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Sample records for adjusted cox proportional

  1. Tree-augmented Cox proportional hazards models.

    PubMed

    Su, Xiaogang; Tsai, Chih-Ling

    2005-07-01

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

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

    PubMed

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

    2012-08-30

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

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

    NASA Technical Reports Server (NTRS)

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

    2003-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

    Fan, Juanjuan; Zhang, Ying

    2016-01-01

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

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

    PubMed

    Austin, Peter C

    2012-12-20

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

  9. 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.

  10. 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.

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

    PubMed

    Laubender, Ruediger P; Bender, Ralf

    2014-02-28

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Lachin, John M.

    2013-01-01

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

  14. Statistical inference for response adaptive randomization procedures with adjusted optimal allocation proportions.

    PubMed

    Zhu, Hongjian

    2016-12-12

    Seamless phase II/III clinical trials have attracted increasing attention recently. They mainly use Bayesian response adaptive randomization (RAR) designs. There has been little research into seamless clinical trials using frequentist RAR designs because of the difficulty in performing valid statistical inference following this procedure. The well-designed frequentist RAR designs can target theoretically optimal allocation proportions, and they have explicit asymptotic results. In this paper, we study the asymptotic properties of frequentist RAR designs with adjusted target allocation proportions, and investigate statistical inference for this procedure. The properties of the proposed design provide an important theoretical foundation for advanced seamless clinical trials. Our numerical studies demonstrate that the design is ethical and efficient.

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

    PubMed

    Lin, Nan Xuan; Henley, William Edward

    2016-12-10

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

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

    NASA Astrophysics Data System (ADS)

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

    2016-11-01

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

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

    PubMed

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

    2016-05-15

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

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

    USGS Publications Warehouse

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

    2003-01-01

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

  19. Adjustments to de Leva-anthropometric regression data for the changes in body proportions in elderly humans.

    PubMed

    Ho Hoang, Khai-Long; Mombaur, Katja

    2015-10-15

    Dynamic modeling of the human body is an important tool to investigate the fundamentals of the biomechanics of human movement. To model the human body in terms of a multi-body system, it is necessary to know the anthropometric parameters of the body segments. For young healthy subjects, several data sets exist that are widely used in the research community, e.g. the tables provided by de Leva. None such comprehensive anthropometric parameter sets exist for elderly people. It is, however, well known that body proportions change significantly during aging, e.g. due to degenerative effects in the spine, such that parameters for young people cannot be used for realistically simulating the dynamics of elderly people. In this study, regression equations are derived from the inertial parameters, center of mass positions, and body segment lengths provided by de Leva to be adjustable to the changes in proportion of the body parts of male and female humans due to aging. Additional adjustments are made to the reference points of the parameters for the upper body segments as they are chosen in a more practicable way in the context of creating a multi-body model in a chain structure with the pelvis representing the most proximal segment.

  20. CMOS temperature sensor using a resistively degenerated common-source amplifier biased by an adjustable proportional-to-absolute-temperature voltage

    NASA Astrophysics Data System (ADS)

    Wang, Ruey-Lue; Fu, Chien-Cheng; Yu, Chi; Hao, Yi-Fan; Shi, Jian-Liang; Lin, Chen-Fu; Liao, Hsin-Hao; Tsai, Hann-Huei; Juang, Ying-Zong

    2014-01-01

    A high-linearity CMOS temperature sensor with pulse output is presented. The temperature core is a resistively degenerated common-source amplifier which gate is biased by a proportional-to-absolute-temperature (PTAT) voltage generator. The source resistor is made of polysilicon which resistance has a PTAT characteristic. The current flowing through the resistor exhibits a PTAT characteristic with high linearity of 99.99% at least for a temperature range from 0 to 125 °C. The PTAT voltage generator can be adjusted by a bias voltage Vb and hence the PTAT current can also be adjusted by the Vb. The PTAT current is mirrored to an added current controlled oscillator which output pulse frequencies also exhibit a PTAT characteristic. For the chip using the 0.35 µm process, the plots of measured pulse frequencies against temperature exhibit the sensitivity of 2.30 to 2.24 kHz/°C with linearity of more than 99.99% at the Vb of 1 to 1.2 V.

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

    PubMed

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

    2006-01-01

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

  2. Data on respiratory variables in critically ill patients with acute respiratory failure placed on proportional assist ventilation with load adjustable gain factors (PAV+).

    PubMed

    Georgopoulos, Dimitris; Xirouchaki, Nectaria; Tzanakis, Nikolaos; Younes, Magdy

    2016-09-01

    The data show respiratory variables in 108 critically ill patients with acute respiratory failure placed on proportional assist ventilation with load adjustable gain factors (PAV+) after at least 36 h on passive mechanical ventilation. PAV+ was continued for 48 h until the patients met pre-defined criteria either for switching to controlled modes or for breathing without ventilator assistance. Data during passive mechanical ventilation and during PAV+ are reported. Data are acquired from the whole population, as well as from patients with and without acute respiratory distress syndrome. The reported variables are tidal volume, driving pressure (ΔP, the difference between static end-inspiratory plateau pressure and positive end-expiratory airway pressure), respiratory system compliance and resistance, and arterial blood gasses. The data are supplemental to our original research article, which described individual ΔP in these patients and examined how it related to ΔP when the same patients were ventilated with passive mechanical ventilation using the currently accepted lung-protective strategy "Driving pressure during assisted mechanical ventilation. Is it controlled by patient brain?" [1].

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

    SciTech Connect

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

    1982-09-01

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

  4. Proportional Hazards Models of Graduation

    ERIC Educational Resources Information Center

    Chimka, Justin R.; Reed-Rhoads, Teri; Barker, Kash

    2008-01-01

    Survival analysis is a statistical tool used to describe the duration between events. Many processes in medical research, engineering, and economics can be described using survival analysis techniques. This research involves studying engineering college student graduation using Cox proportional hazards models. Among male students with American…

  5. 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.

  6. COX-2 chronology

    PubMed Central

    Hawkey, C J

    2005-01-01

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

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

    PubMed

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

    2016-01-01

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

  8. The Moxie of Kathy Cox

    ERIC Educational Resources Information Center

    Johns, Stephanie

    2010-01-01

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

  9. [Application of spline-based Cox regression on analyzing data from follow-up studies].

    PubMed

    Dong, Ying; Yu, Jin-ming; Hu, Da-yi

    2012-09-01

    With R, this study involved the application of the spline-based Cox regression to analyze data related to follow-up studies when the two basic assumptions of Cox proportional hazards regression were not satisfactory. Results showed that most of the continuous covariates contributed nonlinearly to mortality risk while the effects of three covariates were time-dependent. After considering multiple covariates in spline-based Cox regression, when the ankle brachial index (ABI) decreased by 0.1, the hazard ratio (HR) for all-cause death was 1.071. The spline-based Cox regression method could be applied to analyze the data related to follow-up studies when the assumptions of Cox proportional hazards regression were violated.

  10. Coincidence Proportional Counter

    DOEpatents

    Manley, J H

    1950-11-21

    A coincidence proportional counter having a plurality of collecting electrodes so disposed as to measure the range or energy spectrum of an ionizing particle-emitting source such as an alpha source, is disclosed.

  11. 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.

  12. Adaptation through proportion

    NASA Astrophysics Data System (ADS)

    Xiong, Liyang; Shi, Wenjia; Tang, Chao

    2016-08-01

    Adaptation is a ubiquitous feature in biological sensory and signaling networks. It has been suggested that adaptive systems may follow certain simple design principles across diverse organisms, cells and pathways. One class of networks that can achieve adaptation utilizes an incoherent feedforward control, in which two parallel signaling branches exert opposite but proportional effects on the output at steady state. In this paper, we generalize this adaptation mechanism by establishing a steady-state proportionality relationship among a subset of nodes in a network. Adaptation can be achieved by using any two nodes in the sub-network to respectively regulate the output node positively and negatively. We focus on enzyme networks and first identify basic regulation motifs consisting of two and three nodes that can be used to build small networks with proportional relationships. Larger proportional networks can then be constructed modularly similar to LEGOs. Our method provides a general framework to construct and analyze a class of proportional and/or adaptation networks with arbitrary size, flexibility and versatile functional features.

  13. COX-2 and Prostate Cancer Angiogenesis

    DTIC Science & Technology

    2002-03-01

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

  14. Selecting Proportional Reasoning Tasks

    ERIC Educational Resources Information Center

    de la Cruz, Jessica A.

    2013-01-01

    With careful consideration given to task selection, students can construct their own solution strategies to solve complex proportional reasoning tasks while the teacher's instructional goals are still met. Several aspects of the tasks should be considered including their numerical structure, context, difficulty level, and the strategies they are…

  15. Multiwire proportional chamber development

    NASA Technical Reports Server (NTRS)

    Doolittle, R. F.; Pollvogt, U.; Eskovitz, A. J.

    1973-01-01

    The development of large area multiwire proportional chambers, to be used as high resolution spatial detectors in cosmic ray experiments is described. A readout system was developed which uses a directly coupled, lumped element delay-line whose characteristics are independent of the MWPC design. A complete analysis of the delay-line and the readout electronic system shows that a spatial resolution of about 0.1 mm can be reached with the MWPC operating in the strictly proportional region. This was confirmed by measurements with a small MWPC and Fe-55 X-rays. A simplified analysis was carried out to estimate the theoretical limit of spatial resolution due to delta-rays, spread of the discharge along the anode wire, and inclined trajectories. To calculate the gas gain of MWPC's of different geometrical configurations a method was developed which is based on the knowledge of the first Townsend coefficient of the chamber gas.

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

    PubMed Central

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

    2016-01-01

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

  17. Allan Cox 1926”1987

    NASA Astrophysics Data System (ADS)

    Coe, Rob; Dalrymple, Brent

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

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

    PubMed Central

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

    2009-01-01

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

  19. Proportional counter radiation camera

    DOEpatents

    Borkowski, C.J.; Kopp, M.K.

    1974-01-15

    A gas-filled proportional counter camera that images photon emitting sources is described. A two-dimensional, positionsensitive proportional multiwire counter is provided as the detector. The counter consists of a high- voltage anode screen sandwiched between orthogonally disposed planar arrays of multiple parallel strung, resistively coupled cathode wires. Two terminals from each of the cathode arrays are connected to separate timing circuitry to obtain separate X and Y coordinate signal values from pulse shape measurements to define the position of an event within the counter arrays which may be recorded by various means for data display. The counter is further provided with a linear drift field which effectively enlarges the active gas volume of the counter and constrains the recoil electrons produced from ionizing radiation entering the counter to drift perpendicularly toward the planar detection arrays. A collimator is interposed between a subject to be imaged and the counter to transmit only the radiation from the subject which has a perpendicular trajectory with respect to the planar cathode arrays of the detector. (Official Gazette)

  20. Objective Bayesian model selection for Cox regression.

    PubMed

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

    2016-12-20

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

  1. The microstrip proportional counter

    NASA Technical Reports Server (NTRS)

    Ramsey, B. D.

    1992-01-01

    Microstrip detectors in which the usual discrete anode and cathode wires are replaced by conducting strips on an insulating or partially insulating substrate are fabricated using integrated circuit-type photolithographic techniques and hence offer very high spatial accuracy and uniformity, together with the capability of producing extremely fine electrode structures. Microstrip proportional counters have now been variously reported having an energy resolution of better than 11 percent FWHM at 5.9 keV. They have been fabricated with anode bars down to 2 microns and on a variety of substrate materials including thin films which can be molded to different shapes. This review will examine the development of the microstrip detector with emphasis on the qualities which make this detector particularly interesting for use in astronomy.

  2. Gated strip proportional detector

    DOEpatents

    Morris, Christopher L.; Idzorek, George C.; Atencio, Leroy G.

    1987-01-01

    A gated strip proportional detector includes a gas tight chamber which encloses a solid ground plane, a wire anode plane, a wire gating plane, and a multiconductor cathode plane. The anode plane amplifies the amount of charge deposited in the chamber by a factor of up to 10.sup.6. The gating plane allows only charge within a narrow strip to reach the cathode. The cathode plane collects the charge allowed to pass through the gating plane on a set of conductors perpendicular to the open-gated region. By scanning the open-gated region across the chamber and reading out the charge collected on the cathode conductors after a suitable integration time for each location of the gate, a two-dimensional image of the intensity of the ionizing radiation incident on the detector can be made.

  3. Gated strip proportional detector

    DOEpatents

    Morris, C.L.; Idzorek, G.C.; Atencio, L.G.

    1985-02-19

    A gated strip proportional detector includes a gas tight chamber which encloses a solid ground plane, a wire anode plane, a wire gating plane, and a multiconductor cathode plane. The anode plane amplifies the amount of charge deposited in the chamber by a factor of up to 10/sup 6/. The gating plane allows only charge within a narrow strip to reach the cathode. The cathode plane collects the charge allowed to pass through the gating plane on a set of conductors perpendicular to the open-gated region. By scanning the open-gated region across the chamber and reading out the charge collected on the cathode conductors after a suitable integration time for each location of the gate, a two-dimensional image of the intensity of the ionizing radiation incident on the detector can be made.

  4. HNE as an inducer of COX-2.

    PubMed

    Uchida, Koji

    2017-02-09

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

  5. Survival analysis and Cox regression.

    PubMed

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

    2011-01-01

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

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

    PubMed

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

    2014-04-01

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

  7. Clinical outcomes of IgA nephropathy patients with different proportions of crescents

    PubMed Central

    Zhang, Wang; Zhou, Qian; Hong, Lingyao; Chen, Wenfang; Yang, Shicong; Yang, Qiongqiong; Chen, Wei; Yu, Xueqing

    2017-01-01

    Abstract Crescents involving more than 50% of glomeruli in IgA nephropathy (IgAN) signify a rapid deterioration of renal function. However, little is known about the prognosis of IgAN patients presenting crescents in less than 50% of glomeruli. We aimed to investigate the clinicopathological characteristics and outcomes of IgAN patients with different proportions of crescents. From January 2000 to December 2011, biopsy-proven primary IgAN patients with histological crescents formation were enrolled in this retrospective cohort study. The patients were divided into 4 groups on the basis of crescent proportion as follows: <5%, 5% to 9%, 10% to 24%, and ≥25%. The primary endpoint was defined as the doubling of baseline serum creatinine (SCr) and/or end-stage renal disease (ESRD), and the secondary endpoint was death. A total of 538 crescent-featured IgAN patients were followed up and included in the analysis. The median crescent proportion was 8.0%. An increasing crescent proportion was associated with a reduced estimated glomerular filtration rate (eGFR), decreased level of hemoglobin, and increased amount of urine protein excretion. After a median follow-up period of 51 months (range 12–154 months), the endpoint events-free survival rate of the above 4 groups were 69.9%, 47.7%, 43.8%, and 40.6%, respectively (Log rank=13.7, P= 0.003), when we incorporated death with renal outcome as a composite endpoint. Multivariate Cox regression analyses adjusting for eGFR, hypertension, proteinuria, and the Oxford-MEST classification demonstrated the predictive significance of an increasing crescent proportion with renal survival and mortality (each increase by 5% [log-transformed]: HR=1.51, 95% CI 1.08–2.11, P = 0.02). Further comparisons of patients with small proportions of crescents (<5%) and those absent of such pathological lesion showed that the 2 groups of patients had comparable prognosis. An increasing crescent proportion was identified as an independent

  8. Clinical outcomes of IgA nephropathy patients with different proportions of crescents.

    PubMed

    Zhang, Wang; Zhou, Qian; Hong, Lingyao; Chen, Wenfang; Yang, Shicong; Yang, Qiongqiong; Chen, Wei; Yu, Xueqing

    2017-03-01

    Crescents involving more than 50% of glomeruli in IgA nephropathy (IgAN) signify a rapid deterioration of renal function. However, little is known about the prognosis of IgAN patients presenting crescents in less than 50% of glomeruli. We aimed to investigate the clinicopathological characteristics and outcomes of IgAN patients with different proportions of crescents.From January 2000 to December 2011, biopsy-proven primary IgAN patients with histological crescents formation were enrolled in this retrospective cohort study. The patients were divided into 4 groups on the basis of crescent proportion as follows: <5%, 5% to 9%, 10% to 24%, and ≥25%. The primary endpoint was defined as the doubling of baseline serum creatinine (SCr) and/or end-stage renal disease (ESRD), and the secondary endpoint was death.A total of 538 crescent-featured IgAN patients were followed up and included in the analysis. The median crescent proportion was 8.0%. An increasing crescent proportion was associated with a reduced estimated glomerular filtration rate (eGFR), decreased level of hemoglobin, and increased amount of urine protein excretion. After a median follow-up period of 51 months (range 12-154 months), the endpoint events-free survival rate of the above 4 groups were 69.9%, 47.7%, 43.8%, and 40.6%, respectively (Log rank=13.7, P= 0.003), when we incorporated death with renal outcome as a composite endpoint. Multivariate Cox regression analyses adjusting for eGFR, hypertension, proteinuria, and the Oxford-MEST classification demonstrated the predictive significance of an increasing crescent proportion with renal survival and mortality (each increase by 5% [log-transformed]: HR=1.51, 95% CI 1.08-2.11, P = 0.02). Further comparisons of patients with small proportions of crescents (<5%) and those absent of such pathological lesion showed that the 2 groups of patients had comparable prognosis.An increasing crescent proportion was identified as an independent predictor for

  9. Propensity score applied to survival data analysis through proportional hazards models: a Monte Carlo study.

    PubMed

    Gayat, Etienne; Resche-Rigon, Matthieu; Mary, Jean-Yves; Porcher, Raphaël

    2012-01-01

    Propensity score methods are increasingly used in medical literature to estimate treatment effect using data from observational studies. Despite many papers on propensity score analysis, few have focused on the analysis of survival data. Even within the framework of the popular proportional hazard model, the choice among marginal, stratified or adjusted models remains unclear. A Monte Carlo simulation study was used to compare the performance of several survival models to estimate both marginal and conditional treatment effects. The impact of accounting or not for pairing when analysing propensity-score-matched survival data was assessed. In addition, the influence of unmeasured confounders was investigated. After matching on the propensity score, both marginal and conditional treatment effects could be reliably estimated. Ignoring the paired structure of the data led to an increased test size due to an overestimated variance of the treatment effect. Among the various survival models considered, stratified models systematically showed poorer performance. Omitting a covariate in the propensity score model led to a biased estimation of treatment effect, but replacement of the unmeasured confounder by a correlated one allowed a marked decrease in this bias. Our study showed that propensity scores applied to survival data can lead to unbiased estimation of both marginal and conditional treatment effect, when marginal and adjusted Cox models are used. In all cases, it is necessary to account for pairing when analysing propensity-score-matched data, using a robust estimator of the variance.

  10. Visual Manipulatives for Proportional Reasoning.

    ERIC Educational Resources Information Center

    Moore, Joyce L.; Schwartz, Daniel L.

    The use of a visual representation in learning about proportional relations was studied, examining students' understandings of the invariance of a multiplicative relation on both sides of a proportion equation and the invariance of the structural relations that exist in different semantic types of proportion problems. Subjects were 49 high-ability…

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    van Houwelingen, Hans C; Putter, Hein

    2015-04-01

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

  13. Theoretical Investigation of a Proportional-Plus-Flicker Automatic Pilot

    NASA Technical Reports Server (NTRS)

    Seaberg, Ernest C.

    1950-01-01

    The proportional-plus-flicker automatic pilot operates by a nonlinear principle whereby a fast-acting flicker servomotor response is combined with a low-speed proportional servomotor response for the purpose of obtaining supersonic stability and control. Essentially, the autopilot maintains a zero reference about which the output is proportional to the input. However, a flicker response overrides this proportional response at a fixed angle of gimbal displacement on either side of the zero gyroscope reference. Therefore, in contrast to other high speed control systems, the design requirements are simplified because the two components of the proportional-flicker control system are easy to build separately and they can be combined in a relatively simple manner. By application of the proportional-flicker principle, satisfactory stability can be obtained by the proper adjustment of the variable factors in the autopilot mechanism; namely, the proportional gain, the amplitude of flicker control deflection, the autopilot time-lag factor (the time-lag between flicker and proportional operation), and the point in the range that the autopilot switches from a flicker to a proportional system. There is a possibility that these factors can be adjusted so that a more rapid response time (the time to reach steady state) is obtained with the non-linear proportional-flicker autopilot than with a purely linear proportional autopilot. For the main part of this analysis, the proportional part of the system is approximated by a zero-phase-lag proportional autopilot with the assumption that the control surface moves instantaneously at the point where the system switches from flicker to proportional. Good correlation is shown between the results obtained by this method and results obtained by using a close approximation of an actual autopilot transfer function for proportional autopilot operation.

  14. 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

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

    PubMed

    Balandin, Teresa; Castresana, Carmen

    2002-08-01

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

  16. Multiple Ways to Solve Proportions

    ERIC Educational Resources Information Center

    Ercole, Leslie K.; Frantz, Marny; Ashline, George

    2011-01-01

    When solving problems involving proportions, students may intuitively draw on strategies that connect to their understanding of fractions, decimals, and percents. These two statements--"Instruction in solving proportions should include methods that have a strong intuitive basis" and "Teachers should begin instruction with more intuitive…

  17. Proportional Reasoning as Essential Numeracy

    ERIC Educational Resources Information Center

    Dole, Shelley; Hilton, Annette; Hilton, Geoff

    2015-01-01

    This paper reports an aspect of a large research and development project that aimed to promote middle years school teachers' understanding and awareness of the pervasiveness of proportional reasoning as integral to numeracy. Teacher survey data of proportional reasoning across the curriculum were mapped on to a rich model of numeracy. Results…

  18. Estimating Regression Parameters in an Extended Proportional Odds Model

    PubMed Central

    Chen, Ying Qing; Hu, Nan; Cheng, Su-Chun; Musoke, Philippa; Zhao, Lue Ping

    2012-01-01

    The proportional odds model may serve as a useful alternative to the Cox proportional hazards model to study association between covariates and their survival functions in medical studies. In this article, we study an extended proportional odds model that incorporates the so-called “external” time-varying covariates. In the extended model, regression parameters have a direct interpretation of comparing survival functions, without specifying the baseline survival odds function. Semiparametric and maximum likelihood estimation procedures are proposed to estimate the extended model. Our methods are demonstrated by Monte-Carlo simulations, and applied to a landmark randomized clinical trial of a short course Nevirapine (NVP) for mother-to-child transmission (MTCT) of human immunodeficiency virus type-1 (HIV-1). Additional application includes analysis of the well-known Veterans Administration (VA) Lung Cancer Trial. PMID:22904583

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

    DTIC Science & Technology

    2014-12-01

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

  20. Chiropractic Adjustment

    MedlinePlus

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

  1. Adjustment disorder

    MedlinePlus

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

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

    PubMed Central

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

    2008-01-01

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

  3. Bayesian Inference on Proportional Elections

    PubMed Central

    Brunello, Gabriel Hideki Vatanabe; Nakano, Eduardo Yoshio

    2015-01-01

    Polls for majoritarian voting systems usually show estimates of the percentage of votes for each candidate. However, proportional vote systems do not necessarily guarantee the candidate with the most percentage of votes will be elected. Thus, traditional methods used in majoritarian elections cannot be applied on proportional elections. In this context, the purpose of this paper was to perform a Bayesian inference on proportional elections considering the Brazilian system of seats distribution. More specifically, a methodology to answer the probability that a given party will have representation on the chamber of deputies was developed. Inferences were made on a Bayesian scenario using the Monte Carlo simulation technique, and the developed methodology was applied on data from the Brazilian elections for Members of the Legislative Assembly and Federal Chamber of Deputies in 2010. A performance rate was also presented to evaluate the efficiency of the methodology. Calculations and simulations were carried out using the free R statistical software. PMID:25786259

  4. Golgi-Cox Staining Step by Step

    PubMed Central

    Zaqout, Sami; Kaindl, Angela M.

    2016-01-01

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

  5. Saving Money Using Proportional Reasoning

    ERIC Educational Resources Information Center

    de la Cruz, Jessica A.; Garney, Sandra

    2016-01-01

    It is beneficial for students to discover intuitive strategies, as opposed to the teacher presenting strategies to them. Certain proportional reasoning tasks are more likely to elicit intuitive strategies than other tasks. The strategies that students are apt to use when approaching a task, as well as the likelihood of a student's success or…

  6. Social Justice and Proportional Reasoning

    ERIC Educational Resources Information Center

    Simic-Muller, Ksenija

    2015-01-01

    Ratio and proportional reasoning tasks abound that have connections to real-world situations. Examples in this article demonstrate how textbook tasks can easily be transformed into authentic real-world problems that shed light on issues of equity and fairness, such as population growth and crime rates. A few ideas are presented on how teachers can…

  7. Understanding Proportional Reasoning for Teaching

    ERIC Educational Resources Information Center

    Kastberg, Signe E.; D'Ambrosio, Beatriz; Lynch-Davis, Kathleen

    2012-01-01

    Proportional reasoning is an important cornerstone in children's mathematical development. This sort of reasoning has been shown to develop across the early years of schooling (ages 8 to 10) through the middle years (ages 11-14). In the early years, children tend to use additive reasoning to generate solutions to problems, while later comparisons…

  8. Proportional Reasoning with a Pyramid

    ERIC Educational Resources Information Center

    Mamolo, Ami; Sinclair, Margaret; Whiteley, Walter J.

    2011-01-01

    Proportional reasoning pops up in math class in a variety of places, such as while making scaled drawings; finding equivalent fractions; converting units of measurement; comparing speeds, prices, and rates; and comparing lengths, areas, and volume. Students need to be exposed to a variety of representations to develop a sound understanding of this…

  9. [Invariants of the anthropometrical proportions].

    PubMed

    Smolianinov, V V

    2012-01-01

    In this work a general interpretation of a modulor as scales of segments proportions of anthropometrical modules (extremities and a body) is made. The objects of this study were: 1) to reason the idea of the growth modulor; 2) using the modern empirical data, to prove the validity of a principle of linear similarity for anthropometrical segments; 3) to specify the system of invariants for constitutional anthropometrics.

  10. Metacarpal proportions in Australopithecus africanus.

    PubMed

    Green, David J; Gordon, Adam D

    2008-05-01

    Recent work has shown that, despite being craniodentally more derived, Australopithecus africanus had more apelike limb-size proportions than A. afarensis. Here, we test whether the A. africanus hand, as judged by metacarpal shaft and articular proportions, was similarly apelike. More specifically, did A. africanus have a short and narrow first metacarpal (MC1) relative to the other metacarpals? Proportions of both MC breadth and length were considered: the geometric mean (GM) of articular and midshaft measurements of MC1 breadth was compared to those of MC2-4, and MC1 length was compared to MC3 length individually and also to the GM of MC2 and 3 lengths. To compare the extant hominoid sample with an incomplete A. africanus fossil record (11 attributed metacarpals), a resampling procedure imposed sampling constraints on the comparative groups that produced composite intrahand ratios. Resampled ratios in the extant sample are not significantly different from actual ratios based on associated elements, demonstrating the methodological appropriateness of this technique. Australopithecus africanus metacarpals do not differ significantly from the great apes in the comparison of breadth ratios but are significantly greater than chimpanzees and orangutans in both measures of relative length. Conversely, A. africanus has a significantly smaller breadth ratio than modern humans, but does not significantly differ from this group in either measure of relative length. We conclude that the first metacarpals of A. africanus are more apelike in relative breadth while also being more humanlike in relative length, a finding consistent with previous work on A. afarensis hand proportions. This configuration would have likely promoted a high degree of manipulative dexterity, but the relatively slender, apelike first metacarpal suggests that A. africanus did not place the same mechanical demands on the thumb as more recent, stone-tool-producing hominins.

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

    PubMed

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

    2015-11-01

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

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

    PubMed Central

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

    2016-01-01

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

  13. Shaft adjuster

    DOEpatents

    Harry, H.H.

    1988-03-11

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

  14. Shaft adjuster

    DOEpatents

    Harry, Herbert H.

    1989-01-01

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

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

    PubMed

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

    2013-01-01

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

  16. Photodetectors for Scintillator Proportionality Measurement

    SciTech Connect

    Moses, William W.; Choong, Woon-Seng; Hull, Giulia; Payne, Steve; Cherepy, Nerine; Valentine, J.D.

    2010-10-18

    We evaluate photodetectors for use in a Compton Coincidence apparatus designed for measuring scintillator proportionality. There are many requirements placed on the photodetector in these systems, including active area, linearity, and the ability to accurately measure low light levels (which implies high quantum efficiency and high signal-to-noise ratio). Through a combination of measurement and Monte Carlo simulation, we evaluate a number of potential photodetectors, especially photomultiplier tubes and hybrid photodetectors. Of these, we find that the most promising devices available are photomultiplier tubes with high ({approx}50%) quantum efficiency, although hybrid photodetectors with high quantum efficiency would be preferable.

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

    PubMed Central

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

    2012-01-01

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

  18. A note on the empirical likelihood confidence band for hazards ratio with covariate adjustment.

    PubMed

    Zhu, Shihong; Yang, Yifan; Zhou, Mai

    2015-09-01

    In medical studies comparing two treatments in the presence of censored data, the stratified Cox model is an important tool that has the ability to flexibly handle non-proportional hazards while allowing parsimonious covariate adjustment. In order to capture the cumulative treatment effect, the ratio of the treatment specific cumulative baseline hazards is often used as a measure of the treatment effect. Pointwise and simultaneous confidence bands associated with the estimated ratio provide a global picture of how the treatment effect evolves over time. Recently, Dong and Matthews (2012, Biometrics 68, 408-418) proposed to construct a pointwise confidence interval for the ratio using a plug-in type empirical likelihood approach. However, their result on the limiting distribution of the empirical likelihood ratio is generally incorrect and the resulting confidence interval is asymptotically undercovering. In this article, we derive the correct limiting distribution for the likelihood ratio statistic. We also present simulation studies to demonstrate the effectiveness of our approach.

  19. Comparison of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 (COX-2) inhibitors use in Australia and Nova Scotia (Canada)

    PubMed Central

    Barozzi, Nadia; Sketris, Ingrid; Cooke, Charmaine; Tett, Susan

    2009-01-01

    AIMS Cyclooxygenase-2 (COX-2) inhibitors were marketed aggressively and their rapid uptake caused safety concerns and budgetary challenges in Canada and Australia. The objectives of this study were to compare and contrast COX-2 inhibitors and nonselective nonsteroidal anti-inflammatory drug (ns-NSAID) use in Nova Scotia (Canada) and Australia and to identify lessons learned from the two jurisdictions. METHODS Ns-NSAID and COX-2 inhibitor Australian prescription data (concession beneficiaries) were downloaded from the Medicare Australia website (2001–2006). Similar Pharmacare data were obtained for Nova Scotia (seniors and those receiving Community services). Defined daily doses per 1000 beneficiaries day−1 were calculated. COX-2 inhibitors/all NSAIDs ratios were calculated for Australia and Nova Scotia. Ns-NSAIDs were divided into low, moderate and high risk for gastrointestinal side-effects and the proportions of use in each group were determined. Which drugs accounted for 90% of use was also calculated. RESULTS Overall NSAID use was different in Australia and Nova Scotia. However, ns-NSAID use was similar. COX-2 inhibitor dispensing was higher in Australia. The percentage of COX-2 inhibitor prescriptions over the total NSAID use was different in the two countries. High-risk NSAID use was much higher in Australia. Low-risk NSAID prescribing increased in Nova Scotia over time. The low-risk/high-risk ratio was constant throughout over the period in Australia and increased in Nova Scotia. CONCLUSIONS There are significant differences in Australia and Nova Scotia in use of NSAIDs, mainly due to COX-2 prescribing. Nova Scotia has a higher proportion of low-risk NSAID use. Interventions to provide physicians with information on relative benefits and risks of prescribing specific NSAIDs are needed, including determining their impact. PMID:19660008

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

    PubMed Central

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

    2010-01-01

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

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

    SciTech Connect

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

    2006-09-10

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

  2. Proportional Reasoning: A Review of the Literature.

    ERIC Educational Resources Information Center

    Tourniaire, Francoise; Pulos, Steven

    1985-01-01

    The literature on proportional reasoning is reviewed. After methodology is discussed, strategies used to solve proportion problems, variables that influence performance, and training studies are each considered. (MNS)

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

    PubMed

    Yang, Hong-Wei

    2009-10-01

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

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

    PubMed

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

    2009-12-15

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

  5. 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

  6. Comparing proportional hazards and accelerated failure time models for survival analysis.

    PubMed

    Orbe, Jesus; Ferreira, Eva; Núñez-Antón, Vicente

    2002-11-30

    This paper describes a method proposed for a censored linear regression model that can be used in the context of survival analysis. The method has the important characteristic of allowing estimation and inference without knowing the distribution of the duration variable. Moreover, it does not need the assumption of proportional hazards. Therefore, it can be an interesting alternative to the Cox proportional hazards models when this assumption does not hold. In addition, implementation and interpretation of the results is simple. In order to analyse the performance of this methodology, we apply it to two real examples and we carry out a simulation study. We present its results together with those obtained with the traditional Cox model and AFT parametric models. The new proposal seems to lead to more precise results.

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

    PubMed

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

    2013-10-01

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

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

    PubMed

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

    2011-10-15

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

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

    PubMed

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

    2010-02-01

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

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

    PubMed Central

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

    2012-01-01

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

  11. Controlling Time-Dependent Confounding by Health Status and Frailty: Restriction Versus Statistical Adjustment.

    PubMed

    McGrath, Leah J; Ellis, Alan R; Brookhart, M Alan

    2015-07-01

    Nonexperimental studies of preventive interventions are often biased because of the healthy-user effect and, in frail populations, because of confounding by functional status. Bias is evident when estimating influenza vaccine effectiveness, even after adjustment for claims-based indicators of illness. We explored bias reduction methods while estimating vaccine effectiveness in a cohort of adult hemodialysis patients. Using the United States Renal Data System and linked data from a commercial dialysis provider, we estimated vaccine effectiveness using a Cox proportional hazards marginal structural model of all-cause mortality before and during 3 influenza seasons in 2005/2006 through 2007/2008. To improve confounding control, we added frailty indicators to the model, measured time-varying confounders at different time intervals, and restricted the sample in multiple ways. Crude and baseline-adjusted marginal structural models remained strongly biased. Restricting to a healthier population removed some unmeasured confounding; however, this reduced the sample size, resulting in wide confidence intervals. We estimated an influenza vaccine effectiveness of 9% (hazard ratio = 0.91, 95% confidence interval: 0.72, 1.15) when bias was minimized through cohort restriction. In this study, the healthy-user bias could not be controlled through statistical adjustment; however, sample restriction reduced much of the bias.

  12. Trauma, comorbidity, and mortality following diagnoses of severe stress and adjustment disorders: a nationwide cohort study.

    PubMed

    Gradus, Jaimie L; Antonsen, Sussie; Svensson, Elisabeth; Lash, Timothy L; Resick, Patricia A; Hansen, Jens Georg

    2015-09-01

    Longitudinal outcomes following stress or trauma diagnoses are receiving attention, yet population-based studies are few. The aims of the present cohort study were to examine the cumulative incidence of traumatic events and psychiatric diagnoses following diagnoses of severe stress and adjustment disorders categorized using International Classification of Diseases, Tenth Revision, codes and to examine associations of these diagnoses with all-cause mortality and suicide. Data came from a longitudinal cohort of all Danes who received a diagnosis of reaction to severe stress or adjustment disorders (International Classification of Diseases, Tenth Revision, code F43.x) between 1995 and 2011, and they were compared with data from a general-population cohort. Cumulative incidence curves were plotted to examine traumatic experiences and psychiatric diagnoses during the study period. A Cox proportional hazards regression model was used to examine the associations of the disorders with mortality and suicide. Participants with stress diagnoses had a higher incidence of traumatic events and psychiatric diagnoses than did the comparison group. Each disorder was associated with a higher rate of all-cause mortality than that seen in the comparison cohort, and strong associations with suicide were found after adjustment. This study provides a comprehensive assessment of the associations of stress disorders with a variety of outcomes, and we found that stress diagnoses may have long-lasting and potentially severe consequences.

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

    PubMed

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

    2015-08-01

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

  14. Cognitive and Metacognitive Aspects of Proportional Reasoning

    ERIC Educational Resources Information Center

    Modestou, Modestina; Gagatsis, Athanasios

    2010-01-01

    In this study we attempt to propose a new model of proportional reasoning based both on bibliographical and research data. This is impelled with the help of three written tests involving analogical, proportional, and non-proportional situations that were administered to pupils from grade 7 to 9. The results suggest the existence of a…

  15. Body proportions in children with Kabuki syndrome.

    PubMed

    Penders, Bas; Schott, Nina; Gerver, Willem-Jan M; Stumpel, Constance T R M

    2016-03-01

    Facial characteristics, short stature, and skeletal anomalies have been described for the clinical diagnosis of Kabuki Syndrome (KS) in children. However, no studies have investigated body proportions in KS. Knowledge of body proportions in KS may contribute to better insight into the growth pattern and characterization of this genetic disorder. Therefore we compared body proportions of children with KS to normally proportioned controls to investigate if atypical body proportions are part of this genetic disorder. This study was designed and conducted within the setting of the Maastricht University Medical Centre (MUMC+), the official Dutch expert center for Kabuki syndrome. We conducted a cross-sectional study in 32 children (11 children with KS and 21 controls). Body proportions were determined by means of photogrammetric anthropometry, measurements based on digital photography. Body proportions, quantified as body ratios, differ significantly in children with KS from normally proportioned children. Children with KS have larger heads and longer arms proportional to their trunks and have been found to have longer upper arms proportional to their tibia length and feet. Based on deviations in body proportions it was shown possible to discern children with KS from normally proportioned controls.

  16. Improved Margin of Error Estimates for Proportions in Business: An Educational Example

    ERIC Educational Resources Information Center

    Arzumanyan, George; Halcoussis, Dennis; Phillips, G. Michael

    2015-01-01

    This paper presents the Agresti & Coull "Adjusted Wald" method for computing confidence intervals and margins of error for common proportion estimates. The presented method is easily implementable by business students and practitioners and provides more accurate estimates of proportions particularly in extreme samples and small…

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

    SciTech Connect

    Li, H.; Thompson, E.A.

    1994-09-01

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

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

    PubMed

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

    1997-03-14

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

  19. Role of LKB1-CRTC1 on Glycosylated COX-2 and Response to COX-2 Inhibition in Lung Cancer

    PubMed Central

    Cao, Chunxia; Gao, Ruli; Zhang, Min; Amelio, Antonio L.; Fallahi, Mohammad; Chen, Zirong; Gu, Yumei; Hu, Chengbin; Welsh, Eric A.; Engel, Brienne E.; Haura, Eric B.; Cress, W. Douglas; Wu, Lizi; Zajac-Kaye, Maria

    2015-01-01

    Background: Cyclooxygenase-2 (COX-2) directs the synthesis of prostaglandins including PGE-2 linking inflammation with mitogenic signaling. COX-2 is also an anticancer target, however, treatment strategies have been limited by unreliable expression assays and by inconsistent tumor responses to COX-2 inhibition. Methods: We analyzed the TCGA and Director’s Challenge lung cancer datasets (n = 188) and also generated an LKB1-null lung cancer gene signature (n = 53) to search the Broad Institute/Connectivity-MAP (C-MAP) dataset. We performed ChIP analyses, real-time polymerase chain reaction, immunoblotting, and drug testing of tumor cell lines (n = 8) and primary lung adenocarcinoma surgical resections (n = 13). Results: We show that COX-2 is a target of the cAMP/CREB coactivator CRTC1 signaling pathway. In addition, we detected a correlation between LKB1 status, CRTC1 activation, and presence of glycosylated, but not inactive hypoglycosylated COX-2 in primary lung adenocarcinoma. A search of the C-MAP drug database discovered that all high-ranking drugs positively associated with the LKB1-null signature are known CRTC1 activators, including forskolin and six different PGE-2 analogues. Somatic LKB1 mutations are present in 20.0% of lung adenocarcinomas, and we observed growth inhibition with COX-2 inhibitors in LKB1-null lung cancer cells with activated CRTC1 as compared with LKB1-wildtype cells (NS-398, P = .002 and Niflumic acid, P = .006; two-tailed t test). Conclusion: CRTC1 activation is a key event that drives the LKB1-null mRNA signature in lung cancer. We also identified a positive feedback LKB1/CRTC1 signaling loop for COX-2/PGE2 regulation. These data suggest a role for LKB1 status and glycosylated COX-2 as specific biomarkers that provide a framework for selecting patients for COX-2 inhibition studies. PMID:25465874

  20. Is the Proportion of Carbohydrate Intake Associated with the Incidence of Diabetes Complications?—An Analysis of the Japan Diabetes Complications Study

    PubMed Central

    Horikawa, Chika; Yoshimura, Yukio; Kamada, Chiemi; Tanaka, Shiro; Tanaka, Sachiko; Matsunaga, Satoshi; Hanyu, Osamu; Araki, Atsushi; Ito, Hideki; Tanaka, Akira; Ohashi, Yasuo; Akanuma, Yasuo; Sone, Hirohito

    2017-01-01

    The appropriate proportions of macronutritional intake have been controversial in medical nutritional therapy for diabetes, and evidence of the effects of carbohydrate consumption on diabetes complications in prospective settings is sparse. We investigated the relationships between proportions of carbohydrate intake as the % of total energy and diabetes complications in a nationwide cohort of Japanese patients with type 2 diabetes aged 40–70 years with hemoglobin A1c ≥6.5%. The analysis was of 1516 responders to a baseline dietary survey assessed by the Food Frequency Questionnaire based on food groups. Primary outcomes were times to overt nephropathy, diabetic retinopathy, and cardiovascular disease (CVD) after 8 years. Hazard ratios (HRs) for proportions of carbohydrate intake were estimated by Cox regression adjusted for confounders. High carbohydrate intake was significantly related to higher intakes of grain, fruits, and sweets/snacks and lower intakes of soybean and soy products, vegetables, seaweed, meat and processed meat, fish and processed fish, eggs, milk and dairy products, oil, and alcoholic beverages. During the eight-year follow-up, there were 81, 275, and 129 events of overt nephropathy, diabetic retinopathy, and CVD, respectively. After adjustment for confounders, HRs for complications in patients with carbohydrate intake in the second or third tertiles (51.0%–56.4% and ≥56.5%, respectively) compared with carbohydrate intake in the first tertile (<50.9%, referent) were analyzed. No significant associations were shown in the second and third tertiles relative to first tertile (overt nephropathy: 1.05 (95% Confidence Interval, 0.54–2.06) and 0.98 (0.40–2.44); diabetic retinopathy: 1.30 (0.90–1.88) and 1.30 (0.78–2.15); and CVD: 0.95 (0.55–1.63) and 1.37 (0.69–2.72)). By exploring potentially nonlinear relationships, trends for the incidence of diabetes complications according to proportions of carbohydrate intake were not clearly

  1. Students Speak With Gary Cox, EPIC Project Manager

    NASA Video Gallery

    From NASA’s International Space Station Mission Control Center Gary Cox EPIC Project Manager, participates in a Digital Learning Network (DLN) event with students at South Effingham Middle School...

  2. 32. SCIENTISTS ALLAN COX (SEATED), RICHARD DOELL, AND BRENT DALRYMPLE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    32. SCIENTISTS ALLAN COX (SEATED), RICHARD DOELL, AND BRENT DALRYMPLE AT CONTROL PANEL, ABOUT 1965. - U.S. Geological Survey, Rock Magnetics Laboratory, 345 Middlefield Road, Menlo Park, San Mateo County, CA

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

    PubMed

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

    2015-06-16

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

  4. 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.

  5. A Variant in COX-2 Gene Is Associated with Left Main Coronary Artery Disease and Clinical Outcomes of Coronary Artery Bypass Grafting

    PubMed Central

    Liu, Hanning; Sun, Cheng

    2017-01-01

    As a particular severe phenotype of coronary artery disease (CAD), left main coronary artery disease (LMCAD) is heritable. Genetic variants related to prostaglandin metabolism are associated with LMCAD. Cyclooxygenase-2 (COX-2), a key synthase in prostaglandin pathways, displays high density in atherosclerotic lesions and promotes early atherosclerosis in CAD progression. We hypothesized that genetic variants in COX-2 gene contribute to LMCAD phenotype susceptibility compared to more peripheral coronary artery disease (MPCAD). In this study, we genotyped COX-2 rs5275, rs5277, and rs689466 of 1544 CAD patients undergoing coronary artery bypass grafting (CABG) and found that rs5277 C allele carriage was associated with LMCAD (adjusted OR: 1.590; 95% CI: 1.103~2.291; p = 0.013). Furtherly, long-term follow-up data suggested that rs5277 C allele carriage increased risk of major adverse cardiac and cerebrovascular events (MACCE) in the whole cohort (adjusted HR: 1.561; 95% CI: 1.025~2.377; p = 0.038) and LMCAD subgroup (adjusted HR: 2.014; 95% CI: 1.036~3.913; p = 0.039) but not in MPCAD subgroup (adjusted HR: 1.375; 95% CI: 0.791~2.392; p = 0.259). In conclusion, we demonstrate that COX-2 rs5277 C allele increases the risk of left main coronary artery lesion and is also correlated with poor prognosis of LMCAD patients with CABG therapy. PMID:28194409

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

    PubMed Central

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

    2015-01-01

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

  7. CCSSM Challenge: Graphing Ratio and Proportion

    ERIC Educational Resources Information Center

    Kastberg, Signe E.; D'Ambrosio, Beatriz S.; Lynch-Davis, Kathleen; Mintos, Alexia; Krawczyk, Kathryn

    2013-01-01

    A renewed emphasis was placed on ratio and proportional reasoning in the middle grades in the Common Core State Standards for Mathematics (CCSSM). The expectation for students includes the ability to not only compute and then compare and interpret the results of computations in context but also interpret ratios and proportions as they are…

  8. Prospective Elementary School Teachers' Proportional Reasoning

    ERIC Educational Resources Information Center

    Valverde, Gabriela; Castro, Encarnación

    2012-01-01

    We present the findings of a study on prospective elementary teachers' proportional reasoning. After describing some of the teachers' performance in solving multiplicative structure problems that involve ratios and relations of direct proportionality between quantities, we were able to establish classifications of their answers according to…

  9. Examining Prospective Teachers' Understanding of Proportional Reasoning

    ERIC Educational Resources Information Center

    Kitchen, Richard; DePree, Julie

    2004-01-01

    In this article, the authors describe their efforts to assess prospective K-8 teachers' knowledge of proportional reasoning. Based upon their analysis of prospective K-8 teachers' work on a mathematics performance task, they discuss the implications for preparing prospective teachers to teach proportional reasoning to their students. In general,…

  10. Working Memory Mechanism in Proportional Quantifier Verification

    ERIC Educational Resources Information Center

    Zajenkowski, Marcin; Szymanik, Jakub; Garraffa, Maria

    2014-01-01

    The paper explores the cognitive mechanisms involved in the verification of sentences with proportional quantifiers (e.g. "More than half of the dots are blue"). The first study shows that the verification of proportional sentences is more demanding than the verification of sentences such as: "There are seven blue and eight yellow…

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

    PubMed

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

    2014-06-01

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

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

    PubMed

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

    2010-02-01

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

  13. Salt supplementation ameliorates developmental kidney defects in COX-2-/- mice.

    PubMed

    Slattery, Patrick; Frölich, Stefanie; Goren, Itamar; Nüsing, Rolf Michael

    2017-03-08

    Deficiency of cyclooxygenase-2 (COX-2) activity in the early postnatal time course causes impairment of kidney development leading to kidney insufficiency. We hypothesize that impaired NaCl reabsorption during the first days of life is a substantial cause for nephrogenic defects observed in COX-2-/- mice and that salt supplementation corrects these defects. Daily injections of 0.8 mg/g/d NaCl for the first 10 days after birth ameliorated impaired kidney development in COX-2-/- pups resulting in an increase in glomerular size and reduction of immature superficial glomeruli. However, impaired renal subcortical growth was not corrected. Increasing renal tubular flow by volume load or injections of KCl did not relieve the renal histomorphological damage. Administration of torsemide and spironolacton also affected nephrogenesis resulting in diminished glomeruli and cortical thinning. Treatment of COX-2-/- pups with NaCl/DOCA caused a stronger mitigation of glomerular size and also induced a slight but significant growth of cortical tissue mass. After birth renal mRNA expression of NHE3, NKCC2, ROMK, NCCT, ENaC, and Na+/K+-ATPase increased relative to day P2 in wild type mice. However, in COX-2-/- mice a significantly lower expression was observed for NCCT, while DOCA/NaCl treatment significantly increased NHE3 and ROMK expression. Regarding long-term effects of postnatal NaCl/DOCA injections improved kidney function with normalization of pathologically enhanced creatinine and urea plasma levels and albumin excretion was observed. In summary we present evidence that a salt supplementation during the COX-2 dependent time frame of nephrogenesis partly reverses renal morphological defects in COX-2-/- mice and improves kidney function.

  14. Reassessing manual proportions in Australopithecus afarensis.

    PubMed

    Rolian, Campbell; Gordon, Adam D

    2013-11-01

    Previous analyses of hand morphology in Australopithecus afarensis have concluded that this taxon had modern human-like manual proportions, with relatively long thumbs and short fingers. These conclusions are based on the A.L.333 composite fossil assemblage from Hadar, Ethiopia, and are premised on the ability to assign phalanges to a single individual, and to the correct side and digit. Neither assignment is secure, however, given the taphonomy and sample composition at A.L.333. We use a resampling approach that includes the entire assemblage of complete hand elements at Hadar, and takes into account uncertainties in identifying phalanges by individual, side and digit number. This approach provides the most conservative estimates of manual proportions in Au. afarensis. We resampled hand long bone lengths in Au. afarensis and extant hominoids, and obtained confidence limits for distributions of manual proportions in the latter. Results confirm that intrinsic manual proportions in Au. afarensis are dissimilar to Pan and Pongo. However, manual proportions in Au. afarensis often fall at the upper end of the distribution in Gorilla, and very lower end in Homo, corresponding to disproportionately short thumbs and long medial digits in Homo. This suggests that manual proportions in Au. afarensis, particularly metacarpal proportions, were not as derived towards Homo as previously described, but rather are intermediate between gorillas and humans. Functionally, these results suggest Au. afarensis could not produce precision grips with the same efficiency as modern humans, which may in part account for the absence of lithic technology in this fossil taxon.

  15. Allan V. Cox: AGU President 1978”1980

    NASA Astrophysics Data System (ADS)

    Richman, Barbara T.

    When Allan V. Cox was presented AGU's John Adam Fleming Medal in 1969, John Verhoogen described Cox's work as “characterized by painstaking care, proper attention to and use of statistics, and great insight.” Those same thoughts were echoed on February 3, 1987, during the memorial service for Cox, who died in a bicycling accident on January 27. The Stanford Memorial Church was crowded with colleagues, students, and friends.The Fleming Medal was presented to Cox in recognition of his studies on the fluctuation of the geomagnetic field. These studies helped to confirm theories of continental drift and seafloor spreading. The medal is awarded annually by AGU for original research and technical leadership in geomagnetism, atmospheric electricity, aeronomy, and related sciences. In addition to the Fleming Medal, Cox received the Antarctic Service Medal in 1970, the Vetlesen Prize in 1971, and the Arthur L. Day Prize of the National Academy of Sciences in 1984. He was a Fellow of AGU and a member of the National Academy of Sciences.

  16. Proportion of recovered waterfowl bands reported

    USGS Publications Warehouse

    Geis, A.D.; Atwood, E.L.

    1961-01-01

    Data from the annual mail survey of waterfowl hunters in the United States were used to estimate the total numbers of banded waterfowl that were shot. These estimates were compared with Banding Office records to estimate the proportion of recovered bands that was reported. On the average, about two banded birds were recovered for each one reported. The proportion reported was higher for some areas and for some species than for others. The proportion reported was higher when more of the reports came through employees of conservation agencies.

  17. Physiological COX-2 expression in breast epithelium associates with COX-2 levels in ductal carcinoma in situ and invasive breast cancer in young women.

    PubMed

    Fornetti, Jaime; Jindal, Sonali; Middleton, Kara A; Borges, Virginia F; Schedin, Pepper

    2014-04-01

    Cyclooxygenase-2 (COX-2) overexpression is implicated in increased risk and poorer outcomes in breast cancer in young women. We investigated COX-2 regulation in normal premenopausal breast tissue and its relationship to malignancy in young women. Quantitative COX-2 immunohistochemistry was performed on adjacent normal and breast cancer tissues from 96 premenopausal women with known clinical reproductive histories, and on rat mammary glands with distinct ovarian hormone exposures. COX-2 expression in the normal breast epithelium varied more than 40-fold between women and was associated with COX-2 expression levels in ductal carcinoma in situ and invasive cancer. Normal breast COX-2 expression was independent of known breast cancer prognostic indicators, including tumor stage and clinical subtype, indicating that factors regulating physiological COX-2 expression may be the primary drivers of COX-2 expression in breast cancer. Ovarian hormones, particularly at pregnancy levels, were identified as modulators of COX-2 in normal mammary epithelium. However, serial breast biopsy analysis in nonpregnant premenopausal women suggested relatively stable baseline levels of COX-2 expression, which persisted independent of menstrual cycling. These data provide impetus to investigate how baseline COX-2 expression is regulated in premenopausal breast tissue because COX-2 levels in normal breast epithelium may prove to be an indicator of breast cancer risk in young women, and predict the chemopreventive and therapeutic efficacy of COX-2 inhibitors in this population.

  18. PSHREG: a SAS macro for proportional and nonproportional subdistribution hazards regression.

    PubMed

    Kohl, Maria; Plischke, Max; Leffondré, Karen; Heinze, Georg

    2015-02-01

    We present a new SAS macro %pshreg that can be used to fit a proportional subdistribution hazards model for survival data subject to competing risks. Our macro first modifies the input data set appropriately and then applies SAS's standard Cox regression procedure, PROC PHREG, using weights and counting-process style of specifying survival times to the modified data set. The modified data set can also be used to estimate cumulative incidence curves for the event of interest. The application of PROC PHREG has several advantages, e.g., it directly enables the user to apply the Firth correction, which has been proposed as a solution to the problem of undefined (infinite) maximum likelihood estimates in Cox regression, frequently encountered in small sample analyses. Deviation from proportional subdistribution hazards can be detected by both inspecting Schoenfeld-type residuals and testing correlation of these residuals with time, or by including interactions of covariates with functions of time. We illustrate application of these extended methods for competing risk regression using our macro, which is freely available at: http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/statistical-software/pshreg, by means of analysis of a real chronic kidney disease study. We discuss differences in features and capabilities of %pshreg and the recent (January 2014) SAS PROC PHREG implementation of proportional subdistribution hazards modelling.

  19. The role of the LRPPRC (leucine-rich pentatricopeptide repeat cassette) gene in cytochrome oxidase assembly: mutation causes lowered levels of COX (cytochrome c oxidase) I and COX III mRNA

    PubMed Central

    2004-01-01

    Leigh syndrome French Canadian (LSFC) is a variant of cytochrome oxidase deficiency found in Québec and caused by mutations in the LRPPRC (leucine-rich pentatricopeptide repeat cassette) gene. Northern blots showed that the LRPPRC mRNA levels seen in skeletal muscle>heart>placenta>kidney>liver>lung=brain were proportionally almost opposite in strength to the severity of the enzymic cytochrome oxidase defect. The levels of COX (cytochrome c oxidase) I and COX III mRNA visible on Northern blots were reduced in LSFC patients due to the common (A354V, Ala354→Val) founder mutation. The amount of LRPPRC protein found in both fibroblast and liver mitochondria from LSFC patients was consistently reduced to <30% of control levels. Import of [35S]methionine LRPPRC into rat liver mitochondria was slower for the mutant (A354V) protein. A titre of LRPPRC protein was also found in nuclear fractions that could not be easily accounted for by mitochondrial contamination. [35S]Methionine labelling of mitochondrial translation products showed that the translation of COX I, and perhaps COX III, was specifically reduced in the presence of the mutation. These results suggest that the gene product of LRPPRC, like PET 309p, has a role in the translation or stability of the mRNA for mitochondrially encoded COX subunits. A more diffuse distribution of LRPPRC in LSFC cells compared with controls was evident when viewed by immunofluorescence microscopy, with less LRPPRC present in peripheral mitochondria. PMID:15139850

  20. Ribosome-Associated Mba1 Escorts Cox2 from Insertion Machinery to Maturing Assembly Intermediates

    PubMed Central

    Lorenzi, Isotta; Oeljeklaus, Silke; Ronsör, Christin; Bareth, Bettina; Warscheid, Bettina; Dennerlein, Sven

    2016-01-01

    The three conserved core subunits of the cytochrome c oxidase are encoded by mitochondria in close to all eukaryotes. The Cox2 subunit spans the inner membrane twice, exposing the N and C termini to the intermembrane space. For this, the N terminus is exported cotranslationally by Oxa1 and subsequently undergoes proteolytic maturation in Saccharomyces cerevisiae. Little is known about the translocation of the C terminus, but Cox18 has been identified to be a critical protein in this process. Here we find that the scaffold protein Cox20, which promotes processing of Cox2, is in complex with the ribosome receptor Mba1 and translating mitochondrial ribosomes in a Cox2-dependent manner. The Mba1-Cox20 complex accumulates when export of the C terminus of Cox2 is blocked by the loss of the Cox18 protein. While Cox20 engages with Cox18, Mba1 is no longer present at this stage. Our analyses indicate that Cox20 associates with nascent Cox2 and Mba1 to promote Cox2 maturation cotranslationally. We suggest that Mba1 stabilizes the Cox20-ribosome complex and supports the handover of Cox2 to the Cox18 tail export machinery. PMID:27550809

  1. COX-2 gene expression is correlated with cognitive function in recurrent depressive disorder.

    PubMed

    Gałecki, Piotr; Talarowska, Monika; Bobińska, Kinga; Szemraj, Janusz

    2014-02-28

    Cyclooxygenase-2(COX-2) may be a key inflammatory enzyme involved in recurrent depressive disorder(rDD). In rDD group, COX-2 expression were higher and significant correlations occurred between COX-2 expression and cognitive functions. In controls there was no significant association between analysed variables. Thus, the COX-2 enzyme may be important for cognitive functioning in rDD.

  2. Using Resampling to Compare Two Proportions

    ERIC Educational Resources Information Center

    Stephenson, W. Robert; Froelich, Amy G.; Duckworth, William M.

    2010-01-01

    This article shows that when applying resampling methods to the problem of comparing two proportions, students can discover that whether you resample with or without replacement can make a big difference.

  3. Proportionality, just war theory and weapons innovation.

    PubMed

    Forge, John

    2009-03-01

    Just wars are supposed to be proportional responses to aggression: the costs of war must not greatly exceed the benefits. This proportionality principle raises a corresponding 'interpretation problem': what are the costs and benefits of war, how are they to be determined, and a 'measurement problem': how are costs and benefits to be balanced? And it raises a problem about scope: how far into the future do the states of affairs to be measured stretch? It is argued here that weapons innovation always introduces costs, and that these costs cannot be determined in advance of going to war. Three examples, the atomic bomb, the AK-47 and the ancient Greek catapult, are given as examples. It is therefore argued that the proportionality principle is inapplicable prospectively. Some replies to the argument are discussed and rejected. Some more general defences of the proportionality principle are considered and also rejected. Finally, the significance of the argument for Just War Theory as a whole is discussed.

  4. Proportion estimation using prior cluster purities

    NASA Technical Reports Server (NTRS)

    Terrell, G. R. (Principal Investigator)

    1980-01-01

    The prior distribution of CLASSY component purities is studied, and this information incorporated into maximum likelihood crop proportion estimators. The method is tested on Transition Year spring small grain segments.

  5. Seizure following the Use of the COX-2 Inhibitor Etoricoxib

    PubMed Central

    Arnao, Valentina; Riolo, Marianna; Fierro, Brigida

    2017-01-01

    We describe a case of epileptic seizures occurring after the use of a COX-2 inhibitor. A 61-year-old man was admitted to our department because of a generalized tonic-clonic seizure. EEG showed generalized slowdown of the activity. Neuroimaging and blood samples studies did not evidence alterations, but a careful pharmacological history revealed that the patient had taken the COX-2 inhibitor etoricoxib to treat lumbago few days before the onset of clinical symptoms. No seizures were reported after etoricoxib discontinuation and an EEG resulted to be normal two months after this. Conclusion. Knowing the pharmacological history of a patient is important for understanding the clinical presentation and selecting appropriate treatment. This is, to the best of our knowledge, the first reported case of generalized seizures associated with the use of COX-2 inhibitors. PMID:28210513

  6. Molecular Dynamics Simulations of Arachidonic Acid-Derived Pentadienyl Radical Intermediate Complexes with COX-1 and COX-2

    PubMed Central

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

    2008-01-01

    The two cyclooxygenase enzymes, COX-1 and COX-2, are responsible for the committed step in prostaglandin biosynthesis, and are the targets of the non-steroidal anti-inflammatory drugs aspirin, ibuprofen and the COX-2 selective inhibitors, Celebrex™, Vioxx™ and Bextra™. The enzymes are remarkable in that they catalyze two dioxygenations and two cyclizations of the native substrate, arachidonic acid, with near absolute regio- and stereoselectivity. Several theories have been advanced to explain the nature of enzymatic control over this series of reactions, including suggestions of steric shielding and oxygen channeling. As proposed here, selective radical trapping and spin localization in the substrate-derived pentadienyl radical intermediate can also be envisioned. Herein we describe the results of explicit, 10 ns molecular dynamics simulations of both COX-1 and COX-2 with the substrate-derived pentadienyl radical intermediate bound in the active site. The enzymes’ influence on the conformation of the pentadienyl radical was investigated, along with the accessible space above and below the radical plane, and the width of several channels to the active site that could function as access routes for molecular oxygen. Additional simulations demonstrated the extent of molecular oxygen mobility within the active site. The results suggest that spin localization is unlikely to play a role in enzymatic control of this reaction. Instead, a combination of oxygen channeling, steric shielding and selective radical trapping appears to be responsible. This work adds a dynamic perspective to the strong foundation of static structural data available for these enzymes. PMID:16519515

  7. Confidence interval of difference of proportions in logistic regression in presence of covariates.

    PubMed

    Reeve, Russell

    2016-03-16

    Comparison of treatment differences in incidence rates is an important objective of many clinical trials. However, often the proportion is affected by covariates, and the adjustment of the predicted proportion is made using logistic regression. It is desirable to estimate the treatment differences in proportions adjusting for the covariates, similarly to the comparison of adjusted means in analysis of variance. Because of the correlation between the point estimates in the different treatment groups, the standard methods for constructing confidence intervals are inadequate. The problem is more difficult in the binary case, as the comparison is not uniquely defined, and the sampling distribution more difficult to analyze. Four procedures for analyzing the data are presented, which expand upon existing methods and generalize the link function. It is shown that, among the four methods studied, the resampling method based on the exact distribution function yields a coverage rate closest to the nominal.

  8. Novel COX-2 Inhibitor for Breast Cancer Therapy

    DTIC Science & Technology

    2005-07-01

    exothermic, chloroacetic acid (18.14 g, 192 mmol) was added portion wise, and the reaction mixture was re- fluxed for 5 h. This mixture was then poured into...arachadonic acid to prostaglandins (PGs) (Vane and Botting, 1998). Recent studies have shown that high levels of COX-2 are expressed in a large percentage...7.5 0 µM 3 µM 5 µM 8 µM Celebrex A Arachidonic acid (µM) Figure 9: Effect of substrate concentrations on the inactivation of COX-2 by Celebrex (A

  9. Multifocal Fixed Drug Eruption with COX-2 Inhibitor-Celecoxib

    PubMed Central

    Chugh, Shikha; Sarkar, Rashmi; Garg, Vijay K; Singh, Avninder; Keisham, Chitralekha

    2013-01-01

    Cyclooxygenase-2 (COX-2) inhibitors are rapidly becoming the first choice nonsteroidal anti-inflammatory drugs (NSAIDs) for various rheumatological and other painful conditions. However, they might not be as safe or free of side effects as they are considered to be. These COX-2inhibitors may cause a variety of dermatological and systemic side effects of which we should be aware to avoid their indiscriminate use. We hereby report a case of multifocal fixed drug eruption (FDE) with celecoxib which has not yet been reported in Indian settings. PMID:23716804

  10. Multifocal Fixed Drug Eruption with COX-2 Inhibitor-Celecoxib.

    PubMed

    Chugh, Shikha; Sarkar, Rashmi; Garg, Vijay K; Singh, Avninder; Keisham, Chitralekha

    2013-03-01

    Cyclooxygenase-2 (COX-2) inhibitors are rapidly becoming the first choice nonsteroidal anti-inflammatory drugs (NSAIDs) for various rheumatological and other painful conditions. However, they might not be as safe or free of side effects as they are considered to be. These COX-2inhibitors may cause a variety of dermatological and systemic side effects of which we should be aware to avoid their indiscriminate use. We hereby report a case of multifocal fixed drug eruption (FDE) with celecoxib which has not yet been reported in Indian settings.

  11. Pharmacokinetics and dose proportionality of ceftibuten in men.

    PubMed Central

    Lin, C; Lim, J; Radwanski, E; Marco, A; Affrime, M

    1995-01-01

    The pharmacokinetics and dose proportionality of ceftibuten were evaluated in healthy male volunteers receiving single oral doses of 200, 400, and 800 mg of ceftibuten. The drug was absorbed with similar times to the maximum concentration of drug in plasma for all three doses. Concentrations of ceftibuten in plasma increased with increasing dose. Analysis of variance was carried out on the dose-adjusted values for the maximum concentration of drug in plasma and the area under the plasma concentration-time curve; the results indicated that the concentrations in plasma after the 200- and 400-mg doses were dose proportional, and after the 800-mg of dose they were less than dose proportional. The elimination half-life from plasma ranged from 2.0 to 2.3 h and was independent of dose. The total excretion of unchanged ceftibuten in urine accounted for 53 to 68% of the dose, and the renal clearance was estimated to be 53 to 61 ml/min after all doses. The amount of ceftibuten-trans, the major in vitro and in vivo conversion product of ceftibuten, was low in both plasma and urine. PMID:7726498

  12. 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

  13. Testing departure from Hardy-Weinberg proportions.

    PubMed

    Wang, Jian; Shete, Sanjay

    2012-01-01

    The Hardy-Weinberg principle, one of the most important principles in population genetics, was originally developed for the study of allele frequency changes in a population over generations. It is now, however, widely used in studies of human diseases to detect inbreeding, populations stratification, and genotyping errors. For assessment of deviation from the Hardy-Weinberg proportions in data, the most popular approaches include the asymptotic Pearson's chi-square goodness-of-fit test and the exact test. The Pearson's chi-square goodness-of-fit test is simple and straightforward, but it is very sensitive to small sample size or rare allele frequency. The exact test of Hardy-Weinberg proportions is preferable in these situations. The exact test can be performed through complete enumeration of heterozygote genotypes or on the basis of the Markov chain Monte Carlo procedure. In this chapter, we describe the Hardy-Weinberg principle and the commonly used Hardy-Weinberg proportions tests and their applications, and we demonstrate how the chi-square test and exact test of Hardy-Weinberg proportions can be performed step-by-step using the popular software programs SAS, R, and PLINK, which have been widely used in genetic association studies, along with numerical examples. We also discuss recent approaches for testing Hardy-Weinberg proportions in case-control study designs that are better than traditional approaches for testing Hardy-Weinberg proportions in controls only. Finally, we note that deviation from the Hardy-Weinberg proportions in affected individuals can provide evidence for an association between genetic variants and diseases.

  14. COX-1 and COX-2 inhibition in horse blood by phenylbutazone, flunixin, carprofen and meloxicam: an in vitro analysis.

    PubMed

    Beretta, C; Garavaglia, G; Cavalli, M

    2005-10-01

    We report on the inhibitory activity of the NSAIDs meloxicam, carprofen, phenylbutazone and flunixin, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and carprofen are more selective inhibitors of COX-2 than phenylbutazone and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and flunixin (+29.7%) had greater COX-2 selectivity than at IC50, and meloxicam (-41.2%) and carprofen (-12.9%) had lower COX-2 selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level.

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

    PubMed Central

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

    2017-01-01

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

  16. Progress in studying scintillator proportionality: Phenomenological model

    SciTech Connect

    Bizarri, Gregory; Cherepy, Nerine; Choong, Woon-Seng; Hull, Giulia; Moses, William; Payne, Sephen; Singh, Jai; Valentine, John; Vasilev, Andrey; Williams, Richard

    2009-04-30

    We present a model to describe the origin of non-proportional dependence of scintillator light yield on the energy of an ionizing particle. The non-proportionality is discussed in terms of energy relaxation channels and their linear and non-linear dependences on the deposited energy. In this approach, the scintillation response is described as a function of the deposited energy deposition and the kinetic rates of each relaxation channel. This mathematical framework allows both a qualitative interpretation and a quantitative fitting representation of scintillation non-proportionality response as function of kinetic rates. This method was successfully applied to thallium doped sodium iodide measured with SLYNCI, a new facility using the Compton coincidence technique. Finally, attention is given to the physical meaning of the dominant relaxation channels, and to the potential causes responsible for the scintillation non-proportionality. We find that thallium doped sodium iodide behaves as if non-proportionality is due to competition between radiative recombinations and non-radiative Auger processes.

  17. The carboxyl-terminal end of Cox1 is required for feedback assembly regulation of Cox1 synthesis in Saccharomyces cerevisiae mitochondria.

    PubMed

    Shingú-Vázquez, Miguel; Camacho-Villasana, Yolanda; Sandoval-Romero, Luisa; Butler, Christine A; Fox, Thomas D; Pérez-Martínez, Xochitl

    2010-11-05

    Synthesis of the largest cytochrome c oxidase (CcO) subunit, Cox1, on yeast mitochondrial ribosomes is coupled to assembly of CcO. The translational activator Mss51 is sequestered in early assembly intermediate complexes by an interaction with Cox14 that depends on the presence of newly synthesized Cox1. If CcO assembly is prevented, the level of Mss51 available for translational activation is reduced. We deleted the C-terminal 11 or 15 residues of Cox1 by site-directed mutagenesis of mtDNA. Although these deletions did not prevent respiratory growth of yeast, they eliminated the assembly-feedback control of Cox1 synthesis. Furthermore, these deletions reduced the strength of the Mss51-Cox14 interaction as detected by co-immunoprecipitation, confirming the importance of the Cox1 C-terminal residues for Mss51 sequestration. We surveyed a panel of mutations that block CcO assembly for the strength of their effect on Cox1 synthesis, both by pulse labeling and expression of the ARG8(m) reporter fused to COX1. Deletion of the nuclear gene encoding Cox6, one of the first subunits to be added to assembling CcO, caused the most severe reduction in Cox1 synthesis. Deletion of the C-terminal 15 amino acids of Cox1 increased Cox1 synthesis in the presence of each of these mutations, except pet54. Our data suggest a novel activity of Pet54 required for normal synthesis of Cox1 that is independent of the Cox1 C-terminal end.

  18. COX7A1 — EDRN Public Portal

    Cancer.gov

    COX7A1, cytochrome c oxidase subunit VIIa polypeptide 1 (muscle), is one of the polypeptide chains of cytochrome c oxidase, the terminal component of the mitochondrial respiratory chain. This polypeptide is present only in muscle tissues. Other polypeptides of subunit VIIa are present in both muscle and nonmuscle tissues, and are encoded by different genes.

  19. 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.

  20. 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

  1. Boron-10 Lined Proportional Counter Wall Effects

    SciTech Connect

    Siciliano, Edward R.; Kouzes, Richard T.

    2012-05-01

    The Department of Energy Office of Nuclear Safeguards (NA-241) is supporting the project 'Coincidence Counting With Boron-Based Alternative Neutron Detection Technology' at Pacific Northwest National Laboratory (PNNL) for development of an alternative neutron coincidence counter. The goal of this project is to design, build and demonstrate a boron-lined proportional tube based system in the configuration of a coincidence counter. This report provides information about how variations in proportional counter radius and gas pressure in a typical coincident counter design might affect the observed signal from boron-lined tubes. A discussion comparing tubes to parallel plate counters is also included.

  2. Targeting inhibition of COX-2: a review of patents, 2002-2006.

    PubMed

    da Cunha, Elaine F F; Ramalho, Teodorico C; Josa, Daniela; Caetano, Melissa S; de Souza, Thaís C S

    2007-06-01

    The main COX inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs exert anti-inflammatory and analgesic effects through the inhibition of prostaglandin synthesis by blocking COX activity. Currently two COX isoenzymes are known, COX-1 and COX-2. Prostaglandins influenced by COX-1 maintain the integrity of the gastric mucosa. On the other hand, prostaglandins influenced by COX-2 mediate the inflammatory process. The common anti-inflammatory drugs (like aspirin, ibuprofen, and naproxen) all act by blocking the action of both the COX-1 and COX-2 enzymes. The COX-2 inhibitors represent a new class of drugs that do not affect COX-1, but selectively block COX-2. This selective action provides the benefits of reducing inflammation without irritating the stomach. This review will focus on the most recent developments published in the field, paying particular attention to promising COX-2 inhibitors, their chemistry and biological evaluation, and to new chemical and pharmaceutical processes. Moreover, we will discuss recent patents of structural analogs of the COX-2 inhibitors celecoxib and valdecoxib, and novel potential pyridazine, triazole, indole, thione derivatives as a future target for the treatment of inflammation, pain and other diseases.

  3. Canine Conjectures: Using Data for Proportional Reasoning

    ERIC Educational Resources Information Center

    Westenskow, Arla; Moyer-Packenham, Patricia S.

    2011-01-01

    No person, place, or thing can capture the attention of a class of sixth graders like "man's best friend." To prompt students' interest in a series of lessons on proportional relationships, the authors brought in a unique teaching aid--a dog. A family dog was used to supply the measurements for scatter plots and variables so that students could…

  4. Tukey-Like Pairwise Comparisons among Proportions.

    ERIC Educational Resources Information Center

    Williams, Richard H.

    1992-01-01

    A QuickBASIC microcomputer program for conducting Tukey-like pairwise comparisons on "k" independent sample proportions is described. The program can accommodate applications involving equal or unequal sample sizes. Studentized range values are computed and displayed on a computer monitor, each of which represents a simple comparison…

  5. Kitchen Gardens: Contexts for Developing Proportional Reasoning

    ERIC Educational Resources Information Center

    Hilton, Annette; Hilton, Geoff; Dole, Shelley; Goos, Merrilyn; O'Brien, Mia

    2013-01-01

    It is great to see how the sharing of ideas sparks new ideas. In 2011 Lyon and Bragg wrote an "Australian Primary Mathematics Classroom" (APMC) article on the mathematics of kitchen gardens. In this article the authors show how the kitchen garden may be used as a starting point for proportional reasoning. The authors highlight different…

  6. Using Artwork to Explore Proportional Reasoning

    ERIC Educational Resources Information Center

    Bush, Sarah B.; Karp, Karen S.; Nadler, Jennifer; Gibbons, Katie

    2016-01-01

    Having an answer to "When are we ever going to use this in real life?" is important to middle school mathematics teachers. The activity described in this article awakened sixth graders' understanding of how artists use mathematics. By exploring ratio and proportionality in different paintings, students realized the use of proportional…

  7. Research on fluidics, valves, and proportional amplifiers

    NASA Technical Reports Server (NTRS)

    1974-01-01

    Research and development being conducted at the Systems and Controls Laboratory is reviewed. Static characteristics (supply, input, transfer, output, and noise characteristics) of laminar proportional amplifiers were investigated. Other topics discussed include velocity profiles for laminar fluidic jets, speed control systems employing a jet pipe valve, and power amplification with a vortex valve.

  8. Golden Proportions for the Generalized Tribonacci Numbers

    ERIC Educational Resources Information Center

    Shah, Devbhadra V.; Mehta, Darshana A.

    2009-01-01

    It is known that the ratios of consecutive terms of Fibonacci and Tribonacci sequences converge to the fixed ratio. In this article, we consider the generalized form of Tribonacci numbers and derive the "golden proportion" for the whole family of this generalized sequence. (Contains 2 tables.)

  9. Constitutively expressed COX-2 in osteoblasts positively regulates Akt signal transduction via suppression of PTEN activity.

    PubMed

    Li, Ching-Ju; Chang, Je-Ken; Wang, Gwo-Jaw; Ho, Mei-Ling

    2011-02-01

    Cyclooxygenase-2 (COX-2) is thought to be an inducible enzyme, but increasing reports indicate that COX-2 is constitutively expressed in several organs. The status of COX-2 expression in bone and its physiological role remains undefined. Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, which commonly suppress COX-2 activity, were reported to suppress osteoblast proliferation via Akt/FOXO3a/p27(Kip1) signaling, suggesting that COX-2 may be the key factor of the suppressive effects of NSAIDs on proliferation. Although Akt activation correlates with PTEN deficiency and cell viability, the role of COX-2 on PTEN/Akt regulation remains unclear. In this study, we hypothesized that COX-2 may be constitutively expressed in osteoblasts and regulate PTEN/Akt-related proliferation. We examined the localization and co-expression of COX-2 and p-Akt in normal mouse femurs and in cultured mouse (mOBs) and human osteoblasts (hOBs). Our results showed that osteoblasts adjacent to the trabeculae, periosteum and endosteum in mouse femurs constitutively expressed COX-2, while COX-2 co-expressed with p-Akt in osteoblasts sitting adjacent to trabeculae in vivo, and in mOBs and hOBs in vitro. We further used COX-2 siRNA to test the role of COX-2 in Akt signaling in hOBs; COX-2 silencing significantly inhibited PTEN phosphorylation, enhanced PTEN activity, and suppressed p-Akt level and proliferation. However, replenishment of the COX-2 enzymatic product, PGE2, failed to reverse COX-2-dependent Akt phosphorylation. Furthermore, transfection with recombinant human COX-2 (rhCOX-2) significantly reversed COX-2 siRNA-suppressed PTEN phosphorylation, but this effect was reduced when the enzymatic activity of rhCOX-2 was blocked. This finding indicated that the effect of COX-2 on PTEN/Akt signaling is not related to PGE2 but still dependent on COX-2 enzymatic activity. Conversely, COX-1 silencing did not affect PTEN/Akt signaling. Our findings provide

  10. The Arabidopsis COX11 Homolog is Essential for Cytochrome c Oxidase Activity.

    PubMed

    Radin, Ivan; Mansilla, Natanael; Rödel, Gerhard; Steinebrunner, Iris

    2015-01-01

    Members of the ubiquitous COX11 (cytochrome c oxidase 11) protein family are involved in copper delivery to the COX complex. In this work, we characterize the Arabidopsis thaliana COX11 homolog (encoded by locus At1g02410). Western blot analyses and confocal microscopy identified Arabidopsis COX11 as an integral mitochondrial protein. Despite sharing high sequence and structural similarities, the Arabidopsis COX11 is not able to functionally replace the Saccharomyces cerevisiae COX11 homolog. Nevertheless, further analysis confirmed the hypothesis that Arabidopsis COX11 is essential for COX activity. Disturbance of COX11 expression through knockdown (KD) or overexpression (OE) affected COX activity. In KD lines, the activity was reduced by ~50%, resulting in root growth inhibition, smaller rosettes and leaf curling. In OE lines, the reduction was less pronounced (~80% of the wild type), still resulting in root growth inhibition. Additionally, pollen germination was impaired in COX11 KD and OE plants. This effect on pollen germination can only partially be attributed to COX deficiency and may indicate a possible auxiliary role of COX11 in ROS metabolism. In agreement with its role in energy production, the COX11 promoter is highly active in cells and tissues with high-energy demand for example shoot and root meristems, or vascular tissues of source and sink organs. In COX11 KD lines, the expression of the plasma-membrane copper transporter COPT2 and of several copper chaperones was altered, indicative of a retrograde signaling pathway pertinent to copper homeostasis. Based on our data, we postulate that COX11 is a mitochondrial chaperone, which plays an important role for plant growth and pollen germination as an essential COX complex assembly factor.

  11. The Arabidopsis COX11 Homolog is Essential for Cytochrome c Oxidase Activity

    PubMed Central

    Radin, Ivan; Mansilla, Natanael; Rödel, Gerhard; Steinebrunner, Iris

    2015-01-01

    Members of the ubiquitous COX11 (cytochrome c oxidase 11) protein family are involved in copper delivery to the COX complex. In this work, we characterize the Arabidopsis thaliana COX11 homolog (encoded by locus At1g02410). Western blot analyses and confocal microscopy identified Arabidopsis COX11 as an integral mitochondrial protein. Despite sharing high sequence and structural similarities, the Arabidopsis COX11 is not able to functionally replace the Saccharomyces cerevisiae COX11 homolog. Nevertheless, further analysis confirmed the hypothesis that Arabidopsis COX11 is essential for COX activity. Disturbance of COX11 expression through knockdown (KD) or overexpression (OE) affected COX activity. In KD lines, the activity was reduced by ~50%, resulting in root growth inhibition, smaller rosettes and leaf curling. In OE lines, the reduction was less pronounced (~80% of the wild type), still resulting in root growth inhibition. Additionally, pollen germination was impaired in COX11 KD and OE plants. This effect on pollen germination can only partially be attributed to COX deficiency and may indicate a possible auxiliary role of COX11 in ROS metabolism. In agreement with its role in energy production, the COX11 promoter is highly active in cells and tissues with high-energy demand for example shoot and root meristems, or vascular tissues of source and sink organs. In COX11 KD lines, the expression of the plasma-membrane copper transporter COPT2 and of several copper chaperones was altered, indicative of a retrograde signaling pathway pertinent to copper homeostasis. Based on our data, we postulate that COX11 is a mitochondrial chaperone, which plays an important role for plant growth and pollen germination as an essential COX complex assembly factor. PMID:26734017

  12. Developing Essential Understanding of Ratios, Proportions, and Proportional Reasoning for Teaching Mathematics: Grades 6-8

    ERIC Educational Resources Information Center

    Lobato, Joanne; Ellis, Amy; Zbiek, Rose Mary

    2010-01-01

    How do you refute the erroneous claim that all ratios are fractions? This book goes beyond a simple introduction to ratios, proportions, and proportional reasoning. It will help broaden and deepen your mathematical understanding of one of the most challenging topics for students--and teachers--to grasp. It will help you engage your students,…

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2003-08-01

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

  15. Effect of isolated fractions of Harpagophytum procumbens D.C. (devil's claw) on COX-1, COX-2 activity and nitric oxide production on whole-blood assay.

    PubMed

    Anauate, Maria Cecilia; Torres, Luce Maria; de Mello, Suzana Beatriz Veríssimo

    2010-09-01

    The present study evaluates the effect of isolated fractions of Harpagophytum procumbens (devil's claw) on cyclooxygenase (COX-1 and COX-2) activities and NO production using a whole blood assay. The activity of COX-1 was quantified as platelet thromboxane B(2) production in blood clotting and COX-2 as prostaglandin E(2) production in LPS-stimulated whole blood. Total NO(2) (-)/NO(3) (-) concentration was determined by Griess reaction in LPS stimulated blood. Assays were performed by incubation of isolated fractions obtained by flash chromatography monitored with HPLC, TLC and identified by (1)HNMR, containing different amounts of harpagoside with blood from healthy donors. Indomethacin and etoricoxib were the positive controls of COX-1 and COX-2 Inhibition. Data shows that fraction containing the highest concentration of harpagoside inhibited indistinctively COX-1 and COX-2 (37.2 and 29.5% respectively) activity and greatly inhibited NO production (66%). In contrast the fraction including iridoid pool increased COX-2 and did not alter NO and COX-1 activities. The fraction containing cinnamic acid was able to reduce only NO production (67%). Our results demonstrated that the harpagoside fraction is the main responsible for the effect of devils claw on these enzyme activities. However, other components from devil's claw crude extract could antagonize or increase the synthesis of inflammatory mediators.

  16. Proportional reasoning competence among different student populations

    NASA Astrophysics Data System (ADS)

    Wong, King

    2012-10-01

    A collaborative project between Western Washington University, Rutgers University, and New Mexico State University seeks to understand student's competence level on proportional reasoning. We have been collecting and analyzing data from introductory physics and science education courses using a set of assessment tasks. We utilize the notion of constructs to categorize student thinking according to repetitive patterns. Results suggest that, when students confront ratio and proportion problems, they often experience a gap between the mechanics of the mathematical operations and the conscious understanding of what they are doing. In this poster we will share results of our findings from different courses, institutions, and student populations. Supported by NSF grants DUE-1045227, DUE-1045231, DUE-1045250..

  17. Structure Based Library Design (SBLD) for new 1,4-dihydropyrimidine scaffold as simultaneous COX-1/COX-2 and 5-LOX inhibitors.

    PubMed

    Lokwani, Deepak; Azad, Rajaram; Sarkate, Aniket; Reddanna, Pallu; Shinde, Devanand

    2015-08-01

    The various scaffolds containing 1,4-dihydropyrimidine ring were designed by considering the environment of the active site of COX-1/COX-2 and 5-LOX enzymes. The structure-based library design approach, including the focused library design (Virtual Combinatorial Library Design) and virtual screening was used to select the 1,4-dihydropyrimidine scaffold for simultaneous inhibition of both enzyme pathways (COX-1/COX-2 and 5-LOX). The virtual library on each 1,4-dihydropyrimidine scaffold was enumerated in two alternative ways. In first way, the chemical reagents at R groups were filtered by docking of scaffold with single position substitution, that is, only at R1, or R2, or R3, … Rn on COX-2 enzyme using Glide XP docking mode. The structures that do not dock well were removed and the library was enumerated with filtered chemical reagents. In second alternative way, the single position docking stage was bypassed, and the entire library was enumerated using all chemical reagents by docking on the COX-2 enzyme. The entire library of approximately 15,629 compounds obtained from both ways after screening for drug like properties, were further screened for their binding affinity against COX-1 and 5-LOX enzymes using Virtual Screening Workflow. Finally, 142 hits were obtained and divided into two groups based on their binding affinity for COX-1/COX-2 and for both enzyme pathways (COX-1/COX-2 and 5-LOX). The ten molecules were selected, synthesized and evaluated for their COX-1, COX-2 and 5-LOX inhibiting activity.

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

    PubMed Central

    2013-01-01

    Background Cyclooxygenase (COX) and epidermal growth factor receptor (EGFR) activities promote progression of colorectal cancer. Combined treatment against these targets has not been more effective than single treatments alone. Therefore, our aim was to analyze relationships between COX and EGFR in peroperative colorectal tumor biopsies. Method Tumor and colon mucosa tissue were collected at primary intended curative operations in patients according to well-recognized statistical distributions of tumor stages in colorectal cancer. COX-1, COX-2 and EGFR content in tumor and colon mucosa tissue were quantified by western blot and Q-PCR. Results COX-2 protein appeared as two bands, one at 66 kDa in almost all tumor and mucosa samples and one at 74 kDa in 73% of the tumors and in 23% of the mucosa samples. Tumor COX-2 mRNA was not different from the content in mucosa samples, while COX-2 protein was increased in tumor tissue (p < 0.0003). A correlation between 74 kDa COX-2 protein and COX-2 mRNA occurred in tumor tissue, with significantly increasing COX-2 mRNA across tumor stages. EGFR mRNA content was lower in tumor tissue (p < 0.0001), while EGFR protein was similar in tumor and mucosa samples. COX-2 and EGFR proteins showed a positive correlation in mucosa, while a negative correlation occurred in tumor tissue. Tumor tissue with high COX-2 74 kDa protein lacked EGFR protein. Conclusion Our present results are compatible with the theory that COX-2 and EGFR signalling pathways are inversely related in colorectal cancer tissue. This may explain why combinatorial clinical treatments have been less rewarding. PMID:24171795

  19. 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

  20. Gamma heating measurements with proportional counters

    SciTech Connect

    Chiu, H.; Bennett, E.F.; Micklich, B.J.

    1990-05-01

    A new data acquisition technique (the Continuously-varied Bias- voltage Acquisition mode) has been developed and tested for the low-flux broad-energy regime characteristic of existing fusion blanket mock-ups. This method of analysis allows for the acquisition of data spanning several orders of magnitude in energy with a single proportional counter. Utilizing this method, the gamma energy deposition in a mixed neutron and gamma field was measured. 7 refs., 5 figs.

  1. Molecular docking studies of withanolides against Cox-2 enzyme.

    PubMed

    Prabhakaran, Yogeswaran; Dinakaran, Sathis Kumar; Macharala, Sravan Prasad; Ghosh, Somsubhra; Karanam, Sridevi Ranjitha; Kanthasamy, Naveena; Avasarala, Harani

    2012-07-01

    Withaniasomnifera (Ashwaganda) belonging to the family solanaceae is the subject of our present study. Withanoloides which are the major chemical constituents have been proved of interest because of their structural variations in the hybrids of different races. Docking is the process which brings the two structures together. In the present study we focus the extensive use of tool and graphical software for the identification of the binding energy of selected Withanolides like Withaferin -A, Withanolide-D from Withaniasomnifera and to screen the phytoconstituents that will dock/bind to the active sites of COX-2 enzyme. The relief from the symptoms of inflammation and pain can be by the Pharmacological inhibition of COX which involves the prediction of potential ligand for the treatment of inflammation. The energy value of docking between the target and the phytoconstituents under investigation and comparison with Diclofenac sodium was taken into consideration for coming into conclusion regarding the best pose and the binding ability.

  2. Evaluation of Facial Beauty Using Anthropometric Proportions

    PubMed Central

    Milutinovic, Jovana

    2014-01-01

    The improvement of a patient's facial appearance is one of the main goals of contemporary orthodontic treatment. The aim of this investigation was to evaluate the difference in facial proportions between attractive and anonymous females in order to establish objective facial features which are widely considered as beautiful. The study included two groups: first group consisted of 83 Caucasian female subjects between 22 and 28 years of age who were selected from the population of students at the University of Belgrade, and the second group included 24 attractive celebrity Caucasian females. The en face facial photographs were taken in natural head position (NHP). Numerous parameters were recorded on these photographs, in order to establish facial symmetry and correlation with the ideal set of proportions. This study showed significant difference between anonymous and attractive females. Attractive females showed smaller face in general and uniformity of the facial thirds and fifths, and most of the facial parameters meet the criteria of the ideal proportions. PMID:24701166

  3. NASA CONNECT: Proportionality: Modeling the Future

    NASA Technical Reports Server (NTRS)

    2000-01-01

    'Proportionality: Modeling the Future' is the sixth of seven programs in the 1999-2000 NASA CONNECT series. Produced by NASA Langley Research Center's Office of Education, NASA CONNECT is an award-winning series of instructional programs designed to enhance the teaching of math, science and technology concepts in grades 5-8. NASA CONNECT establishes the 'connection' between the mathematics, science, and technology concepts taught in the classroom and NASA research. Each program in the series supports the national mathematics, science, and technology standards; includes a resource-rich teacher guide; and uses a classroom experiment and web-based activity to complement and enhance the math, science, and technology concepts presented in the program. NASA CONNECT is FREE and the programs in the series are in the public domain. Visit our web site and register. http://connect.larc.nasa.gov 'Proportionality: Modeling the Future', students will examine how patterns, measurement, ratios, and proportions are used in the research, development, and production of airplanes.

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

    PubMed

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

    2008-03-01

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

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

    PubMed

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

    2012-10-01

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

  6. [New studies of COX-inhibitors, yet issues remain].

    PubMed

    Wollheim, Frank A

    2003-09-18

    Advantages and risks related to the use of selective COX-2 inhibitors when treating arthritis are currently being scrutinized by authorities and public. The discussion tends towards exaggerated claims for or against their usefulness. The issue of cardiovascular safety is still not finally settled. In an experimental study using patients with severe coronary disease, administration of celecoxib resulted in improved endothelial function together with reduced CRP levels. Gastrointestinal tolerance was studied in patients who had recently recovered from peptic ulcer bleeding. In this group of high risk patients, celecoxib was as safe as combined therapy using omeprazol and diclofenac when given for 6 months. However, both COX inhibitors caused hypertension and adverse renal effects. The second generation of selective inhibitors is being launched. Etoricoxib--related to rofecoxib--was shown to be as potent as indomethacin in the treatment of acute gout, but it caused fewer adverse reactions. In general, however, any advantage of second generation as compared to first generation COX-2 inhibitors remains to be proven. The Swedish Council on Technology Assessment in Health Care, in its "SBU Alert", has published an appraisal of celecoxib and rofecoxib, in which the need for further long-term safety studies is emphasized.

  7. Adjusting for reverse causation to estimate the effect of obesity on mortality after incident heart failure in the Atherosclerosis Risk in Communities (ARIC) study

    PubMed Central

    2016-01-01

    OBJECTIVES: The lower mortality rate of obese patients with heart failure (HF) has been partly attributed to reverse causation bias due to weight loss caused by disease. Using data about weight both before and after HF, this study aimed to adjust for reverse causation and examine the association of obesity both before and after HF with mortality. METHODS: Using the Atherosclerosis Risk in Communities (ARIC) study, 308 patients with data available from before and after the incidence of HF were included. Pre-morbid and post-morbid obesity were defined based on body mass index measurements at least three months before and after incident HF. The associations of pre-morbid and post-morbid obesity and weight change with survival after HF were evaluated using a Cox proportional hazard model. RESULTS: Pre-morbid obesity was associated with higher mortality (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.04 to 2.49) but post-morbid obesity was associated with increased survival (HR, 0.57; 95% CI, 0.37 to 0.88). Adjusting for weight change due to disease as a confounder of the obesity-mortality relationship resulted in the absence of any significant associations between post-morbid obesity and mortality. CONCLUSIONS: This study demonstrated that controlling for reverse causality by adjusting for the confounder of weight change may remove or reverse the protective effect of obesity on mortality among patients with incident HF. PMID:27283142

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

    PubMed

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

    2012-04-01

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

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

    PubMed

    Li, Zhiguo; Owzar, Kouros

    2016-06-01

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

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

    PubMed

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

    2012-06-01

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

  11. Expression of gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX-1, COX-2) in some benign salivary gland tumors.

    PubMed

    Lipari, L; Mauro, A; Gallina, S; Tortorici, S; Buscemi, M; Tete, S; Gerbino, A

    2012-01-01

    Salivary gland tumors, most of which are rare benign tumors, represent a histologically heterogenous group with the greatest diversity of morphological and cellular features. The aim of this study is to analyse the expression and possible interactions between gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX-1, COX-2) in some benign salivary gland tumors. We investigated the expression of gelatinases and cyclooxigenases in control salivary gland, Pleomorphic adenoma and Warthin's tumor through immunohistochemistry and Reverse Transcription - Polymerase Chain Reaction (PCR). We identified the expression of both classes of enzyme in normal samples and in the two types of pathological samples without any quantitative differences. From the present data no significant differences emerge in the expression of these enzymes among the different pathologies examined. Nevertheless, due to the small number of samples included in this study, general statements regarding correlation between the degree of severity of the tumoral pathology and the quantitative expression of these potential tumoral markers can not be made.

  12. Altered arachidonic acid metabolism via COX-1 and COX-2 contributes to the endothelial dysfunction of penile arteries from obese Zucker rats

    PubMed Central

    Sánchez, A; Contreras, C; Villalba, N; Martínez, P; Martínez, AC; Bríones, A; Salaíces, M; García-Sacristán, A; Hernández, M; Prieto, D

    2010-01-01

    Background and purpose: The aim of the current study was to investigate the role of arachidonic acid (AA) metabolism via cyclooxygenase (COX) in the endothelial dysfunction of penile arteries from pre-diabetic, obese Zucker rats (OZR). Experimental approach: Penile arteries from OZR and from lean Zucker rats (LZR) were mounted in microvascular myographs to assess vascular function and COX expression was determined by immunohistochemistry. Key results: Acetylcholine (ACh) and AA elicited relaxations that were impaired in arteries from OZR. Inhibition of both COX-1 and COX-2 reduced the relaxant effects of ACh and AA in LZR but not in OZR. Inhibitors of COX-1 and of the TXA2/PGH2 (TP) receptor enhanced the relaxations induced by AA in both LZR and OZR, whereas COX-2 inhibition enhanced these responses only in OZR. TP receptor blockade did not restore ACh relaxant responses in arteries from OZR. Inhibition of COX-1 increased basal tension in OZR and this contraction was blunted by TP receptor blockade. The vasoconstrictor responses to noradrenaline were augmented by indomethacin and by COX-2 inhibition in LZR but not in OZR. Immunohistochemical staining showed that both COX-1 and COX-2 are expressed in the endothelium of penile arteries from both LZR and OZR. Conclusions and implications: Vasoactive prostanoids were formed via constitutively active COX-1 and COX-2 pathways in normal rat penile arteries. Under conditions of insulin resistance, the release and/or effects of vasodilator prostanoids were impaired, contributing to the blunted endothelium-dependent vasodilatation and to the enhanced vasoconstriction. PMID:20082610

  13. COX-2-dependent stabilization of survivin in non-small cell lung cancer.

    PubMed

    Krysan, Kostyantyn; Merchant, Farrukh H; Zhu, Li; Dohadwala, Mariam; Luo, Jie; Lin, Ying; Heuze-Vourc'h, Nathalie; Põld, Mehis; Seligson, David; Chia, David; Goodglick, Lee; Wang, Hejing; Strieter, Robert; Sharma, Sherven; Dubinett, Steven

    2004-01-01

    Elevated tumor cyclooxygenase 2 (COX-2) expression is associated with increased angiogenesis, tumor invasion and promotion of tumor cell resistance to apoptosis. The mechanism(s) by which COX-2 exerts its cytoprotective effects are not completely understood but may be due to an imbalance of pro- and anti-apoptotic gene expression. To analyze COX-2-dependent gene expression and apoptosis, we created cell lines constitutively expressing COX-2 cDNA in sense and antisense orientations. Whereas COX-2 sense cells have significantly heightened resistance to radiation and drug-induced apoptosis, COX-2 antisense cells are highly sensitive to apoptosis induction. We found that the expression of the anti-apoptotic protein survivin correlated positively with COX-2 expression. A COX-2-dependent modulation of survivin ubiquitination led to its stabilization in COX-2 overexpressing cells, and this effect was replicated by exogenous PGE2 treatment of parental tumor cells. In contrast to previous studies in other cell types, in nonsmall cell lung cancer cells survivin was expressed in a cell cycle-independent manner. When established in SCID mice in vivo, COX-2 antisense-derived tumors had significantly decreased survivin levels while COX-2 sense-derived tumors demonstrated elevated levels compared with controls. In accord with these findings, survivin and COX-2 were frequently upregulated and co-expressed in human lung cancers in situ.

  14. Proportional wire calorimeter for magnet pole tips

    SciTech Connect

    Kraus, D; Ludlam, T; Renardy, J; Willis, W; Zurfluh, E

    1980-01-01

    A total absorption calorimeter is designed to have magnetic properties comparable to those of ordinary steel, and thus can be incorporated into the poles of a spectrometer magnet without compromising the field quality. A test device has been built which consists of an iron structure penetrated by a finegrain pattern of holes, each acting as a proportional tube such that 90% of the volume is occupied by iron. Measurements of the energy and space resolution of this device in a high energy beam will be presented.

  15. Neutron spectrometry with He-3 proportional counters

    SciTech Connect

    Manolopoulou, M.; Fragopoulou, M.; Stoulos, S.; Vagena, E.; Westmeier, W.; Zamani, M.

    2011-07-01

    Helium filled proportional counters are widely used in the field of neutron detection and spectrometry. In this work the response of a commercially available He-3 counter is studied experimentally and calculated with Monte Carlo for the neutron energy range from 230 keV up to about 7 MeV. The calculated response of the system is used to determine neutron yield energy distribution emitted from an extended {sup nat}U/Pb assembly irradiated with 1.6 GeV deuterons. The results are in acceptable agreement with the calculated neutron distribution with DCM-DEM code. (authors)

  16. Impact of COX2 genotype, ER status and body constitution on risk of early events in different treatment groups of breast cancer patients.

    PubMed

    Markkula, Andrea; Simonsson, Maria; Rosendahl, Ann H; Gaber, Alexander; Ingvar, Christian; Rose, Carsten; Jernström, Helena

    2014-10-15

    The COX2 rs5277 (306G>C) polymorphism has been associated with inflammation-associated cancers. In breast cancer, tumor COX-2 expression has been associated with increased estrogen levels in estrogen receptor (ER)-positive and activated Akt-pathway in ER-negative tumors. Our study investigated the impact of COX2 genotypes on early breast cancer events and treatment response in relation to tumor ER status and body constitution. In Sweden, between 2002 and 2008, 634 primary breast cancer patients, aged 25-99 years, were included. Disease-free survival was assessed for 570 rs5277-genotyped patients. Body measurements and questionnaires were obtained preoperatively. Clinical data, patient- and tumor-characteristics were obtained from questionnaires, patients' charts, population registries and pathology reports. Minor allele(C) frequency was 16.1%. Genotype was not linked to COX-2 tumor expression. Median follow-up was 5.1 years. G/G genotype was not associated with early events in patients with ER-positive tumors, adjusted HR 0.77 (0.46-1.29), but conferred an over 4-fold increased risk in patients with ER-negative tumors, adjusted HR 4.41 (1.21-16.02)(p(interaction) = 0.015). Chemotherapy-treated G/G-carriers with a breast volume ≥ 850 ml had an increased risk of early events irrespective of ER status, adjusted HR 8.99 (1.14-70.89). Endocrine-treated C-allele carriers with ER-positive tumors and a breast volume ≥ 850 ml had increased risk of early events, adjusted HR 2.30 (1.12-4.75). COX2 genotype, body constitution and ER status had a combined effect on the risk of early events and treatment response. The high risk for early events in certain subgroups of patients suggests that COX2 genotype in combination with body measurements may identify patients in need of more personalized treatment.

  17. Energy Proportionality for Disk Storage Using Replication

    SciTech Connect

    Kim, Jinoh; Rotem, Doron

    2010-09-09

    Energy saving has become a crucial concern in datacenters as several reports predict that the anticipated energy costs over a three year period will exceed hardware acquisition. In particular, saving energy for storage is of major importance as storage devices (and cooling them off) may contribute over 25 percent of the total energy consumed in a datacenter. Recent work introduced the concept of energy proportionality and argued that it is a more relevant metric than just energy saving as it takes into account the tradeoff between energy consumption and performance. In this paper, we present a novel approach, called FREP (Fractional Replication for Energy Proportionality), for energy management in large datacenters. FREP includes areplication strategy and basic functions to enable flexible energy management. Specifically, our method provides performance guarantees by adaptively controlling the power states of a group of disks based on observed and predicted workloads. Our experiments, using a set of real and synthetic traces, show that FREP dramatically reduces energy requirements with a minimal response time penalty.

  18. Kalman-predictive-proportional-integral-derivative (KPPID)

    SciTech Connect

    Fluerasu, A.; Sutton, M.

    2004-12-17

    With third generation synchrotron X-ray sources, it is possible to acquire detailed structural information about the system under study with time resolution orders of magnitude faster than was possible a few years ago. These advances have generated many new challenges for changing and controlling the state of the system on very short time scales, in a uniform and controlled manner. For our particular X-ray experiments on crystallization or order-disorder phase transitions in metallic alloys, we need to change the sample temperature by hundreds of degrees as fast as possible while avoiding over or under shooting. To achieve this, we designed and implemented a computer-controlled temperature tracking system which combines standard Proportional-Integral-Derivative (PID) feedback, thermal modeling and finite difference thermal calculations (feedforward), and Kalman filtering of the temperature readings in order to reduce the noise. The resulting Kalman-Predictive-Proportional-Integral-Derivative (KPPID) algorithm allows us to obtain accurate control, to minimize the response time and to avoid over/under shooting, even in systems with inherently noisy temperature readings and time delays. The KPPID temperature controller was successfully implemented at the Advanced Photon Source at Argonne National Laboratories and was used to perform coherent and time-resolved X-ray diffraction experiments.

  19. Viking-Age Sails: Form and Proportion

    NASA Astrophysics Data System (ADS)

    Bischoff, Vibeke

    2017-01-01

    Archaeological ship-finds have shed much light on the design and construction of vessels from the Viking Age. However, the exact proportions of their sails remain unknown due to the lack of fully preserved sails, or other definite indicators of their proportions. Key Viking-Age ship-finds from Scandinavia—the Oseberg Ship, the Gokstad Ship and Skuldelev 3—have all revealed traces of rigging. In all three finds, the keelson—with the mast position—is preserved, together with fastenings for the sheets and the tack, indicating the breadth of the sail. The sail area can then be estimated based on practical experience of how large a sail the specific ship can carry, in conjunction with hull form and displacement. This article presents reconstructions of the form and dimensions of rigging and sail based on the archaeological finds, evidence from iconographic and written sources, and ethnographic parallels with traditional Nordic boats. When these sources are analysed, not only do the similarities become apparent, but so too does the relative disparity between the archaeological record and the other sources. Preferential selection in terms of which source is given the greatest merit is therefore required, as it is not possible to afford them all equal value.

  20. ProPortal: A Database for Prochlorococcus

    DOE Data Explorer

    Huang, Katherine [Chisholm lab, MIT

    Prochlorococcus is a marine cyanobacterium that numerically dominates the mid-latitude oceans, and is the smallest known oxygenic phototroph. All isolates described thus far can be assigned to either a tightly clustered high-light (HL) adapted clade, or a more divergent low-light (LL) adapted group. They are closely related to, but distinct from, marine Synechococcus. The genomes of 12 strains have been sequenced and they range in size from 1.6 to 2.6 Mbp. They represent diverse lineages, spanning the rRNA diversity (97 to 99.93% similarity) of cultured representatives of this group. Our analyses of these genomes inform our understanding of how adaptation occurs in the oceans along gradients of light, nutrients, and other environmental factors, providing essential context for interpreting rapidly expanding metagenomic datasets. [Copied from http://proportal.mit.edu/project/prochlorococcus/] ProPortal allows users to browse and search genome date for not only Prochlorococcus, but Cyanophage and Synechococcus. Microarray data, environmental cell concentration data, and metagenome information are also available.

  1. TRIAC/SCR proportional control circuit

    DOEpatents

    Hughes, Wallace J.

    1999-01-01

    A power controller device which uses a voltage-to-frequency converter in conjunction with a zero crossing detector to linearly and proportionally control AC power being supplied to a load. The output of the voltage-to frequency converter controls the "reset" input of a R-S flip flop, while an "0" crossing detector controls the "set" input. The output of the flip flop triggers a monostable multivibrator controlling the SCR or TRIAC firing circuit connected to the load. Logic gates prevent the direct triggering of the multivibrator in the rare instance where the "reset" and "set" inputs of the flip flop are in coincidence. The control circuit can be supplemented with a control loop, providing compensation for line voltage variations.

  2. TRIAC/SCR proportional control circuit

    DOEpatents

    Hughes, W.J.

    1999-04-06

    A power controller device is disclosed which uses a voltage-to-frequency converter in conjunction with a zero crossing detector to linearly and proportionally control AC power being supplied to a load. The output of the voltage-to frequency converter controls the ``reset`` input of a R-S flip flop, while an ``0`` crossing detector controls the ``set`` input. The output of the flip flop triggers a monostable multivibrator controlling the SCR or TRIAC firing circuit connected to the load. Logic gates prevent the direct triggering of the multivibrator in the rare instance where the ``reset`` and ``set`` inputs of the flip flop are in coincidence. The control circuit can be supplemented with a control loop, providing compensation for line voltage variations. 9 figs.

  3. A proportional temperature controller with automatic shutoff

    NASA Astrophysics Data System (ADS)

    Lucich, G. M.; Holland, P. W.

    1980-08-01

    A sensitive, proportional temperature controller useful in the temperature range from 40 to 400 C with an accuracy of plus or minus 0.1 C is described. It is potentially useful for regulating temperatures in air chambers, liquid baths, furnaces and reaction vessels and for other applications. This instrument was developed to control the duration and temperature of the heating cycle of a charcoal filled adsorber that is part of a special helium analyzer. The controller was made from commercially available parts and can be easily modified to provide continuous temperature control. The circuit is solid state and employs no electromechanical devices. Over a 2 year period of use as a component of the special helium analyzer, this temperature controller performed successfully and required no maintenance.

  4. Microstrip proportional counter development at MSFC

    NASA Technical Reports Server (NTRS)

    Fulton, M. A.; Kolodziejczak, J. J.; Ramsey, B. D.

    1992-01-01

    Microstrip detectors are an exciting new development in proportional counter design fabricated using integrated circuit-type photolithography techniques; they therefore offer very high spatial accuracy and uniformity. A development program is underway at NASA-Marshall to produce large-area microstrips for use in an X-ray detector balloon flight program and to investigate the general performance limits of these new devices. Microstrips tested so far have been fabricated both in-house using standard photolithographic techniques and by an outside contractor using electron beam technology. Various substrate materials have been tested along with different electrode configurations. The distributions of pickup on subdivided cathodes on both top and bottom surfaces of the microstrips are also being investigated for use as two-dimensional imaging detectors. Data from these tests in the development of a large-area device will be presented.

  5. Boron-10 Lined Proportional Counter Model Validation

    SciTech Connect

    Lintereur, Azaree T.; Siciliano, Edward R.; Kouzes, Richard T.

    2012-06-30

    The Department of Energy Office of Nuclear Safeguards (NA-241) is supporting the project “Coincidence Counting With Boron-Based Alternative Neutron Detection Technology” at Pacific Northwest National Laboratory (PNNL) for the development of an alternative neutron coincidence counter. The goal of this project is to design, build and demonstrate a boron-lined proportional tube-based alternative system in the configuration of a coincidence counter. This report discusses the validation studies performed to establish the degree of accuracy of the computer modeling methods current used to simulate the response of boron-lined tubes. This is the precursor to developing models for the uranium neutron coincidence collar under Task 2 of this project.

  6. Scaling and universality in proportional elections.

    PubMed

    Fortunato, Santo; Castellano, Claudio

    2007-09-28

    A most debated topic of the last years is whether simple statistical physics models can explain collective features of social dynamics. A necessary step in this line of endeavor is to find regularities in data referring to large-scale social phenomena, such as scaling and universality. We show that, in proportional elections, the distribution of the number of votes received by candidates is a universal scaling function, identical in different countries and years. This finding reveals the existence in the voting process of a general microscopic dynamics that does not depend on the historical, political, and/or economical context where voters operate. A simple dynamical model for the behavior of voters, similar to a branching process, reproduces the universal distribution.

  7. Cox26 is a novel stoichiometric subunit of the yeast cytochrome c oxidase.

    PubMed

    Levchenko, Maria; Wuttke, Jan-Moritz; Römpler, Katharina; Schmidt, Bernhard; Neifer, Klaus; Juris, Lisa; Wissel, Mirjam; Rehling, Peter; Deckers, Markus

    2016-07-01

    The cytochrome c oxidase (COX) is the terminal enzyme of the respiratory chain. The complex accepts electrons from cytochrome c and passes them onto molecular oxygen. This process contributes to energy capture in the form of a membrane potential across the inner membrane. The enzyme complex assembles in a stepwise process from the three mitochondria-encoded core subunits Cox1, Cox2 and Cox3, which associate with nuclear-encoded subunits and cofactors. In the yeast Saccharomyces cerevisiae, the cytochrome c oxidase associates with the bc1-complex into supercomplexes, allowing efficient energy transduction. Here we report on Cox26 as a protein found in respiratory chain supercomplexes containing cytochrome c oxidase. Our analyses reveal Cox26 as a novel stoichiometric structural subunit of the cytochrome c oxidase. A loss of Cox26 affects cytochrome c oxidase activity and respirasome organization.

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

    PubMed

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

    2008-01-01

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

  9. Remotely Adjustable Hydraulic Pump

    NASA Technical Reports Server (NTRS)

    Kouns, H. H.; Gardner, L. D.

    1987-01-01

    Outlet pressure adjusted to match varying loads. Electrohydraulic servo has positioned sleeve in leftmost position, adjusting outlet pressure to maximum value. Sleeve in equilibrium position, with control land covering control port. For lowest pressure setting, sleeve shifted toward right by increased pressure on sleeve shoulder from servovalve. Pump used in aircraft and robots, where hydraulic actuators repeatedly turned on and off, changing pump load frequently and over wide range.

  10. Adjustable Pitot Probe

    NASA Technical Reports Server (NTRS)

    Ashby, George C., Jr.; Robbins, W. Eugene; Horsley, Lewis A.

    1991-01-01

    Probe readily positionable in core of uniform flow in hypersonic wind tunnel. Formed of pair of mating cylindrical housings: transducer housing and pitot-tube housing. Pitot tube supported by adjustable wedge fairing attached to top of pitot-tube housing with semicircular foot. Probe adjusted both radially and circumferentially. In addition, pressure-sensing transducer cooled internally by water or other cooling fluid passing through annulus of cooling system.

  11. Weighted triangulation adjustment

    USGS Publications Warehouse

    Anderson, Walter L.

    1969-01-01

    The variation of coordinates method is employed to perform a weighted least squares adjustment of horizontal survey networks. Geodetic coordinates are required for each fixed and adjustable station. A preliminary inverse geodetic position computation is made for each observed line. Weights associated with each observed equation for direction, azimuth, and distance are applied in the formation of the normal equations in-the least squares adjustment. The number of normal equations that may be solved is twice the number of new stations and less than 150. When the normal equations are solved, shifts are produced at adjustable stations. Previously computed correction factors are applied to the shifts and a most probable geodetic position is found for each adjustable station. Pinal azimuths and distances are computed. These may be written onto magnetic tape for subsequent computation of state plane or grid coordinates. Input consists of punch cards containing project identification, program options, and position and observation information. Results listed include preliminary and final positions, residuals, observation equations, solution of the normal equations showing magnitudes of shifts, and a plot of each adjusted and fixed station. During processing, data sets containing irrecoverable errors are rejected and the type of error is listed. The computer resumes processing of additional data sets.. Other conditions cause warning-errors to be issued, and processing continues with the current data set.

  12. Targeting COX-2 expression by natural compounds: a promising alternative strategy to synthetic COX-2 inhibitors for cancer chemoprevention and therapy.

    PubMed

    Cerella, Claudia; Sobolewski, Cyril; Dicato, Mario; Diederich, Marc

    2010-12-15

    Cyclooxygenase (COX)-2 is a pro-inflammatory immediate early response protein, chronically up-regulated in many pathological conditions. In autoimmune diseases, it is responsible for degenerative effects whereas in cancer, it correlates with poor prognosis. A constitutive expression of COX-2 is triggered since the earliest steps of carcinogenesis. Consequently, strategies aimed at inhibiting COX-2 enzymatic activity have been clinically applied for the treatment of autoimmune disorders; in addition, the same approaches are currently investigated for anti-cancer purposes. However, COX-2 protein inhibitors (i.e., NSAIDs and COXIBs) are not amenable to prolonged administration since they may cause severe side effects, and efforts are underway to identify alternative approaches for chemoprevention/therapy. COX-2 expression is a multi-step process, highly regulated at transcriptional and post-transcriptional levels. Defects in the modulation of one or both of these steps may be found in pathological conditions. Targeting COX-2 expression may therefore represent a promising strategy, by which the same preventive and therapeutic benefits may be gained while avoiding the severe side effects of COX-2 enzymatic inhibition. Naturally occurring compounds derived from plants/organisms represent a huge source of biologically active molecules, that remains largely unexplored. Derived from plants/organisms used in traditional forms of medicine or as dietary supplements, these compounds have been experimentally investigated for their anti-inflammatory and anti-cancer potential. In this review, we will analyze how natural compounds may modulate the multistep regulation of COX-2 gene expression and discuss their potential as a new generation of COX-2 targeting agents alternative to the synthetic COX-2 inhibitors.

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

    PubMed

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

    2012-07-01

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

  14. Exact tests for Hardy-Weinberg proportions.

    PubMed

    Engels, William R

    2009-12-01

    Exact conditional tests are often required to evaluate statistically whether a sample of diploids comes from a population with Hardy-Weinberg proportions or to confirm the accuracy of genotype assignments. This requirement is especially common when the sample includes multiple alleles and sparse data, thus rendering asymptotic methods, such as the common chi(2)-test, unreliable. Such an exact test can be performed using the likelihood ratio as its test statistic rather than the more commonly used probability test. Conceptual advantages in using the likelihood ratio are discussed. A substantially improved algorithm is described to permit the performance of a full-enumeration exact test on sample sizes that are too large for previous methods. An improved Monte Carlo algorithm is also proposed for samples that preclude full enumeration. These algorithms are about two orders of magnitude faster than those currently in use. Finally, methods are derived to compute the number of possible samples with a given set of allele counts, a useful quantity for evaluating the feasibility of the full enumeration procedure. Software implementing these methods, ExactoHW, is provided.

  15. Proportional mortality of 50 years and above

    PubMed Central

    Swaroop, S.; Uemura, K.

    1957-01-01

    In 1954 the United Nations Committee of Experts on International Definition and Measurement of Standards and Levels of Living suggested that for the measurement of levels of living quantifiable or potentially quantifiable components should be considered separately. An attempt is made in the present paper to evolve a single, comprehensive numerical indicator to quantify the component “health, including demographic conditions”. The use of an objective statistical technique as a guide in the selection of such an indicator is suggested. From the application of this technique, it is concluded that the percentage of deaths at the ages 50 years and over to total deaths (proportional mortality) affords a fairly suitable yardstick by which broad inter-country comparisons may be made. This indicator has the advantages of simplicity of calculation, comprehensiveness, availability of data, possibility of international comparability despite the varying quality of basic statistical information, sensitivity for the purpose of inter-country comparisons, and validity for studying levels and trends. PMID:13500159

  16. Patient-specific meta-analysis for risk assessment using multivariate proportional hazards regression.

    PubMed

    Crager, Michael R; Tang, Gong

    We propose a method for assessing an individual patient's risk of a future clinical event using clinical trial or cohort data and Cox proportional hazards regression, combining the information from several studies using meta-analysis techniques. The method combines patient-specific estimates of the log cumulative hazard across studies, weighting by the relative precision of the estimates, using either fixed- or random-effects meta-analysis calculations. Risk assessment can be done for any future patient using a few key summary statistics determined once and for all from each study. Generalizations of the method to logistic regression and linear models are immediate. We evaluate the methods using simulation studies and illustrate their application using real data.

  17. iNOS signaling interacts with COX-2 pathway in colonic fibroblasts.

    PubMed

    Zhu, Yingting; Zhu, Min; Lance, Peter

    2012-10-01

    COX-2 and iNOS are two major inflammatory mediators implicated in colorectal inflammation and cancer. Previously, the role of colorectal fibroblasts involved in regulation of COX-2 and iNOS expression was largely ignored. In addition, the combined interaction of COX-2 and iNOS signalings and their significance in the progression of colorectal inflammation and cancer within the fibroblasts have received little investigation. To address those issues, we investigated the role of colonic fibroblasts in the regulation of COX-2 and iNOS gene expression, and explored possible mechanisms of interaction between COX-2 and iNOS signalings using a colonic CCD-18Co fibroblast line and LPS, a potential stimulator of COX-2 and iNOS. Our results clearly demonstrated that LPS activated COX-2 gene expression and enhanced PGE(2) production, stimulated iNOS gene expression and promoted NO production in the fibroblasts. Interestingly, activation of COX-2 signaling by LPS was not involved in activation of iNOS signaling, while activation of iNOS signaling by LPS contributed in part to activation of COX-2 signaling. Further analysis indicated that PKC plays a major role in the activation and interaction of COX-2 and iNOS signalings induced by LPS in the fibroblasts.

  18. 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

  19. Usefulness of selective COX-2 inhibitors as therapeutic agents against canine mammary tumors.

    PubMed

    Saito, Teruyoshi; Tamura, Dai; Asano, Ryuji

    2014-04-01

    Cyclooxygenase-2 (COX-2) is a key enzyme for converting arachidonic acids to prostanoids, which are known to be induced during inflammation and cancer initiation. Previously, it has been reported that COX inhibitors, such as aspirin, reduce the incidence of human colorectal cancer; therefore, it is widely believed that COX-2 is a potential therapeutic and chemoprevention target for several types of human cancer. However, whether selective COX-2 inhibitors have antitumor effects against canine mammary tumor cells remains unclear. In the present study, to elucidate the antitumor effect of selective COX-2 inhibitors against canine mammary tumors, we investigated the antitumor effects of meloxicam, etodolac and celecoxib using COX-2-expressing canine mammary tumor (CF33) cells. We analyzed the effects of selective COX-2 inhibitors on COX-2 protein expression levels in CF33 cells. Celecoxib (100 µM) was found to induce downregulation of COX-2 protein expression. We examined the effect of selective COX-2 inhibitors on CF33 cell proliferation. All the selective COX-2 inhibitors suppressed CF33 cell growth. Specifically, etodolac and celecoxib inhibited cell proliferation via a decrease in S-phase cells and an increase in G0/G1 arrest. We examined the apoptotic effect of selective COX-2 inhibitors on CF33 cells. Our data suggested that etodolac and celecoxib induced apoptosis in CF33 cells. In particular, celecoxib led to apoptosis mediated by the activation of the mitochondrial apoptosis pathway, including the upregulation of BAX expression, downregulation of Bcl-2 expression and activation of caspase-3/7. Furthermore, celecoxib increased the percentages of cells in both early apoptosis and late apoptosis. Our results revealed that celecoxib induced apoptosis and cell cycle arrest in CF33 cells. The data suggested that celecoxib is the most viable candidate as a therapeutic agent for the treatment of canine mammary tumors. Furthermore, our findings provide the first

  20. Prognostic relevance of cyclooxygenase-2 (COX-2) expression in Chinese patients with prostate cancer.

    PubMed

    Bin, Wu; He, Wang; Feng, Zhang; Xiangdong, Lu; Yong, Chen; Lele, Kou; Hongbin, Zhang; Honglin, Guo

    2011-02-01

    Cyclooxygenase-2 (COX-2), an inducible isoform of cyclooxygenase, has been reported to be correlated with tumorigenesis, tumor progression and metastasis. The present study was designed to investigate the clinicopathological and prognostic significance of COX-2 in Chinese patients with prostate cancer. Firstly, RT-PCR and Western blot assays were performed to detect the expression of COX-2 mRNA and protein in prostate cancer cell lines and 20 tissue samples (tumor or corresponding non-tumor). Next, immunohistochemistry was performed to detect the expression of COX-2 protein in 88 prostate cancer tissue samples. Finally, the correlation between COX-2 expression and clinicopathological factors and patient survival was evaluated. We found that the expression levels of COX-2 mRNA and protein showed significant difference among four prostate cancer cell lines. Moreover, the levels of COX-2 mRNA and protein were significantly higher in prostate cancer tissues than in corresponding non-tumor tissues. COX-2 staining was positive in the cytoplasm of prostate cancer cells. High-COX-2 expression was correlated with the Gleason score (P=0.009), tumor stage (P=0.012), and lymph-node status (P=0.036). Furthermore, patients with high-COX-2 expression showed lower disease-free (P=0.014) and overall survival (P=0.047) rates than those with low-COX-2 expression. Univariate and multivariate analyses suggested that the status of COX-2 protein expression was an independent prognostic indicator for patients' survival. Taken together, higher COX-2 protein expression might provide an independent prognostic marker for Chinese patients with prostate cancer who have undergone surgery.

  1. Dexamethasone damages the rat stomach but not small intestine during inhibition of COX-1.

    PubMed

    Yokota, Aya; Taniguchi, Masaki; Takahira, Yuka; Tanaka, Akiko; Takeuchi, Koji

    2007-06-01

    We previously reported that inhibition of both COX-1 and COX-2 is required for the gastrointestinal ulcerogenic properties of nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of COX-1 up-regulates COX-2 expression, and the prostaglandins (PGs) produced by COX-2 help to maintain the mucosal integrity during inhibition of COX-1. In the present study we investigated whether dexamethasone damages rat gastrointestinal mucosa during inhibition of COX-1 and further developed the idea that COX-2 expression is a key event in the ulcerogenic actions of NSAIDs. Dexamethasone was given p.o. in the absence or presence of SC-560 (a selective COX-1 inhibitor), and the stomach or intestine was examined 8 or 24 hr later, respectively. Neither dexamethasone nor SC-560 alone damaged the gastrointestinal mucosa. In the presence of SC-560, however, dexamethasone damaged the stomach but not small intestine. SC-560 decreased PGE(2) levels in both tissues, with a gradual recovery accompanying the up-regulation of COX-2 expression, and both the recovery of PGE(2) levels and the expression of COX-2 were inhibited by dexamethasone. In the animals treated with SC-560, iNOS expression was up-regulated in the intestinal but not the gastric mucosa, and this response was also inhibited by dexamethasone. These results suggest a risk from steroid therapy in the stomach when COX-2 expression is up-regulated. Dexamethasone does not provoke damage in the intestine, despite inhibiting the up-regulation of COX-2 expression under conditions of PG deficiency; at least one of the reasons is that this agent prevents the expression of iNOS, a major factor in the pathogenesis of intestinal lesions.

  2. COX-2 mRNA expression in esophageal squamous cell carcinoma (ESCC) and effect by NSAID.

    PubMed

    Liu, X; Li, P; Zhang, S-T; You, H; Jia, J-D; Yu, Z-L

    2008-01-01

    To investigate cyclooxygenase-2 (COX-2) mRNA expression in human esophageal squamous cell carcinoma and the effect of a non-steroidal anti-inflammatory drug (NSAID) on it, in order to explore the mechanism of COX-2 in esophageal squamous cell carcinoma (ESCC) carcinogenesis and the ability of NSAID to prevent or treat ESCC. Frozen specimens of human ESCC and adjacent normal esophageal squamous epithelium pairs (n = 22) were examined for COX-2 mRNA expression by reverse-transcription polymerase chain reaction (RT-PCR). After incubation with aspirin (a non-selective COX inhibitor) or Nimesulide (a selective COX-2 inhibitor), the proliferation status of two human esophageal squamous cancer cell lines, EC-9706 and EC-109, was quantified by 3-(4,5-dimethyl-thiazol-2yl)-2,5-diphenyltetrazolium bromide assay. The expression of COX-2 mRNA in these cells was detected by RT-PCR. COX-2 mRNA was expressed in 12 of 22 (54.5%) ESCC tissue samples, but it was undetectable in all the specimens of adjacent normal esophageal squamous epithelium COX-2 mRNA expression. Both aspirin (5-20 mmol/L) and Nimesulide (0.1-0.8 mmol/L) inhibited EC-9706 cell line proliferation and suppressed its COX-2 mRNA expression dose-dependently. However, only aspirin (5-20 mmol/L) could inhibit proliferation in the EC-109 cell line and suppress COX-2 mRNA expression. Nimesulide (0.1-0.8 mmol/L) could neither inhibit EC-109 cell growth nor suppress COX-2 mRNA expression. COX-2 mRNA expression is a frequent phenomenon in human ESCC tissue samples and plays an important role in the carcinogenesis of ESCC. NSAID may be useful in the chemoprevention and therapy of human ESCC and its effects are likely to be mediated by modulating COX-2 activity.

  3. Recirculating valve lash adjuster

    SciTech Connect

    Stoody, R.R.

    1987-02-24

    This patent describes an internal combustion engine with a valve assembly of the type including overhead valves supported by a cylinder head for opening and closing movements in a substantially vertical direction and a rotatable overhead camshaft thereabove lubricated by engine oil pumped by an engine oil pump. A hydraulic lash adjuster with an internal reservoir therein is solely supplied with run-off lubricating oil from the camshaft which oil is pumped into the internal reservoir of the lash adjuster by self-pumping operation of the lash adjuster produced by lateral forces thereon by the rotative operation of the camshaft comprising: a housing of the lash adjuster including an axially extending bore therethrough with a lower wall means of the housing closing the lower end thereof; a first plunger member being closely slidably received in the bore of the housing and having wall means defining a fluid filled power chamber with the lower wall means of the housing; and a second plunger member of the lash adjuster having a portion being loosely slidably received and extending into the bore of the housing for reciprocation therein. Another portion extends upwardly from the housing to operatively receive alternating side-to-side force inputs from operation of the camshaft.

  4. Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer.

    PubMed

    Wilson, Andrew J; Fadare, Oluwole; Beeghly-Fadiel, Alicia; Son, Deok-Soo; Liu, Qi; Zhao, Shilin; Saskowski, Jeanette; Uddin, Md Jashim; Daniel, Cristina; Crews, Brenda; Lehmann, Brian D; Pietenpol, Jennifer A; Crispens, Marta A; Marnett, Lawrence J; Khabele, Dineo

    2015-08-28

    Cyclooxygenase-1 (COX-1) is implicated in ovarian cancer. However, patterns of COX expression and function have been unclear and controversial. In this report, patterns of COX-1 and COX-2 gene expression were obtained from RNA-seq data through The Cancer Genome Atlas. Our analysis revealed markedly higher COX-1 mRNA expression than COX-2 in high-grade serous ovarian cancers (HGSOC) and higher COX-1 expression in HGSOC tumors than 10 other tumor types. High expression of COX-1 in HGSOC tumors was confirmed in an independent tissue microarray. In contrast, lower or similar expression of COX-1 compared to COX-2 was observed in endometrioid, mucinous and clear cell tumors. Stable COX-1 knockdown in HGSOC-representative OVCAR-3 ovarian cancer cells reduced gene expression in multiple pro-tumorigenic pathways. Functional cell viability, clonogenicity, and migration/invasion assays were consistent with transcriptomic changes. These effects were reversed by stable over-expression of COX-1 in SKOV-3 cells. Our results demonstrate a distinct pattern of COX-1 over-expression in HGSOC tumors and strong association of COX-1 with multiple pro-tumorigenic pathways in ovarian cancer cells. These findings provide additional insight into the role of COX-1 in human ovarian cancer and support further development of methods to selectively target COX-1 in the management of HGSOC tumors.

  5. Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer

    PubMed Central

    Wilson, Andrew J.; Fadare, Oluwole; Beeghly-Fadiel, Alicia; Son, Deok-Soo; Liu, Qi; Zhao, Shilin; Saskowski, Jeanette; Uddin, Md. Jashim; Daniel, Cristina; Crews, Brenda; Lehmann, Brian D.; Pietenpol, Jennifer A.; Crispens, Marta A.; Marnett, Lawrence J.; Khabele, Dineo

    2015-01-01

    Cyclooxygenase-1 (COX-1) is implicated in ovarian cancer. However, patterns of COX expression and function have been unclear and controversial. In this report, patterns of COX-1 and COX-2 gene expression were obtained from RNA-seq data through The Cancer Genome Atlas. Our analysis revealed markedly higher COX-1 mRNA expression than COX-2 in high-grade serous ovarian cancers (HGSOC) and higher COX-1 expression in HGSOC tumors than 10 other tumor types. High expression of COX-1 in HGSOC tumors was confirmed in an independent tissue microarray. In contrast, lower or similar expression of COX-1 compared to COX-2 was observed in endometrioid, mucinous and clear cell tumors. Stable COX-1 knockdown in HGSOC-representative OVCAR-3 ovarian cancer cells reduced gene expression in multiple pro-tumorigenic pathways. Functional cell viability, clonogenicity, and migration/invasion assays were consistent with transcriptomic changes. These effects were reversed by stable over-expression of COX-1 in SKOV-3 cells. Our results demonstrate a distinct pattern of COX-1 over-expression in HGSOC tumors and strong association of COX-1 with multiple pro-tumorigenic pathways in ovarian cancer cells. These findings provide additional insight into the role of COX-1 in human ovarian cancer and support further development of methods to selectively target COX-1 in the management of HGSOC tumors. PMID:25972361

  6. In Polytomella sp. mitochondria, biogenesis of the heterodimeric COX2 subunit of cytochrome c oxidase requires two different import pathways.

    PubMed

    Jiménez-Suárez, Alejandra; Vázquez-Acevedo, Miriam; Rojas-Hernández, Andrés; Funes, Soledad; Uribe-Carvajal, Salvador; González-Halphen, Diego

    2012-05-01

    In the vast majority of eukaryotic organisms, the mitochondrial cox2 gene encodes subunit II of cytochrome c oxidase (COX2). However, in some lineages including legumes and chlorophycean algae, the cox2 gene migrated to the nucleus. Furthermore, in chlorophycean algae, this gene was split in two different units. Thereby the COX2 subunit is encoded by two independent nuclear genes, cox2a and cox2b, and mitochondria have to import the cytosol-synthesized COX2A and COX2B subunits and assemble them into the cytochrome c oxidase complex. In the chlorophycean algae Chlamydomonas reinhardtii and Polytomella sp., the COX2A precursor exhibits a long (130-140 residues), cleavable mitochondrial targeting sequence (MTS). In contrast, COX2B lacks an MTS, suggesting that mitochondria use different mechanisms to import each subunit. Here, we explored the in vitro import processes of both, the Polytomella sp. COX2A precursor and the COX2B protein. We used isolated, import-competent mitochondria from this colorless alga. Our results suggest that COX2B is imported directly into the intermembrane space, while COX2A seems to follow an energy-dependent import pathway, through which it finally integrates into the inner mitochondrial membrane. In addition, the MTS of the COX2A precursor is eliminated. This is the first time that the in vitro import of split COX2 subunits into mitochondria has been achieved.

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

    PubMed

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

    2012-08-01

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

  8. Enteric coating of mycophenolate reduces dosage adjustments.

    PubMed

    Brister, K; Yau, C L; Slakey, D

    2009-06-01

    Mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) are bioequivalent. However, the effectiveness of MMF may be limited by gastrointestinal (GI) side effects. This study assessed the relationship between the number of medication dosage adjustments and posttransplantation side effects. In a review of 109 kidney transplant patients, 65 initially received MMF and 44 initially received EC-MPS. The incidences of patient-reported GI complications were significantly different: MMF 45.5% vs EC-MPS 35.3% (P = .0194). The proportions of patients requiring dosage adjustment due to GI complications were MMF 5.9% and EC-MPS 2.3% (P < .0001). Patients receiving MMF were more likely to experience GI complications resulting in dosage adjustment (odds ratio = 9.9; P = .0306). The incidences of acute rejection, cytomegalovirus (CMV), and leukopenia resulting in dosage adjustment were not significantly different. Patients receiving MMF required more immunosuppressive medication adjustments, which may complicate care and decrease overall compliance.

  9. Capping risk adjustment?

    PubMed

    Eugster, Patrick; Sennhauser, Michèle; Zweifel, Peter

    2010-07-01

    When premiums are community-rated, risk adjustment (RA) serves to mitigate competitive insurers' incentive to select favorable risks. However, unless fully prospective, it also undermines their incentives for efficiency. By capping its volume, one may try to counteract this tendency, exposing insurers to some financial risk. This in term runs counter the quest to refine the RA formula, which would increase RA volume. Specifically, the adjuster, "Hospitalization or living in a nursing home during the previous year" will be added in Switzerland starting 2012. This paper investigates how to minimize the opportunity cost of capping RA in terms of increased incentives for risk selection.

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

    NASA Astrophysics Data System (ADS)

    Wei, Chao; Shu, Huisheng; Liu, Yurong

    2016-07-01

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

  11. Sieve estimation of Cox models with latent structures.

    PubMed

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

    2016-12-01

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

  12. COX-2 inhibitors: a story of greed, deception and death.

    PubMed

    Halpern, Georges M

    2005-01-01

    In 1999, drug manufacturers introduced a class of NSAIDs called COX-2 inhibitors or coxibs. The drugs were avidly promoted directly to the consumers and became bestsellers from the start. Arthritis sufferers were eager to take medications that eased joint pain with less risk of causing gastrointestinal pain, bleeding and other side-effects. In the year after their introduction, doctors wrote over 100 million prescriptions for celecoxib (Celebrex) and rofecoxib (Vioxx). Celebrex is the sixth best-selling drug, with sales of more than US$ 4 billion since its debut in 1999. Vioxx had sales of US$ 2.6 billion in 2001. However, the coxibs increase the risk of heart attacks and strokes, and their price, in the USA, is obscene. The manufacturers faced a possibly complicit, toothless and bloodless FDA, and used every maneuvering to fleece the patients. We must now reflect on attitudes that we thought only belong to the tobacco industry. Fortunately, safe and active alternatives exist.

  13. COX-2 over-expression correlates with VEGF and tumour angiogenesis in canine mammary cancer.

    PubMed

    Queiroga, Felisbina L; Pires, Isabel; Parente, Margarida; Gregório, Hugo; Lopes, Carlos S

    2011-07-01

    This study was designed to investigate the possible roles of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in canine mammary cancer angiogenesis. Immunohistochemistry was performed on 70 tumours (28 benign and 42 malignant) in order to detect COX-2 and VEGF expression. Microvessel density (MVD) was determined by CD31 immunolabelling to assess tumour angiogenesis. There was a significantly higher expression of COX-2 (P<0.001), VEGF (P<0.001) and MVD (P<0.001) in malignant compared to benign tumours. In the malignant group, the MVD of COX-2 positive tumours was significantly higher than that of COX-2 negative tumours (P=0.026). A similar association was observed for VEGF (P<0.001) positive tumours. The results from this study suggested that over-expression of COX-2 and VEGF may contribute to increased angiogenesis and aggression in malignant tumours.

  14. 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.

  15. Assessing heterogeneity of treatment effect in a clinical trial with the proportional interactions model.

    PubMed

    Kovalchik, Stephanie A; Varadhan, Ravi; Weiss, Carlos O

    2013-12-10

    Understanding how individuals vary in their response to treatment is an important task of clinical research. For standard regression models, a proportional interactions model first described by Follmann and Proschan (1999) offers a powerful approach for identifying effect modification in a randomized clinical trial when multiple variables influence treatment response. In this paper, we present a framework for using the proportional interactions model in the context of a parallel-arm clinical trial with multiple prespecified candidate effect modifiers. To protect against model misspecification, we propose a selection strategy that considers all possible proportional interactions models. We develop a modified Bonferroni correction for multiple testing that accounts for the positive correlation among candidate models. We describe methods for constructing a confidence interval for the proportionality parameter. In simulation studies, we show that our modified Bonferroni adjustment controls familywise error and has greater power to detect proportional interactions compared with multiplcity-corrected subgroup analyses. We demonstrate our methodology by using the Studies of Left Ventricular Dysfunction Treatment trial, a placebo-controlled randomized clinical trial of the efficacy of enalapril to reduce the risk of death or hospitalization in chronic heart failure patients. An R package called anoint is available for implementing the proportional interactions methodology.

  16. Regulation of COX-2 expression by miR-146a in lung cancer cells.

    PubMed

    Cornett, Ashley L; Lutz, Carol S

    2014-09-01

    Prostaglandins are a class of molecules that mediate cellular inflammatory responses and control cell growth. The oxidative conversion of arachidonic acid to prostaglandin H2 is carried out by two isozymes of cyclooxygenase, COX-1 and COX-2. COX-1 is constitutively expressed, while COX-2 can be transiently induced by external stimuli, such as pro-inflammatory cytokines. Interestingly, COX-2 is overexpressed in numerous cancers, including lung cancer. MicroRNAs (miRNAs) are small RNA molecules that function to regulate gene expression. Previous studies have implicated an important role for miRNAs in human cancer. We demonstrate here that miR-146a expression levels are significantly lower in lung cancer cells as compared with normal lung cells. Conversely, lung cancer cells have higher levels of COX-2 protein and mRNA expression. Introduction of miR-146a can specifically ablate COX-2 protein and the biological activity of COX-2 as measured by prostaglandin production. The regulation of COX-2 by miR-146a is mediated through a single miRNA-binding site present in the 3' UTR. Therefore, we propose that decreased miR-146a expression contributes to the up-regulation and overexpression of COX-2 in lung cancer cells. Since potential miRNA-mediated regulation is a functional consequence of alternative polyadenylation site choice, understanding the molecular mechanisms that regulate COX-2 mRNA alternative polyadenylation and miRNA targeting will give us key insights into how COX-2 expression is involved in the development of a metastatic condition.

  17. Psychological Adjustment and Homosexuality.

    ERIC Educational Resources Information Center

    Gonsiorek, John C.

    In this paper, the diverse literature bearing on the topic of homosexuality and psychological adjustment is critically reviewed and synthesized. The first chapter discusses the most crucial methodological issue in this area, the problem of sampling. The kinds of samples used to date are critically examined, and some suggestions for improved…

  18. Self Adjusting Sunglasses

    NASA Technical Reports Server (NTRS)

    1986-01-01

    Corning Glass Works' Serengeti Driver sunglasses are unique in that their lenses self-adjust and filter light while suppressing glare. They eliminate more than 99% of the ultraviolet rays in sunlight. The frames are based on the NASA Anthropometric Source Book.

  19. Self adjusting inclinometer

    DOEpatents

    Hunter, Steven L.

    2002-01-01

    An inclinometer utilizing synchronous demodulation for high resolution and electronic offset adjustment provides a wide dynamic range without any moving components. A device encompassing a tiltmeter and accompanying electronic circuitry provides quasi-leveled tilt sensors that detect highly resolved tilt change without signal saturation.

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

    SciTech Connect

    Pachkoria, Ketevan; Zhang Hong; Adell, Gunnar; Jarlsfelt, Ingvar; Sun Xiaofeng . E-mail: xiao-feng.sun@ibk.liu.se

    2005-11-01

    Purpose: Radiotherapy has reduced local recurrence of rectal cancers, but the result is not satisfactory. Further biologic factors are needed to identify patients for more effective radiotherapy. Our aims were to investigate the relationship of cyclooxygenase-2 (Cox-2) expression to radiotherapy, and clinicopathologic/biologic variables in rectal cancers with or without radiotherapy. Methods and Materials: Cox-2 expression was immunohistochemically examined in distal normal mucosa (n = 28), in adjacent normal mucosa (n = 107), in primary cancer (n = 138), lymph node metastasis (n = 30), and biopsy (n = 85). The patients participated in a rectal cancer trial of preoperative radiotherapy. Results: Cox-2 expression was increased in primary tumor compared with normal mucosa (p < 0.0001), but there was no significant change between primary tumor and metastasis. Cox-2 positivity was or tended to be related to more p53 and Ki-67 expression, and less apoptosis (p {<=} 0.05). In Cox-2-negative cases of either biopsy (p = 0.01) or surgical samples (p = 0.02), radiotherapy was related to less frequency of local recurrence, but this was not the case in Cox-2-positive cases. Conclusion: Cox-2 expression seemed to be an early event involved in rectal cancer development. Radiotherapy might reduce a rate of local recurrence in the patients with Cox-2 weakly stained tumors, but not in those with Cox-2 strongly stained tumors.

  1. Structural insight into DNA binding and oligomerization of the multifunctional Cox protein of bacteriophage P2.

    PubMed

    Berntsson, Ronnie P-A; Odegrip, Richard; Sehlén, Wilhelmina; Skaar, Karin; Svensson, Linda M; Massad, Tariq; Högbom, Martin; Haggård-Ljungquist, Elisabeth; Stenmark, Pål

    2014-02-01

    The Cox protein from bacteriophage P2 is a small multifunctional DNA-binding protein. It is involved in site-specific recombination leading to P2 prophage excision and functions as a transcriptional repressor of the P2 Pc promoter. Furthermore, it transcriptionally activates the unrelated, defective prophage P4 that depends on phage P2 late gene products for lytic growth. In this article, we have investigated the structural determinants to understand how P2 Cox performs these different functions. We have solved the structure of P2 Cox to 2.4 Å resolution. Interestingly, P2 Cox crystallized in a continuous oligomeric spiral with its DNA-binding helix and wing positioned outwards. The extended C-terminal part of P2 Cox is largely responsible for the oligomerization in the structure. The spacing between the repeating DNA-binding elements along the helical P2 Cox filament is consistent with DNA binding along the filament. Functional analyses of alanine mutants in P2 Cox argue for the importance of key residues for protein function. We here present the first structure from the Cox protein family and, together with previous biochemical observations, propose that P2 Cox achieves its various functions by specific binding of DNA while wrapping the DNA around its helical oligomer.

  2. Alteration of femoral bone morphology and density in COX-2-/- mice.

    PubMed

    Robertson, Galen; Xie, Chao; Chen, Di; Awad, Hani; Schwarz, Edward M; O'Keefe, Regis J; Guldberg, Robert E; Zhang, Xinping

    2006-10-01

    A role of COX-2 in pathological bone destruction and fracture repair has been established; however, few studies have been conducted to examine the involvement of COX-2 in maintaining bone mineral density and bone micro-architecture. In this study, we examined bone morphology in multiple trabecular and cortical regions within the distal and diaphyseal femur of 4-month-old wild-type and COX-2-/- mice using micro-computed tomography. Our results demonstrated that while COX-2-/- female mice had normal bone geometry and trabecular microarchitecture at 4 months of age, the male knockout mice displayed reduced bone volume fraction within the distal femoral metaphysis. Furthermore, male COX-2-/- mice had a significant reduction in cortical bone mineral density within the central cortical diaphysis and distal epiphysis and metaphysis. Consistent with the observed reduction in cortical mineral density, biomechanical testing via 4-point-bending showed that male COX-2-/- mice had a significant increase in postyield deformation, indicating a ductile bone phenotype in male COX-2-/- mice. In conclusion, our study suggests that genetic ablation of COX-2 may have a sex-related effect on cortical bone homeostasis and COX-2 plays a role in maintaining normal bone micro-architecture and density in mice.

  3. Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships

    PubMed Central

    Zarghi, Afshin; Arfaei, Sara

    2011-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the bioconversion of arachidonic acid to inflammatory prostaglandins (PGs). Their use is associated with the side effects such as gastrointestinal and renal toxicity. The therapeutic anti-inflammatory action of NSAIDs is produced by the inhibition of COX-2, while the undesired side effects arise from inhibition of COX-1 activity. Thus, it was though that more selective COX-2 inhibitors would have reduced side effects. Based upon a number of selective COX-2 inhibitors (rofecoxib, celecoxib, valdecoxibetc.) were developed as safer NSAIDs with improved gastric safety profile. However, the recent market removal of some COXIBs such as rofecoxib due to its adverse cardiovascular side effects clearly encourages the researchers to explore and evaluate alternative templates with COX-2 inhibitory activity. Recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Parkinson and Alzheimer’s diseases still continues to attract investigations on the development of COX-2 inhibitors. This review highlights the various structural classes of selective COX-2 inhibitors with special emphasis on their structure-activity relationships. PMID:24250402

  4. Alteration of femoral bone morphology and density in COX-2−/− mice

    PubMed Central

    Robertson, Galen; Xie, Chao; Chen, Di; Awad, Hani; Schwarz, Edward M.; O’Keefe, Regis J.; Guldberg, Robert E.; Zhang, Xinping

    2009-01-01

    A role of COX-2 in pathological bone destruction and fracture repair has been established; however, few studies have been conducted to examine the involvement of COX-2 in maintaining bone mineral density and bone micro-architecture. In this study, we examined bone morphology in multiple trabecular and cortical regions within the distal and diaphyseal femur of 4-month-old wild-type and COX-2−/− mice using micro-computed tomography. Our results demonstrated that while COX-2−/− female mice had normal bone geometry and trabecular microarchitecture at 4 months of age, the male knockout mice displayed reduced bone volume fraction within the distal femoral metaphysis. Furthermore, male COX-2−/− mice had a significant reduction in cortical bone mineral density within the central cortical diaphysis and distal epiphysis and metaphysis. Consistent with the observed reduction in cortical mineral density, biomechanical testing via 4-point-bending showed that male COX-2−/− mice had a significant increase in postyield deformation, indicating a ductile bone phenotype in male COX-2−/− mice. In conclusion, our study suggests that genetic ablation of COX-2 may have a sex-related effect on cortical bone homeostasis and COX-2 plays a role in maintaining normal bone micro-architecture and density in mice. PMID:16731065

  5. COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells.

    PubMed

    Ramer, Robert; Heinemann, Katharina; Merkord, Jutta; Rohde, Helga; Salamon, Achim; Linnebacher, Michael; Hinz, Burkhard

    2013-01-01

    The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-γ in cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-γ mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD(2) and 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) caused a translocation of PPAR-γ to the nucleus and induced a PPAR-γ-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-γ in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-γ and a subsequent nuclear translocation of PPAR-γ by COX-2-dependent PGs.

  6. Electron doping evolution of the neutron spin resonance in NaFe1-xCoxAs

    DOE PAGES

    Zhang, Chenglin; Song, Yu; Carr, Scott Victor; ...

    2016-05-31

    Neutron spin resonance, a collective magnetic excitation coupled to superconductivity, is one of the most prominent features shared by a broad family of unconventional superconductors including copper oxides, iron pnictides, and heavy fermions. In this paper, we study the doping evolution of the resonances in NaFe1–xCoxAs covering the entire superconducting dome. For the underdoped compositions, two resonance modes coexist. As doping increases, the low-energy resonance gradually loses its spectral weight to the high-energy one but remains at the same energy. By contrast, in the overdoped regime we only find one single resonance, which acquires a broader width in both energymore » and momentum but retains approximately the same peak position even when Tc drops by nearly a half compared to optimal doping. Furthermore, these results suggest that the energy of the resonance in electron overdoped NaFe1–xCoxAs is neither simply proportional to Tc nor the superconducting gap but is controlled by the multiorbital character of the system and doped impurity scattering effect.« less

  7. Electron doping evolution of the neutron spin resonance in NaFe1 -xCoxAs

    NASA Astrophysics Data System (ADS)

    Zhang, Chenglin; Lv, Weicheng; Tan, Guotai; Song, Yu; Carr, Scott V.; Chi, Songxue; Matsuda, M.; Christianson, A. D.; Fernandez-Baca, J. A.; Harriger, L. W.; Dai, Pengcheng

    2016-05-01

    Neutron spin resonance, a collective magnetic excitation coupled to superconductivity, is one of the most prominent features shared by a broad family of unconventional superconductors including copper oxides, iron pnictides, and heavy fermions. In this paper, we study the doping evolution of the resonances in NaFe1 -xCoxAs covering the entire superconducting dome. For the underdoped compositions, two resonance modes coexist. As doping increases, the low-energy resonance gradually loses its spectral weight to the high-energy one but remains at the same energy. By contrast, in the overdoped regime we only find one single resonance, which acquires a broader width in both energy and momentum but retains approximately the same peak position even when Tc drops by nearly a half compared to optimal doping. These results suggest that the energy of the resonance in electron overdoped NaFe1 -xCoxAs is neither simply proportional to Tc nor the superconducting gap but is controlled by the multiorbital character of the system and doped impurity scattering effect.

  8. Dual functions of Mss51 couple synthesis of Cox1 to assembly of cytochrome c oxidase in Saccharomyces cerevisiae mitochondria.

    PubMed

    Perez-Martinez, Xochitl; Butler, Christine A; Shingu-Vazquez, Miguel; Fox, Thomas D

    2009-10-01

    Functional interactions of the translational activator Mss51 with both the mitochondrially encoded COX1 mRNA 5'-untranslated region and with newly synthesized unassembled Cox1 protein suggest that it has a key role in coupling Cox1 synthesis with assembly of cytochrome c oxidase. Mss51 is present at levels that are near rate limiting for expression of a reporter gene inserted at COX1 in mitochondrial DNA, and a substantial fraction of Mss51 is associated with Cox1 protein in assembly intermediates. Thus, sequestration of Mss51 in assembly intermediates could limit Cox1 synthesis in wild type, and account for the reduced Cox1 synthesis caused by most yeast mutations that block assembly. Mss51 does not stably interact with newly synthesized Cox1 in a mutant lacking Cox14, suggesting that the failure of nuclear cox14 mutants to decrease Cox1 synthesis, despite their inability to assemble cytochrome c oxidase, is due to a failure to sequester Mss51. The physical interaction between Mss51 and Cox14 is dependent upon Cox1 synthesis, indicating dynamic assembly of early cytochrome c oxidase intermediates nucleated by Cox1. Regulation of COX1 mRNA translation by Mss51 seems to be an example of a homeostatic mechanism in which a positive effector of gene expression interacts with the product it regulates in a posttranslational assembly process.

  9. Network Meta-Analysis Comparing Relatively Selective COX-2 Inhibitors Versus Coxibs for the Prevention of NSAID-Induced Gastrointestinal Injury

    PubMed Central

    Yang, Man; Wang, Hong-Tao; Zhao, Miao; Meng, Wen-Bo; Ou, Jin-Qing; He, Jun-Hui; Zou, Bing; Lei, Ping-Guang

    2015-01-01

    Abstract Currently 2 difference classes of cyclooxygenase (COX)-2 inhibitors, coxibs and relatively selective COX-2 inhibitors, are available for patients requiring nonsteroidal anti-inflammatory drug (NSAID) therapy; their gastroprotective effect is hardly directly compared. The aim of this study was to compare the gastroprotective effect of relatively selective COX-2 inhibitors with coxibs. MEDLINE, EMBASE, and the Cochrane Library (from their inception to March 2015) were searched for potential eligible studies. We included randomized controlled trials comparing coxibs (celecoxib, etoricoxib, parecoxib, and lumiracoxib), relatively selective COX-2 inhibitors (nabumetone, meloxicam, and etodolac), and nonselective NSAIDs with a study duration ≥4 weeks. Comparative effectiveness and safety data were pooled by Bayesian network meta-analysis. The primary outcomes were ulcer complications and symptomatic ulcer. Summary effect-size was calculated as risk ratio (RR), together with the 95% confidence interval (CI). This study included 36 trials with a total of 112,351 participants. Network meta-analyses indicated no significant difference between relatively selective COX-2 inhibitors and coxibs regarding ulcer complications (RR, 1.38; 95% CI, 0.47–3.27), symptomatic ulcer (RR, 1.02; 95% CI, 0.09–3.92), and endoscopic ulcer (RR, 1.18; 95% CI, 0.37–2.96). Network meta-analyses adjusting potential influential factors (age, sex, previous ulcer disease, and follow-up time), and sensitivity analyses did not reveal any major change to the main results. Network meta-analyses suggested that relatively selective COX-2 inhibitors and coxibs were associated with comparable incidences of total adverse events (AEs) (RR, 1.09; 95% CI, 0.93–1.31), gastrointestinal AEs (RR, 1.04; 95% CI, 0.87–1.25), total withdrawals (RR, 1.00; 95% CI, 0.74–1.33), and gastrointestinal AE-related withdrawals (RR, 1.02; 95% CI, 0.57–1.74). Relatively selective COX-2 inhibitors appear to be

  10. Genomic, Lipidomic and Metabolomic Analysis of Cyclooxygenase-null Cells: Eicosanoid Storm, Cross Talk, and Compensation by COX-1.

    PubMed

    Islam, Abul B M M K; Dave, Mandar; Amin, Sonia; Jensen, Roderick V; Amin, Ashok R

    2016-04-01

    The constitutively-expressed cyclooxygenase 1 (COX-1) and the inducible COX-2 are both involved in the conversion of arachidonic acid (AA) to prostaglandins (PGs). However, the functional roles of COX-1 at the cellular level remain unclear. We hypothesized that by comparing differential gene expression and eicosanoid metabolism in lung fibroblasts from wild-type (WT) mice and COX-2(-/-) or COX-1(-/-) mice may help address the functional roles of COX-1 in inflammation and other cellular functions. Compared to WT, the number of specifically-induced transcripts were altered descendingly as follows: COX-2(-/-)>COX-1(-/-)>WT+IL-1β. COX-1(-/-) or COX-2(-/-) cells shared about 50% of the induced transcripts with WT cells treated with IL-1β, respectively. An interactive "anti-inflammatory, proinflammatory, and redox-activated" signature in the protein-protein interactome map was observed in COX-2(-/-) cells. The augmented COX-1 mRNA (in COX-2(-/-) cells) was associated with the upregulation of mRNAs for glutathione S-transferase (GST), superoxide dismutase (SOD), NAD(P)H dehydrogenase quinone 1 (NQO1), aryl hydrocarbon receptor (AhR), peroxiredoxin, phospholipase, prostacyclin synthase, and prostaglandin E synthase, resulting in a significant increase in the levels of PGE2, PGD2, leukotriene B4 (LTB4), PGF1α, thromboxane B2 (TXB2), and PGF2α. The COX-1 plays a dominant role in shifting AA toward the LTB4 pathway and anti-inflammatory activities. Compared to WT, the upregulated COX-1 mRNA in COX-2(-/-) cells generated an "eicosanoid storm". The genomic characteristics of COX-2(-/-) is similar to that of proinflammatory cells as observed in IL-1β induced WT cells. COX-1(-/-) and COX-2(-/-) cells exhibited compensation of various eicosanoids at the genomic and metabolic levels.

  11. Allelic variation in the canine Cox-2 promoter causes hypermethylation of the canine Cox-2 promoter in clinical cases of renal dysplasia

    PubMed Central

    2014-01-01

    Background Novel allelic variants in the promoter of the canine cyclooxygenase-2 (Cox-2) gene are associated with renal dysplasia (RD). These variants consist of either deletions of putative SP1 transcription factor-binding sites or insertions of tandem repeats of SP1-binding sites located in the CpG island just upstream of the ATG translation initiation site. The canine Cox-2 gene was studied because Cox-2-deficient mice have renal abnormalities and a pathology that is strikingly similar to RD in dogs. Findings The allelic variants were associated with hypermethylation of the Cox-2 promoter only in clinical cases of RD. The wild-type allele was never methylated, even in clinical cases that were heterozygous for a mutant allele. In cases that were biopsy-negative, the promoter remained unmethylated, regardless of the genotype. Methylated DNA was found in DNA from various adult tissues of dogs with clinical RD. Conclusions The mechanism of action of the allelic variation in the canine Cox-2 promoter most likely involves variation in the extent of epigenetic downregulation of this gene. This epigenetic downregulation must have occurred early in development because methylated Cox-2 promoter DNA sequences are found in various adult tissues. PMID:24708682

  12. Mathematically modelling proportions of Japanese populations by industry

    NASA Astrophysics Data System (ADS)

    Hirata, Yoshito

    2016-10-01

    I propose a mathematical model for temporal changes of proportions for industrial sectors. I prove that the model keeps the proportions for the primary, the secondary, and the tertiary sectors between 0 and 100% and preserves their total as 100%. The model fits the Japanese historical data between 1950 and 2005 for the population proportions by industry very well. The model also predicts that the proportion for the secondary industry becomes negligible and becomes less than 1% at least around 2080.

  13. Adjustable Autonomy Testbed

    NASA Technical Reports Server (NTRS)

    Malin, Jane T.; Schrenkenghost, Debra K.

    2001-01-01

    The Adjustable Autonomy Testbed (AAT) is a simulation-based testbed located in the Intelligent Systems Laboratory in the Automation, Robotics and Simulation Division at NASA Johnson Space Center. The purpose of the testbed is to support evaluation and validation of prototypes of adjustable autonomous agent software for control and fault management for complex systems. The AA T project has developed prototype adjustable autonomous agent software and human interfaces for cooperative fault management. This software builds on current autonomous agent technology by altering the architecture, components and interfaces for effective teamwork between autonomous systems and human experts. Autonomous agents include a planner, flexible executive, low level control and deductive model-based fault isolation. Adjustable autonomy is intended to increase the flexibility and effectiveness of fault management with an autonomous system. The test domain for this work is control of advanced life support systems for habitats for planetary exploration. The CONFIG hybrid discrete event simulation environment provides flexible and dynamically reconfigurable models of the behavior of components and fluids in the life support systems. Both discrete event and continuous (discrete time) simulation are supported, and flows and pressures are computed globally. This provides fast dynamic simulations of interacting hardware systems in closed loops that can be reconfigured during operations scenarios, producing complex cascading effects of operations and failures. Current object-oriented model libraries support modeling of fluid systems, and models have been developed of physico-chemical and biological subsystems for processing advanced life support gases. In FY01, water recovery system models will be developed.

  14. Precision adjustable stage

    DOEpatents

    Cutburth, Ronald W.; Silva, Leonard L.

    1988-01-01

    An improved mounting stage of the type used for the detection of laser beams is disclosed. A stage center block is mounted on each of two opposite sides by a pair of spaced ball bearing tracks which provide stability as well as simplicity. The use of the spaced ball bearing pairs in conjunction with an adjustment screw which also provides support eliminates extraneous stabilization components and permits maximization of the area of the center block laser transmission hole.

  15. Proportion in Middle-School Mathematics: It's Everywhere

    ERIC Educational Resources Information Center

    Shield, Mal; Dole, Shelley

    2008-01-01

    Proportional thinking is the mathematical basis of a wide range of topics in the middle-school mathematics curriculum. While the concept is obvious in the traditionally-named ratio and proportion sections, proportional thinking is also the key to such diverse topics as rate, gradient of a linear function, similarity, trigonometry and percentage,…

  16. Spatial Proportional Reasoning Is Associated with Formal Knowledge about Fractions

    ERIC Educational Resources Information Center

    Möhring, Wenke; Newcombe, Nora S.; Levine, Susan C.; Frick, Andrea

    2016-01-01

    Proportional reasoning involves thinking about parts and wholes (i.e., about fractional quantities). Yet, research on proportional reasoning and fraction learning has proceeded separately. This study assessed proportional reasoning and formal fraction knowledge in 8- to 10-year-olds. Participants (N = 52) saw combinations of cherry juice and water…

  17. Evaluation of facial divine proportion in North Indian Population

    PubMed Central

    Khan, Naseem Ahmad; Nagar, Amit; Tandon, Pradeep; Singh, Gulshan Kumar; Singh, Alka

    2016-01-01

    Objective: To evaluate the facial divine proportion and its relationship with facial attractiveness in North Indian population. Materials and Methods: For evaluation of various facial proportions, standardized frontal facial photographs of total 300 subjects between 18 and 30 years of age were obtained. Black and white copies of these photographs were presented in front of an evaluation jury for assigning scores of facial attractiveness and finally 130 attractive subjects were selected. These subjects were divided into two groups, Group I (attractive females n = 65) and Group II (attractive males n = 65) and they were further analyzed for various parameters of facial proportions. Unpaired Student's t-test was used to compare both groups. Results: Group I showed that five of seven vertical facial proportions were close to divine proportion (1.618) whereas only two vertical proportions in Group II were close to it. Transverse facial proportions in both groups deviated more from divine proportion (1.618) and were closer to silver proportion (1.414). Conclusions: Most of the facial proportions of attractive females in the North-Indian population were close to the divine proportion. Thus, facial divine proportion could be an important factor in the perception of facial attractiveness of North-Indian attractive females. PMID:27630502

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2013-01-01

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

  20. New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis.

    PubMed

    Hugo, Honor J; Saunders, C; Ramsay, R G; Thompson, E W

    2015-12-01

    The medicinal use of aspirin stretches back to ancient times, before it was manufactured in its pure form in the late 19th century. Its accepted mechanistic target, cyclooxygenase (COX), was discovered in the 1970s and since this landmark discovery, the therapeutic application of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has increased dramatically. The most significant benefits of NSAIDs are in conditions involving chronic inflammation (CI). Given the recognized role of CI in cancer development, the use of long-term NSAID treatment in the prevention of cancer is an enticing possibility. COX-2 is a key driver of CI, and here we review COX-2 expression as a predictor of survival in various cancer types, including breast. Obesity and post-partum involution are natural inflammatory states that are associated with increased breast cancer risk. We outline the COX-2 mediated mechanisms contributing to the growth of cancers. We dissect the cellular mechanism of epithelial-mesenchymal transition (EMT) and how COX-2 may induce this to facilitate tumor progression. Finally we examine the potential regulation of COX-2 by c-Myb, and the possible interplay between c-Myb/COX-2 in proliferation, and hypoxia inducible factor-1 alpha (HIF1α)/COX-2 in invasive pathways in breast cancer.

  1. Immunohistochemical detection of COX-2 in feline and canine actinic keratoses and cutaneous squamous cell carcinoma.

    PubMed

    Bardagí, M; Fondevila, D; Ferrer, L

    2012-01-01

    Cyclooxygenase-2 (COX-2) overexpression and its causal role in epidermal carcinogenesis have been demonstrated in human actinic keratoses (AK) and cutaneous squamous cell carcinoma (SCC). The aim of this study was to determine immunohistochemically the level of expression of COX-2 in feline and canine AK (n=18), SCC (n=36) and inflammatory dermatoses (n=24). COX-2 immunoreactivity was detected in all feline and canine SCC. In all specimens, labelled basal and suprabasal neoplastic keratinocytes were localized within and below areas of superficial erosion or ulceration and only scattered deeper tumour cells were positively labelled. In most cases, positive immunoreactivity of keratinocytes was associated with the presence of granulocytes. COX-2 expression was detected in 3/9 canine and 4/9 feline cases of AK and in only one case was associated with inflammation. Inflammatory dermatoses were characterized by positively labelled epidermal and follicular basal and suprabasal keratinocytes that were always associated with granulocyte exocytosis. These results indicate that further study of the effect of using COX-2 inhibitors in the management and prevention of feline and canine cutaneous SCC is warranted. The association between inflammatory cells and COX-2 expressing epidermal cells opens a new line of research regarding the role of COX-2 in SCC oncogenesis. Moreover, further studies should investigate the role of COX-2 in the pathogenesis and management of AK in animals.

  2. 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…

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

    PubMed Central

    2013-01-01

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

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

    PubMed

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

    2013-05-09

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

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

    PubMed Central

    Yan, Jun; Huang, Jian

    2011-01-01

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

  6. 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.

  7. As-built design specification for proportion estimate software subsystem

    NASA Technical Reports Server (NTRS)

    Obrien, S. (Principal Investigator)

    1980-01-01

    The Proportion Estimate Processor evaluates four estimation techniques in order to get an improved estimate of the proportion of a scene that is planted in a selected crop. The four techniques to be evaluated were provided by the techniques development section and are: (1) random sampling; (2) proportional allocation, relative count estimate; (3) proportional allocation, Bayesian estimate; and (4) sequential Bayesian allocation. The user is given two options for computation of the estimated mean square error. These are referred to as the cluster calculation option and the segment calculation option. The software for the Proportion Estimate Processor is operational on the IBM 3031 computer.

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

    PubMed

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

    2016-04-01

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

  9. IL-20, an anti-angiogenic cytokine that inhibits COX-2 expression.

    PubMed

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

    2005-07-29

    COX-2 overexpression and subsequent PGE(2) production are frequently associated with non-small cell lung cancer and are implicated in tumor-mediated angiogenesis. Here, we report for the first time that IL-20 downregulates COX-2 and PGE(2) in human bronchial epithelial and endothelial cells. Flow cytometry analysis suggests that IL-20-dependent inhibition of COX-2/PGE(2) occurs through the IL-22R1/IL-20R2 dimers. In addition, we report that IL-20 exerts anti-angiogenic effects, inhibiting experimental angiogenesis. IL-20-mediated inhibition of PMA-induced angiogenesis occurs through the COX-2 regulatory pathway. Altogether our findings revealed that IL-20 is a negative modulator of COX-2/PGE(2) and inhibits angiogenesis.

  10. Students' Understanding of Proportional, Inverse Proportional, and Affine Functions: Two Studies on the Role of External Representations

    ERIC Educational Resources Information Center

    De Bock, Dirk; Van Dooren, Wim; Verschaffel, Lieven

    2015-01-01

    We investigated students' understanding of proportional, inverse proportional, and affine functions and the way this understanding is affected by various external representations. In a first study, we focus on students' ability to model textual descriptions of situations with different kinds of representations of proportional, inverse…

  11. Estimating sighting proportions of American alligator nests during helicopter survey

    USGS Publications Warehouse

    Rice, Kenneth G.; Percival, H. Franklin; Woodward, Allan R.

    2000-01-01

    Proportions of American alligator (Alligator mississippiensis) nests sighted during aerial survey in Florida were estimated based upon multiple surveys by different observers. We compared sighting proportions across habitats, nesting seasons, and observer experience levels. The mean sighting proportion across all habitats and years was 0.736 (SE=0.024). Survey counts corrected by the mean sighting proportion reliably predicted total nest counts (7?2=0.933). Sighting proportions did not differ by habitat type (P=0.668) or year P=0.328). Experienced observers detected a greater proportion of nests (P<0.0001) than did either less experienced or inexperienced observers. Reliable estimates of nest abundance can be derived from aerial counts of alligator nests when corrected by the appropriate sighting proportion.

  12. Sensitivity of health risk estimates to air quality adjustment procedure

    SciTech Connect

    Whitfield, R.G.

    1997-06-30

    This letter is a summary of risk results associated with exposure estimates using two-parameter Weibull and quadratic air quality adjustment procedures (AQAPs). New exposure estimates were developed for children and child-occurrences, six urban areas, and five alternative air quality scenarios. In all cases, the Weibull and quadratic results are compared to previous results, which are based on a proportional AQAP.

  13. Preconditioning stress prevents cold restraint stress-induced gastric lesions in rats: roles of COX-1, COX-2, and PLA2.

    PubMed

    Tanaka, Akiko; Hatazawa, Ryo; Takahira, Yuka; Izumi, Nahoko; Filaretova, Ludmila; Takeuchi, Koji

    2007-02-01

    We investigated the protective effect of mild stress on gastric lesions induced by cold-restraint stress, especially concerning prostaglandins (PGs)/cyclo-oxygenase (COX) isozymes. Rats were exposed to severe stress (cold-restraint stress at 10 degrees C for 6 hr) or mild stress (cold-restraint stress at 10 degrees C for 30 min and kept at room temperature for 60 min) followed by severe stress. Severe stress induced gastric lesions, with a concomitant decrease in body temperature (BT). The ulcerogenic response was inhibited by atropine but worsened by indomethacin and SC-560 but not rofecoxib, although none of these agents had any effect on the change in BT. Mild stress suppressed the gastric ulceration and the decrease in BT induced by severe stress, and these effects were reversed by both COX-1 and COX-2 inhibitors. The expression of COX-2 in the stomach was up-regulated from 4 hr after severe stress and this response was slightly expedited by mild stress. COX-2 was also expressed in the hypothalamus under normal and stressed conditions. Quinacrine (phospholipase A(2) inhibitor) attenuated the protective effect of mild stress on the ulceration and decrease in BT caused by severe stress. TA-0910 (TRH analogue) at a low dose also prevented the gastric ulceration and the decrease in BT induced by severe stress. These results suggest that mild stress protects against cold-restraint stress-induced gastric ulceration, and the effect is peripherally and centrally mediated by PGs derived from both COX-1 and COX-2 through the activation of phospholipase A(2). TRH may also be involved in the protective effect of mild stress, probably through regulation of the thermogenic system.

  14. Predictors of Venous Thromboembolism Recurrence, Adjusted for Treatments and Interim Exposures: A Population-based Case-cohort Study

    PubMed Central

    Heit, John A.; Lahr, Brian D.; Ashrani, Aneel A.; Petterson, Tanya M.; Bailey, Kent R.

    2015-01-01

    Background Predictors of venous thromboembolism (VTE) recurrence are uncertain. Objective To identify predictors of VTE recurrence, adjusted for treatments and interim exposures. Materials and Methods Using Rochester Epidemiology Project resources, all Olmsted County, MN residents with objectively-diagnosed incident VTE over the 13-year period, 1988–2000, who survived ≥1 day were followed for first objectively-diagnosed VTE recurrence. For all patients with recurrence, and a random sample of all surviving incident VTE patients (n=415), we collected demographic and baseline characteristics, treatments and interim exposures. In a case-cohort study design, demographic, baseline, treatment and interim exposure characteristics were tested as potential predictors of VTE recurrence using time-dependent Cox proportional hazards modeling. Results Among 1262 incident VTE patients, 306 developed recurrence over 6,440 person-years. Five-year recurrence rates, overall and for cancer-associated, idiopathic and non-cancer secondary VTE, were 24.5%, 43.4%, 27.3% and 18.1%, respectively. In multivariable analysis, interim hospitalization, active cancer, pregnancy, central venous catheter and respiratory infection were associated with increased hazards of recurrence, and warfarin and aspirin were associated with reduced hazards. Adjusting for treatments and these interim risk factors, male sex, baseline active cancer and failure to achieve a therapeutic aPTT in the first 24 hours were independently associated with increased hazards of VTE recurrence over the entire follow-up period, while the hazards of recurrence for patient age, chronic lung disease, leg paresis, prior superficial vein thrombosis and idiopathic VTE varied over the follow-up period. Conclusions Baseline and interim exposures can stratify VTE recurrence risk and may be useful for directing secondary prophylaxis. PMID:26143712

  15. Adjustable Reeds For Weaving

    NASA Technical Reports Server (NTRS)

    Farley, Gary L.

    1994-01-01

    Local characteristics of fabrics varied to suit special applications. Adjustable reed machinery proposed for use in weaving fabrics in various net shapes, widths, yarn spacings, and yarn angles. Locations of edges of fabric and configuration of warp and filling yarns varied along fabric to obtain specified properties. In machinery, reed wires mounted in groups on sliders, mounted on lengthwise rails in reed frame. Mechanisms incorporated to move sliders lengthwise, parallel to warp yarns, by sliding them along rails; move sliders crosswise by translating reed frame rails perpendicular to warp yarns; and crosswise by spreading reed rails within group. Profile of reed wires in group on each slider changed.

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

    PubMed

    McCarty, Mark F

    2012-01-01

    A recent meta-analysis examining long-term mortality in subjects who participated in controlled studies evaluating the impact of daily aspirin on vascular risk, has concluded that aspirin confers substantial protection from cancer mortality. Remarkably, low-dose aspirin was as effective as higher-dose regimens; hence this protection may be achievable with minimal risk. There is reason to believe that this protection stems primarily from inhibition of cox-2 in pre-neoplastic lesions. Since safe aspirin regimens can only achieve a partial and transitory inhibition of cox-2, it may be feasible to complement the cancer-protective benefit of aspirin with other measures which decrease cox-2 expression or which limit the bioactivity of cox-2-derived PGE2. Oxidative stress boosts cox-2 expression by up-regulating activation of NF-kappaB and MAP kinases; NADPH oxidase activation may thus promote carcinogenesis by increasing cox-2 expression while also amplifying oxidant-mediated mutagenesis. A prospective cohort study has observed that relatively elevated serum bilirubin levels are associated with a marked reduction in subsequent cancer mortality; this may reflect bilirubin's physiological role as a potent inhibitor of NADPH oxidase. It may be feasible to mimic this protective effect by supplementing with spirulina, a rich source of a phycobilin which shares bilirubin's ability to inhibit NADPH oxidase. Ancillary antioxidant measures - phase 2 inducing phytochemicals, melatonin, N-acetylcysteine, and astaxanthin - may also aid cox-2 down-regulation. The cancer protection often associated with high-normal vitamin D status may be attributable, in part, to the ability of the activated vitamin D receptor to decrease cox-2 expression while promoting PGE2 catabolism and suppressing the expression of PGE2 receptors. Diets with a relatively low ratio of omega-6 to long-chain omega-3 fats may achieve cancer protection by antagonizing the production and bioactivity of PGE2. Growth

  17. Continuously adjustable Pulfrich spectacles

    NASA Astrophysics Data System (ADS)

    Jacobs, Ken; Karpf, Ron

    2011-03-01

    A number of Pulfrich 3-D movies and TV shows have been produced, but the standard implementation has inherent drawbacks. The movie and TV industries have correctly concluded that the standard Pulfrich 3-D implementation is not a useful 3-D technique. Continuously Adjustable Pulfrich Spectacles (CAPS) is a new implementation of the Pulfrich effect that allows any scene containing movement in a standard 2-D movie, which are most scenes, to be optionally viewed in 3-D using inexpensive viewing specs. Recent scientific results in the fields of human perception, optoelectronics, video compression and video format conversion are translated into a new implementation of Pulfrich 3- D. CAPS uses these results to continuously adjust to the movie so that the viewing spectacles always conform to the optical density that optimizes the Pulfrich stereoscopic illusion. CAPS instantly provides 3-D immersion to any moving scene in any 2-D movie. Without the glasses, the movie will appear as a normal 2-D image. CAPS work on any viewing device, and with any distribution medium. CAPS is appropriate for viewing Internet streamed movies in 3-D.

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

    PubMed Central

    Knox, Alan J.

    2015-01-01

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

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

    PubMed

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

    2016-10-01

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

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

    PubMed

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

    2013-09-01

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

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

    SciTech Connect

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

    2006-02-01

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

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

    SciTech Connect

    Meng, Zhen; Gan, Ye-Hua

    2015-05-01

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

  3. Demethoxycurcumin Preserves Renovascular Function by Downregulating COX-2 Expression in Hypertension

    PubMed Central

    2016-01-01

    Hypertension-associated endothelial dysfunction is largely due to the exaggerated vasoconstrictor generation by cyclooxygenase-2 (COX-2). COX-2 is induced under inflammatory condition. Demethoxycurcumin (DMC) is a major component of Curcuma longa L, which possesses anti-inflammatory action. This study aimed to examine whether DMC protects endothelial function in hypertension by modulating COX-2. Changes in isometric tension showed that in vivo and ex vivo treatment with DMC rescued the attenuated endothelium-dependent relaxations (EDRs) and elevated endothelium-dependent contractions (EDCs) in the renal arteries of SHR, which were also corrected by acute usage of the COX-2 inhibitor celecoxib. The restoration of renovascular activity by DMC was accompanied by the normalization of COX-2 expression. The enhanced COX-2 expression observed in the renal arteries of hypertensive patients was suppressed by incubation of excised arteries with DMC for 12 hrs. In the renal arteries of Wistar-Kyoto rats (WKY), DMC prevented the endothelial dysfunction caused by angiotensin II. The reduction in the generation of nitric oxide (NO) and expression of eNOS phosphorylation (Ser1177) in human umbilical vein endothelial cells caused by angiotensin II (Ang II) were restored by DMC or celecoxib. Our findings suggest that DMC may decrease COX-2 expression and improve endothelial function in hypertension. PMID:28105253

  4. Activation of COX-2/PGE2 Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production.

    PubMed

    Alfajaro, Mia Madel; Choi, Jong-Soon; Kim, Deok-Song; Seo, Ja-Young; Kim, Ji-Yun; Park, Jun-Gyu; Soliman, Mahmoud; Baek, Yeong-Bin; Cho, Eun-Hyo; Kwon, Joseph; Kwon, Hyung-Jun; Park, Su-Jin; Lee, Woo Song; Kang, Mun-Il; Hosmillo, Myra; Goodfellow, Ian; Cho, Kyoung-Oh

    2017-02-01

    Enteric caliciviruses in the genera Norovirus and Sapovirus are important pathogens that cause severe acute gastroenteritis in both humans and animals. Cyclooxygenases (COXs) and their final product, prostaglandin E2 (PGE2), are known to play important roles in the modulation of both the host response to infection and the replicative cycles of several viruses. However, the precise mechanism(s) by which the COX/PGE2 pathway regulates sapovirus replication remains largely unknown. In this study, infection with porcine sapovirus (PSaV) strain Cowden, the only cultivable virus within the genus Sapovirus, markedly increased COX-2 mRNA and protein levels at 24 and 36 h postinfection (hpi), with only a transient increase in COX-1 levels seen at 24 hpi. The treatment of cells with pharmacological inhibitors, such as nonsteroidal anti-inflammatory drugs or small interfering RNAs (siRNAs) against COX-1 and COX-2, significantly reduced PGE2 production, as well as PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We observed that pharmacological inhibition of COX-2 dramatically increased NO production, causing a reduction in PSaV replication that could be restored by inhibition of nitric oxide synthase via the inhibitor N-nitro-l-methyl-arginine ester. This study identified a pivotal role for the COX/PGE2 pathway in the regulation of NO production during the sapovirus life cycle, providing new insights into the life cycle of this poorly characterized family of viruses. Our findings also reveal potential new targets for treatment of sapovirus infection.

  5. UVB Radiation-Induced β-catenin Signaling is Enhanced by COX-2 Expression in Keratinocytes

    PubMed Central

    Smith, Kimberly A.; Tong, Xin; Abu-Yousif, Adnan O.; Mikulec, Carol C.; Gottardi, Cara J.; Fischer, Susan M.; Pelling, Jill C.

    2014-01-01

    UVB radiation is the major carcinogen responsible for skin carcinogenesis, thus elucidation of the molecular pathways altered in skin in response to UVB would reveal novel targets for therapeutic intervention. It is well established that UVB leads to upregulation of cyclooxygenase 2 (COX-2) in the skin which contributes to skin carcinogenesis. Overexpression of COX-2 has been shown to promote colon cancer cell growth through β-catenin signaling, however, little is known about the connection between UVB, COX-2 and β-catenin in the skin. In the present study, we have identified a novel pathway in which UVB induces β-catenin signaling in keratinocytes, which is modulated by COX-2 expression. Exposure of the mouse 308 keratinocyte cell line (308 cells) and primary normal human epidermal keratinocytes (NHEKs) to UVB resulted in increased protein levels of both N-terminally unphosphorylated and total β-catenin. In addition, we found that UVB enhanced β-catenin-dependent TOPflash reporter activity and expression of a downstream β-catenin target gene. We demonstrated that UVB-induced β-catenin signaling is modulated by COX-2, as treatment of keratinocytes with the specific COX-2 inhibitor NS398 blocked UVB induction of β-catenin. Additionally, β-catenin target gene expression was reduced in UVB-treated COX-2 knockout (KO) MEFs compared to wild-type (WT) MEFs. Furthermore, epidermis from UVB-exposed SKH-1 mice exhibited increased N-terminally unphosphorylated and total β-catenin protein levels and increased staining for total β-catenin, and both responses were reduced in COX-2 heterozygous mice. Taken together, these results suggest a novel pathway in which UVB induces β-catenin signaling in keratinocytes which is enhanced by COX-2 expression. PMID:21853475

  6. Soman increases neuronal COX-2 levels: possible link between seizures and protracted neuronal damage.

    PubMed

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

    2010-12-01

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

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

    PubMed Central

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

    2010-01-01

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

  8. Air pollution and lymphocyte phenotype proportions in cord blood.

    PubMed

    Hertz-Picciotto, Irva; Herr, Caroline E W; Yap, Poh-Sin; Dostál, Miroslav; Shumway, Robert H; Ashwood, Paul; Lipsett, Michael; Joad, Jesse P; Pinkerton, Kent E; Srám, Radim J

    2005-10-01

    Effects of air pollution on morbidity and mortality may be mediated by alterations in immune competence. In this study we examined short-term associations of air pollution exposures with lymphocyte immunophenotypes in cord blood among 1,397 deliveries in two districts of the Czech Republic. We measured fine particulate matter < 2.5 microm in diameter (PM2.5) and 12 polycyclic aromatic hydrocarbons (PAHs) in 24-hr samples collected by versatile air pollution samplers. Cord blood samples were analyzed using a FACSort flow cytometer to determine phenotypes of CD3+ T-lymphocytes and their subsets CD4+ and CD8+, CD19+ B-lymphocytes, and natural killer cells. The mothers were interviewed regarding sociodemographic and lifestyle factors, and medical records were abstracted for obstetric, labor and delivery characteristics. During the period 1994 to 1998, the mean daily ambient concentration of PM2.5 was 24.8 microg/m3 and that of PAHs was 63.5 ng/m3. In multiple linear regression models adjusted for temperature, season, and other covariates, average PAH or PM2.5 levels during the 14 days before birth were associated with decreases in T-lymphocyte phenotype fractions (i.e., CD3+ CD4+, and CD8+), and a clear increase in the B-lymphocyte (CD19+) fraction. For a 100-ng/m3 increase in PAHs, which represented approximately two standard deviations, the percentage decrease was -3.3% [95% confidence interval (CI), -5.6 to -1.0%] for CD3+, -3.1% (95% CI, -4.9 to -1.3%) for CD4+, and -1.0% (95% CI, -1.8 to -0.2%) for CD8+ cells. The corresponding increase in the CD19+ cell proportion was 1.7% (95% CI, 0.4 to 3.0%). Associations were similar but slightly weaker for PM2.5. Ambient air pollution may influence the relative distribution of lymphocyte immunophenotypes of the fetus.

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

    NASA Technical Reports Server (NTRS)

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

    1996-01-01

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

  10. Association of COX-2 Promoter Polymorphisms -765G/C and -1195A/G with Migraine

    PubMed Central

    MOZAFFARI, Elahe; DOOSTI, Abbas; ARSHI, Asghar; FAGHANI, Mostafa

    2016-01-01

    Background: Migraine is a common debilitating primary headache disorder with current head pain attacks, which contributes to physical activity dysfunctions in chronic pain phase. PGE2 and PGI2 are two important prostaglandins synthesised by COX-2 enzymes, involved in migraine pain signals. COX-2 modulation is essential in treatment and pathogenesis of migraine. This study aimed to investigating the association between COX-2 gene polymorphisms with the risk of migraine susceptibility in migraine patients with related and unrelated parents. Methods: This case- control study was based on 100 migraine patients and 100 non-migraine subjects in Bushehr province, Iran in 2013. Genomic DNA of blood samples was extracted and genotyping of COX-2-765G>C (rs20417) and COX-2-1195A>G (rs689466) gene variants was investigated by PCR-RFLP method. Statistical analyses were accomplished using the SPSS software package. Results: There was a significant differences in the frequencies of the COX-2-765G>C and COX-2-1195A>G genotypes between migraine patients and controls (P≤0.05). Conclusion: COX-2-765CC, COX-2-765CG, COX-2-1195GG and COX-2-1195AG genotypes can increase the risk of migraine significantly. As the first study in Iran, we are hopeful to achieve greater results about the relevancy of COX-2 gene, migraine and pain signals pathway by repeating these experiments on more samples. PMID:28053929

  11. Large-proportional shrunken bio-replication of shark skin based on UV-curing shrinkage

    NASA Astrophysics Data System (ADS)

    Chen, Huawei; Che, Da; Zhang, Xin; Yue, Yue; Zhang, Deyuan

    2015-01-01

    The shark skin effect has attracted worldwide attention because of its superior drag reduction. As the product of natural selection, the maximum drag reduction of shark skin is found in its normal living environment. Large-proportional shrinkage of shark skin morphology is greatly anticipated for its adaptation to faster fluid flow. One novel approach, large-proportional shrunken bio-replication, is proposed as a method to adjust the optimal drag reduction region of shark skin based on the shrinkage of UV-cured material. The shark skin is taken as a replica template to allow large-proportional shrinking in the drag reduction morphology by taking advantage of the shrinkage of UV-curable material. The accuracy of the large-proportional shrunken bio-replication approach is verified by a comparison between original and shrunken bio-replicated shark skin, which shows that the shrinking ratio can reach 23% and the bio-replication accuracy is higher than 95%. In addition, the translation of the optimum drag reduction peak of natural surface function to various applications and environments is proved by drag reduction experiments.

  12. 34 CFR Appendix to Part 81 - Illustrations of Proportionality

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 1 2013-07-01 2013-07-01 false Illustrations of Proportionality Appendix to Part 81 Education Office of the Secretary, Department of Education GENERAL EDUCATION PROVISIONS ACT-ENFORCEMENT Pt. 81, App. Appendix to Part 81—Illustrations of Proportionality (1) Ineligible beneficiaries. A...

  13. 34 CFR Appendix to Part 81 - Illustrations of Proportionality

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 1 2012-07-01 2012-07-01 false Illustrations of Proportionality Appendix to Part 81 Education Office of the Secretary, Department of Education GENERAL EDUCATION PROVISIONS ACT-ENFORCEMENT Pt. 81, App. Appendix to Part 81—Illustrations of Proportionality (1) Ineligible beneficiaries. A...

  14. 34 CFR Appendix to Part 81 - Illustrations of Proportionality

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 1 2014-07-01 2014-07-01 false Illustrations of Proportionality Appendix to Part 81 Education Office of the Secretary, Department of Education GENERAL EDUCATION PROVISIONS ACT-ENFORCEMENT Pt. 81, App. Appendix to Part 81—Illustrations of Proportionality (1) Ineligible beneficiaries. A...

  15. Longitudinal Enrollment Dynamics and Changes in Ethnic Proportionality.

    ERIC Educational Resources Information Center

    Greaves, Fred

    The Federal Racial/Ethnic Surveys of the Salinas Union High School District were examined to identify changes in ethnic proportions within a particular class from its entry in the 9th grade until the 12th grade. The 9th, 10th, 11th, and 12th grade proportional distributions are reported by school (Alisal High School, North Salinas High School, and…

  16. The Failings of the Law of Definite Proportions

    ERIC Educational Resources Information Center

    Suchow, Lawrence

    1975-01-01

    Indicates that the concept of definite proportions or constant composition should be introduced with qualification. Presents arguments against the Law of Definite Proportions and cites examples in the areas of solid solutions, compounds of the transition and inner transition elements, and in some compounds of the representative elements. (GS)

  17. The Fibonacci Sequence: Proportional Semantic Bases of Children's Aesthetic Preferences.

    ERIC Educational Resources Information Center

    Neperud, Ronald W.; Serlin, Ronald C.

    1984-01-01

    Only at the third- and seventh-grade levels did proportional preferences for Fibonacci figures differ significantly from preferences for other kinds of proportional spatial divisions. Semantic patterns were similar among third and fifth graders, with a change occurring between fifth and seventh grades in keeping with the development of formal…

  18. Understanding Proportional Reasoning in Pre-Service Teachers

    ERIC Educational Resources Information Center

    Johnson, Kim H.

    2013-01-01

    The purpose of this study is to examine the proportional reasoning of pre-service teachers at the beginning of their teacher preparation program using the developmental shifts described by Lobato and Ellis (2010). They cast changes in proportional reasoning as transitions or "shifts" in students' thinking and these shifts can serve as…

  19. COX assembly factor ccdc56 regulates mitochondrial morphology by affecting mitochondrial recruitment of Drp1.

    PubMed

    Ban-Ishihara, Reiko; Tomohiro-Takamiya, Shiho; Tani, Motohiro; Baudier, Jacques; Ishihara, Naotada; Kuge, Osamu

    2015-10-07

    Mitochondria are dynamic organelles that alter their morphology in response to cellular signaling and differentiation through balanced fusion and fission. In this study, we found that the mitochondrial inner membrane ATPase ATAD3A interacted with ccdc56/MITRAC12/COA3, a subunit of the cytochrome oxidase (COX)-assembly complex. Overproduction of ccdc56 in HeLa cells resulted in fragmented mitochondrial morphology, while mitochondria were highly elongated in ccdc56-repressed cells by the defective recruitment of the fission factor Drp1. We also found that mild and chronic inhibition of COX led to mitochondrial elongation, as seen in ccdc56-repressed cells. These results indicate that ccdc56 positively regulates mitochondrial fission via regulation of COX activity and the mitochondrial recruitment of Drp1, and thus, suggest a novel relationship between COX assembly and mitochondrial morphology.

  20. 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.

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

    SciTech Connect

    Castor, J.I.

    1997-10-02

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

  2. Recent Methodologies toward the Synthesis of Valdecoxib: A Potential 3,4-diarylisoxazolyl COX-2 Inhibitor

    PubMed Central

    Dadiboyena, Sureshbabu; Nefzi, Adel

    2011-01-01

    Non-steroidal anti-inflammatory drugs are widely used therapeutic agents in the treatment of inflammation, pain and fever. Cyclooxygenase catalyzes the initial step of biotransformation of arachidonic acid to prostanoids, and exist as three distinct isozymes; COX-I, COX-II and COX-III. Selective COX-II inhibitors are a class of potential anti-inflammatory, analgesic, and antipyretic drugs with reduced gastrointestinal (GI) side effects compared to nonselective inhibitors. 3,4-diarylisoxazole scaffold is recurrently found in a wide variety of NSAIDs, protein kinase inhibitors, hypertensive agents, and estrogen receptor (ER) modulators. In the present review, we document on the recent synthetic strategies of 3,4-diarylisoxazolyl scaffolds of valdecoxib and its relevant structural analogues. PMID:20724040

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

    EPA Science Inventory

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

  4. Delay Adjusted Incidence

    Cancer.gov

    This Infographic shows the National Cancer Institute SEER Incidence Trends. The graphs show the Average Annual Percent Change (AAPC) 2002-2011. For Men, Thyroid: 5.3*,Liver & IBD: 3.6*, Melanoma: 2.3*, Kidney: 2.0*, Myeloma: 1.9*, Pancreas: 1.2*, Leukemia: 0.9*, Oral Cavity: 0.5, Non-Hodgkin Lymphoma: 0.3*, Esophagus: -0.1, Brain & ONS: -0.2*, Bladder: -0.6*, All Sites: -1.1*, Stomach: -1.7*, Larynx: -1.9*, Prostate: -2.1*, Lung & Bronchus: -2.4*, and Colon & Rectum: -3/0*. For Women, Thyroid: 5.8*, Liver & IBD: 2.9*, Myeloma: 1.8*, Kidney: 1.6*, Melanoma: 1.5, Corpus & Uterus: 1.3*, Pancreas: 1.1*, Leukemia: 0.6*, Brain & ONS: 0, Non-Hodgkin Lymphoma: -0.1, All Sites: -0.1, Breast: -0.3, Stomach: -0.7*, Oral Cavity: -0.7*, Bladder: -0.9*, Ovary: -0.9*, Lung & Bronchus: -1.0*, Cervix: -2.4*, and Colon & Rectum: -2.7*. * AAPC is significantly different from zero (p<.05). Rates were adjusted for reporting delay in the registry. www.cancer.gov Source: Special section of the Annual Report to the Nation on the Status of Cancer, 1975-2011.

  5. Nonlinear Hydrostatic Adjustment.

    NASA Astrophysics Data System (ADS)

    Bannon, Peter R.

    1996-12-01

    The final equilibrium state of Lamb's hydrostatic adjustment problem is found for finite amplitude heating. Lamb's problem consists of the response of a compressible atmosphere to an instantaneous, horizontally homogeneous heating. Results are presented for both isothermal and nonisothermal atmospheres.As in the linear problem, the fluid displacements are confined to the heated layer and to the region aloft with no displacement of the fluid below the heating. The region above the heating is displaced uniformly upward for heating and downward for cooling. The amplitudes of the displacements are larger for cooling than for warming.Examination of the energetics reveals that the fraction of the heat deposited into the acoustic modes increases linearly with the amplitude of the heating. This fraction is typically small (e.g., 0.06% for a uniform warming of 1 K) and is essentially independent of the lapse rate of the base-state atmosphere. In contrast a fixed fraction of the available energy generated by the heating goes into the acoustic modes. This fraction (e.g., 12% for a standard tropospheric lapse rate) agrees with the linear result and increases with increasing stability of the base-state atmosphere.The compressible results are compared to solutions using various forms of the soundproof equations. None of the soundproof equations predict the finite amplitude solutions accurately. However, in the small amplitude limit, only the equations for deep convection advanced by Dutton and Fichtl predict the thermodynamic state variables accurately for a nonisothermal base-state atmosphere.

  6. Expression of COX-2 and Bcl-2 in primary fallopian tube carcinoma: correlations with clinicopathologic features.

    PubMed

    Wang, Fang; Sun, Guo-Ping; Zou, Yan-Feng; Wu, Qiang; Wu, Hong-Yang; Wu, Ji-Feng; Zhou, Jia-De; Chen, Ke; Zhang, Xiu-Shan

    2011-01-01

    The aim of this study was to evaluate the expression of COX-2 and Bcl-2 in primary fallopian tube carcinoma (PFTC), as well as their correlations with clinicopathologic features. We studied a cohort of 33 patients with a pathological diagnosis of PFTC. Thirty normal tubal tissues used for controls were obtained from patients diagnosed with uterine myomas. Expression analysis for COX-2 and Bcl-2 was performed using the immunohistochemical technique. The rate of preoperative diagnosis was 18.2%. With a median survival of 61.0 months (95% CI: 43.2 to 78.8 months), the estimated five-year overall survival rate in the 33 patients was 39.0%. Increased expression of COX-2 and Bcl-2 was observed in tumor specimens compared to normal controls (p = 0.026; p = 0.003). The expression rate of COX-2 in node-positive tumors was significantly higher than that of node-negative tumors (p = 0.024). Moreover, the expression rate of COX-2 was statistically significantly higher in patients with infiltration through the serosa (p = 0.019). Positive significant associations were observed between Bcl-2 staining index and FIGO stage (p = 0.015), and between Bcl-2 staining and lymph node metastasis (p = 0.010). There was a significant correlation between COX-2 expression and Bcl-2 staining index (r = 0.517, p = 0.002). We conclude that COX-2 and Bcl-2 may potentially be useful prognostic markers for PFTC. The exact molecular mechanism for correlations between COX-2 and Bcl-2 remains to be elucidated.

  7. Clinical significance of Cox-2, Survivin and Bcl-2 expression in hepatocellular carcinoma (HCC).

    PubMed

    Yang, Yu; Zhu, Jiang; Gou, Hongfeng; Cao, Dan; Jiang, Ming; Hou, Mei

    2011-09-01

    Cox-2, Survivin and Bcl-2 are frequently overexpressed in numerous types of cancers. They are known to be the important regulators of apoptosis. This study was designed to investigate the correlation between the clinical characteristics and the expression of Cox-2, Survivin and Bcl-2 in hepatocellular carcinoma. A total of 63 postoperative hepatocellular carcinoma (HCC) samples, 10 adjacent non-tumor samples and 10 normal liver samples were immunochemically detected for the expression of Cox-2, Survivin and Bcl-2. A median follow-up of 4 years for the 63 HCC patients was conducted. Univariate tests and multivariate Cox regression were performed for statistical analysis. The Kaplan-Meier method was used to analyze the survival. Positive expression of Cox-2 (84.3%) and Survivin (77.8%) was detected significantly more frequently in the HCC samples than in the normal liver tissues (30% and 0, respectively). Bcl-2 was highly expressed in the adjacent non-tumor tissue. Cox-2 was positively correlative to Survivin. Survivin and Bcl-2 were significantly associated with the pathological grade of HCC (P<0.05). Expression of both Cox-2 and Survivin was significantly associated with the poor overall survival (OS) (P=0.0141, P=0.0039). Furthermore, multivariate analysis confirmed the independent prognostic value of Survivin expression, along with tumor size and hepatic function. Cox-2 and Survivin were highly expressed in the HCC tissue. Survivin and Bcl-2 were significantly associated with the pathological grade of HCC. The expression of Survivin was an independent prognostic factor for HCC after a hepatectomy. Treatment that inhibits Survivin may be a promising targeted approach in HCC.

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

    PubMed

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

    1992-12-05

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

  9. Inhibition of COX-2/PGE2 cascade ameliorates cisplatin-induced mesangial cell apoptosis

    PubMed Central

    Yu, Xiaowen; Yang, Yunwen; Yuan, Hui; Wu, Meng; Li, Shuzhen; Gong, Wei; Yu, Jing; Xia, Weiwei; Zhang, Yue; Ding, Guixia; Huang, Songming; Jia, Zhanjun; Zhang, Aihua

    2017-01-01

    Cisplatin is one of the most potent cytotoxic drug for the treatment of many types of cancer. However, the side effects on normal tissues, particularly on the kidney, greatly limited its use in clinic. Emerging evidence demonstrated that cisplatin could directly cause mesangial cell apoptosis, while the potential mechanism is still elusive. Here we examined the contribution of COX-2 in cisplatin-induced mesangial cell apoptosis. Firstly, we found cisplatin induced cell apoptosis in mesangial cells shown by increased number of apoptotic cells in parallel with the upregulation of Bax and the downregulation of Bcl-2. Interestingly, cisplatin-induced cell apoptosis was accompanied by an upregulation of COX-2 at both mRNA and protein levels in dose- and time-dependent manners. Importantly, inhibition of COX-2 via a specific COX-2 inhibitor celecoxib markedly blocked cisplatin-induced mesangial cell apoptosis as evidenced by the decreased number of apoptotic cells, blocked increments of cleaved caspase-3 and Bax, and reversed Bcl-2 downregulation. Meanwhile, cisplatin-induced PGE2 production was markedly blocked by the treatment of celecoxib. In conclusion, this study indicated that COX-2/PGE2 cascade activation mediated cisplatin-induced mesangial cell apoptosis. The findings not only offered new insights into the understanding of cisplatin nephrotoxicity but also provided the therapeutic potential by targeting COX-2/PGE2 cascade in treating cisplatin-induced kidney injury. PMID:28386348

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  12. Odontogenic epithelial proliferation is correlated with COX-2 expression in dentigerous cyst and ameloblastoma

    PubMed Central

    Alsaegh, Mohammed Amjed; Miyashita, Hitoshi; Taniguchi, Takahiro; Zhu, Sheng Rong

    2017-01-01

    Investigation of cyclooxygenase (COX)-2 in dentigerous cyst and ameloblastoma may help to improve understanding of the nature and behavior of odontogenic cysts and tumors, and in addition may eventually represent a definitive target for a pharmacological approach in the management of these lesions. The aim of this study was to evaluate COX-2 expression and its correlation with the proliferation of odontogenic epithelium in these lesions. Dentigerous cysts (n=16) and ameloblastomas (n=17) were evaluated. Detection of Ki-67 and COX-2 protein expression was conducted by immunohistochemistry. Data were statistically analyzed using Mann-Whitney U test and Spearman's rank correlation coefficient. No significant differences were found in the expression of Ki-67 and COX-2 between dentigerous cysts and ameloblastomas (P>0.05). A significant positive correlation (P=0.018) and highly significant positive correlation (P=0.004) were found between Ki-67 and COX-2 expression in the odontogenic epithelium of dentigerous cyst and ameloblastoma, respectively. COX-2 was expressed in the odontogenic epithelium of dentigerous cyst and ameloblastoma. It may contribute to local extension of these lesions by increasing the proliferation of their odontogenic epithelial cells. PMID:28123497

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed Central

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

    2017-01-01

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

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

    SciTech Connect

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

    2008-05-23

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

  16. Effect of COX-2 inhibitor after TNBS-induced colitis in Wistar rats.

    PubMed

    Paiotti, Ana Paula Ribeiro; Miszputen, Sender Jankiel; Oshima, Celina Tizuko Fujiyama; de Oliveira Costa, Henrique; Ribeiro, Daniel Araki; Franco, Marcello

    2009-08-01

    Inflammatory bowel disease (IBD) is a common chronic gastrointestinal disorder characterized by alternating periods of remission and active intestinal inflammation. Some studies suggest that antiinflammatory drugs are a promising alternative for treatment of the disease. Thus, this study aimed to evaluate the effect of lumiracoxib, a selective-cyclooxygenase-2 (COX-2) inhibitor, on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis. Wistar rats (n = 25) were randomized into four groups, as follows: Group (1) Sham group: sham induced-colitis rats; Group (2) TNBS group: nontreated induced-colitis rats; Group (3) Lumiracoxib control group; and Group (4) Lumiracoxib-treated induced-colitis rats. Our results showed that rats from groups 2 and 4 presented similar histopathological damage and macroscopic injury in the distal colon as depicted by significant statistically differences (P < 0.01; P < 0.05) compared to the other two groups. Weak expression of COX-2 mRNA was detected in normal colon cells, while higher levels of COX-2 mRNA were detected in group 2 and group 4. Therapy with lumiracoxib reduced COX-2 expression by 20-30%, but it was still higher and statistically significant compared to data obtained from the lumiracoxib control group. Treatment with the selective COX-2 inhibitor lumiracoxib did not reduce inflammation-associated colonic injury in TNBS-induced experimental colitis. Thus, the use of COX-2 inhibitors for treating IBD should be considered with caution and warrants further experimental investigation to elucidate their applicability.

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2015-11-01

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

  19. Development of proportional reasoning: where young children go wrong.

    PubMed

    Boyer, Ty W; Levine, Susan C; Huttenlocher, Janellen

    2008-09-01

    Previous studies have found that children have difficulty solving proportional reasoning problems involving discrete units until 10 to 12 years of age, but can solve parallel problems involving continuous quantities by 6 years of age. The present studies examine where children go wrong in processing proportions that involve discrete quantities. A computerized proportional equivalence choice task was administered to kindergartners through 4th-graders in Study 1, and to 1st- and 3rd-graders in Study 2. Both studies involved 4 between-subjects conditions that were formed by pairing continuous and discrete target proportions with continuous and discrete choice alternatives. In Study 1, target and choice alternatives were presented simultaneously; in Study 2, target and choice alternatives were presented sequentially. In both studies, children performed significantly worse when both the target and choice alternatives were represented with discrete quantities than when either or both of the proportions involved continuous quantities. Taken together, these findings indicate that children go astray on proportional reasoning problems involving discrete units only when a numerical match is possible, suggesting that their difficulty is due to an overextension of numerical equivalence concepts to proportional equivalence problems.

  20. Development of Proportional Reasoning: Where Young Children Go Wrong

    PubMed Central

    Boyer, Ty W.; Levine, Susan C.; Huttenlocher, Janellen

    2008-01-01

    Previous studies have found that children have difficulty solving proportional reasoning problems involving discrete units until 10- to 12-years of age, but can solve parallel problems involving continuous quantities by 6-years of age. The present studies examine where children go wrong in processing proportions that involve discrete quantities. A computerized proportional equivalence choice task was administered to kindergartners through fourth-graders in Study 1, and to first- and third-graders in Study 2. Both studies involved four between-subjects conditions that were formed by pairing continuous and discrete target proportions with continuous and discrete choice alternatives. In Study 1, target and choice alternatives were presented simultaneously and in Study 2 target and choice alternatives were presented sequentially. In both studies, children performed significantly worse when both the target and choice alternatives were represented with discrete quantities than when either or both of the proportions involved continuous quantities. Taken together, these findings indicate that children go astray on proportional reasoning problems involving discrete units only when a numerical match is possible, suggesting that their difficulty is due to an overextension of numerical equivalence concepts to proportional equivalence problems. PMID:18793078

  1. Activation of COX-2/PGE2 Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production

    PubMed Central

    Alfajaro, Mia Madel; Choi, Jong-Soon; Kim, Deok-Song; Seo, Ja-Young; Kim, Ji-Yun; Park, Jun-Gyu; Soliman, Mahmoud; Baek, Yeong-Bin; Cho, Eun-Hyo; Kwon, Joseph; Kwon, Hyung-Jun; Park, Su-Jin; Lee, Woo Song; Kang, Mun-Il; Hosmillo, Myra

    2016-01-01

    ABSTRACT Enteric caliciviruses in the genera Norovirus and Sapovirus are important pathogens that cause severe acute gastroenteritis in both humans and animals. Cyclooxygenases (COXs) and their final product, prostaglandin E2 (PGE2), are known to play important roles in the modulation of both the host response to infection and the replicative cycles of several viruses. However, the precise mechanism(s) by which the COX/PGE2 pathway regulates sapovirus replication remains largely unknown. In this study, infection with porcine sapovirus (PSaV) strain Cowden, the only cultivable virus within the genus Sapovirus, markedly increased COX-2 mRNA and protein levels at 24 and 36 h postinfection (hpi), with only a transient increase in COX-1 levels seen at 24 hpi. The treatment of cells with pharmacological inhibitors, such as nonsteroidal anti-inflammatory drugs or small interfering RNAs (siRNAs) against COX-1 and COX-2, significantly reduced PGE2 production, as well as PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We observed that pharmacological inhibition of COX-2 dramatically increased NO production, causing a reduction in PSaV replication that could be restored by inhibition of nitric oxide synthase via the inhibitor N-nitro-l-methyl-arginine ester. This study identified a pivotal role for the COX/PGE2 pathway in the regulation of NO production during the sapovirus life cycle, providing new insights into the life cycle of this poorly characterized family of viruses. Our findings also reveal potential new targets for treatment of sapovirus infection. IMPORTANCE Sapoviruses are among the major etiological agents of acute gastroenteritis in both humans and animals, but little is known about sapovirus host factor requirements. Here, using only cultivable porcine sapovirus (PSaV) strain Cowden, we demonstrate that PSaV induced the vitalization of the cyclooxygenase (COX) and prostaglandin E2 (PGE2

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

    PubMed Central

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

    1997-01-01

    DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone) was identified as a novel orally active and highly selective cyclo-oxygenase-2 (COX-2) inhibitor.In CHO cells stably transfected with human COX isozymes, DFU inhibited the arachidonic acid-dependent production of prostaglandin E2 (PGE2) with at least a 1,000 fold selectivity for COX-2 (IC50=41±14 nM) over COX-1 (IC50>50 μM). Indomethacin was a potent inhibitor of both COX-1 (IC50=18±3 nM) and COX-2 (IC50=26±6 nM) under the same assay conditions. The large increase in selectivity of DFU over indomethacin was also observed in COX-1 mediated production of thromboxane B2 (TXB2) by Ca2+ ionophore-challenged human platelets (IC50>50 μM and 4.1±1.7 nM, respectively).DFU caused a time-dependent inhibition of purified recombinant human COX-2 with a Ki value of 140±68 μM for the initial reversible binding to enzyme and a k2 value of 0.11±0.06 s−1 for the first order rate constant for formation of a tightly bound enzyme-inhibitor complex. Comparable values of 62±26 μM and 0.06±0.01 s−1, respectively, were obtained for indomethacin. The enzyme-inhibitor complex was found to have a 1 : 1 stoichiometry and to dissociate only very slowly (t1/2=1–3 h) with recovery of intact inhibitor and active enzyme. The time-dependent inhibition by DFU was decreased by co-incubation with arachidonic acid under non-turnover conditions, consistent with reversible competitive inhibition at the COX active site.Inhibition of purified recombinant human COX-1 by DFU was very weak and observed only at low concentrations of substrate (IC50=63±5 μM at 0.1 μM arachidonic acid). In contrast to COX-2, inhibition was time-independent and rapidly reversible. These data are consistent with a reversible competitive inhibition of COX-1.DFU inhibited lipopolysaccharide (LPS)-induced PGE2 production (COX-2) in a human whole blood assay with a potency (IC50=0.28±0.04 μM) similar

  3. Coexpression of COX-2 and iNOS in Angiogenesis of Superficial Esophageal Squamous Cell Carcinoma.

    PubMed

    Kumagai, Youichi; Sobajima, Jun; Higashi, Morihiro; Ishiguro, Toru; Fukuchi, Minoru; Ishibashi, Keiichiro; Mochiki, Erito; Yakabi, Koji; Kawano, Tatsuyuki; Tamaru, Jun-ichi; Ishida, Hideyuki

    2015-04-01

    Using immunohistochemical staining, the present study was conducted to examine whether cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) affect angiogenesis in early-stage esophageal squamous cell carcinoma (ESCC). We also analyzed the correlation between these two factors. Cyclooxygenase 2, iNOS, and angiogenesis in early-stage ESCC are unclear. Using 10 samples of normal squamous epithelium, 7 samples of low-grade intraepithelial neoplasia (LGIN), and 45 samples of superficial esophageal cancer, we observed the expression of COX-2 and iNOS. We then investigated the COX-2 and iNOS immunoreactivity scores and the correlation between COX-2 or iNOS scores and microvessel density (MVD) using CD34 or CD105. The intensity of COX-2 or iNOS expression differed significantly according to histological type (P < 0.001). The scores of COX-2 and iNOS were lowest for normal squamous epithelium, followed in ascending order by LGIN, carcinoma in situ and tumor invading the lamina propria mucosae (M1-M2 cancer); and tumor invading the muscularis mucosa (M3) or deeper cancer. The differences were significant (P < 0.001). Cancers classified M1-M2 (P < 0.01 and P < 0.05, respectively); M3; or deeper cancer (P < 0.01) had significantly higher COX-2 and iNOS scores than normal squamous epithelium. There was a significant correlation between COX-2 and iNOS scores (P < 0.001, rs = 0.51). Correlations between COX-2 score and CD34-positive MVD or CD105-positive MVD were significant (rs = 0.53, P < 0.001; rs = 0.62, P < 0.001, respectively). Inducible nitric oxide synthase score was also significantly correlated with CD34 MVD and CD105 MVD (rs = 0.45, P < 0.001; rs = 0.60, P < 0.001, respectively). Chemoprevention of COX-2 or iNOS activity may blunt the development of ESCC from precancerous lesions.

  4. Mechanisms by Which 17β-Estradiol (E2) Suppress Neuronal cox-2 Gene Expression

    PubMed Central

    Stacey, Winfred; Bhave, Shreyas; Uht, Rosalie M.

    2016-01-01

    E2 attenuates inflammatory responses by suppressing expression of pro-inflammatory genes. Given that inflammation is increasingly being associated with neurodegenerative and psychiatric processes, we sought to elucidate mechanisms by which E2 down-regulates a component of an inflammatory response, cyclooxygenase– 2 (COX-2) expression. Although inflammatory processes in the brain are usually associated with microglia and astrocytes, we found that the COX-2 gene (cox-2) was expressed in a neuronal context, specifically in an amygdalar cell line (AR-5). Given that COX-2 has been reported to be in neurons in the brain, and that the amygdala is a site involved in neurodegenerative and neuropsychiatric processes, we investigated mechanisms by which E2 could down-regulate cox-2 expression in the AR-5 line. These cells express estrogen receptors alpha (ERα) and beta (ERβ), and as shown here cox-2. At the level of RNA, E2 and the ERβ selective ligand diarylpropionitrile (DPN) both attenuated gene expression, whereas the ERα selective ligand propyl pyrazole triol (PPT) had no effect. Neither ligand increased ERβ at the cox-2 promoter. Rather, DPN decreased promoter occupancy of NF-κB p65 and histone 4 (H4) acetylation. Treatment with the non-specific HDAC inhibitor Trichostatin A (TSA) counteracted DPN’s repressive effects on cox-2 expression. In keeping with the TSA effect, E2 and DPN increased histone deacetylase one (HDAC1) and switch-independent 3A (Sin3A) promoter occupancy. Lastly, even though E2 increased CpG methylation, DPN did not. Taken together, the pharmacological data indicate that ERβ contributes to neuronal cox-2 expression, as measured by RNA levels. Furthermore, ER ligands lead to increased recruitment of HDAC1, Sin3A and a concomitant reduction of p65 occupancy and Ac-H4 levels. None of the events, however, are associated with a significant recruitment of ERβ at the promoter. Thus, ERβ directs recruitment to the cox-2 promoter, but does so in

  5. Expression and function of COX isoforms in renal medulla: evidence for regulation of salt sensitivity and blood pressure.

    PubMed

    Ye, Wenling; Zhang, Hui; Hillas, Elaine; Kohan, Donald E; Miller, R Lance; Nelson, Raoul D; Honeggar, Matthew; Yang, Tianxin

    2006-02-01

    Expression of cyclooxygenase (COX)-2, but not COX-1, in the renal medulla is stimulated by chronic salt loading; yet the functional implication of this phenomenon is incompletely understood. The present study examined the cellular localization and antihypertensive function of high-salt-induced COX-2 expression in the renal medulla, with a parallel assessment of the function of COX-1. COX-2 protein expression in response to high-salt loading, assessed by immunostaining, was found predominantly in inner medullary interstitial cells, whereas COX-1 protein was abundant in collecting duct (CD) and inner medullary interstitial cells and was not affected by high salt. We compared mRNA expressions of COX-1 and COX-2 in CD vs. non-CD cells isolated from aquaporin 2-green fluorescent protein transgenic mice. A low level of COX-2 mRNA, but a high level of COX-1 mRNA, as determined by real-time RT-PCR, was detected in CD compared with non-CD segments. During high-salt intake, chronic infusions of the COX-2 blocker NS-398 and the COX-1 blocker SC-560 into the renal medulla of Sprague-Dawley rats for 5 days induced approximately 30- and 15-mmHg increases in mean arterial pressure, respectively. During similar high-salt intake, COX-1 knockout mice exhibited a gradual, but significant, increase in systolic blood pressure that was associated with a marked suppression of urinary PGE2 excretion. Therefore, we conclude that the two COX isoforms in the renal medulla play a similar role in the stabilization of arterial blood pressure during salt loading.

  6. Proportionality: a valid alternative to correlation for relative data.

    PubMed

    Lovell, David; Pawlowsky-Glahn, Vera; Egozcue, Juan José; Marguerat, Samuel; Bähler, Jürg

    2015-03-01

    In the life sciences, many measurement methods yield only the relative abundances of different components in a sample. With such relative-or compositional-data, differential expression needs careful interpretation, and correlation-a statistical workhorse for analyzing pairwise relationships-is an inappropriate measure of association. Using yeast gene expression data we show how correlation can be misleading and present proportionality as a valid alternative for relative data. We show how the strength of proportionality between two variables can be meaningfully and interpretably described by a new statistic ϕ which can be used instead of correlation as the basis of familiar analyses and visualisation methods, including co-expression networks and clustered heatmaps. While the main aim of this study is to present proportionality as a means to analyse relative data, it also raises intriguing questions about the molecular mechanisms underlying the proportional regulation of a range of yeast genes.

  7. Proportionality: A Valid Alternative to Correlation for Relative Data

    PubMed Central

    Lovell, David; Pawlowsky-Glahn, Vera; Egozcue, Juan José; Marguerat, Samuel; Bähler, Jürg

    2015-01-01

    In the life sciences, many measurement methods yield only the relative abundances of different components in a sample. With such relative—or compositional—data, differential expression needs careful interpretation, and correlation—a statistical workhorse for analyzing pairwise relationships—is an inappropriate measure of association. Using yeast gene expression data we show how correlation can be misleading and present proportionality as a valid alternative for relative data. We show how the strength of proportionality between two variables can be meaningfully and interpretably described by a new statistic ϕ which can be used instead of correlation as the basis of familiar analyses and visualisation methods, including co-expression networks and clustered heatmaps. While the main aim of this study is to present proportionality as a means to analyse relative data, it also raises intriguing questions about the molecular mechanisms underlying the proportional regulation of a range of yeast genes. PMID:25775355

  8. Operability test report for 211BA flow proportional sampler

    SciTech Connect

    Weissenfels, R.D.

    1995-01-01

    This operability report will verify that the 211-BA flow proportional sampler functions as intended by design. The sampler was installed by Project W-007H and is part of BAT/AKART for the BCE liquid effluent stream.

  9. A Weighted Harmonic Means Analysis for the Proportional Unbalanced Design.

    ERIC Educational Resources Information Center

    Bonett, Douglas G.

    1982-01-01

    A weighted harmonic means analysis is presented that incorporates all of the available data, preserves the planned proportionality of the design, and avoids the problems associated with the replacement of missing data with sample estimates. (Author/BW)

  10. Proportion effect in diblock co-oligomer molecular diodes

    NASA Astrophysics Data System (ADS)

    Hu, G. C.; Zhang, G. P.; Li, Y.; Ren, J. F.; Wang, C. K.

    2014-10-01

    Based on ab-initio theory and nonequilibrium Green's function method, the effect of proportion on the rectification in pyrimidinyl-phenyl diblock co-oligomer diodes is investigated in two regimes. For a short co-oligomer diode, it is found that the 1:1 proportion of the two moieties favors the largest rectification ratio. For a long co-oligomer diode, an interesting proportion-dependent variation of the rectifying direction is observed. Furthermore, the optimal proportion for the largest rectification ratio is not 1:1 any longer. A deep understanding can be achieved by analyzing the bias-dependent transmission spectra combined with the evolution of the molecular orbitals.

  11. DC motor proportional control system for orthotic devices

    NASA Technical Reports Server (NTRS)

    Blaise, H. T.; Allen, J. R.

    1972-01-01

    Multi-channel proportional control system for operation of dc motors for use with externally-powered orthotic arm braces is described. Components of circuitry and principles of operation are described. Schematic diagram of control circuit is provided.

  12. Improvements in estimating proportions of objects from multispectral data

    NASA Technical Reports Server (NTRS)

    Horwitz, H. M.; Hyde, P. D.; Richardson, W.

    1974-01-01

    Methods for estimating proportions of objects and materials imaged within the instantaneous field of view of a multispectral sensor were developed further. Improvements in the basic proportion estimation algorithm were devised as well as improved alien object detection procedures. Also, a simplified signature set analysis scheme was introduced for determining the adequacy of signature set geometry for satisfactory proportion estimation. Averaging procedures used in conjunction with the mixtures algorithm were examined theoretically and applied to artificially generated multispectral data. A computationally simpler estimator was considered and found unsatisfactory. Experiments conducted to find a suitable procedure for setting the alien object threshold yielded little definitive result. Mixtures procedures were used on a limited amount of ERTS data to estimate wheat proportion in selected areas. Results were unsatisfactory, partly because of the ill-conditioned nature of the pure signature set.

  13. A Gas Proportional Scintillation Counter with krypton filling

    NASA Astrophysics Data System (ADS)

    Monteiro, C. M. B.; Mano, R. D. P.; Barata, E. C. G. M.; Fernandes, L. M. P.; Freitas, E. D. C.

    2016-12-01

    A Gas Proportional Scintillation Counter filled with pure krypton was studied. Energy resolution below 10% for 5.9-keV X-rays was obtained with this prototype. This value is much better than the energy resolution obtained with proportional counters or other MPGDs with krypton filling. The krypton electroluminescence scintillation and ionisation thresholds were found to be about 0.5 and 3.5 kV cm-1bar-1, respectively.

  14. Proportional reasoning in the learning of chemistry: levels of complexity

    NASA Astrophysics Data System (ADS)

    Ramful, Ajay; Narod, Fawzia Bibi

    2014-03-01

    This interdisciplinary study sketches the ways in which proportional reasoning is involved in the solution of chemistry problems, more specifically, problems involving quantities in chemical reactions (commonly referred to as stoichiometry problems). By building on the expertise of both mathematics and chemistry education research, the present paper shows how the theoretical constructs in proportional reasoning in mathematics education offer rich explanatory accounts of the complexities involved in solving stoichiometry problems. Using Vergnaud's concept of measure spaces, the theoretical analysis shows that proportionality situations are relatively more intricate, involving various layers of complexity in chemistry as compared to those in the mathematics curriculum. Knowledge of proportionality and chemistry are simultaneously required to provide solutions to chemical reactions. Our analysis of a range of stoichiometry situations led us to propose a problem analysis framework involving five levels of difficulty. Further, the specificity of proportionality in stoichiometry is that it can only be established when quantities are interpreted in the unit "mole," a unit which does not have any physical embodiment in terms of a measure of quantity unlike mass and volume. Our analysis of student-teachers' solution to the stoichiometry problems, shows that they tend to incorrectly (probably intuitively) set proportional relationships when two quantities in a reaction are expressed in non-molar quantities such as mass. The data also bring to the fore the primarily formulaic approach that student-teachers use in setting inherent proportionality relationships. An important finding is the interpretation of a chemical equation as a mathematical equation, rather than a statement of proportionality.

  15. Statistical distribution of the difference of two proportions.

    PubMed

    Nadarajah, Saralees; Kotz, Samuel

    2007-08-15

    Differences of two proportions or rates occur most frequently in biomedical research. However, as far as published work in the Statistics in Medicine are concerned, only approximations have been used to study the distribution of such differences. In this Letter, we derive the exact probability distribution of the difference of two proportions. The expression involves a well-known special function. It is expected that this result could be widely useful for medical practitioners.

  16. Treatment of diabetic rats with a peroxynitrite decomposition catalyst prevents induction of renal COX-2.

    PubMed

    Chen, Yu-Jung; Santos, Margarita; Quilley, John

    2011-03-01

    Cyclooxygenase (COX)-2 expression is increased in the kidney of rats made diabetic with streptozotocin and associated with enhanced release of prostaglandins stimulated by arachidonic acid (AA). Treatment of diabetic rats with nitro-L-arginine methyl ester (L-NAME) to inhibit nitric oxide synthase or with tempol to reduce superoxide prevented these changes, suggesting the possibility that peroxynitrite (ONOO) may be the stimulus for the induction of renal COX-2 in diabetes. Consequently, we tested the effects of an ONOO decomposition catalyst, 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron(III) (FeTMPyP), which was administered for 3-4 wk after the induction of diabetes. FeTMPyP treatment normalized the twofold increase in the expression of nitrotyrosine, a marker for ONOO formation, in the diabetic rat and prevented the increase in renal COX-2 expression without modifying the two- to threefold increases in renal release of prostaglandins PGE(2) and 6-ketoPGF(1α) in response to AA. FeTMPyP treatment of diabetic rats reduced the elevated creatinine clearance and urinary excretion of TNF-α and transforming growth factor (TGF)-β, suggesting a renoprotective effect. Double immunostaining of renal sections and immunoprecipitation of COX-2 and nitrotyrosine suggested nitration of COX-2 in diabetic rats. In cultured human umbilical vein endothelial cells (HUVECs) exposed to elevated glucose (450 mg/dl) or ONOO derived from 3-morpholinosydnonimine (SIN-1), expression of COX-2 was increased and was prevented when endothelial cells were treated with FeTMPyP. These results indicate that elevated glucose increases the formation of ONOO, which contributes to the induction of renal COX-2 in the diabetic rat.

  17. Staurosporine synergistically potentiates the deoxycholate-mediated induction of COX-2 expression.

    PubMed

    Saeki, Tohru; Inui, Haruka; Fujioka, Saya; Fukuda, Suguru; Nomura, Ayumi; Nakamura, Yasushi; Park, Eun Young; Sato, Kenji; Kanamoto, Ryuhei

    2014-08-01

    Colorectal cancer is a major cause of cancer-related death in western countries, and thus there is an urgent need to elucidate the mechanism of colorectal tumorigenesis. A diet that is rich in fat increases the risk of colorectal tumorigenesis. Bile acids, which are secreted in response to the ingestion of fat, have been shown to increase the risk of colorectal tumors. The expression of cyclooxygenase (COX)-2, an inducible isozyme of cyclooxygenase, is induced by bile acids and correlates with the incidence and progression of cancers. In this study, we investigated the signal transduction pathways involved in the bile-acid-mediated induction of COX-2 expression. We found that staurosporine (sts), a potent protein kinase C (PKC) inhibitor, synergistically potentiated the deoxycholate-mediated induction of COX-2 expression. Sts did not increase the stabilization of COX-2 mRNA. The sts- and deoxycholate-mediated synergistic induction of COX-2 expression was suppressed by a membrane-permeable Ca(2+) chelator, a phosphoinositide 3-kinase inhibitor, a nuclear factor-κB pathway inhibitor, and inhibitors of canonical and stress-inducible mitogen-activated protein kinase pathways. Inhibition was also observed using PKC inhibitors, suggesting the involvement of certain PKC isozymes (η, θ, ι, ζ, or μ). Our results indicate that sts exerts its potentiating effects via the phosphorylation of p38. However, the effects of anisomycin did not mimic those of sts, indicating that although p38 activation is required, it does not enhance deoxycholate-induced COX-2 expression. We conclude that staurosporine synergistically enhances deoxycholate-induced COX-2 expression in RCM-1 colon cancer cells.

  18. Involvement of COX2-Thromboxane Pathway in TCDD-Induced Precardiac Edema in Developing Zebrafish

    PubMed Central

    Teraoka, Hiroki; Okuno, Yuki; Nijoukubo, Daisuke; Yamakoshi, Ayumi; Peterson, Richard E.; Stegeman, John J.; Kitazawa, Takio; Hiraga, Takeo; Kubota, Akira

    2015-01-01

    The cardiovascular system is one of the most characteristic and important targets for developmental toxicity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in fish larvae. However, knowledge of the mechanism of TCDD-induced edema after heterodimerization of aryl hydrocarbon receptor type 2 (AHR2) and AHR nuclear translocator type 1 (ARNT1) is still limited. In the present study, microscopic analysis with a high-speed camera revealed that TCDD increased the size of a small cavity between the heart and body wall in early eleutheroembryos, a toxic effect that we designate as precardiac edema. A concentration-response curve for precardiac edema at 2 days post fertilization (dpf) showed close similarity to that for conventional pericardial edema at 3 dpf. Precardiac edema caused by TCDD was reduced by morpholino knockdown of AHR2 and ARNT1, as well as by an antioxidant (ascorbic acid). A selective inhibitor of cyclooxygenase type 2 (COX2), NS398, also markedly inhibited TCDD-induced precardiac edema. A thromboxane receptor (TP) antagonist, ICI-192,605 almost abolished TCDD-induced precardiac edema and this effect was cancelled by U46619, a TP agonist, which was not influential in the action of TCDD by itself. Knockdown of COX2b and thromboxane A synthase 1 (TBXS), but not COX2a, strongly reduced TCDD-induced precardiac edema. Knockdown of COX2b was without effect on mesencephalic circulation failure caused by TCDD. The edema by TCDD was also inhibited by knockdown of c-mpl, a thrombopoietin receptor necessary for thromobocyte production. Finally, induction of COX2b, but not COX2a, by TCDD was seen in eleutheroembryos at 3 dpf. These results suggest a role of the COX2b-thromboxane pathway in precardiac edema formation following TCDD exposure in developing zebrafish. PMID:24858302

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

    PubMed Central

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

    2010-01-01

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

  20. Clinical significance of COX-2, GLUT-1 and VEGF expressions in endometrial cancer tissues

    PubMed Central

    Ma, Xiaoping; Hui, Yuzuo; Lin, Li; Wu, Yu; Zhang, Xian; Liu, Peishu

    2015-01-01

    Objective: To analyze the clinical significance of COX-2, GLUT-1 and VEGF expressions in endometrial cancer tissues. Methods: One hundred and eight tissue samples from the patients with endometrial cancer enrolled in our hospital from August 2011 to July 2014 were selected, including 60 normal tissue samples (normal group), 60 neoplastic tissue samples (neoplastic group) and 60 cancer tissue samples (cancer group). All the samples were subjected to immunohistochemical assay to detect the expressions of COX-2, GLUT-1 and VEGF. The clinical data were also investigated for correlation analysis. Results: The positive rates of COX-2 in normal group, neoplastic group and cancer groups were 3.3%, 21.7% and 55.0% respectively. The positive rates of GLUT-1 in normal group, neoplastic group and cancer groups were 3.3%, 25.0% and 70.0% respectively. The positive rates of VEGF in normal group, neoplastic group and cancer groups were 1.7%, 23.3% and 63.3% respectively. With increasing stage of such cancer, decreasing degree of differentiation and lymphatic metastasis, the positive expression rates of COX-2, GLUT-1 and VEGF proteins were raised significantly (P<0.05). Spearman’s correlation analysis showed that the expressions of COX-2 and GLUT-1 (r=0.207, P<0.05), COX-2 and VEGF (r=0.243, P<0.05), as well as GLUT-1 and VEGF (r=0.758, P<0.05) were positively correlated. Conclusion: COX-2, GLUT-1 and VEGF were highly prominent in endometrial cancer, especially in the patients with low degree of differentiation, late stage and metastasis. They functioned synergistically in the onset and progression of this cancer. PMID:26101475

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

    PubMed Central

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

    2014-01-01

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

  2. Niacin and biosynthesis of PGD2 by platelet COX-1 in mice and humans

    PubMed Central

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

    2012-01-01

    The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1–dependent formation of PGD2 and PGE2 followed by COX-2–dependent production of PGE2. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD2 receptor DP1. NSAID-mediated suppression of COX-2–derived PGI2 has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD2. Here, we show that PGD2 biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1–derived PGD2 biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD2 was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD2, like PGI2, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy. PMID:22406532

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

    PubMed

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

    2012-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  5. Empirical study of alginate impression materials by customized proportioning system

    PubMed Central

    2016-01-01

    PURPOSE Alginate mixers available in the market do not have the automatic proportioning unit. In this study, an automatic proportioning unit for the alginate mixer and controller software were designed and produced for a new automatic proportioning unit. With this device, it was ensured that proportioning operation could arrange weight-based alginate impression materials. MATERIALS AND METHODS The variation of coefficient in the tested groups was compared with the manual proportioning. Compression tension and tear tests were conducted to determine the mechanical properties of alginate impression materials. The experimental data were statistically analyzed using one way ANOVA and Tukey test at the 0.05 level of significance. RESULTS No statistically significant differences in modulus of elastisity (P>0.3), tensional/compresional strength (P>0.3), resilience (P>0.2), strain in failure (P>0.4), and tear energy (P>0.7) of alginate impression materials were seen. However, a decrease in the standard deviation of tested groups was observed when the customized machine was used. To verify the efficiency of the system, powder and powder/water mixing were weighed and significant decrease was observed. CONCLUSION It was possible to obtain more mechanically stable alginate impression materials by using the custom-made proportioning unit. PMID:27826387

  6. Close antiplatelet therapy monitoring and adjustment based upon thrombelastography may reduce late-onset bleeding in HeartMate II ecipients

    PubMed Central

    Karimi, Ashkan; Beaver, Thomas M.; Hess, Philip J.; Martin, Tomas D.; Staples, Edward D.; Schofield, Richard S.; Hill, James A.; Aranda, Juan M.; Klodell, Charles T.

    2014-01-01

    OBJECTIVES Bleeding is the most common complication of HeartMate II and is partially attributable to platelet dysfunction; however, antiplatelet therapy is arbitrary in most centres. We investigated how antiplatelet therapy adjustment with thrombelastography affects late-onset bleeding. METHODS Thrombelastography was used to adjust antiplatelet therapy in 57 HeartMate II recipients. Kaplan–Meier survival curves and Cox proportional hazard ratio model were used to identify predictors of late-onset bleeding in univariate and multivariate analysis. Finally, late-onset bleeding rate in our study was compared with the reported rates in other studies in the literature, all of which did not use any test to monitor or adjust antiplatelet therapy. RESULTS Mean follow-up was 347 days. Eighteen late-onset bleeding events occurred in 12 patients, a late-onset bleeding rate of 12/57 (21%) or 0.21 events/patient-year. The Kaplan–Meier survival curves demonstrated that late-onset bleeding was more common in the destination therapy cohort (P = 0.02), in patients older than 60 years (P = 0.04) and in females (P = 0.01), none of which was significant in multivariate analysis at a significance level of 0.05. To further investigate the higher bleeding rate in elderly patients, thrombelastography parameters were compared between younger and older patients at the age cut-off of 60 years which demonstrated a prothrombotic change the day after device implantation in younger patients that was absent in the elderly. There was also a trend towards higher requirement for antiplatelet therapy in younger patients while on device support, but the difference did not reach statistical significance. The average late-onset or gastrointestinal bleeding rate among seven comparable studies in the literature that did not use any monitoring test to adjust antiplatelet therapy was 0.49 events/patient-year. CONCLUSIONS Our study implicates that antiplatelet therapy adjustment with thrombelastography

  7. Spousal Adjustment to Myocardial Infarction.

    ERIC Educational Resources Information Center

    Ziglar, Elisa J.

    This paper reviews the literature on the stresses and coping strategies of spouses of patients with myocardial infarction (MI). It attempts to identify specific problem areas of adjustment for the spouse and to explore the effects of spousal adjustment on patient recovery. Chapter one provides an overview of the importance in examining the…

  8. Nepalese Esthetic Dental (NED) Proportion in Nepalese Population.

    PubMed

    Rokaya, D; Kitisubkanchana, J; Wonglamsam, A; Santiwong, P; Srithavaj, T; Humagain, M

    2015-01-01

    Background Lots of studies on maxillary anterior teeth proportions have been studied in different populations in various countries, but no studies have been conducted in Nepal on the esthetic maxillary anterior teeth proportions. Objective The study was done to investigate the maxillary anterior teeth proportions in a Nepalese population. Teeth proportions in the total population were compared with golden proportion (GP) and golden standard (GS). Method A total of 150 Nepalese subjects were divided in three facial types; broad, average and narrow group. Maxillary anterior teeth were measured from dental casts using digital calipers. The perceived width ratios of lateral to central incisor (LI/CI) and canine to lateral incisor (CN/LI), ratios of mean central incisor length to 2 central incisor widths (CIL/2CIW), and actual width to length ratios (WLRs) (%) were calculated in each facial type and compared. Mean LI/CI, CN/LI and CIL/2CIW in total population were calculated and compared with GP (0.618), and mean WLRs in the total population were compared with GS (80%). All teeth proportions were compared among three facial types. One-sample t-test and one-way ANOVA were performed to analyze the data (α = 0.05). Result The LI/CI, CN/LI, CIL/2CIW and WLRs in three facial types showed no significant difference. The LI/CI, CN/LI and CIL/2CIW in the total population were 66%, 70% and 55% respectively, and were significantly different from GP. The WLRs for CI, LI and CN in the total population were 90%, 86% and 89% respectively and significantly differed from GS. These values were considered to constitute the Nepalese Esthetic Dental (NED) proportion. Conclusion No significant difference of maxillary anterior teeth proportions were observed among three facial types. Teeth proportions in the total population significantly differed from GP and GS. We propose the NED proportion as a guideline for dental treatment in the maxillary anterior region in Nepalese populations.

  9. Proportional counter for X-ray analysis of lunar and planetary surfaces. [a position sensitive scintillating imaging proportional counter

    NASA Technical Reports Server (NTRS)

    1979-01-01

    A position sensitive proportional scintillation detector was developed and evaluated for use in applications involving X-ray imaging as well as spectroscopy. Topics covered include limitations of the proportional scintillation counter for use in space; purification of the xenon gas in the detector, and the operation of the detector system. Results show that the light signal in a proportional scintillation detector remains well localized. With modest electric fields in xenon, the primary electrons from a photoelectric absorption of an X-ray can be brought a distance of a few millimeters to a higher field region without spreading more than a millimeter or so. Therefore, it is possible to make a proportional scintillation detector with good position sensitivity that could be used to calibrate out the difference in light collection over its sensitive volume.

  10. ["Golden proportion" and its application to calculate dentition].

    PubMed

    Vadachkoriia, N R; Gumberidze, N Sh; Mandzhavidze, N A

    2007-01-01

    Within an evolutionary process, the nature has created the standard of aesthetics - a "gold proportion" on the basis of which, the parts of human body, to be more exact, teeth and denture correspond to each other and to own parts by the size, which is the ideal precondition for ideal appearance. The charming smile serves as the proof, that teeth in denture are located by a principle of "gold proportion". A "gold proportion" is the corner stone of beauty and it can be applied with success in stomatology. Proportion is the certain ratio between parts, and proportional means a proper correlation of parts among themselves. It is reputed, that knowledge about "gold proportion" Pythagor has got from products of the Egyptian and Babylon scientists. And this is true, proportions of cult constructions, bas-relieves, pyramids in Giza, home appliances and ornaments from Tutanhamon tomb testify, that under their creation the Egyptian masters were guided by a principle of "gold proportion". The facade of ancient Greek temple Parthenon is built by a principle of "gold proportion". During archeological digs of this temple the compasses which sculptors and architects of an ancient world used has been found. The "gold proportion" is mentioned in the work which has reached us "Beginning" the author is the scientist of antique epoch Euclid. In 1509, in Venice the book of Luka Pacholi the "Divine proportion" has been published, its illustration is attributed to Leonardo de Vinci. This work has been recognized as a "Hymn of a gold proportion". In 1885 the German researcher professor Zeising published his work - "Aesthetic researches". When Zeising has received numerical values of piece length, he saw that they coincided with figures of some numerical sequence, which was offered by the great Italian mathematician of Middle Ages Fibonacci (or Leonardo Pisano). In his composition the "Abacus Book" Leonardo Fibonacci showed aforesaid sequence of numbers, by means of which he has explained

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

    PubMed

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

    2014-11-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    SciTech Connect

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

    2013-04-15

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

  15. Limb-size proportions in Australopithecus afarensis and Australopithecus africanus.

    PubMed

    Green, David J; Gordon, Adam D; Richmond, Brian G

    2007-02-01

    Previous analyses have suggested that Australopithecus africanus possessed more apelike limb proportions than Australopithecus afarensis. However, due to the errors involved in estimating limb length and body size, support for this conclusion has been limited. In this study, we use a new Monte Carlo method to (1) test the hypothesis that A. africanus had greater upper:lower limb-size proportions than A. afarensis and (2) assess the statistical significance of interspecific differences among these taxa, extant apes, and humans. Our Monte Carlo method imposes sampling constraints that reduce extant ape and human postcranial measurements to sample sizes comparable to the fossil samples. Next, composite ratios of fore- and hindlimb geometric means are calculated for resampled measurements from the fossils and comparative taxa. Mean composite ratios are statistically indistinguishable (alpha=0.05) from the actual ratios of extant individuals, indicating that this method conserves each sample's central tendency. When applied to the fossil samples, upper:lower limb-size proportions in A. afarensis are similar to those of humans (p=0.878) and are significantly different from all great ape proportions (p< or =0.034), while Australopithecus africanus is more similar to the apes (p> or =0.180) and significantly different from humans and A. afarensis (p< or =0.031). These results strongly support the hypothesis that A. africanus possessed more apelike limb-size proportions than A. afarensis, suggesting that A. africanus either evolved from a more postcranially primitive ancestor than A. afarensis or that the more apelike limb-size proportions of A. africanus were secondarily derived from an A. afarensis-like ancestor. Among the extant taxa, limb-size proportions correspond with observed levels of forelimb- and hindlimb-dominated positional behaviors. In conjunction with detailed anatomical features linked to arboreality, these results suggest that arboreal posture and

  16. Assessment of facial golden proportions among central Indian population

    PubMed Central

    Saurabh, Rathore; Piyush, Bolya; Sourabh, Bhatt; Preeti, Ojha; Trivedi, Rutvik; Vishnoi, Pradeep

    2016-01-01

    Aim: This study aimed to identify and establish the facial and smile proportions in young adults and to compare the results with ideal or divine proportions, compare the proportions of males and females included in our study population and compare them with those established for Caucasian and Japanese populations. Materials and Methods: Two hundred participants (164 females, 36 males) with Angle's class I malocclusion (M.O). and well-balanced faces were selected and photographed in the frontal repose position. Analysis was done in Adobe Photoshop software. Statistical analysis was done using the Statistical Package for the Social Sciences version 17.0. (IBM Corporation Armonk, New York, United States). Results: Results suggested that females are more near to ideal ratios and males are more deviated from the ideal ratios. The proportions of males and females were not considerably different from each other. In Indian population, upper 3rd facial height (TR-LC) was increased and mid-face height (LC-LN) was decreased; in lower 3rd of the face, LN-CH was slightly increased in comparison to CH-ME. In facial widths, outer canthal width (LC-LC) was greater in the Indian population and mouth width (CH-CH) was normal. When compared with Indian population, Japanese participants had wider noses, outer canthal distance, and bitemporal width. Conclusion: It was concluded that significant difference was found between the proportions of the Indian population and ideal ratio. When Indian population was compared with Japanese and Caucasian populations, some parameters of facial proportions showed significant difference, which leads to the need for establishing standardized norms for various facial proportions in Indian population. PMID:28217534

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

    PubMed

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

    2015-11-01

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

  18. Oms1 associates with cytochrome c oxidase assembly intermediates to stabilize newly synthesized Cox1.

    PubMed

    Bareth, Bettina; Nikolov, Miroslav; Lorenzi, Isotta; Hildenbeutel, Markus; Mick, David U; Helbig, Christin; Urlaub, Henning; Ott, Martin; Rehling, Peter; Dennerlein, Sven

    2016-05-15

    The mitochondrial cytochrome c oxidase assembles in the inner membrane from subunits of dual genetic origin. The assembly process of the enzyme is initiated by membrane insertion of the mitochondria-encoded Cox1 subunit. During complex maturation, transient assembly intermediates, consisting of structural subunits and specialized chaperone-like assembly factors, are formed. In addition, cofactors such as heme and copper have to be inserted into the nascent complex. To regulate the assembly process, the availability of Cox1 is under control of a regulatory feedback cycle in which translation of COX1 mRNA is stalled when assembly intermediates of Cox1 accumulate through inactivation of the translational activator Mss51. Here we isolate a cytochrome c oxidase assembly intermediate in preparatory scale from coa1Δ mutant cells, using Mss51 as bait. We demonstrate that at this stage of assembly, the complex has not yet incorporated the heme a cofactors. Using quantitative mass spectrometry, we define the protein composition of the assembly intermediate and unexpectedly identify the putative methyltransferase Oms1 as a constituent. Our analyses show that Oms1 participates in cytochrome c oxidase assembly by stabilizing newly synthesized Cox1.

  19. Clinicopathological and prognostic significance of COX-2 immunohistochemical expression in breast cancer: a meta-analysis

    PubMed Central

    Xu, Feng; Li, Mengxin; Zhang, Chao; Cui, Jianxiu; Liu, Jun; Li, Jie; Jiang, Hongchuan

    2017-01-01

    The prognostic significance of COX-2 in patients with breast cancer remains controversial. The aims of our meta-analysis are to evaluate its association with clinicopathological characteristics and prognostic value in patients with breast cancer. PubMed, EMBASE, Web of Science, the Ovid Database and Grey literature were systematically searched up to May 2016. Twenty-one studies including 6739 patients with breast cancer were analyzed. The meta-analysis indicated that the incidence difference of COX-2 expression was significant when comparing the lymph node positive group to negative group (OR = 1.76, 95% CI [1.30, 2.39]) and the tumor size ≥ 2cm group to the tumor size < 2cm group (OR = 1.71, 95% CI [1.22, 2.39]). None of other clinicopathological parameters such as the ER status, PR status, HER2 status and the vascular invasion status were associated with COX-2 overexpression. The detection of COX-2 was significantly correlated with the disease-free survival (DFS) of patients (HR = 1.58, 95% CI [1.23, 2.03]) and the overall survival (OS) of patients (HR = 1.51, 95% CI [1.31, 1.72]). Our meta-analysis demonstrates that the presence of high levels of COX-2 is associated with poor prognosis for breast cancer patients and predicts bigger tumor size and lymph node metastasis. PMID:27999206

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

    PubMed Central

    2010-01-01

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

  1. Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies.

    PubMed

    Migliore, Marco; Habrant, Damien; Sasso, Oscar; Albani, Clara; Bertozzi, Sine Mandrup; Armirotti, Andrea; Piomelli, Daniele; Scarpelli, Rita

    2016-02-15

    Non-steroidal anti-inflammatory drugs (NSAIDs) exert their pharmacological effects by inhibiting cyclooxygenase (COX)-1 and COX-2. Though widely prescribed for pain and inflammation, these agents have limited utility in chronic diseases due to serious mechanism-based adverse events such as gastrointestinal damage. Concomitant blockade of fatty acid amide hydrolase (FAAH) enhances the therapeutic effects of the NSAIDs while attenuating their propensity to cause gastrointestinal injury. This favorable interaction is attributed to the accumulation of protective FAAH substrates, such as the endocannabinoid anandamide, and suggests that agents simultaneously targeting COX and FAAH might provide an innovative strategy to combat pain and inflammation with reduced side effects. Here, we describe the rational design and structure-active relationship (SAR) properties of the first class of potent multitarget FAAH-COX inhibitors. A focused SAR exploration around the prototype 10r (ARN2508) led to the identification of achiral (18b) as well as racemic (29a-c and 29e) analogs. Absolute configurational assignment and pharmacological evaluation of single enantiomers of 10r are also presented. (S)-(+)-10r is the first highly potent and selective chiral inhibitor of FAAH-COX with marked in vivo activity, and represents a promising lead to discover novel analgesics and anti-inflammatory drugs.

  2. 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.

  3. 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.

  4. Extracellular histones disarrange vasoactive mediators release through a COX-NOS interaction in human endothelial cells.

    PubMed

    Pérez-Cremades, Daniel; Bueno-Betí, Carlos; García-Giménez, José Luis; Ibañez-Cabellos, José Santiago; Hermenegildo, Carlos; Pallardó, Federico V; Novella, Susana

    2017-02-28

    Extracellular histones are mediators of inflammation, tissue injury and organ dysfunction. Interactions between circulating histones and vascular endothelial cells are key events in histone-mediated pathologies. Our aim was to investigate the implication of extracellular histones in the production of the major vasoactive compounds released by human endothelial cells (HUVECs), prostanoids and nitric oxide (NO). HUVEC exposed to increasing concentrations of histones (0.001 to 100 μg/ml) for 4 hrs induced prostacyclin (PGI2) production in a dose-dependent manner and decreased thromboxane A2 (TXA2) release at 100 μg/ml. Extracellular histones raised cyclooxygenase-2 (COX-2) and prostacyclin synthase (PGIS) mRNA and protein expression, decreased COX-1 mRNA levels and did not change thromboxane A2 synthase (TXAS) expression. Moreover, extracellular histones decreased both, eNOS expression and NO production in HUVEC. The impaired NO production was related to COX-2 activity and superoxide production since was reversed after celecoxib (10 μmol/l) and tempol (100 μmol/l) treatments, respectively. In conclusion, our findings suggest that extracellular histones stimulate the release of endothelial-dependent mediators through an up-regulation in COX-2-PGIS-PGI2 pathway which involves a COX-2-dependent superoxide production that decreases the activity of eNOS and the NO production. These effects may contribute to the endothelial cell dysfunction observed in histone-mediated pathologies.

  5. Adjustable electronic load-alarm relay

    DOEpatents

    Mason, Charles H.; Sitton, Roy S.

    1976-01-01

    This invention is an improved electronic alarm relay for monitoring the current drawn by an AC motor or other electrical load. The circuit is designed to measure the load with high accuracy and to have excellent alarm repeatability. Chattering and arcing of the relay contacts are minimal. The operator can adjust the set point easily and can re-set both the high and the low alarm points by means of one simple adjustment. The relay includes means for generating a signal voltage proportional to the motor current. In a preferred form of the invention a first operational amplifier is provided to generate a first constant reference voltage which is higher than a preselected value of the signal voltage. A second operational amplifier is provided to generate a second constant reference voltage which is lower than the aforementioned preselected value of the signal voltage. A circuit comprising a first resistor serially connected to a second resistor is connected across the outputs of the first and second amplifiers, and the junction of the two resistors is connected to the inverting terminal of the second amplifier. Means are provided to compare the aforementioned signal voltage with both the first and second reference voltages and to actuate an alarm if the signal voltage is higher than the first reference voltage or lower than the second reference voltage.

  6. Limb proportions show developmental plasticity in response to embryo movement

    PubMed Central

    Pollard, A. S.; Charlton, B. G.; Hutchinson, J. R.; Gustafsson, T.; McGonnell, I. M.; Timmons, J. A.; Pitsillides, A. A.

    2017-01-01

    Animals have evolved limb proportions adapted to different environments, but it is not yet clear to what extent these proportions are directly influenced by the environment during prenatal development. The developing skeleton experiences mechanical loading resulting from embryo movement. We tested the hypothesis that environmentally-induced changes in prenatal movement influence embryonic limb growth to alter proportions. We show that incubation temperature influences motility and limb bone growth in West African Dwarf crocodiles, producing altered limb proportions which may, influence post-hatching performance. Pharmacological immobilisation of embryonic chickens revealed that altered motility, independent of temperature, may underpin this growth regulation. Use of the chick also allowed us to merge histological, immunochemical and cell proliferation labelling studies to evaluate changes in growth plate organisation, and unbiased array profiling to identify specific cellular and transcriptional targets of embryo movement. This disclosed that movement alters limb proportions and regulates chondrocyte proliferation in only specific growth plates. This selective targeting is related to intrinsic mTOR (mechanistic target of rapamycin) pathway activity in individual growth plates. Our findings provide new insights into how environmental factors can be integrated to influence cellular activity in growing bones and ultimately gross limb morphology, to generate phenotypic variation during prenatal development. PMID:28165010

  7. How well proportioned are lens and prism spaces?

    NASA Astrophysics Data System (ADS)

    Aurich, R.; Lustig, S.

    2012-09-01

    The cosmic microwave background (CMB) anisotropies in spherical 3-spaces with a non-trivial topology are analysed with a focus on lens- and prism-shaped fundamental cells. The conjecture is tested that well-proportioned spaces lead to a suppression of large-scale anisotropies according to the observed CMB. The focus is put on lens spaces L(p, q) which are supposed to be oddly proportioned. However, there are inhomogeneous lens spaces whose shape of the Voronoi domain depends on the position of the observer within the manifold. Such manifolds possess no fixed measure of the well-proportioned property and allow a predestined test of the well-proportioned conjecture. Topologies having the same Voronoi domain are shown to possess distinct CMB statistics which thus provide a counter-example to the well-proportioned conjecture. The CMB properties are analysed in terms of cyclic subgroups Zp, and a new point of view for the superior behaviour of the Poincaré dodecahedron is found.

  8. Collaboration promotes proportional reasoning about resource distribution in young children.

    PubMed

    Ng, Rowena; Heyman, Gail D; Barner, David

    2011-09-01

    The authors investigated how children and adults evaluate the "niceness" of individuals who engage in resource distribution, with a focus on their sensitivity to the proportion of resources given. Across 3 experiments, subjects evaluated the niceness of a child who gave a quantity of pennies to another child. In Study 1 (N = 30), adults showed sensitivity to the proportion given, whereas 5- and 7-year-old children did not. In Study 2 (N = 74), both younger (3- to 5-year-old) and older (6- to 8-year-old) children were sensitive to proportion only when resources were earned by a giver in collaboration with the recipient rather than by the giver alone. Adults, however, were sensitive to proportion in both cases. In Study 3 (N = 44), the authors tested 5- and 6-year-olds and their parents to be sure that socioeconomic and ethnic differences between samples did not drive results and replicated key findings from Studies 1 and 2. Together, these findings indicate that children favor proportional resource distribution in situations that invoke intuitions about equity. The authors suggest that these intuitions may form the basis for adult notions of fairness and generosity.

  9. Limb proportions show developmental plasticity in response to embryo movement.

    PubMed

    Pollard, A S; Charlton, B G; Hutchinson, J R; Gustafsson, T; McGonnell, I M; Timmons, J A; Pitsillides, A A

    2017-02-06

    Animals have evolved limb proportions adapted to different environments, but it is not yet clear to what extent these proportions are directly influenced by the environment during prenatal development. The developing skeleton experiences mechanical loading resulting from embryo movement. We tested the hypothesis that environmentally-induced changes in prenatal movement influence embryonic limb growth to alter proportions. We show that incubation temperature influences motility and limb bone growth in West African Dwarf crocodiles, producing altered limb proportions which may, influence post-hatching performance. Pharmacological immobilisation of embryonic chickens revealed that altered motility, independent of temperature, may underpin this growth regulation. Use of the chick also allowed us to merge histological, immunochemical and cell proliferation labelling studies to evaluate changes in growth plate organisation, and unbiased array profiling to identify specific cellular and transcriptional targets of embryo movement. This disclosed that movement alters limb proportions and regulates chondrocyte proliferation in only specific growth plates. This selective targeting is related to intrinsic mTOR (mechanistic target of rapamycin) pathway activity in individual growth plates. Our findings provide new insights into how environmental factors can be integrated to influence cellular activity in growing bones and ultimately gross limb morphology, to generate phenotypic variation during prenatal development.

  10. Robust Inhibitory Effects of Conjugated Linolenic Acids on a Cyclooxygenase-related Linoleate 10S-Dioxygenase: Comparison with COX-1 and COX-2

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-10-01

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

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

    PubMed

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

    2007-08-01

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

  13. Myricetin blocks lipoteichoic acid-induced COX-2 expression in human gingival fibroblasts.

    PubMed

    Gutiérrez-Venegas, Gloria; Luna, Oscar Alonso; Arreguín-Cano, Juan Antonio; Hernández-Bermúdez, Cristina

    2014-03-01

    Periodontitis is an infectious disease caused by microorganisms present in dental bacterial plaque. Lipoteichoic acid (LTA) is a component of the external membrane of Gram-positive bacteria. It causes septic shock. Ingested flavonoids have been reported to directly affect the regulation of cyclooxygenase-2 (COX-2) expression induced by bacterial toxins. In this study, we examined the effects of four flavonoids (luteolin, fisetin, morin and myricetin) on the activation of ERK1/2, p38 and AKT, and on the synthesis of COX-2 in human gingival fibroblasts treated with LTA from Streptococcus sanguinis. We found that luteolin and myricetin blocked AKT and p38 activation and that myricetin blocked LTA-induced COX-2 expression. The results of our study are important for elucidating the mechanism of action of flavonoid regulation of inflammatory responses.

  14. Dietary glycerol for quail: association between productive performance and COX III mRNA expression.

    PubMed

    Silva, S C C; Gasparino, E; Batista, E; Tanamati, F; Vesco, A P D; Lala, B; de Oliveira, D P

    2016-05-25

    This study was carry out to evaluate mRNA expression of mitochondrial cytochrome c oxidase III in the Pectoralis superficialis muscle of 28-day-old quails fed diets containing 0, 8, and 12% glycerol. Total RNA was extracted (N = 10) and cDNA was amplified using specifics primers for qRT-PCR. Feed efficiency and feed intake were evaluated. COX III mRNA expression in breast muscle was higher in the group fed with 12% glycerol (0.863 AU); no differences were observed in the expression of this gene between the muscle of animals fed diets without glycerol (0.357 AU) and 8% glycerol (0.415 AU). Quails that showed greater COX III mRNA expression also showed the lowest feed efficiency. These results show that there is a difference in COX III mRNA expression in breast muscle of 28-day-old quail fed diets different concentrations of glycerol.

  15. [Specific inhibitors of cyclooxygenase-2 (COX-2): current knowledge and perspectives].

    PubMed

    Rioda, W T; Nervetti, A

    2001-01-01

    The Authors summarize the current knowledge on a new class of nonsteroidal anti-inflammatory drugs (NSAIDs), the coxib (celecoxib and rofecoxib), in the treatment of rheumatic diseases. Celecoxib and rofecoxib are selective cyclooxygenase-2 (COX-2) inhibitors which possess the same anti-inflammatory and analgesic activities, but a better gastric tolerability compared to the non-selective COX-1 and COX-2 inhibitors. The Authors also report other possible therapeutic effects of these NSADIs as evidenced by the more recent data of the literature. Celecoxib seems to reduce the incidence of new polyps in patients with familial adenomatous polyposis. It has been suggested the use of celecoxib as a protective drug against the development of colorectal cancer. Other (neoplastic) or pre-neoplastic conditions, such as bladder dysplasia, Barret esophagus, attinic keratosis and Alzheimer's disease seem to have benefit from this class of drugs.

  16. Efficacy and Safety of COX-2 Inhibitors in the Clinical Management of Arthritis: Mini Review

    PubMed Central

    Mathew, Sam T.; Devi S, Gayathri; Prasanth, V. V.; Vinod, B.

    2011-01-01

    In the clinical management of arthritis, the choice of nonsteroidal anti inflammatory drug (NSAID) remains confusing and controversial. A common practice on the choice of NSAID in clinical management of arthritis is the risk benefit ratio. The main objective of this review is to addresses the main arguments for the pharmacological and clinical use of COX-2 inhibitors in relation to nonselective NSAIDs for the clinical management of arthritis. This review concluded that, both NSAIDs and COX-2 inhibitors are equally effective and are associated with increased risk of GI, renal, and CV, adverse effects. Complete understanding of the patient's comorbid conditions and concomitant medications, coupled with precise monitoring during the treatment, may help to decrease the threat of adverse effects induced by nonselective NSAIDs and selective COX-2 inhibitors. PMID:22084715

  17. Safety studies on hydraulic proportional valves with electrical position feedback.

    PubMed

    Reinert, Dietmar; Kimura, Tetsuya; Gorgs, Karl-Josef

    2006-01-01

    The authors analysed a proportional valve with electrical position feedback for its failure behaviour. Several failures were introduced into the feedback loop, especially into the 2 solenoids and the inductive position transducer. The behaviour of the valve for square and ramp reference signals was recorded and systematically analysed. It was shown that failures could be detected by monitoring the residual signal from the equipment under control or the residual signal from the sensor. It was possible to achieve the safe position within twice the normal response time of the valve by switching off the current of both solenoids. The application of these results for a new generation of safe proportional valves is discussed. The use of the results of these investigations obviates the need for redundancy of the electrical position monitoring arrangement in a safe proportional valve.

  18. Leg length, proportion, health and beauty: a review.

    PubMed

    Bogin, Barry; Varela-Silva, Maria Inês

    2009-12-01

    Decomposing stature into its major components is proving to be a useful strategy to assess the antecedents of disease, morbidity and death in adulthood. Human leg length (foot + tibia + femur), sitting height (trunk length + head length) and their proportions (for example the relative leg length in proportion to stature, and the sitting height ratio [sitting height/stature x 100], among others) are used as epidemiological markers of risk for overweight (fatness), coronary heart disease, diabetes and certain cancers. There is also wide support for the use of relative leg length as an indicator of the quality of the environment for growth during infancy, childhood and the juvenile years of development. Human beings follow a cephalo-caudal gradient of growth, the pattern of growth common to all mammals. A special feature of the human pattern is that between birth and puberty the legs grow relatively faster than other post-cranial body segments. For groups of children and youth, short stature due to relatively short legs (i.e. a high sitting height ratio) is generally a marker of an adverse environment. The development of human body proportions is the product of environmental x genomic interactions, although few if any specific genes are known. The short stature homeobox-containing gene (SHOX) is the first genomic region that may be relevant to human body proportions. For example, one of the SHOX related disorders is Turner syndrome. However, in most cases research has been showing that environment is a more powerful force to shape leg length and body proportions than genes. Leg length and proportion are important in the perception of human beauty, which is often considered a sign of health and fertility. There are a variety of cosmetic, fashion, and surgical interventions to enhance perceived or actual leg length.

  19. The first characterization of free radicals formed from cellular COX-catalyzed peroxidation.

    PubMed

    Gu, Yan; Xu, Yi; Law, Benedict; Qian, Steven Y

    2013-04-01

    Through free radical-mediated peroxidation, cyclooxygenase (COX) can metabolize dihomo-γ-linolenic acid (DGLA) and arachidonic acid (AA) to form well-known bioactive metabolites, namely, the 1-series of prostaglandins (PGs1) and the 2-series of prostaglandins (PGs2), respectively. Unlike PGs2, which are generally viewed as proinflammatory and procarcinogenic PGs, PGs1 may possess anti-inflammatory and anti-cancer activity. Previous studies using ovine COX along with spin trapping and the LC/ESR/MS technique have shown that certain exclusive free radicals are generated from different free radical reactions in DGLA and AA peroxidation. However, it has been unclear whether the differences were associated with the contrasting bioactivity of DGLA vs AA. The aim of this study was to refine the LC/MS and spin trapping technique to make it possible for the association between free radicals and cancer cell growth to be directly tested. Using a colon cancer cell line, HCA-7 colony 29, and LC/MS along with a solid-phase extraction, we were able to characterize the reduced forms of radical adducts (hydroxylamines) as the free radicals generated from cellular COX-catalyzed peroxidation. For the first time, free radicals formed in the COX-catalyzed peroxidation of AA vs DGLA and their association with cancer cell growth were assessed (cell proliferation via MTS and cell cycle distribution via propidium iodide staining) in the same experimental setting. The exclusive free radicals formed from the COX-catalyzed peroxidation of AA and DGLA were shown to be correlated with the cell growth response. Our results indicate that free radicals generated from the distinct radical reactions in COX-catalyzed peroxidation may represent the novel metabolites of AA and DGLA that correspond to their contrasting bioactivity.

  20. Lovastatin lactone elicits human lung cancer cell apoptosis via a COX-2/PPARγ-dependent pathway

    PubMed Central

    Ramer, Robert; Mittag, Nadine; Hinz, Burkhard

    2016-01-01

    Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) are well-established agents to treat hyperlipidemic states. Experimental and epidemiological evidence further implies an anticancer effect of these substances. This study investigates the mechanism underlying human lung cancer cell death by lovastatin and the role of the prostaglandin (PG)-synthesizing enzyme cyclooxygenase-2 (COX-2) in this process. In A549 and H358 lung carcinoma cells the lipophilic prodrug lovastatin lactone led to a concentration-dependent decrease of viability and induction of DNA fragmentation, whereas its HMG-CoA-inhibitory, ring-open acid form was inactive in this respect. Apoptotic cell death by lovastatin was accompanied by high intracellular levels of the lactone form, by upregulation of COX-2 mRNA and protein, as well as by increased formation of peroxisome proliferator-activated receptor γ (PPARγ)-activating PGD2 and 15-deoxy-Δ12,14-PGJ2. Cells were significantly less sensitive to lovastatin-induced apoptotic cell death, when the expression or activity of COX-2 was suppressed by siRNA or by the COX-2 inhibitor NS-398. Apoptosis by lovastatin was likewise reversed by the PPARγ antagonist GW9662. Fluorescence microscopy analyses revealed a lovastatin-induced cytosol-to-nucleus translocation of PPARγ that was inhibited by NS-398. Collectively, this study demonstrates COX-2 induction and subsequent COX-2-dependent activation of PPARγ as a hitherto unknown mechanism by which lovastatin lactone induces human lung cancer cell death. PMID:26863638

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

    PubMed

    Osman, Wesam M; Youssef, Nermeen S

    2015-01-01

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

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

    PubMed

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

    2014-01-01

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

  3. Licochalcones extracted from Glycyrrhiza inflata inhibit platelet aggregation accompanied by inhibition of COX-1 activity

    PubMed Central

    Okuda-Tanino, Asa; Sugawara, Daiki; Tashiro, Takumi; Iwashita, Masaya; Obara, Yutaro; Moriya, Takahiro; Tsushima, Chisato; Saigusa, Daisuke; Tomioka, Yoshihisa; Ishii, Kuniaki; Nakahata, Norimichi

    2017-01-01

    Licochalcones extracted from Glycyrrhiza inflata are known to have a variety of biological properties such as anti-inflammatory, anti-bacterial, and anti-tumor activities, but their action on platelet aggregation has not yet been reported. Therefore, in this study we investigated the effects of licochalcones on platelet aggregation. Collagen and U46619, a thromboxane A2 receptor agonist, caused rabbit platelet aggregation, which was reversed by pretreatment with licochalcones A, C and D in concentration-dependent manners. Among these compounds, licochalcone A caused the most potent inhibitory effect on collagen-induced platelet aggregation. However, the licochalcones showed marginal inhibitory effects on thrombin or ADP-induced platelet aggregation. In addition to rabbit platelets, licochalcone A attenuated collagen-induced aggregation in human platelets. Because licochalcone A also inhibited arachidonic acid-induced platelet aggregation and production of thromboxane A2 induced by collagen in intact platelets, we further examined the direct interaction of licochalcone A with cyclooxygenase (COX)-1. As expected, licochalcone A caused an inhibitory effect on both COX-1 and COX-2 in vitro. Regarding the effect of licochalcone A on COX-1 enzyme reaction kinetics, although licochalcone A showed a stronger inhibition of prostaglandin E2 synthesis induced by lower concentrations of arachidonic acid, Vmax values in the presence or absence of licochalcone A were comparable, suggesting that it competes with arachidonic acid at the same binding site on COX-1. These results suggest that licochalcones inhibit collagen-induced platelet aggregation accompanied by inhibition of COX-1 activity. PMID:28282426

  4. Licochalcones extracted from Glycyrrhiza inflata inhibit platelet aggregation accompanied by inhibition of COX-1 activity.

    PubMed

    Okuda-Tanino, Asa; Sugawara, Daiki; Tashiro, Takumi; Iwashita, Masaya; Obara, Yutaro; Moriya, Takahiro; Tsushima, Chisato; Saigusa, Daisuke; Tomioka, Yoshihisa; Ishii, Kuniaki; Nakahata, Norimichi

    2017-01-01

    Licochalcones extracted from Glycyrrhiza inflata are known to have a variety of biological properties such as anti-inflammatory, anti-bacterial, and anti-tumor activities, but their action on platelet aggregation has not yet been reported. Therefore, in this study we investigated the effects of licochalcones on platelet aggregation. Collagen and U46619, a thromboxane A2 receptor agonist, caused rabbit platelet aggregation, which was reversed by pretreatment with licochalcones A, C and D in concentration-dependent manners. Among these compounds, licochalcone A caused the most potent inhibitory effect on collagen-induced platelet aggregation. However, the licochalcones showed marginal inhibitory effects on thrombin or ADP-induced platelet aggregation. In addition to rabbit platelets, licochalcone A attenuated collagen-induced aggregation in human platelets. Because licochalcone A also inhibited arachidonic acid-induced platelet aggregation and production of thromboxane A2 induced by collagen in intact platelets, we further examined the direct interaction of licochalcone A with cyclooxygenase (COX)-1. As expected, licochalcone A caused an inhibitory effect on both COX-1 and COX-2 in vitro. Regarding the effect of licochalcone A on COX-1 enzyme reaction kinetics, although licochalcone A showed a stronger inhibition of prostaglandin E2 synthesis induced by lower concentrations of arachidonic acid, Vmax values in the presence or absence of licochalcone A were comparable, suggesting that it competes with arachidonic acid at the same binding site on COX-1. These results suggest that licochalcones inhibit collagen-induced platelet aggregation accompanied by inhibition of COX-1 activity.

  5. COX-2 inhibition affects growth rate of Chlamydia muridarum within epithelial cells.

    PubMed

    Liu, Wei; Dubinett, Steven; Patterson, Simie Lavern A; Kelly, Kathleen A

    2006-02-01

    Chlamydiae alter apoptosis of host target cells, which regulates their growth. Cyclooxygenase-2 (COX-2), the rate-limiting enzyme for prostaglandin E2 (PGE2) production, modulates epithelial cell survival. We addressed whether endogenous PGE2 alters chlamydial growth or apoptosis of epithelial cells infected with Chlamydia muridarum. PGE2 is secreted by infected host cells in the genital tract (GT). Using immunohistochemical techniques, we found that COX-2 enzyme was localized to epithelial cells in the GT in vivo. Pellets of the COX-2 enzyme inhibitor, NS-398, and placebo were implanted in mice subcutaneously and released a constant amount of these chemicals throughout the infection. NS-398-treated mice were found to exhibit 10-fold lower bacterial load than the placebo group on day 3 post infection, suggesting disruption of the chlamydial developmental cycle. To prove this, the human lung adenocarcinoma cell line A549 was then infected with different MOIs of C. muridarum in the presence of multiple concentrations of NS-398 in vitro. There was no difference in inclusion forming units (IFUs) between NS-389-treated and untreated cells. We also found no alterations in C. muridarum IFUs in A549 cells transfected with a 2.0 kb cDNA fragment of human COX-2 cloned in the sense (S) or anti-sense (AS) orientation. However, the inclusion size was reduced and the number of EB was significantly diminished during reinfection in AS-transfected cells. In addition, the absence of COX-2 did not significantly modify apoptosis in infected cells. In total, COX-2 deficiency reduces the infectious burden in vivo and may modulate transmission of the organism.

  6. Evaluation of Bayesian Sequential Proportion Estimation Using Analyst Labels

    NASA Technical Reports Server (NTRS)

    Lennington, R. K.; Abotteen, K. M. (Principal Investigator)

    1980-01-01

    The author has identified the following significant results. A total of ten Large Area Crop Inventory Experiment Phase 3 blind sites and analyst-interpreter labels were used in a study to compare proportional estimates obtained by the Bayes sequential procedure with estimates obtained from simple random sampling and from Procedure 1. The analyst error rate using the Bayes technique was shown to be no greater than that for the simple random sampling. Also, the segment proportion estimates produced using this technique had smaller bias and mean squared errors than the estimates produced using either simple random sampling or Procedure 1.

  7. Cox report and the US-China arms control technical exchange program

    SciTech Connect

    Di Capua, M S

    1999-09-01

    The ACE program furthered the national security interests of the US by promoting technical approaches to the implementation and verification of arms control treaties that the international community embraces. The Cox Committee report suggests that uncontrolled interactions were taking place between US and Chinese nuclear weapons scientists in the course of the ACE program. On the contrary, elaborate controls were in place at the very beginning and remained in place to control the interactions and protect US national security information. The ACE program payoff to national security was just beginning and its suspension, resulting from the Cox reports allegations, is a setback to US-China progress on arms control.

  8. The polyacetylene falcarindiol with COX-1 activity isolated from Aegopodium podagraria L.

    PubMed

    Prior, Rikke M; Lundgaard, Nanna H; Light, Marnie E; Stafford, Gary I; van Staden, Johannes; Jäger, Anna K

    2007-08-15

    Extracts of Aegopodium podagraria L. were screened in vitro for cyclooxygenase-1 (COX-1) inhibitory activity. The isolation of the active compound falcarindiol was achieved by bioassay-guided fractionation. The identification of the active compound was confirmed by (1)H NMR and (13)C NMR. The IC(50)-value of falcarindiol was 0.3 microM in the COX-1 assay. A quantitative determination of the seasonal variation in the content of falcarindiol in different plant parts was carried out by HPLC analysis. The flowers from Aegopodium podagraria collected in June 2006 had the highest concentration of falcarindiol (88 mg/g plant material).

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

    PubMed

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

    2005-09-01

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

  10. Adjustable Induction-Heating Coil

    NASA Technical Reports Server (NTRS)

    Ellis, Rod; Bartolotta, Paul

    1990-01-01

    Improved design for induction-heating work coil facilitates optimization of heating in different metal specimens. Three segments adjusted independently to obtain desired distribution of temperature. Reduces time needed to achieve required temperature profiles.

  11. COX-2 Induces Breast Cancer Stem Cells via EP4/PI3K/AKT/NOTCH/WNT Axis.

    PubMed

    Majumder, Mousumi; Xin, Xiping; Liu, Ling; Tutunea-Fatan, Elena; Rodriguez-Torres, Mauricio; Vincent, Krista; Postovit, Lynne-Marie; Hess, David; Lala, Peeyush K

    2016-09-01

    Cancer stem-like cells (SLC) resist conventional therapies, necessitating searches for SLC-specific targets. We established that cyclo-oxygenase(COX)-2 expression promotes human breast cancer progression by activation of the prostaglandin(PG)E-2 receptor EP4. Present study revealed that COX-2 induces SLCs by EP4-mediated NOTCH/WNT signaling. Ectopic COX-2 over-expression in MCF-7 and SKBR-3 cell lines resulted in: increased migration/invasion/proliferation, epithelial-mesenchymal transition (EMT), elevated SLCs (spheroid formation), increased ALDH activity and colocalization of COX-2 and SLC markers (ALDH1A, CD44, β-Catenin, NANOG, OCT3/4, SOX-2) in spheroids. These changes were reversed with COX-2-inhibitor or EP4-antagonist (EP4A), indicating dependence on COX-2/EP4 activities. COX-2 over-expression or EP4-agonist treatments of COX-2-low cells caused up-regulation of NOTCH/WNT genes, blocked with PI3K/AKT inhibitors. NOTCH/WNT inhibitors also blocked COX-2/EP4 induced SLC induction. Microarray analysis showed up-regulation of numerous SLC-regulatory and EMT-associated genes. MCF-7-COX-2 cells showed increased mammary tumorigenicity and spontaneous multiorgan metastases in NOD/SCID/IL-2Rγ-null mice for successive generations with limiting cell inocula. These tumors showed up-regulation of VEGF-A/C/D, Vimentin and phospho-AKT, down-regulation of E-Cadherin and enrichment of SLC marker positive and spheroid forming cells. MCF-7-COX-2 cells also showed increased lung colonization in NOD/SCID/GUSB-null mice, an effect reversed with EP4-knockdown or EP4A treatment of the MCF-7-COX-2 cells. COX-2/EP4/ALDH1A mRNA expression in human breast cancer tissues were highly correlated with one other, more marked in progressive stage of disease. In situ immunostaining of human breast tumor tissues revealed co-localization of SLC markers with COX-2, supporting COX-2 inducing SLCs. High COX-2/EP4 mRNA expression was linked with reduced survival. Thus, EP4 represents a novel SLC

  12. Interaction of apoptotic cells with macrophages upregulates COX-2/PGE2 and HGF expression via a positive feedback loop.

    PubMed

    Byun, Ji Yeon; Youn, Young-So; Lee, Ye-Ji; Choi, Youn-Hee; Woo, So-Yeon; Kang, Jihee Lee

    2014-01-01

    Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and hepatocyte growth factor (HGF) play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2 expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cells in vitro and in vivo orchestrate the interaction between COX-2/PGE2 and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2 production. Both NS-398 and COX-2-siRNA, as well as the PGE2 receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2 induction. The in vivo relevance of the interaction between the COX-2/PGE2 and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages following in vivo exposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2 and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition.

  13. Elevated COX-2 Expression Promotes Angiogenesis Through EGFR/p38-MAPK/Sp1-Dependent Signalling in Pancreatic Cancer.

    PubMed

    Hu, Hai; Han, Ting; Zhuo, Meng; Wu, Lei-Lei; Yuan, Cuncun; Wu, Lixia; Lei, Wang; Jiao, Feng; Wang, Li-Wei

    2017-03-28

    Cyclooxygenase-2 (COX-2) was stated to be overexpression in various human malignancies associating with angiogenesis, metastasis and chemoresistence. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease displaying many of these characteristics. A common abnormality of PDAC is overexpression of specificity protein-1 (Sp1), which was said to correlate with malignant phenotypes of human cancers. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we found that Sp1 expression was positively correlated with that of COX-2 in PDAC, and that the inhibition or overexpression of Sp1 in PDAC cells leads to decreased or elevated COX-2 expression. Luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays revealed that elevated transcription of COX-2 requires Sp1 binding to sequence positions around -245/-240 of COX-2 promoter. Activated epidermal growth factor receptor (EGFR) and downstream p38 mitogen-activated protein kinase (p38-MAPK) were also profoundly altered in PDAC. The inhibition of EGFR/p38-MAPK signaling resulted in reduced Sp1 activation, decreased COX-2 and vascular endothelial growth factor (VEGF) expression. Thus, Sp1 could transcriptionally activate COX-2 expression in a process relies on activated EGFR/p38-MAPK signaling. Finally, we found that the inhibition of COX-2 leads to decreased angiogenesis in a process dependent on VEGF, which link COX-2 to angiogenesis in PDAC.

  14. 2-Carbaborane-3-phenyl-1H-indoles--synthesis via McMurry reaction and cyclooxygenase (COX) inhibition activity.

    PubMed

    Laube, Markus; Neumann, Wilma; Scholz, Matthias; Lönnecke, Peter; Crews, Brenda; Marnett, Lawrence J; Pietzsch, Jens; Kniess, Torsten; Hey-Hawkins, Evamarie

    2013-02-01

    Cyclooxygenase-2 (COX-2) inhibitors have been the focus of medicinal chemistry efforts for years, and many compounds that exhibit high selectivity and affinity have been developed. As carbaboranes represent interesting pharmacophores as phenyl mimetics in drug development, this paper presents the synthesis of carbaboranyl derivatives of COX-2-selective 2,3-disubstituted indoles. Despite the lability of carbaboranes under reducing conditions, 2-carbaborane-3-phenyl-1H-indoles could be synthesized by McMurry cyclization of the corresponding amides. Whereas the meta-carbaboranyl-substituted derivatives lacked COX inhibitory activity, an ortho-carbaboranyl analogue was active, but showed a selectivity shift toward COX-1.

  15. From Graphical to Mathematical: The Spiral of Golden Proportion

    ERIC Educational Resources Information Center

    Fletcher, Rodney

    2007-01-01

    There has been a lot of material written about logarithmic spirals of golden proportion but this author states that he has never come across an article that states the exact equation of the spiral which ultimately spirals tangentially to the sides of the rectangles. In this article, the author intends to develop such an equation. (Contains 5…

  16. The relation between spatial thinking and proportional reasoning in preschoolers.

    PubMed

    Möhring, Wenke; Newcombe, Nora S; Frick, Andrea

    2015-04-01

    Previous research has indicated a close link between spatial and mathematical thinking. However, what shared processes account for this link? In this study, we focused on the spatial skill of map reading and the mathematical skill of proportional reasoning and investigated whether scaling, or the ability to relate information in different-sized representations, is a shared process. Scaling was experimentally manipulated in both tasks. In the map task, 4- and 5-year-olds (N=50) were asked to point to the same position shown on a map in a larger referent space on a touch screen. The sizes of the maps were varied systematically, such that some trials required scaling and some did not (i.e., the map had the same size as the referent space). In the proportional reasoning task, children were presented with different relative amounts of juice and water and were asked to estimate each mixture on a rating scale. Again, some trials required scaling, but others could be solved by directly mapping the proportional components onto the rating scale. Children's absolute errors in locating targets in the map task were closely related to their performance in the proportional reasoning task even after controlling for age and verbal intelligence. Crucially, this was only true for trials that required scaling, whereas performance on nonscaled trials was not related. These results shed light on the mechanisms involved in the close connection between spatial and mathematical thinking early in life.

  17. Prospective Elementary Teachers' Misunderstandings in Solving Ratio and Proportion Problems

    ERIC Educational Resources Information Center

    Monteiro, Cecilia

    2003-01-01

    This study explores difficulties that prospective elementary mathematics teachers have with the concepts of ratio and proportion, mainly when they are engaged in solving problems using algorithm procedures. These difficulties can be traced back to earlier experiences when they were students of junior and high school. The reflection on these…

  18. Proportional Reasoning in the Learning of Chemistry: Levels of Complexity

    ERIC Educational Resources Information Center

    Ramful, Ajay; Narod, Fawzia Bibi

    2014-01-01

    This interdisciplinary study sketches the ways in which proportional reasoning is involved in the solution of chemistry problems, more specifically, problems involving quantities in chemical reactions (commonly referred to as stoichiometry problems). By building on the expertise of both mathematics and chemistry education research, the present…

  19. Simulation of dynamics of hydraulic system with proportional control valve

    NASA Astrophysics Data System (ADS)

    Bureček, Adam; Hružík, Lumír; Vašina, Martin

    2016-03-01

    Dynamics of a hydraulic system is influenced by several parameters, in this case mainly by proportional control valve, oil bulk modulus, oil viscosity, mass load etc. This paper will be focused on experimental measurement and mathematical simulation of dynamics of a hydraulic system with proportional control valve, linear hydraulic cylinder and mass load. The measurement is performed on experimental equipment that enables realization of dynamic processes of the hydraulic system. Linear hydraulic cylinder with mass load is equipped with position sensor of piston. The movement control of piston rod is ensured by the proportional control valve. The equipment enables to test an influence of parameter settings of regulator of the proportional control valve on position and pressure system responses. The piston position is recorded by magnetostrictive sensor that is located in drilled piston rod side of the linear hydraulic cylinder. Pressures are measured by piezoresistive sensors on the piston side and the piston rod side of the hydraulic cylinder. The measurement is performed during movement of the piston rod with mass load to the required position. There is realized and verified a mathematical model using Matlab SimHydraulics software for this hydraulic system.

  20. Spatio-temporal patterns of proportions of influenza B cases

    PubMed Central

    He, Daihai; Chiu, Alice P. Y.; Lin, Qianying; Yu, Duo

    2017-01-01

    We studied the spatio-temporal patterns of the proportions of influenza B cases out of all typed cases, with data from 139 countries and regions downloaded from the FluNet compiled by the World Health Organization, from January 2006 to October 2015. We restricted our analysis to 34 countries that reported more than 2,000 confirmations for each of types A and B over the study period. Globally, we found that Pearson’s correlation is greater than 0.6 between effective distance from Mexico and the proportions of influenza B cases among the countries during the post-pandemic era (i.e. Week 1, 2010 to Week 40, 2015). Locally, in the United States, the proportions of influenza B cases in the pre-pandemic period (2003–2008) negatively correlated with that in the post-pandemic era (2010–2015) at the regional level. Our study limitations are the country-level variations in both surveillance methods and testing policies. The proportions of influenza B cases displayed wide variations over the study period. Our findings suggest that the 2009 influenza pandemic has an evident impact on the relative burden of the two influenza types. Future studies should examine whether there are other additional factors. This study has potential implications in prioritizing public health control measures. PMID:28067277

  1. Map Scale, Proportion, and Google[TM] Earth

    ERIC Educational Resources Information Center

    Roberge, Martin C.; Cooper, Linda L.

    2010-01-01

    Aerial imagery has a great capacity to engage and maintain student interest while providing a contextual setting to strengthen their ability to reason proportionally. Free, on-demand, high-resolution, large-scale aerial photography provides both a bird's eye view of the world and a new perspective on one's own community. This article presents an…

  2. Macroevolutionary diversity of amniote limb proportions predicted by developmental interactions.

    PubMed

    Young, Nathan M

    2013-11-01

    Mammals, birds, and reptiles exhibit a remarkable diversity of limb proportions. These evolved differences are thought to reflect selection for biomechanical, postural, and locomotor requirements primarily acting on independent variation in later fetal and postnatal segmental growth. However, earlier conserved developmental events also have the potential to impact the evolvability of limb proportions by limiting or biasing initial variation among segments. Notably, proximo-distal patterning of the amniote limb through activation-inhibition dynamics predicts that initial proportions of segments should exhibit both tradeoffs between stylopod and autopod and a diagnostic reduction in variance of the zeugopod. Here it is demonstrated that this developmental "design rule" predicts patterns of macroevolutionary diversity despite the effects of variation in segmental growth over ontogeny, lineage-specific differences in phylogenetic history, or functional adaptation. These results provide critical comparative evidence of a conserved Turing-like mechanism in proximo-distal limb segmentation, and suggest that development has played a previously unrecognized role in the evolvability of limb proportions in a wide range of amniote taxa.

  3. An Investigation of Proportional Reasoning Skills of Middle School Students

    ERIC Educational Resources Information Center

    Ozgun-Koca, S. Asli; Altay, Mesture Kayhan

    2009-01-01

    The purpose of this study was to examine the proportional reasoning skills of Turkish middle school students. It was also aimed at revealing the differences in students' performances in terms of their gender, grade level, and problem types--missing value and numerical comparison. The study was conducted with two sixth and seventh grade classes…

  4. The Structure of Prospective Kindergarten Teachers' Proportional Reasoning

    ERIC Educational Resources Information Center

    Pitta-Pantazi, Demetra; Christou, Constantinos

    2011-01-01

    Lamon ("Teaching fractions and ratios for understanding. Essential content knowledge and instructional strategies for teachers," 2nd edn. Lawrence Erlbaum Associates, Mahwah, 2005) claimed that the development of proportional reasoning relies on various kinds of understanding and thinking processes. The critical components suggested were…

  5. Are Explicit Apologies Proportional to the Offenses They Address?

    ERIC Educational Resources Information Center

    Heritage, John; Raymond, Chase Wesley

    2016-01-01

    We consider here Goffman's proposal of proportionality between virtual offenses and remedial actions, based on the examination of 102 cases of explicit apologies. To this end, we offer a typology of the primary apology formats within the dataset, together with a broad categorization of the types of virtual offenses to which these apologies are…

  6. Modelling boron-lined proportional counter response to neutrons.

    PubMed

    Shahri, A; Ghal-Eh, N; Etaati, G R

    2013-09-01

    The detailed Monte Carlo simulation of a boron-lined proportional counter response to a neutron source has been presented. The MCNP4C and experimental data on different source-moderator geometries have been given for comparison. The influence of different irradiation geometries and boron-lining thicknesses on the detector response has been studied.

  7. Proportionality: A Unifying Theme for the Middle Grades.

    ERIC Educational Resources Information Center

    Lanius, Cynthia S.; Williams, Susan E.

    2003-01-01

    Explains how middle school mathematics topics are often taught as separate, discrete topics without a unifying thread. Discusses the importance of proportionality as a concept with the potential to untie, relate, and clarify many important, complex middle grades ideas into a cohesive theme. (YDS)

  8. Making Sense of Fractions, Ratios, and Proportions. 2002 Yearbook.

    ERIC Educational Resources Information Center

    Litwiller, Bonnie, Ed.; Bright, George, Ed.

    This yearbook contains articles that give insight into students' thinking about factions, ratios, and proportions. Suggestions are offered on how to develop the concepts and skills associated with these topics. The book is divided into elementary, middle school, and professional development sections. Chapters include: (1) "The Development of…

  9. High condylectomy versus proportional condylectomy: is secondary orthognathic surgery necessary?

    PubMed

    Fariña, R; Olate, S; Raposo, A; Araya, I; Alister, J P; Uribe, F

    2016-01-01

    The objective of this study was to assess the need for secondary orthognathic surgery in patients undergoing two different condylectomy protocols for active unilateral condylar hyperplasia (UCH). A retrospective cohort study evaluated UCH patients treated by condylectomy. Two groups were established: group 1 comprised those who had undergone a high condylectomy (5 mm removed) and group 2 comprised those who had undergone a proportional condylectomy (removing the difference observed between the measurements of the hyperplastic and the healthy side). Data analysis was done with the Levene test and t-test; a P-value of <0.05 indicated a statistically significant relationship. Forty-nine patients, with an average age of 19.83 years, were analyzed; 11 were included in group 1 and 38 in group 2. There was no statistical difference between the two groups with regard to age or sex (P=0.781). An average of 5.81 mm was removed in the high condylectomy group, while an average of 9.28 mm was removed in the proportional condylectomy group; this difference was statistically significant (P=0.042). Comparing the two groups, proportional condylectomy reduced the need for secondary orthognathic surgery (P<0.001). The proportional condylectomy can be used as the sole surgical treatment in cases of UCH, thus avoiding the need for secondary orthognathic surgery.

  10. System proportions fluid-flow in response to demand signals

    NASA Technical Reports Server (NTRS)

    1966-01-01

    Control system provides proportioned fluid flow rates in response to demand signals. It compares a digital signal, representing a flow demand, with a reference signal to yield a control voltage to one or more solenoid valves connected to orifices of a predetermined size.

  11. Recommended tests and confidence intervals for paired binomial proportions.

    PubMed

    Fagerland, Morten W; Lydersen, Stian; Laake, Petter

    2014-07-20

    We describe, evaluate, and recommend statistical methods for the analysis of paired binomial proportions. A total of 24 methods are considered. The best tests for association include the asymptotic McNemar test and the McNemar mid- p test. For the difference between proportions, we recommend two simple confidence intervals with closed-form expressions and the asymptotic score interval. The asymptotic score interval is also recommended for the ratio of proportions, as is an interval with closed-form expression based on combining two Wilson score intervals for the single proportion. For the odds ratio, we recommend a transformation of the Wilson score interval and a transformation of the Clopper-Pearson mid- p interval. We illustrate the practical application of the methods using data from a recently published study of airway reactivity in children before and after stem cell transplantation and a matched case-control study of the association between floppy eyelid syndrome and obstructive sleep apnea-hypopnea syndrome.

  12. 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

  13. Long-Term Ambient Residential Traffic–Related Exposures and Measurement Error–Adjusted Risk of Incident Lung Cancer in the Netherlands Cohort Study on Diet and Cancer

    PubMed Central

    Spiegelman, Donna; Beelen, Rob; Hoek, Gerard; Brunekreef, Bert; Schouten, Leo J.; van den Brandt, Piet

    2015-01-01

    Background The International Agency for Research on Cancer (IARC) recently declared air pollution carcinogenic to humans. However, no study of air pollution and lung cancer to date has incorporated adjustment for exposure measurement error, and few have examined specific histological subtypes. Objectives Our aim was to assess the association of air pollution and incident lung cancer in the Netherlands Cohort Study on Diet and Cancer and the impact of measurement error on these associations. Methods The cohort was followed from 1986 through 2003, and 3,355 incident cases were identified. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals, for long-term exposures to nitrogen dioxide (NO2), black smoke (BS), PM2.5 (particulate matter with diameter ≤ 2.5 μm), and measures of roadway proximity and traffic volume, adjusted for potential confounders. Information from a previous validation study was used to correct the effect estimates for measurement error. Results We observed elevated risks of incident lung cancer with exposure to BS [hazard ratio (HR) = 1.16; 95% CI: 1.02, 1.32, per 10 μg/m3], NO2 (HR = 1.29; 95% CI: 1.08, 1.54, per 30 μg/m3), PM2.5 (HR = 1.17; 95% CI: 0.93, 1.47, per 10 μg/m3), and with measures of traffic at the baseline address. The exposures were positively associated with all lung cancer subtypes. After adjustment for measurement error, the HRs increased and the 95% CIs widened [HR = 1.19 (95% CI: 1.02, 1.39) for BS and HR = 1.37 (95% CI: 0.86, 2.17) for PM2.5]. Conclusions These findings add support to a growing body of literature on the effects of air pollution on lung cancer. In addition, they highlight variation in measurement error by pollutant and support the implementation of measurement error corrections when possible. Citation Hart JE, Spiegelman D, Beelen R, Hoek G, Brunekreef B, Schouten LJ, van den Brandt P. 2015. Long-term ambient residential traffic–related exposures and

  14. Digital dual-parameter data acquisition for SP2 hydrogen-filled proportional counters.

    PubMed

    Hawkes, N P; Roberts, N J

    2014-10-01

    Hydrogen-filled proportional counters perform well as neutron spectrometers in the energy region from a few tens of keV up to ∼1.5 MeV. Unfortunately, gamma rays also generate signals in these detectors. It is possible in principle to distinguish the two types of event via the rise time of their respective signal pulses, but the data acquisition system needed for this is complex to assemble and adjust if one uses conventional modular analogue electronics. In this work a digital sampling system, in conjunction with custom software, was used to measure and acquire amplitude and rise time data from type SP2 counters. The interpretation of the data was supported by a Monte Carlo calculation. The performance of the system is compared with that of a conventional 1-parameter analogue system, and the potential of the digital technique to supplant conventional methods is discussed.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  16. [Effect of COX-2 inhibitor celecoxib on proliferation, apoptosis of HL-60 cells and its mechanism].

    PubMed

    Xie, Xia; Li, Jie; Wang, Rui-Cang; Geng, Rui-Li; Wang, Su-Yun; Wang, Chao; Zhao, Xiao-Yun; Hao, Hong-Ling

    2014-06-01

    This study was aimed to investigate the effect of COX-2 inhibitor celecoxib on proliferation, apoptosis of human acute myeloid leukemia cell line HL-60 and its mechanism. HL-60 cells were cultured with different concentrations of celecoxib for 24 h. Cell proliferation was analyzed by CCK-8 assay, cell apoptosis and cell cycle distribution were detected by flow cytometry. Cyclin D1, cyclin E1 and COX-2 mRNA expressions were determined by RT-PCR. The results showed that after the HL-60 cells were treated with different concentrations of celecoxib for 24 h, the cell growth was significantly inhibited in a dose-dependent manner(r = 0.955), IC50 was 63.037 µmol/L of celecoxib. Celecoxib could effectively induce apoptosis in HL-60 cells also in dose-dependent manner(r = 0.988), blocked the HL-60 cells in the G0/G1 phase. The expression of cyclin D1, cyclin E1 and COX-2 mRNA were downregulated. It is concluded that celecoxib can inhibit the proliferation of HL-60 cells in dose-dependent manner, celecoxib causes cell G0/G1 arrest and induces cell apoptosis possibly through down-regulation of the cyclin D1 and cyclin E1 expression, and down-regulation of COX-2 expression respectively.

  17. Structure-based parallel medicinal chemistry approach to improve metabolic stability of benzopyran COX-2 inhibitors.

    PubMed

    Xing, Li; Hamper, Bruce C; Fletcher, Theresa R; Wendling, Jay M; Carter, Jeffery; Gierse, James K; Liao, Subo

    2011-02-01

    Combination of the structure-based design and solid-phase parallel synthesis provided an integrated approach to rapidly develop the structure-activity relationship of benzopyran COX-2 inhibitors. Binding free energies predicted by free energy perturbation theory yielded good agreement with experimental results. New potent and selective lead compounds with improved metabolic properties were identified.

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

    EPA Science Inventory

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

  19. Evidence for a novel mitochondrial promoter preceding the cox2 gene of perennial teosintes.

    PubMed Central

    Newton, K J; Winberg, B; Yamato, K; Lupold, S; Stern, D B

    1995-01-01

    We have characterized two promoters of the cytochrome oxidase subunit 2 (cox2) gene in Zea perennis mitochondria present in maize lines. Initiation at a site 907 bases upstream of the start codon results in the major approximately 1900 nt cox2 transcript. A sequence just upstream of this site conforms to the consensus described for maize mitochondrial promoters and its transcription is correctly initiated in a maize mitochondrial in vitro transcription extract. A second transcription initiation site (-347) is used only when the dominant allele of a nuclear gene, Mct, is present and its use results in an additional, shorter major transcript. Sequences flanking the Mct-dependent transcription initiation site, which we have termed the conditional promoter of cox2 (cpc), do not fit the maize mitochondrial promoter consensus and do not function in the maize in vitro transcription extract. The cpc region does not hybridize with mitochondrial, chloroplast or nuclear DNAs from most maize or teosinte lines. However, the cpc sequence is found in the same position upstream of the cox2 gene in Zea diploperennis mtDNA and it has striking similarity to the previously reported 'ORF of unknown origin' fused to the ATPase subunit 6 gene in maize CMS-C mitochondria. cpc appears to represent a new type of mitochondrial promoter. Further analysis of both conditional and constitutive promoters should help us to better understand the control of transcription in plant mitochondria. Images PMID:7859746

  20. Dual inhibitory effect of Glycyrrhiza glabra (GutGard™) on COX and LOX products.

    PubMed

    Chandrasekaran, C V; Deepak, H B; Thiyagarajan, P; Kathiresan, S; Sangli, Gopal Krishna; Deepak, M; Agarwal, Amit

    2011-02-15

    Glycyrrhiza glabra and its phytoconstituents have been known to possess widespread pharmacological properties as an anti-inflammatory, anti-viral, antitumour and hepatoprotective drug. In this study, we examined the inhibitory potential of extract of G. glabra (GutGard™) root and its phytoconstituents (glabridin, glycyrrhizin, and isoliquiritigenin) on both cyclooxygenase (COX) and lipoxygenase (LOX) products in order to understand the mechanism of its anti-inflammatory action. Inhibitory effect of GutGard™ and its phytoconstituents on lipopolysaccharide (LPS) induced prostaglandin E(2) (PGE(2)), calcimycin (A23187) induced thromboxane (TXB(2)), and leukotriene (LTB(4)) release was studied using murine macrophages (J774A.1) and human neutrophil (HL-60) cells. Results revealed that, G. glabra and glabridin significantly inhibited PGE(2), TXB(2) (COX) and LTB(4) (LOX), while, isoliquiritigenin exerted inhibitory effect only against COX products but failed to suppress LOX product. However, glycyrrhizin at the tested concentrations failed to exhibit inhibitory effect on both COX and LOX products. Here, we report for the first time that G. glabra (almost devoid of glycyrrhizin) exhibits anti-inflammatory property likely through the inhibition of PGE(2), TXB(2) and LTB(4) in mammalian cell assay system, which could be influenced in part by glabridin and isoliquiritigenin.

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

    PubMed

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

    2015-10-01

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

  2. Elevated COX2 expression and PGE2 production by downregulation of RXRα in senescent macrophages

    SciTech Connect

    Chen, Huimin; Ma, Feng; Hu, Xiaona; Jin, Ting; Xiong, Chuhui; Teng, Xiaochun

    2013-10-11

    Highlights: •Downregulation of RXRα in senescent macrophage. •RXRα suppresses NF-κB activity and COX2 expression. •Increased PGE2 production due to downregulation of RXRα. -- Abstract: Increased systemic level of inflammatory cytokines leads to numerous age-related diseases. In senescent macrophages, elevated prostaglandin E2 (PGE2) production contributes to the suppression of T cell function with aging, which increases the susceptibility to infections. However, the regulation of these inflammatory cytokines and PGE2 with aging still remains unclear. We have verified that cyclooxygenase (COX)-2 expression and PGE2 production are higher in LPS-stimulated macrophages from old mice than that from young mice. Downregulation of RXRα, a nuclear receptor that can suppress NF-κB activity, mediates the elevation of COX2 expression and PGE2 production in senescent macrophages. We also have found less induction of ABCA1 and ABCG1 by RXRα agonist in senescent macrophages, which partially accounts for high risk of atherosclerosis in aged population. Systemic treatment with RXRα antagonist HX531 in young mice increases COX2, TNF-α, and IL-6 expression in splenocytes. Our study not only has outlined a mechanism of elevated NF-κB activity and PGE2 production in senescent macrophages, but also provides RXRα as a potential therapeutic target for treating the age-related diseases.

  3. Antinociceptive Effects of Prim-O-Glucosylcimifugin in Inflammatory Nociception via Reducing Spinal COX-2.

    PubMed

    Wu, Liu-Qing; Li, Yu; Li, Yuan-Yan; Xu, Shi-Hao; Yang, Zong-Yong; Lin, Zheng; Li, Jun

    2016-07-01

    We measured anti-nociceptive activity of prim-o-glucosylcimifugin (POG), a molecule from Saposhnikovia divaricate (Turcz) Schischk. Anti-nociceptive or anti-inflammatory effects of POG on a formalin-induced tonic nociceptive response and a complete Freund's adjuvant (CFA) inoculation-induced rat arthritis pain model were studied. Single subcutaneous injections of POG produced potent anti-nociception in both models that was comparable to indomethacin analgesia. Anti-nociceptive activity of POG was dose-dependent, maximally reducing pain 56.6% with an ED50 of 1.6 mg. Rats given POG over time did not develop tolerance. POG also time-dependently reduced serum TNFα, IL-1β and IL-6 in arthritic rats and both POG and indomethacin reduced spinal prostaglandin E2 (PGE2). Like indomethacin which inhibits cyclooxygenase-2 (COX-2) activity, POG dose-dependently decreased spinal COX-2 content in arthritic rats. Additionally, POG, and its metabolite cimifugin, downregulated COX-2 expression in vitro. Thus, POG produced potent anti-nociception by downregulating spinal COX-2 expression.

  4. Current approaches to prevent NSAID-induced gastropathy – COX selectivity and beyond

    PubMed Central

    Becker, Jan C; Domschke, Wolfram; Pohle, Thorsten

    2004-01-01

    Gastrointestinal (GI) toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) is still an important medical and socio-economic problem – despite recent pharmaceutical advances. To prevent NSAID-induced gastropathy, three strategies are followed in clinical routine: (i) coprescription of a gastroprotective drug, (ii) use of selective COX-2 inhibitors, and (iii) eradication of Helicobacter pylori. Proton pump inhibitors are the comedication of choice as they effectively reduce gastrointestinal adverse events of NSAIDs and are safe even in long-term use. Co-medication with vitamin C has only been little studied in the prevention of NSAID-induced gastropathy. Apart from scavenging free radicals it is able to induce haeme-oxgenase 1 in gastric cells, a protective enzyme with antioxidant and vasodilative properties. Final results of the celecoxib outcome study (CLASS study) attenuated the initial enthusiasm about the GI safety of selective COX-2 inhibitors, especially in patients concomitantly taking aspirin for cardiovascular prophylaxis. Helicobacter pylori increases the risk for ulcers particularly in NSAID-naive patients and therefore eradication is recommended prior to long-term NSAID therapy at least in patients at high risk. New classes of COX-inhibitors are currently evaluated in clinical studies with very promising results: NSAIDs combined with a nitric oxide releasing moiety (NO-NSAID) and dual inhibitors of COX and 5-LOX. These drugs offer extended anti-inflammatory potency while sparing gastric mucosa. PMID:15563357

  5. Two cases of human thelaziasis as confirmed by mitochondrial cox1 sequencing in China

    PubMed Central

    Wang, Xiao-Li; Guo, Jiu-Ying; Wang, Xue-Lian; Ma, Xiao-Li; Wang, Yi; An, Chun-Li

    2014-01-01

    Two special cases of human thelaziasis were reported in China: an old farmer with heavy infection by 36 worms and a 7-year-old boy with infection by eight worms. Thelazia callipaeda was morphologically identified and confirmed by mitochondrial cox1 gene sequencing. PMID:25253041

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

    SciTech Connect

    Zhu, Yingting; Zhu, Min; Lance, Peter

    2012-08-31

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

  7. Immunohistochemical COX-2 overexpression correlates with HER-2/neu overexpression in invasive breast carcinomas: a pilot study.

    PubMed

    Çiriş, Ibrahim Metin; Bozkurt, Kemal Kürşat; Başpinar, Sirin; Kapucuoğlu, Fatma Nilgün

    2011-03-15

    Cyclooxygenase-2 (COX-2) is a prostaglandin synthase that catalyzes the synthesis of prostaglandin G2 and H2. It has been shown that COX-2 plays an important role in tumorigenesis of different tumor types and it is thought to take part in breast carcinogenesis. In the present study, we aimed to investigate the relationship of immunohistochemical COX-2 expression with clinicopathological parameters, including HER-2/neu overexpression in invasive breast carcinoma (IBC). Our study population comprised 10 normal breasts, 25 ductal carcinomas in situ (DCIS), and 51 invasive breast carcinomas. Immunohistochemical overexpressions of COX-2 and HER-2/neu were investigated in sections of formalin-fixed, paraffin-embedded blocks by 3 observers. In normal breast, DCIS and IBC, the COX-2 overexpression rate was 0%, 84%, and 58.8%, respectively. In IBC, COX-2 overexpression had a significant relationship with HER-2/neu overexpression (p=0.026) and a high histological grade (p=0.026). COX-2 expression in both DCIS (n=25) and IBC (n=51) was significantly higher than in normal breast tissue (p<0.0001). In addition, the COX-2 expression rate was significantly higher in DCIS than in IBC (p=0.042). Our results indicated that COX-2 overexpression correlates with aggressive phenotypic features, such as HER-2/neu overexpression and high histological grade in IBC. Increased expression of COX-2 in both DCIS and IBC in comparison to normal breast could indicate a role in breast carcinogenesis. COX-2 overexpression may provide a clinically useful biomarker for estimating tumor aggressiveness.

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

    SciTech Connect

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

    2011-12-09

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

  9. The effects of celecoxib, a COX-2 selective inhibitor, on acute inflammation induced in irradiated rats.

    PubMed

    Khayyal, M T; El-Ghazaly, Mona A; El-Hazek, R M; Nada, A S

    2009-10-01

    The potential value of selective and non-selective COX-2 inhibitors in preventing some of the biochemical changes induced by ionizing radiation was studied in rats exposed to carrageenan-induced paw edema and 6-day-old air pouch models. The animals were exposed to different exposure levels of gamma-radiation, namely either to single doses of 2 and 7.5 Gy or a fractionated dose level of 7.5 Gy delivered as 0.5 Gy twice weekly for 7.5 weeks. The inflammatory response produced by carrageenan in irradiated rats was markedly higher than that induced in non-irradiated animals, and depended on the extent of irradiation. Celecoxib, a selective COX-2 inhibitor, in doses of 3, 5, 10, and 15 mg/kg was effective in reducing paw edema in irradiated and non-irradiated rats in a dose-dependent manner as well as diclofenac (3 mg/kg), a non-selective COX inhibitor. Irradiation of animals before the induction of the air pouch by an acute dose of 2 Gy led to a significant increase in leukocytic count, as well as in the level of interleukin-6 (IL-6), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), LTB(4), PGE(2) (as an index of COX-2 activity), TXB(2) (as an index of COX-1 activity), and the plasma level of MDA. This increase in level of these parameters was more marked than that observed in the non-irradiated animals subjected to the inflammagen. The blood GSH level was not affected by the dose of irradiation used, whereas superoxide dismutase (SOD) activity was suppressed. In many respects, celecoxib (5 mg/kg) was as potent as diclofenac in decreasing the elevated levels of IL-6, IL-1beta, TNF-alpha, LTB(4), PGE(2), but lacked any significant effect on TXB(2) level. Since it is mostly selective for COX-2 with a rare effect on COX-1 enzyme, both drugs at the selected dose levels showed no effect on level of MDA, GSH, and SOD activity.

  10. The critical proportion of immune individuals needed to control hepatitis B

    NASA Astrophysics Data System (ADS)

    Ospina, Juan; Hincapié-Palacio, Doracelly

    2016-05-01

    We estimate the critical proportion of immunity (Pc) to control hepatitis B in Medellin - Colombia, based on a random population survey of 2077 individuals of 6-64 years of age. The force of infection (Fi) was estimated according to empirical data of susceptibility by age S(a), assuming a quadratic expression. Parameters were estimated by adjusting data to a nonlinear regression. Fi was defined by -(ds(a)/da)/s(a) and according to the form of the empirical curve S(a) we assume a quadratic expression given by S(a)= Ea2+Ba+C. Then we have the explicit expression for the accumulated Fi by age given by F(a) = -a(Ea+B)/c. The expression of average infection age A is obtained as A = L + EL3/(3C)+BL2/(2C) and the basic reproductive number R0 is obtained as R0 = 1 + 6C/(6C+2EL2+3BL). From the las result we obtain the Pc given by Pc= 6C/(12C+2EL2+3BL). Numerical simulations were performed with the age-susceptibility proportion and initial values (a=0.02, b=20, c=100), obtaining an adjusted coefficient of multiple determination of 64.83%. According to the best estimate, the algebraic expressions for S(a) and the Fi were derived. Using the result of Fi, we obtain A = 30, L =85; R0 CI 95%: 1.42 - 1.64 and Pc: 0-0.29. These results indicate that at the worst case, to maintain control of the disease should be immunes at least 30% of susceptible individuals. Similar results were obtained by sex and residential area.

  11. Adjusting to Chronic Health Conditions.

    PubMed

    Helgeson, Vicki S; Zajdel, Melissa

    2017-01-03

    Research on adjustment to chronic disease is critical in today's world, in which people are living longer lives, but lives are increasingly likely to be characterized by one or more chronic illnesses. Chronic illnesses may deteriorate, enter remission, or fluctuate, but their defining characteristic is that they persist. In this review, we first examine the effects of chronic disease on one's sense of self. Then we review categories of factors that influence how one adjusts to chronic illness, with particular emphasis on the impact of these factors on functional status and psychosocial adjustment. We begin with contextual factors, including demographic variables such as sex and race, as well as illness dimensions such as stigma and illness identity. We then examine a set of dispositional factors that influence chronic illness adjustment, organizing these into resilience and vulnerability factors. Resilience factors include cognitive adaptation indicators, personality variables, and benefit-finding. Vulnerability factors include a pessimistic attributional style, negative gender-related traits, and rumination. We then turn to social environmental variables, including both supportive and unsupportive interactions. Finally, we review chronic illness adjustment within the context of dyadic coping. We conclude by examining potential interactions among these classes of variables and outlining a set of directions for future research.

  12. NORMAL QUALITY OF LIFE AFTER THE COX MAZE PROCEDURE FOR ATRIAL FIBRILLATION.

    PubMed

    Melby, Spencer J; Zierer, Andreas; Lubahn, Jordon G; Bailey, Marci S; Cox, James L; Schuessler, Richard B; Damiano, Ralph J

    2008-05-01

    BACKGROUND/OBJECTIVE: Atrial fibrillation(AF) has been shown in numerous studies to significantly decrease patient quality of life. The Cox-Maze procedure has excellent long-term efficacy in curing AF. However, it is unknown whether this procedure improves long-term quality of life in these patients. The purpose of this study was to examine late quality of life in patients that underwent a lone Cox-Maze procedure. METHODS: Between 1987 and 2003, 163 patients underwent a Cox-Maze procedure for lone AF at our institution. Of these, 68 patients agreed and completed the Medical Outcomes Study Short Form 36 Health Survey. Scores from the age-matched general US population were normalized to a mean of 50 and standard deviation of 10 to facilitate comparison. Collected data were compared to the norm-based score for each domain using a one-sample t-test. Four patients were removed from analysis because of AF recurrence. RESULTS: There were 52 males(81%). Mean age was 52.6±9.5 years. Preoperatively, 37 patients(58%) had paroxysmal and 25 patients(39%) had persistent or permanent AF. The mean duration of AF before surgery was 9.8±8.2 years. There was no statistical difference in norm-based scores between the Cox-Maze procedure group and the age-matched general US population in any of the eight health domains at a mean follow-up of 8.7±3.7 years. CONCLUSION: Our results suggest that the Cox-Maze procedure cures atrial fibrillation in the majority of patients, and that those patients that are cured obtain a normal quality of life as compared to the general population at late follow-up.

  13. Design and synthesis of benzimidazole analogs endowed with oxadiazole as selective COX-2 inhibitor.

    PubMed

    Rathore, Ankita; Rahman, Mujeeb Ur; Siddiqui, Anees Ahamad; Ali, Abuzer; Shaharyar, Mohammad

    2014-12-01

    New molecules of benzimidazole endowed with oxadiazole were designed and synthesized from 2-(2-((pyrimidin-2-ylthio)methyl)-1H-benzo[d]imidazol-1-yl)acetohydrazide as 1-((5-substituted alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl)-2-((pyrimidin-2-ylthio)methyl)-1H-benzimidazoles (5a-r) with the aim to acquire selective cyclooxygenase (COX-2) inhibitor activity. The synthesized compounds were screened by in vitro cyclooxygenase assays to determine COX-1 and COX-2 inhibitory potency and the results showed that they had good-to-remarkable activity with an IC50 range of 11.6-56.1 µM. The most active compounds were further screened for their in vivo anti-inflammatory activity by using the carrageenan-induced rat paw edema model. In vitro anticancer activities of the hybrid compounds were assessed by the National Cancer Institute (NCI), USA, against 60 human cell lines, and the results showed a good spectrum. Compound 5l exhibited significant COX-2 inhibition with an IC50 value of 8.2 µM and a percent protection of 68.4%. Compound 5b evinced moderate cytotoxicity toward the UO-31 cell line of renal cancer. A docking study was performed using Maestro 9.0, to provide the binding mode into the binding sites of the cyclooxygenase enzyme. Hopefully, in the future, compound 5l could serve as a lead compound for developing new COX-2 inhibitors.

  14. GROWTH FACTORS AND COX2 IN WOUND HEALING: AN EXPERIMENTAL STUDY WITH EHRLICH TUMORS

    PubMed Central

    SALGADO, Flávio L. L.; ARTIGIANI-NETO, Ricardo; LOPES-FILHO, Gaspar de Jesus

    2016-01-01

    ABSTRACT Background: Healing is an innate biological phenomenon, and carcinogenesis acquired, but with common humoral and cellular elements. Carcinogenesis interferes negatively in healing. Aim: To evaluate the histological changes in laparotomy scars of healthy Balb/c mice and with an Ehrlich tumor in its various forms of presentation. Methods: Fifty-four mice were divided into three groups of 18 animals. First group was the control; the second had Ehrlich tumor with ascites; and the third had the subcutaneous form of this tumor. Seven days after tumor inoculation, all 54 mice were submitted to laparotomy. All of the animals in the experiment were operated on again on 7th day after surgery, with resection of the scar and subsequent euthanasia of the animal. The scars were sent for histological assessment using immunohistochemical techniques to evaluate Cox-2 (cyclooxygenase 2), VEGF (vascular endothelial growth factor) and FGF (fibroblast growth factor). Semi-quantitatively analysis was done in the laparotomy scars and in the abdominal walls far away from the site of the operation. Results: Assessing the weight of the animals, the correct inoculation of the tumor and weight gain in the group with tumoral ascites was observed. The histological studies showed that groups with the tumor showed a statistically significant higher presence of Cox-2 compared to the control. In the Cox-2 analysis of the abdominal wall, the ascites group showed the most significant difference. VEGF did not present any significant differences between the three groups, regardless of the site. The FGF showed a significant increase in animals with the tumor. Conclusion: Histological findings in both laparotomy scar and the abdominal wall showed that with Ehrlich's neoplasia there was an exacerbated inflammatory response, translated by more intense expression of Cox-2 and greater fibroblast proliferation, translated by more intense expression of FGF, that is, it stimulated both the immediate

  15. Measurements of the performance of multiwire proportional chambers

    NASA Technical Reports Server (NTRS)

    Austin, R. W.; Eglitis, A.; Gregory, J. C.; Metzger, S. A.; Parnell, T. A.; Rutledge, H. F.; Selig, W.; Cumings, N. P.

    1973-01-01

    Data are presented that may be useful in formulating engineering specifications and test procedures for the proportional counter hodoscope to be flown as part of the High Energy Cosmic Ray Experiment on the High Energy Astronomy Observatory (HEAO), Mission A. A collection of preliminary data taken in laboratory tests of multiwire counters with an anode wire spacing of 5 mm and cathode gap spacing of 1 cm is presented. The data are from laboratory development models or counters for balloon flights and were selected to illustrate several aspects of proper and improper counter performance. Most of the data were taken from a large proportional counter hodoscope which has an active area of 0.5 by 0.5 m and 104 wires per plane.

  16. Robotic Lower Limb Exoskeletons Using Proportional Myoelectric Control

    PubMed Central

    Ferris, Daniel P.; Lewis, Cara L.

    2010-01-01

    Robotic lower limb exoskeletons have been built for augmenting human performance, assisting with disabilities, studying human physiology, and re-training motor deficiencies. At the University of Michigan Human Neuromechanics Laboratory, we have built pneumatically-powered lower limb exoskeletons for the last two purposes. Most of our prior research has focused on ankle joint exoskeletons because of the large contribution from plantar flexors to the mechanical work performed during gait. One way we control the exoskeletons is with proportional myoelectric control, effectively increasing the strength of the wearer with a physiological mode of control. Healthy human subjects quickly adapt to walking with the robotic ankle exoskeletons, reducing their overall energy expenditure. Individuals with incomplete spinal cord injury have demonstrated rapid modification of muscle recruitment patterns with practice walking with the ankle exoskeletons. Evidence suggests that proportional myoelectric control may have distinct advantages over other types of control for robotic exoskeletons in basic science and rehabilitation. PMID:19964579

  17. Transmission Line Properties of Nickel-Bodied Proportional Counters

    NASA Astrophysics Data System (ADS)

    Ryu, Jennifer

    2008-10-01

    Simultaneous measurements of neutral current and charged current neutrino scattering events allowed the Sudbury Neutrino Observatory (SNO) to demonstrate definitively neutrino oscillation. The three phases of the SNO detector are distinguished by different techniques of detecting the neutrons produced by neutral current neutrino scattering. In the final phase, nickel-bodied proportional counters filled with ^3He were used as neutral current detectors (NCDs) by observing the charged particles produced by neutron capture on ^3He. If we can understand the electrical transmission properties of the NCDs, we can use the different pulse shapes produced by neutron captures compared to those of alphas to distinguish these events and gain more sensitivity to the neutral current events. We found that because of the ferromagnetism of the nickel, standard calculations provided for proportional counters are not accurate enough. To obtain a better calculation, we directly measured the electrical properties of the transmission line as a function of frequency. This is a presentation of our results.

  18. Measurements of electron attachment by oxygen molecule in proportional counter

    NASA Astrophysics Data System (ADS)

    Tosaki, M.; Kawano, T.; Isozumi, Y.

    2013-11-01

    We present pulse height measurements for 5-keV Auger electrons from a radioactive 55Fe source mounted at the inner cathode surface of cylindrical proportional counter, which is operated with CH4 admixed dry air or N2. A clear shift of the pulse height has been observed by varying the amount of the admixtures; the number of electrons, created in the primary ionization by Auger electrons, is decreased by the electron attachment of the admixtures during their drift from the place near the source to the anode wire. The large gas amplification (typically 104) in the secondary ionization of proportional counter makes it possible to investigate a small change in the number of primary electrons. The electron attenuation cross-section of O2 has been evaluated by analyzing the shifts of the pulse height caused by the electron attachment to dry air and N2.

  19. Multianode cylindrical proportional counter for high count rates

    DOEpatents

    Hanson, J.A.; Kopp, M.K.

    1980-05-23

    A cylindrical, multiple-anode proportional counter is provided for counting of low-energy photons (< 60 keV) at count rates of greater than 10/sup 5/ counts/sec. A gas-filled proportional counter cylinder forming an outer cathode is provided with a central coaxially disposed inner cathode and a plurality of anode wires disposed in a cylindrical array in coaxial alignment with and between the inner and outer cathodes to form a virtual cylindrical anode coaxial with the inner and outer cathodes. The virtual cylindrical anode configuration improves the electron drift velocity by providing a more uniform field strength throughout the counter gas volume, thus decreasing the electron collection time following the detection of an ionizing event. This avoids pulse pile-up and coincidence losses at these high count rates. Conventional RC position encoding detection circuitry may be employed to extract the spatial information from the counter anodes.

  20. Multianode cylindrical proportional counter for high count rates

    DOEpatents

    Hanson, James A.; Kopp, Manfred K.

    1981-01-01

    A cylindrical, multiple-anode proportional counter is provided for counting of low-energy photons (<60 keV) at count rates of greater than 10.sup.5 counts/sec. A gas-filled proportional counter cylinder forming an outer cathode is provided with a central coaxially disposed inner cathode and a plurality of anode wires disposed in a cylindrical array in coaxial alignment with and between the inner and outer cathodes to form a virtual cylindrical anode coaxial with the inner and outer cathodes. The virtual cylindrical anode configuration improves the electron drift velocity by providing a more uniform field strength throughout the counter gas volume, thus decreasing the electron collection time following the detection of an ionizing event. This avoids pulse pile-up and coincidence losses at these high count rates. Conventional RC position encoding detection circuitry may be employed to extract the spatial information from the counter anodes.

  1. Digital neutron radiography using plane converters with multiwire proportional chambers

    SciTech Connect

    Kaplan, S.N.; Director, B.A.; Perez-Mendez, V.; Valentine, K.H.

    1981-12-01

    The work described here was completed more than three years ago, and represents, in large part the PhD and MS thesis research of two of the present authors. Much of it has been reported previously elsewhere. It constitutes an effort to develop and study a moderately low cost, moderate resolution, high sensitivity, on-line method for digital neutron radiography, intended for use where neutron fluence was limited by source strength, or received dose. The basic imaging system consisted of a position-sensitive gas proportional chamber together with its associated imaging electronics, and a plane neutron converter. Enriched-boron, gadolinium, and polyethylene (for fast neutrons) converters were analyzed and tested. Some work was done on digital data enhancement, and efforts to improve spatial resolution included pressurizing the proportional-chamber gas to reduce the track lengths of the neutron-interaction products.

  2. MCCB warm adjustment testing concept

    NASA Astrophysics Data System (ADS)

    Erdei, Z.; Horgos, M.; Grib, A.; Preradović, D. M.; Rodic, V.

    2016-08-01

    This paper presents an experimental investigation in to operating of thermal protection device behavior from an MCCB (Molded Case Circuit Breaker). One of the main functions of the circuit breaker is to assure protection for the circuits where mounted in for possible overloads of the circuit. The tripping mechanism for the overload protection is based on a bimetal movement during a specific time frame. This movement needs to be controlled and as a solution to control this movement we choose the warm adjustment concept. This concept is meant to improve process capability control and final output. The warm adjustment device design will create a unique adjustment of the bimetal position for each individual breaker, determined when the testing current will flow thru a phase which needs to trip in a certain amount of time. This time is predetermined due to scientific calculation for all standard types of amperages and complies with the IEC 60497 standard requirements.

  3. Workability of Mass Concrete. Report 2. Supplemental Proportioning Parameters.

    DTIC Science & Technology

    1996-09-01

    proportions for mass concrete with assurance that the concrete will have adequate workability. The initial phase of this study was to obtain information...Corps of Engineers (HQUSACE), as a part of Civil Works Investigation Studies Work Unit 32768, "Workability of Mass Concrete ." The study was conducted...Paul F. Mlakar, Chief, Concrete and Materials Division (CMD), and Mr. Edward F. O’Neil, Acting Chief, Engineering Mechanics Branch (EMB), CMD. Dr

  4. A complete database for the Einstein imaging proportional counter

    NASA Technical Reports Server (NTRS)

    Helfand, David J.

    1991-01-01

    A complete database for the Einstein Imaging Proportional Counter (IPC) was completed. The original data that makes up the archive is described as well as the structure of the database, the Op-Ed analysis system, the technical advances achieved relative to the analysis of (IPC) data, the data products produced, and some uses to which the database has been put by scientists outside Columbia University over the past year.

  5. Automatic method to manufacture 2D Multiwire Proportional Counter frames

    NASA Astrophysics Data System (ADS)

    Martínez, J. C.; Ramos-Lerate, I.; Fernández, F.; Beltrán, D.; Bordas, J.

    2007-04-01

    In this paper, a complete solution to manufacture anodes and cathodes for a Multiwire Proportional Counter (MWPC) is described. The solution consists of a semiautomatic winding machine and a soldering method by radiation. This method allows manufacturing one frame (electrode) in 3 h with a minimum human intervention. The machine can work with several types of frames and a great accuracy in the position and the stress of the wires can be achieved.

  6. Proportional drift tubes for large area muon detectors

    NASA Technical Reports Server (NTRS)

    Cho, C.; Higashi, S.; Hiraoka, N.; Maruyama, A.; Okusawa, T.; Sato, T.; Suwada, T.; Takahashi, T.; Umeda, H.

    1985-01-01

    A proportional drift chamber which consists of eight rectangular drift tubes with cross section of 10 cm x 5 cm, a sense wire of 100 micron phi gold-plated tungsten wire and the length of 6 m, was tested using cosmic ray muons. Spatial resolution (rms) is between 0.5 and 1 mm over drift space of 50 mm, depending on incident angle and distance from sense wire.

  7. THE ESSENTIAL DIFFERENCE BETWEEN THE TWO OPTIMUM PROPORTIONS FLOCCULATION RATIOS

    PubMed Central

    Boyd, William C.; Purnell, Marjorie A.

    1944-01-01

    The fact that the optimum proportion flocculation ratio is different when determined by the α (Dean and Webb) and β (Ramon) procedures is pointed out. It is demonstrated that this difference is a consequence of the difference in the two methods, and that the two optima, though they may in certain cases lie near together, can never coincide. A new ratio (the ε ratio), intermediate between the α and β ratios, and having theoretical advantages over both of them, is defined. PMID:19871416

  8. Quench gases for xenon- (and krypton-) filled proportional counters

    NASA Technical Reports Server (NTRS)

    Ramsey, B. D.; Agrawal, P. C.

    1988-01-01

    Xenon-filled proportional counters are used extensively in astronomy, particularly in the hard X-ray region. The choice of quench gas can have a significant effect on the operating characteristics of the instrument although the data necessary to make the choice are not easily obtainable. Results which detail the performance obtained from both cylindrical and parallel field geometries for a wide variety of readily available, ultrahigh or research grade purity, quench gases are presented.

  9. Equivalence Between Approximate Dynamic Inversion and Proportional-Integral Control

    DTIC Science & Technology

    2008-09-29

    systems that renders the closed-loop error dynamics independent of the reference model dynamics. The equivalent PI controller will be derived and both of...integral control, PI control . I. INTRODUCTION DYNAMIC inversion (DI) or feedback linearization isa popular control design method that is well suited for...Proportional-Integral (PI) model reference controller realiza- tion. The key characteristic of the equivalent PI controller is that it is largely independent

  10. Comparable-Worth Adjustments: Yes--Comparable-Worth Adjustments: No.

    ERIC Educational Resources Information Center

    Galloway, Sue; O'Neill, June

    1985-01-01

    Two essays address the issue of pay equity and present opinions favoring and opposing comparable-worth adjustments. Movement of women out of traditionally female jobs, the limits of "equal pay," fairness of comparable worth and market-based wages, implementation and efficiency of comparable worth system, and alternatives to comparable…

  11. Energy Proportionality and Performance in Data Parallel Computing Clusters

    SciTech Connect

    Kim, Jinoh; Chou, Jerry; Rotem, Doron

    2011-02-14

    Energy consumption in datacenters has recently become a major concern due to the rising operational costs andscalability issues. Recent solutions to this problem propose the principle of energy proportionality, i.e., the amount of energy consumedby the server nodes must be proportional to the amount of work performed. For data parallelism and fault tolerancepurposes, most common file systems used in MapReduce-type clusters maintain a set of replicas for each data block. A coveringset is a group of nodes that together contain at least one replica of the data blocks needed for performing computing tasks. In thiswork, we develop and analyze algorithms to maintain energy proportionality by discovering a covering set that minimizesenergy consumption while placing the remaining nodes in lowpower standby mode. Our algorithms can also discover coveringsets in heterogeneous computing environments. In order to allow more data parallelism, we generalize our algorithms so that itcan discover k-covering sets, i.e., a set of nodes that contain at least k replicas of the data blocks. Our experimental results showthat we can achieve substantial energy saving without significant performance loss in diverse cluster configurations and workingenvironments.

  12. The proportions of mutagens among chemicals in commerce.

    PubMed

    Zeiger, E; Margolin, B H

    2000-10-01

    It has been estimated that there are approximately 80,000 chemicals in commerce. Thus, it is not possible to test all these substances for mutagenicity and carcinogenicity; it is possible, however, to test or make estimates from selected subsets of these chemicals. For example, in the U.S. National Toxicology Program (NTP), 35% of the chemicals tested for mutagenicity in Salmonella were positive, as were 52% of the chemicals tested for carcinogenicity in rodents. In contrast, in the U.S. EPA Gene-Tox database, the proportions of chemicals that are Salmonella mutagens is 56%. These and other databases may be biased toward positive responses because they generally have been developed to look at specific structural or use classes of chemicals or chemicals suspected of genetic or carcinogenic activity. To address the question of the proportions of mutagens among all chemicals in commerce, a database of 100 chemicals was created from a random selection of chemicals in commerce. These chemicals were tested for mutagenicity in Salmonella and 22% were mutagenic. The mutagenicity of the 46 highest U.S. production organic chemicals was also compiled; 20% were mutagenic. These values provide a more accurate estimate of the proportions of mutagens among chemicals in commerce than can be derived from published mutagenicity databases.

  13. NASA CONNECT: Proportionality: The X-Plane Generation

    NASA Technical Reports Server (NTRS)

    2000-01-01

    'Proportionality: The X-Plane Generation' is the fifth of seven programs in the 1999-2000 NASA CONNECT series. Produced by NASA Langley Research Center's Office of Education, NASA CONNECT is an award-winning series of instructional programs designed to enhance the teaching of math, science and technology concepts in grades 5-8. NASA CONNECT establishes the 'connection' between the mathematics, science, and technology concepts taught in the classroom and NASA research. Each program in the series supports the national mathematics, science, and technology standards; includes a resource-rich teacher guide; and uses a classroom experiment and web-based activity to complement and enhance the math, science, and technology concepts presented in the program. NASA CONNECT is FREE and the programs in the series are in the public domain. Visit our web site and register. http://connect.larc.nasa.gov In 'Proportionality: The X-Plane Generation', students will learn why scaling and proportion are important factors in spacecraft design.

  14. Maximum-likelihood estimation of admixture proportions from genetic data.

    PubMed Central

    Wang, Jinliang

    2003-01-01

    For an admixed population, an important question is how much genetic contribution comes from each parental population. Several methods have been developed to estimate such admixture proportions, using data on genetic markers sampled from parental and admixed populations. In this study, I propose a likelihood method to estimate jointly the admixture proportions, the genetic drift that occurred to the admixed population and each parental population during the period between the hybridization and sampling events, and the genetic drift in each ancestral population within the interval between their split and hybridization. The results from extensive simulations using various combinations of relevant parameter values show that in general much more accurate and precise estimates of admixture proportions are obtained from the likelihood method than from previous methods. The likelihood method also yields reasonable estimates of genetic drift that occurred to each population, which translate into relative effective sizes (N(e)) or absolute average N(e)'s if the times when the relevant events (such as population split, admixture, and sampling) occurred are known. The proposed likelihood method also has features such as relatively low computational requirement compared with previous ones, flexibility for admixture models, and marker types. In particular, it allows for missing data from a contributing parental population. The method is applied to a human data set and a wolflike canids data set, and the results obtained are discussed in comparison with those from other estimators and from previous studies. PMID:12807794

  15. A Method to Quantify Mouse Coat-Color Proportions

    PubMed Central

    Ounpraseuth, Songthip; Rafferty, Tonya M.; McDonald-Phillips, Rachel E.; Gammill, Whitney M.; Siegel, Eric R.; Wheeler, Kristin L.; Nilsson, Erik A.; Cooney, Craig A.

    2009-01-01

    Coat-color proportions and patterns in mice are used as assays for many processes such as transgene expression, chimerism, and epigenetics. In many studies, coat-color readouts are estimated from subjective scoring of individual mice. Here we show a method by which mouse coat color is quantified as the proportion of coat shown in one or more digital images. We use the yellow-agouti mouse model of epigenetic variegation to demonstrate this method. We apply this method to live mice using a conventional digital camera for data collection. We use a raster graphics editing program to convert agouti regions of the coat to a standard, uniform, brown color and the yellow regions of the coat to a standard, uniform, yellow color. We use a second program to quantify the proportions of these standard colors. This method provides quantification that relates directly to the visual appearance of the live animal. It also provides an objective analysis with a traceable record, and it should allow for precise comparisons of mouse coats and mouse cohorts within and between studies. PMID:19404391

  16. Proportion of selected congenital heart defects attributable to recognized risk factors

    PubMed Central

    Simeone, Regina M.; Tinker, Sarah C.; Gilboa, Suzanne M.; Agopian, A.J.; Oster, Matthew E.; Devine, Owen J.; Honein, Margaret A.

    2016-01-01

    Purpose To assess the contribution of multiple risk factors for two congenital heart defects—hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). Methods We used data from the National Birth Defects Prevention Study (1997–2011) to estimate average adjusted population attributable fractions for several recognized risk factors, including maternal prepregnancy overweight–obesity, pregestational diabetes, age, and infant sex. Results There were 594 cases of isolated simple HLHS, 971 cases of isolated simple TOF, and 11,829 controls in the analysis. Overall, 57.0% of HLHS cases and 37.0% of TOF cases were estimated to be attributable to risk factors included in our model. Among modifiable HLHS risk factors, maternal pre-pregnancy overweight–obesity accounted for the largest proportion of cases (6.5%). Among modifiable TOF risk factors, maternal prepregnancy overweight–obesity and maternal age of 35 years or older accounted for the largest proportions of cases (8.3% and 4.3%, respectively). Conclusions Approximately half of HLHS cases and one-third of TOF cases were estimated to be attributable to risk factors included in our models. Interventions targeting factors that can be modified may help reduce the risk of HLHS and TOF development. Additional research into the etiology of HLHS and TOF may reveal other modifiable risk factors that might contribute to primary prevention efforts. PMID:27894567

  17. An upper-limb power-assist exoskeleton using proportional myoelectric control.

    PubMed

    Tang, Zhichuan; Zhang, Kejun; Sun, Shouqian; Gao, Zenggui; Zhang, Lekai; Yang, Zhongliang

    2014-04-10

    We developed an upper-limb power-assist exoskeleton actuated by pneumatic muscles. The exoskeleton included two metal links: a nylon joint, four size-adjustable carbon fiber bracers, a potentiometer and two pneumatic muscles. The proportional myoelectric control method was proposed to control the exoskeleton according to the user's motion intention in real time. With the feature extraction procedure and the classification (back-propagation neural network), an electromyogram (EMG)-angle model was constructed to be used for pattern recognition. Six healthy subjects performed elbow flexion-extension movements under four experimental conditions: (1) holding a 1-kg load, wearing the exoskeleton, but with no actuation and for different periods (2-s, 4-s and 8-s periods); (2) holding a 1-kg load, without wearing the exoskeleton, for a fixed period; (3) holding a 1-kg load, wearing the exoskeleton, but with no actuation, for a fixed period; (4) holding a 1-kg load, wearing the exoskeleton under proportional myoelectric control, for a fixed period. The EMG signals of the biceps brachii, the brachioradialis, the triceps brachii and the anconeus and the angle of the elbow were collected. The control scheme's reliability and power-assist effectiveness were evaluated in the experiments. The results indicated that the exoskeleton could be controlled by the user's motion intention in real time and that it was useful for augmenting arm performance with neurological signal control, which could be applied to assist in elbow rehabilitation after neurological injury.

  18. An Upper-Limb Power-Assist Exoskeleton Using Proportional Myoelectric Control

    PubMed Central

    Tang, Zhichuan; Zhang, Kejun; Sun, Shouqian; Gao, Zenggui; Zhang, Lekai; Yang, Zhongliang

    2014-01-01

    We developed an upper-limb power-assist exoskeleton actuated by pneumatic muscles. The exoskeleton included two metal links: a nylon joint, four size-adjustable carbon fiber bracers, a potentiometer and two pneumatic muscles. The proportional myoelectric control method was proposed to control the exoskeleton according to the user's motion intention in real time. With the feature extraction procedure and the classification (back-propagation neural network), an electromyogram (EMG)-angle model was constructed to be used for pattern recognition. Six healthy subjects performed elbow flexion-extension movements under four experimental conditions: (1) holding a 1-kg load, wearing the exoskeleton, but with no actuation and for different periods (2-s, 4-s and 8-s periods); (2) holding a 1-kg load, without wearing the exoskeleton, for a fixed period; (3) holding a 1-kg load, wearing the exoskeleton, but with no actuation, for a fixed period; (4) holding a 1-kg load, wearing the exoskeleton under proportional myoelectric control, for a fixed period. The EMG signals of the biceps brachii, the brachioradialis, the triceps brachii and the anconeus and the angle of the elbow were collected. The control scheme's reliability and power-assist effectiveness were evaluated in the experiments. The results indicated that the exoskeleton could be controlled by the user's motion intention in real time and that it was useful for augmenting arm performance with neurological signal control, which could be applied to assist in elbow rehabilitation after neurological injury. PMID:24727501

  19. COX-2 is involved in ET-1-induced hypertrophy of neonatal rat cardiomyocytes: role of NFATc3.

    PubMed

    Li, Hong; Gao, Si; Ye, Jiantao; Feng, Xiaojun; Cai, Yi; Liu, Zhiping; Lu, Jing; Li, Qin; Huang, Xiaoyang; Chen, Shaorui; Liu, Peiqing

    2014-02-15

    Endothelin-1 (ET-1) is a critical molecule that involved in heart failure. It has been proved that ET-1 stimulation results in cardiac hypertrophy both in vitro and in vivo, but the mechanisms underlying remain largely unknown. In this study, we reported that cyclooxygenase-2 (COX-2) might be an important mediator of hypertrophic responses to ET-1 stimulation. In the cultured rat neonatal cardiomyocytes, ET-1 significantly upregulated the expression and activity of COX-2, which was accompanied by increase in cell surface area and BNP mRNA level. In contrast, ET-1-dependent cardiomyocyte hypertrophy was abolished by COX-2 selective inhibitors, NS-398 and celecoxib, or by COX-2 RNA interference, but the inhibitory effects could be diminished by pretreatment with PGE2. Furthermore, cyclosporin A (CsA) and knockdown of nuclear factor of activated T-cells c3 (NFATc3) inhibited the expression of COX-2 induced by ET-1, and NFATc3 could also bound to the -GGAAA- sequence in the promoter region of rat COX-2 gene, indicating that calcineurin/NFATc3 signaling participated in the transcriptional regulation of COX-2 following ET-1 treatment. These findings provided further insight into the roles of ET-1 in cardiac hypertrophy and suggested a potential therapeutic strategy against cardiac hypertrophy by inhibiting COX-2.

  20. Design of Fluorine-Containing 3,4-Diarylfuran-2(5H)-ones as Selective COX-1 Inhibitors.

    PubMed

    Uddin, Md Jashim; Elleman, Anna V; Ghebreselasie, Kebreab; Daniel, Cristina K; Crews, Brenda C; Nance, Kellie D; Huda, Tamanna; Marnett, Lawrence J

    2014-11-13

    We report the design and synthesis of fluorine-containing cyclooxygenase-1 (COX-1)-selective inhibitors to serve as prototypes for the development of a COX-1-targeted imaging agent. Deletion of the SO2CH3 group of rofecoxib switches the compound from a COX-2- to a COX-1-selective inhibitor, providing a 3,4-diarylfuran-2(5H)-one scaffold for structure-activity relationship studies of COX-1 inhibition. A wide range of fluorine-containing 3,4-diarylfuran-2(5H)-ones were designed, synthesized, and tested for their ability to selectively inhibit COX-1 in purified protein and human cancer cell assays. Compounds containing a fluoro-substituent on the C-3 phenyl ring and a methoxy-substituent on the C-4 phenyl ring of the 3,4-diarylfuran-2(5H)-one scaffold were the best COX-1-selective agents of those evaluated, exhibiting IC50s in the submicromolar range. These compounds provide the foundation for development of an agent to facilitate radiologic imaging of ovarian cancer expressing elevated levels of COX-1.

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

    PubMed

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

    2016-09-06

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

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

    PubMed

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

    2013-03-01

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

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

    PubMed

    Zhu, Yingting; Zhu, Min; Lance, Peter

    2012-08-31

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

  4. Angiotensin-(1-7)-Induced Plasticity Changes in the Lateral Amygdala Are Mediated by COX-2 and NO

    ERIC Educational Resources Information Center

    Albrecht, Doris

    2007-01-01

    It is known from studies outside the brain that upon binding to its receptor, angiotensin-(1-7) elicits the release of prostanoids and nitric oxide (NO). Cyclooxygenase (COX) is a key enzyme that converts arachidonic acid to prostaglandins. Since there are no data available so far on the role of COX-2 in the amygdala, in a first step we…

  5. COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells.

    PubMed

    Li, Ze-Lei; Ye, Shu-Biao; OuYang, Li-Yin; Zhang, Han; Chen, Yu-Shan; He, Jia; Chen, Qiu-Yan; Qian, Chao-Nan; Zhang, Xiao-Shi; Cui, Jun; Zeng, Yi-Xin; Li, Jiang

    2015-11-01

    The expansion of myeloid-derived suppressor cells (MDSCs) is a common feature of cancer, but its biological roles and molecular mechanism remain unclear. Here, we investigated a molecular link between MDSC expansion and tumor cell metastasis in nasopharyngeal carcinoma (NPC). We demonstrated that MDSCs expanded and were positively correlated with the elevated tumor COX-2 expression and serum IL-6 levels in NPC patients. Importantly, COX-2 and MDSCs were poor predictors of patient disease-free survival (DFS). Knocking down tumor COX-2 expression hampered functional TW03-mediated-MDSC cell (T-MDSC) induction with IL-6 blocking. We identified that T-MDSCs promoted NPC cell migration and invasion by triggering the epithelial-mesenchymal transition (EMT) on cell-to-cell contact, and T-MDSCs enhanced tumor experimental lung metastasis in vivo. Interestingly, the contact between T-MDSCs and NPC cells enhanced tumor COX-2 expression, which subsequently activated the β-catenin/TCF4 pathway, resulting in EMT of the cancer cells. Blocking transforming growth factor β (TGFβ) or inducible nitric oxide synthase (iNOS) significantly abolished the T-MDSC-induced upregulation of COX-2 and EMT scores in NPC cells, whereas the administration of TGFβ or L-arginine supplements upregulated COX-2 expression and EMT scores in NPC cells. These findings reveal that COX-2 is a key factor mediating the interaction between MDSCs and tumor cells, suggesting that the inhibition of COX-2 or MDSCs has the potential to suppress NPC metastasis.

  6. COX2 and PGE2 mediate EGF-induced E-cadherin-independent human ovarian cancer cell invasion.

    PubMed

    Qiu, Xin; Cheng, Jung-Chien; Chang, Hsun-Ming; Leung, Peter C K

    2014-08-01

    Elevated expression of cyclooxygenase 2 (COX2 (PTGS2)) has been reported to occur in human ovarian cancer and to be associated with poor prognosis. We have previously demonstrated that COX2-derived prostaglandin E2 (PGE2) promotes human ovarian cancer cell invasion. We had also demonstrated that epidermal growth factor (EGF) induces human ovarian cancer cell invasion by downregulating the expression of E-cadherin through various signaling pathways. However, it remains unclear whether COX2 and PGE2 are involved in the EGF-induced downregulation of E-cadherin expression and cell invasion in human ovarian cancer cells. In this study, we showed that EGF treatment induces COX2 expression and PGE2 production in SKOV3 and OVCAR5 human ovarian cancer cell lines. Interestingly, COX2 is not required for the EGF-induced downregulation of E-cadherin expression. In addition, EGF treatment activates the phosphatidylinositol-3-kinase (PI3K)/Akt and cAMP response element-binding protein (CREB) signaling pathways, while only the PI3K/Akt pathway is involved in EGF-induced COX2 expression. Moreover, we also showed that EGF-induced cell invasion is attenuated by treatment with a selective COX2 inhibitor, NS-398, as well as PGE2 siRNA. This study demonstrates an important role for COX2 and its derivative, PGE2, in the mediation of the effects of EGF on human ovarian cancer cell invasion.

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

    PubMed Central

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

    2016-01-01

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

  8. Novel Allelic Variants in the Canine Cyclooxgenase-2 (Cox-2) Promoter Are Associated with Renal Dysplasia in Dogs

    PubMed Central

    Whiteley, Mary H.; Bell, Jerold S.; Rothman, Debby A.

    2011-01-01

    Renal dysplasia (RD) in dogs is a complex disease with a highly variable phenotype and mode of inheritance that does not follow a simple Mendelian pattern. Cox-2 (Cyclooxgenase-2) deficient mice have renal abnormalities and a pathology that has striking similarities to RD in dogs suggesting to us that mutations in the Cox-2 gene could be the cause of RD in dogs. Our data supports this hypothesis. Sequencing of the canine Cox-2 gene was done from clinically affected and normal dogs. Although no changes were detected in the Cox-2 coding region, small insertions and deletions of GC boxes just upstream of the ATG translation start site were found. These sequences are putative SP1 transcription factor binding sites that may represent important cis-acting DNA regulatory elements that govern the expression of Cox-2. A pedigree study of a family of Lhasa apsos revealed an important statistical correlation of these mutant alleles with the disease. We examined an additional 22 clinical cases from various breeds. Regardless of the breed or severity of disease, all of these had one or two copies of the Cox-2 allelic variants. We suggest that the unusual inheritance pattern of RD is due to these alleles, either by changing the pattern of expression of Cox-2 or making Cox-2 levels susceptible to influences of other genes or environmental factors that play an unknown but important role in the development of RD in dogs. PMID:21346820

  9. LDPC Codes with Minimum Distance Proportional to Block Size

    NASA Technical Reports Server (NTRS)

    Divsalar, Dariush; Jones, Christopher; Dolinar, Samuel; Thorpe, Jeremy

    2009-01-01

    Low-density parity-check (LDPC) codes characterized by minimum Hamming distances proportional to block sizes have been demonstrated. Like the codes mentioned in the immediately preceding article, the present codes are error-correcting codes suitable for use in a variety of wireless data-communication systems that include noisy channels. The previously mentioned codes have low decoding thresholds and reasonably low error floors. However, the minimum Hamming distances of those codes do not grow linearly with code-block sizes. Codes that have this minimum-distance property exhibit very low error floors. Examples of such codes include regular LDPC codes with variable degrees of at least 3. Unfortunately, the decoding thresholds of regular LDPC codes are high. Hence, there is a need for LDPC codes characterized by both low decoding thresholds and, in order to obtain acceptably low error floors, minimum Hamming distances that are proportional to code-block sizes. The present codes were developed to satisfy this need. The minimum Hamming distances of the present codes have been shown, through consideration of ensemble-average weight enumerators, to be proportional to code block sizes. As in the cases of irregular ensembles, the properties of these codes are sensitive to the proportion of degree-2 variable nodes. A code having too few such nodes tends to have an iterative decoding threshold that is far from the capacity threshold. A code having too many such nodes tends not to exhibit a minimum distance that is proportional to block size. Results of computational simulations have shown that the decoding thresholds of codes of the present type are lower than those of regular LDPC codes. Included in the simulations were a few examples from a family of codes characterized by rates ranging from low to high and by thresholds that adhere closely to their respective channel capacity thresholds; the simulation results from these examples showed that the codes in question have low

  10. Can structural adjustment work for women farmers.

    PubMed

    Mehra, R

    1991-12-01

    This article discusses the impact of structural adjustment programs (SAPs) on women farmers in developing countries. SAPs aim to improve economic efficiency and promote more rapid economic growth. SAPs are introduced in two phases. The first phase involves short-term loans with the condition that the country adopt monetary restraints and currency devaluation measures. In the second phase, long-term loans are given with the provision that the country deregulate their economy and open up markets. The agricultural sector is affected by SAPs because of their importance in employment, income generation, and export earnings. SAPs result in lower farm commodity prices due to currency devaluations and in removal of subsidies, which results in market-sensitive pricing or higher food prices. The impact of SAPs on agriculture vary between countries. In Morocco and Algeria, agriculture expanded under SAPs. In Indonesia, Bolivia, Costa Rica, and Mexico, the agriculture stagnated or declined. Agricultural growth was slowest in Africa. SAPs were somewhat successful in increasing agricultural exports. Food production grew slowly in many adjusting countries. Blame for failures of SAPs has been placed on government failure to implement reforms properly and overly optimistic assumptions about the timing of productive gains. Little attention has focused on the constraints facing women farmers, who are a large proportion of farmers, particularly in sub-Saharan Africa. This article focuses on the issues of limited access to resources, credit, agricultural extension and information, land ownership, education, and time as constraints to women farmers. Women also must ensure household food security. For SAPs to work effectively, complementary policies must be implemented that reallocate available productive resources and new technologies to women and that deal with women's constraints.

  11. 75 FR 33379 - Railroad Cost Recovery Procedures-Productivity Adjustment; Quarterly Rail Cost Adjustment Factor

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-11

    ... Surface Transportation Board Railroad Cost Recovery Procedures--Productivity Adjustment; Quarterly Rail... Railroads that the Board restate the previously published productivity adjustment for the 2003-2007 averaging period (2007 productivity adjustment) so that it tracks the 2007 productivity adjustment...

  12. Mitophagy inhibits proliferation by decreasing cyclooxygenase-2 (COX-2) in arsenic trioxide-treated HepG2 cells.

    PubMed

    Niu, Zhidan; Zhang, Wenya; Gu, Xueyan; Zhang, Xiaoning; Qi, Yongmei; Zhang, Yingmei

    2016-07-01

    Mitochondrial damage can trigger mitophagy and eventually suppress proliferation. However, the effect of mitophagy on proliferation remains unclear. In this study, HepG2 cells were used to assess mitophagy and proliferation arrest in response to As2O3 exposure. The stimulatory effect of As2O3 on mitophagy was investigated by assessing morphology (mitophagosome and mitolysosome) and relevant proteins (PINK1, LC3 II/I, and COX IV). Additionally, the relationship of mitophagy and proliferation was explored through the use of mitophagy inhibitors (CsA, Mdivi-1). Interestingly, the inhibition of mitophagy rescued proliferation arrest by restoring COX-2 protein level and countered the elimination of mitochondria-located COX-2 and up-regulated the COX-2 mRNA level. Taken together, our findings indicated that mitophagy can be induced and can inhibit proliferation by reducing COX-2 in HepG2 cells during As2O3 treatment.

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

    PubMed Central

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

    2014-01-01

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

  14. Prognostic utility of blood pressure-adjusted global and basal systolic longitudinal strain.

    PubMed

    Rhea, Isaac B; Rehman, Shuja; Jarori, Upasana; Choudhry, Muhammad W; Feigenbaum, Harvey; Sawada, Stephen G

    2016-03-01

    Assessment of global longitudinal systolic strain (GLS) and longitudinal systolic strain of the basal segments (BLS) has shown prognostic value in cardiac disorders. However, strain is reduced with increased afterload. We assessed the prognostic value of GLS and BLS adjusted for afterload. GLS and BLS were determined in 272 subjects with normal ejection fraction and no known coronary disease, or significant valve disease. Systolic blood pressure (SP) and diastolic blood pressure (DP) obtained at the time of echocardiography were used to adjust GLS and BLS as follows: strain×SP (mmHg)/120 mmHg and strain×DP (mmHg)/80 mmHg. Patients were followed for cardiac events and mortality. The mean age was 53±15 years and 53% had hypertension. There were 19 cardiac events and 70 deaths over a mean follow-up of 26±14 months. Cox analysis showed that left ventricular mass index (P=0.001), BLS (P<0.001), and DP-adjusted BLS (P<0.001) were independent predictors of cardiac events. DP-adjusted BLS added incremental value (P<0.001) to the other two predictors and had an area under the curve of 0.838 for events. DP (P=0.001), age (P=0.001), ACE inhibitor use (P=0.017), and SP-adjusted BLS (P=0.012) were independent predictors of mortality. SP-adjusted BLS added incremental value (P=0.014) to the other independent predictors. In conclusion, DP-adjusted BLS and SP-adjusted BLS were independent predictors of cardiac events and mortality, respectively. Blood pressure-adjusted strain added incremental prognostic value to other predictors of outcome.

  15. Prognostic utility of blood pressure-adjusted global and basal systolic longitudinal strain

    PubMed Central

    Rhea, Isaac B; Rehman, Shuja; Choudhry, Muhammad W; Feigenbaum, Harvey

    2016-01-01

    Abstract Assessment of global longitudinal systolic strain (GLS) and longitudinal systolic strain of the basal segments (BLS) has shown prognostic value in cardiac disorders. However, strain is reduced with increased afterload. We assessed the prognostic value of GLS and BLS adjusted for afterload. GLS and BLS were determined in 272 subjects with normal ejection fraction and no known coronary disease, or significant valve disease. Systolic blood pressure (SP) and diastolic blood pressure (DP) obtained at the time of echocardiography were used to adjust GLS and BLS as follows: strain×SP (mmHg)/120 mmHg and strain×DP (mmHg)/80 mmHg. Patients were followed for cardiac events and mortality. The mean age was 53±15 years and 53% had hypertension. There were 19 cardiac events and 70 deaths over a mean follow-up of 26±14 months. Cox analysis showed that left ventricular mass index (P=0.001), BLS (P<0.001), and DP-adjusted BLS (P<0.001) were independent predictors of cardiac events. DP-adjusted BLS added incremental value (P<0.001) to the other two predictors and had an area under the curve of 0.838 for events. DP (P=0.001), age (P=0.001), ACE inhibitor use (P=0.017), and SP-adjusted BLS (P=0.012) were independent predictors of mortality. SP-adjusted BLS added incremental value (P=0.014) to the other independent predictors. In conclusion, DP-adjusted BLS and SP-adjusted BLS were independent predictors of cardiac events and mortality, respectively. Blood pressure-adjusted strain added incremental prognostic value to other predictors of outcome. PMID:27249810

  16. Defect in ND2, COX2, ATP6 and COX3 mitochondrial genes as a risk factor for canine mammary tumour.

    PubMed

    Surdyka, M; Slaska, B

    2016-06-09

    The aim of this study was to identify mutations in ND2, COX2, ATP6 and COX3 mitochondrial genes in canine mammary tumour, determine their association with the process of neoplastic transformation, and phenotypic traits of dogs. In total, 93 biological samples, including blood, normal and neoplastic tissue samples from 31 dogs with diagnosed malignant canine mammary tumours were analysed. DNA sequencing of genes as well as bioinformatics and statistical analyses were performed. A total of 28 polymorphic loci and 11 mutations were identified. One of the mutations was blood heteroplasmy and two of the mutations caused an amino acid change in p.N117S and p.A184T. For the first time, mutations in mitochondrial genes were detected in dogs with mammary tumours. A statistically significant association between the presence of mutations and the size and age of dogs was demonstrated. Some of these changes may imply that these are the hotspot mutations of canine mammary tumour.

  17. IL1{beta}-mediated Stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells

    SciTech Connect

    Zhu, Yingting; Zhu, Min; Lance, Peter

    2012-11-15

    COX-2 is a major inflammatory mediator implicated in colorectal inflammation and cancer. However, the exact origin and role of COX-2 on colorectal inflammation and carcinogenesis are still not well defined. Recently, we reported that COX-2 and iNOS signalings interact in colonic CCD18Co fibroblasts. In this article, we investigated whether activation of COX-2 signaling by IL1{beta} in primary colonic fibroblasts obtained from normal and cancer patients play a critical role in regulation of proliferation and invasiveness of human colonic epithelial cancer cells. Our results demonstrated that COX-2 level was significantly higher in cancer associated fibroblasts than that in normal fibroblasts with or without stimulation of IL-1{beta}, a powerful stimulator of COX-2. Using in vitro assays for estimating proliferative and invasive potential, we discovered that the proliferation and invasiveness of the epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts than with normal fibroblasts, with or without stimulation of IL1{beta}. Further analysis indicated that the major COX-2 product, prostaglandin E{sub 2}, directly enhanced proliferation and invasiveness of the epithelial cancer cells in the absence of fibroblasts. Moreover, a selective COX-2 inhibitor, NS-398, blocked the proliferative and invasive effect of both normal and cancer associate fibroblasts on the epithelial cancer cells, with or without stimulation of IL-1{beta}. Those results indicate that activation of COX-2 signaling in the fibroblasts plays a major role in promoting proliferation and invasiveness of the epithelial cancer cells. In this process, PKC is involved in the activation of COX-2 signaling induced by IL-1{beta} in the fibroblasts.

  18. Increased dietary sodium induces COX2 expression by activating NFκB in renal medullary interstitial cells.

    PubMed

    He, Wenjuan; Zhang, Min; Zhao, Min; Davis, Linda S; Blackwell, Timothy S; Yull, Fiona; Breyer, Matthew D; Hao, Chuan-Ming

    2014-02-01

    High salt diet induces renal medullary cyclooxygenase 2 (COX2) expression. Selective blockade of renal medullary COX2 activity in rats causes salt-sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8 % NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6 J mice. Co-immunofluorescence using a COX2 antibody and antibodies against aquaporin-2, ClC-K, aquaporin-1, and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a sevenfold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of enhanced green fluorescent protein (EGFP) expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet-fed C57Bl/6 J mice with selective IκB kinase inhibitor IMD-0354 (8 mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary prostaglandin E2 (PGE2). These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium.

  19. Increased Dietary Sodium Induces COX2 Expression by activating NFκB in Renal Medullary Interstitial Cells

    PubMed Central

    Zhao, Min; Davis, Linda S.; Blackwell, Timothy S.; Yull, Fiona; Breyer, Matthew D.; Hao, Chuan-Ming

    2013-01-01

    High salt diet induces renal medullary COX2 expression. Selective blockade of renal medullary COX2 activity in rats causes salt sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8% NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6J mice. Co-immunofluorescence using a COX2 antibody and antibodies against AQP2, ClC-K, AQP1 and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a 7 fold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of EGFP expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet fed C57Bl/6J mice with selective IκB kinase inhibitor IMD-0354 (8mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary PGE2. These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium. PMID:23900806

  20. Empirical Bayes estimation of proportions with application to cowbird parasitism rates

    USGS Publications Warehouse

    Link, W.A.; Hahn, D.C.

    1996-01-01

    Bayesian models provide a structure for studying collections of parameters such as are considered in the investigation of communities, ecosystems, and landscapes. This structure allows for improved estimation of individual parameters, by considering them in the context of a group of related parameters. Individual estimates are differentially adjusted toward an overall mean, with the magnitude of their adjustment based on their precision. Consequently, Bayesian estimation allows for a more credible identification of extreme values in a collection of estimates. Bayesian models regard individual parameters as values sampled from a specified probability distribution, called a prior. The requirement that the prior be known is often regarded as an unattractive feature of Bayesian analysis and may be the reason why Bayesian analyses are not frequently applied in ecological studies. Empirical Bayes methods provide an alternative approach that incorporates the structural advantages of Bayesian models while requiring a less stringent specification of prior knowledge. Rather than requiring that the prior distribution be known, empirical Bayes methods require only that it be in a certain family of distributions, indexed by hyperparameters that can be estimated from the available data. This structure is of interest per se, in addition to its value in allowing for improved estimation of individual parameters; for example, hypotheses regarding the existence of distinct subgroups in a collection of parameters can be considered under the empirical Bayes framework by allowing the hyperparameters to vary among subgroups. Though empirical Bayes methods have been applied in a variety of contexts, they have received little attention in the ecological literature. We describe the empirical Bayes approach in application to estimation of proportions, using data obtained in a community-wide study of cowbird parasitism rates for illustration. Since observed proportions based on small sample

  1. Adjustable Optical-Fiber Attenuator

    NASA Technical Reports Server (NTRS)

    Buzzetti, Mike F.

    1994-01-01

    Adjustable fiber-optic attenuator utilizes bending loss to reduce strength of light transmitted along it. Attenuator functions without introducing measurable back-reflection or insertion loss. Relatively insensitive to vibration and changes in temperature. Potential applications include cable television, telephone networks, other signal-distribution networks, and laboratory instrumentation.

  2. Dyadic Adjustment: An Ecosystemic Examination.

    ERIC Educational Resources Information Center

    Wilson, Stephan M.; Larson, Jeffry H.; McCulloch, B. Jan; Stone, Katherine L.

    1997-01-01

    Examines the relationship of background, individual, and family influences on dyadic adjustment, using an ecological perspective. Data from 102 married couples were used. Age at marriage for husbands, emotional health for wives, and number of marriage and family problems as well as family life satisfaction for both were related to dyadic…

  3. Problems of Adjustment to School.

    ERIC Educational Resources Information Center

    Bartolini, Leandro A.

    This paper, one of several written for a comprehensive policy study of early childhood education in Illinois, examines and summarizes the literature on the problems of young children in adjusting to starting school full-time and describes the nature and extent of their difficulties in relation to statewide educational policy. The review of studies…

  4. Economic Pressures and Family Adjustment.

    ERIC Educational Resources Information Center

    Haccoun, Dorothy Markiewicz; Ledingham, Jane E.

    The relationships between economic stress on the family and child and parental adjustment were examined for a sample of 199 girls and boys in grades one, four, and seven. These associations were examined separately for families in which both parents were present and in which mothers only were at home. Economic stress was associated with boys'…

  5. High proportion of male faeces in jaguar populations.

    PubMed

    Palomares, Francisco; Roques, Séverine; Chávez, Cuauhtémoc; Silveira, Leandro; Keller, Claudia; Sollmann, Rahel; do Prado, Denise Mello; Torres, Patricia Carignano; Adrados, Begoña; Godoy, José Antonio; de Almeida Jácomo, Anah Tereza; Tôrres, Natália Mundim; Furtado, Mariana Malzoni; López-Bao, José Vicente

    2012-01-01

    Faeces provide relevant biological information which includes, with the application of genetic techniques, the sex and identity of individuals that defecated, thus providing potentially useful data on the behaviour and ecology of individuals, as well as the dynamics and structure of populations. This paper presents estimates of the sex ratio of different felid species (jaguar, Panthera onca; puma, Puma concolor; and ocelot/margay, Leopardus pardalis/Leopardus wiedi) as observed in field collected faeces, and proposes several hypotheses that could explain the strikingly high proportion of faeces from male jaguars. The proportion of male and female faeces was estimated using a non-invasive faecal sampling method in 14 study areas in Mexico and Brazil. Faecal samples were genetically analysed to identify the species, the sex and the individual (the latter only for samples identified as belonging to jaguars). Considering the three species, 72.6% of faeces (n = 493) were from males; however, there were significant differences among them, with the proportion from males being higher for jaguars than for pumas and ocelots/margays. A male-bias was consistently observed in all study areas for jaguar faeces, but not for the other species. For jaguars the trend was the same when considering the number of individuals identified (n = 68), with an average of 4.2±0.56 faeces per male and 2.0±0.36 per female. The observed faecal marking patterns might be related to the behaviour of female jaguars directed toward protecting litters from males, and in both male and female pumas, to prevent interspecific aggressions from male jaguars. The hypothesis that there are effectively more males than females in jaguar populations cannot be discarded, which could be due to the fact that females are territorial and males are not, or a tendency for males to disperse into suboptimal areas for the species.

  6. High Proportion of Male Faeces in Jaguar Populations

    PubMed Central

    Palomares, Francisco; Roques, Séverine; Chávez, Cuauhtémoc; Silveira, Leandro; Keller, Claudia; Sollmann, Rahel; do Prado, Denise Mello; Torres, Patricia Carignano; Adrados, Begoña; Godoy, José Antonio; de Almeida Jácomo, Anah Tereza; Tôrres, Natália Mundim; Furtado, Mariana Malzoni; López-Bao, José Vicente

    2012-01-01

    Faeces provide relevant biological information which includes, with the application of genetic techniques, the sex and identity of individuals that defecated, thus providing potentially useful data on the behaviour and ecology of individuals, as well as the dynamics and structure of populations. This paper presents estimates of the sex ratio of different felid species (jaguar, Panthera onca; puma, Puma concolor; and ocelot/margay, Leopardus pardalis/Leopardus wiedi) as observed in field collected faeces, and proposes several hypotheses that could explain the strikingly high proportion of faeces from male jaguars. The proportion of male and female faeces was estimated using a non-invasive faecal sampling method in 14 study areas in Mexico and Brazil. Faecal samples were genetically analysed to identify the species, the sex and the individual (the latter only for samples identified as belonging to jaguars). Considering the three species, 72.6% of faeces (n = 493) were from males; however, there were significant differences among them, with the proportion from males being higher for jaguars than for pumas and ocelots/margays. A male-bias was consistently observed in all study areas for jaguar faeces, but not for the other species. For jaguars the trend was the same when considering the number of individuals identified (n = 68), with an average of 4.2±0.56 faeces per male and 2.0±0.36 per female. The observed faecal marking patterns might be related to the behaviour of female jaguars directed toward protecting litters from males, and in both male and female pumas, to prevent interspecific aggressions from male jaguars. The hypothesis that there are effectively more males than females in jaguar populations cannot be discarded, which could be due to the fact that females are territorial and males are not, or a tendency for males to disperse into suboptimal areas for the species. PMID:23285226

  7. Functional hand proportion is approximated by the Fibonacci series.

    PubMed

    Choo, K W-Q; Quah, W-K; Chang, G-H; Chan, J Y

    2012-08-01

    The debatable relationship of functional human hand proportion with the Fibonacci series has remained an obscure scientific enigma short of clinical interest. The main difficulty of proving such a relationship lies in defining what should constitute true functional proportion. In this study, we re-evaluate this unique relationship using hand flexion creases as anatomical surrogates for the functional axes of joint rotation. Standardised desktop photocopies of palmar views of both hands in full digital extension and abduction were obtained from 100 healthy male volunteers of Chinese ethnicity. The functional axes were represented by the distal digital crease (distal interphalangeal joint, DIPJ), proximal digital crease (proximal interphalangeal joint, PIPJ), as well as the midpoint between the palmar digital and transverse palmar creases (metacarpophalangeal joint, MCPJ). The ratio of DIPJ-Fingertip:PIPJ-DIPJ:MCPJ-PIPJ (p3:p2:p1) was measured by two independent observers and represented as standard deviation about the mean, and then compared to the theoretical ratio of 1:1:2. Our results showed that, for the 2nd to 5th digits, the p2:p3 ratios were 0.97 ± ± 0.09, 1.10 ± 0.10, 1.04 ± 0.12, and 0.80 ± 0.08, respectively; whilst the p1:p2 ratios were 1.91 ± 0.17, 1.98 ± 0.14, 1.89 ± 0.16, and 2.09 ± 0.24, respectively. When the data were analysed for all digits, they showed a combined p3:p2:p1 ratio of 1:0.98:2.01. In conclusion, our results suggest that functional human hand proportion, as defined by flexion creases, is approximated by the Fibonacci series.

  8. The elite athlete - assessing body shape, size, proportion and composition.

    PubMed

    Kerr, D A; Ackland, T R; Schreiner, A B

    1995-03-01

    In the quest to optimize performance of the elite athlete the sport scientist has sought to determine the ideal physique for a given sport or event. For some sports, specific structural characteristics offer definite performance advantages; for example in rowing, in addition to height, a large arm span has been identified as important. In other sports. such as long distance running, low levels of adiposity or 'fatness' appear to be linked with faster running times. There are four areas where appraisal of the athlete's physique can provide useful information: (1) identification of talented athletes; (2) to assess and monitor the growing athlete; (3) to monitor training and performance; and (4) to determine 'race weight' in weight-category sports. As a research tool a particular method must be reliable and valid. Other considerations include how expensive the method is, if it is suitable for a field situation and if large amounts of data on a number of subjects can be collected quickly. The method should be safe for both the athlete and the tester and provide useful feedback for the athlete or coach. Anthropometry, with training is able to fulfil most of these criteria and is the most widely used method of physique assessment in sports science. Large anthropometric data bases have been collected on elite athletes at Olympic games and world championships according to a standard protocol. Kinanthropometry, which has developed from anthropometry, is concerned with measurement and evaluation of different aspects of human movement and individual variation in body shape, size, proportion and composition. For the assessment of adiposity a sum of skinfolds, usually over six sites, is most commonly used rather than percentage body fat formulae. Muscle mass can be assessed indirectly through girth and corrected girth measurements. Limb lengths and breadths are used to assess skeletal structure and proportional differences in limb size. The anthropometric methods most commonly

  9. Gas amplification factor in neon-nitrogen filled proportional counters

    NASA Astrophysics Data System (ADS)

    Othman, A.

    1988-07-01

    The gas amplification factor in a cylindrical proportional counter filled with NeN 2 Penning mixtures has been measured (over the range 1 < A < 6.4 × 10 3) to verify the validity of the gas gain formulae of Rose and Korff, Khristov, Williams and Sara, Diethorn and Zastawny. This factor has been found to obey Zastawny's formula over the range of variables studied. The formula of Diethorn can be fitted only for small nitrogen concentrations (below 5 × 10 -4). Constants appropriate to the Zastawny and Diethorn formulae have been determined over a wide range of N 2 concentrations from spectroscopically pure Ne up to 11.1% N 2.

  10. Asbestos disease in sheet metal workers: proportional mortality update

    SciTech Connect

    Michaels, D.; Zoloth, S.

    1988-01-01

    This paper, updating the findings of an earlier study, provides additional evidence that sheet metal workers in the construction trades are at increased risk for asbestos-related disease. A proportional analysis of cause of death among 331 New York sheet metal workers found a significantly elevated PMR for lung cancer (PMR = 186). In addition, there were six deaths attributable to mesothelioma (three classified as lung cancer deaths) and three death certificates mentioned asbestosis or pulmonary fibrosis, although none of these three deaths were attributed to these diseases.

  11. Proportion of recovered goose and brant bands that are reported

    USGS Publications Warehouse

    Martinson, R.K.; McCann, J.A.

    1966-01-01

    A few more than one-third of the goose and brant bands recovered by hunters were reported to the Bird Banding Laboratory (a rate of 0.361) during the 1962-64 hunting seasons. We calculated this band-reporting rate by comparing the estimated number of goose and brant bands recovered by hunters, based on a mail questionnaire survey, with the number of bands actually reported to the Bird Banding Laboratory. This band-reporting rate is probably representative only of the 1962-65 period. It is likely that, in earlier years, a greater proportion (perhaps about 0.60) of recovered goose and brant bands were reported.

  12. Wealth distribution under Yard-Sale exchange with proportional taxes

    NASA Astrophysics Data System (ADS)

    Bustos-Guajardo, R.; Moukarzel, Cristian F.

    2016-03-01

    Recent analysis of a Yard-Sale (YS) exchange model supplemented with redistributive proportional taxation suggested an asymptotic behavior P(w)˜1/wμ for the wealth distribution, with a parameter-dependent exponent μ. Revisiting this problem, it is here shown analytically, and confirmed by extensive numerical simulation, that the asymptotic behavior of P(w) is not power-law but rather a Gaussian. When taxation is weak, we furthermore show that a restricted-range power-law behavior appears for wealths around the mean value. The corresponding power-law exponent equals 3/2 when the return distribution has zero mean.

  13. Proportional counter windows for the Bragg Crystal Spectrometer on AXAF

    NASA Technical Reports Server (NTRS)

    Markert, T. H.; Bauer, J. M.; Canizares, C. R.; Isobe, T.; Nenonen, S.; O'Connor, J.; Schattenburg, M. L.; Flanagan, K. A.; Zombeck, M. V.

    1991-01-01

    A Bragg Crystal Spectrometer (BCS) using a gas flow proportional counter as its primary detector is among the instruments under development for AXAF. The BCS will employ windows of 1-micron-thick polyimide coated on both sides with 200 A of Al; this window composition, while X-ray transmitting, will leak gas at a lower rate than the polypropylene film-based windows formerly employed. Accounts are given of the results obtained with additional innovative X-ray window materials currently under development, including diamond and Si-enriched Si3N4.

  14. New Bi-Proportional Methods for Bulgarian Parliamentary Elections

    NASA Astrophysics Data System (ADS)

    Konstantinov, Mihail; Yanev, Kostadin; Pelova, Galina

    2010-10-01

    A disadvantage of the existing bi-proportional system for the Bulgarian parliamentary elections is the large number of discordances (a party list with less votes gets more seats than a party list with more votes) in the seat distributions. Different schemes has been proposed to deal with this phenomenon. In this paper we propose two new methods: 1) augmentation of the electoral regions and 2) introduction of a new electoral region for accounting the votes cast abroad. In this way the number of discordances may be vastly reduced.

  15. The enigma of facial beauty: esthetics, proportions, deformity, and controversy.

    PubMed

    Naini, Farhad B; Moss, James P; Gill, Daljit S

    2006-09-01

    The study of the face and the ability to alter its form have fascinated mankind for thousands of years. The clinical ability to alter dentofacial form, whether through orthodontics, facial growth modification, or surgery, requires an understanding of facial beauty, including the evaluation of facial esthetics, proportions, and symmetry. The purposes of this article were to give a brief contemporary overview of our concepts of facial beauty and esthetics and to consider a long-standing and controversial debate on the treatment of patients with dentofacial deformities.

  16. Three case definitions of malaria and their effect on diagnosis, treatment and surveillance in Cox's Bazar district, Bangladesh.

    PubMed Central

    Montanari, R. M.; Bangali, A. M.; Talukder, K. R.; Baqui, A.; Maheswary, N. P.; Gosh, A.; Rahman, M.; Mahmood, A. H.

    2001-01-01

    In countries where malaria is endemic, routine blood slide examinations remain the major source of data for the public health surveillance system. This approach has become inadequate, however, as the public health emphasis has changed from surveillance of laboratory-confirmed malaria infections to the early detection and treatment of the disease. As a result, it has been advocated that the information collected about malaria be changed radically and should include the monitoring of morbidity and mortality, clinical practice and quality of care. To improve the early diagnosis and prompt treatment (EDPT) of malaria patients, three malaria case definitions (MCDs) were developed, with treatment and reporting guidelines, and used in all static health facilities of Cox's Bazar district, Bangladesh (population 1.5 million). The three MCDs were: uncomplicated malaria (UM); treatment failure malaria (TFM); and severe malaria (SM). The number of malaria deaths was also reported. This paper reviews the rationale and need for MCDs in malaria control programmes and presents an analysis of the integrated surveillance information collected during the three-year period, 1995-97. The combined analysis of slide-based and clinical data and their related indicators shows that blood slide analysis is no longer used to document fever episodes but to support EDPT, with priority given to SM and TFM patients. Data indicate a decrease in the overall positive predictive value of the three MCDs as malaria prevalence decreases. Hence the data quantify the extent to which the mainly clinical diagnosis of UM leads to over-diagnosis and over-treatment in changing epidemiological conditions. Also the new surveillance data show: a halving in the case fatality rate among SM cases (from 6% to 3.1%) attributable to improved quality of care, and a stable proportion of TFM cases (around 7%) against a defined population denominator. Changes implemented in the EDPT of malaria patients and in the

  17. Role of COX-2/mPGES-1/Prostaglandin E2 Cascade in Kidney Injury

    PubMed Central

    Jia, Zhanjun; Zhang, Yue; Ding, Guixia; Heiney, Kristina Marie; Huang, Songming; Zhang, Aihua

    2015-01-01

    COX-2/mPGES-1/PGE2 cascade plays critical roles in modulating many physiological and pathological actions in different organs. In the kidney, this cascade is of high importance in regulating fluid metabolism, blood pressure, and renal hemodynamics. Under some disease conditions, this cascade displays various actions in response to the different pathological insults. In the present review, the roles of this cascade in the pathogenesis of kidney injuries including diabetic and nondiabetic kidney diseases and acute kidney injuries were introduced and discussed. The new insights from this review not only increase the understanding of the pathological role of the COX-2/mPGES-1/PGE2 pathway in kidney injuries, but also shed new light on the innovation of the strategies for the treatment of kidney diseases. PMID:25729216

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

    PubMed Central

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

    2016-01-01

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

  19. A Case of Diphyllobothrium nihonkaiense Infection as Confirmed by Mitochondrial COX1 Gene Sequence Analysis

    PubMed Central

    Park, Sang Hyun; Eom, Keeseon S.; Park, Min Sun; Kwon, Oh Kyoung; Kim, Hyo Sun

    2013-01-01

    Diphyllobothrium nihonkaiense has been reported in Korea as Diphyllobothrium latum because of their close morphologic resemblance. We have identified a human case of D. nihonkaiense infection using the mitochondrial cytochrome c oxidase subunit I (cox1) gene sequence analysis. On 18 February 2012, a patient who had consumed raw fish a month earlier visited our outpatient clinic with a long tapeworm parasite excreted in the feces. The body of the segmented worm was 2 m long and divided into the scolex (head) and proglottids. It was morphologically close to D. nihonkaiense and D. latum. The cox1 gene analysis showed 99.4% (340/342 bp) homology with D. nihonkaiense but only 91.8% (314/342 bp) homology with D. latum. The present study suggested that the Diphyllobothrium spp. infection in Korea should be analyzed with specific DNA sequence for an accurate species identification. PMID:24039292

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

    PubMed

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

    2009-10-01

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

  1. Beyond COX-inhibition: 'side-effects' of ibuprofen on neoplastic development and progression.

    PubMed

    Matos, Paulo; Jordan, Peter

    2015-01-01

    Ibuprofen is a non-steroidal anti-inflammatory drug of generalized use with over-the-counter availability. Population-based studies have provided evidence that its long-term use is associated with a 30-60% decrease in the risk of developing major types of cancer. Initially, the underlying molecular mechanism was thought to be exclusively dependent on its inhibitory effect on cyclooxygenase activity, which is involved in the inflammatory response. However, numerous studies have now shown that the cancer chemopreventive properties of ibuprofen are much more complex and likely involve multiple COX-2-independent effects. Here we review the current knowledge on COX-independent effects of ibuprofen, which affect changes in gene expression or alternative splicing and act through various cell cycle- and apoptosis-regulating pathways, including β-catenin, NF-κB, PPARγ and p53.

  2. Half-metallicity and magnetism of Ti2Ni1-x CoxAl1-y Siy inverse Heusler alloys

    NASA Astrophysics Data System (ADS)

    Zhou, Ting; Feng, Yu; Chen, Xiaorui; Yuan, Hongkuan; Chen, Hong

    2017-02-01

    Half-metallicity and magnetism of Ti2Ni1-x CoxAl1-y Siy, which are obtained by Co/Si substitutions for Ni/Al of inverse Heusler alloy Ti2NiAl, are investigated by first-principle calculations based on density functional theory (DFT). The optimized lattice constants of the doped systems all conform to the Vegard law as the increase of the impurity concentration, and the magnetic moments obey the Slater-Pauling rule when the half-metallicity is retained. The defect formation energies of the codoped systems are lower than those of the monodoped systems due to the charge compensation effects, thus the Co+Si codoping is more favorable in energy than the Co/Si monodoping. Furthermore, for the Co and Si monodoped systems, the Co monodoping retains the minority-spin bandgap unchanged although the Fermi level moves towards high energy region, and the Si monodoping leads to the minority-spin bandgap narrowing and even the loss of half-metallicity at the high concentration, while for the Co+Si codoped systems, the majority of the codoped compounds obviously show more stable half-metallicity and the minority-spin gap get widened. In particular, the minority-spin band gap of the codoped compounds Ti2Ni0.5Co0.5Al0.5Si0.5 , Ti2Ni0.25Co0.75Al0.5Si0.5 , and Ti2NiCo Al0.25Si0.75 are widened distinctly and their Fermi level are adjusted to the middle of the minority-spin gap, indicating that they possess robust half-metallicity and thus they are promising candidates for spintronics applications.

  3. The proportion of elderly in Pennsylvania is slipping but....

    PubMed

    Waldman, H Barry; Cannella, Dolores; Perlman, Steven P

    2013-01-01

    Media reports describing the anticipated increase of tens of millions of elderly residents and their attendant billions of dollar costs for health services during the next decades are difficult for any person to place in proper perspective. As a result, these estimates become "just numbers" not actual people. Census Bureau reports are used at the national, state and county levels to provide an increased meaningful picture when the 65 and older population of Pennsylvania will increase to 22.6 percent of the state population. In 2000, 12.4 percent of the U.S. population was 65 years and older (15.6 percent in Pennsylvania, 1.9 million elderly). Only in the state of Florida was the proportion greater. In 2010, the proportion of elderly in the population of Pennsylvania ranked 4th (behind Florida, West Virginia and Maine). It was tied for 3rd (behind Florida and North Dakota) with 2.5 percent of the population 85 years and over. By 2030, the projected number of elderly in Pennsylvania (22.6 percent of the state population) will rank 11th. But ... "Starting on Jan 1, (2011) our 79-million-strong baby boomer generation will be turning 65 at the rate of one elderly every eight seconds.

  4. Fiber Contraction Approaches for Improving CMC Proportional Limit

    NASA Technical Reports Server (NTRS)

    DiCarlo, James A.; Yun, Hee Mann

    1997-01-01

    The fact that the service life of ceramic matrix composites (CMC) decreases dramatically for stresses above the CMC proportional limit has triggered a variety of research activities to develop microstructural approaches that can significantly improve this limit. As discussed in a previous report, both local and global approaches exist for hindering the propagation of cracks through the CMC matrix, the physical source for the proportional limit. Local approaches include: (1) minimizing fiber diameter and matrix modulus; (2) maximizing fiber volume fraction, fiber modulus, and matrix toughness; and (3) optimizing fiber-matrix interfacial shear strength; all of which should reduce the stress concentration at the tip of cracks pre existing or created in the matrix during CMC service. Global approaches, as with pre-stressed concrete, center on seeking mechanisms for utilizing the reinforcing fiber to subject the matrix to in-situ compressive stresses which will remain stable during CMC service. Demonstrated CMC examples for the viability of this residual stress approach are based on strain mismatches between the fiber and matrix in their free states, such as, thermal expansion mismatch and creep mismatch. However, these particular mismatch approaches are application limited in that the residual stresses from expansion mismatch are optimum only at low CMC service temperatures and the residual stresses from creep mismatch are typically unidirectional and difficult to implement in complex-shaped CMC.

  5. The arcsine is asinine: the analysis of proportions in ecology.

    PubMed

    Warton, David I; Hui, Francis K C

    2011-01-01

    The arcsine square root transformation has long been standard procedure when analyzing proportional data in ecology, with applications in data sets containing binomial and non-binomial response variables. Here, we argue that the arcsine transform should not be used in either circumstance. For binomial data, logistic regression has greater interpretability and higher power than analyses of transformed data. However, it is important to check the data for additional unexplained variation, i.e., overdispersion, and to account for it via the inclusion of random effects in the model if found. For non-binomial data, the arcsine transform is undesirable on the grounds of interpretability, and because it can produce nonsensical predictions. The logit transformation is proposed as an alternative approach to address these issues. Examples are presented in both cases to illustrate these advantages, comparing various methods of analyzing proportions including untransformed, arcsine- and logit-transformed linear models and logistic regression (with or without random effects). Simulations demonstrate that logistic regression usually provides a gain in power over other methods.

  6. Human patellar articular proportions: recent and Pleistocene patterns

    PubMed Central

    TRINKAUS, ERIK

    2000-01-01

    The degrees of mediolateral asymmetry of the patellar articular facet, as well as the median and lateral articular angles of the facet, were compared across samples of recent humans and of Pleistocene archaic and modern fossil humans. All samples exhibit considerable variability in these patellar proportions. The articular angles are similar across the different samples, but there is a trend towards decreasing lateral angles with decreasing robusticity. The archaic humans exhibit significantly more symmetry of the medial and lateral facets than do any of the recent human samples. However, given the variability in medial versus lateral patellofemoral contact forces documented for extant humans and the roles of the distal oblique portions of vastus medialis and vastus lateralis in patellar stabilisation, it is unclear to what extent this variation in patellar articular proportions may affect knee kinesiology. The contrasts may be related to different levels of patellar stability and/or musculoskeletal hypertrophy, but they appear unlikely to have affected primary knee function. PMID:10853969

  7. Adaptive differences in the body proportions of large felids.

    PubMed

    Gonyea, W J

    1976-01-01

    Body proportions of eight species of large felids were studied and the relationship between their morphology, habitat structure and habitat utilization was analyzed. Both Panthera onca and Neofelis nebulosa are exclusive forest dwellers (found exclusively in high densly structured habitats). These felids have the relatively shortest anterior limbs and lumbar spine. In addition, P. onca has the relatively shortest posterior limbs of the large felids, while the posterior limbs of N. nebulosa are relatively long when compared with those of P. onca which seems to be an adaptation for jumping. All large fields use the anterior limbs to make primary contact with their prey. In addition, the prey taken by the forest fields can exceed their own body weight. On the other hand, the cheetah is found in low structured habitats (savanna), and it has the relatively longest limbs and lumbarspine of the large felids. But the cheetah's prey usually weigh less than its own body weight. The cheetah also employs a 'rapid pursuit phase' in hunting and is capable of overtaking its prey. The lion, however, was found to have the body proportions of a forest felid, yet it also resides in low structured habitats. It is postulated that the utilization of large prey by the lion limits the possibilities for morphological adaptations for speed. To increase hunting efficiency, reproductive success, and territorial defense on the plains, lions form prides.

  8. Empirical Relationships between Species Richness, Evenness, and Proportional Diversity.

    PubMed

    Stirling, G; Wilsey, B

    2001-09-01

    Diversity (or biodiversity) is typically measured by a species count (richness) and sometimes with an evenness index; it may also be measured by a proportional statistic that combines both measures (e.g., Shannon-Weiner index or H'). These diversity measures are hypothesized to be positively and strongly correlated, but this null hypothesis has not been tested empirically. We used the results of Caswell's neutral model to generate null relationships between richness (S), evenness (J'), and proportional diversity (H'). We tested predictions of the null model against empirical relationships describing data in a literature survey and in four individual studies conducted across various scales. Empirical relationships between log S or J' and H' differed from the null model when <10 species were tested and in plants, vertebrates, and fungi. The empirical relationships were similar to the null model when >10 and <100 species were tested and in invertebrates. If >100 species were used to estimate diversity, the relation between log S and H' was negative. The strongest predictive models included log S and J'. A path analysis indicated that log S and J' were always negatively related, that empirical observations could not be explained without including indirect effects, and that differences between the partials may indicate ecological effects, which suggests that S and J' act like diversity components or that diversity should be measured using a compound statistic.

  9. 12 CFR 19.240 - Inflation adjustments.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 1 2012-01-01 2012-01-01 false Inflation adjustments. 19.240 Section 19.240... PROCEDURE Civil Money Penalty Inflation Adjustments § 19.240 Inflation adjustments. (a) The maximum amount of each civil money penalty within the OCC's jurisdiction is adjusted in accordance with the...

  10. 12 CFR 19.240 - Inflation adjustments.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 1 2010-01-01 2010-01-01 false Inflation adjustments. 19.240 Section 19.240... PROCEDURE Civil Money Penalty Inflation Adjustments § 19.240 Inflation adjustments. (a) The maximum amount... Civil Penalties Inflation Adjustment Act of 1990 (28 U.S.C. 2461 note) as follows: ER10NO08.001 (b)...

  11. 12 CFR 19.240 - Inflation adjustments.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 1 2011-01-01 2011-01-01 false Inflation adjustments. 19.240 Section 19.240... PROCEDURE Civil Money Penalty Inflation Adjustments § 19.240 Inflation adjustments. (a) The maximum amount... Civil Penalties Inflation Adjustment Act of 1990 (28 U.S.C. 2461 note) as follows: ER10NO08.001 (b)...

  12. Adjusting to University: The Hong Kong Experience

    ERIC Educational Resources Information Center

    Yau, Hon Keung; Sun, Hongyi; Cheng, Alison Lai Fong

    2012-01-01

    Students' adjustment to the university environment is an important factor in predicting university outcomes and is crucial to their future achievements. University support to students' transition to university life can be divided into three dimensions: academic adjustment, social adjustment and psychological adjustment. However, these…

  13. COxSwAIN: Compressive Sensing for Advanced Imaging and Navigation

    NASA Technical Reports Server (NTRS)

    Kurwitz, Richard; Pulley, Marina; LaFerney, Nathan; Munoz, Carlos

    2015-01-01

    The COxSwAIN project focuses on building an image and video compression scheme that can be implemented in a small or low-power satellite. To do this, we used Compressive Sensing, where the compression is performed by matrix multiplications on the satellite and reconstructed on the ground. Our paper explains our methodology and demonstrates the results of the scheme, being able to achieve high quality image compression that is robust to noise and corruption.

  14. Effect of COX-2 (PGE2) and IL-6 on Prostate Cancer Bone Metastases

    DTIC Science & Technology

    2008-02-02

    as indicated, for 14 days. Alkaline phosphatase (ALP) activity in the lysates was assayed by the hydrolysis of p-nitrophenyl phosphate (Sigma) to p... nitrophenol . Absorbance was determined at 405 nm and compared with a p- nitrophenol (Sigma) standard titration curve. ALP activity was normalized to...i.e., the RANKL/OPG/RANK system.1 COX-2, the highly inducible enzyme that catalyzes the conversion of arachidonic acid to prostaglandins, and PGE2

  15. Food Polyphenols Fail to Cause a Biologically Relevant Reduction of COX-2 Activity.

    PubMed

    Willenberg, Ina; Meschede, Anna K; Gueler, Faikah; Jang, Mi-Sun; Shushakova, Nelli; Schebb, Nils Helge

    2015-01-01

    Epidemiologic studies show a correlation between the dietary intake of food polyphenols and beneficial health effects. Several in vitro studies indicate that the anti-inflammatory potential of polyphenols is, at least in part, mediated by a modulation of the enzymes of the arachidonic acid cascade, such as the prostaglandin forming cyclooxygenases (COXs). Evidence that this mode of action can be transferred to the situation in vivo is scarce. This study characterized effects of a subset of polyphenols on COX-2 expression and activity in vitro and compared the potency with known drugs. Next, the in vivo relevance of the observed in vitro effects was tested. Enzyme assays and incubations of polyphenols with the cancer cell line HCA-7 and lipopolysaccharide (LPS) stimulated primary monocytes support the hypothesis that polyphenols can effect COX-2 expression and activity in vitro. The effects were most pronounced in the monocyte assay for wogonin, apigenin, resveratrol and genistein with IC50 values of 1.5 μM, 2.6 μM, 2.8 μM and 7.4 μM. However, these values are 100- to 1000-fold higher in comparison to those of the known pharmaceuticals celecoxib, indomethacin and dexamethasone. In an animal model of LPS induced sepsis, pretreatment with polyphenols (i. p. 100 mg/kg bw) did not result in decreased plasma or tissue prostaglandin levels, whereas the positive control celecoxib effectively attenuated LPS induced prostaglandin formation. These data suggest that despite the moderate potency in vitro, an effect of polyphenols on COX-2 during acute inflammation is unlikely, even if a high dose of polyphenols is ingested.

  16. Pregnancy increases myometrial artery myogenic tone via NOS- or COX-independent mechanisms.

    PubMed

    Eckman, Delrae M; Gupta, Ridhima; Rosenfeld, Charles R; Morgan, Timothy M; Charles, Shelton M; Mertz, Heather; Moore, Lorna G

    2012-08-15

    Myogenic tone (MT) is a primary modulator of blood flow in the resistance vasculature of the brain, kidney, skeletal muscle, and perhaps in other high-flow organs such as the pregnant uterus. MT is known to be regulated by endothelium-derived factors, including products of the nitric oxide synthase (NOS) and/or the cyclooxygenase (COX) pathways. We asked whether pregnancy influenced MT in myometrial arteries (MA), and if so, whether such an effect could be attributed to alterations in NOS and/or COX. MA (200-300 μm internal diameter, 2-3 mm length) were isolated from 10 nonpregnant and 12 pregnant women undergoing elective hysterectomy or cesarean section, respectively. In the absence of NOS and/or COX inhibition, pregnancy was associated with increased MT in endothelium-intact MA compared with MA from nonpregnant women (P < 0.01). The increase in MT was not due to increased Ca(2+) entry via voltage-dependent channels since both groups of MA exhibited similar levels of constriction when exposed to 50 mM KCl. NOS inhibition (N(ω)-nitro-L-arginine methyl ester, L-NAME) or combined NOS/COX inhibition (L-NAME/indomethacin) increased MT in MA from pregnant women (P = 0.001 and P = 0.042, respectively) but was without effect in arteries from nonpregnant women. Indomethacin alone was without effect on MT in MA from either nonpregnant or pregnant women. We concluded that MT increases in MA during human pregnancy and that this effect was partially opposed by enhanced NOS activity.

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

    PubMed

    Yan, Ying; Yi, Grace Y

    2016-07-01

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

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

    PubMed Central

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

    2006-01-01

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

  19. Methanolic extract of adlay seed suppresses COX-2 expression of human lung cancer cells via inhibition of gene transcription.

    PubMed

    Hung, Wen-Chun; Chang, Hui-Chiu

    2003-12-03

    Previous results demonstrated that the methanolic extract of adlay seed exerted an antiproliferative effect on human lung cancer cells in vitro and in vivo and might prevent tobacco carcinogen-induced lung tumorigenesis. In this study, the methanolic extract of adlay seed was tested for its regulation of COX-2 expression of human lung cancer cells. Western blot analysis showed that the methanolic extract of adlay seed inhibited basal and TPA-induced COX-2 expression in a dose-dependent fashion, whereas COX-1 expression was not affected. By using a promoter activity assay, it was found that the methanolic extract inhibited basal and TPA-stimulated COX-2 expression at the transcription level. The effect of the methanolic extract on COX-2 expression in vivo was then investigated. The data demonstrated that treatment of the methanolic extract reduced the PGE(2) level in serum and inhibited COX-2 expression of tumor tissues in nude mice. Taken together, these results suggest that inhibition of COX-2 is one of the mechanisms by which the methanolic extract of adlay seed inhibits cancer growth and prevents lung tumorigenesis.

  20. Estradiol-induced antinociceptive responses on formalin-induced nociception are independent of COX and HPA activation.

    PubMed

    Hunter, Deirtra A; Barr, Gordon A; Amador, Nicole; Shivers, Kai-Yvonne; Kemen, Lynne; Kreiter, Christopher M; Jenab, Shirzad; Inturrisi, Charles E; Quinones-Jenab, Vanya

    2011-07-01

    Estrogen modulates pain perception but how it does so is not fully understood. The aim of this study was to determine if estradiol reduces nociceptive responses in part via hypothalamic-pituitary-adrenal (HPA) axis regulation of cyclooxygenase (COX)-1/COX-2 activity. The first study examined the effects of estradiol (20%) or vehicle with concurrent injection nonsteroidal antiinflammatory drugs (NSAIDs) on formalin-induced nociceptive responding (flinching) in ovariectomized (OVX) rats. The drugs were ibuprofen (COX-1 and COX-2 inhibitor), SC560 (COX-1 inhibitor), or NS398 (COX-2 inhibitor). In a second study, estradiol's effects on formalin-induced nociception were tested in adrenalectomized (ADX), OVX, and ADX+OVX rats. Serum levels of prostaglandins (PG) PGE(2) and corticosterone were measured. Estradiol significantly decreased nociceptive responses in OVX rats with effects during both the first and the second phase of the formalin test. The nonsteroidal antiinflammatory drugs (NSAIDs) did not alter nociception at the doses used here. Adrenalectomy neither altered flinching responses in female rats nor reversed estradiol-induced antinociceptive responses. Estradiol alone had no effect on corticosterone (CORT) or prostaglandin levels after the formalin test, dissociating the effects of estradiol on behavior and these serum markers. Ibuprofen and NS398 significantly reduced PGE2 levels. CORT was not decreased by OVX surgery or by estradiol below that of ADX. Only IBU significantly increased corticosterone levels. Taken together, our results suggest that estradiol-induced antinociception in female rats is independent of COX activity and HPA axis activation.