An artificial neural network improves prediction of observed survival in patients with laryngeal squamous carcinoma.

PubMed

Jones, Andrew S; Taktak, Azzam G F; Helliwell, Timothy R; Fenton, John E; Birchall, Martin A; Husband, David J; Fisher, Anthony C

2006-06-01

The accepted method of modelling and predicting failure/survival, Cox's proportional hazards model, is theoretically inferior to neural network derived models for analysing highly complex systems with large datasets. A blinded comparison of the neural network versus the Cox's model in predicting survival utilising data from 873 treated patients with laryngeal cancer. These were divided randomly and equally into a training set and a study set and Cox's and neural network models applied in turn. Data were then divided into seven sets of binary covariates and the analysis repeated. Overall survival was not significantly different on Kaplan-Meier plot, or with either test model. Although the network produced qualitatively similar results to Cox's model it was significantly more sensitive to differences in survival curves for age and N stage. We propose that neural networks are capable of prediction in systems involving complex interactions between variables and non-linearity.

Multi-omics facilitated variable selection in Cox-regression model for cancer prognosis prediction.

PubMed

Liu, Cong; Wang, Xujun; Genchev, Georgi Z; Lu, Hui

2017-07-15

New developments in high-throughput genomic technologies have enabled the measurement of diverse types of omics biomarkers in a cost-efficient and clinically-feasible manner. Developing computational methods and tools for analysis and translation of such genomic data into clinically-relevant information is an ongoing and active area of investigation. For example, several studies have utilized an unsupervised learning framework to cluster patients by integrating omics data. Despite such recent advances, predicting cancer prognosis using integrated omics biomarkers remains a challenge. There is also a shortage of computational tools for predicting cancer prognosis by using supervised learning methods. The current standard approach is to fit a Cox regression model by concatenating the different types of omics data in a linear manner, while penalty could be added for feature selection. A more powerful approach, however, would be to incorporate data by considering relationships among omics datatypes. Here we developed two methods: a SKI-Cox method and a wLASSO-Cox method to incorporate the association among different types of omics data. Both methods fit the Cox proportional hazards model and predict a risk score based on mRNA expression profiles. SKI-Cox borrows the information generated by these additional types of omics data to guide variable selection, while wLASSO-Cox incorporates this information as a penalty factor during model fitting. We show that SKI-Cox and wLASSO-Cox models select more true variables than a LASSO-Cox model in simulation studies. We assess the performance of SKI-Cox and wLASSO-Cox using TCGA glioblastoma multiforme and lung adenocarcinoma data. In each case, mRNA expression, methylation, and copy number variation data are integrated to predict the overall survival time of cancer patients. Our methods achieve better performance in predicting patients' survival in glioblastoma and lung adenocarcinoma. Copyright © 2017. Published by Elsevier Inc.

Validation of Methods to Control for Immortal Time Bias in a Pharmacoepidemiologic Analysis of Renin–Angiotensin System Inhibitors in Type 2 Diabetes

PubMed Central

Yang, Xilin; Kong, Alice PS; Luk, Andrea OY; Ozaki, Risa; Ko, Gary TC; Ma, Ronald CW; Chan, Juliana CN; So, Wing Yee

2014-01-01

Background Pharmacoepidemiologic analysis can confirm whether drug efficacy in a randomized controlled trial (RCT) translates to effectiveness in real settings. We examined methods used to control for immortal time bias in an analysis of renin–angiotensin system (RAS) inhibitors as the reference cardioprotective drug. Methods We analyzed data from 3928 patients with type 2 diabetes who were recruited into the Hong Kong Diabetes Registry between 1996 and 2005 and followed up to July 30, 2005. Different Cox models were used to obtain hazard ratios (HRs) for cardiovascular disease (CVD) associated with RAS inhibitors. These HRs were then compared to the HR of 0.92 reported in a recent meta-analysis of RCTs. Results During a median follow-up period of 5.45 years, 7.23% (n = 284) patients developed CVD and 38.7% (n = 1519) were started on RAS inhibitors, with 39.1% of immortal time among the users. In multivariable analysis, time-dependent drug-exposure Cox models and Cox models that moved immortal time from users to nonusers both severely inflated the HR, and time-fixed models that included immortal time deflated the HR. Use of time-fixed Cox models that excluded immortal time resulted in a HR of only 0.89 (95% CI, 0.68–1.17) for CVD associated with RAS inhibitors, which is closer to the values reported in RCTs. Conclusions In pharmacoepidemiologic analysis, time-dependent drug exposure models and models that move immortal time from users to nonusers may introduce substantial bias in investigations of the effects of RAS inhibitors on CVD in type 2 diabetes. PMID:24747198

The bitter barricading of prostaglandin biosynthesis pathway: understanding the molecular mechanism of selective cyclooxygenase-2 inhibition by amarogentin, a secoiridoid glycoside from Swertia chirayita.

PubMed

Shukla, Shantanu; Bafna, Khushboo; Sundar, Durai; Thorat, Sunil S

2014-01-01

Swertia chirayita, a medicinal herb inhabiting the challenging terrains and high altitudes of the Himalayas, is a rich source of essential phytochemical isolates. Amarogentin, a bitter secoiridoid glycoside from S. chirayita, shows varied activity in several patho-physiological conditions, predominantly in leishmaniasis and carcinogenesis. Experimental analysis has revealed that amarogentin downregulates the cyclooxygenase-2 (COX-2) activity and helps to curtail skin carcinogenesis in mouse models; however, there exists no account on selective inhibition of the inducible cyclooxygenase (COX) isoform by amarogentin. Hence the computer-aided drug discovery methods were used to unravel the COX-2 inhibitory mechanism of amarogentin and to check its selectivity for the inducible isoform over the constitutive one. The generated theoretical models of both isoforms were subjected to molecular docking analysis with amarogentin and twenty-one other Food and Drug Authority (FDA) approved lead molecules. The post-docking binding energy profile of amarogentin was comparable to the binding energy profiles of the FDA approved selective COX-2 inhibitors. Subsequent molecular dynamics simulation analysis delineated the difference in the stability of both complexes, with amarogentin-COX-2 complex being more stable after 40ns simulation. The total binding free energy calculated by MMGBSA for the amarogentin-COX-2 complex was -52.35 KCal/mol against a binding free energy of -8.57 KCal/mol for amarogentin-COX-1 complex, suggesting a possible selective inhibition of the COX-2 protein by the natural inhibitor. Amarogentin achieves this potential selectivity by small, yet significant, structural differences inherent to the binding cavities of the two isoforms. Hypothetically, it might block the entry of the natural substrates in the hydrophobic binding channel of the COX-2, inhibiting the cyclooxygenation step. To sum up briefly, this work highlights the mechanism of the possible selective COX-2 inhibition by amarogentin and endorses the possibility of obtaining efficient, futuristic and targeted therapeutic agents for relieving inflammation and malignancy from this phytochemical source.

Parametric versus Cox's model: an illustrative analysis of divorce in Canada.

PubMed

Balakrishnan, T R; Rao, K V; Krotki, K J; Lapierre-adamcyk, E

1988-06-01

Recent demographic literature clearly recognizes the importance of survival modes in the analysis of cross-sectional event histories. Of the various survival models, Cox's (1972) partial parametric model has been very popular due to its simplicity, and readily available computer software for estimation, sometimes at the cost of precision and parsimony of the model. This paper focuses on parametric failure time models for event history analysis such as Weibell, lognormal, loglogistic, and exponential models. The authors also test the goodness of fit of these parametric models versus the Cox's proportional hazards model taking Kaplan-Meier estimate as base. As an illustration, the authors reanalyze the Canadian Fertility Survey data on 1st marriage dissolution with parametric models. Though these parametric model estimates were not very different from each other, there seemed to be a slightly better fit with loglogistic. When 8 covariates were used in the analysis, it was found that the coefficients were similar in the models, and the overall conclusions about the relative risks would not have been different. The findings reveal that in marriage dissolution, the differences according to demographic and socioeconomic characteristics may be far more important than is generally found in many studies. Therefore, one should not treat the population as homogeneous in analyzing survival probabilities of marriages, other than for cursory analysis of overall trends.

Assessing uncertainty in published risk estimates using ...

EPA Pesticide Factsheets

Introduction: The National Research Council recommended quantitative evaluation of uncertainty in effect estimates for risk assessment. This analysis considers uncertainty across model forms and model parameterizations with hexavalent chromium [Cr(VI)] and lung cancer mortality as an example. The objective is to characterize model uncertainty by evaluating estimates across published epidemiologic studies of the same cohort.Methods: This analysis was based on 5 studies analyzing a cohort of 2,357 workers employed from 1950-74 in a chromate production plant in Maryland. Cox and Poisson models were the only model forms considered by study authors to assess the effect of Cr(VI) on lung cancer mortality. All models adjusted for smoking and included a 5-year exposure lag, however other latency periods and model covariates such as age and race were considered. Published effect estimates were standardized to the same units and normalized by their variances to produce a standardized metric to compare variability within and between model forms. A total of 5 similarly parameterized analyses were considered across model form, and 16 analyses with alternative parameterizations were considered within model form (10 Cox; 6 Poisson). Results: Across Cox and Poisson model forms, adjusted cumulative exposure coefficients (betas) for 5 similar analyses ranged from 2.47 to 4.33 (mean=2.97, σ2=0.63). Within the 10 Cox models, coefficients ranged from 2.53 to 4.42 (mean=3.29, σ2=0.

Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain

PubMed Central

Wang, Xiao-Min; Wu, Tian-Xia; Hamza, May; Ramsay, Edward S.; Wahl, Sharon M.; Dionne, Raymond A.

2007-01-01

New insights into the biological properties of cyclooxygenase-2 (COX-2) and its response pathway challenge the hypothesis that COX-2 is simply pro-inflammatory and inhibition of COX-2 solely prevents the development of inflammation and ameliorates inflammatory pain. The present study performed a comprehensive analysis of gene/protein expression induced by a selective inhibitor of COX-2, rofecoxib, compared with a non-selective COX inhibitor, ibuprofen, and placebo in a clinical model of acute inflammatory pain (the surgical extraction of impacted third molars) using microarray analysis followed by quantitative RT-PCR verification and Western blotting. Inhibition of COX-2 modulated gene expression related to inflammation and pain, the arachidonic acid pathway, apoptosis/angiogenesis, cell adhesion and signal transduction. Compared to placebo, rofecoxib treatment increased the gene expression of ANXA3 (annexin 3), SOD2 (superoxide dismutase 2), SOCS3 (suppressor of cytokine signaling 3) and IL1RN (IL1 receptor antagonist) which are associated with inhibition of phospholipase A2 and suppression of cytokine signaling cascades, respectively. Both rofecoxib and ibuprofen treatment increased the gene expression of the pro-inflammatory mediators, IL6 and CCL2 (chemokine C-C motif ligand 2), following tissue injury compared to the placebo treatment. These results indicate a complex role for COX-2 in the inflammatory cascade in addition to the well-characterized COX-dependent pathway, as multiple pathways are also involved in rofecoxib-induced anti-inflammatory and analgesic effects at the gene expression level. These findings may also suggest an alternative hypothesis for the adverse effects attributed to selective inhibition of COX-2. PMID:17070997

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

PubMed

Parzen, M; Lipsitz, S R

1999-06-01

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

A random effects meta-analysis model with Box-Cox transformation.

PubMed

Yamaguchi, Yusuke; Maruo, Kazushi; Partlett, Christopher; Riley, Richard D

2017-07-19

In a random effects meta-analysis model, true treatment effects for each study are routinely assumed to follow a normal distribution. However, normality is a restrictive assumption and the misspecification of the random effects distribution may result in a misleading estimate of overall mean for the treatment effect, an inappropriate quantification of heterogeneity across studies and a wrongly symmetric prediction interval. We focus on problems caused by an inappropriate normality assumption of the random effects distribution, and propose a novel random effects meta-analysis model where a Box-Cox transformation is applied to the observed treatment effect estimates. The proposed model aims to normalise an overall distribution of observed treatment effect estimates, which is sum of the within-study sampling distributions and the random effects distribution. When sampling distributions are approximately normal, non-normality in the overall distribution will be mainly due to the random effects distribution, especially when the between-study variation is large relative to the within-study variation. The Box-Cox transformation addresses this flexibly according to the observed departure from normality. We use a Bayesian approach for estimating parameters in the proposed model, and suggest summarising the meta-analysis results by an overall median, an interquartile range and a prediction interval. The model can be applied for any kind of variables once the treatment effect estimate is defined from the variable. A simulation study suggested that when the overall distribution of treatment effect estimates are skewed, the overall mean and conventional I 2 from the normal random effects model could be inappropriate summaries, and the proposed model helped reduce this issue. We illustrated the proposed model using two examples, which revealed some important differences on summary results, heterogeneity measures and prediction intervals from the normal random effects model. The random effects meta-analysis with the Box-Cox transformation may be an important tool for examining robustness of traditional meta-analysis results against skewness on the observed treatment effect estimates. Further critical evaluation of the method is needed.

Semi-parametric regression model for survival data: graphical visualization with R

PubMed Central

2016-01-01

Cox proportional hazards model is a semi-parametric model that leaves its baseline hazard function unspecified. The rationale to use Cox proportional hazards model is that (I) the underlying form of hazard function is stringent and unrealistic, and (II) researchers are only interested in estimation of how the hazard changes with covariate (relative hazard). Cox regression model can be easily fit with coxph() function in survival package. Stratified Cox model may be used for covariate that violates the proportional hazards assumption. The relative importance of covariates in population can be examined with the rankhazard package in R. Hazard ratio curves for continuous covariates can be visualized using smoothHR package. This curve helps to better understand the effects that each continuous covariate has on the outcome. Population attributable fraction is a classic quantity in epidemiology to evaluate the impact of risk factor on the occurrence of event in the population. In survival analysis, the adjusted/unadjusted attributable fraction can be plotted against survival time to obtain attributable fraction function. PMID:28090517

Coastal Storm Surge Analysis: Modeling System Validation. Report 4: Intermediate Submission No. 2.0

DTIC Science & Technology

2013-07-01

Oceanweather Vince Cardone Andrew Cox Wind Field Reconstructions Renaissance Computing Institute (RENCI) Brian Blanton Lisa Stillwell Kevin...Greenwood, V. J. Cardone , and V. R. Swail. 1995. An interactive objective kinematic analysis system. In Proceedings of the 4th International Workshop...A. Cox, V. Cardone , J. Hanson, and B. Blanton. Coastal storm surge analysis: Storm forcing, Submittal 1.3 to FEMA. In preparation. Vicksburg, MS

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

PubMed Central

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

2014-01-01

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

Assessing model uncertainty using hexavalent chromium and ...

EPA Pesticide Factsheets

Introduction: The National Research Council recommended quantitative evaluation of uncertainty in effect estimates for risk assessment. This analysis considers uncertainty across model forms and model parameterizations with hexavalent chromium [Cr(VI)] and lung cancer mortality as an example. The objective of this analysis is to characterize model uncertainty by evaluating the variance in estimates across several epidemiologic analyses.Methods: This analysis compared 7 publications analyzing two different chromate production sites in Ohio and Maryland. The Ohio cohort consisted of 482 workers employed from 1940-72, while the Maryland site employed 2,357 workers from 1950-74. Cox and Poisson models were the only model forms considered by study authors to assess the effect of Cr(VI) on lung cancer mortality. All models adjusted for smoking and included a 5-year exposure lag, however other latency periods and model covariates such as age and race were considered. Published effect estimates were standardized to the same units and normalized by their variances to produce a standardized metric to compare variability in estimates across and within model forms. A total of 7 similarly parameterized analyses were considered across model forms, and 23 analyses with alternative parameterizations were considered within model form (14 Cox; 9 Poisson). Results: Across Cox and Poisson model forms, adjusted cumulative exposure coefficients for 7 similar analyses ranged from 2.47

The Bitter Barricading of Prostaglandin Biosynthesis Pathway: Understanding the Molecular Mechanism of Selective Cyclooxygenase-2 Inhibition by Amarogentin, a Secoiridoid Glycoside from Swertia chirayita

PubMed Central

Sundar, Durai; Thorat, Sunil S.

2014-01-01

Swertia chirayita, a medicinal herb inhabiting the challenging terrains and high altitudes of the Himalayas, is a rich source of essential phytochemical isolates. Amarogentin, a bitter secoiridoid glycoside from S. chirayita, shows varied activity in several patho-physiological conditions, predominantly in leishmaniasis and carcinogenesis. Experimental analysis has revealed that amarogentin downregulates the cyclooxygenase-2 (COX-2) activity and helps to curtail skin carcinogenesis in mouse models; however, there exists no account on selective inhibition of the inducible cyclooxygenase (COX) isoform by amarogentin. Hence the computer-aided drug discovery methods were used to unravel the COX-2 inhibitory mechanism of amarogentin and to check its selectivity for the inducible isoform over the constitutive one. The generated theoretical models of both isoforms were subjected to molecular docking analysis with amarogentin and twenty-one other Food and Drug Authority (FDA) approved lead molecules. The post-docking binding energy profile of amarogentin was comparable to the binding energy profiles of the FDA approved selective COX-2 inhibitors. Subsequent molecular dynamics simulation analysis delineated the difference in the stability of both complexes, with amarogentin-COX-2 complex being more stable after 40ns simulation. The total binding free energy calculated by MMGBSA for the amarogentin-COX-2 complex was −52.35 KCal/mol against a binding free energy of −8.57 KCal/mol for amarogentin-COX-1 complex, suggesting a possible selective inhibition of the COX-2 protein by the natural inhibitor. Amarogentin achieves this potential selectivity by small, yet significant, structural differences inherent to the binding cavities of the two isoforms. Hypothetically, it might block the entry of the natural substrates in the hydrophobic binding channel of the COX-2, inhibiting the cyclooxygenation step. To sum up briefly, this work highlights the mechanism of the possible selective COX-2 inhibition by amarogentin and endorses the possibility of obtaining efficient, futuristic and targeted therapeutic agents for relieving inflammation and malignancy from this phytochemical source. PMID:24603686

Parametric Model Based On Imputations Techniques for Partly Interval Censored Data

NASA Astrophysics Data System (ADS)

Zyoud, Abdallah; Elfaki, F. A. M.; Hrairi, Meftah

2017-12-01

The term ‘survival analysis’ has been used in a broad sense to describe collection of statistical procedures for data analysis. In this case, outcome variable of interest is time until an event occurs where the time to failure of a specific experimental unit might be censored which can be right, left, interval, and Partly Interval Censored data (PIC). In this paper, analysis of this model was conducted based on parametric Cox model via PIC data. Moreover, several imputation techniques were used, which are: midpoint, left & right point, random, mean, and median. Maximum likelihood estimate was considered to obtain the estimated survival function. These estimations were then compared with the existing model, such as: Turnbull and Cox model based on clinical trial data (breast cancer data), for which it showed the validity of the proposed model. Result of data set indicated that the parametric of Cox model proved to be more superior in terms of estimation of survival functions, likelihood ratio tests, and their P-values. Moreover, based on imputation techniques; the midpoint, random, mean, and median showed better results with respect to the estimation of survival function.

Applying Additive Hazards Models for Analyzing Survival in Patients with Colorectal Cancer in Fars Province, Southern Iran

PubMed

Madadizadeh, Farzan; Ghanbarnejad, Amin; Ghavami, Vahid; Zare Bandamiri, Mohammad; Mohammadianpanah, Mohammad

2017-04-01

Introduction: Colorectal cancer (CRC) is a commonly fatal cancer that ranks as third worldwide and third and the fifth in Iranian women and men, respectively. There are several methods for analyzing time to event data. Additive hazards regression models take priority over the popular Cox proportional hazards model if the absolute hazard (risk) change instead of hazard ratio is of primary concern, or a proportionality assumption is not made. Methods: This study used data gathered from medical records of 561 colorectal cancer patients who were admitted to Namazi Hospital, Shiraz, Iran, during 2005 to 2010 and followed until December 2015. The nonparametric Aalen’s additive hazards model, semiparametric Lin and Ying’s additive hazards model and Cox proportional hazards model were applied for data analysis. The proportionality assumption for the Cox model was evaluated with a test based on the Schoenfeld residuals and for test goodness of fit in additive models, Cox-Snell residual plots were used. Analyses were performed with SAS 9.2 and R3.2 software. Results: The median follow-up time was 49 months. The five-year survival rate and the mean survival time after cancer diagnosis were 59.6% and 68.1±1.4 months, respectively. Multivariate analyses using Lin and Ying’s additive model and the Cox proportional model indicated that the age of diagnosis, site of tumor, stage, and proportion of positive lymph nodes, lymphovascular invasion and type of treatment were factors affecting survival of the CRC patients. Conclusion: Additive models are suitable alternatives to the Cox proportionality model if there is interest in evaluation of absolute hazard change, or no proportionality assumption is made. Creative Commons Attribution License

Comparison of Weibull and Lognormal Cure Models with Cox in the Survival Analysis Of Breast Cancer Patients in Rafsanjan.

PubMed

Hoseini, Mina; Bahrampour, Abbas; Mirzaee, Moghaddameh

2017-02-16

Breast cancer is the most common cancer after lung cancer and the second cause of death. In this study we compared Weibull and Lognormal Cure Models with Cox regression on the survival of breast cancer. A cohort study. The current study retrospective cohort study was conducted on 140 patients referred to Ali Ibn Abitaleb Hospital, Rafsanjan southeastern Iran from 2001 to 2015 suffering from breast cancer. We determined and analyzed the effective survival causes by different models using STATA14. According to AIC, log-normal model was more consistent than Weibull. In the multivariable Lognormal model, the effective factors like smoking, second -hand smoking, drinking herbal tea and the last breast-feeding period were included. In addition, using Cox regression factors of significant were the disease grade, size of tumor and its metastasis (p-value<0.05). As Rafsanjan is surrounded by pistachio orchards and pesticides applied by farmers, people of this city are exposed to agricultural pesticides and its harmful consequences. The effect of the pesticide on breast cancer was studied and the results showed that the effect of pesticides on breast cancer was not in agreement with the models used in this study. Based on different methods for survival analysis, researchers can decide how they can reach a better conclusion. This comparison indicates the result of semi-parametric Cox method is closer to clinical experiences evidences.

Box-Cox transformation of left-censored data with application to the analysis of coronary artery calcification and pharmacokinetic data.

PubMed

Han, Cong; Kronmal, Richard

2004-12-15

Box-Cox transformation is investigated for regression models for left-censored data. Examples are provided using coronary calcification data from the Multi-Ethnic Study of Atherosclerosis and pharmacokinetic data of a nicotine nasal spray. Copyright 2004 John Wiley & Sons, Ltd.

NCC-AUC: an AUC optimization method to identify multi-biomarker panel for cancer prognosis from genomic and clinical data.

PubMed

Zou, Meng; Liu, Zhaoqi; Zhang, Xiang-Sun; Wang, Yong

2015-10-15

In prognosis and survival studies, an important goal is to identify multi-biomarker panels with predictive power using molecular characteristics or clinical observations. Such analysis is often challenged by censored, small-sample-size, but high-dimensional genomic profiles or clinical data. Therefore, sophisticated models and algorithms are in pressing need. In this study, we propose a novel Area Under Curve (AUC) optimization method for multi-biomarker panel identification named Nearest Centroid Classifier for AUC optimization (NCC-AUC). Our method is motived by the connection between AUC score for classification accuracy evaluation and Harrell's concordance index in survival analysis. This connection allows us to convert the survival time regression problem to a binary classification problem. Then an optimization model is formulated to directly maximize AUC and meanwhile minimize the number of selected features to construct a predictor in the nearest centroid classifier framework. NCC-AUC shows its great performance by validating both in genomic data of breast cancer and clinical data of stage IB Non-Small-Cell Lung Cancer (NSCLC). For the genomic data, NCC-AUC outperforms Support Vector Machine (SVM) and Support Vector Machine-based Recursive Feature Elimination (SVM-RFE) in classification accuracy. It tends to select a multi-biomarker panel with low average redundancy and enriched biological meanings. Also NCC-AUC is more significant in separation of low and high risk cohorts than widely used Cox model (Cox proportional-hazards regression model) and L1-Cox model (L1 penalized in Cox model). These performance gains of NCC-AUC are quite robust across 5 subtypes of breast cancer. Further in an independent clinical data, NCC-AUC outperforms SVM and SVM-RFE in predictive accuracy and is consistently better than Cox model and L1-Cox model in grouping patients into high and low risk categories. In summary, NCC-AUC provides a rigorous optimization framework to systematically reveal multi-biomarker panel from genomic and clinical data. It can serve as a useful tool to identify prognostic biomarkers for survival analysis. NCC-AUC is available at http://doc.aporc.org/wiki/NCC-AUC. ywang@amss.ac.cn Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Big Data Toolsets to Pharmacometrics: Application of Machine Learning for Time‐to‐Event Analysis

PubMed Central

Gong, Xiajing; Hu, Meng

2018-01-01

Abstract Additional value can be potentially created by applying big data tools to address pharmacometric problems. The performances of machine learning (ML) methods and the Cox regression model were evaluated based on simulated time‐to‐event data synthesized under various preset scenarios, i.e., with linear vs. nonlinear and dependent vs. independent predictors in the proportional hazard function, or with high‐dimensional data featured by a large number of predictor variables. Our results showed that ML‐based methods outperformed the Cox model in prediction performance as assessed by concordance index and in identifying the preset influential variables for high‐dimensional data. The prediction performances of ML‐based methods are also less sensitive to data size and censoring rates than the Cox regression model. In conclusion, ML‐based methods provide a powerful tool for time‐to‐event analysis, with a built‐in capacity for high‐dimensional data and better performance when the predictor variables assume nonlinear relationships in the hazard function. PMID:29536640

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

NASA Astrophysics Data System (ADS)

Freni, Gabriele; Mannina, Giorgio

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

[Comparison of the Cost-Effectiveness of the SOX and COX Regimens in Patients with Unresectable Advanced and Recurrent Colorectal Cancer Using a Clinical Decision Analysis Approach].

PubMed

Nagase, Satoshi; Iyoda, Tomokazu; Kanno, Hiroshi; Akase, Tomohide; Arakawa, Ichiro; Inoue, Tadao; Uetsuka, Yoshio

2016-10-01

Phase III clinical trials have comfirmed that the S-1 plus oxaliplatin(SOX)is inferior to the capecitabine plus oxaliplatin (COX)regimen in the treatment of metastatic colorectal cancer.On the basis of these findings, we compared, using a clinical decision analysis-based approach, the cost-effectiveness of the SOX and COX regimens.Herein, we simulated the expected effects and costs of the SOX and COX regimens using the markov model.Clinical data were obtained from Hong's 2012 report.The cost data comprised the costs for pharmacist labor, material, inspection, and treatment for adverse event, as well as the total cost of care at the advanced stage.The result showed that the expected cost of the SOX and COX regimen was 1,538,330 yen, and 1,429,596 yen, respectively, with an expected survival rate of 29.18 months, and 28.63 months, respectively.The incremental cost-effectiveness ratio of the SOX regimen was 197,698 yen/month; thus, the SOX regimen was found to be more cost-effective that the COX regimen.

In Vivo Physiological Experiments in the Random Positioning Macine: A Study on the Rat Intestinal Transit

NASA Astrophysics Data System (ADS)

Peana, A. T.; Marzocco, S.; Bianco, G.; Autore, G.; Pinto, A.; Pippia, P.

2008-06-01

The aim of this work is to evaluate the rat intestinal transit as well as the expression of enzymes involved in this process and in gastrointestinal homeostasis as ciclooxygenase (COX-1 and COX-2), the inducibile isoform of nitric oxide synthase (iNOS), ICAM-1 and heat shock proteins HSP70 and HSP90. The modeled microgravity conditions were performed utilizing a three-dimensional clinostat, the Random Positioning Machine (RPM). Our results indicate that modeled microgravity significantly reduce rat intestinal transit. Western blot analysis on small intestine tissues of RPM rats reveals a significant increase in iNOS expression, a significant reduction in COX-2 levels, while COX-1 expression remains unaltered, and a significant increase in ICAM-1 and HSP 70 expression. Also a significant increase in HSP 90 stomach expression indicates a strong effect of simulated low g on gastrointestinal homeostasis.

Using Cox's proportional hazards model for prognostication in carcinoma of the upper aero-digestive tract.

PubMed

Wolfensberger, M

1992-01-01

One of the major short comings of the traditional TNM system is its limited potential for prognostication. With the development of multifactorial analysis techniques, such as Cox's proportional hazards model, it has become possible to simultaneously evaluate a large number of prognostic variables. Cox's model allows both the identification of prognostically relevant variables and the quantification of their prognostic influence. These characteristics make it a helpful tool for analysis as well as for prognostication. The goal of the present study was to develop a prognostic index for patients with carcinoma of the upper aero-digestive tract which makes use of all prognostically relevant variables. To accomplish this, the survival data of 800 patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx were analyzed. Sixty-one variables were screened for prognostic significance; of these only 19 variables (including age, tumor location, T, N and M stages, resection margins, capsular invasion of nodal metastases, and treatment modality) were found to significantly correlate with prognosis. With the help of Cox's equation, a prognostic index (PI) was computed for every combination of prognostic factors. To test the proposed model, the prognostic index was applied to 120 patients with carcinoma of the oral cavity or oropharynx. A comparison of predicted and observed survival showed good overall correlation, although actual survival tended to be better than predicted.

Assessing household health expenditure with Box-Cox censoring models.

PubMed

Chaze, Jean-Paul

2005-09-01

In order to assess the combined presence of zero expenditures and a heavily skewed distribution of positive expenditures, the Box-Cox transformation with location parameter is used to define a set of models generalising the standard Tobit, Heckman selection and double-hurdle models. Extended flexibility with respect to previous specifications is introduced, notably regarding negative transformation parameters, which may prove necessary for medical expenditures, and corner-solution outcomes. An illustration is provided by the analysis of household health expenditure in Switzerland. Copyright (c) 2005 John Wiley & Sons, Ltd.

Flexible modeling improves assessment of prognostic value of C-reactive protein in advanced non-small cell lung cancer.

PubMed

Gagnon, B; Abrahamowicz, M; Xiao, Y; Beauchamp, M-E; MacDonald, N; Kasymjanova, G; Kreisman, H; Small, D

2010-03-30

C-reactive protein (CRP) is gaining credibility as a prognostic factor in different cancers. Cox's proportional hazard (PH) model is usually used to assess prognostic factors. However, this model imposes a priori assumptions, which are rarely tested, that (1) the hazard ratio associated with each prognostic factor remains constant across the follow-up (PH assumption) and (2) the relationship between a continuous predictor and the logarithm of the mortality hazard is linear (linearity assumption). We tested these two assumptions of the Cox's PH model for CRP, using a flexible statistical model, while adjusting for other known prognostic factors, in a cohort of 269 patients newly diagnosed with non-small cell lung cancer (NSCLC). In the Cox's PH model, high CRP increased the risk of death (HR=1.11 per each doubling of CRP value, 95% CI: 1.03-1.20, P=0.008). However, both the PH assumption (P=0.033) and the linearity assumption (P=0.015) were rejected for CRP, measured at the initiation of chemotherapy, which kept its prognostic value for approximately 18 months. Our analysis shows that flexible modeling provides new insights regarding the value of CRP as a prognostic factor in NSCLC and that Cox's PH model underestimates early risks associated with high CRP.

Evaluating cardiovascular mortality in type 2 diabetes patients: an analysis based on competing risks Markov chains and additive regression models.

PubMed

Rosato, Rosalba; Ciccone, G; Bo, S; Pagano, G F; Merletti, F; Gregori, D

2007-06-01

Type 2 diabetes represents a condition significantly associated with increased cardiovascular mortality. The aims of the study are: (i) to estimate the cumulative incidence function for cause-specific mortality using Cox and Aalen model; (ii) to describe how the prediction of cardiovascular or other causes mortality changes for patients with different pattern of covariates; (iii) to show if different statistical methods may give different results. Cox and Aalen additive regression model through the Markov chain approach, are used to estimate the cause-specific hazard for cardiovascular or other causes mortality in a cohort of 2865 type 2 diabetic patients without insulin treatment. The models are compared in the estimation of the risk of death for patients of different severity. For younger patients with a better covariates profile, the Cumulative Incidence Function estimated by Cox and Aalen model was almost the same; for patients with the worst covariates profile, models gave different results: at the end of follow-up cardiovascular mortality rate estimated by Cox and Aalen model was 0.26 [95% confidence interval (CI) = 0.21-0.31] and 0.14 (95% CI = 0.09-0.18). Standard Cox and Aalen model capture the risk process for patients equally well with average profiles of co-morbidities. The Aalen model, in addition, is shown to be better at identifying cause-specific risk of death for patients with more severe clinical profiles. This result is relevant in the development of analytic tools for research and resource management within diabetes care.

Survival in Patients with Advanced Non-cystic Fibrosis Bronchiectasis Versus Cystic Fibrosis on the Waitlist for Lung Transplantation.

PubMed

Hayes, Don; Kopp, Benjamin T; Tobias, Joseph D; Woodley, Frederick W; Mansour, Heidi M; Tumin, Dmitry; Kirkby, Stephen E

2015-12-01

Survival in non-cystic fibrosis (CF) bronchiectasis is not well studied. The United Network for Organ Sharing database was queried from 1987 to 2013 to compare survival in adult patients with non-CF bronchiectasis to patients with CF listed for lung transplantation (LTx). Each subject was tracked from waitlist entry date until death or censoring to determine survival differences between the two groups. Of 2112 listed lung transplant candidates with bronchiectasis (180 non-CF, 1932 CF), 1617 were used for univariate Cox and Kaplan-Meier survival function analysis, 1173 for multivariate Cox models, and 182 for matched-pairs analysis based on propensity scores. Compared to CF, patients with non-CF bronchiectasis had a significantly lower mortality by univariate Cox analysis (HR 0.565; 95 % CI 0.424, 0.754; p < 0.001). Adjusting for potential confounders, multivariate Cox models identified a significant reduction in risk for death associated with non-CF bronchiectasis who were lung transplant candidates (HR 0.684; 95 % CI 0.475, 0.985; p = 0.041). Results were consistent in multivariate models adjusting for pulmonary hypertension and forced expiratory volume in one second. Non-CF bronchiectasis with advanced lung disease was associated with significantly lower mortality hazard compared to CF bronchiectasis on the waitlist for LTx. Separate referral and listing criteria for LTx in non-CF and CF populations should be considered.

The Breslow estimator of the nonparametric baseline survivor function in Cox's regression model: some heuristics.

PubMed

Hanley, James A

2008-01-01

Most survival analysis textbooks explain how the hazard ratio parameters in Cox's life table regression model are estimated. Fewer explain how the components of the nonparametric baseline survivor function are derived. Those that do often relegate the explanation to an "advanced" section and merely present the components as algebraic or iterative solutions to estimating equations. None comment on the structure of these estimators. This note brings out a heuristic representation that may help to de-mystify the structure.

A maximum pseudo-profile likelihood estimator for the Cox model under length-biased sampling

PubMed Central

Huang, Chiung-Yu; Qin, Jing; Follmann, Dean A.

2012-01-01

This paper considers semiparametric estimation of the Cox proportional hazards model for right-censored and length-biased data arising from prevalent sampling. To exploit the special structure of length-biased sampling, we propose a maximum pseudo-profile likelihood estimator, which can handle time-dependent covariates and is consistent under covariate-dependent censoring. Simulation studies show that the proposed estimator is more efficient than its competitors. A data analysis illustrates the methods and theory. PMID:23843659

Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation.

PubMed

Badie, Behnam; Schartner, Jill M; Hagar, Aaron R; Prabakaran, Sakthivel; Peebles, Todd R; Bartley, Becky; Lapsiwala, Samir; Resnick, Daniel K; Vorpahl, Jessica

2003-02-01

Cerebral edema is responsible for significant morbidity and mortality in patients harboring malignant gliomas. To examine the role of inflammatory cells in brain edema formation, we studied the expression cyclooxygenase (COX)-2, a key enzyme in arachidonic acid metabolism, by microglia in the C6 rodent glioma model. The expression of COX-2 in primary microglia cultures obtained from intracranial rat C6 gliomas was examined using reverse transcription-PCR, Western analysis, and prostaglandin E(2) (PGE(2)) enzyme immunoassay. Blood-tumor barrier permeability was studied in the same tumor model using magnetic resonance imaging. In contrast to C6 glioma cells, microglia isolated from intracranial C6 tumors produced high levels of PGE(2) through a COX-2-dependent pathway. To test whether the observed microglia COX-2 activity played a role in brain edema formation in gliomas, tumor-bearing rats were treated with rofecoxib, a selective COX-2 inhibitor. Rofecoxib was as effective as dexamethasone in decreasing the diffusion of contrast material into the brain parenchyma (P = 0.01, rofecoxib versus control animals), suggesting a reduction in blood-tumor barrier permeability. These findings suggest that glioma-infiltrating microglia are a major source of PGE(2) production through the COX-2 pathway and support the use of COX-2 inhibitors as possible alternatives to glucocorticoids in the treatment of peritumoral edema in patients with malignant brain tumors.

Cyclooxygenase-2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents.

PubMed

Lin, Chun-Kuang; Tseng, Chin-Kai; Wu, Yu-Hsuan; Liaw, Chih-Chuang; Lin, Chun-Yu; Huang, Chung-Hao; Chen, Yen-Hsu; Lee, Jin-Ching

2017-03-20

Cyclooxygenase-2 (COX-2) is one of the important mediators of inflammation in response to viral infection, and it contributes to viral replication, for example, cytomegalovirus or hepatitis C virus replication. The role of COX-2 in dengue virus (DENV) replication remains unclear. In the present study, we observed an increased level of COX-2 in patients with dengue fever compared with healthy donors. Consistent with the clinical data, an elevated level of COX-2 expression was also observed in DENV-infected ICR suckling mice. Using cell-based experiments, we revealed that DENV-2 infection significantly induced COX-2 expression and prostaglandin E 2 (PGE 2 ) production in human hepatoma Huh-7 cells. The exogenous expression of COX-2 or PGE 2 treatment dose-dependently enhanced DENV-2 replication. In contrast, COX-2 gene silencing and catalytic inhibition sufficiently suppressed DENV-2 replication. In an ICR suckling mouse model, we identified that the COX-2 inhibitor NS398 protected mice from succumbing to life-threatening DENV-2 infection. By using COX-2 promoter-based analysis and specific inhibitors against signaling molecules, we identified that NF-κB and MAPK/JNK are critical factors for DENV-2-induced COX-2 expression and viral replication. Altogether, our results reveal that COX-2 is an important factor for DENV replication and can serve as a potential target for developing therapeutic agents against DENV infection.

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

PubMed Central

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

2015-01-01

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

Flexible mixture modeling via the multivariate t distribution with the Box-Cox transformation: an alternative to the skew-t distribution

PubMed Central

Lo, Kenneth

2011-01-01

Cluster analysis is the automated search for groups of homogeneous observations in a data set. A popular modeling approach for clustering is based on finite normal mixture models, which assume that each cluster is modeled as a multivariate normal distribution. However, the normality assumption that each component is symmetric is often unrealistic. Furthermore, normal mixture models are not robust against outliers; they often require extra components for modeling outliers and/or give a poor representation of the data. To address these issues, we propose a new class of distributions, multivariate t distributions with the Box-Cox transformation, for mixture modeling. This class of distributions generalizes the normal distribution with the more heavy-tailed t distribution, and introduces skewness via the Box-Cox transformation. As a result, this provides a unified framework to simultaneously handle outlier identification and data transformation, two interrelated issues. We describe an Expectation-Maximization algorithm for parameter estimation along with transformation selection. We demonstrate the proposed methodology with three real data sets and simulation studies. Compared with a wealth of approaches including the skew-t mixture model, the proposed t mixture model with the Box-Cox transformation performs favorably in terms of accuracy in the assignment of observations, robustness against model misspecification, and selection of the number of components. PMID:22125375

Flexible mixture modeling via the multivariate t distribution with the Box-Cox transformation: an alternative to the skew-t distribution.

PubMed

Lo, Kenneth; Gottardo, Raphael

2012-01-01

Cluster analysis is the automated search for groups of homogeneous observations in a data set. A popular modeling approach for clustering is based on finite normal mixture models, which assume that each cluster is modeled as a multivariate normal distribution. However, the normality assumption that each component is symmetric is often unrealistic. Furthermore, normal mixture models are not robust against outliers; they often require extra components for modeling outliers and/or give a poor representation of the data. To address these issues, we propose a new class of distributions, multivariate t distributions with the Box-Cox transformation, for mixture modeling. This class of distributions generalizes the normal distribution with the more heavy-tailed t distribution, and introduces skewness via the Box-Cox transformation. As a result, this provides a unified framework to simultaneously handle outlier identification and data transformation, two interrelated issues. We describe an Expectation-Maximization algorithm for parameter estimation along with transformation selection. We demonstrate the proposed methodology with three real data sets and simulation studies. Compared with a wealth of approaches including the skew-t mixture model, the proposed t mixture model with the Box-Cox transformation performs favorably in terms of accuracy in the assignment of observations, robustness against model misspecification, and selection of the number of components.

Network regularised Cox regression and multiplex network models to predict disease comorbidities and survival of cancer.

PubMed

Xu, Haoming; Moni, Mohammad Ali; Liò, Pietro

2015-12-01

In cancer genomics, gene expression levels provide important molecular signatures for all types of cancer, and this could be very useful for predicting the survival of cancer patients. However, the main challenge of gene expression data analysis is high dimensionality, and microarray is characterised by few number of samples with large number of genes. To overcome this problem, a variety of penalised Cox proportional hazard models have been proposed. We introduce a novel network regularised Cox proportional hazard model and a novel multiplex network model to measure the disease comorbidities and to predict survival of the cancer patient. Our methods are applied to analyse seven microarray cancer gene expression datasets: breast cancer, ovarian cancer, lung cancer, liver cancer, renal cancer and osteosarcoma. Firstly, we applied a principal component analysis to reduce the dimensionality of original gene expression data. Secondly, we applied a network regularised Cox regression model on the reduced gene expression datasets. By using normalised mutual information method and multiplex network model, we predict the comorbidities for the liver cancer based on the integration of diverse set of omics and clinical data, and we find the diseasome associations (disease-gene association) among different cancers based on the identified common significant genes. Finally, we evaluated the precision of the approach with respect to the accuracy of survival prediction using ROC curves. We report that colon cancer, liver cancer and renal cancer share the CXCL5 gene, and breast cancer, ovarian cancer and renal cancer share the CCND2 gene. Our methods are useful to predict survival of the patient and disease comorbidities more accurately and helpful for improvement of the care of patients with comorbidity. Software in Matlab and R is available on our GitHub page: https://github.com/ssnhcom/NetworkRegularisedCox.git. Copyright © 2015. Published by Elsevier Ltd.

Statistical modelling for recurrent events: an application to sports injuries

PubMed Central

Ullah, Shahid; Gabbett, Tim J; Finch, Caroline F

2014-01-01

Background Injuries are often recurrent, with subsequent injuries influenced by previous occurrences and hence correlation between events needs to be taken into account when analysing such data. Objective This paper compares five different survival models (Cox proportional hazards (CoxPH) model and the following generalisations to recurrent event data: Andersen-Gill (A-G), frailty, Wei-Lin-Weissfeld total time (WLW-TT) marginal, Prentice-Williams-Peterson gap time (PWP-GT) conditional models) for the analysis of recurrent injury data. Methods Empirical evaluation and comparison of different models were performed using model selection criteria and goodness-of-fit statistics. Simulation studies assessed the size and power of each model fit. Results The modelling approach is demonstrated through direct application to Australian National Rugby League recurrent injury data collected over the 2008 playing season. Of the 35 players analysed, 14 (40%) players had more than 1 injury and 47 contact injuries were sustained over 29 matches. The CoxPH model provided the poorest fit to the recurrent sports injury data. The fit was improved with the A-G and frailty models, compared to WLW-TT and PWP-GT models. Conclusions Despite little difference in model fit between the A-G and frailty models, in the interest of fewer statistical assumptions it is recommended that, where relevant, future studies involving modelling of recurrent sports injury data use the frailty model in preference to the CoxPH model or its other generalisations. The paper provides a rationale for future statistical modelling approaches for recurrent sports injury. PMID:22872683

Monotonic non-linear transformations as a tool to investigate age-related effects on brain white matter integrity: A Box-Cox investigation.

PubMed

Morozova, Maria; Koschutnig, Karl; Klein, Elise; Wood, Guilherme

2016-01-15

Non-linear effects of age on white matter integrity are ubiquitous in the brain and indicate that these effects are more pronounced in certain brain regions at specific ages. Box-Cox analysis is a technique to increase the log-likelihood of linear relationships between variables by means of monotonic non-linear transformations. Here we employ Box-Cox transformations to flexibly and parsimoniously determine the degree of non-linearity of age-related effects on white matter integrity by means of model comparisons using a voxel-wise approach. Analysis of white matter integrity in a sample of adults between 20 and 89years of age (n=88) revealed that considerable portions of the white matter in the corpus callosum, cerebellum, pallidum, brainstem, superior occipito-frontal fascicle and optic radiation show non-linear effects of age. Global analyses revealed an increase in the average non-linearity from fractional anisotropy to radial diffusivity, axial diffusivity, and mean diffusivity. These results suggest that Box-Cox transformations are a useful and flexible tool to investigate more complex non-linear effects of age on white matter integrity and extend the functionality of the Box-Cox analysis in neuroimaging. Copyright © 2015 Elsevier Inc. All rights reserved.

Prognostic factors in multiple myeloma: selection using Cox's proportional hazard model.

PubMed

Pasqualetti, P; Collacciani, A; Maccarone, C; Casale, R

1996-01-01

The pretreatment characteristics of 210 patients with multiple myeloma, observed between 1980 and 1994, were evaluated as potential prognostic factors for survival. Multivariate analysis according to Cox's proportional hazard model identified in the 160 dead patients with myeloma, among 26 different single prognostic variables, the following factors in order of importance: beta 2-microglobulin; bone marrow plasma cell percentage, hemoglobinemia, degree of lytic bone lesions, serum creatinine, and serum albumin. By analysis of these variables a prognostic index (PI), that considers the regression coefficients derived by Cox's model of all significant factors, was obtained. Using this it was possible to separate the whole patient group into three stages: stage I (PI < 1.485, 67 patients), stage II (PI: 1.485-2.090, 76 patients), and stage III (PI > 2.090, 67 patients), with a median survivals of 68, 36 and 13 months (P < 0.0001), respectively. Also the responses to therapy (P < 0.0001) and the survival curves (P < 0.00001) presented significant differences among the three subgroups. Knowledge of these factors could be of value in predicting prognosis and in planning therapy in patients with multiple myeloma.

Big Data Toolsets to Pharmacometrics: Application of Machine Learning for Time-to-Event Analysis.

PubMed

Gong, Xiajing; Hu, Meng; Zhao, Liang

2018-05-01

Additional value can be potentially created by applying big data tools to address pharmacometric problems. The performances of machine learning (ML) methods and the Cox regression model were evaluated based on simulated time-to-event data synthesized under various preset scenarios, i.e., with linear vs. nonlinear and dependent vs. independent predictors in the proportional hazard function, or with high-dimensional data featured by a large number of predictor variables. Our results showed that ML-based methods outperformed the Cox model in prediction performance as assessed by concordance index and in identifying the preset influential variables for high-dimensional data. The prediction performances of ML-based methods are also less sensitive to data size and censoring rates than the Cox regression model. In conclusion, ML-based methods provide a powerful tool for time-to-event analysis, with a built-in capacity for high-dimensional data and better performance when the predictor variables assume nonlinear relationships in the hazard function. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Bootstrap-based methods for estimating standard errors in Cox's regression analyses of clustered event times.

PubMed

Xiao, Yongling; Abrahamowicz, Michal

2010-03-30

We propose two bootstrap-based methods to correct the standard errors (SEs) from Cox's model for within-cluster correlation of right-censored event times. The cluster-bootstrap method resamples, with replacement, only the clusters, whereas the two-step bootstrap method resamples (i) the clusters, and (ii) individuals within each selected cluster, with replacement. In simulations, we evaluate both methods and compare them with the existing robust variance estimator and the shared gamma frailty model, which are available in statistical software packages. We simulate clustered event time data, with latent cluster-level random effects, which are ignored in the conventional Cox's model. For cluster-level covariates, both proposed bootstrap methods yield accurate SEs, and type I error rates, and acceptable coverage rates, regardless of the true random effects distribution, and avoid serious variance under-estimation by conventional Cox-based standard errors. However, the two-step bootstrap method over-estimates the variance for individual-level covariates. We also apply the proposed bootstrap methods to obtain confidence bands around flexible estimates of time-dependent effects in a real-life analysis of cluster event times.

Forecasts of non-Gaussian parameter spaces using Box-Cox transformations

NASA Astrophysics Data System (ADS)

Joachimi, B.; Taylor, A. N.

2011-09-01

Forecasts of statistical constraints on model parameters using the Fisher matrix abound in many fields of astrophysics. The Fisher matrix formalism involves the assumption of Gaussianity in parameter space and hence fails to predict complex features of posterior probability distributions. Combining the standard Fisher matrix with Box-Cox transformations, we propose a novel method that accurately predicts arbitrary posterior shapes. The Box-Cox transformations are applied to parameter space to render it approximately multivariate Gaussian, performing the Fisher matrix calculation on the transformed parameters. We demonstrate that, after the Box-Cox parameters have been determined from an initial likelihood evaluation, the method correctly predicts changes in the posterior when varying various parameters of the experimental setup and the data analysis, with marginally higher computational cost than a standard Fisher matrix calculation. We apply the Box-Cox-Fisher formalism to forecast cosmological parameter constraints by future weak gravitational lensing surveys. The characteristic non-linear degeneracy between matter density parameter and normalization of matter density fluctuations is reproduced for several cases, and the capabilities of breaking this degeneracy by weak-lensing three-point statistics is investigated. Possible applications of Box-Cox transformations of posterior distributions are discussed, including the prospects for performing statistical data analysis steps in the transformed Gaussianized parameter space.

Apigenin inhibits COX-2, PGE2, and EP1 and also initiates terminal differentiation in the epidermis of tumor bearing mice.

PubMed

Kiraly, Alex J; Soliman, Eman; Jenkins, Audrey; Van Dross, Rukiyah T

2016-01-01

Non-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States. NMSC overexpresses cyclooxygenase-2 (COX-2). COX-2 synthesizes prostaglandins such as PGE2 which promote proliferation and tumorigenesis by engaging G-protein-coupled prostaglandin E receptors (EP). Apigenin is a bioflavonoid that blocks mouse skin tumorigenesis induced by the chemical carcinogens, 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the effect of apigenin on the COX-2 pathway has not been examined in the DMBA/TPA skin tumor model. In the present study, apigenin decreased tumor multiplicity and incidence in DMBA/TPA-treated SKH-1 mice. Analysis of the non-tumor epidermis revealed that apigenin reduced COX-2, PGE2, EP1, and EP2 synthesis and also increased terminal differentiation. In contrast, apigenin did not inhibit the COX-2 pathway or promote terminal differentiation in the tumors. Since fewer tumors developed in apigenin-treated animals which contained reduced epidermal COX-2 levels, our data suggest that apigenin may avert skin tumor development by blocking COX-2. Copyright © 2015 Elsevier Ltd. All rights reserved.

Simulation of Oil Slick Transport in Great Lakes Connecting Channels. Volume 1. Theory and Model Formulation

DTIC Science & Technology

1986-03-01

attempted to analyze in detail the 3 hydrodynamic problem defined above (Kerr and Babu, 1970; 5 15 U DePietio and Cox, 1979; and Foda and Cox, 1980...coefficient ET can be related to the magnitude of V’ by the random walk analysis (Fischer, et al., 1979), whereI V’ = (4E T/6t)2 (27) 3 in which 5t = time...Water Management and Planning Branch.. Foda , M. and R.G. Cox, (1980). "The spreading of thin liquid films on a water-air interface," Journal of Fluid

Extended cox regression model: The choice of timefunction

NASA Astrophysics Data System (ADS)

Isik, Hatice; Tutkun, Nihal Ata; Karasoy, Durdu

2017-07-01

Cox regression model (CRM), which takes into account the effect of censored observations, is one the most applicative and usedmodels in survival analysis to evaluate the effects of covariates. Proportional hazard (PH), requires a constant hazard ratio over time, is the assumptionofCRM. Using extended CRM provides the test of including a time dependent covariate to assess the PH assumption or an alternative model in case of nonproportional hazards. In this study, the different types of real data sets are used to choose the time function and the differences between time functions are analyzed and discussed.

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

PubMed Central

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

2013-01-01

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

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

PubMed Central

2014-01-01

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

Flexible modeling improves assessment of prognostic value of C-reactive protein in advanced non-small cell lung cancer

PubMed Central

Gagnon, B; Abrahamowicz, M; Xiao, Y; Beauchamp, M-E; MacDonald, N; Kasymjanova, G; Kreisman, H; Small, D

2010-01-01

Background: C-reactive protein (CRP) is gaining credibility as a prognostic factor in different cancers. Cox's proportional hazard (PH) model is usually used to assess prognostic factors. However, this model imposes a priori assumptions, which are rarely tested, that (1) the hazard ratio associated with each prognostic factor remains constant across the follow-up (PH assumption) and (2) the relationship between a continuous predictor and the logarithm of the mortality hazard is linear (linearity assumption). Methods: We tested these two assumptions of the Cox's PH model for CRP, using a flexible statistical model, while adjusting for other known prognostic factors, in a cohort of 269 patients newly diagnosed with non-small cell lung cancer (NSCLC). Results: In the Cox's PH model, high CRP increased the risk of death (HR=1.11 per each doubling of CRP value, 95% CI: 1.03–1.20, P=0.008). However, both the PH assumption (P=0.033) and the linearity assumption (P=0.015) were rejected for CRP, measured at the initiation of chemotherapy, which kept its prognostic value for approximately 18 months. Conclusion: Our analysis shows that flexible modeling provides new insights regarding the value of CRP as a prognostic factor in NSCLC and that Cox's PH model underestimates early risks associated with high CRP. PMID:20234363

Immunohistochemical localization of cyclooxygenase isoforms in the organ of Corti and the spiral ganglion cells of guinea pig cochlea.

PubMed

Ziegler, E A; Brieger, J; Heinrich, U R; Mann, W J

2004-01-01

Prostaglandins have been used in experimental models and clinical studies for the therapy of sudden hearing loss and tinnitus with conflicting results. However, little is known about the rate-limiting enzymes of prostaglandin synthesis in the inner ear, the generally constitutively expressed cyclooxygenase 1 (COX-1) and the distress-inducible cyclooxygenase 2 (COX-2). To extend our knowledge concerning the physiological expression and localization of these two enzymes, immunohistochemical stainings of the guinea pig cochlea were performed. Light microscopical analysis revealed a homogenous distribution of COX-1 within nearly all cell types of the organ of Corti, but no COX-1 expression in the cuticular plates of pillar cells. COX-2 was found to be expressed in all cell types, with much stronger expression in Hensen cells, neighboring Deiters cells and cuticular plates of outer hair cells. Both COX-1 and COX-2 immunoreactions were also found in the spiral ganglion. We conclude that both COX subtypes are expressed in the guinea pig cochlea under physiological conditions. The prominent expression of the distress-inducible COX-2 isoform in cell types under mechanical stress during noise reception might support the hypothesis of a cytoprotective function of COX products in hearing and in cellular stress situations like intense noise exposure. Copyright (c) 2004 S. Karger AG, Basel.

Prevention of posterior capsular opacification through cyclooxygenase-2 inhibition

PubMed Central

Barden, Curtis A; Lu, Ping; Kusewitt, Donna F.; Colitz, Carmen M. H.

2007-01-01

Purpose To determine if cyclooxygenase-2 (COX-2) is upregulated when lens epithelial cells (LEC) in clinical samples of cataracts and posterior capsule opacification (PCO) undergo epithelial-mesenchymal transition (EMT)-like changes. We also wanted to learn if inhibition of the enzymatic activity of COX-2 could prevent PCO formation. Methods To ensure that EMT-like changes were occurring in LEC, real-time RT-PCR was used to examine expression of EMT markers. Clinical samples of canine cataracts and PCO were examined for COX-2 expression using immunohistochemistry, western blot analysis, and real-time RT-PCR. The COX-2 inhibitors, rofecoxib and celecoxib, were used in an ex vivo model of PCO formation, and the effects on cellular migration, proliferation, and apoptosis were analyzed using immunohistochemistry and western blots. Prostaglandin E2 (PGE2) expression was examined with ELISA. Results Markers of EMT, such as lumican, Snail, Slug, and COX-2 were expressed in LEC. In clinical samples of cataracts and PCO, there was overexpression of COX-2 protein and mRNA. Both rofecoxib and celecoxib were effective at inhibiting PCO formation in our ex vivo model. Prevention of PCO with the COX-2 inhibitors appeared to work through decreased migration and proliferation, and increased apoptosis. Neither of the drugs had a toxic effect on confluent LEC and appeared to inhibit PCO through their pharmacologic action. Synthesis of PGE2 was inhibiting in the capsules treated with the COX-2 inhibiting drugs. Conclusions Extracapsular phacoemulsification cataract surgery is the most common surgical procedure performed in human and veterinary ophthalmology. The most frequent postoperative complication is PCO. The LEC that remain adhered to the lens capsule undergo EMT-like changes, proliferate, and migrate across the posterior lens capsule causing opacities. We have shown that COX-2, a protein associated with EMT, is upregulated in canine cataracts and PCO. Inhibiting the enzymatic activity effectively prevented EMT of LEC in our ex vivo model of PCO through pharmacologic action, and not acute toxicity. These findings indicate that using COX-2 inhibitors in vivo may be an effective technique in preventing PCO. PMID:17563718

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

PubMed

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

2013-05-01

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

The prognostic role of body mass index on mortality amongst the middle-aged and elderly: a competing risk analysis.

PubMed

Ghaem Maralani, Haleh; Tai, Bee Choo; Wong, Tien Y; Tai, E Shyong; Li, Jialiang; Wang, Jie Jin; Mitchell, Paul

2014-01-01

To determine the relationship between body mass index (BMI) including its 5-year changes and mortality, and compare the results obtained using Cox and competing risks models. Our study subjects included 2216 persons aged ≥49 years who participated in the Blue Mountains Eye Study, Australia between 1992 and 1994, and returned for further follow-up examinations between 1997 and 1999. We examined the relationship between BMI and mortality using cubic spline. The Cox and competing risks models were used to assess the associations between baseline BMI and its 5-year changes with all-cause and cause-specific mortality. Amongst subjects aged ≤70 years, the relationship between BMI and all-cause mortality was U-shaped. For those aged >70 years, an L-shaped relationship was seen with no elevation in risk amongst the overweight/obese. Based on the competing risks model, obesity at baseline was associated with increased risk of cardiovascular death and reduction in BMI at 5-year was linked to an increase risk of cancer death amongst those aged ≤70 years. The cause-specific Cox model showed that reduction in BMI at 5-year was associated with cancer-death regardless of age, and with cardiovascular deaths among subjects aged ≤70 years. Cox regression model showed larger magnitude of effect with wider confidence interval as compared with competing risks model. Conditions associated with obesity are more likely to affect mortality among subjects aged ≤70 years, but not among those aged over 70 years. Cox model shows larger magnitude of effect in comparison with competing risks model. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Cyclooxygenase‐2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents

PubMed Central

Lin, Chun-Kuang; Tseng, Chin-Kai; Wu, Yu-Hsuan; Liaw, Chih-Chuang; Lin, Chun-Yu; Huang, Chung-Hao; Chen, Yen-Hsu; Lee, Jin-Ching

2017-01-01

Cyclooxygenase-2 (COX-2) is one of the important mediators of inflammation in response to viral infection, and it contributes to viral replication, for example, cytomegalovirus or hepatitis C virus replication. The role of COX-2 in dengue virus (DENV) replication remains unclear. In the present study, we observed an increased level of COX-2 in patients with dengue fever compared with healthy donors. Consistent with the clinical data, an elevated level of COX-2 expression was also observed in DENV-infected ICR suckling mice. Using cell-based experiments, we revealed that DENV-2 infection significantly induced COX-2 expression and prostaglandin E2 (PGE2) production in human hepatoma Huh-7 cells. The exogenous expression of COX-2 or PGE2 treatment dose-dependently enhanced DENV-2 replication. In contrast, COX-2 gene silencing and catalytic inhibition sufficiently suppressed DENV-2 replication. In an ICR suckling mouse model, we identified that the COX-2 inhibitor NS398 protected mice from succumbing to life-threatening DENV-2 infection. By using COX-2 promoter-based analysis and specific inhibitors against signaling molecules, we identified that NF-κB and MAPK/JNK are critical factors for DENV-2-induced COX-2 expression and viral replication. Altogether, our results reveal that COX-2 is an important factor for DENV replication and can serve as a potential target for developing therapeutic agents against DENV infection. PMID:28317866

Evaluation of methodology for the analysis of 'time-to-event' data in pharmacogenomic genome-wide association studies.

PubMed

Syed, Hamzah; Jorgensen, Andrea L; Morris, Andrew P

2016-06-01

To evaluate the power to detect associations between SNPs and time-to-event outcomes across a range of pharmacogenomic study designs while comparing alternative regression approaches. Simulations were conducted to compare Cox proportional hazards modeling accounting for censoring and logistic regression modeling of a dichotomized outcome at the end of the study. The Cox proportional hazards model was demonstrated to be more powerful than the logistic regression analysis. The difference in power between the approaches was highly dependent on the rate of censoring. Initial evaluation of single-nucleotide polymorphism association signals using computationally efficient software with dichotomized outcomes provides an effective screening tool for some design scenarios, and thus has important implications for the development of analytical protocols in pharmacogenomic studies.

Considerations for analysis of time-to-event outcomes measured with error: Bias and correction with SIMEX.

PubMed

Oh, Eric J; Shepherd, Bryan E; Lumley, Thomas; Shaw, Pamela A

2018-04-15

For time-to-event outcomes, a rich literature exists on the bias introduced by covariate measurement error in regression models, such as the Cox model, and methods of analysis to address this bias. By comparison, less attention has been given to understanding the impact or addressing errors in the failure time outcome. For many diseases, the timing of an event of interest (such as progression-free survival or time to AIDS progression) can be difficult to assess or reliant on self-report and therefore prone to measurement error. For linear models, it is well known that random errors in the outcome variable do not bias regression estimates. With nonlinear models, however, even random error or misclassification can introduce bias into estimated parameters. We compare the performance of 2 common regression models, the Cox and Weibull models, in the setting of measurement error in the failure time outcome. We introduce an extension of the SIMEX method to correct for bias in hazard ratio estimates from the Cox model and discuss other analysis options to address measurement error in the response. A formula to estimate the bias induced into the hazard ratio by classical measurement error in the event time for a log-linear survival model is presented. Detailed numerical studies are presented to examine the performance of the proposed SIMEX method under varying levels and parametric forms of the error in the outcome. We further illustrate the method with observational data on HIV outcomes from the Vanderbilt Comprehensive Care Clinic. Copyright © 2017 John Wiley & Sons, Ltd.

Comparison of Cox's Regression Model and Parametric Models in Evaluating the Prognostic Factors for Survival after Liver Transplantation in Shiraz during 2000-2012.

PubMed

Adelian, R; Jamali, J; Zare, N; Ayatollahi, S M T; Pooladfar, G R; Roustaei, N

2015-01-01

Identification of the prognostic factors for survival in patients with liver transplantation is challengeable. Various methods of survival analysis have provided different, sometimes contradictory, results from the same data. To compare Cox's regression model with parametric models for determining the independent factors for predicting adults' and pediatrics' survival after liver transplantation. This study was conducted on 183 pediatric patients and 346 adults underwent liver transplantation in Namazi Hospital, Shiraz, southern Iran. The study population included all patients undergoing liver transplantation from 2000 to 2012. The prognostic factors sex, age, Child class, initial diagnosis of the liver disease, PELD/MELD score, and pre-operative laboratory markers were selected for survival analysis. Among 529 patients, 346 (64.5%) were adult and 183 (34.6%) were pediatric cases. Overall, the lognormal distribution was the best-fitting model for adult and pediatric patients. Age in adults (HR=1.16, p<0.05) and weight (HR=2.68, p<0.01) and Child class B (HR=2.12, p<0.05) in pediatric patients were the most important factors for prediction of survival after liver transplantation. Adult patients younger than the mean age and pediatric patients weighing above the mean and Child class A (compared to those with classes B or C) had better survival. Parametric regression model is a good alternative for the Cox's regression model.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Yu-Ching; Department of Veterinary Medicine, National Chung Hsing University, Taichung 402, Taiwan; Ho, Heng-Chien

2012-07-15

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

An empirical comparison of statistical tests for assessing the proportional hazards assumption of Cox's model.

PubMed

Ng'andu, N H

1997-03-30

In the analysis of survival data using the Cox proportional hazard (PH) model, it is important to verify that the explanatory variables analysed satisfy the proportional hazard assumption of the model. This paper presents results of a simulation study that compares five test statistics to check the proportional hazard assumption of Cox's model. The test statistics were evaluated under proportional hazards and the following types of departures from the proportional hazard assumption: increasing relative hazards; decreasing relative hazards; crossing hazards; diverging hazards, and non-monotonic hazards. The test statistics compared include those based on partitioning of failure time and those that do not require partitioning of failure time. The simulation results demonstrate that the time-dependent covariate test, the weighted residuals score test and the linear correlation test have equally good power for detection of non-proportionality in the varieties of non-proportional hazards studied. Using illustrative data from the literature, these test statistics performed similarly.

Genomic selection for slaughter age in pigs using the Cox frailty model.

PubMed

Santos, V S; Martins Filho, S; Resende, M D V; Azevedo, C F; Lopes, P S; Guimarães, S E F; Glória, L S; Silva, F F

2015-10-19

The aim of this study was to compare genomic selection methodologies using a linear mixed model and the Cox survival model. We used data from an F2 population of pigs, in which the response variable was the time in days from birth to the culling of the animal and the covariates were 238 markers [237 single nucleotide polymorphism (SNP) plus the halothane gene]. The data were corrected for fixed effects, and the accuracy of the method was determined based on the correlation of the ranks of predicted genomic breeding values (GBVs) in both models with the corrected phenotypic values. The analysis was repeated with a subset of SNP markers with largest absolute effects. The results were in agreement with the GBV prediction and the estimation of marker effects for both models for uncensored data and for normality. However, when considering censored data, the Cox model with a normal random effect (S1) was more appropriate. Since there was no agreement between the linear mixed model and the imputed data (L2) for the prediction of genomic values and the estimation of marker effects, the model S1 was considered superior as it took into account the latent variable and the censored data. Marker selection increased correlations between the ranks of predicted GBVs by the linear and Cox frailty models and the corrected phenotypic values, and 120 markers were required to increase the predictive ability for the characteristic analyzed.

The Effect of Cyclooxygenase Inhibition on Tendon-Bone Healing in an In Vitro Coculture Model

PubMed Central

Schwarting, Tim; Pretzsch, Sebastian; Debus, Florian; Ruchholtz, Steffen; Lechler, Philipp

2015-01-01

The effects of cyclooxygenase (COX) inhibition following the reconstruction of the anterior cruciate ligament remain unclear. We examined the effects of selective COX-2 and nonselective COX inhibition on bone-tendon integration in an in vitro model. We measured the dose-dependent effects of ibuprofen and parecoxib on the viability of lipopolysaccharide- (LPS-) stimulated and unstimulated mouse MC3T3-E1 and 3T3 cells, the influence on gene expression at the osteoblast, interface, and fibroblast regions measured by quantitative PCR, and cellular outgrowth assessed on histological sections. Ibuprofen led to a dose-dependent suppression of MC3T3 cell viability, while parecoxib reduced the viability of 3T3 cultures. Exposure to ibuprofen significantly suppressed expression of Alpl (P < 0.01), Bglap (P < 0.001), and Runx2 (P < 0.01), and although parecoxib reduced expression of Alpl (P < 0.001), Fmod (P < 0.001), and Runx2 (P < 0.01), the expression of Bglap was increased (P < 0.01). Microscopic analysis showed a reduction in cellular outgrowth in LPS-stimulated cultures following exposure to ibuprofen and parecoxib. Nonselective COX inhibition and the specific inhibition of COX-2 led to region-specific reductions in markers of calcification and cell viability. We suggest further in vitro and in vivo studies examining the biologic and biomechanical effects of selective and nonselective COX inhibition. PMID:26063979

The Box-Cox power transformation on nursing sensitive indicators: Does it matter if structural effects are omitted during the estimation of the transformation parameter?

PubMed Central

2011-01-01

Background Many nursing and health related research studies have continuous outcome measures that are inherently non-normal in distribution. The Box-Cox transformation provides a powerful tool for developing a parsimonious model for data representation and interpretation when the distribution of the dependent variable, or outcome measure, of interest deviates from the normal distribution. The objectives of this study was to contrast the effect of obtaining the Box-Cox power transformation parameter and subsequent analysis of variance with or without a priori knowledge of predictor variables under the classic linear or linear mixed model settings. Methods Simulation data from a 3 × 4 factorial treatments design, along with the Patient Falls and Patient Injury Falls from the National Database of Nursing Quality Indicators (NDNQI®) for the 3rd quarter of 2007 from a convenience sample of over one thousand US hospitals were analyzed. The effect of the nonlinear monotonic transformation was contrasted in two ways: a) estimating the transformation parameter along with factors with potential structural effects, and b) estimating the transformation parameter first and then conducting analysis of variance for the structural effect. Results Linear model ANOVA with Monte Carlo simulation and mixed models with correlated error terms with NDNQI examples showed no substantial differences on statistical tests for structural effects if the factors with structural effects were omitted during the estimation of the transformation parameter. Conclusions The Box-Cox power transformation can still be an effective tool for validating statistical inferences with large observational, cross-sectional, and hierarchical or repeated measure studies under the linear or the mixed model settings without prior knowledge of all the factors with potential structural effects. PMID:21854614

The Box-Cox power transformation on nursing sensitive indicators: does it matter if structural effects are omitted during the estimation of the transformation parameter?

PubMed

Hou, Qingjiang; Mahnken, Jonathan D; Gajewski, Byron J; Dunton, Nancy

2011-08-19

Many nursing and health related research studies have continuous outcome measures that are inherently non-normal in distribution. The Box-Cox transformation provides a powerful tool for developing a parsimonious model for data representation and interpretation when the distribution of the dependent variable, or outcome measure, of interest deviates from the normal distribution. The objectives of this study was to contrast the effect of obtaining the Box-Cox power transformation parameter and subsequent analysis of variance with or without a priori knowledge of predictor variables under the classic linear or linear mixed model settings. Simulation data from a 3 × 4 factorial treatments design, along with the Patient Falls and Patient Injury Falls from the National Database of Nursing Quality Indicators (NDNQI® for the 3rd quarter of 2007 from a convenience sample of over one thousand US hospitals were analyzed. The effect of the nonlinear monotonic transformation was contrasted in two ways: a) estimating the transformation parameter along with factors with potential structural effects, and b) estimating the transformation parameter first and then conducting analysis of variance for the structural effect. Linear model ANOVA with Monte Carlo simulation and mixed models with correlated error terms with NDNQI examples showed no substantial differences on statistical tests for structural effects if the factors with structural effects were omitted during the estimation of the transformation parameter. The Box-Cox power transformation can still be an effective tool for validating statistical inferences with large observational, cross-sectional, and hierarchical or repeated measure studies under the linear or the mixed model settings without prior knowledge of all the factors with potential structural effects.

Quantile Regression with Censored Data

ERIC Educational Resources Information Center

Lin, Guixian

2009-01-01

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

A comparison between standard methods and structural nested modelling when bias from a healthy worker survivor effect is suspected: an iron-ore mining cohort study.

PubMed

Björ, Ove; Damber, Lena; Jonsson, Håkan; Nilsson, Tohr

2015-07-01

Iron-ore miners are exposed to extremely dusty and physically arduous work environments. The demanding activities of mining select healthier workers with longer work histories (ie, the Healthy Worker Survivor Effect (HWSE)), and could have a reversing effect on the exposure-response association. The objective of this study was to evaluate an iron-ore mining cohort to determine whether the effect of respirable dust was confounded by the presence of an HWSE. When an HWSE exists, standard modelling methods, such as Cox regression analysis, produce biased results. We compared results from g-estimation of accelerated failure-time modelling adjusted for HWSE with corresponding unadjusted Cox regression modelling results. For all-cause mortality when adjusting for the HWSE, cumulative exposure from respirable dust was associated with a 6% decrease of life expectancy if exposed ≥15 years, compared with never being exposed. Respirable dust continued to be associated with mortality after censoring outcomes known to be associated with dust when adjusting for the HWSE. In contrast, results based on Cox regression analysis did not support that an association was present. The adjustment for the HWSE made a difference when estimating the risk of mortality from respirable dust. The results of this study, therefore, support the recommendation that standard methods of analysis should be complemented with structural modelling analysis techniques, such as g-estimation of accelerated failure-time modelling, to adjust for the HWSE. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Simulation of Oil Slick Transport in Great Lakes Connecting Channels. Theory and Model Formulation

DTIC Science & Technology

1990-02-01

Cox 1979, Foda and Cox 1980). These complex mathemati- cal treatments are not suitable for real field problems. In the present study, a Lagrangian... analysis (Fischer et al. 1979), where 1 cp - 1.0x0 2 g/cm-s - 2A lb/ft-hr. 13 V"= (4ET/t)"/2 (27) where 8t is a time step. Murray (1972), using the... analysis . This is equivalent to excluding the parcels located at a radial distance greater than 2.2 r from the centroid of the slick. This was

MicroRNA-26a/-26b-COX-2-MIP-2 Loop Regulates Allergic Inflammation and Allergic Inflammation-promoted Enhanced Tumorigenic and Metastatic Potential of Cancer Cells*

PubMed Central

Kwon, Yoojung; Kim, Youngmi; Eom, Sangkyung; Kim, Misun; Park, Deokbum; Kim, Hyuna; Noh, Kyeonga; Lee, Hansoo; Lee, Yun Sil; Choe, Jongseon; Kim, Young Myeong; Jeoung, Dooil

2015-01-01

Cyclooxgenase-2 (COX-2) knock-out mouse experiments showed that COX-2 was necessary for in vivo allergic inflammation, such as passive cutaneous anaphylaxis, passive systemic anaphylaxis, and triphasic cutaneous allergic reaction. TargetScan analysis predicted COX-2 as a target of miR-26a and miR-26b. miR-26a/-26b decreased luciferase activity associated with COX-2–3′-UTR. miR-26a/-26b exerted negative effects on the features of in vitro and in vivo allergic inflammation by targeting COX-2. ChIP assays showed the binding of HDAC3 and SNAIL, but not COX-2, to the promoter sequences of miR-26a and miR-26b. Cytokine array analysis showed that the induction of chemokines, such as MIP-2, in the mouse passive systemic anaphylaxis model occurred in a COX-2-dependent manner. ChIP assays showed the binding of HDAC3 and COX-2 to the promoter sequences of MIP-2. In vitro and in vivo allergic inflammation was accompanied by the increased expression of MIP-2. miR-26a/-26b negatively regulated the expression of MIP-2. Allergic inflammation enhanced the tumorigenic and metastatic potential of cancer cells and induced positive feedback involving cancer cells and stromal cells, such as mast cells, macrophages, and endothelial cells. miR-26a mimic and miR-26b mimic negatively regulated the positive feedback between cancer cells and stromal cells and the positive feedback among stromal cells. miR-26a/-26b negatively regulated the enhanced tumorigenic potential by allergic inflammation. COX-2 was necessary for the enhanced metastatic potential of cancer cells by allergic inflammation. Taken together, our results indicate that the miR26a/-26b-COX-2-MIP-2 loop regulates allergic inflammation and the feedback relationship between allergic inflammation and the enhanced tumorigenic and metastatic potential. PMID:25907560

Condition Assessment Modeling for Distribution Systems Using Shared Frailty Analysis

EPA Science Inventory

Condition Assessment (CA) modeling is drawing increasing interest as a methodology for managing drinking water infrastructure. This paper develops a Cox Proportional Hazard (PH)/shared frailty model and applies it to the problem of investment in the repair and replacement of dri...

Fractals and self-organized criticality in anti-inflammatory drugs

NASA Astrophysics Data System (ADS)

Phillips, J. C.

2014-12-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX-1 and COX-2) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective inhibitors. Extensive structural studies of the biology of prostaglandin synthesis and inhibition have explained some of the differences between COX-1 and COX-2 functionality, but others are still unexplained. Notably these include molecular differences that cause COX-1 inhibitors to produce a slight decrease, and COX-2 inhibitors to induce a significant increase, in heart attacks and strokes. These differences were unexpected because of the 60% overall COX-1 and COX-2 sequence similarity and the 1-2 conservation of catalytic sites. Hydropathic analysis shows important bicyclic differences between COX-1 and COX-2 on a large scale outside the catalytic pocket. These differences involve much stronger amphiphilic interactions in COX-2 than in COX-1, and may explain the selective antiplatelet effectiveness of COX-2. Success of the non-Euclidean structural analysis is the result of using the new Brazilian hydropathicity scale based on self-organized criticality (SOC) of universal protein modules.

Empirical evidence for an invariant three-factor structure of the Parental Bonding Instrument in six European countries.

PubMed

Heider, Dirk; Matschinger, Herbert; Bernert, Sebastian; Vilagut, Gemma; Martínez-Alonso, Montserrat; Dietrich, Sandra; Angermeyer, Matthias C

2005-06-30

The objective of the present study was to test the Parental Bonding Instrument's (PBI) three-factor structure (care, overprotection, and authoritarianism) found by [Cox, B.J., Enns, M.W., Clara, I.P. 2000, The Parental Bonding Instrument: confirmatory evidence for a three-factor model in a psychiatric clinical sample and in the National Comorbidity Survey, Social Psychiatry and Psychiatric Epidemiology 35 (2000) 353-357.] on an eight-item short form of the scale. A total of 8813 respondents from the six European countries participating in the ESEMeD project (Belgium, France, Germany, Italy, The Netherlands, and Spain) completed either the PBI-paternal or the PBI-maternal scale. Maximum likelihood confirmatory factor analysis was used to compare the original factor model of Cox et al. with a three-factor solution that emerged from an exploration of the structure with principal component factor analysis. When gender and age subgroups, as well as different countries, were taken into account, the accuracy of the model was confirmed. The fit indices for the new model indicated a generally better model fit than the ones for the model originally developed by Cox et al. Further efforts should be directed to the modeling of the dimension authoritarianism. The results provide the opportunity to estimate the influence of the extracted factors on mental disorders in different countries. The application of the short form of the PBI seems suitable primarily for large epidemiological studies.

Cyclooxygenase inhibitors: From pharmacology to clinical read-outs.

PubMed

Patrignani, Paola; Patrono, Carlo

2015-04-01

Acetylsalicylic acid (aspirin) is a prototypic cyclooxygenase (COX) inhibitor. It was synthesized serendipitously from a natural compound, i.e., salicylic acid, with known analgesic activity. This chemical modification, obtained for the first time in an industrial environment in 1897, endowed aspirin with the unique capacity of acetylating and inactivating permanently COX-isozymes. Traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) were developed to mimic the pharmacological effects of aspirin, using aspirin-sensitive experimental models of pain and inflammation as the template for screening new chemical entities. Among the tNSAIDs, some were endowed with moderate COX- selectivity (e.g., diclofenac), but no studies of sufficient size and duration were performed to show any clinically relevant difference between different members of the class. Similarly, no serious attempts were made to unravel the mechanisms involved in the shared therapeutic and toxic effects of tNSAIDs until the discovery of COX-2. This led to characterizing their main therapeutic effects as being COX-2-dependent and their gastrointestinal (GI) toxicity as being COX-1-dependent, and provided a rationale for developing a new class of selective COX-2 inhibitors, the coxibs. This review will discuss the clinical pharmacology of tNSAIDs and coxibs, and the clinical read-outs of COX-isozyme inhibition. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance." Copyright © 2014 Elsevier B.V. All rights reserved.

Targeted deletion and lipidomic analysis identify epithelial cell COX-2 as a major driver of chemically induced skin cancer.

PubMed

Jiao, Jing; Ishikawa, Tomo-O; Dumlao, Darren S; Norris, Paul C; Magyar, Clara E; Mikulec, Carol; Catapang, Art; Dennis, Edward A; Fischer, Susan M; Herschman, Harvey R

2014-11-01

Pharmacologic and global gene deletion studies demonstrate that cyclooxygenase-2 (PTGS2/COX-2) plays a critical role in DMBA/TPA-induced skin tumor induction. Although many cell types in the tumor microenvironment express COX-2, the cell types in which COX-2 expression is required for tumor promotion are not clearly established. Here, cell type-specific Cox-2 gene deletion reveals a vital role for skin epithelial cell COX-2 expression in DMBA/TPA tumor induction. In contrast, myeloid Cox-2 gene deletion has no effect on DMBA/TPA tumorigenesis. The infrequent, small tumors that develop on mice with an epithelial cell-specific Cox-2 gene deletion have decreased proliferation and increased cell differentiation properties. Blood vessel density is reduced in tumors with an epithelial cell-specific Cox-2 gene deletion, compared with littermate control tumors, suggesting a reciprocal relationship in tumor progression between COX-2-expressing tumor epithelial cells and microenvironment endothelial cells. Lipidomics analysis of skin and tumors from DMBA/TPA-treated mice suggests that the prostaglandins PGE2 and PGF2α are likely candidates for the epithelial cell COX-2-dependent eicosanoids that mediate tumor progression. This study both illustrates the value of cell type-specific gene deletions in understanding the cellular roles of signal-generating pathways in complex microenvironments and emphasizes the benefit of a systems-based lipidomic analysis approach to identify candidate lipid mediators of biologic responses. Cox-2 gene deletion demonstrates that intrinsic COX-2 expression in initiated keratinocytes is a principal driver of skin carcinogenesis; lipidomic analysis identifies likely prostanoid effectors. ©2014 American Association for Cancer Research.

How to use sequence analysis for life course epidemiology? An example on HIV-positive Sub-Saharan migrants in France.

PubMed

Gosselin, Anne; Desgrées du Loû, Annabel; Lelièvre, Eva

2018-06-01

Life course epidemiology is now an established field in social epidemiology; in sociodemography, the quantitative analysis of biographies recently experienced significant trend from event history analysis to sequence analysis. The purpose of this article is to introduce and adapt this methodology to a social epidemiology question, taking the example of the impact of HIV diagnosis on Sub-Saharan migrants' residential trajectories in the Paris region. The sample consists of 640 migrants born in Sub-Saharan Africa receiving HIV care. They were interviewed in healthcare facilities in the Paris region within the PARCOURS project, conducted from 2012 to 2013, using life event history calendars, which recorded year by year their health, family and residential histories. We introduce a two-step methodological approach consisting of (1) sequence analysis by optimal matching to build a typology of migrants' residential pathways before and after diagnosis, and (2) a Cox model of the probability to experience changes in the residential situation. The seven-clusters typology shows that for a majority, the HIV diagnosis did not entail changes in residential situation. However 30% of the migrants experienced a change in their residential situation at time of diagnosis. The Cox model analysis reveals that this residential change was in fact moving in with one's partner (HR 2.99, P<0.000) rather than network rejection. This original combination of sequence analysis and Cox models is a powerful process that could be applied to other themes and constitutes a new approach in the life course epidemiology toolbox. NCT02566148. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Cystic Fibrosis Associated with Worse Survival After Liver Transplantation.

PubMed

Black, Sylvester M; Woodley, Frederick W; Tumin, Dmitry; Mumtaz, Khalid; Whitson, Bryan A; Tobias, Joseph D; Hayes, Don

2016-04-01

Survival in cystic fibrosis patients after liver transplantation and liver-lung transplantation is not well studied. To discern survival rates after liver transplantation and liver-lung transplantation in patients with and without cystic fibrosis. The United Network for Organ Sharing database was queried from 1987 to 2013. Univariate Cox proportional hazards, multivariate Cox models, and propensity score matching were performed. Liver transplant and liver-lung transplant were performed in 212 and 53 patients with cystic fibrosis, respectively. Univariate Cox proportional hazards regression identified lower survival in cystic fibrosis after liver transplant compared to a reference non-cystic fibrosis liver transplant cohort (HR 1.248; 95 % CI 1.012, 1.541; p = 0.039). Supplementary analysis found graft survival was similar across the 3 recipient categories (log-rank test: χ(2) 2.68; p = 0.262). Multivariate Cox models identified increased mortality hazard among cystic fibrosis patients undergoing liver transplantation (HR 2.439; 95 % CI 1.709, 3.482; p < 0.001) and liver-lung transplantation (HR 2.753; 95 % CI 1.560, 4.861; p < 0.001). Propensity score matching of cystic fibrosis patients undergoing liver transplantation to non-cystic fibrosis controls identified a greater mortality hazard in the cystic fibrosis cohort using a Cox proportional hazards model stratified on matched pairs (HR 3.167; 95 % CI 1.265, 7.929, p = 0.014). Liver transplantation in cystic fibrosis is associated with poorer long-term patient survival compared to non-cystic fibrosis patients, although the difference is not due to graft survival.

Joint modelling of repeated measurement and time-to-event data: an introductory tutorial.

PubMed

Asar, Özgür; Ritchie, James; Kalra, Philip A; Diggle, Peter J

2015-02-01

The term 'joint modelling' is used in the statistical literature to refer to methods for simultaneously analysing longitudinal measurement outcomes, also called repeated measurement data, and time-to-event outcomes, also called survival data. A typical example from nephrology is a study in which the data from each participant consist of repeated estimated glomerular filtration rate (eGFR) measurements and time to initiation of renal replacement therapy (RRT). Joint models typically combine linear mixed effects models for repeated measurements and Cox models for censored survival outcomes. Our aim in this paper is to present an introductory tutorial on joint modelling methods, with a case study in nephrology. We describe the development of the joint modelling framework and compare the results with those obtained by the more widely used approaches of conducting separate analyses of the repeated measurements and survival times based on a linear mixed effects model and a Cox model, respectively. Our case study concerns a data set from the Chronic Renal Insufficiency Standards Implementation Study (CRISIS). We also provide details of our open-source software implementation to allow others to replicate and/or modify our analysis. The results for the conventional linear mixed effects model and the longitudinal component of the joint models were found to be similar. However, there were considerable differences between the results for the Cox model with time-varying covariate and the time-to-event component of the joint model. For example, the relationship between kidney function as measured by eGFR and the hazard for initiation of RRT was significantly underestimated by the Cox model that treats eGFR as a time-varying covariate, because the Cox model does not take measurement error in eGFR into account. Joint models should be preferred for simultaneous analyses of repeated measurement and survival data, especially when the former is measured with error and the association between the underlying error-free measurement process and the hazard for survival is of scientific interest. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Hyperalgesia and Persistent Pain after Breast Cancer Surgery: A Prospective Randomized Controlled Trial with Perioperative COX-2 Inhibition

PubMed Central

van Helmond, Noud; Steegers, Monique A.; Filippini-de Moor, Gertie P.; Vissers, Kris C.; Wilder-Smith, Oliver H.

2016-01-01

Background Persistent pain is a challenging clinical problem after breast cancer treatment. After surgery, inflammatory pain and nociceptive input from nerve injury induce central sensitization which may play a role in the genesis of persistent pain. Using quantitative sensory testing, we tested the hypothesis that adding COX-2 inhibition to standard treatment reduces hyperalgesia after breast cancer surgery. A secondary hypothesis was that patients developing persistent pain would exhibit more postoperative hyperalgesia. Methods 138 women scheduled for lumpectomy/mastectomy under general anesthesia with paravertebral block were randomized to COX-2 inhibition (2x40mg parecoxib on day of surgery, thereafter 2x200mg celecoxib/day until day five) or placebo. Preoperatively and 1, 5, 15 days and 1, 3, 6, 12 months postoperatively, we determined electric and pressure pain tolerance thresholds in dermatomes C6/T4/L1 and a 100mm VAS score for pain. We calculated the sum of pain tolerance thresholds and analyzed change in these versus preoperatively using mixed models analysis with factor medication. To assess hyperalgesia in persistent pain patients we performed an additional analysis on patients reporting VAS>30 at 12 months. Results 48 COX-2 inhibition and 46 placebo patients were analyzed in a modified intention to treat analysis. Contrary to our primary hypothesis, change in the sum of tolerance thresholds in the COX-2 inhibition group was not different versus placebo. COX-2 inhibition had an effect on pain on movement at postoperative day 5 (p<0.01). Consistent with our secondary hypothesis, change in sum of pressure pain tolerance thresholds in 11 patients that developed persistent pain was negative versus patients without pain (p<0.01) from day 5 to 1 year postoperatively. Conclusions Perioperative COX-2 inhibition has limited value in preventing sensitization and persistent pain after breast cancer surgery. Central sensitization may play a role in the genesis of persistent postsurgical pain. PMID:27935990

Bayesian Computation for Log-Gaussian Cox Processes: A Comparative Analysis of Methods

PubMed Central

Teng, Ming; Nathoo, Farouk S.; Johnson, Timothy D.

2017-01-01

The Log-Gaussian Cox Process is a commonly used model for the analysis of spatial point pattern data. Fitting this model is difficult because of its doubly-stochastic property, i.e., it is an hierarchical combination of a Poisson process at the first level and a Gaussian Process at the second level. Various methods have been proposed to estimate such a process, including traditional likelihood-based approaches as well as Bayesian methods. We focus here on Bayesian methods and several approaches that have been considered for model fitting within this framework, including Hamiltonian Monte Carlo, the Integrated nested Laplace approximation, and Variational Bayes. We consider these approaches and make comparisons with respect to statistical and computational efficiency. These comparisons are made through several simulation studies as well as through two applications, the first examining ecological data and the second involving neuroimaging data. PMID:29200537

[A SAS marco program for batch processing of univariate Cox regression analysis for great database].

PubMed

Yang, Rendong; Xiong, Jie; Peng, Yangqin; Peng, Xiaoning; Zeng, Xiaomin

2015-02-01

To realize batch processing of univariate Cox regression analysis for great database by SAS marco program. We wrote a SAS macro program, which can filter, integrate, and export P values to Excel by SAS9.2. The program was used for screening survival correlated RNA molecules of ovarian cancer. A SAS marco program could finish the batch processing of univariate Cox regression analysis, the selection and export of the results. The SAS macro program has potential applications in reducing the workload of statistical analysis and providing a basis for batch processing of univariate Cox regression analysis.

Practical application of cure mixture model for long-term censored survivor data from a withdrawal clinical trial of patients with major depressive disorder.

PubMed

Arano, Ichiro; Sugimoto, Tomoyuki; Hamasaki, Toshimitsu; Ohno, Yuko

2010-04-23

Survival analysis methods such as the Kaplan-Meier method, log-rank test, and Cox proportional hazards regression (Cox regression) are commonly used to analyze data from randomized withdrawal studies in patients with major depressive disorder. However, unfortunately, such common methods may be inappropriate when a long-term censored relapse-free time appears in data as the methods assume that if complete follow-up were possible for all individuals, each would eventually experience the event of interest. In this paper, to analyse data including such a long-term censored relapse-free time, we discuss a semi-parametric cure regression (Cox cure regression), which combines a logistic formulation for the probability of occurrence of an event with a Cox proportional hazards specification for the time of occurrence of the event. In specifying the treatment's effect on disease-free survival, we consider the fraction of long-term survivors and the risks associated with a relapse of the disease. In addition, we develop a tree-based method for the time to event data to identify groups of patients with differing prognoses (cure survival CART). Although analysis methods typically adapt the log-rank statistic for recursive partitioning procedures, the method applied here used a likelihood ratio (LR) test statistic from a fitting of cure survival regression assuming exponential and Weibull distributions for the latency time of relapse. The method is illustrated using data from a sertraline randomized withdrawal study in patients with major depressive disorder. We concluded that Cox cure regression reveals facts on who may be cured, and how the treatment and other factors effect on the cured incidence and on the relapse time of uncured patients, and that cure survival CART output provides easily understandable and interpretable information, useful both in identifying groups of patients with differing prognoses and in utilizing Cox cure regression models leading to meaningful interpretations.

In Silico Analysis of the Potential of the Active Compounds Fucoidan and Alginate Derived from Sargassum Sp. as Inhibitors of COX-1 and COX-2

PubMed Central

Dewi, Lestari

2016-01-01

Introduction: The enzyme cyclooxygenase (COX) is an enzyme that catalyzes the formation of one of the mediators of inflammation, the prostaglandins. Inhibition of COX allegedly can improve inflammation-induced pathological conditions. Aim: The purpose of the present study was to evaluate the potential of Sargassum sp. components, Fucoidan and alginate, as COX inhibitors. Material and methods: The study was conducted by means of a computational (in silico) method. It was performed in two main stages, the docking between COX-1 and COX-2 with Fucoidan, alginate and aspirin (for comparison) and the analysis of the amount of interactions formed and the residues directly involved in the process of interaction. Results: Our results showed that both Fucoidan and alginate had an excellent potential as inhibitors of COX-1 and COX-2. Fucoidan had a better potential as an inhibitor of COX than alginate. COX inhibition was expected to provide a more favorable effect on inflammation-related pathological conditions. Conclusion: The active compounds Fucoidan and alginate derived from Sargassum sp. were suspected to possess a good potential as inhibitors of COX-1 and COX-2. PMID:27594740

In Silico Analysis of the Potential of the Active Compounds Fucoidan and Alginate Derived from Sargassum Sp. as Inhibitors of COX-1 and COX-2.

PubMed

Dewi, Lestari

2016-06-01

The enzyme cyclooxygenase (COX) is an enzyme that catalyzes the formation of one of the mediators of inflammation, the prostaglandins. Inhibition of COX allegedly can improve inflammation-induced pathological conditions. The purpose of the present study was to evaluate the potential of Sargassum sp. components, Fucoidan and alginate, as COX inhibitors. The study was conducted by means of a computational (in silico) method. It was performed in two main stages, the docking between COX-1 and COX-2 with Fucoidan, alginate and aspirin (for comparison) and the analysis of the amount of interactions formed and the residues directly involved in the process of interaction. Our results showed that both Fucoidan and alginate had an excellent potential as inhibitors of COX-1 and COX-2. Fucoidan had a better potential as an inhibitor of COX than alginate. COX inhibition was expected to provide a more favorable effect on inflammation-related pathological conditions. The active compounds Fucoidan and alginate derived from Sargassum sp. were suspected to possess a good potential as inhibitors of COX-1 and COX-2.

Rapid development of colitis in NSAID-treated IL-10-deficient mice.

PubMed

Berg, Daniel J; Zhang, Juan; Weinstock, Joel V; Ismail, Hanan F; Earle, Keith A; Alila, Hector; Pamukcu, Rifat; Moore, Steven; Lynch, Richard G

2002-11-01

Interleukin (IL)-10 is an anti-inflammatory and immune regulatory cytokine. IL-10-deficient mice (IL-10(-/-)) develop chronic inflammatory bowel disease (IBD), indicating that endogenous IL-10 is a central regulator of the mucosal immune response. Prostaglandins are lipid mediators that may be important mediators of intestinal inflammation. In this study we assessed the role of prostaglandins in the regulation of mucosal inflammation in the IL-10(-/-) mouse model of IBD. Prostaglandin (PG) synthesis was inhibited with nonselective or cyclooxygenase (COX)-isoform selective inhibitors. Severity of inflammation was assessed histologically. Cytokine production was assessed by ribonuclease protection analysis and enzyme-linked immunosorbent assay. PGE(2) levels were assessed by enzyme immunoassay. COX-1 and COX-2 expression was assessed by Western blot analysis. Nonsteroidal anti-inflammatory drug (NSAID) treatment of wild-type mice had minimal effect on the colon. In contrast, NSAID treatment of 4-week-old IL-10(-/-) mice resulted in rapid development of colitis characterized by infiltration of the lamina propria with macrophages and interferon gamma-producing CD4(+) T cells. Colitis persisted after withdrawal of the NSAID. NSAID treatment decreased colonic PGE(2) levels by 75%. Treatment of IL-10(-/-) mice with sulindac sulfone (which does not inhibit PG production) did not induce colitis whereas the NSAID sulindac induced severe colitis. COX-1- or COX-2-selective inhibitors used alone did not induce IBD in IL-10(-/-) mice. However, the combination of COX-1- and COX-2-selective inhibitors did induce colitis. NSAID treatment of IL-10(-/-) mice results in the rapid development of severe, chronic IBD. Endogenous PGs are important inhibitors of the development of intestinal inflammation in IL-10(-/-) mice.

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

PubMed

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

2017-07-10

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

Direct Lentiviral-Cyclooxygenase 2 Application to the Tendon-Bone Interface Promotes Osteointegration and Enhances Return of the Pull-Out Tensile Strength of the Tendon Graft in a Rat Model of Biceps Tenodesis

PubMed Central

Wergedal, Jon E.; Stiffel, Virginia; Lau, Kin-Hing William

2014-01-01

This study sought to determine if direct application of the lentiviral (LV)-cyclooxygenase 2 (COX2) vector to the tendon-bone interface would promote osteointegration of the tendon graft in a rat model of biceps tenodesis. The LV-COX2 gene transfer strategy was chosen for investigation because a similar COX2 gene transfer strategy promoted bony bridging of the fracture gap during bone repair, which involves similar histologic transitions that occur in osteointegration. Briefly, a 1.14-mm diameter tunnel was drilled in the mid-groove of the humerus of adult Fischer 344 rats. The LV-COX2 or βgal control vector was applied directly into the bone tunnel and onto the end of the tendon graft, which was then pulled into the bone tunnel. A poly-L-lactide pin was press-fitted into the tunnel as interference fixation. Animals were sacrificed at 3, 5, or 8 weeks for histology analysis of osteointegration. The LV-COX2 gene transfer strategy enhanced neo-chondrogenesis at the tendon-bone interface but with only marginal effect on de novo bone formation. The tendon-bone interface of the LV-COX2-treated tenodesis showed the well-defined tendon-to-fibrocartilage-to-bone histologic transitions that are indicative of osteointegration of the tendon graft. The LV-COX2 in vivo gene transfer strategy also significantly enhanced angiogenesis at the tendon-bone interface. To determine if the increased osteointegration was translated into an improved pull-out mechanical strength property, the pull-out tensile strength of the LV-COX2-treated tendon grafts was determined with a pull-out mechanical testing assay. The LV-COX2 strategy yielded a significant improvement in the return of the pull-out strength of the tendon graft after 8 weeks. In conclusion, the COX2-based in vivo gene transfer strategy enhanced angiogenesis, osteointegration and improved return of the pull-out strength of the tendon graft. Thus, this strategy has great potential to be developed into an effective therapy to promote tendon-to-bone healing after tenodesis or related surgeries. PMID:24848992

Effects of cicletanine in the left circumflex coronary artery occlusion-reperfusion canine model of sudden death: analysis of 107 experiments using Cox's proportional hazards model.

PubMed

Jouve, R; Puddu, P E; Langlet, F; Lanti, M; Guillen, J C; Rolland, P H; Serradimigni, A

1988-01-01

Multivariate analysis of survival using Cox's proportional hazards model demonstrates that several clinically measurable covariates are determinants of life-threatening arrhythmias following left circumflex coronary artery occlusion-reperfusion in 107 dogs. These are heart rate, ST segment elevation and mean aortic pressure immediately (3 min) following occlusion, and the presence of early (0-10 min) post-occlusion sustained ventricular tachycardia. The risk of occlusion-reperfusion ventricular fibrillation was determined according to Cox's solution based on ST segment elevation, thus enabling quantification of the role of cicletanine. Since cicletanine-treated dogs had reduced mean ST segment elevation at 3 min post-occlusion, lower incidence of early post-occlusion (0-10 min) sustained ventricular tachycardia, and increased endogenous production of prostacyclin, and the latter was inversely correlated with the level of ST segment elevation, it is concluded that such favourable effects on the ischaemic myocardium were contributory to the improved outcome in these experiments. These effects on the ischaemic myocardium obtained in spite of a hypotensive action in the experimental setting might be regarded as desirable and it is therefore suggested that they should be further investigated by pharmacodynamic studies in human subjects.

Cox regression analysis with missing covariates via nonparametric multiple imputation.

PubMed

Hsu, Chiu-Hsieh; Yu, Mandi

2018-01-01

We consider the situation of estimating Cox regression in which some covariates are subject to missing, and there exists additional information (including observed event time, censoring indicator and fully observed covariates) which may be predictive of the missing covariates. We propose to use two working regression models: one for predicting the missing covariates and the other for predicting the missing probabilities. For each missing covariate observation, these two working models are used to define a nearest neighbor imputing set. This set is then used to non-parametrically impute covariate values for the missing observation. Upon the completion of imputation, Cox regression is performed on the multiply imputed datasets to estimate the regression coefficients. In a simulation study, we compare the nonparametric multiple imputation approach with the augmented inverse probability weighted (AIPW) method, which directly incorporates the two working models into estimation of Cox regression, and the predictive mean matching imputation (PMM) method. We show that all approaches can reduce bias due to non-ignorable missing mechanism. The proposed nonparametric imputation method is robust to mis-specification of either one of the two working models and robust to mis-specification of the link function of the two working models. In contrast, the PMM method is sensitive to misspecification of the covariates included in imputation. The AIPW method is sensitive to the selection probability. We apply the approaches to a breast cancer dataset from Surveillance, Epidemiology and End Results (SEER) Program.

Expression of prostaglandin metabolising enzymes COX-2 and 15-PGDH and VDR in human granulosa cells.

PubMed

Thill, Marc; Becker, Steffi; Fischer, Dorothea; Cordes, Tim; Hornemann, Amadeus; Diedrich, Klaus; Salehin, Darius; Friedrich, Michael

2009-09-01

Prostaglandins (PGs) within the periovulatory follicle are essential for various female reproductive functions such as follicular development and maturation. In animal models, granulosa cells express the PG synthesizing enzyme cyclooxygenase-2 (COX-2) and the PG inactivating enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH). First references suggest a correlation between vitamin D and prostaglandin metabolism through the impact of 1,25(OH)2D3 (calcitriol) on the expression of COX-2 and 15-PGDH. The expression of COX-2, 15-PGDH and the vitamin D receptor (VDR) in human granulosa cells (COV434, hGC and HGL5), which were originally isolated from different stages of follicular maturation, was determined by real-time PCR (RT-PCR) and Western blot analysis. A positive correlation of COX-2 and VDR protein was found in the COV434 and HGL5 cells and an inverse correlation of 15-PGDH and VDR protein levels in all the investigated cell types. There may be a link between VDR, associated target genes and prostaglandin metabolism in human follicular maturation and luteolysis.

XRCC5 cooperates with p300 to promote cyclooxygenase-2 expression and tumor growth in colon cancers

PubMed Central

Hao, Jiajiao; Chen, Miao; Yu, Wendan; Guo, Wei; Chen, Yiming; Huang, Wenlin; Deng, Wuguo

2017-01-01

Cyclooxygenase (COX) is the rate-limiting enzyme in prostaglandins (PGs) biosynthesis. Previous studies indicate that COX-2, one of the isoforms of COX, is highly expressed in colon cancers and plays a key role in colon cancer carcinogenesis. Thus, searching for novel transcription factors regulating COX-2 expression will facilitate drug development for colon cancer. In this study, we identified XRCC5 as a binding protein of the COX-2 gene promoter in colon cancer cells with streptavidin-agarose pulldown assay and mass spectrometry analysis, and found that XRCC5 promoted colon cancer growth through modulation of COX-2 signaling. Knockdown of XRCC5 by siRNAs inhibited the growth of colon cancer cells in vitro and of tumor xenografts in a mouse model in vivo by suppressing COX-2 promoter activity and COX-2 protein expression. Conversely, overexpression of XRCC5 promoted the growth of colon cancer cells by activating COX-2 promoter and increasing COX-2 protein expression. Moreover, the role of p300 (a transcription co-activator) in acetylating XRCC5 to co-regulate COX-2 expression was also evaluated. Immunofluorescence assay and confocal microscopy showed that XRCC5 and p300 proteins were co-located in the nucleus of colon cancer cells. Co-immunoprecipitation assay also proved the interaction between XRCC5 and p300 in nuclear proteins of colon cancer cells. Cell viability assay indicated that the overexpression of wild-type p300, but not its histone acetyltransferase (HAT) domain deletion mutant, increased XRCC5 acetylation, thereby up-regulated COX-2 expression and promoted the growth of colon cancer cells. In contrast, suppression of p300 by a p300 HAT-specific inhibitor (C646) inhibited colon cancer cell growth by suppressing COX-2 expression. Taken together, our results demonstrated that XRCC5 promoted colon cancer growth by cooperating with p300 to regulate COX-2 expression, and suggested that the XRCC5/p300/COX-2 signaling pathway was a potential target in the treatment of colon cancers. PMID:29049411

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

ERIC Educational Resources Information Center

Chen, Chau-Kuang

2005-01-01

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

Genetic deletion of COX-2 diminishes VEGF production in mouse retinal Müller cells.

PubMed

Yanni, Susan E; McCollum, Gary W; Penn, John S

2010-07-01

Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit COX activity, reduce the production of retinal VEGF and neovascularization in relevant models of ocular disease. We hypothesized that COX-2 mediates VEGF production in retinal Müller cells, one of its primary sources in retinal neovascular disease. The purpose of this study was to determine the role of COX-2 and its products in VEGF expression and secretion. These studies have more clearly defined the role of COX-2 and COX-2-derived prostanoids in retinal angiogenesis. Müller cells derived from wild-type and COX-2 null mice were exposed to hypoxia for 0-24 h. COX-2 protein and activity were assessed by western blot analysis and GC-MS, respectively. VEGF production was assessed by ELISA. Wild-type mouse Müller cells were treated with vehicle (0.1% DMSO), 10 microM PGE(2), or PGE(2) + 5 microM H-89 (a PKA inhibitor), for 12 h. VEGF production was assessed by ELISA. Hypoxia significantly increased COX-2 protein (p < 0.05) and activity (p < 0.05), and VEGF production (p < 0.0003). COX-2 null Müller cells produced significantly less VEGF in response to hypoxia (p < 0.05). Of the prostanoids, PGE(2) was significantly increased by hypoxia (p < 0.02). Exogenous PGE(2) significantly increased VEGF production by Müller cells (p < 0.0039), and this effect was inhibited by H-89 (p < 0.055). These data demonstrate that hypoxia induces COX-2, prostanoid production, and VEGF synthesis in Müller cells, and that VEGF production is at least partially COX-2-dependent. Our study suggests that PGE(2), signaling through the EP(2) and/or EP(4) receptor and PKA, mediates the VEGF response of Müller cells. Copyright 2010 Elsevier Ltd. All rights reserved.

Multiple recent horizontal transfers of the cox1 intron in Solanaceae and extended co-conversion of flanking exons

PubMed Central

2011-01-01

Background The most frequent case of horizontal transfer in plants involves a group I intron in the mitochondrial gene cox1, which has been acquired via some 80 separate plant-to-plant transfer events among 833 diverse angiosperms examined. This homing intron encodes an endonuclease thought to promote the intron's promiscuous behavior. A promising experimental approach to study endonuclease activity and intron transmission involves somatic cell hybridization, which in plants leads to mitochondrial fusion and genome recombination. However, the cox1 intron has not yet been found in the ideal group for plant somatic genetics - the Solanaceae. We therefore undertook an extensive survey of this family to find members with the intron and to learn more about the evolutionary history of this exceptionally mobile genetic element. Results Although 409 of the 426 species of Solanaceae examined lack the cox1 intron, it is uniformly present in three phylogenetically disjunct clades. Despite strong overall incongruence of cox1 intron phylogeny with angiosperm phylogeny, two of these clades possess nearly identical intron sequences and are monophyletic in intron phylogeny. These two clades, and possibly the third also, contain a co-conversion tract (CCT) downstream of the intron that is extended relative to all previously recognized CCTs in angiosperm cox1. Re-examination of all published cox1 genes uncovered additional cases of extended co-conversion and identified a rare case of putative intron loss, accompanied by full retention of the CCT. Conclusions We infer that the cox1 intron was separately and recently acquired by at least three different lineages of Solanaceae. The striking identity of the intron and CCT from two of these lineages suggests that one of these three intron captures may have occurred by a within-family transfer event. This is consistent with previous evidence that horizontal transfer in plants is biased towards phylogenetically local events. The discovery of extended co-conversion suggests that other cox1 conversions may be longer than realized but obscured by the exceptional conservation of plant mitochondrial sequences. Our findings provide further support for the rampant-transfer model of cox1 intron evolution and recommend the Solanaceae as a model system for the experimental analysis of cox1 intron transfer in plants. PMID:21943226

Survival analysis of cervical cancer using stratified Cox regression

NASA Astrophysics Data System (ADS)

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

2016-04-01

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

A comparison between the use of Cox regression and the use of partial least squares-Cox regression to predict the survival of kidney-transplant patients

NASA Astrophysics Data System (ADS)

Solimun

2017-05-01

The aim of this research is to model survival data from kidney-transplant patients using the partial least squares (PLS)-Cox regression, which can both meet and not meet the no-multicollinearity assumption. The secondary data were obtained from research entitled "Factors affecting the survival of kidney-transplant patients". The research subjects comprised 250 patients. The predictor variables consisted of: age (X1), sex (X2); two categories, prior hemodialysis duration (X3), diabetes (X4); two categories, prior transplantation number (X5), number of blood transfusions (X6), discrepancy score (X7), use of antilymphocyte globulin(ALG) (X8); two categories, while the response variable was patient survival time (in months). Partial least squares regression is a model that connects the predictor variables X and the response variable y and it initially aims to determine the relationship between them. Results of the above analyses suggest that the survival of kidney transplant recipients ranged from 0 to 55 months, with 62% of the patients surviving until they received treatment that lasted for 55 months. The PLS-Cox regression analysis results revealed that patients' age and the use of ALG significantly affected the survival time of patients. The factor of patients' age (X1) in the PLS-Cox regression model merely affected the failure probability by 1.201. This indicates that the probability of dying for elderly patients with a kidney transplant is 1.152 times higher than that for younger patients.

Effects of low-level laser therapy (LLLT) and diclofenac (topical and intramuscular) as single and combined therapy in experimental model of controlled muscle strain in rats.

PubMed

de Paiva Carvalho, Rodrigo Leal; Leal-Junior, Ernesto Cesar Pinto; Petrellis, Maria Carla; Marcos, Rodrigo Labat; de Carvalho, Maria Helena Catelli; De Nucci, Gilberto; Lopes-Martins, Rodrigo Alvaro Brandão

2013-01-01

Muscle injuries represent ca 30% of sports injuries and excessive stretching of muscle causes more than 90% of injuries. Currently the most used treatments are nonsteroidal anti-inflammatory drugs (NSAIDs), however, in last years, low-level laser therapy (LLLT) is becoming an interesting therapeutic modality. The aim of this study was to evaluate the effect of single and combined therapies (LLLT, topical application of diclofenac and intramuscular diclofenac) on functional and biochemical aspects in an experimental model of controlled muscle strain in rats. Muscle strain was induced by overloading tibialis anterior muscle of rats. Injured groups received either no treatment, or a single treatment with topical or intramuscular diclofenac (TD and ID), or LLLT (3 J, 810 nm, 100 mW) 1 h after injury. Walking track analysis was the functional outcome and biochemical analyses included mRNA expression of COX-1 and COX-2 and blood levels of prostaglandin E2 (PGE2 ). All treatments significantly decreased COX-1 and COX-2 gene expression compared with injury group (P < 0.05). However, LLLT showed better effects than TD and ID regarding PGE2 levels and walking track analysis (P < 0.05). We can conclude that LLLT has more efficacy than topical and intramuscular diclofenac in treatment of muscle strain injury in acute stage. © 2012 Wiley Periodicals, Inc. Photochemistry and Photobiology © 2012 The American Society of Photobiology.

Targeted Deletion and Lipidomic Analysis Identify Epithelial Cell COX-2 as a Major Driver of Chemically-induced Skin Cancer

PubMed Central

Jiao, Jing; Ishikawa, Tomo-o; Dumlao, Darren S.; Norris, Paul C.; Magyar, Clara E.; Mikulec, Carol; Catapang, Art; Dennis, Edward A.; Fischer, Susan M.; Herschman, Harvey R.

2014-01-01

Pharmacologic and global gene deletion studies demonstrate that cyclooxygenase-2 (PTGS2/COX2) plays a critical role in DMBA/TPA-induced skin tumor induction. While many cell types in the tumor microenvironment express COX-2, the cell types in which COX-2 expression is required for tumor promotion are not clearly established. Here, cell-type specific Cox-2 gene deletion reveals a vital role for skin epithelial cell COX-2 expression in DMBA/TPA tumor induction. In contrast, myeloid Cox-2 gene deletion has no effect on DMBA/TPA tumorigenesis. The infrequent, small tumors that develop on mice with an epithelial cell-specific Cox-2 gene deletion have decreased proliferation and increased cell differentiation properties. Blood vessel density is reduced in tumors with an epithelial cell-specific Cox-2 gene deletion, compared to littermate control tumors, suggesting a reciprocal relationship in tumor progression between COX-2 expressing tumor epithelial cells and microenvironment endothelial cells. Lipidomics analysis of skin and tumors from DMBA/TPA-treated mice suggests that the prostaglandins PGE2 and PGF2α are likely candidates for the epithelial cell COX-2-dependent eicosanoids that mediate tumor progression. This study both illustrates the value of cell-type specific gene deletions in understanding the cellular roles of signal-generating pathways in complex microenvironments and emphasizes the benefit of a systems-based lipidomic analysis approach to identify candidate lipid mediators of biological responses. PMID:25063587

Comparison of exact, efron and breslow parameter approach method on hazard ratio and stratified cox regression model

NASA Astrophysics Data System (ADS)

Fatekurohman, Mohamat; Nurmala, Nita; Anggraeni, Dian

2018-04-01

Lungs are the most important organ, in the case of respiratory system. Problems related to disorder of the lungs are various, i.e. pneumonia, emphysema, tuberculosis and lung cancer. Comparing all those problems, lung cancer is the most harmful. Considering about that, the aim of this research applies survival analysis and factors affecting the endurance of the lung cancer patient using comparison of exact, Efron and Breslow parameter approach method on hazard ratio and stratified cox regression model. The data applied are based on the medical records of lung cancer patients in Jember Paru-paru hospital on 2016, east java, Indonesia. The factors affecting the endurance of the lung cancer patients can be classified into several criteria, i.e. sex, age, hemoglobin, leukocytes, erythrocytes, sedimentation rate of blood, therapy status, general condition, body weight. The result shows that exact method of stratified cox regression model is better than other. On the other hand, the endurance of the patients is affected by their age and the general conditions.

Identification of subgroups by risk of graft failure after paediatric renal transplantation: application of survival tree models on the ESPN/ERA-EDTA Registry.

PubMed

Lofaro, Danilo; Jager, Kitty J; Abu-Hanna, Ameen; Groothoff, Jaap W; Arikoski, Pekka; Hoecker, Britta; Roussey-Kesler, Gwenaelle; Spasojević, Brankica; Verrina, Enrico; Schaefer, Franz; van Stralen, Karlijn J

2016-02-01

Identification of patient groups by risk of renal graft loss might be helpful for accurate patient counselling and clinical decision-making. Survival tree models are an alternative statistical approach to identify subgroups, offering cut-off points for covariates and an easy-to-interpret representation. Within the European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry data we identified paediatric patient groups with specific profiles for 5-year renal graft survival. Two analyses were performed, including (i) parameters known at time of transplantation and (ii) additional clinical measurements obtained early after transplantation. The identified subgroups were added as covariates in two survival models. The prognostic performance of the models was tested and compared with conventional Cox regression analyses. The first analysis included 5275 paediatric renal transplants. The best 5-year graft survival (90.4%) was found among patients who received a renal graft as a pre-emptive transplantation or after short-term dialysis (<45 days), whereas graft survival was poorest (51.7%) in adolescents transplanted after long-term dialysis (>2.2 years). The Cox model including both pre-transplant factors and tree subgroups had a significantly better predictive performance than conventional Cox regression (P < 0.001). In the analysis including clinical factors, graft survival ranged from 97.3% [younger patients with estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m(2) and dialysis <20 months] to 34.7% (adolescents with eGFR <60 mL/min/1.73 m(2) and dialysis >20 months). Also in this case combining tree findings and clinical factors improved the predictive performance as compared with conventional Cox model models (P < 0.0001). In conclusion, we demonstrated the tree model to be an accurate and attractive tool to predict graft failure for patients with specific characteristics. This may aid the evaluation of individual graft prognosis and thereby the design of measures to improve graft survival in the poor prognosis groups. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Thrombosis Is Reduced by Inhibition of COX-1, but Unaffected by Inhibition of COX-2, in an Acute Model of Platelet Activation in the Mouse

PubMed Central

Armstrong, Paul C.; Kirkby, Nicholas S.; Zain, Zetty N.; Emerson, Michael; Mitchell, Jane A.; Warner, Timothy D.

2011-01-01

Background Clinical use of selective inhibitors of cyclooxygenase (COX)-2 appears associated with increased risk of thrombotic events. This is often hypothesised to reflect reduction in anti-thrombotic prostanoids, notably PGI2, formed by COX-2 present within endothelial cells. However, whether COX-2 is actually expressed to any significant extent within endothelial cells is controversial. Here we have tested the effects of acute inhibition of COX on platelet reactivity using a functional in vivo approach in mice. Methodology/Principal Findings A non-lethal model of platelet-driven thromboembolism in the mouse was used to assess the effects of aspirin (7 days orally as control) diclofenac (1 mg.kg−1, i.v.) and parecoxib (0.5 mg.kg−1, i.v.) on thrombus formation induced by collagen or the thromboxane (TX) A2-mimetic, U46619. The COX inhibitory profiles of the drugs were confirmed in mouse tissues ex vivo. Collagen and U46619 caused in vivo thrombus formation with the former, but not latter, sensitive to oral dosing with aspirin. Diclofenac inhibited COX-1 and COX-2 ex vivo and reduced thrombus formation in response to collagen, but not U46619. Parecoxib inhibited only COX-2 and had no effect upon thrombus formation caused by either agonist. Conclusions/Significance Inhibition of COX-1 by diclofenac or aspirin reduced thrombus formation induced by collagen, which is partly dependent upon platelet-derived TXA2, but not that induced by U46619, which is independent of platelet TXA2. These results are consistent with the model demonstrating the effects of COX-1 inhibition in platelets, but provide no support for the hypothesis that acute inhibition of COX-2 in the circulation increases thrombosis. PMID:21629780

Bidirectional interactions between indomethacin and the murine intestinal microbiota

PubMed Central

Liang, Xue; Bittinger, Kyle; Li, Xuanwen; Abernethy, Darrell R; Bushman, Frederic D; FitzGerald, Garret A

2015-01-01

The vertebrate gut microbiota have been implicated in the metabolism of xenobiotic compounds, motivating studies of microbe-driven metabolism of clinically important drugs. Here, we studied interactions between the microbiota and indomethacin, a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenases (COX) -1 and -2. Indomethacin was tested in both acute and chronic exposure models in mice at clinically relevant doses, which suppressed production of COX-1- and COX-2-derived prostaglandins and caused small intestinal (SI) damage. Deep sequencing analysis showed that indomethacin exposure was associated with alterations in the structure of the intestinal microbiota in both dosing models. Perturbation of the intestinal microbiome by antibiotic treatment altered indomethacin pharmacokinetics and pharmacodynamics, which is probably the result of reduced bacterial β-glucuronidase activity. Humans show considerable inter-individual differences in their microbiota and their responses to indomethacin — thus, the drug-microbe interactions described here provide candidate mediators of individualized drug responses. DOI: http://dx.doi.org/10.7554/eLife.08973.001 PMID:26701907

Assessing the effect of quantitative and qualitative predictors on gastric cancer individuals survival using hierarchical artificial neural network models.

PubMed

Amiri, Zohreh; Mohammad, Kazem; Mahmoudi, Mahmood; Parsaeian, Mahbubeh; Zeraati, Hojjat

2013-01-01

There are numerous unanswered questions in the application of artificial neural network models for analysis of survival data. In most studies, independent variables have been studied as qualitative dichotomous variables, and results of using discrete and continuous quantitative, ordinal, or multinomial categorical predictive variables in these models are not well understood in comparison to conventional models. This study was designed and conducted to examine the application of these models in order to determine the survival of gastric cancer patients, in comparison to the Cox proportional hazards model. We studied the postoperative survival of 330 gastric cancer patients who suffered surgery at a surgical unit of the Iran Cancer Institute over a five-year period. Covariates of age, gender, history of substance abuse, cancer site, type of pathology, presence of metastasis, stage, and number of complementary treatments were entered in the models, and survival probabilities were calculated at 6, 12, 18, 24, 36, 48, and 60 months using the Cox proportional hazards and neural network models. We estimated coefficients of the Cox model and the weights in the neural network (with 3, 5, and 7 nodes in the hidden layer) in the training group, and used them to derive predictions in the study group. Predictions with these two methods were compared with those of the Kaplan-Meier product limit estimator as the gold standard. Comparisons were performed with the Friedman and Kruskal-Wallis tests. Survival probabilities at different times were determined using the Cox proportional hazards and a neural network with three nodes in the hidden layer; the ratios of standard errors with these two methods to the Kaplan-Meier method were 1.1593 and 1.0071, respectively, revealed a significant difference between Cox and Kaplan-Meier (P < 0.05) and no significant difference between Cox and the neural network, and the neural network and the standard (Kaplan-Meier), as well as better accuracy for the neural network (with 3 nodes in the hidden layer). Probabilities of survival were calculated using three neural network models with 3, 5, and 7 nodes in the hidden layer, and it has been observed that none of the predictions was significantly different from results with the Kaplan-Meier method and they appeared more comparable towards the last months (fifth year). However, we observed better accuracy using the neural network with 5 nodes in the hidden layer. Using the Cox proportional hazards and a neural network with 3 nodes in the hidden layer, we found enhanced accuracy with the neural network model. Neural networks can provide more accurate predictions for survival probabilities compared to the Cox proportional hazards mode, especially now that advances in computer sciences have eliminated limitations associated with complex computations. It is not recommended in order to adding too many hidden layer nodes because sample size related effects can reduce the accuracy. We recommend increasing the number of nodes to a point that increased accuracy continues (decrease in mean standard error), however increasing nodes should cease when a change in this trend is observed.

Personalized dynamic prediction of death according to tumour progression and high-dimensional genetic factors: Meta-analysis with a joint model.

PubMed

Emura, Takeshi; Nakatochi, Masahiro; Matsui, Shigeyuki; Michimae, Hirofumi; Rondeau, Virginie

2017-01-01

Developing a personalized risk prediction model of death is fundamental for improving patient care and touches on the realm of personalized medicine. The increasing availability of genomic information and large-scale meta-analytic data sets for clinicians has motivated the extension of traditional survival prediction based on the Cox proportional hazards model. The aim of our paper is to develop a personalized risk prediction formula for death according to genetic factors and dynamic tumour progression status based on meta-analytic data. To this end, we extend the existing joint frailty-copula model to a model allowing for high-dimensional genetic factors. In addition, we propose a dynamic prediction formula to predict death given tumour progression events possibly occurring after treatment or surgery. For clinical use, we implement the computation software of the prediction formula in the joint.Cox R package. We also develop a tool to validate the performance of the prediction formula by assessing the prediction error. We illustrate the method with the meta-analysis of individual patient data on ovarian cancer patients.

Combined Analysis of COX-2 and p53 Expressions Reveals Synergistic Inverse Correlations with Microsatellite Instability and CpG Island Methylator Phenotype in Colorectal Cancer1

PubMed Central

Ogino, Shuji; Brahmandam, Mohan; Kawasaki, Takako; Kirkner, Gregory J; Loda, Massimo; Fuchs, Charles S

2006-01-01

Abstract Cyclooxygenase-2 (COX-2) overexpression and mutations of p53 (a known COX-2 regulator) are inversely associated with microsatellite instability—high (MSI-H) and CpG island methylator phenotype (CIMP), characterized by extensive promoter methylation, is associated with MSI-H. However, no studies have comprehensively examined interrelations between COX-2, p53, MSI, and CIMP. Using MethyLight, we measured DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16/INK4A), CRABP1, MLH1, and NEUROG1] in relatively unbiased samples of 751 colorectal cancer cases obtained from two large prospective cohorts; 115 (15%) tumors were CIMP-high (≥ 4 of 5 methylated promoters), 251 (33%) were CIMP-low (1 to 3 methylated promoters), and the remaining 385 (51%) were CIMP-0 (no methylated promoters). CIMP-high tumors were much less frequent in COX-2+/p53+ tumors (4.6%) than in COX-2+/p53- tumors (19%; P < .0001), COX-2-/p53+ tumors (17%; P= .04), and COX-2-/p53- tumors (28%; P < .0001). In addition, COX-2+/p53+ tumors were significantly less common in MSI-H CIMP-high tumors (9.7%) than in non-MSI-H CIMP-low/CIMP-0 tumors (44–47%; P< .0001). In conclusion, COX-2 and p53 alterations were synergistically inversely correlated with both MSI-H and CIMP-high. Our data suggest that a combined analysis of COX-2 and p53 may be more useful for the molecular classification of colorectal cancer than either COX-2 or p53 analysis alone. PMID:16820091

Analysis of a genetically structured variance heterogeneity model using the Box-Cox transformation.

PubMed

Yang, Ye; Christensen, Ole F; Sorensen, Daniel

2011-02-01

Over recent years, statistical support for the presence of genetic factors operating at the level of the environmental variance has come from fitting a genetically structured heterogeneous variance model to field or experimental data in various species. Misleading results may arise due to skewness of the marginal distribution of the data. To investigate how the scale of measurement affects inferences, the genetically structured heterogeneous variance model is extended to accommodate the family of Box-Cox transformations. Litter size data in rabbits and pigs that had previously been analysed in the untransformed scale were reanalysed in a scale equal to the mode of the marginal posterior distribution of the Box-Cox parameter. In the rabbit data, the statistical evidence for a genetic component at the level of the environmental variance is considerably weaker than that resulting from an analysis in the original metric. In the pig data, the statistical evidence is stronger, but the coefficient of correlation between additive genetic effects affecting mean and variance changes sign, compared to the results in the untransformed scale. The study confirms that inferences on variances can be strongly affected by the presence of asymmetry in the distribution of data. We recommend that to avoid one important source of spurious inferences, future work seeking support for a genetic component acting on environmental variation using a parametric approach based on normality assumptions confirms that these are met.

Joint model-based clustering of nonlinear longitudinal trajectories and associated time-to-event data analysis, linked by latent class membership: with application to AIDS clinical studies.

PubMed

Huang, Yangxin; Lu, Xiaosun; Chen, Jiaqing; Liang, Juan; Zangmeister, Miriam

2017-10-27

Longitudinal and time-to-event data are often observed together. Finite mixture models are currently used to analyze nonlinear heterogeneous longitudinal data, which, by releasing the homogeneity restriction of nonlinear mixed-effects (NLME) models, can cluster individuals into one of the pre-specified classes with class membership probabilities. This clustering may have clinical significance, and be associated with clinically important time-to-event data. This article develops a joint modeling approach to a finite mixture of NLME models for longitudinal data and proportional hazard Cox model for time-to-event data, linked by individual latent class indicators, under a Bayesian framework. The proposed joint models and method are applied to a real AIDS clinical trial data set, followed by simulation studies to assess the performance of the proposed joint model and a naive two-step model, in which finite mixture model and Cox model are fitted separately.

Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study

PubMed Central

Grove, Erik L; Hansen, Peter Riis; Olesen, Jonas B; Ahlehoff, Ole; Selmer, Christian; Lindhardsen, Jesper; Madsen, Jan Kyst; Køber, Lars; Torp-Pedersen, Christian; Gislason, Gunnar H

2011-01-01

Objective To examine the effect of proton pump inhibitors on adverse cardiovascular events in aspirin treated patients with first time myocardial infarction. Design Retrospective nationwide propensity score matched study based on administrative data. Setting All hospitals in Denmark. Participants All aspirin treated patients surviving 30 days after a first myocardial infarction from 1997 to 2006, with follow-up for one year. Patients treated with clopidogrel were excluded. Main outcome measures The risk of the combined end point of cardiovascular death, myocardial infarction, or stroke associated with use of proton pump inhibitors was analysed using Kaplan-Meier analysis, Cox proportional hazard models, and propensity score matched Cox proportional hazard models. Results 3366 of 19 925 (16.9%) aspirin treated patients experienced recurrent myocardial infarction, stroke, or cardiovascular death. The hazard ratio for the combined end point in patients receiving proton pump inhibitors based on the time dependent Cox proportional hazard model was 1.46 (1.33 to 1.61; P<0.001) and for the propensity score matched model based on 8318 patients it was 1.61 (1.45 to 1.79; P<0.001). A sensitivity analysis showed no increase in risk related to use of H2 receptor blockers (1.04, 0.79 to 1.38; P=0.78). Conclusion In aspirin treated patients with first time myocardial infarction, treatment with proton pump inhibitors was associated with an increased risk of adverse cardiovascular events. PMID:21562004

Application and validation of Cox regression models in a single-center series of double kidney transplantation.

PubMed

Santori, G; Fontana, I; Bertocchi, M; Gasloli, G; Magoni Rossi, A; Tagliamacco, A; Barocci, S; Nocera, A; Valente, U

2010-05-01

A useful approach to reduce the number of discarded marginal kidneys and to increase the nephron mass is double kidney transplantation (DKT). In this study, we retrospectively evaluated the potential predictors for patient and graft survival in a single-center series of 59 DKT procedures performed between April 21, 1999, and September 21, 2008. The kidney recipients of mean age 63.27 +/- 5.17 years included 16 women (27%) and 43 men (73%). The donors of mean age 69.54 +/- 7.48 years included 32 women (54%) and 27 men (46%). The mean posttransplant dialysis time was 2.37 +/- 3.61 days. The mean hospitalization was 20.12 +/- 13.65 days. Average serum creatinine (SCr) at discharge was 1.5 +/- 0.59 mg/dL. In view of the limited numbers of recipient deaths (n = 4) and graft losses (n = 8) that occurred in our series, the proportional hazards assumption for each Cox regression model with P < .05 was tested by using correlation coefficients between transformed survival times and scaled Schoenfeld residuals, and checked with smoothed plots of Schoenfeld residuals. For patient survival, the variables that reached statistical significance were donor SCr (P = .007), donor creatinine cleararance (P = .023), and recipient age (P = .047). Each significant model passed the Schoenfeld test. By entering these variables into a multivariate Cox model for patient survival, no further significance was observed. In the univariate Cox models performed for graft survival, statistical significance was noted for donor SCr (P = .027), SCr 3 months post-DKT (P = .043), and SCr 6 months post-DKT (P = .017). All significant univariate models for graft survival passed the Schoenfeld test. A final multivariate model retained SCr at 6 months (beta = 1.746, P = .042) and donor SCr (beta = .767, P = .090). In our analysis, SCr at 6 months seemed to emerge from both univariate and multivariate Cox models as a potential predictor of graft survival among DKT. Multicenter studies with larger recipient populations and more graft losses should be performed to confirm our findings. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Survival analysis: Part I — analysis of time-to-event

PubMed Central

2018-01-01

Length of time is a variable often encountered during data analysis. Survival analysis provides simple, intuitive results concerning time-to-event for events of interest, which are not confined to death. This review introduces methods of analyzing time-to-event. The Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazards regression modeling method are described with examples of hypothetical data. PMID:29768911

Functional form and risk adjustment of hospital costs: Bayesian analysis of a Box-Cox random coefficients model.

PubMed

Hollenbeak, Christopher S

2005-10-15

While risk-adjusted outcomes are often used to compare the performance of hospitals and physicians, the most appropriate functional form for the risk adjustment process is not always obvious for continuous outcomes such as costs. Semi-log models are used most often to correct skewness in cost data, but there has been limited research to determine whether the log transformation is sufficient or whether another transformation is more appropriate. This study explores the most appropriate functional form for risk-adjusting the cost of coronary artery bypass graft (CABG) surgery. Data included patients undergoing CABG surgery at four hospitals in the midwest and were fit to a Box-Cox model with random coefficients (BCRC) using Markov chain Monte Carlo methods. Marginal likelihoods and Bayes factors were computed to perform model comparison of alternative model specifications. Rankings of hospital performance were created from the simulation output and the rankings produced by Bayesian estimates were compared to rankings produced by standard models fit using classical methods. Results suggest that, for these data, the most appropriate functional form is not logarithmic, but corresponds to a Box-Cox transformation of -1. Furthermore, Bayes factors overwhelmingly rejected the natural log transformation. However, the hospital ranking induced by the BCRC model was not different from the ranking produced by maximum likelihood estimates of either the linear or semi-log model. Copyright (c) 2005 John Wiley & Sons, Ltd.

Flow cytometric analysis of platelet cyclooxygenase-1 and -2 and surface glycoproteins in patients with immune thrombocytopenia and healthy individuals.

PubMed

Rubak, Peter; Kristensen, Steen D; Hvas, Anne-Mette

2017-06-01

Immature platelets may contain more platelet enzymes such as cyclooxygenase (COX)-1 and COX-2 than mature platelets. Patients with immune thrombocytopenia (ITP) have a higher fraction of immature platelets and can therefore be utilized as a biological model for investigating COX-1 and COX-2 platelet expression. The aims were to develop flow cytometric assays for platelet COX-1 and COX-2 and to investigate the COX-1 and COX-2 platelet expression, platelet turnover, and platelet glycoproteins in ITP patients (n = 10) compared with healthy individuals (n = 30). Platelet count and platelet turnover parameters (mean platelet volume (MPV), immature platelet fraction (IPF), and immature platelet count (IPC)) were measured by flow cytometry (Sysmex XE-5000). Platelet COX-1, COX-2, and the glycoproteins (GP)IIb, IX, Ib, Ia, and IIIa were all analyzed by flow cytometry (Navios) and expressed as median fluorescence intensity. COX analyses were performed in both whole blood and platelet rich plasma (PRP), whereas platelet glycoproteins were analyzed in whole blood only. ITP patients had significantly lower platelet count (55 × 10 9 /L) than healthy individuals (240 × 10 9 /L, p < 0.01), but a higher MPV (p = 0.03) and IPF (p < 0.01). IPC was similar for the two groups (p = 0.74). PRP had significantly lower MPV (p < 0.01) and significantly higher platelet count and IPC (both p-values <0.03) when compared with whole blood. IPF was similar for PRP and whole blood (p = 0.18). COX-1 expression was 10 times higher and COX-2 expression was 50% higher in PRP than in whole blood (p COX-1 < 0.01, p COX-2 < 0.01). Platelet COX-1 expression was higher in ITP patients than healthy individuals using whole blood (p COX-1 < 0.01) and PRP, though this was nonsignificant in PRP (p COX-1 = 0.17). In ITP patients, positive correlations were found between platelet turnover and COX-1 expression (all p-values <0.01, rho = 0.80-0.94), whereas healthy individuals showed significant though weaker correlations between platelet turnover and COX-1 and COX-2 expressions (all p-values <0.03, rho = 0.44-0.71). GPIIb, IX, and Ib expression was increased in ITP patients compared with healthy individuals (all p-values < 0.03). GPIIb, IX, Ib, and IIIa showed positive correlations with platelet turnover in ITP patients (all p-values <0.02, rho = 0.71-0.94), but weak and nonsignificant correlations in healthy individuals (all p-values >0.14, rho = 0.11-0.28). In conclusion, ITP patients expressed higher COX-1 and platelet glycoprotein levels than healthy individuals. COX-1 and platelet glycoproteins demonstrated positive correlations with platelet turnover in ITP patients. In healthy individuals, COX-1 and COX-2 expression correlated positively with platelet turnover. PRP was more sensitive compared with whole blood as regards determination of COX. Therefore, PRP is the recommended matrix for investigating COX-1 and COX-2 in platelets.

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

PubMed

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

2013-01-01

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

The competing risks Cox model with auxiliary case covariates under weaker missing-at-random cause of failure.

PubMed

Nevo, Daniel; Nishihara, Reiko; Ogino, Shuji; Wang, Molin

2017-08-04

In the analysis of time-to-event data with multiple causes using a competing risks Cox model, often the cause of failure is unknown for some of the cases. The probability of a missing cause is typically assumed to be independent of the cause given the time of the event and covariates measured before the event occurred. In practice, however, the underlying missing-at-random assumption does not necessarily hold. Motivated by colorectal cancer molecular pathological epidemiology analysis, we develop a method to conduct valid analysis when additional auxiliary variables are available for cases only. We consider a weaker missing-at-random assumption, with missing pattern depending on the observed quantities, which include the auxiliary covariates. We use an informative likelihood approach that will yield consistent estimates even when the underlying model for missing cause of failure is misspecified. The superiority of our method over naive methods in finite samples is demonstrated by simulation study results. We illustrate the use of our method in an analysis of colorectal cancer data from the Nurses' Health Study cohort, where, apparently, the traditional missing-at-random assumption fails to hold.

A joint frailty-copula model between tumour progression and death for meta-analysis.

PubMed

Emura, Takeshi; Nakatochi, Masahiro; Murotani, Kenta; Rondeau, Virginie

2017-12-01

Dependent censoring often arises in biomedical studies when time to tumour progression (e.g., relapse of cancer) is censored by an informative terminal event (e.g., death). For meta-analysis combining existing studies, a joint survival model between tumour progression and death has been considered under semicompeting risks, which induces dependence through the study-specific frailty. Our paper here utilizes copulas to generalize the joint frailty model by introducing additional source of dependence arising from intra-subject association between tumour progression and death. The practical value of the new model is particularly evident for meta-analyses in which only a few covariates are consistently measured across studies and hence there exist residual dependence. The covariate effects are formulated through the Cox proportional hazards model, and the baseline hazards are nonparametrically modeled on a basis of splines. The estimator is then obtained by maximizing a penalized log-likelihood function. We also show that the present methodologies are easily modified for the competing risks or recurrent event data, and are generalized to accommodate left-truncation. Simulations are performed to examine the performance of the proposed estimator. The method is applied to a meta-analysis for assessing a recently suggested biomarker CXCL12 for survival in ovarian cancer patients. We implement our proposed methods in R joint.Cox package.

Sequential cohort design applying propensity score matching to analyze the comparative effectiveness of atorvastatin and simvastatin in preventing cardiovascular events.

PubMed

Helin-Salmivaara, Arja; Lavikainen, Piia; Aarnio, Emma; Huupponen, Risto; Korhonen, Maarit Jaana

2014-01-01

Sequential cohort design (SCD) applying matching for propensity scores (PS) in accrual periods has been proposed to mitigate bias caused by channeling when calendar time is a proxy for strong confounders. We studied the channeling of patients according to atorvastatin and simvastatin initiation in Finland, starting from the market introduction of atorvastatin in 1998, and explored the SCD PS approach to analyzing the comparative effectiveness of atorvastatin versus simvastatin in the prevention of cardiovascular events (CVE). Initiators of atorvastatin or simvastatin use in the 45-75-year age range in 1998-2006 were characterized by their propensity of receiving atorvastatin over simvastatin, as estimated for 17 six-month periods. Atorvastatin (10 mg) and simvastatin (20 mg) initiators were matched 1∶1 on the PS, as estimated for the whole cohort and within each period. Cox regression models were fitted conventionally, and also for the PS matched cohort and the periodically PS matched cohort, to estimate the hazard ratios (HR) for CVEs. Atorvastatin (10 mg) was associated with a 11%-12% lower incidence of CVE in comparison with simvastatin (20 mg). The HR estimates were the same for a conventional Cox model (0.88, 95% confidence interval 0.85-0.91), for the analysis in which the PS was used to match across all periods and the Cox model was adjusted for strong confounders (0.89, 0.85-0.92), and for the analysis in which PS matching was applied within sequential periods (0.88, 0.84-0.92). The HR from a traditional PS matched analysis was 0.80 (0.77-0.83). The SCD PS approach produced effect estimates similar to those obtained in matching for PS within the whole cohort and adjusting the outcome model for strong confounders, but at the cost of efficiency. A traditional PS matched analysis without further adjustment in the outcome model produced estimates further away from unity.

Seven protective miRNA signatures for prognosis of cervical cancer.

PubMed

Liu, Bei; Ding, Jin-Feng; Luo, Jian; Lu, Li; Yang, Fen; Tan, Xiao-Dong

2016-08-30

Cervical cancer is the second cause of cancer death in females in their 20s and 30s, but there were limited studies about its prognosis. This study aims to identify miRNA related to prognosis and study their functions. TCGA data of patients with cervical cancer were used to build univariate Cox's model with single clinical parameter or miRNA expression level. Multivariate Cox's model was built using both clinical information and miRNA expression levels. At last, STRING was used to enrich gene ontology or pathway for validated targets of significant miRNAs, and visualize the interactions among them. Using univariate Cox's model with clinical parameters, we found that two clinical parameters, tobacco use and clinical stage, and seven miRNAs were highly correlated with the survival status. Only using the expression level of miRNA signatures, the model could separate patients into high-risk and low-risk groups successfully. An optimal feature-selected model was proposed based on two clinical parameters and seven miRNAs. Functional analysis of these seven miRNAs showed they were associated to various pathways related to cancer, including MAPK, VEGF and P53 pathways. These results helped the research of identifying targets for targeted therapy which could potentially allow tailoring of treatment for cervical cancer patients.

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

PubMed

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

2015-11-01

Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) are important factors in tumorigenesis and malignant progression; however, studies of their roles in glioblastoma have produced conflicting results. To define the frequencies of COX-2 and 5-LO expression and their correlation with clinicopathological features and prognosis, tumor tissues from 76 cases of newly diagnosed primary ordinary glioblastoma were examined for COX-2 and 5-LO expression by immunohistochemistry. The expression levels of COX-2 and 5-LO and the relationships between the co-expression of COX-2/5-LO and patient age and gender, edema index (EI), Karnofsky Performance Scale and overall survival (OS) were analyzed. COX-2 and 5-LO were expressed in 73.7 % (56/76) and 92.1 % (70/76) of the samples, respectively. Among the clinicopathological characteristics, only age (>60 years) exhibited a significant association with the high expression of COX-2. No statistically significant correlations were found in the 5-LO cohort. A significant positive correlation was revealed between the COX-2 and 5-LO scores (r = 0.374; p = 0.001). The elevated co-expression of COX-2 and 5-LO was observed primarily in the patients over the age of 60 years. Patients with a high expression of COX-2 had a significantly shorter OS (p < 0.01), whereas the immunoexpression of 5-LO was not associated with the OS of patients with glioblastoma. Survival analysis indicated that simultaneous high levels of COX-2 and 5-LO expression were significantly correlated with poor OS and, conversely, that a low/low expression pattern of these two proteins was significantly associated with better OS (p < 0.05). Moreover, the Cox multivariable proportional hazard model showed that a high expression of COX-2, high co-expression of COX-2 and 5-LO, and a high Ki-67 index were significant predictors of shorter OS in primary glioblastoma, independent of age, gender, EI, 5-LO expression and p53 status. The hazard ratios for OS were 2.347 (95 % CI 1.30-4.25, p = 0.005), 1.900 (95 % CI 1.30-2.78, p = 0.001), and 2.210 (95 % CI 1.19-4.09, p = 0.011), respectively. These results suggest that COX-2 and 5-LO play roles in tumorigenesis and the progression of primary glioblastoma and that the co-expression pattern of COX-2/5-LO may be used as an independent prognostic factor in this disease.

Comparison of Statistical Approaches for Dealing With Immortal Time Bias in Drug Effectiveness Studies

PubMed Central

Karim, Mohammad Ehsanul; Gustafson, Paul; Petkau, John; Tremlett, Helen

2016-01-01

In time-to-event analyses of observational studies of drug effectiveness, incorrect handling of the period between cohort entry and first treatment exposure during follow-up may result in immortal time bias. This bias can be eliminated by acknowledging a change in treatment exposure status with time-dependent analyses, such as fitting a time-dependent Cox model. The prescription time-distribution matching (PTDM) method has been proposed as a simpler approach for controlling immortal time bias. Using simulation studies and theoretical quantification of bias, we compared the performance of the PTDM approach with that of the time-dependent Cox model in the presence of immortal time. Both assessments revealed that the PTDM approach did not adequately address immortal time bias. Based on our simulation results, another recently proposed observational data analysis technique, the sequential Cox approach, was found to be more useful than the PTDM approach (Cox: bias = −0.002, mean squared error = 0.025; PTDM: bias = −1.411, mean squared error = 2.011). We applied these approaches to investigate the association of β-interferon treatment with delaying disability progression in a multiple sclerosis cohort in British Columbia, Canada (Long-Term Benefits and Adverse Effects of Beta-Interferon for Multiple Sclerosis (BeAMS) Study, 1995–2008). PMID:27455963

Box-Cox transformation of firm size data in statistical analysis

NASA Astrophysics Data System (ADS)

Chen, Ting Ting; Takaishi, Tetsuya

2014-03-01

Firm size data usually do not show the normality that is often assumed in statistical analysis such as regression analysis. In this study we focus on two firm size data: the number of employees and sale. Those data deviate considerably from a normal distribution. To improve the normality of those data we transform them by the Box-Cox transformation with appropriate parameters. The Box-Cox transformation parameters are determined so that the transformed data best show the kurtosis of a normal distribution. It is found that the two firm size data transformed by the Box-Cox transformation show strong linearity. This indicates that the number of employees and sale have the similar property as a firm size indicator. The Box-Cox parameters obtained for the firm size data are found to be very close to zero. In this case the Box-Cox transformations are approximately a log-transformation. This suggests that the firm size data we used are approximately log-normal distributions.

Functional polymorphisms of cyclooxygenase-2 (COX-2) gene and risk for esophageal squmaous cell carcinoma.

PubMed

Upadhyay, Rohit; Jain, Meenu; Kumar, Shaleen; Ghoshal, Uday Chand; Mittal, Balraj

2009-04-26

Cyclooxygenase-2 (COX-2) influences carcinogenesis through regulation of angiogenesis, apoptosis and cytokine expression. We aimed to evaluate association of COX-2 polymorphisms with predisposition to esophageal squamous cell carcinoma (ESCC), its phenotype variability and modulation of environmental risk in northern Indian population. We genotyped 174 patients with ESCC and 216 controls for COX-2 gene polymorphisms (-765G>C; -1195G>A; -1290A>G; 3'UTR 8473T>C) using PCR-RFLP. Data were statistically analyzed using chi-square test and logistic regression model. COX-2 -765C allele carriers were at increased risk for ESCC (OR=1.66; 95% CI=1.08-2.54; P=0.004). However, -1195G>A; -1290A>G; 3'UTR 8473T>C polymorphisms of COX-2 gene were not significantly associated with ESCC. We observed significantly enhanced risk for ESCC due to interaction between COX-2 -1195GAx-765GC+CC genotypes (OR=4.60; 95% CI=1.63-13.01; P=0.004). High risk to ESCC was also observed with respect to COX-2 haplotypes, A(-1290)G(-1195)C(-765)T(8473) and A(-1290)A(-1195)C(-765)T(8473) [OR=3.35; 95% CI=0.83-13.44; P=0.089; OR=4.28; 95% CI=0.43-42.40; P=0.246] however, it was not statistically significant. Stratification of subjects based on gender showed that females were at higher risk for ESCC due to COX-2 -765C carrier genotypes (OR=2.97; 95% CI=1.23-7.18; P=0.016). In association of genotypes with clinical characteristics, -765C carrier genotype conferred risk of ESCC in middle third of esophagus (OR=1.78; 95% CI=1.08-2.93; P=0.023). In case-only analysis, interaction of environmental risk factors and COX-2 genotypes did not further modulate the risk for ESCC. In summary, COX-2 -765G>C polymorphism confers ESCC susceptibility particularly in females and patients with middle third anatomical location of the tumor. Interaction of COX-2 -1195GA and -765C carrier genotypes also modulates ESCC risk.

The COX-2 inhibitor meloxicam prevents pregnancy when administered as an emergency contraceptive to nonhuman primates.

PubMed

McCann, Nicole C; Lynch, Terrie J; Kim, Soon Ok; Duffy, Diane M

2013-12-01

Cyclooxygenase-2 (COX-2) inhibitors reduce prostaglandin synthesis and disrupt essential reproductive processes. Ultrasound studies in women demonstrated that oral COX-2 inhibitors can delay or prevent follicle collapse associated with ovulation. The goal of this study was to determine if oral administration of a COX-2 inhibitor can inhibit reproductive function with sufficient efficacy to prevent pregnancy in primates. The COX-2 inhibitor meloxicam (or vehicle) was administered orally to proven fertile female cynomolgus macaques using one emergency contraceptive model and three monthly contraceptive models. In the emergency contraceptive model, females were bred with a proven fertile male once 2±1 days before ovulation, returned to the females' home cage, and then received 5 days of meloxicam treatment. In the monthly contraceptive models, females were co-caged for breeding with a proven fertile male for a total of 5 days beginning 2±1 days before ovulation. Animals received meloxicam treatment (1) cycle days 5-22, or (2) every day, or (3) each day of the 5-day breeding period. Female were then assessed for pregnancy. The pregnancy rate with meloxicam administration using the emergency contraception model was 6.5%, significantly lower than the pregnancy rate of 33.3% when vehicle without meloxicam was administered. Pregnancy rates with the three monthly contraceptive models (75%-100%) were not consistent with preventing pregnancy. Oral COX-2 inhibitor administration can prevent pregnancy after a single instance of breeding in primates. While meloxicam may be ineffective for regular contraception, pharmacological inhibition of COX-2 may be an effective method of emergency contraception for women. COX-2 inhibitors can interfere with ovulation, but the contraceptive efficacy of drugs of this class has not been directly tested. This study, conducted in nonhuman primates, is the first to suggest that a COX-2 inhibitor may be effective as an emergency contraceptive. © 2013.

Comparison of statistical approaches dealing with time-dependent confounding in drug effectiveness studies.

PubMed

Karim, Mohammad Ehsanul; Petkau, John; Gustafson, Paul; Platt, Robert W; Tremlett, Helen

2018-06-01

In longitudinal studies, if the time-dependent covariates are affected by the past treatment, time-dependent confounding may be present. For a time-to-event response, marginal structural Cox models are frequently used to deal with such confounding. To avoid some of the problems of fitting marginal structural Cox model, the sequential Cox approach has been suggested as an alternative. Although the estimation mechanisms are different, both approaches claim to estimate the causal effect of treatment by appropriately adjusting for time-dependent confounding. We carry out simulation studies to assess the suitability of the sequential Cox approach for analyzing time-to-event data in the presence of a time-dependent covariate that may or may not be a time-dependent confounder. Results from these simulations revealed that the sequential Cox approach is not as effective as marginal structural Cox model in addressing the time-dependent confounding. The sequential Cox approach was also found to be inadequate in the presence of a time-dependent covariate. We propose a modified version of the sequential Cox approach that correctly estimates the treatment effect in both of the above scenarios. All approaches are applied to investigate the impact of beta-interferon treatment in delaying disability progression in the British Columbia Multiple Sclerosis cohort (1995-2008).

Comparing methods to combine functional loss and mortality in clinical trials for amyotrophic lateral sclerosis

PubMed Central

van Eijk, Ruben PA; Eijkemans, Marinus JC; Rizopoulos, Dimitris

2018-01-01

Objective Amyotrophic lateral sclerosis (ALS) clinical trials based on single end points only partially capture the full treatment effect when both function and mortality are affected, and may falsely dismiss efficacious drugs as futile. We aimed to investigate the statistical properties of several strategies for the simultaneous analysis of function and mortality in ALS clinical trials. Methods Based on the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we simulated longitudinal patterns of functional decline, defined by the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and conditional survival time. Different treatment scenarios with varying effect sizes were simulated with follow-up ranging from 12 to 18 months. We considered the following analytical strategies: 1) Cox model; 2) linear mixed effects (LME) model; 3) omnibus test based on Cox and LME models; 4) composite time-to-6-point decrease or death; 5) combined assessment of function and survival (CAFS); and 6) test based on joint modeling framework. For each analytical strategy, we calculated the empirical power and sample size. Results Both Cox and LME models have increased false-negative rates when treatment exclusively affects either function or survival. The joint model has superior power compared to other strategies. The composite end point increases false-negative rates among all treatment scenarios. To detect a 15% reduction in ALSFRS-R decline and 34% decline in hazard with 80% power after 18 months, the Cox model requires 524 patients, the LME model 794 patients, the omnibus test 526 patients, the composite end point 1,274 patients, the CAFS 576 patients and the joint model 464 patients. Conclusion Joint models have superior statistical power to analyze simultaneous effects on survival and function and may circumvent pitfalls encountered by other end points. Optimizing trial end points is essential, as selecting suboptimal outcomes may disguise important treatment clues. PMID:29593436

Automated Box-Cox Transformations for Improved Visual Encoding.

PubMed

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

2013-01-01

The concept of preconditioning 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 semiautomatically adjust visual parameters. We focus on time-series scaling, axis transformations, and color binning for choropleth maps. We illustrate the usage of this transformation through various examples, and discuss the value and some issues in semiautomatically using these transformations for more effective data visualization.

ROS are critical for endometrial breakdown via NF-κB-COX-2 signaling in a female mouse menstrual-like model.

PubMed

Wu, Bin; Chen, Xihua; He, Bin; Liu, Shuyan; Li, Yunfeng; Wang, Qianxing; Gao, Haijun; Wang, Shufang; Liu, Jianbing; Zhang, Shucheng; Xu, Xiangbo; Wang, Jiedong

2014-09-01

Progesterone withdrawal triggers endometrial breakdown and shedding during menstruation. Menstruation results from inflammatory responses; however, the role of reactive oxygen species (ROS) in menstruation remains unclear. In this study, we explored the role of ROS in endometrial breakdown and shedding. We found that ROS levels were significantly increased before endometrial breakdown in a mouse menstrual-like model. Vaginal smear inspection, morphology of uterine horns, and endometrial histology examination showed that a broad range of ROS scavengers significantly inhibited endometrial breakdown in this model. Furthermore, Western blot and immunohistochemical analysis showed that the intracellular translocation of p50 and p65 from the cytoplasm into the nucleus was blocked by ROS scavengers and real-time PCR showed that cyclooxygenase-2 (COX-2) mRNA expression was decreased by ROS scavengers. Similar changes also occurred in human stromal cells in vitro. Furthermore, Western blotting and real-time PCR showed that one ROS, hydrogen peroxide (H2O2), promoted translocation of p50 and p65 from the cytoplasm to the nucleus and increased COX-2 mRNA expression along with progesterone maintenance. The nuclear factor κB inhibitor MG132 reduced the occurrence of these changes in human stromal cells in vitro. Viewed as a whole, our results provide evidence that certain ROS are important for endometrial breakdown and shedding in a mouse menstrual-like model and function at least partially via nuclear factor-κB/COX-2 signaling. Similar changes observed in human stromal cells could also implicate ROS as important mediators of human menstruation.

Cyclooxygenase metabolites mediate glomerular monocyte chemoattractant protein-1 formation and monocyte recruitment in experimental glomerulonephritis.

PubMed

Schneider, A; Harendza, S; Zahner, G; Jocks, T; Wenzel, U; Wolf, G; Thaiss, F; Helmchen, U; Stahl, R A

1999-02-01

Monocyte chemoattractant protein-1 (MCP-1) has been shown to play a significant role in the recruitment of monocytes/macrophages in experimental glomerulonephritis. Whereas a number of inflammatory mediators have been characterized that are involved in the expression of MCP-1 in renal disease, little is known about repressors of chemokine formation in vivo. We hypothesized that cyclooxygenase (COX) products influence the formation of MCP-1 and affect inflammatory cell recruitment in glomerulonephritis. The effect of COX inhibitors was evaluated in the antithymocyte antibody model and an anti-glomerular basement membrane model of glomerulonephritis. Rats were treated with the COX-1/COX-2 inhibitor indomethacin and the selective COX-2 inhibitors meloxicam and SC 58125. Animals were studied at 1 hour, 24 hours, and 5 days after induction of the disease. Indomethacin, to a lesser degree the selective COX-2 inhibitors, enhanced glomerular MCP-1 and RANTES mRNA levels. Indomethacin enhanced glomerular monocyte chemoattractant activity an the infiltration of monocytes/macrophages at 24 hours and 5 days. Our studies demonstrate that COX products may serve as endogenous repressors of MCP-1 formation in experimental glomerulonephritis. The data suggest that COX-1 and COX-2 products mediate these effects differently because the selective COX-2 inhibitors had less influence on chemokine expression.

Comparing a marginal structural model with a Cox proportional hazard model to estimate the effect of time-dependent drug use in observational studies: statin use for primary prevention of cardiovascular disease as an example from the Rotterdam Study.

PubMed

de Keyser, Catherine E; Leening, Maarten J G; Romio, Silvana A; Jukema, J Wouter; Hofman, Albert; Ikram, M Arfan; Franco, Oscar H; Stijnen, Theo; Stricker, Bruno H

2014-11-01

When studying the causal effect of drug use in observational data, marginal structural modeling (MSM) can be used to adjust for time-dependent confounders that are affected by previous treatment. The objective of this study was to compare traditional Cox proportional hazard models (with and without time-dependent covariates) with MSM to study causal effects of time-dependent drug use. The example of primary prevention of cardiovascular disease (CVD) with statins was examined using up to 17.7 years of follow-up from 4,654 participants of the observational prospective population-based Rotterdam Study. In the MSM model, the weight was based on measurements of established cardiovascular risk factors and co-morbidity. In general, we could not demonstrate important differences in results from the Cox models and MSM. Results from analysis on duration of statin use suggested that substantial residual confounding by indication was not accounted for during the period shortly after statin initiation. In conclusion, although on theoretical grounds MSM is an elegant technique, lack of data on the precise time-dependent confounders, such as indication of treatment or other considerations of the prescribing physician jeopardizes the calculation of valid weights. Confounding remains a hurdle in observational effectiveness research on preventive drugs with a multitude of prescription determinants.

Protein-coding genes combined with long noncoding RNA as a novel transcriptome molecular staging model to predict the survival of patients with esophageal squamous cell carcinoma.

PubMed

Guo, Jin-Cheng; Wu, Yang; Chen, Yang; Pan, Feng; Wu, Zhi-Yong; Zhang, Jia-Sheng; Wu, Jian-Yi; Xu, Xiu-E; Zhao, Jian-Mei; Li, En-Min; Zhao, Yi; Xu, Li-Yan

2018-04-09

Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal carcinoma in China. This study was to develop a staging model to predict outcomes of patients with ESCC. Using Cox regression analysis, principal component analysis (PCA), partitioning clustering, Kaplan-Meier analysis, receiver operating characteristic (ROC) curve analysis, and classification and regression tree (CART) analysis, we mined the Gene Expression Omnibus database to determine the expression profiles of genes in 179 patients with ESCC from GSE63624 and GSE63622 dataset. Univariate cox regression analysis of the GSE63624 dataset revealed that 2404 protein-coding genes (PCGs) and 635 long non-coding RNAs (lncRNAs) were associated with the survival of patients with ESCC. PCA categorized these PCGs and lncRNAs into three principal components (PCs), which were used to cluster the patients into three groups. ROC analysis demonstrated that the predictive ability of PCG-lncRNA PCs when applied to new patients was better than that of the tumor-node-metastasis staging (area under ROC curve [AUC]: 0.69 vs. 0.65, P < 0.05). Accordingly, we constructed a molecular disaggregated model comprising one lncRNA and two PCGs, which we designated as the LSB staging model using CART analysis in the GSE63624 dataset. This LSB staging model classified the GSE63622 dataset of patients into three different groups, and its effectiveness was validated by analysis of another cohort of 105 patients. The LSB staging model has clinical significance for the prognosis prediction of patients with ESCC and may serve as a three-gene staging microarray.

A single-index threshold Cox proportional hazard model for identifying a treatment-sensitive subset based on multiple biomarkers.

PubMed

He, Ye; Lin, Huazhen; Tu, Dongsheng

2018-06-04

In this paper, we introduce a single-index threshold Cox proportional hazard model to select and combine biomarkers to identify patients who may be sensitive to a specific treatment. A penalized smoothed partial likelihood is proposed to estimate the parameters in the model. A simple, efficient, and unified algorithm is presented to maximize this likelihood function. The estimators based on this likelihood function are shown to be consistent and asymptotically normal. Under mild conditions, the proposed estimators also achieve the oracle property. The proposed approach is evaluated through simulation analyses and application to the analysis of data from two clinical trials, one involving patients with locally advanced or metastatic pancreatic cancer and one involving patients with resectable lung cancer. Copyright © 2018 John Wiley & Sons, Ltd.

COX-1 Inhibitors: Beyond Structure Toward Therapy.

PubMed

Vitale, Paola; Panella, Andrea; Scilimati, Antonio; Perrone, Maria Grazia

2016-07-01

Biosynthesis of prostaglandins from arachidonic acid (AA) is catalyzed by cyclooxygenase (COX), which exists as COX-1 and COX-2. AA is in turn released from the cell membrane upon neopathological stimuli. COX inhibitors interfere in this catalytic and disease onset process. The recent prominent discovery involvements of COX-1 are mainly in cancer and inflammation. Five classes of COX-1 inhibitors are known up to now and this classification is based on chemical features of both synthetic compounds and substances from natural sources. Physicochemical interactions identification between such molecules and COX-1 active site was achieved through X-ray, mutagenesis experiments, specific assays and docking investigations, as well as through a pharmacometric predictive model building. All these insights allowed the design of new highly selective COX-1 inhibitors to be tested into those disease models in which COX-1 is involved. Particularly, COX-1 is expressed at high levels in the early to advanced stages of human epithelial ovarian cancer, and it also seems to play a pivotal role in cancer progression. The refinement of COX-1 selective inhibitor structure has progressed to the stage that some of the inhibitors described in this review could be considered as promising active principle ingredients of drugs and hence part of specific therapeutic protocols. This review aims to outline achievements, in the last 5 years, dealing with the identification of highly selective synthetic and from plant extracts COX-1 inhibitors and their theranostic use in neuroinflammation and ovarian cancer. Their gastrotoxic effect is also discussed. © 2016 Wiley Periodicals, Inc.

Properties of added variable plots in Cox's regression model.

PubMed

Lindkvist, M

2000-03-01

The added variable plot is useful for examining the effect of a covariate in regression models. The plot provides information regarding the inclusion of a covariate, and is useful in identifying influential observations on the parameter estimates. Hall et al. (1996) proposed a plot for Cox's proportional hazards model derived by regarding the Cox model as a generalized linear model. This paper proves and discusses properties of this plot. These properties make the plot a valuable tool in model evaluation. Quantities considered include parameter estimates, residuals, leverage, case influence measures and correspondence to previously proposed residuals and diagnostics.

Global Gene Expression Analysis of Canine Osteosarcoma Stem Cells Reveals a Novel Role for COX-2 in Tumour Initiation

PubMed Central

Pang, Lisa Y.; Gatenby, Emma L.; Kamida, Ayako; Whitelaw, Bruce A.; Hupp, Ted R.; Argyle, David J.

2014-01-01

Osteosarcoma is the most common primary bone tumour of both children and dogs. It is an aggressive tumour in both species with a rapid clinical course leading ultimately to metastasis. In dogs and children distant metastasis occurs in >80% of individuals treated by surgery alone. Both canine and human osteosarcoma has been shown to contain a sub-population of cancer stem cells (CSCs), which may drive tumour growth, recurrence and metastasis, suggesting that naturally occurring canine osteosarcoma could act as a preclinical model for the human disease. Here we report the successful isolation of CSCs from primary canine osteosarcoma, as well as established cell lines. We show that these cells can form tumourspheres, and demonstrate relative resistance to chemotherapy. We demonstrate similar results for the human osteosarcma cell lines, U2OS and SAOS2. Utilizing the Affymetrix canine microarray, we are able to definitively show that there are significant differences in global gene expression profiles of isolated osteosarcoma stem cells and the daughter adherent cells. We identified 13,221 significant differences (p = 0.05), and significantly, COX-2 was expressed 141-fold more in CSC spheres than daughter adherent cells. To study the role of COX-2 expression in CSCs we utilized the COX-2 inhibitors meloxicam and mavacoxib. We found that COX-2 inhibition had no effect on CSC growth, or resistance to chemotherapy. However inhibition of COX-2 in daughter cells prevented sphere formation, indicating a potential significant role for COX-2 in tumour initiation. PMID:24416158

Global gene expression analysis of canine osteosarcoma stem cells reveals a novel role for COX-2 in tumour initiation.

PubMed

Pang, Lisa Y; Gatenby, Emma L; Kamida, Ayako; Whitelaw, Bruce A; Hupp, Ted R; Argyle, David J

2014-01-01

Osteosarcoma is the most common primary bone tumour of both children and dogs. It is an aggressive tumour in both species with a rapid clinical course leading ultimately to metastasis. In dogs and children distant metastasis occurs in >80% of individuals treated by surgery alone. Both canine and human osteosarcoma has been shown to contain a sub-population of cancer stem cells (CSCs), which may drive tumour growth, recurrence and metastasis, suggesting that naturally occurring canine osteosarcoma could act as a preclinical model for the human disease. Here we report the successful isolation of CSCs from primary canine osteosarcoma, as well as established cell lines. We show that these cells can form tumourspheres, and demonstrate relative resistance to chemotherapy. We demonstrate similar results for the human osteosarcma cell lines, U2OS and SAOS2. Utilizing the Affymetrix canine microarray, we are able to definitively show that there are significant differences in global gene expression profiles of isolated osteosarcoma stem cells and the daughter adherent cells. We identified 13,221 significant differences (p = 0.05), and significantly, COX-2 was expressed 141-fold more in CSC spheres than daughter adherent cells. To study the role of COX-2 expression in CSCs we utilized the COX-2 inhibitors meloxicam and mavacoxib. We found that COX-2 inhibition had no effect on CSC growth, or resistance to chemotherapy. However inhibition of COX-2 in daughter cells prevented sphere formation, indicating a potential significant role for COX-2 in tumour initiation.

Using Molecular Visualization to Explore Protein Structure and Function and Enhance Student Facility with Computational Tools

ERIC Educational Resources Information Center

Terrell, Cassidy R.; Listenberger, Laura L.

2017-01-01

Recognizing that undergraduate students can benefit from analysis of 3D protein structure and function, we have developed a multiweek, inquiry-based molecular visualization project for Biochemistry I students. This project uses a virtual model of cyclooxygenase-1 (COX-1) to guide students through multiple levels of protein structure analysis. The…

A nonlinear isobologram model with Box-Cox transformation to both sides for chemical mixtures.

PubMed

Chen, D G; Pounds, J G

1998-12-01

The linear logistical isobologram is a commonly used and powerful graphical and statistical tool for analyzing the combined effects of simple chemical mixtures. In this paper a nonlinear isobologram model is proposed to analyze the joint action of chemical mixtures for quantitative dose-response relationships. This nonlinear isobologram model incorporates two additional new parameters, Ymin and Ymax, to facilitate analysis of response data that are not constrained between 0 and 1, where parameters Ymin and Ymax represent the minimal and the maximal observed toxic response. This nonlinear isobologram model for binary mixtures can be expressed as [formula: see text] In addition, a Box-Cox transformation to both sides is introduced to improve the goodness of fit and to provide a more robust model for achieving homogeneity and normality of the residuals. Finally, a confidence band is proposed for selected isobols, e.g., the median effective dose, to facilitate graphical and statistical analysis of the isobologram. The versatility of this approach is demonstrated using published data describing the toxicity of the binary mixtures of citrinin and ochratoxin as well as a new experimental data from our laboratory for mixtures of mercury and cadmium.

A nonlinear isobologram model with Box-Cox transformation to both sides for chemical mixtures.

PubMed Central

Chen, D G; Pounds, J G

1998-01-01

The linear logistical isobologram is a commonly used and powerful graphical and statistical tool for analyzing the combined effects of simple chemical mixtures. In this paper a nonlinear isobologram model is proposed to analyze the joint action of chemical mixtures for quantitative dose-response relationships. This nonlinear isobologram model incorporates two additional new parameters, Ymin and Ymax, to facilitate analysis of response data that are not constrained between 0 and 1, where parameters Ymin and Ymax represent the minimal and the maximal observed toxic response. This nonlinear isobologram model for binary mixtures can be expressed as [formula: see text] In addition, a Box-Cox transformation to both sides is introduced to improve the goodness of fit and to provide a more robust model for achieving homogeneity and normality of the residuals. Finally, a confidence band is proposed for selected isobols, e.g., the median effective dose, to facilitate graphical and statistical analysis of the isobologram. The versatility of this approach is demonstrated using published data describing the toxicity of the binary mixtures of citrinin and ochratoxin as well as a new experimental data from our laboratory for mixtures of mercury and cadmium. PMID:9860894

Scoring and staging systems using cox linear regression modeling and recursive partitioning.

PubMed

Lee, J W; Um, S H; Lee, J B; Mun, J; Cho, H

2006-01-01

Scoring and staging systems are used to determine the order and class of data according to predictors. Systems used for medical data, such as the Child-Turcotte-Pugh scoring and staging systems for ordering and classifying patients with liver disease, are often derived strictly from physicians' experience and intuition. We construct objective and data-based scoring/staging systems using statistical methods. We consider Cox linear regression modeling and recursive partitioning techniques for censored survival data. In particular, to obtain a target number of stages we propose cross-validation and amalgamation algorithms. We also propose an algorithm for constructing scoring and staging systems by integrating local Cox linear regression models into recursive partitioning, so that we can retain the merits of both methods such as superior predictive accuracy, ease of use, and detection of interactions between predictors. The staging system construction algorithms are compared by cross-validation evaluation of real data. The data-based cross-validation comparison shows that Cox linear regression modeling is somewhat better than recursive partitioning when there are only continuous predictors, while recursive partitioning is better when there are significant categorical predictors. The proposed local Cox linear recursive partitioning has better predictive accuracy than Cox linear modeling and simple recursive partitioning. This study indicates that integrating local linear modeling into recursive partitioning can significantly improve prediction accuracy in constructing scoring and staging systems.

The Transfer Velocity Project: A Comprehensive Look at the Transfer Function

ERIC Educational Resources Information Center

Hayward, Craig

2011-01-01

The 1999-2000 Transfer Velocity Project (TVP) cohort of 147,207 community college students is used to develop both a college-level endogenous model, appropriate for applied research and guidance for campus action, and a student-level model. Survival analysis (Cox regression) is employed to evaluate the relative contribution of 53 student-level…

Molecular structure, spectroscopic and docking analysis of 1,3-diphenylpyrazole-4-propionic acid: A good prostaglandin reductase inhibitor

NASA Astrophysics Data System (ADS)

Kavitha, T.; Velraj, G.

2018-03-01

The molecule 1,3-diphenylpyrazole-4-propionic acid (DPPA) was optimized to its minimum energy level using density functional theory (DFT) calculations. The vibrational frequencies of DPPA were calculated along with their potential energy distribution (PED) and the obtained values are validated with the help of experimental calculations. The reactivity nature of the molecule was investigated with the aid of various DFT methods such as global reactivity descriptors, local reactivity descriptors, molecular electrostatic potential (MEP), natural bond orbitals (NBOs), etc. The prediction of activity spectra for substances (PASS) result forecast that, DPPA can be more active as a prostaglandin (PG) reductase inhibitor. The PGs are biologically synthesized by the cyclooxygenase (COX) enzyme which exists in COX1 and COX2 forms. The PGs produced by COX2 enzyme induces inflammation and fungal infections and hence the inhibition of COX2 enzyme is indispensable in anti-inflammation and anti-fungal activities. The docking analysis of DPPA with COX enzymes (both COX1 and COX2) were carried out and eventually, it was found that DPPA can selectively inhibit COX2 enzyme and can serve as a PG reductase inhibitor thereby acting as a lead compound for the treatment of inflammation and fungal diseases.

The effect of delayed graft function on graft and patient survival in kidney transplantation: an approach using competing events analysis.

PubMed

Fonseca, Isabel; Teixeira, Laetitia; Malheiro, Jorge; Martins, La Salete; Dias, Leonídio; Castro Henriques, António; Mendonça, Denisa

2015-06-01

In kidney transplantation, the impact of delayed graft function (DGF) on long-term graft and patient survival is controversial. We examined the impact of DGF on graft and recipient survival by accounting for the possibility that death with graft function may act as a competing risk for allograft failure. We used data from 1281 adult primary deceased-donor kidney recipients whose allografts functioned at least 1 year. The probability of graft loss occurrence is overestimated using the complement of Kaplan-Meier estimates (1-KM). Both the cause-specific Cox proportional hazard regression model (standard Cox) and the subdistribution hazard regression model proposed by Fine and Gray showed that DGF was associated with shorter time to graft failure (csHR = 2.0, P = 0.002; sHR = 1.57, P = 0.009), independent of acute rejection (AR) and after adjusting for traditional factors associated with graft failure. Regarding patient survival, DGF was a predictor of patient death using the cause-specific Cox model (csHR = 1.57, P = 0.029) but not using the subdistribution model. The probability of graft loss from competing end points should not be reported with the 1-KM. Application of a regression model for subdistribution hazard showed that, independent of AR, DGF has a detrimental effect on long-term graft survival, but not on patient survival. © 2015 Steunstichting ESOT.

Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature.

PubMed

Ostergaard, Elsebet; Weraarpachai, Woranontee; Ravn, Kirstine; Born, Alfred Peter; Jønson, Lars; Duno, Morten; Wibrand, Flemming; Shoubridge, Eric A; Vissing, John

2015-03-01

We investigated a subject with an isolated cytochrome c oxidase (COX) deficiency presenting with an unusual phenotype characterised by neuropathy, exercise intolerance, obesity, and short stature. Blue-native polyacrylamide gel electrophoresis (BN-PAGE) analysis showed an almost complete lack of COX assembly in subject fibroblasts, consistent with the very low enzymatic activity, and pulse-labelling mitochondrial translation experiments showed a specific decrease in synthesis of the COX1 subunit, the core catalytic subunit that nucleates assembly of the holoenzyme. Whole exome sequencing identified compound heterozygous mutations (c.199dupC, c.215A>G) in COA3, a small inner membrane COX assembly factor, resulting in a pronounced decrease in the steady-state levels of COA3 protein. Retroviral expression of a wild-type COA3 cDNA completely rescued the COX assembly and mitochondrial translation defects, confirming the pathogenicity of the mutations, and resulted in increased steady-state levels of COX1 in control cells, demonstrating a role for COA3 in the stabilisation of this subunit. COA3 exists in an early COX assembly complex that contains COX1 and other COX assembly factors including COX14 (C12orf62), another single pass transmembrane protein that also plays a role in coupling COX1 synthesis with holoenzyme assembly. Immunoblot analysis showed that COX14 was undetectable in COA3 subject fibroblasts, and that COA3 was undetectable in fibroblasts from a COX14 subject, demonstrating the interdependence of these two COX assembly factors. The mild clinical course in this patient contrasts with nearly all other cases of severe COX assembly defects that are usually fatal early in life, and underscores the marked tissue-specific involvement in mitochondrial diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Molecular Classification Substitutes for the Prognostic Variables Stage, Age, and MYCN Status in Neuroblastoma Risk Assessment.

PubMed

Rosswog, Carolina; Schmidt, Rene; Oberthuer, André; Juraeva, Dilafruz; Brors, Benedikt; Engesser, Anne; Kahlert, Yvonne; Volland, Ruth; Bartenhagen, Christoph; Simon, Thorsten; Berthold, Frank; Hero, Barbara; Faldum, Andreas; Fischer, Matthias

2017-12-01

Current risk stratification systems for neuroblastoma patients consider clinical, histopathological, and genetic variables, and additional prognostic markers have been proposed in recent years. We here sought to select highly informative covariates in a multistep strategy based on consecutive Cox regression models, resulting in a risk score that integrates hazard ratios of prognostic variables. A cohort of 695 neuroblastoma patients was divided into a discovery set (n=75) for multigene predictor generation, a training set (n=411) for risk score development, and a validation set (n=209). Relevant prognostic variables were identified by stepwise multivariable L1-penalized least absolute shrinkage and selection operator (LASSO) Cox regression, followed by backward selection in multivariable Cox regression, and then integrated into a novel risk score. The variables stage, age, MYCN status, and two multigene predictors, NB-th24 and NB-th44, were selected as independent prognostic markers by LASSO Cox regression analysis. Following backward selection, only the multigene predictors were retained in the final model. Integration of these classifiers in a risk scoring system distinguished three patient subgroups that differed substantially in their outcome. The scoring system discriminated patients with diverging outcome in the validation cohort (5-year event-free survival, 84.9±3.4 vs 63.6±14.5 vs 31.0±5.4; P<.001), and its prognostic value was validated by multivariable analysis. We here propose a translational strategy for developing risk assessment systems based on hazard ratios of relevant prognostic variables. Our final neuroblastoma risk score comprised two multigene predictors only, supporting the notion that molecular properties of the tumor cells strongly impact clinical courses of neuroblastoma patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Serotonin and histamine mediate gastroprotective effect of fluoxetine against experimentally-induced ulcers in rats.

PubMed

Salem Sokar, Samia; Elsayed Elsayad, Mageda; Sabri Ali, Hend

2016-09-01

Research in the treatment of gastric ulcer has involved the investigation of new alternatives, such as anti-depressant drugs. The present study was designed to investigate the gastroprotective effects of fluoxetine against indomethacin and alcohol induced gastric ulcers in rats and the potential mechanisms of that effect. Fluoxetine (20 mg/kg) was administered IP for 14 days. For comparative purposes, other rats were treated with ranitidine (30 mg/kg). Thereafter, after 24 h of fasting, INDO (100 mg/kg) or absolute alcohol (5 ml/kg) was administered to all rats (saline was administered to naïve controls) and rats in each group were sacrificed 5 h (for INDO rats) or 1 h (for alcohol rats) later. Macroscopic examination revealed that both fluoxetine and ranitidine decreased ulcer scores in variable ratios, which was supported by microscopic histopathological examination. Biochemical analysis of fluoxetine- or ranitidine-pre-treated host tissues demonstrated reductions in tumor necrosis factor (TNF)-α and myeloperoxidase (MPO) levels and concomitant increases in gastric pH, nitric oxide (NO) and reduced glutathione (GSH) contents. Fluoxetine, more than ranitidine, also resulted in serotonin and histamine levels nearest to control values. Moreover, immuno-histochemical analysis showed that fluoxetine markedly enhanced expression of cyclo-oxygenases COX-1 and COX-2 in both models; in comparison, ranitidine did not affect COX-1 expression in either ulcer model but caused moderate increases in COX-2 expression in INDO-induced hosts and high expression in alcohol-induced hosts. The results here indicated fluoxetine exhibited better gastroprotective effects than ranitidine and this could be due to anti-secretory, anti-oxidant, anti-inflammatory and anti-histaminic effects of the drug, as well as a stabilization of gastric serotonin levels.

Overexpression of COX-2 and LMP1 are correlated with lymph node in Tunisian NPC patients.

PubMed

Fendri, Ali; Khabir, Abdelmajid; Hadhri-Guiga, Boutheina; Sellami-Boudawara, Tahia; Ghorbel, Abdelmoonem; Daoud, Jamel; Frikha, Mounir; Jlidi, Rachid; Gargouri, Ali; Mokdad-Gargouri, Raja

2008-07-01

Cyclooxygenase 2 (COX-2) an inducible form of COX is frequently up-regulated in many human tumours. The expression of COX-2 in nasopharyngeal carcinoma (NPC) and its relationship to clinicopathological features were studied in Tunisian patients. COX-2 mRNA was detected in 91% of tumour tissues. Immunohistochemical analysis showed that COX-2 protein was strongly detected in tumour cells and the staining was mainly cytoplasmic. In contrast, COX-2 mRNA and protein were very low or undetectable in normal nasopharyngeal mucosa. Our result showed a significant association of COX-2 overexpression with the lymph node involvement, however, no correlation was observed with age, tumour stage, histological type and distant metastasis. Moreover, we showed that all tumour specimens co-overexpressed COX-2 and the EBV oncoprotein LMP1 corroborating the fact that LPM1 is known to induce COX-2. Altogether, our data suggests that the COX-2 is overexpressed in NPC biopsies and that is linked to the lymph node involvement.

A simple linear regression method for quantitative trait loci linkage analysis with censored observations.

PubMed

Anderson, Carl A; McRae, Allan F; Visscher, Peter M

2006-07-01

Standard quantitative trait loci (QTL) mapping techniques commonly assume that the trait is both fully observed and normally distributed. When considering survival or age-at-onset traits these assumptions are often incorrect. Methods have been developed to map QTL for survival traits; however, they are both computationally intensive and not available in standard genome analysis software packages. We propose a grouped linear regression method for the analysis of continuous survival data. Using simulation we compare this method to both the Cox and Weibull proportional hazards models and a standard linear regression method that ignores censoring. The grouped linear regression method is of equivalent power to both the Cox and Weibull proportional hazards methods and is significantly better than the standard linear regression method when censored observations are present. The method is also robust to the proportion of censored individuals and the underlying distribution of the trait. On the basis of linear regression methodology, the grouped linear regression model is computationally simple and fast and can be implemented readily in freely available statistical software.

Transcutaneous electrical nerve stimulation attenuates CFA-induced hyperalgesia and inhibits spinal ERK1/2-COX-2 pathway activation in rats

PubMed Central

2013-01-01

Background Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacologic treatment for pain relief. In previous animal studies, TENS effectively alleviated Complete Freund’s Adjuvant (CFA)- or carrageenan-induced inflammatory pain. Although TENS is known to produce analgesia via opioid activation in the brain and at the spinal level, few reports have investigated the signal transduction pathways mediated by TENS. Prior studies have verified the importance of the activation of extracellular signal-regulated kinase (ERK) signal transduction pathway in the spinal cord dorsal horn (SCDH) in acute and persistent inflammatory pains. Here, by using CFA rat model, we tested the efficacy of TENS on inhibiting the expressions of p-ERK1/2 and of its downstream cyclooxygenase-2 (COX-2) and the level of prostaglandin E2 (PGE2) at spinal level. Methods Rats were randomly divided into control, model and TENS groups, and injected subcutaneously with 100 μl CFA or saline in the plantar surface of right hind paw. Rats in the TENS group were treated with TENS (constant aquare wave, 2 Hz and 100 Hz alternating frequencies, intensities ranging from 1 to 2 mA, lasting for 30 min each time) at 5 h and 24 h after injection. Paw withdrawal thresholds (PWTs) were measured with dynamic plantar aesthesiometer at 3d before modeling and 5 h, 6 h, and 25 h after CFA injection. The ipsilateral sides of the lumbar spinal cord dosral horns were harvested for detecting the expressions of p-ERK1/2 and COX-2 by western blot analysis and qPCR, and PGE2 by ELISA. Results CFA-induced periphery inflammation decreased PWTs and increased paw volume of rats. TENS treatment significantly alleviated mechanical hyperalgesia caused by CFA. However, no anti-inflammatory effect of TENS was observed. Expression of p-ERK1/2 protein and COX-2 mRNA was significantly up-regualted at 5 h and 6 h after CFA injection, while COX-2 and PGE2 protein level only increased at 6 h after modeling. Furthermore, the high expression of p-ERK1/2 and COX-2, and over-production of PGE2 induced by CFA, were suppressed by TENS administration. Conclusions TENS may be an effective therapy in controlling inflammatory pain induced by CFA. Its analgesic effect may be associated with the inhibition of activation of the spinal ERK1/2-COX-2 pathway. PMID:23768044

Transcutaneous electrical nerve stimulation attenuates CFA-induced hyperalgesia and inhibits spinal ERK1/2-COX-2 pathway activation in rats.

PubMed

Fang, Jun-Fan; Liang, Yi; Du, Jun-Ying; Fang, Jian-Qiao

2013-06-15

Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacologic treatment for pain relief. In previous animal studies, TENS effectively alleviated Complete Freund's Adjuvant (CFA)- or carrageenan-induced inflammatory pain. Although TENS is known to produce analgesia via opioid activation in the brain and at the spinal level, few reports have investigated the signal transduction pathways mediated by TENS. Prior studies have verified the importance of the activation of extracellular signal-regulated kinase (ERK) signal transduction pathway in the spinal cord dorsal horn (SCDH) in acute and persistent inflammatory pains. Here, by using CFA rat model, we tested the efficacy of TENS on inhibiting the expressions of p-ERK1/2 and of its downstream cyclooxygenase-2 (COX-2) and the level of prostaglandin E2 (PGE2) at spinal level. Rats were randomly divided into control, model and TENS groups, and injected subcutaneously with 100 μl CFA or saline in the plantar surface of right hind paw. Rats in the TENS group were treated with TENS (constant aquare wave, 2 Hz and 100 Hz alternating frequencies, intensities ranging from 1 to 2 mA, lasting for 30 min each time) at 5 h and 24 h after injection. Paw withdrawal thresholds (PWTs) were measured with dynamic plantar aesthesiometer at 3d before modeling and 5 h, 6 h, and 25 h after CFA injection. The ipsilateral sides of the lumbar spinal cord dosral horns were harvested for detecting the expressions of p-ERK1/2 and COX-2 by western blot analysis and qPCR, and PGE2 by ELISA. CFA-induced periphery inflammation decreased PWTs and increased paw volume of rats. TENS treatment significantly alleviated mechanical hyperalgesia caused by CFA. However, no anti-inflammatory effect of TENS was observed. Expression of p-ERK1/2 protein and COX-2 mRNA was significantly up-regualted at 5 h and 6 h after CFA injection, while COX-2 and PGE2 protein level only increased at 6 h after modeling. Furthermore, the high expression of p-ERK1/2 and COX-2, and over-production of PGE2 induced by CFA, were suppressed by TENS administration. TENS may be an effective therapy in controlling inflammatory pain induced by CFA. Its analgesic effect may be associated with the inhibition of activation of the spinal ERK1/2-COX-2 pathway.

Potential interaction of natural dietary bioactive compounds with COX-2.

PubMed

Maldonado-Rojas, Wilson; Olivero-Verbel, Jesus

2011-09-01

Bioactive natural products present in the diet play an important role in several biological processes, and many have been involved in the alleviation and control of inflammation-related diseases. These actions have been linked to both gene expression modulation of pro-inflammatory enzymes, such as cyclooxygenase 2 (COX-2), and to an action involving a direct inhibitory binding on this protein. In this study, several food-related compounds with known gene regulatory action on inflammation have been examined in silico as COX-2 ligands, utilizing AutoDock Vina, GOLD and Surflex-Dock (SYBYL) as docking protocols. Curcumin and all-trans retinoic acid presented the maximum absolute AutoDock Vina-derived binding affinities (9.3 kcal/mol), but genistein, apigenin, cyanidin, kaempferol, and docosahexaenoic acid, were close to this value. AutoDock Vina affinities and GOLD scores for several known COX-2 inhibitors significatively correlated with reported median inhibitory concentrations (R² = 0.462, P < 0.001 and R² = 0.238, P = 0.029, respectively), supporting the computational reliability of the predictions made by our docking simulations. Moreover, docking analysis insinuate the synergistic action of curcumin on celecoxib-induced inhibition of COX-2 may occur allosterically, as this natural compound docks to a place different from the inhibitor binding site. These results suggest that the anti-inflammatory properties of some food-derived molecules could be the result of their direct binding capabilities to COX-2, and this process can be modeled using protein-ligand docking methodologies. Copyright © 2011 Elsevier Inc. All rights reserved.

Cyclooxygenase 2 gene polymorphisms and chronic periodontitis in a North Indian population: a pilot study

PubMed Central

Daing, Anika; Singh, Sarvendra Vikram; Saimbi, Charanjeet Singh; Khan, Mohammad Akhlaq

2012-01-01

Purpose Cyclooxygenase (COX) enzyme catalyzes the production of prostaglandins, which are important mediators of tissue destruction in periodontitis. Single nucleotide polymorphisms of COX2 enzyme have been associated with increasing susceptibility to inflammatory diseases. The present study evaluates the association of two single nucleotide polymorphisms in COX2 gene (-1195G>A and 8473C>T) with chronic periodontitis in North Indians. Methods Both SNPs and their haplotypes were used to explore the associations between COX2 polymorphisms and chronic periodontitis in 56 patients and 60 controls. Genotyping was done by polymerase chain reaction followed by restriction fragment length polymorphism. Chi-square test and logistic regression analysis were performed for association analysis. Results By the individual genotype analysis, mutant genotypes (GA and AA) of COX2 -1195 showed more than a two fold risk (odds ratio [OR]>2) and COX2 8473 (TC and CC) showed a reduced risk for the disease, but the findings were not statistically significant. Haplotype analysis showed that the frequency of the haplotype AT was higher in the case group and a significant association was found for haplotype AT (OR, 1.79; 95% confidence interval, 1.03 to 3.11; P=0.0370) indicating an association between the AT haplotype of COX2 gene SNPs and chronic periodontitis. Conclusions Individual genotypes of both the SNPs were not associated while haplotype AT was found to be associated with chronic periodontitis in North Indians. PMID:23185695

Nimesulide, a COX-2 inhibitor, does not reduce lesion size or number in a nude mouse model of endometriosis.

PubMed

Hull, M L; Prentice, A; Wang, D Y; Butt, R P; Phillips, S C; Smith, S K; Charnock-Jones, D S

2005-02-01

Women with endometriosis have elevated levels of cyclooxygenase-2 (COX-2) in peritoneal macrophages and endometriotic tissue. Inhibition of COX-2 has been shown to reduce inflammation, angiogenesis and cellular proliferation. It may also downregulate aromatase activity in ectopic endometrial lesions. Ectopic endometrial establishment and growth are therefore likely to be suppressed in the presence of COX-2 inhibitors. We hypothesized that COX-2 inhibition would reduce the size and number of ectopic human endometrial lesions in a nude mouse model of endometriosis. The selective COX-2 inhibitor, nimesulide, was administered to estrogen-supplemented nude mice implanted with human endometrial tissue. Ten days after implantation, the number and size of ectopic endometrial lesions were evaluated and compared with lesions from a control group. Immunohistochemical assessment of vascular development and macrophage and myofibroblast infiltration in control and treated lesions was performed. There was no difference in the number or size of ectopic endometrial lesions in control and nimesulide-treated nude mice. Nimesulide did not induce a visually identifiable difference in blood vessel development or macrophage or myofibroblast infiltration in nude mouse explants. The hypothesized biological properties of COX-2 inhibition did not influence lesion number or size in the nude mouse model of endometriosis.

Markov chains and semi-Markov models in time-to-event analysis.

PubMed

Abner, Erin L; Charnigo, Richard J; Kryscio, Richard J

2013-10-25

A variety of statistical methods are available to investigators for analysis of time-to-event data, often referred to as survival analysis. Kaplan-Meier estimation and Cox proportional hazards regression are commonly employed tools but are not appropriate for all studies, particularly in the presence of competing risks and when multiple or recurrent outcomes are of interest. Markov chain models can accommodate censored data, competing risks (informative censoring), multiple outcomes, recurrent outcomes, frailty, and non-constant survival probabilities. Markov chain models, though often overlooked by investigators in time-to-event analysis, have long been used in clinical studies and have widespread application in other fields.

Markov chains and semi-Markov models in time-to-event analysis

PubMed Central

Abner, Erin L.; Charnigo, Richard J.; Kryscio, Richard J.

2014-01-01

A variety of statistical methods are available to investigators for analysis of time-to-event data, often referred to as survival analysis. Kaplan-Meier estimation and Cox proportional hazards regression are commonly employed tools but are not appropriate for all studies, particularly in the presence of competing risks and when multiple or recurrent outcomes are of interest. Markov chain models can accommodate censored data, competing risks (informative censoring), multiple outcomes, recurrent outcomes, frailty, and non-constant survival probabilities. Markov chain models, though often overlooked by investigators in time-to-event analysis, have long been used in clinical studies and have widespread application in other fields. PMID:24818062

Evaluation of protocol change in burn-care management using the Cox proportional hazards model with time-dependent covariates.

PubMed

Ichida, J M; Wassell, J T; Keller, M D; Ayers, L W

1993-02-01

Survival analysis methods are valuable for detecting intervention effects because detailed information from patient records and sensitive outcome measures are used. The burn unit at a large university hospital replaced routine bathing with total body bathing using chlorhexidine gluconate for antimicrobial effect. A Cox proportional hazards model was used to analyse time from admission until either infection with Staphylococcus aureus or discharge for 155 patients, controlling for burn severity and two time-dependent covariates: days until first wound excision and days until first administration of prophylactic antibiotics. The risk of infection was 55 per cent higher in the historical control group, although not statistically significant. There was also some indication that early wound excision may be important as an infection-control measure for burn patients.

Monitoring of Fasciola Species Contamination in Water Dropwort by cox1 Mitochondrial and ITS-2 rDNA Sequencing Analysis.

PubMed

Choi, In-Wook; Kim, Hwang-Yong; Quan, Juan-Hua; Ryu, Jae-Gee; Sun, Rubing; Lee, Young-Ha

2015-10-01

Fascioliasis, a food-borne trematode zoonosis, is a disease primarily in cattle and sheep and occasionally in humans. Water dropwort (Oenanthe javanica), an aquatic perennial herb, is a common second intermediate host of Fasciola, and the fresh stems and leaves are widely used as a seasoning in the Korean diet. However, no information regarding Fasciola species contamination in water dropwort is available. Here, we collected 500 samples of water dropwort in 3 areas in Korea during February and March 2015, and the water dropwort contamination of Fasciola species was monitored by DNA sequencing analysis of the Fasciola hepatica and Fasciola gigantica specific mitochondrial cytochrome c oxidase subunit 1 (cox1) and nuclear ribosomal internal transcribed spacer 2 (ITS-2). Among the 500 samples assessed, the presence of F. hepatica cox1 and 1TS-2 markers were detected in 2 samples, and F. hepatica contamination was confirmed by sequencing analysis. The nucleotide sequences of cox1 PCR products from the 2 F. hepatica-contaminated samples were 96.5% identical to the F. hepatica cox1 sequences in GenBank, whereas F. gigantica cox1 sequences were 46.8% similar with the sequence detected from the cox1 positive samples. However, F. gigantica cox1 and ITS-2 markers were not detected by PCR in the 500 samples of water dropwort. Collectively, in this survey of the water dropwort contamination with Fasciola species, very low prevalence of F. hepatica contamination was detected in the samples.

Predictors of course in obsessive-compulsive disorder: logistic regression versus Cox regression for recurrent events.

PubMed

Kempe, P T; van Oppen, P; de Haan, E; Twisk, J W R; Sluis, A; Smit, J H; van Dyck, R; van Balkom, A J L M

2007-09-01

Two methods for predicting remissions in obsessive-compulsive disorder (OCD) treatment are evaluated. Y-BOCS measurements of 88 patients with a primary OCD (DSM-III-R) diagnosis were performed over a 16-week treatment period, and during three follow-ups. Remission at any measurement was defined as a Y-BOCS score lower than thirteen combined with a reduction of seven points when compared with baseline. Logistic regression models were compared with a Cox regression for recurrent events model. Logistic regression yielded different models at different evaluation times. The recurrent events model remained stable when fewer measurements were used. Higher baseline levels of neuroticism and more severe OCD symptoms were associated with a lower chance of remission, early age of onset and more depressive symptoms with a higher chance. Choice of outcome time affects logistic regression prediction models. Recurrent events analysis uses all information on remissions and relapses. Short- and long-term predictors for OCD remission show overlap.

Docking studies on NSAID/COX-2 isozyme complexes using Contact Statistics analysis

NASA Astrophysics Data System (ADS)

Ermondi, Giuseppe; Caron, Giulia; Lawrence, Raelene; Longo, Dario

2004-11-01

The selective inhibition of COX-2 isozymes should lead to a new generation of NSAIDs with significantly reduced side effects; e.g. celecoxib (Celebrex®) and rofecoxib (Vioxx®). To obtain inhibitors with higher selectivity it has become essential to gain additional insight into the details of the interactions between COX isozymes and NSAIDs. Although X-ray structures of COX-2 complexed with a small number of ligands are available, experimental data are missing for two well-known selective COX-2 inhibitors (rofecoxib and nimesulide) and docking results reported are controversial. We use a combination of a traditional docking procedure with a new computational tool (Contact Statistics analysis) that identifies the best orientation among a number of solutions to shed some light on this topic.

Correlated non-nuclear COX2 and low HER2 expression confers a good prognosis in colorectal cancer.

PubMed

Zhou, Fei-Fei; Huang, Rong; Jiang, Jun; Zeng, Xiao-Hong; Zou, Shu-Qian

2018-06-05

COX2 and HER2 are shown to be critical in the regulation of cancer progression. However, the prognostic value of nuclear COX2 in colorectal cancer (CRC) and its relationship with HER2 still remains unknown. In this study, the expression and biological significance of COX2 and HER2 were evaluated in CRC at mRNA and protein levels. RNA-Seq data of CRC were downloaded from TCGA, and 229 CRC and 50 non-cancerous subjects were enrolled in this study. Bioinformatics and immunohistochemistry analysis was performed based on the obtained data. Survival analysis was conducted to identify factors associated with overall survival of CRC patients. We showed that mRNA and protein levels of COX2 and HER2 were upregulated in CRC compared with the adjacent tissues. COX2 protein levels and nuclear COX2 expression were correlated with a poor prognosis of CRC patients. In addition, we also revealed that nuclear COX2 expression was positively associated with HER2 expression. Non-nuclear COX2 combined with low HER2 expression, was negatively correlated with Duke's stage and lymph node metastasis, predicting the best outcomes for CRC patients. In addition, our data indicated that non-nuclear COX2 combined with low HER2 expression is an independent prognostic factor for CRC after surgical resection. The study suggests that nuclear COX2 in combination with HER2 can serve as potential biomarkers for the clinical diagnosis and prognosis of CRC, and targeted inhibition of COX2 and HER2 might be an alternative strategy for the management of CRC.

Identification of the bacteria scavenging atmospheric CO and evaluation of the impact of land-use change on their distribution and activity

NASA Astrophysics Data System (ADS)

Constant, P.; Quiza, L.; Lalonde, I.

2013-12-01

Soil bacteria scavenging carbon monoxide (CO) are responsible for the biological sink of atmospheric CO. These bacteria mitigate an important fraction of the global emissions of CO from natural and anthropogenic sources. This ubiquitous soil ecosystem service is of critical importance since CO indirectly regulates the atmospheric lifetime of methane - the second most powerful greenhouse gas. So far, only few carboxydovore bacteria were shown to oxidize atmospheric CO. The CO-dehydrogenase (CODH) is the enzyme catalyzing the CO oxidation reaction in these bacteria. The enzyme is a dimer of heterotrimers encoded by the genes coxS, coxM and coxL. CoxL is the large subunit of the CODH. Phylogenetic analyzes revealed that coxL gene sequences encompass two main clusters: BMS and OMP groups but the version conferring a high affinity for CO and the ability to scavenge atmospheric CO is unknown. The objective of this investigation was to relate the diversity of coxL gene sequences with CO soil uptake activity and soil physicochemical properties. For this purpose, we collected soil samples in three neighbouring sites encompassing different land-use types: an undisturbed deciduous forest, a maize field and a larch monoculture. We analyzed (i) coxL diversity in the three environments, using a new coxL PCR detection assay targeting both OMP and BMS groups, (ii) CO oxidation activity using a gas chromatography assay and, (iii) soil physicochemical properties. Our results demonstrate that land-use change exerts a significant impact on coxL diversity as well as CO oxidation activity, with significant loss of the potential CO soil uptake activity following the conversion of native forest to maize or larch plantation. Most of the coxL gene sequences retrieved from the soil samples were not affiliated to sequences derived from microbial genome databases, impairing a taxonomic identification of the potential CO-oxidizing bacteria detected in soil. Canonical ordination analysis allowed us to identify coxL sequences belonging to potential high affinity CO-oxidizing bacteria, in addition to recognise environmental factors influencing their distribution and CO soil uptake activity. The activity increased with total carbon and nitrogen in soil and was inversely correlated to water content, pH, potassium and phosphorus. Candidates belonging to OMP group were identified as potential high affinity CO oxidizing bacteria. These bacteria were enriched in the laboratory and tested for their CO uptake activity. Work is currently in progress to assess the abundance and the CO uptake activity of these microorganisms in soil. Taken together, these results will be implemented into molecular models aimed at predicting CO uptake activity in soil. These models will be utilized to predict the response of the biological sink of CO to global change, while determining how land management practices could protect this important ecosystem service.

Indoleamine-2,3-dioxygenase 1/cyclooxygenase 2 expression prediction for adverse prognosis in colorectal cancer

PubMed Central

Ma, Wen-Juan; Wang, Xing; Yan, Wen-Ting; Zhou, Zhong-Guo; Pan, Zhi-Zhong; Chen, Gong; Zhang, Rong-Xin

2018-01-01

AIM To evaluate indoleamine-2,3-dioxygenase 1/cyclooxygenase 2 (IDO1/COX2) expression as an independent prognostic biomarker for colorectal cancer (CRC) patients. METHODS We retrospectively studied the medical records of 95 patients who received surgical resection from August 2008 to January 2010. All patients were randomly assigned to adjuvant treatment with or without celecoxib groups after surgery. We performed standard immunohistochemistry to assess the expression levels of IDO1/COX2 and evaluated the correlation of IDO1/COX2 with clinicopathological factors and overall survival (OS) outcomes. RESULTS The expression of nuclear IDO1 was significantly correlated with body mass index (P < 0.001), and IDO1 expression displayed no association with sex, age, tumor differentiation, T stage, N stage, carcinoembryonic antigen, cancer antigen 19-9, CD3+ and CD8+ tumor infiltrating lymphocytes, and COX2. In univariate analysis, we found that nuclear IDO1 (P = 0.039), nuclear/cytoplasmic IDO1 [hazard ratio (HR) = 2.044, 95% confidence interval (CI): 0.871-4.798, P = 0.039], nuclear IDO1/COX2 (HR = 3.048, 95%CI: 0.868-10.7, P = 0.0049) and cytoplasmic IDO1/COX2 (HR = 2.109, 95%CI: 0.976-4.558, P = 0.022) all yielded significantly poor OS outcomes. Nuclear IDO1 (P = 0.041), nuclear/cytoplasmic IDO1 (HR = 3.023, 95%CI: 0.585-15.61, P = 0.041) and cytoplasmic IDO1/COX2 (HR = 2.740, 95%CI: 0.764-9.831, P = 0.038) have significantly poor OS outcomes for the CRC celecoxib subgroup. In our multivariate Cox model, high coexpression of cytoplasmic IDO1/COX2 was found to be an independent predictor of poor outcome in CRC (HR = 2.218, 95%CI: 1.011-4.48, P = 0.047) and celecoxib subgroup patients (HR = 3.210, 95%CI: 1.074-9.590, P = 0.037). CONCLUSION Our results showed that cytoplasmic IDO1/COX2 coexpression could be used as an independent poor predictor for OS in CRC. PMID:29853736

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

PubMed

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

2015-08-01

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

[Use of multiple regression models in observational studies (1970-2013) and requirements of the STROBE guidelines in Spanish scientific journals].

PubMed

Real, J; Cleries, R; Forné, C; Roso-Llorach, A; Martínez-Sánchez, J M

In medicine and biomedical research, statistical techniques like logistic, linear, Cox and Poisson regression are widely known. The main objective is to describe the evolution of multivariate techniques used in observational studies indexed in PubMed (1970-2013), and to check the requirements of the STROBE guidelines in the author guidelines in Spanish journals indexed in PubMed. A targeted PubMed search was performed to identify papers that used logistic linear Cox and Poisson models. Furthermore, a review was also made of the author guidelines of journals published in Spain and indexed in PubMed and Web of Science. Only 6.1% of the indexed manuscripts included a term related to multivariate analysis, increasing from 0.14% in 1980 to 12.3% in 2013. In 2013, 6.7, 2.5, 3.5, and 0.31% of the manuscripts contained terms related to logistic, linear, Cox and Poisson regression, respectively. On the other hand, 12.8% of journals author guidelines explicitly recommend to follow the STROBE guidelines, and 35.9% recommend the CONSORT guideline. A low percentage of Spanish scientific journals indexed in PubMed include the STROBE statement requirement in the author guidelines. Multivariate regression models in published observational studies such as logistic regression, linear, Cox and Poisson are increasingly used both at international level, as well as in journals published in Spanish. Copyright © 2015 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

Influence of the Cyclooxygenase-2 Gene -765G/C and -1195G/A Polymorphisms on Development of Ischemic Stroke.

PubMed

Wu, Guangliang; Cai, Haiyan; Cai, Haobin; Chen, Zhao; Tan, Lei; Qin, Xiurong; Cai, Yefeng

2016-09-01

Many studies have investigated the association between the cyclooxygenase-2 (COX-2) gene polymorphism and ischemic stroke. However, results of these studies still remain controversial. To better explain the association between COX-2 polymorphisms (-765G/C and -1195G/A) and ischemic stroke risk, a meta-analysis was performed. Relevant studies were identified from 4 Chinese databases (Chinese Biological Medical Literature database, Chinese National Knowledge Infrastructure database, Chongqing VIP database, and Chinese WANFANG database), PUBMED and EMBASE prior to December 2015. The strength of association between COX-2 polymorphism and ischemic stroke was evaluated by the odds ratio (OR) with 95% confidence interval (CI). Inconsistency index (I(2)) and the Cochran's Q statistic were used to check heterogeneity. Publication bias was evaluated by funnel plots and Egger's regression test. A total of 4086 ischemic stroke cases and 4747 controls were identified. Significant association between COX-2 -765G/C polymorphism and the risk of ischemic stroke was found in Brazilians and the African-Americans. The OR of (CC+GC versus GG) for the Brazilians and African-Americans were (6.328, 95% CI = 2.295-17.448) and (1.644, 95% CI = 1.060-2.551). In addition, the recessive model of the Brazilians gave an OR of 3.621 (95% CI: 1.519-8.630). Furthermore, the (GC versus GG) and the allele model of the African-Americans were (OR: 1.615, 95% CI = 1.015-2.572) and (OR: 1.422, 95% CI = 1.033-1.957). Significant association was also observed for COX-2 -1195G/A polymorphism in the subtypes of small vessel disease (SVD) of ischemic stroke. Our study suggests that COX-2 -765G/C and -1195G/A polymorphisms may contribute to susceptibility of ischemic stroke, specifically in Brazilians and the African-Americans, and those of SVD. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Reporting and methodological quality of survival analysis in articles published in Chinese oncology journals

PubMed Central

Zhu, Xiaoyan; Zhou, Xiaobin; Zhang, Yuan; Sun, Xiao; Liu, Haihua; Zhang, Yingying

2017-01-01

Abstract Survival analysis methods have gained widespread use in the filed of oncology. For achievement of reliable results, the methodological process and report quality is crucial. This review provides the first examination of methodological characteristics and reporting quality of survival analysis in articles published in leading Chinese oncology journals. To examine methodological and reporting quality of survival analysis, to identify some common deficiencies, to desirable precautions in the analysis, and relate advice for authors, readers, and editors. A total of 242 survival analysis articles were included to be evaluated from 1492 articles published in 4 leading Chinese oncology journals in 2013. Articles were evaluated according to 16 established items for proper use and reporting of survival analysis. The application rates of Kaplan–Meier, life table, log-rank test, Breslow test, and Cox proportional hazards model (Cox model) were 91.74%, 3.72%, 78.51%, 0.41%, and 46.28%, respectively, no article used the parametric method for survival analysis. Multivariate Cox model was conducted in 112 articles (46.28%). Follow-up rates were mentioned in 155 articles (64.05%), of which 4 articles were under 80% and the lowest was 75.25%, 55 articles were100%. The report rates of all types of survival endpoint were lower than 10%. Eleven of 100 articles which reported a loss to follow-up had stated how to treat it in the analysis. One hundred thirty articles (53.72%) did not perform multivariate analysis. One hundred thirty-nine articles (57.44%) did not define the survival time. Violations and omissions of methodological guidelines included no mention of pertinent checks for proportional hazard assumption; no report of testing for interactions and collinearity between independent variables; no report of calculation method of sample size. Thirty-six articles (32.74%) reported the methods of independent variable selection. The above defects could make potentially inaccurate, misleading of the reported results, or difficult to interpret. There are gaps in the conduct and reporting of survival analysis in studies published in Chinese oncology journals, severe deficiencies were noted. More endorsement by journals of the report guideline for survival analysis may improve articles quality, and the dissemination of reliable evidence to oncology clinicians. We recommend authors, readers, reviewers, and editors to consider survival analysis more carefully and cooperate more closely with statisticians and epidemiologists. PMID:29390340

Regulatory effect of the AMPK-COX-2 signaling pathway in curcumin-induced apoptosis in HT-29 colon cancer cells.

PubMed

Lee, Yun-Kyoung; Park, Song Yi; Kim, Young-Min; Park, Ock Jin

2009-08-01

AMP-activated protein kinase (AMPK), a highly conserved protein in eukaryotes, functions as a major metabolic switch to maintain energy homeostasis. It also intrinsically regulates the mammalian cell cycle. Moreover, the AMPK cascade has emerged as an important pathway implicated in cancer control. In this study we investigated the effects of curcumin on apoptosis and the regulatory effect of the AMPK-cyclooxygenase-2 (COX-2) pathway in curcumin-induced apoptosis. Curcumin has shown promise as a chemopreventive agent because of its in vivo regression of various animal-model colon cancers. This study focused on exploiting curcumin to apply antitumorigenic effects through modulation of the AMPK-COX-2 cascade. Curcumin exhibited a potent apoptotic effect on HT-29 colon cancer cells at concentrations of 50 micromol/L and above. These apoptotic effects were correlated with the decrease in pAkt and COX-2, as well as the increase in p-AMPK. Cell cycle analysis showed that curcumin induced G(1)-phase arrest. Further study with AMPK synthetic inhibitor Compound C has shown that increased concentrations of Compound C would abolish AMPK expression, accompanied by a marked increase in COX-2 as well as pAkt expression in curcumin-treated HT-29 cells. By inhibiting AMPK with Compound C, we found that curcumin-treated colon cancer cells were no longer undergoing apoptosis; rather, they were proliferative. These results indicate that AMPK is crucial in apoptosis induced by curcumin and further that the pAkt-AMPK-COX-2 cascade or AMPK-pAkt-COX-2 pathway is important in cell proliferation and apoptosis in colon cancer cells.

Determination of dietary iron requirements by full expression of iron-containing cytochrome c oxidase in the heart of broilers from 22 to 42 d of age.

PubMed

Liao, Xiudong; Ma, Chunyan; Lu, Lin; Zhang, Liyang; Luo, Xugang

2017-10-01

The present study was carried out to determine dietary Fe requirements for the full expression of Fe-containing enzyme in broilers chicks from 22 to 42 d of age. At 22 d of age, 288 Arbor Acres male chicks were randomly assigned to one of six treatments with six replicates and fed a basal maize-soyabean-meal diet (control, containing 47·0 mg Fe/kg) or the basal diet supplemented with 20, 40, 60, 80 or 100 mg Fe/kg from FeSO4.7H2O for 21 d. Regression analysis was performed to estimate the optimal dietary Fe level using quadratic models. Liver cytochrome c oxidase (Cox), heart Cox and kidney succinate dehydrogenase mRNA levels as well as heart COX activity were affected (P<0·08) by dietary Fe level, and COX mRNA level and activity in heart of broilers increased quadratically (P<0·03) as dietary Fe level increased. The estimates of dietary Fe requirements were 110 and 104 mg/kg for the full expression of Cox mRNA and for its activity in the heart of broilers, respectively. The results from this study indicate that COX mRNA level and activity in the heart are new and sensitive criteria to evaluate the dietary Fe requirements of broilers, and the dietary Fe requirements would be 104-110 mg/kg to support the full expression of COX in the heart of broiler chicks from 22 to 42 d of age, which are higher than the current National Research Council Fe requirement (80 mg/kg) of broiler chicks from 1 to 21 d or 22 to 42 d of age.

COX-2 expression and function in the hyperalgesic response to paw inflammation in mice

PubMed Central

Jain, Naveen K.; Ishikawa, Tomo-o; Spigelman, Igor; Herschman, Harvey R.

2009-01-01

Peripheral inflammation and edema are often accompanied by primary and secondary hyperalgesia which are mediated by both peripheral and central mechanisms. The role of cyclooxygenase-2 (COX-2)-mediated prostanoid production in hyperalgesia is a topic of substantial current interest. We have established a murine foot-pad inflammation model in which both pharmacologic and genetic tools can be used to characterize the role of COX-2 in hyperalgesia. Zymosan, an extract from yeast, injected into the plantar surface of the hind paw induces an edema response and an increase in COX-2 expression in the hindpaw, spinal cord and brain. Zymosan-induced primary hyperalgesia, measured as a decrease in hindpaw withdrawal latency in response to a thermal stimulus, is long-lasting and is not inhibited by pre-treatment with the systemic COX-2 selective inhibitor, parecoxib (20 mg/kg). In contrast, the central component of hyperalgesia, measured as a reduction in tail flick latency in response to heat, is reduced by parecoxib. Zymosan-induced primary hyperalgesia in Cox-2−/− mice is similar to that of their Cox-2+/+ littermate controls. However, the central component of hyperalgesia is substantially reduced in Cox-2−/− versus Cox-2+/+ mice, and returns to baseline values much more rapidly. Thus pharmacological data suggest, and genetic experiments confirm, (i) that primary hyperalgesia in response to zymosan inflammation in the mouse paw is not mediated by COX-2 function and (ii) that COX-2 function plays a major role in the central component of hyperalgesia in this model of inflammation. PMID:18829279

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

PubMed

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

2014-12-01

Mastitis is a complex disease affecting dairy cows and is considered to be the most costly disease of dairy herds. The hazard of mastitis is a function of many factors, both managerial and environmental, making its control a difficult issue to milk producers. Observational studies of clinical mastitis (CM) often generate datasets with a number of characteristics which influence the analysis of those data: the outcome of interest may be the time to occurrence of a case of mastitis, predictors may change over time (time-dependent predictors), the effects of factors may change over time (time-dependent effects), there are usually multiple hierarchical levels, and datasets may be very large. Analysis of such data often requires expansion of the data into the counting-process format - leading to larger datasets - thus complicating the analysis and requiring excessive computing time. In this study, a nested frailty Cox model with time-dependent predictors and effects was applied to Canadian Bovine Mastitis Research Network data in which 10,831 lactations of 8035 cows from 69 herds were followed through lactation until the first occurrence of CM. The model was fit to the data as a Poisson model with nested normally distributed random effects at the cow and herd levels. Risk factors associated with the hazard of CM during the lactation were identified, such as parity, calving season, herd somatic cell score, pasture access, fore-stripping, and proportion of treated cases of CM in a herd. The analysis showed that most of the predictors had a strong effect early in lactation and also demonstrated substantial variation in the baseline hazard among cows and between herds. A small simulation study for a setting similar to the real data was conducted to evaluate the Poisson maximum likelihood estimation approach with both Gaussian quadrature method and Laplace approximation. Further, the performance of the two methods was compared with the performance of a widely used estimation approach for frailty Cox models based on the penalized partial likelihood. The simulation study showed good performance for the Poisson maximum likelihood approach with Gaussian quadrature and biased variance component estimates for both the Poisson maximum likelihood with Laplace approximation and penalized partial likelihood approaches. Copyright © 2014. Published by Elsevier B.V.

The roles of the cyclo-oxygenases types one and two in prostaglandin synthesis in human fetal membranes at term.

PubMed

Sawdy, R J; Slater, D M; Dennes, W J; Sullivan, M H; Bennett, P R

2000-01-01

The aim of this study was to determine the relative contributions of cyclo-oxygenase (COX) types 1 and 2 to prostaglandin synthesis at term. Fetal membranes were collected from 6 pregnancies after elective caesarean section at term, prior to labour. The presence of COX-1 and COX-2 protein was determined using Western analysis. The relative contributions of the two isoforms of COX to prostaglandin synthesis were determined by incubation of fetal membrane discs with either a COX-2 selective inhibitor, SC236, or a COX-1 selective inhibitor, SC560, and measurement of prostaglandin release during 24 h using enzyme-linked immuno-sorbent assay (ELISA). Both COX-1 and COX-2 protein were demonstrated in amnion and chorion-decidua. The COX-2 selective inhibitor, SC-236, significantly reduced prostaglandin synthesis, both in its COX-2 specific and higher, non-specific concentration ranges. The COX-1 selective inhibitor, SC-560, had no effect upon prostaglandin synthesis in its COX-1 specific concentration range, but did significantly reduce prostaglandin synthesis at higher, non-selective concentrations. Fetal membranes contain both COX-1 and COX-2 at term, but only COX-2 contributes towards prostaglandin synthesis. COX-2 selective NSAI drugs will be as effective as non-selective agents in inhibition of fetal membrane prostaglandin synthesis and may represent a new strategy for tocolysis. Copyright 2000 Harcourt Publishers Ltd.

An ice-ocean coupled model for the Northern Hemisphere

NASA Technical Reports Server (NTRS)

Cheng, Abe; Preller, Ruth

1992-01-01

The Hibler ice model has been modified and adapted to a domain that includes most of the sea ice-covered areas in the Northern Hemisphere. This model, joined with the Cox ocean model, is developed as an enhancement to the U.S. Navy's sea ice forecasting, PIPS, and is termed PIPS2.0. Generally, the modeled ice edge is consistent with the Navy-NOAA Joint Ice Center weekly analysis, and the modeled ice thickness distribution agrees with submarine sonar data in the central Arctic basin.

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

PubMed

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

2012-07-01

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 (π) for the mitochondrial gene cytochrome c oxidase subunit I (cox1). However, several issues relevant to the comparison of h and π 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 π 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 π were calculated using a 456-base region of cox1 that was common to all the data sets (median h=0.70130, median π=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 π was π=0.0081 h(2). 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.

Quantifying parameter uncertainty in stochastic models using the Box Cox transformation

NASA Astrophysics Data System (ADS)

Thyer, Mark; Kuczera, George; Wang, Q. J.

2002-08-01

The Box-Cox transformation is widely used to transform hydrological data to make it approximately Gaussian. Bayesian evaluation of parameter uncertainty in stochastic models using the Box-Cox transformation is hindered by the fact that there is no analytical solution for the posterior distribution. However, the Markov chain Monte Carlo method known as the Metropolis algorithm can be used to simulate the posterior distribution. This method properly accounts for the nonnegativity constraint implicit in the Box-Cox transformation. Nonetheless, a case study using the AR(1) model uncovered a practical problem with the implementation of the Metropolis algorithm. The use of a multivariate Gaussian jump distribution resulted in unacceptable convergence behaviour. This was rectified by developing suitable parameter transformations for the mean and variance of the AR(1) process to remove the strong nonlinear dependencies with the Box-Cox transformation parameter. Applying this methodology to the Sydney annual rainfall data and the Burdekin River annual runoff data illustrates the efficacy of these parameter transformations and demonstrate the value of quantifying parameter uncertainty.

External validation of a Cox prognostic model: principles and methods

PubMed Central

2013-01-01

Background A prognostic model should not enter clinical practice unless it has been demonstrated that it performs a useful role. External validation denotes evaluation of model performance in a sample independent of that used to develop the model. Unlike for logistic regression models, external validation of Cox models is sparsely treated in the literature. Successful validation of a model means achieving satisfactory discrimination and calibration (prediction accuracy) in the validation sample. Validating Cox models is not straightforward because event probabilities are estimated relative to an unspecified baseline function. Methods We describe statistical approaches to external validation of a published Cox model according to the level of published information, specifically (1) the prognostic index only, (2) the prognostic index together with Kaplan-Meier curves for risk groups, and (3) the first two plus the baseline survival curve (the estimated survival function at the mean prognostic index across the sample). The most challenging task, requiring level 3 information, is assessing calibration, for which we suggest a method of approximating the baseline survival function. Results We apply the methods to two comparable datasets in primary breast cancer, treating one as derivation and the other as validation sample. Results are presented for discrimination and calibration. We demonstrate plots of survival probabilities that can assist model evaluation. Conclusions Our validation methods are applicable to a wide range of prognostic studies and provide researchers with a toolkit for external validation of a published Cox model. PMID:23496923

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

NASA Technical Reports Server (NTRS)

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

1998-01-01

New computationally intensive tools for medical survival analyses include recursive partitioning (also called CART) and artificial neural networks. A challenge that remains is to better understand the behavior of these techniques in effort to know when they will be effective tools. Theoretically they may overcome limitations of the traditional multivariable survival technique, the Cox proportional hazards regression model. Experiments were designed to test whether the new tools would, in practice, overcome these limitations. Two datasets in which theory suggests CART and the neural network should outperform the Cox model were selected. The first was a published leukemia dataset manipulated to have a strong interaction that CART should detect. The second was a published cirrhosis dataset with pronounced nonlinear effects that a neural network should fit. Repeated sampling of 50 training and testing subsets was applied to each technique. The concordance index C was calculated as a measure of predictive accuracy by each technique on the testing dataset. In the interaction dataset, CART outperformed Cox (P less than 0.05) with a C improvement of 0.1 (95% Cl, 0.08 to 0.12). In the nonlinear dataset, the neural network outperformed the Cox model (P less than 0.05), but by a very slight amount (0.015). As predicted by theory, CART and the neural network were able to overcome limitations of the Cox model. Experiments like these are important to increase our understanding of when one of these new techniques will outperform the standard Cox model. Further research is necessary to predict which technique will do best a priori and to assess the magnitude of superiority.

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

PubMed

Kim, Joohwee; Vaish, Vivek; Feng, Mingxiao; Field, Kevin; Chatzistamou, Ioulia; Shim, Minsub

2016-10-07

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

Role of phosphorylated extracellular signal-regulated kinase, calcitonin gene-related peptide and cyclooxygenase-2 in experimental rat models of migraine

PubMed Central

DONG, XIAOMENG; HU, YAOZHI; JING, LONG; CHEN, JINBO

2015-01-01

Although migraine is a common neurological condition, the pathomechanism is not yet fully understood. Activation of the trigeminovascular system (TVS) has an important function in this disorder and neurogenic inflammation and central sensitization are important mechanisms underlying this condition. Nitroglycerin (NTG) infusion in rats closely mimics a universally accepted human model of migraine. Electrical stimulation of the trigeminal ganglion (ESTG) of rats can also activate TVS during a migraine attack. Numerous studies have revealed that phosphorylated extracellular signal-regulated kinase (p-ERK), calcitonin gene-related peptide (CGRP) and cyclooxygenase-2 (COX-2) are involved in pain and nociceptive pathways. However, few studies have examined whether p-ERK, CGRP and COX-2 are involved in neurogenic inflammation and central sensitization. In the present study, the expression of p-ERK, CGRP and COX-2 was detected in the dura mater, trigeminal ganglion (TG) and spinal trigeminal nucleus caudalis in NTG-induced rats and ESTG models by immunohistochemistry. The three areas considered were crucial components of the TVS. The selective COX-2 inhibitor nimesulide was used in ESTG rats to examine the association between p-ERK, CGRP and COX-2. The results demonstrated that p-ERK, CGRP and COX-2 mediated neurogenic inflammation and central sensitization in migraine. In addition, the expression of p-ERK and CGRP was attenuated by the COX-2 inhibitor. PMID:25892078

Indomethacin treatment prior to pentylenetetrazole-induced seizures downregulates the expression of il1b and cox2 and decreases seizure-like behavior in zebrafish larvae.

PubMed

Barbalho, Patrícia Gonçalves; Lopes-Cendes, Iscia; Maurer-Morelli, Claudia Vianna

2016-03-09

It has been demonstrated that the zebrafish model of pentylenetetrazole (PTZ)-evoked seizures and the well-established rodent models of epilepsy are similar pertaining to behavior, electrographic features, and c-fos expression. Although this zebrafish model is suitable for studying seizures, to date, inflammatory response after seizures has not been investigated using this model. Because a relationship between epilepsy and inflammation has been established, in the present study we investigated the transcript levels of the proinflammatory cytokines interleukin-1 beta (il1b) and cyclooxygenase-2 (cox2a and cox2b) after PTZ-induced seizures in the brain of zebrafish 7 days post fertilization. Furthermore, we exposed the fish to the nonsteroidal anti-inflammatory drug indomethacin prior to PTZ, and we measured its effect on seizure latency, number of seizure behaviors, and mRNA expression of il1b, cox2b, and c-fos. We used quantitative real-time PCR to assess the mRNA expression of il1b, cox2a, cox2b, and c-fos, and visual inspection was used to monitor seizure latency and the number of seizure-like behaviors. We found a short-term upregulation of il1b, and we revealed that cox2b, but not cox2a, was induced after seizures. Indomethacin treatment prior to PTZ-induced seizures downregulated the mRNA expression of il1b, cox2b, and c-fos. Moreover, we observed that in larvae exposed to indomethacin, seizure latency increased and the number of seizure-like behaviors decreased. This is the first study showing that il1b and cox-2 transcripts are upregulated following PTZ-induced seizures in zebrafish. In addition, we demonstrated the anticonvulsant effect of indomethacin based on (1) the inhibition of PTZ-induced c-fos transcription, (2) increase in seizure latency, and (3) decrease in the number of seizure-like behaviors. Furthermore, anti-inflammatory effect of indomethacin is clearly demonstrated by the downregulation of the mRNA expression of il1b and cox2b. Our results are supported by previous evidences suggesting that zebrafish is a suitable alternative for studying inflammation, seizures, and the effect of anti-inflammatory compounds on seizure suppression.

Simulation program for estimating statistical power of Cox's proportional hazards model assuming no specific distribution for the survival time.

PubMed

Akazawa, K; Nakamura, T; Moriguchi, S; Shimada, M; Nose, Y

1991-07-01

Small sample properties of the maximum partial likelihood estimates for Cox's proportional hazards model depend on the sample size, the true values of regression coefficients, covariate structure, censoring pattern and possibly baseline hazard functions. Therefore, it would be difficult to construct a formula or table to calculate the exact power of a statistical test for the treatment effect in any specific clinical trial. The simulation program, written in SAS/IML, described in this paper uses Monte-Carlo methods to provide estimates of the exact power for Cox's proportional hazards model. For illustrative purposes, the program was applied to real data obtained from a clinical trial performed in Japan. Since the program does not assume any specific function for the baseline hazard, it is, in principle, applicable to any censored survival data as long as they follow Cox's proportional hazards model.

Effects of Cyclooxygenase on the Urothelium of the Urinary Bladder of Mice Exposed to Pelvic Radiation.

PubMed

Ozbilgin, M Kemal; Onal, Tuna; Ozcan, Cemil; Temel, Merve; Aktas, Caner; Gareveran, Manuchehr Salehi; Uluer, Elgin Turkoz; Inan, Sevinc; Kurtman, Cengiz

2016-04-01

To determine the role of cyclooxygenase (COX) expression in the urothelium of the urinary bladder during radiation injury caused by pelvic radiotherapy for cancer therapy. Twenty-four male Swiss Albino mice were separated into 4 groups. The first group was the control group (Group 1) and the second, third, and fourth groups were euthanized after 24 hours (Group 2), 48 hours (Group 3), and 7 days (Group 4), respectively. A single-fractioned 10 Gy of ionizing radiation was applied to all mice's pelvic zone with Co-60. Bladders were removed completely from the pelvic region. Histochemical analysis using hematoxylin and eosin and immunohistochemical analysis using anti-COX-1 and COX-2 antibodies were performed on tissue samples. The immunoreactivities of the urinary bladder were quantified using H-score measurement, and statistical comparison was performed. In the immunohistochemical examination the COX-1 immunoreactivities were found to be higher in the urothelium of the bladder in the radiation exposed groups than in the normal control group (group 1) (p < 0.005). Additionally, high immunoreactivity of COX-2 molecule was established in groups 2, 3, and 4 of radiation groups as compared to group 1 (p < 0.005) in examination of the urothelium. COX-1 and COX-2 immunoreactivities in the submucosa were detected higher in group 4 than in the other groups (p < 0.005). COX-1 and COX-2 expressions in the urothelium and subepithelium of the urinary bladder were investigated in mice during the acute radiation response. The expression of COX-1 and COX-2 in the urothelium seems to prevent bladder damage from radiation, supplying differentiation and restoration of the urothelium.

QSAR analyses of conformationally restricted 1,5-diaryl pyrazoles as selective COX-2 inhibitors: application of connection table representation of ligands.

PubMed

Prasanna, S; Manivannan, E; Chaturvedi, S C

2005-04-15

As a part of our continuing efforts in discerning the structural and physicochemical requirements for selective COX-2 over COX-1 inhibition among the fused pyrazole ring systems, herein we report the QSAR analyses of the title compounds. The conformational flexibility of the title compounds was examined using a simple connection table representation. The conformational investigation was aided by calculating a connection table parameter called fraction of rotable bonds, b_rotR encompassing the number of rotable bonds and b_count, the number of bonds including implicit hydrogens of each ligand. The hydrophobic and steric correlation of the title compounds towards selective COX-2 inhibition was reported previously in one of our recent publications. In this communication, we attempt to calculate Wang-Ford charges of the non-hydrogen common atoms of AM1 optimized geometries of the title compounds. Owing to the partial conformational flexibility of title compounds, conformationally restricted and unrestricted descriptors were calculated from MOE. Correlation analysis of these 2D, 3D and Wang-Ford charges was accomplished by linear regression analysis. 2D molecular descriptor b_single, 3D molecular descriptors glob, std_dim3 showed significant contribution towards COX-2 inhibitory activity. Balaban J, a connectivity topological index showed a negative and positive contribution towards COX-1 and selective COX-2 over COX-1 inhibition, respectively. Wang-Ford charges calculated on C(7) showed a significant contribution towards COX-1 inhibitory activity whereas charges calculated on C(8) were crucial in governing the selectivity of COX-2 over COX-1 inhibition among these congeners.

Advantage of the modified Lunn-McNeil technique over Kalbfleisch-Prentice technique in competing risks

NASA Astrophysics Data System (ADS)

Lukman, Iing; Ibrahim, Noor A.; Daud, Isa B.; Maarof, Fauziah; Hassan, Mohd N.

2002-03-01

Survival analysis algorithm is often applied in the data mining process. Cox regression is one of the survival analysis tools that has been used in many areas, and it can be used to analyze the failure times of aircraft crashed. Another survival analysis tool is the competing risks where we have more than one cause of failure acting simultaneously. Lunn-McNeil analyzed the competing risks in the survival model using Cox regression with censored data. The modified Lunn-McNeil technique is a simplify of the Lunn-McNeil technique. The Kalbfleisch-Prentice technique is involving fitting models separately from each type of failure, treating other failure types as censored. To compare the two techniques, (the modified Lunn-McNeil and Kalbfleisch-Prentice) a simulation study was performed. Samples with various sizes and censoring percentages were generated and fitted using both techniques. The study was conducted by comparing the inference of models, using Root Mean Square Error (RMSE), the power tests, and the Schoenfeld residual analysis. The power tests in this study were likelihood ratio test, Rao-score test, and Wald statistics. The Schoenfeld residual analysis was conducted to check the proportionality of the model through its covariates. The estimated parameters were computed for the cause-specific hazard situation. Results showed that the modified Lunn-McNeil technique was better than the Kalbfleisch-Prentice technique based on the RMSE measurement and Schoenfeld residual analysis. However, the Kalbfleisch-Prentice technique was better than the modified Lunn-McNeil technique based on power tests measurement.

Low-level laser therapy (LLLT) reduces the COX-2 mRNA expression in both subplantar and total brain tissues in the model of peripheral inflammation induced by administration of carrageenan.

PubMed

Prianti, Antonio Carlos Guimarães; Silva, José Antonio; Dos Santos, Regiane Feliciano; Rosseti, Isabela Bueno; Costa, Maricilia Silva

2014-07-01

In the classical model of edema formation and hyperalgesia induced by carrageenan administration in rat paw, the increase in prostaglandin E2 (PGE2) production in the central nervous system (CNS) contributes to the severity of the inflammatory and pain responses. Prostaglandins are generated by the cyclooxygenase (COX). There are two distinct COX isoforms, COX-1 and COX-2. In inflammatory tissues, COX-2 is greatly expressed producing proinflammatory prostaglandins (PGs). Low-level laser therapy (LLLT) has been used in the treatment of inflammatory pathologies, reducing both pain and acute inflammatory process. Herein we studied the effect of LLLT on both COX-2 and COX-1 messenger RNA (mRNA) expression in either subplantar or brain tissues taken from rats treated with carrageenan. The experiment was designed as follows: A1 (saline), A2 (carrageenan-0.5 mg/paw), A3 (carrageenan-0.5 mg/paw + LLLT), A4 (carrageenan-1.0 mg/paw), and A5 (carrageenan-1.0 mg/paw + LLLT). Animals from the A3 and A5 groups were irradiated at 1 h after carrageenan administration, using a diode laser with an output power of 30 mW and a wavelength of 660 nm. The laser beam covered an area of 0.785 cm(2), resulting in an energy dosage of 7.5 J/cm(2). Both COX-2 and COX-1 mRNAs were measured by RT-PCR. Six hours after carrageenan administration, COX-2 mRNA expression was significantly increased both in the subplantar (2.2-4.1-fold) and total brain (8.65-13.79-fold) tissues. COX-1 mRNA expression was not changed. LLLT (7.5 J/cm(2)) reduced significantly the COX-2 mRNA expression both in the subplantar (~2.5-fold) and brain (4.84-9.67-fold) tissues. The results show that LLLT is able to reduce COX-2 mRNA expression. It is possible that the mechanism of LLLT decreasing hyperalgesia is also related to its effect in reducing the COX-2 expression in the CNS.

The Selective Cyclooxygenase-2 Inhibitor, the Compound 11b Improves Haloperidol Induced Catatonia by Enhancing the Striatum Dopaminergic Neurotransmission

PubMed Central

Fathi-Moghaddam, Hadi; Shafiee Ardestani, Mehdi; Saffari, Mostafa; Jabbari Arabzadeh, Ali; Elmi, Mitra

2010-01-01

A substantial amount of evidence has proposed an important role for Cyclooxygenase-2 (COX-2) enzyme in brain diseases and affiliate disorders. The purpose of this research was studying the effects of COX-2 selective inhibition on haloperidol-induced catatonia in an animal model of drug overdose and Parkinson’s disease (PD). In this study, the effect of acute and Sub-chronic oral administration of a new selective COX-2 inhibitor, i.e. the compound 11b or 1-(Phenyl)-5-(4-methylsulfonylphenyl)-2-ethylthioimidazole, in a dosage of 2, 4 and 8 mg/kg on haloperidol-induced catatonia was evaluated and compared to the standard drug scopolamine (1 mg/kg) by microanalysis of Striatum dopaminergic neurotransmission. The results showed a very high potency for 11b in improving the catalepsy by enhancing the dopaminergic neurotranmission (p < 0.05). In addition, statistical analysis showed the dose- and time-dependent behavior of the observed protective effect of 11b against the haloperidol-induced catatonia and enhancement of the dopaminergic neurotransmission. These findings are additional pharmacological data that suggest the effectiveness of COX-2 inhibition in treatment of schizophreny-associated rigidity. PMID:24381603

Attrition in Psychotherapy: A Survival Analysis

ERIC Educational Resources Information Center

Roseborough, David John; McLeod, Jeffrey T.; Wright, Florence I.

2016-01-01

Purpose: Attrition is a common problem in psychotherapy and can be defined as clients ending treatment before achieving an optimal response. Method: This longitudinal, archival study utilized data for 3,728 clients, using the Outcome Questionnaire 45.2. A Cox regression proportional hazards (hazard ratios) model was used in order to better…

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

PubMed

Armstrong, R A

2014-01-01

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

Comparison of Statistical Approaches for Dealing With Immortal Time Bias in Drug Effectiveness Studies.

PubMed

Karim, Mohammad Ehsanul; Gustafson, Paul; Petkau, John; Tremlett, Helen

2016-08-15

In time-to-event analyses of observational studies of drug effectiveness, incorrect handling of the period between cohort entry and first treatment exposure during follow-up may result in immortal time bias. This bias can be eliminated by acknowledging a change in treatment exposure status with time-dependent analyses, such as fitting a time-dependent Cox model. The prescription time-distribution matching (PTDM) method has been proposed as a simpler approach for controlling immortal time bias. Using simulation studies and theoretical quantification of bias, we compared the performance of the PTDM approach with that of the time-dependent Cox model in the presence of immortal time. Both assessments revealed that the PTDM approach did not adequately address immortal time bias. Based on our simulation results, another recently proposed observational data analysis technique, the sequential Cox approach, was found to be more useful than the PTDM approach (Cox: bias = -0.002, mean squared error = 0.025; PTDM: bias = -1.411, mean squared error = 2.011). We applied these approaches to investigate the association of β-interferon treatment with delaying disability progression in a multiple sclerosis cohort in British Columbia, Canada (Long-Term Benefits and Adverse Effects of Beta-Interferon for Multiple Sclerosis (BeAMS) Study, 1995-2008). © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Compensatory Hypertrophy Induced by Ventricular Cardiomyocyte Specific COX-2 Expression in Mice

PubMed Central

Streicher, John M.; Kamei, Kenichiro; Ishikawa, Tomo-o; Herschman, Harvey; Wang, Yibin

2010-01-01

Cyclooxygenase-2 (COX-2) is an important mediator of inflammation in stress and disease states. Recent attention has focused on the role of COX-2 in human heart failure and diseases, due to the finding that highly specific COX-2 inhibitors (i.e. Vioxx) increased the risk of myocardial infarction and stroke in chronic users. However, the specific impact of COX-2 expression in the intact heart remains to be determined. We report here the development of a transgenic mouse model, using a loxP-Cre approach, that displays robust COX-2 overexpression and subsequent prostaglandin synthesis specifically in ventricular myocytes. Histological, functional and molecular analyses showed that ventricular myocyte specific COX-2 overexpression led to cardiac hypertrophy and fetal gene marker activation, but with preserved cardiac function. Therefore, specific induction of COX-2 and prostaglandin in vivo is sufficient to induce compensated hypertrophy and molecular remodeling. PMID:20170663

Molecular characterization of Taenia multiceps isolates from Gansu Province, China by sequencing of mitochondrial cytochrome C oxidase subunit 1.

PubMed

Li, Wen Hui; Jia, Wan Zhong; Qu, Zi Gang; Xie, Zhi Zhou; Luo, Jian Xun; Yin, Hong; Sun, Xiao Lin; Blaga, Radu; Fu, Bao Quan

2013-04-01

A total of 16 Taenia multiceps isolates collected from naturally infected sheep or goats in Gansu Province, China were characterized by sequences of mitochondrial cytochrome c oxidase subunit 1 (cox1) gene. The complete cox1 gene was amplified for individual T. multiceps isolates by PCR, ligated to pMD18T vector, and sequenced. Sequence analysis indicated that out of 16 T. multiceps isolates 10 unique cox1 gene sequences of 1,623 bp were obtained with sequence variation of 0.12-0.68%. The results showed that the cox1 gene sequences were highly conserved among the examined T. multiceps isolates. However, they were quite different from those of the other Taenia species. Phylogenetic analysis based on complete cox1 gene sequences revealed that T. multiceps isolates were composed of 3 genotypes and distinguished from the other Taenia species.

Molecular Characterization of Taenia multiceps Isolates from Gansu Province, China by Sequencing of Mitochondrial Cytochrome C Oxidase Subunit 1

PubMed Central

Li, Wen Hui; Jia, Wan Zhong; Qu, Zi Gang; Xie, Zhi Zhou; Luo, Jian Xun; Yin, Hong; Sun, Xiao Lin; Blaga, Radu

2013-01-01

A total of 16 Taenia multiceps isolates collected from naturally infected sheep or goats in Gansu Province, China were characterized by sequences of mitochondrial cytochrome c oxidase subunit 1 (cox1) gene. The complete cox1 gene was amplified for individual T. multiceps isolates by PCR, ligated to pMD18T vector, and sequenced. Sequence analysis indicated that out of 16 T. multiceps isolates 10 unique cox1 gene sequences of 1,623 bp were obtained with sequence variation of 0.12-0.68%. The results showed that the cox1 gene sequences were highly conserved among the examined T. multiceps isolates. However, they were quite different from those of the other Taenia species. Phylogenetic analysis based on complete cox1 gene sequences revealed that T. multiceps isolates were composed of 3 genotypes and distinguished from the other Taenia species. PMID:23710087

COX-2 and Prostate Cancer Angiogenesis

DTIC Science & Technology

2001-03-01

the optimal dosing and timing of a COX-2 inhibitor (NS398) in an animal model of human prostate cancer, (2)and (3) the mechanisms underlying the...cancer tissues (14) and that a COX-2 inhibitor selectively induces apoptosis in a prostate cancer cell line (15). We also demonstrated that treatment of...human prostate tumor-bearing mice with a selective COX-2 inhibitor (NS-398) significantly reduces tumor size, microvessel density and levels of a

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

DTIC Science & Technology

2014-12-01

production was also increased in TSC2-deficient cells. In preclinical models, both Celecoxib and aspirin reduced tumor development. LAM patients had...increased by aspirin treatment, indicative of functional COX-2 expression in the LAM airway. In vitro, 15-epi-lipoxin-A4 reduced the proliferation of...inhibit COX-2 pharmacologically, we treated TSC2-deficient cells with aspirin or NS398, and found that both agents reduced COX-2 protein levels and

Recurrence risk model for esophageal cancer after radical surgery.

PubMed

Lu, Jincheng; Tao, Hua; Song, Dan; Chen, Cheng

2013-10-01

The aim of the present study was to construct a risk assessment model which was tested by disease-free survival (DFS) of esophageal cancer after radical surgery. A total of 164 consecutive esophageal cancer patients who had undergone radical surgery between January 2005 and December 2006 were retrospectively analyzed. The cutpoint of value at risk (VaR) was inferred by stem-and-leaf plot, as well as by independent-samples t-test for recurrence-free time, further confirmed by crosstab chi-square test, univariate analysis and Cox regression analysis for DFS. The cutpoint of VaR was 0.3 on the basis of our model. The rate of recurrence was 30.3% (30/99) and 52.3% (34/65) in VaR <0.3 and VaR ≥0.3 (chi-square test, (χ) (2) =7.984, P=0.005), respectively. The 1-, 3-, and 5-year DFS of esophageal cancer after radical surgery was 70.4%, 48.7%, and 45.3%, respectively in VaR ≥0.3, whereas 91.5%, 75.8%, and 67.3%, respectively in VaR <0.3 (Log-rank test, (χ) (2) =9.59, P=0.0020), and further confirmed by Cox regression analysis [hazard ratio =2.10, 95% confidence interval (CI): 1.2649-3.4751; P=0.0041]. The model could be applied for integrated assessment of recurrence risk after radical surgery for esophageal cancer.

Recurrence risk model for esophageal cancer after radical surgery

PubMed Central

Tao, Hua; Song, Dan; Chen, Cheng

2013-01-01

Objective The aim of the present study was to construct a risk assessment model which was tested by disease-free survival (DFS) of esophageal cancer after radical surgery. Methods A total of 164 consecutive esophageal cancer patients who had undergone radical surgery between January 2005 and December 2006 were retrospectively analyzed. The cutpoint of value at risk (VaR) was inferred by stem-and-leaf plot, as well as by independent-samples t-test for recurrence-free time, further confirmed by crosstab chi-square test, univariate analysis and Cox regression analysis for DFS. Results The cutpoint of VaR was 0.3 on the basis of our model. The rate of recurrence was 30.3% (30/99) and 52.3% (34/65) in VaR <0.3 and VaR ≥0.3 (chi-square test, χ2 =7.984, P=0.005), respectively. The 1-, 3-, and 5-year DFS of esophageal cancer after radical surgery was 70.4%, 48.7%, and 45.3%, respectively in VaR ≥0.3, whereas 91.5%, 75.8%, and 67.3%, respectively in VaR <0.3 (Log-rank test, χ2 =9.59, P=0.0020), and further confirmed by Cox regression analysis [hazard ratio =2.10, 95% confidence interval (CI): 1.2649-3.4751; P=0.0041]. Conclusions The model could be applied for integrated assessment of recurrence risk after radical surgery for esophageal cancer. PMID:24255579

Redox-regulated dynamic interplay between Cox19 and the copper-binding protein Cox11 in the intermembrane space of mitochondria facilitates biogenesis of cytochrome c oxidase

PubMed Central

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

2015-01-01

Members of the twin Cx9C protein family constitute the largest group of proteins in the intermembrane space (IMS) of mitochondria. Despite their conserved nature and their essential role in the biogenesis of the respiratory chain, the molecular function of twin Cx9C proteins is largely unknown. We performed a SILAC-based quantitative proteomic analysis to identify interaction partners of the conserved twin Cx9C protein Cox19. We found that Cox19 interacts in a dynamic manner with Cox11, a copper transfer protein that facilitates metalation of the Cu(B) center of subunit 1 of cytochrome c oxidase. The interaction with Cox11 is critical for the stable accumulation of Cox19 in mitochondria. Cox19 consists of a helical hairpin structure that forms a hydrophobic surface characterized by two highly conserved tyrosine-leucine dipeptides. These residues are essential for Cox19 function and its specific binding to a cysteine-containing sequence in Cox11. Our observations suggest that an oxidative modification of this cysteine residue of Cox11 stimulates Cox19 binding, pointing to a redox-regulated interplay of Cox19 and Cox11 that is critical for copper transfer in the IMS and thus for biogenesis of cytochrome c oxidase. PMID:25926683

Antitumor effect of the selective COX-2 inhibitor celecoxib on endometrial adenocarcinoma in vitro and in vivo

PubMed Central

XIAO, YITAO; TENG, YINCHENG; ZHANG, RUI; LUO, LAIMIN

2012-01-01

The aim of this study was to investigate the antitumor effect of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib on endometrial adenocarcinoma in mice. Various amounts of celecoxib were added to HEC-1B cells in vitro for different durations. Cell cycle and apoptosis were analyzed using flow cytometry. HEC-1B cytostasis, invasiveness and COX-2 expression were examined by MTT, transwell cabin and western blot assays, respectively. An in vivo human endometrial adenocarcinoma model was established in BALB/c nude mice using HEC-1B cells. For two weeks, the celecoxib groups were treated with celecoxib 2 or 4 mg/day via oral administration and the control group was treated with saline. Tumor volume, growth curves and the inhibition rate (IR) were recorded. COX-2 expression levels and microvessel density (MVD) were investigated using an immunohistochemical technique. In the celecoxib groups, cell proliferation was significantly inhibited in a concentration- and time-dependent manner. The proportion of cells in the G0/G1 phase increased within 24 h after the addition of celecoxib whereas those in the S and G2/M phases decreased with an increasing apoptosis peak (sub-G1) and apoptosis rate. The microporous Matrigel-coated polycarbonate membrane of the Transwell cabin was traversable for the HEC-1B cells. The invasiveness was attenuated when the celecoxib concentration was increased. The tumor growth was also greatly inhibited when the celecoxib concentration was increased. The tumor IRs were 32.4 and 48.6% following treatment with 2 and 4 mg/day celecoxib, respectively. COX-2 was mainly expressed in the cytoplasm of the tumor cells. In the celecoxib groups, the COX-2 expression levels were concentration-dependent. The COX-2 expression level and MVD decreased when the celecoxib concentration was increased. The results of dependability analysis revealed that the COX-2 expression level was positively correlated with MVD (r=0.921; P<0.01). The antitumor effect of celecoxib on endometrial adenocarcinoma in nude mice may be related to the inhibition of COX-2 expression and microangiogenesis. PMID:23226798

A medicinal extract of Scutellaria baicalensis and Acacia catechu acts as a dual inhibitor of cyclooxygenase and 5-lipoxygenase to reduce inflammation.

PubMed

Burnett, B P; Jia, Q; Zhao, Y; Levy, R M

2007-09-01

A mixed extract containing two naturally occurring flavonoids, baicalin from Scutellaria baicalensis and catechin from Acacia catechu, was tested for cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibition via enzyme, cellular, and in vivo models. The 50% inhibitory concentration for inhibition of both ovine COX-1 and COX-2 peroxidase enzyme activities was 15 microg/mL, while the mixed extract showed a value for potato 5-LOX enzyme activity of 25 microg/mL. Prostaglandin E2 generation was inhibited by the mixed extract in human osteosarcoma cells expressing COX-2, while leukotriene production was inhibited in both human cell lines, immortalized THP-1 monocyte and HT-29 colorectal adenocarcinoma. In an arachidonic acid-induced mouse ear swelling model, the extract decreased edema in a dose-dependent manner. When arachidonic acid was injected directly into the intra-articular space of mouse ankle joints, the mixed extract abated the swelling and restored function in a rotary drum walking model. These results suggest that this natural, flavonoid mixture acts via "dual inhibition" of COX and LOX enzymes to reduce production of pro-inflammatory eicosanoids and attenuate edema in an in vivo model of inflammation.

Conservative Secondary Shell Substitution In Cyclooxygenase-2 Reduces Inhibition by Indomethacin Amides and Esters via Altered Enzyme Dynamics

PubMed Central

2015-01-01

The cyclooxygenase enzymes (COX-1 and COX-2) are the therapeutic targets of nonsteroidal anti-inflammatory drugs (NSAIDs). Neutralization of the carboxylic acid moiety of the NSAID indomethacin to an ester or amide functionality confers COX-2 selectivity, but the molecular basis for this selectivity has not been completely revealed through mutagenesis studies and/or X-ray crystallographic attempts. We expressed and assayed a number of divergent secondary shell COX-2 active site mutants and found that a COX-2 to COX-1 change at position 472 (Leu in COX-2, Met in COX-1) reduced the potency of enzyme inhibition by a series of COX-2-selective indomethacin amides and esters. In contrast, the potencies of indomethacin, arylacetic acid, propionic acid, and COX-2-selective diarylheterocycle inhibitors were either unaffected or only mildly affected by this mutation. Molecular dynamics simulations revealed identical equilibrium enzyme structures around residue 472; however, calculations indicated that the L472M mutation impacted local low-frequency dynamical COX constriction site motions by stabilizing the active site entrance and slowing constriction site dynamics. Kinetic analysis of inhibitor binding is consistent with the computational findings. PMID:26704937

Relative Expression of Vitamin D Hydroxylases, CYP27B1 and CYP24A1, and of Cyclooxygenase-2 and Heterogeneity of Human Colorectal Cancer in Relation to Age, Gender, Tumor Location, and Malignancy: Results from Factor and Cluster Analysis.

PubMed

Brozek, Wolfgang; Manhardt, Teresa; Kállay, Enikö; Peterlik, Meinrad; Cross, Heide S

2012-07-26

Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1,25-(OH)2D3 and prostaglandin cellular signaling networks. The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases, i.e., CYP27B1-encoded 25-hydroxyvitamin D-1a-hydroxylase and CYP24A1-encoded 25-hydroxyvitamin D-24-hydroxylase, and inflammation-induced cyclooxygenase-2 (COX-2). Data from 105 cancer patients on CYP27B1, VDR, CYP24A1, and COX-2 mRNA expression in relation to tumor grade, anatomical location, gender and age were fit into a multivariate model of exploratory factor analysis. Nearly identical results were obtained by the principal factor and the maximum likelihood method, and these were confirmed by hierarchical cluster analysis: Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis: (i) Escape of COX-2 activity from restraints by the CYP27B1/VDR system can initiate cancer growth anywhere in the colorectum regardless of age and gender; (ii) variations in COX-2 expression are mainly responsible for differences in cancer incidence in relation to tumor location; (iii) advancing age has a strong gender-specific influence on cancer incidence; (iv) progression from well differentiated to undifferentiated cancer is solely associated with a rise in CYP24A1 expression.

Relative Expression of Vitamin D Hydroxylases, CYP27B1 and CYP24A1, and of Cyclooxygenase-2 and Heterogeneity of Human Colorectal Cancer in Relation to Age, Gender, Tumor Location, and Malignancy: Results from Factor and Cluster Analysis

PubMed Central

Brozek, Wolfgang; Manhardt, Teresa; Kállay, Enikö; Peterlik, Meinrad; Cross, Heide S.

2012-01-01

Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1,25-(OH)2D3 and prostaglandin cellular signaling networks. The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases, i.e., CYP27B1-encoded 25-hydroxyvitamin D-1α-hydroxylase and CYP24A1-encoded 25-hydroxyvitamin D-24-hydroxylase, and inflammation-induced cyclooxygenase-2 (COX-2). Data from 105 cancer patients on CYP27B1, VDR, CYP24A1, and COX-2 mRNA expression in relation to tumor grade, anatomical location, gender and age were fit into a multivariate model of exploratory factor analysis. Nearly identical results were obtained by the principal factor and the maximum likelihood method, and these were confirmed by hierarchical cluster analysis: Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis: (i) Escape of COX-2 activity from restraints by the CYP27B1/VDR system can initiate cancer growth anywhere in the colorectum regardless of age and gender; (ii) variations in COX-2 expression are mainly responsible for differences in cancer incidence in relation to tumor location; (iii) advancing age has a strong gender-specific influence on cancer incidence; (iv) progression from well differentiated to undifferentiated cancer is solely associated with a rise in CYP24A1 expression. PMID:24213465

Dolastatin 15, a mollusk linear peptide, and Celecoxib, a selective cyclooxygenase-2 inhibitor, prevent preneoplastic colonic lesions and induce apoptosis through inhibition of the regulatory transcription factor NF-κB and an inflammatory protein, iNOS.

PubMed

Piplani, Honit; Vaish, Vivek; Sanyal, Sankar Nath

2012-11-01

The marine ecosystem is a unique and enormously rich source of natural products with potential chemopreventive applications in cancer. In the present study, we explored the chemopreventive role and the molecular mechanism of Dolastatin, a linear peptide from an Indian Ocean mollusk, and Celecoxib, a well-established cyclooxygenase-2 (COX-2) inhibitor in an individual as well as in a combination regimen in 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colon carcinogenesis in a rat model. After a 6-week treatment with DMH, morphological analysis revealed a marked occurrence of preneoplastic features in the colonic mucosa, whereas histologically well-characterized dysplasia and hyperplasia were observed in DMH-treated animals. Simultaneous administration of Celecoxib and Dolastatin reduced these features significantly. DMH treatment affected the number of apoptotic cells in colonic enterocytes, which reverted to the normal level with the use of Celecoxib and Dolastatin. Inflammation remains the dominant molecular mechanism in the development of multiple plaque lesions, the carcinogenic lesions in a DMH-induced process that may be mediated by COX-2. Western blot and immunofluorescence analysis revealed a higher expression of COX-2 and nuclear factor-κB, the transcription factors responsible for proinflammatory proteins such as TNFα, and also the inducible nitric oxide synthase in the DMH group, which was further recovered significantly with the use of Celecoxib and Dolastatin. In-silico molecular docking analysis of Dolastatin as a ligand with various regulatory proteins suggests that although the peptide failed to dock to COX-2, it successfully did so with inducible nitric oxide synthase, thereby indicating the potential of this inflammatory protein as a molecular anticancer target in colon carcinogenesis.

A comparison of time dependent Cox regression, pooled logistic regression and cross sectional pooling with simulations and an application to the Framingham Heart Study.

PubMed

Ngwa, Julius S; Cabral, Howard J; Cheng, Debbie M; Pencina, Michael J; Gagnon, David R; LaValley, Michael P; Cupples, L Adrienne

2016-11-03

Typical survival studies follow individuals to an event and measure explanatory variables for that event, sometimes repeatedly over the course of follow up. The Cox regression model has been used widely in the analyses of time to diagnosis or death from disease. The associations between the survival outcome and time dependent measures may be biased unless they are modeled appropriately. In this paper we explore the Time Dependent Cox Regression Model (TDCM), which quantifies the effect of repeated measures of covariates in the analysis of time to event data. This model is commonly used in biomedical research but sometimes does not explicitly adjust for the times at which time dependent explanatory variables are measured. This approach can yield different estimates of association compared to a model that adjusts for these times. In order to address the question of how different these estimates are from a statistical perspective, we compare the TDCM to Pooled Logistic Regression (PLR) and Cross Sectional Pooling (CSP), considering models that adjust and do not adjust for time in PLR and CSP. In a series of simulations we found that time adjusted CSP provided identical results to the TDCM while the PLR showed larger parameter estimates compared to the time adjusted CSP and the TDCM in scenarios with high event rates. We also observed upwardly biased estimates in the unadjusted CSP and unadjusted PLR methods. The time adjusted PLR had a positive bias in the time dependent Age effect with reduced bias when the event rate is low. The PLR methods showed a negative bias in the Sex effect, a subject level covariate, when compared to the other methods. The Cox models yielded reliable estimates for the Sex effect in all scenarios considered. We conclude that survival analyses that explicitly account in the statistical model for the times at which time dependent covariates are measured provide more reliable estimates compared to unadjusted analyses. We present results from the Framingham Heart Study in which lipid measurements and myocardial infarction data events were collected over a period of 26 years.

Unilateral robotic hybrid mini-maze: a novel experimental approach.

PubMed

Moslemi, Mohammad; Rawashdeh, Badi; Meyer, Mark; Nguyen, Duy; Poston, Robert; Gharagozloo, Farid

2016-03-01

A complete Cox maze IV procedure is difficult to accomplish using current endoscopic and minimally invasive techniques. These techniques are hampered by inability to adequately dissect the posterior structures of the heart and place all necessary lesions. We present a novel approach, using robotic technology, that achieves placement of all the lesions of the complete maze procedure. In three cadaveric human models, the technical feasibility of using robotic instruments through the right chest to dissect the posterior structures of the heart and place all Cox maze lesions was performed. The entire posterior aspect of the heart was dissected in the cadaveric model facilitating successful placement of all Cox maze IV lesions with robotic assistance through minimally invasive incisions. The robotic Cox maze IV procedure through the novel right thoracic approach is feasible. This obviates the need for sternotomy and avoids the associated morbidity of the conventional Cox-maze procedure. Copyright © 2015 John Wiley & Sons, Ltd.

Role of cyclooxygenase isoforms in the altered excitatory motor pathways of human colon with diverticular disease.

PubMed

Fornai, M; Colucci, R; Antonioli, L; Ippolito, C; Segnani, C; Buccianti, P; Marioni, A; Chiarugi, M; Villanacci, V; Bassotti, G; Blandizzi, C; Bernardini, N

2014-08-01

The COX isoforms (COX-1, COX-2) regulate human gut motility, although their role under pathological conditions remains unclear. This study examines the effects of COX inhibitors on excitatory motility in colonic tissue from patients with diverticular disease (DD). Longitudinal muscle preparations, from patients with DD or uncomplicated cancer (controls), were set up in organ baths and connected to isotonic transducers. Indomethacin (COX-1/COX-2 inhibitor), SC-560 (COX-1 inhibitor) or DFU (COX-2 inhibitor) were assayed on electrically evoked, neurogenic, cholinergic and tachykininergic contractions, or carbachol- and substance P (SP)-induced myogenic contractions. Distribution and expression of COX isoforms in the neuromuscular compartment were assessed by RT-PCR, Western blot and immunohistochemical analysis. In control preparations, neurogenic cholinergic contractions were enhanced by COX inhibitors, whereas tachykininergic responses were blunted. Carbachol-evoked contractions were increased by indomethacin or SC-560, but not DFU, whereas all inhibitors reduced SP-induced motor responses. In preparations from DD patients, COX inhibitors did not affect electrically evoked cholinergic contractions. Both indomethacin and DFU, but not SC-560, decreased tachykininergic responses. COX inhibitors did not modify carbachol-evoked motor responses, whereas they counteracted SP-induced contractions. COX-1 expression was decreased in myenteric neurons, whereas COX-2 was enhanced in glial cells and smooth muscle. In control colon, COX-1 and COX-2 down-regulate cholinergic motility, whereas both isoforms enhance tachykininergic motor activity. In the presence of DD, there is a loss of modulation by both COX isoforms on the cholinergic system, whereas COX-2 displays an enhanced facilitatory control on tachykininergic contractile activity. © 2014 The British Pharmacological Society.

Role of cyclooxygenase isoforms in the altered excitatory motor pathways of human colon with diverticular disease

PubMed Central

Fornai, M; Colucci, R; Antonioli, L; Ippolito, C; Segnani, C; Buccianti, P; Marioni, A; Chiarugi, M; Villanacci, V; Bassotti, G; Blandizzi, C; Bernardini, N

2014-01-01

BACKGROUND AND PURPOSE The COX isoforms (COX-1, COX-2) regulate human gut motility, although their role under pathological conditions remains unclear. This study examines the effects of COX inhibitors on excitatory motility in colonic tissue from patients with diverticular disease (DD). EXPERIMENTAL APPROACH Longitudinal muscle preparations, from patients with DD or uncomplicated cancer (controls), were set up in organ baths and connected to isotonic transducers. Indomethacin (COX-1/COX-2 inhibitor), SC-560 (COX-1 inhibitor) or DFU (COX-2 inhibitor) were assayed on electrically evoked, neurogenic, cholinergic and tachykininergic contractions, or carbachol- and substance P (SP)-induced myogenic contractions. Distribution and expression of COX isoforms in the neuromuscular compartment were assessed by RT-PCR, Western blot and immunohistochemical analysis. KEY RESULTS In control preparations, neurogenic cholinergic contractions were enhanced by COX inhibitors, whereas tachykininergic responses were blunted. Carbachol-evoked contractions were increased by indomethacin or SC-560, but not DFU, whereas all inhibitors reduced SP-induced motor responses. In preparations from DD patients, COX inhibitors did not affect electrically evoked cholinergic contractions. Both indomethacin and DFU, but not SC-560, decreased tachykininergic responses. COX inhibitors did not modify carbachol-evoked motor responses, whereas they counteracted SP-induced contractions. COX-1 expression was decreased in myenteric neurons, whereas COX-2 was enhanced in glial cells and smooth muscle. CONCLUSIONS AND IMPLICATIONS In control colon, COX-1 and COX-2 down-regulate cholinergic motility, whereas both isoforms enhance tachykininergic motor activity. In the presence of DD, there is a loss of modulation by both COX isoforms on the cholinergic system, whereas COX-2 displays an enhanced facilitatory control on tachykininergic contractile activity. PMID:24758697

In vitro enantioselective pharmacodynamics of Carprofen and Flunixin-meglumine in feedlot cattle.

PubMed

Miciletta, M; Cuniberti, B; Barbero, R; Re, G

2014-02-01

The activity of the anti-inflammatory agents Flunixin-meglumine (FLU), RS (±) Carprofen (CPF) and S (+) CPF on bovine cyclooxygenases (COXs) has been characterized in feedlot calves using an in vitro whole blood model. The drugs showed equivalent efficacy in their inhibitory activity on COXs, and the rank order of potency for both COX-1 and COX-2 inhibition was FLU > S (+) CPF > RS (±) CPF. Our results indicated that FLU is a nonselective inhibitor of bovine COXs, whereas RS (±) CPF and S (+) CPF exhibited different degrees of preferential inhibition of COX-2 isoenzyme. The rank order of IC50 COX-1: IC50 COX-2 potency ratios was in fact S (+) CPF (51.882) > RS (±) CPF (13.964) > FLU (0.606), and the calculated percentage inhibition of COX-1 corresponding to COX-2 inhibition values comprised between 80% and 95% was comprised between 57.697 and 79.865 for FLU, 33.373 and 51.319 for RS (±) CPF, and 0.230 and 4.622 for S (+) CPF, respectively. These findings are discussed in relation to the prediction of the clinical relevance of COX inhibition by the test drugs in cattle. © 2013 John Wiley & Sons Ltd.

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

NASA Technical Reports Server (NTRS)

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

2003-01-01

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

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

PubMed

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

2013-07-01

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

Derivation of the linear-logistic model and Cox's proportional hazard model from a canonical system description.

PubMed

Voit, E O; Knapp, R G

1997-08-15

The linear-logistic regression model and Cox's proportional hazard model are widely used in epidemiology. Their successful application leaves no doubt that they are accurate reflections of observed disease processes and their associated risks or incidence rates. In spite of their prominence, it is not a priori evident why these models work. This article presents a derivation of the two models from the framework of canonical modeling. It begins with a general description of the dynamics between risk sources and disease development, formulates this description in the canonical representation of an S-system, and shows how the linear-logistic model and Cox's proportional hazard model follow naturally from this representation. The article interprets the model parameters in terms of epidemiological concepts as well as in terms of general systems theory and explains the assumptions and limitations generally accepted in the application of these epidemiological models.

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

PubMed

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

2015-01-01

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

The First Chameleon Transcriptome: Comparative Genomic Analysis of the OXPHOS System Reveals Loss of COX8 in Iguanian Lizards

PubMed Central

Bar-Yaacov, Dan; Bouskila, Amos; Mishmar, Dan

2013-01-01

Recently, we found dramatic mitochondrial DNA divergence of Israeli Chamaeleo chamaeleon populations into two geographically distinct groups. We aimed to examine whether the same pattern of divergence could be found in nuclear genes. However, no genomic resource is available for any chameleon species. Here we present the first chameleon transcriptome, obtained using deep sequencing (SOLiD). Our analysis identified 164,000 sequence contigs of which 19,000 yielded unique BlastX hits. To test the efficacy of our sequencing effort, we examined whether the chameleon and other available reptilian transcriptomes harbored complete sets of genes comprising known biochemical pathways, focusing on the nDNA-encoded oxidative phosphorylation (OXPHOS) genes as a model. As a reference for the screen, we used the human 86 (including isoforms) known structural nDNA-encoded OXPHOS subunits. Analysis of 34 publicly available vertebrate transcriptomes revealed orthologs for most human OXPHOS genes. However, OXPHOS subunit COX8 (Cytochrome C oxidase subunit 8), including all its known isoforms, was consistently absent in transcriptomes of iguanian lizards, implying loss of this subunit during the radiation of this suborder. The lack of COX8 in the suborder Iguania is intriguing, since it is important for cellular respiration and ATP production. Our sequencing effort added a new resource for comparative genomic studies, and shed new light on the evolutionary dynamics of the OXPHOS system. PMID:24009133

The first Chameleon transcriptome: comparative genomic analysis of the OXPHOS system reveals loss of COX8 in Iguanian lizards.

PubMed

Bar-Yaacov, Dan; Bouskila, Amos; Mishmar, Dan

2013-01-01

Recently, we found dramatic mitochondrial DNA divergence of Israeli Chamaeleo chamaeleon populations into two geographically distinct groups. We aimed to examine whether the same pattern of divergence could be found in nuclear genes. However, no genomic resource is available for any chameleon species. Here we present the first chameleon transcriptome, obtained using deep sequencing (SOLiD). Our analysis identified 164,000 sequence contigs of which 19,000 yielded unique BlastX hits. To test the efficacy of our sequencing effort, we examined whether the chameleon and other available reptilian transcriptomes harbored complete sets of genes comprising known biochemical pathways, focusing on the nDNA-encoded oxidative phosphorylation (OXPHOS) genes as a model. As a reference for the screen, we used the human 86 (including isoforms) known structural nDNA-encoded OXPHOS subunits. Analysis of 34 publicly available vertebrate transcriptomes revealed orthologs for most human OXPHOS genes. However, OXPHOS subunit COX8 (Cytochrome C oxidase subunit 8), including all its known isoforms, was consistently absent in transcriptomes of iguanian lizards, implying loss of this subunit during the radiation of this suborder. The lack of COX8 in the suborder Iguania is intriguing, since it is important for cellular respiration and ATP production. Our sequencing effort added a new resource for comparative genomic studies, and shed new light on the evolutionary dynamics of the OXPHOS system.

Nomogram Prediction of Overall Survival After Curative Irradiation for Uterine Cervical Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seo, YoungSeok; Yoo, Seong Yul; Kim, Mi-Sook

Purpose: The purpose of this study was to develop a nomogram capable of predicting the probability of 5-year survival after radical radiotherapy (RT) without chemotherapy for uterine cervical cancer. Methods and Materials: We retrospectively analyzed 549 patients that underwent radical RT for uterine cervical cancer between March 1994 and April 2002 at our institution. Multivariate analysis using Cox proportional hazards regression was performed and this Cox model was used as the basis for the devised nomogram. The model was internally validated for discrimination and calibration by bootstrap resampling. Results: By multivariate regression analysis, the model showed that age, hemoglobin levelmore » before RT, Federation Internationale de Gynecologie Obstetrique (FIGO) stage, maximal tumor diameter, lymph node status, and RT dose at Point A significantly predicted overall survival. The survival prediction model demonstrated good calibration and discrimination. The bootstrap-corrected concordance index was 0.67. The predictive ability of the nomogram proved to be superior to FIGO stage (p = 0.01). Conclusions: The devised nomogram offers a significantly better level of discrimination than the FIGO staging system. In particular, it improves predictions of survival probability and could be useful for counseling patients, choosing treatment modalities and schedules, and designing clinical trials. However, before this nomogram is used clinically, it should be externally validated.« less

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

PubMed Central

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

2015-01-01

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

Box–Cox Transformation and Random Regression Models for Fecal egg Count Data

PubMed Central

da Silva, Marcos Vinícius Gualberto Barbosa; Van Tassell, Curtis P.; Sonstegard, Tad S.; Cobuci, Jaime Araujo; Gasbarre, Louis C.

2012-01-01

Accurate genetic evaluation of livestock is based on appropriate modeling of phenotypic measurements. In ruminants, fecal egg count (FEC) is commonly used to measure resistance to nematodes. FEC values are not normally distributed and logarithmic transformations have been used in an effort to achieve normality before analysis. However, the transformed data are often still not normally distributed, especially when data are extremely skewed. A series of repeated FEC measurements may provide information about the population dynamics of a group or individual. A total of 6375 FEC measures were obtained for 410 animals between 1992 and 2003 from the Beltsville Agricultural Research Center Angus herd. Original data were transformed using an extension of the Box–Cox transformation to approach normality and to estimate (co)variance components. We also proposed using random regression models (RRM) for genetic and non-genetic studies of FEC. Phenotypes were analyzed using RRM and restricted maximum likelihood. Within the different orders of Legendre polynomials used, those with more parameters (order 4) adjusted FEC data best. Results indicated that the transformation of FEC data utilizing the Box–Cox transformation family was effective in reducing the skewness and kurtosis, and dramatically increased estimates of heritability, and measurements of FEC obtained in the period between 12 and 26 weeks in a 26-week experimental challenge period are genetically correlated. PMID:22303406

Box-Cox Transformation and Random Regression Models for Fecal egg Count Data.

PubMed

da Silva, Marcos Vinícius Gualberto Barbosa; Van Tassell, Curtis P; Sonstegard, Tad S; Cobuci, Jaime Araujo; Gasbarre, Louis C

2011-01-01

Accurate genetic evaluation of livestock is based on appropriate modeling of phenotypic measurements. In ruminants, fecal egg count (FEC) is commonly used to measure resistance to nematodes. FEC values are not normally distributed and logarithmic transformations have been used in an effort to achieve normality before analysis. However, the transformed data are often still not normally distributed, especially when data are extremely skewed. A series of repeated FEC measurements may provide information about the population dynamics of a group or individual. A total of 6375 FEC measures were obtained for 410 animals between 1992 and 2003 from the Beltsville Agricultural Research Center Angus herd. Original data were transformed using an extension of the Box-Cox transformation to approach normality and to estimate (co)variance components. We also proposed using random regression models (RRM) for genetic and non-genetic studies of FEC. Phenotypes were analyzed using RRM and restricted maximum likelihood. Within the different orders of Legendre polynomials used, those with more parameters (order 4) adjusted FEC data best. Results indicated that the transformation of FEC data utilizing the Box-Cox transformation family was effective in reducing the skewness and kurtosis, and dramatically increased estimates of heritability, and measurements of FEC obtained in the period between 12 and 26 weeks in a 26-week experimental challenge period are genetically correlated.

Gas chromatography-mass spectrometry analysis of di-n-octyl disulfide in a straight oil metalworking fluid: application of differential permeation and Box-Cox transformation.

PubMed

Xu, Wenhai; Que Hee, Shane S

2006-01-06

The aim of this study was to identify and quantify an unknown peak in the chromatogram of a very complex mixture, a straight oil metalworking fluid (MWF). The fraction that permeated through a thin nitrile polymer membrane had less mineral oil background than the original MWF did at the retention time of the unknown peak, thus facilitating identification by total ion current (TIC) gas chromatography-mass spectrometry (GC-MS). The peak proved to be di-n-octyl disulfide (DOD) through retention time and mass spectral comparisons. Quantitation of DOD was by extracted ion chromatogram analysis of the DOD molecular ion (mass-to-charge ratio (m/z) 290), and of the m/z 71 ion for the internal standard, n-triacontane. Linear models of the area ratio (y) of these two ions versus DOD concentration showed a systematic negative bias at low concentrations, a common occurrence in analysis. The linear model of y(0.8) (from Box-Cox power transformation) versus DOD concentration showed negligible bias from the lowest measured standard of 1.51 mg/L to the highest concentration tested at 75.5 mg/L. The intercept did not differ statistically from zero. The concentration of DOD in the MWF was then calculated to be 0.398+/-0.034% (w/w) by the internal standard method, and 0.387+/-0.036% (w/w) by the method of standard additions. These two results were not significantly different at p < or = 0.05. The Box-Cox transformation is therefore recommended when the data for standards are non-linear.

Development and Validation of a qRT-PCR Classifier for Lung Cancer Prognosis

PubMed Central

Chen, Guoan; Kim, Sinae; Taylor, Jeremy MG; Wang, Zhuwen; Lee, Oliver; Ramnath, Nithya; Reddy, Rishindra M; Lin, Jules; Chang, Andrew C; Orringer, Mark B; Beer, David G

2011-01-01

Purpose This prospective study aimed to develop a robust and clinically-applicable method to identify high-risk early stage lung cancer patients and then to validate this method for use in future translational studies. Patients and Methods Three published Affymetrix microarray data sets representing 680 primary tumors were used in the survival-related gene selection procedure using clustering, Cox model and random survival forest (RSF) analysis. A final set of 91 genes was selected and tested as a predictor of survival using a qRT-PCR-based assay utilizing an independent cohort of 101 lung adenocarcinomas. Results The RSF model built from 91 genes in the training set predicted patient survival in an independent cohort of 101 lung adenocarcinomas, with a prediction error rate of 26.6%. The mortality risk index (MRI) was significantly related to survival (Cox model p < 0.00001) and separated all patients into low, medium, and high-risk groups (HR = 1.00, 2.82, 4.42). The MRI was also related to survival in stage 1 patients (Cox model p = 0.001), separating patients into low, medium, and high-risk groups (HR = 1.00, 3.29, 3.77). Conclusions The development and validation of this robust qRT-PCR platform allows prediction of patient survival with early stage lung cancer. Utilization will now allow investigators to evaluate it prospectively by incorporation into new clinical trials with the goal of personalized treatment of lung cancer patients and improving patient survival. PMID:21792073

Survival analysis of postoperative nausea and vomiting in patients receiving patient-controlled epidural analgesia.

PubMed

Lee, Shang-Yi; Hung, Chih-Jen; Chen, Chih-Chieh; Wu, Chih-Cheng

2014-11-01

Postoperative nausea and vomiting as well as postoperative pain are two major concerns when patients undergo surgery and receive anesthetics. Various models and predictive methods have been developed to investigate the risk factors of postoperative nausea and vomiting, and different types of preventive managements have subsequently been developed. However, there continues to be a wide variation in the previously reported incidence rates of postoperative nausea and vomiting. This may have occurred because patients were assessed at different time points, coupled with the overall limitation of the statistical methods used. However, using survival analysis with Cox regression, and thus factoring in these time effects, may solve this statistical limitation and reveal risk factors related to the occurrence of postoperative nausea and vomiting in the following period. In this retrospective, observational, uni-institutional study, we analyzed the results of 229 patients who received patient-controlled epidural analgesia following surgery from June 2007 to December 2007. We investigated the risk factors for the occurrence of postoperative nausea and vomiting, and also assessed the effect of evaluating patients at different time points using the Cox proportional hazards model. Furthermore, the results of this inquiry were compared with those results using logistic regression. The overall incidence of postoperative nausea and vomiting in our study was 35.4%. Using logistic regression, we found that only sex, but not the total doses and the average dose of opioids, had significant effects on the occurrence of postoperative nausea and vomiting at some time points. Cox regression showed that, when patients consumed a higher average dose of opioids, this correlated with a higher incidence of postoperative nausea and vomiting with a hazard ratio of 1.286. Survival analysis using Cox regression showed that the average consumption of opioids played an important role in postoperative nausea and vomiting, a result not found by logistic regression. Therefore, the incidence of postoperative nausea and vomiting in patients cannot be reliably determined on the basis of a single visit at one point in time. Copyright © 2014. Published by Elsevier Taiwan.

Cancer Survival Estimates Due to Non-Uniform Loss to Follow-Up and Non-Proportional Hazards

PubMed

K M, Jagathnath Krishna; Mathew, Aleyamma; Sara George, Preethi

2017-06-25

Background: Cancer survival depends on loss to follow-up (LFU) and non-proportional hazards (non-PH). If LFU is high, survival will be over-estimated. If hazard is non-PH, rank tests will provide biased inference and Cox-model will provide biased hazard-ratio. We assessed the bias due to LFU and non-PH factor in cancer survival and provided alternate methods for unbiased inference and hazard-ratio. Materials and Methods: Kaplan-Meier survival were plotted using a realistic breast cancer (BC) data-set, with >40%, 5-year LFU and compared it using another BC data-set with <15%, 5-year LFU to assess the bias in survival due to high LFU. Age at diagnosis of the latter data set was used to illustrate the bias due to a non-PH factor. Log-rank test was employed to assess the bias in p-value and Cox-model was used to assess the bias in hazard-ratio for the non-PH factor. Schoenfeld statistic was used to test the non-PH of age. For the non-PH factor, we employed Renyi statistic for inference and time dependent Cox-model for hazard-ratio. Results: Five-year BC survival was 69% (SE: 1.1%) vs. 90% (SE: 0.7%) for data with low vs. high LFU respectively. Age (<45, 46-54 & >54 years) was a non-PH factor (p-value: 0.036). However, survival by age was significant (log-rank p-value: 0.026), but not significant using Renyi statistic (p=0.067). Hazard ratio (HR) for age using Cox-model was 1.012 (95%CI: 1.004 -1.019) and the same using time-dependent Cox-model was in the other direction (HR: 0.997; 95% CI: 0.997- 0.998). Conclusion: Over-estimated survival was observed for cancer with high LFU. Log-rank statistic and Cox-model provided biased results for non-PH factor. For data with non-PH factors, Renyi statistic and time dependent Cox-model can be used as alternate methods to obtain unbiased inference and estimates. Creative Commons Attribution License

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

PubMed Central

Herschman, Harvey

2014-01-01

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

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

PubMed

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

2014-06-01

In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2(flox/flox) mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2(flox/flox);K14Cre(+) mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2(flox/flox);K14Cre(+) papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2(flox/flox); LysMCre(+) myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A global goodness-of-fit test for receiver operating characteristic curve analysis via the bootstrap method.

PubMed

Zou, Kelly H; Resnic, Frederic S; Talos, Ion-Florin; Goldberg-Zimring, Daniel; Bhagwat, Jui G; Haker, Steven J; Kikinis, Ron; Jolesz, Ferenc A; Ohno-Machado, Lucila

2005-10-01

Medical classification accuracy studies often yield continuous data based on predictive models for treatment outcomes. A popular method for evaluating the performance of diagnostic tests is the receiver operating characteristic (ROC) curve analysis. The main objective was to develop a global statistical hypothesis test for assessing the goodness-of-fit (GOF) for parametric ROC curves via the bootstrap. A simple log (or logit) and a more flexible Box-Cox normality transformations were applied to untransformed or transformed data from two clinical studies to predict complications following percutaneous coronary interventions (PCIs) and for image-guided neurosurgical resection results predicted by tumor volume, respectively. We compared a non-parametric with a parametric binormal estimate of the underlying ROC curve. To construct such a GOF test, we used the non-parametric and parametric areas under the curve (AUCs) as the metrics, with a resulting p value reported. In the interventional cardiology example, logit and Box-Cox transformations of the predictive probabilities led to satisfactory AUCs (AUC=0.888; p=0.78, and AUC=0.888; p=0.73, respectively), while in the brain tumor resection example, log and Box-Cox transformations of the tumor size also led to satisfactory AUCs (AUC=0.898; p=0.61, and AUC=0.899; p=0.42, respectively). In contrast, significant departures from GOF were observed without applying any transformation prior to assuming a binormal model (AUC=0.766; p=0.004, and AUC=0.831; p=0.03), respectively. In both studies the p values suggested that transformations were important to consider before applying any binormal model to estimate the AUC. Our analyses also demonstrated and confirmed the predictive values of different classifiers for determining the interventional complications following PCIs and resection outcomes in image-guided neurosurgery.

Cox-nnet: An artificial neural network method for prognosis prediction of high-throughput omics data.

PubMed

Ching, Travers; Zhu, Xun; Garmire, Lana X

2018-04-01

Artificial neural networks (ANN) are computing architectures with many interconnections of simple neural-inspired computing elements, and have been applied to biomedical fields such as imaging analysis and diagnosis. We have developed a new ANN framework called Cox-nnet to predict patient prognosis from high throughput transcriptomics data. In 10 TCGA RNA-Seq data sets, Cox-nnet achieves the same or better predictive accuracy compared to other methods, including Cox-proportional hazards regression (with LASSO, ridge, and mimimax concave penalty), Random Forests Survival and CoxBoost. Cox-nnet also reveals richer biological information, at both the pathway and gene levels. The outputs from the hidden layer node provide an alternative approach for survival-sensitive dimension reduction. In summary, we have developed a new method for accurate and efficient prognosis prediction on high throughput data, with functional biological insights. The source code is freely available at https://github.com/lanagarmire/cox-nnet.

Measurement of soil carbon oxidation state and oxidative ratio by 13C nuclear magnetic resonance

USGS Publications Warehouse

Hockaday, W.C.; Masiello, C.A.; Randerson, J.T.; Smernik, R.J.; Baldock, J.A.; Chadwick, O.A.; Harden, J.W.

2009-01-01

The oxidative ratio (OR) of the net ecosystem carbon balance is the ratio of net O2 and CO2 fluxes resulting from photosynthesis, respiration, decomposition, and other lateral and vertical carbon flows. The OR of the terrestrial biosphere must be well characterized to accurately estimate the terrestrial CO2 sink using atmospheric measurements of changing O2 and CO2 levels. To estimate the OR of the terrestrial biosphere, measurements are needed of changes in the OR of aboveground and belowground carbon pools associated with decadal timescale disturbances (e.g., land use change and fire). The OR of aboveground pools can be measured using conventional approaches including elemental analysis. However, measuring the OR of soil carbon pools is technically challenging, and few soil OR data are available. In this paper we test three solid-state nuclear magnetic resonance (NMR) techniques for measuring soil OR, all based on measurements of the closely related parameter, organic carbon oxidation state (Cox). Two of the three techniques make use of a molecular mixing model which converts NMR spectra into concentrations of a standard suite of biological molecules of known C ox. The third technique assigns Cox values to each peak in the NMR spectrum. We assess error associated with each technique using pure chemical compounds and plant biomass standards whose Cox and OR values can be directly measured by elemental analyses. The most accurate technique, direct polarization solid-state 13C NMR with the molecular mixing model, agrees with elemental analyses to ??0.036 Cox units (??0.009 OR units). Using this technique, we show a large natural variability in soil Cox and OR values. Soil Cox values have a mean of -0.26 and a range from -0.45 to 0.30, corresponding to OR values of 1.08 ?? 0.06 and a range from 0.96 to 1.22. We also estimate the OR of the carbon flux from a boreal forest fire. Analysis of soils from nearby intact soil profiles imply that soil carbon losses associated with the fire had an OR of 1.091 (??0.003). Fire appears to be a major factor driving the soil C pool to higher oxidation states and lower OR values. Episodic fluxes caused by disturbances like fire may have substantially different ORs from ecosystem respiration fluxes and therefore should be better quantified to reduce uncertainties associated with our understanding of the global atmospheric carbon budget. Copyright 2009 by the American Geophysical Union.

A Box-Cox normal model for response times.

PubMed

Klein Entink, R H; van der Linden, W J; Fox, J-P

2009-11-01

The log-transform has been a convenient choice in response time modelling on test items. However, motivated by a dataset of the Medical College Admission Test where the lognormal model violated the normality assumption, the possibilities of the broader class of Box-Cox transformations for response time modelling are investigated. After an introduction and an outline of a broader framework for analysing responses and response times simultaneously, the performance of a Box-Cox normal model for describing response times is investigated using simulation studies and a real data example. A transformation-invariant implementation of the deviance information criterium (DIC) is developed that allows for comparing model fit between models with different transformation parameters. Showing an enhanced description of the shape of the response time distributions, its application in an educational measurement context is discussed at length.

Cyclooxygenase 2 Promotes Parathyroid Hyperplasia in ESRD

PubMed Central

Zhang, Qian; Qiu, Junsi; Li, Haiming; Lu, Yanwen; Wang, Xiaoyun; Yang, Junwei; Wang, Shaoqing; Zhang, Liyin; Gu, Yong; Hao, Chuan-Ming

2011-01-01

Hyperplasia of the PTG underlies the secondary hyperparathyroidism (SHPT) observed in CKD, but the mechanism underlying this hyperplasia is incompletely understood. Because aberrant cyclooxygenase 2 (COX2) expression promotes epithelial cell proliferation, we examined the effects of COX2 on the parathyroid gland in uremia. In patients with ESRD who underwent parathyroidectomy, clusters of cells within the parathyroid glands had increased COX2 expression. Some COX2-positive cells exhibited two nuclei, consistent with proliferation. Furthermore, nearly 78% of COX2-positive cells expressed proliferating cell nuclear antigen (PCNA). In the 5/6-nephrectomy rat model, rats fed a high-phosphate diet had significantly higher serum PTH levels and larger parathyroid glands than sham-operated rats. Compared with controls, the parathyroid glands of uremic rats exhibited more PCNA-positive cells and greater COX2 expression in the chief cells. Treatment with COX2 inhibitor celecoxib significantly reduced PCNA expression, attenuated serum PTH levels, and reduced the size of the glands. In conclusion, COX2 promotes the pathogenesis of hyperparathyroidism in ESRD, suggesting that inhibiting the COX2 pathway could be a potential therapeutic target. PMID:21335517

Density functional theory analysis and molecular docking evaluation of 1-(2, 5-dichloro-4-sulfophenyl)-3-methyl-5-pyrazolone as COX2 inhibitor against inflammatory diseases

NASA Astrophysics Data System (ADS)

Kavitha, T.; Velraj, G.

2017-08-01

The molecular structure of 1-(2, 5-Dichloro-4-Sulfophenyl)-3-Methyl-5-Pyrazolone (DSMP) was optimized using DFT/B3LYP/6-31++G(d,p) level and its corresponding experimental as well as theoretical FT-IR, FT-Raman vibrational frequencies and UV-Vis spectral analysis were carried out. The vibrational assignments and total energy distributions of each vibration were presented with the aid of Veda 4xx software. The molecular electrostatic potential, HOMO-LUMO energies, global and local reactivity descriptors and natural bond orbitals were analyzed in order to find the most possible reactive sites of the molecule and it was found that DSMP molecule possess enhanced nucleophilic activity. One of the common known COX2 inhibitor, celecoxib (CXB) was also found to exhibit similar reactivity properties and hence DSMP was also expected to inhibit COX enzymes. In order to detect the COX inhibition nature of DSMP, molecular docking analysis was carried out with the help of Autodock software. For that, the optimized structure was in turn used for docking DSMP with COX enzymes. The binding energy scores and inhibitory constant values reveal that the DSMP molecule possess good binding affinity and low inhibition constant towards COX2 enzyme and hence it can be used as an anti-inflammatory drug after carrying out necessary biological tests.

Molecular Basis for Cyclooxygenase Inhibition by the Non-steroidal Anti-inflammatory Drug Naproxen

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duggan, Kelsey C.; Walters, Matthew J.; Musee, Joel

Naproxen ((S)-6-methoxy-{alpha}-methyl-2-naphthaleneacetic acid) is a powerful non-selective non-steroidal anti-inflammatory drug that is extensively used as a prescription and over-the-counter medication. Naproxen exhibits gastrointestinal toxicity, but its cardiovascular toxicity may be reduced compared with other drugs in its class. Despite the fact that naproxen has been marketed for many years, the molecular basis of its interaction with cyclooxygenase (COX) enzymes is unknown. We performed a detailed study of naproxen-COX-2 interactions using site-directed mutagenesis, structure-activity analysis, and x-ray crystallography. The results indicate that each of the pendant groups of the naphthyl scaffold are essential for COX inhibition, and only minimal substitutions aremore » tolerated. Mutation of Trp-387 to Phe significantly reduced inhibition by naproxen, a result that appears unique to this inhibitor. Substitution of S or CH2 for the O atom of the p-methoxy group yielded analogs that were not affected by the W387F substitution and that exhibited increased COX-2 selectivity relative to naproxen. Crystallization and x-ray analysis yielded structures of COX-2 complexed to naproxen and its methylthio analog at 1.7 and 2.3 {angstrom} resolution, respectively. The combination of mutagenesis, structure analysis, and x-ray crystallography provided comprehensive information on the unique interactions responsible for naproxen binding to COX-2.« less

Reporting and methodological quality of survival analysis in articles published in Chinese oncology journals.

PubMed

Zhu, Xiaoyan; Zhou, Xiaobin; Zhang, Yuan; Sun, Xiao; Liu, Haihua; Zhang, Yingying

2017-12-01

Survival analysis methods have gained widespread use in the filed of oncology. For achievement of reliable results, the methodological process and report quality is crucial. This review provides the first examination of methodological characteristics and reporting quality of survival analysis in articles published in leading Chinese oncology journals.To examine methodological and reporting quality of survival analysis, to identify some common deficiencies, to desirable precautions in the analysis, and relate advice for authors, readers, and editors.A total of 242 survival analysis articles were included to be evaluated from 1492 articles published in 4 leading Chinese oncology journals in 2013. Articles were evaluated according to 16 established items for proper use and reporting of survival analysis.The application rates of Kaplan-Meier, life table, log-rank test, Breslow test, and Cox proportional hazards model (Cox model) were 91.74%, 3.72%, 78.51%, 0.41%, and 46.28%, respectively, no article used the parametric method for survival analysis. Multivariate Cox model was conducted in 112 articles (46.28%). Follow-up rates were mentioned in 155 articles (64.05%), of which 4 articles were under 80% and the lowest was 75.25%, 55 articles were100%. The report rates of all types of survival endpoint were lower than 10%. Eleven of 100 articles which reported a loss to follow-up had stated how to treat it in the analysis. One hundred thirty articles (53.72%) did not perform multivariate analysis. One hundred thirty-nine articles (57.44%) did not define the survival time. Violations and omissions of methodological guidelines included no mention of pertinent checks for proportional hazard assumption; no report of testing for interactions and collinearity between independent variables; no report of calculation method of sample size. Thirty-six articles (32.74%) reported the methods of independent variable selection. The above defects could make potentially inaccurate, misleading of the reported results, or difficult to interpret.There are gaps in the conduct and reporting of survival analysis in studies published in Chinese oncology journals, severe deficiencies were noted. More endorsement by journals of the report guideline for survival analysis may improve articles quality, and the dissemination of reliable evidence to oncology clinicians. We recommend authors, readers, reviewers, and editors to consider survival analysis more carefully and cooperate more closely with statisticians and epidemiologists. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Myeloid Cell COX-2 deletion reduces mammary tumor growth through enhanced cytotoxic T-lymphocyte function

PubMed Central

Chen, Edward P.; Markosyan, Nune; Connolly, Emma; Lawson, John A.; Li, Xuanwen; Grant, Gregory R.; Grosser, Tilo; FitzGerald, Garret A.; Smyth, Emer M.

2014-01-01

Cyclooxygenase-2 (COX-2) expression is associated with poor prognosis across a range of human cancers, including breast cancer. The contribution of tumor cell-derived COX-2 to tumorigenesis has been examined in numerous studies; however, the role of stromal-derived COX-2 is ill-defined. Here, we examined how COX-2 in myeloid cells, an immune cell subset that includes macrophages, influences mammary tumor progression. In mice engineered to selectively lack myeloid cell COX-2 [myeloid-COX-2 knockout (KO) mice], spontaneous neu oncogene-induced tumor onset was delayed, tumor burden reduced, and tumor growth slowed compared with wild-type (WT). Similarly, growth of neu-transformed mammary tumor cells as orthotopic tumors in immune competent syngeneic myeloid-COX-2 KO host mice was reduced compared with WT. By flow cytometric analysis, orthotopic myeloid-COX-2 KO tumors had lower tumor-associated macrophage (TAM) infiltration consistent with impaired colony stimulating factor-1-dependent chemotaxis by COX-2 deficient macrophages in vitro. Further, in both spontaneous and orthotopic tumors, COX-2-deficient TAM displayed lower immunosuppressive M2 markers and this was coincident with less suppression of CD8+ cytotoxic T lymphocytes (CTLs) in myeloid-COX-2 KO tumors. These studies suggest that reduced tumor growth in myeloid-COX-2 KO mice resulted from disruption of M2-like TAM function, thereby enhancing T-cell survival and immune surveillance. Antibody-mediated depletion of CD8+, but not CD4+ cells, restored tumor growth in myeloid-COX-2 KO to WT levels, indicating that CD8+ CTLs are dominant antitumor effectors in myeloid-COX-2 KO mice. Our studies suggest that inhibition of myeloid cell COX-2 can potentiate CTL-mediated tumor cytotoxicity and may provide a novel therapeutic approach in breast cancer therapy. PMID:24590894

Dual oxidase 1: A predictive tool for the prognosis of hepatocellular carcinoma patients.

PubMed

Chen, Shengsen; Ling, Qingxia; Yu, Kangkang; Huang, Chong; Li, Ning; Zheng, Jianming; Bao, Suxia; Cheng, Qi; Zhu, Mengqi; Chen, Mingquan

2016-06-01

Dual oxidase 1 (DUOX1), which is the main source of reactive oxygen species (ROS) production in the airway, can be silenced in human lung cancer and hepatocellular carcinomas. However, the prognostic value of DUOX1 expression in hepatocellular carcinoma patients is still unclear. We investigated the prognostic value of DUOX1 expression in liver cancer patients. DUOX1 mRNA expression was determined in tumor tissues and non-tumor tissues by real‑time PCR. For evaluation of the prognostic value of DUOX1 expression, Kaplan-Meier method and Cox's proportional hazards model (univariate analysis and multivariate analysis) were employed. A simple risk score was devised by using significant variables obtained from the Cox's regression analysis to further predict the HCC patient prognosis. We observed a reduced DUOX1 mRNA level in the cancer tissues in comparison to the non‑cancer tissues. More importantly, Kaplan-Meier analysis showed that patients with high DUOX1 expression had longer disease-free survival and overall survival compared with those with low expression of DUOX1. Cox's regression analysis indicated that DUOX1 expression, age, and intrahepatic metastasis may be significant prognostic factors for disease-free survival and overall survival. Finally, we found that patients with total scores of >2 and >1 were more likely to relapse and succumb to the disease than patients whose total scores were ≤2 and ≤1. In conclusion, DUOX1 expression in liver tumors is a potential prognostic tool for patients. The risk scoring system is useful for predicting the survival of liver cancer patients after tumor resection.

Synthesis, biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors.

PubMed

Grover, Jagdeep; Kumar, Vivek; Sobhia, M Elizabeth; Jachak, Sanjay M

2014-10-01

As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds (3a-d, 3h, 3k and 3q) were identified as potential and selective COX-2 inhibitors (COX-2 IC50's in 1.79-4.35μM range; COX-2 selectivity index (SI)=6.8-16.7 range). Compound 3b emerged as most potent (COX-2 IC50=1.79μM; COX-1 IC50 >30μM) and selective COX-2 inhibitor (SI >16.7). Further, compound 3b displayed superior anti-inflammatory activity (59.86% inhibition of edema at 5h) in comparison to celecoxib (51.44% inhibition of edema at 5h) in carrageenan-induced rat paw edema assay. Structure-activity relationship studies suggested that N-phenyl ring substituted with p-CF3 substituent (3b, 3k and 3q) leads to more selective inhibition of COX-2. To corroborate obtained experimental biological data, molecular docking study was carried out which revealed that compound 3b showed stronger binding interaction with COX-2 as compared to COX-1. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Mutation of COX6A1 Causes a Recessive Axonal or Mixed Form of Charcot-Marie-Tooth Disease

PubMed Central

Tamiya, Gen; Makino, Satoshi; Hayashi, Makiko; Abe, Akiko; Numakura, Chikahiko; Ueki, Masao; Tanaka, Atsushi; Ito, Chizuru; Toshimori, Kiyotaka; Ogawa, Nobuhiro; Terashima, Tomoya; Maegawa, Hiroshi; Yanagisawa, Daijiro; Tooyama, Ikuo; Tada, Masayoshi; Onodera, Osamu; Hayasaka, Kiyoshi

2014-01-01

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247−10_247−6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT. PMID:25152455

Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression.

PubMed

Chen, Jing-Yi; Li, Chien-Feng; Kuo, Cheng-Chin; Tsai, Kelvin K; Hou, Ming-Feng; Hung, Wen-Chun

2014-07-25

Expression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, the clinical significance of stromal IDO and the regulation of stromal IDO are unclear. Metabolomics and enzyme-linked immunosorbent assay (ELISA) were used to study the effect of cyclooxygenase-2 (COX-2)-overexpressing breast cancer cells on IDO expression in co-cultured human breast fibroblasts. Biochemical inhibitors and short-hairpin RNA (shRNA) were used to clarify how prostaglandin E2 (PGE2) upregulates IDO expression. Associations of stromal IDO with clinicopathologic parameters were tested in tumor specimens. An orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth. Kynurenine, the metabolite generated by IDO, increases in the supernatant of fibroblasts co-cultured with COX-2-overexpressing breast cancer cells. PGE2 released by cancer cells upregulates IDO expression in fibroblasts through an EP4/signal transducer and activator of transcription 3 (STAT3)-dependent pathway. Conversely, fibroblast-secreted kynurenine promotes the formation of the E-cadherin/Aryl hydrocarbon receptor (AhR)/S-phase kinase-associated protein 2 (Skp2) complex, resulting in degradation of E-cadherin to increase breast cancer invasiveness. The enhancement of motility of breast cancer cells induced by co-culture with fibroblasts is suppressed by the IDO inhibitor 1-methyl-tryptophan. Pathological analysis demonstrates that upregulation of stromal IDO is a poor prognosis factor and is associated with of COX-2 overexpression. Co-expression of cancer COX-2 and stromal IDO predicts a worse disease-free and metastasis-free survival. Finally, COX-2 and IDO inhibitors inhibit tumor growth in vivo. Integration of metabolomics and molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2, and IDO promotes tumor progression and predicts poor patient survival.

Correlation analysis between expression of PCNA, Ki-67 and COX-2 and X-ray features in mammography in breast cancer.

PubMed

Qiu, Xiaoming; Mei, Jixin; Yin, Jianjun; Wang, Hong; Wang, Jinqi; Xie, Ming

2017-09-01

This study investigated expression of proliferating cell nuclear antigen (PCNA), proliferation-associated nuclear antigen (Ki-67) and cyclooxygenase-2 (COX-2) in tissues of breast invasive ductal carcinoma, and analyzed the correlations between these indexes and X-ray features in mammography. A total of 90 patients who were admitted to Huangshi Central Hospital and diagnosed as breast invasive ductal carcinoma from January 2014 to January 2016 were selected. The expression of PCNA, Ki-67 and COX-2 in cancer tissues and cancer-adjacent normal tissues of patients were detected by immunohistochemical staining, and X-ray features in mammography of patients were observed. By using Spearman correlation analysis, the correlations between expression of PCNA, Ki-67 and COX-2 and X-ray features in mammography in breast cancer were investigated. As a result, the positive expression rates of PCNA, Ki-67 and COX-2 in cancer tissues of the patient groups were respectively 42.2, 45.6 and 51.1%, which were significantly higher than those in cancer-adjacent normal tissues of the control group (p<0.05). PCNA, Ki-67 and COX-2 expression in cancer tissues of the patient group was associated with clinical staging and lymphatic metastasis (p<0.05), but had no correlation with age and tumor size (p>0.05). PCNA, Ki-67 and COX-2 expression in cancer tissues of the patient group had no correlation with the existence of lumps and localized density-increased shadows (p>0.05), but were associated with manifestations of architectural distortion, calcification as well as skin and nipple depression (p<0.05). Spearman correlation analysis revealed that there was a significantly positive correlation between the expression of PCNA and COX-2 in cancer tissues of the patient group (r=0.676, p<0.05); there was a significantly positive correlation between the expression of Ki-67 and COX-2 (r=0.724, p<0.05); PCNA expression had no obvious correlation with the expression of Ki-67 (p>0.05). In conclusion, PCNA, Ki-67 and COX-2 expression is of great significance in the occurrence, invasion and metastasis of breast invasive ductal carcinoma. There is a strong correlation between PCNA, Ki-67 and COX-2 expression levels and X-ray features in mammography in breast invasive ductal carcinoma. The application of X-ray features in mammography can evaluate the expression levels of PCNA, Ki-67 and COX-2 in tissues of breast invasive ductal carcinoma, thereby prospectively predicting biological behavior of these cancer cells and patient prognosis.

Analgesic Effect of the Newly Developed S(+)-Flurbiprofen Plaster on Inflammatory Pain in a Rat Adjuvant-Induced Arthritis Model.

PubMed

Sugimoto, Masanori; Toda, Yoshihisa; Hori, Miyuki; Mitani, Akiko; Ichihara, Takahiro; Sekine, Shingo; Hirose, Takuya; Endo, Hiromi; Futaki, Nobuko; Kaku, Shinsuke; Otsuka, Noboru; Matsumoto, Hideo

2016-02-01

Preclinical Research This article describes the properties of a novel topical NSAID (Nonsteroidal anti-inflammatory drug) patch, SFPP (S(+)-flurbiprofen plaster), containing the potent cyclooxygenase (COX) inhibitor, S(+)-flurbiprofen (SFP). The present studies were conducted to confirm human COX inhibition and absorption of SFP and to evaluate the analgesic efficacy of SFPP in a rat adjuvant-induced arthritis (AIA) model. COX inhibition by SFP, ketoprofen and loxoprofen was evaluated using human recombinant COX proteins. Absorption of SFPP, ketoprofen and loxoprofen from patches through rat skin was assessed 24 h after application. The AIA model was induced by injecting Mycobacterium tuberculosis followed 20 days later by the evaluation of the prostaglandin PGE2 content of the inflamed paw and the pain threshold. SFP exhibited more potent inhibitory activity against COX-1 (IC50  = 8.97 nM) and COX-2 (IC50  = 2.94 nM) than the other NSAIDs evaluated. Absorption of SFP was 92.9%, greater than that of ketoprofen and loxoprofen from their respective patches. Application of SFPP decreased PGE2 content from 15 min to 6 h and reduced paw hyperalgesia compared with the control, ketoprofen and loxoprofen patches. SFPP showed analgesic efficacy, and was superior to the ketoprofen and loxoprofen patches, which could be through the potent COX inhibitory activity of SFP and greater skin absorption. The results suggested SFPP can be expected to exert analgesic effect clinically. © 2016 The Authors Drug Development Research Published by Wiley Periodicals, Inc.

In-plane anisotropy of the electric field gradient in Ba(Fe 1 -xCox)2As2 observed by 75As NMR

NASA Astrophysics Data System (ADS)

Toyoda, Masayuki; Ichikawa, Akihiro; Kobayashi, Yoshiaki; Sato, Masatoshi; Itoh, Masayuki

2018-05-01

We have performed 75As NMR measurements on single crystals to investigate the nematic behavior via the in-plane anisotropy of the electronic state at the As site far from Co impurities in the representative iron arsenides Ba (Fe1-xCox) 2As2 . From the analysis of the angular dependence of the NMR satellites in the c plane using the binominal distribution, we find that there is the in-plane fourfold symmetry breaking, namely, the orthorhombic-type anisotropy in the electric field gradient (EFG) at the As site with no Co atom at the nearest neighboring Fe sites even in the tetragonal phase of both BaFe2As2 and Ba (Fe1-xCox) 2As2(x ≠0 ) . The NMR spectrum in the antiferromagnetically ordered state of BaFe2As2 is shown not to support a nanotwin model on the basis of the nematic order proposed from the pair-distribution analysis of neutron scattering data. Based on results of the x and temperature T dependences of the in-plane anisotropy in the wide x and T ranges, the symmetry breaking is concluded to come from the local orthorhombic domains induced by disorder such as Co impurities or lattice imperfections. Furthermore, we find that the asymmetry parameter of EFG η obeys the Curie-Weiss law which may be governed by nematic susceptibility, and the Weiss temperature becomes zero at xc˜0.05 in Ba (Fe1-xCox) 2As2 .

Analysis of the cytochrome c oxidase subunit II (COX2) gene in giant panda, Ailuropoda melanoleuca.

PubMed

Ling, S S; Zhu, Y; Lan, D; Li, D S; Pang, H Z; Wang, Y; Li, D Y; Wei, R P; Zhang, H M; Wang, C D; Hu, Y D

2017-01-23

The giant panda, Ailuropoda melanoleuca (Ursidae), has a unique bamboo-based diet; however, this low-energy intake has been sufficient to maintain the metabolic processes of this species since the fourth ice age. As mitochondria are the main sites for energy metabolism in animals, the protein-coding genes involved in mitochondrial respiratory chains, particularly cytochrome c oxidase subunit II (COX2), which is the rate-limiting enzyme in electron transfer, could play an important role in giant panda metabolism. Therefore, the present study aimed to isolate, sequence, and analyze the COX2 DNA from individuals kept at the Giant Panda Protection and Research Center, China, and compare these sequences with those of the other Ursidae family members. Multiple sequence alignment showed that the COX2 gene had three point mutations that defined three haplotypes, with 60% of the sequences corresponding to haplotype I. The neutrality tests revealed that the COX2 gene was conserved throughout evolution, and the maximum likelihood phylogenetic analysis, using homologous sequences from other Ursidae species, showed clustering of the COX2 sequences of giant pandas, suggesting that this gene evolved differently in them.

The influence of acute resistance exercise on cyclooxygenase-1 and -2 activity and protein levels in human skeletal muscle.

PubMed

Carroll, Chad C; O'Connor, Devin T; Steinmeyer, Robert; Del Mundo, Jonathon D; McMullan, David R; Whitt, Jamie A; Ramos, Jahir E; Gonzales, Rayna J

2013-07-01

This study evaluated the activity and content of cyclooxygenase (COX)-1 and -2 in response to acute resistance exercise (RE) in human skeletal muscle. Previous work suggests that COX-1, but not COX-2, is the primary COX isoform elevated with resistance exercise in human skeletal muscle. COX activity, however, has not been assessed after resistance exercise in humans. It was hypothesized that RE would increase COX-1 but not COX-2 activity. Muscle biopsies were taken from the vastus lateralis of nine young men (25 ± 1 yr) at baseline (preexercise), 4, and 24 h after a single bout of knee extensor RE (three sets of 10 repetitions at 70% of maximum). Tissue lysate was assayed for COX-1 and COX-2 activity. COX-1 and COX-2 protein levels were measured via Western blot analysis. COX-1 activity increased at 4 h (P < 0.05) compared with preexercise, but returned to baseline at 24 h (PRE: 60 ± 10, 4 h: 106 ± 22, 24 h: 72 ± 8 nmol PGH2·g total protein(-1)·min(-1)). COX-2 activity was elevated at 4 and 24 h after RE (P < 0.05, PRE: 51 ± 7, 4 h: 100 ± 19, 24 h: 98 ± 14 nmol PGH2·g total protein(-1)·min(-1)). The protein level of COX-1 was not altered (P > 0.05) with acute RE. In contrast, COX-2 protein levels were nearly 3-fold greater (P > 0.05) at 4 h and 5-fold greater (P = 0.06) at 24 h, compared with preexercise. In conclusion, COX-1 activity increases transiently with exercise independent of COX-1 protein levels. In contrast, both COX-2 activity and protein levels were elevated with exercise, and this elevation persisted to at least 24 h after RE.

Predictors of survival among hemodialysis patients: effect of perceived family support.

PubMed

Christensen, A J; Wiebe, J S; Smith, T W; Turner, C W

1994-11-01

The authors examined the role of perceived family support and symptoms of depression as predictors of survival in a sample of 78 in-center hemodialysis patients. Cox regression analysis revealed significant effects for family support (p < .005), blood urea nitrogen (p < .01), and age (p < .005). The effect for depression was not significant. The Cox model indicated that a 1-point increase on the family support measure was associated with a 13% reduction in the hazard rate (i.e., mortality). Estimated 5-year mortality rates among low family support patients were approximately 3 times higher than estimated mortality for high support patients. Differences in patient adherence to the dietary and medication regimens failed to explain the significant effect of family support.

Enzymologic and pharmacologic profile of loxoprofen sodium and its metabolites.

PubMed

Noguchi, Masahiro; Kimoto, Aishi; Gierse, James Kevin; Walker, Mark Crossfield; Zweifel, Ben Scott; Nozaki, Kazutoshi; Sasamata, Masao

2005-11-01

We investigated the mechanism of inhibition of loxoprofen sodium, a non-steroidal anti-inflammatory drug (NSAID), and its active metabolite (loxoprofen-SRS) on cyclooxygenase (COX). In in vitro assays, loxoprofen sodium appeared inactive against recombinant human COX-1 and COX-2, whereas loxoprofen-SRS inhibited both. In the investigation of kinetic behavior, loxoprofen-SRS showed time-dependent inhibition for both isozymes. Human whole blood assay also showed that loxoprofen-SRS possesses the profile of a non-selective inhibitor for COX. In a rat air pouch model, oral administration of loxoprofen sodium lowered prostaglandin (PG) E2 in both fluid exudates of the inflammatory pouch and stomach tissue with ED50 values of 2.0 and 2.1 mg/kg, respectively. Additionally, platelet thromboxane B2 production was also inhibited by loxoprofen sodium (ED50 of 0.34 mg/kg). In a rat carrageenan-induced paw edema model, loxoprofen sodium dose-dependently reduced the paw edema, accompanied by a decrease in PGE2 content in inflamed paw exudates. These findings suggest that the COX inhibitory activity of loxoprofen sodium is attributable to its active metabolite, loxoprofen-SRS, and that loxoprofen-SRS shows non-selective inhibition for COX.

Training artificial neural networks directly on the concordance index for censored data using genetic algorithms.

PubMed

Kalderstam, Jonas; Edén, Patrik; Bendahl, Pär-Ola; Strand, Carina; Fernö, Mårten; Ohlsson, Mattias

2013-06-01

The concordance index (c-index) is the standard way of evaluating the performance of prognostic models in the presence of censored data. Constructing prognostic models using artificial neural networks (ANNs) is commonly done by training on error functions which are modified versions of the c-index. Our objective was to demonstrate the capability of training directly on the c-index and to evaluate our approach compared to the Cox proportional hazards model. We constructed a prognostic model using an ensemble of ANNs which were trained using a genetic algorithm. The individual networks were trained on a non-linear artificial data set divided into a training and test set both of size 2000, where 50% of the data was censored. The ANNs were also trained on a data set consisting of 4042 patients treated for breast cancer spread over five different medical studies, 2/3 used for training and 1/3 used as a test set. A Cox model was also constructed on the same data in both cases. The two models' c-indices on the test sets were then compared. The ranking performance of the models is additionally presented visually using modified scatter plots. Cross validation on the cancer training set did not indicate any non-linear effects between the covariates. An ensemble of 30 ANNs with one hidden neuron was therefore used. The ANN model had almost the same c-index score as the Cox model (c-index=0.70 and 0.71, respectively) on the cancer test set. Both models identified similarly sized low risk groups with at most 10% false positives, 49 for the ANN model and 60 for the Cox model, but repeated bootstrap runs indicate that the difference was not significant. A significant difference could however be seen when applied on the non-linear synthetic data set. In that case the ANN ensemble managed to achieve a c-index score of 0.90 whereas the Cox model failed to distinguish itself from the random case (c-index=0.49). We have found empirical evidence that ensembles of ANN models can be optimized directly on the c-index. Comparison with a Cox model indicates that near identical performance is achieved on a real cancer data set while on a non-linear data set the ANN model is clearly superior. Copyright © 2013 Elsevier B.V. All rights reserved.

Anti-cancer Effects of a Novel Quinoline Derivative 83b1 on Human Esophageal Squamous Cell Carcinoma through Down-Regulation of COX-2 mRNA and PGE2.

PubMed

Pun, Ivan Ho Yuen; Chan, Dessy; Chan, Sau Hing; Chung, Po Yee; Zhou, Yuan Yuan; Law, Simon; Lam, Alfred King Yin; Chui, Chung Hin; Chan, Albert Sun Chi; Lam, Kim Hung; Tang, Johnny Cheuk On

2017-01-01

83b1 is a novel quinoline derivative that has been shown to inhibit cancer growth in human esophageal squamous cell carcinoma (ESCC). This study was conducted to comprehensively evaluate the cytotoxic effects of 83b1 on a series of ESCC cell lines and investigate the mechanisms by which 83b1 suppresses cancer growth based on molecular docking analysis. A series of ESCC and nontumor immortalized cell lines were exposed to 83b1 and cisplatin (CDDP) in a dose-dependent manner, and the cytotoxicity was examined by a MTS assay kit. Prediction of the molecular targets of 83b1 was conducted by molecular docking analysis. Expression of cyclooxygenase 2 (COX-2) mRNA and COX-2-derived prostaglandin E 2 (PGE 2 ) were measured by quantitative real-time polymerase chain reaction and enzymelinked immuno-sorbent assay, respectively. In vivo anti-tumor effect was determined using a nude mice xenografted model transplanted with an ESCC cell line, KYSE-450. 83b1 showed the significant anti-cancer effects on all ESCC cell lines compared to CDDP; however, 83b1 revealed much lower toxic effects on non-tumor cell lines than CDDP. The predicted molecular target of 83b1 is peroxisome proliferator-activated receptor delta (PPARδ), which is a widely known oncoprotein. Additionally the expression of COX-2 mRNA and COX-2-derived PGE 2 were down-regulated by 83b1 in a dose-dependent manner in ESCC cell lines. Furthermore, 83b1 was shown to significantly reduce the tumor size in nude mice xenograft. The results of this study suggest that the potential anti-cancer effects of 83b1 on human esophageal cancers occur through the possible oncotarget, PPARδ, and down-regulation of the cancer related genes and molecules.

Coexpression of aPKCλ/ι and IL-6 in prostate cancer tissue correlates with biochemical recurrence.

PubMed

Ishiguro, Hitoshi; Akimoto, Kazunori; Nagashima, Yoji; Kagawa, Eriko; Sasaki, Takeshi; Sano, Jin-yu; Takagawa, Ryo; Fujinami, Kiyoshi; Sasaki, Kazunori; Aoki, Ichiro; Ohno, Shigeo; Kubota, Yoshinobu; Uemura, Hiroji

2011-08-01

Atypical protein kinase C λ/ι (aPKCλ/ι) and interleukin-6 (IL-6) have been implicated in prostate cancer progression, the mechanisms of which have been demonstrated both in vitro and in vivo. However, the clinical significance of the correlation between the expressions of these factors remains to be clarified. In the present study, we report a significant correlation between aPKCλ/ι and IL-6 proteins in prostate cancer tissue by immunohistochemical staining. We evaluated the association of both proteins by analyzing clinicopathological parameters using chi-square test, Kaplan-Meier with log-rank test, and a Cox proportional hazard regression model in univariate and multivariate analyses. The results again showed that the expression of aPKCλ/ι and IL-6 correlates in prostate cancer tissue (P < 0.001). Atypical protein kinase C λ/ι was also found to correlate with the Gleason score (P < 0.001) and with biochemical recurrence after prostatectomy (P = 0.02). Furthermore, aPKCλ/ι correlated with biochemical recurrence in a Kaplan-Meier and log-rank test (P = 0.01) and Cox analysis (P = 0.02 in the univariate analysis, P = 0.02 in the multivariate analysis). The coexpression of aPKCλ/ι and IL-6 also correlated with biochemical recurrence by Kaplan-Meier and log-rank test (P = 0.005) and Cox analysis (P = 0.01 in the univariate analysis, P = 0.03 in the multivariate analysis). These results indicate a strong correlation between aPKCλ/ι and IL-6 in prostate tumors, and that the aPKCλ/ι-IL-6 axis is a reliable prognostic factor for the biochemical recurrence of this cancer. © 2011 Japanese Cancer Association.

Utility of COX1 phylogenetics to differentiate between locally acquired and imported Plasmodium knowlesi infections in Singapore

PubMed Central

Loh, Jin Phang; Gao, Qiu Han Christine; Lee, Vernon J; Tetteh, Kevin; Drakeley, Chris

2016-01-01

INTRODUCTION Although there have been several phylogenetic studies on Plasmodium knowlesi (P. knowlesi), only cytochrome c oxidase subunit 1 (COX1) gene analysis has shown some geographical differentiation between the isolates of different countries. METHODS Phylogenetic analysis of locally acquired P. knowlesi infections, based on circumsporozoite, small subunit ribosomal ribonucleic acid (SSU rRNA), merozoite surface protein 1 and COX1 gene targets, was performed. The results were compared with the published sequences of regional isolates from Malaysia and Thailand. RESULTS Phylogenetic analysis of the circumsporozoite, SSU rRNA and merozoite surface protein 1 gene sequences for regional P. knowlesi isolates showed no obvious differentiation that could be attributed to their geographical origin. However, COX1 gene analysis showed that it was possible to differentiate between Singapore-acquired P. knowlesi infections and P. knowlesi infections from Peninsular Malaysia and Sarawak, Borneo, Malaysia. CONCLUSION The ability to differentiate between locally acquired P. knowlesi infections and imported P. knowlesi infections has important utility for the monitoring of P. knowlesi malaria control programmes in Singapore. PMID:26805667

Utility of COX1 phylogenetics to differentiate between locally acquired and imported Plasmodium knowlesi infections in Singapore.

PubMed

Loh, Jin Phang; Gao, Qiu Han Christine; Lee, Vernon J; Tetteh, Kevin; Drakeley, Chris

2016-12-01

Although there have been several phylogenetic studies on Plasmodium knowlesi (P. knowlesi), only cytochrome c oxidase subunit 1 (COX1) gene analysis has shown some geographical differentiation between the isolates of different countries. Phylogenetic analysis of locally acquired P. knowlesi infections, based on circumsporozoite, small subunit ribosomal ribonucleic acid (SSU rRNA), merozoite surface protein 1 and COX1 gene targets, was performed. The results were compared with the published sequences of regional isolates from Malaysia and Thailand. Phylogenetic analysis of the circumsporozoite, SSU rRNA and merozoite surface protein 1 gene sequences for regional P. knowlesi isolates showed no obvious differentiation that could be attributed to their geographical origin. However, COX1 gene analysis showed that it was possible to differentiate between Singapore-acquired P. knowlesi infections and P. knowlesi infections from Peninsular Malaysia and Sarawak, Borneo, Malaysia. The ability to differentiate between locally acquired P. knowlesi infections and imported P. knowlesi infections has important utility for the monitoring of P. knowlesi malaria control programmes in Singapore. Copyright: © Singapore Medical Association

An anti-inflammatory molecular mechanism of action of α-mangostin, the major xanthone from the pericarp of Garcinia mangostana: an in silico, in vitro and in vivo approach.

PubMed

Mohan, Syam; Syam, Suvitha; Abdelwahab, Siddig Ibrahim; Thangavel, Neelaveni

2018-06-28

α-Mangostin (αMN) is a xanthone present in the pericarp of Garcinia mangostana Linn. which is mentioned in Ayurveda and is a widely used functional food supplement. However, its anti-inflammatory mechanism is not well studied. Hence, we used in silico, in vitro and in vivo models to provide information of the mechanism on how αMN could prevent inflammation. Firstly, molecular docking was used to find out the binding energy of αMN with NFκB and COX proteins. Secondly, LPS induced RAW 264.7 cells were used to measure the production of cytokines, the prevention of translocation of NFκB and the inhibition of COX-1 and -2 enzymes. Finally, carrageenan-induced peritonitis was used in vivo to check cytokine release, leukocyte migration and vascular permeability. The in silico modelling had showed that αMN has the lowest binding energy with COX-2 and NFκB proteins. αMN has been found to inhibit the production of PGE2 and nitric oxide, and iNOS protein expression. TNF-α and IL-6 cytokines were inhibited significantly (p < 0.05) at 8 and 14 μg ml-1 concentration. αMN at higher doses inhibits the translocation of NFκB together with suppressing the COX-2 enzymes, but not COX-1. αMN inhibited the total leukocyte migration, predominantly, neutrophils in vivo. The level of TNFα and IL-1β was significantly (p < 0.05) reduced in the peritoneal fluids as measured by ELISA analysis. Taken together, these results demonstrate that αMN acts well as an anti-inflammatory agent via inhibiting the hallmark mechanisms of inflammation. It can be considered as a potential alternative lead compound. In addition, the current results support the traditional use of this fruit pericarp as a functional food.

Twenty five years long survival analysis of an individual shortleaf pine trees

Treesearch

Pradip Saud; Thomas B. Lynch; James M. Guldin

2016-01-01

A semi parametric cox proportion hazard model is preferred when censored data and survival time information is available (Kleinbaum and Klein 1996; Alison 2010). Censored data are observations that have incomplete information related to survival time or event time of interest. In repeated forest measurements, usually observations are either right censored or...

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colleselli, Daniela; Bijuklic, Klaudija; Mosheimer, Birgit A.

2006-09-10

Growing evidence indicates that inducible cyclooxygenase-2 (COX-2) is involved in the pathogenesis of inflammatory disorders and various types of cancer. Endothelial progenitor cells recruited from the bone marrow have been shown to be involved in the formation of new vessels in malignancies and discussed for being a key point in tumour progression and metastasis. However, until now, nothing is known about an interaction between COX and endothelial progenitor cells (EPC). Expression of COX-1 and COX-2 was detected by semiquantitative RT-PCR and Western blot. Proliferation kinetics, cell cycle distribution and rate of apoptosis were analysed by MTT test and FACS analysis.more » 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.« less

Cyclooxygenase-2 is an obligatory factor in methamphetamine-induced neurotoxicity.

PubMed

Thomas, David M; Kuhn, Donald M

2005-05-01

Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. The mechanisms underlying its neurotoxicity are not fully understood, but considerable evidence points to oxidative stress as a probable mechanism. A recent microarray analysis of gene expression changes caused by methamphetamine revealed that cyclooxygenase-2 (COX-2) was induced along with its transcription factor CCAAT/enhancer-binding protein (Thomas DM, Francescutti-Verbeem DM, Liu X, and Kuhn DM, 2004). We report presently that methamphetamine increases striatal expression of COX-2 protein. Cyclooxygenase-1 (COX-1) expression was not changed. Mice bearing a null mutation of the gene for COX-2 were resistant to methamphetamine-induced neurotoxicity. COX-1 knockouts, like wild-type mice, showed extensive dopamine nerve terminal damage. Selective inhibitors of COX-1 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl pyrazole (SC-560)], COX-2 [N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulfonamide (NS-398), rofecoxib], or COX-3 (antipyrine) or a nonselective inhibitor of the COX-1/2 isoforms (ketoprofen) did not protect mice from neurotoxicity. Finally, methamphetamine did not change striatal prostaglandin E(2) content. Taken together, these data suggest that COX-2 is an obligatory factor in methamphetamine-induced neurotoxicity. The functional aspect of COX-2 that contributes to drug-induced neurotoxicity does not appear to be its prostaglandin synthetic capacity. Instead, the peroxidase activity associated with COX-2, which can lead to the formation of reactive oxygen species and dopamine quinones, can account for its role.

Potentially functional COX-2-1195G>A polymorphism increases the risk of digestive system cancers: a meta-analysis.

PubMed

Dong, Jing; Dai, Juncheng; Zhang, Mingfeng; Hu, Zhibin; Shen, Hongbing

2010-06-01

Three potentially functional polymorphisms: -765G>C, -1195G>A, and 8473T>C in the cyclooxygenase-2 (COX-2) gene were identified and proposed to be associated with cancer susceptibility. The aim of this meta-analysis was to evaluate the association between these three polymorphisms and the risk of cancer in diverse populations. All case-control studies published up to November 2009 on the association between the three polymorphisms of COX-2 and cancer risk were identified by searching PubMed. The cancer risk associated with the three polymorphisms of the COX-2 gene was estimated for each study by OR together with its 95% confidence interval (CI), respectively. A total of 47 case-control studies were included, and variant genotypes GA/AA of -1195G>A were associated with a significantly increased cancer risk (GA/AA vs GG: odds ratio [OR], 1.29; 95% CI, 1.18-1.41; P(heterogeneity) = 0.113), and this significant association was mainly observed within cancers of the digestive system (e.g. colorectal, gastric, esophageal, oral, biliary tract, gallbladder, and pancreatic) without between-study heterogeneity (GA/AA vs GG: OR, 1.36; 95% CI; 1.23-1.51; P(heterogeneity) = 0.149). Furthermore, a stratification analysis showed that the risk of COX-2-1195G>A associated with cancers in the digestive system was more evident among Asians than Caucasians. However, for COX-2-765G>C and 8473T>C, no convincing association between the two polymorphisms and risk of cancer or cancer type was observed. The effect of three potentially functional polymorphisms (-765G>C, -1195G>A, and 8473T>C) in the COX-2 gene on cancer risk provided evidence that the COX-2-1195G>A polymorphism was significantly associated with increased risk of digestive system cancers, especially among Asian populations.

Immunohistochemical analysis of cyclooxygenase-2 and brain fatty acid binding protein expression in grades I-II meningiomas: correlation with tumor grade and clinical outcome after radiotherapy.

PubMed

Kang, Hyun-Cheol; Kim, Il Han; Park, Charn Il; Park, Sung-Hye

2014-10-01

This study was done to evaluate the association of cyclooxygenase 2 (COX-2) and brain fatty acid binding protein (BFABP) with tumor grade and outcome of grades I-II meningiomas treated with radiotherapy. From 1996 to 2008, 40 patients with intracranial grades I-II meningiomas were treated with radiotherapy. Immunohistochemical staining for COX-2 and BFABP were performed on formalin-fixed paraffin-embedded tissues. COX-2 expression was significantly associated with BFABP status and both COX-2 (P < 0.01) and BFABP (P = 0.01) expression were stronger in the grade II meningiomas than in grade I tumors. Among the clinicopathologic factors, age and COX-2 status were prognostic in progression-free survival. Patients with moderate or strong COX-2 expression had worse outcome than those with negative or weak COX-2 expression (P = 0.03) after controlling for potential confounders. Our results suggest that the molecular biomarker COX-2 has prognostic significance in intracranial grades I-II meningiomas following radiotherapy. © 2014 Japanese Society of Neuropathology.

Relationship of clinical factors to the use of Cox-2 selective NSAIDs within an arthritis population in a large HMO.

PubMed

Bull, Scott A; Conell, Carol; Campen, David H

2002-01-01

To investigate the degree to which physicians use clinical factors to focus use of Cox-2 selective NSAIDs within an arthritis population. Diagnostic codes in the medical records of a large group-model HMO in northern California with approximately 3 million members were examined to identify patients with either rheumatoid arthritis (RA) or non-RA (osteoarthritis or degenerative joint disease). RA and non-RA patients were stratified in deciles of relative risk for gastrointestinal (GI) complications according to patient characteristics identified on the Standardized Calculator of Risk for Events (SCORE) that were associated with use of Cox-2 selective NSAIDs. (The SCORE tool stratifies patients by risk of serious GI complications using patient characteristics that are assigned points during an office visit, including age, health status, diagnosis of rheumatoid arthritis, corticosteroid use, and history of GI ulcer or bleed.) The second stage of analysis examined the percentage of arthritis patients in each SCORE-risk decile who received a Cox-2 selective NSAID, lower-risk NSAID, or traditional NSAID during calendar year 1999. The study population consisted of 144,360 members with an arthritis diagnosis, approximately 4.8% of members in this HMO. The mean age was 62.8 years (SD = 14.1), 61% were female, 10,449 (7%) had rheumatoid arthritis (RA), and 133,911 (93%) had non-rheumatoid arthritis. A diagnosis of RA was the most significant predictor of Cox-2 NSAID use (OR=2.4; 95% CI=1.6-3.5), followed by a history of GI problems (OR=1.5; 95% CI=1.4- 1.6). Female gender, chronic steroid use, and age each increased the odds of receiving a Cox-2 selective NSAID by about 35% (P<0.001 for all). Approximately 8.3% of patients in the highest decile of risk and 1.5% of patients in the lowest decile of risk received a Cox-2 selective NSAID. Clinical characteristics of patients identified on the SCORE (GI-risk) tool were strongly associated with use of Cox-2-selective NSAIDs in this HMO. A 5.5-fold difference in utilization of Cox-2 selective NSAIDs was found among patients determined to be in the highest-risk decile versus patients in the lowest-risk decile. Future research should investigate how nonclinical factors play a role in the treatment decisions made by physicians.

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

PubMed Central

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

2008-01-01

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. PMID:18453539

[Suppression of COX-2 protein to cell apoptosis in non-small cell lung cancer].

PubMed

Sun, Limei; Zhao, Yue; Wang, Lujian; Song, Min; Song, Jiye

2007-06-20

One of mechanisms of carcinogenesis is suppression of cell apoptosis which leads to accumulation of aberrant cells. The aim of this study is to investigate cell apoptosis and COX-2 protein expression in non-small cell lung cancer (NSCLC). Cell apoptosis, expression of COX-2 and microvessel density (MVD) were detcted in 111 NSCLC samples by TdT-mediated dUTP nick end labeling (TUNEL) technique and immunohistochemical staining. The positive rate of COX-2 protein expression was 67.6% (75/111), and there were 53 patients with high level cell apoptosis (47.7%). Expression of COX-2 protien was significantly related to TNM stages (P=0.025) and lymph node metastasis (P=0.018). The MVD in NSCLC tissues with positive COX-2 expression was significantly higher than that in negative expression ones (P=0.000). COX model showed that lymph node metastasis (P=0.006) and positive expression of COX-2 protein (P=0.000) were independent prognostic factors of NSCLC. The expression of COX-2 protein may suppress cell apoptosis of tumor, and it may serve as a potential marker of prognosis for NSCLC.

Inhibitory activity of tryptanthrin on prostaglandin and leukotriene synthesis.

PubMed

Danz, Henning; Stoyanova, Stefka; Thomet, Olivier A R; Simon, Hans-Uwe; Dannhardt, Gerd; Ulbrich, Holger; Hamburger, Matthias

2002-10-01

The indolo[2,1- b]quinazoline alkaloid tryptanthrin has previously been identified as the cyclooxygenase-2 (COX-2) inhibitory principle in the extract ZE550 prepared from the medicinal plant Isatis tinctoria (Brassicaceae). We here investigated the potential inhibitory activity of tryptanthrin and ZE550 on COX-2, COX-1 in cellular and cell-free systems. A certain degree of selectivity towards COX-2 was observed when COX-1-dependent formation of thromboxane B(2) (TxB(2)) in HEL cells and COX-2-dependent formation of 6-ketoprostaglandin F(1alpha) (6-keto-PGF(1alpha)) in Mono Mac 6 and RAW 264.7 cells were compared. Preferential inhibition of COX-2 by two orders of magnitude was found in phorbol myristate acetate (PMA) activated bovine aortic coronary endothelial cells (BAECs). Assays with purified COX isoenzymes from sheep confirmed the high selectivity towards COX-2. The leukotriene B(4) (LTB(4)) release from calcium ionophore-stimulated human granulocytes (neutrophils) was used as a model to determine 5-lipoxygenase (5-LOX) activity. Tryptanthrin and the extract ZE550 inhibited LTB(4) release in a dose dependent manner and with a potency comparable to that of the clinically used 5-LOX inhibitor zileuton.

Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic.

PubMed Central

Masferrer, J L; Zweifel, B S; Manning, P T; Hauser, S D; Leahy, K M; Smith, W G; Isakson, P C; Seibert, K

1994-01-01

We have examined the role of cyclooxygenase 2 (COX-2) in a model of inflammation in vivo. Carrageenan administration to the subcutaneous rat air pouch induces a rapid inflammatory response characterized by high levels of prostaglandins (PGs) and leukotrienes in the fluid exudate. The time course of the induction of COX-2 mRNA and protein coincided with the production of PGs in the pouch tissue and cellular infiltrate. Carrageenan-induced COX-2 immunoreactivity was localized to macrophages obtained from the fluid exudate as well as to the inner surface layer of cells within the pouch lining. Dexamethasone inhibited both COX-2 expression and PG synthesis in the fluid exudate but failed to inhibit PG synthesis in the stomach. Furthermore, NS-398, a selective COX-2 inhibitor, and indomethacin, a nonselective COX-1/COX-2 inhibitor, blocked proinflammatory PG synthesis in the air pouch. In contrast, only indomethacin blocked gastric PG and, additionally, produced gastric lesions. These results suggest that inhibitors of COX-2 are potent antiinflammatory agents which do not produce the typical side effects (e.g., gastric ulcers) associated with the nonselective, COX-1-directed antiinflammatory drugs. Images PMID:8159730

Design, Synthesis, and Evaluation of New Tripeptides as COX-2 Inhibitors.

PubMed

Vernieri, Ermelinda; Gomez-Monterrey, Isabel; Milite, Ciro; Grieco, Paolo; Musella, Simona; Bertamino, Alessia; Scognamiglio, Ilaria; Alcaro, Stefano; Artese, Anna; Ortuso, Francesco; Novellino, Ettore; Sala, Marina; Campiglia, Pietro

2013-01-01

Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are mediators of inflammation. It exists mainly in two isoforms COX-1 and COX-2. The conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal side effects because they inhibit both isoforms. Recent data demonstrate that the overexpression of these enzymes, and in particular of cyclooxygenases-2, promotes multiple events involved in tumorigenesis; in addition, numerous studies show that the inhibition of cyclooxygenases-2 can delay or prevent certain forms of cancer. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and offer a new perspective for a further use of COX-2 inhibitors. The present study extends the evaluation of the COX activity to all 20(3) possible natural tripeptide sequences following a rational approach consisting in molecular modeling, synthesis, and biological tests. Based on data obtained from virtual screening, only those peptides with better profile of affinity have been selected and classified into two groups called S and E. Our results suggest that these novel compounds may have potential as structural templates for the design and subsequent development of the new selective COX-2 inhibitors drugs.

Cyclooxygenase-2 inhibitors modulate skin aging in a catalytic activity-independent manner

PubMed Central

Lee, Mi Eun; Kim, So Ra; Lee, Seungkoo; Jung, Yu-Jin; Choi, Sun Shim; Kim, Woo Jin

2012-01-01

It has been proposed that the pro-inflammatory catalytic activity of cyclooxygenase-2 (COX-2) plays a key role in the aging process. However, it remains unclear whether the COX-2 activity is a causal factor for aging and whether COX-2 inhibitors could prevent aging. We here examined the effect of COX-2 inhibitors on aging in the intrinsic skin aging model of hairless mice. We observed that among two selective COX-2 inhibitors and one non-selective COX inhibitor studied, only NS-398 inhibited skin aging, while celecoxib and aspirin accelerated skin aging. In addition, NS-398 reduced the expression of p53 and p16, whereas celecoxib and aspirin enhanced their expression. We also found that the aging-modulating effect of the inhibitors is closely associated with the expression of type I procollagen and caveolin-1. These results suggest that pro-inflammatory catalytic activity of COX-2 is not a causal factor for aging at least in skin and that COX-2 inhibitors might modulate skin aging by regulating the expression of type I procollagen and caveolin-1. PMID:22771771

Cox-nnet: An artificial neural network method for prognosis prediction of high-throughput omics data

PubMed Central

Ching, Travers; Zhu, Xun

2018-01-01

Artificial neural networks (ANN) are computing architectures with many interconnections of simple neural-inspired computing elements, and have been applied to biomedical fields such as imaging analysis and diagnosis. We have developed a new ANN framework called Cox-nnet to predict patient prognosis from high throughput transcriptomics data. In 10 TCGA RNA-Seq data sets, Cox-nnet achieves the same or better predictive accuracy compared to other methods, including Cox-proportional hazards regression (with LASSO, ridge, and mimimax concave penalty), Random Forests Survival and CoxBoost. Cox-nnet also reveals richer biological information, at both the pathway and gene levels. The outputs from the hidden layer node provide an alternative approach for survival-sensitive dimension reduction. In summary, we have developed a new method for accurate and efficient prognosis prediction on high throughput data, with functional biological insights. The source code is freely available at https://github.com/lanagarmire/cox-nnet. PMID:29634719

A simple approach to power and sample size calculations in logistic regression and Cox regression models.

PubMed

Vaeth, Michael; Skovlund, Eva

2004-06-15

For a given regression problem it is possible to identify a suitably defined equivalent two-sample problem such that the power or sample size obtained for the two-sample problem also applies to the regression problem. For a standard linear regression model the equivalent two-sample problem is easily identified, but for generalized linear models and for Cox regression models the situation is more complicated. An approximately equivalent two-sample problem may, however, also be identified here. In particular, we show that for logistic regression and Cox regression models the equivalent two-sample problem is obtained by selecting two equally sized samples for which the parameters differ by a value equal to the slope times twice the standard deviation of the independent variable and further requiring that the overall expected number of events is unchanged. In a simulation study we examine the validity of this approach to power calculations in logistic regression and Cox regression models. Several different covariate distributions are considered for selected values of the overall response probability and a range of alternatives. For the Cox regression model we consider both constant and non-constant hazard rates. The results show that in general the approach is remarkably accurate even in relatively small samples. Some discrepancies are, however, found in small samples with few events and a highly skewed covariate distribution. Comparison with results based on alternative methods for logistic regression models with a single continuous covariate indicates that the proposed method is at least as good as its competitors. The method is easy to implement and therefore provides a simple way to extend the range of problems that can be covered by the usual formulas for power and sample size determination. Copyright 2004 John Wiley & Sons, Ltd.

Selective cyclooxygenase-2 inhibitor suppresses renal thromboxane production but not proliferative lesions in the MRL/lpr murine model of lupus nephritis.

PubMed

Oates, Jim C; Halushka, Perry V; Hutchison, Florence N; Ruiz, Philip; Gilkeson, Gary S

2011-02-01

Proliferative lupus nephritis (LN) is marked by increased renal thromboxane (TX) A₂ production. Targeting the TXA₂ receptor or TXA₂ synthase effectively improves renal function in humans with LN and improves glomerular pathology in murine LN. This study was designed to address the following hypotheses: (1) TXA₂ production in the MRL/MpJ-Tnfrsf6(lpr)/J (MRL/lpr) model of proliferative LN is cyclooxygenase (COX)-2 dependent and (2) COX2 inhibitor therapy improves glomerular filtration rate (GFR), proteinuria, markers of innate immune response and glomerular pathology. Twenty female MRL/lpr and 20 BALB/cJ mice were divided into 2 equal treatment groups: (1) SC-236, a moderately selective COX2 inhibitor or (2) vehicle. After treatment from the age of 10 to 20 weeks, the effectiveness of inhibition of TXA₂ was determined by measuring urine TXB₂. Response endpoints measured at the age of 20 weeks were renal function (GFR), proteinuria, urine nitrate + nitrite (NO(x)) and glomerular histopathology. SC-236 therapy reduced surrogate markers of renal TXA₂ production during early, active glomerulonephritis. When this pharmacodynamic endpoint was reached, therapy improved GFR. Parallel reductions in markers of the innate immune response (urine NO(x)) during therapy were observed. However, the beneficial effect of SC-236 therapy on GFR was only transient, and renal histopathology was not improved in late disease. These data demonstrate that renal TXA2 production is COX2 dependent in murine LN and suggest that NO production is directly or indirectly COX2 dependent. However, COX2 inhibitor therapy in this model failed to improve renal pathology, making COX2 inhibition a less attractive approach for treating LN.

Validation of a heteroscedastic hazards regression model.

PubMed

Wu, Hong-Dar Isaac; Hsieh, Fushing; Chen, Chen-Hsin

2002-03-01

A Cox-type regression model accommodating heteroscedasticity, with a power factor of the baseline cumulative hazard, is investigated for analyzing data with crossing hazards behavior. Since the approach of partial likelihood cannot eliminate the baseline hazard, an overidentified estimating equation (OEE) approach is introduced in the estimation procedure. It by-product, a model checking statistic, is presented to test for the overall adequacy of the heteroscedastic model. Further, under the heteroscedastic model setting, we propose two statistics to test the proportional hazards assumption. Implementation of this model is illustrated in a data analysis of a cancer clinical trial.

The Application of Extended Cox Proportional Hazard Method for Estimating Survival Time of Breast Cancer

NASA Astrophysics Data System (ADS)

Husain, Hartina; Astuti Thamrin, Sri; Tahir, Sulaiha; Mukhlisin, Ahmad; Mirna Apriani, M.

2018-03-01

Breast cancer is one type of cancer that is the leading cause of death worldwide. This study aims to model the factors that affect the survival time and rate of cure of breast cancer patients. The extended cox model, which is a modification of the proportional hazard cox model in which the proportional hazard assumptions are not met, is used in this study. The maximum likelihood estimation approach is used to estimate the parameters of the model. This method is then applied to medical record data of breast cancer patient in 2011-2016, which is taken from Hasanuddin University Education Hospital. The results obtained indicate that the factors that affect the survival time of breast cancer patients are malignancy and leukocyte levels.

Clinical and multiple gene expression variables in survival analysis of breast cancer: Analysis with the hypertabastic survival model

PubMed Central

2012-01-01

Background We explore the benefits of applying a new proportional hazard model to analyze survival of breast cancer patients. As a parametric model, the hypertabastic survival model offers a closer fit to experimental data than Cox regression, and furthermore provides explicit survival and hazard functions which can be used as additional tools in the survival analysis. In addition, one of our main concerns is utilization of multiple gene expression variables. Our analysis treats the important issue of interaction of different gene signatures in the survival analysis. Methods The hypertabastic proportional hazards model was applied in survival analysis of breast cancer patients. This model was compared, using statistical measures of goodness of fit, with models based on the semi-parametric Cox proportional hazards model and the parametric log-logistic and Weibull models. The explicit functions for hazard and survival were then used to analyze the dynamic behavior of hazard and survival functions. Results The hypertabastic model provided the best fit among all the models considered. Use of multiple gene expression variables also provided a considerable improvement in the goodness of fit of the model, as compared to use of only one. By utilizing the explicit survival and hazard functions provided by the model, we were able to determine the magnitude of the maximum rate of increase in hazard, and the maximum rate of decrease in survival, as well as the times when these occurred. We explore the influence of each gene expression variable on these extrema. Furthermore, in the cases of continuous gene expression variables, represented by a measure of correlation, we were able to investigate the dynamics with respect to changes in gene expression. Conclusions We observed that use of three different gene signatures in the model provided a greater combined effect and allowed us to assess the relative importance of each in determination of outcome in this data set. These results point to the potential to combine gene signatures to a greater effect in cases where each gene signature represents some distinct aspect of the cancer biology. Furthermore we conclude that the hypertabastic survival models can be an effective survival analysis tool for breast cancer patients. PMID:23241496

Does buccal cancer have worse prognosis than other oral cavity cancers?

PubMed

Camilon, P Ryan; Stokes, William A; Fuller, Colin W; Nguyen, Shaun A; Lentsch, Eric J

2014-06-01

To determine whether buccal squamous cell carcinoma has worse overall survival (OS) and disease-specific survival (DSS) than cancers in the rest of the oral cavity. Retrospective analysis of a large population database. We began with a Kaplan-Meier analysis of OS and DSS for buccal versus nonbuccal tumors with unmatched data, followed by an analysis of cases matched for race, age at diagnosis, stage at diagnosis, and treatment modality. This was supported by a univariate Cox regression comparing buccal cancer to nonbuccal cancer, followed by a multivariate Cox regression that included all significant variables studied. With unmatched data, buccal cancer had significantly lesser OS and DSS values than cancers in the rest of the oral cavity (P < .001). After case matching, the differences between OS and DSS for buccal cancer versus nonbuccal oral cancer were no longer significant. Univariate Cox regression models with respect to OS and DSS showed a significant difference between buccal cancer and nonbuccal cancer. However, with multivariate analysis, buccal hazard ratios for OS and DSS were not significant. With the largest series of buccal carcinoma to date, our study concludes that the OS and DSS of buccal cancer are similar to those of cancers in other oral cavity sites once age at diagnosis, tumor stage, treatment, and race are taken into consideration. The previously perceived poor prognosis of buccal carcinoma may be due to variations in tumor presentation, such as later stage and older patient age. 2b. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

Clinicopathological and prognostic significance of cyclooxygenase-2 expression in head and neck cancer: A meta-analysis

PubMed Central

Guo, Qiaojuan; Ren, Hui; Hu, Yanping; Xie, Tao

2016-01-01

Several studies have assessed the clinicopathological and prognostic value of cyclooxygenase-2 (COX-2) expression in patients with head and neck cancer (HNC), but their results remain controversial. To address this issue, a meta-analysis was carried out. A total of 29 studies involving 2430 patients were subjected to final analysis. Our results indicated that COX-2 expression was not statistically associated with advanced tumor stage (OR, 1.23; 95% CI, 0.98–1.55) but correlated with high risk of lymph node metastasis (OR, 1.28; 95% CI, 1.03–1.60) and advanced TNM stage (OR, 1.33; 95% CI, 1.06–1.66). Moreover, COX-2 expression had significant effect on poor OS (HR, 1.93; 95% CI, 1.29–2.90), RFS (HR, 2.02; 95% CI, 1.00–4.08) and DFS (HR, 5.14; 95% CI, 2.84–9.31). The results of subgroup analyses revealed that COX-2 expression was related with high possibility of lymph node metastasis in oral cancer (OR, 1.49; 95% CI, 1.01–2.20) and advanced TNM stage in oral cancer (OR, 1.58; 95% CI, 1.05–2.37) and no site-specific HNC (OR, 1.64; 95% CI, 1.02–2.62). However, subgroup analyses only showed a tendency without statistically significant association between COX-2 expression and survival. Significant heterogeneity was not found when analyzing clinicopathological data, but it appeared when considering survival data. No publication bias was detected in this study. This meta-analysis suggested that COX-2 expression could act as a prognostic factor for patients with HNC. PMID:27323811

Estimation of the cure rate in Iranian breast cancer patients.

PubMed

Rahimzadeh, Mitra; Baghestani, Ahmad Reza; Gohari, Mahmood Reza; Pourhoseingholi, Mohamad Amin

2014-01-01

Although the Cox's proportional hazard model is the popular approach for survival analysis to investigate significant risk factors of cancer patient survival, it is not appropriate in the case of log-term disease free survival. Recently, cure rate models have been introduced to distinguish between clinical determinants of cure and variables associated with the time to event of interest. The aim of this study was to use a cure rate model to determine the clinical associated factors for cure rates of patients with breast cancer (BC). This prospective cohort study covered 305 patients with BC, admitted at Shahid Faiazbakhsh Hospital, Tehran, during 2006 to 2008 and followed until April 2012. Cases of patient death were confirmed by telephone contact. For data analysis, a non-mixed cure rate model with Poisson distribution and negative binomial distribution were employed. All analyses were carried out using a developed Macro in WinBugs. Deviance information criteria (DIC) were employed to find the best model. The overall 1-year, 3-year and 5-year relative survival rates were 97%, 89% and 74%. Metastasis and stage of BC were the significant factors, but age was significant only in negative binomial model. The DIC also showed that the negative binomial model had a better fit. This study indicated that, metastasis and stage of BC were identified as the clinical criteria for cure rates. There are limited studies on BC survival which employed these cure rate models to identify the clinical factors associated with cure. These models are better than Cox, in the case of long-term survival.

Accuracy and Precision in Measurements of Biomass Oxidative Ratio and Carbon Oxidation State

NASA Astrophysics Data System (ADS)

Gallagher, M. E.; Masiello, C. A.; Randerson, J. T.; Chadwick, O. A.; Robertson, G. P.

2007-12-01

Ecosystem oxidative ratio (OR) is a critical parameter in the apportionment of anthropogenic CO2 between the terrestrial biosphere and ocean carbon reservoirs. OR is the ratio of O2 to CO2 in gas exchange fluxes between the terrestrial biosphere and atmosphere. Ecosystem OR is linearly related to biomass carbon oxidation state (Cox), a fundamental property of the earth system describing the bonding environment of carbon in molecules. Cox can range from -4 to +4 (CH4 to CO2). Variations in both Cox and OR are driven by photosynthesis, respiration, and decomposition. We are developing several techniques to accurately measure variations in ecosystem Cox and OR; these include elemental analysis, bomb calorimetry, and 13C nuclear magnetic resonance spectroscopy. A previous study, comparing the accuracy and precision of elemental analysis versus bomb calorimetry for pure chemicals, showed that elemental analysis-based measurements are more accurate, while calorimetry- based measurements yield more precise data. However, the limited biochemical range of natural samples makes it possible that calorimetry may ultimately prove most accurate, as well as most cost-effective. Here we examine more closely the accuracy of Cox and OR values generated by calorimetry on a large set of natural biomass samples collected from the Kellogg Biological Station-Long Term Ecological Research (KBS-LTER) site in Michigan.

Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity

PubMed Central

Ching, Tsui-Ting; Chiang, Wei-Chung; Chen, Ching-Shih; Hsu, Ao-Lin

2011-01-01

Summary One goal of aging research is to develop interventions that combat age-related illnesses and slow aging. Although numerous mutations have been shown to achieve this in various model organisms, only a handful of chemicals have been identified to slow aging. Here we report that celecoxib, a non-steroidal anti-inflammatory drug (NSAID) widely used to treat pain and inflammation, extends C. elegans lifespan and delays the age-associated physiological changes, such as motor activity declines. Celecoxib also delays the progression of age-related proteotoxicity as well as tumor growth in C. elegans. Celecoxib was originally developed as a potent COX-2 inhibitor. However, the result from a structural-activity analysis demonstrated that the anti-aging effect of celecoxib might be independent of its COX-2 inhibitory activity, as analogs of celecoxib that lack cyclooxygenase-2 (COX-2) inhibitory activity produces a similar effect on lifespan. Furthermore, we found that celecoxib acts directly on 3’-phosphoinositide-dependent kinase-1 (PDK-1), a component of the insulin/IGF-1 signaling (IIS) cascade to increase lifespan. PMID:21348927

Candidate chromosome 1 disease susceptibility genes for Sjogren’s syndrome xerostomia are narrowed by novel NOD.B10 congenic mice

PubMed Central

Mongini, Patricia K. A.; Kramer, Jill M.; Ishikawa, Tomo-o; Herschman, Harvey; Esposito, Donna

2014-01-01

Sjogren’s syndrome (SS) is characterized by salivary gland leukocytic infiltrates and impaired salivation (xerostomia). Cox-2 (Ptgs2) is located on chromosome 1 within the span of the Aec2 region. In an attempt to demonstrate that COX-2 drives antibody-dependent hyposalivation, NOD.B10 congenic mice bearing a Cox-2flox gene were generated. A congenic line with non-NOD alleles in Cox-2-flanking genes failed manifest xerostomia. Further backcrossing yielded disease-susceptible NOD.B10 Cox-2flox lines; fine genetic mapping determined that critical Aec2 genes lie within a 1.56 to 2.17 Mb span of DNA downstream of Cox-2. Bioinformatics analysis revealed that susceptible and non-susceptible lines exhibit non-synonymous coding SNPs in 8 protein-encoding genes of this region, thereby better delineating candidate Aec2 alleles needed for SS xerostomia. PMID:24685748

Prognostic Impact of Loop Diuretics in Patients With Chronic Heart Failure　- Effects of Addition of Renin-Angiotensin-Aldosterone System Inhibitors and β-Blockers.

PubMed

Miura, Masanobu; Sugimura, Koichiro; Sakata, Yasuhiko; Miyata, Satoshi; Tadaki, Soichiro; Yamauchi, Takeshi; Onose, Takeo; Tsuji, Kanako; Abe, Ruri; Oikawa, Takuya; Kasahara, Shintaro; Nochioka, Kotaro; Takahashi, Jun; Shimokawa, Hiroaki

2016-05-25

It remains to be elucidated whether addition of renin-angiotensin-aldosterone system (RAAS) inhibitors and/or β-blockers to loop diuretics has a beneficial prognostic impact on chronic heart failure (CHF) patients. From the Chronic Heart failure Analysis and Registry in the Tohoku district 2 (CHART-2) Study (n=10,219), we enrolled 4,134 consecutive patients with symptomatic stage C/D CHF (mean age, 69.3 years, 67.7% male). We constructed Cox models for composite of death, myocardial infarction, stroke and HF admission. On multivariate inverse probability of treatment weighted (IPTW) Cox modeling, loop diuretics use was associated with worse prognosis with hazard ratio (HR) 1.28 (P<0001). Furthermore, on IPTW multivariate Cox modeling for multiple treatments, both low-dose (<40 mg/day) and high-dose (≥40 mg/day) loop diuretics were associated with worse prognosis with HR 1.32 and 1.56, respectively (both P<0.001). Triple blockade with RAS inhibitor(s), mineral corticoid (aldosterone) receptor antagonist(s) (MRA), and β-blocker(s) was significantly associated with better prognosis in those on low-dose but not on high-dose loop diuretics. Chronic use of loop diuretics is significantly associated with worse prognosis in CHF patients in a dose-dependent manner, whereas the triple combination of RAAS inhibitor(s), MRA, and β-blocker(s) is associated with better prognosis when combined with low-dose loop diuretics. (Circ J 2016; 80: 1396-1403).

Box-Cox Mixed Logit Model for Travel Behavior Analysis

NASA Astrophysics Data System (ADS)

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

2010-09-01

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

Resveratrol decreases noise-induced cyclooxygenase-2 expression in the rat cochlea.

PubMed

Seidman, Michael D; Tang, Wenxue; Bai, Venkatesh Uma; Ahmad, Nadir; Jiang, Hao; Media, Joseph; Patel, Nimisha; Rubin, Cory J; Standring, Robert T

2013-05-01

Our previous studies have demonstrated the efficacy of resveratrol, a grape constituent noted for its antioxidant and anti-inflammatory properties, in reducing temporary threshold shifts and decreasing cochlear hair cell damage following noise exposure. This study was designed to identify the potential protective mechanism of resveratrol by measuring its effect on cyclooxygenase-2 (COX-2) protein expression and reactive oxygen species (ROS) formation following noise exposure. Controlled animal intervention study. Otology Laboratory, Henry Ford Health System. Twenty-two healthy male Fischer 344 rats (2-3 months old) were exposed to acoustic trauma of variable duration with or without intervention. An additional 20 healthy male rats were used to study COX-2 expression at different time points during and following treatment of 24 hours of noise exposure. Cochlear harvest was performed at various time intervals for measurement of COX-2 protein expression via Western blot analysis and immunostaining. Peripheral blood was also obtained for ROS analysis using flow cytometry. Acoustic trauma exposure resulted in a progressive up-regulation of COX-2 protein expression, commencing at 8 hours and peaking at 32 hours. Similarly, ROS production increased after noise exposure. However, treatment with resveratrol reduced noise-induced COX-2 expression as well as ROS formation in the blood as compared with the controls. COX-2 levels are induced dramatically following noise exposure. This increased expression may be a potential mechanism of noise-induced hearing loss (NIHL) and a possible mechanism of resveratrol's ability to mitigate NIHL by its ability to reduce COX-2 expression.

VEGF expression and the effect of NSAIDs on ascites cell proliferation in the hen model of ovarian cancer.

PubMed

Urick, M E; Giles, J R; Johnson, P A

2008-09-01

We aimed to determine the expression of vascular endothelial growth factor (VEGF) and the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the proliferation of cells isolated from ascites in the hen model of ovarian cancer. Ovarian tumor and normal ovary were collected from hens and ascites cells were isolated from hens with ovarian cancer. Quantitative real-time PCR was used to quantify mRNA expression. Immunohistochemical and/or Western blot analyses were used to localize protein expression in ovarian tumors, normal ovaries, and ascites cells. Cells were treated with a nonspecific, COX-1-specific, or COX-2-specific NSAID and proliferation was determined. VEGF mRNA was increased in ascites cells and there was a trend for a correlation between VEGF mRNA in ascites cells and ascites volume. VEGF protein was localized to theca cells of normal ovaries, in glandular areas of tumors, and to the cytoplasm of ascites cells. Aspirin and a COX-1-specific inhibitor decreased the proliferation of ascites cells, whereas a COX-2-specific inhibitor did not. VEGF may play a role in ovarian cancer progression in the hen and the proliferation of ascites cells can be decreased by targeting the COX-1 but not COX-2 pathway.

Azoxymethane protects intestinal stem cells and reduces crypt epithelial mitosis through a COX-1-dependent mechanism.

PubMed

Riehl, Terrence E; George, Robert J; Sturmoski, Mark A; May, Randal; Dieckgraefe, Brian; Anant, Shrikant; Houchen, Courtney W

2006-12-01

Azoxymethane (AOM) is a potent DNA-damaging agent and carcinogen that induces intestinal and colonic tumors in rodents. Evaluation of the stem cell population by colony formation assay reveals that, within 8 h after treatment, AOM (10 mg/kg) elicited a prosurvival response. In wild-type (WT) mice, AOM treatment induced a 2.5-fold increase in intestinal crypt stem cell survival. AOM treatment increased stem cell survival in cyclooxygenase (COX)-2(-/-) but not COX-1(-/-) mice, confirming a role of COX-1 in the AOM-induced increase in stem cell survival. COX-1 mRNA and protein expression as well as COX-1-derived PGE(2) synthesis were increased 8 h after AOM treatment. Immunohistochemical staining of COX-1 demonstrated expression of the enzyme in the crypt epithelial cells, especially in the columnar epithelial cells between the Paneth cells adjacent to the stem cell zone. WT mice receiving AOM exhibited increased intestinal apoptosis and a simultaneous reduction in crypt mitotic figures within 8 h of injection. There were no significant differences in baseline or AOM-induced intestinal epithelial apoptosis between WT and COX-1(-/-) mice, but there was a complete reversal of the AOM-mediated reduction in mitosis in COX-1(-/-) mice. This suggests that COX-1-derived PGE(2) may play a key role in the early phase of intestinal tumorigenesis in response to DNA damage and suggests that COX-1 may be a potential therapeutic target in this model of colon cancer.

The relationship between the effect of pravastatin and risk factors for coronary heart disease in Japanese patients with hypercholesterolemia.

PubMed

Ishikawa, Toshitsugu; Mizuno, Kyoichi; Nakaya, Noriaki; Ohashi, Yasuo; Tajima, Naoko; Kushiro, Toshio; Teramoto, Tamio; Uchiyama, Shinichiro; Nakamura, Haruo

2008-10-01

Several epidemiologic studies in Japan have shown the risk factors for coronary heart disease (CHD) in the general population. The present analysis determined the risk factors for CHD in the MEGA Study, a large primary prevention trial with pravastatin in Japanese with hypercholesterolemia. The relationship between each baseline characteristic and the risk of CHD for the 5-year study period were evaluated using the Cox proportional hazard model. The multivariable predictors of CHD were sex, age, high-density lipoprotein-cholesterol (HDL-C), diabetes mellitus (DM), hypertension (HT), and history of smoking. Serum total and low-density lipoprotein-cholesterol were not independent risk factors for CHD in the current analysis. In addition, the effect of pravastatin was evaluated by subgroups in each risk factor using the interaction in a Cox model. Diet plus pravastatin treatment reduced CHD risk by 14-43% compared with diet alone, regardless of the presence or absence of risk factors. The risk factors for CHD were sex, age, DM, HT, smoking, and low HDL-C in the MEGA Study. The pravastatin treatment was effective for reducing the risk of CHD, regardless of the presence of risk factors.

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

PubMed

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

2016-12-01

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

Oral 2-hydroxyoleic acid inhibits reflex hypersensitivity and open-field-induced anxiety after spared nerve injury.

PubMed

Avila-Martin, G; Galan-Arriero, I; Ferrer-Donato, A; Busquets, X; Gomez-Soriano, J; Escribá, P V; Taylor, J

2015-01-01

Recently, fatty acids have been shown to modulate sensory function in animal models of neuropathic pain. In this study, the antinociceptive effect of 2-hydroxyoleic acid (2-OHOA) was assessed following spared nerve injury (SNI) with reflex and cerebrally mediated behavioural responses. Initial antinociceptive behavioural screening of daily administration of 2-OHOA (400 mg/kg, p.o.) was assessed in Wistar rats by measuring hindlimb reflex hypersensitivity to von Frey and thermal plate stimulation up to 7 days after SNI, while its modulatory effect on lumbar spinal dorsal horn microglia reactivity was assessed with OX-42 immunohistochemistry. In vitro the effect of 2-OHOA (120 μM) on cyclooxygenase protein expression (COX-2/COX-1 ratio) in lipopolysaccharide-activated macrophage cells was tested with Western blot analysis. Finally, the effects of 2-OHOA treatment on the place escape aversion paradigm (PEAP) and the open-field-induced anxiety test were tested at 21 days following nerve injury compared with vehicle-treated sham and pregabalin-SNI (30 mg/kg, p.o.) control groups. Oral 2-OHOA significantly reduced ipsilateral mechanical and thermal hypersensitivity up to 7 days after SNI. Additionally 2-OHOA decreased the COX-2/COX-1 ratio in lipopolysaccharide-activated macrophage cells and OX-42 expression within the ipsilateral lumbar spinal dorsal horn 7 days after SNI. 2-OHOA significantly restored inner-zone exploration in the open-field test compared with the vehicle-treated sham group at 21 days after SNI. Oral administration of the modified omega 9 fatty acid, 2-OHOA, mediates antinociception and prevents open-field-induced anxiety in the SNI model in Wistar rats, which is mediated by an inhibition of spinal dorsal horn microglia activation. © 2014 European Pain Federation - EFIC®

Endoplasmic reticulum stress (ER-stress) by 2-deoxy-D-glucose (2DG) reduces cyclooxygenase-2 (COX-2) expression and N-glycosylation and induces a loss of COX-2 activity via a Src kinase-dependent pathway in rabbit articular chondrocytes.

PubMed

Yu, Seon-Mi; Kim, Song-Ja

2010-11-30

Endoplasmic reticulum (ER) stress regulates a wide range of cellular responses including apoptosis, proliferation, inflammation, and differentiation in mammalian cells. In this study, we observed the role of 2-deoxy-D-glucose (2DG) on inflammation of chondrocytes. 2DG is well known as an inducer of ER stress, via inhibition of glycolysis and glycosylation. Treatment of 2DG in chondrocytes considerably induced ER stress in a dose- and time-dependent manner, which was demonstrated by a reduction of glucose regulated protein of 94 kDa (grp94), an ER stress-inducible protein, as determined by a Western blot analysis. In addition, induction of ER stress by 2DG led to the expression of COX-2 protein with an apparent molecular mass of 66-70kDa as compared with the normally expressed 72-74 kDa protein. The suppression of ER stress with salubrinal (Salub), a selective inhibitor of eif2-alpha dephosphorylation, successfully prevented grp94 induction and efficiently recovered 2DG- modified COX-2 molecular mass and COX-2 activity might be associated with COX-2 N-glycosylation. Also, treatment of 2DG increased phosphorylation of Src in chondrocytes. The inhibition of the Src signaling pathway with PP2 (Src tyrosine kinase inhibitor) suppressed grp94 expression and restored COX-2 expression, N-glycosylation, and PGE2 production, as determined by a Western blot analysis and PGE2 assay. Taken together, our results indicate that the ER stress induced by 2DG results in a decrease of the transcription level, the molecular mass, and the activity of COX-2 in rabbit articular chondrocytes via a Src kinase-dependent pathway.

Design, Synthesis and Biological Evaluation of Novel Peptide-Like Analogues as Selective COX-2 Inhibitors

PubMed Central

Ahmaditaba, Mohammad Ali; Houshdar Tehrani, Mohammad Hassan; Zarghi, Afshin; Shahosseini, Sorayya; Daraei, Bahram

2018-01-01

A new series of peptide-like derivatives containing different aromatic amino acids and possessing pharmacophores of COX-2 inhibitors as SO2Me or N3 attached to the para position of an end phenyl ring was synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. The synthetic reactions were based on the solid phase peptide synthesis method using Wang resin. One of the analogues, i.e., compound 2d, as the representative of these series was recognized as the most effective and the highest selective COX-2 inhibitor with IC50 value of 0.08 μM and COX-2 selectivity index of 351.2, among the other synthesized compounds. Molecular docking study was operated to determine possible binding models of compound 2d to COX-2 enzyme. The study showed that the p-azido-phenyl fragment of 2d occupied inside the secondary COX-2 binding site (Arg513, and His90). The structure-activity relationships acquired disclosed that compound 2d with 4-(azido phenyl) group as pharmacophore and histidine as amino acid gives the essential geometry to provide inhibition of the COX-2 enzyme with high selectivity. Compound 2d can be a good candidate for the development of new hits of COX-2 inhibitors.

Chemopreventive effects of NSAIDs as inhibitors of cyclooxygenase-2 and inducers of apoptosis in experimental lung carcinogenesis.

PubMed

Setia, Shruti; Vaish, Vivek; Sanyal, Sankar Nath

2012-07-01

Roles of cyclooxygenase (COX) enzyme and intrinsic pathway of apoptosis have been explored for the chemopreventive effects of non-steroidal anti-inflammatory drugs (NSAIDs) on 9,10-dimethyl benz(a)anthracene (DMBA)-induced lung cancer in rat model. 16 weeks after the administration of DMBA, morphological analysis revealed the occurrences of tumours and lesions, which were regressed considerably with the co-administration of indomethacin and etoricoxib, the two NSAIDs under investigation. DMBA group was marked by hyperplasia and dysplasia as observed by histological examination, and these features were corrected to a large extent by the two NSAIDs. Elevated levels of COX-2 were seen in the DMBA group, the enzyme responsible for prostaglandin synthesis during inflammation and cancer, whilst the expression of the constitutive isoform, COX-1, was equally expressed in all the groups. Apoptosis was quantified by studying the activities of apaf-1, caspase-9, and 3 by immunofluorescence and western blots. Their activities were found to diminish in the DMBA-treated animals as compared to the other groups. Fluorescent co-staining of the isolated broncho-alveolar lavage cells showed reduced number of apoptotic cells in the DMBA group, indicating decrease in apoptosis after carcinogen administration. The present results thus suggest that the mechanism of cancer chemoprevention of NSAIDs may include the suppression of COX-2 and the induction of apoptosis.

Lipid Adjustment for Chemical Exposures: Accounting for Concomitant Variables

PubMed Central

Li, Daniel; Longnecker, Matthew P.; Dunson, David B.

2013-01-01

Background Some environmental chemical exposures are lipophilic and need to be adjusted by serum lipid levels before data analyses. There are currently various strategies that attempt to account for this problem, but all have their drawbacks. To address such concerns, we propose a new method that uses Box-Cox transformations and a simple Bayesian hierarchical model to adjust for lipophilic chemical exposures. Methods We compared our Box-Cox method to existing methods. We ran simulation studies in which increasing levels of lipid-adjusted chemical exposure did and did not increase the odds of having a disease, and we looked at both single-exposure and multiple-exposures cases. We also analyzed an epidemiology dataset that examined the effects of various chemical exposures on the risk of birth defects. Results Compared with existing methods, our Box-Cox method produced unbiased estimates, good coverage, similar power, and lower type-I error rates. This was the case in both single- and multiple-exposure simulation studies. Results from analysis of the birth-defect data differed from results using existing methods. Conclusion Our Box-Cox method is a novel and intuitive way to account for the lipophilic nature of certain chemical exposures. It addresses some of the problems with existing methods, is easily extendable to multiple exposures, and can be used in any analyses that involve concomitant variables. PMID:24051893

[Study on factors influencing survival in patients with advanced gastric carcinoma after resection by Cox's proportional hazard model].

PubMed

Wang, S; Sun, Z; Wang, S

1996-11-01

A prospective follow-up study of 539 advanced gastric carcinoma patients after resection was undertaken between 1 January 1980 and 31 December 1989, with a follow-up rate of 95.36%. A multivariate analysis of possible factors influencing survival of these patients was performed, and their predicting models of survival rates was established by Cox proportional hazard model. The results showed that the major significant prognostic factors influencing survival of these patients were rate and station of lymph node metastases, type of operation, hepatic metastases, size of tumor, age and location of tumor. The most important factor was the rate of lymph node metastases. According to their regression coefficients, the predicting value (PV) of each patient was calculated, then all patients were divided into five risk groups according to PV, their predicting models of survival rates after resection were established in groups. The goodness-fit of estimated predicting models of survival rates were checked by fitting curve and residual plot, and the estimated models tallied with the actual situation. The results suggest that the patients with advanced gastric cancer after resection without lymph node metastases and hepatic metastases had a better prognosis, and their survival probability may be predicted according to the predicting model of survival rates.

Meta-analysis of individual registry results enhances international registry collaboration.

PubMed

Paxton, Elizabeth W; Mohaddes, Maziar; Laaksonen, Inari; Lorimer, Michelle; Graves, Stephen E; Malchau, Henrik; Namba, Robert S; Kärrholm, John; Rolfson, Ola; Cafri, Guy

2018-03-28

Background and purpose - Although common in medical research, meta-analysis has not been widely adopted in registry collaborations. A meta-analytic approach in which each registry conducts a standardized analysis on its own data followed by a meta-analysis to calculate a weighted average of the estimates allows collaboration without sharing patient-level data. The value of meta-analysis as an alternative to individual patient data analysis is illustrated in this study by comparing the risk of revision of porous tantalum cups versus other uncemented cups in primary total hip arthroplasties from Sweden, Australia, and a US registry (2003-2015). Patients and methods - For both individual patient data analysis and meta-analysis approaches a Cox proportional hazard model was fit for time to revision, comparing porous tantalum (n = 23,201) with other uncemented cups (n = 128,321). Covariates included age, sex, diagnosis, head size, and stem fixation. In the meta-analysis approach, treatment effect size (i.e., Cox model hazard ratio) was calculated within each registry and a weighted average for the individual registries' estimates was calculated. Results - Patient-level data analysis and meta-analytic approaches yielded the same results with the porous tantalum cups having a higher risk of revision than other uncemented cups (HR (95% CI) 1.6 (1.4-1.7) and HR (95% CI) 1.5 (1.4-1.7), respectively). Adding the US cohort to the meta-analysis led to greater generalizability, increased precision of the treatment effect, and similar findings (HR (95% CI) 1.6 (1.4-1.7)) with increased risk of porous tantalum cups. Interpretation - The meta-analytic technique is a viable option to address privacy, security, and data ownership concerns allowing more expansive registry collaboration, greater generalizability, and increased precision of treatment effects.

Non-Asymptotic Oracle Inequalities for the High-Dimensional Cox Regression via Lasso.

PubMed

Kong, Shengchun; Nan, Bin

2014-01-01

We consider finite sample properties of the regularized high-dimensional Cox regression via lasso. Existing literature focuses on linear models or generalized linear models with Lipschitz loss functions, where the empirical risk functions are the summations of independent and identically distributed (iid) losses. The summands in the negative log partial likelihood function for censored survival data, however, are neither iid nor Lipschitz.We first approximate the negative log partial likelihood function by a sum of iid non-Lipschitz terms, then derive the non-asymptotic oracle inequalities for the lasso penalized Cox regression using pointwise arguments to tackle the difficulties caused by lacking iid Lipschitz losses.

Non-Asymptotic Oracle Inequalities for the High-Dimensional Cox Regression via Lasso

PubMed Central

Kong, Shengchun; Nan, Bin

2013-01-01

We consider finite sample properties of the regularized high-dimensional Cox regression via lasso. Existing literature focuses on linear models or generalized linear models with Lipschitz loss functions, where the empirical risk functions are the summations of independent and identically distributed (iid) losses. The summands in the negative log partial likelihood function for censored survival data, however, are neither iid nor Lipschitz.We first approximate the negative log partial likelihood function by a sum of iid non-Lipschitz terms, then derive the non-asymptotic oracle inequalities for the lasso penalized Cox regression using pointwise arguments to tackle the difficulties caused by lacking iid Lipschitz losses. PMID:24516328

Confidence intervals for the first crossing point of two hazard functions.

PubMed

Cheng, Ming-Yen; Qiu, Peihua; Tan, Xianming; Tu, Dongsheng

2009-12-01

The phenomenon of crossing hazard rates is common in clinical trials with time to event endpoints. Many methods have been proposed for testing equality of hazard functions against a crossing hazards alternative. However, there has been relatively few approaches available in the literature for point or interval estimation of the crossing time point. The problem of constructing confidence intervals for the first crossing time point of two hazard functions is considered in this paper. After reviewing a recent procedure based on Cox proportional hazard modeling with Box-Cox transformation of the time to event, a nonparametric procedure using the kernel smoothing estimate of the hazard ratio is proposed. The proposed procedure and the one based on Cox proportional hazard modeling with Box-Cox transformation of the time to event are both evaluated by Monte-Carlo simulations and applied to two clinical trial datasets.

Cyclo-oxygenase-2 contributes to constitutive prostanoid production in rat kidney and brain

PubMed Central

2005-01-01

Cyclo-oxygenases (COXs) catalyse the synthesis of PGH2 (prostaglandin H2), which serves as the common substrate for the production of PGE2, PGD2, PGF2α, prostacyclin (or PGI2) and TXs (thromboxanes). While COX-1 is the major isoform responsible for prostanoid synthesis in healthy tissues, little information is available on the contribution of constitutive COX-2 to the various prostanoid synthetic pathways under non-inflammatory conditions. To evaluate further the role of COX-2 in prostanoid biosynthesis, rats were acutely treated with the selective COX-1 inhibitor SC-560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] or the selective COX-2 inhibitors MF tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulphonyl)phenyl)-2-(5H)-furanone] and DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2-(5H)-furanone]. Selected tissues were then processed for a complete analysis of their prostanoid content by liquid chromatography MS. Whereas the treatment with SC-560 caused a 60–70% inhibition in the total prostanoid content of most tissues examined, a significant decrease (35–50%) in total prostanoid content following selective COX-2 inhibition was solely detected for kidney and brain tissues. Analysis of the individual prostanoids reveals significant inhibition of 6-oxo-PGF1α, PGE2, PGD2, PGF2α and TXB2 in the kidney and inhibition of all these prostanoids with the exception of PGD2 in the forebrain. These results demonstrate that constitutively expressed COX-2 contributes to the production of prostanoids in kidney and brain for each of the PGE2, PGI2 and TXB2 pathways under non-inflammatory conditions. Approaches to modulate inflammation through specific inhibition of terminal synthases, such as mPGES-1 (microsomal PGE2 synthase-1), thus have the potential to differ from COX-2 inhibitors and non-selective non-steroidal anti-inflammatory drugs with regard to effects on constitutive prostanoid synthesis and on renal function. PMID:16008526

Public injury prevention system in the Italian manufacturing sector: What types of inspection are more effective?

PubMed

Farina, Elena; Bena, Antonella; Fedeli, Ugo; Mastrangelo, Giuseppe; Veronese, Michela; Agnesi, Roberto

2016-04-01

Literature suggests that more research is needed to clarify the effect of workplace inspections by governmental officers on injury rates. This paper aims to compare comprehensive and partial inspections in Italian manufacturing companies. Survival analysis was applied to the period free from injuries following inspection by means of the Kaplan-Meier method and of Cox models. Kaplan-Meier curves show that, compared to companies with a partial inspection, companies which had a comprehensive inspection had a higher survival through the entire period. Adjusting for confounders, the Cox model confirms a significant preventive effect of comprehensive inspection for companies with 10-30 employees, but not for those with >30 employees. The results suggest that the effect on injuries is greater if all aspects of safety are addressed during the inspection instead of focusing on a single aspect. These findings are interesting because they can help in planning effective prevention activities. © 2016 Wiley Periodicals, Inc.

CoMFA, LeapFrog and blind docking studies on sulfonanilide derivatives acting as selective aromatase expression regulators.

PubMed

Gueto, Carlos; Torres, Juan; Vivas-Reyes, Ricardo

2009-09-01

Aromatase, the enzyme responsible for estrogen biosynthesis, is an attractive target in the treatment of hormone-dependent breast cancer. In this manuscript, the structure-based drug design approach of sulfonanilide analogues as potential selective aromatase expression regulators (SAERs) is described. Receptor-independent CoMFA (Comparative Molecular Field Analysis) maps were employed for generating a pseudocavity for LeapFrog calculation. A robust model, using 45 and 10 molecules in the training and test sets, respectively, was developed producing statistically significant results with cross-validated and conventional correlation coefficients of 0.656 and 0.956, respectively. This model was used to predict the activity of newly proposed molecules as SAERs candidates being two magnitude orders more potent than the previously reported compounds. Also in the present study, the computational blind docking method using eHiTS is tested on molecules study group and COX-2 enzyme. Future perspectives of the method in the screening of SAERs candidates with no COX-2 inhibitory activity are discussed.

Box-Cox transformation for QTL mapping.

PubMed

Yang, Runqing; Yi, Nengjun; Xu, Shizhong

2006-01-01

The maximum likelihood method of QTL mapping assumes that the phenotypic values of a quantitative trait follow a normal distribution. If the assumption is violated, some forms of transformation should be taken to make the assumption approximately true. The Box-Cox transformation is a general transformation method which can be applied to many different types of data. The flexibility of the Box-Cox transformation is due to a variable, called transformation factor, appearing in the Box-Cox formula. We developed a maximum likelihood method that treats the transformation factor as an unknown parameter, which is estimated from the data simultaneously along with the QTL parameters. The method makes an objective choice of data transformation and thus can be applied to QTL analysis for many different types of data. Simulation studies show that (1) Box-Cox transformation can substantially increase the power of QTL detection; (2) Box-Cox transformation can replace some specialized transformation methods that are commonly used in QTL mapping; and (3) applying the Box-Cox transformation to data already normally distributed does not harm the result.

Assessment of trend and seasonality in road accident data: an Iranian case study.

PubMed

Razzaghi, Alireza; Bahrampour, Abbas; Baneshi, Mohammad Reza; Zolala, Farzaneh

2013-06-01

Road traffic accidents and their related deaths have become a major concern, particularly in developing countries. Iran has adopted a series of policies and interventions to control the high number of accidents occurring over the past few years. In this study we used a time series model to understand the trend of accidents, and ascertain the viability of applying ARIMA models on data from Taybad city. This study is a cross-sectional study. We used data from accidents occurring in Taybad between 2007 and 2011. We obtained the data from the Ministry of Health (MOH) and used the time series method with a time lag of one month. After plotting the trend, non-stationary data in mean and variance were removed using Box-Cox transformation and a differencing method respectively. The ACF and PACF plots were used to control the stationary situation. The traffic accidents in our study had an increasing trend over the five years of study. Based on ACF and PACF plots gained after applying Box-Cox transformation and differencing, data did not fit to a time series model. Therefore, neither ARIMA model nor seasonality were observed. Traffic accidents in Taybad have an upward trend. In addition, we expected either the AR model, MA model or ARIMA model to have a seasonal trend, yet this was not observed in this analysis. Several reasons may have contributed to this situation, such as uncertainty of the quality of data, weather changes, and behavioural factors that are not taken into account by time series analysis.

Estimation of variance in Cox's regression model with shared gamma frailties.

PubMed

Andersen, P K; Klein, J P; Knudsen, K M; Tabanera y Palacios, R

1997-12-01

The Cox regression model with a shared frailty factor allows for unobserved heterogeneity or for statistical dependence between the observed survival times. Estimation in this model when the frailties are assumed to follow a gamma distribution is reviewed, and we address the problem of obtaining variance estimates for regression coefficients, frailty parameter, and cumulative baseline hazards using the observed nonparametric information matrix. A number of examples are given comparing this approach with fully parametric inference in models with piecewise constant baseline hazards.

Simultaneous confidence bands for Cox regression from semiparametric random censorship.

PubMed

Mondal, Shoubhik; Subramanian, Sundarraman

2016-01-01

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

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

PubMed

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

2015-12-01

We recently reported the synthesis of NOSH-aspirin, a novel hybrid that releases both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e. ortho-NOSH-aspirin (o-NOSH-aspirin). In the present study, we compared the effects of the positional isomers of NOSH-ASA (o-NOSH-aspirin, m-NOSH-aspirin and p-NOSH-aspirin) to that of aspirin on growth of HT-29 and HCT 15 colon cancer cells, belonging to the same histological subtype, but with different expression of cyclooxygenase (COX) enzymes; HT-29 express both COX-1 and COX-2, whereas HCT 15 is COX-null. We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells. Since the parent compound aspirin, inhibits both COX-1 and COX-2, we also evaluated the effects of these compounds on COX-1 and COX-2 enzyme activities and also performed modeling of the interactions between the positional isomers of NOSH-aspirin and COX-1 and COX-2 enzymes. We observed that the three positional isomers of NOSH aspirin inhibited the growth of both colon cancer cell lines with IC50s in the nano-molar range. In particular in HT-29 cells the IC50s for growth inhibition were: o-NOSH-ASA, 0.04±0.011 µM; m-NOSH-ASA, 0.24±0.11 µM; p-NOSH-ASA, 0.46±0.17 µM; and in HCT 15 cells the IC50s for o-NOSH-ASA, m-NOSH-ASA, and p-NOSH-ASA were 0.062 ±0.006 µM, 0.092±0.004 µM, and 0.37±0.04 µM, respectively. The IC50 for aspirin in both cell lines was >5mM at 24h. The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis. All 3 positional isomers of NOSH-aspirin preferentially inhibited COX-1 over COX-2. These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Mutational analysis of the Saccharomyces cerevisiae cytochrome c oxidase assembly protein Cox11p.

PubMed

Banting, Graham S; Glerum, D Moira

2006-03-01

Cox11p is an integral protein of the inner mitochondrial membrane that is essential for cytochrome c oxidase assembly. The bulk of the protein is located in the intermembrane space and displays high levels of evolutionary conservation. We have analyzed a collection of site-directed and random cox11 mutants in an effort to further define essential portions of the molecule. Of the alleles studied, more than half had no apparent effect on Cox11p function. Among the respiration deficiency-encoding alleles, we identified three distinct phenotypes, which included a set of mutants with a misassembled or partially assembled cytochrome oxidase, as indicated by a blue-shifted cytochrome aa(3) peak. In addition to the shifted spectral signal, these mutants also display a specific reduction in the levels of subunit 1 (Cox1p). Two of these mutations are likely to occlude a surface pocket behind the copper-binding domain in Cox11p, based on analogy with the Sinorhizobium meliloti Cox11 solution structure, thereby suggesting that this pocket is crucial for Cox11p function. Sequential deletions of the matrix portion of Cox11p suggest that this domain is not functional beyond the residues involved in mitochondrial targeting and membrane insertion. In addition, our studies indicate that Deltacox11, like Deltasco1, displays a specific hypersensitivity to hydrogen peroxide. Our studies provide the first evidence at the level of the cytochrome oxidase holoenzyme that Cox1p is the in vivo target for Cox11p and suggest that Cox11p may also have a role in the response to hydrogen peroxide exposure.

Comparative analysis of COX-2, vascular endothelial growth factor and microvessel density in human renal cell carcinomas.

PubMed

Hemmerlein, B; Galuschka, L; Putzer, N; Zischkau, S; Heuser, M

2004-12-01

Cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) are frequently up-regulated in malignant tumours and play a role in proliferation, apoptosis, angiogenesis and tumour invasion. In the present study, the expression of COX-2 and VEGF in renal cell carcinoma (RCC) was analysed and correlated with the microvessel density (MVD). COX-2 and VEGF were analysed by realtime reverse transcriptase-polymerase chain reaction and immunohistochemistry. The MVD was assessed by CD31 immunohistochemistry. The expression of COX-2 and VEGF was determined in the RCC cell lines A498 and Caki-1 under short-term hypoxia and in multicellular tumour cell aggregates. COX-2 was expressed in RCC by tumour epithelia, endothelia and macrophages in areas of cystic tumour regression and tumour necrosis. COX-2 protein in RCC was not altered in comparison with normal renal tissue. VEGF mRNA was up-regulated in RCC and positively correlated with MVD. RCC with high up-regulation of VEGF mRNA showed weak intracytoplasmic expression of VEGF in tumour cells. Intracytoplasmic VEGF protein expression was negatively correlated with MVD. In RCC with necrosis the MVD was reduced in comparison with RCC without necrosis. A498 RCC cells down-regulated COX-2 and up-regulated VEGF under conditions of hypoxia. In Caki-1 cells COX-2 expression remained stable, whereas VEGF was significantly up-regulated. In multicellular A498 cell aggregates COX-2 and VEGF were up-regulated centrally, whereas no gradient was found in Caki-1 cells. COX-2 and VEGF are potential therapeutic targets because COX-2 and VEGF are expressed in RCC and associated cell populations such as endothelia and monocytes/macrophages.

ASP6537, a novel highly selective cyclooxygenase-1 inhibitor, exerts potent antithrombotic effect without "aspirin dilemma".

PubMed

Sakata, Chinatsu; Kawasaki, Tomihisa; Kato, Yasuko; Abe, Masaki; Suzuki, Ken-ichi; Ohmiya, Makoto; Funatsu, Toshiyuki; Morita, Yoshiaki; Okada, Masamichi

2013-07-01

Aspirin inhibits both the cyclooxygenase (COX)-1-dependent production of thromboxane A2 (TXA2) in platelets and COX-2-dependent production of anti-aggregatory prostaglandin I2 (PGI2) in vessel walls, resulting in "aspirin dilemma." Our objective is to investigate whether ASP6537 can overcome aspirin dilemma and exert a potent antithrombotic effect without a concurrent ulcerogenic effect. We evaluated the inhibitory effects of ASP6537 on recombinant human COX-1 (rhCOX-1) and rhCOX-2 activities using a COX-1/2 selectivity test. To determine whether ASP6537 induces aspirin dilemma, we examined the effects of ASP6537 on in vitro TXA2 and PGI2 metabolite production from platelets and isolated aorta of guinea pigs, and on plasma concentrations of TXA2 and PGI2 metabolites in aged rats. Finally, we evaluated the antithrombotic effects and ulcerogenic activity of ASP6537 using an electrically induced carotid arterial thrombosis model and a gastric ulcer model in guinea pigs. The IC50 ratios of rhCOX-2 to rhCOX-1 for ASP6537 and aspirin were >142,000 and 1.63 fold, respectively. ASP6537 inhibited TXA2 production more selectively than aspirin in in vitro and in vivo TXA2/PGI2 production studies. ASP6537 exerted a significant antithrombotic effect at ≥3 mg/kg, while aspirin tended to inhibit thrombosis at 300 mg/kg but it was not statistically significant. Further, ASP6537 did not induce ulcer formation at 100 mg/kg, whereas aspirin exhibited an ulcerogenic effect at doses of ≥100 mg/kg. ASP6537 functions as a highly selective COX-1 inhibitor with a superior ability to aspirin for normalizing TXA2/PGI2 balance, and exerts antithrombotic effect without ulcerogenic effect. Copyright © 2013 Elsevier Ltd. All rights reserved.

Virtual Dual inhibition of COX-2 / 5-LOX enzymes based on binding properties of alpha-amyrins, the anti-inflammatory compound as a promising anti-cancer drug.

PubMed

Ranjbar, Mohammad Mehdi; Assadolahi, Vahideh; Yazdani, Mohsen; Nikaein, Donya; Rashidieh, Behnam

2016-01-01

Hydro-alcoholic fruit extract of Cordia myxa was considerably effective on curing acute inflammation in mouse model. Previous studies suggested significant anti-inflammatory activities as well as potential anticancer agent of α-amyrins in seeds. Inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipooxygenase (5-LOX) is significant in cancer prevention and therapeutics although this inhibition with chemo-drugs has its own side-effects. It is shown that these enzymes pathways are related to several cancers including colon, breast and lung cancer. This study was conducted based on Cordia species' α-amyrins as a safer natural anti-cancer compound for inhibition of COX-2 and 5-LOX enzymes by molecular docking. The X-ray crystal structure of COX2 / 5-LOX enzymes and α-amyrins was retrieved and energetically minimized respectively. The binding site and surface of enzymes were detected. Docking studies were performed by AutoDock 4.2 using Lamarckian genetic algorithm (LGA). Finally drug likeness, molecular pharmacokinetic properties and toxicity of α-amyrins was calculated. Molecular Docking revealed hydrogen and hydrophobic interactions between α-amyrins with both active sites of COX-2 and 5-LOX enzymes. Interestingly, it covalently bonded to Fe cofactor of 5-LOX enzyme and chelated this molecule. Base on binding energies (∆G) α-amyrin has more inhibitory effects on 5-LOX (-10.45 Kcal/mol) than COX-2 (-8.02 Kcal/mol). Analysis of molecular pharmacokinetic parameters suggested that α-amyrins complied with most sets of Lipinski's rules, and so it could be a suitable ligand for docking studies. Eventually, bioactivity score showed α-amyrins possess considerable biological activities as nuclear receptor, enzyme inhibitor, GPCR and protease inhibitor ligand. These results clearly demonstrate that α-amyrins could act as potential highly selective COX-/5-LOX inhibitor. Also, it is a safe compound in comparison with classical non-steroidal anti-inflammatory drugs (NSAIDs) that are known as cancer preventive agents, since it is free of side effects on human body and it can be a promising drug for cancer therapeutics.

Virtual Dual inhibition of COX-2 / 5-LOX enzymes based on binding properties of alpha-amyrins, the anti-inflammatory compound as a promising anti-cancer drug

PubMed Central

Ranjbar, Mohammad Mehdi; Assadolahi, Vahideh; Yazdani, Mohsen; Nikaein, Donya; Rashidieh, Behnam

2016-01-01

Hydro-alcoholic fruit extract of Cordia myxa was considerably effective on curing acute inflammation in mouse model. Previous studies suggested significant anti-inflammatory activities as well as potential anticancer agent of α-amyrins in seeds. Inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipooxygenase (5-LOX) is significant in cancer prevention and therapeutics although this inhibition with chemo-drugs has its own side-effects. It is shown that these enzymes pathways are related to several cancers including colon, breast and lung cancer. This study was conducted based on Cordia species' α-amyrins as a safer natural anti-cancer compound for inhibition of COX-2 and 5-LOX enzymes by molecular docking. The X-ray crystal structure of COX2 / 5-LOX enzymes and α-amyrins was retrieved and energetically minimized respectively. The binding site and surface of enzymes were detected. Docking studies were performed by AutoDock 4.2 using Lamarckian genetic algorithm (LGA). Finally drug likeness, molecular pharmacokinetic properties and toxicity of α-amyrins was calculated. Molecular Docking revealed hydrogen and hydrophobic interactions between α-amyrins with both active sites of COX-2 and 5-LOX enzymes. Interestingly, it covalently bonded to Fe cofactor of 5-LOX enzyme and chelated this molecule. Base on binding energies (∆G) α-amyrin has more inhibitory effects on 5-LOX (-10.45 Kcal/mol) than COX-2 (-8.02 Kcal/mol). Analysis of molecular pharmacokinetic parameters suggested that α-amyrins complied with most sets of Lipinski's rules, and so it could be a suitable ligand for docking studies. Eventually, bioactivity score showed α-amyrins possess considerable biological activities as nuclear receptor, enzyme inhibitor, GPCR and protease inhibitor ligand. These results clearly demonstrate that α-amyrins could act as potential highly selective COX-/5-LOX inhibitor. Also, it is a safe compound in comparison with classical non-steroidal anti-inflammatory drugs (NSAIDs) that are known as cancer preventive agents, since it is free of side effects on human body and it can be a promising drug for cancer therapeutics. PMID:27231478

Involvement of COX-2 in nickel elution from a wire implanted subcutaneously in mice.

PubMed

Sato, Taiki; Kishimoto, Yu; Asakawa, Sanki; Mizuno, Natsumi; Hiratsuka, Masahiro; Hirasawa, Noriyasu

2016-07-01

Many types of medical alloys include nickel (Ni), and the elution of Ni ions from these materials causes toxicities and inflammation. We have previously reported that inflammation enhances Ni elution, although the molecular mechanisms underlying this effect remain unclear. In this study, we investigated how inflammatory responses enhanced Ni elution in a wire-implantation mouse model. Subcutaneous implantation of Ni wire induced the expression of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) mRNA in the surrounding tissues. Immunostaining analysis showed that cells expressing COX-2 were mainly fibroblast-like cells 8h after implantation of a Ni wire, but were mainly infiltrated leukocytes at 24h. NiCl2 induced the expression of COX-2 mRNA in primary fibroblasts, neutrophils, RAW 264 cells, and THP-1 cells, indicating that Ni ions can induce COX-2 expression in various types of cells. The elution of Ni ions from the implanted Ni wire at 8h was reduced by dexamethasone (Dex), indomethacin (Ind), or celecoxib (Cel) treatment. Ni wire implantation induced an increase in mRNA levels for anaerobic glycolytic pathway components glucose transporter 1 (GLUT1), hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 4 (MCT4); the expression of these genes was also inhibited by Dex, Ind, and Cel. In primary fibroblasts, the expression of these mRNAs and the production of lactate were induced by NiCl2 and further potentiated by PGE2. Furthermore, Ni wire-induced infiltration of inflammatory leukocytes was significantly reduced by Dex, Ind, or Cel. Depletion of neutrophils with a specific antibody caused reduction of both leukocyte infiltration and Ni elution. These results indicate that Ni ions eluted from wire induced COX-2 expression, which further promoted elution of Ni ions by increasing lactate production and leukocyte infiltration. Since COX inhibitors and Dex reduced the elution of Ni ions, these drugs may be useful for prevention of metal-related inflammation and allergy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

COX-2 expression in papillary thyroid carcinoma (PTC) in cytological material obtained by fine needle aspiration biopsy (FNAB)

PubMed Central

2011-01-01

Background COX-2 is an enzyme isoform that catalyses the formation of prostanoids from arachidonic acid. An increased COX-2 gene expression is believed to participate in carcinogenesis. Recent studies have shown that COX-2 up-regulation is associated with the development of numerous neoplasms, including skin, colorectal, breast, lung, stomach, pancreas and liver cancers. COX-2 products stimulate endothelial cell proliferation and their overexpression has been demonstrated to be involved in the mechanism of decreased resistance to apoptosis. Suppressed angiogenesis was found in experimental animal studies as a consequence of null mutation of COX-2 gene in mice. Despite the role of COX-2 expression remains a subject of numerous studies, its participation in carcinogenesis or the thyroid cancer progression remains unclear. Methods Twenty three (23) patients with cytological diagnosis of PTC were evaluated. After FNAB examination, the needle was washed out with a lysis buffer and the obtained material was used for COX-2 expression estimation. Total RNA was isolated (RNeasy Micro Kit), and RT reactions were performed. β-actin was used as endogenous control. Relative COX-2 expression was assessed in real-time PCR reactions by an ABI PRISM 7500 Sequence Detection System, using the ΔΔCT method. Results COX-2 gene expression was higher in patients with PTC, when compared to specimens from patients with non-toxic nodular goitre (NTG). Conclusions The preliminary results may indicate COX-2 role in thyroid cancer pathogenesis, however the observed variability in results among particular subjects requires additional clinical data and tumor progression analysis. PMID:21214962

COX-2 expression in papillary thyroid carcinoma (PTC) in cytological material obtained by fine needle aspiration biopsy (FNAB).

PubMed

Krawczyk-Rusiecka, Kinga; Wojciechowska-Durczyńska, Katarzyna; Cyniak-Magierska, Anna; Adamczewski, Zbigniew; Gałecka, Elżbieta; Lewiński, Andrzej

2011-01-10

COX-2 is an enzyme isoform that catalyses the formation of prostanoids from arachidonic acid. An increased COX-2 gene expression is believed to participate in carcinogenesis. Recent studies have shown that COX-2 up-regulation is associated with the development of numerous neoplasms, including skin, colorectal, breast, lung, stomach, pancreas and liver cancers. COX-2 products stimulate endothelial cell proliferation and their overexpression has been demonstrated to be involved in the mechanism of decreased resistance to apoptosis. Suppressed angiogenesis was found in experimental animal studies as a consequence of null mutation of COX-2 gene in mice. Despite the role of COX-2 expression remains a subject of numerous studies, its participation in carcinogenesis or the thyroid cancer progression remains unclear. Twenty three (23) patients with cytological diagnosis of PTC were evaluated. After FNAB examination, the needle was washed out with a lysis buffer and the obtained material was used for COX-2 expression estimation. Total RNA was isolated (RNeasy Micro Kit), and RT reactions were performed. β-actin was used as endogenous control. Relative COX-2 expression was assessed in real-time PCR reactions by an ABI PRISM 7500 Sequence Detection System, using the ΔΔCT method. COX-2 gene expression was higher in patients with PTC, when compared to specimens from patients with non-toxic nodular goitre (NTG). The preliminary results may indicate COX-2 role in thyroid cancer pathogenesis, however the observed variability in results among particular subjects requires additional clinical data and tumor progression analysis.

Essential oil of Artemisia argyi suppresses inflammatory responses by inhibiting JAK/STATs activation.

PubMed

Chen, Lin-Lin; Zhang, Hao-Jun; Chao, Jung; Liu, Jun-Feng

2017-05-23

Artemisia argyi is a herbal medicine traditionally used in Asia for the treatment of bronchitis, dermatitis and arthritis. Recent studies revealed the anti-inflammatory effect of essential oil in this plant. However, the mechanisms underlying the therapeutic potential have not been well elucidated. The present study is aimed to verify its anti-inflammatory effect and investigate the probable mechanisms. The essential oil from Artemisia argyi (AAEO) was initially tested against LPS-induced production of inflammatory mediators and cytokines in RAW264.7 macrophages. Protein and mRNA expressions of iNOS and COX-2 were determined by Western blotting and RT-PCR analysis, respectively. The effects on the activation of MAPK/NF-κB/AP-1 and JAK/STATs pathway were also investigated by western blot. Meanwhile, in vivo anti-inflammatory effect was examined by histologic and immunohistochemical analysis in TPA-induced mouse ear edema model. The results of in vitro experiments showed that AAEO dose-dependently suppressed the release of pro-inflammatory mediators (NO, PGE 2 and ROS) and cytokines (TNF-α, IL-6, IFN-β and MCP-1) in LPS-induced RAW264.7 macrophages. It down-regulated iNOS and COX-2 protein and mRNA expression but did not affect the activity of these two enzymes. AAEO significantly inhibited the phosphorylation of JAK2 and STAT1/3, but not the activation of MAPK and NF-κB cascades. In animal model, oral administration of AAEO significantly attenuated TPA-induced mouse ear edema and decreased the protein level of COX-2. AAEO suppresses inflammatory responses via down-regulation of the JAK/STATs signaling and ROS scavenging, which could contribute, at least in part, to the anti-inflammatory effect of AAEO. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

COX2 Inhibition Reduces Aortic Valve Calcification In Vivo

PubMed Central

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

2016-01-01

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

Mining gene link information for survival pathway hunting.

PubMed

Jing, Gao-Jian; Zhang, Zirui; Wang, Hong-Qiang; Zheng, Hong-Mei

2015-08-01

This study proposes a gene link-based method for survival time-related pathway hunting. In this method, the authors incorporate gene link information to estimate how a pathway is associated with cancer patient's survival time. Specifically, a gene link-based Cox proportional hazard model (Link-Cox) is established, in which two linked genes are considered together to represent a link variable and the association of the link with survival time is assessed using Cox proportional hazard model. On the basis of the Link-Cox model, the authors formulate a new statistic for measuring the association of a pathway with survival time of cancer patients, referred to as pathway survival score (PSS), by summarising survival significance over all the gene links in the pathway, and devise a permutation test to test the significance of an observed PSS. To evaluate the proposed method, the authors applied it to simulation data and two publicly available real-world gene expression data sets. Extensive comparisons with previous methods show the effectiveness and efficiency of the proposed method for survival pathway hunting.

Expectation Maximization Algorithm for Box-Cox Transformation Cure Rate Model and Assessment of Model Misspecification Under Weibull Lifetimes.

PubMed

Pal, Suvra; Balakrishnan, Narayanaswamy

2018-05-01

In this paper, we develop likelihood inference based on the expectation maximization algorithm for the Box-Cox transformation cure rate model assuming the lifetimes to follow a Weibull distribution. A simulation study is carried out to demonstrate the performance of the proposed estimation method. Through Monte Carlo simulations, we also study the effect of model misspecification on the estimate of cure rate. Finally, we analyze a well-known data on melanoma with the model and the inferential method developed here.

Albumin-induced podocyte injury and protection are associated with regulation of COX-2.

PubMed Central

Agrawal, Shipra; Guess, Adam J.; Chanley, Melinda A.; Smoyer, and William E.

2014-01-01

Albuminuria is both a hallmark and a risk factor for progressive glomerular disease, and results in increased exposure of podocytes to serum albumin with its associated factors. Here in vivo and in vitro models of serum albumin overload were used to test the hypothesis that albumin-induced proteinuria and podocyte injury directly correlate with COX-2 induction. Albumin induced COX-2, MCP-1, CXCL1 and the stress protein HSP25 in both rat glomeruli and cultured podocytes, while B7-1 and HSP70i were also induced in podocytes. Podocyte exposure to albumin induced both mRNA and protein and enhanced the mRNA stability of COX-2, a key regulator of renal hemodynamics and inflammation, which renders podocytes susceptible to injury. Podocyte exposure to albumin also stimulated several kinases (p38 MAPK, MK2, JNK/SAPK and ERK1/2), inhibitors of which (except JNK/SAPK) down-regulated albumin-induced COX-2. Inhibition of AMPK, PKC and NFκB also down-regulated albumin-induced COX-2. Critically, albumin-induced COX-2 was also inhibited by glucocorticoids and thiazolidinediones, both of which directly protect podocytes against injury. Furthermore, specific albumin-associated fatty acids were identified as important contributors to COX-2 induction, podocyte injury and proteinuria. Thus, COX-2 is associated with podocyte injury during albuminuria, as well as with the known podocyte protection imparted by glucocorticoids and thiazolidinediones. Moreover, COX-2 induction, podocyte damage and albuminuria appear mediated largely by serum albumin-associated fatty acids. PMID:24918154

ELASTIC NET FOR COX'S PROPORTIONAL HAZARDS MODEL WITH A SOLUTION PATH ALGORITHM.

PubMed

Wu, Yichao

2012-01-01

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.

The structure of DSM-IV-TR personality disorder diagnoses in NESARC: a reanalysis.

PubMed

Trull, Timothy J; Vergés, Alvaro; Wood, Phillip K; Sher, Kenneth J

2013-12-01

Cox, Clara, Worobec, and Grant (2012) recently presented results from a series of analyses aimed at identifying the factor structure underlying the DSM-IV-TR (APA, 2000) personality diagnoses assessed in the large NESARC study. Cox et al. (2012) concluded that the best fitting model was one that modeled three lower-order factors (the three clusters of PDs as outlined by DSM-IV-TR), which in turn loaded on a single PD higher-order factor. Our reanalyses of the NESARC Wave 1 and Wave 2 data for personality disorder diagnoses revealed that the best fitting model was that of a general PD factor that spans each of the ten DSM-IV PD diagnoses, and our reanalyses do not support the three-cluster hierarchical structure outlined by Cox et al. (2012) and DSM-IV-TR. Finally, we note the importance of modeling the Wave 2 assessment method factor in analyses of NESARC PD data.

Increased risk of incident stroke associated with the cyclooxygenase 2 (COX-2) G-765C polymorphism in African-Americans: the Atherosclerosis Risk in Communities Study.

PubMed

Kohsaka, Shun; Volcik, Kelly A; Folsom, Aaron R; Wu, Kenneth K; Ballantyne, Christie M; Willerson, James T; Boerwinkle, Eric

2008-02-01

A hallmark feature of atherosclerosis is inflammation mediated by prostaglandins (PGs) catalyzed by the enzyme cyclooxygenase (COX). The present study explored whether the COX-2 G-765C polymorphism contributes to increased incidence of coronary heart disease (CHD) or stroke in the large prospective Atherosclerosis Risk in Communities (ARIC) Study. Incidences of CHD and stroke were identified through annual follow-up and hospital and death certificate surveillance. The study included 1488 incident CHD and 527 stroke events after an average of 14 years of follow-up. The frequency of the -765C variant allele was markedly different between African-Americans and whites, therefore all analyses were performed separately by race. Due to the small number of persons with the -765CC genotype, heterozygous and homozygous variant genotypes were combined for this analysis. The COX-2 G-765C polymorphism was not a significant predictor of CHD in either racial group, but it was a significant predictor of incident stroke in African-Americans. After adjustment for age and gender, the hazard rate ratio for developing stroke for the CG+CC genotypes relative to the GG genotype was 1.34 (95% confidence interval [CI] 1.03-1.74, P=0.03) in African-Americans. This result was essentially unchanged when established predictors such as smoking, diabetes and hypertension were added to the model (HRR 1.34, 95%CI 1.03-1.76, P=0.03). We have found the COX-2 G-765C polymorphism to be a risk factor for incident stroke in African-Americans. This study provides additional evidence for utilizing inflammation-related genetic polymorphisms for identifying individuals at increased risk for stroke.

Cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs and the risk of myocardial infarction and cerebrovascular accident.

PubMed

Abraham, N S; El-Serag, H B; Hartman, C; Richardson, P; Deswal, A

2007-04-15

To assess degree of cyclooxygenase-2 (COX-2) selectivity of a non-steroidal anti-inflammatory drug (NSAID) and risk of myocardial infarction (MI) or cerebrovascular accident (CVA). Prescription fill data were linked to medical records of a merged VA-Medicare dataset. NSAIDs were categorized by Cox-2 selectivity. Incidence of CVA and MI within 180 days of index prescription was assessed using Cox-proportional hazards models adjusted for gender, race, cardiovascular and pharmacological risk factors and propensity for prescription of highly COX-2 selective NSAIDs. Of 384,322 patients (97.5% men and 85.4% white), 79.4% were prescribed a poorly selective, 16.4% a moderately selective and 4.2% a highly selective NSAID. There were 985 incident cases of MI and 586 cases of CVA in >145 870 person-years. Highly selective agents had the highest rate of MI (12.3 per 1000 person-years; [95% CI: 12.2-12.3]) and CVA (8.1 per 1000 person-years; [95% CI: 8.0-8.2]). Periods without NSAID exposure were associated with lowest risk. In adjusted models, highly selective COX-2 selective NSAIDs were associated with a 61% increase in CVA and a 47% increase in MI, when compared with poorly selective NSAIDs. The risk of MI and CVA increases with any NSAID. Highly COX-2 selective NSAIDs confer the greatest risk.

A generalized multivariate regression model for modelling ocean wave heights

NASA Astrophysics Data System (ADS)

Wang, X. L.; Feng, Y.; Swail, V. R.

2012-04-01

In this study, a generalized multivariate linear regression model is developed to represent the relationship between 6-hourly ocean significant wave heights (Hs) and the corresponding 6-hourly mean sea level pressure (MSLP) fields. The model is calibrated using the ERA-Interim reanalysis of Hs and MSLP fields for 1981-2000, and is validated using the ERA-Interim reanalysis for 2001-2010 and ERA40 reanalysis of Hs and MSLP for 1958-2001. The performance of the fitted model is evaluated in terms of Pierce skill score, frequency bias index, and correlation skill score. Being not normally distributed, wave heights are subjected to a data adaptive Box-Cox transformation before being used in the model fitting. Also, since 6-hourly data are being modelled, lag-1 autocorrelation must be and is accounted for. The models with and without Box-Cox transformation, and with and without accounting for autocorrelation, are inter-compared in terms of their prediction skills. The fitted MSLP-Hs relationship is then used to reconstruct historical wave height climate from the 6-hourly MSLP fields taken from the Twentieth Century Reanalysis (20CR, Compo et al. 2011), and to project possible future wave height climates using CMIP5 model simulations of MSLP fields. The reconstructed and projected wave heights, both seasonal means and maxima, are subject to a trend analysis that allows for non-linear (polynomial) trends.

Quality Reporting of Multivariable Regression Models in Observational Studies: Review of a Representative Sample of Articles Published in Biomedical Journals.

PubMed

Real, Jordi; Forné, Carles; Roso-Llorach, Albert; Martínez-Sánchez, Jose M

2016-05-01

Controlling for confounders is a crucial step in analytical observational studies, and multivariable models are widely used as statistical adjustment techniques. However, the validation of the assumptions of the multivariable regression models (MRMs) should be made clear in scientific reporting. The objective of this study is to review the quality of statistical reporting of the most commonly used MRMs (logistic, linear, and Cox regression) that were applied in analytical observational studies published between 2003 and 2014 by journals indexed in MEDLINE.Review of a representative sample of articles indexed in MEDLINE (n = 428) with observational design and use of MRMs (logistic, linear, and Cox regression). We assessed the quality of reporting about: model assumptions and goodness-of-fit, interactions, sensitivity analysis, crude and adjusted effect estimate, and specification of more than 1 adjusted model.The tests of underlying assumptions or goodness-of-fit of the MRMs used were described in 26.2% (95% CI: 22.0-30.3) of the articles and 18.5% (95% CI: 14.8-22.1) reported the interaction analysis. Reporting of all items assessed was higher in articles published in journals with a higher impact factor.A low percentage of articles indexed in MEDLINE that used multivariable techniques provided information demonstrating rigorous application of the model selected as an adjustment method. Given the importance of these methods to the final results and conclusions of observational studies, greater rigor is required in reporting the use of MRMs in the scientific literature.

Prostanoid receptor EP2 as a therapeutic target.

PubMed

Ganesh, Thota

2014-06-12

Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small molecule discovery targeted either to enhance or to block the function of this receptor.

Early increased density of cyclooxygenase-2 (COX-2) immunoreactive neurons in Down syndrome.

PubMed

Mulet, Maria; Blasco-Ibáńez, José Miguel; Crespo, Carlos; Nácher, Juan; Varea, Emilio

2017-01-01

Neuroinflammation is one of the hallmarks of Alzheimer's disease. One of the enzymes involved in neuroinflammation, even in early stages of the disease, is COX-2, an inducible cyclooxygenase responsible for the generation of eicosanoids and for the generation of free radicals. Individuals with Down syndrome develop Alzheimer's disease early in life. Previous studies pointed to the possible overexpression of COX-2 and correlated it to brain regions affected by the disease. We analysed the COX-2 expression levels in individuals with Down syndrome and in young, adult and old mice of the Ts65Dn mouse model for Down syndrome. We have observed an overexpression of COX-2 in both, Down syndrome individuals and mice. Importantly, mice already presented an overexpression of COX-2 at postnatal day 30, before neurodegeneration begins; which suggests that neuroinflammation may underlie the posterior neurodegeneration observed in individuals with Down syndrome and in Ts65Dn mice and could be a factor for the premature appearance of Alzheimer's disease..

RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism.

PubMed

Aslanukov, Azamat; Bhowmick, Reshma; Guruju, Mallikarjuna; Oswald, John; Raz, Dorit; Bush, Ronald A; Sieving, Paul A; Lu, Xinrong; Bock, Cheryl B; Ferreira, Paulo A

2006-10-01

The Ran-binding protein 2 (RanBP2) is a large multimodular and pleiotropic protein. Several molecular partners with distinct functions interacting specifically with selective modules of RanBP2 have been identified. Yet, the significance of these interactions with RanBP2 and the genetic and physiological role(s) of RanBP2 in a whole-animal model remain elusive. Here, we report the identification of two novel partners of RanBP2 and a novel physiological role of RanBP2 in a mouse model. RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI) via its leucine-rich domain. The leucine-rich domain of RanBP2 also exhibits strong chaperone activity toward intermediate and mature folding species of Cox11 supporting a chaperone role of RanBP2 in the cytosol during Cox11 biogenesis. Cox11 partially colocalizes with HKI, thus supporting additional and distinct roles in cell function. Cox11 is a strong inhibitor of HKI, and RanBP2 suppresses the inhibitory activity of Cox11 over HKI. To probe the physiological role of RanBP2 and its role in HKI function, a mouse model harboring a genetically disrupted RanBP2 locus was generated. RanBP2(-/-) are embryonically lethal, and haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system. Inbred RanBP2(+/-) mice also exhibit deficits in growth rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis. These phenotypes are accompanied by a decrease in the electrophysiological responses of photosensory and postreceptoral neurons. Hence, RanBP2 and its partners emerge as critical modulators of neuronal HKI, glucose catabolism, energy homeostasis, and targets for metabolic, aging disorders and allied neuropathies.

New Coumarin Derivatives as Potent Selective COX-2 Inhibitors: Synthesis, Anti-Inflammatory, QSAR, and Molecular Modeling Studies.

PubMed

Dawood, Dina H; Batran, Rasha Z; Farghaly, Thoraya A; Khedr, Mohammed A; Abdulla, Mohamed M

2015-12-01

Two new series of coumarin derivatives incorporating thiazoline and thiazolidinone moieties were designed, synthesized, and investigated in vivo for their anti-inflammatory activities using the carrageenan-induced rat paw edema model and in vitro for their inhibitory activities against the human cyclooxygenase (COX)-1 and COX-2 isoforms. Most of the synthesized compounds demonstrated exceptionally high in vivo anti-inflammatory activity and displayed superior GI safety profiles (0-7% ulceration) as compared to indomethacin. All the bioactive compounds showed in vitro high affinity and selectivity toward the COX-2 isoenzyme, compared to the reference celecoxib with IC50 values ranging from 0.31 to 0.78 μM. The ethyl thiosemicarbazone 2b, thiazoline derivatives 3a, 3b, 5b, 6a, and 7f, and the thiazolidinone compounds 8b and 9a showed the highest in vivo and in vitro anti-inflammatory activities with remarkable COX-2 selectivity. Quantitative structure-activity relationship study (QSAR) was done and resulted in a highly predictive power R(2) (0.908). A molecular docking study revealed a relationship between the docking affinity and the biological results. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cyclo-oxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer.

PubMed

Costa, C; Soares, R; Reis-Filho, J S; Leitão, D; Amendoeira, I; Schmitt, F C

2002-06-01

Cyclo-oxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin biosynthesis. COX-2 is induced by a wide variety of stimuli, and present during inflammation. COX-2 overexpression has been observed in colon, head and neck, lung, prostate, stomach, and breast cancer. In colon and gastric cancer, COX-2 expression was associated with angiogenesis. The aim of this study was to determine the relation between COX-2 expression and angiogenesis in breast cancer, and to correlate the expression of this enzyme with classic clinicopathological parameters. COX-2 expression was investigated by immunohistochemistry and western blotting analysis. The expression of COX-2 was then related to age, histological grade, nodal status, oestrogen receptor status, p53 expression,c-erb-B2 overexpression, mitotic counts, MIB-1 labelling index, apoptotic index, sialyl-Tn expression, transforming growth factor alpha expression, microvessel density, and disease free survival in 46 patients with invasive ductal breast carcinoma. By means of immunohistochemistry, COX-2 expression was detected in eight of the 46 carcinomas studied. Western blotting showed COX-2 protein expression in the same breast tumours, but not in normal adjacent tissues. The density of microvessels immunostained with anti-F-VIII related antigen was significantly higher in patients with COX-2 expression than in those without expression (p = 0.03). In addition, COX-2 was significantly associated with the presence of sialyl-Tn expression (p = 0.02), lymph node metastasis (p = 0.03), a high apoptotic index (p = 0.03), and a short disease free survival (p = 0.03) in univariate analyses. These data suggest that COX-2 expression is associated with angiogenesis, lymph node metastasis, and apoptosis in human breast cancer. Moreover, these results warrant further studies with larger series of patients to confirm the association with short disease free survival in patients with breast cancer.

Survival in Adult Lung Transplant Recipients Receiving Pediatric Versus Adult Donor Allografts.

PubMed

Hayes, Don; Whitson, Bryan A; Ghadiali, Samir N; Lloyd, Eric A; Tobias, Joseph D; Mansour, Heidi M; Black, Sylvester M

2015-10-01

Recent evidence showed that pediatric donor lungs increased rates of allograft failure in adult lung transplant recipients; however, the influence on survival is unclear. The United Network for Organ Sharing (UNOS) database was queried from 2005 to 2013 for adult lung transplant recipients (≥18 years) to assess survival differences among donor age categories (<18 years, 18 to 29 years, 30 to 59 years, ≥60 years). Of 12,297 adult lung transplants, 12,209 were used for univariate Cox models and Kaplan-Meier (KM) analysis and 11,602 for multivariate Cox models. A total of 1,187 adult recipients received pediatric donor lungs compared with 11,110 receiving adult donor organs. Univariate and multivariate Cox models found no difference in survival between donor ages 0 to 17 and donor ages 18 to 29, whereas donor ages 60 and older were significantly associated with increased mortality hazard, relative to the modal category of donor ages 30 to 59 (adjusted hazard ratio = 1.381; 95% confidence interval = 1.188% to 1.606%; p < 0.001). Interactions between recipient and donor age range found that the oldest donor age range was negatively associated with survival among middle-aged (30 to 59) and older (≥60) lung transplant recipients. Pediatric donor lung allografts were not negatively associated with survival in adult lung transplant recipients; however, the oldest donor age range was associated with increased mortality hazard for adult lung transplant recipients. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Non-Steroidal Anti-Inflammatory Drugs and Cardiovascular Outcomes in Women: Results from the Women’s Health Initiative

PubMed Central

Bavry, Anthony A.; Thomas, Fridtjof; Allison, Matthew; Johnson, Karen C.; Howard, Barbara V.; Hlatky, Mark; Manson, JoAnn E.; Limacher, Marian C.

2014-01-01

Background Conclusive data regarding cardiovascular (CV) toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) are sparse. We hypothesized that regular NSAID use is associated with increased risk for CV events in post-menopausal women, and that this association is stronger with greater cyclooxygenase (cox)-2 compared with cox-1 inhibition. Methods and Results Post-menopausal women enrolled in the Women’s Health Initiative (WHI) were classified as regular users or non-users of non-aspirin NSAIDs. Cox regression examined NSAID use as a time-varying covariate and its association with the primary outcome of total CV disease defined as CV death, nonfatal myocardial infarction, or nonfatal stroke. Secondary analyses considered the association of selective cox-2 inhibitors (e.g., celecoxib), non-selective agents with cox-2>cox-1 inhibition (e.g., naproxen), and non-selective agents with cox-1>cox-2 inhibition (e.g., ibuprofen) with the primary outcome. Overall, 160,801 participants were available for analysis (mean follow-up 11.2 years). Regular NSAID use at some point in time was reported by 53,142 participants. Regular NSAID use was associated with an increased hazard for CV events versus no NSAID use (HR=1.10[95% CI 1.06–1.15], Pitalic>0.001). Selective cox-2 inhibitors were associated with a modest increased hazard for CV events (HR=1.13[1.04–1.23], P=0.004; celecoxib only HR=1.13[1.01–1.27], P=0.031). Among aspirin users, concomitant selective cox-2 inhibitor use was no longer associated with increased hazard for CV events. There was an increased risk for agents with cox-2>cox-1 inhibition (HR=1.17[1.10–1.24], Pbold>0.001; naproxen only HR=1.22[1.12–1.34], P<0.001). This harmful association remained among concomitant aspirin users. We did not observe a risk elevation for agents with cox-1>cox-2 inhibition (HR=1.01[0.95–1.07], P=0.884; ibuprofen only HR=1.00[0.93–1.07], P=0.996). Conclusions Regular use of selective cox-2 inhibitors and non-selective NSAIDs with cox-2>cox-1 inhibition showed a modestly increased hazard for CV events. Non-selective agents with cox-1>cox-2 inhibition were not associated with increased CV risk. Clinical Trial Registration www.clinicaltrials.gov NCT00000611 PMID:25006185

An appreciation of Richard Threlkeld Cox

NASA Astrophysics Data System (ADS)

Tribus, Myron

2002-05-01

Richard T. Cox's contributions to the foundations of probability theory and inductive logic are not generally appreciated or understood. This paper reviews his life and accomplishments, especially those in his book The Algebra of Probable Inference and his final publication Inference and Inquiry which, in this author's opinion, has the potential to influence in a significant way the design and analysis of self organizing systems which learn from experience. A simple application to the simulation of a neuron is presented as an example of the power of Cox's contribution.

Development of a five-year mortality model in systemic sclerosis patients by different analytical approaches.

PubMed

Beretta, Lorenzo; Santaniello, Alessandro; Cappiello, Francesca; Chawla, Nitesh V; Vonk, Madelon C; Carreira, Patricia E; Allanore, Yannick; Popa-Diaconu, D A; Cossu, Marta; Bertolotti, Francesca; Ferraccioli, Gianfranco; Mazzone, Antonino; Scorza, Raffaella

2010-01-01

Systemic sclerosis (SSc) is a multiorgan disease with high mortality rates. Several clinical features have been associated with poor survival in different populations of SSc patients, but no clear and reproducible prognostic model to assess individual survival prediction in scleroderma patients has ever been developed. We used Cox regression and three data mining-based classifiers (Naïve Bayes Classifier [NBC], Random Forests [RND-F] and logistic regression [Log-Reg]) to develop a robust and reproducible 5-year prognostic model. All the models were built and internally validated by means of 5-fold cross-validation on a population of 558 Italian SSc patients. Their predictive ability and capability of generalisation was then tested on an independent population of 356 patients recruited from 5 external centres and finally compared to the predictions made by two SSc domain experts on the same population. The NBC outperformed the Cox-based classifier and the other data mining algorithms after internal cross-validation (area under receiving operator characteristic curve, AUROC: NBC=0.759; RND-F=0.736; Log-Reg=0.754 and Cox= 0.724). The NBC had also a remarkable and better trade-off between sensitivity and specificity (e.g. Balanced accuracy, BA) than the Cox-based classifier, when tested on an independent population of SSc patients (BA: NBC=0.769, Cox=0.622). The NBC was also superior to domain experts in predicting 5-year survival in this population (AUROC=0.829 vs. AUROC=0.788 and BA=0.769 vs. BA=0.67). We provide a model to make consistent 5-year prognostic predictions in SSc patients. Its internal validity, as well as capability of generalisation and reduced uncertainty compared to human experts support its use at bedside. Available at: http://www.nd.edu/~nchawla/survival.xls.

IL1{beta}-mediated Stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Yingting, E-mail: yitizhu@yahoo.com; Tissue Tech Inc, Miami, FL 33173; Zhu, Min

2012-11-15

COX-2 is a major inflammatory mediator implicated in colorectal inflammation and cancer. However, the exact origin and role of COX-2 on colorectal inflammation and carcinogenesis are still not well defined. Recently, we reported that COX-2 and iNOS signalings interact in colonic CCD18Co fibroblasts. In this article, we investigated whether activation of COX-2 signaling by IL1{beta} in primary colonic fibroblasts obtained from normal and cancer patients play a critical role in regulation of proliferation and invasiveness of human colonic epithelial cancer cells. Our results demonstrated that COX-2 level was significantly higher in cancer associated fibroblasts than that in normal fibroblasts withmore » or without stimulation of IL-1{beta}, a powerful stimulator of COX-2. Using in vitro assays for estimating proliferative and invasive potential, we discovered that the proliferation and invasiveness of the epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts than with normal fibroblasts, with or without stimulation of IL1{beta}. Further analysis indicated that the major COX-2 product, prostaglandin E{sub 2}, directly enhanced proliferation and invasiveness of the epithelial cancer cells in the absence of fibroblasts. Moreover, a selective COX-2 inhibitor, NS-398, blocked the proliferative and invasive effect of both normal and cancer associate fibroblasts on the epithelial cancer cells, with or without stimulation of IL-1{beta}. Those results indicate that activation of COX-2 signaling in the fibroblasts plays a major role in promoting proliferation and invasiveness of the epithelial cancer cells. In this process, PKC is involved in the activation of COX-2 signaling induced by IL-1{beta} in the fibroblasts.« less

Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1.

PubMed

Ruud, Johan; Nilsson, Anna; Engström Ruud, Linda; Wang, Wenhua; Nilsberth, Camilla; Iresjö, Britt-Marie; Lundholm, Kent; Engblom, David; Blomqvist, Anders

2013-03-01

It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia-cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia-cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing mice was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE(2) levels in plasma - a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE(2)-levels in the cerebrospinal fluid. Neutralization of plasma PGE(2) with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1) affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP(4) receptors selectively in the nervous system developed anorexia. These observations suggest that COX-enzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE(2) and neuronal EP(4) signaling. Copyright © 2013 Elsevier Inc. All rights reserved.

Determination of Dietary Iron Requirements by Full Expression of Iron-Containing Enzymes in Various Tissues of Broilers.

PubMed

Ma, Xinyan; Liao, Xiudong; Lu, Lin; Li, Sufen; Zhang, Liyang; Luo, Xugang

2016-11-01

The current dietary iron requirement (80 mg/kg) of broilers is mainly based on growth, hemoglobin concentration, or hematocrit data obtained in a few early studies; however, expressions of iron-containing enzymes might be more sensitive novel criteria to evaluate dietary iron requirements. The objective of this study was to determine dietary iron requirements of broilers for the full expression of succinate dehydrogenase (SDH), catalase, and cytochrome c oxidase (COX) in various tissues. A total of 336 1-d-old Arbor Acres male chicks were randomly assigned to 1 of 7 treatments with 6 replicates and fed a basal corn and soybean-meal diet (control, containing 67 mg Fe/kg) and the basal diet supplemented with 20, 40, 60, 80, 100, or 120 mg Fe/kg from FeSO 4 ⋅ 7H 2 O for 21 d. Regression analysis was performed to estimate the optimal dietary iron concentration with the use of broken-line or quadratic models. SDH activity in the liver and heart, COX and catalase activity in the liver, Sdh mRNA levels in the liver, and Cox mRNA levels in the liver and heart of broilers were affected (P < 0.027) by supplemental iron concentration, and increased quadratically (P < 0.004) as dietary iron concentration increased. Dietary iron requirements estimated on the basis of fitted broken-line or quadratic-curve models (P < 0.005) of the above indexes were 97-136 mg/kg. SDH activity in the liver and heart, COX and catalase activity in the liver, Sdh mRNA levels in the liver, and Cox mRNA levels in the liver and heart are, to our knowledge, new and sensitive criteria to evaluate the dietary iron requirements of broilers, and the dietary iron requirements would be 97-136 mg/kg to support the full expression of the above iron-containing enzymes in various tissues of broiler chicks from 1 to 21 d of age, which are higher than the current NRC iron requirement. © 2016 American Society for Nutrition.

Maternal segmental disomy in Leigh syndrome with cytochrome c oxidase deficiency caused by homozygous SURF1 mutation.

PubMed

van Riesen, A K J; Antonicka, H; Ohlenbusch, A; Shoubridge, E A; Wilichowski, E K G

2006-04-01

Cytochrome c oxidase deficiency (COX) is the most frequent cause of Leigh syndrome (LS), a mitochondrial subacute necrotizing encephalomyelopathy. Most of these LS (COX-) patients show mutations in SURF1 on chromosome 9 (9q34), which encodes a protein essential for the assembly of the COX complex. We describe a family whose first-born boy developed characteristic features of LS. Severe COX deficiency in muscle was caused by a novel homozygous nonsense mutation in SURF1. Segregation analysis of this mutation in the family was incompatible with autosomal recessive inheritance but consistent with a maternal disomy. Haplotype analysis of microsatellite markers confirmed isodisomy involving nearly the complete long arm of chromosome 9 (9q21-9tel). No additional physical abnormalities were present in the boy, suggesting that there are no imprinted genes on the long arm of chromosome 9 which are crucial for developmental processes. This case of segmental isodisomy illustrates that genotyping of parents is crucial for correct genetic counseling.

Molecular docking, molecular modeling, and molecular dynamics studies of azaisoflavone as dual COX-2 inhibitors and TP receptor antagonists.

PubMed

Hadianawala, Murtuza; Mahapatra, Amarjyoti Das; Yadav, Jitender K; Datta, Bhaskar

2018-02-26

Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques. Flavonoids were selected as a starting point based on their known COX-2 inhibitory and TP receptor antagonist activity. Iterative design and docking studies resulted in the evolution of a new class scaffold replacing the benzopyran-4-one ring of flavonoids with quinolin-4-one. The docking and binding parameters of these new compounds are found to be promising in comparison to those of selective COX-2 inhibitors, such as SC-558 and celecoxib. Owing to the lack of structural information, a model for the TP receptor was generated using a threading base alignment method with loop optimization performed using an ab initio method. The model generated was validated against known antagonists for TP receptor using docking/MMGBSA. Finally, the molecules that were designed for selective COX-2 inhibition were docked into the active site of the TP receptor. Iterative structural modifications and docking on these molecules generated a series which displays optimum docking scores and binding interaction for both targets. Molecular dynamics studies on a known TP receptor antagonist and a designed molecule show that both molecules remain in contact with protein throughout the simulation and interact in similar binding modes. Graphical abstract ᅟ.

Targeted Deletions of COX-2 and Atherogenesis in Mice

PubMed Central

Hui, Yiqun; Ricciotti, Emanuela; Crichton, Irene; Yu, Zhou; Wang, Dairong; Stubbe, Jane; Wang, Miao; Puré, Ellen; FitzGerald, Garret A.

2010-01-01

Background While the dominant product of vascular cyclooxygenase (COX)-2, prostacyclin (PGI2), restrains atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of COX-2 in macrophages (Mac) and T cells (TC) to atherogenesis. Methods and Results Deletion of Mac COX-2 (MacKO) was attained using LysMCre mice and suppressed completely lipopolysaccharide (LPS) stimulated Mac prostaglandin (PG) formation and LPS evoked systemic PG biosynthesis by ∼ 30%. LPS stimulated COX-2 expression was suppressed in polymorphonuclear leucocytes (PMN) isolated from MacKOs, but PG formation was not even detected in PMN supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic LdlR KOs. Deletion of Mac COX-2 appeared to remove a restraint on COX-2 expression in lesional non-leukocyte (CD45 and CD11b negative) vascular cells that express vascular cell adhesion molecule and variably, α-smooth muscle actin and vimentin, portending a shift in PG profile and consequent atheroprotection. Basal expression of COX-2 was minimal in TCs, but use of CD4Cre to generate TC knockouts (TCKOs) depressed its modest upregulation by anti-CD3ε. However, biosynthesis of PGs, TC composition in lymphatic organs and atherogenesis in LDLR KOs were unaltered in TCKOs. Conclusions Mac COX-2, primarily a source of thromboxane A2 and PGE2, promotes atherogenesis and exerts a restraint on enzyme expression by lesional cells suggestive of vascular smooth muscle cells, a prominent source of atheroprotective PGI2. TC COX-2 does not influence detectably TC development or function nor atherogenesis in mice. PMID:20530000

Houttuynia cordata, a novel and selective COX-2 inhibitor with anti-inflammatory activity.

PubMed

Li, Weifeng; Zhou, Ping; Zhang, Yanmin; He, Langchong

2011-01-27

Houttuynia cordata Thunb. (Saururaceae; HC) has been long used in traditional oriental medicine for the treatment of inflammation diseases. Modern research has implicated inducible cyclooxygenase-2 (COX-2) as a key regulator of the inflammatory process. In the present study, we aimed to investigate the effect of HC on COX-2. We examined the effects of HC on lipopolysaccharide (LPS)-induced prostaglandin (PG) E(2) production, an indirect indicator of COX-2 activity, and COX-2 gene and protein expression in mouse peritoneal macrophages. LPS-induced mouse peritoneal macrophages were employed as an in vitro model system. LPS-induced PGE(2) production was assessed by enzyme-linked immunosorbant assay and COX-2 protein expression was assessed by Western blot assay. The results showed that HC was able to inhibit the release of LPS-induced PGE(2) from mouse peritoneal macrophages (IC50 value: 44.8 μg/mL). Moreover, the inhibitory activity of HC essential oil elicited a dose-dependent inhibition of COX-2 enzyme activity (IC50 value: 30.9 μg/mL). HC was also found to cause reduction in LPS-induced COX-2 mRNA and protein expression, but did not affect COX-1 expression. The non-steroidal anti-inflammatory drug (NSAID) and specific COX-2 inhibitor NS398 functioned similarly in LPS-induced mouse peritoneal macrophages. Taken together, our data suggest HC mediates inhibition of COX-2 enzyme activity and can affect related gene and protein expression. HC works by a mechanism of action similar to that of NSAIDs. These results add a novel aspect to the biological profile of HC. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Identification of novel Cyclooxygenase-2-dependent genes in Helicobacter pylori infection in vivo

PubMed Central

Walduck, Anna K; Weber, Matthias; Wunder, Christian; Juettner, Stefan; Stolte, Manfred; Vieth, Michael; Wiedenmann, Bertram; Meyer, Thomas F; Naumann, Michael; Hoecker, Michael

2009-01-01

Background Helicobacter pylori is a crucial determining factor in the pathogenesis of benign and neoplastic gastric diseases. Cyclooxygenase-2 (Cox-2) is the inducible key enzyme of arachidonic acid metabolism and is a central mediator in inflammation and cancer. Expression of the Cox-2 gene is up-regulated in the gastric mucosa during H. pylori infection but the pathobiological consequences of this enhanced Cox-2 expression are not yet characterized. The aim of this study was to identify novel genes down-stream of Cox-2 in an in vivo model, thereby identifying potential targets for the study of the role of Cox- 2 in H. pylori pathogenesis and the initiation of pre- cancerous changes. Results Gene expression profiles in the gastric mucosa of mice treated with a specific Cox-2 inhibitor (NS398) or vehicle were analysed at different time points (6, 13 and 19 wk) after H. pylori infection. H. pylori infection affected the expression of 385 genes over the experimental period, including regulators of gastric physiology, proliferation, apoptosis and mucosal defence. Under conditions of Cox-2 inhibition, 160 target genes were regulated as a result of H. pylori infection. The Cox-2 dependent subset included those influencing gastric physiology (Gastrin, Galr1), epithelial barrier function (Tjp1, connexin45, Aqp5), inflammation (Icam1), apoptosis (Clu) and proliferation (Gdf3, Igf2). Treatment with NS398 alone caused differential expression of 140 genes, 97 of which were unique, indicating that these genes are regulated under conditions of basal Cox-2 expression. Conclusion This study has identified a panel of novel Cox-2 dependent genes influenced under both normal and the inflammatory conditions induced by H. pylori infection. These data provide important new links between Cox-2 and inflammatory processes, epithelial repair and integrity. PMID:19317916

Cyclooxygenase-2 inhibitor blocks the production of West Nile virus-induced neuroinflammatory markers in astrocytes.

PubMed

Verma, Saguna; Kumar, Mukesh; Nerurkar, Vivek R

2011-03-01

Inflammatory immune responses triggered initially to clear West Nile virus (WNV) infection later become detrimental and contribute to the pathological processes such as blood-brain barrier (BBB) disruption and neuronal death, thus complicating WNV-associated encephalitis (WNVE). It has been demonstrated previously that WNV infection in astrocytes results in induction of multiple matrix metalloproteinases (MMPs), which mediate BBB disruption. Cyclooxygenase (COX) enzymes and their product, prostaglandin E2 (PGE2), modulate neuroinflammation and regulate the production of multiple inflammatory molecules including MMPs. Therefore, this study determined and characterized the pathophysiological consequences of the expression of COX enzymes in human brain cortical astrocytes (HBCAs) following WNV infection. Whilst COX-1 mRNA expression did not change, WNV infection significantly induced RNA and protein expression of COX-2 in HBCAs. Similarly, PGE2 production was also enhanced significantly in infected HBCAs and was blocked in the presence of the COX-2-specific inhibitor NS-398, thus suggesting that COX-2, and not COX-1, was the source of the increased PGE2. Treatment of infected HBCAs with NS-398 attenuated the expression of MMP-1, -3 and -9 in a dose-dependent manner. Similarly, expression of interleukin-1β, -6 and -8, which were markedly elevated in infected HBCAs, exhibited a significant reduction in their levels in the presence of NS-398. These results provide direct evidence that WNV-induced COX-2/PGE2 is involved in modulating the expression of multiple neuroinflammatory mediators, thereby directly linking COX-2 with WNV disease pathogenesis. The ability of COX-2 inhibitors to modulate WNV-induced COX-2 and PGE2 signalling warrants further investigation in an animal model as a potential approach for clinical management of neuroinflammation associated with WNVE.

Suppression of IL-1beta-induced COX-2 expression by trichostatin A (TSA) in human endometrial stromal cells.

PubMed

Wu, Yan; Guo, Sun-Wei

2007-11-01

Over-production of cyclooxygenase-2 (COX-2) plays an important role in the positive feedback loop that leads to proliferation and inflammation in endometriosis. Following our observation that histone deacetylase inhibitors (HDACIs) trichostatin A (TSA) and valproic acid (VPA) can suppress proliferation of endometrial stromal cells, we sought to determine whether TSA suppresses IL-1beta-induced COX-2 expression in endometrial stromal cells. In vitro study using a recently established immortalized endometrial stromal cell line. The stromal cells were pretreated with TSA before stimulation with IL-1beta, and COX-2 gene and protein expression was measured by real-time quantitative RT-PCR and Western blot analysis, respectively. IL-1beta stimulated COX-2 expression in a concentration-dependent manner in endometrial stromal cells. The induced COX-2 gene and protein expression were suppressed by TSA pretreatment. TSA suppresses IL-1beta-induced COX-2 gene and protein expression in endometrial stromal cells. This finding, coupled with the findings that TSA and another HDACI, valproic acid, suppress proliferation and induce cell cycle arrest, suggests that HDACIs are a promising class of compound that has therapeutic potential for endometriosis.

Comparison and validation of statistical methods for predicting power outage durations in the event of hurricanes.

PubMed

Nateghi, Roshanak; Guikema, Seth D; Quiring, Steven M

2011-12-01

This article compares statistical methods for modeling power outage durations during hurricanes and examines the predictive accuracy of these methods. Being able to make accurate predictions of power outage durations is valuable because the information can be used by utility companies to plan their restoration efforts more efficiently. This information can also help inform customers and public agencies of the expected outage times, enabling better collective response planning, and coordination of restoration efforts for other critical infrastructures that depend on electricity. In the long run, outage duration estimates for future storm scenarios may help utilities and public agencies better allocate risk management resources to balance the disruption from hurricanes with the cost of hardening power systems. We compare the out-of-sample predictive accuracy of five distinct statistical models for estimating power outage duration times caused by Hurricane Ivan in 2004. The methods compared include both regression models (accelerated failure time (AFT) and Cox proportional hazard models (Cox PH)) and data mining techniques (regression trees, Bayesian additive regression trees (BART), and multivariate additive regression splines). We then validate our models against two other hurricanes. Our results indicate that BART yields the best prediction accuracy and that it is possible to predict outage durations with reasonable accuracy. © 2011 Society for Risk Analysis.

Optimization of Acid Orange 7 Degradation in Heterogeneous Fenton-like Reaction Using Fe3-xCoxO4 Catalyst

NASA Astrophysics Data System (ADS)

Ibrahim, M. Z.; Alrozi, R.; Zubir, N. A.; Bashah, N. A.; Ali, S. A. Md; Ibrahim, N.

2018-05-01

The oxidation process such as heterogeneous Fenton and/or Fenton-like reactions is considered as an effective and efficient method for treatment of dye degradation. In this study, the degradation of Acid Orange 7 (AO7) was investigated by using Fe3-xCoxO4 as a heterogeneous Fenton-like catalyst. Response surface methodology (RSM) was used to optimize the operational parameters condition and the interaction of two or more parameters. The parameter studies were catalyst dosage (X1 ), pH (X2 ) and H2O2 concentration (X3 ) towards AO7 degradation. Based on analysis of variance (ANOVA), the derived quadratic polynomial model was significant whereby the predicted values matched the experimental values with regression coefficient of R2 = 0.9399. The optimum condition for AO7 degradation was obtained at catalyst dosage of 0.84 g/L, pH of 3 and H2O2 concentration of 46.70 mM which resulted in 86.30% removal of AO7 dye. These findings present new insights into the influence of operational parameters in the heterogeneous Fenton-like oxidation of AO7 using Fe3-xCoxO4 catalyst.

Design, Synthesis and Biological Evaluation of4-(Imidazolylmethyl)-2-(4-methylsulfonyl phenyl)-Quinoline Derivatives as Selective COX-2 Inhibitors and In-vitro Anti-breast Cancer Agents

PubMed Central

Ghodsi, Razieh; Azizi, Ebrahim; Zarghi, Afshin

2016-01-01

A new group of 4-(Imidazolylmethyl)quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors and in-vitroanti breast cancer agents. In-vitro COX-1 and COX-2 inhibition studies showed that all the compounds were potent and selective inhibitors of the COX-2 isozyme with IC50 values in the potent range 0.063-0.090 µM, and COX-2 selectivity indexes in the 179.9 to 547.6 range. Molecular modeling studies indicated that the methylsulfonyl substituent can be inserted into the secondary pocket of COX-2 active site for interactions with Arg513. Cytotoxicity of quinolines 9a-e against human breast cancer MCF-7 and T47D cell lines were also evaluated. All the compounds 9a-e were more cytotoxic against MCF-7 cells in comparison with those of T47D which express aromatase mRNA less than MCF-7 cells.The data showed that the increase of lipophilic properties of substituents on the C-7 and C-8 quinoline ring increased their cytotoxicity on MCF-7cells andCOX-2 inhibitory activity. Among the quinolines 9a-e, 4-((1H-Imidazol-1-yl)methyl) 7,8,9,10-tetrahydro-2-(4-methylsulfonylphenyl)-benzo[h]quinoline (9d)was identified as the most potent andselective COX-2inhibitor as well as the most cytotoxic agent against MCF-7 cells. PMID:27610157

Anti-inflammatory, cyclooxygenase (COX)-2, COX-1 inhibitory, and free radical scavenging effects of Rumex nepalensis.

PubMed

Gautam, Raju; Karkhile, Kailas V; Bhutani, Kamlesh K; Jachak, Sanjay M

2010-10-01

Evaluation of the topical anti-inflammatory activity of chloroform and ethyl acetate extracts of RUMEX NEPALENSIS roots in a TPA-induced acute inflammation mouse model demonstrated a significant reduction in ear edema. The extracts were further tested on purified enzymes for COX-1 and COX-2 inhibition to elucidate their mechanism of action, and a strong inhibition was observed. Six anthraquinones and two naphthalene derivatives were isolated from the ethyl acetate extract. Among the isolated compounds, emodin was found to be a potent inhibitor with slight selectivity towards COX-2, and nepodin exhibited selectivity towards COX-1. Emodin, endocrocin, and nepodin also exhibited significant topical anti-inflammatory activity in mice. Interestingly, nepodin showed better radical scavenging activity than trolox and ascorbic acid against DPPH and ABTS radicals. The strong radical scavenging activity of chloroform and ethyl acetate extracts could be explained by the presence of nepodin as well as by the high phenolic content of the ethyl acetate extract. Thus, the anti-inflammatory effect of R. NEPALENSIS roots was assumed to be mediated through COX inhibition by anthraquinones and naphthalene derivatives and through the radical scavenging activities of naphthalene derivatives. © Georg Thieme Verlag KG Stuttgart · New York.

FOXP3 inhibits cancer stem cell self-renewal via transcriptional repression of COX2 in colorectal cancer cells.

PubMed

Liu, Shuo; Zhang, Cun; Zhang, Kuo; Gao, Yuan; Wang, Zhaowei; Li, Xiaoju; Cheng, Guang; Wang, Shuning; Xue, Xiaochang; Li, Weina; Zhang, Wei; Zhang, Yingqi; Xing, Xianghui; Li, Meng; Hao, Qiang

2017-07-04

Colon cancer stem cell (cCSC) is considered as the seed cell of colon cancer initiation and metastasis. Cyclooxygenase-2 (COX2), a downstream target of NFκB, is found to be essential in promoting cancer stem cell renewal. However, how COX2 is dysregulated in cCSCs is largely unknown. In this study, we found that the expression of transcription factor FOXP3 was much lower in the spheroids than that in the parental tumor cells. Overexpression of FOXP3 significantly decreased the numbers of spheres, reduced the side population. Accordingly, FOXP3 expression decreased the tumor size and weight in the xenograft model. The tumor inhibitory effects of FOXP3 were rarely seen when COX2 was additionally knocked down. Mechanically, FOXP3 transcriptionally repressed COX2 expression via interacting with and thus inhibiting p65 activity on the putative NFκB response elements in COX2 promoter. Taken together, we here revealed possible involvement of FOXP3 in regulating cCSC self-renewal via tuning COX2 expression, and thus providing a new target for the eradication of colon cancer stem cells.

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

PubMed Central

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

2009-01-01

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

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

PubMed

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

2009-11-04

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

Regularization Paths for Cox's Proportional Hazards Model via Coordinate Descent.

PubMed

Simon, Noah; Friedman, Jerome; Hastie, Trevor; Tibshirani, Rob

2011-03-01

We introduce a pathwise algorithm for the Cox proportional hazards model, regularized by convex combinations of ℓ 1 and ℓ 2 penalties (elastic net). Our algorithm fits via cyclical coordinate descent, and employs warm starts to find a solution along a regularization path. We demonstrate the efficacy of our algorithm on real and simulated data sets, and find considerable speedup between our algorithm and competing methods.

Bayesian multivariate hierarchical transformation models for ROC analysis.

PubMed

O'Malley, A James; Zou, Kelly H

2006-02-15

A Bayesian multivariate hierarchical transformation model (BMHTM) is developed for receiver operating characteristic (ROC) curve analysis based on clustered continuous diagnostic outcome data with covariates. Two special features of this model are that it incorporates non-linear monotone transformations of the outcomes and that multiple correlated outcomes may be analysed. The mean, variance, and transformation components are all modelled parametrically, enabling a wide range of inferences. The general framework is illustrated by focusing on two problems: (1) analysis of the diagnostic accuracy of a covariate-dependent univariate test outcome requiring a Box-Cox transformation within each cluster to map the test outcomes to a common family of distributions; (2) development of an optimal composite diagnostic test using multivariate clustered outcome data. In the second problem, the composite test is estimated using discriminant function analysis and compared to the test derived from logistic regression analysis where the gold standard is a binary outcome. The proposed methodology is illustrated on prostate cancer biopsy data from a multi-centre clinical trial.

Bayesian multivariate hierarchical transformation models for ROC analysis

PubMed Central

O'Malley, A. James; Zou, Kelly H.

2006-01-01

SUMMARY A Bayesian multivariate hierarchical transformation model (BMHTM) is developed for receiver operating characteristic (ROC) curve analysis based on clustered continuous diagnostic outcome data with covariates. Two special features of this model are that it incorporates non-linear monotone transformations of the outcomes and that multiple correlated outcomes may be analysed. The mean, variance, and transformation components are all modelled parametrically, enabling a wide range of inferences. The general framework is illustrated by focusing on two problems: (1) analysis of the diagnostic accuracy of a covariate-dependent univariate test outcome requiring a Box–Cox transformation within each cluster to map the test outcomes to a common family of distributions; (2) development of an optimal composite diagnostic test using multivariate clustered outcome data. In the second problem, the composite test is estimated using discriminant function analysis and compared to the test derived from logistic regression analysis where the gold standard is a binary outcome. The proposed methodology is illustrated on prostate cancer biopsy data from a multi-centre clinical trial. PMID:16217836

Actinic cheilitis: epithelial expression of COX-2 and its association with mast cell tryptase and PAR-2.

PubMed

Rojas, I Gina; Martínez, Alejandra; Brethauer, Ursula; Grez, Patricia; Yefi, Roger; Luza, Sandra; Marchesani, Francisco J

2009-03-01

Cyclooxygenase-2 (COX-2) is overexpressed in various types of human malignancies, including oral cancers. Recent studies have shown that mast cell-derived protease tryptase can induce COX-2 expression by the cleavage of proteinase-activated receptor-2 (PAR-2). Actinic cheilitis (AC) is a premalignant form of lip cancer characterized by an increased density of tryptase-positive mast cells. To investigate the possible contribution of tryptase to COX-2 overexpression during early lip carcinogenesis, normal lip (n=24) and AC (n=45) biopsies were processed for COX-2, PAR-2 and tryptase detection, using RT-PCR and immunohistochemistry. Expression scores were obtained for each marker and tested for statistical significance using Mann-Whitney and Spearmann's correlation tests as well as multivariate logistic regression analysis. Increased epithelial co-expression of COX-2 and PAR-2, as well as, elevated subepithelial density of tryptase-positive mast cells were found in AC as compared to normal lip (P<0.001). COX-2 overexpression was found to be a significant predictor of AC (P<0.034, forward stepwise, Wald), and to be correlated with both tryptase-positive mast cells and PAR-2 expression (P<0.01). The results suggest that epithelial COX-2 overexpression is a key event in AC, which is associated with increased tryptase-positive mast cells and PAR-2. Therefore, tryptase may contribute to COX-2 up-regulation by epithelial PAR-2 activation during early lip carcinogenesis.

Handling nonnormality and variance heterogeneity for quantitative sublethal toxicity tests.

PubMed

Ritz, Christian; Van der Vliet, Leana

2009-09-01

The advantages of using regression-based techniques to derive endpoints from environmental toxicity data are clear, and slowly, this superior analytical technique is gaining acceptance. As use of regression-based analysis becomes more widespread, some of the associated nuances and potential problems come into sharper focus. Looking at data sets that cover a broad spectrum of standard test species, we noticed that some model fits to data failed to meet two key assumptions-variance homogeneity and normality-that are necessary for correct statistical analysis via regression-based techniques. Failure to meet these assumptions often is caused by reduced variance at the concentrations showing severe adverse effects. Although commonly used with linear regression analysis, transformation of the response variable only is not appropriate when fitting data using nonlinear regression techniques. Through analysis of sample data sets, including Lemna minor, Eisenia andrei (terrestrial earthworm), and algae, we show that both the so-called Box-Cox transformation and use of the Poisson distribution can help to correct variance heterogeneity and nonnormality and so allow nonlinear regression analysis to be implemented. Both the Box-Cox transformation and the Poisson distribution can be readily implemented into existing protocols for statistical analysis. By correcting for nonnormality and variance heterogeneity, these two statistical tools can be used to encourage the transition to regression-based analysis and the depreciation of less-desirable and less-flexible analytical techniques, such as linear interpolation.

A general Bayesian framework for calibrating and evaluating stochastic models of annual multi-site hydrological data

NASA Astrophysics Data System (ADS)

Frost, Andrew J.; Thyer, Mark A.; Srikanthan, R.; Kuczera, George

2007-07-01

SummaryMulti-site simulation of hydrological data are required for drought risk assessment of large multi-reservoir water supply systems. In this paper, a general Bayesian framework is presented for the calibration and evaluation of multi-site hydrological data at annual timescales. Models included within this framework are the hidden Markov model (HMM) and the widely used lag-1 autoregressive (AR(1)) model. These models are extended by the inclusion of a Box-Cox transformation and a spatial correlation function in a multi-site setting. Parameter uncertainty is evaluated using Markov chain Monte Carlo techniques. Models are evaluated by their ability to reproduce a range of important extreme statistics and compared using Bayesian model selection techniques which evaluate model probabilities. The case study, using multi-site annual rainfall data situated within catchments which contribute to Sydney's main water supply, provided the following results: Firstly, in terms of model probabilities and diagnostics, the inclusion of the Box-Cox transformation was preferred. Secondly the AR(1) and HMM performed similarly, while some other proposed AR(1)/HMM models with regionally pooled parameters had greater posterior probability than these two models. The practical significance of parameter and model uncertainty was illustrated using a case study involving drought security analysis for urban water supply. It was shown that ignoring parameter uncertainty resulted in a significant overestimate of reservoir yield and an underestimation of system vulnerability to severe drought.

Causal Mediation Analysis of Survival Outcome with Multiple Mediators.

PubMed

Huang, Yen-Tsung; Yang, Hwai-I

2017-05-01

Mediation analyses have been a popular approach to investigate the effect of an exposure on an outcome through a mediator. Mediation models with multiple mediators have been proposed for continuous and dichotomous outcomes. However, development of multimediator models for survival outcomes is still limited. We present methods for multimediator analyses using three survival models: Aalen additive hazard models, Cox proportional hazard models, and semiparametric probit models. Effects through mediators can be characterized by path-specific effects, for which definitions and identifiability assumptions are provided. We derive closed-form expressions for path-specific effects for the three models, which are intuitively interpreted using a causal diagram. Mediation analyses using Cox models under the rare-outcome assumption and Aalen additive hazard models consider effects on log hazard ratio and hazard difference, respectively; analyses using semiparametric probit models consider effects on difference in transformed survival time and survival probability. The three models were applied to a hepatitis study where we investigated effects of hepatitis C on liver cancer incidence mediated through baseline and/or follow-up hepatitis B viral load. The three methods show consistent results on respective effect scales, which suggest an adverse estimated effect of hepatitis C on liver cancer not mediated through hepatitis B, and a protective estimated effect mediated through the baseline (and possibly follow-up) of hepatitis B viral load. Causal mediation analyses of survival outcome with multiple mediators are developed for additive hazard and proportional hazard and probit models with utility demonstrated in a hepatitis study.

Preliminary analysis on hybrid Box-Jenkins - GARCH modeling in forecasting gold price

NASA Astrophysics Data System (ADS)

Yaziz, Siti Roslindar; Azizan, Noor Azlinna; Ahmad, Maizah Hura; Zakaria, Roslinazairimah; Agrawal, Manju; Boland, John

2015-02-01

Gold has been regarded as a valuable precious metal and the most popular commodity as a healthy return investment. Hence, the analysis and prediction of gold price become very significant to investors. This study is a preliminary analysis on gold price and its volatility that focuses on the performance of hybrid Box-Jenkins models together with GARCH in analyzing and forecasting gold price. The Box-Cox formula is used as the data transformation method due to its potential best practice in normalizing data, stabilizing variance and reduces heteroscedasticity using 41-year daily gold price data series starting 2nd January 1973. Our study indicates that the proposed hybrid model ARIMA-GARCH with t-innovation can be a new potential approach in forecasting gold price. This finding proves the strength of GARCH in handling volatility in the gold price as well as overcomes the non-linear limitation in the Box-Jenkins modeling.

Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice.

PubMed

Praticò, D; Tillmann, C; Zhang, Z B; Li, H; FitzGerald, G A

2001-03-13

The cyclooxygenase (COX) product, prostacyclin (PGI(2)), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI(2) biosynthesis substantially in humans. Because deletion of the PGI(2) receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF(1alpha) by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI(2) biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 +/- 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.

Cyclooxygenase-2 expression and oxidative DNA adducts in murine intestinal adenomas: modification by dietary curcumin and implications for clinical trials.

PubMed

Tunstall, R G; Sharma, R A; Perkins, S; Sale, S; Singh, R; Farmer, P B; Steward, W P; Gescher, A J

2006-02-01

The natural polphenol, curcumin, retards the growth of intestinal adenomas in the Apc(Min+) mouse model of human familial adenomatous polyposis. In other preclinical models, curcumin downregulates the transcription of the enzyme cyclooxygenase-2 (COX-2) and decreases levels of two oxidative DNA adducts, the pyrimidopurinone adduct of deoxyguanosine (M1dG) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG). We have studied COX-2 protein expression and oxidative DNA adduct levels in intestinal adenoma tissue from Apc(Min+) mice to try and differentiate between curcumin's direct pharmacodynamic effects and indirect effects via its inhibition of adenoma growth. Mice received dietary curcumin (0.2%) for 4 or 14 weeks. COX-2 protein, M1dG and 8-oxo-dG levels were measured by Western blot, immunochemical assay and liquid chromatography-mass spectrometry, respectively. In control Apc(Min+) mice, the levels of all three indices measured in adenoma tissue were significantly higher than levels in normal mucosa. Lifetime administration of curcumin reduced COX-2 expression by 66% (P = 0.01), 8-oxo-dG levels by 24% (P < 0.05) and M1dG levels by 39% (P < 0.005). Short-term feeding did not affect total adenoma number or COX-2 expression, but decreased M1dG levels by 43% (P < 0.01). COX-2 protein levels related to adenoma size. These results demonstrate the utility of measuring these oxidative DNA adduct levels to show direct antioxidant effects of dietary curcumin. The effects of long-term dietary curcumin on COX-2 protein levels appear to reflect retardation of adenoma development.

Heterotypic contact reveals a COX-2-mediated suppression of osteoblast differentiation by endothelial cells: A negative modulatory role for prostanoids in VEGF-mediated cell: cell communication?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clarkin, Claire E.; Garonna, Elena; Pitsillides, Andrew A.

In bone, angiogenesis must be initiated appropriately, but limited once remodelling or repair is complete. Our recent findings have supported a role for prostaglandins (PG), known modulators of osteoblast (OB) and endothelial cell (EC) behaviour, in facilitating VEGF-mediated paracrine communication from OBs to 'remotely located' ECs, but the mechanism(s) regulating OB:EC crosstalk when these cells are closely opposed are undefined. In this study we have examined: (i) the effects of exogenous PGE{sub 2} on VEGF-driven events in ECs, and (ii) the role of endogenous COX-2-derived prostanoids in mediating communication between intimately opposed OBs and ECs in direct contact. Exposure ofmore » ECs to PGE{sub 2} increased ERK1/2 phosphorylation, COX-2 induction, 6-keto-PGF{sub 1{alpha}} release and EC proliferation. In contrast, PGE{sub 2} attenuated VEGF{sub 165}-induced VEGFR2/Flk1 phosphorylation, ERK1/2 activation and proliferation of ECs, suggesting that exogenous PGE{sub 2} restricts the actions of VEGF. However, the COX-2-selective inhibitor, NS398, also attenuated VEGF-induced proliferation, implying a distinct role for endogenous COX-2 activity in regulating EC behaviour. To examine the effect of OB:EC proximity and the role of COX-2 products further, we used a confrontational co-culture model. These studies showed that COX-2 blockade with NS398 enhanced EC-dependent increases in OB differentiation, that this effect was reversed by exogenous PGH{sub 2} (immediate COX-2 product), and that exogenous VEGF did not influence EC-dependent OB differentiation under these conditions. Our findings indicate that locally produced prostanoids may serve distinct roles depending on OB:EC proximity and negatively modulate VEGF-mediated changes in EC behaviour when these cells are closely opposed to control angiogenesis during bone (re)modelling.« less

A novel sulindac derivative lacking COX-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model

PubMed Central

Zhang, Yong; Zhang, Jinhui; Wang, Lei; Quealy, Emily; Gary, Bernard D.; Reynolds, Robert C.; Piazza, Gary A.; Lü, Junxuan

2016-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) including sulindac are well-documented to be highly effective for cancer chemoprevention. However, their cyclooxygenase (COX) inhibitory activities cause severe gastrointestinal and cardiovascular toxicities, limiting their chronic use. Recent studies suggest that COX-independent mechanisms may be responsible for the chemopreventive benefits of the NSAIDs, and support the potential for development of a novel generation of sulindac derivatives lacking COX inhibition for cancer chemoprevention. A prototypic sulindac derivative with a N,N-dimethylammonium substitution, referred to as sulindac sulfide amide (SSA) was recently identified to be devoid of COX inhibitory activity yet displays much more potent tumor cell growth inhibitory activity in vitro compared to sulindac sulfide. In this study, we investigated the androgen receptor (AR) signaling pathway as a potential target for its COX-independent antineoplastic mechanism and evaluated its chemopreventive efficacy against prostate carcinogenesis using the TRAMP mouse model. The results showed that SSA significantly suppressed the growth of human and mouse prostate cancer cells expressing AR in strong association with G1 arrest, and decreased AR level and AR-dependent transactivation. Dietary SSA consumption from 6 to 24 weeks of age dramatically attenuated prostatic growth and suppressed AR-dependent glandular epithelial lesion progression via repressing cell proliferation in the TRAMP mice, whereas it did not significantly impact neuroendocrine carcinoma growth. Overall, the results suggest that SSA may be a chemopreventive candidate against prostate glandular epithelial carcinogenesis. PMID:20587701

Cyclooxygenase-2 expression after preoperative chemoradiotherapy correlates with more frequent esophageal cancer recurrence

PubMed Central

Yoshikawa, Reigetsu; Fujiwara, Yoshinori; Koishi, Kenji; Kojima, Syoudou; Matsumoto, Tomohiro; Yanagi, Hidenori; Yamamura, Takehira; Hashimoto-Tamaoki, Tomoko; Nishigami, Takashi; Tsujimura, Tohru

2007-01-01

AIM: To investigate the relationship between cycloo-xygenase-2 (COX-2), and vascular endothelial growth factor (VEGF), and to determine the clinical significance of this relationship in esophageal cancer patients undergoing chemoradiotherapy (CRT). METHODS: Immunohistochemical staining was used to evaluate COX-2 and VEGF expression in 40 patients with histologically-confirmed esophageal squamous carcinoma (ESCC) who were undergoing preoperative CRT. RESULTS: Fourteen out of 40 ESCC patients showed a pathological complete response (CR) after CRT. COX-2 and VEGF protein expressions were observed in the cytoplasm of 17 and 13 tumors, respectively, with null expression in 9 and 13 tumors, respectively. COX-2 expression was strongly correlated with VEGF expression (P < 0.05). There were also significant associations between COX-2 expression, tumor recurrence, and lymph-node involvement (P = 0.0277 and P = 0.0095, respectively). COX-2 expression and VEGF expression had significant prognostic value for disease-free survival (log-rank test; P = 0.0073 and P = 0.0341, respectively), but not for overall survival, as assessed by univariate analysis. CONCLUSION: Our results suggest that COX-2 expression correlates with VEGF expression and might be a useful prognostic factor for more frequent tumor recurrence in ESCC patients undergoing neoadjuvant CRT. These findings support the use of anti-angiogenic COX-2 inhibitors in the treatment of ESCC. PMID:17511025

At what scale should microarray data be analyzed?

PubMed

Huang, Shuguang; Yeo, Adeline A; Gelbert, Lawrence; Lin, Xi; Nisenbaum, Laura; Bemis, Kerry G

2004-01-01

The hybridization intensities derived from microarray experiments, for example Affymetrix's MAS5 signals, are very often transformed in one way or another before statistical models are fitted. The motivation for performing transformation is usually to satisfy the model assumptions such as normality and homogeneity in variance. Generally speaking, two types of strategies are often applied to microarray data depending on the analysis need: correlation analysis where all the gene intensities on the array are considered simultaneously, and gene-by-gene ANOVA where each gene is analyzed individually. We investigate the distributional properties of the Affymetrix GeneChip signal data under the two scenarios, focusing on the impact of analyzing the data at an inappropriate scale. The Box-Cox type of transformation is first investigated for the strategy of pooling genes. The commonly used log-transformation is particularly applied for comparison purposes. For the scenario where analysis is on a gene-by-gene basis, the model assumptions such as normality are explored. The impact of using a wrong scale is illustrated by log-transformation and quartic-root transformation. When all the genes on the array are considered together, the dependent relationship between the expression and its variation level can be satisfactorily removed by Box-Cox transformation. When genes are analyzed individually, the distributional properties of the intensities are shown to be gene dependent. Derivation and simulation show that some loss of power is incurred when a wrong scale is used, but due to the robustness of the t-test, the loss is acceptable when the fold-change is not very large.

Analysis and prediction of rainfall trends over Bangladesh using Mann-Kendall, Spearman's rho tests and ARIMA model

NASA Astrophysics Data System (ADS)

Rahman, Mohammad Atiqur; Yunsheng, Lou; Sultana, Nahid

2017-08-01

In this study, 60-year monthly rainfall data of Bangladesh were analysed to detect trends. Modified Mann-Kendall, Spearman's rho tests and Sen's slope estimators were applied to find the long-term annual, dry season and monthly trends. Sequential Mann-Kendall analysis was applied to detect the potential trend turning points. Spatial variations of the trends were examined using inverse distance weighting (IDW) interpolation. AutoRegressive integrated moving average (ARIMA) model was used for the country mean rainfall and for other two stations data which depicted the highest and the lowest trend in the Mann-Kendall and Spearman's rho tests. Results showed that there is no significant trend in annual rainfall pattern except increasing trends for Cox's Bazar, Khulna, Satkhira and decreasing trend for Srimagal areas. For the dry season, only Bogra area represented significant decreasing trend. Long-term monthly trends demonstrated a mixed pattern; both negative and positive changes were found from February to September. Comilla area showed a significant decreasing trend for consecutive 3 months while Rangpur and Khulna stations confirmed the significant rising trends for three different months in month-wise trends analysis. Rangpur station data gave a maximum increasing trend in April whereas a maximum decreasing trend was found in August for Comilla station. ARIMA models predict +3.26, +8.6 and -2.30 mm rainfall per year for the country, Cox's Bazar and Srimangal areas, respectively. However, all the test results and predictions revealed a good agreement among them in the study.

Prognostic value of inflammation-based scores in patients with osteosarcoma

PubMed Central

Liu, Bangjian; Huang, Yujing; Sun, Yuanjue; Zhang, Jianjun; Yao, Yang; Shen, Zan; Xiang, Dongxi; He, Aina

2016-01-01

Systemic inflammation responses have been associated with cancer development and progression. C-reactive protein (CRP), Glasgow prognostic score (GPS), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and neutrophil-platelet score (NPS) have been shown to be independent risk factors in various types of malignant tumors. This retrospective analysis of 162 osteosarcoma cases was performed to estimate their predictive value of survival in osteosarcoma. All statistical analyses were performed by SPSS statistical software. Receiver operating characteristic (ROC) analysis was generated to set optimal thresholds; area under the curve (AUC) was used to show the discriminatory abilities of inflammation-based scores; Kaplan-Meier analysis was performed to plot the survival curve; cox regression models were employed to determine the independent prognostic factors. The optimal cut-off points of NLR, PLR, and LMR were 2.57, 123.5 and 4.73, respectively. GPS and NLR had a markedly larger AUC than CRP, PLR and LMR. High levels of CRP, GPS, NLR, PLR, and low level of LMR were significantly associated with adverse prognosis (P < 0.05). Multivariate Cox regression analyses revealed that GPS, NLR, and occurrence of metastasis were top risk factors associated with death of osteosarcoma patients. PMID:28008988

A new computer code for discrete fracture network modelling

NASA Astrophysics Data System (ADS)

Xu, Chaoshui; Dowd, Peter

2010-03-01

The authors describe a comprehensive software package for two- and three-dimensional stochastic rock fracture simulation using marked point processes. Fracture locations can be modelled by a Poisson, a non-homogeneous, a cluster or a Cox point process; fracture geometries and properties are modelled by their respective probability distributions. Virtual sampling tools such as plane, window and scanline sampling are included in the software together with a comprehensive set of statistical tools including histogram analysis, probability plots, rose diagrams and hemispherical projections. The paper describes in detail the theoretical basis of the implementation and provides a case study in rock fracture modelling to demonstrate the application of the software.

Tumor gene expression and prognosis in breast cancer patients with 10 or more positive lymph nodes.

PubMed

Cobleigh, Melody A; Tabesh, Bita; Bitterman, Pincas; Baker, Joffre; Cronin, Maureen; Liu, Mei-Lan; Borchik, Russell; Mosquera, Juan-Miguel; Walker, Michael G; Shak, Steven

2005-12-15

This study, along with two others, was done to develop the 21-gene Recurrence Score assay (Oncotype DX) that was validated in a subsequent independent study and is used to aid decision making about chemotherapy in estrogen receptor (ER)-positive, node-negative breast cancer patients. Patients with >or=10 nodes diagnosed from 1979 to 1999 were identified. RNA was extracted from paraffin blocks, and expression of 203 candidate genes was quantified using reverse transcription-PCR (RT-PCR). Seventy-eight patients were studied. As of August 2002, 77% of patients had distant recurrence or breast cancer death. Univariate Cox analysis of clinical and immunohistochemistry variables indicated that HER2/immunohistochemistry, number of involved nodes, progesterone receptor (PR)/immunohistochemistry (% cells), and ER/immunohistochemistry (% cells) were significantly associated with distant recurrence-free survival (DRFS). Univariate Cox analysis identified 22 genes associated with DRFS. Higher expression correlated with shorter DRFS for the HER2 adaptor GRB7 and the macrophage marker CD68. Higher expression correlated with longer DRFS for tumor protein p53-binding protein 2 (TP53BP2) and the ER axis genes PR and Bcl2. Multivariate methods, including stepwise variable selection and bootstrap resampling of the Cox proportional hazards regression model, identified several genes, including TP53BP2 and Bcl2, as significant predictors of DRFS. Tumor gene expression profiles of archival tissues, some more than 20 years old, provide significant information about risk of distant recurrence even among patients with 10 or more nodes.

Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6).

PubMed

Cingolani, Gino; Panella, Andrea; Perrone, Maria Grazia; Vitale, Paola; Di Mauro, Giuseppe; Fortuna, Cosimo G; Armen, Roger S; Ferorelli, Savina; Smith, William L; Scilimati, Antonio

2017-09-29

The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Resveratrol and curcumin as protective agents in an experimental rat model of intestinal ischemia and reperfusion.

PubMed

Cucolas, Cristina; Daneasa, Alexandra Ioana; Olteanu, Diana; Decea, Nicoleta; Moldovan, Remus; Tabaran, Flaviu; Filip, Gabriela Adriana

2016-05-30

The aim of this study was to evaluate the protective effects of resveratrol and curcumin in an experimental rat model of intestinal ischemia-reperfusion (I/R). Forty-eight adult Wistar rats were used: 12 animals undergoing the sham surgery and 36 animals undergoing laparotomy, with 15 min of mesentric artery clamping. The animals from the latter group (n = 12) were pretreated, for 1 week, with vehicle (CTR), resveratrol (RES), and curcumin (CUR). After 1 h and 6 h of reperfusion, respectively, cyclooxigenase (COX)-2, mucin-1, E-cadherin, nuclear factor (NK)-κB expressions, and tumor necrosis factor related apoptosis-inducing ligand (TRAIL) were assessed in the small intestine. Oxidative stress markers were determined in tissue homogenate and serum, and histopathological analysis was performed. Pretreatment with RES decreased the expression of COX-2 and NF-κB at both intervals and increased E-cadherin (p < 0.05) and mucin-1 production after 1 h. CUR had a beneficial effect on COX-2, NF-κB, and E-cadherin expressions, both after 1 h and after 6 h (p < 0.0001). The two compounds increased TRAIL levels and had a protective effect on oxidative stress and histopathological lesions, both after 1 h and after 6 h. Our results suggested that RES and CUR had beneficial effects in intestinal I/R and may represent a promising option for complementary treatment of this pathological condition.

Misspecification of Cox regression models with composite endpoints

PubMed Central

Wu, Longyang; Cook, Richard J

2012-01-01

Researchers routinely adopt composite endpoints in multicenter randomized trials designed to evaluate the effect of experimental interventions in cardiovascular disease, diabetes, and cancer. Despite their widespread use, relatively little attention has been paid to the statistical properties of estimators of treatment effect based on composite endpoints. We consider this here in the context of multivariate models for time to event data in which copula functions link marginal distributions with a proportional hazards structure. We then examine the asymptotic and empirical properties of the estimator of treatment effect arising from a Cox regression model for the time to the first event. We point out that even when the treatment effect is the same for the component events, the limiting value of the estimator based on the composite endpoint is usually inconsistent for this common value. We find that in this context the limiting value is determined by the degree of association between the events, the stochastic ordering of events, and the censoring distribution. Within the framework adopted, marginal methods for the analysis of multivariate failure time data yield consistent estimators of treatment effect and are therefore preferred. We illustrate the methods by application to a recent asthma study. Copyright © 2012 John Wiley & Sons, Ltd. PMID:22736519

Potential use of COX-2–aromatase inhibitor combinations in breast cancer

PubMed Central

Bundred, N J; Barnes, N L P

2005-01-01

Cyclooxygenase-2 (COX-2) is overexpressed in several epithelial tumours, including breast cancer. Cyclooxygenase-2-positive tumours tend to be larger, higher grade, node-positive and HER-2/neu-positive. High COX-2 expression is associated with poor prognosis. Cyclooxygenase-2 inhibition reduces the incidence of tumours in animal models, inhibits the development of invasive cancer in colorectal cancer and reduces the frequency of polyps in familial adenomatous polyposis (FAP). These effects may be as a result of increased apoptosis, reduced angiogenesis and/or proliferation. Studies of COX-2 inhibitors in breast cancer are underway both alone and in combination with other agents. There is evidence to suggest that combining COX-2 inhibitors with aromatase inhibitors, growth factor receptor blockers, or chemo- or radiotherapy may be particularly effective. Preliminary results from combination therapy with celecoxib and exemestane in postmenopausal women with advanced breast cancer showed that the combination increased the time to recurrence. Up to 80% of ductal carcinomas in situ (DCISs) express COX-2, therefore COX-2 inhibition may be of particular use in this situation. Cyclooxygenase-2 expression correlates strongly with expression of HER-2/neu. As aromatase inhibitors appear particularly effective in patients with HER-2/neu-positive tumours, the combination of aromatase inhibitors and COX-2 inhibitors may be particularly useful in both DCIS and invasive cancer. PMID:16100520

BFLCRM: A BAYESIAN FUNCTIONAL LINEAR COX REGRESSION MODEL FOR PREDICTING TIME TO CONVERSION TO ALZHEIMER’S DISEASE*

PubMed Central

Lee, Eunjee; Zhu, Hongtu; Kong, Dehan; Wang, Yalin; Giovanello, Kelly Sullivan; Ibrahim, Joseph G

2015-01-01

The aim of this paper is to develop a Bayesian functional linear Cox regression model (BFLCRM) with both functional and scalar covariates. This new development is motivated by establishing the likelihood of conversion to Alzheimer’s disease (AD) in 346 patients with mild cognitive impairment (MCI) enrolled in the Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI-1) and the early markers of conversion. These 346 MCI patients were followed over 48 months, with 161 MCI participants progressing to AD at 48 months. The functional linear Cox regression model was used to establish that functional covariates including hippocampus surface morphology and scalar covariates including brain MRI volumes, cognitive performance (ADAS-Cog), and APOE status can accurately predict time to onset of AD. Posterior computation proceeds via an efficient Markov chain Monte Carlo algorithm. A simulation study is performed to evaluate the finite sample performance of BFLCRM. PMID:26900412

Instability of g-mode oscillations in white dwarf stars

NASA Technical Reports Server (NTRS)

Keeley, D. A.

1979-01-01

A white dwarf model with M = 6 solar masses, Te = 12,000 K, and L = 1.2 x 10 to the 31st erg/sec provided by Cox has been tested for linear stability of radial oscillations. The radial mode instability first reported for this model by Cox, et al. (1979) has been confirmed. The growth rates obtained are comparable to the rates found by Cox. A sequence of l = 2 g-modes has also been found to be unstable. The e-folding times range from around 10 to the 11th periods for a 137 second mode (1 radial node) to less than 100 periods for a 629 second mode (17 nodes). It is likely that the latter rate is too high because the eigenfunction has been forced to vanish at the non-zero inner radius of the model, at which the Brunt-Vaisala frequency is barely less than the mode frequency.

[Inhibitory effect of nimesulide and oxaliplatin on tumor growth and lymphatic metastasis of transplanted human lung cancer in nude mice].

PubMed

Lang, Zhe; Chen, Gang; Wang, Dong-chang

2012-10-01

This study was designed to evaluate the inhibitory effect of nimesulide in combination with oxaliplatin on tumor growth, expression of COX-2, VEGF-C, VEGFR-3, survivin and β-catenin, and lymphatic metastasis in lung cancer xenograft in nude mice, and to discuss the possible synergistic effect of nimesulide in combination with oxaliplatin. Human lung cancer A549 cells were injected into BALB/c nude mice subcutaneously. Thirty-three healthy male nude mice were randomly divided into 4 groups: the control group, nimesulide group, oxaliplatin group and nimesulide combined with oxaliplatin group. Transplanted tumor tissues were collected and the expressions of COX-2, VEGF-C, VEGFR-3, survivin, β-catenin protein were detected by immunohistochemistry, and RT-PCR assay was used to assess the expression of tumor COX-2, VEGF-C, VEGFR-3, survivin and β-catenin mRNA. SPSS 16.0 was used for statistical analysis. Data were present as (x(-) ± s), and the means were compared by analysis of variance test. Tumor inhibition rates of the nimesulide group, oxaliplatin group and nimesulide + oxaliplatin group were 39.73%, 48.04% and 65.94%, respectively. Immunohistochemical and RT-PCR analysis showed that compared with the control group, the expression levels of COX-2, VEGF-C, VEGFR-3, survivin and β-catenin of the nimesulide group were significantly reduced (all P < 0.05). Compared with the control group, statistical analysis of variance showed that the expression levels of COX-2, VEGF-C and VEGFR-3 of the oxaliplatin group were significantly increased (P < 0.05), the expression levels of survivin and β-catenin protein and mRNA of the oxaliplatin group were significantly reduced (P < 0.05). Compared with the control group, the expression levels of COX-2, VEGF-C, VEGFR-3, survivin and β-catenin of the nimesulide + oxaliplatin group were significantly reduced (all P < 0.05). Both nimesulide alone or in combination with oxaliplatin can significantly inhibit the growth of lung cancer xenografts in nude mice and the expression levels of COX-2, VEGF-C, VEGFR-3, survivin and β-catenin. Oxaliplatin can significantly inhibit the growth of lung cancer xenografts in nude mice, and the expression of survivin and β-catenin. Nimesulide in combination with oxaliplatin enhances the antitumor effect of oxaliplatin.

Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: A phase II trial and literature review.

PubMed

Yokouchi, Hiroshi; Kanazawa, Kenya; Ishida, Takashi; Oizumi, Satoshi; Shinagawa, Naofumi; Sukoh, Noriaki; Harada, Masao; Ogura, Shigeaki; Munakata, Mitsuru; Dosaka-Akita, Hirotoshi; Isobe, Hiroshi; Nishimura, Masaharu

2014-09-01

Several preclinical and clinical studies have demonstrated that cyclooxygenase-2 (COX-2) inhibitors are efficient for the treatment of non-small-cell lung cancer (NSCLC). However, two recent phase III clinical trials using COX-2 inhibitors in combination with platinum-based chemotherapy failed to demonstrate a survival benefit. Thus, validation and discussion regarding the usefulness of COX-2 inhibitors for patients with NSCLC are required. We conducted a prospective trial using COX-2 inhibitors for the treatment of 50 NSCLC patients accrued between April, 2005 and July, 2006. Patients with untreated advanced NSCLC received oral meloxicam (150 mg daily), carboplatin (area under the curve = 5 mg/ml × min on day 1) and docetaxel (60 mg/m 2 on day 1) every 3 weeks. The primary endpoint was response rate. The response and disease control rates were 36.0 and 76.0%, respectively. The time-to-progression (TTP) and overall survival (OS) were 5.7 months [95% confidence interval (CI): 4.6-6.7] and 13.7 months (95% CI: 11.4-15.9), respectively. The 1-year survival ratio was 56.0%. Grade 3 neuropathy was observed in only 1 patient. We performed tumor immunohistochemistry for COX-2 and p27 and investigated the correlation between their expression and clinical outcome. COX-2 expression in the tumor tended to correlate with a higher response rate (50.0% in the high- and 18.2% in the low-COX-2 group; P=0.092). Based on our results and previous reports, various trial designs, such as the prospective use of COX-2 inhibitors only for patients with COX-2-positive NSCLC, including the exploratory analysis of biomarkers associated with the COX-2 pathway, may be worth further consideration.

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

PubMed

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

2016-06-20

The design of multitarget-directed ligands is a promising strategy for discovering innovative drugs. Here, we report a mechanistic study that clarifies key aspects of the dual inhibition of the fatty acid amide hydrolase (FAAH) and the cyclooxygenase (COX) enzymes by a new multitarget-directed ligand named ARN2508 (2-[3-fluoro-4-[3-(hexylcarbamoyloxy)phenyl]phenyl]propanoic acid). This potent dual inhibitor combines, in a single scaffold, the pharmacophoric elements often needed to block FAAH and COX, that is, a carbamate moiety and the 2-arylpropionic acid functionality, respectively. Molecular modeling and molecular dynamics simulations suggest that ARN2508 uses a noncovalent mechanism of inhibition to block COXs, while inhibiting FAAH via the acetylation of the catalytic Ser241, in line with previous experimental evidence for covalent FAAH inhibition. This study proposes the molecular basis for the dual FAAH/COX inhibition by this novel hybrid scaffold, stimulating further experimental studies and offering new insights for the rational design of novel anti-inflammatory agents that simultaneously act on FAAH and COX. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Predicting a future lifetime through Box-Cox transformation.

PubMed

Yang, Z

1999-09-01

In predicting a future lifetime based on a sample of past lifetimes, the Box-Cox transformation method provides a simple and unified procedure that is shown in this article to meet or often outperform the corresponding frequentist solution in terms of coverage probability and average length of prediction intervals. Kullback-Leibler information and second-order asymptotic expansion are used to justify the Box-Cox procedure. Extensive Monte Carlo simulations are also performed to evaluate the small sample behavior of the procedure. Certain popular lifetime distributions, such as Weibull, inverse Gaussian and Birnbaum-Saunders are served as illustrative examples. One important advantage of the Box-Cox procedure lies in its easy extension to linear model predictions where the exact frequentist solutions are often not available.

The linear transformation model with frailties for the analysis of item response times.

PubMed

Wang, Chun; Chang, Hua-Hua; Douglas, Jeffrey A

2013-02-01

The item response times (RTs) collected from computerized testing represent an underutilized source of information about items and examinees. In addition to knowing the examinees' responses to each item, we can investigate the amount of time examinees spend on each item. In this paper, we propose a semi-parametric model for RTs, the linear transformation model with a latent speed covariate, which combines the flexibility of non-parametric modelling and the brevity as well as interpretability of parametric modelling. In this new model, the RTs, after some non-parametric monotone transformation, become a linear model with latent speed as covariate plus an error term. The distribution of the error term implicitly defines the relationship between the RT and examinees' latent speeds; whereas the non-parametric transformation is able to describe various shapes of RT distributions. The linear transformation model represents a rich family of models that includes the Cox proportional hazards model, the Box-Cox normal model, and many other models as special cases. This new model is embedded in a hierarchical framework so that both RTs and responses are modelled simultaneously. A two-stage estimation method is proposed. In the first stage, the Markov chain Monte Carlo method is employed to estimate the parametric part of the model. In the second stage, an estimating equation method with a recursive algorithm is adopted to estimate the non-parametric transformation. Applicability of the new model is demonstrated with a simulation study and a real data application. Finally, methods to evaluate the model fit are suggested. © 2012 The British Psychological Society.

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

PubMed

Asano, Junichi; Hirakawa, Akihiro; Hamada, Chikuma

2014-01-01

A cure rate model is a survival model incorporating the cure rate with the assumption that the population contains both uncured and cured individuals. It is a powerful statistical tool for prognostic studies, especially in cancer. The cure rate is important for making treatment decisions in clinical practice. The proportional hazards (PH) cure model can predict the cure rate for each patient. This contains a logistic regression component for the cure rate and a Cox regression component to estimate the hazard for uncured patients. A measure for quantifying the predictive accuracy of the cure rate estimated by the Cox PH cure model is required, as there has been a lack of previous research in this area. We used the Cox PH cure model for the breast cancer data; however, the area under the receiver operating characteristic curve (AUC) could not be estimated because many patients were censored. In this study, we used imputation-based AUCs to assess the predictive accuracy of the cure rate from the PH cure model. We examined the precision of these AUCs using simulation studies. The results demonstrated that the imputation-based AUCs were estimable and their biases were negligibly small in many cases, although ordinary AUC could not be estimated. Additionally, we introduced the bias-correction method of imputation-based AUCs and found that the bias-corrected estimate successfully compensated the overestimation in the simulation studies. We also illustrated the estimation of the imputation-based AUCs using breast cancer data. Copyright © 2014 John Wiley & Sons, Ltd.

Emodin plays an interventional role in epileptic rats via multidrug resistance gene 1 (MDR1).

PubMed

Yang, Tao; Kong, Bin; Kuang, Yongqin; Cheng, Lin; Gu, Jianwen; Zhang, Junhai; Shu, Haifeng; Yu, Sixun; Yang, Xiaokun; Cheng, Jingming; Huang, Haidong

2015-01-01

To observe the interventional effects of emodin in epileptic rats and elucidate its possible mechanism of action. Thirty-six female Wistar rats were randomly divided into normal control group, model group (intraperitoneal injection of kainic acid) and emodin group (intraperitoneal injection of kainic acid+emodin intervention). The rat epilepsy model was confirmed by behavioral tests and electroencephalography. The protein levels of P-glycoprotein and N-methyl-D-aspartate (NMDA) receptor in cerebral vascular tissue were analyzed by western blotting, and mRNA levels of multidrug resistance gene 1 (MDR1) and cyclooxygenase-2 (COX-2) were analyzed by real-time PCR. COX-2 and P-glycoprotein levels in the brains were detected by immunohistochemical assay. The seizures were relieved in emodin group. Laser scanning confocal microscopy showed P-glycoprotein fluorescence increased significantly after seizures, indicating that epilepsy can induce overexpression of P-glycoprotein. Compared with control group, protein levels of P-glycoprotein and NMDA receptor in cerebral vascular tissue were significantly higher in model group, and mRNA levels of MDR1 and COX-2 were also significantly increased. Compared with model group, P-glycoprotein and NMDA receptor levels in cerebral vascular tissue were significantly decreased in emodin group (P<0.05), and the levels of MDR1 and COX-2 were down-regulated (P<0.05). In the rat brain, seizures could significantly increase COX-2 and P-glycoprotein levels, while emodin intervention was able to significantly reduce the levels of both. These findings suggest that epileptic seizures are tightly associated with up-regulated MDR1 gene, and emodin shows good antagonistic effects on epileptic rats, possibly through inhibition of MDR1 gene and its associated genes.

Association of Protein Translation and Extracellular Matrix Gene Sets with Breast Cancer Metastasis: Findings Uncovered on Analysis of Multiple Publicly Available Datasets Using Individual Patient Data Approach.

PubMed

Chowdhury, Nilotpal; Sapru, Shantanu

2015-01-01

Microarray analysis has revolutionized the role of genomic prognostication in breast cancer. However, most studies are single series studies, and suffer from methodological problems. We sought to use a meta-analytic approach in combining multiple publicly available datasets, while correcting for batch effects, to reach a more robust oncogenomic analysis. The aim of the present study was to find gene sets associated with distant metastasis free survival (DMFS) in systemically untreated, node-negative breast cancer patients, from publicly available genomic microarray datasets. Four microarray series (having 742 patients) were selected after a systematic search and combined. Cox regression for each gene was done for the combined dataset (univariate, as well as multivariate - adjusted for expression of Cell cycle related genes) and for the 4 major molecular subtypes. The centre and microarray batch effects were adjusted by including them as random effects variables. The Cox regression coefficients for each analysis were then ranked and subjected to a Gene Set Enrichment Analysis (GSEA). Gene sets representing protein translation were independently negatively associated with metastasis in the Luminal A and Luminal B subtypes, but positively associated with metastasis in Basal tumors. Proteinaceous extracellular matrix (ECM) gene set expression was positively associated with metastasis, after adjustment for expression of cell cycle related genes on the combined dataset. Finally, the positive association of the proliferation-related genes with metastases was confirmed. To the best of our knowledge, the results depicting mixed prognostic significance of protein translation in breast cancer subtypes are being reported for the first time. We attribute this to our study combining multiple series and performing a more robust meta-analytic Cox regression modeling on the combined dataset, thus discovering 'hidden' associations. This methodology seems to yield new and interesting results and may be used as a tool to guide new research.

Association of Protein Translation and Extracellular Matrix Gene Sets with Breast Cancer Metastasis: Findings Uncovered on Analysis of Multiple Publicly Available Datasets Using Individual Patient Data Approach

PubMed Central

Chowdhury, Nilotpal; Sapru, Shantanu

2015-01-01

Introduction Microarray analysis has revolutionized the role of genomic prognostication in breast cancer. However, most studies are single series studies, and suffer from methodological problems. We sought to use a meta-analytic approach in combining multiple publicly available datasets, while correcting for batch effects, to reach a more robust oncogenomic analysis. Aim The aim of the present study was to find gene sets associated with distant metastasis free survival (DMFS) in systemically untreated, node-negative breast cancer patients, from publicly available genomic microarray datasets. Methods Four microarray series (having 742 patients) were selected after a systematic search and combined. Cox regression for each gene was done for the combined dataset (univariate, as well as multivariate – adjusted for expression of Cell cycle related genes) and for the 4 major molecular subtypes. The centre and microarray batch effects were adjusted by including them as random effects variables. The Cox regression coefficients for each analysis were then ranked and subjected to a Gene Set Enrichment Analysis (GSEA). Results Gene sets representing protein translation were independently negatively associated with metastasis in the Luminal A and Luminal B subtypes, but positively associated with metastasis in Basal tumors. Proteinaceous extracellular matrix (ECM) gene set expression was positively associated with metastasis, after adjustment for expression of cell cycle related genes on the combined dataset. Finally, the positive association of the proliferation-related genes with metastases was confirmed. Conclusion To the best of our knowledge, the results depicting mixed prognostic significance of protein translation in breast cancer subtypes are being reported for the first time. We attribute this to our study combining multiple series and performing a more robust meta-analytic Cox regression modeling on the combined dataset, thus discovering 'hidden' associations. This methodology seems to yield new and interesting results and may be used as a tool to guide new research. PMID:26080057

Identification of cyclin B1 and Sec62 as biomarkers for recurrence in patients with HBV-related hepatocellular carcinoma after surgical resection.

PubMed

Weng, Li; Du, Juan; Zhou, Qinghui; Cheng, Binbin; Li, Jun; Zhang, Denghai; Ling, Changquan

2012-06-08

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Frequent tumor recurrence after surgery is related to its poor prognosis. Although gene expression signatures have been associated with outcome, the molecular basis of HCC recurrence is not fully understood, and there is no method to predict recurrence using peripheral blood mononuclear cells (PBMCs), which can be easily obtained for recurrence prediction in the clinical setting. According to the microarray analysis results, we constructed a co-expression network using the k-core algorithm to determine which genes play pivotal roles in the recurrence of HCC associated with the hepatitis B virus (HBV) infection. Furthermore, we evaluated the mRNA and protein expressions in the PBMCs from 80 patients with or without recurrence and 30 healthy subjects. The stability of the signatures was determined in HCC tissues from the same 80 patients. Data analysis included ROC analysis, correlation analysis, log-lank tests, and Cox modeling to identify independent predictors of tumor recurrence. The tumor-associated proteins cyclin B1, Sec62, and Birc3 were highly expressed in a subset of samples of recurrent HCC; cyclin B1, Sec62, and Birc3 positivity was observed in 80%, 65.7%, and 54.2% of the samples, respectively. The Kaplan-Meier analysis revealed that high expression levels of these proteins was associated with significantly reduced recurrence-free survival. Cox proportional hazards model analysis revealed that cyclin B1 (hazard ratio [HR], 4.762; p = 0.002) and Sec62 (HR, 2.674; p = 0.018) were independent predictors of HCC recurrence. These results revealed that cyclin B1 and Sec62 may be candidate biomarkers and potential therapeutic targets for HBV-related HCC recurrence after surgery.

Analysis of the cytochrome c oxidase subunit 1 (COX1) gene reveals the unique evolution of the giant panda.

PubMed

Hu, Yao-Dong; Pang, Hui-Zhong; Li, De-Sheng; Ling, Shan-Shan; Lan, Dan; Wang, Ye; Zhu, Yun; Li, Di-Yan; Wei, Rong-Ping; Zhang, He-Min; Wang, Cheng-Dong

2016-11-05

As the rate-limiting enzyme of the mitochondrial respiratory chain, cytochrome c oxidase (COX) plays a crucial role in biological metabolism. "Living fossil" giant panda (Ailuropoda melanoleuca) is well-known for its special bamboo diet. In an effort to explore functional variation of COX1 in the energy metabolism behind giant panda's low-energy bamboo diet, we looked at genetic variation of COX1 gene in giant panda, and tested for its selection effect. In 1545 base pairs of the gene from 15 samples, 9 positions were variable and 1 mutation leaded to an amino acid sequence change. COX1 gene produces six haplotypes, nucleotide (pi), haplotype diversity (Hd). In addition, the average number of nucleotide differences (k) is 0.001629±0.001036, 0.8083±0.0694 and 2.517, respectively. Also, dN/dS ratio is significantly below 1. These results indicated that giant panda had a low population genetic diversity, and an obvious purifying selection of the COX1 gene which reduces synthesis of ATP determines giant panda's low-energy bamboo diet. Phylogenetic trees based on the COX1 gene were constructed to demonstrate that giant panda is the sister group of other Ursidae. Copyright © 2016 Elsevier B.V. All rights reserved.

Upregulation of intrinsic apoptotic pathway in NSAIDs mediated chemoprevention of experimental lung carcinogenesis.

PubMed

Setia, Shruti; Sanyal, Sankar N

2012-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibition of cyclooxygenase-2 (COX-2), which is overexpressed in cancer. The role of COX-2 and apoptosis were evaluated in 9,10-dimethylbenz(a)anthracene (DMBA)-induced lung cancer in rat and chemoprevention with indomethacin, a traditional NSAID and etoricoxib, a selective COX-2 inhibitor. The animals were divided into Control, DMBA, DMBA+ indomethacin and DMBA+ etoricoxib groups. They received a single intratracheal instillation of DMBA while NSAIDs were given orally daily for 32 weeks. Besides morphology and histology of lungs, RT-PCR, western blots and immunohistochemistry were performed for the expression of apoptotic proteins and COX enzymes. Apoptosis was studied by DNA fragmentation and fluorescent staining. The occurrence of tumors and lesions was noted in the DMBA animals, besides constricted alveolar spaces and hyperplasia. COX-1 was found to be uniformly expressed while COX-2 level was raised significantly in DMBA group. The apoptotic proteins, apaf-1, caspase-9 and caspase-3 were highly diminished in DMBA group but restored to normal level in NSAIDs groups. Also, apoptosis was suppressed in carcinogen group by DNA fragmentation analysis and fluorescent staining of the lung cells while co-administration of NSAIDs along with DMBA led to the restoration of apoptosis. DMBA administration to the rats led to tumorigenesis in the lungs, had no effects on COX-1 expression, while elevating the COX-2 levels and suppressing apoptosis. The treatment with NSAIDs led to the amelioration of these effects. However, etoricoxib which is a COX-2 specific inhibitor, was found to be more effective than the traditional NSAID, indomethacin.

Human umbilical vein: involvement of cyclooxygenase-2 pathway in bradykinin B1 receptor-sensitized responses.

PubMed

Errasti, A E; Rey-Ares, V; Daray, F M; Rogines-Velo, M P; Sardi, S P; Paz, C; Podestá, E J; Rothlin, R P

2001-08-01

In isolated human umbilical vein (HUV), the contractile response to des-Arg9-bradykinin (des-Arg9-BK), selective BK B1 receptor agonist, increases as a function of the incubation time. Here, we evaluated whether cyclooxygenase (COX) pathway is involved in BK B1-sensitized response obtained in 5-h incubated HUV rings. The effect of different concentrations of indomethacin, sodium salicylate, ibuprofen, meloxicam, lysine clonixinate or NS-398 administrated 30 min before concentration-response curves (CRC) was studied. All treatments produced a significant rightward shift of the CRC to des-Arg9-BK in a concentration-dependent manner, which provides pharmacological evidence that COX pathway is involved in the BK B1 responses. Moreover, in this tissue, the NS-398 pKb (5.2) observed suggests that COX-2 pathway is the most relevant. The strong correlation between published pIC50 for COX-2 and the NSAIDs' pKbs estimated further supports the hypothesis that COX-2 metabolites are involved in BK B1 receptor-mediated responses. In other rings, indomethacin (30, 100 micromol/l) or NS-398 (10, 30 micromol/l) produced a significant rightward shift of the CRC to BK, selective BK B2 agonist, and its pKbs were similar to the values to inhibit BK B1 receptor responses, suggesting that COX-2 pathway also is involved in BK B2 receptor responses. Western blot analysis shows that COX-1 and COX-2 isoenzymes are present before and after 5-h in vitro incubation and apparently COX-2 does not suffer additional induction.

Missense mutations in SURF1 associated with deficient cytochrome c oxidase assembly in Leigh syndrome patients.

PubMed

Poyau, A; Buchet, K; Bouzidi, M F; Zabot, M T; Echenne, B; Yao, J; Shoubridge, E A; Godinot, C

2000-02-01

We have studied the fibroblasts of three patients suffering from Leigh syndrome associated with cytochrome c oxidase deficiency (LS-COX-). Their mitochondrial DNA was functional and all nuclear COX subunits had a normal sequence. The expression of transcripts encoding mitochondrial and nuclear COX subunits was normal or slightly increased. Similarly, the OXA1 transcript coding for a protein involved in COX assembly was increased. However, several COX-protein subunits were severely depressed, indicating deficient COX assembly. Surf1, a factor involved in COX biogenesis, was recently reported as mutated in LS-COX- patients, all mutations predicting a truncated protein. Sequence analysis of SURF1 gene in our three patients revealed seven heterozygous mutations, six of which were new : an insertion, a nonsense mutation, a splicing mutation of intron 7 in addition to three missense mutations. The mutation G385 A (Gly124-->Glu) changes a Gly that is strictly conserved in Surfl homologs of 12 species. The substitution G618 C (Asp202-->His), changing an Asp that is conserved only in mammals, appears to be a polymorphism. The mutation T751 C changes Ile246 to Thr, a position at which a hydrophobic amino acid is conserved in all eukaryotic and some bacterial species. Replacing Ile246 by Thr disrupts a predicted beta sheet structure present in all higher eukaryotes. COX activity could be restored in fibroblasts of the three patients by complementation with a retroviral vector containing normal SURF1 cDNA. These mutations identify domains essential to Surf1 protein structure and/or function.

Briaviolides K–N, New Briarane-Type Diterpenoids from Cultured Octocoral Briareum violaceum

PubMed Central

Xu, Jing-Hao; Lai, Kuei-Hung; Su, Yin-Di; Chang, Yu-Chia; Peng, Bo-Rong; Wen, Zhi-Hong

2018-01-01

Four new briarane diterpenoids, briaviolides K–N (1–4), have been obtained from the cultured-type octocoral Briareum violaceum. Using a spectroscopic approach, the structures of briaranes 1–4 were identified. This study employed an in vitro model of lipopolysaccharide (LPS)-induced inflammation in the murine macrophage RAW 264.7 cell line, and found that among the four briaranes, briarane 2 possessed anti-inflammatory activity against inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expressions in cells. In addition, principal component analysis using the chemical global positioning system (ChemGPS) for natural products (ChemGPS-NP) was employed in order to analyze the structure-activity relationship (SAR), and the results indicated that the ring conformation of the compound has a leading role in suppressing the expressions of pro-inflammatory iNOS and COX-2 proteins in macrophages. PMID:29495481

Synthesis, anti-inflammatory evaluation in vivo and docking studies of some new 5-(benzo[b]furan-2-ylmethyl)-6-methyl-pyridazin-3(2H)-one derivatives

NASA Astrophysics Data System (ADS)

Boukharsa, Youness; Lakhlili, Wiame; El harti, Jaouad; Meddah, Bouchra; Tiendrebeogo, Ramata Yvette; Taoufik, Jamal; El Abbes Faouzi, My; Ibrahimi, Azeddine; Ansar, M'hammed

2018-02-01

Seven novel 5-(benzo[b]furan-2-ylmethyl)-6-methyl-pyridazin-3(2H)-one derivatives (6a to 6g) have been synthesized by the condensation of appropriate 3-(benzofuran-2-ylmethylene)-4-oxopentanoic acid and hydrazine hydrate in ethanol. Structures of all compounds were elucidated by elemental analysis, IR, 1H NMR and 13C NMR. These compounds were tested for their anti-inflammatory activity in carrageenan-induced rat paw edema model. In silico molecular docking study has been executed to study the binding interactions of the synthesized compounds with COX-2 protein. Compounds 6a, 6b, 6e and 6g showed a good anti-inflammatory activity at 50 mg/kg compared with the indometacin at 10 mg/kg and the aspirin at 150 mg/kg and good binding affinity with COX-2.

Mortality in East African shorthorn zebu cattle under one year: predictors of infectious-disease mortality.

PubMed

Thumbi, Samuel M; Bronsvoort, Mark B M de C; Kiara, Henry; Toye, P G; Poole, Jane; Ndila, Mary; Conradie, Ilana; Jennings, Amy; Handel, Ian G; Coetzer, J A W; Steyl, Johan; Hanotte, Olivier; Woolhouse, Mark E J

2013-09-08

Infectious livestock diseases remain a major threat to attaining food security and are a source of economic and livelihood losses for people dependent on livestock for their livelihood. Knowledge of the vital infectious diseases that account for the majority of deaths is crucial in determining disease control strategies and in the allocation of limited funds available for disease control. Here we have estimated the mortality rates in zebu cattle raised in a smallholder mixed farming system during their first year of life, identified the periods of increased risk of death and the risk factors for calf mortality, and through analysis of post-mortem data, determined the aetiologies of calf mortality in this population. A longitudinal cohort study of 548 zebu cattle was conducted between 2007 and 2010. Each calf was followed during its first year of life or until lost from the study. Calves were randomly selected from 20 sub-locations and recruited within a week of birth from different farms over a 45 km radius area centered on Busia in the Western part of Kenya. The data comprised of 481.1 calf years of observation. Clinical examinations, sample collection and analysis were carried out at 5 week intervals, from birth until one year old. Cox proportional hazard models with frailty terms were used for the statistical analysis of risk factors. A standardized post-mortem examination was conducted on all animals that died during the study and appropriate samples collected. The all-cause mortality rate was estimated at 16.1 (13.0-19.2; 95% CI) per 100 calf years at risk. The Cox models identified high infection intensity with Theileria spp., the most lethal of which causes East Coast Fever disease, infection with Trypanosome spp., and helminth infections as measured by Strongyle spp. eggs per gram of faeces as the three important infections statistically associated with infectious disease mortality in these calves. Analysis of post-mortem data identified East Coast Fever as the main cause of death accounting for 40% of all deaths, haemonchosis 12% and heartwater disease 7%. The findings demonstrate the impact of endemic parasitic diseases in indigenous animals expected to be well adapted against disease pressures. Additionally, agreement between results of Cox models using data from simple diagnostic procedures and results from post-mortem analysis underline the potential use such diagnostic data to reduce calf mortality. The control strategies for the identified infectious diseases have been discussed.

Combining Gene Signatures Improves Prediction of Breast Cancer Survival

PubMed Central

Zhao, Xi; Naume, Bjørn; Langerød, Anita; Frigessi, Arnoldo; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Lingjærde, Ole Christian

2011-01-01

Background Several gene sets for prediction of breast cancer survival have been derived from whole-genome mRNA expression profiles. Here, we develop a statistical framework to explore whether combination of the information from such sets may improve prediction of recurrence and breast cancer specific death in early-stage breast cancers. Microarray data from two clinically similar cohorts of breast cancer patients are used as training (n = 123) and test set (n = 81), respectively. Gene sets from eleven previously published gene signatures are included in the study. Principal Findings To investigate the relationship between breast cancer survival and gene expression on a particular gene set, a Cox proportional hazards model is applied using partial likelihood regression with an L2 penalty to avoid overfitting and using cross-validation to determine the penalty weight. The fitted models are applied to an independent test set to obtain a predicted risk for each individual and each gene set. Hierarchical clustering of the test individuals on the basis of the vector of predicted risks results in two clusters with distinct clinical characteristics in terms of the distribution of molecular subtypes, ER, PR status, TP53 mutation status and histological grade category, and associated with significantly different survival probabilities (recurrence: p = 0.005; breast cancer death: p = 0.014). Finally, principal components analysis of the gene signatures is used to derive combined predictors used to fit a new Cox model. This model classifies test individuals into two risk groups with distinct survival characteristics (recurrence: p = 0.003; breast cancer death: p = 0.001). The latter classifier outperforms all the individual gene signatures, as well as Cox models based on traditional clinical parameters and the Adjuvant! Online for survival prediction. Conclusion Combining the predictive strength of multiple gene signatures improves prediction of breast cancer survival. The presented methodology is broadly applicable to breast cancer risk assessment using any new identified gene set. PMID:21423775

Abalone visceral extract inhibit tumor growth and metastasis by modulating Cox-2 levels and CD8+ T cell activity.

PubMed

Lee, Choong-Gu; Kwon, Ho-Keun; Ryu, Jae Ha; Kang, Sung Jin; Im, Chang-Rok; Ii Kim, Jae; Im, Sin-Hyeog

2010-10-20

Abalone has long been used as a valuable food source in East Asian countries. Although the nutritional importance of abalone has been reported through in vitro and in vivo studies, there is little evidence about the potential anti-tumor effects of abalone visceral extract. The aim of the present study is to examine anti-tumor efficacy of abalone visceral extract and to elucidate its working mechanism. In the present study, we used breast cancer model using BALB/c mouse-derived 4T1 mammary carcinoma and investigated the effect of abalone visceral extract on tumor development. Inhibitory effect against tumor metastasis was assessed by histopathology of lungs. Cox-2 productions by primary and secondary tumor were measured by real-time RT-PCR and immunoblotting (IB). Proliferation assay based on [3H]-thymidine incorporation and measurement of cytokines and effector molecules by RT-PCR were used to confirm tumor suppression efficacy of abalone visceral extract by modulating cytolytic CD8+ T cells. The cytotoxicity of CD8+ T cell was compared by JAM test. Oral administration of abalone visceral extract reduced tumor growth (tumor volume and weight) and showed reduced metastasis as confirmed by decreased level of splenomegaly (spleen size and weight) and histological analysis of the lung metastasis (gross analysis and histological staining). Reduced expression of Cox-2 (mRNA and protein) from primary tumor and metastasized lung was also detected. In addition, treatment of abalone visceral extract increased anti-tumor activities of CD8+ T cells by increasing the proliferation capacity and their cytolytic activity. Our results suggest that abalone visceral extract has anti-tumor effects by suppressing tumor growth and lung metastasis through decreasing Cox-2 expression level as well as promoting proliferation and cytolytic function of CD8+ T cells.

Abalone visceral extract inhibit tumor growth and metastasis by modulating Cox-2 levels and CD8+ T cell activity

PubMed Central

2010-01-01

Background Abalone has long been used as a valuable food source in East Asian countries. Although the nutritional importance of abalone has been reported through in vitro and in vivo studies, there is little evidence about the potential anti-tumor effects of abalone visceral extract. The aim of the present study is to examine anti-tumor efficacy of abalone visceral extract and to elucidate its working mechanism. Methods In the present study, we used breast cancer model using BALB/c mouse-derived 4T1 mammary carcinoma and investigated the effect of abalone visceral extract on tumor development. Inhibitory effect against tumor metastasis was assessed by histopathology of lungs. Cox-2 productions by primary and secondary tumor were measured by real-time RT-PCR and immunoblotting (IB). Proliferation assay based on [3H]-thymidine incorporation and measurement of cytokines and effector molecules by RT-PCR were used to confirm tumor suppression efficacy of abalone visceral extract by modulating cytolytic CD8+ T cells. The cytotoxicity of CD8+ T cell was compared by JAM test. Results Oral administration of abalone visceral extract reduced tumor growth (tumor volume and weight) and showed reduced metastasis as confirmed by decreased level of splenomegaly (spleen size and weight) and histological analysis of the lung metastasis (gross analysis and histological staining). Reduced expression of Cox-2 (mRNA and protein) from primary tumor and metastasized lung was also detected. In addition, treatment of abalone visceral extract increased anti-tumor activities of CD8+ T cells by increasing the proliferation capacity and their cytolytic activity. Conclusions Our results suggest that abalone visceral extract has anti-tumor effects by suppressing tumor growth and lung metastasis through decreasing Cox-2 expression level as well as promoting proliferation and cytolytic function of CD8+ T cells. PMID:20961430

Optimal transformations leading to normal distributions of positron emission tomography standardized uptake values.

PubMed

Scarpelli, Matthew; Eickhoff, Jens; Cuna, Enrique; Perlman, Scott; Jeraj, Robert

2018-01-30

The statistical analysis of positron emission tomography (PET) standardized uptake value (SUV) measurements is challenging due to the skewed nature of SUV distributions. This limits utilization of powerful parametric statistical models for analyzing SUV measurements. An ad-hoc approach, which is frequently used in practice, is to blindly use a log transformation, which may or may not result in normal SUV distributions. This study sought to identify optimal transformations leading to normally distributed PET SUVs extracted from tumors and assess the effects of therapy on the optimal transformations. The optimal transformation for producing normal distributions of tumor SUVs was identified by iterating the Box-Cox transformation parameter (λ) and selecting the parameter that maximized the Shapiro-Wilk P-value. Optimal transformations were identified for tumor SUV max distributions at both pre and post treatment. This study included 57 patients that underwent 18 F-fluorodeoxyglucose ( 18 F-FDG) PET scans (publically available dataset). In addition, to test the generality of our transformation methodology, we included analysis of 27 patients that underwent 18 F-Fluorothymidine ( 18 F-FLT) PET scans at our institution. After applying the optimal Box-Cox transformations, neither the pre nor the post treatment 18 F-FDG SUV distributions deviated significantly from normality (P  >  0.10). Similar results were found for 18 F-FLT PET SUV distributions (P  >  0.10). For both 18 F-FDG and 18 F-FLT SUV distributions, the skewness and kurtosis increased from pre to post treatment, leading to a decrease in the optimal Box-Cox transformation parameter from pre to post treatment. There were types of distributions encountered for both 18 F-FDG and 18 F-FLT where a log transformation was not optimal for providing normal SUV distributions. Optimization of the Box-Cox transformation, offers a solution for identifying normal SUV transformations for when the log transformation is insufficient. The log transformation is not always the appropriate transformation for producing normally distributed PET SUVs.

Optimal transformations leading to normal distributions of positron emission tomography standardized uptake values

NASA Astrophysics Data System (ADS)

Scarpelli, Matthew; Eickhoff, Jens; Cuna, Enrique; Perlman, Scott; Jeraj, Robert

2018-02-01

The statistical analysis of positron emission tomography (PET) standardized uptake value (SUV) measurements is challenging due to the skewed nature of SUV distributions. This limits utilization of powerful parametric statistical models for analyzing SUV measurements. An ad-hoc approach, which is frequently used in practice, is to blindly use a log transformation, which may or may not result in normal SUV distributions. This study sought to identify optimal transformations leading to normally distributed PET SUVs extracted from tumors and assess the effects of therapy on the optimal transformations. Methods. The optimal transformation for producing normal distributions of tumor SUVs was identified by iterating the Box-Cox transformation parameter (λ) and selecting the parameter that maximized the Shapiro-Wilk P-value. Optimal transformations were identified for tumor SUVmax distributions at both pre and post treatment. This study included 57 patients that underwent 18F-fluorodeoxyglucose (18F-FDG) PET scans (publically available dataset). In addition, to test the generality of our transformation methodology, we included analysis of 27 patients that underwent 18F-Fluorothymidine (18F-FLT) PET scans at our institution. Results. After applying the optimal Box-Cox transformations, neither the pre nor the post treatment 18F-FDG SUV distributions deviated significantly from normality (P  >  0.10). Similar results were found for 18F-FLT PET SUV distributions (P  >  0.10). For both 18F-FDG and 18F-FLT SUV distributions, the skewness and kurtosis increased from pre to post treatment, leading to a decrease in the optimal Box-Cox transformation parameter from pre to post treatment. There were types of distributions encountered for both 18F-FDG and 18F-FLT where a log transformation was not optimal for providing normal SUV distributions. Conclusion. Optimization of the Box-Cox transformation, offers a solution for identifying normal SUV transformations for when the log transformation is insufficient. The log transformation is not always the appropriate transformation for producing normally distributed PET SUVs.

Cyclooxygenase-2 deficiency impairs muscle-derived stem cell-mediated bone regeneration via cellular autonomous and non-autonomous mechanisms.

PubMed

Gao, Xueqin; Usas, Arvydas; Lu, Aiping; Kozemchak, Adam; Tang, Ying; Poddar, Minakshi; Sun, Xuying; Cummins, James H; Huard, Johnny

2016-08-01

This study investigated the role of cyclooxygenase-2 (COX-2) expression by donor and host cells in muscle-derived stem cell (MDSC)-mediated bone regeneration utilizing a critical size calvarial defect model. We found that BMP4/green fluorescent protein (GFP)-transduced MDSCs formed significantly less bone in COX-2 knock-out (Cox-2KO) than in COX-2 wild-type (WT) mice. BMP4/GFP-transduced Cox-2KO MDSCs also formed significantly less bone than transduced WT MDSCs when transplanted into calvarial defects created in CD-1 nude mice. The impaired bone regeneration in the Cox-2KO MDSCBMP4/GFP group is associated with downregulation of BMP4-pSMAD1/5 signaling, decreased osteogenic differentiation and lowered proliferation capacity after transplantation, compared with WT MDSCBMP4/GFP cells. The Cox-2KO MDSCBMP4/GFP group demonstrated a reduction in cell survival and direct osteogenic differentiation in vitro These effects were mediated in part by the downregulation of Igf1 and Igf2. In addition, the Cox-2KO MDSCBMP4/GFP cells recruited fewer macrophages than the WT MDSC/BMP4/GFP cells in the early phase after injury. We concluded that the bone regeneration capacity of Cox-2KO MDSCs was impaired because of a reduction in cell proliferation and survival capacities, reduction in osteogenic differentiation and a decrease in the ability of the cells to recruit host cells to the injury site. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Comparison of Cox's and relative survival models when estimating the effects of prognostic factors on disease-specific mortality: a simulation study under proportional excess hazards.

PubMed

Le Teuff, Gwenaël; Abrahamowicz, Michal; Bolard, Philippe; Quantin, Catherine

2005-12-30

In many prognostic studies focusing on mortality of persons affected by a particular disease, the cause of death of individual patients is not recorded. In such situations, the conventional survival analytical methods, such as the Cox's proportional hazards regression model, do not allow to discriminate the effects of prognostic factors on disease-specific mortality from their effects on all-causes mortality. In the last decade, the relative survival approach has been proposed to deal with the analyses involving population-based cancer registries, where the problem of missing information on the cause of death is very common. However, some questions regarding the ability of the relative survival methods to accurately discriminate between the two sources of mortality remain open. In order to systematically assess the performance of the relative survival model proposed by Esteve et al., and to quantify its potential advantages over the Cox's model analyses, we carried out a series of simulation experiments, based on the population-based colon cancer registry in the French region of Burgundy. Simulations showed a systematic bias induced by the 'crude' conventional Cox's model analyses when individual causes of death are unknown. In simulations where only about 10 per cent of patients died of causes other than colon cancer, the Cox's model over-estimated the effects of male gender and oldest age category by about 17 and 13 per cent, respectively, with the coverage rate of the 95 per cent CI for the latter estimate as low as 65 per cent. In contrast, the effect of higher cancer stages was under-estimated by 8-28 per cent. In contrast to crude survival, relative survival model largely reduced such problems and handled well even such challenging tasks as separating the opposite effects of the same variable on cancer-related versus other-causes mortality. Specifically, in all the cases discussed above, the relative bias in the estimates from the Esteve et al.'s model was always below 10 per cent, with the coverage rates above 81 per cent. Copyright 2005 John Wiley & Sons, Ltd.

Elucidating the role of Cyclooxygenase-2 in the pathogenesis of oral lichen planus - an immunohistochemical study with supportive histochemical analysis.

PubMed

Singh, Pratyush; Grover, Jasleen; Byatnal, Aditi Amit; Guddattu, Vasudeva; Radhakrishnan, Raghu; Solomon, Monica Charlotte

2017-05-01

Oral lichen planus (OLP) is a chronic, inflammatory disorder that affects the oral mucous membrane. During an inflammatory response, several chemokines and cytokines are released by the cells of the immune system. Activation of MMPs, along with mast cell-derived chymase and tryptase, degrades the basement membrane structural proteins, resulting in basement membrane breaks. To investigate the association between the COX-2 expressions, presence of intact or degranulating mast cells within the connective tissue and the extent of basement membrane discontinuity in OLP cases. This study included a total of 50 formalin-fixed paraffin-embedded specimens (FFPE) of histologically confirmed cases of idiopathic oral lichen planus. A retrospective cross-sectional analysis was carried out by immunohistochemistry to study the epithelial expression of COX-2 and by the use of special stains such as toluidine blue and periodic acid-Schiff (PAS) to study the mast cell count and basement membrane changes in the oral mucosal tissue, respectively. There was a significant (P = 0.03) association between the COX-2 expressions and mast cell count. As the intensity of COX-2 expression increased from mild to moderate or severe, the number of mast cell count almost doubled. Interaction between upregulation of COX-2, mast cell and basement membrane sets a vicious cycle which relates to the chronic nature of the disease. Inhibitors of COX-2 may reduce the inflammatory process preceding the immune dysregulation in OLP. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A dual inhibitor of cyclooxygenase and 5-lipoxygenase protects against kainic acid-induced brain injury.

PubMed

Minutoli, Letteria; Marini, Herbert; Rinaldi, Mariagrazia; Bitto, Alessandra; Irrera, Natasha; Pizzino, Gabriele; Pallio, Giovanni; Calò, Margherita; Adamo, Elena Bianca; Trichilo, Vincenzo; Interdonato, Monica; Galfo, Federica; Squadrito, Francesco; Altavilla, Domenica

2015-06-01

Systemic administration of kainic acid causes inflammation and apoptosis in the brain, resulting in neuronal loss. Dual cyclooxygenase/5-lipoxygenase (COX/5-LOX) inhibitors could represent a possible neuroprotective approach in preventing glutamate excitotoxicity. Consequently, we investigated the effects of a dual inhibitor of COX/5-LOX following intraperitoneal administration of kainic acid (KA, 10 mg/kg) in rats. Animals were randomized to receive either the dual inhibitor of COX/5-LOX (flavocoxid, 20 mg/kg i.p.) or its vehicle (1 ml/kg i.p.) 30 min after KA administration. Sham brain injury rats were used as controls. We evaluated protein expression of phosphorylated extracellular signal-regulated kinase (p-ERK1/2) and tumor necrosis factor alpha (TNF-α) as well as levels of malondialdehyde (MDA), prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the hippocampus. Animals were also observed for monitoring behavioral changes according to Racine Scale. Finally, histological analysis and brain edema evaluation were carried out. Treatment with the dual inhibitor of COX/5-LOX decreased protein expression of p-ERK1/2 and TNF-α in hippocampus, markedly reduced MDA, LTB4 and PGE2 hippocampal levels, and also ameliorated brain edema. Histological analysis showed a reduction in cell damage in rats treated with the dual inhibitor of COX/5-LOX, particularly in hippocampal subregion CA3c. Moreover, flavocoxid significantly improved behavioral signs following kainic acid administration. Our results suggest that dual inhibition of COX/5-LOX by flavocoxid has neuroprotective effects during kainic acid-induced excitotoxicity.

Markov Transition Model to Dementia with Death as a Competing Event.

PubMed

Wei, Shaoceng; Xu, Liou; Kryscio, Richard J

2014-12-01

This study evaluates the effect of death as a competing event to the development of dementia in a longitudinal study of the cognitive status of elderly subjects. A multi-state Markov model with three transient states: intact cognition, mild cognitive impairment (M.C.I.) and global impairment (G.I.) and one absorbing state: dementia is used to model the cognitive panel data; transitions among states depend on four covariates age, education, prior state (intact cognition, or M.C.I., or G.I.) and the presence/absence of an apolipoprotein E-4 allele (APOE4). A Weibull model and a Cox proportional hazards (Cox PH) model are used to fit the survival from death based on age at entry and the APOE4 status. A shared random effect correlates this survival time with the transition model. Simulation studies determine the sensitivity of the maximum likelihood estimates to the violations of the Weibull and Cox PH model assumptions. Results are illustrated with an application to the Nun Study, a longitudinal cohort of 672 participants 75+ years of age at baseline and followed longitudinally with up to ten cognitive assessments per nun.

Markov Transition Model to Dementia with Death as a Competing Event

PubMed Central

Wei, Shaoceng; Xu, Liou; Kryscio, Richard J.

2014-01-01

This study evaluates the effect of death as a competing event to the development of dementia in a longitudinal study of the cognitive status of elderly subjects. A multi-state Markov model with three transient states: intact cognition, mild cognitive impairment (M.C.I.) and global impairment (G.I.) and one absorbing state: dementia is used to model the cognitive panel data; transitions among states depend on four covariates age, education, prior state (intact cognition, or M.C.I., or G.I.) and the presence/absence of an apolipoprotein E-4 allele (APOE4). A Weibull model and a Cox proportional hazards (Cox PH) model are used to fit the survival from death based on age at entry and the APOE4 status. A shared random effect correlates this survival time with the transition model. Simulation studies determine the sensitivity of the maximum likelihood estimates to the violations of the Weibull and Cox PH model assumptions. Results are illustrated with an application to the Nun Study, a longitudinal cohort of 672 participants 75+ years of age at baseline and followed longitudinally with up to ten cognitive assessments per nun. PMID:25110380

Application of random survival forests in understanding the determinants of under-five child mortality in Uganda in the presence of covariates that satisfy the proportional and non-proportional hazards assumption.

PubMed

Nasejje, Justine B; Mwambi, Henry

2017-09-07

Uganda just like any other Sub-Saharan African country, has a high under-five child mortality rate. To inform policy on intervention strategies, sound statistical methods are required to critically identify factors strongly associated with under-five child mortality rates. The Cox proportional hazards model has been a common choice in analysing data to understand factors strongly associated with high child mortality rates taking age as the time-to-event variable. However, due to its restrictive proportional hazards (PH) assumption, some covariates of interest which do not satisfy the assumption are often excluded in the analysis to avoid mis-specifying the model. Otherwise using covariates that clearly violate the assumption would mean invalid results. Survival trees and random survival forests are increasingly becoming popular in analysing survival data particularly in the case of large survey data and could be attractive alternatives to models with the restrictive PH assumption. In this article, we adopt random survival forests which have never been used in understanding factors affecting under-five child mortality rates in Uganda using Demographic and Health Survey data. Thus the first part of the analysis is based on the use of the classical Cox PH model and the second part of the analysis is based on the use of random survival forests in the presence of covariates that do not necessarily satisfy the PH assumption. Random survival forests and the Cox proportional hazards model agree that the sex of the household head, sex of the child, number of births in the past 1 year are strongly associated to under-five child mortality in Uganda given all the three covariates satisfy the PH assumption. Random survival forests further demonstrated that covariates that were originally excluded from the earlier analysis due to violation of the PH assumption were important in explaining under-five child mortality rates. These covariates include the number of children under the age of five in a household, number of births in the past 5 years, wealth index, total number of children ever born and the child's birth order. The results further indicated that the predictive performance for random survival forests built using covariates including those that violate the PH assumption was higher than that for random survival forests built using only covariates that satisfy the PH assumption. Random survival forests are appealing methods in analysing public health data to understand factors strongly associated with under-five child mortality rates especially in the presence of covariates that violate the proportional hazards assumption.

Impact of Insecticide-Treated Net Ownership on All-Cause Child Mortality in Malawi, 2006-2010.

PubMed

Florey, Lia S; Bennett, Adam; Hershey, Christine L; Bhattarai, Achuyt; Nielsen, Carrie F; Ali, Doreen; Luhanga, Misheck; Taylor, Cameron; Eisele, Thomas P; Yé, Yazoume

2017-09-01

Insecticide-treated nets (ITNs) have been shown to be highly effective at reducing malaria morbidity and mortality in children. However, there are limited studies that assess the association between increasing ITN coverage and child mortality over time, at the national level, and under programmatic conditions. Two analytic approaches were used to examine this association: a retrospective cohort analysis of individual children and a district-level ecologic analysis. To evaluate the association between household ITN ownership and all-cause child mortality (ACCM) at the individual level, data from the 2010 Demographic and Health Survey (DHS) were modeled in a Cox proportional hazards framework while controlling for numerous environmental, household, and individual confounders through the use of exact matching. To evaluate population-level association between ITN ownership and ACCM between 2006 and 2010, program ITN distribution data and mortality data from the 2006 Multiple Indicator Cluster Survey and the 2010 DHS were aggregated at the district level and modeled using negative binomial regression. In the Cox model controlling for household, child and maternal health factors, children between 1 and 59 months in households owning an ITN had significantly lower mortality compared with those without an ITN (hazard ratio = 0.75, 95% confidence interval [CI] = 0.62-90). In the district-level model, higher ITN ownership was significantly associated with lower ACCM (incidence rate ratio = 0.77; 95% CI = 0.60-0.98). These findings suggest that increasing ITN ownership may have contributed to the decline in ACCM during 2006-2010 in Malawi and represent a novel use of district-level data from nationally representative surveys.

Comparison of the risk factors effects between two populations: two alternative approaches illustrated by the analysis of first and second kidney transplant recipients

PubMed Central

2013-01-01

Background Whereas the prognosis of second kidney transplant recipients (STR) compared to the first ones has been frequently analyzed, no study has addressed the issue of comparing the risk factor effects on graft failure between both groups. Methods Here, we propose two alternative strategies to study the heterogeneity of risk factors between two groups of patients: (i) a multiplicative-regression model for relative survival (MRS) and (ii) a stratified Cox model (SCM) specifying the graft rank as strata and assuming subvectors of the explicatives variables. These developments were motivated by the analysis of factors associated with time to graft failure (return-to-dialysis or patient death) in second kidney transplant recipients (STR) compared to the first ones. Estimation of the parameters was based on partial likelihood maximization. Monte-Carlo simulations associated with bootstrap re-sampling was performed to calculate the standard deviations for the MRS. Results We demonstrate, for the first time in renal transplantation, that: (i) male donor gender is a specific risk factor for STR, (ii) the adverse effect of recipient age is enhanced for STR and (iii) the graft failure risk related to donor age is attenuated for STR. Conclusion While the traditional Cox model did not provide original results based on the renal transplantation literature, the proposed relative and stratified models revealed new findings that are useful for clinicians. These methodologies may be of interest in other medical fields when the principal objective is the comparison of risk factors between two populations. PMID:23915191

Cyclooxygenase Inhibition in Sepsis: Is There Life after Death?

PubMed Central

Aronoff, David M.

2012-01-01

Prostaglandins are important mediators and modulators of the inflammatory response to infection. The prostaglandins participate in the pathogenesis of hemodynamic collapse, organ failure, and overwhelming inflammation that characterize severe sepsis and shock. In light of this, cyclooxygenase (COX) inhibiting pharmacological agents have been extensively studied for their capacity to ameliorate the aberrant physiological and immune responses during severe sepsis. Animal models of sepsis, using the systemic administration of pathogen-associated molecular patterns (PAMPs) or live pathogens, have been used to examine the effectiveness of COX inhibition as a treatment for severe sepsis. These studies have largely shown beneficial effects on mortality. However, human studies have failed to show clinical utility of COX inhibitor treatment in severely septic patients. Why this approach “worked” in animals but not in humans might reflect differences in the controlled nature of animal investigations compared to human studies. This paper contrasts the impact of COX inhibitors on mortality in animal models of sepsis and human studies of sepsis and examines potential reasons for differences between these two settings. PMID:22665954

Preserved heart function and maintained response to cardiac stresses in a genetic model of cardiomyocyte-targeted deficiency of cyclooxygenase-2

PubMed Central

Papanicolaou, Kyriakos N.; Streicher, John M.; Ishikawa, Tomo-o; Herschman, Harvey; Wang, Yibin; Walsh, Kenneth

2010-01-01

Cyclooxygenase-1 and -2 are rate-limiting enzymes in the formation of a wide array of bioactive lipid mediators collectively known as prostanoids (prostaglandins, prostacyclins, thromboxanes). Evidence from clinical trials shows that selective inhibition of the second isoenzyme (cyclooxygenase-2, or Cox-2) is associated with increased risk for serious cardiovascular events and findings from animal-based studies have suggested protective roles of Cox-2 for the heart. To further characterize the function of Cox-2 in the heart, mice with loxP sites flanking exons 4 and 5 of Cox-2 were rendered knockout specifically in cardiac myocytes (Cox-2 CKO mice) via cre-mediated recombination. Baseline cardiac performance of CKO mice remained unchanged and closely resembled that of control mice. Furthermore, myocardial infarct size induced after in vivo ischemia/reperfusion (I/R) injury was comparable between CKO and control mice. In addition, cardiac hypertrophy and function four weeks after transverse aortic constriction (TAC) was found to be similar between the two groups. Assessment of Cox-2 expression in purified adult cardiac cells isolated after I/R and TAC suggests that the dominant source of Cox-2 is found in the non-myocyte fraction. In conclusion, our animal-based analyses together with the cell-based observations portray a limited role of cardiomyocyte-produced Cox-2 at baseline and in the context of ischemic or hemodynamic challenge. PMID:20399788

A comparison of Cox and logistic regression for use in genome-wide association studies of cohort and case-cohort design.

PubMed

Staley, James R; Jones, Edmund; Kaptoge, Stephen; Butterworth, Adam S; Sweeting, Michael J; Wood, Angela M; Howson, Joanna M M

2017-06-01

Logistic regression is often used instead of Cox regression to analyse genome-wide association studies (GWAS) of single-nucleotide polymorphisms (SNPs) and disease outcomes with cohort and case-cohort designs, as it is less computationally expensive. Although Cox and logistic regression models have been compared previously in cohort studies, this work does not completely cover the GWAS setting nor extend to the case-cohort study design. Here, we evaluated Cox and logistic regression applied to cohort and case-cohort genetic association studies using simulated data and genetic data from the EPIC-CVD study. In the cohort setting, there was a modest improvement in power to detect SNP-disease associations using Cox regression compared with logistic regression, which increased as the disease incidence increased. In contrast, logistic regression had more power than (Prentice weighted) Cox regression in the case-cohort setting. Logistic regression yielded inflated effect estimates (assuming the hazard ratio is the underlying measure of association) for both study designs, especially for SNPs with greater effect on disease. Given logistic regression is substantially more computationally efficient than Cox regression in both settings, we propose a two-step approach to GWAS in cohort and case-cohort studies. First to analyse all SNPs with logistic regression to identify associated variants below a pre-defined P-value threshold, and second to fit Cox regression (appropriately weighted in case-cohort studies) to those identified SNPs to ensure accurate estimation of association with disease.

The anti-tumor effect of HDAC inhibition in a human pancreas cancer model is significantly improved by the simultaneous inhibition of cyclooxygenase 2.

PubMed

Peulen, Olivier; Gonzalez, Arnaud; Peixoto, Paul; Turtoi, Andrei; Mottet, Denis; Delvenne, Philippe; Castronovo, Vincent

2013-01-01

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death worldwide, with no satisfactory treatment to date. In this study, we tested whether the combined inhibition of cyclooxygenase-2 (COX-2) and class I histone deacetylase (HDAC) may results in a better control of pancreatic ductal adenocarcinoma. The impact of the concomitant HDAC and COX-2 inhibition on cell growth, apoptosis and cell cycle was assessed first in vitro on human pancreas BxPC-3, PANC-1 or CFPAC-1 cells treated with chemical inhibitors (SAHA, MS-275 and celecoxib) or HDAC1/2/3/7 siRNA. To test the potential antitumoral activity of this combination in vivo, we have developed and characterized, a refined chick chorioallantoic membrane tumor model that histologically and proteomically mimics human pancreatic ductal adenocarcinoma. The combination of HDAC1/3 and COX-2 inhibition significantly impaired proliferation of BxPC-3 cells in vitro and stalled entirely the BxPC-3 cells tumor growth onto the chorioallantoic membrane in vivo. The combination was more effective than either drug used alone. Consistently, we showed that both HDAC1 and HDAC3 inhibition induced the expression of COX-2 via the NF-kB pathway. Our data demonstrate, for the first time in a Pancreatic Ductal Adenocarcinoma (PDAC) model, a significant action of HDAC and COX-2 inhibitors on cancer cell growth, which sets the basis for the development of potentially effective new combinatory therapies for pancreatic ductal adenocarcinoma patients.

Analgesic Effect of the Newly Developed S(+)‐Flurbiprofen Plaster on Inflammatory Pain in a Rat Adjuvant‐Induced Arthritis Model

PubMed Central

Toda, Yoshihisa; Hori, Miyuki; Mitani, Akiko; Ichihara, Takahiro; Sekine, Shingo; Hirose, Takuya; Endo, Hiromi; Futaki, Nobuko; Kaku, Shinsuke; Otsuka, Noboru; Matsumoto, Hideo

2016-01-01

ABSTRACT Preclinical Research This article describes the properties of a novel topical NSAID (Nonsteroidal anti‐inflammatory drug) patch, SFPP (S(+)‐flurbiprofen plaster), containing the potent cyclooxygenase (COX) inhibitor, S(+)‐flurbiprofen (SFP). The present studies were conducted to confirm human COX inhibition and absorption of SFP and to evaluate the analgesic efficacy of SFPP in a rat adjuvant‐induced arthritis (AIA) model. COX inhibition by SFP, ketoprofen and loxoprofen was evaluated using human recombinant COX proteins. Absorption of SFPP, ketoprofen and loxoprofen from patches through rat skin was assessed 24 h after application. The AIA model was induced by injecting Mycobacterium tuberculosis followed 20 days later by the evaluation of the prostaglandin PGE2 content of the inflamed paw and the pain threshold. SFP exhibited more potent inhibitory activity against COX‐1 (IC50 = 8.97 nM) and COX‐2 (IC50 = 2.94 nM) than the other NSAIDs evaluated. Absorption of SFP was 92.9%, greater than that of ketoprofen and loxoprofen from their respective patches. Application of SFPP decreased PGE2 content from 15 min to 6 h and reduced paw hyperalgesia compared with the control, ketoprofen and loxoprofen patches. SFPP showed analgesic efficacy, and was superior to the ketoprofen and loxoprofen patches, which could be through the potent COX inhibitory activity of SFP and greater skin absorption. The results suggested SFPP can be expected to exert analgesic effect clinically. Drug Dev Res 76 : 20–28, 2016. © 2016 Wiley Periodicals, Inc. PMID:26763139

Altered metabolic activity in the developing brain of rats predisposed to high versus low depression-like behavior

PubMed Central

Melendez-Ferro, Miguel; Perez-Costas, Emma; Glover, Matthew E.; Jackson, Nateka L.; Stringfellow, Sara A.; Pugh, Phyllis C.; Fant, Andrew D.; Clinton, Sarah M.

2016-01-01

Individual differences in human temperament can increase risk for psychiatric disorders like depression and anxiety. Our laboratory utilized a rat model of temperamental differences to assess neurodevelopmental factors underlying emotional behavior differences. Rats selectively bred for low novelty exploration (Low Responders, LR) display high levels of anxiety- and depression-like behavior compared to High Novelty Responder (HR) rats. Using transcriptome profiling, the present study uncovered vast gene expression differences in the early postnatal HR versus LR limbic brain, including changes in genes involved in cellular metabolism. These data led us to hypothesize that rats prone to high (versus low) anxiety/depression-like behavior exhibit distinct patterns of brain metabolism during the first weeks of life, which may reflect disparate patterns of synaptogenesis and brain circuit development. Thus, in a second experiment we examined activity of Cytochrome C Oxidase (COX), an enzyme responsible for ATP production and a correlate of metabolic activity, to explore functional energetic differences in HR/LR early postnatal brain. We found that HR rats display higher COX activity in the amygdala and specific hippocampal subregions compared to LRs during the first 2 weeks of life. Correlational analysis examining COX levels across several brain regions and multiple early postnatal time points suggested desynchronization in the developmental timeline of the limbic HR versus LR brain during the first two postnatal weeks. These early divergent COX activity levels may reflect altered circuitry or synaptic activity in the early postnatal HR/LR brain, which could contribute to the emergence of their distinct behavioral phenotypes. PMID:26979051

Molecular docking, synthesis and biological screening of mefenamic acid derivatives as anti-inflammatory agents.

PubMed

Savjani, Jignasa K; Mulamkattil, Suja; Variya, Bhavesh; Patel, Snehal

2017-04-15

Drug induced gastrointestinal ulceration, renal side effects and hepatotoxicity are the main causes of numerous Non-Steroidal Anti-inflammatory Drugs (NSAIDs). Cyclooxygenase-2 (COX-2) inhibitors discovered to decrease the gastrointestinal issues, but unfortunately, most of them are associated with major cardiovascular adverse effects. Along these lines, various new strategies and frameworks were developed wherein basic alterations of the present medications were accounted for. The aim of the study was to prepare derivatives of mefenamic acid to evaluate anti-inflammatory activity with fewer adverse reactions. In this study, molecular docking investigations of outlined derivatives were done utilizing Protein Data Bank (PDB ID-4PH9). Synthesis of heterocyclic compounds was carried out utilizing Dicyclohexylcarbodiimide/4-Dimethylaminopyridine (DCC/DMAP) coupling. Acute toxicity prediction was performed using free online GUSAR (General Unrestricted Structure-Activity Relationships) software. The study indicated most of the compounds under safe category. In-vitro pharmacological assessment of heterocyclic compounds was done for COX-1 and COX-2 enzymes for the determination of selectivity. In vivo pharmacological screening for anti-inflammatory activity and ED 50 value were determined utilizing carrageenan induced rat paw edema. Gastro intestinal safety study was carried out on selected compounds and found to be devoid of any gastric ulcer toxicity. Most of the compounds indicated high scores as compared to standard during molecular modelling, analysis and displayed interactions with active amino acids of a COX-2 enzyme. The pharmacological screening uncovered that compound substituted with p-bromophenyl indicated maximum potency. Copyright © 2017 Elsevier B.V. All rights reserved.

Molecular characterization of freshwater snails in the genus Bulinus: a role for barcodes?

PubMed Central

Kane, Richard A; Stothard, J Russell; Emery, Aidan M; Rollinson, David

2008-01-01

Background Reliable and consistent methods are required for the identification and classification of freshwater snails belonging to the genus Bulinus (Gastropoda, Planorbidae) which act as intermediate hosts for schistosomes of both medical and veterinary importance. The current project worked towards two main objectives, the development of a cost effective, simple screening method for the routine identification of Bulinus isolates and the use of resultant sequencing data to produce a model of relationships within the group. Results Phylogenetic analysis of the DNA sequence for a large section (1009 bp) of the mitochondrial gene cytochrome oxidase subunit 1 (cox1) for isolates of Bulinus demonstrated superior resolution over that employing the second internal transcribed spacer (its2) of the ribosomal gene complex. Removal of transitional substitutions within cox1 because of saturation effects still allowed identification of snails at species group level. Within groups, some species could be identified with ease but there were regions where the high degree of molecular diversity meant that clear identification of species was problematic, this was particularly so within the B. africanus group. Conclusion The sequence diversity within cox1 is such that a barcoding approach may offer the best method for characterization of populations and species within the genus from different geographical locations. The study has confirmed the definition of some accepted species within the species groups but additionally has revealed some unrecognized isolates which underlines the need to use molecular markers in addition to more traditional methods of identification. A barcoding approach based on part of the cox1 gene as defined by the Folmer primers is proposed. PMID:18544153

A fast identification algorithm for Box-Cox transformation based radial basis function neural network.

PubMed

Hong, Xia

2006-07-01

In this letter, a Box-Cox transformation-based radial basis function (RBF) neural network is introduced using the RBF neural network to represent the transformed system output. Initially a fixed and moderate sized RBF model base is derived based on a rank revealing orthogonal matrix triangularization (QR decomposition). Then a new fast identification algorithm is introduced using Gauss-Newton algorithm to derive the required Box-Cox transformation, based on a maximum likelihood estimator. The main contribution of this letter is to explore the special structure of the proposed RBF neural network for computational efficiency by utilizing the inverse of matrix block decomposition lemma. Finally, the Box-Cox transformation-based RBF neural network, with good generalization and sparsity, is identified based on the derived optimal Box-Cox transformation and a D-optimality-based orthogonal forward regression algorithm. The proposed algorithm and its efficacy are demonstrated with an illustrative example in comparison with support vector machine regression.

The coxBAC Operon Encodes a Cytochrome c Oxidase Required for Heterotrophic Growth in the Cyanobacterium Anabaena variabilis Strain ATCC 29413

PubMed Central

Schmetterer, Georg; Valladares, Ana; Pils, Dietmar; Steinbach, Susanne; Pacher, Margit; Muro-Pastor, Alicia M.; Flores, Enrique; Herrero, Antonia

2001-01-01

Three genes, coxB, coxA, and coxC, found in a clone from a gene library of the cyanobacterium Anabaena variabilis strain ATCC 29413, were identified by hybridization with an oligonucleotide specific for aa3-type cytochrome c oxidases. Deletion of these genes from the genome of A. variabilis strain ATCC 29413 FD yielded strain CSW1, which displayed no chemoheterotrophic growth and an impaired cytochrome c oxidase activity. Photoautotrophic growth of CSW1, however, was unchanged, even with dinitrogen as the nitrogen source. A higher cytochrome c oxidase activity was detected in membrane preparations from dinitrogen-grown CSW1 than from nitrate-grown CSW1, but comparable activities of respiratory oxygen uptake were found in the wild type and in CSW1. Our data indicate that the identified cox gene cluster is essential for fructose-dependent growth in the dark, but not for growth on dinitrogen, and that other terminal respiratory oxidases are expressed in this cyanobacterium. Transcription analysis showed that coxBAC constitutes an operon which is expressed from two transcriptional start points. The use of one of them was stimulated by fructose. PMID:11591688

Impact of Blood Type, Functional Polymorphism (T-1676C) of the COX-1 Gene Promoter and Clinical Factors on the Development of Peptic Ulcer during Cardiovascular Prophylaxis with Low-Dose Aspirin

PubMed Central

Wang, Pin-Yao; Chen, Hsiu-Ping; Chen, Angela; Tsay, Feng-Woei; Kao, Sung-Shuo; Peng, Nan-Jing; Tseng, Hui-Hwa; Hsu, Ping-I

2014-01-01

Aims. To investigate the impact of blood type, functional polymorphism (T-1676C) of the COX-1 gene promoter, and clinical factors on the development of peptic ulcer during cardiovascular prophylaxis with low-dose aspirin. Methods. In a case-control study including 111 low-dose aspirin users with peptic ulcers and 109 controls (asymptomatic aspirin users), the polymorphism (T-1676C) of the COX-1 gene promoter was genotyped, and blood type, H pylori status, and clinical factors were assessed. Results. Univariate analysis showed no significant differences in genotype frequencies of the COX-1 gene at position -1676 between the peptic ulcer group and control group. Multivariate analysis revealed that blood type O, advanced age, history of peptic ulcer, and concomitant use of NSAID were the independent risk factors for the development of peptic ulcer with the odds ratios of the 2.1, 3.1, 27.6, and 2.9, respectively. Conclusion. The C-1676T polymorphism in the COX-1 gene promoter is not a risk factor for ulcer formation during treatment with low-dose aspirin. Blood type O, advanced age, history of peptic ulcer, and concomitant use of NSAID are of independent significance in predicting peptic ulcer development during treatment with low-dose aspirin. PMID:25243161

In situ aromatase expression in primary tumor is associated with estrogen receptor expression but is not predictive of response to endocrine therapy in advanced breast cancer

PubMed Central

2009-01-01

Background New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved in the synthesis of aromatase, has been suggested as a surrogate marker for aromatase expression. Methods Primary tumor material was retrospectively collected from 88 patients who participated in a randomized clinical trial comparing the AI letrozole to the anti-estrogen tamoxifen for first-line treatment of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression. Results Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP. Conclusion TMAs are not suitable for IHC analysis of in situ aromatase expression and we did not find COX-2 expression in carcinoma cells to be a surrogate marker for aromatase. In situ aromatase expression in tumor cells is associated with ER expression and may thus point towards good prognosis. Aromatase expression in cancer cells is not predictive of response to endocrine therapy, indicating that in situ estrogen synthesis may not be the major source of intratumoral estrogen. However, aromatase expression in combination with high PR expression may select letrozole treated patients with longer TTP. Trial registration Sub-study of trial P025 for advanced breast cancer. PMID:19531212

Evaluation of the role of the cyclooxygenase signaling pathway during inflammation in skin and muscle tissues of ball pythons (Python regius).

PubMed

Sadler, Ryan A; Schumacher, Juergen P; Rathore, Kusum; Newkirk, Kim M; Cole, Grayson; Seibert, Rachel; Cekanova, Maria

2016-05-01

OBJECTIVE To determine degrees of production of cyclooxygenase (COX)-1 and -2 and other mediators of inflammation in noninflamed and inflamed skin and muscle tissues in ball pythons (Python regius). ANIMALS 6 healthy adult male ball pythons. PROCEDURES Biopsy specimens of noninflamed skin and muscle tissue were collected from anesthetized snakes on day 0. A 2-cm skin and muscle incision was then made 5 cm distal to the biopsy sites with a CO2 laser to induce inflammation. On day 7, biopsy specimens of skin and muscle tissues were collected from the incision sites. Inflamed and noninflamed tissue specimens were evaluated for production of COX-1, COX-2, phosphorylated protein kinase B (AKT), total AKT, nuclear factor κ-light-chain-enhancer of activated B cells, phosphorylated extracellular receptor kinases (ERKs) 1 and 2, and total ERK proteins by western blot analysis. Histologic evaluation was performed on H&E-stained tissue sections. RESULTS All biopsy specimens of inflamed skin and muscle tissues had higher histologic inflammation scores than did specimens of noninflamed tissue. Inflamed skin specimens had significantly greater production of COX-1 and phosphorylated ERK than did noninflamed skin specimens. Inflamed muscle specimens had significantly greater production of phosphorylated ERK and phosphorylated AKT, significantly lower production of COX-1, and no difference in production of COX-2, compared with production in noninflamed muscle specimens. CONCLUSIONS AND CLINICAL RELEVANCE Production of COX-1, but not COX-2, was significantly greater in inflamed versus noninflamed skin specimens from ball pythons. Additional research into the reptilian COX signaling pathway is warranted.

[Identification of potentially invasive species of black flies [Diptera: Simuliidae] from Armenia based on an analysis of variability in the mtDNA barcode of the cox1 gene and chromosomal polymorphism].

PubMed

Andrianov, B V; Goryacheva, I I; Vlasov, S V; Gorelova, T V; Harutyunova, M V; Harutyunova, K V; Mayilyan, K R; Zakharov, I A

2015-03-01

Black flies (Diptera, Simuliidae) are well known for their medical, environmental, and veterinary importance. The simuliid fauna of Armenia includes 53 species. A number of dominant species are of ecological importance. Complex analysis, which involved morphometric, cytogenetic, and molecular genetic approaches, was conducted to characterize the species status of black flies inhabiting the territory of Armenia. It was shown that the predominant simuliid species, Simulium paraequinum and Simulium kiritshenkoi, belong to a group of species with minimal variability of the cox1 gene. The recently discovered species, Simulium noellery and Simulium [B.] erythrocephalum, which are new to Armenia, can be considered as potentially invasive, which is supported by the low level of variability of the cox1 gene.

Evaluating the risk of water distribution system failure: A shared frailty model

NASA Astrophysics Data System (ADS)

Clark, Robert M.; Thurnau, Robert C.

2011-12-01

Condition assessment (CA) Modeling is drawing increasing interest as a technique that can assist in managing drinking water infrastructure. This paper develops a model based on the application of a Cox proportional hazard (PH)/shared frailty model and applies it to evaluating the risk of failure in drinking water networks using data from the Laramie Water Utility (located in Laramie, Wyoming, USA). Using the risk model a cost/ benefit analysis incorporating the inspection value method (IVM), is used to assist in making improved repair, replacement and rehabilitation decisions for selected drinking water distribution system pipes. A separate model is developed to predict failures in prestressed concrete cylinder pipe (PCCP). Various currently available inspection technologies are presented and discussed.

Integrated Cox's model for predicting survival time of glioblastoma multiforme.

PubMed

Ai, Zhibing; Li, Longti; Fu, Rui; Lu, Jing-Min; He, Jing-Dong; Li, Sen

2017-04-01

Glioblastoma multiforme is the most common primary brain tumor and is highly lethal. This study aims to figure out signatures for predicting the survival time of patients with glioblastoma multiforme. Clinical information, messenger RNA expression, microRNA expression, and single-nucleotide polymorphism array data of patients with glioblastoma multiforme were retrieved from The Cancer Genome Atlas. Patients were separated into two groups by using 1 year as a cutoff, and a logistic regression model was used to figure out any variables that can predict whether the patient was able to live longer than 1 year. Furthermore, Cox's model was used to find out features that were correlated with the survival time. Finally, a Cox model integrated the significant clinical variables, messenger RNA expression, microRNA expression, and single-nucleotide polymorphism was built. Although the classification method failed, signatures of clinical features, messenger RNA expression levels, and microRNA expression levels were figured out by using Cox's model. However, no single-nucleotide polymorphisms related to prognosis were found. The selected clinical features were age at initial diagnosis, Karnofsky score, and race, all of which had been suggested to correlate with survival time. Both of the two significant microRNAs, microRNA-221 and microRNA-222, were targeted to p27 Kip1 protein, which implied the important role of p27 Kip1 on the prognosis of glioblastoma multiforme patients. Our results suggested that survival modeling was more suitable than classification to figure out prognostic biomarkers for patients with glioblastoma multiforme. An integrated model containing clinical features, messenger RNA levels, and microRNA expression levels was built, which has the potential to be used in clinics and thus to improve the survival status of glioblastoma multiforme patients.

Modulation of the neurological and vascular complications by grape seed extract in a rat model of spinal cord ischemia-reperfusion injury by downregulation of both osteopontin and cyclooxygenase-2.

PubMed

Sakr, Hussein F; Abbas, Amr M; Bin-Jaliah, Ismaeel

2016-07-01

In this study, we investigated the effects of grape seed extract (GSE) on the expression of osteopontin (OPN) and cyclooxygenase-2 (COX-2) in a rat model of spinal cord ischemia-reperfusion injury (SC-IRI). Fifty male rats were divided into 5 groups: control (CON); control + GSE (CON + GSE) (received GSE for 28 days); sham operated (Sham); IRI; and IRI + GSE. SC-IRI was induced by clamping the aorta just above the bifurcation for 45 min, and then the clamp was released for 48 h for reperfusion. IRI + GSE group received GSE for 28 days before SC-IRI. Sensory, motor, and placing/stepping reflex assessment was performed. Prostaglandin E2 (PGE2), thiobarbituric acid reactive substances (TBARs), and total antioxidant capacity (TAC) were measured in spinal cord homogenate. Immunohistochemical examination of the spinal cord for OPN and COX-2 were carried out. SC-IRI resulted in significant increase in plasma nitrite/nitrate level and spinal cord homogenate levels of TBARs and PGE2, and OPN and COX-2 expression with significant decrease in TAC. GSE improves the sensory and motor functions through decreasing OPN and COX-2 expression with reduction of oxidative stress parameters. We conclude a neuroprotective effect of GSE in SC-IRI through downregulating COX-2 and OPN expression plus its antioxidants effects.

Safety risks for patients with aspirin-exacerbated respiratory disease after acute exposure to selective nonsteroidal anti-inflammatory drugs and COX-2 inhibitors: Meta-analysis of controlled clinical trials.

PubMed

Morales, Daniel R; Lipworth, Brian J; Guthrie, Bruce; Jackson, Cathy; Donnan, Peter T; Santiago, Virginia H

2014-07-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause bronchospasm in susceptible patients with asthma, often termed aspirin-exacerbated respiratory disease (AERD), with the risk being greatest after acute exposure. Selective NSAIDs that preferentially inhibit COX-2 might be safer. We sought to systematically evaluate changes in symptoms and pulmonary function after acute selective NSAID or COX-2 inhibitor exposure in patients with the AERD phenotype. A systematic review of databases was performed to identify all blinded, placebo-controlled clinical trials evaluating acute selective NSAID or COX-2 inhibitor exposure in patients with AERD. Effect estimates for changes in respiratory function and symptoms were pooled by using fixed-effects meta-analysis, with heterogeneity investigated. No significant difference in respiratory symptoms (risk difference, -0.01; 95% CI, -0.03 to 0.01; P = .57), decrease in FEV1 of 20% or greater (RD, 0.00; 95% CI, -0.02 to 0.02; P = .77), or nasal symptoms (RD, -0.01; 95% CI, -0.04 to 0.02; P = .42) occurred with COX-2 inhibitors (eg, celecoxib). Selective NSAID exposure caused respiratory symptoms in approximately 1 in 13 patients with AERD (RD, 0.08; 95% CI, 0.02 to 0.14; P = .01). No significant differences were found according to leukotriene antagonist exposure or whether NSAIDs were randomly allocated. According to clinical trial evidence in patients with stable mild-to-moderate asthma with AERD, acute exposure to COX-2 inhibitors is safe, and selective NSAIDs exhibit a small risk. Thus COX-2 inhibitors could be used in patients with AERD or in patients with general asthma unwilling to risk nonselective NSAID exposure when oral challenge tests are unavailable. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Contribution of reactive oxygen species to migration/invasion of human glioblastoma cells U87 via ERK-dependent COX-2/PGE(2) activation.

PubMed

Chiu, Wen-Ta; Shen, Shing-Chuan; Chow, Jyh-Ming; Lin, Cheng-Wei; Shia, Ling-Tin; Chen, Yen-Chou

2010-01-01

In the presence of 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation, an increase in the migration/invasion of U87 glioblastoma cells was detected by a wound healing assay, transwell analysis, and spheroid formation assay by inducing matrix metalloproteinase-9 (MMP-9) enzyme activity via a gelatin zymographic analysis. A dose- and time-dependent increase in cyclooxygenase-2 (COX-2) gene expression with elevated prostaglandin E(2) (PGE(2)) production was identified in TPA- but not in 4alpha-TPA (a respective inactive compound)-treated U87 cells TPA-induced migration/invasion was significantly blocked by adding the COX-2-specific inhibitor, NS398, through a reduction in PGE(2) production. Data from the pharmacological studies using specific chemical inhibitors showed that activation of protein kinase C (PKC) and extracellular signal-regulated kinases (ERKs) was involved in TPA-induced migration/invasion, COX-2 protein expression, and MMP-9 activation. Stimulation of intracellular peroxide production by TPA was detected by a DCHF-DA assay, and the addition of superoxide dismutase (SOD) or tempol significantly inhibited TPA-induced migration/invasion and COX-2 protein expression accompanied by a decrease in peroxide production. An increase in NADPH oxidase activity by TPA was examined, and TPA-induced migration/invasion was blocked by adding DPI, an NADPH oxidase inhibitor. Additionally, the natural flavonoids quercetin (QE), baicalein (BE), and myricetin (ME) effectively blocked TPA-induced migration/invasion while simultaneously inhibiting COX-2/PGE(2) production, MMP-9 enzyme activity, and peroxide production in U87 cells. The contribution of ROS production to the migration/invasion of U87 glioblastoma cells via ERK-activated COX-2/PGE(2) and MMP-9 induction was first investigated here, and agents such as QE, BE, and ME with the ability to block these events possess the potential to be developed for use against migration/invasion by glioblastomas.

Involvement of cyclooxygenase-2 in carbachol-induced positive inotropic response in mouse isolated left atrium.

PubMed

Hara, Yukio; Ike, Asako; Tanida, Riyo; Okada, Muneyoshi; Yamawaki, Hideyuki

2009-12-01

The mouse heart is expected to have characteristic contractile properties. However, basic information on the function of the mouse heart has not been accumulated sufficiently. In this study, the involvement of cyclooxygenase (COX)-2 in carbachol (CCh)-induced inotropic response was investigated in mouse isolated left atrium. Influences of CCh and their mechanisms of action on developed tension elicited by electrical stimulation were examined pharmacologically. The presence of COX-2 in atrium was examined by Western blotting and immunohistochemical analysis. CCh (3 microM for 15 min) produced a biphasic inotropic response: a transient decrease in contractile force followed by a late increase. Atropine suppressed the biphasic inotropic response to CCh. A muscarinic M(3) receptor antagonist, 4-diphenyl-acetoxy-N-methlpiperidine, inhibited the late positive inotropic action. Blockade of prostaglandin (PG) E(2) or F(2alpha) receptor by 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809) or 9alpha, 15R-dihydroxy-11beta-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta 5Z, 13E-dien-1-oic acid (AL8810), respectively, significantly suppressed the positive inotropic response to CCh. A nonselective COX inhibitor, indomethacin, and a selective COX-2 inhibitor, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398) inhibited the positive response. A COX-1 inhibitor, valeroyl salicylate, did not affect the positive response. The positive response was almost completely abolished in the endocardial endothelium-deprived atria. Existence of COX-2 in endocardial endothelium was confirmed by Western blotting and immunohistochemical analysis. The present study indicated that the CCh-induced positive inotropic response was mediated by PGs, possibly PGE(2) and PGF(2alpha), released in part from endocardial endothelium. Furthermore, for the first time, we demonstrated that the production of PGs depended in part on COX-2 in endocardial endothelium through the muscarinic M(3) receptor stimulation.

COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats.

PubMed

Muñoz, Mercedes; Sánchez, Ana; Pilar Martínez, María; Benedito, Sara; López-Oliva, Maria-Elvira; García-Sacristán, Albino; Hernández, Medardo; Prieto, Dolores

2015-07-01

Obesity is related to vascular dysfunction through inflammation and oxidative stress and it has been identified as a risk factor for chronic renal disease. In the present study, we assessed the specific relationships among reactive oxygen species (ROS), cyclooxygenase 2 (COX-2), and endothelial dysfunction in renal interlobar arteries from a genetic model of obesity/insulin resistance, the obese Zucker rats (OZR). Relaxations to acetylcholine (ACh) were significantly reduced in renal arteries from OZR compared to their counterpart, the lean Zucker rat (LZR), suggesting endothelial dysfunction. Blockade of COX with indomethacin and with the selective blocker of COX-2 restored the relaxations to ACh in obese rats. Selective blockade of the TXA2/PGH2 (TP) receptor enhanced ACh relaxations only in OZR, while inhibition of the prostacyclin (PGI2) receptor (IP) enhanced basal tone and inhibited ACh vasodilator responses only in LZR. Basal production of superoxide was increased in arteries of OZR and involved NADPH and xanthine oxidase activation and NOS uncoupling. Under conditions of NOS blockade, ACh induced vasoconstriction and increased ROS generation that were augmented in arteries from OZR and blunted by COX-2 inhibition and by the ROS scavenger tempol. Hydrogen peroxide (H2O2) evoked both endothelium- and vascular smooth muscle (VSM)-dependent contractions, as well as ROS generation that was reduced by COX-2 inhibition. In addition, COX-2 expression was enhanced in both VSM and endothelium of renal arteries from OZR. These results suggest that increased COX-2-dependent vasoconstriction contributes to renal endothelial dysfunction through enhanced (ROS) generation in obesity. COX-2 activity is in turn upregulated by ROS. Copyright © 2015 Elsevier Inc. All rights reserved.

Integration of Statistical and Physical Models of Short Fatigue Crack Growth.

DTIC Science & Technology

1987-02-01

M.R. James and B.N. Cox, *Fundamental Characterization of Surface Microplasticity ," Final Report on NSF Grant No. DMR-8310652, July 1986. 23. W.L...Dec. 1985. 24. W.L. Morris, B.N. Cox and M.R. James, " Microplastic Deformation of Al 2219- T85 I," to be published in Acta Metall. 25. B.N. Cox, W.L...Morris and M.R. James, "Two-Stage Microplastic Surface Defor- mation in Al 2219-T851," to be published in Acta Metall. 26. W.L. Morris, M.R. James and

Relationship between serum levels of triglycerides and vascular inflammation, measured as COX-2, in arteries from diabetic patients: a translational study

PubMed Central

2013-01-01

Background Inflammation is a common feature in the majority of cardiovascular disease, including Diabetes Mellitus (DM). Levels of pro-inflammatory markers have been found in increasing levels in serum from diabetic patients (DP). Moreover, levels of Cyclooxygenase-2 (COX-2) are increased in coronary arteries from DP. Methods Through a cross-sectional design, patients who underwent CABG were recruited. Vascular smooth muscle cells (VSMC) were cultured and COX-2 was measured by western blot. Biochemical and clinical data were collected from the medical record and by blood testing. COX-2 expression was analyzed in internal mammary artery cross-sections by confocal microscopy. Eventually, PGI2 and PGE2 were assessed from VSMC conditioned media by ELISA. Results Only a high glucose concentration, but a physiological concentration of triglycerides exposure of cultured human VSMC derived from non-diabetic patients increased COX-2 expression .Diabetic patients showed increasing serum levels of glucose, Hb1ac and triglycerides. The bivariate analysis of the variables showed that triglycerides was positively correlated with the expression of COX-2 in internal mammary arteries from patients (r2 = 0.214, P < 0.04). Conclusions We conclude that is not the glucose blood levels but the triglicerydes leves what increases the expression of COX-2 in arteries from DP. PMID:23642086

Influence of Pulmonary Hypertension on Patients With Idiopathic Pulmonary Fibrosis Awaiting Lung Transplantation.

PubMed

Hayes, Don; Black, Sylvester M; Tobias, Joseph D; Kirkby, Stephen; Mansour, Heidi M; Whitson, Bryan A

2016-01-01

The influence of varying levels of pulmonary hypertension (PH) on survival in idiopathic pulmonary fibrosis is not well defined. The United Network for Organ Sharing database was queried from 2005 to 2013 to identify first-time lung transplant candidates listed for lung transplantation who were tracked from waitlist entry date until death or censoring to determine the influence of PH on patients with advanced lung disease. Using data for right heart catheterization measurements, mild PH was defined as mean pulmonary artery pressure of 25 mm Hg or more, and severe as 35 mm Hg or more. Of 6,657 idiopathic pulmonary fibrosis patients, 6,651 were used for univariate analysis, 6,126 for Kaplan-Meier survival function, 6,013 for multivariate Cox models, and 5,186 (mild PH) and 2,014 (severe PH) for propensity score matching, respectively. Univariate Cox proportional hazards analysis found significant differences in survival for mild PH (hazard ratio [HR] 1.689, 95% confidence interval [CI]: 1.434 to 1.988, p < 0.001) and severe PH (HR 2.068, 95% CI: 1.715 to 2.493, p < 0.001). Further assessment by multivariate Cox models identified significant risk for death for mild PH (HR 1.433, 95% CI: 1.203 to 1.706, p < 0.001) and severe PH (HR 1.597, 95% CI: 1.308 to 1.949, p < 0.001). Propensity score matching confirmed the risk for death for mild PH (HR 1.530, 95% CI: 1.189 to 1.969, p = 0.001) and severe PH (HR 2.103, 95% CI: 1.436 to 3.078, p < 0.001). The manifestation of PH, even with mild severity, is associated with significantly increased risk for death among patients with idiopathic pulmonary fibrosis awaiting lung transplantation, so referral should be considered early in the disease course. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Urinary proteomics for prediction of mortality in patients with type 2 diabetes and microalbuminuria.

PubMed

Currie, Gemma E; von Scholten, Bernt Johan; Mary, Sheon; Flores Guerrero, Jose-Luis; Lindhardt, Morten; Reinhard, Henrik; Jacobsen, Peter K; Mullen, William; Parving, Hans-Henrik; Mischak, Harald; Rossing, Peter; Delles, Christian

2018-04-06

The urinary proteomic classifier CKD273 has shown promise for prediction of progressive diabetic nephropathy (DN). Whether it is also a determinant of mortality and cardiovascular disease in patients with microalbuminuria (MA) is unknown. Urine samples were obtained from 155 patients with type 2 diabetes and confirmed microalbuminuria. Proteomic analysis was undertaken using capillary electrophoresis coupled to mass spectrometry to determine the CKD273 classifier score. A previously defined CKD273 threshold of 0.343 for identification of DN was used to categorise the cohort in Kaplan-Meier and Cox regression models with all-cause mortality as the primary endpoint. Outcomes were traced through national health registers after 6 years. CKD273 correlated with urine albumin excretion rate (UAER) (r = 0.481, p = <0.001), age (r = 0.238, p = 0.003), coronary artery calcium (CAC) score (r = 0.236, p = 0.003), N-terminal pro-brain natriuretic peptide (NT-proBNP) (r = 0.190, p = 0.018) and estimated glomerular filtration rate (eGFR) (r = 0.265, p = 0.001). On multivariate analysis only UAER (β = 0.402, p < 0.001) and eGFR (β = - 0.184, p = 0.039) were statistically significant determinants of CKD273. Twenty participants died during follow-up. CKD273 was a determinant of mortality (log rank [Mantel-Cox] p = 0.004), and retained significance (p = 0.048) after adjustment for age, sex, blood pressure, NT-proBNP and CAC score in a Cox regression model. A multidimensional biomarker can provide information on outcomes associated with its primary diagnostic purpose. Here we demonstrate that the urinary proteomic classifier CKD273 is associated with mortality in individuals with type 2 diabetes and MA even when adjusted for other established cardiovascular and renal biomarkers.

Survival curve estimation with dependent left truncated data using Cox's model.

PubMed

Mackenzie, Todd

2012-10-19

The Kaplan-Meier and closely related Lynden-Bell estimators are used to provide nonparametric estimation of the distribution of a left-truncated random variable. These estimators assume that the left-truncation variable is independent of the time-to-event. This paper proposes a semiparametric method for estimating the marginal distribution of the time-to-event that does not require independence. It models the conditional distribution of the time-to-event given the truncation variable using Cox's model for left truncated data, and uses inverse probability weighting. We report the results of simulations and illustrate the method using a survival study.

Risk of manic switch associated with antidepressant therapy in pediatric bipolar depression.

PubMed

Bhowmik, Debajyoti; Aparasu, Rajender R; Rajan, Suja S; Sherer, Jeffrey T; Ochoa-Perez, Melissa; Chen, Hua

2014-12-01

The purpose of this study was to assess the risk of manic switch associated with antidepressants in Medicaid-enrolled pediatric patients with bipolar depression. This retrospective cohort study involved 2003-2007 Medicaid Analytic eXtract (MAX) data from four geographically diverse states. The study sample included children and adolescents (ages 6-18 years) who had received a diagnosis of bipolar disorder on two or more separate occasions or during a hospital discharge, followed by a diagnosis of depression. According to the pharmacotherapy received by these patients in the 30 days around the index bipolar depression diagnosis, patients were categorized into five mutually exclusive groups. Manic switch was defined as having received a diagnosis of mania within 6 weeks after the initiation of bipolar depression treatment. Relative risks of manic switch between antidepressant monotherapy/polytherapy and their alternatives were assessed using Cox proportional hazards model. The robustness of the conventional Cox proportional hazards model toward possible bias caused by unobserved confounders was tested using instrumental variable analysis, and the uncertainty regarding manic switch definition was tested by altering the duration of follow-up. After applying all the selection criteria, 179 antidepressant monotherapy, 1047 second-generation antipsychotic (SGA) monotherapy, 570 mood stabilizer monotherapy, 445 antidepressant polytherapy, and 1906 SGA-mood stabilizer polytherapy users were identified. In Cox proportional hazard analyses, both antidepressant monotherapy and polytherapy exhibited higher risk of manic switch than their alternatives (antidepressant monotherapy vs. SGA monotherapy, hazard ratio [HR]=2.87 [95% CI: 1.10-7.49]; antidepressant monotherapy vs. mood stabilizer monotherapy, HR=1.41 [95% CI: 0.52-3.80); antidepressant polytherapy vs. SGA-mood stabilizer polytherapy, HR=1.61 [95% CI: 0.90-2.89]). However, only the comparison between antidepressant monotherapy and SGA monotherapy was statistically significant. The instrumental variable analysis did not detect endogeneity of the treatment variables. Extending the follow-up period from 6 weeks to 8 and 12 weeks generated findings consistent with the main analysis. Study findings indicated a higher risk of manic switch associated with antidepressant monotherapy than with SGA monotherapy in pediatric patients with bipolar depression. The finding supported the clinical practice of cautious prescribing of antidepressants for brief periods.

Determining delayed admission to intensive care unit for mechanically ventilated patients in the emergency department.

PubMed

Hung, Shih-Chiang; Kung, Chia-Te; Hung, Chih-Wei; Liu, Ber-Ming; Liu, Jien-Wei; Chew, Ghee; Chuang, Hung-Yi; Lee, Wen-Huei; Lee, Tzu-Chi

2014-08-23

The adverse effects of delayed admission to the intensive care unit (ICU) have been recognized in previous studies. However, the definitions of delayed admission varies across studies. This study proposed a model to define "delayed admission", and explored the effect of ICU-waiting time on patients' outcome. This retrospective cohort study included non-traumatic adult patients on mechanical ventilation in the emergency department (ED), from July 2009 to June 2010. The primary outcomes measures were 21-ventilator-day mortality and prolonged hospital stays (over 30 days). Models of Cox regression and logistic regression were used for multivariate analysis. The non-delayed ICU-waiting was defined as a period in which the time effect on mortality was not statistically significant in a Cox regression model. To identify a suitable cut-off point between "delayed" and "non-delayed", subsets from the overall data were made based on ICU-waiting time and the hazard ratio of ICU-waiting hour in each subset was iteratively calculated. The cut-off time was then used to evaluate the impact of delayed ICU admission on mortality and prolonged length of hospital stay. The final analysis included 1,242 patients. The time effect on mortality emerged after 4 hours, thus we deduced ICU-waiting time in ED > 4 hours as delayed. By logistic regression analysis, delayed ICU admission affected the outcomes of 21 ventilator-days mortality and prolonged hospital stay, with odds ratio of 1.41 (95% confidence interval, 1.05 to 1.89) and 1.56 (95% confidence interval, 1.07 to 2.27) respectively. For patients on mechanical ventilation at the ED, delayed ICU admission is associated with higher probability of mortality and additional resource expenditure. A benchmark waiting time of no more than 4 hours for ICU admission is recommended.

Calorie intake and patient outcomes in severe acute kidney injury: findings from The Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy (RENAL) study trial

PubMed Central

2014-01-01

Introduction Current practice in the delivery of caloric intake (DCI) in patients with severe acute kidney injury (AKI) receiving renal replacement therapy (RRT) is unknown. We aimed to describe calorie administration in patients enrolled in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy (RENAL) study and to assess the association between DCI and clinical outcomes. Methods We performed a secondary analysis in 1456 patients from the RENAL trial. We measured the dose and evolution of DCI during treatment and analyzed its association with major clinical outcomes using multivariable logistic regression, Cox proportional hazards models, and time adjusted models. Results Overall, mean DCI during treatment in ICU was low at only 10.9 ± 9 Kcal/kg/day for non-survivors and 11 ± 9 Kcal/kg/day for survivors. Among patients with a lower DCI (below the median) 334 of 729 (45.8%) had died at 90-days after randomization compared with 316 of 727 (43.3%) patients with a higher DCI (above the median) (P = 0.34). On multivariable logistic regression analysis, mean DCI carried an odds ratio of 0.95 (95% confidence interval (CI): 0.91-1.00; P = 0.06) per 100 Kcal increase for 90-day mortality. DCI was not associated with significant differences in renal replacement (RRT) free days, mechanical ventilation free days, ICU free days and hospital free days. These findings remained essentially unaltered after time adjusted analysis and Cox proportional hazards modeling. Conclusions In the RENAL study, mean DCI was low. Within the limits of such low caloric intake, greater DCI was not associated with improved clinical outcomes. Trial registration ClinicalTrials.gov number, NCT00221013 PMID:24629036

Rebamipide induces the gastric mucosal protective factor, cyclooxygenase-2, via activation of 5'-AMP-activated protein kinase.

PubMed

Lee, Sunyoung; Jeong, Seongkeun; Kim, Wooseong; Kim, Dohoon; Yang, Yejin; Yoon, Jeong-Hyun; Kim, Byung Joo; Min, Do Sik; Jung, Yunjin

2017-01-29

Rebamipide, an amino acid derivative of 2(1H)-quinolinone, has been used for mucosal protection, healing of gastroduodenal ulcers, and treatment of gastritis. Induction of cyclooxygenase (COX)-2, a gastric mucosal protective factor, by rebamipide has been suggested as the major mechanism of the drug action. However, how rebamipide induces COX-2 at the molecular level needs further investigation. In this study, the molecular mechanism underlying the induction of COX-2 by rebamipide was investigated. In gastric carcinoma cells and macrophage cells, rebamipide induced phosphorylation of AMP-activated protein kinase (AMPK), leading to phosphorylation of acetyl-CoA carboxylase (ACC), a substrate of AMPK. The induction of COX-2 by rebamipide was dependent on AMPK activation because compound C, an AMPK inhibitor, abolished COX-2 induction by rebamipide. In a mouse ulcer model, rebamipide protected against hydrochloric acid/ethanol-induced gastric ulcer, and these protective effects were deterred by co-administration of compound C. In parallel, in the gastric tissues, rebamipide increased the phosphorylation AMPK, whereas compound C reduced the levels of COX-2 and phosphorylated ACC, which were increased by rebamipide. Taken together, the activation of AMPK by rebamipide may be a molecular mechanism that contributes to induction of COX-2, probably resulting in protection against gastric ulcers. Copyright © 2016 Elsevier Inc. All rights reserved.

Fluid shear stress induces upregulation of COX-2 and PGI2 release in endothelial cells via a pathway involving PECAM-1, PI3K, FAK, and p38.

PubMed

Russell-Puleri, Sparkle; Dela Paz, Nathaniel G; Adams, Diana; Chattopadhyay, Mitali; Cancel, Limary; Ebong, Eno; Orr, A Wayne; Frangos, John A; Tarbell, John M

2017-03-01

Vascular endothelial cells play an important role in the regulation of vascular function in response to mechanical stimuli in both healthy and diseased states. Prostaglandin I 2 (PGI 2 ) is an important antiatherogenic prostanoid and vasodilator produced in endothelial cells through the action of the cyclooxygenase (COX) isoenzymes COX-1 and COX-2. However, the mechanisms involved in sustained, shear-induced production of COX-2 and PGI 2 have not been elucidated but are determined in the present study. We used cultured endothelial cells exposed to steady fluid shear stress (FSS) of 10 dyn/cm 2 for 5 h to examine shear stress-induced induction of COX-2/PGI 2 Our results demonstrate the relationship between the mechanosensor platelet endothelial cell adhesion molecule-1 (PECAM-1) and the intracellular mechanoresponsive molecules phosphatidylinositol 3-kinase (PI3K), focal adhesion kinase (FAK), and mitogen-activated protein kinase p38 in the FSS induction of COX-2 expression and PGI 2 release. Knockdown of PECAM-1 (small interference RNA) expression inhibited FSS-induced activation of α 5 β 1 -integrin, upregulation of COX-2, and release of PGI 2 in both bovine aortic endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs). Furthermore, inhibition of the PI3K pathway (LY294002) substantially inhibited FSS activation of α 5 β 1 -integrin, upregulation of COX-2 gene and protein expression, and release of PGI 2 in BAECs. Inhibition of integrin-associated FAK (PF573228) and MAPK p38 (SB203580) also inhibited the shear-induced upregulation of COX-2. Finally, a PECAM-1 -/- mouse model was characterized by reduced COX-2 immunostaining in the aorta and reduced plasma PGI 2 levels compared with wild-type mice, as well as complete inhibition of acute flow-induced PGI 2 release compared with wild-type animals. NEW & NOTEWORTHY In this study we determined the major mechanotransduction pathway by which blood flow-driven shear stress activates cyclooxygenase-2 (COX-2) and prostaglandin I 2 (PGI 2 ) release in endothelial cells. Our work has demonstrated for the first time that COX-2/PGI 2 mechanotransduction is mediated by the mechanosensor platelet endothelial cell adhesion molecule-1 (PECAM-1). Copyright © 2017 the American Physiological Society.

Fluid shear stress induces upregulation of COX-2 and PGI2 release in endothelial cells via a pathway involving PECAM-1, PI3K, FAK, and p38

PubMed Central

Russell-Puleri, Sparkle; dela Paz, Nathaniel G.; Adams, Diana; Chattopadhyay, Mitali; Cancel, Limary; Ebong, Eno; Orr, A. Wayne; Frangos, John A.

2017-01-01

Vascular endothelial cells play an important role in the regulation of vascular function in response to mechanical stimuli in both healthy and diseased states. Prostaglandin I2 (PGI2) is an important antiatherogenic prostanoid and vasodilator produced in endothelial cells through the action of the cyclooxygenase (COX) isoenzymes COX-1 and COX-2. However, the mechanisms involved in sustained, shear-induced production of COX-2 and PGI2 have not been elucidated but are determined in the present study. We used cultured endothelial cells exposed to steady fluid shear stress (FSS) of 10 dyn/cm2 for 5 h to examine shear stress-induced induction of COX-2/PGI2. Our results demonstrate the relationship between the mechanosensor platelet endothelial cell adhesion molecule-1 (PECAM-1) and the intracellular mechanoresponsive molecules phosphatidylinositol 3-kinase (PI3K), focal adhesion kinase (FAK), and mitogen-activated protein kinase p38 in the FSS induction of COX-2 expression and PGI2 release. Knockdown of PECAM-1 (small interference RNA) expression inhibited FSS-induced activation of α5β1-integrin, upregulation of COX-2, and release of PGI2 in both bovine aortic endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs). Furthermore, inhibition of the PI3K pathway (LY294002) substantially inhibited FSS activation of α5β1-integrin, upregulation of COX-2 gene and protein expression, and release of PGI2 in BAECs. Inhibition of integrin-associated FAK (PF573228) and MAPK p38 (SB203580) also inhibited the shear-induced upregulation of COX-2. Finally, a PECAM-1−/− mouse model was characterized by reduced COX-2 immunostaining in the aorta and reduced plasma PGI2 levels compared with wild-type mice, as well as complete inhibition of acute flow-induced PGI2 release compared with wild-type animals. NEW & NOTEWORTHY In this study we determined the major mechanotransduction pathway by which blood flow-driven shear stress activates cyclooxygenase-2 (COX-2) and prostaglandin I2 (PGI2) release in endothelial cells. Our work has demonstrated for the first time that COX-2/PGI2 mechanotransduction is mediated by the mechanosensor platelet endothelial cell adhesion molecule-1 (PECAM-1). PMID:28011582

Indomethacin-Induced Apoptosis in Esophageal Adenocarcinoma Cells Involves Upregulation of Bax and Translocation of Mitochondrial Cytochrome C Independent of COX-2 Expression1

PubMed Central

Aggarwal, Sanjeev; Taneja, Neelam; Lin, Lin; Orringer, Mark B; Rehemtulla, Alnawaz; Beer, David G

2000-01-01

Abstract The prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to exert a chemopreventive effect in esophageal and other gastrointestinal tumors. The precise mechanism by which this occurs, however, is unknown. While the inhibition of COX-2 as a potential explanation for this chemopreventive effect has gained a great deal of support, there also exists evidence supporting the presence of cyclooxygenase-independent pathways through which NSAIDs may exert their effects. In this study, immunohistochemical analysis of 29 Barrett's epithelial samples and 60 esophageal adenocarcinomas demonstrated abundant expression of the COX-2 protein in Barrett's epithelium, but marked heterogeneity of expression in esophageal adenocarcinomas. The three esophageal adenocarcinoma cell lines, Flo-1, Bic-1, and Seg-1, also demonstrated varying expression patterns for COX-1 and COX-2. Indomethacin induced apoptosis in all three cell lines, however, in both a time- and dose-dependent manner. In Flo-1 cells, which expressed almost undetectable levels of COX-1 and COX-2, and in Seg-1, which expressed significant levels of COX-1 and COX-2, indomethacin caused upregulation of the pro-apoptotic protein Bax. The upregulation of Bax was accompanied by the translocation of mitochondrial cytochrome c to the cytoplasm, and activation of caspase 9. Pre-treatment of both cell lines with the specific caspase 9 inhibitor, z-LEHD-FMK, as well as the broad-spectrum caspase inhibitor, z-VAD-FMK, blocked the effect of indomethacin-induced apoptosis. These data demonstrate that induction of apoptosis by indomethacin in esophageal adenocarcinoma cells is associated with the upregulation of Bax expression and mitochondrial cytochrome c translocation, and does not correlate with the expression of COX-2. This may have important implications for identifying new therapeutic targets in this deadly disease. PMID:11005569

DNA-hypomethylating agent, 5'-azacytidine, induces cyclooxygenase-2 expression via the PI3-kinase/Akt and extracellular signal-regulated kinase-1/2 pathways in human HT1080 fibrosarcoma cells.

PubMed

Yu, Seon-Mi; Kim, Song-Ja

2015-10-01

The cytosine analogue 5'-azacytidine (5'-aza) induces DNA hypomethylation by inhibiting DNA methyltransferase. In clinical trials, 5'-aza is widely used in epigenetic anticancer treatments. Accumulated evidence shows that cyclooxygenase-2 (COX-2) is overexpressed in various cancers, indicating that it may play a critical role in carcinogenesis. However, few studies have been performed to explore the molecular mechanism underlying the increased COX-2 expression. Therefore, we tested the hypothesis that 5'-aza regulates COX-2 expression and prostaglandin E2 (PGE2) production. The human fibrosarcoma cell line HT1080, was treated with various concentrations of 5'-aza for different time periods. Protein expressions of COX-2, DNA (cytosine-5)-methyltransferase 1 (DNMT1), pAkt, Akt, extracellular signal-regulated kinase (ERK), and phosphorylated ERK (pERK) were determined using western blot analysis, and COX-2 mRNA expression was determined using RT-PCR. PGE2 production was evaluated using the PGE2 assay kit. The localization and expression of COX-2 were determined using immunofluorescence staining. Treatment with 5'-aza induces protein and mRNA expression of COX-2. We also observed that 5'-aza-induced COX-2 expression and PGE2 production were inhibited by S-adenosylmethionine (SAM), a methyl donor. Treatment with 5'-aza phosphorylates PI3-kinase/Akt and ERK-1/2; inhibition of these pathways by LY294002, an inhibitor of PI3-kinase/Akt, or PD98059, an inhibitor of ERK-1/2, respectively, prevents 5'-aza-induced COX-2 expression and PGE2 production. Overall, these observations indicate that the hypomethylating agent 5'-aza modulates COX-2 expression via the PI3-kinase/Akt and ERK-1/2 pathways in human HT1080 fibrosarcoma cells.

Fungal origin by horizontal transfer of a plant mitochondrial group I intron in the chimeric CoxI gene of Peperomia.

PubMed

Vaughn, J C; Mason, M T; Sper-Whitis, G L; Kuhlman, P; Palmer, J D

1995-11-01

We present phylogenetic evidence that a group I intron in an angiosperm mitochondrial gene arose recently by horizontal transfer from a fungal donor species. A 1,716-bp fragment of the mitochondrial coxI gene from the angiosperm Peperomia polybotrya was amplified via the polymerase chain reaction and sequenced. Comparison to other coxI genes revealed a 966-bp group I intron, which, based on homology with the related yeast coxI intron aI4, potentially encodes a 279-amino-acid site-specific DNA endonuclease. This intron, which is believed to function as a ribozyme during its own splicing, is not present in any of 19 coxI genes examined from other diverse vascular plant species. Phylogenetic analysis of intron origin was carried out using three different tree-generating algorithms, and on a variety of nucleotide and amino acid data sets from the intron and its flanking exon sequences. These analyses show that the Peperomia coxI gene intron and exon sequences are of fundamentally different evolutionary origin. The Peperomia intron is more closely related to several fungal mitochondrial introns, two of which are located at identical positions in coxI, than to identically located coxI introns from the land plant Marchantia and the green alga Prototheca. Conversely, the exon sequence of this gene is, as expected, most closely related to other angiosperm coxI genes. These results, together with evidence suggestive of co-conversion of exonic markers immediately flanking the intron insertion site, lead us to conclude that the Peperomia coxI intron probably arose by horizontal transfer from a fungal donor, using the double-strand-break repair pathway. The donor species may have been one of the symbiotic mycorrhizal fungi that live in close obligate association with most plants.

Evaluation of long-term survival: use of diagnostics and robust estimators with Cox's proportional hazards model.

PubMed

Valsecchi, M G; Silvestri, D; Sasieni, P

1996-12-30

We consider methodological problems in evaluating long-term survival in clinical trials. In particular we examine the use of several methods that extend the basic Cox regression analysis. In the presence of a long term observation, the proportional hazard (PH) assumption may easily be violated and a few long term survivors may have a large effect on parameter estimates. We consider both model selection and robust estimation in a data set of 474 ovarian cancer patients enrolled in a clinical trial and followed for between 7 and 12 years after randomization. Two diagnostic plots for assessing goodness-of-fit are introduced. One shows the variation in time of parameter estimates and is an alternative to PH checking based on time-dependent covariates. The other takes advantage of the martingale residual process in time to represent the lack of fit with a metric of the type 'observed minus expected' number of events. Robust estimation is carried out by maximizing a weighted partial likelihood which downweights the contribution to estimation of influential observations. This type of complementary analysis of long-term results of clinical studies is useful in assessing the soundness of the conclusions on treatment effect. In the example analysed here, the difference in survival between treatments was mostly confined to those individuals who survived at least two years beyond randomization.

Prognostic significance of hemoglobin level in patients with congestive heart failure and normal ejection fraction.

PubMed

Varadarajan, Padmini; Gandhi, Siddharth; Sharma, Sanjay; Umakanthan, Branavan; Pai, Ramdas G

2006-10-01

Previous studies have shown low hemoglobin (Hb) to have an adverse effect on survival in patients with congestive heart failure (CHF) and reduced left ventricular (LV) ejection fraction (EF); but its effect on survival in patients with CHF and normal EF is not known. This study sought to determine whether low Hb has an effect on survival in patients with both CHF and normal EF. Detailed chart reviews were performed by medical residents on 2,246 patients (48% with normal EF) with a discharge diagnosis of CHF in a large tertiary care hospital from 1990 to 1999. The CHF diagnosis was validated using the Framingham criteria. Mortality data were obtained from the National Death Index. Survival analysis was performed using Kaplan-Meier and Cox regression models. By Kaplan-Meier analysis, low Hb (< 12 gm/dl) compared with normal hemoglobin was associated with a lower 5-year survival in patients with CHF and both normal (38 vs. 50%, p = 0.0008) and reduced (35 vs. 48%, p = 0.0009) EF. Using the Cox regression model, low Hb was an independent predictor of mortality after adjusting for age, gender, renal dysfunction, diabetes mellitus, hypertension, and EF in both groups of patients. Low Hb has an independent adverse effect on survival in patients with CHF and both normal and reduced EF in both groups of patients.

[Psychiatric readmissions: individual and organizational factors].

PubMed

Plancke, Laurent; Amariei, Alina; Flament, Clara; Dumesnil, Chloé

2017-01-01

Psychiatric readmission often constitutes a criterion to assess the effects of various therapies, as well as the impact of organizational changes in the healthcare system. It is used to characterize relapse or decompensation. The purpose of this study was to determine readmission rates and identify individual and organizational factors associated with significant variations in these rates. Adult psychiatric readmissions were identified from the full-time hospital stays registered in psychiatric wards in 2011-2012 in the Nord and Pas-de-Calais departments of France, available in the medical the RimP psychiatric admission database. Readmission rates for various follow-up periods after discharge were measured by Kaplan-Meier survival analysis and multivariate analysis was conducted using the Cox proportional hazards model. Approximately 30,000 adults were hospitalized full-time in psychiatric units of the region during the study period. The 24-month readmission rate was 51.6% (95%CI: 50.8-52.3%). The Cox model showed that a diagnosis of schizophrenia (F2 - HR = 1.72 - 95%CI: 1.61-1.84 - p < 0.001) and personality disorder (F6 - HR = 1.45 - 95%CI: 1.32-1.58 - p < 0.001) was associated with a higher readmission rate. Readmission rates were higher among dependent patients in non-profit private hospitals. Psychiatric readmission is a very frequent event and is linked to organizational as well as individual factors.

Advanced Online Survival Analysis Tool for Predictive Modelling in Clinical Data Science.

PubMed

Montes-Torres, Julio; Subirats, José Luis; Ribelles, Nuria; Urda, Daniel; Franco, Leonardo; Alba, Emilio; Jerez, José Manuel

2016-01-01

One of the prevailing applications of machine learning is the use of predictive modelling in clinical survival analysis. In this work, we present our view of the current situation of computer tools for survival analysis, stressing the need of transferring the latest results in the field of machine learning to biomedical researchers. We propose a web based software for survival analysis called OSA (Online Survival Analysis), which has been developed as an open access and user friendly option to obtain discrete time, predictive survival models at individual level using machine learning techniques, and to perform standard survival analysis. OSA employs an Artificial Neural Network (ANN) based method to produce the predictive survival models. Additionally, the software can easily generate survival and hazard curves with multiple options to personalise the plots, obtain contingency tables from the uploaded data to perform different tests, and fit a Cox regression model from a number of predictor variables. In the Materials and Methods section, we depict the general architecture of the application and introduce the mathematical background of each of the implemented methods. The study concludes with examples of use showing the results obtained with public datasets.

Advanced Online Survival Analysis Tool for Predictive Modelling in Clinical Data Science

PubMed Central

Montes-Torres, Julio; Subirats, José Luis; Ribelles, Nuria; Urda, Daniel; Franco, Leonardo; Alba, Emilio; Jerez, José Manuel

2016-01-01

One of the prevailing applications of machine learning is the use of predictive modelling in clinical survival analysis. In this work, we present our view of the current situation of computer tools for survival analysis, stressing the need of transferring the latest results in the field of machine learning to biomedical researchers. We propose a web based software for survival analysis called OSA (Online Survival Analysis), which has been developed as an open access and user friendly option to obtain discrete time, predictive survival models at individual level using machine learning techniques, and to perform standard survival analysis. OSA employs an Artificial Neural Network (ANN) based method to produce the predictive survival models. Additionally, the software can easily generate survival and hazard curves with multiple options to personalise the plots, obtain contingency tables from the uploaded data to perform different tests, and fit a Cox regression model from a number of predictor variables. In the Materials and Methods section, we depict the general architecture of the application and introduce the mathematical background of each of the implemented methods. The study concludes with examples of use showing the results obtained with public datasets. PMID:27532883

Prognostic impact of peritonitis in hemodialysis patients: A national-wide longitudinal study in Taiwan

PubMed Central

Lee, Cheng-Chia; Wu, Patricia W.; Chang, Chee-Jen; Tian, Ya-Chung; Yang, Chih-Wei

2017-01-01

Background Peritonitis has been independently associated with increased morbidity and mortality in peritoneal dialysis patients. However, there are few reports on peritonitis in hemodialysis patients. We aim at investigating both the risk profiles and prognostic impact of peritonitis in hemodialysis patients. Methods This nation-wide longitudinal study uses claims data obtained from the Taiwan National Health Insurance Research Database. A total of 80,733 incident hemodialysis patients of age ≥ 20 years without a history of peritonitis were identified between January 1, 1998 and December 31, 2009. Predictors of peritonitis events were estimated using Cox proportional hazard models. Time-dependent Cox proportional hazard models were used to estimate hazard ratio for mortality attributed to peritonitis exposure. Results Of 80,733 incident hemodialysis patients over a 13-year study period, peritonitis was diagnosed in 935 (1.16%), yielding an incidence rate of 2.91 per 1000 person-years. Female gender, liver cirrhosis and polycystic kidney disease were three of the most significant factors for peritonitis in both non-diabetic and diabetic hemodialysis patients. The cumulative survival rate of patients with peritonitis was 38.8% at 1 year and 10.1% at 5 years. A time-dependent Cox multivariate analysis showed that peritonitis had significantly increased hazard ratio for all cause mortality. Additionally, the risk of mortality remained significantly higher for non-diabetic hemodialysis patients that experienced peritonitis. Conclusions The risk of peritonitis in hemodialysis patients is higher in female gender, liver cirrhosis and polycystic kidney disease. Although peritonitis is a rare condition, it is associated with significantly poorer outcome in hemodialysis patients. PMID:28301536

Prognostic impact of peritonitis in hemodialysis patients: A national-wide longitudinal study in Taiwan.

PubMed

Lu, Yueh-An; Tu, Kun-Hua; Lee, Cheng-Chia; Wu, Patricia W; Chang, Chee-Jen; Tian, Ya-Chung; Yang, Chih-Wei; Chu, Pao-Hsien

2017-01-01

Peritonitis has been independently associated with increased morbidity and mortality in peritoneal dialysis patients. However, there are few reports on peritonitis in hemodialysis patients. We aim at investigating both the risk profiles and prognostic impact of peritonitis in hemodialysis patients. This nation-wide longitudinal study uses claims data obtained from the Taiwan National Health Insurance Research Database. A total of 80,733 incident hemodialysis patients of age ≥ 20 years without a history of peritonitis were identified between January 1, 1998 and December 31, 2009. Predictors of peritonitis events were estimated using Cox proportional hazard models. Time-dependent Cox proportional hazard models were used to estimate hazard ratio for mortality attributed to peritonitis exposure. Of 80,733 incident hemodialysis patients over a 13-year study period, peritonitis was diagnosed in 935 (1.16%), yielding an incidence rate of 2.91 per 1000 person-years. Female gender, liver cirrhosis and polycystic kidney disease were three of the most significant factors for peritonitis in both non-diabetic and diabetic hemodialysis patients. The cumulative survival rate of patients with peritonitis was 38.8% at 1 year and 10.1% at 5 years. A time-dependent Cox multivariate analysis showed that peritonitis had significantly increased hazard ratio for all cause mortality. Additionally, the risk of mortality remained significantly higher for non-diabetic hemodialysis patients that experienced peritonitis. The risk of peritonitis in hemodialysis patients is higher in female gender, liver cirrhosis and polycystic kidney disease. Although peritonitis is a rare condition, it is associated with significantly poorer outcome in hemodialysis patients.

Adjusted variable plots for Cox's proportional hazards regression model.

PubMed

Hall, C B; Zeger, S L; Bandeen-Roche, K J

1996-01-01

Adjusted variable plots are useful in linear regression for outlier detection and for qualitative evaluation of the fit of a model. In this paper, we extend adjusted variable plots to Cox's proportional hazards model for possibly censored survival data. We propose three different plots: a risk level adjusted variable (RLAV) plot in which each observation in each risk set appears, a subject level adjusted variable (SLAV) plot in which each subject is represented by one point, and an event level adjusted variable (ELAV) plot in which the entire risk set at each failure event is represented by a single point. The latter two plots are derived from the RLAV by combining multiple points. In each point, the regression coefficient and standard error from a Cox proportional hazards regression is obtained by a simple linear regression through the origin fit to the coordinates of the pictured points. The plots are illustrated with a reanalysis of a dataset of 65 patients with multiple myeloma.

Utilization of nonsteroidal anti-inflammatory drugs and antisecretory agents: a managed care claims analysis.

PubMed

Ofman, Joshua J; Badamgarav, Enkhe; Henning, James M; Knight, Kevin; Laine, Loren

2004-06-15

To describe patients initiating nonsteroidal anti-inflammatory drug (NSAID) therapy with regard to gastrointestinal and cardiac risks and patterns of antisecretory agent use, and to explore the relation between therapy type and subsequent outcomes. We studied patients aged 18 years or older who had continuous coverage from 1998 to 2001 and who had initiated treatment with cyclooxygenase-2 (COX-2) selective inhibitors or nonselective NSAIDs. Patients were categorized with respect to gastrointestinal and cardiac risk profiles. Proton pump inhibitor use within 15 days of initiating NSAID therapy was considered prophylactic. Logistic regression analysis was used to evaluate associations between treatment and hospitalization events, cardiac events, and health care costs. We identified 106,564 eligible NSAID initiators: 65.2% used COX-2 inhibitors and 34.8% used traditional NSAIDs. Users of COX-2 inhibitors were more likely to be at higher risk of gastrointestinal bleeding and cardiac events than were NSAID users. Proton pump inhibitor prophylaxis was most common among users of COX-2 inhibitors, but was only 11% in patients at high risk of gastrointestinal bleeding. There were no differences among treatment groups in terms of gastrointestinal or cardiac events. Initiation of COX-2 inhibitor therapy was associated with greater total health care costs. Although we found that COX-2 inhibitors were used more frequently than were traditional NSAIDs in certain groups of patients with varying cardiac or gastrointestinal risk, we did not find that their use resulted in reductions in clinical events, cotherapy with proton pump inhibitors, or costs, suggesting that a better understanding of the relation between NSAID treatment strategies and outcomes in patients with differing risk characteristics is needed.

Hepatocyte growth factor regulates cyclooxygenase-2 expression via β-catenin, Akt, and p42/p44 MAPK in human bronchial epithelial cells

PubMed Central

Lee, Young H.; Suzuki, Yuichiro J.; Griffin, Autumn J.; Day, Regina M.

2008-01-01

Hepatocyte growth factor (HGF) is upregulated in response to lung injury and has been implicated in tissue repair through its antiapoptotic and proliferative activities. Cyclooxygenase-2 (COX-2) is an inducible enzyme in the biosynthetic pathway of prostaglandins, and its activation has been shown to play a role in cell growth. Here, we report that HGF induces gene transcription of COX-2 in human bronchial epithelial cells (HBEpC). Treatment of HBEpC with HGF resulted in phosphorylation of the HGF receptor (c-Met), activation of Akt, and upregulation of COX-2 mRNA. Adenovirus-mediated gene transfer of a dominant negative (DN) Akt mutant revealed that HGF increased COX-2 mRNA in an Akt-dependent manner. COX-2 promoter analysis in luciferase reporter constructs showed that HGF regulation required the β-catenin-responsive T cell factor-4 binding element (TBE). The HGF activation of the COX-2 gene transcription was blocked by DN mutant of β-catenin or by inhibitors that blocked activation of Akt. Inhibition of p42/p44 MAPK pathway blocked HGF-mediated activation of β-catenin gene transcription but not Akt activation, suggesting that p42/p44 MAPK acts in a parallel mechanism for β-catenin activation. We also found that inhibition of COX-2 with NS-398 blocked HGF-induced growth in HBEpC. Together, the results show that the HGF increases COX-2 gene expression via an Akt-, MAPK-, and β-catenin-dependent pathway in HBEpC. PMID:18245266

Aggravation of Alzheimer's disease due to the COX-2-mediated reciprocal regulation of IL-1β and Aβ between glial and neuron cells.

PubMed

Wang, Pu; Guan, Pei-Pei; Wang, Tao; Yu, Xin; Guo, Jian-Jun; Wang, Zhan-You

2014-08-01

Alzheimer's disease (AD) is the most common form of dementia and displays the characteristics of chronic neurodegenerative disorders; amyloid plaques (AP) that contain amyloid β-protein (Aβ) accumulate in AD, which is also characterized by tau phosphorylation. Epidemiological evidence has demonstrated that long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) markedly reduces the risk of AD by inhibiting the expression of cyclooxygenase 2 (COX-2). Although the levels of COX-2 and its metabolic product prostaglandin (PG)E2 are elevated in the brain of AD patients, the mechanisms for the development of AD remain unknown. Using human- or mouse-derived glioblastoma and neuroblastoma cell lines as model systems, we delineated the signaling pathways by which COX-2 mediates the reciprocal regulation of interleukin-1β (IL-1β) and Aβ between glial and neuron cells. In glioblastoma cells, COX-2 regulates the synthesis of IL-1β in a PGE2 -dependent manner. Moreover, COX-2-derived PGE2 signals the activation of the PI3-K/AKT and PKA/CREB pathways via cyclic AMP; these pathways transactivate the NF-κB p65 subunit via phosphorylation at Ser 536 and Ser 276, leading to IL-1β synthesis. The secretion of IL-1β from glioblastoma cells in turn stimulates the expression of COX-2 in human or mouse neuroblastoma cells. Similar regulatory mechanisms were found for the COX-2 regulation of BACE-1 expression in neuroblastoma cells. More importantly, Aβ deposition mediated the inflammatory response of glial cells via inducing the expression of COX-2 in glioblastoma cells. These findings not only provide new insights into the mechanisms of COX-2-induced AD but also initially define the therapeutic targets of AD. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Mastl overexpression is associated with epithelial to mesenchymal transition and predicts a poor clinical outcome in gastric cancer.

PubMed

Sun, Xian-Jun; Li, Yan-Liang; Wang, Long-Gang; Liu, Li-Qing; Ma, Heng; Hou, Wen-Hong; Yu, Jin-Ming

2017-12-01

Microtubule-associated serine/threonine kinase like (Mastl) is deregulated in a number of types of human malignancy and may be a kinase target for cancer treatment. The aim of the present study was to determine the Mastl expression in gastric cancer and to clarify its clinical and prognostic significance. Immunohistochemistry was performed on a cohort of 126 postoperative gastric cancer samples to detect the expression of Mastl and two epithelial to mesenchymal transition (EMT) markers, epithelial-cadherin and Vimentin. The χ 2 test, Kaplan-Meier estimator analysis and Cox's regression model were used to analyze the data. Upregulated Mastl protein expression was observed in the gastric cancer tissues compared with that in the adjacent non-cancerous gastric tissues. Increased Mastl expression was identified in 54/126 (42.9%) gastric cancer samples, and was significantly associated with lymph node metastasis, tumor relapse, EMT status and poor overall survival. Additional analysis demonstrated that the Mastl expression level stratified the patient outcome in stage III, but not stage II tumor subgroups. Cox's regression analysis revealed that increased Mastl expression was an independent prognostic factor for patients with gastric cancer. Mastl expression may be a valuable prognostic marker and a potential target for patients with gastric cancer.

Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury.

PubMed

Shiow, Lawrence R; Favrais, Geraldine; Schirmer, Lucas; Schang, Anne-Laure; Cipriani, Sara; Andres, Christian; Wright, Jaclyn N; Nobuta, Hiroko; Fleiss, Bobbi; Gressens, Pierre; Rowitch, David H

2017-12-01

Inflammation is a major risk factor for neonatal white matter injury (NWMI), which is associated with later development of cerebral palsy. Although recent studies have demonstrated maturation arrest of oligodendrocyte progenitor cells (OPCs) in NWMI, the identity of inflammatory mediators with direct effects on OPCs has been unclear. Here, we investigated downstream effects of pro-inflammatory IL-1β to induce cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) production in white matter. First, we assessed COX2 expression in human fetal brain and term neonatal brain affected by hypoxic-ischemic encephalopathy (HIE). In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells. In human term neonatal HIE cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with "A2" reactivity. Next, we show that OPCs express the EP1 receptor for PGE2, and PGE2 acts directly on OPCs to block maturation in vitro. Pharmacologic blockade with EP1-specific inhibitors (ONO-8711, SC-51089), or genetic deficiency of EP1 attenuated effects of PGE2. In an IL-1β-induced model of NWMI, astrocytes also exhibit "A2" reactivity and induce COX2. Furthermore, in vivo inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment. These findings suggest that neonatal white matter astrocytes can develop "A2" reactivity that contributes to OPC maturation arrest in NWMI through induction of COX2-PGE2 signaling, a pathway that can be targeted for neonatal neuroprotection. © 2017 Wiley Periodicals, Inc.

Lentiviral Infection of Rhesus Macaques Causes Long-Term Injury to Cortical and Hippocampal Projections of Prostaglandin-Expressing Cholinergic Basal Forebrain Neurons

PubMed Central

Depboylu, Candan; Weihe, Eberhard; Eiden, Lee E.

2011-01-01

The simian immunodeficiency virus (SIV) macaque model resembles human HIV-AIDS and associated brain dysfunction. Altered expression of synaptic markers and transmitters in neuro-AIDS has been reported, but limited data exist for the cholinergic system and lipid mediators such as prostaglandins. Here, we analyzed cholinergic basal forebrain neurons with their telencephalic projections and the rate-limiting enzymes for prostaglandin synthesis, cyclooxygenases 1 and 2 (COX1 and 2) in brains of SIV-infected macaques with and without encephalitis and antiretroviral therapy, and uninfected controls. COX1 but not COX2 was co-expressed with markers of cholinergic phenotype, i.e. choline acetyltransferase and vesicular acetylcholine transporter (VAChT), in basal forebrain neurons of monkey, as well as human samples. COX1 was decreased in basal forebrain neurons in macaques with AIDS vs. uninfected and asymptomatic SIV-infected macaques. VAChT-positive fiber density was reduced in frontal, parietal and hippocampal-entorhinal cortex. Although brain SIV burden and associated COX1- and COX2-positive mononuclear and endothelial inflammatory reactions were mostly reversed in AIDS-diseased macaques that received 6-chloro-2′,3′-dideoxyguanosine treatment, decreased VAChT-positive terminal density and reduced cholinergic COX1 expression were not. Thus, COX1 expression is a feature of primate cholinergic basal forebrain neurons; it may be functionally important and a critical biomarker of cholinergic dysregulation accompanying lentiviral encephalopathy. These results imply that insufficiently prompt initiation of antiretroviral therapy in lentiviral infection may lead to neurostructurally unremarkable but neurochemically prominent, irreversible brain damage. PMID:22157616

CRE-Mediated Transcription and COX-2 Expression in the Pilocarpine Model of Status Epilepticus

PubMed Central

Lee, Boyoung; Dziema, Heather; Lee, Kyu Hyun; Choi, Yun-Sik; Obrietan, Karl

2007-01-01

Status epilepticus (SE) triggers neuronal death, reactive gliosis and remodeling of synaptic circuitry, thus leading to profound pathological alterations in CNS physiology. These processes are, in part, regulated by the rapid upregulation of both cytotoxic and cytoprotective genes. One pathway that may couple SE to transcriptionally-dependent alterations in CNS physiology is the CREB (cAMP response element-binding protein)/CRE (cAMP response element) cascade. Here, we utilized the pilocarpine model of SE on a mouse strain transgenic for a CRE-reporter construct (β-galactosidase) to begin to characterize how seizure activity regulates the activation state of the CREB/CRE pathway in both glia and neurons of the hippocampus. SE triggered a rapid (4–8 hrs post SE) but transient increase in CRE-mediated gene expression in the neuronal sublayers. In contrast to neurons, SE induced a lasting increase (up to 20 days) in CRE-mediated transcription in both reactive astrocytes and microglia. CRE-mediated gene expression correlated with expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2). To examine the role of CREB in SE-induced COX-2 expression, we generated a transgenic mouse strain that expresses A-CREB, a potent repressor of CREB-dependent transcription. In these animals, the capacity of SE to stimulate COX-2 expression was markedly attenuated, indicating that CREB is a key intermediate in SE-induced COX-2 expression. Collectively these data show that SE triggers two waves of CREB-mediated gene expression, a transient wave in neurons and a long-lasting wave in reactive glial cells, and that CREB couples SE to COX-2 expression. PMID:17029965

[Non-steroidal anti-inflammatory drug induced gastropathy and preventive effects of teprenone on the gastropathy in rats].

PubMed

Ma, Juan; Yuan, Gang; Chen, Min-hu

2006-10-31

To construct the model of non-steroidal anti-inflammatory drug (NSAID) induced gastropathy and observe the preventive effects of Teprenone on it in rats. Ninety-one male Sprague-Dawley (SD) rats were divided into normal saline group, model group (I) and prophylaxis group (II). Group I includes four subgroups (Ia, Ib, Ic, Id) treated by indomethacin (5 mgxkg(-1)xd(-1)), combination of indomethacin (5 mgxkg(-1)xd(-1)) and prednisone (10 mgxkg(-1)xd(-1)), celecoxib (100 mgxkg(-1)xd(-1)) and combination of celecoxib (100 mgxkg(-1)xd(-1)) and prednisone (10 mgxkg(-1)xd(-1)) respectively. Group II also includes four subgroups (IIa, IIb, IIc, IId) pretreated by teprenone (12 mgxkg(-1)xd(-1)) compared with group I. Lesion index (LI), pathohistology index, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) mRNA detected by RT-PCR were observed after 4 days. Compared with normal saline group, LI (11.00 (1.00 - 22.5), 8.50 (0.75 - 14.50), 11.00 (3.50 - 14.75), P < 0.01) of three model subgroups (Ia, Ib, Id), and pathohistology indexes (1.00 (0.00 - 1.25), 2.00 (0.00 - 5.00), 1.00 (0.00 - 3.00), 2.00 (0.00 - 2.00), P < 0.01) of the whole model group increased significantly (P < 0.05). Compared with corresponding model subgroups, LIs (0.00 (0.00 - 0.25), 1.00 (0.00 - 1.50), 0.00 (0.00 - 0.00), 0.00 (0.00 - 1.00), P < 0.05) and pathohistology indexes (0.00 (0.00 - 0.00), 0.00 (0.00 - 0.50), 0.00 (0.00 - 0.25), 0.00 (0.00 - 0.50), P < 0.05) of prophylaxis subgroups were decreased significantly (P < 0.05). There was obvious difference in LI between Ic and Ia as well as between Ic and Id (P < 0.05). Compared with normal saline group, COX-1 mRNA expression of the groups (Ia, Ib, Id, IIa, IIb and IId) increased (0.384 +/- 0.031, 0.354 +/- 0.026, 0.753 +/- 0.049, 0.366 +/- 0.035, 0.381 +/- 0.036, 0.766 +/- 0.401, P < 0.001) while COX-2 mRNA expression of the above groups decreased statistically (0.483 +/- 0.056, 0.448 +/- 0.046, 0.461 +/- 0.050, 0.479 +/- 0.032, P < 0.001). These results suggested gastric mucosa lesions could be resulted from COX-2 inhibitors but better than those induced by traditional NSAID. Prednisone could promote the risk in NSAID induced gastropathy. In addition to COX-1 inhibition, other factors might also involved in NSAID induced gastropathy. Teprenone could prevented from NSAID induced gastropathy but the actions might be not associated with COXs.

Modelling of chemical degradation of blended cement-based materials by leaching cycles with Callovo-Oxfordian porewater

NASA Astrophysics Data System (ADS)

Olmeda, Javier; Henocq, Pierre; Giffaut, Eric; Grivé, Mireia

2017-06-01

The present work describes a thermodynamic model based on pore water replacement cycles to simulate the chemical evolution of blended cement (BFS + FA) by interaction with external Callovo-Oxfordian (COx) pore water. In the framework of the radioactive waste management, the characterization of the radionuclide behaviour (solubility/speciation, adsorption) in cementitious materials needs to be done for several chemical degradation states (I to IV). In particular, in the context of the deep geological radioactive waste disposal project (Cigéo), cement-based materials will be chemically evolved with time in contact with the host-rock (COx formation). The objective of this study is to provide an equilibrium solution composition for each degradation state for a CEM-V cement-based material to support the adsorption and diffusion experiments reproducing any state of degradation. Calculations have been performed at 25 °C using the geochemical code PhreeqC and an up-to-date thermodynamic database (ThermoChimie v.9.0.b) coupled to SIT approach for ionic strength correction. The model replicates experimental data with accuracy. The approach followed in this study eases the analysis of the chemical evolution in both aqueous and solid phase to obtain a fast assessment of the geochemical effects associated to an external water intrusion of variable composition on concrete structures.

Measurement and modeling of diameter distributions of particulate matter in terrestrial solutions

NASA Astrophysics Data System (ADS)

Levia, Delphis F.; Michalzik, Beate; Bischoff, Sebastian; NäThe, Kerstin; Legates, David R.; Gruselle, Marie-Cecile; Richter, Susanne

2013-04-01

Particulate matter (PM) plays an important role in biogeosciences, affecting biosphere-atmosphere interactions and ecosystem health. This is the first known study to quantify and model PM diameter distributions of bulk precipitation, throughfall, stemflow, and organic layer (Oa) solution. Solutions were collected from a European beech (Fagus sylvatica L.) forest during leafed and leafless periods. Following scanning electron microscopy and image analysis, PM distributions were quantified and then modeled with the Box-Cox transformation. Based on an analysis of 43,278 individual particulates, median PM diameter of all solutions was around 3.0 µm. All PM diameter frequency distributions were skewed significantly to the right. Optimal power transformations of PM diameter distributions were between -1.00 and -1.56. The utility of this model reconstruction would be that large samples having a similar probability density function can be developed for similar forests. Further work on the shape and chemical composition of particulates is warranted.

The Effects of Decomposition on the Oxidative Ratio and Carbon Oxidation State of Organic Matter

NASA Astrophysics Data System (ADS)

Gallagher, M. E.; Masiello, C. A.; Clark, N.; Randerson, J. T.; Robertson, G. P.

2006-12-01

Ecosystem oxidative ratio (OR) and the related parameter carbon oxidation state (Cox) are critical in the apportionment of anthropogenic CO2 between the terrestrial biosphere and ocean reservoirs. OR is the ratio of O2 to CO2 in gas exchange fluxes between the biosphere and the atmosphere (Fba and Fab). Accurate measurements of OR have been challenging (Seibt et al. 2004); instead we approach the problem by measuring Cox and calculating OR from biomass reservoirs. Cox can range from -4 to +4 (CH4 to CO2) and is driven by photosynthesis, respiration, and decomposition. The net OR of the biosphere varies with ecosystem type, and this can affect the apportionment of anthropogenic CO2 between the terrestrial biosphere and ocean reservoirs (Randerson et al. 2006). This makes it essential to constrain ecosystem Cox and OR values. Although small variations in global ecosystem OR have the potential to cause shifts in atmospheric O2 concentrations, no whole ecosystem measurements of Cox yet exist. To constrain ORba and ORab, and improve our understanding of how decomposition affects Cox, we performed a litter bag experiment at the Kellogg Biological Station-Long Term Ecological Research (KBS-LTER) in Michigan at the end of the 2005 agricultural season. We placed 15 corn biomass litter bags in an agricultural field and collected 3 bags at 2, 4, 7, 26, and 29 weeks. These samples were analyzed for %C, %H, %N, and %O via elemental analysis, and these data were used to calculate Cox. Aboveground Cox was measured similarly. We anticipated that the Cox of the corn litter would become more reduced with decomposition, as the percentage of carbohydrates would decrease with time, while that of protein, lignin, and lipids would increase (Baldock et al. 2004). We report differences between the Cox of biomass fixation and biomass degradation from our experiments. Using simple assumptions about ecosystem nitrogen cycling, we convert Cox to OR and report the existence or absence of a temporal offset between ORab and ORba within an agricultural ecosystem.

The Ethical Foundation of Critical Pedagogy in Contemporary Academia: (Self)-Reflection and Complicity in the Process of Teaching

ERIC Educational Resources Information Center

Rabikowska, Marta

2009-01-01

In this paper an ethical approach to educational methodology is discussed in relation to the philosophies of Emanuel Levinas and Robert Cox. Cox's anti-essentialist understanding of historical materialism and Levinas' metaphysical idealism are applied to an analysis of the (self)-reflective methods required today in Higher Education in the UK,…

The Cox proportional Hazard model on duration of birth process

NASA Astrophysics Data System (ADS)

Wuryandari, Triastuti; Haryatmi Kartiko, Sri; Danardono

2018-05-01

The duration of birth process, which is measured from the birth sign until baby born, is one important factor to the whole outcome of delivery process. There is a method of birth process that given relaxing and gentle treatment to the mother caled as gentlebirth. Gentlebirth is a method of birth process that combines brain science, birth science and technology to empower positive birth without pain. However the effect of method to the duration of birth process is still need empirical investigations. Therefore, the objective of this paper is to analyze the duration of birth process using the appropriate statistical methods for durational data, survival data or time to event data. Since there are many variables or factor that may affect the duration, a regression model is considerated. The flexibility of the Cox Proportional Hazard Model in the sense that there is no distributional assumption required, makes the Cox Model as the appropriate model and method to analyze the duration birth process. It is concluded that the Gentlebirth method affects on duration of birth process, with Hazard Ratio of 2.073, showing that the duration of birth process with gentlebirth method is faster than the other method.

Adherence to oral anticoagulants in patients with atrial fibrillation-a population-based retrospective cohort study linking health information systems in the Valencia region, Spain: a study protocol.

PubMed

Sanfélix-Gimeno, G; Rodríguez-Bernal, C L; Hurtado, I; Baixáuli-Pérez, C; Librero, J; Peiró, S

2015-10-19

Adherence to oral anticoagulation (OAC) treatment, vitamin K antagonists or new oral anticoagulants, is an essential element for effectiveness. Information on adherence to OAC in atrial fibrillation (AF) and the impact of adherence on clinical outcomes using real-world data barely exists. We aim to describe the patterns of adherence to OAC over time in patients with AF, estimate the associated factors and their impact on clinical events, and assess the same issues with conventional measures of primary and secondary adherence-proportion of days covered (PDC) and persistence-in routine clinical practice. This is a population-based retrospective cohort study including all patients with AF treated with OAC from 2010 to date in Valencia, Spain; data will be obtained from diverse electronic records of the Valencia Health Agency. adherence trajectories. (1) primary non-adherence; (2) secondary adherence: (a) PDC, (b) persistence. Clinical outcomes: hospitalisation for haemorrhagic or thromboembolic events and death during follow-up. (1) description of baseline characteristics, adherence patterns (trajectory models or latent class growth analysis models) and conventional adherence measures; (2) logistic or Cox multivariate regression models, to assess the associations between adherence measures and the covariates, and logistic multinomial regression models, to identify characteristics associated with each trajectory; (3) Cox proportional hazard models, to assess the relationship between adherence and clinical outcomes, with propensity score adjustment applied to further control for potential confounders; (4) to estimate the importance of different healthcare levels in the variations of adherence, logistic or Cox multilevel regression models. This study has been approved by the corresponding Clinical Research Ethics Committee. We plan to disseminate the project's findings through peer-reviewed publications and presentations at relevant health conferences. Policy reports will also be prepared in order to promote the translation of our findings into policy and clinical practice. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

A class of Box-Cox transformation models for recurrent event data.

PubMed

Sun, Liuquan; Tong, Xingwei; Zhou, Xian

2011-04-01

In this article, we propose a class of Box-Cox transformation models for recurrent event data, which includes the proportional means models as special cases. The new model offers great flexibility in formulating the effects of covariates on the mean functions of counting processes while leaving the stochastic structure completely unspecified. For the inference on the proposed models, we apply a profile pseudo-partial likelihood method to estimate the model parameters via estimating equation approaches and establish large sample properties of the estimators and examine its performance in moderate-sized samples through simulation studies. In addition, some graphical and numerical procedures are presented for model checking. An example of application on a set of multiple-infection data taken from a clinic study on chronic granulomatous disease (CGD) is also illustrated.

Lactobacillus fermentum ZYL0401 Attenuates Lipopolysaccharide-Induced Hepatic TNF-α Expression and Liver Injury via an IL-10- and PGE2-EP4-Dependent Mechanism

PubMed Central

Lv, Longxian; Yang, Jianzhuan; Lu, Haifeng; Li, Lanjuan

2015-01-01

Lipopolysaccharide (LPS) has essential role in the pathogenesis of D-galactosamine-sensitized animal models and alcoholic liver diseases of humans, by stimulating release of pro-inflammatory mediators that cause hepatic damage and intestinal barrier impairment. Oral pretreatment of probiotics has been shown to attenuate LPS-induced hepatic injury, but it is unclear whether the effect is direct or due to improvement in the intestinal barrier. The present study tested the hypothesis that pretreatment with probiotics enables the liver to withstand directly LPS-induced hepatic injury and inflammation. In a mouse model of LPS-induced hepatic injury, the levels of hepatic tumor necrosis factor-alpha (TNF-α) and serum alanine aminotransferase (ALT) of mice with depleted intestinal commensal bacteria were not significantly different from that of the control models. Pre-feeding mice for 10 days with Lactobacillus fermentum ZYL0401 (LF41), significantly alleviated LPS-induced hepatic TNF-α expression and liver damage. After LF41 pretreatment, mice had dramatically more L.fermentum-specific DNA in the ileum, significantly higher levels of ileal cyclooxygenase (COX)-2 and interleukin 10 (IL-10) and hepatic prostaglandin E2 (PGE2). However, hepatic COX-1, COX-2, and IL-10 protein levels were not changed after the pretreatment. There were also higher hepatic IL-10 protein levels after LPS challenge in LF41-pretreaed mice than in the control mice. Attenuation of hepatic TNF-α was mediated via the PGE2/E prostanoid 4 (EP4) pathway, and serum ALT levels were attenuated in an IL-10-dependent manner. A COX-2 blockade abolished the increase in hepatic PGE2 and IL-10 associated with LF41. In LF41-pretreated mice, a blockade of IL-10 caused COX-2-dependent promotion of hepatic PGE2, without affecting hepatic COX-2levels. In LF41-pretreated mice, COX2 prevented enhancing TNF-α expression in both hepatic mononuclear cells and the ileum, and averted TNF-α-mediated increase in intestinal permeability. Together, we demonstrated that LF41 pre-feeding enabled the liver to alleviate LPS-induced hepatic TNF-α expression and injury via a PGE2-EP4- and IL-10-dependent mechanism. PMID:25978374

Feature selection through validation and un-censoring of endovascular repair survival data for predicting the risk of re-intervention.

PubMed

Attallah, Omneya; Karthikesalingam, Alan; Holt, Peter J E; Thompson, Matthew M; Sayers, Rob; Bown, Matthew J; Choke, Eddie C; Ma, Xianghong

2017-08-03

Feature selection (FS) process is essential in the medical area as it reduces the effort and time needed for physicians to measure unnecessary features. Choosing useful variables is a difficult task with the presence of censoring which is the unique characteristic in survival analysis. Most survival FS methods depend on Cox's proportional hazard model; however, machine learning techniques (MLT) are preferred but not commonly used due to censoring. Techniques that have been proposed to adopt MLT to perform FS with survival data cannot be used with the high level of censoring. The researcher's previous publications proposed a technique to deal with the high level of censoring. It also used existing FS techniques to reduce dataset dimension. However, in this paper a new FS technique was proposed and combined with feature transformation and the proposed uncensoring approaches to select a reduced set of features and produce a stable predictive model. In this paper, a FS technique based on artificial neural network (ANN) MLT is proposed to deal with highly censored Endovascular Aortic Repair (EVAR). Survival data EVAR datasets were collected during 2004 to 2010 from two vascular centers in order to produce a final stable model. They contain almost 91% of censored patients. The proposed approach used a wrapper FS method with ANN to select a reduced subset of features that predict the risk of EVAR re-intervention after 5 years to patients from two different centers located in the United Kingdom, to allow it to be potentially applied to cross-centers predictions. The proposed model is compared with the two popular FS techniques; Akaike and Bayesian information criteria (AIC, BIC) that are used with Cox's model. The final model outperforms other methods in distinguishing the high and low risk groups; as they both have concordance index and estimated AUC better than the Cox's model based on AIC, BIC, Lasso, and SCAD approaches. These models have p-values lower than 0.05, meaning that patients with different risk groups can be separated significantly and those who would need re-intervention can be correctly predicted. The proposed approach will save time and effort made by physicians to collect unnecessary variables. The final reduced model was able to predict the long-term risk of aortic complications after EVAR. This predictive model can help clinicians decide patients' future observation plan.

The Learning Process of Supervisees Who Engage in the Reflecting Team Model within Group Supervision: A Grounded Theory Inquiry

ERIC Educational Resources Information Center

Pender, Rebecca Lynn

2012-01-01

In recent years, counselor educators have begun to incorporate the use of the reflecting team process with the training of counselors. Specifically, the reflecting team has been used in didactic courses (Cox, 2003; Landis & Young, 1994; Harrawood, Wilde & Parmanand, 2011) and in supervision (Cox, 1997; Prest, Darden, & Keller, 1990;…

Infrared (810-nm) low-level laser therapy on rat experimental knee inflammation.

PubMed

Pallotta, Rodney Capp; Bjordal, Jan Magnus; Frigo, Lúcio; Leal Junior, Ernesto Cesar Pinto; Teixeira, Simone; Marcos, Rodrigo Labat; Ramos, Luciano; Messias, Felipe de Moura; Lopes-Martins, Rodrigo Alvaro Brandão

2012-01-01

Arthritis of the knee is the most common type of joint inflammatory disorder and it is associated with pain and inflammation of the joint capsule. Few studies address the effects of the 810-nm laser in such conditions. Here we investigated the effects of low-level laser therapy (LLLT; infrared, 810-nm) in experimentally induced rat knee inflammation. Thirty male Wistar rats (230-250 g) were anesthetized and injected with carrageenan by an intra-articular route. After 6 and 12 h, all animals were killed by CO(2) inhalation and the articular cavity was washed for cellular and biochemical analysis. Articular tissue was carefully removed for real-time PCR analysis in order to evaluate COX-1 and COX-2 expression. LLLT was able to significantly inhibit the total number of leukocytes, as well as the myeloperoxidase activity with 1, 3, and 6 J (Joules) of energy. This result was corroborated by cell counting showing the reduction of polymorphonuclear cells at the inflammatory site. Vascular extravasation was significantly inhibited at the higher dose of energy of 10 J. Both COX-1 and 2 gene expression were significantly enhanced by laser irradiation while PGE(2) production was inhibited. Low-level laser therapy operating at 810 nm markedly reduced inflammatory signs of inflammation but increased COX-1 and 2 gene expression. Further studies are necessary to investigate the possible production of antiinflammatory mediators by COX enzymes induced by laser irradiation in knee inflammation.

Cox Regression Models with Functional Covariates for Survival Data.

PubMed

Gellar, Jonathan E; Colantuoni, Elizabeth; Needham, Dale M; Crainiceanu, Ciprian M

2015-06-01

We extend the Cox proportional hazards model to cases when the exposure is a densely sampled functional process, measured at baseline. The fundamental idea is to combine penalized signal regression with methods developed for mixed effects proportional hazards models. The model is fit by maximizing the penalized partial likelihood, with smoothing parameters estimated by a likelihood-based criterion such as AIC or EPIC. The model may be extended to allow for multiple functional predictors, time varying coefficients, and missing or unequally-spaced data. Methods were inspired by and applied to a study of the association between time to death after hospital discharge and daily measures of disease severity collected in the intensive care unit, among survivors of acute respiratory distress syndrome.

Noninfectious Fever in the Near-Term Pregnant Rat Induces Fetal Brain Inflammation: A Model for the Consequences of Epidural-Associated Maternal Fever.

PubMed

Segal, Scott; Pancaro, Carlo; Bonney, Iwona; Marchand, James E

2017-12-01

Women laboring with epidural analgesia experience fever much more frequently than do women who chose other forms of analgesia, and maternal intrapartum fever is associated with numerous adverse consequences, including brain injury in the fetus. We developed a model of noninfectious inflammatory fever in the near-term pregnant rat to simulate the pathophysiology of epidural-associated fever and hypothesized that it would produce fetal brain inflammation. Twenty-four pregnant Sprague-Dawley rats were studied at 20 days gestation (term: 22 days). Dams were treated by injection of rat recombinant interleukin (IL)-6 or vehicle at 90-minute intervals, and temperature was monitored every 30 minutes. Eight hours after the first treatment, dams were delivered of fetuses and then killed. Maternal IL-6 was measured at delivery. Fetal brains (n = 24) were processed and stained for ED-1/CD68, a marker for activated microglia, and cell counts in the lateral septal and hippocampal brain regions were measured. Fetal brains were also stained for cyclooxygenase-2 (COX-2), a downstream marker of neuroinflammation. Eight fetal brains were further analyzed for quantitative forebrain COX-2 by Western blotting compared to a β-actin standard. Maternal temperature and IL-6 levels were compared between treatments, as were cell counts, COX-2 staining, and COX-2 levels by Mann-Whitney U test, repeated-measures analysis of variance, or Fisher exact test, as appropriate. Injection of rat IL-6 at 90-minute intervals produced an elevation of maternal temperature compared to vehicle (P < .0001). IL-6 levels were elevated to clinically relevant levels at delivery in IL-6 compared to vehicle-treated animals (mean ± standard deviation: 923 ± 97 vs 143 ± 94 pg/mL, P = .0006). ED-1-stained cells were present in significantly higher numbers in fetal brains from IL-6 compared to saline-treated dams (median [interquartile range]: caudal hippocampus, 99 [94-104] and 64 [57-68], respectively, P = .002; lateral septum, 102 [96-111] and 68 [65-69], respectively, P = .002), as well as COX-2 immunostaining (lateral septum, 22 [20-26] and 17 [15-18], respectively, P = .005; dorsal hippocampus, 27 [22-32] and 16 [14-19], respectively, P = .013) and quantitative COX-2 Western blotting activity (mean ± standard error of the mean: vehicle, 0% of β-actin intensity versus IL-6, 41.5% ± 24%, P < .001). Noninfectious inflammatory fever is inducible in the near-term pregnant rat by injection of IL-6 at levels comparable to those observed during human epidural labor analgesia. Maternal IL-6 injection causes neuroinflammation in the fetus.

Redox and non-redox mechanism of in vitro cyclooxygenase inhibition by natural quinones.

PubMed

Landa, Premysl; Kutil, Zsofia; Temml, Veronika; Vuorinen, Anna; Malik, Jan; Dvorakova, Marcela; Marsik, Petr; Kokoska, Ladislav; Pribylova, Marie; Schuster, Daniela; Vanek, Tomas

2012-03-01

In this study, ten anthra-, nine naphtho-, and five benzoquinone compounds of natural origin and five synthetic naphthoquinones were assessed, using an enzymatic in vitro assay, for their potential to inhibit cyclooxygenase-1 and -2 (COX-1 and COX-2), the key enzymes of the arachidonic acid cascade. IC₅₀ values comparable with COX reference inhibitor indomethacin were recorded for several quinones (primin, alkannin, diospyrin, juglone, 7-methyljuglone, and shikonin). For some of the compounds, we suggest the redox potential of quinones as the mechanism responsible for in vitro COX inhibition because of the quantitative correlation with their pro-oxidant effect. Structure-relationship activity studies revealed that the substitutions at positions 2 and 5 play the key roles in the COX inhibitory and pro-oxidant actions of naphthoquinones. In contrast, the redox mechanism alone could not explain the activity of primin, embelin, alkannin, and diospyrin. For these four quinones, molecular modeling suggested similar binding modes as for conventional nonsteroidal anti-inflammatory drugs (NSAIDs). © Georg Thieme Verlag KG Stuttgart · New York.

Arylhydrazone derivatives of naproxen as new analgesic and anti-inflammatory agents: Design, synthesis and molecular docking studies.

PubMed

Azizian, Homa; Mousavi, Zahra; Faraji, Hamidreza; Tajik, Mohammad; Bagherzadeh, Kowsar; Bayat, Peyman; Shafiee, Abbas; Almasirad, Ali

2016-06-01

A series of new arylidenehydrazone derivatives of naproxen were synthesized and evaluated for their analgesic and anti-inflammatory activities. Some of the synthesized analogues showed comparable activities when compared against naproxen for their analgesic and anti-inflammatory properties. 2-(6-methoxy-2-naphthyl)-N'-[(pyridine-4-yl)methylene]propanoic acid hydrazide 4j was found to be the most active analgesic agent. 2-(6-methoxy-2-naphthyl)-N'-[4-nitrobenzylidene]propanoic acid hydrazide 4g showed highest anti-inflammatory activity in comparison to the naproxen. Molecular modeling study of the synthesized compounds suggested that the designed molecules were well located and bound to the COX-1 and COX-2 active sites. Compound 4g showed the highest selectivity for COX-2 (RCOX-2/COX-1=1.94) and higher affinity rather than naproxen in COX-2 active site (RCOX-2/naproxen=1.28). Moreover, the structural analyses confirmed that the E-ap rotamer is the preferred structure for the arylidenehydrazone derivatives. Copyright © 2016 Elsevier Inc. All rights reserved.

Leigh syndrome associated with a novel mutation in the COX15 gene.

PubMed

Miryounesi, Mohammad; Fardaei, Majid; Tabei, Seyed Mohammadbagher; Ghafouri-Fard, Soudeh

2016-06-01

Leigh syndrome (LS) is a subacute necrotizing encephalomyelopathy with a diverse range of symptoms, such as psychomotor delay or regression, weakness, hypotonia, truncal ataxia, intention tremor as well as lactic acidosis in the blood, cerebrospinal fluid or urine. Both nuclear gene defects and mutations of the mitochondrial genome have been detected in these patients. Here we report a 7-year-old girl with hypotonia, tremor, developmental delay and psychomotor regression. However, serum lactate level as well as brain magnetic resonance imaging were normal. Mutational analysis has revealed a novel mutation in exon 4 of COX15 gene (c.415C>G) which results in p.Leu139Val. Previous studies have demonstrated that COX15 mutations are associated with typical LS as well as fatal infantile hypertrophic cardiomyopathy. Consequently, clinical manifestations of COX15 mutations may be significantly different in patients. Such information is of practical importance in genetic counseling.

Comparison of Statistical Approaches Dealing with Time-dependent Confounding in Drug Effectiveness Studies

PubMed Central

Karim, Mohammad Ehsanul; Petkau, John; Gustafson, Paul; Platt, Robert W.; Tremlett, Helen

2017-01-01

In longitudinal studies, if the time-dependent covariates are affected by the past treatment, time-dependent confounding may be present. For a time-to-event response, marginal structural Cox models (MSCMs) are frequently used to deal with such confounding. To avoid some of the problems of fitting MSCM, the sequential Cox approach has been suggested as an alternative. Although the estimation mechanisms are different, both approaches claim to estimate the causal effect of treatment by appropriately adjusting for time-dependent confounding. We carry out simulation studies to assess the suitability of the sequential Cox approach for analyzing time-to-event data in the presence of a time-dependent covariate that may or may not be a time-dependent confounder. Results from these simulations revealed that the sequential Cox approach is not as effective as MSCM in addressing the time-dependent confounding. The sequential Cox approach was also found to be inadequate in the presence of a time-dependent covariate. We propose a modified version of the sequential Cox approach that correctly estimates the treatment effect in both of the above scenarios. All approaches are applied to investigate the impact of beta-interferon treatment in delaying disability progression in the British Columbia Multiple Sclerosis cohort (1995 – 2008). PMID:27659168

[Value of the albumin to globulin ratio in predicting severity and prognosis in myasthenia gravis patients].

PubMed

Yang, D H; Su, Z Q; Chen, Y; Chen, Z B; Ding, Z N; Weng, Y Y; Li, J; Li, X; Tong, Q L; Han, Y X; Zhang, X

2016-03-08

To assess the predictive value of the albumin to globulin ratio (AGR) in evaluation of disease severity and prognosis in myasthenia gravis patients. A total of 135 myasthenia gravis (MG) patients were enrolled between February 2009 and March 2015. The AGR was detected on the first day of hospitalization and ranked from lowest to highest, and the patients were divided into three equal tertiles according to the AGR values, which were T1 (AGR <1.34), T2 (1.34≤AGR≤1.53) and T3 (AGR>1.53). The Kaplan-Meier curve was used to evaluate the prognostic value of AGR. Cox model analysis was used to evaluate the relevant factors. Multivariate Logistic regression analysis was used to find the predictors of myasthenia crisis during hospitalization. The median length of hospital stay for each tertile was: for the T1 21 days (15-35.5), T2 18 days (14-27.5), and T3 16 days (12-22.5) (P<0.01), and Kaplan-Meier curves showed significant difference among the three groups. In the univariate model, serum albumin, creatinine, AGR and MGFA clinical classification were related to prognosis of myasthenia gravis. At the multivariate Cox regression analysis, the AGR (P<0.001) and MGFA clinical classification (P<0.001) were independent predictive factors of disease severity and prognosis in myasthenia gravis patients. Respectively, the hazard ratio (HR) were 4.655 (95% CI: 2.355-9.202) and 0.596 (95% CI: 0.492-0.723). Multivariate Logistic regression analysis showed the AGR (P<0.001) and MGFA clinical classification were related to myasthenia crisis. The AGR may represent a simple, potentially useful predictive biomarker for evaluating the disease severity and prognosis of patients with myasthenia gravis.

Genetic polymorphisms in pre-miRNAs predict the survival of non-small-cell lung cancer in Chinese population: a cohort study and a meta-analysis

PubMed Central

Xia, Lingzi; Yin, Zhihua; Li, Xuelian; Ren, Yangwu; Zhang, Haibo; Zhao, Yuxia; Zhou, Baosen

2017-01-01

Background To explore the association of genetic polymorphisms in pre-miRNA 30c-1 rs928508 and pre-miRNA 27a rs895819 with non-small-cell lung cancer prognosis. Materials and Methods 480 patients from five hospitals were enrolled in this prospective cohort study. They were followed up for five years. The association between genotypes and overall survival was assessed by Cox proportional hazards regression models. A meta-analysis was conducted to provide evidence for the effect of microRNA 27a rs895819 on cancer survival. Results G-allele containing genotypes of microRNA 30c-1 polymorphisms and C-allele containing genotypes of microRNA 27a were significantly associated with poorer overall survival. Multivariate Cox regression models indicated that these genetic polymorhpisms were independently predictive factors of poorer overall survival. In stratified analysis, the effect was observed in many strata. The significant joint effect was also observed in our study. Patients with G allele of microRNA 30c-1 rs928508 and C allele of microRNA 27a rs895819 had the poorer overall survival than patients with C allele of rs928508 and T allele of rs895819. The effect of the microRNA 27a rs895819 on non-small cell lung cancer overall survival was supported by the meta-analysis results. Conclusions The two single nucleotide polymorphisms in microRNA 30c-1 and microRNA 27a can predict the outcome of non-small cell lung cancer patients and they may decrease the sensitivity to anti-cancer drugs. PMID:29100439

The Influence of Total Nodes Examined, Number of Positive Nodes, and Lymph Node Ratio on Survival After Surgical Resection and Adjuvant Chemoradiation for Pancreatic Cancer: A Secondary Analysis of RTOG 9704

DOE Office of Scientific and Technical Information (OSTI.GOV)

Showalter, Timothy N.; Winter, Kathryn A.; Berger, Adam C., E-mail: adam.berger@jefferson.edu

2011-12-01

Purpose: Lymph node status is an important predictor of survival in pancreatic cancer. We performed a secondary analysis of Radiation Therapy Oncology Group (RTOG) 9704, an adjuvant chemotherapy and chemoradiation trial, to determine the influence of lymph node factors-number of positive nodes (NPN), total nodes examined (TNE), and lymph node ratio (LNR ratio of NPN to TNE)-on OS and disease-free survival (DFS). Patient and Methods: Eligible patients from RTOG 9704 form the basis of this secondary analysis of lymph node parameters. Actuarial estimates for OS and DFS were calculated using Kaplan-Meier methods. Cox proportional hazards models were performed to evaluatemore » associations of NPN, TNE, and LNR with OS and DFS. Multivariate Cox proportional hazards models were also performed. Results: There were 538 patients enrolled in the RTOG 9704 trial. Of these, 445 patients were eligible with lymph nodes removed. Overall median NPN was 1 (min-max, 0-18). Increased NPN was associated with worse OS (HR = 1.06, p = 0.001) and DFS (HR = 1.05, p = 0.01). In multivariate analyses, both NPN and TNE were associated with OS and DFS. TNE > 12, and >15 were associated with increased OS for all patients, but not for node-negative patients (n = 142). Increased LNR was associated with worse OS (HR = 1.01, p < 0.0001) and DFS (HR = 1.006, p = 0.002). Conclusion: In patients who undergo surgical resection followed by adjuvant chemoradiation, TNE, NPN, and LNR are associated with OS and DFS. This secondary analysis of a prospective, cooperative group trial supports the influence of these lymph node parameters on outcomes after surgery and adjuvant therapy using contemporary techniques.« less

SCD-HeFT: Use of RR Interval Statistics for Long-term Risk Stratification for Arrhythmic Sudden Cardiac Death

PubMed Central

Au-yeung, Wan-tai M.; Reinhall, Per; Poole, Jeanne E.; Anderson, Jill; Johnson, George; Fletcher, Ross D.; Moore, Hans J.; Mark, Daniel B.; Lee, Kerry L.; Bardy, Gust H.

2015-01-01

Background In the SCD-HeFT a significant fraction of the congestive heart failure (CHF) patients ultimately did not die suddenly from arrhythmic causes. CHF patients will benefit from better tools to identify if ICD therapy is needed. Objective To identify predictor variables from baseline SCD-HeFT patients’ RR intervals that correlate to arrhythmic sudden cardiac death (SCD) and mortality and to design an ICD therapy screening test. Methods Ten predictor variables were extracted from pre-randomization Holter data from 475 patients enrolled in the SCD-HeFT ICD arm using novel and traditional heart rate variability methods. All variables were correlated to SCD using Mann Whitney-Wilcoxon test and receiver operating characteristic analysis. ICD therapy screening tests were designed by minimizing the cost of false classifications. Survival analysis, including log-rank test and Cox models, was also performed. Results α1 and α2 from detrended fluctuation analysis, the ratio of low to high frequency power, the number of PVCs per hour and heart rate turbulence slope are all statistically significant for predicting the occurrences of SCD (p<0.001) and survival (log-rank p<0.01). The most powerful multivariate predictor tool using the Cox Proportional Hazards was α2 with a hazard ratio of 0.0465 (95% CI: 0.00528 – 0.409, p<0.01). Conclusion Predictor variables from RR intervals correlate to the occurrences of SCD and distinguish survival among SCD-HeFT ICD patients. We believe SCD prediction models should incorporate Holter based RR interval analysis to refine ICD patient selection especially in removing patients who are unlikely to benefit from ICD therapy. PMID:26096609

Chemoprevention of Head and Neck Cancer by Simultaneous Blocking of Epidermal Growth Factor Receptor and Cyclooxygenase-2 Signaling Pathways: Preclinical and Clinical Studies

PubMed Central

Shin, Dong M.; Zhang, Hongzheng; Saba, Nabil; Chen, Amy; Nannapaneni, Sreenivas; Amin, A.R.M. Ruhul; Müller, Susan; Lewis, Melinda; Sica, Gabriel; Kono, Scott; Brandes, Johann C.; Grist, William; Moreno-Williams, Rachel; Beitler, Jonathan J.; Thomas, Sufi M.; Chen, Zhengjia; Shin, Hyung Ju C.; Grandis, Jennifer R.; Khuri, Fadlo R.; Chen, Zhuo Georgia

2013-01-01

Purpose We investigated the efficacy and underlying molecular mechanism of a novel chemopreventive strategy combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with cyclooxygenase-2 inhibitor (COX-2I). Experimental Design We examined the inhibition of tumor cell growth by combined EGFR-TKI (erlotinib) and COX-2I (celecoxib) treatment using head and neck cancer (HNC) cell lines and a preventive xenograft model. We studied the antiangiogenic activity of these agents and examined the affected signaling pathways by immunoblotting analysis in tumor cell lysates and immunohistochemistry (IHC) and enzyme immunoassay (EIA) analyses on the mouse xenograft tissues and blood, respectively. Biomarkers in these signaling pathways were studied by IHC, EIA, and an antibody array analysis in samples collected from participants in a phase I chemoprevention trial of erlotinib and celecoxib. Results The combined treatment inhibited HNC cell growth significantly more potently than either single agent alone in cell line and xenograft models, and resulted in greater inhibition of cell cycle progression at G1 phase than either single drug. The combined treatment modulated the EGFR and mTOR signaling pathways. A phase I chemoprevention trial of combined erlotinib and celecoxib revealed an overall pathologic response rate of 71% at time of data analysis. Analysis of tissue samples from participants consistently showed downregulation of EGFR, pERK and pS6 levels after treatment, which correlated with clinical response. Conclusion Treatment with erlotinib combined with celecoxib offers an effective chemopreventive approach through inhibition of EGFR and mTOR pathways, which may serve as potential biomarkers to monitor the intervention of this combination in the clinic. PMID:23422093

A multivariate analysis of prognostic factors for melanoma patients with lesions greater than or equal to 3.65 mm in thickness. The importance of revealing alternative Cox models.

PubMed Central

Day, C L; Lew, R A; Mihm, M C; Sober, A J; Harris, M N; Kopf, A W; Fitzpatrick, T B; Harrist, T J; Golomb, F M; Postel, A; Hennessey, P; Gumport, S L; Raker, J W; Malt, R A; Cosimi, A B; Wood, W C; Roses, D F; Gorstein, F; Rigel, D; Friedman, R J; Mintzis, M M; Grier, R W

1982-01-01

Fourteen prognostic factors were examined in 79 patients with clinical Stage I melanoma greater than or equal to 3.65 mm in thickness. All nine patients with melanoma of the hands or feet died of melanoma. A Cox proportional hazards (multivariate) analysis of the remaining 70 patients showed that a combination of the following four variables best predicted bony or visceral metastases: 1) a nearly absent or minimal lymphocyte response at the base of the tumor, 2) histologic type other than superficial spreading melanoma, 3) location on the trunk, and 4) positive nodes or no initial node dissection. Ulceration and/or ulceration width were not useful in predicting outcome either singly or in combination with other variables. Patients with negative lymph nodes and primary tumors of the trunk, hands, and feet did not do better than patients with positive nodes at those sites. Conversely, non of 16 patients with negative lymph nodes and extremity melanomas (excluding the hands and feet) or head and neck melanomas developed visceral or bony metastases (i.e., five-year disease-free survival rate 100%). PMID:7055383

[Establishment of the prediction model for ischemic cardiovascular disease of elderly male population under current health care program].

PubMed

Chen, Jin-hong; Wu, Hai-yun; He, Kun-lun; He, Yao; Qin, Yin-he

2010-10-01

To establish and verify the prediction model for ischemic cardiovascular disease (ICVD) among the elderly population who were under the current health care programs. Statistical analysis on data from physical examination, hospitalization of the past years, from questionnaire and telephone interview was carried out in May, 2003. Data was from a hospital which implementing a health care program. Baseline population with a proportion of 4:1 was randomly selected to generate both module group and verification group. Baseline data was induced to make the verification group into regression model of module group and to generate the predictive value. Distinguished ability with area under ROC curve and the predictive veracity were verified through comparing the predictive incidence rate and actual incidence rate of every deciles group by Hosmer-Lemeshow test. Predictive veracity of the prediction model at population level was verified through comparing the predictive 6-year incidence rates of ICVD with actual 6-year accumulative incidence rates of ICVD with error rate calculated. The samples included 2271 males over the age of 65 with 1817 people for modeling population and 454 for verified population. All of the samples were stratified into two layers to establish hierarchical Cox proportional hazard regression model, including one advanced age group (greater than or equal to 75 years old), and another elderly group (less than 75 years old). Data from the statically analysis showed that the risk factors in aged group were age, systolic blood pressure, serum creatinine level, fasting blood glucose level, while protective factor was high density lipoprotein;in advanced age group, the risk factors were body weight index, systolic blood pressure, serum total cholesterol level, serum creatinine level, fasting blood glucose level, while protective factor was HDL-C. The area under the ROC curve (AUC) and 95%CI were 0.723 and 0.687 - 0.759 respectively. Discriminating power was good. All individual predictive ICVD cumulative incidence and actual incidence were analyzed using Hosmer-Lemeshow test, χ(2) = 1.43, P = 0.786, showing that the predictive veracity was good. The stratified Cox Hazards Regression model was used to establish prediction model of the aged male population under a certain health care program. The common prediction factor of the two age groups were: systolic blood pressure, serum creatinine level, fasting blood glucose level and HDL-C. The area under the ROC curve of the verification group was 0.723, showing that the distinguished ability was good and the predict ability at the individual level and at the group level were also satisfactory. It was feasible to using Cox Proportional Hazards Regression Model for predicting the population groups.

Impact of Insecticide-Treated Net Ownership on All-Cause Child Mortality in Malawi, 2006–2010

PubMed Central

Florey, Lia S.; Bennett, Adam; Hershey, Christine L.; Bhattarai, Achuyt; Nielsen, Carrie F.; Ali, Doreen; Luhanga, Misheck; Taylor, Cameron; Eisele, Thomas P.; Yé, Yazoume

2017-01-01

Abstract. Insecticide-treated nets (ITNs) have been shown to be highly effective at reducing malaria morbidity and mortality in children. However, there are limited studies that assess the association between increasing ITN coverage and child mortality over time, at the national level, and under programmatic conditions. Two analytic approaches were used to examine this association: a retrospective cohort analysis of individual children and a district-level ecologic analysis. To evaluate the association between household ITN ownership and all-cause child mortality (ACCM) at the individual level, data from the 2010 Demographic and Health Survey (DHS) were modeled in a Cox proportional hazards framework while controlling for numerous environmental, household, and individual confounders through the use of exact matching. To evaluate population-level association between ITN ownership and ACCM between 2006 and 2010, program ITN distribution data and mortality data from the 2006 Multiple Indicator Cluster Survey and the 2010 DHS were aggregated at the district level and modeled using negative binomial regression. In the Cox model controlling for household, child and maternal health factors, children between 1 and 59 months in households owning an ITN had significantly lower mortality compared with those without an ITN (hazard ratio = 0.75, 95% confidence interval [CI] = 0.62–90). In the district-level model, higher ITN ownership was significantly associated with lower ACCM (incidence rate ratio = 0.77; 95% CI = 0.60–0.98). These findings suggest that increasing ITN ownership may have contributed to the decline in ACCM during 2006–2010 in Malawi and represent a novel use of district-level data from nationally representative surveys. PMID:28990922

Random Survival Forest in practice: a method for modelling complex metabolomics data in time to event analysis.

PubMed

Dietrich, Stefan; Floegel, Anna; Troll, Martina; Kühn, Tilman; Rathmann, Wolfgang; Peters, Anette; Sookthai, Disorn; von Bergen, Martin; Kaaks, Rudolf; Adamski, Jerzy; Prehn, Cornelia; Boeing, Heiner; Schulze, Matthias B; Illig, Thomas; Pischon, Tobias; Knüppel, Sven; Wang-Sattler, Rui; Drogan, Dagmar

2016-10-01

The application of metabolomics in prospective cohort studies is statistically challenging. Given the importance of appropriate statistical methods for selection of disease-associated metabolites in highly correlated complex data, we combined random survival forest (RSF) with an automated backward elimination procedure that addresses such issues. Our RSF approach was illustrated with data from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, with concentrations of 127 serum metabolites as exposure variables and time to development of type 2 diabetes mellitus (T2D) as outcome variable. Out of this data set, Cox regression with a stepwise selection method was recently published. Replication of methodical comparison (RSF and Cox regression) was conducted in two independent cohorts. Finally, the R-code for implementing the metabolite selection procedure into the RSF-syntax is provided. The application of the RSF approach in EPIC-Potsdam resulted in the identification of 16 incident T2D-associated metabolites which slightly improved prediction of T2D when used in addition to traditional T2D risk factors and also when used together with classical biomarkers. The identified metabolites partly agreed with previous findings using Cox regression, though RSF selected a higher number of highly correlated metabolites. The RSF method appeared to be a promising approach for identification of disease-associated variables in complex data with time to event as outcome. The demonstrated RSF approach provides comparable findings as the generally used Cox regression, but also addresses the problem of multicollinearity and is suitable for high-dimensional data. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Modulation of LOX and COX pathways via inhibition of amyloidogenesis contributes to mitoprotection against β-amyloid oligomer-induced toxicity in an animal model of Alzheimer's disease in rats.

PubMed

Kalra, Jaspreet; Kumar, Puneet; Majeed, Abu Bakar Abdul; Prakash, Atish

2016-01-01

Several lines of evidence indicate that beta amyloid (β-A) production, neurofibrillary tangles and neuroinflammation are interrelated in the pathogenesis of Alzheimer's disease (AD). AD is associated with enhanced β-A production and accumulation resulting in neuroinflammation probably via activation of lipoxygenase (LOX) and cyclooxygenase (COX) pathways. Therefore, the present study was designed to investigate the role of LOX and COX inhibitors (zafirlukast and valdecoxib) in amyloidogenesis in β-A1-42 oligomer induced experimental AD in rats. The behavioral activities were assessed using actophotometer, novel object recognition test (ORT), Morris water maze (MWM) followed by biochemical assessments, determination of proinflammatory cytokines and mediators (TNF-α, IL-1β and PGE2), β-A1-42 levels and histopathological analysis. ICV administration of β-A1-42 oligomer produced significant impairment in memory consolidation. In addition to this significant increase in mito-oxidative stress, neuroinflammatory markers, acetylcholinesterase (AChE) toxicity, β-A1-42 level, neuronal cell death and neuroinflammation are more profound in β-A1-42 oligomer treated AD rats. Administration of zafirlukast (15 and 30mg/kg), and valdecoxib (5 and 10mg/kg) significantly improved the behavioral performances and showed significant reversal of mito-oxidative damage declining the neuroinflammation in β-A1-42 oligomer treated rats. Furthermore, more profound effects were observed at the sub-therapeutic dose combination of zafirlukast (15mg/kg) and valdecoxib (5mg/kg). The results of the present study indicate that protective effects of zafirlukast and valdecoxib are achieved through the blockade of release of LOX and COX metabolites therefore, representing a new therapeutic target for treating AD and other neurodegenerative disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Feature Screening in Ultrahigh Dimensional Cox's Model.

PubMed

Yang, Guangren; Yu, Ye; Li, Runze; Buu, Anne

Survival data with ultrahigh dimensional covariates such as genetic markers have been collected in medical studies and other fields. In this work, we propose a feature screening procedure for the Cox model with ultrahigh dimensional covariates. The proposed procedure is distinguished from the existing sure independence screening (SIS) procedures (Fan, Feng and Wu, 2010, Zhao and Li, 2012) in that the proposed procedure is based on joint likelihood of potential active predictors, and therefore is not a marginal screening procedure. The proposed procedure can effectively identify active predictors that are jointly dependent but marginally independent of the response without performing an iterative procedure. We develop a computationally effective algorithm to carry out the proposed procedure and establish the ascent property of the proposed algorithm. We further prove that the proposed procedure possesses the sure screening property. That is, with the probability tending to one, the selected variable set includes the actual active predictors. We conduct Monte Carlo simulation to evaluate the finite sample performance of the proposed procedure and further compare the proposed procedure and existing SIS procedures. The proposed methodology is also demonstrated through an empirical analysis of a real data example.

Inflammation-based prognostic score is a useful predictor of postoperative outcome in patients with extrahepatic cholangiocarcinoma.

PubMed

Oshiro, Yukio; Sasaki, Ryoko; Fukunaga, Kiyoshi; Kondo, Tadashi; Oda, Tatsuya; Takahashi, Hideto; Ohkohchi, Nobuhiro

2013-03-01

Recent studies have revealed that the Glasgow prognostic score (GPS), an inflammation-based prognostic score, is useful for predicting outcome in a variety of cancers. This study sought to investigate the significance of GPS for prognostication of patients who underwent surgery with extrahepatic cholangiocarcinoma. We retrospectively analyzed a total of 62 patients who underwent resection for extrahepatic cholangiocarcinoma. We calculated the GPS as follows: patients with both an elevated C-reactive protein (>10 mg/L) and hypoalbuminemia (<35 g/L) were allocated a score of 2; patients with one or none of these abnormalities were allocated a s ore of 1 or 0, respectively. Prognostic significance was analyzed by the log-rank test and a Cox proportional hazards model. Overall survival rate was 25.5 % at 5 years for all 62 patients. Venous invasion (p = 0.01), pathological primary tumor category (p = 0.013), lymph node metastasis category (p < 0.001), TNM stage (p < 0.001), and GPS (p = 0.008) were significantly associated with survival by univariate analysis. A Cox model demonstrated that increased GPS was an independent predictive factor with poor prognosis. The preoperative GPS is a useful predictor of postoperative outcome in patients with extrahepatic cholangiocarcinoma.

Low Survival Rates of Oral and Oropharyngeal Squamous Cell Carcinoma

PubMed Central

da Silva Júnior, Francisco Feliciano; dos Santos, Karine de Cássia Batista; Ferreira, Stefania Jeronimo

2017-01-01

Aim To assess the epidemiological and clinical factors that influence the prognosis of oral and oropharyngeal squamous cell carcinoma (SCC). Methods One hundred and twenty-one cases of oral and oropharyngeal SCC were selected. The survival curves for each variable were estimated using the Kaplan-Meier method. The Cox regression model was applied to assess the effect of the variables on survival. Results Cancers at an advanced stage were observed in 103 patients (85.1%). Cancers on the tongue were more frequent (23.1%). The survival analysis was 59.9% in one year, 40.7% in two years, and 27.8% in 5 years. There was a significant low survival rate linked to alcohol intake (p = 0.038), advanced cancer staging (p = 0.003), and procedures without surgery (p < 0.001). When these variables were included in the Cox regression model only surgery procedures (p = 0.005) demonstrated a significant effect on survival. Conclusion The findings suggest that patients who underwent surgery had a greater survival rate compared with those that did not. The low survival rates and the high percentage of patients diagnosed at advanced stages demonstrate that oral and oropharyngeal cancer patients should receive more attention. PMID:28638410

Comparison of indexing times among articles from medical, nursing, and pharmacy journals.

PubMed

Rodriguez, Ryan W

2016-04-15

Results of an analysis of the times to indexing of articles published in medical, nursing, and pharmacy journals are reported. MEDLINE data were retrieved for articles published in selected general practice medical, nursing, and pharmacy journals and entered into the PubMed system in 2012 and 2013. Collected data included PubMed entry date, date of indexing with Medical Subject Headings (MeSH) terms, and publication characteristics. Survival analysis was performed to assess the primary outcome of time to indexing. Cox proportional hazards models were developed to assess the effect of healthcare discipline and source journal on the primary outcome. Data were collected for 19,259 articles, of which 78.7%, 12.6%, and 8.7% originated from medical, nursing, and pharmacy journals, respectively. For medical, pharmacy, and nursing journals, 97.8%, 90.8%, and 50.1% of articles, respectively, were indexed within one year of PubMed entry; the corresponding median (interquartile range) times to indexing were 52 (20-68), 186 (150-246), and 252 (168-301) days. Unadjusted hazard ratios derived from Cox models indicated that indexing within one year was significantly less likely for articles published in pharmacy or nursing journals versus medical journals and for articles from all evaluated journals versus a designated reference publication (New England Journal of Medicine). Analysis of major medical, nursing, and pharmacy journals found that articles from nursing and pharmacy journals were indexed with MeSH terms more slowly than articles from medical journals. Journal identity was significantly associated with time to indexing. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Tissue Platinum Concentration and Tumor Response in Non–Small-Cell Lung Cancer

PubMed Central

Kim, Eric S.; Lee, J. Jack; He, Guangan; Chow, Chi-Wan; Fujimoto, Junya; Kalhor, Neda; Swisher, Stephen G.; Wistuba, Ignacio I.; Stewart, David J.; Siddik, Zahid H.

2012-01-01

Purpose Platinum resistance is a major limitation in the treatment of advanced non–small-cell lung cancer (NSCLC). Reduced intracellular drug accumulation is one of the most consistently identified features of platinum-resistant cell lines, but clinical data are limited. We assessed the effects of tissue platinum concentrations on response and survival in NSCLC. Patients and Methods We measured total platinum concentrations by flameless atomic absorption spectrophotometry in 44 archived fresh-frozen NSCLC specimens from patients who underwent surgical resection after neoadjuvant platinum-based chemotherapy. Tissue platinum concentration was correlated with percent reduction in tumor size on post- versus prechemotherapy computed tomography scans. The relationship between tissue platinum concentration and survival was assessed by univariate and multicovariate Cox proportional hazards regression model analysis and Kaplan-Meier analysis. Results Tissue platinum concentration correlated significantly with percent reduction in tumor size (P < .001). The same correlations were seen with cisplatin, carboplatin, and all histology subgroups. Furthermore, there was no significant impact of potential variables such as number of cycles and time lapse from last chemotherapy on platinum concentration. Patients with higher platinum concentration had longer time to recurrence (P = .034), progression-free survival (P = .018), and overall survival (P = .005) in the multicovariate Cox model analysis after adjusting for number of cycles. Conclusion This clinical study established a relationship between tissue platinum concentration and response in NSCLC. It suggests that reduced platinum accumulation might be an important mechanism of platinum resistance in the clinical setting. Further studies investigating factors that modulate intracellular platinum concentration are warranted. PMID:22891266

Impact of Donor Arterial Partial Pressure of Oxygen on Outcomes After Lung Transplantation in Adult Cystic Fibrosis Recipients.

PubMed

Hayes, Don; Kopp, Benjamin T; Kirkby, Stephen E; Reynolds, Susan D; Mansour, Heidi M; Tobias, Joseph D; Tumin, Dmitry

2016-08-01

Donor PaO2 levels are used for assessing organs for lung transplantation (LTx), but survival implications of PaO2 levels in adult cystic fibrosis (CF) patients receiving LTx are unclear. UNOS registry data spanning 2005-2013 were used to test for associations of donor PaO2 with patient survival and bronchiolitis obliterans syndrome (BOS) in adult (age ≥ 18 years) first-time LTx recipients diagnosed with CF. The analysis included 1587 patients, of whom 1420 had complete data for multivariable Cox models. No statistically significant differences among donor PaO2 categories of ≤200, 201-300, 301-400, or >400 mmHg were found in univariate survival analysis (log-rank test p = 0.290). BOS onset did not significantly differ across donor PaO2 categories (Chi-square p = 0.480). Multivariable Cox models of patient survival supported the lack of difference across donor PaO2 categories. Interaction analysis found a modest difference in survival between the two top categories of donor PaO2 when examining patients with body mass index (BMI) in the lowest decile (≤16.5 kg/m(2)). Donor PaO2 was not associated with survival or BOS onset in adult CF patients undergoing LTx. Notwithstanding statistically significant interactions between donor PaO2 and BMI, there was no evidence of post-LTx survival risk associated with donor PaO2 below conventional thresholds in any subgroup of adults with CF.

Bacterial Infections Change Natural History of Cirrhosis Irrespective of Liver Disease Severity.

PubMed

Dionigi, Elena; Garcovich, Matteo; Borzio, Mauro; Leandro, Gioacchino; Majumdar, Avik; Tsami, Aikaterini; Arvaniti, Vasiliki; Roccarina, Davide; Pinzani, Massimo; Burroughs, Andrew K; O'Beirne, James; Tsochatzis, Emmanuel A

2017-04-01

We assessed the prognostic significance of infections in relation to current prognostic scores and explored if infection could be considered per se a distinct clinical stage in the natural history of cirrhosis. We included consecutive patients with cirrhosis admitted to a tertiary referral liver unit for at least 48 h over a 2-year period. Diagnosis of infection was based on positive cultures or strict established criteria. We used competing risk analysis and propensity score matching for data analysis. 501 patients (63% male, 48% alcoholic liver disease, median Model of End-stage Liver Disease (MELD)=17) underwent 781 admissions over the study period. Portal hypertensive bleeding and complicated ascites were the commonest reasons of admission. The incidence of proven bacterial infection was 25.6% (60% community acquired and 40% nosocomial). Survival rates at 3, 6, 12, and 30 months were 83%, 77%, 71%, and 62% in patients without diagnosis of infection, vs. 50%, 46%, 41%, and 34% in patients with diagnosis of infection. Overall survival was independently associated with MELD score (hazards ratio (HR) 1.099), intensive care (ITU) stay (HR 1.967) and bacterial infection (HR 2.226). Bacterial infection was an independent predictor of survival even when patients who died within the first 30 days were excluded from the analysis in Cox regression (HR 2.013) and competing risk Cox models in all patients (HR 1.46) and propensity risk score-matched infected and non-infected patients (HR 1.67). Infection most likely represents a distinct prognostic stage of cirrhosis, which affects survival irrespective of disease severity, even after recovery from the infective episode.

Survival analysis in hematologic malignancies: recommendations for clinicians

PubMed Central

Delgado, Julio; Pereira, Arturo; Villamor, Neus; López-Guillermo, Armando; Rozman, Ciril

2014-01-01

The widespread availability of statistical packages has undoubtedly helped hematologists worldwide in the analysis of their data, but has also led to the inappropriate use of statistical methods. In this article, we review some basic concepts of survival analysis and also make recommendations about how and when to perform each particular test using SPSS, Stata and R. In particular, we describe a simple way of defining cut-off points for continuous variables and the appropriate and inappropriate uses of the Kaplan-Meier method and Cox proportional hazard regression models. We also provide practical advice on how to check the proportional hazards assumption and briefly review the role of relative survival and multiple imputation. PMID:25176982

Reduced COX-2 expression in aged mice is associated with impaired fracture healing.

PubMed

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

2009-02-01

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

Assessment of the Risk of Fractures Because of Service on Diesel Submarines: A Retrospective Cohort Study.

PubMed

Saad, Amit; Kala, Carmel; Ohayon, Sharon; Feldman, Lior; Galili, Eran; Yanir, Yoav; Nemet, Dan; Netzer, Itamar

2015-07-01

Submariners are known to have decreased bone mass following periods of long submersion. We examined whether this produces a higher predilection to fractures. This is a retrospective cohort study. Data were collected from the computerized medical records of 457 consecutive submariners (serving 1091.42 man-years). The control group included 3,219 consecutive sailors, (serving 5845.04 man-years). Groups were stratified according to age at induction, body mass index, place of birth, and status of service (i.e., compulsory versus professional). Analysis of fracture incidence and comparison of proportions between the groups was conducted using χ(2) tests and Fisher's exact test. The hazard ratio for fractures was performed using a survival analysis regression model for each group (Cox Proportional Hazard Model). Nineteen submariners (4.2%) and 94 sailors (2.9%) were shown to have fractures during their service (RR = 1.42, p = 0.15). A Cox proportional hazard model was employed. No statistically significant difference was found between the 2 groups (HR = 1.037, p = 0.89). No correlation was found between length of service and risk of fracture. Most fractures suffered by submariners occurred outside their work environment. Submariners are repeatedly exposed to prolonged submersions that are deleterious to bone strength. However, no statistically significant difference in the incidence of fractures was found between submariners and surface sailors. This is an important finding for the bone and occupational health of submariners in general. Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.