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Univariate Shrinkage in the Cox Model for High Dimensional Data  

PubMed Central

We propose a method for prediction in Cox's proportional model, when the number of features (regressors), p, exceeds the number of observations, n. The method assumes that the features are independent in each risk set, so that the partial likelihood factors into a product. As such, it is analogous to univariate thresholding in linear regression and nearest shrunken centroids in classification. We call the procedure Cox univariate shrinkage and demonstrate its usefulness on real and simulated data. The method has the attractive property of being essentially univariate in its operation: the features are entered into the model based on the size of their Cox score statistics. We illustrate the new method on real and simulated data, and compare it to other proposed methods for survival prediction with a large number of predictors.

Tibshirani, Robert J.



Univariate shrinkage in the cox model for high dimensional data.  


We propose a method for prediction in Cox's proportional model, when the number of features (regressors), p, exceeds the number of observations, n. The method assumes that the features are independent in each risk set, so that the partial likelihood factors into a product. As such, it is analogous to univariate thresholding in linear regression and nearest shrunken centroids in classification. We call the procedure Cox univariate shrinkage and demonstrate its usefulness on real and simulated data. The method has the attractive property of being essentially univariate in its operation: the features are entered into the model based on the size of their Cox score statistics. We illustrate the new method on real and simulated data, and compare it to other proposed methods for survival prediction with a large number of predictors. PMID:19409065

Tibshirani, Robert J



Proportional hazards (Cox) regression  

Microsoft Academic Search

PROPORTIONAL HAZARDS (Cox) REGRESSION is a powerful analytic tool for testing whether several factors (e.g., cigarette smoking, hypertension) are independently related to the rate (over time) of a specific event (e.g., heart attack yes\\/no). It can also be used to control for baseline differences between groups in nonrandomized studies and randomized clinical trials (RCTs). The availability of desktop computers and

Mitchell H. Katz; Walter W. Hauck



Cox's Regression Model for Counting Processes: A Large Sample Study  

Microsoft Academic Search

The Cox regression model for censored survival data specifies that covariates have a proportional effect on the hazard function of the life-time distribution of an individual. In this paper we discuss how this model can be extended to a model where covariate processes have a proportional effect on the intensity process of a multivariate counting process. This permits a statistical

P. K. Andersen; R. D. Gill



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

ERIC Educational Resources Information Center

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…

Chen, Chau-Kuang



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

ERIC Educational Resources Information Center

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…

Vidal, Sherry


Optimal designs for estimating the control values in multi-univariate regression models  

Microsoft Academic Search

This paper considers a linear regression model with a one-dimensional control variable x and an m-dimensional response vector y=(y1,…,ym). The components of y are correlated with a known covariance matrix. Based on the assumed regression model, it is of interest to obtain a suitable estimation of the corresponding control value for a given target vector T=(T1,…,Tm) on the expected responses.

Chun-Sui Lin; Mong-Na Lo Huang



The analysis of survival data in nephrology: basic concepts and methods of Cox regression  

Microsoft Academic Search

How much does the survival of one group differ from the survival of another group? How do differences in age in these two groups affect such a comparison? To obtain a quantity to compare the survival of different patient groups and to account for confounding effects, a multiple regression technique for survival data is needed. Cox regression is perhaps the

Paul C van Dijk; Kitty J Jager; Aeilko H Zwinderman; Carmine Zoccali; Friedo W Dekker




Microsoft Academic Search

Parameter estimates of logistic and Cox regression models are biased for finite samples. In a simulation study we investigated for both models the behaviour of the bias in relation to sample size and further parameters. In the case of a dichotomous explanatory variable x the magnitude of the bias is strongly influenced by the baseline risk defined by the constants

Ingo Langner; Ralf Bender; Rebecca Lenz-Tönjes; Helmut Küchenhoff; Maria Blettner


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

PubMed Central

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, TGF? (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.



Accommodating measurements below a limit of detection: a novel application of Cox regression.  


In environmental epidemiology, measurements of exposure biomarkers often fall below the assay's limit of detection. Existing methods for handling this problem, including deletion, substitution, parametric regression, and multiple imputation, can perform poorly if the proportion of "nondetects" is high or parametric models are mis-specified. We propose an approach that treats the measured analyte as the modeled outcome, implying a role reversal when the analyte is a putative cause of a health outcome. Following a scale reversal as well, our approach uses Cox regression to model the analyte, with confounder adjustment. The method makes full use of quantifiable analyte measures, while appropriately treating nondetects as censored. Under the proportional hazards assumption, the hazard ratio for a binary health outcome is interpretable as an adjusted odds ratio: the odds for the outcome at any particular analyte concentration divided by the odds given a lower concentration. Our approach is broadly applicable to cohort studies, case-control studies (frequency matched or not), and cross-sectional studies conducted to identify determinants of exposure. We illustrate the method with cross-sectional survey data to assess sex as a determinant of 2,3,7,8-tetrachlorodibenzo-p-dioxin concentration and with prospective cohort data to assess the association between 2,4,4'-trichlorobiphenyl exposure and psychomotor development. PMID:24671072

Dinse, Gregg E; Jusko, Todd A; Ho, Lindsey A; Annam, Kaushik; Graubard, Barry I; Hertz-Picciotto, Irva; Miller, Frederick W; Gillespie, Brenda W; Weinberg, Clarice R



The Relationship Between Intimate Partner Violence and PTSD? An Application of Cox Regression with Time-Varying Covariates  

Microsoft Academic Search

This study uses Cox regression with time-varying covariates to examine the relationship between intimate partner violence and posttraumatic stress disorder (PTSD) in a random sample of Japanese American women and immigrant women from Japan (N = 211). Because applications of survival analysis in trauma research are scarce, this paper presents the utility of this analytical approach by contrasting it with

Mieko Yoshihama; Julie Horrocks



Experiments to Determine Whether Recursive Partitioning (CART) or an Artificial Neural Network Overcomes Theoretical Limitations of Cox Proportional Hazards Regression  

Microsoft Academic Search

New computationally intensive tools for medical survival analyses include recursive patitioning (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

Michael W. Kattan; Kenneth R. Hess; J. Robert Beck



A Comparison of Multiple Imputation and Fully Augmented Weighted Estimators for Cox Regression with Missing Covariates  

PubMed Central

Several approaches exist for handling missing covariates in the Cox proportional hazards model. The multiple imputation (MI) is relatively easy to implement with various software available and results in consistent estimates if the imputation model is correct. On the other hand, the fully augmented weighted estimators (FAWEs) recover a substantial proportion of the efficiency and have the doubly robust property. In this paper, we compare the FAWEs and the MI through a comprehensive simulation study. For the MI, we consider the multiple imputation by chained equation (MICE) and focus on two imputation methods: Bayesian linear regression imputation and predictive mean matching. Simulation results show that the imputation methods can be rather sensitive to model misspecification and may have large bias when the censoring time depends on the missing covariates. In contrast, the FAWEs allow the censoring time to depend on the missing covariates and are remarkably robust as long as getting either the conditional expectations or the selection probability correct due to the doubly robust property. The comparison suggests that the FAWEs show the potential for being a competitive and attractive tool for tackling the analysis of survival data with missing covariates.

Qi, Lihong; Wang, Ying-Fang; He, Yulei



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)

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.

Kattan, Michael W.; Hess, Kenneth R.; Kattan, Michael W.



Survival of patients with nonseminomatous germ cell cancer: a review of the IGCC classification by Cox regression and recursive partitioning.  


The International Germ Cell Consensus (IGCC) classification identifies good, intermediate and poor prognosis groups among patients with metastatic nonseminomatous germ cell tumours (NSGCT). It uses the risk factors primary site, presence of nonpulmonary visceral metastases and tumour markers alpha-fetoprotein (AFP), human chorionic gonadotrophin (HCG) and lactic dehydrogenase (LDH). The IGCC classification is easy to use and remember, but lacks flexibility. We aimed to examine the extent of any loss in discrimination within the IGCC classification in comparison with alternative modelling by formal weighing of the risk factors. We analysed survival of 3048 NSGCT patients with Cox regression and recursive partitioning for alternative classifications. Good, intermediate and poor prognosis groups were based on predicted 5-year survival. Classifications were further refined by subgrouping within the poor prognosis group. Performance was measured primarily by a bootstrap corrected c-statistic to indicate discriminative ability for future patients. The weights of the risk factors in the alternative classifications differed slightly from the implicit weights in the IGCC classification. Discriminative ability, however, did not increase clearly (IGCC classification, c=0.732; Cox classification, c=0.730; Recursive partitioning classification, c=0.709). Three subgroups could be identified within the poor prognosis groups, resulting in classifications with five prognostic groups and slightly better discriminative ability (c=0.740). In conclusion, the IGCC classification in three prognostic groups is largely supported by Cox regression and recursive partitioning. Cox regression was the most promising tool to define a more refined classification. British Journal of Cancer (2004) 90, 1176-1183. doi:10.1038/sj.bjc.6601665 Published online 24 February 2004 PMID:15026798

van Dijk, M R; Steyerberg, E W; Stenning, S P; Dusseldorp, E; Habbema, J D F



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

PubMed Central

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

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



Bayesian variable selection for the Cox regression model with missing covariates  

Microsoft Academic Search

In this paper, we develop Bayesian methodology and computational algorithms for variable subset selection in Cox proportional\\u000a hazards models with missing covariate data. A new joint semi-conjugate prior for the piecewise exponential model is proposed\\u000a in the presence of missing covariates and its properties are examined. The covariates are assumed to be missing at random\\u000a (MAR). Under this new prior,

Joseph G. Ibrahim; Ming-Hui Chen; Sungduk Kim



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


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

Liu, Zhenqiu; Jiang, Feng



Bayesian variable selection for the Cox regression model with missing covariates  

PubMed Central

In this paper, we develop Bayesian methodology and computational algorithms for variable subset selection in Cox proportional hazards models with missing covariate data. A new joint semi-conjugate prior for the piecewise exponential model is proposed in the presence of missing covariates and its properties are examined. The covariates are assumed to be missing at random (MAR). Under this new prior, a version of the Deviance Information Criterion (DIC) is proposed for Bayesian variable subset selection in the presence of missing covariates. Monte Carlo methods are developed for computing the DICs for all possible subset models in the model space. A Bone Marrow Transplant (BMT) dataset is used to illustrate the proposed methodology.

Chen, Ming-Hui; Kim, Sungduk



A Comparison of the Polytomous Logistic Regression and Joint Cox Proportional Hazards Models for Evaluating Multiple Disease Subtypes in Prospective Cohort Studies  

PubMed Central

Background Polytomous logistic regression models are commonly used in case-control studies of cancer to directly compare the risks associated with an exposure variable across multiple cancer subtypes. However, the validity, accuracy and efficiency of this approach for prospective cohort studies have not been formally evaluated. Methods We investigated the performance of the polytomous logistic regression model and compared it to an alternative approach based on a joint Cox proportional hazards model using simulation studies. We then applied both methods to a prospective cohort study to assess whether the association of breast cancer with body size differs according to estrogen and progesterone receptor-defined subtypes. Results Our simulations showed that the polytomous logistic regression model but not the joint Cox regression model yielded biased results in comparing exposure and disease subtype associations when the baseline hazards for different disease subtypes are non-proportional. For this reason, an analysis of a real data set was based on the joint Cox proportional hazards model and showed that body size has a significantly greater association with estrogen and progesterone positive breast cancer than with other subtypes. Conclusions Because of the limitations of the polytomous logistic regression model for the comparison of exposure-disease associations across disease subtypes, the joint Cox proportional hazards model is recommended over the polytomous logistic regression model in prospective cohort studies. Impact The paper will promote the use of the joint Cox model in a prospective cohort study. Examples of SAS and S-plus programming codes are provided to facilitate use by non-statisticians.

Xue, Xiaonan; Kim, Mimi Y.; Gaudet, Mia M.; Park, Yikyung; Heo, Moonseong; Hollenbeck, Albert R.; Strickler, Howard D.; Gunter, Marc J.



Inhibition of COX-2 in Colon Cancer Modulates Tumor Growth and MDR-1 Expression to Enhance Tumor Regression in Therapy-Refractory Cancers In Vivo12  

PubMed Central

Higher cyclooxygenase 2 (COX-2) expression is often observed in aggressive colorectal cancers (CRCs). Here, we attempt to examine the association between COX-2 expression in therapy-refractory CRC, how it affects chemosensitivity, and whether, in primary tumors, it is predictive of clinical outcomes. Our results revealed higher COX-2 expression in chemoresistant CRC cells and tumor xenografts. In vitro, the combination of either aspirin or celecoxib with 5-fluorouracil (5-FU) was capable of improving chemosensitivity in chemorefractory CRC cells, but a synergistic effect with 5-FU could only be demonstrated with celecoxib. To examine the potential clinical significance of these observations, in vivo studies were undertaken, which also showed that the greatest tumor regression was achieved in chemoresistant xenografts after chemotherapy in combination with celecoxib, but not aspirin. We also noted that these chemoresistant tumors with higher COX-2 expression had a more aggressive growth rate. Given the dramatic response to a combination of celecoxib + 5-FU, the possibility that celecoxib may modulate chemosensitivity as a result of its ability to inhibit MDR-1 was examined. In addition, assessment of a tissue microarray consisting of 130 cases of CRCs revealed that, in humans, higher COX-2 expression was associated with poorer survival with a 68% increased risk of mortality, indicating that COX-2 expression is a marker of poor clinical outcome. The findings of this study point to a potential benefit of combining COX-2 inhibitors with current regimens to achieve better response in the treatment of therapy-refractory CRC and in using COX-2 expression as a prognostic marker to help identify individuals who would benefit the greatest from closer follow-up and more aggressive therapy.

Rahman, Mahbuba; Selvarajan, Krithika; Hasan, Mohammad R; Chan, Annie P; Jin, Chaoyang; Kim, Jieun; Chan, Simon K; Le, Nhu D; Kim, Young-Bae; Tai, Isabella T



Inhibition of COX-2 in colon cancer modulates tumor growth and MDR-1 expression to enhance tumor regression in therapy-refractory cancers in vivo.  


Higher cyclooxygenase 2 (COX-2) expression is often observed in aggressive colorectal cancers (CRCs). Here, we attempt to examine the association between COX-2 expression in therapy-refractory CRC, how it affects chemosensitivity, and whether, in primary tumors, it is predictive of clinical outcomes. Our results revealed higher COX-2 expression in chemoresistant CRC cells and tumor xenografts. In vitro, the combination of either aspirin or celecoxib with 5-fluorouracil (5-FU) was capable of improving chemosensitivity in chemorefractory CRC cells, but a synergistic effect with 5-FU could only be demonstrated with celecoxib. To examine the potential clinical significance of these observations, in vivo studies were undertaken, which also showed that the greatest tumor regression was achieved in chemoresistant xenografts after chemotherapy in combination with celecoxib, but not aspirin. We also noted that these chemoresistant tumors with higher COX-2 expression had a more aggressive growth rate. Given the dramatic response to a combination of celecoxib + 5-FU, the possibility that celecoxib may modulate chemosensitivity as a result of its ability to inhibit MDR-1 was examined. In addition, assessment of a tissue microarray consisting of 130 cases of CRCs revealed that, in humans, higher COX-2 expression was associated with poorer survival with a 68% increased risk of mortality, indicating that COX-2 expression is a marker of poor clinical outcome. The findings of this study point to a potential benefit of combining COX-2 inhibitors with current regimens to achieve better response in the treatment of therapy-refractory CRC and in using COX-2 expression as a prognostic marker to help identify individuals who would benefit the greatest from closer follow-up and more aggressive therapy. PMID:22904679

Rahman, Mahbuba; Selvarajan, Krithika; Hasan, Mohammad R; Chan, Annie P; Jin, Chaoyang; Kim, Jieun; Chan, Simon K; Le, Nhu D; Kim, Young-Bae; Tai, Isabella T



Univariate and Bivariate Data  

NSDL National Science Digital Library

This lesson is designed to introduce students to the difference between univariate and bivariate data, and how the two can be represented graphically. This lesson provides links to model discussions and online graphing applets, as well as suggested ways to integrate them into the lesson. Finally, the lesson provides links to follow-up lessons designed for use in succession with the current one.




Univariate Probability Distributions  

ERIC Educational Resources Information Center

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…

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



Factors Determining Disease Duration in Alzheimer's Disease: A Postmortem Study of 103 Cases Using the Kaplan-Meier Estimator and Cox Regression  

PubMed Central

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.

Armstrong, R. A.



Some Univariate-Multivariate Generalizations.  

ERIC Educational Resources Information Center

The mathematical extension from scalars to matrices as a prerequisite for univariate to multivariate generalizations of statistical concepts and methods is discussed. One reason for several alternative techniques is the multitude of ways to generalize from univariate concepts to multivariate concepts. The additional complexity, and lack of…

Huberty, Carl J.


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

PubMed Central

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.



Prediction of late results following valve replacement in aortic valve stenosis. Seventeen years of follow-up examined with the Cox regression analysis.  


A total of 122 patients (mean age: 55 years, range 20-75 years) were alive 30 days after isolated aortic valve replacement (AVR) performed in 1965-73 for aortic valve stenosis (AS). Cold chemical Bretschneider cardioplegia was used in all operations. The maximum follow-up was 17 years, mean 9 years. The 10-year cumulative survival +/- SE was 63 +/- 4%. Twenty-one preoperative clinical, invasive and valve-related variables were entered into a Cox regression analysis. Variables with independent predictive value regarding long-term survival were: Left ventricular failure (regression coefficient: b = 1.078, p less than 0.0002), age (b = 0.749, p less than 0.009), pulse pressure (b = -0.663, p less than 0.02) and cardio-thoracic index (CTI) (b = 0.603, p less than 0.04). Based on these variables, a prognostic index with 16 different risk groups was made. In the "best" group (n = 8), the observed 10-year survival +/- SE was 88 +/- 11%, compared to 13 +/- 12% for the "worst" group (n = 8). Multivariate analysis of complication-free survival showed that the total valve-related complication-rate (VRC) (4.2/100 pat.-yrs) was influenced by valve type (Starr-Edwards ball valves, n = 118, versus Lillehei-Kaster and Smeelof-Cutter valves, n = 4) and CTI. The valve- and heart-related events (VRC together with late myocardial infarctions and pacemaker implantations, 6.5/100 pat.-yrs) depended on CTI and previous myocardial infarction. No predictors of thromboembolism (1.6/100 pat.-yrs) or coumarin-related hemorrhage (1.8/100 pat.-yrs) could be identified.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2447672

Lund, O; Vaeth, M



Screening of cerebral infarction-related genetic markers using a Cox regression analysis between onset age and heterozygosity at randomly selected short tandem repeat loci.  


The aim of this paper is to explore whether the heterozygosity at the 9 CODIS short tandem repeats (STR) loci including D3S1358, vWA, FGA, D8S1179, D21S11, D18S51, D5S818, D13S317 and D7S820 is associated with the risk of atherosclerotic cerebral infarction (CI). The DNA samples were collected from patients with CI (n = 72) and people over the age of 90 years without CI (n = 59). Alleles of the STR loci were determined using the STR Profiler Plus PCR amplification kit. The relationship between the age of onset and heterozygosity was determined with the Cox regression method. A correlation between the age of onset and heterozygosity was observed for the D8S1179 locus (p < 0.05). It implied that regions in the vicinity of locus D8S1179 may harbor susceptibility genes for CI. The analysis of heterozygosity for particular loci as genetic markers using our new study design may be an efficient and reliable approach to estimate genetic predispositions. PMID:22476643

Hui, Liu; Jun, Tian; Jing, Ye; Yu, Weijian



Cox Regression for Survey Data

For complex sampling designs, the program maximizes a weighted partial log-likelihood and calculates robust design-based standard errors (assuming with-replacement sampling at the first stage). For further details see Binder, DA (1992), Biometrika, 79, pp. 139-47.


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


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 PMID:23112827

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



Symmetrized Nearest Neighbor Regression Estimates.  

National Technical Information Service (NTIS)

The authors consider univariate nonparametric regression. Two standard nonparametric regression function estimates are kernel estimates and nearest neighbor estimates. Mack noted that both methods can be defined with respect to a kernel or weighting funct...

R. J. Carroll W. Hardle



Log-normal censored regression model detecting prognostic factors in gastric cancer: A study of 3018 cases  

PubMed Central

AIM: To investigate the efficiency of Cox proportional hazard model in detecting prognostic factors for gastric cancer. METHODS: We used the log-normal regression model to evaluate prognostic factors in gastric cancer and compared it with the Cox model. Three thousand and eighteen gastric cancer patients who received a gastrectomy between 1980 and 2004 were retrospectively evaluated. Clinic-pathological factors were included in a log-normal model as well as Cox model. The akaike information criterion (AIC) was employed to compare the efficiency of both models. Univariate analysis indicated that age at diagnosis, past history, cancer location, distant metastasis status, surgical curative degree, combined other organ resection, Borrmann type, Lauren’s classification, pT stage, total dissected nodes and pN stage were prognostic factors in both log-normal and Cox models. RESULTS: In the final multivariate model, age at diagnosis, past history, surgical curative degree, Borrmann type, Lauren’s classification, pT stage, and pN stage were significant prognostic factors in both log-normal and Cox models. However, cancer location, distant metastasis status, and histology types were found to be significant prognostic factors in log-normal results alone. According to AIC, the log-normal model performed better than the Cox proportional hazard model (AIC value: 2534.72 vs 1693.56). CONCLUSION: It is suggested that the log-normal regression model can be a useful statistical model to evaluate prognostic factors instead of the Cox proportional hazard model.

Wang, Bin-Bin; Liu, Cai-Gang; Lu, Ping; Latengbaolide, A; Lu, Yang



Use of Penalized Splines in Extended Cox-Type Additive Hazard Regression to Flexibly Estimate the Effect of Time-varying Serum Uric Acid on Risk of Cancer Incidence: A Prospective, Population-Based Study in 78,850 Men  

PubMed Central

Purpose We sough to investigate the effect of serum uric acid (SUA) levels on risk of cancer incidence in men and to flexibly determine the shape of this association by using a novel analytical approach. Methods A population-based cohort of 78,850 Austrian men who received 264,347 serial SUA measurements was prospectively followed-up for a median of 12.4 years. Data were collected between 1985 and 2003. Penalized splines (P-splines) in extended Cox-type additive hazard regression were used to flexibly model the association between SUA, as a time-dependent covariate, and risk of overall and site-specific cancer incidence and to calculate adjusted hazard ratios with their 95% confidence intervals. Results During follow-up 5189 incident cancers were observed. Restricted maximum-likelihood optimizing P-spline models revealed a moderately J-shaped effect of SUA on risk of overall cancer incidence, with statistically significantly increased hazard ratios in the upper third of the SUA distribution. Increased SUA (?8.00 mg/dL) further significantly increased risk for several site-specific malignancies, with P-spline analyses providing detailed insight about the shape of the association with these outcomes. Conclusions Our study is the first to demonstrate a dose–response association between SUA and cancer incidence in men, simultaneously reporting on the usefulness of a novel methodological framework in epidemiologic research.

Strasak, Alexander M.; Lang, Stefan; Kneib, Thomas; Brant, Larry J.; Klenk, Jochen; Hilbe, Wolfgang; Oberaigner, Willi; Ruttmann, Elfriede; Kaltenbach, Lalit; Concin, Hans; Diem, Gunter; Pfeiffer, Karl P.; Ulmer, Hanno



Bayesian Nonparametric Covariance Regression  

Microsoft Academic Search

Although there is a rich literature on methods for allowing the variance in a univariate regression model to vary with predictors, time and other factors, relatively little has been done in the multivariate case. Our focus is on developing a class of nonparametric covariance regression models, which allow an unknown p x p covariance matrix to change flexibly with predictors.

Emily Fox; David Dunson



COX-1 and COX-3 inhibitors.  


Low doses of aspirin reduce both pain and fever, whereas the anti-inflammatory action of aspirin requires a much higher dose. It is possible that inhibition of cyclooxygenase (COX)-1 is the major action of aspirin involved in its analgesic and antipyretic effects, and inhibition of COX-2 is responsible for its anti-inflammatory action. We compared the analgesic effects of an aspirin-like drug (diclofenac) and a centrally acting analgesic (paracetamol) in the mouse stretching test and confirmed that the analgesic action of the aspirin-like drug was peripheral. Two possible sites have been postulated for the antipyretic action of non-steroid anti-inflammatory drugs; (a) inhibition of COX in endothelial cells of hypothalamic blood vessels or (b) inhibition of COX synthesising prostaglandins near sensory receptors of sub-diaphragmatic vagal afferents. The antipyretic action of aspirin may be mediated by inhibition of COX-3 in hypothalamic endothelial cells or by inhibition of COX-1 localised close to sensory receptors of peripheral vagal afferents. It is also possible that both enzymes are involved in the antipyretic action of aspirin. Whereas lipopolysaccharide (LPS)-induced fever is attenuated in COX-2 gene-deleted mice, suggesting that COX-2 is responsible for this type of fever, the COX-1 gene may also be important in temperature regulation and in mediating the pyresis that occurs in the absence of infection. PMID:14592546

Botting, Regina



Univariate and Multivariate Analysis of Categorical Variables.  

ERIC Educational Resources Information Center

Recent trends in the analysis of categorical or nominal variables were discussed for univariate, multivariate, and psychometric problems. It was shown that several statistical procedures commonly used with these problems have analogues which can be applied to assessing categorical variables. (Author/CTM)

Koslowsky, Meni



Univariate input models for stochastic simulation  

Microsoft Academic Search

Techniques are presented for modeling and randomly sampling many of the multivariate probabilistic input processes that drive discrete-event simulation experiments. Emphasis is given to bivariate and trivariate extensions of the univariate beta, Johnson, and Bézier dist ribution families because of the flexibility of these families to model a wide range of shapes for the marginal distributions while also representing the

Michael E. Kuhl; Julie S. Ivy; Emily K. Lada; Natalie M. Steiger; Mary Ann Flanigan Wagner; James R. Wilson



Univariate normalization of bispectrum using Hölder's inequality.  


Considering that many biological systems including the brain are complex non-linear systems, suitable methods capable of detecting these non-linearities are required to study the dynamical properties of these systems. One of these tools is the third order cummulant or cross-bispectrum, which is a measure of interfrequency interactions between three signals. For convenient interpretation, interaction measures are most commonly normalized to be independent of constant scales of the signals such that its absolute values are bounded by one, with this limit reflecting perfect coupling. Although many different normalization factors for cross-bispectra were suggested in the literature these either do not lead to bounded measures or are themselves dependent on the coupling and not only on the scale of the signals. In this paper we suggest a normalization factor which is univariate, i.e., dependent only on the amplitude of each signal and not on the interactions between signals. Using a generalization of Hölder's inequality it is proven that the absolute value of this univariate bicoherence is bounded by zero and one. We compared three widely used normalizations to the univariate normalization concerning the significance of bicoherence values gained from resampling tests. Bicoherence values are calculated from real EEG data recorded in an eyes closed experiment from 10 subjects. The results show slightly more significant values for the univariate normalization but in general, the differences are very small or even vanishing in some subjects. Therefore, we conclude that the normalization factor does not play an important role in the bicoherence values with regard to statistical power, although a univariate normalization is the only normalization factor which fulfills all the required conditions of a proper normalization. PMID:24975293

Shahbazi, Forooz; Ewald, Arne; Nolte, Guido



COX1 and COX3 inhibitors  

Microsoft Academic Search

Low doses of aspirin reduce both pain and fever, whereas the anti-inflammatory action of aspirin requires a much higher dose. It is possible that inhibition of cyclooxygenase (COX)-1 is the major action of aspirin involved in its analgesic and antipyretic effects, and inhibition of COX-2 is responsible for its anti-inflammatory action. We compared the analgesic effects of an aspirin-like drug

Regina Botting



Genetic analyses of longitudinal phenotype data: a comparison of univariate methods and a multivariate approach  

PubMed Central

Background We explored three approaches to heritability and linkage analyses of longitudinal total cholesterol levels (CHOL) in the Genetic Analysis Workshop 13 simulated data without knowing the answers. The first two were univariate approaches and used 1) baseline measure at exam one or 2) summary measures such as mean and slope from multiple exams. The third method was a multivariate approach that directly models multiple measurements on a subject. A variance components model (SOLAR) was employed in the univariate approaches. A mixed regression model with polynomials was employed in the multivariate approach and implemented in SAS/IML. Results Using the baseline measure at exam 1, we detected all baseline or slope genes contributing a substantial amount (0.08) of variance (LOD > 3). Compared to the baseline measure, the mean measures yielded slightly higher LOD at the slope genes, and a lower LOD at the baseline genes. The slope measure produced a somewhat lower LOD for the slope gene than did the mean measure. Descriptive information on the pattern of changes in gene effects with age was estimated for three linked loci by the third approach. Conclusion We found simple univariate methods may be effective to detect genes affecting longitudinal phenotypes but may not fully reveal temporal trends in gene effects. The relative efficiency of the univariate methods to detect genes depends heavily on the underlying model. Compared with the univariate approaches, the multivariate approach provided more information on temporal trends in gene effects at the cost of more complicated modelling and more intense computations.

Yang, Qiong; Chazaro, Irmarie; Cui, Jing; Guo, Chao-Yu; Demissie, Serkalem; Larson, Martin; Atwood, Larry D; Cupples, L Adrienne; DeStefano, Anita L



Multivariate Multiple Regression in Communication Research.  

ERIC Educational Resources Information Center

This paper examines the multivariate multiple regression model and explores its applicability to communication research. The first section discusses partitioning of a data matrix, as a heuristic device for distinguishing among alternative regression models. Section two examines various aspects of univariate multiple regression, including the form…

Monge, Peter R.


Detection limit estimator for multivariate calibration by an extension of the IUPAC recommendations for univariate methods.  


A methodology is proposed to estimate the limit of detection (LOD) of analytical methods when multivariate calibration is applied. It tries to follow the same premises as the IUPAC methodology for univariate calibration. The mathematical support is given and algorithms such as partial least squares (PLS) regression, PLS2 and principal component regression (PCR) are used. Only multivariate raw data are used; that is, no surrogate univariate signal is deduced. Non-linearities are allowed. Near infrared (NIR) data of 5 component pseudo-gasoline samples together with simulated fluorescence synchronous spectra of binary mixtures (first order data) are used for evaluation. Experimental verification is performed using different kinds of data, namely: binary mixtures of bentazone and fenamiphos (very overlapped spectra, second order data) obtained by sequential injection (SI), and kinetic data of the reaction between the Fenton's reagent (FR) and pesticides such as atrazine, bentazone and alachlor (individual or binary mixtures, second order data). Results are always compared with independent methods previously proposed in the literature, based in the use of surrogate univariate signals. In general, similar results are found and no statistically significant differences seem to be present, except in a few cases when complex chemical systems are involved. PMID:18365124

Ostra, Miren; Ubide, Carlos; Vidal, Maider; Zuriarrain, Juan



COX-2 and the kidneys.  


The kidney is the second most frequent target of serious adverse effects of non-steroidal antiinflammatory drugs (NSAIDs). The renal side effects of NSAIDs related to inhibition of cyclooxygenase (COX) comprise reduction in renal blood flow (RBF) and glomerular filtration rate (GFR), sodium/water retention, water intoxication and hyperkalemia. The discovery of two COX-isoenzymes, a constitutive COX-1, serving homeostatic prostanoid synthesis, and an inducible COX-2, responsible for proinflammatory prosta noid production, led to the development of new NSAIDs: Preferential and specific COX-2 inhibitors, promising minimal NSAID-typical toxicity with equivalent efficacy. However, we learned that there is no clear distinction in "physiologic" constitutive COX-1 and "inflammatory" inducible COX-2. This is particular true for the kidney of humans and other mammalians, where COX-2 was found constitutively in meaningful amounts. Animal experiments and clinical trials with preferential and specific COX-2 inhibitors revealed that COX-2 is the critical enzyme for sodium excretion, renin release and likely antagonism of antidiuretic hormone. Additionally, a significant role of COX-2 for nephro genesis is suggested. For renal hemodynamics the given evidence point to COX-1 as the predominant enzyme, but further investigations are required. In summary, the gain of renal safety by use of preferential or specific COX-2 inhibitors is small or negligible with respect to sodium retention, hyperkalemia and probably water intoxication. These drugs may be advantageous regarding renal perfusion, but presently the same precautions as for conventional NSAIDs must be used. PMID:11102561

Stichtenoth, D O; Frölich, J C



A Matlab Code for Univariate Time Series Forecasting  

Microsoft Academic Search

This M-File forecasts univariate time series such as stock prices with a feedforward neural networks. It finds best (minimume RMSE) network automatically and uses early stopping method for solving overfitting problem.

Shapour Mohammadi; Hossein Abbasi-Nejad



An Introduction to Kernel and Nearest-Neighbor Nonparametric Regression  

Microsoft Academic Search

Nonparametric regression is a set of techniques for estimating a regression curve without making strong assumptions about the shape of the true regression function. These techniques are therefore useful for building and checking parametric models, as well as for data description. Kernel and nearest-neighbor regression estimators are local versions of univariate location estimators, and so they can readily be introduced

N. S. Altman



Regression Estimation from an Individual Stable Sequence  

Microsoft Academic Search

We consider univariate regression estimation from an individual (non-random) sequence , which is stable in the sense that for each interval (i) the limiting relative frequency of A under x1, x2,… is governed by an unknown probability distribution ?, and (ii) the limiting average of those yi with x ? A is governed by an unknown regression function m(·).A computationally

Gusztáv Morvai; Sanjeev R. Kulkarni; Andrew B. Nobel



Bayesian Geoadditive Seemingly Unrelated Regression 1  

Microsoft Academic Search

Summary Parametric seemingly unrelated regression (SUR) models are a common tool for multivariate regression analysis when error variables are reason- ably correlated, so that separate univariate analysis may result in inefficient estimates of covariate effects. A weakness of parametric models is that they require strong assumptions on the functional form of possibly nonlinear effects of metrical covariates. In this paper,

Stefan Lang; B. Adebayo; Ludwig Fahrmeir; Winfried J. Steiner


Global optimization of univariate Lipschitz functions: I. Survey and properties  

Microsoft Academic Search

We consider the following global optimization problems for a univariate Lipschitz functionf defined on an interval [a, b]: Problem P: find a globally optimal value off and a corresponding point; Problem P': find a globallye-optimal value off and a corresponding point; Problem Q: localize all globally optimal points; Problem Q': find a set of disjoint subintervals of small length whose

Pierre Hansen; Brigitte Jaumard; Shi-hui Lu



On Timonov's algorithm for global optimization of univariate Lipschitz functions  

Microsoft Academic Search

Timonov proposes an algorithm for global maximization of univariate Lipschitz functions in which successive evaluation points are chosen in order to ensure at each iteration a maximal expected reduction of the “region of indeterminacy”, which contains all globally optimal points. It is shown that such an algorithm does not necessarily converge to a global optimum.

Pierre Hansen; Brigitte Jaumard; Shi-Hui Lu



Univariable Optimal Discriminant Analysis: One-Tailed Hypotheses.  

ERIC Educational Resources Information Center

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)

Soltysik, Robert C.; Yarnold, Paul R.



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

ERIC Educational Resources Information Center

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…

Burdenski, Thomas K., Jr.


On the Decidability of Sparse Univariate Polynomial Interpolation  

Microsoft Academic Search

We consider the problem of determining whether or not there exists a sparse univariate polynomial that interpolates a given setS={(xi,yi)} of points. Several important cases are resolved, e.g., the case when thexi's are all positive rational numbers. But the general problem remains open.

Allan Borodin; Prasoon Tiwari



Univariate and Bivariate Loglinear Models for Discrete Test Score Distributions.  

ERIC Educational Resources Information Center

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…

Holland, Paul W.; Thayer, Dorothy T.



The Robust Inference for the Cox Proportional Hazards Model  

Microsoft Academic Search

We derive the asymptotic distribution of the maximum partial likelihood estimator ? for the vector of regression coefficients ? under a possibly misspecified Cox proportional hazards model. As in the parametric setting, this estimator ? converges to a well-defined constant vector ?*. In addition, the random vector n (? – ?*) is asymptotically normal with mean 0 and with a

D. Y. Lin; L. J. Wei



The Moxie of Kathy Cox  

ERIC Educational Resources Information Center

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…

Johns, Stephanie



Cox Proportional-Hazards Regression for Survival Data  

Microsoft Academic Search

Survival analysis examines and models the time it takes for events to occur. The prototypical such event is death, from which the name'survival analysis'and much of its terminology derives, but the ambit of application of survival analysis is much broader. Essentially the same methods are employed in a variety of disciplines under various rubrics-for example,'event-history analysis'in sociology. In this appendix,

John Fox


Expression profiling of colorectal carcinomas using tissue microarrays: cell cycle regulatory proteins p21, p27, and p53 as immunohistochemical prognostic markers in univariate and multivariate analysis.  


With the rapidly growing understanding of tumor biology, molecular staging of cancer is expected to improve prognostication. This would be particularly important for cancers amenable to adjuvant treatment, such as colorectal carcinomas. To generate data for this, the tissue microarray technique may prove useful. Tissue microarrays were constructed with triplicate cores (0.6 mm diameter) from the invasive margins of a consecutive single-institution series of 184 colorectal carcinomas. Immunostaining for p53, p21, p27, Ecadherin, and beta-catenin was scored. Tumor cell proliferation was assessed by mitotic indices and Ki-67 labeling, apoptosis by quantification of apoptotic bodies. Reduced nuclear immunostaining for p21 (<10%) and p27 (< or =50%) and reduced membranous expression of Ecadherin were significantly associated with a poorer clinical course by univariate analysis. beta-catenin immunostaining had no prognostic impact. Mitotic and apoptotic indices as well as Ki-67 labeling below the median were indicators of poor prognosis. Complete absence of p53 nuclear staining was a significant adverse prognostic factor. By Cox regression, p53 = 0%, p53 = 0%, in combination with p27 < or = 50%, the mitotic index and the combined mitotic and apoptotic index added prognostic information to UICC stage. The authors found that growth pattern, lymphohistiocytic response, lymphatic permeation, and venous spread, too, each was a strong prognosticator in addition to UICC stage. The results support that tissue microarrays are a useful tool for screening immunohistochemical markers for prognostic use. An immunopanel of p21, p27, and p53 could be useful for prognostication in colorectal carcinoma in addition to UICC stage. PMID:15354735

Prall, Friedrich; Ostwald, Christiane; Nizze, Horst; Barten, Malte



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

PubMed Central

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.

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



Constructing Generalized FGM Copulas by Means of Certain Univariate Distributions  

Microsoft Academic Search

In this paper we focus on specific generalized Fairlie- Gumbel-Morgenstern (or Sarmanov) copulas which are generated by a\\u000a single function (so-called generator or generator function) defined on the unit interval. In particular, we introduce a class\\u000a of generators based on density-quantile functions of certain univariate distributions. Many of the generator functions from\\u000a the literature are recovered as special cases. Moreover,

Matthias Fischer; Ingo Klein



Restoration of E-cadherin expression by selective Cox-2 inhibition and the clinical relevance of the epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma  

PubMed Central

Background The epithelial-to-mesenchymal transition (EMT) accompanied by the downregulation of E-cadherin has been thought to promote metastasis. Cyclooxygenase-2 (Cox-2) is presumed to contribute to cancer progression through its multifaceted function, and recently its inverse relationship with E-cadherin was suggested. The aim of the present study was to investigate whether selective Cox-2 inhibitors restore the expression of E-cadherin in head and neck squamous cell carcinoma (HNSCC) cells, and to examine the possible correlations of the expression levels of EMT-related molecules with clinicopathological factors in HNSCC. Methods We used quantitative real-time PCR to examine the effects of three selective Cox-2 inhibitors, i.e., celecoxib, NS-398, and SC-791 on the gene expressions of E-cadherin (CDH-1) and its transcriptional repressors (SIP1, Snail, Twist) in the human HNSCC cell lines HSC-2 and HSC-4. To evaluate the changes in E-cadherin expression on the cell surface, we used a flowcytometer and immunofluorescent staining in addition to Western blotting. We evaluated and statistically analyzed the clinicopathological factors and mRNA expressions of Cox-2, CDH-1 and its repressors in surgical specimens of 40 patients with tongue squamous cell carcinoma (TSCC). Results The selective Cox-2 inhibitors upregulated the E-cadherin expression on the cell surface of the HNSCC cells through the downregulation of its transcriptional repressors. The extent of this effect depended on the baseline expression levels of both E-cadherin and Cox-2 in each cell line. A univariate analysis showed that higher Cox-2 mRNA expression (p?=?0.037), lower CDH-1 mRNA expression (p?=?0.020), and advanced T-classification (p?=?0.036) were significantly correlated with lymph node metastasis in TSCC. A multivariate logistic regression revealed that lower CDH-1 mRNA expression was the independent risk factor affecting lymph node metastasis (p?=?0.041). Conclusions These findings suggest that the appropriately selective administration of certain Cox-2 inhibitors may have an anti-metastatic effect through suppression of the EMT by restoring E-cadherin expression. In addition, the downregulation of CDH-1 resulting from the EMT may be closely involved in lymph node metastasis in TSCC.



The pyrrole moiety as a template for COX-1/COX-2 inhibitors.  


Aroyl- and thiophene-substituted pyrrole derivatives have been synthesized as a new class of COX-1/COX-2 inhibitors. The inhibition of COX-1 was evaluated in a biological system using bovine PMNLs as the enzyme source, whereas LPS-stimulated human monocytes served as the enzyme source for inducible COX-2. The determination of the concentration of arachidonic acid metabolites was performed by HPLC for COX-1 and RIA for COX-2. Variation of the substitution pattern led to a series of active compounds which showed inhibition for COX-1 and COX-2. Structural requirements for the development of COX-1/COX-2 inhibitors are discussed. PMID:10889329

Dannhardt, G; Kiefer, W; Krämer, G; Maehrlein, S; Nowe, U; Fiebich, B



Inference of identity of source using univariate and bivariate methods.  


In this study we explore the inference of identity of source using a two-dimensional feature vector. As an example, we study the use of the Bayesian framework for the estimation of the value of evidence of color measurements for identity of source of blue ballpoint pen inks. Univariate as well as bivariate analyses are carried out for color data that was acquired with a flatbed scanner. While this might not be the best method to discriminate inks, we will use it as an example to estimate what the value of the evidence is, however low or high it may be. It is hoped that this exercise is instructional, as a similar approach can readily be applied in other situations. PMID:20120605

Berger, C E H



Wavelet kernel penalized estimation for non-equispaced design regression  

Microsoft Academic Search

The paper considers regression problems with univariate design points. The design points are irregular and no assumptions on their distribution are imposed. The regression function is retrieved by a wavelet based reproducing kernel Hilbert space (RKHS) technique with the penalty equal to the sum of blockwise RKHS norms. In order to simplify numerical optimization, the problem is replaced by an

Umberto Amato; Anestis Antoniadis; Marianna Pensky



Efficient Estimation of an Additive Quantile Regression Model  

Microsoft Academic Search

In this paper, two non-parametric estimators are proposed for estimating the components of an additive quantile regression model. The first estimator is a computationally convenient approach which can be viewed as a more viable alternative to existing kernel-based approaches. The second estimator involves sequential fitting by univariate local polynomial quantile regressions for each additive component with the other additive components




Bayesian regression in SAS software.  


Bayesian methods have been found to have clear utility in epidemiologic analyses involving sparse-data bias or considerable background information. Easily implemented methods for conducting Bayesian analyses by data augmentation have been previously described but remain in scant use. Thus, we provide guidance on how to do these analyses with ordinary regression software. We describe in detail and provide code for the implementation of data augmentation for Bayesian and semi-Bayes regression in SAS® software, and illustrate their use in a real logistic-regression analysis. For comparison, the same model was fitted using the Markov-chain Monte Carlo (MCMC) procedure. The two methods required a similar number of steps and yielded similar results, although for the main example, data augmentation ran in about 0.5% of the time required for MCMC. We also provide online appendices with details and examples for conditional logistic, Poisson and Cox proportional-hazards regression. PMID:23230299

Sullivan, Sheena G; Greenland, Sander



Quantile Regression  

Microsoft Academic Search

Quantile regression, as introduced by Koenker and Bassett (1978), may be viewed as an extension of classical least squares estimation of conditional mean models to the estimation of an ensemble of models for several conditional quantile functions. The central special case is the median regression estimator which minimizes a sum of absolute errors. Other conditional quantile functions are estimated by

Roger Koenker; Kevin F. Hallock




PubMed Central

For least squares regression, Efron et al. (2004) proposed an efficient solution path algorithm, the least angle regression (LAR). They showed that a slight modification of the LAR leads to the whole LASSO solution path. Both the LAR and LASSO solution paths are piecewise linear. Recently Wu (2011) extended the LAR to generalized linear models and the quasi-likelihood method. In this work we extend the LAR further to handle Cox’s proportional hazards model. The goal is to develop a solution path algorithm for the elastic net penalty (Zou and Hastie (2005)) in Cox’s proportional hazards model. This goal is achieved in two steps. First we extend the LAR to optimizing the log partial likelihood plus a fixed small ridge term. Then we define a path modification, which leads to the solution path of the elastic net regularized log partial likelihood. Our solution path is exact and piecewise determined by ordinary differential equation systems.

Wu, Yichao



COX-2 and Prostate Cancer Angiogenesis.  

National Technical Information Service (NTIS)

Cyclooxygenase-2 (COX-2) is an inducible enzyme which catalyzes the conversion of arachidonic acid to prostaglandins and has previously been demonstrated to play a role in carcinogenesis. We demonstrated that COX-2 and one of its major prostaglandin produ...

A. C. Levine



COX-2 and Prostate Cancer Angiogenesis.  

National Technical Information Service (NTIS)

Cyclooxygenase-2 (COx-2%) is an inducible enzyme which catalyzes the conversion of arachidonic acid to prostaglandins and has previously been demonstrated to play a role in carcinogenesis. We demonstrated that COX-2 and one of its major prostaglandin prod...

A. C. Levine



Cox-2 and Prostate Cancer Angiogenesis.  

National Technical Information Service (NTIS)

Cyclooxygenase-2 (COX-2) is an inducible enzyme which catalyzes the conversion of arachidonic acid to prostaglandins and has previously been demonstrated to play a role in carcinogenesis. We demonstrated that COX-2 and one of its major prostaglandin produ...

A. C. Levine



Runoff Forecasting with General Regression Neural Networks and Multilayer Perceptrons Networks  

Microsoft Academic Search

Numerous studies have been conducted to forecast univariate hydrological time series using Artificial Neural Networks, and most of them are conducted with Multilayer Perceptrons Networks (MLP). In the present study, a simple one-parameter neural network model, General Regression Neural Networks (GRNN), is proposed for forecasting univariate time series. The proposed GRNN approach employs the theory of phase-space to reconstruct the

M. Islam; B. Sivakumar; W. W. Wallender



Detecting and Dealing with Outliers in Univariate and Multivariate Contexts.  

ERIC Educational Resources Information Center

Because multivariate statistics are increasing in popularity with social science researchers, the challenge of detecting multivariate outliers warrants attention. Outliers are defined as cases which, in regression analyses, generally lie more than three standard deviations from Yhat and therefore distort statistics. There are, however, some…

Wiggins, Bettie Caroline


COX1, and not COX2 activity, regulates airway function: relevance to aspirin-sensitive asthma  

Microsoft Academic Search

Cyclooxygenase (COX) -1 and COX-2 are expressed in airway cells, where their activities influence functions such as airway hyperreactivity. Clin- ical data show that mixed COX-1\\/COX-2 inhibitors such as aspirin, but not COX-2 selective inhibitors such as rofecoxib, induce bronchoconstriction and asthma in sensitive individuals. This anomaly has not yet been explained. Here, we have used tissue from genetically modified

Louise S. Harrington; Ruth Lucas; Shaun K. McMaster; Laura Moreno; Glenis Scadding; Timothy D. Warner; Jane A. Mitchell



Locally Weighted Projection Regression: An O(n) Algorithm for Incremental Learning in High Dimensional Space  

Microsoft Academic Search

Abstract Locally weighted projection regression is a new algorithm that achieves nonlinear function approximation in high dimensional spaces with redundant and irrelevant input dimensions. At its core, it uses locally linear models, spanned by a small number,of univariate regressions in selected directions in input space. This paper evaluates different methods,of projection regression and derives a nonlinear function approximator based on

S. Vijayakumar; S. Schaal



Stabilization of Cox1p intermediates by the Cox14p-Coa3p complex  

PubMed Central

Cox14p and Coa3p have been shown to regulate translation of the mitochondrial COX1 mRNA and to be required for assembly of cytochrome oxidase. We present evidence that Cox14p and Coa3p stabilize previously identified Cox1p intermediates and that in the absence of either protein, Cox1p aggregates with itself and other mitochondrial gene products, including cytochrome b, Var1p and Cox2p. Our evidence suggests that Cox1p assembly intermediates are in close proximity to other mitochondrially translated proteins and that an important function of Cox14p and Coa3p is to prevent Cox1 from entering into unproductive aggregation pathways.

McStay, Gavin P.; Su, Chen Hsien; Tzagoloff, Alexander



Spherical regression  

Microsoft Academic Search

Methods are introduced for regressing points on the surface of one sphere on points on another. Complex variables and stereographic projection are used to deal with theoretical problems of directional statistics much as they have been used historically to deal with problems in non-Euclidean geometry. The complex plane harbours the group of Möbius transformations, and stereographic projection is used as

T. D. Downs



Linear Regression  

NSDL National Science Digital Library

This site, created by Michelle Lacey of Yale University, gives an explanation, a definition and an example of linear regression. Topics include: least-squares, residuals, extrapolation, outliers, and influential observations. Lacey's presentation is thoughtful in its layout. The author intertwines useful graphs within her textual explanations, this makes it accessible for almost any mathematics audience. Overall, this is a useful resource.

Lacey, Michelle



Cyclooxygenase (COX)-1 activity precedes the COX-2 induction in A?-induced neuroinflammation.  


Two different isoforms of cyclooxygenases, COX-1 and COX-2, are constitutively expressed under normal physiological conditions of the central nervous system, and accumulating data indicate that both isoforms may be involved in different pathological conditions. However, the distinct role of COX-1 and COX-2 and the probable interaction between them in neuroinflammatory conditions associated with Alzheimer's disease are conflicting issues. The aim of this study was to elucidate the comparable role of each COX isoform in neuroinflammatory response induced by ?-amyloid peptide (A?). Using histological and biochemical methods, 13 days after stereotaxic injection of A? into the rat prefrontal cortex, hippocampal neuroinflammation and neuronal injury were confirmed by increased expression of tumor necrosis factor-alpha (TNF-?) and COX-2, elevated levels of prostaglandin E2 (PGE2), astrogliosis, activation of caspase-3, and neuronal cell loss. Selective COX-1 or COX-2 inhibitors, SC560 and NS398, respectively, were chronically used to explore the role of COX-1 and COX-2. Treatment with either COX-1 or COX-2 selective inhibitor or their combination equally decreased the level of TNF-?, PGE2, and cleaved caspase-3 and attenuated astrogliosis and neuronal cell loss. Interestingly, treatment with COX-1 selective inhibitor or the combined COX inhibitors prevented the induction of COX-2. These results indicate that the activity of both isoforms is detrimental in neuroinflammatory conditions associated with A?, but COX-1 activity is necessary for COX-2 induction and COX-2 activity seems to be the main source of PGE2 increment. PMID:20549385

Dargahi, Leila; Nasiraei-Moghadam, Shiva; Abdi, Azadeh; Khalaj, Leila; Moradi, Fatemeh; Ahmadiani, Abolhassan



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

ERIC Educational Resources Information Center

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…

Tanguma, Jesus


Bootstrapping to Test for Nonzero Population Correlation Coefficients Using Univariate Sampling  

ERIC Educational Resources Information Center

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"

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



QSAR investigations on benzylideneamino and phenyliminomethyl scaffolds for selective COX-2 inhibiton: a Hansch approach.  


Cyclooxygenase inhibitory and selectivity profile of a combined series of thirty one aryl sulphonamide compounds possessing 4-benzylideneamino or 4-phenyliminomethyl scaffolds were subjected to QSAR study using Hansch approach. The compounds in the selected series were characterized using classical aromatic substituent constants like hydrophobicity (pi), molar refractivity (MR), Hammett electronic (sigma), electronic field effect (F), resonance effect (R), and some indicator variables encoding molecular group contributions. Statistically significant QSAR models were generated using multiple regression analysis and cross-validation tools. The derived QSAR models demonstrated that the COX-2 selectivity over COX-1 is predominantly influenced by the central core -N=C- of the diaryl system. Further, the study also indicated that the electronic properties and structural variation in the para position of the phenyl ring (B) governs the COX-2 selectivity of the title compounds. The derived results reveal the important structural features significant for improved COX-2 inhibitory activity and selectivity of these novel aryl sulfonamides. PMID:19534677

Manivannan, E; Chaturvedi, S C



The Cox3p assembly module of yeast cytochrome oxidase  

PubMed Central

Yeast cytochrome oxidase (COX) was previously inferred to assemble from three modules, each containing one of the three mitochondrially encoded subunits and a different subset of the eight nuclear gene products that make up this respiratory complex. Pull-down assays of pulse-labeled mitochondria enabled us to characterize Cox3p subassemblies that behave as COX precursors and contain Cox4p, Cox7p, and Cox13p. Surprisingly, Cox4p is a constituent of two other complexes, one of which was previously proposed to be an intermediate of Cox1p biogenesis. This suggests that Cox4p, which contacts Cox1p and Cox3p in the holoenzyme, can be incorporated into COX by two alternative pathways. In addition to subunits of COX, some Cox3p intermediates contain Rcf1p, a protein associated with the supercomplex that stabilizes the interaction of COX with the bc1 (ubiquinol-cytochrome c reductase) complex. Finally, our results indicate that although assembly of the Cox1p module is not contingent on the presence of Cox3p, the converse is not true, as none of the Cox3p subassemblies were detected in a mutant blocked in translation of Cox1p. These studies support our proposal that Cox3p and Cox1p are separate assembly modules with unique compositions of ancillary factors and subunits derived from the nuclear genome.

Su, Chen-Hsien; McStay, Gavin P.; Tzagoloff, Alexander



COX23, a homologue of COX17, is required for cytochrome oxidase assembly.  


Deletion of reading frame YHR116W of the Saccharomyces cerevisiae nuclear genome elicits a respiratory deficiency. The encoded product, here named Cox23p, is shown to be required for the expression of cytochrome oxidase. Cox23p is homologous to Cox17p, a water-soluble copper protein previously implicated in the maturation of the Cu(A) center of cytochrome oxidase. The respiratory defect of a cox23 null mutant is rescued by high concentrations of copper in the medium but only when the mutant harbors COX17 on a high copy plasmid. Overexpression of Cox17p by itself is not a sufficient condition to rescue the mutant phenotype. Cox23p, like Cox17p, is detected in the intermembrane space of mitochondria and in the postmitochondrial supernatant fraction, the latter consisting predominantly of cytosolic proteins. Because Cox23p and Cox17p are not part of a complex, the requirement of both for cytochrome oxidase assembly suggests that they function in a common pathway with Cox17p acting downstream of Cox23p. PMID:15145942

Barros, Mario H; Johnson, Alisha; Tzagoloff, Alexander



Simulation from a known Cox MSM using standard parametric models for the g-formula.  


It is routinely argued that, unlike standard regression-based estimates, inverse probability weighted (IPW) estimates of the parameters of a correctly specified Cox marginal structural model (MSM) may remain unbiased in the presence of a time-varying confounder affected by prior treatment. Previously proposed methods for simulating from a known Cox MSM lack knowledge of the law of the observed outcome conditional on the measured past. Although unbiased IPW estimation does not require this knowledge, standard regression-based estimates rely on correct specification of this law. Thus, in typical high-dimensional settings, such simulation methods cannot isolate bias due to complex time-varying confounding as it may be conflated with bias due to misspecification of the outcome regression model. In this paper, we describe an approach to Cox MSM data generation that allows for a comparison of the bias of IPW estimates versus that of standard regression-based estimates in the complete absence of model misspecification. This approach involves simulating data from a standard parametrization of the likelihood and solving for the underlying Cox MSM. We prove that solutions exist and computations are tractable under many data-generating mechanisms. We show analytically and confirm in simulations that, in the absence of model misspecification, the bias of standard regression-based estimates for the parameters of a Cox MSM is indeed a function of the coefficients in observed data models quantifying the presence of a time-varying confounder affected by prior treatment. We discuss limitations of this approach including that implied by the 'g-null paradox'. PMID:24151138

Young, Jessica G; Tchetgen Tchetgen, Eric J



Immunohistochemical Evaluation of COX-1 and COX-2 Expression in Keloid and Hypertrophic Scar.  


: Both keloids (KLs) and hypertrophic scars (HSs) are considered as dermal fibroproliferative diseases that differ clinically and histopathologically. Although several factors have been postulated in the etiopathogenesis of these conditions, there has been growing evidence to suggest the role of COXs in the pathogenesis of abnormal wound healing because of the reduction of formation of KL and HS in patients using nonsteroidal anti-inflammatory drugs and a COX-2 inhibitor. The aim of the present work is to evaluate the pattern and localization of COX-1 and COX-2 expression in KL and HS compared with surgical scars. COX-1 and COX-2 were analyzed on skin biopsies of 30 patients who presented with KL (15) and HS (15) and 10 normal surgical scars (controls). Both COX-1 and COX-2 were expressed not only in dermal components (fibroblasts, inflammatory cells, and endothelial cells) but also in keratinocytes of the overlying epidermis in the different studied scar lesions. The percentage of COX-1 expression increased progressively from surgical scar (40%) to HS (53.3%) to KL (100%) with a statistically significant difference (P = 0.002). COX-2 was expressed in 100% of surgical scars, 73.3% of HS and 86.7% of KL with the absence of significant differences (P > 0.05). The significant difference in COX-1 expression between HS and KL may refer to the presence of different pathways for the emergence of these diseases. The expression of COX-2 in all scars (normal or abnormal) indicates its active role as an inflammatory mediator. Keratinocytes play an active role in induction of scarring by up-regulation of inflammatory mediators, such as COX-1 and COX-2. PMID:24061401

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



Hybrid fluorescent conjugates of COX-2 inhibitors: search for a COX-2 isozyme imaging cancer biomarker.  


The observation that the cyclooxygenase-2 (COX-2) isozyme is over-expressed in multiple types of cancer, relative to that in adjacent non-cancerous tissue, prompted this investigation to prepare a group of hybrid fluorescent conjugates wherein the COX inhibitors ibuprofen, (S)-naproxen, acetyl salicylic acid, a chlororofecoxib analog and celecoxib were coupled via a linker group to an acridone, dansyl or rhodamine B fluorophore. Within this group of compounds, the ibuprofen-acridone conjugate (10) showed potent and selective COX-2 inhibition (COX-2 IC(50)=0.67 ?M; SI=110.6), but its fluorescence emission (?(em)=417, 440 nm) was not suitable for fluorescent imaging of cancer cells that over-express the COX-2 isozyme. In comparison, the celecoxib-dansyl conjugate (25) showed a slightly lower COX-2 potency and selectivity (COX-2 IC(50)=1.1 ?M; SI>90) than the conjugate 10, and it possesses a better fluorescence emission (?(em)=500 nm). Ultimately, a celecoxib-rhodamine B conjugate (28) that exhibited moderate COX-2 potency and selectivity (COX-2 IC(50)=3.9 ?M; SI>25) having the best fluorescence emission (?(em)=580 nm) emerged as the most promising biomarker for fluorescence imaging using a colon cancer cell line that over-expresses the COX-2 isozyme. PMID:23200247

Bhardwaj, Atul; Kaur, Jatinder; Sharma, Sai Kiran; Huang, Zhangjian; Wuest, Frank; Knaus, Edward E



Is COX-2 a perpetrator or a protector? Selective COX-2 inhibitors remain controversial.  


COX-2(cyclooxygenase-2) has sparked a surge in pharmaceutical interest since its discovery at the beginning of the 1990s. Several COX-2 selective inhibitors that avoid gastrointestinal side effects have been successfully launched into the market in recent years. The first selective COX-2 inhibitor, celecoxib, entered the market in December 1998 [corrected] However, there are a few organs that physiologically and functionally express COX-2, particularly the glomeruli of the kidney and the cortex of the brain. Inhibition of COX-2 expression in these organs possibly causes heart attack and stroke in long-term COX-2 inhibitor users. Recently, a USA Food and Drug Agency (FDA) advisory panel re-evaluated COX-2 inhibitors and unanimously concluded that the entire class of COX-2 inhibitors increase the risk of cardiovascular problems. Thus the use of COX-2 inhibitors is still controversial, and there is a challenge for not only pharmacologists, but also the pharmaceutical industry, to develop improved painkilling and anti-inflammatory drugs. This may involve exploring a new generation of COX-2 inhibitors with different inhibitory mechanisms through computer-aided design, screening different sources of inhibitors with lower selectivity, or seeking completely new targets. Synthetic COX-2 inhibitors have high selectivity and the advantage of irreversible inhibition, whereas naturally derived COX-2 inhibitors have lower selectivity and fewer side effects, with the medical effects in general not being as striking as those achieved using synthetic inhibitors. This review discusses the mechanism of COX-2 inhibitor therapy and a possible new way of exploration in the development of anti-inflammatory, analgetic, and antipyretic drugs. PMID:16038624

Luo, Cheng; He, Ming-liang; Bohlin, Lars



Locally Weighted Projection Regression : An O(n) Algorithm for Incremental Real Time Learning in High Dimensional Space  

Microsoft Academic Search

Locally weighted projection regression is a new algorithm that achieves nonlinear function ap- proximation in high dimensional spaces with re- dundant and irrelevant input dimensions. At its core, it uses locally linear models, spanned by a small number of univariate regressions in se- lected directions in input space. This paper eval- uates different methods of projection regression and derives a

Sethu Vijayakumar; Stefan Schaal



Cyclooxygenase (COX) Inhibitors and the Newborn Kidney  

PubMed Central

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.

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



Weighted scores method for regression models with dependent data.  


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

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



Regression: A Bibliography.  

ERIC Educational Resources Information Center

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.…

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


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


We have identified a new plant gene, AtCOX17, encoding a protein that shares sequence similarity to COX17, a Cu-binding protein from yeast (Saccharomyces cerevisiae) and vertebrates that mediates the delivery of Cu to the mitochondria for the assembly of a functional cytochrome oxidase complex. The newly characterized Arabidopsis protein has six Cys residues at positions corresponding to those known to coordinate Cu binding in the yeast homolog. Moreover, we show that the Arabidopsis COX17 cDNA complements a COX17 mutant of yeast restoring the respiratory deficiency associated with that mutation. These two lines of evidence indicate that the plant protein identified here is a functional equivalent of yeast COX17 and might serve as a Cu delivery protein for the plant mitochondria. COX17 was identified by investigating the hypersensitive response-like necrotic response provoked in tobacco (Nicotiana tabacum) leaves after harpin inoculation. AtCOX17 expression was activated by high concentrations of Cu, bacterial inoculation, salicylic acid treatment, and treatments that generated NO and hydrogen peroxide. All of the conditions inducing COX17 are known to inhibit mitochondrial respiration and to produce an increase of reactive oxygen species, suggesting that gene induction occurs in response to stress situations that interfere with mitochondrial function. PMID:12177498

Balandin, Teresa; Castresana, Carmen



Distribution of constitutive (COX-1) and inducible (COX-2) cyclooxygenase in postviral human liver cirrhosis: a possible role for COX-2 in the pathogenesis of liver cirrhosis  

PubMed Central

Aims: Prostaglandins produced by the action of cyclooxygenases (COX) are important mediators of systemic vasodilatation and inflammation in liver cirrhosis. The aim of this study was to investigate the distribution of COX-1 and COX–2 in postviral cirrhosis. Methods: The immunohistochemical expression of the constitutive (COX-1) and the inducible (COX-2) isoenzymes was investigated in 15 patients with cirrhosis after hepatitis B and C infection; three normal control livers were also analysed. Results: COX-2 was absent from normal liver but was highly expressed in cirrhosis, mainly in the inflammatory, sinusoidal, vascular endothelial, and biliary epithelial cells. Low amounts of COX-1 were expressed in both normal and cirrhotic livers, exclusively in sinusoidal and vascular endothelial cells, with no differences seen between normal and cirrhotic livers. Conclusions: COX-2 is overexpressed in liver cirrhosis, and possibly contributes to prostaglandin overproduction, which may be a major component of the inflammation and hyperdynamic circulation associated with cirrhosis. Because COX-2 is thought to contribute to tumour development, high COX-2 production could be a contributor to hepatocellular carcinoma development in cirrhosis. The finding of COX-2 and not COX-1 upregulation in cirrhosis could provide a possible new role for selective COX-2 inhibitors in reducing inflammation and minimising the occurrence of hepatocellular carcinoma in patients with cirrhosis.

Mohammed, N A; El-Aleem, S A; El-Hafiz, H A; McMahon, R F T



Functional form diagnostics for Cox's proportional hazards model.  


We propose a new type of residual and an easily computed functional form test for the Cox proportional hazards model. The proposed test is a modification of the omnibus test for testing the overall fit of a parametric regression model, developed by Stute, González Manteiga, and Presedo Quindimil (1998, Journal of the American Statistical Association93, 141-149), and is based on what we call censoring consistent residuals. In addition, we develop residual plots that can be used to identify the correct functional forms of covariates. We compare our test with the functional form test of Lin, Wei, and Ying (1993, Biometrika80, 557-572) in a simulation study. The practical application of the proposed residuals and functional form test is illustrated using both a simulated data set and a real data set. PMID:15032776

León, Larry F; Tsai, Chih-Ling



Partial residuals for the proportional hazards regression model  

Microsoft Academic Search

SUMMARY Residuals are defined for the proportional hazards regression model introduced by Cox (1972). These residuals can be plotted against time to test the proportional hazards assumption. Histograms of these residuals can be used to examine fit and detect outlying covariate values.




Resistance exercise and cyclooxygenase (COX) expression in human skeletal muscle: implications for COX-inhibiting drugs and protein synthesis  

Microsoft Academic Search

ABSTRACT We have,shown,that ibuprofen and,acetaminophen,block cyclooxygenase,(COX) synthesis of prostaglandin PGF2? and the muscle,protein synthesis increase following resistance exercise. Confusingly, these two drugs are purported to work through different mechanisms, with acetaminophen apparently unable to block COX and ibuprofen able to non-specifically block COX-1 and,COX-2. A recently discovered intron-retaining COX, now known to have three variants, has been shown to be

E. M. Weinheimer; B. Jemiolo; C. C. Carroll; M. P. Harber; J. M. Haus; N. A. Burd; J. K. LeMoine; S. W. Trappe; T. A. Trappe



Sagbi bases of Cox–Nagata rings  

Microsoft Academic Search

We degenerate Cox-Nagata rings to toric algebras by means of sagbi bases\\u000ainduced by configurations over the rational function field. For del Pezzo\\u000asurfaces, this degeneration implies the Batyrev-Popov conjecture that these\\u000arings are presented by ideals of quadrics. For the blow-up of projective\\u000an-space at n+3 points, sagbi bases of Cox-Nagata rings establish a link between\\u000athe Verlinde formula

Bernd Sturmfels; Zhiqiang Xu



Oxidative switches in functioning of mammalian copper chaperone Cox17.  


Cox17, a copper chaperone for cytochrome-c oxidase, is an essential and highly conserved protein in eukaryotic organisms. Yeast and mammalian Cox17 share six conserved cysteine residues, which are involved in complex redox reactions as well as in metal binding and transfer. Mammalian Cox17 exists in three oxidative states, each characterized by distinct metal-binding properties: fully reduced mammalian Cox17(0S-S) binds co-operatively to four Cu+; Cox17(2S-S), with two disulfide bridges, binds to one of either Cu+ or Zn2+; and Cox17(3S-S), with three disulfide bridges, does not bind to any metal ions. The E(m) (midpoint redox potential) values for two redox couples of Cox17, Cox17(3S-S)<-->Cox17(2S-S) (E(m1)) and Cox17(2S-S)<-->Cox17(0S-S) (E(m2)), were determined to be -197 mV and -340 mV respectively. The data indicate that an equilibrium exists in the cytosol between Cox17(0S-S) and Cox17(2S-S), which is slightly shifted towards Cox17(0S-S). In the IMS (mitochondrial intermembrane space), the equilibrium is shifted towards Cox17(2S-S), enabling retention of Cox17(2S-S) in the IMS and leading to the formation of a biologically competent form of the Cox17 protein, Cox17(2S-S), capable of copper transfer to the copper chaperone Sco1. XAS (X-ray absorption spectroscopy) determined that Cu4Cox17 contains a Cu4S6-type copper-thiolate cluster, which may provide safe storage of an excess of copper ions. PMID:17672825

Voronova, Anastassia; Meyer-Klaucke, Wolfram; Meyer, Thomas; Rompel, Annette; Krebs, Bernt; Kazantseva, Jekaterina; Sillard, Rannar; Palumaa, Peep



Fuzzy Regression in Hydrology  

Microsoft Academic Search

A general methodology for fuzzy regression is developed and illustrated by an actual hydrological case study. Fuzzy regression may be used whenever a relationship between variables is imprecise and\\/or data are inaccurate and\\/or sample sizes are insufficient. In such cases fuzzy regression may be used as a complement or an alternative to statistical regression analysis. In fuzzy regression, several ``goodness

Andras Bardossy; Istvan Bogardi; Lucien Duckstein



Accuracy of Conventional and Marginal Structural Cox Model Estimators: A Simulation Study  

Microsoft Academic Search

Marginal structural models (MSM) provide a powerful tool to control for confounding by a time-dependent covariate without inappropriately adjusting for its role as a variable affected by treatment (Hernán et al., 2000). In this paper, we demonstrate that it is possible to fit a marginal structural Cox model directly, rather than the typical approach of using pooled logistic regression, using

Yongling Xiao; Michal Abrahamowicz; Erica E. M. Moodie



Choice of time-scale in Cox's model analysis of epidemiologic cohort data: a simulation study  

Microsoft Academic Search

SUMMARY Cox's regression model is widely used for assessing associations between potential risk factors and disease occurrence in epidemiologic cohort studies. Although age is often a strong determinant of disease risk, authors have frequently used time-on-study instead of age as the time-scale, as for clinical trials. Unless the baseline hazard is an exponential function of age, this approach can yield

Anne C. M. Thiebaut; Jacques Benichou


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

SciTech Connect

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

Johnson, M.E. (Los Alamos National Lab., NM); Tolley, H.D.; Bryson, M.C.; Goldman, A.S.



A Simulation Comparison of Univariate and Multivariate Analyses of a Multi-Factor Repeated Measures Design.  

ERIC Educational Resources Information Center

Although it is widely known that special assumptions are needed for univariate analysis of repeated measures data, researchers seldom examine their data for violation of these assumptions. This paper reviews ways in which repeated measures analyses are usually handled and describes limitations of these methods. A design with two within subject…

Berger, Dale E.; Selhorst, Susan C.


Genetic analyses of longitudinal phenotype data: a comparison of univariate methods and a multivariate approach  

Microsoft Academic Search

BACKGROUND: We explored three approaches to heritability and linkage analyses of longitudinal total cholesterol levels (CHOL) in the Genetic Analysis Workshop 13 simulated data without knowing the answers. The first two were univariate approaches and used 1) baseline measure at exam one or 2) summary measures such as mean and slope from multiple exams. The third method was a multivariate

Qiong Yang; Irmarie Chazaro; Jing Cui; Chao-Yu Guo; Serkalem Demissie; Martin Larson; Larry D Atwood; L Adrienne Cupples; Anita L DeStefano



Selection Strategies for Univariate Loglinear Smoothing Models and Their Effect on Equating Function Accuracy  

ERIC Educational Resources Information Center

In this study, we compared 12 statistical strategies proposed for selecting loglinear models for smoothing univariate test score distributions and for enhancing the stability of equipercentile equating functions. The major focus was on evaluating the effects of the selection strategies on equating function accuracy. Selection strategies' influence…

Moses, Tim; Holland, Paul W.



A general algorithm fob, univariate and multivariate goodness of pit tests based on graphical representation  

Microsoft Academic Search

This paper presents a general algorithm tor assessing the distributional assumptions. Empirical distributions of the corresponding test statistics are obtained and examples are given to illustrate various applications of the proposed test. By using the squared radii and angles, it is shown that the problem of assessing multivariate normality can be reduced to that of testing for a univariate distribution.

Aydin Ozturk



Univariate and Multivariate Autoregressive Time Series Models of Offensive Baseball Performance: 1901-2005  

Microsoft Academic Search

This paper sets out to estimate univariate time series models on a selected set of offensive baseball measures from 1901 to 2005. The measures include homeruns, bases on balls, runs batted in, doubles, and stolen bases. The paper next estimates the trends in these statistics simultaneously using a vector autoregressive time series model. Along the way, tests of assumptions underlying

David Kaplan



Univariate Polynomials: Nearly Optimal Algorithms for Numerical Factorization and Root-finding  

Microsoft Academic Search

To approximate all roots (zeros) of a univariate polynomial, we develop two eective algorithms and combine them in a single recursive process. One algorithm computes a basic well isolated zero-free annulus on the complex plane, whereas another algorithm numerically splits the input polynomial of the nth degree into two factors balanced in the degrees and with the zero sets separated

Victor Y. Pan



Optimal estimation of univariate black-box Lipschitz functions with upper and lower error bounds  

Microsoft Academic Search

We are given an unknown univariate Lipschitz continuous function that we wish to estimate by evaluating the function sequentially at distinct points. We provide a procedure for recursively selecting this sequence of points so that, averaging over points in the domain the resulting worst case error between the estimating and actual functions is minimized. Upper and lower bounds on these

Zelda B. Zabinsky; Robert L. Smith; Birna P. Kristinsdottir



A Comparative Study on DDF Curve with Bivariate and Univariate Model  

NASA Astrophysics Data System (ADS)

DDF(or IDF) curve is consisted with rainfall depth(or intensity), duration and frequency, and it is useful to see how rainfall changes in various conditions. Furthermore, recently, multivariate frequency analysis is applied to hydrology because of its scalability. In this study, to obtain DDF curve, rainfall quantile is estimated by both of univariate and bivariate(rainfall depth and duration) frequency analysis. For bivariate model, three copula models which are Frank, Gumbel-Hougaard, and Joe, are used in this study. Copula model has been studied widely for various fields, and it is flexible for marginal distribution than other conventional bivariate models. Hourly recorded data(1961~2010) of Seoul weather station from Korea Meteorological Administration (KMA) is applied for frequency analysis, and inter-event time definition is used for identification of rainfall events. For estimate parameters of copula models, maximum pseudo-likelihood estimation method which is semi-parametric method is used. Gumbel distribution is examined and used for rainfall depth, and generalized extreme value (GEV) distribution is examined and used for duration. As a result, 4 DDF curves are obtained (univariate, 3 copula models). In compared to univariate model, rainfall quantile of bivariate model unaffected by duration. In detail, Frank model shows closest trend along the duration, and Joe model doesn`t show the little changes along the duration. Change of rainfall quantile from bivariate model along the duration is less significant than univariate model as varying nonexceedance probability.

Joo, K.; Choi, S.; Heo, J.



A thurstonian pairwise choice model with univariate and multivariate spline transformations  

Microsoft Academic Search

A probabilistic choice model is developed for paired comparisons data about psychophysical stimuli. The model is based on Thurstone's Law of Comparative Judgment Case V and assumes that each stimulus is measured on a small number of physical variables. The utility of a stimulus is related to its values on the physical variables either by means of an additive univariate

Geert De Soete; Suzanne Winsberg



Genotype × × environment interaction for grain yield of some lentil genotypes and relationship among univariate stability statistics  

Microsoft Academic Search

Lentil (Lens culinaris Medik.) is traditionally grown as a rain fed crop, particularly in the Middle East; its seed is a rich source of protein for human consumption in developing countries such as Iran and others. The stability of 11 different lentil genotypes was investigated using 19 univariate stability parameters. Field experiments were conducted in 20 rain-fed environments in Iran's

H. Dehghani; S. H. Sabaghpour; N. Sabaghnia


Univariate analysis of test day milk yields of British Holstein?Friesian heifers using Gibbs sampling  

Microsoft Academic Search

Estimates of posterior distributions of genetic and phenotypic parameters and functions of them for individual test day milk yield are obtained for 28 873 British Holstein?Friesian heifers, the progeny of 40 proven and 649 unproven sires, using restricted maximum likelihood (REML) and Gibbs sampling methods with a univariate sire model. Results from the two methods are then compared. It is

Mehmet Z. Firat; Chris M. Theobald; Robin Thompson



Confidence Bands for the Median Survival Time as a Function of the Covariates in the Cox Model.  

National Technical Information Service (NTIS)

The proportional hazards model of Cox (1972) specifies that the hazard rate for an individual with covariate vector x is a certain equation where beta sub o is a vector of unknown-regression coefficients and lambda, the underlying baseline hazard rate, is...

D. Burr H. Doss



A simple method for estimating relative risk using logistic regression  

PubMed Central

Background Odds ratios (OR) significantly overestimate associations between risk factors and common outcomes. The estimation of relative risks (RR) or prevalence ratios (PR) has represented a statistical challenge in multivariate analysis and, furthermore, some researchers do not have access to the available methods. Objective: To propose and evaluate a new method for estimating RR and PR by logistic regression. Methods A provisional database was designed in which events were duplicated but identified as non-events. After, a logistic regression was performed and effect measures were calculated, which were considered RR estimations. This method was compared with binomial regression, Cox regression with robust variance and ordinary logistic regression in analyses with three outcomes of different frequencies. Results ORs estimated by ordinary logistic regression progressively overestimated RRs as the outcome frequency increased. RRs estimated by Cox regression and the method proposed in this article were similar to those estimated by binomial regression for every outcome. However, confidence intervals were wider with the proposed method. Conclusion This simple tool could be useful for calculating the effect of risk factors and the impact of health interventions in developing countries when other statistical strategies are not available.



Radionuclide concentrations in salt pans in the coastal area of Cox’s bazar, Bangladesh  

Microsoft Academic Search

Radionuclide concentrations of 226Ra, 232Th, 137Cs, 134Cs and 40K in samples of water, soil and salt from three gradients of salt pans (reservoir, condenser and crystalliser) in the coastal area of Cox’s Bazar, Bangladesh and in samples of refined salts were measured using ?-spectrometry. The activities of 226Ra in the salt pans were found to be in the range 3·18±1·02Bql-1

M. N. Alam; M. I. Chowdhury; M. Zafar; M. Kamal; S. Ghose; A. H. M. Kamal



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

PubMed Central

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.

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



Simple Logistic Regression  

NSDL National Science Digital Library

This page has two calculators. One will cacluate a simple logistic regression, while the other calculates the predicted probability and odds ratio. There is also a brief tutorial covering logistic regression using an example involving infant gestational age and breast feeding. Please note, however, that the logistic regression accomplished by this page is based on a simple, plain-vanilla empirical regression.

Lowry, Richard, 1940-



Mass univariate analysis of event-related brain potentials/fields I: a critical tutorial review.  


Event-related potentials (ERPs) and magnetic fields (ERFs) are typically analyzed via ANOVAs on mean activity in a priori windows. Advances in computing power and statistics have produced an alternative, mass univariate analyses consisting of thousands of statistical tests and powerful corrections for multiple comparisons. Such analyses are most useful when one has little a priori knowledge of effect locations or latencies, and for delineating effect boundaries. Mass univariate analyses complement and, at times, obviate traditional analyses. Here we review this approach as applied to ERP/ERF data and four methods for multiple comparison correction: strong control of the familywise error rate (FWER) via permutation tests, weak control of FWER via cluster-based permutation tests, false discovery rate control, and control of the generalized FWER. We end with recommendations for their use and introduce free MATLAB software for their implementation. PMID:21895683

Groppe, David M; Urbach, Thomas P; Kutas, Marta



Mass univariate analysis of event-related brain potentials/fields I: A critical tutorial review  

PubMed Central

Event-related potentials (ERPs) and magnetic fields (ERFs) are typically analyzed via ANOVAs on mean activity in a priori windows. Advances in computing power and statistics have produced an alternative, mass univariate analyses consisting of thousands of statistical tests and powerful corrections for multiple comparisons. Such analyses are most useful when one has little a priori knowledge of effect locations or latencies, and for delineating effect boundaries. Mass univariate analyses complement and, at times, obviate traditional analyses. Here we review this approach as applied to ERP/ERF data and four methods for multiple comparison correction: strong control of the family-wise error rate (FWER) via permutation tests, weak control of FWER via cluster-based permutation tests, false discovery rate control, and control of the generalized FWER. We end with recommendations for their use and introduce free MATLAB software for their implementation.

Groppe, David M.; Urbach, Thomas P.; Kutas, Marta



An empirical comparison of univariate and multivariate meta-analyses for categorical outcomes.  


Treatment effects for multiple outcomes can be meta-analyzed separately or jointly, but no systematic empirical comparison of the two approaches exists. From the Cochrane Library of Systematic Reviews, we identified 45 reviews, including 1473 trials and 258,675 patients, that contained two or three univariate meta-analyses of categorical outcomes for the same interventions that could also be analyzed jointly. Eligible were meta-analyses with at least seven trials reporting all outcomes for which the cross-classification tables were exactly recoverable (e.g., outcomes were mutually exclusive, or one was a subset of the other). This ensured known correlation structures. Outcomes in 40 reviews had an is-subset-of relationship, and those in 5 were mutually exclusive. We analyzed these data with univariate and multivariate models based on discrete and approximate likelihoods. Discrete models were fit in the Bayesian framework using slightly informative priors. The summary effects for each outcome were similar with univariate and multivariate meta-analyses (both using the approximate and discrete likelihoods); however, the multivariate model with the discrete likelihood gave smaller between-study variance estimates, and narrower predictive intervals for new studies. When differences in the summary treatment effects were examined, the multivariate models gave similar summary estimates but considerably longer (shorter) uncertainty intervals because of positive (negative) correlation between outcome treatment effects. It is unclear whether any of the examined reviews would change their overall conclusions based on multivariate versus univariate meta-analyses, because extra-analytical and context-specific considerations contribute to conclusions and, secondarily, because numerical differences were often modest. PMID:24285290

Trikalinos, Thomas A; Hoaglin, David C; Schmid, Christopher H



Analysis of Type I Error Rates of Univariate and Multivariate Procedures in Repeated Measures Designs  

Microsoft Academic Search

We compared the robustness of univariate and multivariate statistical procedures to control Type I error rates when the normality and homocedasticity assumptions were not fulfilled. The procedures we evaluated are the mixed model adjusted by means of the SAS Proc Mixed module, and Bootstrap-F approach, Brown–Forsythe multivariate approach, Welch–James multivariate approach, and Welch–James multivariate approach with robust estimators. The results

Pablo Livacic-Rojas; Guillermo Vallejo; Paula Fernández



Assessment of yield stability in sorghum using univariate and multivariate statistical approaches.  


The experiment was carried out to estimate GEI in sorghum for grain yield using univariate and multivariate statistical approaches based on two sets of performance trials (T1 and T2). While T1 consisted of 15 genotypes and tested in 8 environments, T2 that consisted of 13 genotypes was carried out in 13 environments. Because the combined ANOVA of each trial revealed significant differences among the genotypes, among the environments and GEI, the five univariate stability estimates: CV(i), S(i)(2), W(i)(2), sigma(i)(2), b(i) and Sd(i)(2) were evaluated for ranking the genotypes. There was positive rank-correlation between CVi and S(i)(2) and among W(i)(2), sigma(i)(2), b(i). Sd(i)(2) had significant positive rank-correlation with sigma(i)(2) and bi in T1 but weak rank-correlation with the remaining parameters in both trials. The three types of univariate stability estimates and the only multivariate stability estimate, the AMMI analysis declared genotypes 2 and 5 to be the most stable in T1, but they gave quite unrelated ranking in T2. Because of the lack of correspondence among the tested stability estimates in the two trials, it was difficult to reach a conclusion on producing genotype recommendation based on the univariate statistical approach. However, as GEI has multivariate nature, the multivariate approach is believed to give more robust inference. Hence, some stable genotypes were suggested using the AMMI model for sorghum growing dry lowlands of the country. PMID:18439231

Adugna, Asfaw



Univariate and multivariate forecasting of hourly solar radiation with artificial intelligence techniques  

Microsoft Academic Search

This paper introduces a new approach for the forecasting of mean hourly global solar radiation received by a horizontal surface. In addition to the traditional linear methods, several artificial-intelligence-based techniques are studied. These include linear, feed-forward, recurrent Elman and Radial Basis neural networks alongside the adaptive neuro-fuzzy inference scheme. The problem is examined initially for the univariate case, and is

A. Sfetsos; A. H. Coonick



A new non-polynomial univariate interpolation formula of Hermite type  

Microsoft Academic Search

A new C\\u000a ? interpolant is presented for the univariate Hermite interpolation problem. It differs from the classical solution in that\\u000a the interpolant is of non?polynomial nature. Its basis functions are a set of simple, compact support, transcendental functions.\\u000a The interpolant can be regarded as a truncated Multipoint Taylor series. It has essential singularities at the sample points,\\u000a but is

Ghislain Franssens



A univariate dimension-reduction method for multi-dimensional integration in stochastic mechanics  

Microsoft Academic Search

This paper presents a new, univariate dimension-reduction method for calculating statistical moments of response of mechanical systems subject to uncertainties in loads, material properties, and geometry. The method involves an additive decomposition of a multi-dimensional response function into multiple one-dimensional functions, an approximation of response moments by moments of single random variables, and a moment-based quadrature rule for numerical integration.

S. Rahman; H. Xu



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

NASA Astrophysics Data System (ADS)

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.

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



Unite and conquer: univariate and multivariate approaches for finding differentially expressed gene sets  

PubMed Central

Motivation: Recently, many univariate and several multivariate approaches have been suggested for testing differential expression of gene sets between different phenotypes. However, despite a wealth of literature studying their performance on simulated and real biological data, still there is a need to quantify their relative performance when they are testing different null hypotheses. Results: In this article, we compare the performance of univariate and multivariate tests on both simulated and biological data. In the simulation study we demonstrate that high correlations equally affect the power of both, univariate as well as multivariate tests. In addition, for most of them the power is similarly affected by the dimensionality of the gene set and by the percentage of genes in the set, for which expression is changing between two phenotypes. The application of different test statistics to biological data reveals that three statistics (sum of squared t-tests, Hotelling's T2, N-statistic), testing different null hypotheses, find some common but also some complementing differentially expressed gene sets under specific settings. This demonstrates that due to complementing null hypotheses each test projects on different aspects of the data and for the analysis of biological data it is beneficial to use all three tests simultaneously instead of focusing exclusively on just one. Contact: Supplementary information: Supplementary data are available at Bioinformatics online.

Glazko, Galina V.; Emmert-Streib, Frank



Employing Linear Regression in Regression Tree Leaves  

Microsoft Academic Search

. The advantage of using linear regressionin the leaves of a regression tree is analysed in thepaper. It is carried out how this modification affectsthe construction, pruning and interpretation of a regressiontree. The modification is tested on artificialand real-life domains. The results show that the modificationis beneficial as it leads to smaller classificationerrors of induced regression trees. Keywords: machinelearning, TDIDT,

Aram Karalic



Endothelium-mediated control of vascular tone: COX-1 and COX-2 products  

PubMed Central

Endothelium-dependent contractions contribute to endothelial dysfunction in various animal models of aging, diabetes and cardiovascular diseases. In the spontaneously hypertensive rat, the archetypal model for endothelium-dependent contractions, the production of the endothelium-derived contractile factors (EDCF) involves an increase in endothelial intracellular calcium concentration, the production of reactive oxygen species, the predominant activation of cyclooxygenase-1 (COX-1) and to a lesser extent that of COX-2, the diffusion of EDCF towards the smooth muscle cells and the subsequent stimulation of their thromboxane A2-endoperoxide TP receptors. Endothelium-dependent contractions are also observed in various models of hypertension, aging and diabetes. They generally also involve the generation of COX-1- and/or COX-2-derived products and the activation of smooth muscle TP receptors. Depending on the model, thromboxane A2, PGH2, PGF2?, PGE2 and paradoxically PGI2 can all act as EDCFs. In human, the production of COX-derived EDCF is a characteristic of the aging and diseased blood vessels, with essential hypertension causing an earlier onset and an acceleration of this endothelial dysfunction. As it has been observed in animal models, COX-1, COX-2 or both isoforms can contribute to these endothelial dysfunctions. Since in most cases, the activation of TP receptors is the common downstream effector, selective antagonists of this receptor should curtail endothelial dysfunction and be of therapeutic interest in the treatment of cardiovascular disorders. LINKED ARTICLES This article is part of a themed issue on Vascular Endothelium in Health and Disease. To view the other articles in this issue visit

Feletou, Michel; Huang, Yu; Vanhoutte, Paul M



Thinking outside the box about COX-1 in Alzheimer's disease.  


This article from Coma et al. shows that a salicylic acid derivative Triflusal, a platelet aggregation inhibitor and irreversible inhibitor of COX-1, can correct defects in axonal curvature and cognition in an AD transgenic mouse model (Tg2576) (Coma et al., 2010). Here we discuss the controversy over the role of COX-1 in AD, which has not been considered carefully in part due to the presumed adverse gastrointestinal effects of COX-1 antagonism. However, recent clinical data from this group as well as other groups challenges this assumption that COX-1 antagonism will be associated with side effects. Most importantly this article raises critical questions about the role of COX-1, versus COX-2 versus both in Abeta pathogenesis. The animal model data in this article as well as the recently published trial data suggest that COX-1 may play an important role in early pathogenesis and should not be ignored as a potential target for early intervention. PMID:20206264

Frautschy, Sally A



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


Although nonsteroidal anti-inflammatory drugs often cause ulcers in the duodenum in humans, the role of cyclooxygenase (COX) isoforms in the pathogenesis of duodenal ulcers has not been fully elucidated. We examined in cats the 1) ulcerogenic effects of selective COX-1 (SC-560, ketorolac) and COX-2 (celecoxib, meloxicam) inhibitors on the gastrointestinal mucosa, 2) effect of feeding and cimetidine on the expression of COX isoforms and prostaglandin E(2) (PGE(2)) level in the duodenum, and 3) localization of COX isoforms in the duodenum. COX inhibitors were administered after the morning meal in cats once daily for 3 days. Gastrointestinal lesions were examined on day 4. Localization and expression of COX isoforms (by immunohistochemistry, Western blot) and PGE(2) level (by enzyme immunoassay) were examined. Results were as follows. First, selective COX-1 or COX-2 inhibitors alone produced marked ulcers in the duodenum but did not cause obvious lesions in the small intestine. Coadministration of SC-560 and celecoxib produced marked lesions in the small intestine. Second, feeding increased both the expression of COX isoforms and PGE(2) level in the duodenum, and the effects were markedly inhibited by pretreatment with cimetidine. Third, COX-1 was localized in goblet and Brunner's gland cells, Meissner's and Auerbach's plexus, smooth muscle cells, and arterioles; and COX-2 was observed in capillaries, venules, and basal granulated cells. The expression of COX isoforms in the duodenum is up-regulated by feeding, and inhibition of either COX-1 or COX-2 causes ulcers in the duodenum, suggesting that both isoforms play an important role in the protection of the duodenal mucosa. PMID:23008503

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



Inhibition of COX in ocular tissues: an in vitro model to identify selective COX-2 inhibitors.  


The aim of this work was to study the regulation of LPS-stimulated PGE 2 synthesis by traditional NSAIDs (piroxicam and diclofenac) and a selective COX-2 inhibitor (NS-398), in cultured bovine corneal endothelial cells and retinal pigmentary epithelial cells. The IC50 values of piroxicam and diclofenac were compared with IC50 values of NS-398, diclofenac, in both types of cells, showed higher potency than piroxicam. Diclofenac seemed to be a COX-2 inhibitor because its IC50 values were similar to the IC50 values of NS-398. We suggest that this in vitro cell assay system could be useful for identifying compounds that selectively inhibit COX-2 in ocular tissues. PMID:11322639

García-Cabanes, C; Palmero, M; Bellot, J L; Castillo, M; Orts, A



Factor analysis regression  

Microsoft Academic Search

In the presence of multicollinearity the literature points to principal component regression (PCR) as an estimation method\\u000a for the regression coefficients of a multiple regression model. Due to ambiguities in the interpretation, involved by the\\u000a orthogonal transformation of the set of explanatory variables, the method could not yet gain wide acceptance. Factor analysis\\u000a regression (FAR) provides a model-based estimation method

Reinhold Kosfeld; Jørgen Lauridsen



Partial least squares (PLS) regression for the analysis of instrument measurements and sensory meat quality data  

Microsoft Academic Search

The partial least squares (PLS) regression technique was used to examine meat quality data derived from instruments (including Warner–Bratzler shear force and Instron Compression) and sensory panels. The data related to beef longissimus dorsi muscles collected during trials to study the effect of hot boning on meat quality. The univariate analysis of tenderness showed that over 60% of the variation

P. J. Toscas; F. D. Shaw; S. L. Beilken



Cancer chemoprevention by cyclooxygenase 2 (COX-2) blockade: results of case control studies.  


Significant use of selective cyclooxygenase-2 (COX-2) blocking agents prescribed for the treatment of arthritis during 1999 to 2005 facilitates epidemiologic investigations to illuminate their chemopreventive effects against human cancer. We therefore conducted a set of case control studies of selective COX-2 blocking agents to determine their chemopreventive potential for the four major cancers: breast, prostate, colon, and lung. Newly diagnosed cases (323 breast cancer patients, 229 prostate cancer patients, 326 colon cancer patients, and 486 lung cancer patients) were ascertained during 2002 to September 30, 2004, at The James Cancer Hospital and Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio. All cases of invasive cancer were confirmed by examination of the pathology report. Healthy controls without cancer were ascertained from hospital screening clinics during the same time period. Controls were frequency matched at a rate of 2:1 to the cases by age, gender, and county of residence. We collected information on type, frequency, and duration of use of selective COX-2 inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Other potentially important risk factors (smoking, drinking, body mass, medical history, blood pressure and cholesterol medications, family history of cancer, occupational history, and reproductive history for women) were also recorded for each subject. Estimates of odds ratios were obtained with adjustment for age and other potential confounders using logistic regression analysis. Use of selective COX-2 inhibitors resulted in a significant risk reduction for each type of cancer (71% for breast cancer, 55% for prostate cancer, 70% for colon cancer, and 79% for lung cancer) and an overall 68% risk reduction for all four cancers. This investigation demonstrates that COX-2 blocking agents have strong potential for the chemoprevention of cancers of the breast, prostate, colon and lung. PMID:17612052

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



Inference on the Univariate Frailty Model: A Bayesian Reference Analysis Approach  

NASA Astrophysics Data System (ADS)

In this work we present an approach involving objective Bayesian reference analysis to the Frailty model with univariate survival time and sources of heterogeneity that are not captured by covariates. The derivation unconditional hazard and survival leads to the Lomax distribution, also known as the Pareto distribution of the second kind. This distribution has an important position in life testing to adjust data from business failures. Reference analysis, introduced by Bernardo (1979) produce a new solution for this problem. The results are illustrated with survival data analyzed in the literature and simulated data.

Tomazella, Vera Lucia D.; Martins, Camila Bertini; Bernardo, Jose Miguel



Univariate polynomial equation providing on-lattice higher-order models of thermal lattice Boltzmann theory  

NASA Astrophysics Data System (ADS)

A univariate polynomial equation is presented. It provides on-lattice higher-order models of the thermal lattice Boltzmann equation. The models can be accurate up to any required level and can be applied to regular lattices, which allow efficient and accurate approximate solutions of the Boltzmann equation. We derive models approaching the complete Galilean invariant and providing accuracy of the fourth-order moment and beyond. We simulate one-dimensional thermal shock tube problems to illustrate the accuracy of our models. Moreover, we show the remarkably enhanced stability obtained by our models and our discretized equilibrium distributions.

Shim, Jae Wan



Utilizing PHREG for Cox Proportional Hazards Regression Modeling with Time-Varying Covariates  

Microsoft Academic Search

When conducting time-to-event analyses for prospective clinical studies (where data is collected at time intervals), it is appropriate to utilize all information available. Missing data issues can also arise when modeling data of this nature. Conventions such as Last Value Carried Forward (LVCF) may be used to account for the missingness in covariates. In this paper, we describe an easy

Marla Husnik; Eugene Huang


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

SciTech Connect

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.

Colleselli, Daniela [Pneumology Service-Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck (Austria); Bijuklic, Klaudija [Inflammation Research, Laboratory Division of General Internal Medicine, Department of Internal Medicine, Medical University of Innsbruck (Austria); Mosheimer, Birgit A. [Inflammation Research, Laboratory Division of General Internal Medicine, Department of Internal Medicine, Medical University of Innsbruck (Austria); Kaehler, Christian M. [Pneumology Service-Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck (Austria)]. E-mail:



The Mitochondrial Genome of Conus textile, coxI-coxII Intergenic Sequences and Conoidean Evolution  

PubMed Central

The cone snails belong to the superfamily Conoidea, comprising ?10,000 venomous marine gastropods. We determined the complete mitochondrial DNA sequence of Conus textile. The gene order is identical in Conus textile, Lophiotoma cerithiformis (another Conoidean gastropod), and the neogastropod Ilyanassa obsoleta, (not in the superfamily Conoidea). However, the intergenic interval between the coxI/coxII genes, was much longer in C. textile (165 bp) than in any other previously analyzed gastropod. We used the intergenic region to evaluate evolutionary patterns. In most neogastropods and three conidean families the intergenic interval is small (<30 nucleotides). Within Conus, the variation is from 130-170 bp, and each different clade within Conus has a narrower size distribution. In Conasprella, a subgenus traditionally assigned to Conus, the intergenic regions vary between 200-500 bp, suggesting that the species in Conasprella are not congeneric with Conus. The intergenic region was used for phylogenetic analysis of a group of fish-hunting Conus, despite the short length resolution was better than using standard markers. Thus, the coxI/coxII intergenic region can be used both to define evolutionary relationships between species in a clade, and to understand broad evolutionary patterns across the large superfamily Conoidea.

Bandyopadhyay, Pradip K; Stevenson, Bradford J.; Ownby, John-Paul; Cady, Matthew T.; Watkins, Maren; Olivera, Baldomero M.



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

NASA Astrophysics Data System (ADS)

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.

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



A Guideline to Univariate Statistical Analysis for LC/MS-Based Untargeted Metabolomics-Derived Data  

PubMed Central

Several metabolomic software programs provide methods for peak picking, retention time alignment and quantification of metabolite features in LC/MS-based metabolomics. Statistical analysis, however, is needed in order to discover those features significantly altered between samples. By comparing the retention time and MS/MS data of a model compound to that from the altered feature of interest in the research sample, metabolites can be then unequivocally identified. This paper reports on a comprehensive overview of a workflow for statistical analysis to rank relevant metabolite features that will be selected for further MS/MS experiments. We focus on univariate data analysis applied in parallel on all detected features. Characteristics and challenges of this analysis are discussed and illustrated using four different real LC/MS untargeted metabolomic datasets. We demonstrate the influence of considering or violating mathematical assumptions on which univariate statistical test rely, using high-dimensional LC/MS datasets. Issues in data analysis such as determination of sample size, analytical variation, assumption of normality and homocedasticity, or correction for multiple testing are discussed and illustrated in the context of our four untargeted LC/MS working examples.

Vinaixa, Maria; Samino, Sara; Saez, Isabel; Duran, Jordi; Guinovart, Joan J.; Yanes, Oscar



Reduced risk of human lung cancer by selective cyclooxygenase 2 (COX-2) blockade: results of a case control study.  


We conducted a case control study of selective cyclooxygenase-2 (COX-2) blocking agents and lung cancer. A total of 492 newly diagnosed lung cancer cases were ascertained during January 1, 2002 to September 30, 2004, at The Ohio State University Medical Center, Columbus, Ohio. All cases were confirmed by examination of the pathology report. Healthy population controls without cancer were ascertained during the same time period. Controls were frequency matched at a rate of 2:1 to the cases by age, gender, and county of residence. We collected information on type, frequency, and duration of use of selective COX-2 inhibitors (primarily celecoxib or rofecoxib) and nonselective NSAIDs such as ibuprofen and aspirin. Estimates of odds ratios (OR) were obtained with adjustment for cigarette smoking, age and other potential confounders using logistic regression analysis. Odds Ratios for selective COX-2 inhibitors were adjusted for past use of other NSAIDs. Use of any selective COX-2 inhibitor for more than one year produced a significant (60%) reduction in the risk of lung cancer (OR=0.40, 95% CI=0.19-0.81). Observed risk reductions were consistent for men (OR=0.26, 95% CI=0.10-0.62) and women (OR=0.52, 95% CI=0.24-1.13) and for individual COX-2 inhibitors (OR=0.28, 95% CI=-0.12-0.67, for celecoxib and OR=0.55, 95% CI=0.19-1.56, for rofecoxib). Intake of ibuprofen or aspirin also produced significant risk reductions (OR=0.40, 95% CI=0.23-0.73 and OR=0.53, 95% CI=0.34-0.82, respectively), whereas acetaminophen, an analgesic with negligible COX-2 activity, had no effect on the risk (OR=1.36, 95% CI=0.53-3.37). This investigation demonstrates for the first time that selective COX-2 blocking agents have strong potential for the chemoprevention of human lung cancer. PMID:17589567

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



Analysis of the effects of cyclooxygenase (COX)-1 and COX-2 in spinal nociceptive transmission using indomethacin, a non-selective COX inhibitor, and NS-398, a COX-2 selective inhibitor.  


Prostaglandins are now thought to play an important role in nociceptive information transmission in the spinal cord. Prostaglandins are known to be produced by cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid. Two forms of COX have been identified: COX-1, which is constitutively expressed in most tissues and organs, and COX-2, which is an inducible enzyme and is localized primarily in inflammatory cells and tissues. COX-2 mRNA has been reported to be expressed in the brain in normal rats. We investigated the role of COX-1 and COX-2 in the spinal nociceptive transmission during the rat formalin test and the hot plate test using indomethacin, a non-selective COX-1 and COX-2 inhibitor, and NS398, a selective COX-2 inhibitor. In the formalin test, drugs were administered intrathecally or intraperitoneally 10 min before (pre-treatment study) or 7 min after (post-treatment study) the formalin injection. Both intrathecally administered indomethacin and NS398 inhibited the formalin induced flinching behavior in a dose-dependent manner in the pre-treatment study, but not in the post-treatment study. Both indomethacin and NS398 had no effect on the hot plate test at a dose which depressed the formalin induced flinching behavior. These data suggested that COX-2 is expressed in the central nervous system, including the spinal cord, and that COX-2 plays an important role in the spinal nociceptive transmission during the formalin test, but not during the hot plate test. PMID:8955930

Yamamoto, T; Nozaki-Taguchi, N



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


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

Misra, Shashank; Sharma, Kulbhushan



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

NASA Astrophysics Data System (ADS)

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.

Ismail, A.; Hassan, Noor I.



Explorations in statistics: regression  

NSDL National Science Digital Library

This article 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. Regression helps us answer three questions: does some variable Y depend on another variable X; if so, what is the nature of the relationship between Y and X; and for some value of X, what value of Y do we predict? Residual plots are an essential component of a thorough regression analysis: they help us decide if our statistical regression model of the relationship between Y and X is appropriate.

PhD Douglas Curran-Everett (National Jewish Medical and Research Center Div. Biostatistics, Depts. Prev. Med./Biometrics, Physiology/Biophys)



Censored quantile regression with recursive partitioning-based weights.  


Censored quantile regression provides a useful alternative to the Cox proportional hazards model for analyzing survival data. It directly models the conditional quantile of the survival time and hence is easy to interpret. Moreover, it relaxes the proportionality constraint on the hazard function associated with the popular Cox model and is natural for modeling heterogeneity of the data. Recently, Wang and Wang (2009. Locally weighted censored quantile regression. Journal of the American Statistical Association 103, 1117-1128) proposed a locally weighted censored quantile regression approach that allows for covariate-dependent censoring and is less restrictive than other censored quantile regression methods. However, their kernel smoothing-based weighting scheme requires all covariates to be continuous and encounters practical difficulty with even a moderate number of covariates. We propose a new weighting approach that uses recursive partitioning, e.g. survival trees, that offers greater flexibility in handling covariate-dependent censoring in moderately high dimensions and can incorporate both continuous and discrete covariates. We prove that this new weighting scheme leads to consistent estimation of the quantile regression coefficients and demonstrate its effectiveness via Monte Carlo simulations. We also illustrate the new method using a widely recognized data set from a clinical trial on primary biliary cirrhosis. PMID:23975800

Wey, Andrew; Wang, Lan; Rudser, Kyle



Recurrent events and the exploding Cox model  

PubMed Central

Counting process models have played an important role in survival and event history analysis for more than 30 years. Nevertheless, almost all models that are being used have a very simple structure. Analyzing recurrent events invites the application of more complex models with dynamic covariates. We discuss how to define valid models in such a setting. One has to check carefully that a suggested model is well defined as a stochastic process. We give conditions for this to hold. Some detailed discussion is presented in relation to a Cox type model, where the exponential structure combined with feedback lead to an exploding model. In general, counting process models with dynamic covariates can be formulated to avoid explosions. In particular, models with a linear feedback structure do not explode, making them useful tools in general modeling of recurrent events.

Gjessing, Hakon K.; R?ysland, Kjetil; Pena, Edsel A.; Aalen, Odd O.



The Heme a Synthase Cox15 Associates with Cytochrome c Oxidase Assembly Intermediates during Cox1 Maturation  

PubMed Central

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.

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



Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers.  


Steady-state inhibitory activity of rofecoxib (Vioxx) on COX-2 versus COX-1 was compared with that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole-blood assays were used to determine the effect on COX-2 and COX-1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX-2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]-induced PGE2 generation over 8 hours on day 6 vs. baseline) was -2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, rofecoxib 12.5 mg, rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX-1 (measured as TXB2 generation in clotting whole blood) were -5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11-dehydro TXB2, a COX-1-derived product. These data support the contention that rofecoxib is the only drug of the regimens tested that uniquely inhibits COX-2 without affecting COX-1. PMID:11028250

Van Hecken, A; Schwartz, J I; Depré, M; De Lepeleire, I; Dallob, A; Tanaka, W; Wynants, K; Buntinx, A; Arnout, J; Wong, P H; Ebel, D L; Gertz, B J; De Schepper, P J



Spatiotemporal linear mixed effects modeling for the mass-univariate analysis of longitudinal neuroimage data.  


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

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



First Instances of Univariate and Tensor-product Multivariate Generalized Expo-Rational Finite Elements  

NASA Astrophysics Data System (ADS)

We consider a construction of finite elements (FE) which is, in some sense, dual to the construction of generalized expo-rational B-splines (GERBS)[1, 2]. The main result is the introduction of univariate and multivariate tensor-product GERBS-based FE which exhibit Hermite interpolatory properties. The derivation of these results is based on the theory of C?-smooth expo-rational B-splines (ERBS) and Ck-smooth, k = 0,1,2,... piecewise polynomial GERBS called Euler Beta-function B-splines. We provide visualization of the approximations of some model curves and surfaces using the new FE, as well as of the size and distribution of the error of these approximations.

Dechevsky, Lubomir T.; Zanaty, Peter



Mass Univariate Analysis of Event-Related Brain Potentials/Fields II: Simulation Studies  

PubMed Central

Mass univariate analysis is a relatively new approach for the study of ERPs/ERFs. It consists of many statistical tests and one of several powerful corrections for multiple comparisons. Multiple comparison corrections differ in their power and permissiveness. Moreover, some methods are not guaranteed to work or may be overly sensitive to uninteresting deviations from the null hypothesis. Here we report the results of simulations assessing the accuracy, permissiveness, and power of six popular multiple comparison corrections (permutation-based control of the family-wise error rate: FWER, weak control of FWER via cluster-based permutation tests, permutation based control of the generalized FWER, and three false discovery rate control procedures) using realistic ERP data. In addition, we look at the sensitivity of permutation tests to differences in population variance. These results will help researchers apply and interpret these procedures.

Groppe, David M.; Urbach, Thomas P.; Kutas, Marta



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

PubMed Central

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

Sokolowski, Grzegorz; Baldys-Waligorska, Agata; Trofimiuk, Malgorzata; Adamek, Dariusz; Hubalewska-Dydejczyk, Alicja; Golkowski, Filip



A structural-dynamical characterization of human Cox17.  


Human Cox17 is a key mitochondrial copper chaperone responsible for supplying copper ions, through the assistance of Sco1, Sco2, and Cox11, to cytochrome c oxidase, the terminal enzyme of the mitochondrial energy transducing respiratory chain. A structural and dynamical characterization of human Cox17 in its various functional metallated and redox states is presented here. The NMR solution structure of the partially oxidized Cox17 (Cox17(2S-S)) consists of a coiled coil-helix-coiled coil-helix domain stabilized by two disulfide bonds involving Cys(25)-Cys(54) and Cys(35)-Cys(44), preceded by a flexible and completely unstructured N-terminal tail. In human Cu(I)Cox17(2S-S) the copper(I) ion is coordinated by the sulfurs of Cys(22) and Cys(23), and this is the first example of a Cys-Cys binding motif in copper proteins. Copper(I) binding as well as the formation of a third disulfide involving Cys(22) and Cys(23) cause structural and dynamical changes only restricted to the metal-binding region. Redox properties of the disulfides of human Cox17, here investigated, strongly support the current hypothesis that the unstructured fully reduced Cox17 protein is present in the cytoplasm and enters the intermembrane space (IMS) where is then oxidized by Mia40 to Cox17(2S-S), thus becoming partially structured and trapped into the IMS. Cox17(2S-S) is the functional species in the IMS, it can bind only one copper(I) ion and is then ready to enter the pathway of copper delivery to cytochrome c oxidase. The copper(I) form of Cox17(2S-S) has features specific for copper chaperones. PMID:18093982

Banci, Lucia; Bertini, Ivano; Ciofi-Baffoni, Simone; Janicka, Anna; Martinelli, Manuele; Kozlowski, Henryk; Palumaa, Peep



Mutational analysis of the mitochondrial copper metallochaperone Cox17.  


The copper metallochaperone Cox17 is proposed to shuttle Cu(I) ions to the mitochondrion for the assembly of cytochrome c oxidase. The Cu(I) ions are liganded by cysteinyl thiolates. Mutational analysis on the yeast Cox17 reveals three of the seven cysteinyl residues to be critical for Cox17 function, and these three residues are present in a Cys-Cys-Xaa-Cys sequence motif. Single substitution of any of these three cysteines with serines results in a nonfunctional cytochrome oxidase complex. Cells harboring such a mutation fail to grow on nonfermentable carbon sources and have no cytochrome c oxidase activity in isolated mitochondria. Wild-type Cox17 purified as untagged protein binds three Cu(I) ions/molecule. Mutant proteins lacking only one of these critical Cys residues retain the ability to bind three Cu(I) ions and are imported within the mitochondria. In contrast, Cox17 molecules with a double Cys --> Ser mutation exhibit no Cu(I) binding but are still localized to the mitochondria. Thus, mitochondrial uptake of Cox17 is not restricted to the Cu(I) conformer of Cox17. COX17 was originally cloned by virtue of complementation of a mutant containing a nonfunctional Cys --> Tyr substitution at codon 57. The mutant C57Y Cox17 fails to accumulate within the mitochondria but retains the ability to bind three Cu(I) ions. A C57S Cox17 variant is functional, and a quadruple Cox17 mutant with C16S/C36S/C47S/C57S substitutions binds three Cu(I) ions. Thus, only three cysteinyl residues are important for the ligation of three Cu(I) ions. A novel mode of Cu(I) binding is predicted. PMID:10970896

Heaton, D; Nittis, T; Srinivasan, C; Winge, D R



No Association of nineteen COX-2 gene variants to preclinical markers of atherosclerosis The Cardiovascular Risk in Young Finns Study  

PubMed Central

Backgroud The role of cyclooxygenase-2 (COX-2) single nucleotide polymorphisms has mostly been studied in relation to advanced atherosclerosis, but little is known how they contribute to preclinical disease. In the present study we analyzed whether COX-2 gene variants associate independently with the early subclinical markers of atherosclerosis, carotid intima-media thickness and carotid artery distensibility in a population of young healthy Caucasian adults. Methods SNPs for association analysis were collected from the COX-2 gene and 5?kb up- and downstream of it. There were 19 SNPs available for analysis, four genotyped and fifteen imputed. Genotype data was available for 2442 individuals participating in the Cardiovascular Risk in Young Finns Study. Genotype imputation was performed using MACH 1.0 and HapMap II CEU (release 22) samples as reference. Association analysis was performed using linear regression with an additive model. PLINK was used for true genotyped SNPs and ProbABEL for imputed genotype dosages. False discovery rate was used to take into account multiple testing bias. Results Two of the COX-2 variants (rs689470, rs689462) associated with distensibility (p?=?0.005) under the linear regression additive model. After adjustment with gender, age, body mass index and smoking status, association between these SNPs and distensibility remained significant (p?=?0.031). Subjects carrying the minor alleles had higher value of carotid artery distensibility compared to the major allele homozygotes. However, after correcting p-values for multiple testing bias using false discovery rate, association was lost. Another COX-2 variant rs4648261 associated with mean carotid intima-media thickness (p?=?0.046) and maximal carotid intima-media thickness (p?=?0.048) in the linear regression model. Subjects carrying the minor allele of rs4648261 had lower values of mean and maximal carotid intima-media thickness compared to subjects homozygote for major allele. After adjustments the associations were lost with both mean and maximal carotid intima-media thickness. Thus, no statistically significant associations of the studied COX-2 variants with carotid artery distensibility or carotid intima-media thickness were found. Conclusions Our results suggest that in a Finnish population, there are no significant associations between COX-2 variants and early atherosclerotic changes in young adulthood.



Morse-Smale Regression  

PubMed Central

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.

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



Lesson 6: Linear Regression  

NSDL National Science Digital Library

Using real world data, this lesson introduces linear regression using lines of best fit that may calculated by hand by selecting two pints that appear to fall on the line of best fit. The lesson could also be used with a calculator to find the actual regression line. Interpolation and extrapolation are also introduced as well as scatter plots.



DISCUSS: Regression and Correlation  

NSDL National Science Digital Library

This module introduces correlation and regression through topics like scatterplots, lines, slopes, intercepts, applications of regression analysis, the line of best fit, goodness of fit, assumptions and how to check them, prediction, interpolation, extrapolation, and reliability. Excel spreadsheets are used to provide examples and exercises.

Hunt, Neville; Nicholson, James; Tyrrell, Sidney



Multiple Instance Regression  

Microsoft Academic Search

This paper introduces multiple instance re- gression, a variant of multiple regression in which each data point may be described by more than one vector of values for the inde- pendent variables. The goals of this work are to (1) understand the computational com- plexity of the multiple instance regression task and (2) develop an ecien t algorithm that is

Soumya Ray; David Page



Extremal quantile regression  

Microsoft Academic Search

Quantile regression is an important tool for estimation of conditional quantiles of a response Y given a vector of covariates X. It can be used to measure the effect of covariates not only in the center of a distribution, but also in the upper and lower tails. This paper develops a theory of quantile regression in the tails. Specifically, it

Victor Chernozhukov



Gini's Multiple Regressions  

Microsoft Academic Search

Two regression methods can be interpreted as based on Gini's mean difference (GMD). One relies on a weighted average of slopes defined between adjacent observations and the other is based on minimization of the GMD of the errors. The properties of the former approach are investigated in a multiple regression framework. These estimators have representations that resemble the OLS estimators,

Edna Schechtman; Shlomo Yitzhaki


Cointegrating Polynomial Regressions  

Microsoft Academic Search

This paper develops a fully modified OLS estimator for cointegrating polynomial regressions, i.e. for regressions including deterministic variables, integrated processes and powers of integrated processes as explanatory variables and stationary errors. The errors are allowed to be serially correlated and the regressors are allowed to be endogenous. The paper thus extends the fully modified approach developed in Phillips and Hansen

Seung Hyun Hong; Martin Wagner



Multivariable Cox Proportional Hazard Model by SAS PHREG & Validation by Bootstrapping Using SAS Randomizers With Applications Involving Electrocardiology and Organ Transplants  

Microsoft Academic Search

The paper presents statistical procedures of multivariable model building for survival analysis of patients undergoing surgery with many preoperative risk factors. In the first example we have added electrocardiologic risk factors to the traditional clinical and demographic risk factors. All analyses were performed on SAS 6.12. The procedure described here mainly concentrates on Cox's regression analysis with risk factors assumed

Sudhanshu K. Ghoshal


Novel COX-2 Inhibitor for Breast Cancer Therapy.  

National Technical Information Service (NTIS)

Recent studies have shown that NSAIDS such as aspirin reduce the incidence of human cancers by inhibiting the enzyme Cyclooxygenase (COX), which plays a key role in arachidonic acid metabolism. It is now known that COX exists in at leas two isoforms, term...

E. P. Reddy



Investigating univariate temporal patterns for intrinsic connectivity networks based on complexity and low-frequency oscillation: a test-retest reliability study.  


Intrinsic connectivity networks (ICNs) are composed of spatial components and time courses. The spatial components of ICNs were discovered with moderate-to-high reliability. So far as we know, few studies focused on the reliability of the temporal patterns for ICNs based their individual time courses. The goals of this study were twofold: to investigate the test-retest reliability of temporal patterns for ICNs, and to analyze these informative univariate metrics. Additionally, a correlation analysis was performed to enhance interpretability. Our study included three datasets: (a) short- and long-term scans, (b) multi-band echo-planar imaging (mEPI), and (c) eyes open or closed. Using dual regression, we obtained the time courses of ICNs for each subject. To produce temporal patterns for ICNs, we applied two categories of univariate metrics: network-wise complexity and network-wise low-frequency oscillation. Furthermore, we validated the test-retest reliability for each metric. The network-wise temporal patterns for most ICNs (especially for default mode network, DMN) exhibited moderate-to-high reliability and reproducibility under different scan conditions. Network-wise complexity for DMN exhibited fair reliability (ICC<0.5) based on eyes-closed sessions. Specially, our results supported that mEPI could be a useful method with high reliability and reproducibility. In addition, these temporal patterns were with physiological meanings, and certain temporal patterns were correlated to the node strength of the corresponding ICN. Overall, network-wise temporal patterns of ICNs were reliable and informative and could be complementary to spatial patterns of ICNs for further study. PMID:24042040

Wang, X; Jiao, Y; Tang, T; Wang, H; Lu, Z



Estrogen stimulation of COX-2-derived PGI2 confers atheroprotection.  


Although selective cyclooxygenase-2 (COX-2) inhibitors provide relief from pain and inflammation, they also reduce the formation of the atheroprotective prostaglandin I2 (PGI2). They do not reduce the formation of the COX-1-derived thromboxane A2 (TXA2), however, which is both atherogenic and a potent vasoconstrictor. For this reason, the effects of TXA2 might be exacerbated during extended therapy with COX-2 inhibitors, potentially predisposing patients to heart attack and stroke. Recent studies have demonstrated that the atheroprotective effects of estrogen are induced through PGI2 production, through COX-2 activation. This explains how estrogen production in pre-menopausal females is beneficial for the heart and also raises the possibility that COX-2 inhibitors might be particularly hazardous to females. PMID:15950485

Shah, Bukhtiar H



COX-2 inhibitors as adjunctive therapy in schizophrenia.  


Cyclooxygenase-2 (COX-2) is constitutively expressed in the central nervous system, and is thought to have an important functional role therein. COX-2 interacts with neurotransmitters such as acetylcholine, 5-hydroxytryptamine and glutamate but is also involved in the regulation of the central nervous system immune system and in inflammation via the effects of prostaglandins, in particular prostaglandin E2. A general therapeutic effect of the COX-2 inhibitor celecoxib on symptoms of schizophrenia was observed during a prospective, randomised, double-blind study of celecoxib add-on treatment to the atypical antipsychotic risperidone. The results from this trial of adjunctive therapy with a COX-2 inhibitor in schizophrenia are encouraging, and the findings support the view that an immunological/inflammatory process is involved in the pathogenesis of the disease. The add-on to an antipsychotic design of the study was chosen due to ethical reasons; in less acute schizophrenic states a monotherapy with COX-2 inhibitors would be interesting. From a theoretical point of view, other psychiatric indications for selective COX-2 inhibitors are discussed. COX-2 inhibitors have failed to show therapeutic effects in Alzheimer's disease but studies from basic research and a clinical perspective suggest it has an effect on disturbed cognition. In depression, however, signs of inflammation have been described for many years. Although results of clinical studies with COX-2 inhibitors in depression are still lacking, clinical improvement of a depressive syndrome has been observed in patients who have been treated with the COX-2 inhibitor rofecoxib due to other indications. These preliminary clinical data are encouraging for clinical therapeutic effects of the selective COX-2 inhibitors in psychiatric disorders, although these effects have to be confirmed in larger clinical studies. PMID:15268640

Müller, Norbert; Strassnig, Martin; Schwarz, Markus J; Ulmschneider, Markus; Riedel, Michael




PubMed Central

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.

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



The Association of Four Common Polymorphisms from Four Candidate Genes (COX-1, COX-2, ITGA2B, ITGA2) with Aspirin Insensitivity: A Meta-Analysis  

PubMed Central

Objective Evidence is mounting suggesting that a strong genetic component underlies aspirin insensitivity. To generate more information, we aimed to evaluate the association of four common polymorphisms (rs3842787, rs20417, rs201184269, rs1126643) from four candidate genes (COX-1, COX-2, ITGA2B, ITGA2) with aspirin insensitivity via a meta-analysis. Methods and Results In total, there were 4 (353/595), 6 (344/698), 10 (588/878) and 7 (209/676) articles (patients/controls) qualified for rs3842787, rs20417, rs20118426 and rs1126643, respectively. The data were extracted in duplicate and analyzed by STATA software (Version 11.2). The risk estimate was expressed as odds ratio (OR) and 95% confidence interval (95% CI). Analyses of the full data set indicated significant associations of rs20417 (OR; 95% CI; P: 1.86; 1.44–2.41; <0.0005) and rs1126643 (2.37; 1.44–3.89; 0.001) with aspirin insensitivity under allelic model. In subgroup analyses, the risk estimate for rs1126643 was greatly potentiated among patients with aspirin semi-resistance relative to those with aspirin resistance, especially under dominant model (aspirin semi-resistance: 5.44; 1.42–20.83; 0.013 versus aspirin resistance: 1.96; 1.07–3.6; 0.03). Further grouping articles by ethnicity observed a stronger prediction of all, but rs20417, examined polymorphisms for aspirin insensitivity in Chinese than in Caucasians. Finally, meta-regression analyses observed that the differences in percentage of coronary artery disease (P?=?0.034) and averaged platelet numbers (P?=?0.012) between two groups explained a large part of heterogeneity for rs20417 and rs1126643, respectively. Conclusion Our findings provide strong evidence that COX-2 and ITGA2 genetic defects might increase the risk of having aspirin insensitivity, especially for aspirin semi-resistance and in Chinese populations.

Weng, Zhiyuan; Li, Xiaobo; Li, Yuqiong; Lin, Jinxiu; Peng, Feng; Niu, Wenquan



Understanding logistic regression analysis.  


Logistic regression is used to obtain odds ratio in the presence of more than one explanatory variable. The procedure is quite similar to multiple linear regression, with the exception that the response variable is binomial. The result is the impact of each variable on the odds ratio of the observed event of interest. The main advantage is to avoid confounding effects by analyzing the association of all variables together. In this article, we explain the logistic regression procedure using examples to make it as simple as possible. After definition of the technique, the basic interpretation of the results is highlighted and then some special issues are discussed. PMID:24627710

Sperandei, Sandro



Bayesian logistic regression analysis  

NASA Astrophysics Data System (ADS)

In this paper we present a Bayesian logistic regression analysis. It is found that if one wishes to derive the posterior distribution of the probability of some event, then, together with the traditional Bayes Theorem and the integrating out of nuissance parameters, the Jacobian transformation is an essential added ingredient. The application of the product rule gives the posterior of the unknown logistic regression coefficients. The Jacobian transformation then maps the posterior of these regression coefficients to the posterior of the corresponding probability of some event and some nuisance parameters. Finally, by way of the sumrule the nuissance parameters are integrated out.

van Erp, N.; van Gelder, P.



Sequential univariate gating approach to study the effects of erythropoietin in murine bone marrow.  


Analysis of multicolor flow cytometric data is traditionally based on the judgment of an expert, generally time consuming, sometimes incomplete and often subjective in nature. In this article, we investigate another statistical method using a Sequential Univariate Gating (SUG) algorithm to identify regions of interest between two groups of multivariate flow cytometric data. The metric used to differentiate between the groups of univariate distributions in SUG is the Kolmogorov-Smirnov distance (D) statistic. The performance of the algorithm is evaluated by applying it to a known three-color data set looking at activation of CD4+ and CD8+ lymphocytes with anti-CD3 antibody treatment and comparing the results to the expert analysis. The algorithm is then applied to a four-color data set used to study the effects of recombinant human erythropoietin (rHuEPO) on several murine bone marrow populations. SUG was used to identify regions of interest in the data and results compared to expert analysis and the current state-of-the-art statistical method, Frequency Difference Gating (FDG). Cluster analysis was then performed to identify subpopulations responding differently to rHuEPO. Expert analysis, SUG and FDG identified regions in the data that showed activation of CD4+ and CD8+ lymphocytes with anti-CD3 treatment. In the rHuEPO treated data sets, the expert and SUG identified a dose responsive expansion of only the erythroid precursor population. In contrast, FDG resulted in identification of regions of interest both in the erythroid precursors as well as in other bone marrow populations. Clustering within the regions of interest defined by SUG resulted in identification of four subpopulations of erythroid precursors that are morphologically distinct and show a differential response to rHuEPO treatment. Greatest expansion is seen in the basophilic and poly/orthochromic erythroblast populations with treatment. Identification of populations of interest can be performed using SUG in less subjective, time efficient, biologically interpretable manner that corroborates with the expert analysis. The results suggest that basophilic erythroblasts cells or their immediate precursors are an important target for the effects of rHuEPO in murine bone marrow. The MATLAB implementation of the method described in the article, both experimental data and other supplemental materials are freely available at PMID:18496852

Achuthanandam, Ram; Quinn, John; Capocasale, Renold J; Bugelski, Peter J; Hrebien, Leonid; Kam, Moshe



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


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

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



Orthogonal Distance Regression.  

National Technical Information Service (NTIS)

Orthogonal Distance Regression (ODR) is the name given to the computational problem associated with finding the maximum likelihood estimators of measurement error models in the case of normally distributed errors. The authors examine the stable and effici...

P. T. Boggs J. R. Donaldson



Yeast cox17 solution structure and Copper(I) binding.  


Cox17 is a 69-residue cysteine-rich, copper-binding protein that has been implicated in the delivery of copper to the Cu(A) and Cu(B) centers of cytochrome c oxidase via the copper-binding proteins Sco1 and Cox11, respectively. According to isothermal titration calorimetry experiments, fully reduced Cox17 binds one Cu(I) ion with a K(a) of (6.15 +/- 5.83) x 10(6) M(-1). The solution structures of both apo and Cu(I)-loaded Cox17 reveal two alpha helices preceded by an extensive, unstructured N-terminal region. This region is reminiscent of intrinsically unfolded proteins. The two structures are very similar overall with residues in the copper-binding region becoming more ordered in Cu(I)-loaded Cox17. Based on the NMR data, the Cu(I) ion has been modeled as two-coordinate with ligation by conserved residues Cys(23) and Cys(26). This site is similar to those observed for the Atx1 family of copper chaperones and is consistent with reported mutagenesis studies. A number of conserved, positively charged residues may interact with complementary surfaces on Sco1 and Cox11, facilitating docking and copper transfer. Taken together, these data suggest that Cox17 is not only well suited to a copper chaperone function but is specifically designed to interact with two different target proteins. PMID:15465825

Abajian, Carnie; Yatsunyk, Liliya A; Ramirez, Benjamin E; Rosenzweig, Amy C



Genetic variants in COX-2, non-steroidal anti-inflammatory drugs, and breast cancer risk: the Western New York Exposures and Breast Cancer (WEB) Study.  


Chronic inflammation has been consistently associated with cancers of several sites, including the breast, and inhibition of inflammation through the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been inversely associated with risk. As NSAIDs bind with cyclooxygenase-2 (COX-2), genetic variation in COX-2 may influence breast cancer risk by affecting inflammatory response and response to NSAID use. We identified eight single nucleotide polymorphisms (SNPs) for COX-2 and examined their association with risk of breast cancer in a population-based case-control study in Western New York. Cases had incident, first primary, histologically confirmed breast cancer (n = 1077). Controls (n = 1910) were randomly selected from NY Department of Motor Vehicles records (< 65) or Medicare rolls (? 65). Participants were queried on adult lifetime use of aspirin and recent use of ibuprofen. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). One SNP, rs2745559, was associated with an increased risk of breast cancer (OR 1.23, 95% CI 1.03-1.46). Associations with other variants were not evident. Significant interaction (P interaction = 0.04) between recent aspirin use and rs4648261 was also observed. Variation in COX-2 was modestly associated with breast cancer risk, indicating that COX-2 may play a role in breast carcinogenesis. Better understanding of the role of COX-2 genetic variation and interaction with NSAID use in breast carcinogenesis has potential to inform prevention strategies. PMID:20676755

Brasky, Theodore M; Bonner, Matthew R; Moysich, Kirsten B; Ochs-Balcom, Heather M; Marian, Catalin; Ambrosone, Christine B; Nie, Jing; Tao, Meng Hua; Edge, Stephen B; Trevisan, Maurizio; Shields, Peter G; Freudenheim, Jo L



spBayes: An R Package for Univariate and Multivariate Hierarchical Point-referenced Spatial Models  

PubMed Central

Scientists and investigators in such diverse fields as geological and environmental sciences, ecology, forestry, disease mapping, and economics often encounter spatially referenced data collected over a fixed set of locations with coordinates (latitude–longitude, Easting–Northing etc.) in a region of study. Such point-referenced or geostatistical data are often best analyzed with Bayesian hierarchical models. Unfortunately, fitting such models involves computationally intensive Markov chain Monte Carlo (MCMC) methods whose efficiency depends upon the specific problem at hand. This requires extensive coding on the part of the user and the situation is not helped by the lack of available software for such algorithms. Here, we introduce a statistical software package, spBayes, built upon the R statistical computing platform that implements a generalized template encompassing a wide variety of Gaussian spatial process models for univariate as well as multivariate point-referenced data. We discuss the algorithms behind our package and illustrate its use with a synthetic and real data example.

Finley, Andrew O.; Banerjee, Sudipto; Carlin, Bradley P.



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

USGS Publications Warehouse

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.

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



Inducing Polynomial Equations for Regression  

Microsoft Academic Search

Regression methods aim at inducing models of numeric data. While most state-of-the-art machine learning methods for regression fo- cus on inducing piecewise regression models (regression and model trees), we investigate the predictive performance of regression models based on polynomial equations. We present Ciper, an ecien t method for induc- ing polynomial equations and empirically evaluate its predictive perfor- mance on

Peter Ljubi


p50-associated COX-2 extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-?B complexes  

PubMed Central

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-?B, and occludes it from the COX-2 promoter, potentially facilitating interaction with activation-competent NF-?B 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:

Krawczyk, Michal; Emerson, Beverly M



Origins of prostaglandin E2: involvements of cyclooxygenase (COX)-1 and COX-2 in human and rat systems.  


Prostaglandin (PG) E2 is a major cyclooxygenase (COX) product at inflammatory sites where it contributes to local increases in blood flow, edema formation, and pain sensitization. Using rats in vivo and rat and human blood in vitro, we have examined the roles of COX-1 and COX-2 in the production of PGE2. In anesthetized rats treated with bacterial lipopolysaccharide (LPS) to induce the expression of COX-2, the marked increase in PGE2 production that followed bolus intravenous injection of arachidonic acid (3 mg x kg(-1)) was strongly inhibited by diclofenac but largely unaffected by the COX-2-selective inhibitor DFP (5,5- dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone). In rat blood in vitro, aspirin strongly inhibited the production of PGE2 that followed either acute exposure to calcium ionophore, A23187 (calcimycin) (50 microM, 15 min), or incubation with LPS for 18 h. In contrast, human whole blood only produced significant levels of PGE2 when incubated with LPS. Rat leukocytes expressed COX-2 and produced PGE2 when exposed to LPS but not when acutely stimulated with A23187. Rat platelets, but not human platelets, also produced significant amounts of PGE2 when acutely stimulated with A23187. These data show that when exposed to an inflammatory stimulus, rat whole blood produces increased levels of PGE2 through induction of COX-2 in blood leukocytes. Rat blood, unlike human blood, may also produce copious amounts of PGE2 via the actions of COX-1 enzyme constitutively present in platelets. These data may well explain why in rats COX-2-selective inhibitors have been reported not to produce the full anti-inflammatory effects associated with standard nonsteroid anti-inflammatory drugs. PMID:12438520

Giuliano, Francesco; Warner, Timothy D



Functional promoter -765 G > C variant in COX-2 gene is associated with the susceptibility of breast cancer in Chinese Han women  

PubMed Central

Background Cyclooxygenase (COX) is a rate-limiting enzyme in prostaglandins synthesis which exists in two isoforms, COX-1 and COX-2. Over-expression of COX-2 was considered to increase the proliferation and enhance the invasiveness of breast cancer cells. It was suggested that genetic variations in COX-2 could influence its expression. Herein, the present study was aimed to investigate the associations between two mostly studied functional polymorphisms (-765 G?>?C and 8473 C?>?T) in COX-2 and breast cancer risk in Chinese Han women. Methods In the hospital-based case-control study, 465 breast cancer patients and 799 cancer-free controls were genotyped for the COX-2 -765 G?>?C and 8473 C?>?T polymorphisms using TaqMan assay. We estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) using the logistic regression. Results Compared with the wild genotype of -765 G?>?C, we found a statistically significant increased risk of breast cancer associated with the variant genotypes [GC/CC vs. GG: OR?=?1.56, 95% CI?=?1.11–2.21]. In the stratified analysis, the increased risk was more predominant among the subgroups of younger subjects (OR?=?1.61, 95% CI?=?1.00–2.61). Furthermore, the variant genotypes were associated with large tumor size (OR?=?3.01, 95% CI?=?1.47–6.12). No significant association was observed for the 8473 C?>?T polymorphism. Conclusions Our results suggest that the functional -765 G?>?C polymorphism in the promoter of COX-2 may influence the susceptibility and progression of breast cancer in the Chinese Han population.



Latent Regression Analysis.  


Finite mixture models have come to play a very prominent role in modelling data. The finite mixture model is predicated on the assumption that distinct latent groups exist in the population. The finite mixture model therefore is based on a categorical latent variable that distinguishes the different groups. Often in practice distinct sub-populations do not actually exist. For example, disease severity (e.g. depression) may vary continuously and therefore, a distinction of diseased and not-diseased may not be based on the existence of distinct sub-populations. Thus, what is needed is a generalization of the finite mixture's discrete latent predictor to a continuous latent predictor. We cast the finite mixture model as a regression model with a latent Bernoulli predictor. A latent regression model is proposed by replacing the discrete Bernoulli predictor by a continuous latent predictor with a beta distribution. Motivation for the latent regression model arises from applications where distinct latent classes do not exist, but instead individuals vary according to a continuous latent variable. The shapes of the beta density are very flexible and can approximate the discrete Bernoulli distribution. Examples and a simulation are provided to illustrate the latent regression model. In particular, the latent regression model is used to model placebo effect among drug treated subjects in a depression study. PMID:20625443

Tarpey, Thaddeus; Petkova, Eva



Latent Regression Analysis  

PubMed Central

Finite mixture models have come to play a very prominent role in modelling data. The finite mixture model is predicated on the assumption that distinct latent groups exist in the population. The finite mixture model therefore is based on a categorical latent variable that distinguishes the different groups. Often in practice distinct sub-populations do not actually exist. For example, disease severity (e.g. depression) may vary continuously and therefore, a distinction of diseased and not-diseased may not be based on the existence of distinct sub-populations. Thus, what is needed is a generalization of the finite mixture’s discrete latent predictor to a continuous latent predictor. We cast the finite mixture model as a regression model with a latent Bernoulli predictor. A latent regression model is proposed by replacing the discrete Bernoulli predictor by a continuous latent predictor with a beta distribution. Motivation for the latent regression model arises from applications where distinct latent classes do not exist, but instead individuals vary according to a continuous latent variable. The shapes of the beta density are very flexible and can approximate the discrete Bernoulli distribution. Examples and a simulation are provided to illustrate the latent regression model. In particular, the latent regression model is used to model placebo effect among drug treated subjects in a depression study.

Tarpey, Thaddeus; Petkova, Eva



Anthropometry of Women of the U.S. Army -- 1977. Report Number 2. The Basic Univariate Statistics.  

National Technical Information Service (NTIS)

This report, the second in a series, summarizes the univariate statistics obtained in an anthropometric survey of women in the U.S. Army conducted at Fort Sam Houston, Texas; Fort McClellan, Alabama; Walter Reed Medical Center, the District of Columbia; a...

E. Churchill J. T. McConville R. M. White T. Churchill



Modeling and forecasting monthly patient volume at a primary health care clinic using univariate time-series analysis  

Microsoft Academic Search

Two univariate time-series analysis methods have been used to model and forecast the monthly patient volume at the family and community medicine primary health care clinic of King Faisal University, Al-Khobar, Saudi Arabia. Models were based on nine years of data and forecasts made for 2 years. The optimum ARIMA model selected is an autoregressive model of the fourth order

R. E Abdel-Aal; A. M Mangoud



Students Speak With Gary Cox, EPIC Project Manager  

NASA Video Gallery

From NASAâ??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...


Characterization of the copper chaperone Cox17 of Saccharomyces cerevisiae.  


Assembly of functional cytochrome oxidase in yeast requires Cox17, which has been postulated to deliver copper ions to the mitochondrion for insertion into the enzyme. This role for Cox17 is supported by the observation that it binds copper as a binuclear cuprous-thiolate cluster. X-ray absorption spectroscopy, together with UV-visible absorption and emission spectroscopy, indicates the presence of bound cuprous ions, trigonally coordinated by thiolate ligands. Analysis of the EXAFS shows three Cu-S bonds at 2.26 A, plus a short Cu-Cu distance of 2.7 A, indicating a binuclear cluster in Cox17. The cuprous-thiolate cluster in Cox17 is substantially more labile than structurally related clusters in metallothioneins. PMID:9585572

Srinivasan, C; Posewitz, M C; George, G N; Winge, D R



Univariate and multivariate methods for chemical mapping of cervical cancer cells  

NASA Astrophysics Data System (ADS)

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 1?m 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.

Duraipandian, Shiyamala; Zheng, Wei; Huang, Zhiwei



Detection of Patient Subgroups with Differential Expression in Omics Data: A Comprehensive Comparison of Univariate Measures  

PubMed Central

Detection of yet unknown subgroups showing differential gene or protein expression is a frequent goal in the analysis of modern molecular data. Applications range from cancer biology over developmental biology to toxicology. Often a control and an experimental group are compared, and subgroups can be characterized by differential expression for only a subgroup-specific set of genes or proteins. Finding such genes and corresponding patient subgroups can help in understanding pathological pathways, diagnosis and defining drug targets. The size of the subgroup and the type of differential expression determine the optimal strategy for subgroup identification. To date, commonly used software packages hardly provide statistical tests and methods for the detection of such subgroups. Different univariate methods for subgroup detection are characterized and compared, both on simulated and on real data. We present an advanced design for simulation studies: Data is simulated under different distributional assumptions for the expression of the subgroup, and performance results are compared against theoretical upper bounds. For each distribution, different degrees of deviation from the majority of observations are considered for the subgroup. We evaluate classical approaches as well as various new suggestions in the context of omics data, including outlier sum, PADGE, and kurtosis. We also propose the new FisherSum score. ROC curve analysis and AUC values are used to quantify the ability of the methods to distinguish between genes or proteins with and without certain subgroup patterns. In general, FisherSum for small subgroups and -test for large subgroups achieve best results. We apply each method to a case-control study on Parkinson's disease and underline the biological benefit of the new method.

Ahrens, Maike; Turewicz, Michael; Casjens, Swaantje; May, Caroline; Pesch, Beate; Stephan, Christian; Woitalla, Dirk; Gold, Ralf; Bruning, Thomas; Meyer, Helmut E.



On the Fringe: Community Dynamics at Cox Ranch Pueblo  

Microsoft Academic Search

Cox Ranch Pueblo is the center of a sizable Chaco-period (A.D. 1050-1130) community in the southern Cibola region. The Cox Ranch Pueblo Community Research Project has been exploring the connections distant communities may have had with a center in Chaco Canyon. The site contains numerous roomblocks and a great house that possesses a number of attributes consistent with Chaco-style buildings.

Andrew I. Duff


Aromatase and COX in Breast Cancer: Enzyme inhibitors and beyond  

PubMed Central

Aromatase expression and enzyme activity in breast cancer patients is greater in or near the tumor tissue compared with the normal breast tissue. Complex regulation of aromatase expression in human tissues involves alternative promoter sites that provide tissue-specific control. Previous studies in our laboratories suggested a strong association between aromatase (CYP19) gene expression and the expression of cyclooxygenase (COX) genes. Additionally, nonsteroidal anti-inflammatory drugs (NSAIDs) and COX selective inhibitors can suppress CYP19 gene expression and decrease aromatase activity. Our current hypothesis is that pharmacological regulation of aromatase and/or cyclooxygenases can act locally to decrease the biosynthesis of estrogen and may provide additional therapy options for patients with hormone-dependent breast cancer. Two pharmacological approaches are being developed, one involving mRNA silencing by selective siRNA molecules and the second utilizing small molecule drug design. In the first approach, short interfering RNAs (siRNA) were designed against either human aromatase mRNA or human COX-2 mRNA. Treatment of breast cancer cells with siAROMs completely masked the aromatase enzyme activity. Treatment with COX-2 siRNAs decreased the expression of COX-2 mRNA; furthermore, the siCOX-2-mediated decrease also resulted in suppression of CYP19 mRNA. The small molecule drug design approach focuses on the synthesis and biological evaluation of a novel series of sulfonanilide analogs derived from the COX-2 selective inhibitors. The compounds suppress aromatase enzyme activity in SK-BR-3 breast cancer cells in a dose and time dependent manner, and structure activity analysis does not find a correlation between aromatase suppression and COX inhibition. Real-time PCR analysis demonstrates that the sulfonanilide analogs decrease aromatase gene transcription in breast cells. Thus, these results suggest that the siRNAs and novel sulfonanilides targeting aromatase expression may be valuable tools for selective regulation of aromatase in breast cancer.

Brueggemeier, Robert W.; Su, Bin; Sugimoto, Yasuro; Diaz-Cruz, Edgar S.; Davis, Danyetta D.



Inducing Polynomial Equations for Regression  

Microsoft Academic Search

Abstract. Regression methods aim at inducing models of numeric data. While most state-of-the-art machine learning methods for regression focus on inducing piecewise regression models (regression and model trees), we investigate the predictive performance of regression models based on polynomial equations. We present Ciper, an ecien t method for inducing polynomial equations and empirically evaluate its predictive performance,on standard regression tasks.

Ljupco Todorovski; Peter Ljubic; Saso Dzeroski



Illuminations: Least Squares Regression  

NSDL National Science Digital Library

Created by Illuminations: Resources for Teaching Mathematics, this unit plan contains nine lessons about interpreting the slope and y-intercept of least squares regression lines in the context of real-life data. The applet included allows students to plot the data and calculate the correlation coefficient and the equation of the regression line. Students will view the data in tabular, graphic, and algebraic form and will be able to discuss and display their work. This is a wonderful collection of interactive statistical lessons. They can easily be translated into classroom activities.



COX-2 inhibitor reduces skeletal muscle hypertrophy in mice  

PubMed Central

Anti-inflammatory strategies are often used to reduce muscle pain and soreness that can result from high-intensity muscular activity. However, studies indicate that components of the acute inflammatory response may be required for muscle repair and growth. The hypothesis of this study was that cyclooxygenase (COX)-2 activity is required for compensatory hypertrophy of skeletal muscle. We used the synergist ablation model of skeletal muscle hypertrophy, along with the specific COX-2 inhibitor NS-398, to investigate the role of COX-2 in overload-induced muscle growth in mice. COX-2 was expressed in plantaris muscles during compensatory hypertrophy and was localized mainly in or near muscle cell nuclei. Treatment with NS-398 blunted the increases in mass and protein content in overloaded muscles compared with vehicle-treated controls. Additionally, the COX-2 inhibitor decreased activity of the urokinase type plasminogen activator, macrophage accumulation, and cell proliferation, all of which are required for hypertrophy after synergist ablation. Expression of insulin-like growth factor-1 and phosphorylation of Akt, mammalian target of rapamycin, and p70S6K were increased following synergist ablation, but were not affected by NS-398. Additionally, expression of atrogin-1 was reduced during hypertrophy, but was also not affected by NS-398. These results demonstrate that COX-2 activity is required for skeletal muscle hypertrophy, possibly through facilitation of extracellular protease activity, macrophage accumulation, and cell proliferation.

Novak, Margaret L; Billich, William; Smith, Sierra M.; Sukhija, Kunal B.; McLoughlin, Thomas J.; Hornberger, Troy A.; Koh, Timothy J.



COX-2 selective nonsteroidal anti-inflammatory drugs: current status.  


Since, their introduction, COX (cyclooxygenase enzyme)-2 specific inhibitors have become a rapidly growing segment of the prescription drug market. Researchers have recently focused on the potentially lethal side effects associated with their. FDA has banned the use of nimesulide (hepatotoxic) in pediatric patients and rofecoxib (cardiovascular complications) in both adults and children. COX-2 inhibitors may decrease vascular prostacyclin production and may tip the balance in favour of prothrombotic eicosanoids (thromboxane A2) and lead to increased cardiovascular thrombotic events. COX-2 inhibitors can also result into increase blood pressure, macular eruptions, urticaria, pseudoporphyria, erythema multiforme, oedema, worsening of heart failure, fatal allergic vasculitis and aggravation of doxorubicin-mediated cardiac injury. The COX-2 enzyme is also involved in the development of many organ systems, and its inhibition may lead to various congenital defects in neonates. It has been reported that COX-2 inhibitors also interfere with implantation, hence their use should be avoided in sexually active women at risk of pregnancy. However, presently the choice of COX-2 selective inhibitors for a particular patient should be based upon their relative efficacy, toxicity, concomitant drug use, concurrent disease states, hepatic and renal function and relative cost. PMID:15926604

Mahajan, A; Sharma, Rashmi



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


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

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



Multivariate Adaptive Regression Splines  

Microsoft Academic Search

A new method is presented for flexible regression modeling of high dimensional data. The model takes the form of an expansion in product spline basis functions, where the number of basis functions as well as the parameters associated with each one (product degree and knot locations) are automatically determined by the data. This procedure is motivated by the recursive partitioning

Jerome H. Friedman



Multiple Linear Regressions Analysis  

NSDL National Science Digital Library

This online calculator allows users to enter sixteen observations with up to four dependent variables and calculates the regression equation, the fitted values, R-Squared, the F-Statistic, mean, variance, first order serial-correlation, second order serial-correlation, the Durbin-Watson statistic, and the mean absolute errors. It also tests normality and gives the i-th residuals.

Arsham, Hossein



Multiple linear regression analysis  

NASA Technical Reports Server (NTRS)

Program rapidly selects best-suited set of coefficients. User supplies only vectors of independent and dependent data and specifies confidence level required. Program uses stepwise statistical procedure for relating minimal set of variables to set of observations; final regression contains only most statistically significant coefficients. Program is written in FORTRAN IV for batch execution and has been implemented on NOVA 1200.

Edwards, T. R.



Multiple Linear Regression  

NSDL National Science Digital Library

This site, created by Michelle Lacey of Yale University, gives an explanation, a definition and an example of multiple linear regression. Topics include: confidence intervals, tests of significance, and squared multiple correlation. While brief, this is still a valuable site for anyone interested in statistics.

Lacey, Michelle



Modern Regression Discontinuity Analysis  

ERIC Educational Resources Information Center

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…

Bloom, Howard S.



Incomplete Orthogonal Distance Regression  

Microsoft Academic Search

A common method of fitting curves and surfaces to data is to minimize the sum of squares of the orthogonal distances from the data points to the curve or surface, a process known as orthogonal distance regression. Here we consider fitting geometrical objects to data when some orthogonal distances are not available. Methods based on the Gauss–Newton method are developed,

A. Atieg; G. A. Watson



Logistic Regression Diagnostics  

Microsoft Academic Search

A maximum likelihood fit of a logistic regression model (and other similar models) is extremely sensitive to outlying responses and extreme points in the design space. We develop diagnostic measures to aid the analyst in detecting such observations and in quantifying their effect on various aspects of the maximum likelihood fit. The elements of the fitting process which constitute the

Daryl Pregibon



Explorations in Statistics: Regression  

ERIC Educational Resources Information Center

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.…

Curran-Everett, Douglas



Comparative Inhibitory Activity of Rofecoxib, Meloxicam, Diclofenac, Ibuprofen, and Naproxen on COX2 versus COX1 in Healthy Volunteers  

Microsoft Academic Search

Steady-state inhibitory activity of rofecoxib (Vioxx™) on COX-2 versus COX-1 was compared with that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the

Anne Van Hecken; Jules I. Schwartz; Marleen Depré; Inge De Lepeleire; Aimee Dallob; Wesley Tanaka; Kathleen Wynants; Agnes Buntinx; Jef Arnout; Peggy H. Wong; David L. Ebel; Barry J. Gertz; Paul J. De Schepper



COX-2-dependent and COX-2-independent mode of action of celecoxib in human liver cancer cells.  


Celecoxib (Celebrex((R)), Pfizer) is a selective cyclooxygenase-2 (COX-2) inhibitor with chemopreventive and antitumor effects. However, it is now well known that celecoxib has several COX-2-independent activities. To better understand COX-2-independent molecular mechanisms underlying the antitumor activity of celecoxib, we investigated the expression profile of the celecoxib-treated COX-2-positive (Huh7) and COX-2-negative (HepG2) liver cancer cell lines, using microarray analysis. Celecoxib treatment resulted in significantly altered expression levels of 240 and 403 transcripts in Huh7 and HepG2 cells, respectively. Confirmation of the microarray results was performed for selected genes by semiquantitative RT-PCR. A pathway/functional analysis of celecoxib-affected transcripts, using ingenuity pathway analysis and exploring biological association networks, revealed that celecoxib modulates expression of numerous genes involved in a variety of cellular processes, including cell death, cellular growth and proliferation, lipid metabolism, and energy turnover. Some of these processes were common for both HCC cell lines and seem to be coupled with NF-?B signaling, while others were cell-specific and possibly linked to the presence or the absence of COX-2 activity in the corresponding cell line. Many novel genes emerged from our analyses that were not previously reported to be affected by celecoxib. Further studies on selected celecoxib-responsive genes will establish if they may serve as potential molecular targets for more effective therapeutic strategies in HCC. PMID:21410330

Cervello, Melchiorre; Bachvarov, Dimcho; Cusimano, Antonella; Sardina, Francesca; Azzolina, Antonina; Lampiasi, Nadia; Giannitrapani, Lydia; McCubrey, James A; Montalto, Giuseppe



Multivariate Real-Time Signal Extraction by a Robust Adaptive Regression Filter  

Microsoft Academic Search

We propose a new regression-based filter for extracting signals online from multivariate high frequency time series. It separates relevant signals of several variables from noise and (multivariate) outliers.Unlike parallel univariate filters, the new procedure takes into account the local covariance structure between the single time series components. It is based on high-breakdown estimates, which makes it robust against (patches of)

Matthias Borowski; Karen Schettlinger; Ursula Gather



Regression Versus No Regression in the Autistic Disorder: Developmental Trajectories  

Microsoft Academic Search

Developmental regression is a complex phenomenon which occurs in 20–49% of the autistic population. Aim of the study was to\\u000a assess possible differences in the development of regressed and non-regressed autistic preschoolers. We longitudinally studied\\u000a 40 autistic children (18 regressed, 22 non-regressed) aged 2–6 years. The following developmental areas were considered fundamental\\u000a in the first years of life, and were assessed

P. Bernabei; A. Cerquiglini; F. Cortesi; C. D’Ardia



Specific copper transfer from the Cox17 metallochaperone to both Sco1 and Cox11 in the assembly of yeast cytochrome C oxidase.  


The assembly of the copper sites in cytochrome c oxidase involves a series of accessory proteins, including Cox11, Cox17, and Sco1. The two mitochondrial inner membrane proteins Cox11 and Sco1 are thought to be copper donors to the Cu(B) and Cu(A) sites of cytochrome oxidase, respectively, whereas Cox17 is believed to be the copper donor to Sco1 within the intermembrane space. In this report we show Cox17 is a specific copper donor to both Sco1 and Cox11. Using in vitro studies with purified proteins, we demonstrate direct copper transfer from CuCox17 to Sco1 or Cox11. The transfer is specific because no transfer occurs to heterologous proteins, including bovine serum albumin and carbonic anhydrase. In addition, a C57Y mutant of Cox17 fails to transfer copper to Sco1 but is competent for copper transfer to Cox11. The in vitro transfer studies were corroborated by a yeast cytoplasm expression system. Soluble domains of Sco1 and Cox11, lacking the mitochondrial targeting sequence and transmembrane domains, were expressed in the yeast cytoplasm. Metallation of these domains was strictly dependent on the co-expression of Cox17. Thus, Cox17 represents a novel copper chaperone that delivers copper to two proteins. PMID:15199057

Horng, Yih-Chern; Cobine, Paul A; Maxfield, Andrew B; Carr, Heather S; Winge, Dennis R



Artificial neural networks versus proportional hazards Cox models to predict 45-year all-cause mortality in the Italian Rural Areas of the Seven Countries Study  

PubMed Central

Background Projection pursuit regression, multilayer feed-forward networks, multivariate adaptive regression splines and trees (including survival trees) have challenged classic multivariable models such as the multiple logistic function, the proportional hazards life table Cox model (Cox), the Poisson’s model, and the Weibull’s life table model to perform multivariable predictions. However, only artificial neural networks (NN) have become popular in medical applications. Results We compared several Cox versus NN models in predicting 45-year all-cause mortality (45-ACM) by 18 risk factors selected a priori: age; father life status; mother life status; family history of cardiovascular diseases; job-related physical activity; cigarette smoking; body mass index (linear and quadratic terms); arm circumference; mean blood pressure; heart rate; forced expiratory volume; serum cholesterol; corneal arcus; diagnoses of cardiovascular diseases, cancer and diabetes; minor ECG abnormalities at rest. Two Italian rural cohorts of the Seven Countries Study, made up of men aged 40 to 59 years, enrolled and first examined in 1960 in Italy. Cox models were estimated by: a) forcing all factors; b) a forward-; and c) a backward-stepwise procedure. Observed cases of deaths and of survivors were computed in decile classes of estimated risk. Forced and stepwise NN were run and compared by C-statistics (ROC analysis) with the Cox models. Out of 1591 men, 1447 died. Model global accuracies were extremely high by all methods (ROCs > 0.810) but there was no clear-cut superiority of any model to predict 45-ACM. The highest ROCs (> 0.838) were observed by NN. There were inter-model variations to select predictive covariates: whereas all models concurred to define the role of 10 covariates (mainly cardiovascular risk factors), family history, heart rate and minor ECG abnormalities were not contributors by Cox models but were so by forced NN. Forced expiratory volume and arm circumference (two protectors), were not selected by stepwise NN but were so by the Cox models. Conclusions There were similar global accuracies of NN versus Cox models to predict 45-ACM. NN detected specific predictive covariates having a common thread with physical fitness as related to job physical activity such as arm circumference and forced expiratory volume. Future attention should be concentrated on why NN versus Cox models detect different predictors.



Ridge regression signal processing  

NASA Technical Reports Server (NTRS)

The introduction of the Global Positioning System (GPS) into the National Airspace System (NAS) necessitates the development of Receiver Autonomous Integrity Monitoring (RAIM) techniques. In order to guarantee a certain level of integrity, a thorough understanding of modern estimation techniques applied to navigational problems is required. The extended Kalman filter (EKF) is derived and analyzed under poor geometry conditions. It was found that the performance of the EKF is difficult to predict, since the EKF is designed for a Gaussian environment. A novel approach is implemented which incorporates ridge regression to explain the behavior of an EKF in the presence of dynamics under poor geometry conditions. The basic principles of ridge regression theory are presented, followed by the derivation of a linearized recursive ridge estimator. Computer simulations are performed to confirm the underlying theory and to provide a comparative analysis of the EKF and the recursive ridge estimator.

Kuhl, Mark R.



[Regression of atherosclerosis lesions].  


The regression of even advanced atherosclerotic vascular lesions is now well-documented in various animal species (dogs, pigs, rabbits, birds and monkeys). In man, well-controlled studies in selected groups of patients have already shown that a reduction of luminal stenosis may take place. After a reliable morphological und morphometric validation has been obtained, non-invasive and easily applicable methods are available which allow reproducible documentation of the reduction in lesions. PMID:2686177

Weber, G; Resi, L; Tanganelli, P



Multiple Regression Analysis  

Microsoft Academic Search

\\u000a So far we have considered only one regressor X besides the constant in the regression equation. Economic relationships usually include more than one regressor. For example,\\u000a a demand equation for a product will usually include real price of that product in addition to real income as well as real\\u000a price of a competitive product and the advertising expenditures on this

Badi H. Baltagi


Generating survival times to simulate Cox proportional hazards models.  


Simulation studies present an important statistical tool to investigate the performance, properties and adequacy of statistical models in pre-specified situations. One of the most important statistical models in medical research is the proportional hazards model of Cox. In this paper, techniques to generate survival times for simulation studies regarding Cox proportional hazards models are presented. A general formula describing the relation between the hazard and the corresponding survival time of the Cox model is derived, which is useful in simulation studies. It is shown how the exponential, the Weibull and the Gompertz distribution can be applied to generate appropriate survival times for simulation studies. Additionally, the general relation between hazard and survival time can be used to develop own distributions for special situations and to handle flexibly parameterized proportional hazards models. The use of distributions other than the exponential distribution is indispensable to investigate the characteristics of the Cox proportional hazards model, especially in non-standard situations, where the partial likelihood depends on the baseline hazard. A simulation study investigating the effect of measurement errors in the German Uranium Miners Cohort Study is considered to illustrate the proposed simulation techniques and to emphasize the importance of a careful modelling of the baseline hazard in Cox models. PMID:15724232

Bender, Ralf; Augustin, Thomas; Blettner, Maria



Clinical effects of COX-2 inhibitors on cognition in schizophrenia.  


An activation of pro-inflammatory cytokines in the central nervous system is associated with cognitive disturbances. This process is mediated by prostaglandins and cyclo-oxygenase-2 (COX-2). COX-2 inhibitors have been suggested to show beneficial effects in disorders associated with cognitive disturbance, although clinical effects on cognition have not been shown until today. Data from a schizophrenia study were reevaluated under the aspect whether an effect on the positive and negative syndrome scale (PANSS) factor cognition can be observed during therapy with the COX-2 inhibitor celecoxib add on to risperidone in comparison to riperidone alone. Beside the effect on the PANSS total score, the effect on the cognition factor was the most pronounced using the analysis of covariance compared to all other factors of the PANSS (p < 0.06). Although suggestions of basic research led to an expected therapeutic effect of COX-2 inhibitors on cognition, this effect could not yet be shown clinically. In schizophrenia, the effect on cognition contributes to the therapeutic effect of COX-2 inhibitors. PMID:15549344

Müller, Norbert; Riedel, Michael; Schwarz, Markus J; Engel, Rolf R



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


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 290Torr (0.4atm) 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

Benderro, Girriso F; LaManna, Joseph C



Suppression of Intestinal Polyposis in Apc ?716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX2)  

Microsoft Academic Search

Two cyclooxygenase isozymes catalyze conversion of arachidonic acid to prostaglandin H2: constitutive COX-1 and inducible COX-2. To assess the role of COX-2 in colorectal tumorigenisis, we determined the effects of COX-2 gene (Ptgs2) knockouts and a novel COX-2 inhibitor on Apc?716knockout mice, a model of human familial adenomatous polyposis. A Ptgs2null mutation reduced the number and size of the intestinal

Masanobu Oshima; Joseph E Dinchuk; Stacia L Kargman; Hiroko Oshima; Bruno Hancock; Elizabeth Kwong; James M Trzaskos; Jilly F Evans; Makoto M Taketo



Knock-down of the COX3 and COX17 gene expression of cytochrome c oxidase in the unicellular green alga Chlamydomonas reinhardtii  

Microsoft Academic Search

The COX3 gene encodes a core subunit of mitochondrial cytochrome c oxidase (complex IV) whereas the COX17 gene encodes a chaperone delivering copper to the enzyme. Mutants of these two genes were isolated by RNA interference in\\u000a the microalga Chlamydomonas. The COX3 mRNA was completely lacking in the cox3-RNAi mutant and no activity and assembly of complex IV were detected.

Claire Remacle; Nadine Coosemans; Frédéric Jans; Marc Hanikenne; Patrick Motte; Pierre Cardol



A new synthesis analysis method for building logistic regression prediction models.  


Synthesis analysis refers to a statistical method that integrates multiple univariate regression models and the correlation between each pair of predictors into a single multivariate regression model. The practical application of such a method could be developing a multivariate disease prediction model where a dataset containing the disease outcome and every predictor of interest is not available. In this study, we propose a new version of synthesis analysis that is specific to binary outcomes. We show that our proposed method possesses desirable statistical properties. We also conduct a simulation study to assess the robustness of the proposed method and compare it to a competing method. Copyright © 2014 John Wiley & Sons, Ltd. PMID:24634227

Sheng, Elisa; Zhou, Xiao Hua; Chen, Hua; Hu, Guizhou; Duncan, Ashlee



The Prostaglandin Synthase 2/cyclooxygenase 2 (PTGS2/ COX2) rs5277 Polymorphism Does not Influence Risk of Colorectal Cancer in an Iranian Population.  


Background: The prostaglandin-endoperoxide synthase 2 [PTGS2, commonly known as cyclooxygenase-2 (COX-2)] is an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue and involved in the synthesis of prostaglandins and thromboxanes, regulators of processes such as inflammation, cell proliferation, and angiogenesis, all relevant for cancer development. We investigated whether a functional genetic polymorphism, rs5277, in COX-2 may have a risk-modifying effect on sporadic colorectal cancer in an Iranian population. Materials and Methods: We conducted a case-control study on 167 patients with colorectal cancer and 197 cancer-free controls in Taleghani Hospital in Tehran, Iran, between 2007 and 2011. Peripheral blood samples of both groups were processed for DNA extraction and genotyping of the COX-2 gene polymorphism (rs5277) using PCR-RFLP. RFLP results were confirmed by direct sequencing. Logistic regression analysis was performed to calculate the adjusted odds ratio (OR) and 95% confidence interval (95% CI). Results: There was no significant difference in the distribution of COX-2 gene rs5277 polymorphism genotype and the allelic form, among CRC patients compared with the healthy control group (p: 0.867). Conclusions: Our results suggest that rs5277 polymorphism in COX2 could not be a good prognostic indicator for patients with CRC. PMID:24870748

Khorshidi, Fatemeh; Haghighi, Mahdi Montazer; Nazemalhosseini Mojarad, Ehsan; Azimzadeh, Pedram; Damavand, Behzad; Vahedi, Mohsen; Almasi, Shohreh; Aghdaei, Hamid Asadzadeh; Zali, Mohammad Reza



On computing standard errors for marginal structural Cox models.  


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

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



COX-2 in the neurodegenerative process of Parkinson's disease  

PubMed Central

The enzyme cyclooxygenase-2 (COX-2), responsible for the first committed step in the synthesis of several important mediators which are involved in both initiation and resolution of inflammation, and the subsequent generation of prostaglandins (PGs) upon activation has been shown to participate in the neurodegenerative processes of a variety of diseases. This review looks particular at the role of COX-2 in the pathogenesis of Parkinson's disease, involving the generation of PGs and the role of the two different parts of the cyclooxygenase—cyclooxygenase and peroxidase activity.

Teismann, Peter



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


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

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



Steganalysis using logistic regression  

NASA Astrophysics Data System (ADS)

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.

Lubenko, Ivans; Ker, Andrew D.



[Comparative analysis of variability of three mitochondrial genes of cytochrome oxidase complex (cox1, cox2, and cox3) in wild and domestic carp (Cyprinus carpio L.)].  


For the first time, we studied the polymorphism of three mitochondrial genes of the cytochrome oxidase complex (cox1, cox2, and cox3) in natural populations of wild carp living in the Volga, Amur, and Don River Basins, as well as in European Hungarian carp and two pedigree lines of Ropsha carp of domestic breeding. The highest level of nucleotide and haplotype diversity in the studied samples was detected for the cox1 gene (pi = 0.61, h = 100%). Two lines of the Ropsha carp (pi = 0.61, h = 100%) and the Far East population of Amur wild carp from Shershikh strait (Am: pi = 0.20, h = 70%) were the most polymorphic for three genes. The second sample of Amur wild carp from the Amur River (Ac), as well as the samples of Volga and Don wild carp and Hungarian carp had lower values of variability. The presence of two main genealogical lines of the wild carp and carp was demonstrated based on the total sequence of three genes, as well as the corresponding amino acid sequences in the studied area. One of these lines (line I) is typical of the sample of Amur wild carp (Am) and three members of the Ropsha carp. Line II is developed by sequences of Volga, Don, and Amur wild carp (Ac), as well as European Hungarian carp and seven other members of the Ropsha carp. Three to four sublines, which differ in nucleotide and amino acid substitutions, were found within the lines. Possible reasons for the origin of genomic variability in wild carp, as well as in European and Russian breeds of carp, are discussed. PMID:23516901

Torgunakova, O A; Egorova, T A; Semenova, S K



Performance of random forests and logic regression methods using mini-exome sequence data  

PubMed Central

Machine learning approaches are an attractive option for analyzing large-scale data to detect genetic variants that contribute to variation of a quantitative trait, without requiring specific distributional assumptions. We evaluate two machine learning methods, random forests and logic regression, and compare them to standard simple univariate linear regression, using the Genetic Analysis Workshop 17 mini-exome data. We also apply these methods after collapsing multiple rare variants within genes and within gene pathways. Linear regression and the random forest method performed better when rare variants were collapsed based on genes or gene pathways than when each variant was analyzed separately. Logic regression performed better when rare variants were collapsed based on genes rather than on pathways.



The Cox-Maze Procedure for Lone Atrial Fibrillation: A Single Center Experience over Two Decades  

PubMed Central

Background The Cox-Maze procedure (CMP) has achieved high success rates in the therapy of atrial fibrillation (AF) while becoming progressively less invasive. This report evaluates our experience with the CMP in the treatment of lone AF over two decades and compares the original cut-and-sew CMP-III to the ablation-assisted CMP-IV, which uses bipolar radiofrequency and cryoenergy to create the original lesion pattern. Methods and Results Data were collected prospectively on 212 consecutive patients (mean age: 53.5±10.4, 78% males), who underwent a stand-alone CMP from 1992 through 2010. Median duration of preoperative AF was 6 (IQR 2.9–11.5) years, with 48% paroxysmal and 52% persistent or longstanding persistent AF. Univariate analysis with preoperative and perioperative variables used as covariates for the CMP-III (n=112) and the CMP-IV (n=100) was performed. Overall, 30-day mortality was 1.4% with no intraoperative deaths. Freedom from AF was 93% and freedom from AF off antiarrhythmics was 82% at a mean follow-up time of 3.6 ± 3.1 years. Freedom from symptomatic AF at 10 years was 85%. Only one late stroke occurred with 80% of patients being off anticoagulation. The less invasive CMP-IV had significantly shorter cross-clamp times (41±13 vs. 92±26 minutes, p<0.001) while achieving high success rates with 90% freedom from AF and 84% freedom from AF off antiarrhythmics at 2 years. Conclusions The CMP, while simplified and shortened by alternative energy sources, has excellent results even with improved follow-up and stricter definition of failure.

Weimar, Timo; Schena, Stefano; Bailey, Marci S.; Maniar, Hersh S.; Schuessler, Richard B.; Cox, James L.; Damiano, Ralph J.



Laser-induced breakdown spectroscopy of steel: a comparison of univariate and multivariate calibration methods.  


Laser-induced breakdown spectroscopy (LIBS) was carried out on twenty-three low to high alloy steel samples to quantify their concentrations of chromium, nickel, and manganese. LIBS spectral data were correlated to known concentrations of the samples and three calibration methods were compared. A standard LIBS calibration technique using peak area integration normalized by an internal standard was compared to peak area integration normalized by total light and the multivariate statistical technique of partial least squares. For the partial least squares analysis, the PLS-1 algorithm was used, where a predictive model is generated for each element separately. Partial least squares regression coefficients show that the algorithm correctly identifies the atomic emission peaks of interest for each of the elements. Predictive capabilities of each calibration approach were quantified by calculating the standard and relative errors of prediction. The performance of partial least squares is on par with using iron as an internal standard but has the key advantage that it can be applied to samples where the concentrations of all elements are unknown. PMID:20149276

Stipe, Christopher B; Hensley, Brian D; Boersema, Jeffrey L; Buckley, Steven G



Multiple Regression with Stationary Errors.  

National Technical Information Service (NTIS)

A practical computing technique is presented for the joint estimation of regression coefficients and the error spectrum in regression problems with stationary errors. In problems where unweighted least squares is not efficient, the procedure gives an esti...

D. B. Duncan R. H. Jones



COX-2 Protects against Atherosclerosis Independently of Local Vascular Prostacyclin: Identification of COX-2 Associated Pathways Implicate Rgl1 and Lymphocyte Networks  

PubMed Central

Cyxlo-oxygenase (COX)-2 inhibitors, including traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with increased cardiovascular side effects, including myocardial infarction. We and others have shown that COX-1 and not COX-2 drives vascular prostacyclin in the healthy cardiovascular system, re-opening the question of how COX-2 might regulate cardiovascular health. In diseased, atherosclerotic vessels, the relative contribution of COX-2 to prostacyclin formation is not clear. Here we have used apoE?/?/COX-2?/? mice to show that, whilst COX-2 profoundly limits atherosclerosis, this protection is independent of local prostacyclin release. These data further illustrate the need to look for new explanations, targets and pathways to define the COX/NSAID/cardiovascular risk axis. Gene expression profiles in tissues from apoE?/?/COX-2?/? mice showed increased lymphocyte pathways that were validated by showing increased T-lymphocytes in plaques and elevated plasma Th1-type cytokines. In addition, we identified a novel target gene, rgl1, whose expression was strongly reduced by COX-2 deletion across all examined tissues. This study is the first to demonstrate that COX-2 protects vessels against atherosclerotic lesions independently of local vascular prostacyclin and uses systems biology approaches to identify new mechanisms relevant to development of next generation NSAIDs.

Kirkby, Nicholas S.; Lundberg, Martina H.; Wright, William R.; Warner, Timothy D.; Paul-Clark, Mark J.; Mitchell, Jane A.



Time-adaptive quantile regression  

Microsoft Academic Search

An algorithm for time-adaptive quantile regression is presented. The algorithm is based on the simplex algorithm, and the linear optimization formulation of the quantile regression problem is given. The observations have been split to allow a direct use of the simplex algorithm. The simplex method and an updating procedure are combined into a new algorithm for time-adaptive quantile regression, which

Jan Kloppenborg Møller; Henrik Aalborg Nielsen; Henrik Madsen



Poisson Regression for Clustered Data  

Microsoft Academic Search

We compare five methods for parameter estimation of a Poisson regression model for clustered data: (1) ordinary (naive) Poisson regression (OP), which ignores intracluster correlation, (2) Poisson regression with fixed cluster-specific intercepts (FI), (3) a generalized estimating equations (GEE) approach with an equi-correlation matrix, (4) an exact generalized estimating equations (EGEE) approach with an exact covariance matrix, and (5) maximum

Eugene Demidenko



Tumor formation in a mouse model of colitis-associated colon cancer does not require COX-1 or COX-2 expression  

PubMed Central

Cyclooxygenase-2 (COX-2), a key enzyme of prostanoid biosynthesis, plays an important role in both hereditary and spontaneous colon cancer. Individuals with ulcerative colitis are also at high risk for colorectal cancer. To investigate the role of Cox-2 in colitis-associated colon cancer, we subjected Cox-2 luciferase-knock-in mice and Cox-2-knockout mice to a well-known mouse model of colitis-associated cancer in which animals are treated with a single-azoxymethane (AOM) injection followed by dextran sulfate sodium (DSS) administration. Tumors induced by AOM and DSS expressed significantly higher Cox-2 levels when compared with surrounding areas of colon, as detected both by luciferase reporter gene expression driven from the endogenous Cox-2 promoter and by western blotting of COX-2 protein in Cox-2 luciferase heterozygous knock-in mice. Immunofluorescence revealed that tumor stromal fibroblasts, macrophages and endothelial cells express COX-2 protein. In contrast, little COX-2 expression was observed in myofibroblasts or epithelial cells. Despite a significant elevation of COX-2 expression in AOM/DSS-induced colon tumors in wild-type mice, similar tumors developed in AOM/DSS-treated Cox-2?/?- and Cox-1?/?-knockout mice. These results indicate that cyclooxygenase-derived prostanoids are not major players in colitis-associated cancer. In contrast, tumor formation induced by multiple injections of AOM (with no DSS-induced colitis) did not occur in Cox-2?/?-knockout mice. Our data suggest that the mechanism of colorectal tumor promotion in colitis-associated cancer differs from the mechanism of tumor promotion for hereditary and sporadic colorectal cancer.

Ishikawa, Tomo-o; Herschman, Harvey R.



Regression to the Mean  

NSDL National Science Digital Library

Created by David Lane of Rice University, this is a simulation illustrating the regression toward the mean phenomenon. The author has created a specific case study to explore, he states it as: "In this simulation, a group of students takes a test made up of 100 true/false questions. Each student knows the answers to a specific number of questions and guesses at the remaining. Students get one point for each question they answer correctly and lose one point for each question they answer incorrectly." After completing this study, students can then input their data into the interactive applet. Eleven exercise questions will then test the students knowledge and understanding of their findings.

Lane, David M.



Ridge regression processing  

NASA Technical Reports Server (NTRS)

Current navigation requirements depend on a geometric dilution of precision (GDOP) criterion. As long as the GDOP stays below a specific value, navigation requirements are met. The GDOP will exceed the specified value when the measurement geometry becomes too collinear. A new signal processing technique, called Ridge Regression Processing, can reduce the effects of nearly collinear measurement geometry; thereby reducing the inflation of the measurement errors. It is shown that the Ridge signal processor gives a consistently better mean squared error (MSE) in position than the Ordinary Least Mean Squares (OLS) estimator. The applicability of this technique is currently being investigated to improve the following areas: receiver autonomous integrity monitoring (RAIM), coverage requirements, availability requirements, and precision approaches.

Kuhl, Mark R.



The univariant curve liquid = forsterite + anorthite + diopside in the system CMAS at 1 bar: solid solutions and melt structure  

Microsoft Academic Search

One atmosphere liquid-present experiments were carried out in the CMAS system using an ordinary quench furnace apparatus. The runs, including reversal and duplicate experiments, describe the univariant curve l=fo+an+ di between the invariant points Q: l+fo+an=di+sp and F: l+fo=an+di+oen, located respectively at 1245±1° C and 1244±1° C. The thermal divide on this curve M3: l= fo+an+di is located at 1275±1°

Guy Libourel; Pierre Boivin; Gordon M. Biggar



Method of studying the synchronization of self-sustained oscillations using continuous wavelet analysis of univariant data  

NASA Astrophysics Data System (ADS)

A new method for detecting the synchronization of a self-sustained oscillator under an external action with a linearly increasing frequency is proposed. It is based on the continuous wavelet transformation of univariant data (scalar time series). The efficiency of the method is demonstrated with a modified asymmetric van der Pol oscillator, Rössler oscillator, and experimental physiological data. In the last case, synchronization between rhythmic processes of different order in the cardiovascular and respiratory systems of the man is demonstrated using only the time series of the R-R intervals.

Koronovskii, A. A.; Ponomarenko, V. I.; Prokhorov, M. D.; Hramov, A. E.



Smoking and COX-2 Functional Polymorphisms Interact to Increase the Risk of Gastric Cardia Adenocarcinoma in Chinese Population  

PubMed Central

Background Over-expression and increased activity of cyclooxygenase (COX)-2 induced by smoking has been implicated in the development of cancer. This study aimed to explore the interaction between smoking and functional polymorphisms of COX-2 in modulation of gastric cardia adenocarcinoma (GCA) risk. Methods and Findings Three COX-2 polymorphisms, including –1195G>A (rs689466), –765G>C (rs20417), and 587Gly>Arg (rs3218625), were genotyped in 357 GCA patients and 985 controls. In the multivariate logistic regression analysis, we found that the –1195AA, –765GC, and 587Arg/Arg genotypes were associated with increased risk of GCA (OR?=?1.50, 95% CI?=?1.05–2.13; OR?=?2.06, 95% CI?=?1.29–3.29 and OR?=?1.67, 95% CI?=?1.04–2.66, respectively). Haplotype association analysis showed that compared with G?1195-G?765- GGly587Arg, the A?1195-C?765-AGly587Arg conferred an increased risk of GCA (OR?=?2.49, 95% CI?=?1.54–4.01). Moreover, significant multiplicative interactions were observed between smoking and these three polymorphisms of –1195G>A, –765G>C, and 587Gly>Arg, even after correction by false discovery rate (FDR) method for multiple comparisons (FDR-Pinteraction?=?0.006, 5.239×10?4 and 0.017, respectively). Similarly, haplotypes incorporating these three polymorphisms also showed significant interaction with smoking in the development of GCA (P for multiplicative interaction?=?2.65×10?6). Conclusion These findings indicated that the functional polymorphisms of COX-2, in interaction with smoking, may play a substantial role in the development of GCA.

Wang, Ying; Yuan, Ju-Xiang; Wang, Peng; Sun, Chuang; Zhang, Zhi; Song, Wen-Guang; Miao, Xiao-Ping



Metal-binding mechanism of Cox17, a copper chaperone for cytochrome c oxidase.  


Cox17, a copper chaperone for cytochrome c oxidase, is an essential and highly conserved protein. The structure and mechanism of functioning of Cox17 are unknown, and even its metalbinding stoichiometry is elusive. In the present study, we demonstrate, using electrospray ionization-MS, that porcine Cox17 binds co-operatively four Cu+ ions. Cu4Cox17 is stable at pH values above 3 and fluorescence spectra indicate the presence of a solvent-shielded multinuclear Cu(I) cluster. Combining our results with earlier EXAFS results on yeast CuCox17, we suggest that Cu4Cox17 contains a Cu4S6-type cluster. At supramillimolar concentrations, dithiothreitol extracts metals from Cu4Cox17, and an apparent copper dissociation constant KCu=13 fM was calculated from these results. Charge-state distributions of different Cox17 forms suggest that binding of the first Cu+ ion to Cox17 causes a conformational change from an open to a compact state, which may be the rate-limiting step in the formation of Cu4Cox17. Cox17 binds non-co-operatively two Zn2+ ions, but does not bind Ag+ ions, which highlights its extremely high metal-binding specificity. We further demonstrate that porcine Cox17 can also exist in partly oxidized (two disulphide bridges) and fully oxidized (three disulphide bridges) forms. Partly oxidized Cox17 can bind one Cu+ or Zn2+ ion, whereas fully oxidized Cox17 does not bind metals. The metal-binding properties of Cox17 imply that, in contrast with other copper chaperones, Cox17 is designed for the simultaneous transfer of up to four copper ions to partner proteins. Metals can be released from Cox17 by non-oxidative as well as oxidative mechanisms. PMID:15142040

Palumaa, Peep; Kangur, Liina; Voronova, Anastassia; Sillard, Rannar



Assessment of the Relative Contribution of COX-1 and COX-2 Isoforms to Ischemia-induced Oxidative Damage and Neurodegeneration Following Transient Global Cerebral Ischemia  

PubMed Central

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

Candelario-Jalil, Eduardo; Gonzalez-Falcon, Armando; Garcia-Cabrera, Michel; Alvarez, Dalia; Al-Dalain, Said; Martinez, Gregorio; Sonia Leon, Olga; Springer, Joe E.



COX-2 expression is predictive for early relapse and aromatase inhibitor resistance in patients with ductal carcinoma in situ of the breast, and is a target for treatment.  


Background:Stratification of patients for treatment of ductal carcinoma in situ (DCIS) is suboptimal, with high systemic overtreatment rates.Methods:A training set of 95 tumours from women with pure DCIS were immunostained for proteins involved in cell survival, hypoxia, growth factor and hormone signalling. A generalised linear regression with regularisation and variable selection was applied to a multiple covariate Cox survival analysis with recurrence-free survival 10-fold cross-validation and leave-one-out iterative approach were used to build and test the model that was validated using an independent cohort of 58 patients with pure DCIS. The clinical role of a COX-2-targeting agent was then tested in a proof-of-concept neoadjuvant randomised trial in ER-positive DCIS treated with exemestane 25?mg?day(-1)±celecoxib 800?mg?day(-1).Results:The COX-2 expression was an independent prognostic factor for early relapse in the training (HR 37.47 (95% CI: 5.56-252.74) P=0.0001) and independent validation cohort (HR 3.9 (95% CI: 1.8-8.3) P=0.002). There was no significant interaction with other clinicopathological variables. A statistically significant reduction of Ki-67 expression after treatment with exemestane±celecoxib was observed (P<0.02) with greater reduction in the combination arm (P<0.004). Concomitant reduction in COX-2 expression was statistically significant in the exemestane and celecoxib arm (P<0.03) only.Conclusions:In patients with DCIS, COX-2 may predict recurrence, aiding clinical decision making. A combination of an aromatase inhibitor and celecoxib has significant biological effect and may be integrated into treatment of COX2-positive DCIS at high risk of recurrence. PMID:24874483

Generali, D; Buffa, F M; Deb, S; Cummings, M; Reid, L E; Taylor, M; Andreis, D; Allevi, G; Ferrero, G; Byrne, D; Martinotti, M; Bottini, A; Harris, A L; Lakhani, S R; Fox, S B



Knock-down of the COX3 and COX17 gene expression of cytochrome c oxidase in the unicellular green alga Chlamydomonas reinhardtii.  


The COX3 gene encodes a core subunit of mitochondrial cytochrome c oxidase (complex IV) whereas the COX17 gene encodes a chaperone delivering copper to the enzyme. Mutants of these two genes were isolated by RNA interference in the microalga Chlamydomonas. The COX3 mRNA was completely lacking in the cox3-RNAi mutant and no activity and assembly of complex IV were detected. The cox17-RNAi mutant presented a reduced level of COX17 mRNA, a reduced activity of the cytochrome c oxidase but no modification of its amount. The cox3-RNAi mutant had only 40% of the wild-type rate of dark respiration which was cyanide-insensitive. The mutant presented a 60% decrease of H(2)O(2) production in the dark compared to wild type, which probably accounts for a reduced electron leakage by respiratory complexes III and IV. In contrast, the cox17-RNAi mutant showed no modification of respiration and of H(2)O(2) production in the dark but a two to threefold increase of H(2)O(2) in the light compared to wild type and the cox3-RNAi mutant. The cox17-RNAi mutant was more sensitive to cadmium than the wild-type and cox3-RNAi strains. This suggested that besides its role in complex IV assembly, Cox17 could have additional functions in the cell such as metal detoxification or Reactive Oxygen Species protection or signaling. Concerning Cox3, its role in Chlamydomonas complex IV is similar to that of other eukaryotes although this subunit is encoded in the nuclear genome in the alga contrary to the situation found in all other organisms. PMID:20700628

Remacle, Claire; Coosemans, Nadine; Jans, Frédéric; Hanikenne, Marc; Motte, Patrick; Cardol, Pierre



EGF receptor and COX-1/COX-2 enzyme proteins as related to corresponding mRNAs in human per-operative biopsies of colorectal cancer  

PubMed Central

Background Cyclooxygenase (COX) and epidermal growth factor receptor (EGFR) activities promote progression of colorectal cancer. Combined treatment against these targets has not been more effective than single treatments alone. Therefore, our aim was to analyze relationships between COX and EGFR in peroperative colorectal tumor biopsies. Method Tumor and colon mucosa tissue were collected at primary intended curative operations in patients according to well-recognized statistical distributions of tumor stages in colorectal cancer. COX-1, COX-2 and EGFR content in tumor and colon mucosa tissue were quantified by western blot and Q-PCR. Results COX-2 protein appeared as two bands, one at 66 kDa in almost all tumor and mucosa samples and one at 74 kDa in 73% of the tumors and in 23% of the mucosa samples. Tumor COX-2 mRNA was not different from the content in mucosa samples, while COX-2 protein was increased in tumor tissue (p < 0.0003). A correlation between 74 kDa COX-2 protein and COX-2 mRNA occurred in tumor tissue, with significantly increasing COX-2 mRNA across tumor stages. EGFR mRNA content was lower in tumor tissue (p < 0.0001), while EGFR protein was similar in tumor and mucosa samples. COX-2 and EGFR proteins showed a positive correlation in mucosa, while a negative correlation occurred in tumor tissue. Tumor tissue with high COX-2 74 kDa protein lacked EGFR protein. Conclusion Our present results are compatible with the theory that COX-2 and EGFR signalling pathways are inversely related in colorectal cancer tissue. This may explain why combinatorial clinical treatments have been less rewarding.



A Renovated Cook's Distance Based On The Buckley-James Estimate In Censored Regression  

Microsoft Academic Search

There have been various methods created based on the regression ideas to resolve the problem of data set contain- ing censored observations, i.e. the Buckley-James method, Miller's method, Cox method, and Koul-Susarla-Van Ryzin estimators. Even though comparison studies show the Buckley-James method performs better than some other methods, it is still rarely used by researchers mainly because of the limited

Nazrina Aziz; Dong Q. Wang



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


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

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



COX-3 and the mechanism of action of paracetamol/acetaminophen.  


Paracetamol produces analgesia in the mouse writhing test through a central action which is paralleled by a reduction in brain PGE(2) concentrations. In contrast, diclofenac has a peripheral analgesic action in this test. Paracetamol-induced hypothermia is also accompanied by a reduction in brain PGE(2) concentrations in C57/Bl6 mice. This hypothermic effect of paracetamol was reduced in COX-1 but not in COX-2 gene-deleted mice. These results support the view that analgesia and hypothermia due to paracetamol are mediated by inhibition of a third COX isoenzyme (designated COX-3). In cultured mouse macrophages, COX-2 is induced by treatment with LPS or with high concentrations of diclofenac. Diclofenac-induced COX-2 is inhibited with low concentrations of paracetamol, whereas LPS-induced COX-2 is insensitive to paracetamol inhibition. The mechanisms of induction and possibly the functions of these two COX-2 enzymes are also different. PMID:15626590

Botting, Regina; Ayoub, Samir S



Use of Inhibitors of Soluble Epoxide Hydrolase to Synergize Activity of COX and 5-LOX Inhibitors.  

National Technical Information Service (NTIS)

The invention relates to methods, compositions, and uses of those compositions for making medicaments, for potentiating the beneficial effects of inhibitors of COX-1, COX-2, and 5-LOX, and reducing adverse effects, by also administering inhibitors of solu...

A. B. Inceoglu B. D. Hammock K. Schmelzer



Bayesian Spatial Quantile Regression  

PubMed Central

Tropospheric ozone is one of the six criteria pollutants regulated by the United States Environmental Protection Agency under the Clean Air Act and has been linked with several adverse health effects, including mortality. Due to the strong dependence on weather conditions, ozone may be sensitive to climate change and there is great interest in studying the potential effect of climate change on ozone, and how this change may affect public health. In this paper we develop a Bayesian spatial model to predict ozone under different meteorological conditions, and use this model to study spatial and temporal trends and to forecast ozone concentrations under different climate scenarios. We develop a spatial quantile regression model that does not assume normality and allows the covariates to affect the entire conditional distribution, rather than just the mean. The conditional distribution is allowed to vary from site-to-site and is smoothed with a spatial prior. For extremely large datasets our model is computationally infeasible, and we develop an approximate method. We apply the approximate version of our model to summer ozone from 1997–2005 in the Eastern U.S., and use deterministic climate models to project ozone under future climate conditions. Our analysis suggests that holding all other factors fixed, an increase in daily average temperature will lead to the largest increase in ozone in the Industrial Midwest and Northeast.

Reich, Brian J.; Fuentes, Montserrat; Dunson, David B.



Multinomial logistic regression ensembles.  


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

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



Bayesian Spatial Quantile Regression.  


Tropospheric ozone is one of the six criteria pollutants regulated by the United States Environmental Protection Agency under the Clean Air Act and has been linked with several adverse health effects, including mortality. Due to the strong dependence on weather conditions, ozone may be sensitive to climate change and there is great interest in studying the potential effect of climate change on ozone, and how this change may affect public health. In this paper we develop a Bayesian spatial model to predict ozone under different meteorological conditions, and use this model to study spatial and temporal trends and to forecast ozone concentrations under different climate scenarios. We develop a spatial quantile regression model that does not assume normality and allows the covariates to affect the entire conditional distribution, rather than just the mean. The conditional distribution is allowed to vary from site-to-site and is smoothed with a spatial prior. For extremely large datasets our model is computationally infeasible, and we develop an approximate method. We apply the approximate version of our model to summer ozone from 1997-2005 in the Eastern U.S., and use deterministic climate models to project ozone under future climate conditions. Our analysis suggests that holding all other factors fixed, an increase in daily average temperature will lead to the largest increase in ozone in the Industrial Midwest and Northeast. PMID:23459794

Reich, Brian J; Fuentes, Montserrat; Dunson, David B



COX-2/EGFR expression and survival among women with adenocarcinoma of the lung  

PubMed Central

Previous studies suggest that cyclooxygenase-2 (COX-2) expression may predict survival among patients with non-small cell lung cancer. COX-2 may interact with epidermal growth factor receptor (EGFR), suggesting that combined COX-2/EGFR expression may provide predictive value. The extent to which their independent or combined expression is associated with prognosis in women with adenocarcinoma of the lung is unknown. In the present study, we examined relationships between COX-2 expression (n?=?238), EGFR expression (n?=?158) and dual COX-2/EGFR expression (n?=?157) and survival among women with adenocarcinoma of the lung. Overall survival was estimated by constructing Cox proportional hazards models adjusting for other significant variables and stratifying by stage at diagnosis and race. Clinical or demographic parameters were not associated with either COX-2 or EGFR expression. Patients with COX-2-positive tumors tended to have poorer prognosis than did patients with COX-2-negative tumors [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.01–2.78]. African-Americans with COX-2-positive tumors had a statistically non-significant higher risk of death than African-Americans with COX-2-negative tumors (HR 5.58, 95% CI 0.64–48.37). No association between COX-2 expression and survival was observed among Caucasians (HR 1.29, 95% CI 0.72–2.30). EGFR expression was associated with a 44% reduction in the risk of death (HR 0.56, 95% CI 0.32–0.98). COX-2?/EGFR+ tumor expression, but not COX-2+/EGFR+ tumor expression, was associated with survival when compared with other combined expression results. In conclusion, COX-2 and EGFR expression, but not combined COX-2+/EGFR+ expression, independently predict survival of women with adenocarcinoma of the lung.

Van Dyke, Alison L.; Cote, Michele L.; Prysak, Geoffrey M.; Claeys, Gina B.; Wenzlaff, Angie S.; Murphy, Valerie C.; Lonardo, Fulvio; Schwartz, Ann G.



Deficiency of COX1 causes natriuresis and enhanced sensitivity to ACE inhibition  

Microsoft Academic Search

Deficiency of COX-1 causes natriuresis and enhanced sensitivity to ACE inhibition.BackgroundProstanoid products of the cyclo-oxygenase (COX) pathway of arachidonic acid metabolism modulate blood pressure (BP) and sodium homeostasis. Conventional non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit both COX isoforms (COX-1 and -2), cause sodium retention, exacerbate hypertension, and interfere with the efficacy of certain anti-hypertensive agents such as angiotensin-converting enzyme (ACE)

Krairerk Athirakul; Hyung-Suk Kim; Laurent P Audoly; Oliver Smithies; Thomas M Coffman



siRNA-mediated knock-down of COX-2 in melanocytes suppresses melanogenesis.  


Cyclooxygenase-2 (COX-2) is an enzyme induced in response to multiple mitogenic and inflammatory stimuli, including UV light. UV-induced COX-2 expression induces production of prostaglandin E2 (PGE2) in keratinocytes, which mediates inflammation and cell proliferation. Until recently, studies regarding COX-2 and PGE2 in the skin have focused on keratinocytes and skin cancer and the effect of PGs produced by keratinocytes on melanocytes. However, the effects of COX-2 itself or COX-2 inhibitors on melanogenesis are not well known. Therefore, to establish the role of COX-2 in melanogenesis, we investigated the effects of knock-down of COX-2 in melanocytes on melanin production and the expression of melanogenic molecules through silencing of COX-2 expression with COX-2 short interfering RNA (siRNA). COX-2 knock-down in melanocytes decreased the expressions of tyrosinase, TRP-1, TRP-2, gp100 and MITF and also reduced tyrosinase enzyme activity. Furthermore, COX-2 siRNA-transfected melanocytes showed markedly reduced alpha-melanocyte stimulating hormone (?-MSH)-induced melanin production. In addition, ?-MSH-induced COX-2 expression in both scrambled siRNA-transfected and COX-2 siRNA-transfected melanocytes was greater than ?-MSH-untreated cells. Our results suggest that COX-2 might be a candidate target for the development of anti-melanogenic agents and ?-MSH-induced pigmentation could be closely associated with COX-2 expression. COX-2 inhibitors might therefore be of particular use in whitening cosmetics for hyperpigmentation disorders such as melasma, postinflammatory hyperpigmentation and solar lentigo. PMID:22506937

Kim, Ji Y; Shin, Jae Y; Kim, Miri R; Hann, Seung-Kyung; Oh, Sang H



Linear regression in astronomy. II  

NASA Technical Reports Server (NTRS)

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.

Feigelson, Eric D.; Babu, Gutti J.



Skyrmion Lattice Domains in Fe1-xCoxSi  

NASA Astrophysics Data System (ADS)

The strongly doped semiconductor Fe1-xCoxSi displays a dome of helimagnetic order for 0.05 <= x <= 0.7. We report small angle neutron scattering of the magnetic structure in the skyrmion lattice phase of Fe1-xCoxSi for x = 0.2 and magnetic field parallel to a crystallographic (100) direction. We observe twelve equally spaced maxima of scattering intensity on a ring, with an underlying six-fold symmetry of two sets of six spots. The intensity distribution suggests the formation of two degenerate skyrmion lattice domain populations with respect to the four-fold symmetry of the (100) directions in the scattering plane.

Adams, T.; Mühlbauer, S.; Neubauer, A.; Münzer, W.; Jonietz, F.; Georgii, R.; Pedersen, B.; Böni, P.; Rosch, A.; Pfleiderer, C.



Characterization of human SCO1 and COX17 genes in mitochondrial cytochrome-c-oxidase deficiency.  


At least three proteins, COX17p, SCO1p, and its homologue SCO2p are thought to be involved in mitochondrial copper transport to cytochrome-c-oxidase (COX), the terminal enzyme of the respiratory chain. Recently, we and others have shown that mutations in SCO2 are associated with a lethal infantile hypertrophic cardiomyopathy (HCMP) with COX-deficiency. The majority of patients with a similar phenotype were, however, negative for SCO2 mutations, suggesting the other genes as candidates for this disorder. Here we report on the genomic organization of SCO1 and COX17 on human chromosomes 17 and 3 respectively, and the complete sequence analysis of COX17 and SCO1 in 30 patients with COX deficiency. Using a panel of human:mouse-monochromosomal hybrids, the expression of COX17 was specifically restricted to chromosome 3, indicating that the previously reported sequence on chromosome 13 represents a pseudogene. DNA sequence analysis of SCO1 and COX17 in nine patients with severe COX deficiency and fatal HCMP, and in 21 patients with other COX deficiency disorders, did not reveal any pathogenic mutations or polymorphisms. We conclude that neither SCO1 nor COX17 are common causes of COX deficiency disorders. PMID:11027508

Horvath, R; Lochmüller, H; Stucka, R; Yao, J; Shoubridge, E A; Kim, S H; Gerbitz, K D; Jaksch, M



Cox17 is functional when tethered to the mitochondrial inner membrane.  


Cox17 is an essential protein in the assembly of cytochrome c oxidase within the mitochondrion. Cox17 is implicated in providing copper ions for formation of CuA and CuB sites in the oxidase complex. To address whether Cox17 is functional in shuttling copper ions to the mitochondrion, Cox17 was tethered to the mitochondrial inner membrane by a fusion to the transmembrane domain of the inner membrane protein, Sco2. The copper-binding domain of Sco2 that projects into the inter-mitochondrial membrane space was replaced with Cox17. The Sco2/Cox17 fusion protein containing the mitochondrial import sequence and transmembrane segment of Sco2 is exclusively localized within the mitochondrion. The Sco2/Cox17 protein restores respiratory growth and normal cytochrome oxidase activity in cox17Delta cells. These studies suggest that the function of Cox17 is confined to the mitochondrial intermembrane space. Domain mapping of yeast Cox17 reveals that the carboxyl-terminal segment of the protein has a function within the intermembrane space that is independent of copper ion binding. The essential C-terminal function of Cox17 maps to a candidate amphipathic helix that is important for mitochondrial uptake and retention of the Cox17 protein. This motif can be spatially separated from the N-terminal copper-binding functional motif. Possible roles of the C-terminal motif are discussed. PMID:14615477

Maxfield, Andrew B; Heaton, Daren N; Winge, Dennis R



Kinetics and docking studies of a COX-2 inhibitor isolated from Terminalia bellerica fruits.  


Triphala is an Ayurvedic herbal formulation consisting of equal parts of three myrobalans: Terminalia chebula, Terminalia bellerica and Emblica officinalis. We recently reported that chebulagic acid (CA) isolated from Terminalia chebula is a potent COX-2/5-LOX dual inhibitor. In this study, compounds isolated from Terminalia bellerica were tested for inhibition against COX and 5-LOX. One of the fractionated compounds showed potent inhibition against COX enzymes with no inhibition against 5-LOX. It was identified as gallic acid (GA) by LC-MS, NMR and IR analyses. We report here the inhibitory effects of GA, with an IC(50) value of 74 nM against COX-2 and 1500 nM for COX-1, showing ?20 fold preference towards COX-2. Further docking studies revealed that GA binds in the active site of COX-2 at the non-steroidal anti-inflammatory drug (NSAID) binding site. The carboxylate moiety of GA interacts with Arg120 and Glu524. Based on substrate dependent kinetics, GA was found to be a competitive inhibitor of both COX-1 and COX-2, with more affinity towards COX-2. Taken together, our studies indicate that GA is a selective inhibitor of COX-2. Being a small natural product with selective and reversible inhibition of COX-2, GA would form a lead molecule for developing potent anti-inflammatory drug candidates. PMID:20441561

Reddy, Tamatam Chandramohan; Aparoy, Polamarasetty; Babu, Neela Kishore; Kumar, Kotha Anil; Kalangi, Suresh Kumar; Reddanna, Pallu



The relationship between mucosal cyclooxygenase-2 (COX2) expression and experimental radiation-induced mucositis  

Microsoft Academic Search

Although cycloooxygenase-2 (COX-2) is upregulated by factors associated with oral mucositis, its role in the pathogenesis of mucositis has not been studied. We investigated the kinetics of mucosal COX-2 expression following radiation exposure, and assessed its relationship to the development of oral mucositis in an established animal model using immunohistochemical endpoints. While little or no COX-2 expression was observed in

S. T. Sonis; K. E. O'Donnell; R. Popat; C. Bragdon; S. Phelan; D. Cocks; J. B. Epstein



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


Motivated by a previously published study of HIV treatment, we simulated data subject to time-varying confounding affected by prior treatment to examine some finite-sample properties of marginal structural Cox proportional hazards models. We compared (a)?unadjusted, (b)?regression-adjusted, (c)?unstabilized, and (d)?stabilized marginal structural (inverse probability-of-treatment [IPT] weighted) model estimators of effect in terms of bias, standard error, root mean squared error (MSE), and 95% confidence limit coverage over a range of research scenarios, including relatively small sample sizes and 10 study assessments. In the base-case scenario resembling the motivating example, where the true hazard ratio was 0.5, both IPT-weighted analyses were unbiased, whereas crude and adjusted analyses showed substantial bias towards and across the null. Stabilized IPT-weighted analyses remained unbiased across a range of scenarios, including relatively small sample size; however, the standard error was generally smaller in crude and adjusted models. In many cases, unstabilized weighted analysis showed a substantial increase in standard error compared with other approaches. Root MSE was smallest in the IPT-weighted analyses for the base-case scenario. In situations where time-varying confounding affected by prior treatment was absent, IPT-weighted analyses were less precise and therefore had greater root MSE compared with adjusted analyses. The 95% confidence limit coverage was close to nominal for all stabilized IPT-weighted but poor in crude, adjusted, and unstabilized IPT-weighted analysis. Under realistic scenarios, marginal structural Cox proportional hazards models performed according to expectations based on large-sample theory and provided accurate estimates of the hazard ratio. PMID:22492660

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



Genomic structure of mouse copper chaperone, COX17.  


Coxl7p was first cloned as a cytoplasmic copper chaperone from yeast mutant and recent works suggested the existence of mammalian homologues. Previous report has shown that a gel filtration fraction of heart extract containing porcine Coxl7p peptide promoted the survival of NIH3T3 fibroblast cells. In the present study, we first cloned DNA fragments of the mouse COX17 gene. The mouse COX17 spans approximately 6kb and consists of three exons. It was mapped to the center of chromosome 16, using a radiation hybrid-mapping panel. The major transcription start site is 80 bp upstream of the ATG initiation codon as determined by rapid amplification of cDNA ends (5'-RACE) analysis. Two potential polyadenylation sites are 3233 and 3293 bp downstream of the termination codon, respectively. Transient transfection of reporter plasmids containing portions of the mouse COX17 5'-flanking region into AtT-20 and NIH3T3 cells allowed the localization of the essential promoter to a 0.8 kb region upstream of the transcription starting site. Furthermore, the transfected luciferase activity was much higher in AtT-20 than NIH3T3. According to sequence analysis of the approximately 0.8kb 5'-flanking region, GC rich segments including consensus sequences for binding of the transcription factor Sp1, but no TATA/CAAT boxes, exist in the region of the transcription start site. Besides the GC box, binding sites for NRF-1 and 2 known as specific transcription factors for COX subunits are also localized around the transcription starting site. PMID:11913776

Takahashi, Y; Kako, K; Ohmura, K; Tsumori, K; Ohmasa, Y; Kashiwabara, S; Baba, T; Munekatat, E



Modelling geomagnetic reversals as a Gaussian Cox Process  

NASA Astrophysics Data System (ADS)

The mean rate of reversal of the geomagnetic field, as recorded in the Geomagnetic Polarity Time Scale (GPTS), has long been an object of study. The significance of the apparent long-term variations in the mean rate of reversals - including the occurrence of superchrons - has been debated, as has the possible origins of these variations in external control of the geodynamo (e.g. by the time-varying boundary conditions imposed by mantle convection). Here we model the long-term variations in the reversal rate nonparametrically, in terms of an inhomogeneous Poisson process. Specifically, we consider a Gaussian Cox process, a type of doubly-stochastic Poisson process where the mean rate (or intensity) is modelled in terms of a Gaussian process. Such processes are amenable to likelihood-based inference using Bayesian Markov Chain Monte-Carlo (MCMC) methods, which we employ to provide posterior distributions of the model parameters. The specification of a Gaussian process requires a covariance function, relating the intensity at nearby times; crucially, however, the timescale of the covariance function is not prescribed, but appears as a model hyperparameter, whose posterior distribution is an important output of the analysis. For the geodynamo, this hyperparameter should robustly characterise the timescale of long-term variations. Two different types of Gaussian Cox process are considered: a Log Gaussian Cox Process, applied to binned reversal data; and a Sigmoidal Gaussian Cox Process, applied to the discrete reversal data using a technique involving latent variables. Different MCMC algorithms for sampling the posterior distribution of the model parameters are investigated for both types of process, to check (and to optimise) the convergence of the MCMC chains. This analysis is applied to different records of the GPTS, including those of Cande & Kent (1995) and Gradstein & Ogg (1996). The implications of this analysis for the geodynamo, and the possibility of comparable analysis of the output of numerical geodynamo simulations, are discussed.

Sarson, Graeme; Boys, Richard; Golightly, Andrew; Henderson, Daniel



LC-MS/MS confirms that COX-1 drives vascular prostacyclin whilst gene expression pattern reveals non-vascular sites of COX-2 expression.  


There are two schools of thought regarding the cyclooxygenase (COX) isoform active in the vasculature. Using urinary prostacyclin markers some groups have proposed that vascular COX-2 drives prostacyclin release. In contrast, we and others have found that COX-1, not COX-2, is responsible for vascular prostacyclin production. Our experiments have relied on immunoassays to detect the prostacyclin breakdown product, 6-keto-PGF1? and antibodies to detect COX-2 protein. Whilst these are standard approaches, used by many laboratories, antibody-based techniques are inherently indirect and have been criticized as limiting the conclusions that can be drawn. To address this question, we measured production of prostanoids, including 6-keto-PGF1?, by isolated vessels and in the circulation in vivo using liquid chromatography tandem mass spectrometry and found values essentially identical to those obtained by immunoassay. In addition, we determined expression from the Cox2 gene using a knockin reporter mouse in which luciferase activity reflects Cox2 gene expression. Using this we confirm the aorta to be essentially devoid of Cox2 driven expression. In contrast, thymus, renal medulla, and regions of the brain and gut expressed substantial levels of luciferase activity, which correlated well with COX-2-dependent prostanoid production. These data are consistent with the conclusion that COX-1 drives vascular prostacyclin release and puts the sparse expression of Cox2 in the vasculature in the context of the rest of the body. In doing so, we have identified the thymus, gut, brain and other tissues as target organs for consideration in developing a new understanding of how COX-2 protects the cardiovascular system. PMID:23874970

Kirkby, Nicholas S; Zaiss, Anne K; Urquhart, Paula; Jiao, Jing; Austin, Philip J; Al-Yamani, Malak; Lundberg, Martina H; MacKenzie, Louise S; Warner, Timothy D; Nicolaou, Anna; Herschman, Harvey R; Mitchell, Jane A



LC-MS/MS Confirms That COX-1 Drives Vascular Prostacyclin Whilst Gene Expression Pattern Reveals Non-Vascular Sites of COX-2 Expression  

PubMed Central

There are two schools of thought regarding the cyclooxygenase (COX) isoform active in the vasculature. Using urinary prostacyclin markers some groups have proposed that vascular COX-2 drives prostacyclin release. In contrast, we and others have found that COX-1, not COX-2, is responsible for vascular prostacyclin production. Our experiments have relied on immunoassays to detect the prostacyclin breakdown product, 6-keto-PGF1? and antibodies to detect COX-2 protein. Whilst these are standard approaches, used by many laboratories, antibody-based techniques are inherently indirect and have been criticized as limiting the conclusions that can be drawn. To address this question, we measured production of prostanoids, including 6-keto-PGF1?, by isolated vessels and in the circulation in vivo using liquid chromatography tandem mass spectrometry and found values essentially identical to those obtained by immunoassay. In addition, we determined expression from the Cox2 gene using a knockin reporter mouse in which luciferase activity reflects Cox2 gene expression. Using this we confirm the aorta to be essentially devoid of Cox2 driven expression. In contrast, thymus, renal medulla, and regions of the brain and gut expressed substantial levels of luciferase activity, which correlated well with COX-2-dependent prostanoid production. These data are consistent with the conclusion that COX-1 drives vascular prostacyclin release and puts the sparse expression of Cox2 in the vasculature in the context of the rest of the body. In doing so, we have identified the thymus, gut, brain and other tissues as target organs for consideration in developing a new understanding of how COX-2 protects the cardiovascular system.

Kirkby, Nicholas S.; Zaiss, Anne K.; Urquhart, Paula; Jiao, Jing; Austin, Philip J.; Al-Yamani, Malak; Lundberg, Martina H.; MacKenzie, Louise S.; Warner, Timothy D.; Nicolaou, Anna; Herschman, Harvey R.; Mitchell, Jane A.



Hepatic Ischemia and Reperfusion Injury in the Absence of Myeloid Cell-Derived COX-2 in Mice  

PubMed Central

Cyclooxygenase-2 (COX-2) is a mediator of hepatic ischemia and reperfusion injury (IRI). While both global COX-2 deletion and pharmacologic COX-2 inhibition ameliorate liver IRI, the clinical use of COX-2 inhibitors has been linked to increased risks of heart attack and stroke. Therefore, a better understanding of the role of COX-2 in different cell types may lead to improved therapeutic strategies for hepatic IRI. Macrophages of myeloid origin are currently considered to be important sources of the COX-2 in damaged livers. Here, we used a Cox-2flox conditional knockout mouse (COX-2?M/?M) to examine the function of COX-2 expression in myeloid cells during liver IRI. COX-2?M/?M mice and their WT control littermates were subjected to partial liver ischemia followed by reperfusion. COX-2?M/?M macrophages did not express COX-2 upon lipopolysaccharide stimulation and COX-2?M/?M livers showed reduced levels of COX-2 protein post-IRI. Nevertheless, selective deletion of myeloid cell-derived COX-2 failed to ameliorate liver IRI; serum transaminases and histology were comparable in both COX-2?M/?M and WT mice. COX-2?M/?M livers, like WT livers, developed extensive necrosis, vascular congestion, leukocyte infiltration and matrix metalloproteinase-9 (MMP-9) expression post-reperfusion. In addition, myeloid COX-2 deletion led to a transient increase in IL-6 levels after hepatic reperfusion, when compared to controls. Administration of celecoxib, a selective COX-2 inhibitor, resulted in significantly improved liver function and histology in both COX-2?M/?M and WT mice post-reperfusion, providing evidence that COX-2-mediated liver IRI is caused by COX-2 derived from a source(s) other than myeloid cells. In conclusion, these results support the view that myeloid COX-2, including myeloid-macrophage COX-2, is not responsible for the hepatic IRI phenotype.

Duarte, Sergio; Kato, Hiroyuki; Kuriyama, Naohisa; Suko, Kathryn; Ishikawa, Tomo-o; Busuttil, Ronald W.; Herschman, Harvey R.; Coito, Ana J.



Inhibition of haematogenous metastasis of colon cancer in mice by a selective COX2 inhibitor, JTE-522  

Microsoft Academic Search

It is proposed that non-steroidal anti-inflammatory drugs (NSAIDs) reduce colorectal tumorigenesis by inhibition of cyclooxygenase (COX). COX is a key enzyme in the conversion of arachidonic acid to prostaglandins and two isoforms of COX have been characterized, COX-1 and COX-2. Multiple studies have shown that COX-2 is expressed at high levels in colorectal tumours and play a role in colorectal

S Tomozawa; H Nagawa; N Tsuno; K Hatano; T Osada; J Kitayama; E Sunami; M E Nita; S Ishihara; H Yano; T Tsuruo; Y Shibata; T Muto



Hepatic ischemia and reperfusion injury in the absence of myeloid cell-derived COX-2 in mice.  


Cyclooxygenase-2 (COX-2) is a mediator of hepatic ischemia and reperfusion injury (IRI). While both global COX-2 deletion and pharmacologic COX-2 inhibition ameliorate liver IRI, the clinical use of COX-2 inhibitors has been linked to increased risks of heart attack and stroke. Therefore, a better understanding of the role of COX-2 in different cell types may lead to improved therapeutic strategies for hepatic IRI. Macrophages of myeloid origin are currently considered to be important sources of the COX-2 in damaged livers. Here, we used a Cox-2flox conditional knockout mouse (COX-2-M/-M) to examine the function of COX-2 expression in myeloid cells during liver IRI. COX-2-M/-M mice and their WT control littermates were subjected to partial liver ischemia followed by reperfusion. COX-2-M/-M macrophages did not express COX-2 upon lipopolysaccharide stimulation and COX-2-M/-M livers showed reduced levels of COX-2 protein post-IRI. Nevertheless, selective deletion of myeloid cell-derived COX-2 failed to ameliorate liver IRI; serum transaminases and histology were comparable in both COX-2-M/-M and WT mice. COX-2-M/-M livers, like WT livers, developed extensive necrosis, vascular congestion, leukocyte infiltration and matrix metalloproteinase-9 (MMP-9) expression post-reperfusion. In addition, myeloid COX-2 deletion led to a transient increase in IL-6 levels after hepatic reperfusion, when compared to controls. Administration of celecoxib, a selective COX-2 inhibitor, resulted in significantly improved liver function and histology in both COX-2-M/-M and WT mice post-reperfusion, providing evidence that COX-2-mediated liver IRI is caused by COX-2 derived from a source(s) other than myeloid cells. In conclusion, these results support the view that myeloid COX-2, including myeloid-macrophage COX-2, is not responsible for the hepatic IRI phenotype. PMID:24819536

Duarte, Sergio; Kato, Hiroyuki; Kuriyama, Naohisa; Suko, Kathryn; Ishikawa, Tomo-O; Busuttil, Ronald W; Herschman, Harvey R; Coito, Ana J



Error bounds in cascading regressions  

USGS Publications Warehouse

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.

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



An efficient alternative to the stratified Cox model analysis.  


Consider a typical two-treatment randomized clinical trial involving a time-to-event endpoint, with randomization stratified by a categorical prognostic factor (for example gender). At the design stage, it is often assumed that the treatment hazard ratio (HR) is constant across the strata, and the data are commonly analyzed using the stratified Cox proportional hazards model. We caution that this ubiquitous approach is needlessly risky because departures from the assumption of the HR being the same for all the strata can result in a notably biased and/or less powerful analysis. An alternative approach is proposed in which first the [log] HR is estimated separately for each stratum using an unstratified Cox model, and then the stratum-specific estimates are combined for overall inference using either sample size or 'minimum risk' stratum weights. The advantages of the proposed two-step analysis versus the common one-step stratified Cox model analysis are illustrated using simulations that were conducted to support the design of a vaccine clinical trial. PMID:22437375

Mehrotra, Devan V; Su, Shu-Chih; Li, Xiaoming



Survival of patients with nonseminomatous germ cell cancer: a review of the IGCC classification by Cox regression and recursive partitioning  

Microsoft Academic Search

The International Germ Cell Consensus (IGCC) classification identifies good, intermediate and poor prognosis groups among patients with metastatic nonseminomatous germ cell tumours (NSGCT). It uses the risk factors primary site, presence of nonpulmonary visceral metastases and tumour markers alpha-fetoprotein (AFP), human chorionic gonadotrophin (HCG) and lactic dehydrogenase (LDH). The IGCC classification is easy to use and remember, but lacks flexibility.

M R van Dijk; E W Steyerberg; S P Stenning; E Dusseldorp; J D F Habbema; van Dijk



The cardiac copper chaperone proteins Sco1 and CCS are up-regulated, but Cox 1 and Cox4 are down-regulated, by copper deficiency.  


Copper is ferried in a cell complexed to chaperone proteins, and in the heart much copper is required for cytochrome c oxidase (Cox). It is not completely understood how copper status affects the levels of these proteins. Here we determined if dietary copper deficiency could up- or down-regulate select copper chaperone proteins and Cox subunits 1 and 4 in cardiac tissue of rats. Sixteen weanling male Long-Evans rats were randomized into treatment groups, one group receiving a copper-deficient diet (<1 mg Cu/kg diet) and one group receiving a diet containing adequate copper (6 mg Cu/kg diet) for 5 weeks. Hearts were removed, weighed, and non-myofibrillar proteins separated to analyze for levels of CCS, Sco1, Ctr1, Cox17, Cox1, and Cox4 by SDS-PAGE and Western blotting. No changes were observed in the concentrations of CTR1 and Cox17 between copper-adequate and copper-deficient rats. CCS and Sco1 were up-regulated and Cox1 and Cox4 were both down-regulated as a result of copper deficiency. These data suggest that select chaperone proteins and may be up-regulated, and Cox1 and 4 down-regulated, by a dietary copper deficiency, whereas others appear not to be affected by copper status. PMID:20878365

Getz, Jean; Lin, Dingbo; Medeiros, Denis M



A Regularization Corrected Score Method for Nonlinear Regression Models with Covariate Error  

PubMed Central

Summary Many regression analyses involve explanatory variables that are measured with error, and failing to account for this error is well known to lead to biased point and interval estimates of the regression coefficients. We present here a new general method for adjusting for covariate error. Our method consists of an approximate version of the Stefanski-Nakamura corrected score approach, using the method of regularization to obtain an approximate solution of the relevant integral equation. We develop the theory in the setting of classical likelihood models; this setting covers, for example, linear regression, nonlinear regression, logistic regression, and Poisson regression. The method is extremely general in terms of the types of measurement error models covered, and is a functional method in the sense of not involving assumptions on the distribution of the true covariate. We discuss the theoretical properties of the method and present simulation results in the logistic regression setting (univariate and multivariate). For illustration, we apply the method to data from the Harvard Nurses’ Health Study concerning the relationship between physical activity and breast cancer mortality in the period following a diagnosis of breast cancer.

Zucker, David M.; Gorfine, Malka; Li, Yi; Tadesse, Mahlet; Spiegelman, Donna



Evaluation of standard and advanced preprocessing methods for the univariate analysis of blood serum 1H-NMR spectra.  


Proton nuclear magnetic resonance ((1)H-NMR)-based metabolomics enables the high-resolution and high-throughput assessment of a broad spectrum of metabolites in biofluids. Despite the straightforward character of the experimental methodology, the analysis of spectral profiles is rather complex, particularly due to the requirement of numerous data preprocessing steps. Here, we evaluate how several of the most common preprocessing procedures affect the subsequent univariate analyses of blood serum spectra, with a particular focus on how the standard methods perform compared to more advanced examples. Carr-Purcell-Meiboom-Gill 1D (1)H spectra were obtained for 240 serum samples from healthy subjects of the Asklepios study. We studied the impact of different preprocessing steps--integral (standard method) and probabilistic quotient normalization; no, equidistant (standard), and adaptive-intelligent binning; mean (standard) and maximum bin intensity data summation--on the resonance intensities of three different types of metabolites: triglycerides, glucose, and creatinine. The effects were evaluated by correlating the differently preprocessed NMR data with the independently measured metabolite concentrations. The analyses revealed that the standard methods performed inferiorly and that a combination of probabilistic quotient normalization after adaptive-intelligent binning and maximum intensity variable definition yielded the best overall results (triglycerides, R = 0.98; glucose, R = 0.76; creatinine, R = 0.70). Therefore, at least in the case of serum metabolomics, these or equivalent methods should be preferred above the standard preprocessing methods, particularly for univariate analyses. Additional optimization of the normalization procedure might further improve the analyses. PMID:20714889

De Meyer, Tim; Sinnaeve, Davy; Van Gasse, Bjorn; Rietzschel, Ernst-R; De Buyzere, Marc L; Langlois, Michel R; Bekaert, Sofie; Martins, José C; Van Criekinge, Wim



Regression Testing as a Service  

Microsoft Academic Search

Selective regression testing involves retesting of software systems with a subset of the test suite to verify that modifications have not adversely impacted existing functions. Although this problem has been heavily researched, it has never been discussed in the context of SaaS (Software as a service). This paper presents the specific requirements, challenges and benefits in delivering regression test selection

Sheng Huang; Zhong Jie Li; Ying Liu; Jun Zhu



A general regression neural network  

Microsoft Academic Search

A memory-based network that provides estimates of continuous variables and converges to the underlying (linear or nonlinear) regression surface is described. The general regression neural network (GRNN) is a one-pass learning algorithm with a highly parallel structure. It is shown that, even with sparse data in a multidimensional measurement space, the algorithm provides smooth transitions from one observed value to

Donald F. Specht



Wild bootstrap for quantile regression.  


The existing theory of the wild bootstrap has focused on linear estimators. In this note, we broaden its validity by providing a class of weight distributions that is asymptotically valid for quantile regression estimators. As most weight distributions in the literature lead to biased variance estimates for nonlinear estimators of linear regression, we propose a modification of the wild bootstrap that admits a broader class of weight distributions for quantile regression. A simulation study on median regression is carried out to compare various bootstrap methods. With a simple finite-sample correction, the wild bootstrap is shown to account for general forms of heteroscedasticity in a regression model with fixed design points. PMID:23049133

Feng, Xingdong; He, Xuming; Hu, Jianhua



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


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

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



A Logistic Regression Model for Predicting Axillary Lymph Node Metastases in Early Breast Carcinoma Patients  

PubMed Central

Nodal staging in breast cancer is a key predictor of prognosis. This paper presents the results of potential clinicopathological predictors of axillary lymph node involvement and develops an efficient prediction model to assist in predicting axillary lymph node metastases. Seventy patients with primary early breast cancer who underwent axillary dissection were evaluated. Univariate and multivariate logistic regression were performed to evaluate the association between clinicopathological factors and lymph node metastatic status. A logistic regression predictive model was built from 50 randomly selected patients; the model was also applied to the remaining 20 patients to assess its validity. Univariate analysis showed a significant relationship between lymph node involvement and absence of nm-23 (p = 0.010) and Kiss-1 (p = 0.001) expression. Absence of Kiss-1 remained significantly associated with positive axillary node status in the multivariate analysis (p = 0.018). Seven clinicopathological factors were involved in the multivariate logistic regression model: menopausal status, tumor size, ER, PR, HER2, nm-23 and Kiss-1. The model was accurate and discriminating, with an area under the receiver operating characteristic curve of 0.702 when applied to the validation group. Moreover, there is a need discover more specific candidate proteins and molecular biology tools to select more variables which should improve predictive accuracy.

Xie, Fei; Yang, Houpu; Wang, Shu; Zhou, Bo; Tong, Fuzhong; Yang, Deqi; Zhang, Jiaqing



What do differences between multi-voxel and univariate analysis mean? How subject-, voxel-, and trial-level variance impact fMRI analysis.  


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

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



Lanostane triterpenoids and triterpene glycosides from the fruit body of Fomitopsis pinicola and their inhibitory activity against COX-1 and COX-2.  


Two new lanostane triterpenoids (1, 2) and 10 new lanostane triterpene glycosides (3-12) have been isolated from the fruit bodies of Fomitopsis pinicola. Their structures were established primarily by NMR experiments and chemical methods, and their biological activity against COX-1 and COX-2 was investigated. PMID:15679320

Yoshikawa, Kazuko; Inoue, Megumi; Matsumoto, Yuki; Sakakibara, Chika; Miyataka, Hideki; Matsumoto, Hitoshi; Arihara, Shigenobu



COX-2 inhibition in schizophrenia and major depression.  


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

Müller, Norbert; Schwarz, Markus J



COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence.  


Antidepressant and antipsychotic drugs, predominantly serotonin and/or norepinephrine reuptake inhibitors and dopamine D2-antagonizing antipsychotic compounds, have several limitations. In addition, the exact pathophysiological mechanism leading to serotonergic, noradrenergic and dopaminergic dysfunction in psychotic disorders remains unclear. It has been postulated that an inflammatory mechanism may be involved in the pathogenesis of both depression and psychotic disorders. Furthermore, the differential activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and of the tryptophan/kynurenine metabolic pathway, resulting in the increased production of kynurenic acid in schizophrenia, and a possible increase in quinolinic acid in depression, also may play a key role in these diseases. Such differences are associated with an imbalance in glutamatergic neurotransmission that may contribute to increased levels of NMDA agonism in depression and NMDA antagonism in schizophrenia. In addition, immunological imbalance results in the increased production of PGE2 in schizophrenia and depression, as well as increased COX-2 expression in schizophrenia. Although there is evidence supporting the hypothesis that interactions between immune system components, IDO, the serotonergic system and glutamatergic neurotransmission play a key role in schizophrenia and depression, several gaps in knowledge remain, such as regarding the role of genetics, disease course, gender and different psychopathological states. There is evidence indicating that anti-inflammatory therapy may have beneficial effects in schizophrenia and major depression (MD). COX-2 inhibitors have been tested in animal models and in preliminary clinical trials, demonstrating favorable activity compared with placebo, both in schizophrenia and MD. However, the effects of COX-2 inhibition in the CNS, as well as toward different components of the inflammatory system, kynurenine metabolism and glutamatergic neurotransmission, require further evaluation, which should include clinical trials with larger numbers of patients. The potential inflammatory mechanism in schizophrenia and MD, and the possible therapeutic advantages of targeting this mechanism in the treatment of these disorders is discussed in this review. PMID:20047157

Müller, Norbert



Additive Hazard Regression Models: An Application to the Natural History of Human Papillomavirus  

PubMed Central

There are several statistical methods for time-to-event analysis, among which is the Cox proportional hazards model that is most commonly used. However, when the absolute change in risk, instead of the risk ratio, is of primary interest or when the proportional hazard assumption for the Cox proportional hazards model is violated, an additive hazard regression model may be more appropriate. In this paper, we give an overview of this approach and then apply a semiparametric as well as a nonparametric additive model to a data set from a study of the natural history of human papillomavirus (HPV) in HIV-positive and HIV-negative women. The results from the semiparametric model indicated on average an additional 14 oncogenic HPV infections per 100 woman-years related to CD4 count < 200 relative to HIV-negative women, and those from the nonparametric additive model showed an additional 40 oncogenic HPV infections per 100 women over 5 years of followup, while the estimated hazard ratio in the Cox model was 3.82. Although the Cox model can provide a better understanding of the exposure disease association, the additive model is often more useful for public health planning and intervention.

Xie, Xianhong; Strickler, Howard D.; Xue, Xiaonan



US Defense Intelligence Agency (DIA) Scoops Cox Report  

NSDL National Science Digital Library

In light of the Final Report of the Select Committee on US National Security and Military/ Commercial Concerns with the People's Republic of China, or the Cox Report, the National Security Archive (NSA), located at George Washington University, has released a Defense Estimative Brief published by the US Defense Intelligence Agency in April 1984. The four-page brief, obtained by the NSA through a Freedom of Information Act request, details Chinese efforts to enhace its nuclear capability through "overt contact with US scientists and technology, and the covert acquisition of US technology."


characterization of the cytochrome c oxidase assembly factor Cox19 of Saccharomyces cerevisiae.  


Cox19 is an important accessory protein in the assembly of cytochrome c oxidase in yeast. The protein is functional when tethered to the mitochondrial inner membrane, suggesting its functional role within the intermembrane space. Cox19 resembles Cox17 in having a twin CX(9)C sequence motif that adopts a helical hairpin in Cox17. The function of Cox17 appears to be a Cu(I) donor protein in the assembly of the copper centers in cytochrome c oxidase. Cox19 also resembles Cox17 in its ability to coordinate Cu(I). Recombinant Cox19 binds 1 mol eq of Cu(I) per monomer and exists as a dimeric protein. Cox19 isolated from the mitochondrial intermembrane space contains variable quantities of copper, suggesting that Cu(I) binding may be a transient property. Cysteinyl residues important for Cu(I) binding are also shown to be important for the in vivo function of Cox19. Thus, a correlation exists in the ability to bind Cu(I) and in vivo function. PMID:17237235

Rigby, Kevin; Zhang, Limei; Cobine, Paul A; George, Graham N; Winge, Dennis R



Mechanisms of adiponectin-mediated COX-2 induction and protection against iron injury in mouse hepatocytes.  


Adiponectin (APN)-mediated cyclooxygenase (COX)-2 induction is known to have various protective effects on cardiovascular diseases. However, the molecular mechanisms of APN-mediated COX-2 induction and its protection against iron-mediated injury in hepatocytes are still unclear. Herein, we show that AMP-mediated peroxisome proliferator-activated receptor (PPAR)alpha activation was attributable to COX-2 induction by APN, which was further confirmed by identifying novel functional PPAR responsive elements (PPREs) in the mouse COX-2 promoter region. Prostaglandin (PG)I2 and PGE2, metabolites of COX-2, time-dependently increased in hepatocytes treated with APN. Interestingly, beraprost and misoprostol, respective agonists for PGI2 and PGE2, mimicked the protective effects of APN in iron-mediated inflammation in hepatocytes. The iron dextran-activated nuclear factor (NF)-kappaB pathway was correlated with the increased production of inflammatory cytokines including tumor necrosis factor-alpha, intercellular adhesion molecule-1, and monocyte chemotactic protein-1. This was eliminated by administration of APN, whereas blockage of PPARalpha activation, an upstream regulator of COX-2 induction by APN, and COX-2 activation reversed the anti-inflammatory effect of APN, suggesting the crucial role of COX-2 in this event. Herein, we demonstrate that APN-mediated COX-2 induction through a PPARalpha-dependent mechanism, and COX-2 exerted an anti-inflammatory effect of APN in hepatocytes subjected to iron challenge. PMID:20583136

Lee, Fei-Peng; Jen, Chih-Yu; Chang, Chih-Cheng; Chou, Ying; Lin, Heng; Chou, Chih-Ming; Juan, Shu-Hui



Multiple Regression and Its Discontents  

ERIC Educational Resources Information Center

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.

Snell, Joel C.; Marsh, Mitchell



Multiple Correlation versus Multiple Regression.  

ERIC Educational Resources Information Center

Describes differences between multiple correlation analysis (MCA) and multiple regression analysis (MRA), showing how these approaches involve different research questions and study designs, different inferential approaches, different analysis strategies, and different reported information. (SLD)

Huberty, Carl J.



Regression Estimation of Surface Winds.  

National Technical Information Service (NTIS)

Regression equations for estimating surface wind at 10 terminals in the estern United States were derived and tested on independent data. The predictors used were observed wind at initial time, 1000- and 500-mb geostrophic winds, and 1000-mb temperature. ...

H. R. Glahn



Star Library: Regression - Residuals - Why?  

NSDL National Science Digital Library

Residual plots and other diagnostics are important to deciding whether or not linear regression is appropriate for a set of data. Many students might believe that if the correlation coefficient is strong enough, these diagnostic checks are not important. The data set included in this activity was created to lure students into a situation that looks on the surface to be appropriate for the use of linear regression but is instead based (loosely) on a quadratic function.

Miller, Jacqueline B.



Basis Selection for Wavelet Regression  

NASA Technical Reports Server (NTRS)

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.

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



Automatic Bayesian quantile regression curve fitting  

Microsoft Academic Search

Quantile regression, including median regression, as a more completed statistical model than mean regression, is now well\\u000a known with its wide spread applications. Bayesian inference on quantile regression or Bayesian quantile regression has attracted\\u000a much interest recently. Most of the existing researches in Bayesian quantile regression focus on parametric quantile regression,\\u000a though there are discussions on different ways of modeling

Colin Chen; Keming Yu



A method for analyzing clustered interval-censored data based on Cox's model.  


Methods for analyzing interval-censored data are well established. Unfortunately, these methods are inappropriate for the studies with correlated data. In this paper, we focus on developing a method for analyzing clustered interval-censored data. Our method is based on Cox's proportional hazard model with piecewise-constant baseline hazard function. The correlation structure of the data can be modeled by using Clayton's copula or independence model with proper adjustment in the covariance estimation. We establish estimating equations for the regression parameters and baseline hazards (and a parameter in copula) simultaneously. Simulation results confirm that the point estimators follow a multivariate normal distribution, and our proposed variance estimations are reliable. In particular, we found that the approach with independence model worked well even when the true correlation model was derived from Clayton's copula. We applied our method to a family-based cohort study of pandemic H1N1 influenza in Taiwan during 2009-2010. Using the proposed method, we investigate the impact of vaccination and family contacts on the incidence of pH1N1 influenza. PMID:22911905

Kor, Chew-Teng; Cheng, Kuang-Fu; Chen, Yi-Hau



Nonlinear multiple imputation for continuous covariate within semiparametric Cox model: application to HIV data in Senegal.  


Multiple imputation is commonly used to impute missing covariate in Cox semiparametric regression setting. It is to fill each missing data with more plausible values, via a Gibbs sampling procedure, specifying an imputation model for each missing variable. This imputation method is implemented in several softwares that offer imputation models steered by the shape of the variable to be imputed, but all these imputation models make an assumption of linearity on covariates effect. However, this assumption is not often verified in practice as the covariates can have a nonlinear effect. Such a linear assumption can lead to a misleading conclusion because imputation model should be constructed to reflect the true distributional relationship between the missing values and the observed values. To estimate nonlinear effects of continuous time invariant covariates in imputation model, we propose a method based on B-splines function. To assess the performance of this method, we conducted a simulation study, where we compared the multiple imputation method using Bayesian splines imputation model with multiple imputation using Bayesian linear imputation model in survival analysis setting. We evaluated the proposed method on the motivated data set collected in HIV-infected patients enrolled in an observational cohort study in Senegal, which contains several incomplete variables. We found that our method performs well to estimate hazard ratio compared with the linear imputation methods, when data are missing completely at random, or missing at random. PMID:23712767

Mbougua, Jules Brice Tchatchueng; Laurent, Christian; Ndoye, Ibra; Delaporte, Eric; Gwet, Henri; Molinari, Nicolas



Cox's Chair Revisited: Can Spinning Alter Mood States?  

PubMed Central

Although there is clinical and historical evidence for a vivid relation between the vestibular and emotional systems, the neuroscientific underpinnings are poorly understood. The “spin doctors” of the nineteenth century used spinning chairs (e.g., Cox’s chair) to treat conditions of mania or elevated arousal. On the basis of a recent study on a hexapod motion-simulator, in this prototypic investigation we explore the impact of yaw stimulation on a spinning chair on mood states. Using a controlled experimental stimulation paradigm on a unique 3-D-turntable at the University of Zurich we included 11 healthy subjects and assessed parameters of mood states and autonomic nervous system activity. The Multidimensional Mood State Questionnaire and Visual Analog Scales (VAS) were used to assess changes of mood in response to a 100?s yaw stimulation. In addition heart rate was continuously monitored during the experiment. Subjects indicated feeling less “good,” “relaxed,” “comfortable,” and “calm” and reported an increased alertness after vestibular stimulation. However, there were no objective adverse effects of the stimulation. Accordingly, heart rate did not significantly differ in response to the stimulation. This is the first study in a highly controlled setting using the historical approach of stimulating the vestibular system to impact mood states. It demonstrates a specific interaction between the vestibular system and mood states and thereby supports recent experimental findings with a different stimulation technique. These results may inspire future research on the clinical potential of this method.

Winter, Lotta; Wollmer, M. Axel; Laurens, Jean; Straumann, Dominik; Kruger, Tillmann H. C.



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


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

Kraus, Sarah; Naumov, Inna; Arber, Nadir



Bayesian inference for finite mixtures of univariate and multivariate skew-normal and skew-t distributions.  


Skew-normal and skew-t distributions have proved to be useful for capturing skewness and kurtosis in data directly without transformation. Recently, finite mixtures of such distributions have been considered as a more general tool for handling heterogeneous data involving asymmetric behaviors across subpopulations. We consider such mixture models for both univariate as well as multivariate data. This allows robust modeling of high-dimensional multimodal and asymmetric data generated by popular biotechnological platforms such as flow cytometry. We develop Bayesian inference based on data augmentation and Markov chain Monte Carlo (MCMC) sampling. In addition to the latent allocations, data augmentation is based on a stochastic representation of the skew-normal distribution in terms of a random-effects model with truncated normal random effects. For finite mixtures of skew normals, this leads to a Gibbs sampling scheme that draws from standard densities only. This MCMC scheme is extended to mixtures of skew-t distributions based on representing the skew-t distribution as a scale mixture of skew normals. As an important application of our new method, we demonstrate how it provides a new computational framework for automated analysis of high-dimensional flow cytometric data. Using multivariate skew-normal and skew-t mixture models, we could model non-Gaussian cell populations rigorously and directly without transformation or projection to lower dimensions. PMID:20110247

Frühwirth-Schnatter, Sylvia; Pyne, Saumyadipta



An application of univariate and multivariate approaches in FMRI to quantifying the hemispheric lateralization of acoustic and linguistic processes.  


The question of hemispheric lateralization of neural processes is one that is pertinent to a range of subdisciplines of cognitive neuroscience. Language is often assumed to be left-lateralized in the human brain, but there has been a long running debate about the underlying reasons for this. We addressed this problem with fMRI by identifying the neural responses to amplitude and spectral modulations in speech and how these interact with speech intelligibility to test previous claims for hemispheric asymmetries in acoustic and linguistic processes in speech perception. We used both univariate and multivariate analyses of the data, which enabled us to both identify the networks involved in processing these acoustic and linguistic factors and to test the significance of any apparent hemispheric asymmetries. We demonstrate bilateral activation of superior temporal cortex in response to speech-derived acoustic modulations in the absence of intelligibility. However, in a contrast of amplitude-modulated and spectrally modulated conditions that differed only in their intelligibility (where one was partially intelligible and the other unintelligible), we show a left dominant pattern of activation in STS, inferior frontal cortex, and insula. Crucially, multivariate pattern analysis showed that there were significant differences between the left and the right hemispheres only in the processing of intelligible speech. This result shows that the left hemisphere dominance in linguistic processing does not arise because of low-level, speech-derived acoustic factors and that multivariate pattern analysis provides a method for unbiased testing of hemispheric asymmetries in processing. PMID:22066589

McGettigan, Carolyn; Evans, Samuel; Rosen, Stuart; Agnew, Zarinah K; Shah, Poonam; Scott, Sophie K



Duplexes of 21 nucleotide RNA specific for COX II mediates RNA interference in cultured bovine aortic coronary endothelial cells (BAECs)  

Microsoft Academic Search

The present study was conducted to utilize a double-stranded RNA (dsRNA) specific for cyclooxygenase (COX) II and demonstrate inhibition of the expression of COX II protein and its product PGE. A 21-dsRNA specific for COX II was introduced by lipofectamine into a primary cell culture of bovine aortic coronary endothelial cells (BAECs). BAECs basally express COX I but not COX

Tian Xiuzhu; Laurence Shore; Yehudah Stram; Shulamit Michaeli; Haim Brietbart; Mordechai Shemesh



Clinical features, survival times and COX-1 and COX-2 expression in cats with transitional cell carcinoma of the urinary bladder treated with meloxicam.  


Records of 11 cats with transitional cell carcinoma of the urinary bladder, which had been treated with meloxicam, were reviewed for signalment, duration of clinical signs prior to diagnosis, results of diagnostic imaging, whether or not concurrent surgery was performed and survival. Immunohistochemical expression of cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2) was assessed in the tumours of seven cats. Tumour location varied greatly. The cats had a mean age of 13 years. Three cats had a previous diagnosis of feline idiopathic cystitis of up to 2008 days duration. Ten of the cats showed clinical improvement (reduction of haematuria and/or dysuria), with a mean survival time (MST) of 311 days (range 10-1064); 1-year survival of 50%. All seven bladders assessed for COX staining were COX-1 positive and five were COX-2 positive. The MST for the COX-2-positive cats was 123 days, the MST for the COX-2-negative cases was 375 days. PMID:22408147

Bommer, Nicholas X; Hayes, Alison M; Scase, Timothy J; Gunn-Moore, Danièlle A



Association between COX-2 Expression and Effectiveness of COX-2 Inhibitors in Phase II Trial in Patients with Metastatic Colorectal Adenocarcinoma  

PubMed Central

Aim The role for the cyclooxygenase-2 (COX-2) pathway in colorectal carcinogenesis has been suggested in pre-clinical models. In a previously reported phase II trial, the addition of COX-2 inhibitor celecoxib to irinotecan and capecitabine did not appear to significantly increase the activity of chemotherapy in patients with metastatic colorectal carcinoma (mCRC). We evaluated COX-2 expression in the available tumors from patients enrolled by immunohistochemistry and its correlation with clinical outcome. Patients and Methods Fifty-one patients with mCRC were enrolled in the phase II study between June 2002 and November 2005. Patients received a combination of irinotecan 70 mg/m2 over 30 min i.v. on days 1 and 8, capecitabine 1,000 mg/m2 twice per day orally on days 1-14 and the COX-2 inhibitor celecoxib at a daily dose of 800 mg continuously. Cycles were repeated every 21 days. Formalin-fixed paraffin-embedded tumor tissue samples were available for 17 patients enrolled on that study. COX-2 expression was evaluated by immunohistochemistry and correlated with clinical outcome. Results In the phase II study, the objective response rate was 41%. The median time to progression was 7.7 months and median survival time was 21.2 months. Tumor COX-2 expression by immunohistochemistry was assessed for 17 patients enrolled in that same phase II study. While not statistically significant, the response rate was better for patients in the low COX-2 expression group, while time to progression and overall survival was longer in patients in the high COX-2 expression group. This discrepancy can be partially attributed to the small sample size. Conclusion In the previously published phase II study, the addition of celecoxib to irinotecan and capecitabine did not appear to significantly increase the activity of chemotherapy. COX-2 expression by immunohistochemistry was neither prognostic nor predictive for response.

Almhanna, Khaldoun; El-Rayes, Bassel; Sethi, Seema; Dyson, Gregory; Heilbrun, Lance; Philip, Philip A; Sarkar, Fazlul



Modulation of COX2 expression in peripheral blood cells by increased intake of fruit and vegetables?  

Microsoft Academic Search

Background:Enhanced cyclooxygenase-2 (COX-2) expression is associated with carcinogenesis, ischemia, angiogenesis, inflammation, and neurodegeneration. The preventing effect of aspirin and nonsteroidal anti-inflammatory drugs is partly due to inhibition of the COX-2 enzyme. Fruit and vegetables (FVs) contain numerous compounds that may decrease disease risk by several different mechanisms, for example through the inhibition of COX-2 activity.Objective:We tested the hypothesis that an

K Almendingen; A Brevik; D A Nymoen; H T Hilmarsen; P A Andresen; L F Andersen; M Vatn



Probiotics Regulate the Expression of COX2 in Intestinal Epithelial Cells  

Microsoft Academic Search

Cyclooxygenase-2 (COX) 2 promotes intestinal wound healing but elicits also proinflammatory effects and has been implicated in colorectal carcinogenesis. Thus, a balanced expression of COX-2 is essential for intestinal homeostasis. This study was designed to evaluate the regulation of COX-2 by probiotic organisms and to characterize ligands and receptors involved. Colo320 and SW480 intestinal epithelial cells (IEC) were stimulated with

Jan-Michel Otte; Rudja Mahjurian-Namari; Stephan Brand; Ilka Werner; Wolfgang E. Schmidt; Frank Schmitz



IL20, an anti-angiogenic cytokine that inhibits COX2 expression  

Microsoft Academic Search

COX-2 overexpression and subsequent PGE2 production are frequently associated with non-small cell lung cancer and are implicated in tumor-mediated angiogenesis. Here, we report for the first time that IL-20 downregulates COX-2 and PGE2 in human bronchial epithelial and endothelial cells. Flow cytometry analysis suggests that IL-20-dependent inhibition of COX-2\\/PGE2 occurs through the IL-22R1\\/IL-20R2 dimers. In addition, we report that IL-20

Nathalie Heuzé-Vourc’h; Ming Liu; Harnisha Dalwadi; Felicita E. Baratelli; Li Zhu; Lee Goodglick; Mehis Põld; Sherven Sharma; Ruben D. Ramirez; Jerry W. Shay; John D. Minna; Robert M. Strieter; Steven M. Dubinett



Synergistic Regulation of COX2 Expression by Bombesin and Transforming Growth Factor-?  

Microsoft Academic Search

Overexpression of cyclooxygenase-2 (COX-2), an inducible enzyme regulating prostaglandin release, is mechanistically linked\\u000a to the development, growth, and spread of gastrointestinal (GI) cancers. GI peptide bombesin (BBS) was reported to stimulate\\u000a COX-2 gene expression. Here we show that TGF-?1 dramatically enhances the BBS-induced expression of COX-2 mRNA and protein,\\u000a and the release of PGE2 in the model rat intestinal epithelial

Yan-Shi Guo; Zihong Chen; Xiao-Dong Wen; Tien C. Ko; Courtney M. Townsend Jr; Mark R. Hellmich



Selective COX2 Inhibition Improves Endothelial Function in Coronary Artery Disease  

Microsoft Academic Search

Background—There is an ongoing debate as to whether the gastrointestinal safety of COX-2 inhibition compared with nonsteroidal antiinflammatory drugs (NSAIDs) may come at the cost of increased cardiovascular events. In view of the large number of patients at cardiovascular risk requiring chronic analgesic therapy with COX-2 inhibitors for arthritic and other inflammatory conditions, the effects of selective COX-2 inhibition on

Rémy Chenevard; David Hürlimann; Markus Béchir; Frank Enseleit; Lukas Spieker; Matthias Hermann; Walter Riesen; Steffen Gay; Renate E. Gay; Michel Neidhart; Beat Michel; Thomas F. Lüscher; Georg Noll; Frank Ruschitzka



COX-2 Gene Promoter Methylation in Patients Infected with Helicobacter Pylori  

PubMed Central

Cyclooxygenase (COX) plays a critical role in peptic ulcer development. COX-2 contains CpG islands in promoter area, which suggests possible epigenetic mechanisms of gene silencing. We evaluated COX-2 gene promoter methylation levels in the gastric mucosa of patients with various gastric diseases. DNA was extracted from endoscopic biopsy materials collected from the gastric mucosa. The methylation levels of the COX-2 gene promoter were measured quantitatively by using pyrosequencing. COX-2 mRNA expression in Kato III and AGS cells was measured using real-time PCR. COX-2 gene promoter methylation levels were significantly higher in Helicobacter pylori (HP)-positive cases than in HP-negative cases (27.5% vs. 8.1%, respectively, P < 0.001). COX-2 gene promoter methylation levels in patients in whom HP was successfully eradicated were significantly lower than those in HP-positive cases (18.7% vs. 27.5%, respectively, P < 0.01). We then investigated the effects of COX-2 gene promoter methylation on its mRNA expression in vitro. COX-2 mRNA expression was not observed in Kato III cells, despite the addition of the protein kinase C stimulator ?-phorbol 12,13-dibutyrate (PDBu). COX-2 expression was observed after the addition of the demethylating agent 5-Aza-dC and was enhanced by PDBu. HP infection caused a significant increase in the methylation levels of the COX-2 gene promoter in the gastric mucosa. In addition to transcriptional regulation, COX-2 expression is regulated through epigenetic mechanisms.

Michikawa, Yosuke; Yasuda, Hiroshi; Watanabe, Yoshiyuki; Oikawa, Ritsuko; Ohishi, Yoshichika; Maehata, Tadateru; Itoh, Fumio



Expression of COX2 in Stomach Cancers and Its Relation to Their Biological Features  

Microsoft Academic Search

Background\\/Aim: Cyclooxygenase-2 (COX-2) is one of the key isoenzymes in the production of prostaglandins, and is believed to be involved in carcinogenesis. This study was conducted to examine the role of COX-2 in the development and biological behavior of stomach cancer. Methods: Expression of COX-2 at the mRNA and protein levels was analyzed using RT-PCR and immunoblotting assay in 50

Shao-Liang Han; Huai-Jing Tang; Ya-Wei Hua; She-Qing Ji; Dong-Xin Lin



In vitro and ex vivo inhibition of COX isoforms by robenacoxib in the cat: a comparative study.  


Robenacoxib is a novel nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animals. Whole blood assays were used to characterize in the cat the pharmacodynamics of robenacoxib for inhibition of the cyclooxygenase (COX) isoforms, COX-1 and COX-2, in comparison with other NSAIDs. Based on in vitro IC(50) COX-1:IC(50) COX-2 ratios, robenacoxib was COX-2 selective (ratio = 32.2), diclofenac (ratio = 3.9) and meloxicam (ratio = 2.7) were only weakly COX-2 preferential, and ketoprofen (ratio = 0.049) was COX-1 selective. In an in vivo pharmacokinetic ex vivo pharmacodynamic study, after both p.o. (1-2 mg/kg) and subcutaneous (2 mg/kg) dosing, robenacoxib achieved peak blood concentrations rapidly (T(max) ?= 1 h for both administration routes) and was cleared from blood relatively rapidly (mean residence time was 1.70 h after p.o. and 1.79 h after subcutaneous dosing). In ex vivo COX isoform inhibition assays, orally (1-2 mg/kg) or subcutaneously (2 mg/kg) administered robenacoxib significantly inhibited COX-2, with a relatively short duration of action in the central compartment, and had no effect on COX-1. Therefore robenacoxib was COX-2 selective and spared COX-1 in vivo. In contrast, meloxicam (0.3 mg/kg via subcutaneous injection) inhibited both COX-1 and COX-2 isoforms significantly for at least 24 h, indicating nonselectivity in vivo. PMID:20840388

Schmid, V B; Seewald, W; Lees, P; King, J N



Diagnostics for multiple regression problems  

SciTech Connect

In the last 10 to 15 years there has been much work done in trying to improve linear regression results. Individuals have analyzed the susceptibility of least-squares results to values far removed from the center of the independent variable observations. They have studied the problem of heavy-tailed residuals, and they have studied the problem of collinearity. From these studies have come ridge regression techniques, robust regression techniques, regression on principal components, etc. However, many practitioners view these methods with suspicion (and ignorance), and prefer to continue using the usual least-squares procedures to fit their models, even though their results might not be answering the question they think. In reaction to this, statisticians are spending more time analyzing how the individual observations affect the least squares results. In the last few years approximately 10 papers and one text have appeared that address the problem of how to study the influence of the individual observations. This report is a study of the recent work done in linear regression diagnostics. It is concerned with analyzing the effect of one case at a time, since the methods to analyze this situation are relatively straight-forward and are not prohibitive computationally.

Daly, J.C.



A selective requirement for copper-dependent activation of cytochrome c oxidase by Cox17p.  


Cox17p is cloned from yeast as a chaperone to deliver copper to the mitochondria of assembly for cytochrome c oxidase (CCO). In mammals, CCO is a key enzyme for cellular respiration and a defect in its function is associated with severe neonatal or infantile lactic acidosis and early death. Recently, we found that Cox17p is not only required for mitochondrial oxidative phosphorylation but also is essential for embryonic growth and development in COX17 gene-deficient mice. To investigate its biochemical features, recombinant human Cox17p was overexpressed and purified without a purification tag. It specifically binds Cu(I) at a molar copper content of 3.3+/-0.04 under reduced conditions and significantly activates the mitochondrial CCO in vitro. Although the Cu-Cox17p complex was maintained between pH values from 5.0 to 7.7, Cu was completely released from Cox17p at pH 8.0. An acute exposure of excess amount of copper ion to mouse cells resulted in a significant reduction of Cox17p mRNA expression, whereas copper starvation maintained the Cox17p transcription level. These results suggest that the stringent selectivity of Cox17p for copper is required for CCO activation, to prevent copper overload, or promote the supply of copper. PMID:15504366

Kako, Koichiro; Takehara, Akio; Arai, Hidenori; Onodera, Takashi; Takahashi, Yoshinori; Hanagata, Hiroshi; Ogra, Yasumitsu; Takagi, Hiroaki; Kodama, Hiroko; Suzuki, Kazuo T; Munekata, Eisuke; Fukamizu, Akiyoshi



Mutagenesis reveals a specific role for Cox17p in copper transport to cytochrome oxidase.  


The provision of copper to cytochrome oxidase is one of the requisite steps in the assembly of the holoenzyme. Several proteins are involved in this process including Cox17p, Sco1p, and Cox11p. Cox17p, an 8-kDa protein, is the only molecule thought to be involved in shuttling copper from the cytoplasm into mitochondria. Given the small size of Cox17p, we have taken a random and site-directed mutagenesis approach to studying structure-function relationships in Cox17p. Mutations have been generated in 70% of the Cox17p amino acid residues, with only a small subset leading to a detectable respiration-deficient phenotype. We have characterized the respiration-deficient cox17 mutants and found in addition to the expected cytochrome oxidase deficiency, a specific lack of Cox2p and the presence of a misassembled cytochrome oxidase in a subset of mutants. These results suggest that Cox17p is involved upstream of Sco1p in delivering copper specifically to subunit 2 of cytochrome oxidase and predict the existence of a subunit 1-specific copper chaperone. PMID:12788943

Punter, Fiona A; Glerum, D Moira



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

PubMed Central

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.

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



Significance of Cox-2 expression in rectal cancers with or without preoperative radiotherapy  

SciTech Connect

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.

Pachkoria, Ketevan [Department of Oncology, Institute of Biomedicine and Surgery, University of Linkoeping, Linkoeping (Sweden); Zhang Hong [Department of Dermatology, Institute of Biomedicine and Surgery, University of Linkoeping, Linkoeping (Sweden); Adell, Gunnar [Department of Oncology, Institute of Biomedicine and Surgery, University of Linkoeping, Linkoeping (Sweden); Jarlsfelt, Ingvar [Department of Pathology and Cytology, Joenkoeping Hospital, Joenkoeping (Sweden); Sun Xiaofeng [Department of Oncology, Institute of Biomedicine and Surgery, University of Linkoeping, Linkoeping (Sweden)]. E-mail:



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

PubMed Central

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.



Causal univariate spatial-temporal autoregressive moving averages (STARMA) modelling of target information to generate tasking of a world-wide sensor system. Master's thesis  

Microsoft Academic Search

The Department of Defense employs a resource limited world-wide sensor system to detect certain events of interest. The purpose of this research was to establish a methodology using a univariate causal STARMA model for forecasting the relative probability of an event occurring in a geographical location during a time block of the day. These relative probabilities are used as input




AgeDisplay: an EXCEL workbook to evaluate and display univariate geochronological data using binned frequency histograms and probability density distributions  

Microsoft Academic Search

Univariate diagrams such as binned frequency histograms and probability density distributions are often used for the initial assessment and communication of geochronological data. Both diagram types are estimates of the sample distribution and both have inherent limitations that are not widely appreciated. Binned frequency histograms are effective at conveying frequency information, but analytical error is discarded and appearance is vulnerable

Keith N. Sircombe



Multiple Regression Technique for Detecting Outliers.  

National Technical Information Service (NTIS)

The ordinary least squares regression method is not a reliable tool in regression analysis without first diagnosing possible outliers present in the data set. The least median of squares regression technique (Rousseeuw 1982), which is designed to lessen t...

A. Leroy P. Rousseeuw



Regression models in physiological research.  


Regression models play a significant role for appropriate interpretations of complex phenomena of biomedical sciences. In the present paper an attempt has been made to critically review the applications of regression models in physiological research pertaining to the solutions of various defence oriented problems of indirect estimation of human endurances, fitness, physical work capacity, energy expenditure at different work rates, body density and lean body mass from body measurements at high altitude, ventilatory 'norms' for wider age groups from physical characteristics, heat output and index finger temperature from ambient temperature, leg muscle volume and fat free mass from X-ray radiographs and stature, total body volume from anthropometric measurements, thermoregulatory efficiency at different environmental situations etc. These regression models are of practical significance for screening personnel in defence services, mines, industrial work, sports and the like. PMID:11372464

Verma, S S



Regression Verification Using Impact Summaries  

NASA Technical Reports Server (NTRS)

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 leveragin

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



Functional regression via variational Bayes  

PubMed Central

We introduce variational Bayes methods for fast approximate inference in functional regression analysis. Both the standard cross-sectional and the increasingly common longitudinal settings are treated. The methodology allows Bayesian functional regression analyses to be conducted without the computational overhead of Monte Carlo methods. Confidence intervals of the model parameters are obtained both using the approximate variational approach and nonparametric resampling of clusters. The latter approach is possible because our variational Bayes functional regression approach is computationally efficient. A simulation study indicates that variational Bayes is highly accurate in estimating the parameters of interest and in approximating the Markov chain Monte Carlo-sampled joint posterior distribution of the model parameters. The methods apply generally, but are motivated by a longitudinal neuroimaging study of multiple sclerosis patients. Code used in simulations is made available as a web-supplement.

Goldsmith, Jeff; Wand, Matt P.; Crainiceanu, Ciprian





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Automated Box-Cox Transformations for Improved Visual Encoding.  


This concept of pre-conditioning data (utilizing a power transformation as an initial step) for analysis and visualization is well established within the statistical community and is employed as part of statistical modeling and analysis. Such transformations condition the data to various inherent assumptions of statistical inference procedures, as well as making the data more symmetric and easier to visualize and interpret. In this paper, we explore the use of the Box-Cox family of power transformations to semi-automatically adjust visual parameters. We focus on time series scaling, axis transformations and color binning for choropleth maps. We illustrate the usage of this transformation using various examples, and discuss the value and some issues in semi-automatically using these transformations for more effective data visualization. PMID:22350197

Maciejewski, Ross; Pattath, Avin; Ko, Sungahn; Hafen, Ryan; Cleveland, William S; Ebert, David S



Bayesian variable selection in regression  

SciTech Connect

This paper is concerned with the selection of subsets of ''predictor'' variables in a linear regression model for the prediction of a ''dependent'' variable. We take a Bayesian approach and assign a probability distribution to the dependent variable through a specification of prior distributions for the unknown parameters in the regression model. The appropriate posterior probabilities are derived for each submodel and methods are proposed for evaluating the family of prior distributions. Examples are given that show the application of the Bayesian methodology. 23 refs., 3 figs.

Mitchell, T.J.; Beauchamp, J.J.



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


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

MacNab, Ying C



Box-Cox Mixed Logit Model for Travel Behavior Analysis  

NASA Astrophysics Data System (ADS)

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.

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



Developing Stochastic Deep Drainage Surfaces In Cox's Creek Catchment  

NASA Astrophysics Data System (ADS)

Deep drainage (DD) can contribute to water table rise and salinity, and is a complex function of rainfall, land management and soil hydraulic properties. Because each of these components is uncertain and variable in time and space, this study developed a method to estimate DD risk based on the mechanistic soil water model SWAP using 50 realisations of stochastic rainfall, land use and soil hydraulic properties using a Monte Carlo approach. DD was predicted at 143 soil points in the Cox’s Creek catchment in northern NSW Australia. Realisations of the stochastic daily rainfall were generated at each soil point using an annual mean adjusted Poisson model, DD values were subsequently translated to probabilities of exceeding 100mm/year and spatially predicted over the study area to produce risk maps for the different scenarios. The results showed that DD is episodic with the predominantly summer rainfall in the area, the monthly variability of DD is extremely high depending on when heavy rainfall occurred in relation to different land uses. As expected, the highest probability exceeding 100mm/year DD was for irrigated crop rotations (99%) followed by continuous wheat (59%), then opportunity cropping (46%) and the least for native vegetation (12.5%). Opportunity cropping with sorghum (42%) had the lowest probability to exceed 100mm/year compared to continuous wheat and other opportunity cropping systems and could be one of options for reducing DD in the area. Variation in soil hydraulic properties had less impact on probability of exceeding 100mm/year than variations in land use, which might be explained by soil properties determining the suitability for a certain land use.

Bennett, S.; Vervoort, R. W.; Bishop, T. F.; Hydrology Research Lab



Synthesis, biological evaluation, molecular docking and theoretical evaluation of ADMET properties of nepodin and chrysophanol derivatives as potential cyclooxygenase (COX-1, COX-2) inhibitors.  


Nepodin and chrysophanol, isolated from Rumex nepalensis roots, showed significant cyclooxygenase (COX) inhibitory activity. To further optimize these lead molecules and study structure activity relationship (SAR), eighteen derivatives of nepodin and nine derivatives of chrysophanol were synthesized and evaluated for COX-1 and COX-2 inhibitory potential. Among the synthesized compounds, four nepodin (1f, 1g, 1h and 1i) and three chrysophanol (2e, 2f and 2h) derivatives displayed more pronounced COX-2 inhibition than their respective lead molecule. Further, compounds 1f, 1g, 2e and 2h exhibited better anti-inflammatory activity than ibuprofen in carrageenan-induced rat paw edema assay. Taking into account the in vitro and in vivo results, molecular docking and in silico prediction of ADMET properties of compounds were carried out respectively. PMID:24763362

Grover, Jagdeep; Kumar, Vivek; Singh, Vikram; Bairwa, Khemraj; Sobhia, M Elizabeth; Jachak, Sanjay M



Spin-dependent variable range hopping and magnetoresistance in Ti1-xCoxO2 and Zn1-xCoxO magnetic semiconductor films  

NASA Astrophysics Data System (ADS)

Magnetic transport properties in Ti1-xCoxO2 and Zn1-xCoxO magnetic semiconductors have been studied experimentally and theoretically. A linear relation of ln? versus T-1/2 (? is sheet resistance and T is temperature), which shows different slopes and intersections at different magnetic fields, was observed experimentally in the low temperature range. The spin-dependent variable range hopping model has been proposed by taking into account the electron-electron Coulomb interaction and the spin-spin exchange interaction in the same frame, which can well describe the observed magnetic transport properties in Ti1-xCoxO2 and Zn1-xCoxO magnetic semiconductors.

Yan, Shi-shen; Liu, J. P.; Mei, L. M.; Tian, Y. F.; Song, H. Q.; Chen, Y. X.; Liu, G. L.



The mitochondrial copper metallochaperone Cox17 exists as an oligomeric, polycopper complex.  


Cox17 is the candidate copper metallochaperone for delivery of copper ions to the mitochondrion for assembly of cytochrome c oxidase. Cox17 purified as a recombinant molecule lacking any purification tag binds three Cu(I) ions per monomer in a polycopper cluster as shown by X-ray absorption spectroscopy. The CuCox17 complex exists in a dimer/tetramer equilibrium with a 20 microM k(d). The spectroscopic data do not discern whether the dimeric complex forms a single hexanuclear Cu(I) cluster or two separate trinuclear Cu(I) clusters. The Cu(I) cluster(s) exhibit(s) predominantly trigonal Cu(I) coordination. The cluster(s) in Cox17 resemble(s) the polycopper clusters in Ace1 and the Cup1 metallothionein in being pH-stable and luminescent. The physical properties of the CuCox17 complex purified as an untagged molecule differ from those reported previously for a GST-Cox17 fusion protein. The CuCox17 cluster is distinct from the polycopper cluster in Cup1 in being labile to ligand exchange. CuCox17 localized within the intermitochondrial membrane space appears to be predominantly tetrameric, whereas the cytosolic CuCox17 is primarily a dimeric species. Cys-->Ser substitutions at Cys23, Cys24, or Cys26 abolish the Cox17 function and prevent tetramerization, although Cu(I) binding is largely unaffected. Thus, the oligomeric state of Cox17 may be important to its physiological function. PMID:11170391

Heaton, D N; George, G N; Garrison, G; Winge, D R



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

PubMed Central

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.

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.



COX-2 overexpression increases malignant potential of human glioma cells through Id1.  


Increased COX-2 expression directly correlates with glioma grade and is associated with shorter survival in glioblastoma (GBM) patients. COX-2 is also regulated by epidermal growth factor receptor signaling which is important in the pathogenesis of GBMs. However, COX-2 expression has not been previously shown to directly alter malignancy of GBMs. Id1 is a member of the helix-loop-helix (HLH) family of transcriptional repressors that act as dominant-negative inhibitors of basic-HLH factors. This factor has been shown to be regulated by COX-2 in breast carcinoma cells and recent studies suggest that Id1 may also be involved in the genesis/progression of gliomas. We now show that COX-2 increases the aggressiveness of GBM cells. GBM cells with COX-2 overexpression show increased growth of colonies in soft agar. Tumorigenesis in vivo is also increased in both subcutaneous flank and orthotopic intracranial tumor models. COX-2 overexpression induces Id1 expression in two GBM cell lines suggesting a role for Id1 in glioma transformation/tumorigenesis. Furthermore, we find direct evidence of a role for Id1 with significant suppression of in vitro transformation and in vivo tumorigenesis in COX-2-overexpressing GBM cells where Id1 has been knocked down. In fact, Id1 is even more efficient at enhancing transformation/tumorigenesis of GBM cells than COX-2. Finally, GBM cells with COX-2 or Id1 overexpression show greater migration/invasive potential and tumors that arise from these cells also display increased microvessel density, results in line with the increased malignant potential seen in these cells. Thus, COX-2 enhances the malignancy of GBM cells through induction of Id1. PMID:24659686

Xu, Kaiming; Wang, Lanfang; Shu, Hui-Kuo G



COX-2 overexpression increases malignant potential of human glioma cells through Id1  

PubMed Central

Increased COX-2 expression directly correlates with glioma grade and is associated with shorter survival in glioblastoma (GBM) patients. COX-2 is also regulated by epidermal growth factor receptor signaling which is important in the pathogenesis of GBMs. However, COX-2 expression has not been previously shown to directly alter malignancy of GBMs. Id1 is a member of the helix-loop-helix (HLH) family of transcriptional repressors that act as dominant-negative inhibitors of basic-HLH factors. This factor has been shown to be regulated by COX-2 in breast carcinoma cells and recent studies suggest that Id1 may also be involved in the genesis/progression of gliomas. We now show that COX-2 increases the aggressiveness of GBM cells. GBM cells with COX-2 overexpression show increased growth of colonies in soft agar. Tumorigenesis in vivo is also increased in both subcutaneous flank and orthotopic intracranial tumor models. COX-2 overexpression induces Id1 expression in two GBM cell lines suggesting a role for Id1 in glioma transformation/tumorigenesis. Furthermore, we find direct evidence of a role for Id1 with significant suppression of in vitro transformation and in vivo tumorigenesis in COX-2-overexpressing GBM cells where Id1 has been knocked down. In fact, Id1 is even more efficient at enhancing transformation/tumorigenesis of GBM cells than COX-2. Finally, GBM cells with COX-2 or Id1 overexpression show greater migration/invasive potential and tumors that arise from these cells also display increased microvessel density, results in line with the increased malignant potential seen in these cells. Thus, COX-2 enhances the malignancy of GBM cells through induction of Id1.

Xu, Kaiming; Wang, Lanfang; Shu, Hui-Kuo G.



Prognostic Significance and Clinicopathological Associations of COX-2 SNP in Patients with Nonsmall Cell Lung Cancer  

PubMed Central

Background. To further improve the screening, diagnosis, and therapy of patients with nonsmall cell lung cancer (NSCLC) additional diagnostic tools are urgently needed. Gene expression of Cyclooxygenase-2 (COX-2) has been linked to prognosis in patients with NSCLC. The role of the COX-2 926G>C Single Nucleotide Polymorphism (SNP) in patients with NSCLC remains unclear. The aim of this study was to investigate the potential of the COX-2 926G>C SNP as a molecular marker in this disease. Methods. COX-2 926G>C SNP was analyzed in surgically resected tumor tissue of 85 patients with NSCLC using a PCR-based RFLP technique. Results. The COX-2 926G>C SNP genotypes were detected with the following frequencies: GG n = 62 (73%), GC n = 20 (23%), CC n = 3 (4%). There were no associations between COX-2 SNP genotype and histology, grading or gender detectable. COX-2 SNP was significantly associated with tumor stage (P = .032) and lymph node status (P = .016, Chi-square test). With a median followup of 85.9 months, the median survival was 59.7 months. There were no associations seen between the COX-2 SNP genotype and patients prognosis. Conclusions. The COX-2 926G>C SNP is detectable at a high frequency in patients with NSCLC. The COX-2 926G>C SNP genotype is not a prognostic molecular marker in this disease. However, patients with the GC or CC genotype seem more susceptible to lymph node metastases and higher tumor stage than patients with the GG genotype. The results suggest COX-2 926G>C SNP as a molecular marker for lymph node involvement in this disease.

Grimminger, Peter P.; Stohlmacher, Jan; Vallbohmer, Daniel; Schneider, Paul M.; Holscher, Arnulf H.; Metzger, Ralf; Danenberg, Peter V.; Brabender, Jan



Prognostic Significance and Clinicopathological Associations of COX-2 SNP in Patients with Nonsmall Cell Lung Cancer.  


Background. To further improve the screening, diagnosis, and therapy of patients with nonsmall cell lung cancer (NSCLC) additional diagnostic tools are urgently needed. Gene expression of Cyclooxygenase-2 (COX-2) has been linked to prognosis in patients with NSCLC. The role of the COX-2 926G>C Single Nucleotide Polymorphism (SNP) in patients with NSCLC remains unclear. The aim of this study was to investigate the potential of the COX-2 926G>C SNP as a molecular marker in this disease. Methods. COX-2 926G>C SNP was analyzed in surgically resected tumor tissue of 85 patients with NSCLC using a PCR-based RFLP technique. Results. The COX-2 926G>C SNP genotypes were detected with the following frequencies: GG n = 62 (73%), GC n = 20 (23%), CC n = 3 (4%). There were no associations between COX-2 SNP genotype and histology, grading or gender detectable. COX-2 SNP was significantly associated with tumor stage (P = .032) and lymph node status (P = .016, Chi-square test). With a median followup of 85.9 months, the median survival was 59.7 months. There were no associations seen between the COX-2 SNP genotype and patients prognosis. Conclusions. The COX-2 926G>C SNP is detectable at a high frequency in patients with NSCLC. The COX-2 926G>C SNP genotype is not a prognostic molecular marker in this disease. However, patients with the GC or CC genotype seem more susceptible to lymph node metastases and higher tumor stage than patients with the GG genotype. The results suggest COX-2 926G>C SNP as a molecular marker for lymph node involvement in this disease. PMID:20016751

Grimminger, Peter P; Stöhlmacher, Jan; Vallböhmer, Daniel; Schneider, Paul M; Hölscher, Arnulf H; Metzger, Ralf; Danenberg, Peter V; Brabender, Jan



Clinical features, survival times and COX1 and COX2 expression in cats with transitional cell carcinoma of the urinary bladder treated with meloxicam  

Microsoft Academic Search

Records of 11 cats with transitional cell carcinoma of the urinary bladder, which had been treated with meloxicam, were reviewed for signalment, duration of clinical signs prior to diagnosis, results of diagnostic imaging, whether or not concurrent surgery was performed and survival. Immunohistochemical expression of cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2) was assessed in the tumours of seven cats. Tumour location

Nicholas X Bommer; Alison M Hayes; Timothy J Scase; Danièlle A Gunn-Moore



Sulforaphane suppresses lipopolysaccharide-induced cyclooxygenase-2 (COX2) expression through the modulation of multiple targets in COX2 gene promoter  

Microsoft Academic Search

Sulforaphane is a natural, biologically active compound extracted from cruciferous vegetables such as broccoli and cabbage. It possesses potent anti-inflammation and anti-cancer properties. The mechanism by which sulforaphane suppresses COX-2 expression remains poorly understood. In the present report, we investigated the effect of sulforaphane on the expression of COX-2 in lipopolysaccharide (LPS)-activated Raw 264.7 cells. Sulforaphane significantly suppressed the LPS-induced

Kyung Jin Woo; Taeg Kyu Kwon



Optimum Designs in Regression Problems  

Microsoft Academic Search

Although regression problems have been considered by workers in all sciences for many years, until recently relatively little attention has been paid to the optimum design of experiments in such problems. At what values of the independent variable should one take observations, and in what proportions? The purpose of this paper is to develop useful computational procedures for finding optimum

J. Kiefer; J. Wolfowitz



Is the Gasoline Tax Regressive?  

Microsoft Academic Search

Claims of the regressivity of gasoline taxes typically rely on annual surveys of consumer income and expenditures which show that gasoline expenditures are a larger fraction of income for very low income households than for middle or high-income households. This paper argues that annual expenditure provides a more reliable indicator of household well-being than annual income. It uses data from

James M. Poterba



Cactus: An Introduction to Regression  

ERIC Educational Resources Information Center

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…

Hyde, Hartley



Building Your Own Regression Model  

ERIC Educational Resources Information Center

Spreadsheets to explore regression with an algebra 2 class in a medium-sized rural high school are presented. The use of spreadsheets can help students develop sophisticated understanding of mathematical models and use them to describe real-world phenomena.

Horton, Robert, M.; Phillips, Vicki; Kenelly, John



Fitting a Multiple Regression Function.  

National Technical Information Service (NTIS)

A statistical problem which finds a wide range of applications is the estimation of a regression function. In this document an estimate is proposed when there are at least two independent regressors. This is not a direct generalization of the Priestley-Ch...

I. A. Ahmad P. E. Lin



Fungible Weights in Multiple Regression  

ERIC Educational Resources Information Center

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…

Waller, Niels G.



Weighting Regressions by Propensity Scores  

ERIC Educational Resources Information Center

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…

Freedman, David A.; Berk, Richard A.



Smoothness Priors and Nonlinear Regression  

Microsoft Academic Search

In applications, the linear multiple regression model is often modified to allow for nonlinearity in an independent variable. It is argued here that in practice it may often be desirable to specify a Bayesian prior that the unknown functional form is \\

Robert J. Shiller



Standards for Regression Discontinuity Designs  

ERIC Educational Resources Information Center

Regression discontinuity (RD) designs are increasingly used by researchers to obtain unbiased estimates of the effects of education-related interventions. These designs are applicable when a continuous "scoring" rule is used to assign the intervention to study units (for example, school districts, schools, or students). Under an RD design, the…

Schochet, P.; Cook, T.; Deke, J.; Imbens, G.; Lockwood, J. R.; Porter, J.; Smith, J.



Regression, Prediction, and Model Building  

NSDL National Science Digital Library

This tutorial, created by Thomas W. McFarland of Nova Southeastern University, explains the theory and use of multiple regression and demonstrates it with an example on SAT scores and GPA. Data sets are provided in both SPSS and Minitab code. This is a good resource for both students and teachers interested in a more in-depth study of statistics.

Macfarland, Thomas W.



Logistic Regression with Random Coefficients.  

ERIC Educational Resources Information Center

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…

Longford, Nicholas T.


Diversity of sponge mitochondrial introns revealed by cox 1 sequences of Tetillidae  

Microsoft Academic Search

BACKGROUND: Animal mitochondrial introns are rare. In sponges and cnidarians they have been found in the cox 1 gene of some spirophorid and homosclerophorid sponges, as well as in the cox 1 and nad 5 genes of some Hexacorallia. Their sporadic distribution has raised a debate as to whether these mobile elements have been vertically or horizontally transmitted among their

Amir Szitenberg; Chagai Rot; Micha Ilan; Dorothée Huchon



Dietary Zinc Modulation of COX2 Expression and Lingual and Esophageal Carcinogenesis in Rats  

Microsoft Academic Search

Background: Cancer of the upper aerodigestive tract, includ- ing esophageal and tongue carcinomas, is a major cause of cancer deaths worldwide. Esophageal and tongue cancers have both been associated with dietary zinc deficiency (ZD), and cyclooxygenase (COX-2) is often overexpressed in these cancers. Using rat models, we examined whether zinc regu- lates COX-2 expression in these cancers. Method: Expression of

Louise Y. Y. Fong; Liang Zhang; Yubao Jiang; John L. Farber



Role of PPAR? in COX-2 activation in mycobacterial pulmonary inflammation  

PubMed Central

Preliminary studies show that intranasal (i.n.) administration of BCG in mice induces M1 activation of alveolar macrophages (MØ) that increase TNF-? production and cyclooxygenase-2 (COX-2) expression but reduce constitutive peroxisome proliferator-activated receptor gamma (PPAR?) expression. However, COX-2 is catalytically inactive for prostaglandin E2 release, unlike COX-2 active in M1 activation in vitro by BCG. In this study, we determined the role of PPAR? for BCG-induced M1 activation in vivo and in vitro. We found that treatment of mice with GW9662, a PPAR? antagonist, prior to i.n. BCG, partially restored PPAR? expression, and decreased TNF-? production and COX-2 expression. But COX-2 was still inactive. The decreased effects on TNF-? and COX-2 were also observed when alveolar MØ were treated in vitro with GW9662/BCG, but COX-2 was still active. Our results indicate that PPAR? up-regulates M1 activation of alveolar MØ, but inactive COX-2 formation is independent of PPAR? in mycobacterial pulmonary inflammation.

Kogiso, Mari; Shinohara, Tsutomu; Dorey, C. Kathleen; Shibata, Yoshimi



Knockdown of human COX17 affects assembly and supramolecular organization of cytochrome c oxidase.  


Assembly of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, requires a concerted activity of a number of chaperones and factors for the insertion of subunits, accessory proteins, cofactors and prosthetic groups. It is now well accepted that the multienzyme complexes of the respiratory chain are organized in vivo as supramolecular functional structures, so-called supercomplexes. Here, we investigate the role of COX17 in the biogenesis of the respiratory chain in HeLa cells. In accordance with its predicted function as a copper chaperone and its role in formation of the binuclear copper centre of cytochrome c oxidase, COX17 siRNA knockdown affects activity and assembly of cytochrome c oxidase. While the abundance of cytochrome c oxidase dimers seems to be unaffected, blue native gel electrophoresis reveals the disappearance of COX-containing supercomplexes as an early response. We observe the accumulation of a novel approximately 150 kDa complex that contains Cox1, but not Cox2. This observation may indicate that the absence of Cox17 interferes with copper delivery to Cox2, but not to Cox1. We suggest that supercomplex formation is not simply due to assembly of completely assembled complexes. An interdependent assembly scenario for the formation of supercomplexes that rather requires the coordinated synthesis and association of individual complexes, is proposed. PMID:19393246

Oswald, C; Krause-Buchholz, U; Rödel, G



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


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

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




Microsoft Academic Search

INTRODUCTION. Cyclooxygenase 2 (COX-2) is a key enzyme in the production of prostaglandins (PGs) and represents an important target for treatment and prevention of colorectal cancer (1). However, the molecular mechanisms by which COX-2 regulates colon epithelial cell morphology and stress fiber formation are not well understood. The normal morphology of colon epithelial cells is established and maintained by adherens

Yu-Wen E. Chang; Terry W. Chance; Jerry W. Marlin; Rolf Jakobi


Mutations in COX7B Cause Microphthalmia with Linear Skin Lesions, an Unconventional Mitochondrial Disease  

PubMed Central

Microphthalmia with linear skin lesions (MLS) is an X-linked dominant male-lethal disorder associated with mutations in holocytochrome c-type synthase (HCCS), which encodes a crucial player of the mitochondrial respiratory chain (MRC). Unlike other mitochondrial diseases, MLS is characterized by a well-recognizable neurodevelopmental phenotype. Interestingly, not all clinically diagnosed MLS cases have mutations in HCCS, thus suggesting genetic heterogeneity for this disorder. Among the possible candidates, we analyzed the X-linked COX7B and found deleterious de novo mutations in two simplex cases and a nonsense mutation, which segregates with the disease, in a familial case. COX7B encodes a poorly characterized structural subunit of cytochrome c oxidase (COX), the MRC complex IV. We demonstrated that COX7B is indispensable for COX assembly, COX activity, and mitochondrial respiration. Downregulation of the COX7B ortholog (cox7B) in medaka (Oryzias latipes) resulted in microcephaly and microphthalmia that recapitulated the MLS phenotype and demonstrated an essential function of complex IV activity in vertebrate CNS development. Our results indicate an evolutionary conserved role of the MRC complexes III and IV for the proper development of the CNS in vertebrates and uncover a group of mitochondrial diseases hallmarked by a developmental phenotype.

Indrieri, Alessia; van Rahden, Vanessa Alexandra; Tiranti, Valeria; Morleo, Manuela; Iaconis, Daniela; Tammaro, Roberta; D'Amato, Ilaria; Conte, Ivan; Maystadt, Isabelle; Demuth, Stephanie; Zvulunov, Alex; Kutsche, Kerstin; Zeviani, Massimo; Franco, Brunella



COX-2 expression in stromal fibroblasts self-limits their numbers in lymph node inflammatory responses.  


We previously reported the expression of cyclooxygenase (COX)-2 in draining lymph nodes during carrageenin-induced pleurisy of rats. Here, we analyzed histological and immunohistochemical characteristics of COX-2-expressing cells. After carrageenin administration into the pleural cavity of rats, parathymic lymph nodes were enlarged beginning at 8h and peaking from 24 to 48h. Lymphatic follicles disappeared 16h after injection, and numerous macrophages and fibroblasts were observed in the cortical region. COX-2-expressing cells in the cortical region showed characteristic dendritic processes from 16 to 48h and primarily co-localized with stromal fibroblastic reticular cell markers, ?-smooth muscle actin (?-SMA), and desmin. Expression of ?-SMA increased following COX-2 expression. Nimesulide, a COX-2 inhibitor, increased the dendritic processes of COX-2-expressing cells as well as expression of both COX-2 and ?-SMA. These results suggest that COX-2-expressing cells may be stromal fibroblastic cells, which negatively self-regulate their proliferation and modulate tissue remodeling of draining lymph nodes at inflammatory sites. PMID:23587942

Kawamura, Michiko; Tada, Yosihito; Kadoya, Yuichi; Obata, Shuichi; Harada, Yoshiteru



The 2?-Trifluoromethyl Analogue of Indomethacin Is a Potent and Selective COX-2 Inhibitor  

PubMed Central

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



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

PubMed Central

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

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



Improving Your Data Transformations: Applying the Box-Cox Transformation  

ERIC Educational Resources Information Center

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…

Osborne, Jason W.



Urinary tract obstruction induces transient accumulation of COX-2-derived prostanoids in kidney tissue  

PubMed Central

Inhibitors of cyclooxygenase (COX)-2 prevent suppression of aquaporin-2 and reduce polyuria in the acute phase after release of bilateral ureteral obstruction (BUO). We hypothesized that BUO leads to COX-2-mediated local accumulation of prostanoids in inner medulla (IM) tissue. To test this, rats were subjected to BUO and treated with selective COX-1 or COX-2 inhibitors. Tissue was examined at 2, 6, 12, and 24 h after BUO. COX-2 protein abundance increased in IM 12 and 24 h after onset of BUO but did not change in cortex. COX-1 did not change at any time points in any region. A full profile of all five primary prostanoids was obtained by mass spectrometric determination of PGE2, PGF2?, 6-keto-PGF1?, PGD2, and thromboxane (Tx) B2 concentrations in kidney cortex/outer medulla and IM fractions. IM concentration of PGE2, 6-keto-PGF1?, and PGF2? was increased at 6 h BUO, and PGE2 and PGF2? increased further at 12 h BUO. TxB2 increased after 12 h BUO. 6-keto-PGF1? remained significantly increased after 24 h BUO. The COX-2 inhibitor parecoxib lowered IM PGE2, TxB2, 6-keto-PGF1?, and PGF2? below vehicle-treated BUO and sham rats at 6, 12 and, 24 h BUO. The COX-1 inhibitor SC-560 lowered PGE2, PGF2?, and PGD2 in IM compared with untreated 12 h BUO, but levels remained significantly above sham. In cortex tissue, PGE2 and 6-keto-PGF1? concentrations were elevated at 6 h only. In conclusion, COX-2 activity contributes to the transient increase in prostacyclin metabolite 6-keto-PGF1? and TxB2 concentration in the kidney IM, and COX-2 is the predominant isoform that is responsible for accumulation of PGE2 and PGF2? with minor, but significant, contributions from COX-1. PGD2 synthesis is mediated exclusively by COX-1. In BUO, therapeutic interventions aimed at the COX-prostanoid pathway should target primarily COX-2.

N?rregaard, Rikke; Jensen, Boye L; Topcu, Sukru Oguzkan; Wang, Guixian; Schweer, Horst; Nielsen, S?ren



Dual inhibition of 5-LOX and COX-2 suppresses esophageal squamous cell carcinoma.  


COX-2 and 5-LOX are up-regulated in ESCC. This study aims to determine the efficacy of COX-2 inhibitor, 5-LOX inhibitor and their combination on ESCC. Nimesulide can suppress cell growth and promote apoptosis, accompanied with a decrease of PGE(2) production. AA861 has the similar effect with a down-regulation of LTB(4). In animal experiment, the tumor volumes in drug-treated groups were significantly smaller with the lowest rates of Ki-67 positive cells. In conclusion, either COX-2 inhibitor or 5-LOX inhibitor can suppress ESCC. Dual inhibition of COX-2 and 5-LOX pathway may present a superior anticancer efficacy to either inhibition of COX-2 or 5-LOX alone. PMID:21652147

Shi, Hai-yun; Lv, Fu-jing; Zhu, Sheng-tao; Wang, Qing-gang; Zhang, Shu-tian



COX-2 inhibitors for the prevention of heterotopic ossification after THA.  


Nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent heterotopic ossification after total hip arthroplasty (THA). Cyclooxygenase 2 (COX-2) inhibitors may minimize side effects. The goal of this review was to compare the effectiveness and side effects of the perioperative use of selective COX-2 inhibitors with those of conventional NSAIDs in patients undergoing THA. We followed the systematic reviews' updated methods of the Cochrane Collaboration Back Review Group and searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. We identified all randomized controlled trials until April 2009 enrolling THA patients and comparing COX-2 inhibitors to NSAIDs. We assessed their methodological quality and extracted data. Five randomized controlled trials were included. Prevention of heterotopic ossification and side effects with COX-2 inhibitors were significant in 2 studies. Discontinuation for side effects was not significant. COX-2 inhibitors do not prevent heterotopic ossification after THA significantly better than conventional NSAIDs, while they are advantageous regarding side effects. PMID:21661680

Vasileiadis, George I; Sioutis, Ioannis C; Mavrogenis, Andreas F; Vlasis, Konstantinos; Babis, George C; Papagelopoulos, Panayiotis J



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


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

Sato, Itaru; Kofujita, Hisayoshi; Tsuda, Shuji



On the comparison of population-level estimates of haplotype and nucleotide diversity: a case study using the gene cox1 in animals  

PubMed Central

Estimates of genetic diversity represent a valuable resource for biodiversity assessments and are increasingly used to guide conservation and management programs. The most commonly reported estimates of DNA sequence diversity in animal populations are haplotype diversity (h) and nucleotide diversity (?) for the mitochondrial gene cytochrome c oxidase subunit I (cox1). However, several issues relevant to the comparison of h and ? within and between studies remain to be assessed. We used population-level cox1 data from peer-reviewed publications to quantify the extent to which data sets can be re-assembled, to provide a standardized summary of h and ? estimates, to explore the relationship between these metrics and to assess their sensitivity to under-sampling. Only 19 out of 42 selected publications had archived data that could be unambiguously re-assembled; this comprised 127 population-level data sets (n?15) from 23 animal species. Estimates of h and ? were calculated using a 456-base region of cox1 that was common to all the data sets (median h=0.70130, median ?=0.00356). Non-linear regression methods and Bayesian information criterion analysis revealed that the most parsimonious model describing the relationship between the estimates of h and ? was ?=0.0081h2. Deviations from this model can be used to detect outliers due to biological processes or methodological issues. Subsampling analyses indicated that samples of n>5 were sufficient to discriminate extremes of high from low population-level cox1 diversity, but samples of n?25 are recommended for greater accuracy.

Goodall-Copestake, W P; Tarling, G A; Murphy, E J



MIDAS Regressions: Further Results and New Directions  

Microsoft Academic Search

We explore mixed data sampling (henceforth MIDAS) regression models. The regressions involve time series data sampled at different frequencies. Volatility and related processes are our prime focus, though the regression method has wider applications in macroeconomics and finance, among other areas. The regressions combine recent developments regarding estimation of volatility and a not-so-recent literature on distributed lag models. We study

Eric Ghysels; Arthur Sinko; Rossen Valkanov



On study of kernel regression function polygons  

Microsoft Academic Search

In the case of the random design nonparametric regression, the regression function estimate is produced practically by joining every two consecutive kernel estimates of regression function values by a straight line segment. Hence, it is of polygon type, and is called the kernel regression function polygon (KRFP) in this paper. The KRFP is analyzed by its asymptotic integrated mean square

Wen-Shuenn Deng; C. K. Chu



Regression Test Selection for C++ Software  

Microsoft Academic Search

Regression testing is an important but expensive software maintenance activity performed with the aim of providing condence in modied software. Regression test selection techniques reduce the cost of regression testing by selecting test cases for a modied program from a previously existing test suite. Many researchers have addressed the regression test selection problem for procedural language software, but few have

Gregg Rothermel; Mary Jean Harrold; Jeinay Dedhia



Quantile regression model and application profile  

Microsoft Academic Search

This paper compares the modeling process in the quantile regression and linear regression for the similarities and differences, in the model building, parameter estimation, computer implementation. and specific examples of these four aspects described quantile regression model better than linear regression mode.

Zhou Lihui




Microsoft Academic Search





Outliers and Residual Distributions in Logistic Regression  

Microsoft Academic Search

Detection of outliers and other diagnostics based on residuals have gained widespread use in linear regression. Logistic regression has been both blessed and hindered by this development. Certainly logistic regression requires procedures to detect global and local model weaknesses. Thus the wealth of work done in linear regression provides guides and suggestions that may, with care and ingenuity, be applied

Dennis E. Jennings



Wnt/?-Catenin Signaling Enhances Cyclooxygenase-2 (COX2) Transcriptional Activity in Gastric Cancer Cells  

PubMed Central

Background Increased expression of the cyclooxygenase-2 enzyme (COX2) is one of the main characteristics of gastric cancer (GC), which is a leading cause of death in the world, particularly in Asia and South America. Although the Wnt/?-catenin signaling pathway has been involved in the transcriptional activation of the COX2 gene, the precise mechanism modulating this response is still unknown. Methodology/Principal Findings Here we studied the transcriptional regulation of the COX2 gene in GC cell lines and assessed whether this phenomenon is modulated by Wnt/?-catenin signaling. We first examined the expression of COX2 mRNA in GC cells and found that there is a differential expression pattern consistent with high levels of nuclear-localized ?-catenin. Pharmacological treatment with either lithium or valproic acid and molecular induction with purified canonical Wnt3a significantly enhanced COX2 mRNA expression in a dose- and time-dependent manner. Serial deletion of a 1.6 Kbp COX2 promoter fragment and gain- or loss-of-function experiments allowed us to identify a minimal Wnt/?-catenin responsive region consisting of 0.8 Kbp of the COX2 promoter (pCOX2-0.8), which showed maximal response in gene-reporter assays. The activity of this pCOX2-0.8 promoter region was further confirmed by site-directed mutagenesis and DNA-protein binding assays. Conclusions/Significance We conclude that the pCOX2-0.8 minimal promoter contains a novel functional T-cell factor/lymphoid enhancer factor (TCF/LEF)-response element (TBE Site II; -689/-684) that responds directly to enhanced Wnt/?-catenin signaling and which may be important for the onset/progression of GC.

Nunez, Felipe; Bravo, Soraya; Cruzat, Fernando; Montecino, Martin; De Ferrari, Giancarlo V.



Over-expression of COX-2 mRNA in colorectal cancer  

PubMed Central

Background Cyclooxygenase-2 (COX-2, PTGS2) is an enzyme involved in the synthesis of prostaglandins and thromboxanes, which are regulators of biologic processes such as inflammation, cell proliferation and angiogenesis. COX-2 over-expression was reported in many (pre) malignant tissues, but data strongly vary and seem to depend on the methodology used. Methods Normal colorectal mucosa and paired cancerous tissue from 60 patients with colorectal cancer was investigated for the levels of COX-2 mRNA by real-time quantitative Polymerase Chain Reaction (qPCR). COX-2 levels were expressed relative to either: tissue weight or levels of the housekeeping genes beta-2 microglobulin (B2M) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Results COX-2 mRNA levels, normalized with respect to tissue weight or mRNA levels of the housekeeping genes B2M or GAPDH, were over-expressed in 80%, 70% and 40% of the colorectal tumor tissues, as compared to the paired adjacent normal colorectal mucosa samples, respectively. Highest mRNA COX-2 ratios tumor/normal were measured when expressed per mg tissue (mean ratio 21.6). When normalized with respect to the housekeeping genes B2M or GAPDH, mean tumor/normal ratios were 16.1 and 7.5, respectively. Conclusion Expression of COX-2 mRNA levels per mg tissue is most simple in comparison to normalization with respect to the housekeeping genes B2M or GAPDH. Levels of COX-2 mRNA are found over-expressed in almost 80% of the colorectal tumors, compared to paired adjacent normal colorectal mucosa, suggesting a role of COX-2 as a potential biomarker for cancer risk, whereas inhibitors of COX-2 could be of value in chemoprevention of colon cancer.



Ordinal Regression with Sparse Bayesian  

NASA Astrophysics Data System (ADS)

In this paper, a probabilistic framework for ordinal prediction is proposed, which can be used in modeling ordinal regression. A sparse Bayesian treatment for ordinal regression is given by us, in which an automatic relevance determination prior over weights is used. The inference techniques based on Laplace approximation is adopted for model selection. By this approach accurate prediction models can be derived, which typically utilize dramatically fewer basis functions than the comparable supported vector based and Gaussian process based approaches while offering a number of additional advantages. Experimental results on the real-world data set show that the generalization performance competitive with support vector-based method and Gaussian process-based method.

Chang, Xiao; Zheng, Qinghua; Lin, Peng


Inhibition of COX-1 and COX-2 activity by plasma of human volunteers after ingestion of French maritime pine bark extract (Pycnogenol).  


There is evidence from several studies that supplementation with French maritime pine bark extract (Pycnogenol) improves inflammatory symptoms in vivo. However, the molecular pharmacological basis for the observed effects has not been fully uncovered yet. Direct inhibitory effects of plant extracts or components upon cyclooxygenase (COX) activity have been repeatedly reported, but the question remained whether sufficiently high in vivo concentrations of bioactive compounds could be achieved in humans. The purpose of the present study was to determine a possible inhibition of the enzymatic activity of COX-1 and COX-2 by serum samples of human volunteers after intake of French maritime pine bark extract. This methodology considered that the serum samples would contain any bioavailable active principle. Therefore, we obtained blood samples before and after 5 days administration of 200 mg Pycnogenol to five healthy humans. The plasma moderately inhibited both COX-1 and COX-2 activities ex vivo. In a second approach, 10 volunteers received a single dose of 300 mg Pycnogenol. Only 30 min after ingestion of the pine bark extract the serum samples induced a statistically significant increase in the inhibition of both COX-1 (P < 0.02) and COX-2 (P < 0.002). This suggests a strikingly rapid bioavailability of bioeffective compounds after oral intake of the extract. Thus, we provide evidence that Pycnogenol exerts effects by inhibition of eicosanoid generating enzymes which is consistent with reported clinical anti-inflammatory and platelet inhibitory effects in vivo. The next challenge is to identify the active principle(s) that are rapidly bioavailable in human plasma. PMID:16330178

Schäfer, Angelika; Chovanová, Zuzana; Muchová, Jana; Sumegová, Katarína; Liptáková, Anna; Duracková, Zdenka; Högger, Petra



Robust, Adaptive Functional Regression in Functional Mixed Model Framework  

PubMed Central

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.

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



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

NASA Astrophysics Data System (ADS)

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.

Larrinaga, Asier R.



Minimizing the cancer-promotional activity of cox-2 as a central strategy in cancer prevention.  


A recent meta-analysis examining long-term mortality in subjects who participated in controlled studies evaluating the impact of daily aspirin on vascular risk, has concluded that aspirin confers substantial protection from cancer mortality. Remarkably, low-dose aspirin was as effective as higher-dose regimens; hence this protection may be achievable with minimal risk. There is reason to believe that this protection stems primarily from inhibition of cox-2 in pre-neoplastic lesions. Since safe aspirin regimens can only achieve a partial and transitory inhibition of cox-2, it may be feasible to complement the cancer-protective benefit of aspirin with other measures which decrease cox-2 expression or which limit the bioactivity of cox-2-derived PGE2. Oxidative stress boosts cox-2 expression by up-regulating activation of NF-kappaB and MAP kinases; NADPH oxidase activation may thus promote carcinogenesis by increasing cox-2 expression while also amplifying oxidant-mediated mutagenesis. A prospective cohort study has observed that relatively elevated serum bilirubin levels are associated with a marked reduction in subsequent cancer mortality; this may reflect bilirubin's physiological role as a potent inhibitor of NADPH oxidase. It may be feasible to mimic this protective effect by supplementing with spirulina, a rich source of a phycobilin which shares bilirubin's ability to inhibit NADPH oxidase. Ancillary antioxidant measures - phase 2 inducing phytochemicals, melatonin, N-acetylcysteine, and astaxanthin - may also aid cox-2 down-regulation. The cancer protection often associated with high-normal vitamin D status may be attributable, in part, to the ability of the activated vitamin D receptor to decrease cox-2 expression while promoting PGE2 catabolism and suppressing the expression of PGE2 receptors. Diets with a relatively low ratio of omega-6 to long-chain omega-3 fats may achieve cancer protection by antagonizing the production and bioactivity of PGE2. Growth factors such as IGF-I increase cox-2 expression by several complementary mechanisms; hence, decreased cox-2 activity may play a role in the remarkably low mortality from "Western" cancers enjoyed by Third World cultures in which systemic growth factor activity was minimized by quasi-vegan diets complemented by leanness and excellent muscle insulin sensitivity. Practical strategies for achieving a modest degree of calorie restriction may also have potential for down-regulating cox-2 expression while decreasing cancer risk. Soy isoflavones, linked to reduced cancer risk in Asian epidemiology, may suppress cox-2 induction by activating ERbeta. In aggregate, these considerations suggest that a comprehensive lifestyle strategy targeting cox-2 expression and bioactivity may have tremendous potential for cancer prevention. PMID:22001128

McCarty, Mark F



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

NASA Technical Reports Server (NTRS)

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.

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



Flavocoxid Inhibits Phospholipase A2, Peroxidase Moieties of the Cyclooxygenases (COX), and 5-Lipoxygenase, Modifies COX-2 Gene Expression, and Acts as an Antioxidant  

PubMed Central

The multiple mechanisms of action for flavocoxid relating to arachidonic acid (AA) formation and metabolism were studied in vitro. Flavocoxid titrated into rat peritoneal macrophage cultures inhibited cellular phospholipase A2 (PLA2) (IC50 = 60??g/mL). In in vitro enzyme assays, flavocoxid showed little anti-cyclooxygenase (CO) activity on COX-1/-2 enzymes, but inhibited the COX-1 (IC50 = 12.3) and COX-2 (IC50 = 11.3??g/mL) peroxidase (PO) moieties as well as 5-lipoxygenase (5-LOX) (IC50 = 110??g/mL). No detectable 5-LOX inhibition was found for multiple traditional and COX-2 selective NSAIDs. Flavocoxid also exhibited strong and varied antioxidant capacities in vitro and decreased nitrite levels (IC50 = 38??g/mL) in rat peritoneal macrophages. Finally, in contrast to celecoxib and ibuprofen, which upregulated the cox-2 gene, flavocoxid strongly decreased expression. This work suggests that clinically favourable effects of flavocoxid for management of osteoarthritis (OA) are achieved by simultaneous modification of multiple molecular pathways relating to AA metabolism, oxidative induction of inflammation, and neutralization of reactive oxygen species (ROS).

Burnett, Bruce P.; Bitto, Alessandra; Altavilla, Domenica; Squadrito, Francesco; Levy, Robert M.; Pillai, Lakshmi



Flavocoxid inhibits phospholipase A2, peroxidase moieties of the cyclooxygenases (COX), and 5-lipoxygenase, modifies COX-2 gene expression, and acts as an antioxidant.  


The multiple mechanisms of action for flavocoxid relating to arachidonic acid (AA) formation and metabolism were studied in vitro. Flavocoxid titrated into rat peritoneal macrophage cultures inhibited cellular phospholipase A2 (PLA(2)) (IC(50) = 60??g/mL). In in vitro enzyme assays, flavocoxid showed little anti-cyclooxygenase (CO) activity on COX-1/-2 enzymes, but inhibited the COX-1 (IC(50) = 12.3) and COX-2 (IC(50) = 11.3??g/mL) peroxidase (PO) moieties as well as 5-lipoxygenase (5-LOX) (IC(50) = 110??g/mL). No detectable 5-LOX inhibition was found for multiple traditional and COX-2 selective NSAIDs. Flavocoxid also exhibited strong and varied antioxidant capacities in vitro and decreased nitrite levels (IC(50) = 38??g/mL) in rat peritoneal macrophages. Finally, in contrast to celecoxib and ibuprofen, which upregulated the cox-2 gene, flavocoxid strongly decreased expression. This work suggests that clinically favourable effects of flavocoxid for management of osteoarthritis (OA) are achieved by simultaneous modification of multiple molecular pathways relating to AA metabolism, oxidative induction of inflammation, and neutralization of reactive oxygen species (ROS). PMID:21765617

Burnett, Bruce P; Bitto, Alessandra; Altavilla, Domenica; Squadrito, Francesco; Levy, Robert M; Pillai, Lakshmi



Cox-2 inhibition enhances the activity of sunitinib in human renal cell carcinoma xenografts  

PubMed Central

Background: Sunitinib (Su), a tyrosine kinase inhibitor of VEGFR, is effective at producing tumour response in clear cell renal cell carcinoma (cRCC), but resistance to therapy is inevitable. As COX-2 is a known mediator of tumour growth, we explored the potential benefit of COX-2 inhibition in combination with VEGFR inhibition in attempts at delaying tumour progression on Su. Methods: COX-2 expression was compared with areas of hypoxia in tumours that progressed on Su vs untreated tumours. Mice bearing human cRCC xenografts were treated with Su and the COX-2 inhibitor, celecoxib, and the effects on tumour growth were assessed. Sequential vs concurrent regimens were compared. Results: COX-2 expression was increased in cRCC xenografts in areas of tumour hypoxia. The combination of Su and celecoxib achieved longer times to tumour progression compared to treatment with either agent alone or to untreated control animals in four models. This effect was seen with concurrent but not with sequential therapy. Conclusion: COX-2 inhibition can extend the effectiveness of VEGFR inhibition. This effect is dependent on the timing of therapy. Clinical trials combining Su and COX-2 inhibitors should be considered as a means delaying time to progression on sunitinib in patients with metastatic cRCC.

Wang, X; Zhang, L; O'Neill, A; Bahamon, B; Alsop, D C; Mier, J W; Goldberg, S N; Signoretti, S; Atkins, M B; Wood, C G; Bhatt, R S



Niacin and biosynthesis of PGD?by platelet COX-1 in mice and humans.  


The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1-dependent formation of PGD? and PGE? followed by COX-2-dependent production of PGE?. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD? receptor DP1. NSAID-mediated suppression of COX-2-derived PGI? has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD?. Here, we show that PGD? biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1-derived PGD? biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD? was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD?, like PGI?, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy. PMID:22406532

Song, Wen-Liang; Stubbe, Jane; Ricciotti, Emanuela; Alamuddin, Naji; Ibrahim, Salam; Crichton, Irene; Prempeh, Maxwell; Lawson, John A; Wilensky, Robert L; Rasmussen, Lars Melholt; Puré, Ellen; FitzGerald, Garret A



The influence of Cox-2 and bioactive lipids on hematological cancersa  

PubMed Central

Inflammation is implicated in the progression of multiple types of cancers including lung, colorectal, breast and hematological malignancies. Cyclooxygenases (Cox) -1 and -2 are important enzymes involved in the regulation of inflammation. Elevated Cox-2 expression is associated with a poor cancer prognosis. Hematological malignancies, which are among the top 10 most predominant cancers in the USA, express high levels of Cox-2. Current therapeutic approaches against hematological malignances are insufficient as many patients develop resistance or relapse. Therefore, targeting Cox-2 holds promise as a therapeutic approach to treat hematological malignancies. NSAIDs and Cox-2 selective inhibitors are anti-inflammatory drugs that decrease prostaglandin and thromboxane production while promoting the synthesis of specialized proresolving mediators. Here, we review the evidence regarding the applicability of NSAIDs, such as aspirin, as well as Cox-2 specific inhibitors, to treat hematological malignancies. Furthermore, we discuss how FDA-approved Cox inhibitors can be used as anti-cancer drugs alone or in combination with existing chemotherapeutic treatments.

Ramon, Sesquile; Woeller, Collynn F.; Phipps, Richard P.



Prostacyclin mediates endothelial COX-2-dependent neuroprotective effects during excitotoxic brain injury  

PubMed Central

In a previous study, we found that intracerebral administration of excitotoxin (RS)-(tetrazole-5yl) glycine caused increased neural damage in the brain in an endothelial COX-2 deleted mouse line (Tie2Cre COX-2flox/flox). In this study, we investigated whether prostacyclin might mediate this endothelial COX-2-dependent neuroprotection. Administration of excitotoxin into the striatum induced the production of prostacyclin (PGI2) in wild type, but not in endothelial COX-2 deleted mice. Inhibition of PGI2 synthase exacerbated brain lesions induced by the excitotoxin in wild type, but not in endothelial COX-2 deleted mice. Administration of a PGI2 agonist reduced neural damage in both wild type and endothelial COX-2 deleted mice. Increased PGI2 synthase expression was found in infiltrating neutrophils. In an ex vivo assay, PGI2 reduced the excitotoxin-induced calcium influx into neurons, suggesting a cellular mechanism for PGI2 mediated neuroprotection. These results reveal that PGI2 mediates endothelial COX-2 dependent neuroprotection.

An, Ying; Belevych, Natalya; Wang, Yufen; Zhang, Hao; Nasse, Jason S; Herschman, Harvey; Chen, Qun; Tarr, Andrew; Liu, Xiaoyu; Quan, Ning



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

PubMed Central

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.

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



Cyclooxygenase-2 (COX-2): first immunohistochemical marker distinguishing early cutaneous melanomas from benign melanocytic skin tumours.  


We have reported recently that changes in expression level of COX-2 are correlated with development and progression of human melanoma. In this study, we investigated whether the COX-2 expression level might be a useful immunohistochemical marker for distinguishing cutaneous melanomas from benign melanocytic lesions. Up to now, immunohistochemical markers have not ensured satisfactory sensitivity and specificity of differential pathologic diagnosis of melanoma. The expression of COX-2 was determined immunohistochemically in formalin-fixed, paraffin-embedded specimens of 33 early Clark I/II melanomas and 58 naevi. Mean COX-2 expression in melanomas was significantly stronger than in naevi (P approximately 10(-13)). A simple diagnostic algorithm using threshold values of the COX-2 expression level allows for differentiation between early melanomas and naevi with high sensitivity (Se) and specificity (Sp) (for Se between 91 and 100%, Sp values change between 96.5 and 51.7%). Areas under the receiver operating characteristic curves were, respectively, 0.97+/-0.02 and 0.86+/-0.04 for the COX-2 expression in central and border regions of the lesions. For all the melanomas (not only the early ones),the respective areas under the ROC curve values were 0.98+/-0.01 and 0.97+/-0.02. In conclusion, COX-2 is the first immunohistochemical marker that allows the distinguishing of early melanomas from benign melanocytic lesions with both high sensitivity and specificity. PMID:17505259

Chwirot, Barbara W; Ku?bicki, ?ukasz



The expression of Cox17p in rodent tissues and cells.  


Previous works have reported the isolation of a novel polypeptide from porcine heart. Structural analysis has shown that it is a mammalian homologue of Cox17p, believed essential for the assembly of functional cytochrome c oxidase and delivery of copper ions to the mitochondrion for insertion into the enzyme in yeast. Although the human, mouse and porcine homologs of this small protein have already been cloned or purified, the function of Cox17p in the mammalian system has not yet been elucidated. To investigate the physiological function of Cox17p in mammals, we performed Northern blot analysis using probes containing the mouse and rat sequences obtained by RT-PCR. The hybridization signals were detected in all mouse tissues, but notably intense signals were observed in heart, brain and kidney RNA samples. Some of the neuroendocrine and endocrine cell lines showed higher expression levels than fibroblasts. The highest expression level of Cox17p mRNA in mouse brain was observed in the pituitary sample. While in rat heart, Cox17p mRNA expression was detected from early development, in rat brain, embryonic and postnatal changes in the expression were observed. Immunocytochemical analysis showed that Cox17p immunoreactivity was strong in the pituitary cell line, AtT-20. These findings suggested that Cox17p is not only part of the respiratory chain but also involved in brain and endocrine functions. PMID:11054125

Kako, K; Tsumori, K; Ohmasa, Y; Takahashi, Y; Munekata, E



Prostacyclin mediates endothelial COX-2-dependent neuroprotective effects during excitotoxic brain injury.  


In a previous study, we found that intracerebral administration of excitotoxin (RS)-(tetrazole-5yl) glycine caused increased neural damage in the brain in an endothelial COX-2 deleted mouse line (Tie2Cre COX-2(flox/flox) ). In this study, we investigated whether prostacyclin might mediate this endothelial COX-2-dependent neuroprotection. Administration of excitotoxin into the striatum induced the production of prostacyclin (PGI2) in wild type, but not in endothelial COX-2 deleted mice. Inhibition of PGI2 synthase exacerbated brain lesions induced by the excitotoxin in wild type, but not in endothelial COX-2 deleted mice. Administration of a PGI2 agonist reduced neural damage in both wild type and endothelial COX-2 deleted mice. Increased PGI2 synthase expression was found in infiltrating neutrophils. In an ex vivo assay, PGI2 reduced the excitotoxin-induced calcium influx into neurons, suggesting a cellular mechanism for PGI2 mediated neuroprotection. These results reveal that PGI2 mediates endothelial COX-2 dependent neuroprotection. PMID:24971026

An, Ying; Belevych, Natalya; Wang, Yufen; Zhang, Hao; Nasse, Jason S; Herschman, Harvey; Chen, Qun; Tarr, Andrew; Liu, Xiaoyu; Quan, Ning



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


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. PMID:24954754

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



Toxicity assessment of organic pollutants: reliability of bioluminescence inhibition assay and univariate QSAR models using freshly prepared Vibrio fischeri.  


The toxicity of 14 industrially relevant organic chemicals was determined using freshly grown Vibrio fischeri bioluminescence inhibition assay. The results were compared to lyophilized V. fischeri, 96h fish, 48h Daphnia magna and 95h green algae bioassays. Reliability of octanol-water partition coefficient (K(ow)), and first order simple and valence molecular connectivity index ((1)chi, (1)chi(v)) based regression models for predicting toxicity to V. fischeri was studied. Correlations were obtained between freshly grown V. fischeri data (Log(EC50)) and Log(K(ow)), molecular connectivity indices ((1)chi, (1)chi(v)), energy of the highest occupied (E(HOMO)) and lowest unoccupied (E(LUMO)) molecular orbitals, and their difference (E(LUMO)-E(HOMO)). A good match was observed between V. fischeri assay conducted with freshly grown and lyophilized culture (r2=0.90). Good correlations (r2>0.95) were obtained with all the other bioassays after excluding compounds with Log(K(ow)) less than 2.0. Available regression models based on Log(K(ow)) and (1)chi(v) yielded lower toxicity values. V. fischeri bioassay showed fairly good correlation with Log(K(ow)), (1)chi and (1)chi(v) (r2>0.75) but poor correlation with E(HOMO), E(LUMO) and (E(LUMO)-E(HOMO)) in presence of polar compounds. E(HOMO) and E(LUMO) values are affected by polarity and can be used along with Log(K(ow)) and (1)chi(v) for generating better predictive models. PMID:18701087

Parvez, Shahid; Venkataraman, Chandra; Mukherji, Suparna



Cell proliferation activity unrelated to COX-2 expression in ovarian tumors.  


The objective of this study was to assess the expression of Cyclooxygenase-2 (COX-2) and cell proliferation activity (Ki67 expression) in benign, borderline, and malignant serous and mucinous ovarian tumors. Expression of COX-2 and Ki67 proteins were evaluated by immunohistochemistry, in paraffin-embedded sections of ovarian epithelial tumors. The study included 113 serous (67 benign, 15 borderline, and 31 malignant) and 85 mucinous (48 benign, 28 borderline, and 9 malignant) tumors, removed from women who underwent laparotomy between January 1997 and December 2003. From benign to malignant tumors, there was a progressive positive trend in COX-2 expression in both serous and mucinous tumors, more evident in mucinous ones (P < 0.001). Comparing histologic types, COX-2 expression was more prominent in serous than in mucinous benign tumors (P < 0.01), but this difference was not significant in the borderline (P= 0.11) or malignant categories (P= 0.71). There was a progressive Ki67 positivity in line with the tumor histologic gradient for both serous (P < 0.01) and mucinous lesions (P < 0.01), but this increasing expression did not correlate with COX-2 expression in the present series (P= 0.78). There was a higher COX-2 expression in serous ovarian adenomas than in mucinous ones. COX-2 positivity increases in line with the morphologic gradient, from benign to malignant in both histologic types, but it was more prominent in mucinous lesions, pointing to different oncogenic pathways related to different histologic types. A correlation between the expression of COX-2 and Ki67 was not found, suggesting that COX-2 may be required for carcinogenesis, but this pathway is not responsible for cell proliferation in ovarian tumors. PMID:17504375

Yoshida, A; Sarian, L O; Andrade, L A L A; Pignataro, F; Pinto, G A; Derchain, S F M



Methylation status and overexpression of COX-2 in Tunisian patients with ductal invasive breast carcinoma.  


Inflammation and hormonal signalling induce the cyclooxygenase-2 (COX-2) expression in solid tumours including breast cancer, which in turn affects cell proliferation, apoptosis and metastasis. The aim of this study was to investigate the expression of COX-2 and its association with clinical parameters, patient's survival, hormones receptors (oestrogen, progesterone), ERBB2 and TP53 expression in 83 cases of infiltrating ductal breast carcinomas. Moreover, the methylation status at the CpG islands of the COX-2 gene promoter was also explored in 70 specimens. We showed that tumours exhibiting moderate to intense COX-2 immunostaining were significantly more frequent in patients over 45 years old (p = 0.027). Moreover, a high level of COX-2 expression correlated with a shorter survival time (p log-rank = 0.04) and was an independent prognostic factor (p = 0.022; HR 6.4; 95% CI = 1.3-31.4). On the other hand, hypermethylation of the COX-2 gene promoter was observed in 27% of cases and strongly associated with smaller tumours (<5 cm, p = 0.011). Furthermore, patients with methylated COX-2 pattern have a better 4-year disease-free survival (p = 0.022) as well as a prolonged overall survival (p log-rank test = 0.034). In conclusion, we showed that high COX-2 expression was associated with reduced survival and was an independent prognostic factor. However, hypermethylation of the COX-2 promoter correlated with a better overall survival in Tunisian patients with breast carcinoma. PMID:21153458

Karray-Chouayekh, Sondes; Trifa, Fatma; Khabir, Abdelmajid; Boujelbene, Noureddine; Sellami-Boudawara, Tahia; Daoud, Jamel; Frikha, Mounir; Gargouri, Ali; Mokdad-Gargouri, Raja



Mapping the functional interaction of Sco1 and Cox2 in cytochrome oxidase biogenesis.  


Sco1 is implicated in the copper metallation of the Cu(A) site in Cox2 of cytochrome oxidase. The structure of Sco1 in the metallated and apo-conformers revealed structural dynamics primarily in an exposed region designated loop 8. The structural dynamics of loop 8 in Sco1 suggests it may be an interface for interactions with Cox17, the Cu(I) donor and/or Cox2. A series of conserved residues in the sequence motif (217)KKYRVYF(223) on the leading edge of this loop are shown presently to be important for yeast Sco1 function. Cells harboring Y219D, R220D, V221D, and Y222D mutant Sco1 proteins failed to restore respiratory growth or cytochrome oxidase activity in sco1Delta cells. The mutant proteins are stably expressed and are competent to bind Cu(I) and Cu(II) normally. Specific Cu(I) transfer from Cox17 to the mutant apo-Sco1 proteins proceeds normally. In contrast, using two in vivo assays that permit monitoring of the transient Sco1-Cox2 interaction, the mutant Sco1 molecules appear compromised in a function with Cox2. The mutants failed to suppress the respiratory defect of cox17-1 cells unlike wild-type SCO1. In addition, the mutants failed to suppress the hydrogen peroxide sensitivity of sco1Delta cells. These studies implicate different surfaces on Sco1 for interaction or function with Cox17 and Cox2. PMID:18390903

Rigby, Kevin; Cobine, Paul A; Khalimonchuk, Oleh; Winge, Dennis R



Ubiquitin-proteasomal degradation of COX-2 in TGF-? stimulated human endometrial cells is mediated through endoplasmic reticulum mannosidase I.  


Cyclooxygenase (COX)-2 is a key regulatory enzyme in the production of prostaglandins (PG) during various physiological processes. Mechanisms of COX-2 regulation in human endometrial stromal cells (human endometrial stromal cells) are not fully understood. In this study, we investigate the role of TGF-? in the regulation of COX-2 in human uterine stromal cells. Each TGF-? isoform decreases COX-2 protein level in human uterine stromal cells in Smad2/3-dependent manner. The decrease in COX-2 is accompanied by a decrease in PG synthesis. Knockdown of Smad4 using specific small interfering RNA prevents the decrease in COX-2 protein, confirming that Smad pathway is implicated in the regulation of COX-2 expression in human endometrial stromal cells. Pretreatment with 26S proteasome inhibitor, MG132, significantly restores COX-2 protein and PG synthesis, indicating that COX-2 undergoes proteasomal degradation in the presence of TGF-?. In addition, each TGF-? isoform up-regulates endoplasmic reticulum (ER)-mannosidase I (ERManI) implying that COX-2 degradation is mediated through ER-associated degradation pathway in these cells. Furthermore, inhibition of ERManI activity using the mannosidase inhibitor (kifunensine), or small interfering RNA-mediated knockdown of ERManI, prevents TGF-?-induced COX-2 degradation. Taken together, these studies suggest that TGF-? promotes COX-2 degradation in a Smad-dependent manner by up-regulating the expression of ERManI and thereby enhancing ER-associated degradation and proteasomal degradation pathways. PMID:22109885

Singh, Mohan; Chaudhry, Parvesh; Parent, Sophie; Asselin, Eric



Extension of Cox Proportional Hazard Model for Estimation of Interrelated Age-Period-Cohort Effects on Cancer Survival  

PubMed Central

In the frame of the Cox proportional hazard (PH) model, a novel two-step procedure for estimating age-period-cohort (APC) effects on the hazard function of death from cancer was developed. In the first step, the procedure estimates the influence of joint APC effects on the hazard function, using Cox PH regression procedures from a standard software package. In the second step, the coefficients for age at diagnosis, time period and birth cohort effects are estimated. To solve the identifiability problem that arises in estimating these coefficients, an assumption that neighboring birth cohorts almost equally affect the hazard function was utilized. Using an anchoring technique, simple procedures for obtaining estimates of interrelated age at diagnosis, time period and birth cohort effect coefficients were developed. As a proof-of-concept these procedures were used to analyze survival data, collected in the SEER database, on white men and women diagnosed with LC in 1975–1999 and the age at diagnosis, time period and birth cohort effect coefficients were estimated. The PH assumption was evaluated by a graphical approach using log-log plots. Analysis of trends of these coefficients suggests that the hazard of death from LC for a given time from cancer diagnosis: (i) decreases between 1975 and 1999; (ii) increases with increasing the age at diagnosis; and (iii) depends upon birth cohort effects. The proposed computing procedure can be used for estimating joint APC effects, as well as interrelated age at diagnosis, time period and birth cohort effects in survival analysis of different types of cancer.

Mdzinarishvili, Tengiz; Gleason, Michael X.; Kinarsky, Leo; Sherman, Simon



Illustrated techniques for performing the Cox-Maze IV procedure through a right mini-thoracotomy.  


The Cox-Maze IV procedure has replaced the "cut-and-sew" technique of the original Cox-Maze operation with lines of ablation created using bipolar radiofrequency (RF) and cryothermal energy devices. In select patients, this procedure can be performed through a right mini-thoracotomy. This illustrated review is the first to detail the complete steps of the Cox-Maze IV procedure performed through a right mini-thoracotomy with careful attention paid to operative anatomy and advice. Pre- and post-operative management and outcomes are also discussed. This should be a practical guide for the practicing cardiac surgeon. PMID:24516807

Robertson, Jason O; Saint, Lindsey L; Leidenfrost, Jeremy E; Damiano, Ralph J



Multiple imputation in quantile regression  

PubMed Central

Summary We propose a multiple imputation estimator for parameter estimation in a quantile regression model when some covariates are missing at random. The estimation procedure fully utilizes the entire dataset to achieve increased efficiency, and the resulting coefficient estimators are root-n consistent and asymptotically normal. To protect against possible model misspecification, we further propose a shrinkage estimator, which automatically adjusts for possible bias. The finite sample performance of our estimator is investigated in a simulation study. Finally, we apply our methodology to part of the Eating at American’s Table Study data, investigating the association between two measures of dietary intake.

Wei, Ying; Ma, Yanyuan; Carroll, Raymond J.



Regression analysis of cytopathological data  

SciTech Connect

Epithelial cells from the human body are frequently labelled according to one of several ordered levels of abnormality, ranging from normal to malignant. The label of the most abnormal cell in a specimen determines the score for the specimen. This paper presents a model for the regression of specimen scores against continuous and discrete variables, as in host exposure to carcinogens. Application to data and tests for adequacy of model fit are illustrated using sputum specimens obtained from a cohort of former asbestos workers.

Whittemore, A.S.; McLarty, J.W.; Fortson, N.; Anderson, K.



A general semiparametric hazards regression model: efficient estimation and structure selection.  


We consider a general semiparametric hazards regression model that encompasses the Cox 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 accelerated 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. PMID:23824784

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



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


(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



Linear regression for face recognition.  


In this paper, we present a novel approach of face identification by formulating the pattern recognition problem in terms of linear regression. Using a fundamental concept that patterns from a single-object class lie on a linear subspace, we develop a linear model representing a probe image as a linear combination of class-specific galleries. The inverse problem is solved using the least-squares method and the decision is ruled in favor of the class with the minimum reconstruction error. The proposed Linear Regression Classification (LRC) algorithm falls in the category of nearest subspace classification. The algorithm is extensively evaluated on several standard databases under a number of exemplary evaluation protocols reported in the face recognition literature. A comparative study with state-of-the-art algorithms clearly reflects the efficacy of the proposed approach. For the problem of contiguous occlusion, we propose a Modular LRC approach, introducing a novel Distance-based Evidence Fusion (DEF) algorithm. The proposed methodology achieves the best results ever reported for the challenging problem of scarf occlusion. PMID:20603520

Naseem, Imran; Togneri, Roberto; Bennamoun, Mohammed



Variable Selection in ROC Regression  

PubMed Central

Regression models are introduced into the receiver operating characteristic (ROC) analysis to accommodate effects of covariates, such as genes. If many covariates are available, the variable selection issue arises. The traditional induced methodology separately models outcomes of diseased and nondiseased groups; thus, separate application of variable selections to two models will bring barriers in interpretation, due to differences in selected models. Furthermore, in the ROC regression, the accuracy of area under the curve (AUC) should be the focus instead of aiming at the consistency of model selection or the good prediction performance. In this paper, we obtain one single objective function with the group SCAD to select grouped variables, which adapts to popular criteria of model selection, and propose a two-stage framework to apply the focused information criterion (FIC). Some asymptotic properties of the proposed methods are derived. Simulation studies show that the grouped variable selection is superior to separate model selections. Furthermore, the FIC improves the accuracy of the estimated AUC compared with other criteria.



Using multivariate adaptive regression splines to estimate subadult age from diaphyseal dimensions.  


Subadult age estimation is considered the most accurate parameter estimated in a subadult biological profile, even though the methods are deficient and the samples from which they are based are inappropriate. The current study addresses the problems that plague subadult age estimation and creates age estimation models from diaphyseal dimensions of modern children. The sample included 1,310 males and females between the ages of birth and 12 years. Eighteen diaphyseal length and breadth measurements were obtained from Lodox Statscan radiographic images generated at two institutions in Cape Town, South Africa, between 2007 and 2012. Univariate and multivariate age estimation models were created using multivariate adaptive regression splines. k-fold cross-validated 95% prediction intervals (PIs) were created for each model, and the precision of each model was assessed. The diaphyseal length models generated the narrowest PIs (2 months to 6 years) for all univariate models. The majority of multivariate models had PIs that ranged from 3 months to 5 and 6 years. Mean bias approximated 0 for each model, but most models lost precision after 10 years of age. Univariate diaphyseal length models are recommended for younger children, whereas multivariate models are recommended for older children where the inclusion of more variables minimized the size of the PIs. If diaphyseal lengths are not available, multivariate breadth models are recommended. The present study provides applicable age estimation formulae and explores the advantages and disadvantages of different subadult age estimation models using diaphyseal dimensions. Am J Phys Anthropol 154:376-386, 2014. © 2014 Wiley Periodicals, Inc. PMID:24782395

Stull, Kyra E; L'Abbé, Ericka N; Ousley, Stephen D



Covariate Measurement Error in Logistic Regression.  

National Technical Information Service (NTIS)

In a logistic regression model when covariates are subject to measurement error the naive estimator, obtained by regressing on the observed covariates, is asymptotically biased. This reprint introduces a bias-adjusted estimator and two estimators appropri...

L. A. Stefanski R. J. Carroll



Efficient methods for estimating constrained parameters with applications to lasso logistic regression  

PubMed Central

Fitting logistic regression models is challenging when their parameters are restricted. In this article, we first develop a quadratic lower-bound (QLB) algorithm for optimization with box or linear inequality constraints and derive the fastest QLB algorithm corresponding to the smallest global majorization matrix. The proposed QLB algorithm is particularly suited to problems to which EM-type algorithms are not applicable (e.g., logistic, multinomial logistic, and Cox’s proportional hazards models) while it retains the same EM ascent property and thus assures the monotonic convergence. Secondly, we generalize the QLB algorithm to penalized problems in which the penalty functions may not be totally differentiable. The proposed method thus provides an alternative algorithm for estimation in lasso logistic regression, where the convergence of the existing lasso algorithm is not generally ensured. Finally, by relaxing the ascent requirement, convergence speed can be further accelerated. We introduce a pseudo-Newton method that retains the simplicity of the QLB algorithm and the fast convergence of the Newton method. Theoretical justification and numerical examples show that the pseudo-Newton method is up to 71 (in terms of CPU time) or 107 (in terms of number of iterations) times faster than the fastest QLB algorithm and thus makes bootstrap variance estimation feasible. Simulations and comparisons are performed and three real examples (Down syndrome data, kyphosis data, and colon microarray data) are analyzed to illustrate the proposed methods.

Tian, Guo-Liang; Tang, Man-Lai; Fang, Hong-Bin; Tan, Ming



GETTING MILES AWAY FROM TERMAN: Did the CRPS Fund Catharine Cox Miles's Unsilenced Psychology of Sex?  

Microsoft Academic Search

Psychologist Catharine Cox Miles (1890–1984) is often remembered as the junior author, with Lewis Terman, of Sex and Personality. Written with support from the Committee for Research on the Problems of Sex (CRPS), Sex and Personality introduced the \\

Peter Hegarty



Indomethacin Analogues that Enhance Doxorubicin Cytotoxicity in Multidrug Resistant Cells without Cox Inhibitory Activity  

PubMed Central

Conformationally restricted indomethacin analogues were designed and prepared from the corresponding 2-substituted indoles, which were synthesized by a one-pot isomerization/enamide-ene metathesis as the key reaction. Conformational analysis by calculations, NMR studies, and X-ray crystallography suggested that these analogues were conformationally restricted in the s-cis or the s-trans form due to the 2-substituent as expected. Their biological activities on cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, and modulation of MRP-1-mediated multidrug resistance (MDR) are described. Some of these indomethacin analogues enhanced doxorubicin cytotoxicity, although they do not have any COX inhibitory activity, which suggests that the MDR-modulating effect of an NSAID can be unassociated with its COX-inhibitory activity. This may be an entry into the combination chemotherapy of doxorubicin with a MDR modulator.



Celebration of the contributions of Art Cox to stellar pulsation interpretations  

SciTech Connect

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.

Castor, J.I.



Effect of COX-2 Inhibitors on the Aromatase Gene (CYP19) Expression in Human Breast Cancer.  

National Technical Information Service (NTIS)

Aromatase (CYP19) is responsible for estrogen biosynthesis, and CYP- 19 and cyclooxygenase-2 (COX-2) are both overexpressed in human breast cancers. Prostaglandin activates the CYP19 promotor and increases gene expression therefore we hypothesized that ce...

C. L. Shapiro



Recent Methodologies toward the Synthesis of Valdecoxib: A Potential 3,4-diarylisoxazolyl COX-2 Inhibitor  

PubMed Central

Non-steroidal anti-inflammatory drugs are widely used therapeutic agents in the treatment of inflammation, pain and fever. Cyclooxygenase catalyzes the initial step of biotransformation of arachidonic acid to prostanoids, and exist as three distinct isozymes; COX-I, COX-II and COX-III. Selective COX-II inhibitors are a class of potential anti-inflammatory, analgesic, and antipyretic drugs with reduced gastrointestinal (GI) side effects compared to nonselective inhibitors. 3,4-diarylisoxazole scaffold is recurrently found in a wide variety of NSAIDs, protein kinase inhibitors, hypertensive agents, and estrogen receptor (ER) modulators. In the present review, we document on the recent synthetic strategies of 3,4-diarylisoxazolyl scaffolds of valdecoxib and its relevant structural analogues.

Dadiboyena, Sureshbabu; Nefzi, Adel



Sparse Kernel Partial Least Squares Regression  

Microsoft Academic Search

\\u000a Partial Least Squares Regression (PLS) and its kernel version (KPLS) have become competitive regression approaches. KPLS performs\\u000a as well as or better than support vector regression (SVR) for moderately-sized problems with the advantages of simple implementation,\\u000a less training cost, and easier tuning of parameters. Unlike SVR, KPLS requires manipulation of the full kernel matrix and\\u000a the resulting regression function requires

Michinari Momma; Kristin P. Bennett



Semiparametric regression during 2003-2007*  

PubMed Central

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.

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



Role of Cyclooxygenase 2 (COX-2) in Prognosis of Breast Cancer.  


COX-2 regulates tumour growth, invasion and metastasis in breast cancer. This study investigated the association between COX-2 expression in human breast cancer versus the expression of ER, PR, HER-2/neu, as well as its association with other established prognostic indicators like age, menopausal status, tumour size, lymph nodal status, stage, grade, NPI and histological subtype, and aims to validate the role of overexpression of COX-2 as a prognostic marker in patients with breast cancer in Indian subcontinent. In this hospital based study of 123 breast cancer patients (Group-A) and 76 female patients with benign breast disease (Group-B) attending a Comprehensive Breast Clinic at a reputed institute in Eastern India, COX-2 protein expression was measured from breast tissue using the Western Blot Technique. COX-2 mRNA expression was measured by RT-PCR Technique. ER, PR and HER-2/neu status was measured by immunohistochemistry methods. COX-2 was not expressed in the control group. The proportion of COX-2 positive tumours was significantly higher in patients of age >50 years [52(91.2 %), p?COX-2 expression was seen in ER-negative [66(95.7 %), p?COX-2 positivity was found to be 2.74 times more for postmenopausal status, 6.90 times more for large size tumours (? 2.5), 34.37 times more for node positive tumours, 9.26 times more with ER negative patients and 5.88 times more for PR negative patients. COX-2 expression is associated with established indicators of poor prognosis such as postmenopausal status, age >50 year, advanced stage of disease, large tumour size, higher grade, lymph node metastasis, NPI???5.4, ER negativity, PR negativity and HER-2/neu positivity. Thus, COX-2 expression implies aggressive tumour biology, and may play an important role as a prognostic marker. PMID:24669166

Jana, Debarshi; Sarkar, Diptendra Kumar; Ganguly, Suvro; Saha, Shilpi; Sa, Gaurisankar; Manna, Asim Kumar; Banerjee, Abhirup; Mandal, Syamsundar