for the development of ulcer related complications. In conclusion, we believe that the introduction of selective COX-2 inhibitors will revolutionize the treatment of pain and inflammation. However, additional basic and clinical studies are required to address the pharmacologic and therapeutic uncertainties for this class of drugs. PMID:10953541

  1. Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

    SciTech Connect

    Meng, Zhen; Gan, Ye-Hua

    2015-05-01

    Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocation and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.

  2. Isolation of linoleic and alpha-linolenic acids as COX-1 and -2 inhibitors in rose hip.

    PubMed

    Jäger, A K; Petersen, K N; Thomasen, G; Christensen, S Brøgger

    2008-07-01

    Rose hip has previously shown clinical efficacy in the treatment of osteoarthritis, and organic solvent extracts of rose hip have showed inhibition of cyclooxygenase-1 and -2. A petroleum ether extract of rose hip was fractioned by VLC on silica; on a C-18 column and by HPLC. Each step was COX-1/2 activity-guided. The bioassay-guided fractionation led to the isolation of linoleic acid (the IC50 for COX-1 was 85 microm and 0.6 microM for COX-2) and alpha-linolenic acid (the IC50 for COX-1 was 52 microM and 12 microM for COX-2). The COX-2/COX-1 ratio was 0.007 for linoleic acid and 0.2 for alpha-linolenic acid. Linoleic acid and alpha-linolenic acid contribute to the COX-1 and -2 inhibitory activity of rose hip. PMID:18389471

  3. Multiple Origins of Eukaryotic cox15 Suggest Horizontal Gene Transfer from Bacteria to Jakobid Mitochondrial DNA.

    PubMed

    He, Ding; Fu, Cheng-Jie; Baldauf, Sandra L

    2016-01-01

    The most gene-rich and bacterial-like mitochondrial genomes known are those of Jakobida (Excavata). Of these, the most extreme example to date is the Andalucia godoyi mitochondrial DNA (mtDNA), including a cox15 gene encoding the respiratory enzyme heme A synthase (HAS), which is nuclear-encoded in nearly all other mitochondriate eukaryotes. Thus cox15 in eukaryotes appears to be a classic example of mitochondrion-to-nucleus (endosymbiotic) gene transfer, with A. godoyi uniquely retaining the ancestral state. However, our analyses reveal two highly distinct HAS types (encoded by cox15-1 and cox15-2 genes) and identify A. godoyi mitochondrial cox15-encoded HAS as type-1 and all other eukaryotic cox15-encoded HAS as type-2. Molecular phylogeny places the two HAS types in widely separated clades with eukaryotic type-2 HAS clustering with the bulk of α-proteobacteria (>670 sequences), whereas A. godoyi type-1 HAS clusters with an eclectic set of bacteria and archaea including two α-proteobacteria missing from the type-2 clade. This wide phylogenetic separation of the two HAS types is reinforced by unique features of their predicted protein structures. Meanwhile, RNA-sequencing and genomic analyses fail to detect either cox15 type in the nuclear genome of any jakobid including A. godoyi. This suggests that not only is cox15-1 a relatively recent acquisition unique to the Andalucia lineage but also the jakobid last common ancestor probably lacked both cox15 types. These results indicate that uptake of foreign genes by mtDNA is more taxonomically widespread than previously thought. They also caution against the assumption that all α-proteobacterial-like features of eukaryotes are ancient remnants of endosymbiosis. PMID:26412445

  4. Soman Increases Neuronal COX-2 Levels: Possible Link between Seizures and Protracted Neuronal Damage

    PubMed Central

    Angoa-Pérez, Mariana; Kreipke, Christian W.; Thomas, David M.; Van Shura, Kerry E.; Lyman, Megan; McDonough, John H.; Kuhn, Donald M.

    2010-01-01

    Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4 hr to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity. PMID:20600289

  5. Cyclooxygenases in human and mouse skin and cultured human keratinocytes: association of COX-2 expression with human keratinocyte differentiation

    NASA Technical Reports Server (NTRS)

    Leong, J.; Hughes-Fulford, M.; Rakhlin, N.; Habib, A.; Maclouf, J.; Goldyne, M. E.

    1996-01-01

    Epidermal expression of the two isoforms of the prostaglandin H-generating cyclooxygenase (COX-1 and COX-2) was evaluated both by immunohistochemistry performed on human and mouse skin biopsy sections and by Western blotting of protein extracts from cultured human neonatal foreskin keratinocytes. In normal human skin, COX-1 immunostaining is observed throughout the epidermis whereas COX-2 immunostaining increases in the more differentiated, suprabasilar keratinocytes. Basal cell carcinomas express little if any COX-1 or COX-2 immunostaining whereas both isozymes are strongly expressed in squamous cell carcinomas deriving from a more differentiated layer of the epidermis. In human keratinocyte cultures, raising the extracellular calcium concentration, a recognized stimulus for keratinocyte differentiation, leads to an increased expression of both COX-2 protein and mRNA; expression of COX-1 protein, however, shows no significant alteration in response to calcium. Because of a recent report that failed to show COX-2 in normal mouse epidermis, we also looked for COX-1 and COX-2 immunostaining in sections of normal and acetone-treated mouse skin. In agreement with a previous report, some COX-1, but no COX-2, immunostaining is seen in normal murine epidermis. However, following acetone treatment, there is a marked increase in COX-1 expression as well as the appearance of significant COX-2 immunostaining in the basal layer. These data suggest that in human epidermis as well as in human keratinocyte cultures, the expression of COX-2 occurs as a part of normal keratinocyte differentiation whereas in murine epidermis, its constitutive expression is absent, but inducible as previously published.

  6. Robust, Adaptive Functional Regression in Functional Mixed Model Framework

    PubMed Central

    Zhu, Hongxiao; Brown, Philip J.; Morris, Jeffrey S.

    2012-01-01

    Functional data are increasingly encountered in scientific studies, and their high dimensionality and complexity lead to many analytical challenges. Various methods for functional data analysis have been developed, including functional response regression methods that involve regression of a functional response on univariate/multivariate predictors with nonparametrically represented functional coefficients. In existing methods, however, the functional regression can be sensitive to outlying curves and outlying regions of curves, so is not robust. In this paper, we introduce a new Bayesian method, robust functional mixed models (R-FMM), for performing robust functional regression within the general functional mixed model framework, which includes multiple continuous or categorical predictors and random effect functions accommodating potential between-function correlation induced by the experimental design. The underlying model involves a hierarchical scale mixture model for the fixed effects, random effect and residual error functions. These modeling assumptions across curves result in robust nonparametric estimators of the fixed and random effect functions which down-weight outlying curves and regions of curves, and produce statistics that can be used to flag global and local outliers. These assumptions also lead to distributions across wavelet coefficients that have outstanding sparsity and adaptive shrinkage properties, with great flexibility for the data to determine the sparsity and the heaviness of the tails. Together with the down-weighting of outliers, these within-curve properties lead to fixed and random effect function estimates that appear in our simulations to be remarkably adaptive in their ability to remove spurious features yet retain true features of the functions. We have developed general code to implement this fully Bayesian method that is automatic, requiring the user to only provide the functional data and design matrices. It is efficient enough to handle large data sets, and yields posterior samples of all model parameters that can be used to perform desired Bayesian estimation and inference. Although we present details for a specific implementation of the R-FMM using specific distributional choices in the hierarchical model, 1D functions, and wavelet transforms, the method can be applied more generally using other heavy-tailed distributions, higher dimensional functions (e.g. images), and using other invertible transformations as alternatives to wavelets. PMID:22308015

  7. Ciglitazone mediates COX-2 dependent suppression of PGE2 in human Non-Small Cell Lung Cancer cells

    PubMed Central

    Hazra, Saswati; Dubinett, Steven M

    2007-01-01

    Summary Background Cycloxygenase-2 (COX-2) overexpression and subsequent prostaglandin E2 (PGE2) production are frequently associated with human non-small cell lung cancer (NSCLC) and are involved in tumor proliferation, invasion, angiogenesis, and resistance to apoptosis. Here we report that ciglitazone downregulates PGE2 in NSCLC cells. Methods PGE2 ELISA assay and COX-2 ELISA assay were performed for measuring PGE2 and COX-2 respectively in NSCLC. The mRNA level of COX-2 was measured by semi-quantitative RT-PCR. The transient transfection experiments were performed to measure COX-2 and PPRE promoter activity in NSCLC. Western blots were unitized to measure PGE synthase (PGES) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) protein expression. Results COX-2 ELISA assays suggested that ciglitazone-dependent inhibition of PGE2 occurs through the suppression of COX-2. Ciglitazone treatment suppressed COX-2 mRNA expression and COX-2 promoter activity while upregulating peroxisome proliferator-response element (PPRE) promoter activity. Ciglitazone did not modify the expression of enzymes downstream of COX-2 including PGES and 15-PGDH. Utilization of a dominant-negative PPARγ showed that the suppression of COX-2 and PGE2 by ciglitazone is mediated via non-PPAR pathways. Conclusion Taken together, our findings suggest that ciglitazone is a negative modulator of COX-2/PGE2 in NSCLC. PMID:17697767

  8. Multiatlas segmentation as nonparametric regression.

    PubMed

    Awate, Suyash P; Whitaker, Ross T

    2014-09-01

    This paper proposes a novel theoretical framework to model and analyze the statistical characteristics of a wide range of segmentation methods that incorporate a database of label maps or atlases; such methods are termed as label fusion or multiatlas segmentation. We model these multiatlas segmentation problems as nonparametric regression problems in the high-dimensional space of image patches. We analyze the nonparametric estimator's convergence behavior that characterizes expected segmentation error as a function of the size of the multiatlas database. We show that this error has an analytic form involving several parameters that are fundamental to the specific segmentation problem (determined by the chosen anatomical structure, imaging modality, registration algorithm, and label-fusion algorithm). We describe how to estimate these parameters and show that several human anatomical structures exhibit the trends modeled analytically. We use these parameter estimates to optimize the regression estimator. We show that the expected error for large database sizes is well predicted by models learned on small databases. Thus, a few expert segmentations can help predict the database sizes required to keep the expected error below a specified tolerance level. Such cost-benefit analysis is crucial for deploying clinical multiatlas segmentation systems. PMID:24802528

  9. Feature Selection and Cancer Classification via Sparse Logistic Regression with the Hybrid L1/2 +2 Regularization.

    PubMed

    Huang, Hai-Hui; Liu, Xiao-Ying; Liang, Yong

    2016-01-01

    Cancer classification and feature (gene) selection plays an important role in knowledge discovery in genomic data. Although logistic regression is one of the most popular classification methods, it does not induce feature selection. In this paper, we presented a new hybrid L1/2 +2 regularization (HLR) function, a linear combination of L1/2 and L2 penalties, to select the relevant gene in the logistic regression. The HLR approach inherits some fascinating characteristics from L1/2 (sparsity) and L2 (grouping effect where highly correlated variables are in or out a model together) penalties. We also proposed a novel univariate HLR thresholding approach to update the estimated coefficients and developed the coordinate descent algorithm for the HLR penalized logistic regression model. The empirical results and simulations indicate that the proposed method is highly competitive amongst several state-of-the-art methods. PMID:27136190

  10. Feature Selection and Cancer Classification via Sparse Logistic Regression with the Hybrid L1/2 +2 Regularization

    PubMed Central

    Huang, Hai-Hui; Liu, Xiao-Ying; Liang, Yong

    2016-01-01

    Cancer classification and feature (gene) selection plays an important role in knowledge discovery in genomic data. Although logistic regression is one of the most popular classification methods, it does not induce feature selection. In this paper, we presented a new hybrid L1/2 +2 regularization (HLR) function, a linear combination of L1/2 and L2 penalties, to select the relevant gene in the logistic regression. The HLR approach inherits some fascinating characteristics from L1/2 (sparsity) and L2 (grouping effect where highly correlated variables are in or out a model together) penalties. We also proposed a novel univariate HLR thresholding approach to update the estimated coefficients and developed the coordinate descent algorithm for the HLR penalized logistic regression model. The empirical results and simulations indicate that the proposed method is highly competitive amongst several state-of-the-art methods. PMID:27136190

  11. Celebration of the contributions of Art Cox to stellar pulsation interpretations

    SciTech Connect

    Castor, J.I.

    1997-10-02

    A roughly chronological account is given of Arthur N. Coxs published work of 1953-1996 in, mostly, stellar pulsation theory, with a digression into stellar opacity. When possible, his work is placed in the context of the contemporary efforts.

  12. COX-2 expression induced by diesel particles involves chromatin modification and degradation of HDAC1

    EPA Science Inventory

    Cyclooxygenase-2 (COX-2) plays an important role in the inflammatory response induced by physiologic and stress stimuli. Exposure to diesel exhaust particulate matter (DEP) has been shown to induce pulmonary inflammation and exacerbate asthma and chronic obstructive pulmonary dis...

  13. Role of Surf1 in heme recruitment for bacterial COX biogenesis.

    PubMed

    Hannappel, Achim; Bundschuh, Freya A; Ludwig, Bernd

    2012-06-01

    Biogenesis of the mitochondrial cytochrome c oxidase (COX) is a highly complex process involving subunits encoded both in the nuclear and the organellar genome; in addition, a large number of assembly factors participate in this process. The soil bacterium Paracoccus denitrificans is an interesting alternative model for the study of COX biogenesis events because the number of chaperones involved is restricted to an essential set acting in the metal centre formation of oxidase, and the high degree of sequence homology suggests the same basic mechanisms during early COX assembly. Over the last years, studies on the P. denitrificans Surf1 protein shed some light on this important assembly factor as a heme a binding protein associated with Leigh syndrome in humans. Here, we summarise our current knowledge about Surf1 and its role in heme a incorporation events during bacterial COX biogenesis. This article is part of a Special Issue entitled: Biogenesis/Assembly of Respiratory Enzyme Complexes. PMID:21945856

  14. Students Speak With Gary Cox, EPIC Project Manager - Duration: 19 minutes.

    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...

  15. Post-Training Cyclooxygenase-2 (COX-2) Inhibition Impairs Memory Consolidation

    PubMed Central

    Teather, Lisa A.; Packard, Mark G.; Bazan, Nicolas G.

    2002-01-01

    Evidence indicates that prostanoids, such as prostaglandins, play a regulatory role in several forms of neural plasticity, including long-term potentiation, a cellular model for certain forms of learning and memory. In these experiments, the significance of the COX isoforms cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in post-training memory processes was assessed. Adult male Long-Evans rats underwent an eight-trial (30-sec intertrial interval) training session on a hippocampus-dependent (hidden platform) or dorsal striatal–dependent (visible platform) tasks in a water maze. After the completion of training, rats received an intraperitoneal injection of the nonselective COX inhibitor indomethacin, the COX-1–specific inhibitor piroxicam, the COX-2–specific inhibitor N-[2-cyclohexyloxy-4-nitrophenyl]-methanesulfonamide (NS-398), vehicle (45% 2-hydroxypropyl-β-cyclodextrin in distilled water), or saline. On a two-trial retention test session 24 h later, latency to mount the escape platform was used as a measure of memory. In the hidden platform task, the retention test escape latencies of rats administered indomethacin (5 and 10 mg/kg) or NS-398 (2 and 5 mg/kg) were significantly higher than those of vehicle-treated rats, indicating an impairment in retention. Injections of indomethacin or NS-398 that were delayed 2 h post-training had no effect on retention. Post-training indomethacin or NS-398 had no influence on retention of the visible platform version of the water maze at any of the doses administered. Furthermore, selective inhibition of COX-1 via post-training piroxicam administration had no effect on retention of either task. These findings indicate that COX-2 is a required biochemical component mediating the consolidation of hippocampal-dependent memory. PMID:11917005

  16. Cyclooxygenase-2 (COX-2) expression in high-risk premalignant oral lesions.

    PubMed

    Sudbø, Jon; Ristimäki, Ari; Sondresen, Jan Erik; Kildal, Wanja; Boysen, Morten; Koppang, Hanna S; Reith, Albrecht; Risberg, Björn; Nesland, Jahn M; Bryne, Magne

    2003-07-01

    Emerging data indicate a link between genetic instability and up-regulation of cyclooxygenase-2 (COX-2). To see if individuals at high risk of oral cancer are candidates for treatment with selective COX-2 inhibitors (coxibs), levels of COX-2 expression in healthy, premalignant and cancerous oral mucosa were compared with the occurrence of DNA ploidy status as a genetic risk marker of oral cancer. COX-2 gene product was evaluated immunohistochemically in 30 healthy persons, in 22 patients with dysplastic lesions without previous or concomitant carcinomas, and in 29 patients with oral carcinomas. The immunohistochemical findings were verified by western blotting. COX-2 expression was correlated to DNA content as a genetic risk marker of oral cancer. COX-2 was up-regulated from healthy to premalignant to cancerous oral mucosa. Thus, COX-2 expression was found in 1 case of healthy oral mucosa (3%). All specimens from healthy mucosa had a normal DNA content. In patients with premalignancies. In 29 patients with oral carcinomas, cyclooxygenase-2 expression was observed in 26 (88%), and aneuploidy was observed in 25 cases (94%, P=0.04). Notably, of 22 patients with dysplastic lesions, COX-2 was exclusively expressed in a subgroup of nine patients (41%) identified to be at high risk of cancer by the aberrant DNA content of their lesions. Seven of these patients were followed for 5 years or more. An oral carcinoma developed in six of them (85%; P=0.02). These findings emphasize the need to determine whether coxibs can reduce the risk of oral cancer in patients with high-risk precancerous lesions. PMID:12747975

  17. Antinociception and the new COX inhibitors: research approaches and clinical perspectives.

    PubMed

    Herrero, Juan F; Romero-Sandoval, E Alfonso; Gaitan, Gema; Mazario, Javier

    2003-01-01

    New generations of cyclooxygenase (COX) inhibitors are more potent and efficacious than their traditional parent compounds. They are also safer than the classic non-steroidal anti-inflammatory drugs (NSAIDs) and are starting to be used not only for low to moderate intensity pain, but also for high intensity pain. Three different strategies have been followed to improve the pharmacological profile of COX inhibitors: 1. Development of COX-2 selective inhibitors. This is based on the initial hypothesis that considered COX-2 as the enzyme responsible for the generation of prostaglandins only in inflammation, and, therefore, uniquely responsible for inflammation, pain and fever. Initial expectations gave rise to controversial results, still under discussion. The second generation of these compounds is being developed and should contribute to clarifying both their efficacy and the specific functions of the COX enzymes. 2. Modified non-selective COX inhibitors. Molecules like nitro-NSAIDs or tromethamine salt derivatives have been synthesized considering that both COX-1 and COX-2 are responsible for the synthesis of prostaglandins involved either in homeostatic functions or inflammation. Nitroaspirin, nitroparacetamol or dexketoprofen trometamol are some examples of molecules that are already showing an important clinical efficacy. The modifications performed in their structures seem to lower the unwanted side effects as well as to enhance their analgesic efficacy. 3. Combined therapy of classic NSAIDs with other drugs. This strategy looks for improvements in the incidence of adverse effects or to take advantage of the synergistic enhancement of their therapeutic effects. Some of the molecules resulting from these strategies are very valuable as therapeutic agents and open a wide range of possibilities in the treatment of high intensity pain, including neuropathic pain, and opiate sparing therapy. PMID:14530796

  18. Estimation of green grass/herb biomass from airborne hyperspectral imagery using spectral indices and partial least squares regression

    NASA Astrophysics Data System (ADS)

    Cho, Moses Azong; Skidmore, Andrew; Corsi, Fabio; van Wieren, Sipke E.; Sobhan, Istiak

    2007-12-01

    The main objective was to determine whether partial least squares (PLS) regression improves grass/herb biomass estimation when compared with hyperspectral indices, that is normalised difference vegetation index (NDVI) and red-edge position (REP). To achieve this objective, fresh green grass/herb biomass and airborne images (HyMap) were collected in the Majella National Park, Italy in the summer of 2005. The predictive performances of hyperspectral indices and PLS regression models were then determined and compared using calibration ( n = 30) and test ( n = 12) data sets. The regression model derived from NDVI computed from bands at 740 and 771 nm produced a lower standard error of prediction (SEP = 264 g m -2) on the test data compared with the standard NDVI involving bands at 665 and 801 nm (SEP = 331 g m -2), but comparable results with REPs determined by various methods (SEP = 261 to 295 g m -2). PLS regression models based on original, derivative and continuum-removed spectra produced lower prediction errors (SEP = 149 to 256 g m -2) compared with NDVI and REP models. The lowest prediction error (SEP = 149 g m -2, 19% of mean) was obtained with PLS regression involving continuum-removed bands. In conclusion, PLS regression based on airborne hyperspectral imagery provides a better alternative to univariate regression involving hyperspectral indices for grass/herb biomass estimation in the Majella National Park.

  19. Simultaneous targeting of 5-LOX-COX and EGFR blocks progression of pancreatic ductal adenocarcinoma

    PubMed Central

    Rao, Chinthalapally V.; Janakiram, Naveena B.; Madka, Venkateshwar; Devarkonda, Vishal; Brewer, Misty; Biddick, Laura; Lightfoot, Stan; Steele, Vernon E.; Mohammed, Altaf

    2015-01-01

    Cyclooxygenase-2 (COX-2), 5-Lipoxygenase (5-LOX), and epidermal growth factor receptor (EGRF) are over-expressed in human pancreatic ductal adenocarcinoma (PDAC). Using next-generation sequencing (NGS) analysis, we show significant increase in COX-2, 5-LOX, and EGFR expression during PDAC progression. Targeting complementary pathways will achieve better treatment efficacy than a single agent high-dose strategy that could increase risk of side effects and tumor resistance. To target COX-2, 5-LOX, and EGFR simultaneously, we tested effects of licofelone (dual 5-LOX-COX inhibitor), and gefitinib (EGFR inhibitor), individually and in combination, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PDAC using genetically engineered mice. Individually, licofelone (L) and gefitinib (G) significantly inhibited incidence of PDAC in male (72% L, 90% G, p < 0.0001) and female (90% L, 85% G, p < 0.0001) mice. The combination drug treatment produced complete inhibition of PDAC in both genders. Pancreata of mice receiving combination treatment showed significantly fewer Dclk1-positive cancer stem-like cells, inhibition of COX-2, 5-LOX, PCNA, EGFR and β-catenin expression (p < 0.05–0.0002), increased p21 expression. Significant changes in tumor immune responses and desmoplastic reaction was observed by NGS analysis in combination treatment (p < 0.05). In summary, early simultaneous targeting of 5-LOX-COX- and EGFR pathways may provide additive inhibitory effects leading to complete suppression of PDAC. PMID:26429877

  20. Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation

    PubMed Central

    Hermanson, Daniel J.; Hartley, Nolan D.; Gamble-George, Joyonna; Brown, Naoko; Shonesy, Brian C.; Kingsley, Phillip J.; Colbran, Roger J.; Reese, Jeffrey

    2013-01-01

    Augmentation of endogenous cannabinoid (eCB) signaling represents an emerging approach to the treatment of affective disorders. Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid to form prostaglandins, but also inactivates eCBs in vitro. However, the viability of COX-2 as a therapeutic target for in vivo eCB augmentation has not been explored. Here we utilized medicinal chemistry and in vivo analytical and behavioral pharmacological approaches to demonstrate a key role for COX-2 in the regulation of endocannabinoid (eCB) levels in vivo. A novel pharmacological strategy involving “substrate-selective” inhibition of COX-2 was used to augment eCB signaling without affecting related non-eCB lipids or prostaglandin synthesis. Behaviorally, substrate-selective inhibition of COX-2reducedanxiety-like behaviors in mice via increasede CB signaling. These data elucidate a key role for COX-2 in the regulation of eCB signaling and suggest substrate-selective pharmacology represents a viable approach for eCB augmentation with broad therapeutic potential. PMID:23912944

  1. Down-regulation of cyclooxygenase-2 (COX-2) by cannabidiolic acid in human breast cancer cells.

    PubMed

    Takeda, Shuso; Okazaki, Hiroyuki; Ikeda, Eriko; Abe, Satomi; Yoshioka, Yasushi; Watanabe, Kazuhito; Aramaki, Hironori

    2014-01-01

    Metastases are known to be responsible for approximately 90% of breast cancer-related deaths. Cyclooxygenase-2 (COX-2) is involved not only in inflammatory processes, but also in the metastasis of cancer cells; it is expressed in 40% of human invasive breast cancers. To comprehensively analyze the effects of cannabidiolic acid (CBDA), a selective COX-2 inhibitor found in the fiber-type cannabis plant (Takeda et al., 2008), on COX-2 expression and the genes involved in metastasis, we performed a DNA microarray analysis of human breast cancer MDA-MB-231 cells, which are invasive breast cancer cells that express high levels of COX-2, treated with CBDA for 48 hr at 25 µM. The results obtained revealed that COX-2 and Id-1, a positive regulator of breast cancer metastasis, were down-regulated (0.19-fold and 0.52-fold, respectively), while SHARP1 (or BHLHE41), a suppressor of breast cancer metastasis, was up-regulated (1.72-fold) and CHIP (or STUB1) was unaffected (1.03-fold). These changes were confirmed by real-time RT-PCR analyses. Taken together, the results obtained here demonstrated that i) CBDA had dual inhibitory effects on COX-2 through down-regulation and enzyme inhibition, and ii) CBDA may possess the ability to suppress genes that are positively involved in the metastasis of cancer cells in vitro. PMID:25242400

  2. Expression of COX-2 and bcl-2 in oral lichen planus lesions and lichenoid reactions

    PubMed Central

    Arreaza, Alven J; Rivera, Helen; Correnti, María

    2014-01-01

    Oral lichen planus and lichenoid reactions are autoimmune type inflammatory conditions of the oral mucosa with similar clinical and histological characteristics. Recent data suggest that oral lichenoid reactions (OLR) present a greater percentage of malignant transformation than oral lichen planus (OLP). Objective To compare the expression of bcl-2 and COX-2 in OLP and OLR. Methods The study population consisted of 65 cases; 34 cases diagnosed as OLR and 31 as OLP. A retrospective study was done, and bcl-2 and COX-2 expression was semiquantitatively analysed. Results Fifty-three per cent (18/34) of the ORL samples tested positive for COX-2, whereas in the OLP group, 81% of the samples (25/31) immunostained positive for COX-2. The Fisher’s exact test for the expression of COX-2 revealed that there are significant differences between the two groups, P = 0.035. With respect to the expression of the bcl-2 protein, 76% (26/34) of the samples were positive in OLR, while 97% (30/31) were positive in the group with OLP. The Fisher’s exact test for the expression of bcl-2 revealed that there are significant statistical differences between the two groups, P = 0.028. Conclusions The expression of bcl-2 and COX-2 was more commonly expressed in OLP when compared with OLR. PMID:24834112

  3. 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

  4. PPARδ is pro-tumorigenic in a mouse model of COX-2-induced mammary cancer

    PubMed Central

    Ghosh, Mallika; Ai, Youxi; Narko, Kirsi; Wang, Zhenglong; Peters, Jeffrey M.; Hla, Timothy

    2009-01-01

    Cyclooxygenase-2 (COX-2), overexpressed in inflammatory conditions and cancer, regulates angiogenesis and tumorigenesis via the production of biologically active prostanoids. Previously, we showed that COX-2 over-expression in the mammary gland of transgenic mice induces an angiogenic switch and transforms the mammary epithelium into invasive mammary carcinoma. Since COX-2-derived prostanoids can activate the nuclear receptor PPARδ, we crossed Pparδ−/− mice with COX-2 transgenic mice in the FVB/N background. PPARδ was expressed constitutively in the mammary gland of virgin, pregnant and lactating mice. Mammary hyperplasia and tumorigenesis in the COX-2 transgenic mice was markedly reduced in the Pparδ−/− mice compared to their wild type counterparts. Analysis of the mammary tissues indicated that immunoreactive Ki-67, cyclin D1 and phosphorylated histone 3 (Phospho H3) were reduced in Pparδ−/− mice, suggesting that PPARδ activation regulates cell proliferation in the mammary gland. We postulate that activation of the nuclear receptor PPARδ by COX-2-derived prostanoids may be involved in the proliferation of mammary epithelial cells and therefore contribute to mammary cancer development. PMID:19101649

  5. DPPC regulates COX-2 expression in monocytes via phosphorylation of CREB

    SciTech Connect

    Morris, R.H.K. Tonks, A.J.; Jones, K.P.; Ahluwalia, M.K.; Thomas, A.W.; Tonks, A.; Jackson, S.K.

    2008-05-23

    The major phospholipid in pulmonary surfactant dipalmitoyl phosphatidylcholine (DPPC) has been shown to modulate inflammatory responses. Using human monocytes, this study demonstrates that DPPC significantly increased PGE{sub 2} (P < 0.05) production by 2.5-fold when compared to untreated monocyte controls. Mechanistically, this effect was concomitant with an increase in COX-2 expression which was abrogated in the presence of a COX-2 inhibitor. The regulation of COX-2 expression was independent of NF-{kappa}B activity. Further, DPPC increased the phosphorylation of the cyclic AMP response element binding protein (CREB; an important nuclear transcription factor important in regulating COX-2 expression). In addition, we also show that changing the fatty acid groups of PC (e.g. using L-{alpha}-phosphatidylcholine {beta}-arachidonoyl-{gamma}-palmitoyl (PAPC)) has a profound effect on the regulation of COX-2 expression and CREB activation. This study provides new evidence for the anti-inflammatory activity of DPPC and that this activity is at least in part mediated via CREB activation of COX-2.

  6. 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

  7. Chamomile, a novel and selective COX-2 inhibitor with anti-inflammatory activity

    PubMed Central

    Srivastava, Janmejai K; Pandey, Mitali; Gupta, Sanjay

    2009-01-01

    Aims Inducible cyclooxygenase (COX-2) has been implicated in the process of inflammation and carcinogenesis. Chamomile has long been used in traditional medicine for the treatment of inflammatory diseases. In this study we aimed to investigate whether chamomile interferes with the COX-2 pathway. Main Methods We used lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as an in vitro model for our studies. Key Findings Chamomile treatment inhibited the release of LPS-induced prostaglandin E(2) in RAW 264.7 macrophages. This effect was found to be due to inhibition of COX-2 enzyme activity by chamomile. In addition, chamomile caused reduction in LPS-induced COX-2 mRNA and protein expression, without affecting COX-1 expression. The non-steroidal anti-inflammatory drug, sulindac and a specific COX-2 inhibitor, NS398, were shown to act similarly in LPS-activated RAW 264.7 cells. Our data suggest that chamomile works by a mechanism of action similar to that attributed to non-steroidal anti-inflammatory drugs. Significance These findings add a novel aspect to the biological profile of chamomile which might be important for understanding the usefulness of aqueous chamomile extract in the form of tea in preventing inflammation and cancer. PMID:19788894

  8. ?9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling.

    PubMed

    Chen, Rongqing; Zhang, Jian; Fan, Ni; Teng, Zhao-Qian; Wu, Yan; Yang, Hongwei; Tang, Ya-Ping; Sun, Hao; Song, Yunping; Chen, Chu

    2013-11-21

    Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here, we show that synaptic and cognitive impairments following repeated exposure to ?(9)-tetrahydrocannabinol (?(9)-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids in thebrain. COX-2 induction by ?(9)-THC is mediated via CB1 receptor-coupled G protein ?? subunits. Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated ?(9)-THC exposures. Ablation of COX-2 also eliminates ?(9)-THC-impaired hippocampal long-term synaptic plasticity, working, and fear memories. Importantly, the beneficial effects of decreasing ?-amyloid plaques and neurodegeneration by ?(9)-THC in Alzheimer's disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2. PMID:24267894

  9. Ester Prodrugs of Ketoprofen: Synthesis, In Vitro Stability, In Vivo Biological Evaluation and In Silico Comparative Docking Studies Against COX-1 and COX-2.

    PubMed

    Ahmed, Musa; Azam, Faizul; Gbaj, Abdul; Zetrini, Abdulmottaleb E; Abodlal, Amna Salem; Rghigh, Abir; Elmahdi, Eman; Hamza, Amel; Salama, Mabruk; Bensaber, Salah M

    2016-01-01

    Prompted by the ineptness of the currently used non-steroidal antiinflammatory drugs (NSAIDs) to control gastric mucosal and renal adverse reactions, several ester prodrugs of ketoprofen were synthesized and characterized by IR, 1H NMR and mass spectral data. Physicochemical properties such as aqueous solubility, octanol-water partition coefficient log P, chemical stability and enzymatic hydrolysis of the synthesized molecules have been studied to assess their potential as prodrugs. The obtained results confirmed that all ester prodrugs are chemically stable, possess increased lipophilicity compared to their parent compounds and converted to the active drugs in vivo. All of the tested ester prodrugs exhibited marked anti-inflammatory activity ranging from 91.8% to 113.3% in comparison with the parent drug, ketoprofen. A mutual prodrug obtained from two antiinflammatory molecules, ketoprofen and salicylic acid has been noted to potentiate the activity making it most active molecule of the series. The ulcerogenic index of the ester prodrugs was significantly lower than the parent drug, ketoprofen. Comparative docking studies against X-ray crystal structures of COX-1 and COX-2 further provided understanding of their interaction with the cyclooxygenases that will facilitate design of better inhibitors (or prodrugs) with sufficient specificity for COX-2 against COX-1. The study offers an innovative strategy for finding a molecule with safer therapeutic profile for longterm treatment of inflammatory diseases. PMID:26785683

  10. Semiparametric regression during 2003–2007*

    PubMed Central

    Ruppert, David; Wand, M.P.; Carroll, Raymond J.

    2010-01-01

    Semiparametric regression is a fusion between parametric regression and nonparametric regression that integrates low-rank penalized splines, mixed model and hierarchical Bayesian methodology – thus allowing more streamlined handling of longitudinal and spatial correlation. We review progress in the field over the five-year period between 2003 and 2007. We find semiparametric regression to be a vibrant field with substantial involvement and activity, continual enhancement and widespread application. PMID:20305800

  11. Bayesian Unimodal Density Regression for Causal Inference

    ERIC Educational Resources Information Center

    Karabatsos, George; Walker, Stephen G.

    2011-01-01

    Karabatsos and Walker (2011) introduced a new Bayesian nonparametric (BNP) regression model. Through analyses of real and simulated data, they showed that the BNP regression model outperforms other parametric and nonparametric regression models of common use, in terms of predictive accuracy of the outcome (dependent) variable. The other,…

  12. Developmental Regression in Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Rogers, Sally J.

    2004-01-01

    The occurrence of developmental regression in autism is one of the more puzzling features of this disorder. Although several studies have documented the validity of parental reports of regression using home videos, accumulating data suggest that most children who demonstrate regression also demonstrated previous, subtle, developmental differences.…

  13. Standards for Standardized Logistic Regression Coefficients

    ERIC Educational Resources Information Center

    Menard, Scott

    2011-01-01

    Standardized coefficients in logistic regression analysis have the same utility as standardized coefficients in linear regression analysis. Although there has been no consensus on the best way to construct standardized logistic regression coefficients, there is now sufficient evidence to suggest a single best approach to the construction of a…

  14. Building Regression Models: The Importance of Graphics.

    ERIC Educational Resources Information Center

    Dunn, Richard

    1989-01-01

    Points out reasons for using graphical methods to teach simple and multiple regression analysis. Argues that a graphically oriented approach has considerable pedagogic advantages in the exposition of simple and multiple regression. Shows that graphical methods may play a central role in the process of building regression models. (Author/LS)

  15. Standards for Standardized Logistic Regression Coefficients

    ERIC Educational Resources Information Center

    Menard, Scott

    2011-01-01

    Standardized coefficients in logistic regression analysis have the same utility as standardized coefficients in linear regression analysis. Although there has been no consensus on the best way to construct standardized logistic regression coefficients, there is now sufficient evidence to suggest a single best approach to the construction of a

  16. Spontaneous regression of pulmonary metastatic melanoma.

    PubMed

    Ong, Sook Fen; Harden, Michael; Irandoust, Shabnam; Lee, Richard Wai Wing

    2016-03-01

    Spontaneous regression of metastatic melanoma is a rare event with only 76 cases having been reported since 1866. The precise mechanism of regression remains unknown. We present a case of a man with spontaneous regression of pulmonary metastatic melanoma confirmed on histopathology accompanied by reduction in fluorodeoxyglucose-activity on serial positron emission tomography/computed tomography scan. PMID:26839692

  17. Predictive factors for the regression of canine transmissible venereal tumor during vincristine therapy.

    PubMed

    Scarpelli, Karime C; Valladão, Maria L; Metze, Konradin

    2010-03-01

    Canine transmissible venereal tumor (CTVT) is a neoplasm transmitted by transplantation. Monochemotherapy with vincristine is considered to be effective, but treatment time until complete clinical remission may vary. The aim of this study was to determine which clinical data at diagnosis could predict the responsiveness of CTVT to vincristine chemotherapy. One hundred dogs with CTVT entered this prospective study. The animals were treated with vincristine sulfate (0.025 mg/kg) at weekly intervals until the tumor had macroscopically disappeared. The time to complete remission was recorded. A multivariate Cox regression model indicated that larger tumor mass, increased age and therapy during hot and rainy months were independent significant unfavorable predictive factors retarding remission, whereas sex, weight, status as owned dog or breed were of no predictive relevance. Further studies are necessary to investigate whether these results are due to changes in immunological response mechanisms in animals with a diminished immune surveillance, resulting in delays in tumor regression. PMID:19109042

  18. Mechanisms of Vessel Pruning and Regression.

    PubMed

    Korn, Claudia; Augustin, Hellmut G

    2015-07-01

    The field of angiogenesis research has primarily focused on the mechanisms of sprouting angiogenesis. Yet vascular networks formed by vessel sprouting subsequently undergo extensive vascular remodeling to form a functional and mature vasculature. This "trimming" includes distinct processes of vascular pruning, the regression of selected vascular branches. In some situations complete vascular networks may undergo physiological regression. Vessel regression is an understudied yet emerging field of research. This review summarizes the state-of-the-art of vessel pruning and regression with a focus on the cellular processes and the molecular regulators of vessel maintenance and regression. PMID:26151903

  19. Estimating equivalence with quantile regression

    USGS Publications Warehouse

    Cade, B.S.

    2011-01-01

    Equivalence testing and corresponding confidence interval estimates are used to provide more enlightened statistical statements about parameter estimates by relating them to intervals of effect sizes deemed to be of scientific or practical importance rather than just to an effect size of zero. Equivalence tests and confidence interval estimates are based on a null hypothesis that a parameter estimate is either outside (inequivalence hypothesis) or inside (equivalence hypothesis) an equivalence region, depending on the question of interest and assignment of risk. The former approach, often referred to as bioequivalence testing, is often used in regulatory settings because it reverses the burden of proof compared to a standard test of significance, following a precautionary principle for environmental protection. Unfortunately, many applications of equivalence testing focus on establishing average equivalence by estimating differences in means of distributions that do not have homogeneous variances. I discuss how to compare equivalence across quantiles of distributions using confidence intervals on quantile regression estimates that detect differences in heterogeneous distributions missed by focusing on means. I used one-tailed confidence intervals based on inequivalence hypotheses in a two-group treatment-control design for estimating bioequivalence of arsenic concentrations in soils at an old ammunition testing site and bioequivalence of vegetation biomass at a reclaimed mining site. Two-tailed confidence intervals based both on inequivalence and equivalence hypotheses were used to examine quantile equivalence for negligible trends over time for a continuous exponential model of amphibian abundance. ?? 2011 by the Ecological Society of America.

  20. Harmonic regression and scale stability.

    PubMed

    Lee, Yi-Hsuan; Haberman, Shelby J

    2013-10-01

    Monitoring a very frequently administered educational test with a relatively short history of stable operation imposes a number of challenges. Test scores usually vary by season, and the frequency of administration of such educational tests is also seasonal. Although it is important to react to unreasonable changes in the distributions of test scores in a timely fashion, it is not a simple matter to ascertain what sort of distribution is really unusual. Many commonly used approaches for seasonal adjustment are designed for time series with evenly spaced observations that span many years and, therefore, are inappropriate for data from such educational tests. Harmonic regression, a seasonal-adjustment method, can be useful in monitoring scale stability when the number of years available is limited and when the observations are unevenly spaced. Additional forms of adjustments can be included to account for variability in test scores due to different sources of population variations. To illustrate, real data are considered from an international language assessment. PMID:24092490

  1. COX-1 inhibitory activity in extracts from Eucomis L'Herit. species.

    PubMed

    Taylor, J L; van Staden, J

    2001-05-01

    Non-steroidal anti-inflammatory compounds can relieve pain and inflammation associated with elevated levels of prostaglandins in the body and are proposed to be the agents responsible for the action of traditional herbal remedies associated with the reduction of pain, fever and inflammation. Primarily the bulbs and in some instances the leaves and roots, of Eucomis L 'Herit. species are widely utilized in South African traditional medicine for this purpose. A measure of the anti-inflammatory activity of plant extracts can be generated using the cyclooxygenase (COX-1) assay. High levels of COX-1 inhibitory activity were detected in crude extracts prepared from the leaves, bulbs and roots of Eucomis species. Of the 11 species tested, 9 species exhibited moderate COX-1 inhibitory activity (40-70%) for the aqueous bulb extracts. All 11 species showed COX-1 inhibitory activity of +/-70% or higher, for the ethanol bulb extracts. The bulb and root extracts (ethanol) showed, in general, the highest levels of COX-1 inhibitory activity, but most species exhibited no significant difference in activity between plant parts. Generally (for 7 of the 11 species), these levels did not differ significantly in specimens harvested in summer and in winter. IC50 values were calculated to be 72 microg ml(-1) for the bulb extract of E. autumnalis autumnalis, and 27 microg ml(-1) for the root extracts. The corresponding IC50 value for the leaf extract was estimated to be 15 microg ml(-1). The COX-1 inhibitors were relatively stable over time, both in solution (ethanol) and in the dried plant material. Extracts tested over a period of three years did not differ significantly in COX-1 inhibitory activity. These experimental results validate the extensive use of this plant in southern African traditional medicine. PMID:11297860

  2. Quantification of Burkholderia coxL Genes in Hawaiian Volcanic Deposits▿

    PubMed Central

    Weber, C. F.; King, G. M.

    2010-01-01

    Isolation of multiple carbon monoxide (CO)-oxidizing Burkholderia strains and detection by culture-independent approaches suggest that Burkholderia may be an important component of CO-oxidizing communities in Hawaiian volcanic deposits. The absolute and relative abundance of the bacteria in these communities remains unknown, however. In this study, a quantitative PCR (Q-PCR) approach has been developed to enumerate Burkholderia coxL genes (large subunit of carbon monoxide dehydrogenase). This represents the first attempt to enumerate coxL genes from CO oxidizers in environmental samples. coxL copy numbers have been determined for samples from three sites representing a vegetation gradient on a 1959 volcanic deposit that included unvegetated cinders (bare), edges of vegetated sites (edge), and sites within tree stands (canopy). Q-PCR has also been used to estimate copy numbers of Betaproteobacteria 16S rRNA gene copy numbers and total Bacteria 16S rRNA. coxL genes could not be detected in the bare site (detection limit, ≥4.7 × 103 copies per reaction) but average 1.0 × 108 ± 2.4 × 107 and 8.6 × 108 ± 7.6 ×107 copies g−1 (dry weight) in edge and canopy sites, respectively, which differ statistically (P = 0.0007). Average Burkholderia coxL gene copy numbers, expressed as a percentage of total Bacteria 16S rRNA gene copy numbers, are 6.2 and 0.7% for the edge and canopy sites, respectively. Although the percentage of Burkholderia coxL is lower in the canopy site, significantly greater gene copy numbers demonstrate that absolute abundance of coxL increases in vegetated sites and contributes to the expansion of CO oxidizer communities during biological succession on volcanic deposits. PMID:20139318

  3. Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

    PubMed Central

    Abdulhag, Ulla Najwa; Soiferman, Devorah; Schueler-Furman, Ora; Miller, Chaya; Shaag, Avraham; Elpeleg, Orly; Edvardson, Simon; Saada, Ann

    2015-01-01

    Isolated cytochrome c oxidase (COX) deficiency is a prevalent cause of mitochondrial disease and is mostly caused by nuclear-encoded mutations in assembly factors while rarely by mutations in structural subunits. We hereby report a case of isolated COX deficiency manifesting with encephalomyopathy, hydrocephalus and hypertropic cardiomyopathy due to a missense p.R20C mutation in the COX6B1 gene, which encodes an integral, nuclear-encoded COX subunit. This novel mutation was predicted to be severe in silico. In accord, enzymatic activity was undetectable in muscle and fibroblasts, was severely decreased in lymphocytes and the COX6B1 protein was barely detectable in patient's muscle mitochondria. Complementation with the wild-type cDNA by a lentiviral construct restored COX activity, and mitochondrial function was improved by 5-aminoimidazole-4-carboxamide ribonucleotide, resveratrol and ascorbate in the patient's fibroblasts. We suggest that genetic analysis of COX6B1should be included in the investigation of isolated COX deficiency, including patients with cardiac defects. Initial measurement of COX activity in lymphocytes may be useful as it might circumvent the need for invasive muscle biopsy. The evaluation of ascorbate supplementation to patients with mutated COX6B1 is warranted. PMID:24781756

  4. Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy.

    PubMed

    Abdulhag, Ulla Najwa; Soiferman, Devorah; Schueler-Furman, Ora; Miller, Chaya; Shaag, Avraham; Elpeleg, Orly; Edvardson, Simon; Saada, Ann

    2015-02-01

    Isolated cytochrome c oxidase (COX) deficiency is a prevalent cause of mitochondrial disease and is mostly caused by nuclear-encoded mutations in assembly factors while rarely by mutations in structural subunits. We hereby report a case of isolated COX deficiency manifesting with encephalomyopathy, hydrocephalus and hypertropic cardiomyopathy due to a missense p.R20C mutation in the COX6B1 gene, which encodes an integral, nuclear-encoded COX subunit. This novel mutation was predicted to be severe in silico. In accord, enzymatic activity was undetectable in muscle and fibroblasts, was severely decreased in lymphocytes and the COX6B1 protein was barely detectable in patient's muscle mitochondria. Complementation with the wild-type cDNA by a lentiviral construct restored COX activity, and mitochondrial function was improved by 5-aminoimidazole-4-carboxamide ribonucleotide, resveratrol and ascorbate in the patient's fibroblasts. We suggest that genetic analysis of COX6B1should be included in the investigation of isolated COX deficiency, including patients with cardiac defects. Initial measurement of COX activity in lymphocytes may be useful as it might circumvent the need for invasive muscle biopsy. The evaluation of ascorbate supplementation to patients with mutated COX6B1 is warranted. PMID:24781756

  5. Straight line fitting and predictions: On a marginal likelihood approach to linear regression and errors-in-variables models

    NASA Astrophysics Data System (ADS)

    Christiansen, Bo

    2015-04-01

    Linear regression methods are without doubt the most used approaches to describe and predict data in the physical sciences. They are often good first order approximations and they are in general easier to apply and interpret than more advanced methods. However, even the properties of univariate regression can lead to debate over the appropriateness of various models as witnessed by the recent discussion about climate reconstruction methods. Before linear regression is applied important choices have to be made regarding the origins of the noise terms and regarding which of the two variables under consideration that should be treated as the independent variable. These decisions are often not easy to make but they may have a considerable impact on the results. We seek to give a unified probabilistic - Bayesian with flat priors - treatment of univariate linear regression and prediction by taking, as starting point, the general errors-in-variables model (Christiansen, J. Clim., 27, 2014-2031, 2014). Other versions of linear regression can be obtained as limits of this model. We derive the likelihood of the model parameters and predictands of the general errors-in-variables model by marginalizing over the nuisance parameters. The resulting likelihood is relatively simple and easy to analyze and calculate. The well known unidentifiability of the errors-in-variables model is manifested as the absence of a well-defined maximum in the likelihood. However, this does not mean that probabilistic inference can not be made; the marginal likelihoods of model parameters and the predictands have, in general, well-defined maxima. We also include a probabilistic version of classical calibration and show how it is related to the errors-in-variables model. The results are illustrated by an example from the coupling between the lower stratosphere and the troposphere in the Northern Hemisphere winter.

  6. Cyclopamine and jervine induce COX-2 overexpression in human erythroleukemia cells but only cyclopamine has a pro-apoptotic effect

    SciTech Connect

    Ghezali, Lamia; Leger, David Yannick; Limami, Youness; Cook-Moreau, Jeanne; Beneytout, Jean-Louis; Liagre, Bertrand

    2013-04-15

    Erythroleukemia is generally associated with a very poor response and survival to current available therapeutic agents. Cyclooxygenase-2 (COX-2) has been described to play a crucial role in the proliferation and differentiation of leukemia cells, this enzyme seems to play an important role in chemoresistance in different cancer types. Previously, we demonstrated that diosgenin, a plant steroid, induced apoptosis in HEL cells with concomitant COX-2 overexpression. In this study, we investigated the antiproliferative and apoptotic effects of cyclopamine and jervine, two steroidal alkaloids with similar structures, on HEL and TF1a human erythroleukemia cell lines and, for the first time, their effect on COX-2 expression. Cyclopamine, but not jervine, inhibited cell proliferation and induced apoptosis in these cells. Both compounds induced COX-2 overexpression which was responsible for apoptosis resistance. In jervine-treated cells, COX-2 overexpression was NF-κB dependent. Inhibition of NF-κB reduced COX-2 overexpression and induced apoptosis. In addition, cyclopamine induced apoptosis and COX-2 overexpression via PKC activation. Inhibition of the PKC pathway reduced both apoptosis and COX-2 overexpression in both cell lines. Furthermore, we demonstrated that the p38/COX-2 pathway was involved in resistance to cyclopamine-induced apoptosis since p38 inhibition reduced COX-2 overexpression and increased apoptosis in both cell lines. - Highlights: ► Cyclopamine alone but not jervine induces apoptosis in human erythroleukemia cells. ► Cyclopamine and jervine induce COX-2 overexpression. ► COX-2 overexpression is implicated in resistance to cyclopamine-induced apoptosis. ► Apoptotic potential of jervine is restrained by NF-κB pathway activation. ► PKC is involved in cyclopamine-induced apoptosis and COX-2 overexpression.

  7. Virtual screening of compounds from the patchouli oil of Pogostemon herba for COX-1 inhibition

    PubMed Central

    Raharjo, Sentot Joko; Fatchiyah, Fatchiyah

    2013-01-01

    Our interest is to identify compounds from the patchouli oil of Pogostemon herba to inhibit the cyclooxygenase-1 (COX-1) enzyme activity. The data for the major compounds (alpha-patchouli alcohol isomer (CD521903, CD442384, and/or CD6432585), alphabulnusene, seychellene and alpha-guaiene) of patchouli oil were explored from the PubChem database. The compounds to COX-1 interactions were studied using the molecular docking tools Hex 6.12 and LeadIT2 Bisolve. The interactions were further visualized using the Chimera 1.7s viewer software tool. The analysis of the major compounds of patchouli oil showed that alpha-Patchouli alcohol (CD521903) binds to COX-1 at many active sites including: Leu223B, Asp228B, Leu237B, Arg332B, Trp138A, Glu139A, Ser142A, and Asn143A. Further analysis revealed that these binding sites are maintained by hydrogen bonds with Ser142A, Glu139A, and Asp228B. The interaction energy between COX-1 and alpha-patchouli alcohol (CD521903) is -6 kJ/mol (without solvent) and -15 kJ/ mol (with solvent DMSO). These theoretical data suggests alpha-patchouli alcohol as a potential inhibitor of the COX-1 enzyme. However, these observations should be investigated and confirmed using experimental evidence. PMID:23559751

  8. Antiinflammatory and neuroprotective actions of COX2 inhibitors in the injured brain

    PubMed Central

    Strauss, Kenneth I.

    2008-01-01

    Overexpression of COX2 appears to be both a marker and an effector of neural damage after a variety of acquired brain injuries, and in natural or pathological aging of the brain. COX2 inhibitors may be neuroprotective in the brain by reducing prostanoid and free radical synthesis, or by directing arachidonic acid down alternate metabolic pathways. The arachidonic acid shunting hypothesis proposes that COX2 inhibitors' neuroprotective effects may be mediated by increased formation of potentially beneficial eicosanoids. Under conditions where COX2 activity is inhibited, arachidonic acid accumulates or is converted to eicosanoids via lipoxygenases and cytochrome P450 (CYP) epoxygenases. Several P450 eicosanoids have been demonstrated to have beneficial effects in the brain and/or periphery. We suspect that arachidonic acid shunting may be as important to functional recovery after brain injuries as altered prostanoid formation per se. Thus, COX2 inhibition and arachidonic acid shunting have therapeutic implications beyond the suppression of prostaglandin synthesis and free radical formation. PMID:17996418

  9. Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model

    PubMed Central

    Woods, Ashley K.; Bartos, Amanda; Heyward, Christa Y.; Lob, Heinrich E.; Isroff, Catherine E.; Butler, Scott D.; Shapiro, Stephanie E.; Dey, Sudhansu K.; Davisson, Robin L.

    2016-01-01

    Preeclampsia (PE) is a disorder of pregnancy that manifests as late gestational maternal hypertension and proteinuria and can be life-threatening to both the mother and baby. It is believed that abnormal placentation is responsible for the cascade of events leading to the maternal syndrome. Embryo implantation is critical to establishing a healthy pregnancy. Defective implantation can cause adverse “ripple effects,” leading to abnormal decidualization and placentation, retarded fetal development, and poor pregnancy outcomes, such as PE and fetal growth restriction. The precise mechanism(s) of implantation defects that lead to PE remain elusive. BPH/5 mice, which spontaneously develop the cardinal features of PE, show peri-implantation defects including upregulation of Cox2 and IL-15 at the maternal-fetal interface. This was associated with decreased decidual natural killer (dNK) cells, which have important roles in establishing placental perfusion. Interestingly, a single administration of a Cox2 inhibitor (celecoxib) during decidualization restrained Cox2 and IL-15 expression, restored dNK cell numbers, improved fetal growth, and attenuated late gestational hypertension in BPH/5 female mice. This study provides evidence that decidual overexpression of Cox2 and IL-15 may trigger the adverse pregnancy outcomes reflected in the preeclamptic syndrome, underscoring the idea that Cox2 inhibitor treatment is an effective strategy for the prevention of PE-associated fetal and maternal morbidity and mortality. PMID:27159542

  10. Effects of selective cyclooxygenase-2 and non-selective COX inhibition on myocardial function and perfusion

    PubMed Central

    Robich, Michael P.; Chu, Louis M.; Burgess, Thomas A.; Feng, Jun; Bianchi, Cesario; Sellke, Frank W.

    2011-01-01

    Non-selective NSAIDs and selective cyclooxygenase-2 (COX-2) inhibitors are purported to increase adverse cardiovascular events. We hypothesized COX-2 inhibitors would alter myocardial blood flow, microvascular reactivity, oxidative stress, and prostaglandin levels. Adult Yorkshire swine were divided into three groups: no drug (control, n=7), a non-selective COX inhibitor (naproxen 400mg daily, NAP, n=7), or a selective COX-2 inhibitor (celecoxib 200mg daily, CBX, n=7). After 7 weeks physiologic measurements were taken and tissue harvested. Animals in the CBX group demonstrated significantly higher blood pressure and rate pressure product. The NAP and CBX groups demonstrated an increased microvascular contraction response to serotonin. The NAP group showed increased myocardial levels of thromboxane and lower levels of prostacyclin. Levels of protein oxidative stress were increased in the CBX group. Myocardial apoptosis was lowest in the NAP group. Immunoblotting demonstrated decreased VEGF and phospho-eNOS expression in the NAP and CBX groups. Myocardial TNFα was increased in both the NAP and CBX groups. Immunostaining for thromboxane A2 synthase and receptor demonstrated expression within the vascular smooth muscle and no observable differences between groups. Non-selective and selective COX inhibition does not alter myocardial perfusion, but results in altered myocardial and vascular physiology that may have implications regarding cardiovascular risk. PMID:21233641

  11. Role of COX-2 in cough reflex sensitivity to inhaled capsaicin in patients with sinobronchial syndrome

    PubMed Central

    2010-01-01

    Background Sinobronchial syndrome is a cause of chronic productive cough. Inflammatory mediators are involved in the pathophysiology of chronic productive cough. Accumulating evidences indicate that cyclooxygenase (COX)-2, one of the inducible isoforms of COX, is a key element in the pathophysiological process of a number of inflammatory disorders. However, little is known about the role of COX-2 in chronic productive cough in patients with sinobronchial syndrome known as neutrophilic bronchial inflammation. Methods The effect of etodolac, a potent COX-2 inhibitor, on cough response to inhaled capsaicin was examined in 15 patients with sinobronchial syndrome in a randomized, placebo-controlled cross-over study. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of airway cough reflex sensitivity. Results The cough threshold was significantly (p < 0.03) increased after two-week treatment with etodolac (200 mg twice a day orally) compared with placebo [37.5 (GSEM 1.3) vs. 27.2 (GSEM 1.3) μM]. Conclusions These findings indicate that COX-2 may be a possible modulator augmenting airway cough reflex sensitivity in patients with sinobronchial syndrome. PMID:20696045

  12. In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis.

    PubMed

    Viscomi, Carlo; Bottani, Emanuela; Civiletto, Gabriele; Cerutti, Raffaele; Moggio, Maurizio; Fagiolari, Gigliola; Schon, Eric A; Lamperti, Costanza; Zeviani, Massimo

    2011-07-01

    Increased mitochondrial biogenesis by activation of PPAR- or AMPK/PGC-1α-dependent homeostatic pathways has been proposed as a treatment for mitochondrial disease. We tested this hypothesis on three recombinant mouse models characterized by defective cytochrome c-oxidase (COX) activity: a knockout (KO) mouse for Surf1, a knockout/knockin mouse for Sco2, and a muscle-restricted KO mouse for Cox15. First, we demonstrated that double-recombinant animals overexpressing PGC-1α in skeletal muscle on a Surf1 KO background showed robust induction of mitochondrial biogenesis and increase of mitochondrial respiratory chain activities, including COX. No such effect was obtained by treating both Surf1(-/-) and Cox15(-/-) mice with the pan-PPAR agonist bezafibrate, which instead showed adverse effects in either model. Contrariwise, treatment with the AMPK agonist AICAR led to partial correction of COX deficiency in all three models, and, importantly, significant motor improvement up to normal in the Sco2(KO/KI) mouse. These results open new perspectives for therapy of mitochondrial disease. PMID:21723506

  13. STIM1 overexpression promotes colorectal cancer progression, cell motility and COX-2 expression.

    PubMed

    Wang, J-Y; Sun, J; Huang, M-Y; Wang, Y-S; Hou, M-F; Sun, Y; He, H; Krishna, N; Chiu, S-J; Lin, S; Yang, S; Chang, W-C

    2015-08-13

    Tumor metastasis is the major cause of death among cancer patients, with >90% of cancer-related death attributable to the spreading of metastatic cells to secondary organs. Store-operated Ca(2+) entry (SOCE) is the predominant Ca(2+) entry mechanism in most cancer cells, and stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum (ER) Ca(2+) sensor for store-operated channels. Here we reported that the STIM1 was overexpressed in colorectal cancer (CRC) patients. STIM1 overexpression in CRC was significantly associated with tumor size, depth of invasion, lymph node metastasis status and serum levels of carcinoembryonic antigen. Furthermore, ectopic expression of STIM1 promoted CRC cell motility, while depletion of STIM1 with short hairpin RNA inhibited CRC cell migration. Our data further suggested that STIM1 promoted CRC cell migration through increasing the expression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2). Importantly, ectopically expressed COX-2 or exogenous PGE2 were able to rescue migration defect in STIM1 knockdown CRC cells, and inhibition of COX-2 with ibuprofen and indomethacin abrogated STIM1-mediated CRC cell motility. In short, our data provided clinicopathological significance for STIM1 and SOCE in CRC progression, and implicated a role for COX-2 in STIM1-mediated CRC metastasis. Our studies also suggested a new approach to inhibit STIM1-mediated metastasis with COX-2 inhibitors. PMID:25381814

  14. Reduction in cancer risk by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors

    PubMed Central

    Harris, Randall E; Beebe, Joanne; Alshafie, Galal A

    2012-01-01

    We conducted a series of epidemiologic studies to evaluate the chemopreventive effects of aspirin, ibuprofen, and selective cyxlooxygenase-2 (COX-2) inhibitors (coxibs) against cancers of the breast, colon, prostate, and lung. Composite results across all four cancer sites revealed that regular intake of 325 mg aspirin, 200 mg ibuprofen, or standard dosages of coxibs (200 mg celecoxib or 25 mg rofecoxib) produced risk reductions of 49%, 59%, and 64%, respectively. Use of coxibs for at least 2 years was associated with risk reductions of 71%, 70%, 55%, and 60% for breast cancer, colon cancer, prostate cancer and lung cancer, respectively. Effects of ibuprofen were similar to selective coxibs, and slightly stronger than aspirin. These observed effects are consistent with the relative COX-2 selectivity of ibuprofen, coxibs, and aspirin. Acetaminophen, an analgesic without COX-2 activity, had no effect. Overexpression of COX-2 and increased prostaglandin biosynthesis correlates with carcinogenesis and metastasis at most anatomic sites. These results indicate that regular intake of nonselective or selective COX-2 inhibiting agents protects against the development of major forms of cancer.

  15. Regression From Pre-Diabetes to Normal Glucose Regulation in the Diabetes Prevention Program

    PubMed Central

    Perreault, Leigh; Kahn, Steven E.; Christophi, Costas A.; Knowler, William C.; Hamman, Richard F.

    2009-01-01

    OBJECTIVE Participants in the Diabetes Prevention Program (DPP) randomized to intensive lifestyle modification (ILS) or metformin had a significantly reduced incidence of diabetes compared with those randomized to placebo, yet most were still at risk because they had pre-diabetes. We explored the effect of baseline characteristics, weight change, ILS, and metformin on regression from pre-diabetes to the lowest-risk state of normal glucose regulation (NGR) defined by American Diabetes Association criteria. RESEARCH DESIGN AND METHODS The DPP was a prospective randomized trial. Cox proportional hazards modeling was used to identify predictors of regression from pre-diabetes to NGR over 3 years of follow-up. RESULTS Lower baseline fasting (hazard ratio 1.52, P < 0.01) and 2-h (1.24, P < 0.01) glucose predicted regression to NGR, as did younger age (1.07, P < 0.01) and greater insulin secretion (1.09, P = 0.04). ILS (2.05, P < 0.01) and weight loss (1.34, P < 0.01) had significant and independent effects on regression. A nonsignificant trend for regression was also observed for metformin (1.25, P = 0.06), male sex (1.17, P = 0.08), and insulin sensitivity (1.07, P = 0.09). In those entering the study with both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), male sex and insulin sensitivity predicted regression to isolated IFG, whereas ILS, metformin, female sex, and greater insulin secretion predicted regression to isolated IGT. CONCLUSIONS Insulin secretion, and other biologic processes retained with younger age, are key in restoring NGR in people with pre-diabetes. However, NGR may also be attained through weight loss and additional aspects of ILS. PMID:19587364

  16. Combined therapy with COX-2 inhibitor and 20-HETE inhibitor reduces colon tumor growth and the adverse effects of ischemic stroke associated with COX-2 inhibition.

    PubMed

    Zhang, Yi; Hoda, Md Nasrul; Zheng, Xuan; Li, Weiguo; Luo, Pengcheng; Maddipati, Krishna Rao; Seki, Tsugio; Ergul, Adviye; Wang, Mong-Heng

    2014-09-15

    20-Hydroxyeicosatetraenoic acid (20-HETE), Cyp4a-derived eicosanoid, is a lipid mediator that promotes tumor growth, as well as causing detrimental effects in cerebral circulation. We determined whether concurrent inhibition of cyclooxygenase-2 (COX-2) and 20-HETE affects colon tumor growth and ischemic stroke outcomes. The expression of Cyp4a and COXs and production of 20-HETE and PGE2 were determined in murine colon carcinoma (MC38) cells. We then examined the effects of combined treatment with rofecoxib, a potent COX-2 inhibitor, and HET0016, a potent Cyp4a inhibitor, on the growth and proliferation of MC38 cells. Subsequently, we tested the effects of HET0016 plus rofecoxib in MC38 tumor and ischemic stroke models. Cyp4a and COXs are highly expressed in MC38 cells. Respectively, HET0016 and rofecoxib inhibited 20-HETE and PGE2 formation in MC38 cells. Moreover, rofecoxib combined with HET0016 had greater inhibitory effects on the growth and proliferation of MC38 cells than did rofecoxib alone. Importantly, rofecoxib combined with HET0016 provided greater inhibition on tumor growth than did rofecoxib alone in MC38 tumor-bearing mice. Prolonged treatment with rofecoxib selectively induced circulating 20-HETE levels and caused cerebrovascular damage after ischemic stroke, whereas therapy with rofecoxib and HET0016 attenuated 20-HETE levels and reduced rofecoxib-induced cerebrovascular damage and stroke outcomes during anti-tumor therapy. Thus these results demonstrate that combination therapy with rofecoxib and HET0016 provides a new treatment of colon tumor, which can not only enhance the anti-tumor efficacy of rofecoxib, but also reduce rofecoxib-induced cerebrovascular damage and stroke outcomes. PMID:24990856

  17. Robust inhibitory effects of conjugated linolenic acids on a cyclooxygenase-related linoleate 10S-dioxygenase: Comparison with COX-1 and COX-2.

    PubMed

    Mashhadi, Zahra; Boeglin, William E; Brash, Alan R

    2015-10-01

    There are many reports of the anti-inflammatory, anti-cancer, and anti-atherosclerotic activities of conjugated linolenic acids (cLNA). They constitute a small percentage of fatty acids in the typical human diet, although up to 80% of the fatty acids in certain fruits such as pomegranate. In the course of studying a bacterial fatty acid dioxygenase (Nostoc linoleate 10S-DOX, an ancient relative of mammalian cyclooxygenases), we detected strong inhibitory activity in a commercial sample of linoleic acid. We identified two cLNA isomers, β-eleostearic (9E,11E,13E-18:3) and β-calendic acid (8E,10E,12E-18:3), as responsible for that striking inhibition with a Ki of ~49nM and ~125nM, respectively, the most potent among eight cLNA tested. We also examined the effects of all eight cLNA on the activity of COX-1 and COX-2. Jacaric acid (8Z,10E,12Z-18:3) and its 12E isomer, 8Z,10E,12E-18:3, strongly inhibit the activity of COX-1 with a Ki of ~1.7 and ~1.1μM, respectively. By contrast, COX-2 was ≤30% inhibited at 10μM concentrations of the cLNA. Identifying the activities of the naturally occurring fatty acids is of interest in terms of understanding their interaction with the enzymes, and for explaining the mechanistic basis of their biological effects. The study also highlights the potential presence of inhibitory fatty acids in commercial lipids prepared from natural sources. Analysis of seven commercial samples of linoleic acid by HPLC and UV spectroscopy is illustrated as supplementary data. PMID:26209563

  18. Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation

    PubMed Central

    Hermanson, Daniel J.; Gamble-George, Joyonna C.; Marnett, Lawrence J.; Patel, Sachin

    2014-01-01

    Pharmacologic augmentation of endogenous cannabinoid (eCB) signaling is an emerging therapeutic approach for the treatment of a broad range of pathophysiological conditions. Thus far, pharmacological approaches have focused on inhibition of canonical eCB inactivation pathways, fatty acid amide hydrolase for anandamide and monoacylglycerol lipase for 2-arachidonoylglycerol. Here we review experimental evidence that cyclooxygenase-2-mediated eCB oxygenation represents a third mechanism for terminating eCB action at cannabinoid receptors. We describe the development, molecular mechanisms, and in vivo validation of “substrate-selective” COX-2 inhibitors that prevent eCB inactivation by COX-2 without affecting the prostaglandin generation from arachidonic acid. Lastly, we review recent data on the potential therapeutic applications of substrate-selective COX-2 inhibitors with a focus on neuropsychiatric disorders. PMID:24845457

  19. Identification and initial characterisation of a Plasmodium falciparum Cox17 copper metallochaperone.

    PubMed

    Choveaux, David L; Krause, Robert G E; Przyborski, Jude M; Goldring, J P Dean

    2015-01-01

    Copper is an essential micronutrient for all living organisms as an important catalytic co-factor for key enzymes. In higher eukaryotes intracellular copper is distributed by copper metallochaperones. Copper chelators such as neocuproine and tetrathiomolybdate inhibit Plasmodium falciparum erythrocytic development, indicating a requirement for copper by the parasite. A screen of the P. falciparum genome database identified eight potential copper-requiring protein orthologs, including four candidate copper metallochaperones implicated in the delivery of copper to cytochrome-c oxidase. A P. falciparum Cox17 ortholog (PfCox17) was recombinantly expressed and the purified protein bound reduced copper in vitro. PfCox17 was localised to the parasite cytoplasm. Characterisation of plasmodial proteins involved in copper metabolism will help us understand the role of this essential microelement in plasmodial homeostasis. PMID:25447123

  20. LRGS: Linear Regression by Gibbs Sampling

    NASA Astrophysics Data System (ADS)

    Mantz, Adam B.

    2016-02-01

    LRGS (Linear Regression by Gibbs Sampling) implements a Gibbs sampler to solve the problem of multivariate linear regression with uncertainties in all measured quantities and intrinsic scatter. LRGS extends an algorithm by Kelly (2007) that used Gibbs sampling for performing linear regression in fairly general cases in two ways: generalizing the procedure for multiple response variables, and modeling the prior distribution of covariates using a Dirichlet process.

  1. COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells

    PubMed Central

    Fujita, Mitsugu; Kohanbash, Gary; Fellows-Mayle, Wendy; Hamilton, Ronald L.; Komohara, Yoshihiro; Decker, Stacy A.; Ohlfest, John R.; Okada, Hideho

    2011-01-01

    Epidemiological studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) and reduced glioma risks in humans. Most NSAIDs function as cyclooxygenase-2 (COX-2) inhibitors that prevent production of prostaglandin E2 (PGE2). Since PGE2 induces expansion of myeloid-derived suppressor cells (MDSCs), we hypothesized that COX-2 blockade would suppress gliomagenesis by inhibiting MDSC development and accumulation in the tumor microenvironment (TME). In mouse models of glioma, treatment with the COX-2 inhibitors acetylsalicylic acid (ASA) or celecoxib inhibited systemic PGE2 production and delayed glioma development. ASA treatment also reduced the MDSC-attracting chemokine CCL2 in the TME along with numbers of CD11b+Ly6GhiLy6Clo granulocytic MDSCs in both the bone marrow and TME. In support of this evidence that COX-2 blockade blocked systemic development of MDSCs and their CCL2-mediated accumulation in the TME, there were defects in these processes in glioma-bearing Cox2-deficient and Ccl2-deficient mice. Conversely, these mice or ASA-treated wild-type mice displayed enhanced expression of CXCL10 and infiltration of cytotoxic T lymphocytes (CTL) in the TME, consistent with a relief of MDSC-mediated immune suppression. Antibody-mediated depletion of MDSCs delayed glioma growth in association with an increase in CXCL10 and CTLs in the TME, underscoring a critical role for MDSCs in glioma development. Lastly, Cxcl10-deficient mice exhibited reduced CTL infiltration of tumors, establishing that CXCL10 limited this pathway of immune suppression. Taken together, our findings show that the COX-2 pathway promotes gliomagenesis by directly supporting systemic development of MDSC and their accumulation in the TME, where they limit CTL infiltration. PMID:21324923

  2. Molecular docking and analgesic studies of Erythrina variegata׳s derived phytochemicals with COX enzymes.

    PubMed

    Uddin, Mir Muhammad Nasir; Emran, Talha Bin; Mahib, Muhammad Mamunur Rashid; Dash, Raju

    2014-01-01

    Secondary metabolites from plants are a good source for the NSAID drug development. We studied the analgesic activity of ethanolic extract of Erythrina variegata L. (Fabaceae) followed by molecular docking analysis. The analgesic activity of Erythrina variegata L. is evaluated by various methods viz., acetic acid-induced writhing test, hot plate and tail immersion test. Subsequently, molecular docking analysis has been performed to identify compounds having activity against COX-1 and COX-2 enzymes by using GOLD docking fitness. The result of preliminary phytochemical screening revealed that the extract contains alkaloids and flavonoids. In analgesic activity tests, the extract at the doses of 50, 100 and 200 mg/kg body weight (b.w.) produced a increase in pain threshold in a dose dependent manner. In acetic acid induced writhing test, the inhibitory effect was similar to the reference drug diclofenac sodium. The extract showed 18.89% writhing inhibitory effect at the dose 200 mg/kg b.w., whereas diclofenac sodium showed 79.42% inhibition of writhing at a dose of 10 mg/kg b.w. The results of tail immersion and hot plate test also showed potential analgesic activity of the extract which is also comparable to the standard drug morphine (5 mg/kg b.w.). Docking studies shows that phaseollin of Erythrina variegata L. has the best fitness score against the COX-1 which is 56.64 and 59.63 for COX- 2 enzyme. Phaseollin of Erythrina variegata L. detected with significant fitness score and hydrogen bonding against COX-1 and COX-2 is reported for further validation. PMID:25489172

  3. Combined use of COX-1 and VEGF immunohistochemistry refines the histopathologic prognosis of renal cell carcinoma

    PubMed Central

    Osman, Wesam M; Youssef, Nermeen S

    2015-01-01

    The course of RCC is asymptomatic, resulting in 25-30% of patients presenting with metastatic disease at time of diagnosis. The development of novel agents targeting angiogenesis and signal transduction pathways has improved patient outcomes. Role of cyclooxygenase in cancer development has been the subject of close scrutiny. COX-1 has been recognized to be involved in regulation of angiogenesis. To date, no immunohistochemical studies have been performed to assess the possible association between COX-1 and VEGF in RCC. This study is designed to evaluate the relationship between these two proteins in RCC. Also, the relationship between their combined immunohistochemical expression and different clinicopathological prognostic parameters in RCC is investigated. Immunohistochemical expression of COX-1 and VEGF was evaluated retrospectively on 64 cases of primary RCC including: 45 clear cell carcinoma, 12 papillary carcinoma and 7 of chromophope carcinoma. High COX-1 expression was detected in 62.5% of RCCs with a significant association with tumor grade (P=0.028), and highly significant relationship with tumor size and stage (P=0.001). There was a highly significant relationship between the VEGF score and tumor size (P=0.001), and stage (P=0.006). There was a positive correlation between COX-1 and VEGF expression score (P=0.001). Combined expression of both markers predicts high stage tumors (stage III/IV). Immunohistochemical expression of COX-1 and VEGF is associated with poor prognostic parameters in RCC. Their combined expression has a beneficial role in prediction of high stage tumors (III/IV). PMID:26339385

  4. COX-2 dependent regulation of mechanotransduction in human breast cancer cells

    PubMed Central

    Yoon, A-Rum; Stasinopoulos, Ioannis; Kim, Jae Hun; Yong, Hwan Mee; Kilic, Onur; Wirtz, Denis; Bhujwalla, Zaver M; An, Steven S

    2015-01-01

    The ability of living cells to exert physical forces upon their surrounding is a necessary prerequisite for diverse biological processes, such as local cellular migrations in wound healing to metastatic-invasion of cancer. How forces are coopted in metastasis has remained unclear, however, because the mechanical interplay between cancer cells and the various stromal components has not been experimentally accessible. Current dogma implicates inflammation in these mechanical processes. Using Fourier transform traction microscopy, we measured the force-generating capacity of human breast cancer cells occupying a spectrum of invasiveness as well as basal and inducible COX-2 expression (MCF-7COX-2. Both COX-2-silenced and COX-2-expressing cells expressed EP2 and EP4 receptors, but not EP1 and EP3. Exogenous addition of PGE2 increased cell tractions and stiffened the underlying cytoskeletal network. To our knowledge this is the first report linking the expression of COX-2 with mechanotransduction of human breast cancer cells, and the regulation of COX-2-PGE2-EP signaling with physical properties of the tumor microenvironment. Drug treatments aimed at reducing this mechanical interplay may have therapeutic potential in the treatment of breast cancer. PMID:25701047

  5. Effects of selective cyclooxygenase-2 and non-selective COX inhibition on ischemic myocardium

    PubMed Central

    Robich, Michael P.; Chu, Louis M.; Feng, Jun; Burgess, Thomas A.; Laham, Roger J.; Bianchi, Cesario; Sellke, Frank W.

    2010-01-01

    Objective We sought to explore the effects of non-selective COX and selective COX-2 inhibition on collateral development in a model of chronic myocardial ischemia. We hypothesized that COX-2 inhibitors will negatively effect angiogenic and inflammatory pathways. Methods Yorkshire swine were made chronically ischemic by placing an ameroid constrictor on the left circumflex coronary artery. Swine were divided into three groups and given: no drug (control, n=7), a non-selective COX inhibitor (naproxen 400mg daily, NAP, n=7), or a selective COX-2 inhibitor (celecoxib 200mg daily, CBX, n=7). After 7 weeks, coronary angiography was performed. Myocardial function and microvascular reactivity were assessed. Serum and myocardial tissue were analyzed for prostaglandin levels and markers of inflammation and angiogenesis. Results The CBX group demonstrated significantly increased mean arterial pressure and decreased left ventricular function. Myocardial perfusion in the CBX group was similar to the control, but less than in the NAP group. Coronary microvascular contraction in the collateral dependent territory was increased in the NAP group, but minimally affected in the CBX group. Oxidative stress and apoptosis were increased in the CBX group. Expression of angiogenic markers, VEGF and phospho-eNOS (ser1177), and tissue levels of prostacyclin were decreased in both the CBX and NAP groups. The NAP group had diminished expression of endostatin. Conclusion The effects of selective and non-selective COX inhibition are more complex than previously published, but they do not decrease collateral dependent blood flow to the myocardium in our model of chronic myocardial ischemia. PMID:20804993

  6. Virtual screening for novel COX-2 inhibitors using the ZINC database

    PubMed Central

    Sudha, Kotaprolu Naga; Shakira, Mohammed; Prasanthi, Paturi; Sarika, Nalla; Kumar, Ch Narasimha; Babu, Padavala Ajay

    2008-01-01

    Cyclooxygenase-2 (COX-2) enzyme binds to arachidonic acid and releases metabolites that are used to induce pain and inflammation. COX-2 selective inhibitors such as celecoxib, rofecoxib and valdecoxib are currently used to reduce inflammatory response. However, they lack anti-thrombotic activity and hence lead to cardiovascular and renal liabilities apart from gastrointestinal irritation. Therefore, there is still a need to develop more potent COX-2 inhibitors. In this paper, we report the screening of various compounds from the ZINC database (contains 4.6 million small molecule compounds) using the eHiTS (electronic High Throughput Screening) software tool against the COX-2 protein. The strategy employed can be conveniently split into two categories, viz. screening and docking, respectively. Screening was performed using molecular constraints tool to filter compounds with physico-chemical properties similar to the 6COX bound ligand SC-558. The analysis resulted in 1042 Lipinski compliant hits which are docked and scored to identify structurally novel ligands that make similar interactions to those of known ligands or may have different interactions with other parts of the binding site. Our screening approach identified two molecules ZINC00663976 (eHITS score of -7.135 kcal/mol) and ZINC02062094 (eHITS score of -7.242 kcal/mol) from the ZINC database. Their energy scores are better than the 6COX bound co-crystallized ligand SC-558 with an eHiTS score of -6.559 kcal/mol. Both the ligands were docked within the binding pocket forming interactions with Leu352, Phe518, Met522, Val523, Ala527 and Ser353. Visual inspection suggested similar orientation and binding mode for ZINC02062094 with SC-558 ligand. The NH group of the ligand formed hydrogen bond interactions with the backbone NH of Ala527. PMID:18685718

  7. Virtual screening for novel COX-2 inhibitors using the ZINC database.

    PubMed

    Sudha, Kotaprolu Naga; Shakira, Mohammed; Prasanthi, Paturi; Sarika, Nalla; Kumar, Ch Narasimha; Babu, Padavala Ajay

    2008-01-01

    Cyclooxygenase-2 (COX-2) enzyme binds to arachidonic acid and releases metabolites that are used to induce pain and inflammation. COX-2 selective inhibitors such as celecoxib, rofecoxib and valdecoxib are currently used to reduce inflammatory response. However, they lack anti-thrombotic activity and hence lead to cardiovascular and renal liabilities apart from gastrointestinal irritation. Therefore, there is still a need to develop more potent COX-2 inhibitors. In this paper, we report the screening of various compounds from the ZINC database (contains 4.6 million small molecule compounds) using the eHiTS (electronic High Throughput Screening) software tool against the COX-2 protein. The strategy employed can be conveniently split into two categories, viz. screening and docking, respectively. Screening was performed using molecular constraints tool to filter compounds with physico-chemical properties similar to the 6COX bound ligand SC-558. The analysis resulted in 1042 Lipinski compliant hits which are docked and scored to identify structurally novel ligands that make similar interactions to those of known ligands or may have different interactions with other parts of the binding site. Our screening approach identified two molecules ZINC00663976 (eHITS score of -7.135 kcal/mol) and ZINC02062094 (eHITS score of -7.242 kcal/mol) from the ZINC database. Their energy scores are better than the 6COX bound co-crystallized ligand SC-558 with an eHiTS score of -6.559 kcal/mol. Both the ligands were docked within the binding pocket forming interactions with Leu352, Phe518, Met522, Val523, Ala527 and Ser353. Visual inspection suggested similar orientation and binding mode for ZINC02062094 with SC-558 ligand. The NH group of the ligand formed hydrogen bond interactions with the backbone NH of Ala527. PMID:18685718

  8. Genetic deletion of COX-2 prevents increased renin expression in response to ACE inhibition.

    PubMed

    Cheng, H F; Wang, J L; Zhang, M Z; Wang, S W; McKanna, J A; Harris, R C

    2001-03-01

    Cyclooxygenase-2 (COX-2) is expressed in macula densa (MD) and surrounding cortical thick ascending limb of the loop of Henle (cTALH) and is involved in regulation of renin production. We and others have previously found that selective COX-2 inhibitors can inhibit renal renin production (Cheng HF, Wang JL, Zhang MZ, Miyazaki Y, Ichikawa I, McKanna JA, and Harris RC. J Clin Invest 103: 953-961, 1999; Harding P, Sigmon DH, Alfie ME, Huang PL, Fishman MC, Beierwaltes WH, and Carretero OA. Hypertension 29: 297-302, 1997; Traynor TR, Smart A, Briggs JP, and Schnermann J. Am J Physiol Renal Physiol 277: F706-F710, 1999; Wang JL, Cheng HF, and Harris RC. Hypertension 34: 96-101, 1999). In the present studies, we utilized mice with genetic deletions of the COX-2 gene in order to investigate further the potential role of COX-2 in mediation of the renin-angiotensin system (RAS). Age-matched wild-type (+/+), heterozygotes (+/-), and homozygous null mice (-/-) were administered the angiotensin-converting enzyme inhibitor (ACEI), captopril, for 7 days. ACEI failed to significantly increase plasma renin activity, renal renin mRNA expression, and renal renin activity in (-/-) mice. ACEI increased the number of cells expressing immunoreactive renin in the (+/+) mice both by inducing more juxtaglomerular cells to express immunoreactive renin and by recruiting additional renin-expressing cells in the more proximal afferent arteriole. In contrast, there was minimal recruitment of renin-expressing cells in the more proximal afferent arteriole of the -/- mice. In summary, these results indicate that ACEI-mediated increases in renal renin production were defective in COX-2 knockout (K/O) mice and provide further indication that MD COX-2 is an important mediator of the renin-angiotensin system. PMID:11181406

  9. Effects of prostaglandins and COX-inhibiting drugs on skeletal muscle adaptations to exercise

    PubMed Central

    Liu, Sophia Z.

    2013-01-01

    It has been ∼40 yr since the discovery that PGs are produced by exercising skeletal muscle and since the discovery that inhibition of PG synthesis is the mechanism of action of what are now known as cyclooxygenase (COX)-inhibiting drugs. Since that time, it has been established that PGs are made during and after aerobic and resistance exercise and have a potent paracrine and autocrine effect on muscle metabolism. Consequently, it has also been determined that orally consumed doses of COX inhibitors can profoundly influence muscle PG synthesis, muscle protein metabolism, and numerous other cellular processes that regulate muscle adaptations to exercise loading. Although data from acute human exercise studies, as well as animal and cell-culture data, would predict that regular consumption of a COX inhibitor during exercise training would dampen the typical muscle adaptations, the chronic data do not support this conjecture. From the studies in young and older individuals, lasting from 1.5 to 4 mo, no interfering effects of COX inhibitors on muscle adaptations to resistance-exercise training have been noted. In fact, in older individuals, a substantial enhancement of muscle mass and strength has been observed. The collective findings of the PG/COX-pathway regulation of skeletal muscle responses and adaptations to exercise are compelling. Considering the discoveries in other areas of COX regulation of health and disease, there is certainly an interesting future of investigation in this re-emerging area, especially as it pertains to older individuals and the condition of sarcopenia, as well as exercise training and performance of individuals of all ages. PMID:23539318

  10. Timosaponin AIII inhibits melanoma cell migration by suppressing COX-2 and in vivo tumor metastasis.

    PubMed

    Kim, Ki Mo; Im, A-Rang; Kim, Seung Hyung; Hyun, Jin Won; Chae, Sungwook

    2016-02-01

    Melanoma is the leading cause of death from skin disease, due in large part to its propensity to metastasize. We examined the effects of timosaponin AIII, a compound isolated from Anemarrhena asphodeloides Bunge, on melanoma cancer cell migration and the molecular mechanisms underlying these effects using B16-F10 and WM-115 melanoma cells lines. Overexpression of COX-2, its metabolite prostaglandin E2 (PGE2 ), and PGE2 receptors (EP2 and EP4) promoted cell migration in vitro. Exposure to timosaponin AIII resulted in concentration-dependent inhibition of cell migration, which was associated with reduced levels of COX-2, PGE2 , and PGE2 receptors. Transient transfection of COX-2 siRNA also inhibited cell migration. Exposure to 12-O-tetradecanoylphorbal-13-acetate enhanced cell migration, whereas timosaponin AIII inhibited 12-O-tetradecanoylphorbal-13-acetate-induced cell migration and reduced basal levels of EP2 and EP4. Moreover, timosaponin AIII inhibited activation of nuclear factor-kappa B (NF-?B), an upstream regulator of COX-2 in B16-F10 cells. Consistent with our in vitro findings, in vivo studies showed that timosaponin AIII treatment significantly reduced the total number of metastatic nodules in the mouse lung and improved histological alterations in B16-F10-injected C57BL/6 mice. In addition, C57BL/6 mice treated with timosaponin AIII showed reduced expression of COX-2 and NF-?B in the lung. Together, these results indicate that timosaponin AIII has the capacity to inhibit melanoma cell migration, an essential step in the process of metastasis, by inhibiting expression of COX-2, NF-?B, PGE2, and PGE2 receptors. PMID:26595378

  11. Geodesic least squares regression on information manifolds

    SciTech Connect

    Verdoolaege, Geert

    2014-12-05

    We present a novel regression method targeted at situations with significant uncertainty on both the dependent and independent variables or with non-Gaussian distribution models. Unlike the classic regression model, the conditional distribution of the response variable suggested by the data need not be the same as the modeled distribution. Instead they are matched by minimizing the Rao geodesic distance between them. This yields a more flexible regression method that is less constrained by the assumptions imposed through the regression model. As an example, we demonstrate the improved resistance of our method against some flawed model assumptions and we apply this to scaling laws in magnetic confinement fusion.

  12. [Estimation of median regression from measured values].

    PubMed

    Schmerling, S; Peil, J

    1989-01-01

    The median regression function is defined and demonstrated by examples. A lemma with sufficient conditions for continuity and differentiation of the median regression function is proved. Its estimation from a random sample is deduced firstly based on the empirical distribution function and secondly based on a kernel estimation with Gaussian kernels. Both estimations are demonstrated by GALTONS historical example. A comparison between the empirical median regression function and the empirical regression of the first kind is made by an example. A hint for curve fitting with the median estimation equation is also given by an example. PMID:2806838

  13. Quantile regression applied to spectral distance decay

    USGS Publications Warehouse

    Rocchini, D.; Cade, B.S.

    2008-01-01

    Remotely sensed imagery has long been recognized as a powerful support for characterizing and estimating biodiversity. Spectral distance among sites has proven to be a powerful approach for detecting species composition variability. Regression analysis of species similarity versus spectral distance allows us to quantitatively estimate the amount of turnover in species composition with respect to spectral and ecological variability. In classical regression analysis, the residual sum of squares is minimized for the mean of the dependent variable distribution. However, many ecological data sets are characterized by a high number of zeroes that add noise to the regression model. Quantile regressions can be used to evaluate trend in the upper quantiles rather than a mean trend across the whole distribution of the dependent variable. In this letter, we used ordinary least squares (OLS) and quantile regressions to estimate the decay of species similarity versus spectral distance. The achieved decay rates were statistically nonzero (p < 0.01), considering both OLS and quantile regressions. Nonetheless, the OLS regression estimate of the mean decay rate was only half the decay rate indicated by the upper quantiles. Moreover, the intercept value, representing the similarity reached when the spectral distance approaches zero, was very low compared with the intercepts of the upper quantiles, which detected high species similarity when habitats are more similar. In this letter, we demonstrated the power of using quantile regressions applied to spectral distance decay to reveal species diversity patterns otherwise lost or underestimated by OLS regression. ?? 2008 IEEE.

  14. In situ calibration using univariate analyses based on the onboard ChemCam targets: first prediction of Martian rock and soil compositions

    NASA Astrophysics Data System (ADS)

    Fabre, C.; Cousin, A.; Wiens, R. C.; Ollila, A.; Gasnault, O.; Maurice, S.; Sautter, V.; Forni, O.; Lasue, J.; Tokar, R.; Vaniman, D.; Melikechi, N.

    2014-09-01

    Curiosity rover landed on August 6th, 2012 in Gale Crater, Mars and it possesses unique analytical capabilities to investigate the chemistry and mineralogy of the Martian soil. In particular, the LIBS technique is being used for the first time on another planet with the ChemCam instrument, and more than 75,000 spectra have been returned in the first year on Mars. Curiosity carries body-mounted calibration targets specially designed for the ChemCam instrument, some of which are homgeneous glasses and others that are fine-grained glass-ceramics. We present direct calibrations, using these onboard standards to infer elements and element ratios by ratioing relative peak areas. As the laser spot size is around 300 μm, the LIBS technique provides measurements of the silicate glass compositions representing homogeneous material and measurements of the ceramic targets that are comparable to fine-grained rock or soil. The laser energy and the auto-focus are controlled for all sequences used for calibration. The univariate calibration curves present relatively to very good correlation coefficients with low RSDs for major and ratio calibrations. Trace element calibration curves (Li, Sr, and Mn), down to several ppm, can be used as a rapid tool to draw attention to remarkable rocks and soils along the traverse. First comparisons to alpha-particle X-ray spectroscopy (APXS) data, on selected targets, show good agreement for most elements and for Mg# and Al/Si estimates. SiO2 estimates using univariate cannot be yet used. Na2O and K2O estimates are relevant for high alkali contents, but probably under estimated due to the CCCT initial compositions. Very good results for CaO and Al2O3 estimates and satisfactory results for FeO are obtained.

  15. Study of the Cox-Thompson inverse scattering method with a Coulomb potential

    NASA Astrophysics Data System (ADS)

    Hilk, Daniel; Scheid, Werner; Palmai, Tamas; Apagyi, Barnabas

    2010-06-01

    In order to learn more about the precision of the inversion by the Cox-Thompson method, we investigated the inversion of phase shifts of a singular potential, namely of a Coulomb potential. Using asymptotically Riccati-Bessel functions as reference functions, we could only approximately reproduce the singularity of the Coulomb potential at the origin. We also show uncertainties in the inverted potential due to different minima in the minimization solution of the nonlinear equations of the Cox-Thompson procedure. As a result, we conclude that one has to take much care with the inversion of experimental phase shifts suffering from measurement errors.

  16. Leigh Syndrome with COX deficiency and SURF1 gene mutations: MR imaging findings.

    PubMed

    Rossi, Andrea; Biancheri, Roberta; Bruno, Claudio; Di Rocco, Maja; Calvi, Angela; Pessagno, Alice; Tortori-Donati, Paolo

    2003-01-01

    Mutations in the nuclear SURF1 gene are specifically associated with cytochrome c oxidase (COX)-deficient Leigh syndrome. MR imaging abnormalities in three children with this condition involved the subthalamic nuclei, medulla, inferior cerebellar peduncles, and substantia nigra in all cases. The dentate nuclei and central tegmental tracts were involved in two cases each (all instances), and the putamina, interpeduncular nucleus, and pallido-cortical-nigro-cortical tracts in one. MR imaging pattern recognition can suggest an underlying COX deficiency and should prompt investigators to search for SURF1 gene mutations. PMID:12812953

  17. Normalization Ridge Regression in Practice I: Comparisons Between Ordinary Least Squares, Ridge Regression and Normalization Ridge Regression.

    ERIC Educational Resources Information Center

    Bulcock, J. W.

    The problem of model estimation when the data are collinear was examined. Though the ridge regression (RR) outperforms ordinary least squares (OLS) regression in the presence of acute multicollinearity, it is not a problem free technique for reducing the variance of the estimates. It is a stochastic procedure when it should be nonstochastic and it…

  18. Molecular modeling, synthesis and screening of some new 4-thiazolidinone derivatives with promising selective COX-2 inhibitory activity.

    PubMed

    Unsal-Tan, Oya; Ozadali, Keriman; Piskin, Kevser; Balkan, Ayla

    2012-11-01

    In order to develop new selective cyclooxygenase-2 inhibitors, a series of novel 2-aryl-3-(4-sulfamoyl/methylsulfonylphenylamino)-4-thiazolidinones were designed. Molecular modeling studies with COX-2 enzyme were performed by using MOE program. The designed compounds with reasonable binding modes and high docking scores were synthesized. Their COX-1/COX-2 inhibitory activities were evaluated in vitro, using NS-398 and indomethacine as reference compounds. Compounds possessing methyl group (3d and 4d) on the phenyl ring exhibited highly COX-2 inhibitory selectivity and potency. PMID:23047224

  19. Discovery of potential and selective COX-1 inhibitory leads using pharmacophore modelling, in silico screening and in vitro evaluation.

    PubMed

    Balaji, Bhaskar; Hariharan, Sivaram; Shah, Darshit B; Ramanathan, Muthiah

    2014-10-30

    Cyclooxygenase -1 (COX-1) selective inhibitors are anticipated to be potential therapeutic agents for thrombosis, tumorigenesis, atherosclerosis, neuroprotection, and oxidative stress. In this study, a 3D-QSAR pharmacophore model was developed for potent and selective COX-1 inhibition based on 44 compounds from four different scaffolds using Phase, Schrödinger. One (hydrogen-bond) acceptor, one hydrophobic, and two aromatic sites (AHRR) contribute to COX-1 inhibitory activity. Test and decoy sets were used to corroborate the best hypothesis and the validated hypothesis was used to screen the SPECS database. The resultant hits were filtered by standard precision (SP) and extra precision (XP) modes of docking using Glide, Schrödinger which yielded five hits. Free energy calculations were carried out to quantify the affinity differences of the hits towards COX enzymes. These five hits were subjected to in vitro COX (ovine) inhibitory activity studies. The hits displayed potent COX-1 inhibitory activity and good selectivity versus COX-2 enzyme. The compounds also protected the nitric oxide (NO) induced cell death mediated by COX-1 in mouse macrophages cell line. Hence, we hypothesize that these compounds could be promising leads for the design of superior COX-1 inhibitors and insights gained from further exploration of the same could provide pertinent clues for the treatment of the conditions mentioned above. PMID:25203777

  20. Ursodeoxycholic acid suppresses Cox-2 expression in colon cancer: roles of Ras, p38, and CCAAT/enhancer-binding protein.

    PubMed

    Khare, Sharad; Mustafi, Reba; Cerda, Sonia; Yuan, Weihua; Jagadeeswaran, Sujatha; Dougherty, Urszula; Tretiakova, Maria; Samarel, Allen; Cohen, Greg; Wang, Julia; Moore, Christopher; Wali, Ramesh; Holgren, Cory; Joseph, Loren; Fichera, Alessandro; Li, Yan Chun; Bissonnette, Marc

    2008-01-01

    In the azoxymethane (AOM) model of experimental rodent colon cancer, cholic acid and its colonic metabolite deoxycholic acid (DCA) strongly promote tumorigenesis. In contrast, we showed that ursodeoxycholic acid (UDCA), a low abundance bile acid, inhibited AOM tumorigenesis. Dietary UDCA also blocked the development of tumors with activated Ras and suppressed cyclooxygenase-2 (Cox-2) upregulation in AOM tumors. In this study, we compared the effect of dietary supplementation with tumor-promoting cholic acid to chemopreventive UDCA on Cox-2 expression in AOM tumors. Cholic acid enhanced Cox-2 upregulation in AOM tumors, whereas UDCA inhibited this increase and concomitantly decreased CCAAT/enhancer binding protein beta (C/EBPbeta), a transcriptional regulator of Cox-2. In HCA-7 colon cancer cells, DCA activated Ras and increased C/EBPbeta and Cox-2 by a mechanism requiring the mitogen-activated protein kinase p38. UDCA inhibited DCA-induced p38 activation and decreased C/EBPbeta and Cox-2 upregulation. Using transient transfections, UDCA inhibited Cox-2 promoter and C/EBP reporter activation by DCA. Transfection with dominant-negative (17)N-Ras abolished DCA-induced p38 activation and C/EBPbeta and Cox-2 upregulation. Taken together, these studies have identified a transcriptional pathway regulating Cox-2 expression involving Ras, p38, and C/EBPbeta that is inhibited by UDCA. These signal transducers are novel targets of UDCA's chemopreventive actions. PMID:18444174

  1. The brown and brite adipocyte marker Cox7a1 is not required for non-shivering thermogenesis in mice

    PubMed Central

    Maurer, Stefanie F.; Fromme, Tobias; Grossman, Lawrence I.; Hüttemann, Maik; Klingenspor, Martin

    2015-01-01

    The cytochrome c oxidase subunit isoform Cox7a1 is highly abundant in skeletal muscle and heart and influences enzyme activity in these tissues characterised by high oxidative capacity. We identified Cox7a1, well-known as brown adipocyte marker gene, as a cold-responsive protein of brown adipose tissue. We hypothesised a mechanistic relationship between cytochrome c oxidase activity and Cox7a1 protein levels affecting the oxidative capacity of brown adipose tissue and thus non-shivering thermogenesis. We subjected wildtype and Cox7a1 knockout mice to different temperature regimens and tested characteristics of brown adipose tissue activation. Cytochrome c oxidase activity, uncoupling protein 1 expression and maximal norepinephrine-induced heat production were gradually increased during cold-acclimation, but unaffected by Cox7a1 knockout. Moreover, the abundance of uncoupling protein 1 competent brite cells in white adipose tissue was not influenced by presence or absence of Cox7a1. Skin temperature in the interscapular region of neonates was lower in uncoupling protein 1 knockout pups employed as a positive control, but not in Cox7a1 knockout pups. Body mass gain and glucose tolerance did not differ between wildtype and Cox7a1 knockout mice fed with high fat or control diet. We conclude that brown adipose tissue function in mice does not require the presence of Cox7a1. PMID:26635001

  2. Selective COX-2 inhibitors, NSAIDs and congestive heart failure: differences between new and recurrent cases

    PubMed Central

    McGettigan, Patricia; Han, Pearline; Jones, Lisa; Whitaker, Diana; Henry, David

    2008-01-01

    AIMS To quantify the association between treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors and hospitalization due to congestive heart failure (CHF); to determine if the risk varies between first and subsequent episodes of CHF. METHODS We conducted a case–control study of the relationship between recent use of NSAIDs and COX-2 inhibitors and hospitalization with CHF. Cases (n = 530) were patients admitted to hospital with a primary diagnosis of CHF. Controls (n = 1054) were subjects without CHF who were admitted to the same hospitals as the cases. They were frequency matched to cases on the basis of age and sex. Structured interviews were used to obtain information on a number of study factors, including recent use of NSAIDs and COX-2 inhibitors. Relative risks (RRs) were estimated from exposure odds ratios, adjusted for a range of potential confounders. RESULTS Overall, NSAIDs and COX-2 inhibitors had been taken by 249 (23.6%) controls in the week before admission to hospital. Use of any NSAID/COX-2 inhibitor was recorded in 81/285 (28.4%) first-time cases compared with 38/245 (15.5%) in recurrent cases: difference 12.9% (95% confidence interval 5.9, 19.8) (P = 0.0004). The adjusted RRs for first hospital admission for CHF with different drug exposures were: NSAIDs 1.1 (0.67, 1.83), rofecoxib 1.29 (0.78, 2.13) and celecoxib 1.47 (0.85, 2.53). CONCLUSIONS We found weak and statistically nonsignificant associations between use of NSAIDs and COX-2 inhibitors and hospitalization with CHF. This low RR is consistent with the results of recently published studies, but not with early studies that found an approximate doubling of risk with use of NSAIDs. The dilution of risk and the significantly lower levels of prescribing for recurrent than for first-time cases of heart failure suggest that prescribing doctors heeded messages that NSAIDs may precipitate CHF in vulnerable individuals, and that they have applied the same message to selective COX-2 inhibitors. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Pharmaco-epidemiological studies have shown that in susceptible individuals, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors increase the risk of developing congestive heart failure (CHF). Recently published studies have found lower relative risk (RR) estimates than the initial studies published in 1998–2000. It is unclear whether the level of risk is elevated equally in first time and recurrent cases of CHF. WHAT THIS STUDY ADDS This study found low-level, statistically nonsignificant elevations of risk with NSAIDs and COX-2 inhibitors.There was a much higher level of recent use of NSAIDs/COX-2 inhibitors among first-time cases than among recurrent cases of CHF.The dilution of the RR over successive studies, and the differences between first-time and recurrent cases noted here, suggest that prescribing doctors have heeded advice about the cardiovascular risks of NSAIDs and extended this practice to selective COX-2 inhibitors. PMID:18384446

  3. Hierarchical Regression Analysis in Structural Equation Modeling.

    ERIC Educational Resources Information Center

    de Jong, Peter F.

    1999-01-01

    Describes how a hierarchical regression analysis may be conducted in structural equation modeling. The main procedure is to perform a Cholesky or triangular decomposition of the intercorrelations among the latest predictors. Provides an example of a hierarchical regression analysis with latent variables. (SLD)

  4. A measure to identify regression outliers

    NASA Astrophysics Data System (ADS)

    Ramaboa, Kutlwano K. K. M.; Underhill, Les G.

    2014-12-01

    In this paper we describe a measure that can be used to detect regression outliers. Observations that deviate from the bulk of the data can easily influence the fit of the least squares regression line, and the residuals, which take the response variable,y, into account, are often examined to determine the observations that may have influenced the fit of the least squares regression line, hence affecting other regression estimates. One drawback of using transformed residuals such as the Studentized residuals is that they may fail to identify the regression outliers when these observations are being accommodated by the least squares fit, thus we propose a measure that is based on the role that each observation plays in the displacement of other observations from the fitted least squares regression line. The proposed measure is based on the off-diagonal values of the hat matrix, and illustrated on three data sets that have appeared in the literature on regression diagnostics. A comparison is also made using popular MM estimator used to obtain robust regression estimates to illustrate the value of the proposed measure.

  5. Illustration of Regression towards the Means

    ERIC Educational Resources Information Center

    Govindaraju, K.; Haslett, S. J.

    2008-01-01

    This article presents a procedure for generating a sequence of data sets which will yield exactly the same fitted simple linear regression equation y = a + bx. Unless rescaled, the generated data sets will have progressively smaller variability for the two variables, and the associated response and covariate will "regress" towards their…

  6. Deriving the Regression Equation without Using Calculus

    ERIC Educational Resources Information Center

    Gordon, Sheldon P.; Gordon, Florence S.

    2004-01-01

    Probably the one "new" mathematical topic that is most responsible for modernizing courses in college algebra and precalculus over the last few years is the idea of fitting a function to a set of data in the sense of a least squares fit. Whether it be simple linear regression or nonlinear regression, this topic opens the door to applying the…

  7. Dealing with Outliers: Robust, Resistant Regression

    ERIC Educational Resources Information Center

    Glasser, Leslie

    2007-01-01

    Least-squares linear regression is the best of statistics and it is the worst of statistics. The reasons for this paradoxical claim, arising from possible inapplicability of the method and the excessive influence of "outliers", are discussed and substitute regression methods based on median selection, which is both robust and resistant, are…

  8. A Regression-Based Linear Classification Procedure.

    ERIC Educational Resources Information Center

    LaMotte, Lynn Roy; McWhorter, Archer, Jr.

    1981-01-01

    A linear regression function is developed for use in a classification procedure. The procedure is applied to faculty merit review data, resulting in an interpretable regression function and within-sample classifications as good as a four-funtion discriminant analysis. (Author/BW)

  9. Regression Analysis and the Sociological Imagination

    ERIC Educational Resources Information Center

    De Maio, Fernando

    2014-01-01

    Regression analysis is an important aspect of most introductory statistics courses in sociology but is often presented in contexts divorced from the central concerns that bring students into the discipline. Consequently, we present five lesson ideas that emerge from a regression analysis of income inequality and mortality in the USA and Canada.

  10. HPV Vaccine Triggers Regression of Precancers.

    PubMed

    2015-12-01

    According to a phase IIb clinical trial, an investigational DNA vaccine that targets the human papillomavirus caused precancerous cervical lesions to regress or disappear. The vaccine stimulated production of CD8+ T cells that make perforin, a protein that helps kill infected cervical cells, and eliminated the virus in 81% of women whose lesions regressed. PMID:26487304

  11. Suppression Situations in Multiple Linear Regression

    ERIC Educational Resources Information Center

    Shieh, Gwowen

    2006-01-01

    This article proposes alternative expressions for the two most prevailing definitions of suppression without resorting to the standardized regression modeling. The formulation provides a simple basis for the examination of their relationship. For the two-predictor regression, the author demonstrates that the previous results in the literature are

  12. Regions of Significance in Multiple Regression Analysis

    ERIC Educational Resources Information Center

    Takane, Yoshio; Cramer, Elliott M.

    1975-01-01

    This paper considers the case of two predictor variables. Figures are obtained which show the regions of significance of joint regression coefficients, regression coefficients considered separately, and the multiple correlation. The intersection of these regions of significance and non-significance illustrates how the various apparent…

  13. Developmental regression in autism spectrum disorders.

    PubMed

    Rogers, Sally J

    2004-01-01

    The occurrence of developmental regression in autism is one of the more puzzling features of this disorder. Although several studies have documented the validity of parental reports of regression using home videos, accumulating data suggest that most children who demonstrate regression also demonstrated previous, subtle, developmental differences. Counter to clinical intuition, the earlier development of social, language, and attachment behaviors followed by regression does not seem to support later recovery of skills or better developmental outcomes compared to children who never had speech or typical social responsivity. In fact, this regressive group may have somewhat greater developmental impairment than the nonregressive group, though the two groups do not appear to present different behavioral phenotypes. Although autism is not the only condition in which regression occurs, it appears to be the most frequent condition. Other disorders that demonstrate an early regression with no known etiology include total blindness from birth and childhood disintegrative disorder, both of which demonstrate behavioral relations to autism. In addition, two biological conditions with known etiologies also involve regression with some behaviors resembling autism behavioral phenotype: Rett syndrome (a genetic disorder; see Glaze, this issue) and Landau-Kleffner syndrome (see McVicar and Shinnar, this issue), which involves a seizure disorder. PMID:15362172

  14. Regression Analysis: Legal Applications in Institutional Research

    ERIC Educational Resources Information Center

    Frizell, Julie A.; Shippen, Benjamin S., Jr.; Luna, Andrew L.

    2008-01-01

    This article reviews multiple regression analysis, describes how its results should be interpreted, and instructs institutional researchers on how to conduct such analyses using an example focused on faculty pay equity between men and women. The use of multiple regression analysis will be presented as a method with which to compare salaries of…

  15. Regression of environmental noise in LIGO data

    NASA Astrophysics Data System (ADS)

    Tiwari, V.; Drago, M.; Frolov, V.; Klimenko, S.; Mitselmakher, G.; Necula, V.; Prodi, G.; Re, V.; Salemi, F.; Vedovato, G.; Yakushin, I.

    2015-08-01

    We address the problem of noise regression in the output of gravitational-wave (GW) interferometers, using data from the physical environmental monitors (PEM). The objective of the regression analysis is to predict environmental noise in the GW channel from the PEM measurements. One of the most promising regression methods is based on the construction of Wiener-Kolmogorov (WK) filters. Using this method, the seismic noise cancellation from the LIGO GW channel has already been performed. In the presented approach the WK method has been extended, incorporating banks of Wiener filters in the time-frequency domain, multi-channel analysis and regulation schemes, which greatly enhance the versatility of the regression analysis. Also we present the first results on regression of the bi-coherent noise in the LIGO data.

  16. COX-2-Derived PGE2 Promotes Injury-induced Vascular Neointimal Hyperplasia through the EP3 Receptor

    PubMed Central

    Zhang, Jian; Zou, Fangfang; Tang, Juan; Zhang, Qianqian; Gong, Yanjun; Wang, Qingsong; Shen, Yujun; Xiong, Lixia; Breyer, Richard; Lararus, Michael; Funk, Colin D.; Yu, Ying

    2014-01-01

    Rationale Vascular smooth muscle cell (VSMC) migration and proliferation are the hallmarks of restenosis pathogenesis after angioplasty. Cyclooxygenase (COX)-derived prostaglandin (PG)E2 is implicated in the vascular remodeling response to injury. However, its precise molecular role remains unknown. Objective This study investigates the impact of COX-2-derived PGE2 on neointima formation after injury. Methods and Results Vascular remodeling was induced by wire-injury in femoral arteries of mice. Both neointima formation and the restenosis ratio were diminished in COX-2 KO mice as compared to controls, whereas these parameters were enhanced in COX-1>COX-2 mice where COX-1 is governed by COX-2 regulatory elements. PG profile analysis revealed that the reduced PGE2 by COX-2 deficiency, but not PGI2, could be rescued by COX-1 replacement, indicating COX-2-derived PGE2 enhanced neointima formation. Through multiple approaches, the EP3 receptor was identified to mediate the VSMC migration response to various stimuli. Disruption of EP3 impaired VSMC polarity for directional migration by depressing small GTPase activity and retarded vascular neointimal hyperplasia while overexpression of EP3α and EP3β aggravated neointima formation. Inhibition or deletion of EP3α/β, a Gαs protein-coupled receptor, activated thecAMP/PKA pathway and depressed activation of RhoA in VSMCs. PGE2 could stimulate PI3K/Akt/GSK3β signaling in VSMCs through Gβγ subunits upon EP3α/β activation. Abolition of EP3 suppressed PI3K signaling and reduced GTPase activity in VSMCs, and altered cell polarity and directional migration. Conclusions COX-2-derived PGE2 facilitated the neointimal hyperplasia response to injury through EP3α/β-mediated cAMP/PKA and PI3K pathways, indicating EP3 inhibition maybe a promising therapeutic strategy for percutaneous transluminal coronary angioplasty. PMID:23595951

  17. COX2 activity promotes organic osmolyte accumulation and adaptation of renal medullary interstitial cells to hypertonic stress.

    PubMed

    Moeckel, Gilbert W; Zhang, Li; Fogo, Agnes B; Hao, Chuan-Ming; Pozzi, Ambra; Breyer, Matthew D

    2003-05-23

    The mechanism by which COX2 inhibition decreases renal cell survival is poorly understood. In the present study we examined the effect of COX2 activity on organic osmolyte accumulation in renal medulla and in cultured mouse renal medullary interstitial cells (MMICs) and its role in facilitating cell survival. Hypertonicity increased accumulation of the organic osmolytes inositol, sorbitol, and betaine in cultured mouse medullary interstitial cells. Pretreatment of MMICs with a COX2-specific inhibitor (SC58236, 10 micromol/liter) dramatically reduced osmolyte accumulation (by 79 +/- 9, 57 +/- 12, and 96 +/- 10% for inositol, sorbitol, and betaine respectively, p < 0.05). Similarly, 24 h of dehydration increased inner medullary inositol, sorbitol, and betaine concentrations in vivo by 85 +/- 10, 197 +/- 28, and 190 +/- 24 pmol/microg of protein, respectively, but this increase was also blunted (by 100 +/- 5, 66 +/- 15, and 81 +/- 9% for inositol, sorbitol, and betaine, respectively, p < 0.05) by pretreatment with an oral COX2 inhibitor. Dehydrated COX2-/- mice also exhibited an impressive defect in sorbitol accumulation (88 +/- 9% less than wild type, p < 0.05) after dehydration. COX2 inhibition (COX2 inhibitor-treated or COX2-/- MMICs) dramatically reduced the expression of organic osmolyte uptake mechanisms including betaine (BGT1) and sodium-myo-inositol transporter and aldose reductase mRNA expression under hypertonic conditions. Importantly, preincubation of COX2 inhibitor-treated MMICs with organic osmolytes restored their ability to survive hypertonic stress. In conclusion, osmolyte accumulation in the kidney inner medulla is dependent on COX2 activity, and providing exogenous osmolytes reverses COX2-induced cell death. These findings may have implications for the pathogenesis of analgesic nephropathy. PMID:12637551

  18. Mutagenic analysis of Cox11 of Rhodobacter sphaeroides: insights into the assembly of Cu(B) of cytochrome c oxidase.

    PubMed

    Thompson, Audie K; Smith, Daniel; Gray, Jimmy; Carr, Heather S; Liu, Aimin; Winge, Dennis R; Hosler, Jonathan P

    2010-07-13

    The Cu(I) chaperone Cox11 is required for the insertion of Cu(B) into cytochrome c oxidase (CcO) of mitochondria and many bacteria, including Rhodobacter sphaeroides. Exploration of the copper binding stoichiometry of R. sphaeroides Cox11 led to the finding that an apparent tetramer of both mitochondrial and bacterial Cox11 binds more copper than the sum of the dimers, providing another example of the flexibility of copper binding by Cu(I)-S clusters. Site-directed mutagenesis has been used to identify components of Cox11 that are not required for copper binding but are absolutely required for the assembly of Cu(B), including conserved Cys-35 and Lys-123. In contrast to earlier proposals, Cys-35 is not required for dimerization of Cox11 or for copper binding. These findings, and the location of Cys-35 at the C-terminus of the predicted transmembrane helix and thereby close to the surface of the membrane, allow a proposal that Cys-35 is involved in the transfer of copper from the Cu(I) cluster of Cox11 to the Cu(B) ligands His-333 and His-334 during the folding of CcO subunit I. Lys-123 is located near the Cu(I) cluster of Cox11, in an area otherwise devoid of charged residues. From the analysis of several Cox11 mutants, including K123E, -L, and -R, we conclude that a previous proposal that Lys-123 provides charge balance for the stabilization of the Cu(I) cluster is unlikely to account for its absolute requirement for Cox11 function. Rather, consideration of the properties of Lys-123 and the apparent specificity of Cox11 suggest that Lys-123 plays a role in the interaction of Cox11 with its target. PMID:20524628

  19. Triptolide inhibits COX-2 expression by regulating mRNA stability in TNF-{alpha}-treated A549 cells

    SciTech Connect

    Sun, Lixin; Zhang, Shuang; Jiang, Zhenzhou; Huang, Xin; Wang, Tao; Huang, Xiao; Li, Han; Zhang, Luyong

    2011-12-09

    Highlights: Black-Right-Pointing-Pointer Triptolide inhibited COX-2 expression and the half-life of COX-2 mRNA is decreased. Black-Right-Pointing-Pointer The HuR protein shuttling from nucleus to cytoplasm is inhibited by triptolide. Black-Right-Pointing-Pointer Triptolide inhibited 3 Prime -UTR fluorescence reporter gene activity. Black-Right-Pointing-Pointer COX-2 mRNA binding to HuR is decreased by triptolide in pull-down experiments. -- Abstract: Cyclooxygenase-2 (COX-2) over-expression is frequently associated with human non-small-cell lung cancer (NSCLC) and involved in tumor proliferation, invasion, angiogenesis and resistance to apoptosis. In the present study, the effects of triptolide on COX-2 expression in A549 cells were investigated and triptolide was found to inhibit TNF-{alpha}-induced COX-2 expression. In our further studies, it was found that triptolide decreased the half-life of COX-2 mRNA dramatically and that it inhibited 3 Prime -untranslated region (3 Prime -UTR) fluorescence reporter gene activity. Meanwhile, triptolide inhibited the HuR shuttling from nucleus to cytoplasm. After triptolide treatment, decreased COX-2 mRNA in pull-down experiments with anti-HuR antibodies was observed, indicating that the decreased cytoplasmic HuR is responsible for the decreased COX-2 mRNA. Taken together, our results provided evidence for the first time that triptolide inhibited COX-2 expression by COX-2 mRNA stability modulation and post-transcriptional regulation. These results provide a novel mechanism of action for triptolide which may be important in the treatment of lung cancer.

  20. Stromal COX-2 signaling activated by deoxycholic acid mediates proliferation and invasiveness of colorectal epithelial cancer cells

    SciTech Connect

    Zhu, Yingting; Tissue Tech Inc., Miami, FL 33173 ; Zhu, Min; Lance, Peter

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer Human colonic cancer associated fibroblasts are major sources of COX-2 and PGE{sub 2}. Black-Right-Pointing-Pointer The fibroblasts interact with human colonic epithelial cancer cells. Black-Right-Pointing-Pointer Activation of COX-2 signaling in the fibroblasts affects behavior of the epithelia. Black-Right-Pointing-Pointer Protein Kinase C controls the activation of COX-2 signaling. -- Abstract: COX-2 is a major regulator implicated in colonic cancer. However, how COX-2 signaling affects colonic carcinogenesis at cellular level is not clear. In this article, we investigated whether activation of COX-2 signaling by deoxycholic acid (DCA) in primary human normal and cancer associated fibroblasts play a significant role in regulation of proliferation and invasiveness of colonic epithelial cancer cells. Our results demonstrated while COX-2 signaling can be activated by DCA in both normal and cancer associated fibroblasts, the level of activation of COX-2 signaling is significantly greater in cancer associated fibroblasts than that in normal fibroblasts. In addition, we discovered that the proliferative and invasive potential of colonic epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts pre-treated with DCA than with normal fibroblasts pre-treated with DCA. Moreover, COX-2 siRNA attenuated the proliferative and invasive effect of both normal and cancer associate fibroblasts pre-treated with DCA on the colonic cancer cells. Further studies indicated that the activation of COX-2 signaling by DCA is through protein kinase C signaling. We speculate that activation of COX-2 signaling especially in cancer associated fibroblasts promotes progression of colonic cancer.

  1. Systematic revision of the mealybug genus Delottococcus Cox & Ben-Dov (Hemiptera: Pseudococcidae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A systematic revision of the mealybug genus Delottococcus Cox & Ben-Dov is presented. Nine species are treated, including D. millari which is described as new. The 8 previously described species are: Delottococcus aberiae (De Lotto), D. confusus (De Lotto), D. elisabethae (Brain), D. euphorbiae (E...

  2. ZN2+ INDUCES COX-2 EXPRESSION THROUGH DOWNREGULATION OF LIPID PHOSPHATASE PTEN

    EPA Science Inventory

    Zn2+ Induces COX-2 Expression through Downregulation of Lipid Phosphatase PTEN
    Weidong Wu*, James M. Samet, Philip A. Bromberg*?, Young E. Whang?, and Lee M. Graves* ?
    *CEMALB, ?Department of Medicine, and ?Department of Pharmacology, UNC-Chapel Hill, NC27599; Human Studie...

  3. A COX2 PHYLOGENETIC HYPOTHESIS FOR THE DOWNY MILDEWS AND WHITE RUSTS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mitochondrially encoded cox2 sequences were used to infer evolutionary relationships of downy mildew and white rust taxa in a data set of 36 peronosporomycete isolates. The data set of 599 aligned nucleotides was analyzed using neighbor joining, maximum parsimony, and maximum likelihood. These phylo...

  4. Isoorientin, a Selective Inhibitor of Cyclooxygenase-2 (COX-2) from the Tubers of Pueraria tuberosa.

    PubMed

    Sumalatha, Manne; Munikishore, Rachakunta; Rammohan, Aluru; Gunasekar, Duvvuru; Kumar, Kotha Anil; Reddy, Kakularam Kumar; Azad, Rajaram; Reddanna, Pallu; Bodo, Bernard

    2015-10-01

    Bioassay-guided fraction of the methanol extract of the roots of Pueraria tuberose DC yielded puerarin, an isoflavone C-glycoside (PT-1), isoorientin, a flavone C-glycoside (PT-2) and mangiferin, a xanthone C-glycoside (PT-3). The extracts and the isolated compounds were screened for potent anti-inflammatory components inhibiting the cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX), the target enzymes of inflammation, by employing spectroscopic/polorographic methods. Among these, isoorientin was found to be a potent inhibitor of COX-2with an IC50 value of 39 μM. Docking studies were carried out to understand the interactions of isorientin (PT-2) with COX-2.The structures of the isolates were determined by mass spectrometry and 2D-NMR techniques including HSQC, HMBC, NOESY and 1H-1H COSY experiments. Although isoorientin and mangiferin have been reported from several plant sources, this is the first report of their isolation from a Pueraria species. PMID:26669106

  5. COX-2 inhibition prevents insulin-dependent diabetes in low-dose streptozotocin-treated mice.

    PubMed

    Tabatabaie, T; Waldon, A M; Jacob, J M; Floyd, R A; Kotake, Y

    2000-07-01

    Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease believed to be caused by an inflammatory process in the pancreas leading to selective destruction of the beta cells. Inducible cyclooxygenase (COX-2) is expressed under inflammatory conditions and its product prostaglandin E(2) (PGE(2)) is an important inflammation mediator. We report here that administration of the selective COX-2 inhibitor NS-398 prevents the onset of diabetes in mice brought on by multiple low-doses of streptozotocin (STZ). Histological observations indicated that STZ-mediated destruction of beta cells was prevented by NS-398 treatment. Delayed (day 3) administration of NS-398 was also protective in this model. No protective effect was observed when NS-398 was administered prior to a high, toxic dose of STZ. These results demonstrate the critical importance of COX-2 activity in autoimmune destruction of beta cells, and point to the fact that COX-2 inhibition can potentially develop into a preventive therapy against IDDM. PMID:10873667

  6. Potentiality of the cox1 gene in the taxonomic resolution of soil fungi.

    PubMed

    Molitor, Claire; Inthavong, Beatrice; Sage, Lucile; Geremia, Roberto A; Mouhamadou, Bello

    2010-01-01

    We explored the potential of the cox1 gene in the species resolution of soil fungi and compared it with the nuclear internal transcribed spacer (ITS) and small subunit (SSU)-rDNA. Conserved primers allowing the amplification of the fungal cox1 gene were designed, and a total of 47 isolates of Zygomycota and Ascomycota were investigated. The analysis revealed a lack of introns in >90% of the isolates. Comparison of the species of each of the six studied genera showed high interspecific sequence polymorphisms. Indeed, the average of nucleotide variations (4.2-11%) according to the genus, due mainly to the nucleotide substitutions, led to the taxonomic resolution of all the species studied regarding both ITS and SSU-rDNA, in which <88% were discriminated. The phylogenetic analysis performed after alignment of the cox1 gene across distant fungal species was in accordance with the well-known taxonomic position of the species studied and no overlap was observed between intra- and interspecific variations. These results clearly demonstrated that the cox1 sequences could provide good molecular markers for the determination of the species composition of environmental samples and constitute an important advance to study soil fungal biodiversity. PMID:19909345

  7. Simultaneous Targeting of COX-2 and AKT Using Selenocoxib-1-GSH to Inhibit Melanoma

    PubMed Central

    Gowda, Raghavendra; Madhunapantula, SubbaRao V.; Desai, Dhimant; Amin, Shantu; Robertson, Gavin P.

    2012-01-01

    Melanoma is a highly metastatic and deadly disease. An agent simultaneously targeting COX-2, PI3K/Akt and MAPK signaling pathways that are deregulated in up to 70% of sporadic melanoma might be an effective treatment but no agent of this type exists. To develop a single drug inhibiting COX-2 and PI3K/Akt signaling (and increasing MAPK pathway activity to inhibitory levels as a result of Akt inhibition), a selenium-containing glutathione (GSH) analog of celecoxib, called selenocoxib-1-GSH was synthesized. It killed melanoma cells with an average IC50 of 7.66 mol/L compared to control celecoxib at 55.6 mol/L. The IC50 range for normal cells was 36.341.2 mol/L compared to 7.66 mol/L for cancer cells. Selenocoxib-1-GSH reduced xenografted tumor development by ~70% with negligible toxicity by targeting COX-2, like celecoxib, and having new inhibitory properties acting as a PI3K/Akt inhibitor (and MAPK pathway activator to inhibitory levels due to Akt inhibition). The consequence of this inhibitory activity was an ~80% decrease in cultured cell proliferation and a ~200% increase in apoptosis following 24 hours treatment with 15.5 mol/L of drug. Thus, this study details development of selenocoxib-1-GSH, which is a non-toxic agent that targets the COX-2 and PI3K/Akt signaling pathways in melanomas to inhibit tumor development. PMID:23112250

  8. Shy1 couples Cox1 translational regulation to cytochrome c oxidase assembly.

    PubMed

    Mick, David U; Wagner, Karina; van der Laan, Martin; Frazier, Ann E; Perschil, Inge; Pawlas, Magdalena; Meyer, Helmut E; Warscheid, Bettina; Rehling, Peter

    2007-10-17

    Cytochrome c oxidase (complex IV) of the respiratory chain is assembled from nuclear and mitochondrially-encoded subunits. Defects in the assembly process lead to severe human disorders such as Leigh syndrome. Shy1 is an assembly factor for complex IV in Saccharomyces cerevisiae and mutations of its human homolog, SURF1, are the most frequent cause for Leigh syndrome. We report that Shy1 promotes complex IV biogenesis through association with different protein modules; Shy1 interacts with Mss51 and Cox14, translational regulators of Cox1. Additionally, Shy1 associates with the subcomplexes of complex IV that are potential assembly intermediates. Formation of these subcomplexes depends on Coa1 (YIL157c), a novel assembly factor that cooperates with Shy1. Moreover, partially assembled forms of complex IV bound to Shy1 and Cox14 can associate with the bc1 complex to form transitional supercomplexes. We suggest that Shy1 links Cox1 translational regulation to complex IV assembly and supercomplex formation. PMID:17882259

  9. Elevated COX2 expression and PGE2 production by downregulation of RXRα in senescent macrophages

    SciTech Connect

    Chen, Huimin; Ma, Feng; Hu, Xiaona; Jin, Ting; Xiong, Chuhui; Teng, Xiaochun

    2013-10-11

    Highlights: •Downregulation of RXRα in senescent macrophage. •RXRα suppresses NF-κB activity and COX2 expression. •Increased PGE2 production due to downregulation of RXRα. -- Abstract: Increased systemic level of inflammatory cytokines leads to numerous age-related diseases. In senescent macrophages, elevated prostaglandin E2 (PGE2) production contributes to the suppression of T cell function with aging, which increases the susceptibility to infections. However, the regulation of these inflammatory cytokines and PGE2 with aging still remains unclear. We have verified that cyclooxygenase (COX)-2 expression and PGE2 production are higher in LPS-stimulated macrophages from old mice than that from young mice. Downregulation of RXRα, a nuclear receptor that can suppress NF-κB activity, mediates the elevation of COX2 expression and PGE2 production in senescent macrophages. We also have found less induction of ABCA1 and ABCG1 by RXRα agonist in senescent macrophages, which partially accounts for high risk of atherosclerosis in aged population. Systemic treatment with RXRα antagonist HX531 in young mice increases COX2, TNF-α, and IL-6 expression in splenocytes. Our study not only has outlined a mechanism of elevated NF-κB activity and PGE2 production in senescent macrophages, but also provides RXRα as a potential therapeutic target for treating the age-related diseases.

  10. Current approaches to prevent NSAID-induced gastropathy – COX selectivity and beyond

    PubMed Central

    Becker, Jan C; Domschke, Wolfram; Pohle, Thorsten

    2004-01-01

    Gastrointestinal (GI) toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) is still an important medical and socio-economic problem – despite recent pharmaceutical advances. To prevent NSAID-induced gastropathy, three strategies are followed in clinical routine: (i) coprescription of a gastroprotective drug, (ii) use of selective COX-2 inhibitors, and (iii) eradication of Helicobacter pylori. Proton pump inhibitors are the comedication of choice as they effectively reduce gastrointestinal adverse events of NSAIDs and are safe even in long-term use. Co-medication with vitamin C has only been little studied in the prevention of NSAID-induced gastropathy. Apart from scavenging free radicals it is able to induce haeme-oxgenase 1 in gastric cells, a protective enzyme with antioxidant and vasodilative properties. Final results of the celecoxib outcome study (CLASS study) attenuated the initial enthusiasm about the GI safety of selective COX-2 inhibitors, especially in patients concomitantly taking aspirin for cardiovascular prophylaxis. Helicobacter pylori increases the risk for ulcers particularly in NSAID-naive patients and therefore eradication is recommended prior to long-term NSAID therapy at least in patients at high risk. New classes of COX-inhibitors are currently evaluated in clinical studies with very promising results: NSAIDs combined with a nitric oxide releasing moiety (NO-NSAID) and dual inhibitors of COX and 5-LOX. These drugs offer extended anti-inflammatory potency while sparing gastric mucosa. PMID:15563357

  11. Partial likelihood ratio tests for the Cox model under complex sampling.

    PubMed

    Lumley, Thomas; Scott, Alastair

    2013-01-15

    We develop an analog of the likelihood ratio test for Cox proportional hazards models fitted to sample survey data. We look at methods for computing the asymptotic distribution and at ways of improving the small-sample performance. The methods are illustrated with examples using data from the National Health and Nutrition Examination Survey and from a stratified case-cohort study. PMID:22806928

  12. Two cases of human thelaziasis as confirmed by mitochondrial cox1 sequencing in China

    PubMed Central

    Wang, Xiao-Li; Guo, Jiu-Ying; Wang, Xue-Lian; Ma, Xiao-Li; Wang, Yi; An, Chun-Li

    2014-01-01

    Two special cases of human thelaziasis were reported in China: an old farmer with heavy infection by 36 worms and a 7-year-old boy with infection by eight worms. Thelazia callipaeda was morphologically identified and confirmed by mitochondrial cox1 gene sequencing. PMID:25253041

  13. The relative importance of imaging markers for the prediction of Alzheimer's disease dementia in mild cognitive impairment — Beyond classical regression

    PubMed Central

    Teipel, Stefan J.; Kurth, Jens; Krause, Bernd; Grothe, Michel J.

    2015-01-01

    Selecting a set of relevant markers to predict conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) has become a challenging task given the wealth of regional pathologic information that can be extracted from multimodal imaging data. Here, we used regularized regression approaches with an elastic net penalty for best subset selection of multiregional information from AV45-PET, FDG-PET and volumetric MRI data to predict conversion from MCI to AD. The study sample consisted of 127 MCI subjects from ADNI-2 who had a clinical follow-up between 6 and 31 months. Additional analyses assessed the effect of partial volume correction on predictive performance of AV45- and FDG-PET data. Predictor variables were highly collinear within and across imaging modalities. Penalized Cox regression yielded more parsimonious prediction models compared to unpenalized Cox regression. Within single modalities, time to conversion was best predicted by increased AV45-PET signal in posterior medial and lateral cortical regions, decreased FDG-PET signal in medial temporal and temporobasal regions, and reduced gray matter volume in medial, basal, and lateral temporal regions. Logistic regression models reached up to 72% cross-validated accuracy for prediction of conversion status, which was comparable to cross-validated accuracy of non-linear support vector machine classification. Regularized regression outperformed unpenalized stepwise regression when number of parameters approached or exceeded the number of training cases. Partial volume correction had a negative effect on the predictive performance of AV45-PET, but slightly improved the predictive value of FDG-PET data. Penalized regression yielded more parsimonious models than unpenalized stepwise regression for the integration of multiregional and multimodal imaging information. The advantage of penalized regression was particularly strong with a high number of collinear predictors. PMID:26199870

  14. Epigenetic change in e-cardherin and COX-2 to predict chronic periodontitis

    PubMed Central

    2010-01-01

    Background DNA methylation of certain genes frequently occurs in neoplastic cells. Although the cause remains unknown, many genes have been identified with such atypical methylation in neoplastic cells. The hypermethylation of E-Cadherin and Cyclooxygenase 2 (COX-2) in chronic inflammation such as chronic periodontitis may demonstrate mild lesion/mutation epigenetic level. This study compares the hypermethylation status of E-Cadherin and COX-2 genes which are often found in breast cancer patients with that in chronic periodontitis. Methods Total DNA was extracted from the blood samples of 108 systemically healthy non-periodontitis subjects, and the gingival tissues and blood samples of 110 chronic periodontitis patient as well as neoplastic tissues of 106 breast cancer patients. Methylation-specific PCR for E-Cadherin and COX-2 was performed on these samples and the PCR products were analyzed on 2% agarose gel. Results Hypermethylation of E-Cadherin and COX-2 was observed in 38% and 35% of the breast cancer samples, respectively. In chronic periodontitis patients the detection rate was 25% and 19% respectively, and none was found in the systemically healthy non-periodontitis control subjects. The hypermethylation status was shown to be correlated among the three groups with statistical significance (p < 0.0001). The methylation of CpG islands in E-Cadherin and COX-2 genes in periodontitis patients occurs more frequently in periodontitis patients than in the control subjects, but occurs less frequently than in the breast cancer patients. Conclusions This set of data shows that the epigenetic change in E-Cadherin and Cyclooxygenase-2 is associated with chronic periodontitis. The epigenetic changes presented in chronic inflammation patients might demonstrate an irreversible destruction in the tissues or organs similar to the effects of cancer. Chronic periodontitis to some extent might be associated with DNA hypermethylation which is related to cancer risk factors. PMID:21047437

  15. Artesunate inhibits the growth and induces apoptosis of human gastric cancer cells by downregulating COX-2.

    PubMed

    Zhang, Ping; Luo, He-Sheng; Li, Ming; Tan, Shi-Yun

    2015-01-01

    Artesunate, a derivative of artemisinin isolated from Artemisia annua L., has been traditionally used to treat malaria, and artesunate has demonstrated cytotoxic effects against a variety of cancer cells. However, there is little available information about the antitumor effects of artesunate on human gastric cancer cells. In the present study, we investigated the antitumor effect of artesunate on human gastric cancer cells and whether its antitumor effect is associated with reduction in COX-2 expression. The effects of artesunate on the growth and apoptosis of gastric cancer cells were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometric analysis of annexin V-fluorescein isothiocyanate/propidium iodide staining, rhodamine 123 staining, and Western blot analysis. Results indicate that artesunate exhibits antiproliferative effects and apoptosis-inducing activities. Artesunate markedly inhibited gastric cancer cell proliferation in a time- and dose-dependent manner and induced apoptosis in gastric cancer cells a dose-dependent manner, which was associated with a reduction in COX-2 expression. Treatment with the selective COX-2 inhibitor celecoxib, or transient transfection of gastric cancer cells with COX-2 siRNA, also inhibited cell proliferation and induced apoptosis. Furthermore, the treatment with artesunate promoted the expression of proapoptotic factor Bax and suppressed the expression of antiapoptotic factor Bcl-2. In addition, caspase-3 and caspase-9 were activated, and artesunate induced loss of mitochondrial membrane potential, suggesting that the apoptosis is mediated by mitochondrial pathways. These results demonstrate that artesunate has an effect on anti-gastric cancer cells. One of the antitumor mechanisms of artesunate may be that its inhibition of COX-2 led to reduced proliferation and induction of apoptosis, connected with mitochondrial dysfunction. Artesunate might be a potential therapeutic agent for gastric cancer. PMID:25945055

  16. Association between COX-2 gene polymorphisms and risk of hepatocellular carcinoma development: a meta-analysis

    PubMed Central

    Lu, Si-Cong; Zhong, Jian-Hong; Tan, Jun-Tao; Tang, Hua-Lin; Liu, Xiao-Guang; Xiang, Bang-De; Li, Le-Qun; Peng, Tao

    2015-01-01

    Objective To investigate the association between cyclo-oxygenase-2 (COX-2) polymorphism and the risk of hepatocellular carcinoma (HCC) development. Design Systematic review and meta-analysis of COX-2 polymorphism and risk of HCC development among people with or without HCC. Data sources EMBASE, PubMed, Public Library of Science, SCOPUS, Web of Knowledge and Chinese National Knowledge Infrastructure were searched for all clinical and experimental case–control studies of COX-2 polymorphism and HCC risk. Studies published up to March 2015 were included. Review method Ten studies were included for data extraction, which were mainly from Asian countries. Results 2538 people with HCC and 3714 without HCC were found to satisfy the inclusion criteria and included in the review. The associations of specific genotypes in the eight polymorphic variants of COX-2 and the risk of HCC development were analysed. GG genotype at the A-1195G polymorphism may be associated with a reduced risk of HCC development: the OR across all studies was 0.87 (95% CI 0.75 to 1.02) for the G allele versus the A allele, 0.72 (0.53 to 0.97) for GG versus AA, 0.72 (0.57 to 0.92) for GG versus GA+AA and 1.05 (0.77 to 1.44) for AA versus GA+GG. Similar results were found when the meta-analysis was repeated separately for the Chinese subgroup. However, more reliable data are needed to demonstrate associations between variants in G-765C, T+8473C, A-1290G, G-899C and introns 1, 5 and 6 polymorphisms and the risk of HCC development. Conclusions Only the COX-2 A-1195G gene polymorphism may be associated with a decreased risk of HCC development. These conclusions should be verified in further studies. PMID:26438136

  17. Modelling of filariasis in East Java with Poisson regression and generalized Poisson regression models

    NASA Astrophysics Data System (ADS)

    Darnah

    2016-04-01

    Poisson regression has been used if the response variable is count data that based on the Poisson distribution. The Poisson distribution assumed equal dispersion. In fact, a situation where count data are over dispersion or under dispersion so that Poisson regression inappropriate because it may underestimate the standard errors and overstate the significance of the regression parameters, and consequently, giving misleading inference about the regression parameters. This paper suggests the generalized Poisson regression model to handling over dispersion and under dispersion on the Poisson regression model. The Poisson regression model and generalized Poisson regression model will be applied the number of filariasis cases in East Java. Based regression Poisson model the factors influence of filariasis are the percentage of families who don't behave clean and healthy living and the percentage of families who don't have a healthy house. The Poisson regression model occurs over dispersion so that we using generalized Poisson regression. The best generalized Poisson regression model showing the factor influence of filariasis is percentage of families who don't have healthy house. Interpretation of result the model is each additional 1 percentage of families who don't have healthy house will add 1 people filariasis patient.

  18. Investigating bias in squared regression structure coefficients

    PubMed Central

    Nimon, Kim F.; Zientek, Linda R.; Thompson, Bruce

    2015-01-01

    The importance of structure coefficients and analogs of regression weights for analysis within the general linear model (GLM) has been well-documented. The purpose of this study was to investigate bias in squared structure coefficients in the context of multiple regression and to determine if a formula that had been shown to correct for bias in squared Pearson correlation coefficients and coefficients of determination could be used to correct for bias in squared regression structure coefficients. Using data from a Monte Carlo simulation, this study found that squared regression structure coefficients corrected with Pratt's formula produced less biased estimates and might be more accurate and stable estimates of population squared regression structure coefficients than estimates with no such corrections. While our findings are in line with prior literature that identified multicollinearity as a predictor of bias in squared regression structure coefficients but not coefficients of determination, the findings from this study are unique in that the level of predictive power, number of predictors, and sample size were also observed to contribute bias in squared regression structure coefficients. PMID:26217273

  19. Extraendothelial and constitutive COX-2 expression is involved in the contractile effect of angiotensin II in the rat aorta.

    TOXLINE Toxicology Bibliographic Information

    Castillo-Hernández MC; Martinez-Godinez MA; Guevara-Balcazar G; Miliar-Garcia A; Mancilla J; Lopez-Mayorga RM; Castillo-Henkel EF; Castillo-Henkel C

    2010-10-01

    1 The role of the extraendothelial and constitutive isoforms of cyclo-oxygenase-2 (COX-2) in the contractile effect of angiotensin II (Ang II) was investigated using thoracic and abdominal aortic rings without endothelium from young Wistar rats. 2 Ang II elicited similar contractions in both aortic segments, and the effect was inhibited by pretreatment with NS398 (a selective COX-2 inhibitor) but not SC-560 [selective cyclo-oxygenase-1 (COX-1) inhibitor]. 3 COX-2 mRNA was expressed under basal conditions in both aortic segments. Additionally, Ang II increased COX-2 mRNA expression in the abdominal but not the thoracic segment, while cycloheximide (a protein synthesis inhibitor) did not affect the contractile response to Ang II in either of the two segments; this suggests that the effect is not associated with de novo COX-2 synthesis. 4 In conclusion, the basal amount of COX-2 found in aortic smooth muscle cells is sufficient to explain the production of the prostanoids related to the contractile effect of Ang II. The production of these prostanoids, which are derived from constitutive COX-2, occurs independently of the endothelium vascular system.

  20. Design of Fluorine-Containing 3,4-Diarylfuran-2(5H)-ones as Selective COX-1 Inhibitors.

    PubMed

    Uddin, Md Jashim; Elleman, Anna V; Ghebreselasie, Kebreab; Daniel, Cristina K; Crews, Brenda C; Nance, Kellie D; Huda, Tamanna; Marnett, Lawrence J

    2014-11-13

    We report the design and synthesis of fluorine-containing cyclooxygenase-1 (COX-1)-selective inhibitors to serve as prototypes for the development of a COX-1-targeted imaging agent. Deletion of the SO2CH3 group of rofecoxib switches the compound from a COX-2- to a COX-1-selective inhibitor, providing a 3,4-diarylfuran-2(5H)-one scaffold for structure-activity relationship studies of COX-1 inhibition. A wide range of fluorine-containing 3,4-diarylfuran-2(5H)-ones were designed, synthesized, and tested for their ability to selectively inhibit COX-1 in purified protein and human cancer cell assays. Compounds containing a fluoro-substituent on the C-3 phenyl ring and a methoxy-substituent on the C-4 phenyl ring of the 3,4-diarylfuran-2(5H)-one scaffold were the best COX-1-selective agents of those evaluated, exhibiting IC50s in the submicromolar range. These compounds provide the foundation for development of an agent to facilitate radiologic imaging of ovarian cancer expressing elevated levels of COX-1. PMID:25408841

  1. 1,2-Diaryl-2-hydroxyiminoethanones as dual COX-1 and ?-amyloid aggregation inhibitors: biological evaluation and in silico study.

    PubMed

    Irannejad, Hamid; Unsal Tan, Oya; Ozadali, Keriman; Dadashpour, Sakineh; Tuylu Kucukkilinc, Tuba; Ahangar, Nematollah; Ahmadnejad, Mahsa; Emami, Saeed

    2015-04-01

    To find out new agents for treating inflammatory-involved diseases such as Alzheimer's disease, a series of 1,2-diaryl-2-hydroxyiminoethanones containing vicinal diaryl pharmacophore of COX inhibitors were tested by a set of in vitro, in vivo, and computational studies. The in vivo study of compounds indicated their prominent anti-inflammatory ability at the doses of 10 and 20 mg/kg comparable to celecoxib (10 mg/kg). Further in vitro COX-1/COX-2 evaluations revealed that 4-methoxy derivative 3 had a high selective COX-1 inhibitory activity (COX-1, IC50=0.12 ?m, SI>833). To evaluate their potential use against Alzheimer's disease, in vitro evaluation of ?-amyloid fibril formation using A?(1-40) and A?(1-42) peptides was performed. The evaluation of their antiaggregation ability gave impressive results and comparable to rifampicin and indomethacin. Conformational study of compound 3 and subsequent docking of its restrained analogs on both active sites of COX-1 and COX-2 could provide a proof of its COX-1 selectivity as well as molecular dynamic simulation could elucidate and give more insight into the amyloid disaggregation mechanisms leading to rational design of inhibitors. PMID:25227162

  2. Angiotensin-(1-7)-Induced Plasticity Changes in the Lateral Amygdala Are Mediated by COX-2 and NO

    ERIC Educational Resources Information Center

    Albrecht, Doris

    2007-01-01

    It is known from studies outside the brain that upon binding to its receptor, angiotensin-(1-7) elicits the release of prostanoids and nitric oxide (NO). Cyclooxygenase (COX) is a key enzyme that converts arachidonic acid to prostaglandins. Since there are no data available so far on the role of COX-2 in the amygdala, in a first step we…

  3. Angiotensin-(1-7)-Induced Plasticity Changes in the Lateral Amygdala Are Mediated by COX-2 and NO

    ERIC Educational Resources Information Center

    Albrecht, Doris

    2007-01-01

    It is known from studies outside the brain that upon binding to its receptor, angiotensin-(1-7) elicits the release of prostanoids and nitric oxide (NO). Cyclooxygenase (COX) is a key enzyme that converts arachidonic acid to prostaglandins. Since there are no data available so far on the role of COX-2 in the amygdala, in a first step we

  4. Regression of altitude-produced cardiac hypertrophy.

    NASA Technical Reports Server (NTRS)

    Sizemore, D. A.; Mcintyre, T. W.; Van Liere, E. J.; Wilson , M. F.

    1973-01-01

    The rate of regression of cardiac hypertrophy with time has been determined in adult male albino rats. The hypertrophy was induced by intermittent exposure to simulated high altitude. The percentage hypertrophy was much greater (46%) in the right ventricle than in the left (16%). The regression could be adequately fitted to a single exponential function with a half-time of 6.73 plus or minus 0.71 days (90% CI). There was no significant difference in the rates of regression for the two ventricles.

  5. Sparse Multivariate Regression With Covariance Estimation

    PubMed Central

    Rothman, Adam J.; Levina, Elizaveta; Zhu, Ji

    2014-01-01

    We propose a procedure for constructing a sparse estimator of a multivariate regression coefficient matrix that accounts for correlation of the response variables. This method, which we call multivariate regression with covariance estimation (MRCE), involves penalized likelihood with simultaneous estimation of the regression coefficients and the covariance structure. An efficient optimization algorithm and a fast approximation are developed for computing MRCE. Using simulation studies, we show that the proposed method outperforms relevant competitors when the responses are highly correlated. We also apply the new method to a finance example on predicting asset returns. An R-package containing this dataset and code for computing MRCE and its approximation are available online. PMID:24963268

  6. Spontaneous Regression of Primitive Merkel Cell Carcinoma

    PubMed Central

    2015-01-01

    Merkel cell carcinoma (MCC) is a rare, aggressive skin tumor that mainly occurs in the elderly with a generally poor prognosis. Like all skin cancers, its incidence is rising. Despite the poor prognosis, a few reports of spontaneous regression have been published. We describe the case of a 89-year-old male patient who presented two MCC lesions of the scalp. Following biopsy the lesions underwent complete regression with no clinical evidence of residual tumor up to 24 months. The current knowledge of MCC and the other cases of spontaneous regression described in the literature are reviewed. PMID:26788270

  7. Synthesis, cyclooxygenase inhibition, anti-inflammatory evaluation and ulcerogenic liability of novel triarylpyrazoline derivatives as selective COX-2 inhibitors.

    PubMed

    Abdellatif, Khaled R A; Abdelgawad, Mohamed A; Labib, Madlen B; Zidan, Taha H

    2015-12-15

    A new series of triarylpyrazoline derivatives 8a-p containing the most important COX-2 pharmacophore (SO2CH3 or/and SO2NH2) were synthesized by reaction of propen-1-one derivatives 6a-h with different phenyl hydrazine hydrochloride derivatives 7a-b in aqueous ethanol. All prepared compounds were evaluated for their in vitro COX-1/COX-2 inhibitory activity and the in vivo anti-inflammatory activity. All compounds were more selective for COX-2 isozyme than COX-1 isozyme and showed good in vivo anti-inflammatory activity. Compounds 8g, 8j and 8o showed the highest anti-inflammatory activity and were less ulcerogenic (Ulcer Index=6.85, 7.7, 5.92, respectively) than indomethacin (Ulcer Index=12.3) and comparable to celecoxib (Ulcer Index=4.85). PMID:26546221

  8. Cox17 Protein Is an Auxiliary Factor Involved in the Control of the Mitochondrial Contact Site and Cristae Organizing System*

    PubMed Central

    Chojnacka, Magdalena; Gornicka, Agnieszka; Oeljeklaus, Silke; Warscheid, Bettina; Chacinska, Agnieszka

    2015-01-01

    The mitochondrial contact site and cristae organizing system (MICOS) is a recently discovered protein complex that is crucial for establishing and maintaining the proper inner membrane architecture and contacts with the outer membrane of mitochondria. The ways in which the MICOS complex is assembled and its integrity is regulated remain elusive. Here, we report a direct link between Cox17, a protein involved in the assembly of cytochrome c oxidase, and the MICOS complex. Cox17 interacts with Mic60, thereby modulating MICOS complex integrity. This interaction does not involve Sco1, a partner of Cox17 in transferring copper ions to cytochrome c oxidase. However, the Cox17-MICOS interaction is regulated by copper ions. We propose that Cox17 is a newly identified factor involved in maintaining the architecture of the MICOS complex. PMID:25918166

  9. Increased Dietary Sodium Induces COX2 Expression by activating NFκB in Renal Medullary Interstitial Cells

    PubMed Central

    Zhao, Min; Davis, Linda S.; Blackwell, Timothy S.; Yull, Fiona; Breyer, Matthew D.; Hao, Chuan-Ming

    2013-01-01

    High salt diet induces renal medullary COX2 expression. Selective blockade of renal medullary COX2 activity in rats causes salt sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8% NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6J mice. Co-immunofluorescence using a COX2 antibody and antibodies against AQP2, ClC-K, AQP1 and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a 7 fold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of EGFP expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet fed C57Bl/6J mice with selective IκB kinase inhibitor IMD-0354 (8mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary PGE2. These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium. PMID:23900806

  10. NOS and COX isoforms and abnormal microvessel responses to CO2 and H+ in hyperoxia-injured lungs.

    PubMed

    Naoki, K; Kudo, H; Suzuki, K; Takeshita, K; Miyao, N; Ishii, M; Sato, N; Suzuki, Y; Tsumura, H; Yamaguchi, K

    2002-07-01

    The aim of the present study was to compare microvessel responses to hypercapnic and isocapnic acidosis in hyperoxia-injured lungs and to assess the role of constitutive and inducible forms of nitric oxide synthase (NOS) and cyclo-oxygenase (COX). Real-time confocal luminescence microscopy was used to measure changes in the diameter of acinar arterioles, venules and capillaries in response to stimulation with hypercapnic and isocapnic acidosis in isolated rat lungs injured by 90% oxygen exposure for 48 h. Observations were made with and without inhibition of constitutive (endothelial constitutive NOS (ecNOS) and COX-1) and inducible isoforms (iNOS and COX-2) of NOS and COX. Upregulation of NOS was assessed by measuring enzyme levels in lung homogenates by Western blot analysis and enhancement of the COX-related pathway was judged from perfusate concentrations of 6-ketoprostaglandin F1alpha. ecNOS and COX-1, but not iNOS and COX-2, were upregulated in hyperoxia-injured lungs. The nitric oxide produced by ecNOS attenuated COX-1 activity in injured arterioles and venules, but carbon dioxide enhanced it, leading to paradoxical dilatation of these microvessels under hypercapnic conditions with ecNOS inhibition. Although a high hydrogen ion concentration was unnecessary for excitation of COX-1, venule constriction in response to H+ was enhanced by COX-1 inhibition. Constitutive, but not inducible, isoforms of cyclo-oxygenase and nitric oxide synthase play an important role in abnormal microvessel responses to carbon dioxide and hydrogen ions in hyperoxia-injured lungs. PMID:12166580

  11. IL1{beta}-mediated Stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells

    SciTech Connect

    Zhu, Yingting; Tissue Tech Inc, Miami, FL 33173 ; Zhu, Min; Lance, Peter

    2012-11-15

    COX-2 is a major inflammatory mediator implicated in colorectal inflammation and cancer. However, the exact origin and role of COX-2 on colorectal inflammation and carcinogenesis are still not well defined. Recently, we reported that COX-2 and iNOS signalings interact in colonic CCD18Co fibroblasts. In this article, we investigated whether activation of COX-2 signaling by IL1{beta} in primary colonic fibroblasts obtained from normal and cancer patients play a critical role in regulation of proliferation and invasiveness of human colonic epithelial cancer cells. Our results demonstrated that COX-2 level was significantly higher in cancer associated fibroblasts than that in normal fibroblasts with or without stimulation of IL-1{beta}, a powerful stimulator of COX-2. Using in vitro assays for estimating proliferative and invasive potential, we discovered that the proliferation and invasiveness of the epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts than with normal fibroblasts, with or without stimulation of IL1{beta}. Further analysis indicated that the major COX-2 product, prostaglandin E{sub 2}, directly enhanced proliferation and invasiveness of the epithelial cancer cells in the absence of fibroblasts. Moreover, a selective COX-2 inhibitor, NS-398, blocked the proliferative and invasive effect of both normal and cancer associate fibroblasts on the epithelial cancer cells, with or without stimulation of IL-1{beta}. Those results indicate that activation of COX-2 signaling in the fibroblasts plays a major role in promoting proliferation and invasiveness of the epithelial cancer cells. In this process, PKC is involved in the activation of COX-2 signaling induced by IL-1{beta} in the fibroblasts.

  12. A new bivariate negative binomial regression model

    NASA Astrophysics Data System (ADS)

    Faroughi, Pouya; Ismail, Noriszura

    2014-12-01

    This paper introduces a new form of bivariate negative binomial (BNB-1) regression which can be fitted to bivariate and correlated count data with covariates. The BNB regression discussed in this study can be fitted to bivariate and overdispersed count data with positive, zero or negative correlations. The joint p.m.f. of the BNB1 distribution is derived from the product of two negative binomial marginals with a multiplicative factor parameter. Several testing methods were used to check overdispersion and goodness-of-fit of the model. Application of BNB-1 regression is illustrated on Malaysian motor insurance dataset. The results indicated that BNB-1 regression has better fit than bivariate Poisson and BNB-2 models with regards to Akaike information criterion.

  13. TWSVR: Regression via Twin Support Vector Machine.

    PubMed

    Khemchandani, Reshma; Goyal, Keshav; Chandra, Suresh

    2016-02-01

    Taking motivation from Twin Support Vector Machine (TWSVM) formulation, Peng (2010) attempted to propose Twin Support Vector Regression (TSVR) where the regressor is obtained via solving a pair of quadratic programming problems (QPPs). In this paper we argue that TSVR formulation is not in the true spirit of TWSVM. Further, taking motivation from Bi and Bennett (2003), we propose an alternative approach to find a formulation for Twin Support Vector Regression (TWSVR) which is in the true spirit of TWSVM. We show that our proposed TWSVR can be derived from TWSVM for an appropriately constructed classification problem. To check the efficacy of our proposed TWSVR we compare its performance with TSVR and classical Support Vector Regression(SVR) on various regression datasets. PMID:26624223

  14. Conventional univariate versus multivariate spectrophotometric assisted techniques for simultaneous determination of perindopril arginin and amlodipine besylate in presence of their degradation products.

    PubMed

    Hegazy, Maha A; Abbas, Samah S; Zaazaa, Hala E; Essam, Hebatallah M

    2015-11-01

    The resolving power of spectrophotometric assisted mathematical techniques were demonstrated for the simultaneous determination of perindopril arginin (PER) and amlodipine besylate (AML) in presence of their degradation products. The conventional univariate methods include the absorptivity factor method (AFM) and absorption correction method (ACM), which were able to determine the two drugs, simultaneously, but not in the presence of their degradation products. In both methods, amlodipine was determined directly at 360 nm in the concentration range of 8-28 μg mL(-1), on the other hand perindopril was determined by AFM at 222.2 nm and by ACM at 208 nm in the concentration range of 10-70 μg mL(-1). Moreover, the applied multivariate calibration methods were able for the determination of perindopril and amlodipine in presence of their degradation products using concentration residuals augmented classical least squares (CRACLS) and partial least squares (PLS). The proposed multivariate methods were applied to 19 synthetic samples in the concentration ranges of 60-100 μg mL(-1) perindopril and 20-40 μg mL(-1) amlodipine. Commercially available tablet formulations were successfully analysed using the developed methods without interference from other dosage form additives except PLS model, which failed to determine both drugs in their pharmaceutical dosage form. PMID:26123511

  15. The Geometry of Enhancement in Multiple Regression

    ERIC Educational Resources Information Center

    Waller, Niels G.

    2011-01-01

    In linear multiple regression, "enhancement" is said to occur when R[superscript 2] = b[prime]r greater than r[prime]r, where b is a p x 1 vector of standardized regression coefficients and r is a p x 1 vector of correlations between a criterion y and a set of standardized regressors, x. When p = 1 then b [is congruent to] r and enhancement cannot

  16. The Geometry of Enhancement in Multiple Regression

    ERIC Educational Resources Information Center

    Waller, Niels G.

    2011-01-01

    In linear multiple regression, "enhancement" is said to occur when R[superscript 2] = b[prime]r greater than r[prime]r, where b is a p x 1 vector of standardized regression coefficients and r is a p x 1 vector of correlations between a criterion y and a set of standardized regressors, x. When p = 1 then b [is congruent to] r and enhancement cannot…

  17. O-desmethylquinine as a cyclooxygenase-2 (COX-2) inhibitors using AutoDock Vina

    NASA Astrophysics Data System (ADS)

    Damayanti, Sophi; Mahardhika, Andhika Bintang; Ibrahim, Slamet; Chong, Wei Lim; Lee, Vannajan Sanghiran; Tjahjono, Daryono Hadi

    2014-10-01

    Computational approach was employed to evaluate the biological activity of novel cyclooxygenase-2 COX-2 inhibitor, O-desmethylquinine, in comparison to quinine as common inhibitor which can also be used an agent of antipyretic, antimalaria, analgesic and antiinflamation. The molecular models of the compound were constructed and optimized with the density function theory with at the B3LYP/6-31G (d,p) level using Gaussian 09 program. Molecular docking studies of the compounds were done to obtain the COX-2 complex structures and their binding energies were analyzed using the AutoDock Vina. The results of docking of the two ligands were comparable and cannot be differentiated from the energy scoring function with AutoDock Vina.

  18. Skin tight: macrophage-specific COX-2 induction links salt handling in kidney and skin.

    PubMed

    Stegbauer, Johannes; Coffman, Thomas M

    2015-11-01

    The relationship between dietary salt intake and the associated risk of hypertension and cardiovascular disease is an important public health concern. In this issue of the JCI, a study by Zhang and associates shows that consumption of a high-sodium diet induces expression of cyclooxygenase-2 (COX-2) in macrophages, resulting in enhanced levels of prostaglandin E2 (PGE2), autocrine activation of the macrophage E-prostanoid 4 (EP4) receptor, and subsequent triggering of parallel pathways in the kidney and in skin that help dispose of excess sodium. The authors found that blockade or genetic elimination of the COX-2/PGE2/EP4 receptor pathway in hematopoietic cells causes salt-sensitive hypertension in mice. These studies illuminate an unexpected central role for the macrophage in coordinating homeostatic responses to dietary salt intake and suggest a complex pathophysiology for hypertension associated with NSAID use. PMID:26495835

  19. Aerobic oxidation of hydroxymethylfurfural and furfural by using heterogeneous Cox Oy -N@C catalysts.

    PubMed

    Deng, Jin; Song, Hai-Jie; Cui, Min-Shu; Du, Yi-Ping; Fu, Yao

    2014-12-01

    2,5-Furandicarboxylic acid (FDCA) is considered to be a promising replacement for terephthalic acid since they share similar structures and properties. In contrast to FDCA, 2,5-furandicarboxylic acid methyl (FDCAM) has properties that allow it to be easily purified. In this work, we reported an oxidative esterification of 5-hydroxymethylfurfural (HMF) and furfural to prepare corresponding esters over Cox Oy -N@C catalysts using O2 as benign oxidant. High yield and selectivity of FDCAM and methyl 2-furoate were obtained under optimized conditions. Factors which influenced the product distribution were examined thoroughly. The Cox Oy -N@C catalysts were recycled five times and no significant loss of activity was detected. Characterization of the catalysts could explain such phenomena. Using XPS and TGA, we made a thorough investigation of the effects of ligand and pyrolysis temperature on catalyst activity. PMID:25353711

  20. Discovering genetic associations with high-dimensional neuroimaging phenotypes: A sparse reduced-rank regression approach.

    PubMed

    Vounou, Maria; Nichols, Thomas E; Montana, Giovanni

    2010-11-15

    There is growing interest in performing genome-wide searches for associations between genetic variants and brain imaging phenotypes. While much work has focused on single scalar valued summaries of brain phenotype, accounting for the richness of imaging data requires a brain-wide, genome-wide search. In particular, the standard approach based on mass-univariate linear modelling (MULM) does not account for the structured patterns of correlations present in each domain. In this work, we propose sparse reduced rank regression (sRRR), a strategy for multivariate modelling of high-dimensional imaging responses (measurements taken over regions of interest or individual voxels) and genetic covariates (single nucleotide polymorphisms or copy number variations), which enforces sparsity in the regression coefficients. Such sparsity constraints ensure that the model performs simultaneous genotype and phenotype selection. Using simulation procedures that accurately reflect realistic human genetic variation and imaging correlations, we present detailed evaluations of the sRRR method in comparison with the more traditional MULM approach. In all settings considered, sRRR has better power to detect deleterious genetic variants compared to MULM. Important issues concerning model selection and connections to existing latent variable models are also discussed. This work shows that sRRR offers a promising alternative for detecting brain-wide, genome-wide associations. PMID:20624472

  1. Testosterone induces leucocyte migration by NADPH oxidase-driven ROS- and COX2-dependent mechanisms.

    PubMed

    Chignalia, Andreia Z; Oliveira, Maria Aparecida; Debbas, Victor; Dull, Randal O; Laurindo, Francisco R M; Touyz, Rhian M; Carvalho, Maria Helena C; Fortes, Zuleica B; Tostes, Rita C

    2015-07-01

    The mechanisms whereby testosterone increases cardiovascular risk are not clarified. However, oxidative stress and inflammation seem to be determinants. Herein, we sought to determine whether exogenous testosterone, at physiological levels, induces leucocyte migration, a central feature in immune and inflammatory responses and the mediating mechanisms. We hypothesized that testosterone induces leucocyte migration via NADPH oxidase (NADPHox)-driven reactive oxygen species (ROS) and cyclooxygenase (COX)-dependent mechanisms. Sixteen-week-old Wistar rats received an intraperitoneal injection (5 ml) of either testosterone (10(-7) mol/l) or saline. Rats were pre-treated with 5 ml of sodium salicylate (SS, non-selective COX inhibitor, 1.25 × 10(-3) mol/l, 1 h prior to testosterone or saline), flutamide (androgen receptor antagonist, 10(-5) mol/l), apocynin (NADPHox inhibitor, 3 × 10(-4) mol/l), N-[2-Cyclohexyloxy-4-nitrophenyl]methanesulfonamide (NS398, COX2 inhibitor, 10(-4) mol/l) or saline, 4 h before testosterone or saline administration. Leucocyte migration was assessed 24 h after testosterone administration by intravital microscopy of the mesenteric bed. Serum levels of testosterone were measured by radioimmunoassay. NADPHox activity was assessed in membrane fractions of the mesenteric bed by dihydroethidium (DHE) fluorescence and in isolated vascular smooth muscle cells (VSMC) by HPLC. NADPHox subunits and VCAM (vascular cell adhesion molecule) expression were determined by immunoblotting. Testosterone administration did not change serum levels of endogenous testosterone, but increased venular leucocyte migration to the adventia, NADPHox activity and expression (P < 0.05). These effects were blocked by flutamide. SS inhibited testosterone-induced leucocyte migration (P<0.05). Apocynin and NS398 abolished testosterone-induced leucocyte migration and NADPHox activity (P<0.05). Testosterone induces leucocyte migration via NADPHox- and COX2-dependent mechanisms and may contribute to inflammatory processes and oxidative stress in the vasculature potentially increasing cardiovascular risk. PMID:25700020

  2. COxSwAIN: Compressive Sensing for Advanced Imaging and Navigation

    NASA Technical Reports Server (NTRS)

    Kurwitz, Richard; Pulley, Marina; LaFerney, Nathan; Munoz, Carlos

    2015-01-01

    The COxSwAIN project focuses on building an image and video compression scheme that can be implemented in a small or low-power satellite. To do this, we used Compressive Sensing, where the compression is performed by matrix multiplications on the satellite and reconstructed on the ground. Our paper explains our methodology and demonstrates the results of the scheme, being able to achieve high quality image compression that is robust to noise and corruption.

  3. NSAIDs and serious cardiovascular disorders: especially cox-2 inhibitors and diclofenac.

    PubMed

    2016-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) used as analgesics expose patients to cardiovascular risks that can be predicted from their pharmacological properties. As of mid-2015, what is known about the cardiovascular harms of the NSAIDs of choice, ibuprofen and naproxen? Most of the data from comparative trials of NSAIDs concern cox-2 inhibitors, diclofenac, ibuprofen and naproxen. Few studies have addressed the serious cardiovascular effects of other NSAIDs. In 2013, a U.K. team published a large meta-analysis of hundreds of randomised trials comparing NSAIDs with placebo or one NSAID with another NSAID. Compared with placebo, a statistically significant increase in the risk of serious cardiovascular adverse effects was demonstrated with cox-2 inhibitors and with diclofenac (about +40%). This risk is mainly due to an increase in myocardial infarctions and vascular deaths. Another meta-analysis found similar results in terms of cardiovascular deaths. The results of epidemiological studies are consistent with those of randomised clinical trials. According to meta-analyses of randomised trials, high-dose ibuprofen increases cardiovascular risks to the same degree as diclofenac or cox-2 inhibitors. The risk seems to mainly apply to daily doses of 2400 mg, a finding borne out by epidemiological studies that showed no increased risk with ibuprofen 1200 mg. Two meta-analyses of clinical trials showed that all NSAIDs roughly double the risk of heart failure. One meta-analysis showed a small, statistically significant increase in the risk of atrial fibrillation. In practice, from a cardiovascular perspective, the NSAIDs of choice are ibuprofen, on condition that the dose does not exceed 1200 mg per day, and naproxen. In contrast, it would appear from the study data that cox-2 inhibitors, diclofenac and high-dose ibuprofen (2400 mg per day) are best avoided. As for other NSAIDs, the clinical data are too sparse to allow a meaningful comparison with the better studied NSAIDs. It is advisable to avoid using these other drugs. PMID:26942254

  4. Enhancing the pharmacodynamic profile of a class of selective COX-2 inhibiting nitric oxide donors.

    PubMed

    Biava, Mariangela; Battilocchio, Claudio; Poce, Giovanna; Alfonso, Salvatore; Consalvi, Sara; Di Capua, Angela; Calderone, Vincenzo; Martelli, Alma; Testai, Lara; Sautebin, Lidia; Rossi, Antonietta; Ghelardini, Carla; Di Cesare Mannelli, Lorenzo; Giordani, Antonio; Persiani, Stefano; Colovic, Milena; Dovizio, Melania; Patrignani, Paola; Anzini, Maurizio

    2014-01-15

    We report herein the development, synthesis, physicochemical and pharmacological characterization of a novel class of pharmacodynamic hybrids that selectively inhibit cyclooxygenase-2 (COX-2) isoform and present suitable nitric oxide releasing properties. The replacement of the ester moiety with the amide group gave access to in vivo more stable and active derivatives that highlighted outstanding pharmacological properties. In particular, the glycine derivative proved to be extremely active in suppressing hyperalgesia and edema. PMID:24373735

  5. Cox-Maze IV in Total Anomalous Pulmonary Venous Drainage After Sutureless Repair.

    PubMed

    Haller, Christoph; Kirsh, Joel A; Van Arsdell, Glen; Honjo, Osami

    2016-04-01

    Modifications of conventional ablation strategies can make arrhythmia surgery more efficient after primary sutureless repair of total anomalous pulmonary venous drainage. We present a surgical technique performed in a 3-year-old patient who experienced ongoing atrial arrhythmia after sutureless repair. A new modified Cox-Maze IV procedure was performed, which respects the special characteristics of patients after sutureless repairs, showing good short-term results. PMID:27000590

  6. Frequent, Phylogenetically Local Horizontal Transfer of the cox1 Group I Intron in Flowering Plant Mitochondria

    PubMed Central

    Cho, Yangrae; Mower, Jeffrey P.; Alverson, Andrew J.; Palmer, Jeffrey D.

    2008-01-01

    Horizontal gene transfer is surprisingly common among plant mitochondrial genomes. The first well-established case involves a homing group I intron in the mitochondrial cox1 gene shown to have been frequently acquired via horizontal transfer in angiosperms. Here, we report extensive additional sampling of angiosperms, including 85 newly sequenced introns from 30 families. Analysis of all available data leads us to conclude that, among the 640 angiosperms (from 212 families) whose cox1 intron status has been characterized thus far, the intron has been acquired via roughly 70 separate horizontal transfer events. We propose that the intron was originally seeded into angiosperms by a single transfer from fungi, with all subsequent inferred transfers occurring from one angiosperm to another. The pattern of angiosperm-to-angiosperm transfer is biased toward exchanges between plants belonging to the same family. Illegitimate pollination is proposed as one potential factor responsible for this pattern, given that aberrant, cross-species pollination is more likely between close relatives. Other potential factors include shared vectoring agents or common geographic locations. We report the first apparent cases of loss of the cox1 intron; losses are accompanied by retention of the exonic coconversion tract, which is located immediately downstream of the intron and which is a product of the intron's self-insertion mechanism. We discuss the many reasons why the cox1 intron is so frequently and detectably transferred, and rarely lost, and conclude that it should be regarded as the canary in the coal mine with respect to horizontal transfer in angiosperm mitochondria. PMID:18524785

  7. cPLA2 Is Protective Against COX Inhibitor–Induced Intestinal Damage

    PubMed Central

    Montrose, David C.; Kadaveru, Krishna; Ilsley, Jillian N. M.; Root, Sierra H.; Rajan, Thiruchanduri V.; Ramesh, Manish; Nichols, Frank C.; Liang, Bruce T.; Sonin, Dmitry; Hand, Arthur R.; Zarini, Simona; Murphy, Robert C.; Belinsky, Glenn S.; Nakanishi, Masako; Rosenberg, Daniel W.

    2010-01-01

    Cytosolic phospholipase A2 (cPLA2) is the rate-limiting enzyme responsible for the generation of prostaglandins (PGs), which are bioactive lipids that play critical roles in maintaining gastrointestinal (GI) homeostasis. There has been a long-standing association between administration of cyclooxygenase (COX) inhibitors and GI toxicity. GI injury is thought to be induced by suppressed production of GI-protective PGs as well as direct injury to enterocytes. The present study sought to determine how pan-suppression of PG production via a genetic deletion of cPLA2 impacts the susceptibility to COX inhibitor–induced GI injury. A panel of COX inhibitors including celecoxib, rofecoxib, sulindac, and aspirin were administered via diet to cPLA2− / − and cPLA2+ / + littermates. Administration of celecoxib, rofecoxib, and sulindac, but not aspirin, resulted in acute lethality (within 2 weeks) in cPLA2− / − mice, but not in wild-type littermates. Histomorphological analysis revealed severe GI damage following celecoxib exposure associated with acute bacteremia and sepsis. Intestinal PG levels were reduced equivalently in both genotypes following celecoxib exposure, indicating that PG production was not likely responsible for the differential sensitivity. Gene expression profiling in the small intestines of mice identified drug-related changes among a panel of genes including those involved in mitochondrial function in cPLA2− / − mice. Further analysis of enterocytic mitochondria showed abnormal morphology as well as impaired ATP production in the intestines from celecoxib-exposed cPLA2− / − mice. Our data demonstrate that cPLA2 appears to be an important component in conferring protection against COX inhibitor–induced enteropathy, which may be mediated through affects on enterocytic mitochondria. PMID:20562220

  8. Nutritional supplements, COX-2 and IGF-1 expression in men on active surveillance for prostate cancer

    PubMed Central

    Weinberg, Vivian; Magbanua, Mark J.; Sosa, Eduardo; Simko, Jeffry; Shinohara, Katsuto; Federman, Scot; Mattie, Mike; Hughes-Fulford, Millie; Haqq, Christopher; Carroll, Peter R.

    2010-01-01

    Background Nutritional factors are associated with reduced risk of prostate cancer progression, yet mechanisms remain unclear. We examined the effects of lycopene and fish oil supplements versus placebo on the normal prostate microenvironment, among men pursuing active surveillance for low-burden prostate cancer. We hypothesized that lycopene or fish oil supplements would down-regulate insulin-like growth factor-1 (IGF-1) and cyclooxygenase 2 (COX-2) gene expression, respectively, reflecting putative proliferation (IGF-1) and inflammatory (COX-2) pathways relevant to carcinogenesis. Methods We conducted a 3-month randomized, double-blinded, clinical trial comparing prostate tissue gene expression profiles (assessed by qRT–PCR) among men with favorable-risk prostate cancer receiving either 30 mg/day lycopene, 3 g/day fish oil (including 1,098 mg eicosapentaenoic and 549 mg docosahexaenoic fatty acids) or placebo. Results Among 69 men (22 assigned to lycopene, 21 to fish, and 26 to placebo), there was no difference in the change from baseline to the 3 months in IGF-1 expression level between the placebo and lycopene arms (p = 0.93) nor in COX-2 expression between the placebo and fish arms (p = 0.99). Conclusion Compared to placebo, 3-month intervention with lycopene or fish oil did not significantly change IGF-1 and COX-2 gene expression in the normal prostate microenvironment in men with low-burden prostate cancer. Further analysis of global gene expression profiles may shed light on the bioactivity and relevance of these nutrients in prostate cancer. PMID:21103921

  9. LincRNA-Cox2 Promotes Late Inflammatory Gene Transcription in Macrophages through Modulating SWI/SNF-Mediated Chromatin Remodeling.

    PubMed

    Hu, Guoku; Gong, Ai-Yu; Wang, Yang; Ma, Shibin; Chen, Xiqiang; Chen, Jing; Su, Chun-Jen; Shibata, Annemarie; Strauss-Soukup, Juliane K; Drescher, Kristen M; Chen, Xian-Ming

    2016-03-15

    Long intergenic noncoding RNAs (lincRNAs) are long noncoding transcripts (>200 nt) from the intergenic regions of annotated protein-coding genes. One of the most highly induced lincRNAs in macrophages upon TLR ligation is lincRNA-Cox2, which was recently shown to mediate the activation and repression of distinct classes of immune genes in innate immune cells. We report that lincRNA-Cox2, located at chromosome 1 proximal to the PG-endoperoxide synthase 2 (Ptgs2/Cox2) gene, is an early-primary inflammatory gene controlled by NF-κB signaling in murine macrophages. Functionally, lincRNA-Cox2 is required for the transcription of NF-κB-regulated late-primary inflammatory response genes stimulated by bacterial LPS. Specifically, lincRNA-Cox2 is assembled into the switch/sucrose nonfermentable (SWI/SNF) complex in cells after LPS stimulation. This resulting lincRNA-Cox2/SWI/SNF complex can modulate the assembly of NF-κB subunits to the SWI/SNF complex, and ultimately, SWI/SNF-associated chromatin remodeling and transactivation of the late-primary inflammatory-response genes in macrophages in response to microbial challenge. Therefore, our data indicate a new regulatory role for NF-κB-induced lincRNA-Cox2 as a coactivator of NF-κB for the transcription of late-primary response genes in innate immune cells through modulation of epigenetic chromatin remodeling. PMID:26880762

  10. A Mutation of COX6A1 Causes a Recessive Axonal or Mixed Form of Charcot-Marie-Tooth Disease

    PubMed Central

    Tamiya, Gen; Makino, Satoshi; Hayashi, Makiko; Abe, Akiko; Numakura, Chikahiko; Ueki, Masao; Tanaka, Atsushi; Ito, Chizuru; Toshimori, Kiyotaka; Ogawa, Nobuhiro; Terashima, Tomoya; Maegawa, Hiroshi; Yanagisawa, Daijiro; Tooyama, Ikuo; Tada, Masayoshi; Onodera, Osamu; Hayasaka, Kiyoshi

    2014-01-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247−10_247−6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT. PMID:25152455

  11. Structural and antiferromagnetic properties of Ba(Fe1 -x -yCoxRhy )2As2 compounds

    NASA Astrophysics Data System (ADS)

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

    2016-03-01

    We present a systematic investigation of the electrical, structural, and antiferromagnetic properties for the series of Ba (Fe1-x-yCoxRhy) 2As2 compounds with fixed x ≈0.027 and 0 ≤y ≤0.035 . We compare our results for the Co-Rh doped Ba (Fe1-x-yCoxRhy) 2As2 compounds with the Co doped Ba (Fe1-xCox) 2As2 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-yCoxRhy) 2As2 and Ba (Fe1-xCox) 2As2 compounds are very similar when the total number of 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, for example, the temperature difference between the structural and antiferromagnetic transition temperatures and the incommensurability of the antiferromangetic peaks, are different between Ba (Fe1-x-yCoxRhy) 2As2 and Ba (Fe1-xCox) 2As2 compounds.

  12. Monitoring of Fasciola Species Contamination in Water Dropwort by cox1 Mitochondrial and ITS-2 rDNA Sequencing Analysis.

    PubMed

    Choi, In-Wook; Kim, Hwang-Yong; Quan, Juan-Hua; Ryu, Jae-Gee; Sun, Rubing; Lee, Young-Ha

    2015-10-01

    Fascioliasis, a food-borne trematode zoonosis, is a disease primarily in cattle and sheep and occasionally in humans. Water dropwort (Oenanthe javanica), an aquatic perennial herb, is a common second intermediate host of Fasciola, and the fresh stems and leaves are widely used as a seasoning in the Korean diet. However, no information regarding Fasciola species contamination in water dropwort is available. Here, we collected 500 samples of water dropwort in 3 areas in Korea during February and March 2015, and the water dropwort contamination of Fasciola species was monitored by DNA sequencing analysis of the Fasciola hepatica and Fasciola gigantica specific mitochondrial cytochrome c oxidase subunit 1 (cox1) and nuclear ribosomal internal transcribed spacer 2 (ITS-2). Among the 500 samples assessed, the presence of F. hepatica cox1 and 1TS-2 markers were detected in 2 samples, and F. hepatica contamination was confirmed by sequencing analysis. The nucleotide sequences of cox1 PCR products from the 2 F. hepatica-contaminated samples were 96.5% identical to the F. hepatica cox1 sequences in GenBank, whereas F. gigantica cox1 sequences were 46.8% similar with the sequence detected from the cox1 positive samples. However, F. gigantica cox1 and ITS-2 markers were not detected by PCR in the 500 samples of water dropwort. Collectively, in this survey of the water dropwort contamination with Fasciola species, very low prevalence of F. hepatica contamination was detected in the samples. PMID:26537044

  13. 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.

  14. The Spatiotemporal Role of COX-2 in Osteogenic and Chondrogenic Differentiation of Periosteum-Derived Mesenchymal Progenitors in Fracture Repair

    PubMed Central

    Huang, Chunlan; Xue, Ming; Chen, Hongli; Jiao, Jing; Herschman, Harvey R.; O'Keefe, Regis J.; Zhang, Xinping

    2014-01-01

    Periosteum provides a major source of mesenchymal progenitor cells for bone fracture repair. Combining cell-specific targeted Cox-2 gene deletion approaches with in vitro analyses of the differentiation of periosteum-derived mesenchymal progenitor cells (PDMPCs), here we demonstrate a spatial and temporal role for Cox-2 function in the modulation of osteogenic and chondrogenic differentiation of periosteal progenitors in fracture repair. Prx1Cre-targeted Cox-2 gene deletion in mesenchyme resulted in marked reduction of intramembraneous and endochondral bone repair, leading to accumulation of poorly differentiated mesenchyme and immature cartilage in periosteal callus. In contrast, Col2Cre-targeted Cox-2 gene deletion in cartilage resulted in a deficiency primarily in cartilage conversion into bone. Further cell culture analyses using Cox-2 deficient PDMPCs demonstrated reduced osteogenic differentiation in monolayer cultures, blocked chondrocyte differentiation and hypertrophy in high density micromass cultures. Gene expression microarray analyses demonstrated downregulation of a key set of genes associated with bone/cartilage formation and remodeling, namely Sox9, Runx2, Osx, MMP9, VDR and RANKL. Pathway analyses demonstrated dysregulation of the HIF-1, PI3K-AKT and Wnt pathways in Cox-2 deficient cells. Collectively, our data highlight a crucial role for Cox-2 from cells of mesenchymal lineages in modulating key pathways that control periosteal progenitor cell growth, differentiation, and angiogenesis in fracture repair. PMID:24988184

  15. Homocysteine induces COX-2 expression in macrophages through ROS generated by NMDA receptor-calcium signaling pathways.

    PubMed

    Lee, Y S; Lee, S J; Seo, K W; Bae, J U; Park, S Y; Kim, C D

    2013-05-01

    Homocysteine (Hcy) at elevated levels is a putative risk factor for many cardiovascular disorders including atherosclerosis. In the present study, we investigated the effect of Hcy on the expression of cyclooxygenase (COX)-2 in murine macrophages and the mechanisms involved. Hcy increased the expression of COX-2 mRNA and protein in dose- and time-dependent manners, but did not affect COX-1 expression. Hcy-induced COX-2 expression was attenuated not only by the calcium chelators, EGTA and BAPTA-AM, but also by an antioxidant, N-acetylcysteine. Calcium chelators also attenuated Hcy-induced reactive oxygen species (ROS) production in macrophages, indicating that Hcy-induced COX-2 expression might be mediated through ROS generated by calcium-dependent signaling pathways. In another series of experiments, Hcy increased the intracellular concentration of calcium in a dose-dependent manner, which was attenuated by MK-801, an N-methyl-D-aspartate (NMDA) receptor inhibitor, but not by bicuculline, a gamma-aminobutyric acid receptor inhibitor. Molecular inhibition of NMDA receptor using small interfering RNA also attenuated Hcy-induced increases in intracellular calcium. Furthermore, both ROS production and Hcy-induced COX-2 expression were also inhibited by MK-801 as well as by molecular inhibition of NMDA receptor. Taken together, these findings suggest that Hcy enhances COX-2 expression in murine macrophages by ROS generated via NMDA receptor-mediated calcium signaling pathways. PMID:23485152

  16. Monitoring of Fasciola Species Contamination in Water Dropwort by cox1 Mitochondrial and ITS-2 rDNA Sequencing Analysis

    PubMed Central

    Choi, In-Wook; Kim, Hwang-Yong; Quan, Juan-Hua; Ryu, Jae-Gee; Sun, Rubing; Lee, Young-Ha

    2015-01-01

    Fascioliasis, a food-borne trematode zoonosis, is a disease primarily in cattle and sheep and occasionally in humans. Water dropwort (Oenanthe javanica), an aquatic perennial herb, is a common second intermediate host of Fasciola, and the fresh stems and leaves are widely used as a seasoning in the Korean diet. However, no information regarding Fasciola species contamination in water dropwort is available. Here, we collected 500 samples of water dropwort in 3 areas in Korea during February and March 2015, and the water dropwort contamination of Fasciola species was monitored by DNA sequencing analysis of the Fasciola hepatica and Fasciola gigantica specific mitochondrial cytochrome c oxidase subunit 1 (cox1) and nuclear ribosomal internal transcribed spacer 2 (ITS-2). Among the 500 samples assessed, the presence of F. hepatica cox1 and 1TS-2 markers were detected in 2 samples, and F. hepatica contamination was confirmed by sequencing analysis. The nucleotide sequences of cox1 PCR products from the 2 F. hepatica-contaminated samples were 96.5% identical to the F. hepatica cox1 sequences in GenBank, whereas F. gigantica cox1 sequences were 46.8% similar with the sequence detected from the cox1 positive samples. However, F. gigantica cox1 and ITS-2 markers were not detected by PCR in the 500 samples of water dropwort. Collectively, in this survey of the water dropwort contamination with Fasciola species, very low prevalence of F. hepatica contamination was detected in the samples. PMID:26537044

  17. Influence of cyclooxygenase-2 (COX-2) gene promoter polymorphism -765 on graft loss after renal transplantation.

    PubMed

    Courivaud, C; Bamoulid, J; Loupy, A; Deschamps, M; Ferrand, C; Le Corre, D; Tiberghien, P; Chalopin, J-M; Legendre, C; Thervet, E; Saas, P; Ducloux, D

    2009-12-01

    A G-->C polymorphism has been identified in the human cyclooxygenase-2 (COX-2) gene promoter at position -765 with C allele leading to a decreased promoter activity with low prostaglandin E2 (PGE2) production. PGE2 has strong immunomodulatory properties that could influence graft survival. We studied the association between this polymorphism and allograft failure in two independent cohorts of renal transplant recipients (RTRs) including a total of 603 patients. The functional effect of COX-2 gene promoter polymorphism was analyzed by measuring serum levels of PGE2. Median follow-up was 8.7 and 7.9 years for the first and second cohort, respectively. Analysis of 603 patients identified 20 CC (3.3%), 179 GC (29.7%) and 404 GG (67%) carriers. Patients with the GG genotype had significantly higher serum PGE2 concentrations than patients with the C allele. Carriers with a C allele have an independent increased risk of graft loss (hazard ratio (HR) 2.43 [95% CI 1.19-4.97], p = 0.015 for cohort 1; HR 1.72 [95% CI 0.99-3.77], p = 0.051 for cohort 2) compared to GG patients. COX-2 gene promoter polymorphism at position -765 (G-->C) is associated with a higher rate of graft loss in RTRs. Such findings may be used to influence immunosuppressive strategies and optimize patient management. PMID:19788502

  18. CoxFey@C Composites with Tunable Atomic Ratios for Excellent Electromagnetic Absorption Properties.

    PubMed

    Lv, Hualiang; Ji, Guangbin; Zhang, Haiqian; Li, Meng; Zuo, Zhongzheng; Zhao, Yue; Zhang, Baoshan; Tang, Dongming; Du, Youwei

    2015-01-01

    The shell on the nano-magnetic absorber can prevent oxidation, which is very important for its practical utilization. Generally, the nonmagnetic shell will decrease the integral magnetic loss and thus weaken the electromagnetic absorption. However, maintaining the original absorption properties of the magnetic core is a major challenge. Here, we designed novel and facile CoxFey@C composites by reducing CoxFe3-xO4@phenolic resin (x = 1, 0.5 and 0.25). High saturation magnetization value (Ms) of CoxFey particle, as a core, shows the interesting magnetic loss ability. Meanwhile, the carbon shell may increase the integral dielectric loss. The resulting composite shows excellent electromagnetic absorption properties. For example, at a coating thickness of 2 mm, the RLmin value can reach to -23 dB with an effective frequency range of 7 GHz (11-18 GHz). The mechanisms of the improved microwave absorption properties are discussed. PMID:26659124

  19. Genomic selection for slaughter age in pigs using the Cox frailty model.

    PubMed

    Santos, V S; Martins Filho, S; Resende, M D V; Azevedo, C F; Lopes, P S; Guimarães, S E F; Glória, L S; Silva, F F

    2015-01-01

    The aim of this study was to compare genomic selection methodologies using a linear mixed model and the Cox survival model. We used data from an F2 population of pigs, in which the response variable was the time in days from birth to the culling of the animal and the covariates were 238 markers [237 single nucleotide polymorphism (SNP) plus the halothane gene]. The data were corrected for fixed effects, and the accuracy of the method was determined based on the correlation of the ranks of predicted genomic breeding values (GBVs) in both models with the corrected phenotypic values. The analysis was repeated with a subset of SNP markers with largest absolute effects. The results were in agreement with the GBV prediction and the estimation of marker effects for both models for uncensored data and for normality. However, when considering censored data, the Cox model with a normal random effect (S1) was more appropriate. Since there was no agreement between the linear mixed model and the imputed data (L2) for the prediction of genomic values and the estimation of marker effects, the model S1 was considered superior as it took into account the latent variable and the censored data. Marker selection increased correlations between the ranks of predicted GBVs by the linear and Cox frailty models and the corrected phenotypic values, and 120 markers were required to increase the predictive ability for the characteristic analyzed. PMID:26505412

  20. Imidazolineoxyl N-oxide induces COX-2 in endothelial cells: role of free radicals.

    PubMed

    Camacho, Mercedes; Martinez-Gonzalez, Jose; Rodriguez, Cristina; Siguero, Laura; Seriola, Cristina; Romero, Jose-Maria; Vila, Luis

    2012-01-01

    cPTIO (2-[4-carboxyphenyl]-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) exerts beneficial actions on systemic inflammatory response. Besides its nitric oxide (NO) scavenging properties cPTIO could exert beneficial effects through modulation of arachidonic acid metabolism. We studied the effect of cPTIO on the biosynthesis of vasoactive prostaglandins (PG) by endothelial cells. Human cord umbilical vein endothelial cells (HUVEC) were treated with cPTIO, and expression of cycloxygenase (COX) isoenzymes in terms of mRNA and protein was determined by real-time-PCR and immunoblotting. Release of PGE2 (as index of untransformed PGH2 release) and 6-oxo-PGF1alpha (PGI2 stable metabolite) was determined by enzyme-immunoassay. cPTIO significantly increases the release of untransformed PGH2 associated to the induction of COX-2 expression. Experiments with NO-synthase inhibitors and radical scavengers showed that induction of COX-2 by cPTIO was mediated by free radical species, likely caused by the mobilization of NO from cellular stores. Finally, using specific signal-transduction inhibitors we show the involvement of Src/PI3-K/PKC pathway. Additional effects other than a direct NO scavenging activity may confer therapeutic advantages to cPTIO as compared with NO-synthase inhibitors for the treatment of systemic inflammation-associated vascular hyporeactivity. PMID:22652668

  1. Licofelone--clinical update on a novel LOX/COX inhibitor for the treatment of osteoarthritis.

    PubMed

    Alvaro-Gracia, J M

    2004-02-01

    Licofelone, a competitive inhibitor of 5-lipoxygenase, cyclooxygenase (COX)-1 and COX-2, is currently in clinical development for the treatment of osteoarthritis (OA). Licofelone decreases the production of proinflammatory leukotrienes and prostaglandins-which are involved in the pathophysiology of OA and in gastrointestinal (GI) damage induced by NSAIDs-and has the potential to combine good analgesic and anti-inflammatory effects with excellent GI tolerability. Initial endoscopy data in healthy volunteers have demonstrated that licofelone is well tolerated and has a GI safety profile similar to placebo and significantly better than naproxen. These tolerability results were confirmed in patients with OA in two separate randomized studies. Furthermore, a long-term study (52 weeks) has shown that licofelone is at least as effective as naproxen in the treatment of OA. Licofelone also appears to be as effective as the selective COX-2 inhibitor celecoxib in the treatment of the signs and symptoms of OA. Licofelone has a GI safety profile similar to that of celecoxib, but may offer the advantage of fewer incidences or worsening of peripheral oedema. Preliminary data have also shown that licofelone coadministration with low-dose aspirin does not lead to increased GI toxicity. The emerging clinical data for licofelone indicate that it is an effective and well-tolerated therapy that could offer safety advantages over current treatment options, and that it could be suitable for the long-term treatment of a broad spectrum of patients with OA. PMID:14752172

  2. Kaempferol inhibits UVB-induced COX-2 expression by suppressing Src kinase activity

    PubMed Central

    Lee, Kyung Mi; Lee, Ki Won; Jung, Sung Keun; Lee, Eun Jung; Heo, Yong-Seok; Bode, Ann M.; Lubet, Ronald A.; Lee, Hyong Joo; Dong, Zigang

    2010-01-01

    Ultraviolet (UV) radiation is the primary environmental risk factor in the development of nonmelanoma skin cancer, and UVB in particular promotes tumor growth through various signaling pathways. Kaempferol, a flavonoid with anti-inflammatory and anti-oxidative properties, has been studied as a chemopreventive agent; however, little is known regarding its effects on UVB-induced photo-carcinogenesis. Here, we examined the effect of kaempferol on UVB-induced skin inflammation. We found that kaempferol suppressed UVB-induced cyclooxygenase-2 (COX-2) protein expression in mouse skin epidermal JB6 P+ cells and attenuated the UVB-induced transcriptional activities of cox-2 and activator protein-1 (AP-1). Kaempferol attenuated the UVB-induced phosphorylation of several mitogen-activated protein kinases (MAPKs), including ERKs, p38, and JNKs, but had no effect on the phosphorylation of the upstream MAPK regulator Src. However, in vitro and ex vivo kinase assays demonstrated that kaempferol suppressed Src kinase activity. Furthermore, in vivo data from mouse skin support the idea that kaempferol suppresses UVB-induced COX-2 expression by blocking Src kinase activity. A pull-down assay revealed that kaempferol competes with ATP for direct binding to Src. Docking data suggest that kaempferol docks easily into the ATP-binding site of Src, which is located between the N and C lobes of the kinase domain. Taken together, these results suggest that kaempferol is a potent chemopreventive agent against skin cancer through its inhibitory interaction with Src. PMID:20599768

  3. 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.

  4. Comparing Smoothing Techniques for Fitting the Nonlinear Effect of Covariate in Cox Models

    PubMed Central

    Roshani, Daem; Ghaderi, Ebrahim

    2016-01-01

    Background and Objective: Cox model is a popular model in survival analysis, which assumes linearity of the covariate on the log hazard function, While continuous covariates can affect the hazard through more complicated nonlinear functional forms and therefore, Cox models with continuous covariates are prone to misspecification due to not fitting the correct functional form for continuous covariates. In this study, a smooth nonlinear covariate effect would be approximated by different spline functions. Material and Methods: We applied three flexible nonparametric smoothing techniques for nonlinear covariate effect in the Cox models: penalized splines, restricted cubic splines and natural splines. Akaike information criterion (AIC) and degrees of freedom were used to smoothing parameter selection in penalized splines model. The ability of nonparametric methods was evaluated to recover the true functional form of linear, quadratic and nonlinear functions, using different simulated sample sizes. Data analysis was carried out using R 2.11.0 software and significant levels were considered 0.05. Results: Based on AIC, the penalized spline method had consistently lower mean square error compared to others to selection of smoothed parameter. The same result was obtained with real data. Conclusion: Penalized spline smoothing method, with AIC to smoothing parameter selection, was more accurate in evaluate of relation between covariate and log hazard function than other methods. PMID:27041809

  5. COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARδ activation

    PubMed Central

    Ghosh, Mallika; Wang, Haibin; Ai, Youxi; Romeo, Elisa; Luyendyk, James P.; Peters, Jeffrey M.; Mackman, Nigel; Dey, Sudhansu K.; Hla, Timothy

    2007-01-01

    Although cyclooxygenase (COX)-2 inhibitors (coxibs) are effective in controlling inflammation, pain, and tumorigenesis, their use is limited by the recent revelation of increased adverse cardiovascular events. The mechanistic basis of this side effect is not well understood. We show that the metabolism of endocannabinoids by the endothelial cell COX-2 coupled to the prostacyclin (PGI2) synthase (PGIS) activates the nuclear receptor peroxisomal proliferator–activated receptor (PPAR) δ, which negatively regulates the expression of tissue factor (TF), the primary initiator of blood coagulation. Coxibs suppress PPARδ activity and induce TF expression in vascular endothelium and elevate circulating TF activity in vivo. Importantly, PPARδ agonists suppress coxib-induced TF expression and decrease circulating TF activity. We provide evidence that COX-2–dependent attenuation of TF expression is abrogated by coxibs, which may explain the prothrombotic side-effects for this class of drugs. Furthermore, PPARδ agonists may be used therapeutically to suppress coxib-induced cardiovascular side effects. PMID:17724132

  6. CoxFey@C Composites with Tunable Atomic Ratios for Excellent Electromagnetic Absorption Properties

    PubMed Central

    Lv, Hualiang; Ji, Guangbin; Zhang, Haiqian; Li, Meng; Zuo, Zhongzheng; Zhao, Yue; Zhang, Baoshan; Tang, Dongming; Du, Youwei

    2015-01-01

    The shell on the nano-magnetic absorber can prevent oxidation, which is very important for its practical utilization. Generally, the nonmagnetic shell will decrease the integral magnetic loss and thus weaken the electromagnetic absorption. However, maintaining the original absorption properties of the magnetic core is a major challenge. Here, we designed novel and facile CoxFey@C composites by reducing CoxFe3−xO4@phenolic resin (x = 1, 0.5 and 0.25). High saturation magnetization value (Ms) of CoxFey particle, as a core, shows the interesting magnetic loss ability. Meanwhile, the carbon shell may increase the integral dielectric loss. The resulting composite shows excellent electromagnetic absorption properties. For example, at a coating thickness of 2 mm, the RLmin value can reach to −23 dB with an effective frequency range of 7 GHz (11–18 GHz). The mechanisms of the improved microwave absorption properties are discussed. PMID:26659124

  7. The Respiratory Chain Supercomplex Organization Is Independent of COX7a2l Isoforms

    PubMed Central

    Mourier, Arnaud; Matic, Stanka; Ruzzenente, Benedetta; Larsson, Nils-Göran; Milenkovic, Dusanka

    2014-01-01

    Summary The organization of individual respiratory chain complexes into supercomplexes or respirasomes has attracted great interest because of the implications for cellular energy conversion. Recently, it was reported that commonly used mouse strains harbor a short COX7a2l (SCAFI) gene isoform that supposedly precludes the formation of complex IV-containing supercomplexes. This claim potentially has serious implications for numerous mouse studies addressing important topics in metabolism, including adaptation to space flights. Using several complementary experimental approaches, we show that mice with the short COX7a2l isoform have normal biogenesis and steady-state levels of complex IV-containing supercomplexes and consequently have normal respiratory chain function. Furthermore, we use a mouse knockout of Lrpprc and show that loss of complex IV compromises respirasome formation. We conclude that the presence of the short COX7a2l isoform in the commonly used C57BL/6 mouse strains does not prevent their use in metabolism research. PMID:25470551

  8. The respiratory chain supercomplex organization is independent of COX7a2l isoforms.

    PubMed

    Mourier, Arnaud; Matic, Stanka; Ruzzenente, Benedetta; Larsson, Nils-Göran; Milenkovic, Dusanka

    2014-12-01

    The organization of individual respiratory chain complexes into supercomplexes or respirasomes has attracted great interest because of the implications for cellular energy conversion. Recently, it was reported that commonly used mouse strains harbor a short COX7a2l (SCAFI) gene isoform that supposedly precludes the formation of complex IV-containing supercomplexes. This claim potentially has serious implications for numerous mouse studies addressing important topics in metabolism, including adaptation to space flights. Using several complementary experimental approaches, we show that mice with the short COX7a2l isoform have normal biogenesis and steady-state levels of complex IV-containing supercomplexes and consequently have normal respiratory chain function. Furthermore, we use a mouse knockout of Lrpprc and show that loss of complex IV compromises respirasome formation. We conclude that the presence of the short COX7a2l isoform in the commonly used C57BL/6 mouse strains does not prevent their use in metabolism research. PMID:25470551

  9. CoxFey@C Composites with Tunable Atomic Ratios for Excellent Electromagnetic Absorption Properties

    NASA Astrophysics Data System (ADS)

    Lv, Hualiang; Ji, Guangbin; Zhang, Haiqian; Li, Meng; Zuo, Zhongzheng; Zhao, Yue; Zhang, Baoshan; Tang, Dongming; Du, Youwei

    2015-12-01

    The shell on the nano-magnetic absorber can prevent oxidation, which is very important for its practical utilization. Generally, the nonmagnetic shell will decrease the integral magnetic loss and thus weaken the electromagnetic absorption. However, maintaining the original absorption properties of the magnetic core is a major challenge. Here, we designed novel and facile CoxFey@C composites by reducing CoxFe3-xO4@phenolic resin (x = 1, 0.5 and 0.25). High saturation magnetization value (Ms) of CoxFey particle, as a core, shows the interesting magnetic loss ability. Meanwhile, the carbon shell may increase the integral dielectric loss. The resulting composite shows excellent electromagnetic absorption properties. For example, at a coating thickness of 2 mm, the RLmin value can reach to -23 dB with an effective frequency range of 7 GHz (11-18 GHz). The mechanisms of the improved microwave absorption properties are discussed.

  10. BMP-2 induces ATF4 phosphorylation in chondrocytes through a COX-2/PGE2 dependent signaling pathway

    PubMed Central

    Li, Tian-Fang; Yukata, Kiminori; Yin, Guoyong; Sheu, Tzongjen; Maruyama, Takamitsu; Jonason, Jennifer H.; Hsu, Wei; Zhang, Xinping; Xiao, Guozhi; Konttinen, Yrjo T.; Chen, Di; O’Keefe, Regis J.

    2014-01-01

    Objective BMP-2 is approved for fracture non-union and spine fusion. We aimed to further dissect its downstream signaling events in chondrocytes with the ultimate goal to develop novel therapeutics that can mimic BMP-2 effect but have less complications. Methods BMP-2 effect on COX-2 expression was examined using RT-PCR and Western blot analysis. Genetic approach was used to identify the signaling pathway mediating the BMP-2 effect. Similarly, the pathway transducing the PGE2 effect on ATF4 was investigated. Immunoprecipitation was performed to assess the complex formation after PGE2 binding. Results BMP-2 increased COX-2 expression in primary mouse costosternal chondrocytes (PMCSC). The results from the C9 Tet-off system demonstrated that endogenous BMP-2 also upregulated COX-2 expression. Genetic approaches using PMCSC from ALK2fx/fx, ALK3fx/fx, ALK6−/−, and Smad1fx/fx mice established that BMP-2 regulated COX-2 through activation of ALK3-Smad1 signaling. PGE-2 EIA showed that BMP-2 increased PGE2 production in PMCSC. ATF4 is a transcription factor that regulates bone formation. While PGE2 did not have significant effect on ATF4 expression, it induced ATF4 phosphorylation. In addition to stimulating COX-2 expression, BMP-2 also induced phosphorylation of ATF4. Using COX-2 deficient chondrocytes, we demonstrated that the BMP-2 effect on ATF4 was COX-2-dependent. Tibial fracture samples from COX-2−/− mice showed reduced phospho-ATF4 immunoreactivity compared to WT ones. PGE2 mediated ATF4 phosphorylation involved signaling primarily through the EP2 and EP4 receptors and PGE2 induced an EP4-ERK1/2-RSK2 complex formation. Conclusions BMP-2 regulates COX-2 expression through ALK3-Smad1 signaling, and PGE2 induces ATF4 phosphorylation via EP4-ERK1/2-RSK2 axis. PMID:24418675

  11. LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

    SciTech Connect

    Sun Haipeng; Xu Beibei; Sheveleva, Elena; Chen, Qin M.

    2008-10-01

    Glucocorticoids induce COX-2 expression in rat cardiomyocytes. While investigating whether phosphatidylinositol 3 kinase (PI3K) plays a role in corticosterone (CT)-induced COX-2, we found that LY294002 (LY29) but not wortmannin (WM) attenuates CT from inducing COX-2 gene expression. Expression of a dominant-negative mutant of p85 subunit of PI3K failed to inhibit CT from inducing COX-2 expression. CT did not activate PI3K/AKT signaling pathway whereas LY29 and WM decreased the activity of PI3K. LY303511 (LY30), a structural analogue and a negative control for PI3K inhibitory activity of LY29, also suppressed COX-2 induction. These data suggest PI3K-independent mechanisms in regulating CT-induced COX-2 expression. LY29 and LY30 do not inhibit glucocorticoid receptor transactivity. Both compounds have been reported to inhibit Casein Kinase 2 activity and modulate potassium and calcium levels independent of PI3K, while LY29 has been reported to inhibit mammalian Target of Rapamycin (mTOR), and DNA-dependent Protein Kinase (DNA-PK). Inhibitor of Casein Kinase 2 (CK2), mTOR or DNA-PK failed to prevent CT from inducing COX-2 expression. Tetraethylammonium (TEA), a potassium channel blocker, and nimodipine, a calcium channel blocker, both attenuated CT from inducing COX-2 gene expression. CT was found to increase intracellular Ca{sup 2+} concentration, which can be inhibited by LY29, TEA or nimodipine. These data suggest a possible role of calcium instead of PI3K in CT-induced COX-2 expression in cardiomyocytes.

  12. LY294002 Inhibits Glucocorticoid Induced COX-2 Gene Expression in Cardiomyocytes through a Phosphatidylinositol 3 Kinase Independent Mechanism

    PubMed Central

    Sun, Haipeng; Xu, Beibei; Sheveleva, Elena; Chen, Qin M.

    2014-01-01

    Glucocorticoids induce COX-2 expression in rat cardiomyocytes. While investigating whether phosphatidylinositol 3 kinase (PI3K) plays a role in corticosterone (CT) induced COX-2, we found that LY294002 (LY29) but not wortmannin (WM) attenuates CT from inducing COX-2 gene expression. Expression of a dominant-negative mutant of p85 subunit of PI3K failed to inhibit CT from inducing COX-2 expression. CT did not activate PI3K/AKT signaling pathway whereas LY29 and WM decreased the activity of PI3K. LY303511 (LY30), a structural analogue and a negative control for PI3K inhibitory activity of LY29, also suppressed COX-2 induction. These data suggest PI3K independent mechanisms in regulating CT induced COX-2 expression. LY29 and LY30 do not inhibit glucocorticoid receptor transactivity. Both compounds have been reported to inhibit Casein Kinase 2 activity and modulate potassium and calcium levels independent of PI3K, while LY29 has been reported to inhibit mammalian Target of Rapamycin (mTOR), DNA-dependent Protein Kinase (DNA-PK). Inhibitor of Casein Kinase 2 (CK2), mTOR or DNA-PK failed to prevent CT from inducing COX-2 expression. Tetraethylammonium (TEA), a potassium channel blocker, and nimodipine, a calcium channel blocker, both attenuated CT from inducing COX-2 gene expression. CT was found to increase intracellular Ca2+ concentration, which can be inhibited by LY29, TEA or nimodipine. These data suggest a possible role of calcium instead of PI3K in CT induced COX-2 expression in cardiomyocytes. PMID:18657281

  13. Regression models for estimating coseismic landslide displacement

    USGS Publications Warehouse

    Jibson, R.W.

    2007-01-01

    Newmark's sliding-block model is widely used to estimate coseismic slope performance. Early efforts to develop simple regression models to estimate Newmark displacement were based on analysis of the small number of strong-motion records then available. The current availability of a much larger set of strong-motion records dictates that these regression equations be updated. Regression equations were generated using data derived from a collection of 2270 strong-motion records from 30 worldwide earthquakes. The regression equations predict Newmark displacement in terms of (1) critical acceleration ratio, (2) critical acceleration ratio and earthquake magnitude, (3) Arias intensity and critical acceleration, and (4) Arias intensity and critical acceleration ratio. These equations are well constrained and fit the data well (71% < R2 < 88%), but they have standard deviations of about 0.5 log units, such that the range defined by the mean ?? one standard deviation spans about an order of magnitude. These regression models, therefore, are not recommended for use in site-specific design, but rather for regional-scale seismic landslide hazard mapping or for rapid preliminary screening of sites. ?? 2007 Elsevier B.V. All rights reserved.

  14. Hierarchical regression for analyses of multiple outcomes.

    PubMed

    Richardson, David B; Hamra, Ghassan B; MacLehose, Richard F; Cole, Stephen R; Chu, Haitao

    2015-09-01

    In cohort mortality studies, there often is interest in associations between an exposure of primary interest and mortality due to a range of different causes. A standard approach to such analyses involves fitting a separate regression model for each type of outcome. However, the statistical precision of some estimated associations may be poor because of sparse data. In this paper, we describe a hierarchical regression model for estimation of parameters describing outcome-specific relative rate functions and associated credible intervals. The proposed model uses background stratification to provide flexible control for the outcome-specific associations of potential confounders, and it employs a hierarchical "shrinkage" approach to stabilize estimates of an exposure's associations with mortality due to different causes of death. The approach is illustrated in analyses of cancer mortality in 2 cohorts: a cohort of dioxin-exposed US chemical workers and a cohort of radiation-exposed Japanese atomic bomb survivors. Compared with standard regression estimates of associations, hierarchical regression yielded estimates with improved precision that tended to have less extreme values. The hierarchical regression approach also allowed the fitting of models with effect-measure modification. The proposed hierarchical approach can yield estimates of association that are more precise than conventional estimates when one wishes to estimate associations with multiple outcomes. PMID:26232395

  15. Discovery and Replication of Gene Influences on Brain Structure Using LASSO Regression.

    PubMed

    Kohannim, Omid; Hibar, Derrek P; Stein, Jason L; Jahanshad, Neda; Hua, Xue; Rajagopalan, Priya; Toga, Arthur W; Jack, Clifford R; Weiner, Michael W; de Zubicaray, Greig I; McMahon, Katie L; Hansell, Narelle K; Martin, Nicholas G; Wright, Margaret J; Thompson, Paul M

    2012-01-01

    We implemented least absolute shrinkage and selection operator (LASSO) regression to evaluate gene effects in genome-wide association studies (GWAS) of brain images, using an MRI-derived temporal lobe volume measure from 729 subjects scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sparse groups of SNPs in individual genes were selected by LASSO, which identifies efficient sets of variants influencing the data. These SNPs were considered jointly when assessing their association with neuroimaging measures. We discovered 22 genes that passed genome-wide significance for influencing temporal lobe volume. This was a substantially greater number of significant genes compared to those found with standard, univariate GWAS. These top genes are all expressed in the brain and include genes previously related to brain function or neuropsychiatric disorders such as MACROD2, SORCS2, GRIN2B, MAGI2, NPAS3, CLSTN2, GABRG3, NRXN3, PRKAG2, GAS7, RBFOX1, ADARB2, CHD4, and CDH13. The top genes we identified with this method also displayed significant and widespread post hoc effects on voxelwise, tensor-based morphometry (TBM) maps of the temporal lobes. The most significantly associated gene was an autism susceptibility gene known as MACROD2. We were able to successfully replicate the effect of the MACROD2 gene in an independent cohort of 564 young, Australian healthy adult twins and siblings scanned with MRI (mean age: 23.8 ± 2.2 SD years). Our approach powerfully complements univariate techniques in detecting influences of genes on the living brain. PMID:22888310

  16. 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. PMID:26319435

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

    PubMed Central

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

    2015-01-01

    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, 0.040.011M; m-NOSH-ASA, 0.240.11M; p-NOSH-ASA, 0.460.17M; and in HCT 15 cells the IC50s for o-NOSH-ASA, m-NOSH-ASA, and p-NOSH-ASA were 0.062 0.006M, 0.0920.004M, and 0.370.04M, 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. PMID:26319435

  18. Backpropagation and regression: comparative utility for neuropsychologists.

    PubMed

    Parsons, Thomas D; Rizzo, Albert A; Buckwalter, J Galen

    2004-02-01

    The aim of this research was to compare the data analytic applicability of a backpropagated neural network with that of regression analysis. Thirty individuals between the ages of 64 and 86 (Mean age = 73.6; Mean years education = 15.4; % women = 50) participated in a study designed to validate a new test of spatial ability administered in virtual reality. As part of this project a standard neuropsychological battery was administered. Results from the multiple regression model R(2) = .21, p < .28; Standard Error = 18.01) were compared with those of a backpropagated ANN (R(2) = .39, p < .02; Standard Error = 13.07). This 18% increase in prediction of a common neuropsychological problem demonstrated that an ANN has the potential to outperform a regression. PMID:14972697

  19. Uncertainty quantification in DIC with Kriging regression

    NASA Astrophysics Data System (ADS)

    Wang, Dezhi; DiazDelaO, F. A.; Wang, Weizhuo; Lin, Xiaoshan; Patterson, Eann A.; Mottershead, John E.

    2016-03-01

    A Kriging regression model is developed as a post-processing technique for the treatment of measurement uncertainty in classical subset-based Digital Image Correlation (DIC). Regression is achieved by regularising the sample-point correlation matrix using a local, subset-based, assessment of the measurement error with assumed statistical normality and based on the Sum of Squared Differences (SSD) criterion. This leads to a Kriging-regression model in the form of a Gaussian process representing uncertainty on the Kriging estimate of the measured displacement field. The method is demonstrated using numerical and experimental examples. Kriging estimates of displacement fields are shown to be in excellent agreement with 'true' values for the numerical cases and in the experimental example uncertainty quantification is carried out using the Gaussian random process that forms part of the Kriging model. The root mean square error (RMSE) on the estimated displacements is produced and standard deviations on local strain estimates are determined.

  20. Efficient Regressions via Optimally Combining Quantile Information*

    PubMed Central

    Zhao, Zhibiao; Xiao, Zhijie

    2014-01-01

    We develop a generally applicable framework for constructing efficient estimators of regression models via quantile regressions. The proposed method is based on optimally combining information over multiple quantiles and can be applied to a broad range of parametric and nonparametric settings. When combining information over a fixed number of quantiles, we derive an upper bound on the distance between the efficiency of the proposed estimator and the Fisher information. As the number of quantiles increases, this upper bound decreases and the asymptotic variance of the proposed estimator approaches the Cramér-Rao lower bound under appropriate conditions. In the case of non-regular statistical estimation, the proposed estimator leads to super-efficient estimation. We illustrate the proposed method for several widely used regression models. Both asymptotic theory and Monte Carlo experiments show the superior performance over existing methods. PMID:25484481

  1. Pipe performance analysis with nonparametric regression

    NASA Astrophysics Data System (ADS)

    Liu, Zheng; Hu, Yafei; Wu, Wei

    2011-04-01

    Asbestos cement (AC) water mains were installed extensively in North America, Europe, and Australia during 1920s-1980s and subject to a high breakage rate in recent years in some utilities. It is essential to understand how the influential factors contribute to the degradation and failure of AC pipes. The historical failure data collected from twenty utilities are used in this study to explore the correlation between pipe condition and its working environment. In this paper, we applied four nonparametric regression methods to model the relationship between pipe failure represented by average break rates and influential variables including pipe age and internal and external working environmental parameters. The nonparametric regression models do not take a predetermined form but it needs information derived from data. The feasibility of using a nonparametric regression model for the condition assessment of AC pipes is investigated and understood.

  2. Effects of COX-2 inhibition on spinal nociception: the role of endocannabinoids

    PubMed Central

    Staniaszek, LE; Norris, LM; Kendall, DA; Barrett, DA; Chapman, V

    2010-01-01

    Background and purpose: Recent studies suggest that the effects of cyclooxygenase-2 (COX-2) inhibition are mediated by cannabinoid receptor activation. However, some non-steroidal anti-inflammatory drugs inhibit the enzyme fatty acid amide hydrolase, which regulates levels of some endocannabinoids. Whether COX-2 directly regulates levels of endocannabinoids in vivo is unclear. Here, the effect of the COX-2 inhibitor nimesulide, which does not inhibit fatty acid amide hydrolase, on spinal nociceptive processing was determined. Effects of nimesulide on tissue levels of endocannabinoids and related compounds were measured and the role of cannabinoid 1 (CB1) receptors was determined. Experimental approach: Effects of spinal and peripheral administration of nimesulide (1–100 µg per 50 µL) on mechanically evoked responses of rat dorsal horn neurones were measured, and the contribution of the CB1 receptor was determined with the antagonist AM251 (N-(piperidin-1-yl)-5-(-4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), in anaesthetized rats. Effects of nimesulide on spinal levels of endocannabinoids and related compounds were quantified using liquid chromatography-tandem mass spectrometry. Key results: Spinal, but not peripheral, injection of nimesulide (1–100 µg per 50 µL) significantly reduced mechanically evoked responses of dorsal horn neurones. Inhibitory effects of spinal nimesulide were blocked by the CB1 receptor antagonist AM251 (1 µg per 50 µL), but spinal levels of endocannabinoids were not elevated. Indeed, both anandamide and N-oleoylethanolamide (OEA) were significantly decreased by nimesulide. Conclusions and implications: Although the inhibitory effects of COX-2 blockade on spinal neuronal responses by nimesulide were dependent on CB1 receptors, we did not detect a concomitant elevation in anandamide or 2-AG. Further understanding of the complexities of endocannabinoid catabolism by multiple enzymes is essential to understand their contribution to COX-2-mediated analgesia. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x PMID:20590570

  3. Type I Error Rates and Statistical Power for the James Second-Order Test and the Univariate F Test in Two-Way Fixed-Effects ANOVA Models under Heteroscedasticity and/or Nonnormality.

    ERIC Educational Resources Information Center

    Hsiung, Tung-Hsing; Olejnik, Stephen

    This study investigated the robustness of the James second-order test (James 1951; Wilcox, 1989) and the univariate F test under a two-factor fixed-effect analysis of variance (ANOVA) model in which cell variances were heterogeneous and/or distributions were nonnormal. With computer-simulated data, Type I error rates and statistical power for the…

  4. Type I Error Rates and Statistical Power for the James Second-Order Test and the Univariate F Test in Two-Way Fixed-Effects ANOVA Models under Heteroscedasticity and/or Nonnormality.

    ERIC Educational Resources Information Center

    Hsiung, Tung-Hsing; Olejnik, Stephen

    1996-01-01

    Type I error rates and statistical power for the univariate F test and the James second-order test were estimated for the two-factor fixed-effects completely randomized design. Results reveal that the F test Type I error rate can exceed the nominal significance level when cell variances differ. (SLD)

  5. A tutorial on Bayesian Normal linear regression

    NASA Astrophysics Data System (ADS)

    Klauenberg, Katy; Wübbeler, Gerd; Mickan, Bodo; Harris, Peter; Elster, Clemens

    2015-12-01

    Regression is a common task in metrology and often applied to calibrate instruments, evaluate inter-laboratory comparisons or determine fundamental constants, for example. Yet, a regression model cannot be uniquely formulated as a measurement function, and consequently the Guide to the Expression of Uncertainty in Measurement (GUM) and its supplements are not applicable directly. Bayesian inference, however, is well suited to regression tasks, and has the advantage of accounting for additional a priori information, which typically robustifies analyses. Furthermore, it is anticipated that future revisions of the GUM shall also embrace the Bayesian view. Guidance on Bayesian inference for regression tasks is largely lacking in metrology. For linear regression models with Gaussian measurement errors this tutorial gives explicit guidance. Divided into three steps, the tutorial first illustrates how a priori knowledge, which is available from previous experiments, can be translated into prior distributions from a specific class. These prior distributions have the advantage of yielding analytical, closed form results, thus avoiding the need to apply numerical methods such as Markov Chain Monte Carlo. Secondly, formulas for the posterior results are given, explained and illustrated, and software implementations are provided. In the third step, Bayesian tools are used to assess the assumptions behind the suggested approach. These three steps (prior elicitation, posterior calculation, and robustness to prior uncertainty and model adequacy) are critical to Bayesian inference. The general guidance given here for Normal linear regression tasks is accompanied by a simple, but real-world, metrological example. The calibration of a flow device serves as a running example and illustrates the three steps. It is shown that prior knowledge from previous calibrations of the same sonic nozzle enables robust predictions even for extrapolations.

  6. Topics in route-regression analysis

    USGS Publications Warehouse

    Geissler, P.H.; Sauer, J.R.

    1990-01-01

    The route-regression method has been used in recent years to analyze data from roadside surveys. With this method, a population trend is estimated for each route in a region, then regional trends are estimated as a weighted mean of the individual route trends. This method can accurately incorporate data that is unbalanced by changes in years surveyed and observer differences. We suggest that route-regression methodology is most efficient in the estimation of long-term (>5 year) trends, and tends to provide conservative results for low-density species.

  7. Heritability Estimation using Regression Models for Correlation

    PubMed Central

    Lee, Hye-Seung; Paik, Myunghee Cho; Rundek, Tatjana; Sacco, Ralph L; Dong, Chuanhui; Krischer, Jeffrey P

    2012-01-01

    Heritability estimates a polygenic effect on a trait for a population. Reliable interpretation of heritability is critical in planning further genetic studies to locate a gene responsible for the trait. This study accommodates both single and multiple trait cases by employing regression models for correlation parameter to infer the heritability. Sharing the properties of regression approach, the proposed methods are exible to incorporate non-genetic and/or non-additive genetic information in the analysis. The performances of the proposed model are compared with those using the likelihood approach through simulations and carotid Intima Media Thickness analysis from Northern Manhattan family Study. PMID:22457844

  8. Characterizing and estimating rice brown spot disease severity using stepwise regression, principal component regression and partial least-square regression.

    PubMed

    Liu, Zhan-yu; Huang, Jing-feng; Shi, Jing-jing; Tao, Rong-xiang; Zhou, Wan; Zhang, Li-Li

    2007-10-01

    Detecting plant health conditions plays a key role in farm pest management and crop protection. In this study, measurement of hyperspectral leaf reflectance in rice crop (Oryzasativa L.) was conducted on groups of healthy and infected leaves by the fungus Bipolaris oryzae (Helminthosporium oryzae Breda. de Hann) through the wavelength range from 350 to 2,500 nm. The percentage of leaf surface lesions was estimated and defined as the disease severity. Statistical methods like multiple stepwise regression, principal component analysis and partial least-square regression were utilized to calculate and estimate the disease severity of rice brown spot at the leaf level. Our results revealed that multiple stepwise linear regressions could efficiently estimate disease severity with three wavebands in seven steps. The root mean square errors (RMSEs) for training (n=210) and testing (n=53) dataset were 6.5% and 5.8%, respectively. Principal component analysis showed that the first principal component could explain approximately 80% of the variance of the original hyperspectral reflectance. The regression model with the first two principal components predicted a disease severity with RMSEs of 16.3% and 13.9% for the training and testing dataset, respectively. Partial least-square regression with seven extracted factors could most effectively predict disease severity compared with other statistical methods with RMSEs of 4.1% and 2.0% for the training and testing dataset, respectively. Our research demonstrates that it is feasible to estimate the disease severity of rice brown spot using hyperspectral reflectance data at the leaf level. PMID:17910117

  9. Demonstration of a Fiber Optic Regression Probe

    NASA Technical Reports Server (NTRS)

    Korman, Valentin; Polzin, Kurt A.

    2010-01-01

    The capability to provide localized, real-time monitoring of material regression rates in various applications has the potential to provide a new stream of data for development testing of various components and systems, as well as serving as a monitoring tool in flight applications. These applications include, but are not limited to, the regression of a combusting solid fuel surface, the ablation of the throat in a chemical rocket or the heat shield of an aeroshell, and the monitoring of erosion in long-life plasma thrusters. The rate of regression in the first application is very fast, while the second and third are increasingly slower. A recent fundamental sensor development effort has led to a novel regression, erosion, and ablation sensor technology (REAST). The REAST sensor allows for measurement of real-time surface erosion rates at a discrete surface location. The sensor is optical, using two different, co-located fiber-optics to perform the regression measurement. The disparate optical transmission properties of the two fiber-optics makes it possible to measure the regression rate by monitoring the relative light attenuation through the fibers. As the fibers regress along with the parent material in which they are embedded, the relative light intensities through the two fibers changes, providing a measure of the regression rate. The optical nature of the system makes it relatively easy to use in a variety of harsh, high temperature environments, and it is also unaffected by the presence of electric and magnetic fields. In addition, the sensor could be used to perform optical spectroscopy on the light emitted by a process and collected by fibers, giving localized measurements of various properties. The capability to perform an in-situ measurement of material regression rates is useful in addressing a variety of physical issues in various applications. An in-situ measurement allows for real-time data regarding the erosion rates, providing a quick method for empirically anchoring any analysis geared towards lifetime qualification. Erosion rate data over an operating envelope could also be useful in the modeling detailed physical processes. The sensor has been embedded in many regressing media for the purposes of proof-of-concept testing. A gross demonstration of its capabilities was performed using a sanding wheel to remove layers of metal. A longer-term demonstration measurement involved the placement of the sensor in a brake pad, monitoring the removal of pad material associated with the normal wear-and-tear of driving. It was used to measure the regression rates of the combustable media in small model rocket motors and road flares. Finally, a test was performed using a sand blaster to remove small amounts of material at a time. This test was aimed at demonstrating the unit's present resolution, and is compared with laser profilometry data obtained simultaneously. At the lowest resolution levels, this unit should be useful in locally quantifying the erosion rates of the channel walls in plasma thrusters. .

  10. Development of Antioxidant COX-2 Inhibitors as Radioprotective Agents for Radiation Therapy-A Hypothesis-Driven Review.

    PubMed

    Laube, Markus; Kniess, Torsten; Pietzsch, Jens

    2016-01-01

    Radiation therapy (RT) evolved to be a primary treatment modality for cancer patients. Unfortunately, the cure or relief of symptoms is still accompanied by radiation-induced side effects with severe acute and late pathophysiological consequences. Inhibitors of cyclooxygenase-2 (COX-2) are potentially useful in this regard because radioprotection of normal tissue and/or radiosensitizing effects on tumor tissue have been described for several compounds of this structurally diverse class. This review aims to substantiate the hypothesis that antioxidant COX-2 inhibitors are promising radioprotectants because of intercepting radiation-induced oxidative stress and inflammation in normal tissue, especially the vascular system. For this, literature reporting on COX inhibitors exerting radioprotective and/or radiosensitizing action as well as on antioxidant COX inhibitors will be reviewed comprehensively with the aim to find cross-points of both and, by that, stimulate further research in the field of radioprotective agents. PMID:27104573

  11. Locating the Extrema of Fungible Regression Weights

    ERIC Educational Resources Information Center

    Waller, Niels G.; Jones, Jeff A.

    2009-01-01

    In a multiple regression analysis with three or more predictors, every set of alternate weights belongs to an infinite class of "fungible weights" (Waller, Psychometrica, "in press") that yields identical "SSE" (sum of squared errors) and R[superscript 2] values. When the R[superscript 2] using the alternate weights is a fixed value, fungible

  12. Suppressor Variables in Multiple Regression/Correlation.

    ERIC Educational Resources Information Center

    Smith, Richard L.; And Others

    1992-01-01

    Different approaches to defining suppression in multiple regression/correlation are compared, and their differences are illustrated. A test for determining the significance of a suppressor effect, which is based on the definition of suppression of W. F. Velicer, is extended to the general multiple predictor case and analysis of variance. (SLD)

  13. Change Scores and Regression Suppressor Conditions.

    ERIC Educational Resources Information Center

    Glasnapp, Douglas R.

    1984-01-01

    The concept of change is related to suppressor variable conditions in a least square regression model. The domain of conditions necessary for a weighted change score composite to emerge as an underlying construct is mapped and the information loss through arbitrary assignment of weights to a change composite is explored. (Author/BW)

  14. Moving the Bar: Transformations in Linear Regression.

    ERIC Educational Resources Information Center

    Miranda, Janet

    The assumption that is most important to the hypothesis testing procedure of multiple linear regression is the assumption that the residuals are normally distributed, but this assumption is not always tenable given the realities of some data sets. When normal distribution of the residuals is not met, an alternative method can be initiated. As an…

  15. A Constrained Linear Estimator for Multiple Regression

    ERIC Educational Resources Information Center

    Davis-Stober, Clintin P.; Dana, Jason; Budescu, David V.

    2010-01-01

    "Improper linear models" (see Dawes, Am. Psychol. 34:571-582, "1979"), such as equal weighting, have garnered interest as alternatives to standard regression models. We analyze the general circumstances under which these models perform well by recasting a class of "improper" linear models as "proper" statistical models with a single predictor. We…

  16. Predicting Social Trust with Binary Logistic Regression

    ERIC Educational Resources Information Center

    Adwere-Boamah, Joseph; Hufstedler, Shirley

    2015-01-01

    This study used binary logistic regression to predict social trust with five demographic variables from a national sample of adult individuals who participated in The General Social Survey (GSS) in 2012. The five predictor variables were respondents' highest degree earned, race, sex, general happiness and the importance of personally assisting…

  17. Assessing risk factors for periodontitis using regression

    NASA Astrophysics Data System (ADS)

    Lobo Pereira, J. A.; Ferreira, Maria Cristina; Oliveira, Teresa

    2013-10-01

    Multivariate statistical analysis is indispensable to assess the associations and interactions between different factors and the risk of periodontitis. Among others, regression analysis is a statistical technique widely used in healthcare to investigate and model the relationship between variables. In our work we study the impact of socio-demographic, medical and behavioral factors on periodontal health. Using regression, linear and logistic models, we can assess the relevance, as risk factors for periodontitis disease, of the following independent variables (IVs): Age, Gender, Diabetic Status, Education, Smoking status and Plaque Index. The multiple linear regression analysis model was built to evaluate the influence of IVs on mean Attachment Loss (AL). Thus, the regression coefficients along with respective p-values will be obtained as well as the respective p-values from the significance tests. The classification of a case (individual) adopted in the logistic model was the extent of the destruction of periodontal tissues defined by an Attachment Loss greater than or equal to 4 mm in 25% (AL≥4mm/≥25%) of sites surveyed. The association measures include the Odds Ratios together with the correspondent 95% confidence intervals.

  18. A Spline Regression Model for Latent Variables

    ERIC Educational Resources Information Center

    Harring, Jeffrey R.

    2014-01-01

    Spline (or piecewise) regression models have been used in the past to account for patterns in observed data that exhibit distinct phases. The changepoint or knot marking the shift from one phase to the other, in many applications, is an unknown parameter to be estimated. As an extension of this framework, this research considers modeling the…

  19. REGRESSION METHODS FOR DATA WITH INCOMPLETE COVARIATES

    EPA Science Inventory

    Modern statistical methods in chronic disease epidemiology allow simultaneous regression of disease status on several covariates. hese methods permit examination of the effects of one covariate while controlling for those of others that may be causally related to the disease. owe...

  20. Genetics Home Reference: caudal regression syndrome

    MedlinePlus

    ... disorder. Some researchers believe that a disruption of fetal development around day 28 of pregnancy causes caudal regression ... away from the lower areas of the developing fetus. Decreased blood flow to these areas is thought to interfere with their development and result in the signs and symptoms of ...

  1. Revisiting Regression in Autism: Heller's "Dementia Infantilis"

    ERIC Educational Resources Information Center

    Westphal, Alexander; Schelinski, Stefanie; Volkmar, Fred; Pelphrey, Kevin

    2013-01-01

    Theodor Heller first described a severe regression of adaptive function in normally developing children, something he termed dementia infantilis, over one 100 years ago. Dementia infantilis is most closely related to the modern diagnosis, childhood disintegrative disorder. We translate Heller's paper, Uber Dementia Infantilis, and discuss…

  2. Student Selection and the Special Regression Model.

    ERIC Educational Resources Information Center

    Deck, Dennis D.

    The feasibility of constructing composite scores which will yield pretest measures having all the properties required by the special regression model is explored as an alternative to the single pretest score usually used in student selection for Elementary Secondary Education Act Title I compensatory education programs. Reading data, including…

  3. A Skew-Normal Mixture Regression Model

    ERIC Educational Resources Information Center

    Liu, Min; Lin, Tsung-I

    2014-01-01

    A challenge associated with traditional mixture regression models (MRMs), which rest on the assumption of normally distributed errors, is determining the number of unobserved groups. Specifically, even slight deviations from normality can lead to the detection of spurious classes. The current work aims to (a) examine how sensitive the commonly…

  4. Creativity and Regression on the Rorschach.

    ERIC Educational Resources Information Center

    Lazar, Billie S.

    This paper describes the results of a study to further test and replicate previous studies partially supporting Kris's view that creativity is a regression in the service of the ego. For this sample of 42 female art and business college students, it was predicted that (1) highly creative Ss (measured by the Torrance Tests) produce more, and more…

  5. Assumptions of Multiple Regression: Correcting Two Misconceptions

    ERIC Educational Resources Information Center

    Williams, Matt N.; Gomez Grajales, Carlos Alberto; Kurkiewicz, Dason

    2013-01-01

    In 2002, an article entitled "Four assumptions of multiple regression that researchers should always test" by Osborne and Waters was published in "PARE." This article has gone on to be viewed more than 275,000 times (as of August 2013), and it is one of the first results displayed in a Google search for "regression…

  6. Categorical Variables in Multiple Regression: Some Cautions.

    ERIC Educational Resources Information Center

    O'Grady, Kevin E.; Medoff, Deborah R.

    1988-01-01

    Limitations of dummy coding and nonsense coding as methods of coding categorical variables for use as predictors in multiple regression analysis are discussed. The combination of these approaches often yields estimates and tests of significance that are not intended by researchers for inclusion in their models. (SLD)

  7. A Skew-Normal Mixture Regression Model

    ERIC Educational Resources Information Center

    Liu, Min; Lin, Tsung-I

    2014-01-01

    A challenge associated with traditional mixture regression models (MRMs), which rest on the assumption of normally distributed errors, is determining the number of unobserved groups. Specifically, even slight deviations from normality can lead to the detection of spurious classes. The current work aims to (a) examine how sensitive the commonly

  8. Bootstrap inference longitudinal semiparametric regression model

    NASA Astrophysics Data System (ADS)

    Pane, Rahmawati; Otok, Bambang Widjanarko; Zain, Ismaini; Budiantara, I. Nyoman

    2016-02-01

    Semiparametric regression contains two components, i.e. parametric and nonparametric component. Semiparametric regression model is represented by yt i=μ (x˜'ti,zt i)+εt i where μ (x˜'ti,zt i)=x˜'tiβ ˜+g (zt i) and yti is response variable. It is assumed to have a linear relationship with the predictor variables x˜'ti=(x1 i 1,x2 i 2,…,xT i r) . Random error εti, i = 1, …, n, t = 1, …, T is normally distributed with zero mean and variance σ2 and g(zti) is a nonparametric component. The results of this study showed that the PLS approach on longitudinal semiparametric regression models obtain estimators β˜^t=[X'H(λ)X]-1X'H(λ )y ˜ and g˜^λ(z )=M (λ )y ˜ . The result also show that bootstrap was valid on longitudinal semiparametric regression model with g^λ(b )(z ) as nonparametric component estimator.

  9. Evaluating Aptness of a Regression Model

    ERIC Educational Resources Information Center

    Matson, Jack E.; Huguenard, Brian R.

    2007-01-01

    The data for 104 software projects is used to develop a linear regression model that uses function points (a measure of software project size) to predict development effort. The data set is particularly interesting in that it violates several of the assumptions required of a linear model; but when the data are transformed, the data set satisfies…

  10. Semiparametric Allelic Tests for Mapping Multiple Phenotypes: Binomial Regression and Mahalanobis Distance.

    PubMed

    Majumdar, Arunabha; Witte, John S; Ghosh, Saurabh

    2015-12-01

    Binary phenotypes commonly arise due to multiple underlying quantitative precursors and genetic variants may impact multiple traits in a pleiotropic manner. Hence, simultaneously analyzing such correlated traits may be more powerful than analyzing individual traits. Various genotype-level methods, e.g., MultiPhen (O'Reilly et al. []), have been developed to identify genetic factors underlying a multivariate phenotype. For univariate phenotypes, the usefulness and applicability of allele-level tests have been investigated. The test of allele frequency difference among cases and controls is commonly used for mapping case-control association. However, allelic methods for multivariate association mapping have not been studied much. In this article, we explore two allelic tests of multivariate association: one using a Binomial regression model based on inverted regression of genotype on phenotype (Binomial regression-based Association of Multivariate Phenotypes [BAMP]), and the other employing the Mahalanobis distance between two sample means of the multivariate phenotype vector for two alleles at a single-nucleotide polymorphism (Distance-based Association of Multivariate Phenotypes [DAMP]). These methods can incorporate both discrete and continuous phenotypes. Some theoretical properties for BAMP are studied. Using simulations, the power of the methods for detecting multivariate association is compared with the genotype-level test MultiPhen's. The allelic tests yield marginally higher power than MultiPhen for multivariate phenotypes. For one/two binary traits under recessive mode of inheritance, allelic tests are found to be substantially more powerful. All three tests are applied to two different real data and the results offer some support for the simulation study. We propose a hybrid approach for testing multivariate association that implements MultiPhen when Hardy-Weinberg Equilibrium (HWE) is violated and BAMP otherwise, because the allelic approaches assume HWE. PMID:26493781

  11. Neuroprotection mediated by the EP₄ receptor avoids the detrimental side effects of COX-2 inhibitors following ischaemic injury.

    PubMed

    Akram, Asha; Gibson, Claire L; Grubb, Blair D

    2013-02-01

    Although COX-2 inhibition in animal models of ischaemia has shown neuroprotection, clinical trials revealed long term side effects with COX-2 inhibitors. A more focussed approach is necessary to retain the therapeutic effects of prostaglandins. This study investigated the role of the PGE(2) EP(4) receptor using both in vitro and in vivo models of ischaemia. To demonstrate whether targeting the EP(4) receptor is as neuroprotective as COX-2 inhibition, simultaneous experiments were carried out using a selective COX-2 inhibitor. Organotypic hippocampal sliced cultures, exposed to 2 h of oxygen glucose deprivation, were treated with; DMSO only, COX-2 inhibitor (NS-398), EP(4) agonist (L-902688) or EP(4) antagonist (GW627368X) and cell death was assessed. The EP(4) agonist and the COX-2 inhibitor significantly reduced cell death following in vitro ischaemia, whereas treatment with the EP(4) antagonist significantly increased cell death in hippocampal cultures. Following a 1 h occlusion of middle cerebral artery, mice were treated with the COX-2 inhibitor (10 mg kg, I.P), EP(4) agonist (0.75 μg/kg, I.P) or vehicle (I.P), at the onset of reperfusion and again at 24 h post stroke. The COX-2 inhibitor and EP(4) agonist treated animals showed a significant reduction in infarct volume (P < .05) at 48 h post stroke compared to the vehicle treated group. These results show that selective activation of the EP(4) receptor following acute ischaemic damage is neuroprotective, and support the concept of targeting protective prostaglandin receptor signalling as a potential therapeutic target for cerebral stroke. PMID:23041537

  12. T-614, a novel antirheumatic drug, inhibits both the activity and induction of cyclooxygenase-2 (COX-2) in cultured fibroblasts.

    PubMed

    Tanaka, K; Kawasaki, H; Kurata, K; Aikawa, Y; Tsukamoto, Y; Inaba, T

    1995-04-01

    To elucidate the mechanism for the selective inhibition of prostaglandin E2 (PGE2) production in inflammatory tissue by T-614 (3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-o ne), its effects on both the activity and the induction of cyclooxygenase (COX)-2 were investigated in vitro. T-614 inhibited the activity of purified COX-2 enzyme (IC50: 7.7 micrograms/ml), but was inactive against both COX-1 activities of microsomal and purified enzymes (IC50: > 300 micrograms/ml). On the other hand, when the inhibition of PGE2 production by T-614 was examined in the cultured fibroblasts stimulated with bradykinin, T-614 at 1 microgram/ml or less inhibited PGE2 release more effectively than that in the above cell-free system. Therefore, we examined which of the COX enzymes was expressed in bradykinin-stimulated fibroblasts by using both the reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blot analyses. As a result, COX-1 mRNA was constitutively expressed in the cells, whereas COX-2 mRNA was not detected without stimulation with bradykinin, but was expressed within 30 min when stimulated. Furthermore, it was found that the addition of T-614 reduced the COX-2 mRNA levels in 30 min after stimulation. These studies suggest that at least some of inhibitory effects of T-614 on prostanoids production are mediated by the synergy of the inhibition of COX-2 activity and the inhibition of induction, and such an action of T-614 may explain the pharmacological properties of this drug. PMID:7650864

  13. Synthesis, biological evaluation and docking analysis of a new series of methylsulfonyl and sulfamoyl acetamides and ethyl acetates as potent COX-2 inhibitors.

    PubMed

    Consalvi, Sara; Alfonso, Salvatore; Di Capua, Angela; Poce, Giovanna; Pirolli, Adele; Sabatino, Manuela; Ragno, Rino; Anzini, Maurizio; Sartini, Stefania; La Motta, Concettina; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Biava, Mariangela

    2015-02-15

    We report herein the synthesis, biological evaluation and docking analysis of a new series of methylsulfonyl, sulfamoyl acetamides and ethyl acetates that selectively inhibit cyclooxygenase-2 (COX-2) isoform. Among the newly synthesized compounds, some of them were endowed with a good activity against COX-2 and a good selectivity COX-2/COX-1 in vitro as well as a desirable analgesic activity in vivo, proving that replacement of the ester moiety with an amide group gave access to more stable derivatives, characterized by a good COX-inhibition. PMID:25596758

  14. Ultrastructural and immunohistochemical analysis of rat uroepithelial cell junctions after partial bladder outlet obstruction and selective COX-2 inhibitor treatment.

    PubMed

    Celik-Ozenci, Ciler; Ustunel, Ismail; Erdogru, Tibet; Seval, Yasemin; Korgun, Emin Turkay; Baykara, Mehmet; Demir, Ramazan

    2006-01-01

    The present study was undertaken to evaluate alterations in uroepithelial cell junctional complexes in partial bladder outlet obstruction (PBOO) of rat bladders using ultrastructural morphometry and immunohistochemistry, and to determine whether selective COX-2 inhibitors have any effects on these structures. A total of 18 male rats were separated into three groups of six rats each: (1) sham-operated animals served as controls; (2) a PBOO group, without further treatment (3) and a group that immediately after PBOO, received treatment for 4 weeks with oral Celecoxib, a selective COX-2 inhibitor. Uroepithelial cell junctions were evaluated using transmission electron microscopy combined with morphometry. Results were also assessed by E-cadherin and alpha-catenin immunohistochemistry. Morphometrical analysis of ultrastructural evaluations revealed that 4 weeks of PBOO caused a significant reduction in the electron density of zonula adherens and zonula occludens junctional complexes. Moreover, some desmosomes located between the deeper cells of the uroepithelium showed signs of disintegration. Selective COX-2 inhibitor treatment during 4 weeks of PBOO showed protective effects on adherens and occludens junctions, as well as on desmosomes. Immunohistochemical analysis of E-cadherin confirmed that the decreased E-cadherin immunolabelling in 4 weeks of PBOO was prevented by selective COX-2 inhibitor treatment. Based on ultrastructural morphometrical analysis, we conclude that PBOO alone and in combination with selective COX-2 inhibitors can have considerable effects on uroepithelial cellular junctions. Our findings provide a novel area of investigation regarding the selective use of COX-2 inhibitors following PBOO. PMID:16253314

  15. Global Gene Expression Analysis of Canine Osteosarcoma Stem Cells Reveals a Novel Role for COX-2 in Tumour Initiation

    PubMed Central

    Pang, Lisa Y.; Gatenby, Emma L.; Kamida, Ayako; Whitelaw, Bruce A.; Hupp, Ted R.; Argyle, David J.

    2014-01-01

    Osteosarcoma is the most common primary bone tumour of both children and dogs. It is an aggressive tumour in both species with a rapid clinical course leading ultimately to metastasis. In dogs and children distant metastasis occurs in >80% of individuals treated by surgery alone. Both canine and human osteosarcoma has been shown to contain a sub-population of cancer stem cells (CSCs), which may drive tumour growth, recurrence and metastasis, suggesting that naturally occurring canine osteosarcoma could act as a preclinical model for the human disease. Here we report the successful isolation of CSCs from primary canine osteosarcoma, as well as established cell lines. We show that these cells can form tumourspheres, and demonstrate relative resistance to chemotherapy. We demonstrate similar results for the human osteosarcma cell lines, U2OS and SAOS2. Utilizing the Affymetrix canine microarray, we are able to definitively show that there are significant differences in global gene expression profiles of isolated osteosarcoma stem cells and the daughter adherent cells. We identified 13,221 significant differences (p = 0.05), and significantly, COX-2 was expressed 141-fold more in CSC spheres than daughter adherent cells. To study the role of COX-2 expression in CSCs we utilized the COX-2 inhibitors meloxicam and mavacoxib. We found that COX-2 inhibition had no effect on CSC growth, or resistance to chemotherapy. However inhibition of COX-2 in daughter cells prevented sphere formation, indicating a potential significant role for COX-2 in tumour initiation. PMID:24416158

  16. Palbociclib inhibits epithelial-mesenchymal transition and metastasis in breast cancer via c-Jun/COX-2 signaling pathway

    PubMed Central

    Zheng, Qiufan; Shi, Dingbo; Xia, Wen; Tian, Yun; Tang, Yanlai; Wang, Jingshu; Xiao, Xiangshen; Deng, Wuguo; Wang, Shusen

    2015-01-01

    Palbociclib, a highly selective CDK4/6 inhibitor, has been shown to be a novel anti-tumor agent that suppresses breast cancer cell proliferation. However, its anti-metastasis activity remains controversial. In the present study, we evaluated whether palbociclib prevented breast cancer cell metastasis and revealed its regulatory mechanism. We found that palbociclib inhibited migration and invasion in the breast cancer cells MDA-MB-231 and T47D. The epithelial-mesenchymal transition (EMT) markers, vimentin and Snail, were down-regulated with palbociclib treatment. Moreover, we revealed that this inhibition was mediated by the c-Jun/COX-2 pathway. COX-2 was decreased after palbociclib treatment. The production of PGE2 was also reduced along with COX-2. Additionally, our data showed that c-Jun, a crucial transcriptional regulator of COX-2, was down-regulated by palbociclib. We found that palbociclib weakened the COX-2 promoter binding activity of c-Jun and prevented its translocation from the cytoplasm to cell nuclei. Bioluminescence imaging and tail intravenous injection were used to evaluate the anti-metastasis effect of palbociclib in vivo. The data demonstrated that palbociclib reduced breast cancer metastasis to the lung. These results therefore demonstrated that the anti-metastasis activity of palbociclib is mediated via the c-Jun/COX-2 signaling pathway by inhibiting EMT in breast cancer cells. PMID:26540629

  17. Possible roles of COX-1 in learning and memory impairment induced by traumatic brain injury in mice

    PubMed Central

    Shang, J.L.; Cheng, Q.; Yang, W.F.; Zhang, M.; Cui, Y.; Wang, Y.F.

    2014-01-01

    People who suffer from traumatic brain injury (TBI) often experience cognitive deficits in spatial reference and working memory. The possible roles of cyclooxygenase-1 (COX-1) in learning and memory impairment in mice with TBI are far from well known. Adult mice subjected to TBI were treated with the COX-1 selective inhibitor SC560. Performance in the open field and on the beam walk was then used to assess motor and behavioral function 1, 3, 7, 14, and 21 days following injury. Acquisition of spatial learning and memory retention was assessed using the Morris water maze on day 15 post-TBI. The expressions of COX-1, prostaglandin E2 (PGE2), interleukin (IL)-6, brain-derived neurotrophic factor (BDNF), platelet-derived growth factor BB (PDGF-BB), synapsin-I, and synaptophysin were detected in TBI mice. Administration of SC560 improved performance of beam walk tasks as well as spatial learning and memory after TBI. SC560 also reduced expressions of inflammatory markers IL-6 and PGE2, and reversed the expressions of COX-1, BDNF, PDGF-BB, synapsin-I, and synaptophysin in TBI mice. The present findings demonstrated that COX-1 might play an important role in cognitive deficits after TBI and that selective COX-1 inhibition should be further investigated as a potential therapeutic approach for TBI. PMID:25387671

  18. Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies.

    PubMed

    Pacheu-Grau, David; Bareth, Bettina; Dudek, Jan; Juris, Lisa; Vögtle, F-Nora; Wissel, Mirjam; Leary, Scot C; Dennerlein, Sven; Rehling, Peter; Deckers, Markus

    2015-06-01

    Three mitochondria-encoded subunits form the catalytic core of cytochrome c oxidase, the terminal enzyme of the respiratory chain. COX1 and COX2 contain heme and copper redox centers, which are integrated during assembly of the enzyme. Defects in this process lead to an enzyme deficiency and manifest as mitochondrial disorders in humans. Here we demonstrate that COA6 is specifically required for COX2 biogenesis. Absence of COA6 leads to fast turnover of newly synthesized COX2 and a concomitant reduction in cytochrome c oxidase levels. COA6 interacts transiently with the copper-containing catalytic domain of newly synthesized COX2. Interestingly, similar to the copper metallochaperone SCO2, loss of COA6 causes cardiomyopathy in humans. We show that COA6 and SCO2 interact and that corresponding pathogenic mutations in each protein affect complex formation. Our analyses define COA6 as a constituent of the mitochondrial copper relay system, linking defects in COX2 metallation to cardiac cytochrome c oxidase deficiency. PMID:25959673

  19. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex.

    PubMed Central

    Kaufmann, W E; Worley, P F; Pegg, J; Bremer, M; Isakson, P

    1996-01-01

    Postnatal development and adult function of the central nervous system are dependent on the capacity of neurons to effect long-term changes of specific properties in response to neural activity. This neuronal response has been demonstrated to be tightly correlated with the expression of a set of regulatory genes which include transcription factors as well as molecules that can directly modify cellular signaling. It is hypothesized that these proteins play a role in activity-dependent response. Previously, we described the expression and regulation in brain of an inducible form of prostaglandin synthase/cyclooxygenase, termed COX-2. COX-2 is a rate-limiting enzyme in prostanoid synthesis and its expression is rapidly regulated in developing and adult forebrain by physiological synaptic activity. Here we demonstrate that COX-2 immunoreactivity is selectively expressed in a subpopulation of excitatory neurons in neo-and allocortices, hippocampus, and amygdala and is compartmentalized to dendritic arborizations. Moreover, COX-2 immunoreactivity is present in dendritic spines, which are specialized structures involved in synaptic signaling. The developmental profile of COX-2 expression in dendrites follows well known histogenetic gradients and coincides with the critical period for activity-dependent synaptic remodeling. These results suggest that COX-2, and its diffusible prostanoid products, may play a role in postsynaptic signaling of excitatory neurons in cortex and associated structures. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:8637870

  20. AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/?-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 ?-catenin-dependent pathway. Here, we show that AE also induces expression of the Cox-2 gene and activates ?-catenin in mouse bone marrow cells. Inhibition of COX suppresses ?-catenin activation and serial replating of AE(+) mouse HSPCs. Genetic knockdown of ?-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/?-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