Survival curve estimation with dependent left truncated data using Cox's model.

PubMed

Mackenzie, Todd

2012-10-19

The Kaplan-Meier and closely related Lynden-Bell estimators are used to provide nonparametric estimation of the distribution of a left-truncated random variable. These estimators assume that the left-truncation variable is independent of the time-to-event. This paper proposes a semiparametric method for estimating the marginal distribution of the time-to-event that does not require independence. It models the conditional distribution of the time-to-event given the truncation variable using Cox's model for left truncated data, and uses inverse probability weighting. We report the results of simulations and illustrate the method using a survival study.

A Novel Cytoplasmic Male Sterility in Brassica napus (inap CMS) with Carpelloid Stamens via Protoplast Fusion with Chinese Woad

PubMed Central

Kang, Lei; Li, Pengfei; Wang, Aifan; Ge, Xianhong; Li, Zaiyun

2017-01-01

A novel cytoplasmic male sterility (CMS) in Brassica napus (inap CMS) was selected from the somatic hybrid with Isatis indigotica (Chinese woad) by recurrent backcrossing. The male sterility was caused by the conversion of tetradynamous stamens into carpelloid structures with stigmatoid tissues at their tips and ovule-like tissues in the margins, and the two shorter stamens into filaments without anthers. The feminized development of the stamens resulted in the complete lack of pollen grains, which was stable in different years and environments. The pistils of inap CMS displayed normal morphology and good seed-set after pollinated by B. napus. Histological sections showed that the developmental alteration of the stamens initiated at the stage of stamen primordium differentiation. AFLP analysis of the nuclear genomic composition with 23 pairs of selective primers detected no woad DNA bands in inap CMS. Twenty out of 25 mitochondrial genes originated from I. indigotica, except for cox2-2 which was the recombinant between cox2 from woad and cox2-2 from rapeseed. The novel cox2-2 was transcribed in flower buds of inap CMS weakly and comparatively with the fertile B. napus addition line Me harboring one particular woad chromosome. The restorers of other autoplasmic and alloplasmic CMS systems in rapeseed failed to restore the fertility of inap CMS and the screening of B. napus wide resources found no fertility restoration variety, showing its distinct origin and the related mechanism of sterility. The reasons for the mitochondrial rearrangements and the breeding of the restorer for the novel CMS system were discussed. PMID:28428799

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

NASA Astrophysics Data System (ADS)

Joachimi, B.; Taylor, A. N.

2011-09-01

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

Design, synthesis and biological screening of some pyridinylpyrazole and pyridinylisoxazole derivatives as potential anti-inflammatory, analgesic, antipyretic and antimicrobial agents.

PubMed

El-Hawash, Soad A M; Soliman, Raafat; Youssef, Amal M; Ragab, Hanan M A; Elzahhar, Perihan A S; El-Ashmawey, Ibrahim M; Abdel Wahab, Abeer E; Shaat, Iman A

2014-05-01

A series of substituted pyridinylpyrazole (or isoxazole) derivatives were synthesized and evaluated for their anti-inflammatory (AI) activity using formalin-induced paw edema bioassays. Their inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) were also determined. The analgesic activity of the same compounds was evaluated using rat-tail withdrawal technique. Their antipyretic activity was also evaluated. The results revealed that compounds 4a,b, 6a, 8a, 14c and 15a exhibited significant AI and analgesic activities. Compounds 5a, 6a and 8a displayed good antipyretic activity. Compounds 14c and 15a showed good COX-2 inhibitory activity and weak inhibition of COX-1. Additionally, the most active compounds were shown to have a large safety margin (ALD50 >300-400 mg / Kg) and minimal ulcerogenic potentialities when administered orally at a dose of 300 mg/Kg. Docking studies for 14c and 15a with COX-2 showed good binding profile. Antimicrobial evaluation proved that most of the compounds exhibited distinctive activity against the gram negative bacteria, P. aeruginosa and E coli.

Breast cancer cell cyclooxygenase-2 expression alters extracellular matrix structure and function and numbers of cancer associated fibroblasts.

PubMed

Krishnamachary, Balaji; Stasinopoulos, Ioannis; Kakkad, Samata; Penet, Marie-France; Jacob, Desmond; Wildes, Flonne; Mironchik, Yelena; Pathak, Arvind P; Solaiyappan, Meiyappan; Bhujwalla, Zaver M

2017-03-14

Cyclooxygenase-2 (COX-2) is a critically important mediator of inflammation that significantly influences tumor angiogenesis, invasion, and metastasis. We investigated the role of COX-2 expressed by triple negative breast cancer cells in altering the structure and function of the extracellular matrix (ECM). COX-2 downregulation effects on ECM structure and function were investigated using magnetic resonance imaging (MRI) and second harmonic generation (SHG) microscopy of tumors derived from triple negative MDA-MB-231 breast cancer cells, and a derived clone stably expressing a short hairpin (shRNA) molecule downregulating COX-2. MRI of albumin-GdDTPA was used to characterize macromolecular fluid transport in vivo and SHG microscopy was used to quantify collagen 1 (Col1) fiber morphology. COX-2 downregulation decreased Col1 fiber density and altered macromolecular fluid transport. Immunohistochemistry identified significantly fewer activated cancer associated fibroblasts (CAFs) in low COX-2 expressing tumors. Metastatic lung nodules established by COX-2 downregulated cells were infrequent, smaller, and contained fewer Col1 fibers.COX-2 overexpression studies were performed with tumors derived from triple negative SUM-149 breast cancer cells lentivirally transduced to overexpress COX-2. SHG microscopy identified significantly higher Col1 fiber density in COX-2 overexpressing tumors with an increase of CAFs. These data expand upon the roles of COX-2 in shaping the structure and function of the ECM in primary and metastatic tumors, and identify the potential role of COX-2 in modifying the number of CAFs in tumors that may have contributed to the altered ECM.

Fractals and self-organized criticality in anti-inflammatory drugs

NASA Astrophysics Data System (ADS)

Phillips, J. C.

2014-12-01

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

Effect of young age, positive margins, and triple negative status on disease recurrence after breast conserving therapy

PubMed Central

Sakulchairungreung, Bundit; Chirappapha, Prakasit; Suvikapakornkul, Ronnarat; Wasuthit, Yodying; Sukarayothin, Thongchai; Leesombatpaiboon, Montchai; Kongdan, Youwanush

2016-01-01

Background To determine the risk factors for disease recurrence after breast conserving therapy (BCT) for breast cancer in a group of South-East Asian women. Methods Medical and pathological records of women who underwent BCT during the 10-year period from 2001 to 2010 were reviewed. Data collected included age ≤35 years defined as the young, type of operation, pathological data, hormonal receptor (HR) status, human epidermal growth factor receptor-2 (HER-2) expression status, and surgical margin status. Data on adjuvant therapy were also collected. Main outcomes were overall breast cancer recurrence, locoregional, and distant recurrence. Risk factors for each type of recurrence were identified using Cox proportional hazards regression models. Results There were 294 BCTs in 290 patients during the study period. The overwhelming majority (91%) had early stage (stages I-II) breast cancers. Young age patients constituted 9% of all patients, and triple negative cancers (HR negative and HER-2 negative) were seen in 19%. Involved margins on initial surgery were found in 9% of cases, and after reoperation, only 2% had involved margins. After a median follow-up of 50 months, and a maximum follow-up of 135 months, there were 30 recurrences and 6 deaths. Of the 30 recurrences, 19 included locoregional, 20 included distant, and 13 had in-breast recurrences. The disease-free survival at 10 years was 82.5% (95% CI: 74.8% to 88.1%), and the cumulative in-breast recurrence was 9.3% (95% CI: 4.9% to 17.2%) at 10 years. Multivariable Cox regression analysis revealed that young age, larger tumor size, involved margins, and no breast irradiation were associated with higher risk of locoregional recurrence. Triple negative status, larger tumor size, more positive nodes, and involved margins were associated with higher risk of distant recurrence. Conclusions We found young age to be a significant prognosticator of locoregional recurrence, and triple negative status of distant recurrence. Involved surgical margin status was associated with both recurrences. Tumor size was associated with both recurrences, and axillary lymph node metastasis was associated with distant recurrence. PMID:26855904

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

PubMed Central

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

2014-01-01

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

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

Marginal versus joint Box-Cox transformation with applications to percentile curve construction for IgG subclasses and blood pressures.

PubMed

He, Xuming; Ng, K W; Shi, Jian

2003-02-15

When age-specific percentile curves are constructed for several correlated variables, the marginal method of handling one variable at a time has typically been used. We address the question, frequently asked by practitioners, of whether we can achieve efficiency gains by joint estimation. We focus on a simple but common method of Box-Cox transformation and assess the statistical impact of a joint transformation to multivariate normality on the percentile curve estimation for correlated variables. We find that there is little gain from the joint transformation for estimating percentiles around the median but a noticeable reduction in variances is possible for estimating extreme percentiles that are usually of main interest in medical and biological applications. Our study is motivated by problems in constructing percentile charts for IgG subclasses of children and for blood pressures in adult populations, both of which are discussed in the paper as examples, and yet our general findings are applicable to a wide range of other problems. Copyright 2003 John Wiley & Sons, Ltd.

Crystallization of recombinant cyclo-oxygenase-2

NASA Astrophysics Data System (ADS)

Stevens, Anna M.; Pawlitz, Jennifer L.; Kurumbail, Ravi G.; Gierse, James K.; Moreland, Kirby T.; Stegeman, Roderick A.; Loduca, Jina Y.; Stallings, William C.

1999-01-01

The integral membrane protein, prostaglandin H 2 synthase, or cyclo-oxygenase (COX), catalyses the first step in the conversion of arachidonic acid to prostaglandins (PGs) and is the target of nonsteroidal anti-inflammatory drugs (NSAIDs). Two isoforms are known. The constitutive enzyme, COX-1, is present in most tissues and is responsible for the physiological production of PGs. The isoform responsible for the elevated production of PGs during inflammation is COX-2 which is induced specifically at inflammatory sites. Three-dimensional structures of inhibitor complexes of COX-2, and of site variants of COX-2 which mimic COX-1, provide insight into the structural basis for selective inhibition of COX-2. Additionally, structures of COX-2 mutants and complexes with the substrate can provide a clearer understanding of the catalytic mechanism of the reaction. A crystallization protocol has been developed for COX-2 which reproducibly yields diffraction quality crystals. Polyethyleneglycol 550 monomethylether (MMP550) and MgCl 2 were systematically varied and used in conjunction with the detergent β- D-octylglucopyranoside ( β-OG). As a result of many crystallization trials, we determined that the initial β-OG concentration should be held constant, allowing the salt concentration to modulate the critical micelle concentration (CMC) of the detergent. Over 25 crystal structures have been solved using crystals generated from this system. Most crystals belong to the space group P2 12 12, with lattice constants of a=180, b=134, c=120 Å in a pseudo body-centered lattice.

Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis.

PubMed

Benish, Marganit; Bartal, Inbal; Goldfarb, Yael; Levi, Ben; Avraham, Roi; Raz, Amiram; Ben-Eliyahu, Shamgar

2008-07-01

COX inhibitors and beta-blockers were recently suggested to reduce cancer progression through inhibition of tumor proliferation and growth factor secretion, induction of tumor apoptosis, and prevention of cellular immune suppression during the critical perioperative period. Here we evaluated the perioperative impact of clinically applicable drugs from these categories in the context of surgery, studying natural killer (NK) cell activity and resistance to experimental metastases. F344 rats were treated with COX-1 inhibitors (SC560), COX-2 inhibitors (indomethacin, etodolac, or celecoxib), a beta-blocker (propranolol), or a combination of a COX-2 inhibitor and a beta-blocker (etodolac and propranolol). Rats underwent laparotomy, and were inoculated intravenously with syngeneic MADB106 tumor cells for the assessment of lung tumor retention (LTR). Additionally, the impact of these drug regimens on postoperative levels of NK cytotoxicity was studied in peripheral blood and marginating-pulmonary leukocytes. Surgery increased MADB106 LTR. COX-2 inhibition, but not COX-1 inhibition, reduced postoperative LTR. Etodolac and propranolol both attenuated the deleterious impact of surgery, and their combined use abolished it. Surgery decreased NK cytotoxicity per NK cell in both immune compartments, and only the combination of etodolac and propranolol significantly attenuated these effects. Lastly, the initiation of drug treatment three days prior to surgery yielded the same beneficial effects as a single pre-operative administration, but, as discussed, prolonged treatment may be more advantageous clinically. Excess prostaglandin and catecholamine release contributes to postoperative immune-suppression. Treatment combining perioperative COX-2 inhibition and beta-blockade is practical in operated cancer patients, and our study suggests potential immunological and clinical benefits.

Persistency of use of COX-2-specific inhibitors and non-specific non-steroidal anti-inflammatory drugs (NSAIDs) in Quebec.

PubMed

Moride, Y; Ducruet, T; Rochon, S; Lavoie, F

2003-11-01

The effectiveness of pharmacological therapies is dependent in part on patient persistency with the prescribed therapeutic regimen. In the case of non-specific non-steroidal anti-inflammatory drugs (NSAIDs), effectiveness is often compromised by undesirable side-effects, poor compliance or discontinuation of therapy. While patterns of utilization of non-specific NSAIDs have been investigated, few data are available on the patterns of persistency for cyclooxygenase (COX)-2-specific inhibitors. This study used a provincial health-care system database in Quebec, Canada, to determine the duration of treatment in new users of COX-2-specific inhibitors and non-specific NSAIDs over the first 3 months of treatment, and to characterize the factors associated with treatment persistency. Results demonstrate that the median duration of treatment was longer among patients initially prescribed COX-2-specific inhibitors (30 days and 23 days for celecoxib and rofecoxib respectively) than in those prescribed non-selective NSAIDs (10 days). Although the percentage of patients remaining on COX-2-specific drugs declined over the course of treatment, few patients on either celecoxib or rofecoxib switched drugs, either to the other COX-2-specific inhibitor or to non-specific NSAIDs. Factors associated with persistent drug use were: COX-2-specific inhibitors, age, and the use of gastroprotective agents either at treatment initiation or during follow-up. Dosage, chronic disease score and prescriber's specialty were only marginally associated with persistency. Prior use of gastroprotective agents was associated with lower persistency. Although the limitations of this study, which included lack of information on the indication for the prescription and the reason for switch or discontinuation, preclude definite conclusions regarding patterns of use of these drugs, the data suggest that the use of COX-2-specific inhibitors may result in increased persistency with treatment.

Patterns of care and outcomes of adjuvant therapy for high-risk head and neck cancer after surgery.

PubMed

Osborn, Virginia Wedell; Givi, Babak; Rineer, Justin; Roden, Dylan; Sheth, Niki; Lederman, Ariel; Katsoulakis, Evangelia; Hu, Kenneth; Schreiber, David

2018-06-01

Postoperative chemoradiotherapy (CRT) is considered standard of care in patients with locally advanced head and neck cancer with positive margins and/or extracapsular extension (ECE). The National Cancer Data Base (NCDB) was queried to identify patients with squamous cell carcinoma of the head and neck with stages III to IVB disease or with positive margins and/or ECE diagnosed between 2004 and 2012 receiving postoperative radiotherapy (RT). Using univariable and multivariable logistic and Cox regression, we assessed for predictors of CRT use and covariables impacting overall survival (OS), including in a propensity-matched subset. Of 12 224 patients, 67.1% with positive margins and/or ECE received CRT as well as 54.0% without positive margins and/or ECE. The 5-year OS was 61.6% for RT alone versus 67.4% for CRT. In the propensity-matched cohort, OS benefit persisted with CRT, including in a subset with positive margins and/or ECE but not without. Postoperative CRT seems underutilized with positive margins and/or ECE and overutilized without positive margins and/or ECE. The CRT was associated with improved OS but the benefit persisted only in the subset with positive margins and/or ECE. © 2018 Wiley Periodicals, Inc.

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

Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6).

PubMed

Cingolani, Gino; Panella, Andrea; Perrone, Maria Grazia; Vitale, Paola; Di Mauro, Giuseppe; Fortuna, Cosimo G; Armen, Roger S; Ferorelli, Savina; Smith, William L; Scilimati, Antonio

2017-09-29

The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Length of positive surgical margin after radical prostatectomy as a predictor of biochemical recurrence.

PubMed

Shikanov, Sergey; Song, Jie; Royce, Cassandra; Al-Ahmadie, Hikmat; Zorn, Kevin; Steinberg, Gary; Zagaja, Gregory; Shalhav, Arieh; Eggener, Scott

2009-07-01

Length and location of positive surgical margins are independent predictors of biochemical recurrence after open radical prostatectomy. We assessed their impact on biochemical recurrence in a large robotic prostatectomy series. Data were collected prospectively from 1,398 men undergoing robotic radical prostatectomy for clinically localized prostate cancer from 2003 to 2008 at a single institution. The associations of preoperative prostate specific antigen, pathological Gleason score, pathological stage and positive surgical margin parameters (location, length and focality) with biochemical recurrence rate were evaluated. Margin status and length were measured by a single uropathologist. Biochemical recurrence was defined as serum prostate specific antigen greater than 0.1 ng/ml on 2 consecutive tests. Cox regression models were constructed to evaluate predictors of biochemical recurrence. Of 1,398 consecutive patients who underwent robotic prostatectomy positive margins were present in 243 (17%) (11% of pathological T2 and 41% of T3). Preoperative prostate specific antigen, pathological stage, Gleason score, margin status, and margin length as a continuous and categorical variable (less than 1, 1 to 3, more than 3 mm) were independent predictors of biochemical recurrence. Patients with negative margins and those with a positive margin less than 1 mm had similar rates of biochemical recurrence (log rank test p = 0.18). Surgical margin location was not independently associated with biochemical recurrence. Margin status and length are independent predictors of biochemical recurrence following robotic radical prostatectomy. Although longer followup and validation studies are necessary for confirmation, patients with a positive margin less than 1 mm appear to have similar recurrence rates as those with negative margins.

Properties of the Bivariate Delayed Poisson Process

DTIC Science & Technology

1974-07-01

and Lewis (1972) in their Berkeley Symposium paper and here their analysis of the bivariate Poisson processes (without Poisson noise) is carried... Poisson processes . They cannot, however, be independent Poisson processes because their events are associated in pairs by the displace- ment centres...process because its marginal processes for events of each type are themselves (univariate) Poisson processes . Cox and Lewis (1972) assumed a

Feature Screening in Ultrahigh Dimensional Cox's Model.

PubMed

Yang, Guangren; Yu, Ye; Li, Runze; Buu, Anne

Survival data with ultrahigh dimensional covariates such as genetic markers have been collected in medical studies and other fields. In this work, we propose a feature screening procedure for the Cox model with ultrahigh dimensional covariates. The proposed procedure is distinguished from the existing sure independence screening (SIS) procedures (Fan, Feng and Wu, 2010, Zhao and Li, 2012) in that the proposed procedure is based on joint likelihood of potential active predictors, and therefore is not a marginal screening procedure. The proposed procedure can effectively identify active predictors that are jointly dependent but marginally independent of the response without performing an iterative procedure. We develop a computationally effective algorithm to carry out the proposed procedure and establish the ascent property of the proposed algorithm. We further prove that the proposed procedure possesses the sure screening property. That is, with the probability tending to one, the selected variable set includes the actual active predictors. We conduct Monte Carlo simulation to evaluate the finite sample performance of the proposed procedure and further compare the proposed procedure and existing SIS procedures. The proposed methodology is also demonstrated through an empirical analysis of a real data example.

Structural Basis for Certain Naturally Occurring Bioflavonoids to Function as Reducing Co-Substrates of Cyclooxygenase I and II

PubMed Central

Zhu, Bao Ting

2010-01-01

Background Recent studies showed that some of the dietary bioflavonoids can strongly stimulate the catalytic activity of cyclooxygenase (COX) I and II in vitro and in vivo, presumably by facilitating enzyme re-activation. In this study, we sought to understand the structural basis of COX activation by these dietary compounds. Methodology/Principal Findings A combination of molecular modeling studies, biochemical analysis and site-directed mutagenesis assay was used as research tools. Three-dimensional quantitative structure-activity relationship analysis (QSAR/CoMFA) predicted that the ability of bioflavonoids to activate COX I and II depends heavily on their B-ring structure, a moiety known to be associated with strong antioxidant ability. Using the homology modeling and docking approaches, we identified the peroxidase active site of COX I and II as the binding site for bioflavonoids. Upon binding to this site, bioflavonoid can directly interact with hematin of the COX enzyme and facilitate the electron transfer from bioflavonoid to hematin. The docking results were verified by biochemical analysis, which reveals that when the cyclooxygenase activity of COXs is inhibited by covalent modification, myricetin can still stimulate the conversion of PGG2 to PGE2, a reaction selectively catalyzed by the peroxidase activity. Using the site-directed mutagenesis analysis, we confirmed that Q189 at the peroxidase site of COX II is essential for bioflavonoids to bind and re-activate its catalytic activity. Conclusions/Significance These findings provide the structural basis for bioflavonoids to function as high-affinity reducing co-substrates of COXs through binding to the peroxidase active site, facilitating electron transfer and enzyme re-activation. PMID:20808785

Marginal regression analysis of recurrent events with coarsened censoring times.

PubMed

Hu, X Joan; Rosychuk, Rhonda J

2016-12-01

Motivated by an ongoing pediatric mental health care (PMHC) study, this article presents weakly structured methods for analyzing doubly censored recurrent event data where only coarsened information on censoring is available. The study extracted administrative records of emergency department visits from provincial health administrative databases. The available information of each individual subject is limited to a subject-specific time window determined up to concealed data. To evaluate time-dependent effect of exposures, we adapt the local linear estimation with right censored survival times under the Cox regression model with time-varying coefficients (cf. Cai and Sun, Scandinavian Journal of Statistics 2003, 30, 93-111). We establish the pointwise consistency and asymptotic normality of the regression parameter estimator, and examine its performance by simulation. The PMHC study illustrates the proposed approach throughout the article. © 2016, The International Biometric Society.

Risk factors for positive margins in conservative surgery for breast cancer after neoadjuvant chemotherapy.

PubMed

Bouzón, Alberto; Acea, Benigno; García, Alejandra; Iglesias, Ángela; Mosquera, Joaquín; Santiago, Paz; Seoane, Teresa

2016-01-01

Breast conservative surgery after neoadjuvant chemotherapy intends to remove any residual tumor with negative margins. The purpose of this study was to analyze the preoperative clinical-pathological factors influencing the margin status after conservative surgery in breast cancer patients receiving neoadjuvant chemotherapy. A retrospective study of 91 breast cancer patients undergoing neoadjuvant chemotherapy (92 breast lesions) during the period 2006 to 2013. A Cox regression analysis to identify baseline tumor characteristics associated with positive margins after breast conservative surgery was performed. Of all cases, 71 tumors were initially treated with conservative surgery after neoadjuvant chemotherapy. Pathologic exam revealed positive margins in 16 of the 71 cases (22.5%). The incidence of positive margins was significantly higher in cancers with initial size >5cm (P=.021), in cancers with low tumor grade (P=.031), and in patients with hormone receptor-positive cancer (P=.006). After a median follow-up of 45.2 months, 7 patients of the 71 treated with conservative surgery had disease recurrence (9.8%). There was no significant difference in terms of disease-free survival according to the margin status (P=.596). A baseline tumor size >5cm, low tumor grade and hormone receptor-positive status increase the risk for surgical margin involvement in breast conservative surgery after neoadjuvant chemotherapy. Copyright © 2016 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

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

PubMed Central

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

2014-01-01

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

COX-1 Inhibitors: Beyond Structure Toward Therapy.

PubMed

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

2016-07-01

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

Incidence of HIV Infection in Young Gay, Bisexual, and Other YMSM: The P18 Cohort Study.

PubMed

Halkitis, Perry; Kapadia, Farzana; Ompad, Danielle

2015-08-01

HIV infections continue to rise in a new generation of young gay, bisexual, and other young men who have sex with men (YMSM) despite 3 decades of HIV prevention and recent biomedical technologies to deter infection. To examine the incidence of HIV and the demographic, behavioral, and structural factors associated with incident infections. A prospective cohort study. Six hundred YMSM who were aged 18-19 years at baseline. At baseline, 6 prevalent cases of HIV were detected. Over the course of 36 months and 6 additional waves of data collection, we identified 43 (7.2%) incident cases of HIV. Incident infections were marginally higher among those residing in neighborhoods with higher rates of HIV prevalence. Using Cox proportional hazards models, we detected that hazard ratios (HRs) for time to HIV seroconversion were significantly higher for black YMSM (HR = 7.46) and mixed/other race YMSM (HR = 7.99), and older age at sexual debut with another man was associated with a lower risk of HIV seroconversion (HR = 0.50), whereas low perceived familial socioeconomic status was marginally associated with an increased risk for HIV seroconversion (HR = 2.45). These findings support the disparities for HIV that exist within the population of sexual minority men and suggest that we attend to behavioral, structural, and social conditions to effectively tailor HIV prevention for a new generation of YMSM with keen eyes to the conditions faced by racial and ethnic minority YMSM, which heightened their risk for acquiring HIV.

Exploring the Subtleties of Inverse Probability Weighting and Marginal Structural Models.

PubMed

Breskin, Alexander; Cole, Stephen R; Westreich, Daniel

2018-05-01

Since being introduced to epidemiology in 2000, marginal structural models have become a commonly used method for causal inference in a wide range of epidemiologic settings. In this brief report, we aim to explore three subtleties of marginal structural models. First, we distinguish marginal structural models from the inverse probability weighting estimator, and we emphasize that marginal structural models are not only for longitudinal exposures. Second, we explore the meaning of the word "marginal" in "marginal structural model." Finally, we show that the specification of a marginal structural model can have important implications for the interpretation of its parameters. Each of these concepts have important implications for the use and understanding of marginal structural models, and thus providing detailed explanations of them may lead to better practices for the field of epidemiology.

Retrospective cohort study of prognostic factors in patients with oral cavity and oropharyngeal squamous cell carcinoma.

PubMed

Carrillo, José F; Carrillo, Liliana C; Cano, Ana; Ramirez-Ortega, Margarita C; Chanona, Jorge G; Avilés, Alejandro; Herrera-Goepfert, Roberto; Corona-Rivera, Jaime; Ochoa-Carrillo, Francisco J; Oñate-Ocaña, Luis F

2016-04-01

Prognostic factors in oral cavity and oropharyngeal squamous cell carcinoma (SCC) are debated. The purpose of this study was to investigate the association of prognostic factors with oncologic outcomes. Patients with oral cavity and oropharyngeal SCC treated from 1997 to 2012 were included in this retrospective cohort study. Associations of prognostic factors with locoregional recurrence (LRR) or overall survival (OS) were analyzed using the logistic regression and the Cox models. Six hundred thirty-four patients were included in this study; tumor size, surgical margins, and N classification were associated with LRR (p < .0001); considering histopathology: perineural invasion, lymphocytic infiltration, infiltrative borders, and N classification were significant determinants of LRR. Tumor size, N classification, alcoholism, and surgical margins were associated with OS (p < .0001); considering pathologic prognostic factors, perivascular invasion, islands borders, and surgical margins were independently associated with OS (p < .0001). Surgical margins, perineural and perivascular invasion, lymphocytic infiltration, and infiltrative patterns of tumor invasion are significant prognostic factors in oral cavity and oropharyngeal SCC. © 2015 Wiley Periodicals, Inc.

Opened Proton Pump Inhibitor Capsules Reduce Time to Healing Compared With Intact Capsules for Marginal Ulceration Following Roux-en-Y Gastric Bypass.

PubMed

Schulman, Allison R; Chan, Walter W; Devery, Aiofe; Ryan, Michele B; Thompson, Christopher C

2017-04-01

Marginal ulceration, or ulceration at the gastrojejunal anastomosis, is a common complication of Roux-en-Y gastric bypass (RYGB). Acidity likely contributes to the pathophysiology, and proton pump inhibitors (PPIs) frequently are prescribed for treatment. However, patients with gastric bypass only have a small gastric pouch and rapid small-bowel transit, which limits the opportunity for capsule breakdown and PPI absorption. Soluble PPIs (open capsules [OCs]) might be absorbed more easily than intact capsules (ICs). We compared time to ulcer healing, number of endoscopic procedures, and use of health care for patients with marginal ulceration who received PPIs in OC vs IC form. We performed a retrospective study of 164 patients diagnosed with marginal ulceration who underwent RYGB at the Brigham and Women's Hospital from 2000 through 2015. Patients received high-dose PPIs and underwent repeat endoscopy every 3 months until ulcer healing was confirmed. We used time-to-event analysis with a Cox proportional hazards model to evaluate the association between mode of PPI administration and time to ulcer healing, in addition to Cox multivariate regression analysis. Total charge (procedural and maintenance) was determined by comparison of categorized charges incurred from time of ulcer diagnosis to resolution. The primary outcome was time to healing of marginal ulceration in RYGB patients receiving high-dose PPIs in OC vs IC form. A total of 162 patients were included (115 received OC and 49 received IC). All patients were followed up until ulcer healing was confirmed. The median time to ulcer healing was 91.0 days for the OC group vs 342.0 days for the IC group (P < .001). OC was the only independent predictor of time to ulcer healing (P < .001) when we controlled for known risk factors. The number of endoscopic procedures (P = .02) and overall health care utilization (P = .05) were lower in the OC than the IC group. Patients with marginal ulceration after RYGB who receive OC PPIs have shorter ulcer healing times, fewer endoscopic procedures, and use less health care resources compared with patients who receive IC PPIs. Given these results and the high prevalence of marginal ulceration in this patient population, the use of OC PPIs is a low-risk, low-cost alternative that should be considered. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Neuropsychiatric Symptoms and Alzheimer's Disease Biomarkers Predict Driving Decline: Brief Report.

PubMed

Babulal, Ganesh M; Stout, Sarah H; Head, Denise; Holtzman, David M; Fagan, Anne M; Morris, John C; Roe, Catherine M

2017-01-01

We examined whether neuropsychiatric symptoms (NPS) interact with cerebrospinal fluid (CSF) biomarkers (amyloid-β42 [Aβ42], tau, phosphorylated tau181 [ptau181], tau/Aβ42, and ptau181/Aβ42) of Alzheimer's disease pathology to predict driving decline among cognitively-normal older adults (N = 116) aged ≥65. Cox proportional hazards models examined time to receiving a rating of marginal or fail on the driving test. Age, education, and gender were adjusted in the models. Participants with more abnormal CSF (Aβ42, tau/Aβ42, ptau181/Aβ42) and NPS were faster to receive a marginal/fail on the road test compared to those without NPS. NPS interact with abnormal CSF biomarkers to impact driving performance among cognitively-normal older adults.

Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study.

PubMed

Heffron, Renee; Donnell, Deborah; Rees, Helen; Celum, Connie; Mugo, Nelly; Were, Edwin; de Bruyn, Guy; Nakku-Joloba, Edith; Ngure, Kenneth; Kiarie, James; Coombs, Robert W; Baeten, Jared M

2012-01-01

Hormonal contraceptives are used widely but their effects on HIV-1 risk are unclear. We aimed to assess the association between hormonal contraceptive use and risk of HIV-1 acquisition by women and HIV-1 transmission from HIV-1-infected women to their male partners. In this prospective study, we followed up 3790 heterosexual HIV-1-serodiscordant couples participating in two longitudinal studies of HIV-1 incidence in seven African countries. Among injectable and oral hormonal contraceptive users and non-users, we compared rates of HIV-1 acquisition by women and HIV-1 transmission from women to men. The primary outcome measure was HIV-1 seroconversion. We used Cox proportional hazards regression and marginal structural modelling to assess the effect of contraceptive use on HIV-1 risk. Among 1314 couples in which the HIV-1-seronegative partner was female (median follow-up 18·0 [IQR 12·6-24·2] months), rates of HIV-1 acquisition were 6·61 per 100 person-years in women who used hormonal contraception and 3·78 per 100 person-years in those who did not (adjusted hazard ratio 1·98, 95% CI 1·06-3·68, p=0·03). Among 2476 couples in which the HIV-1-seronegative partner was male (median follow-up 18·7 [IQR 12·8-24·2] months), rates of HIV-1 transmission from women to men were 2·61 per 100 person-years in couples in which women used hormonal contraception and 1·51 per 100 person-years in couples in which women did not use hormonal contraception (adjusted hazard ratio 1·97, 95% CI 1·12-3·45, p=0·02). Marginal structural model analyses generated much the same results to the Cox proportional hazards regression. Women should be counselled about potentially increased risk of HIV-1 acquisition and transmission with hormonal contraception, especially injectable methods, and about the importance of dual protection with condoms to decrease HIV-1 risk. Non-hormonal or low-dose hormonal contraceptive methods should be considered for women with or at-risk for HIV-1. US National Institutes of Health and the Bill & Melinda Gates Foundation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Magnetic structure in Mn1 -xCoxGe compounds

NASA Astrophysics Data System (ADS)

Altynbaev, E.; Siegfried, S.-A.; Strauß, P.; Menzel, D.; Heinemann, A.; Fomicheva, L.; Tsvyashchenko, A.; Grigoriev, S.

2018-04-01

The magnetic system of the pseudobinary compound Mn1 -xCoxGe has been studied using small-angle neutron scattering and susceptibility measurements. It is found that Mn1 -xCoxGe orders magnetically at low temperatures in the whole concentration range of x ∈[0 /0.9 ] . Four different states of the magnetic structure have been found at low temperatures: the long-range-ordered (LRO) short-period helical magnetic structure at x

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

PubMed

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

2016-03-01

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

Marginal Iodine Deficiency Affects Dendritic Spine Development by Disturbing the Function of Rac1 Signaling Pathway on Cytoskeleton.

PubMed

Min, Hui; Dong, Jing; Wang, Yi; Wang, Yuan; Yu, Ye; Shan, Zhongyan; Xi, Qi; Teng, Weiping; Chen, Jie

2017-01-01

Iodine deficiency (ID)-induced thyroid hormone (TH) insufficient during development leads to impairments of brain function, such as learning and memory. Marginal ID has been defined as subtle insufficiency of TH, characterized as low thyroxine (T 4 ) levels, whether marginal ID potentially had adverse effects on the development of hippocampus and the underlying mechanisms remain unclear. Thus, in the present study, we established Wistar rat models with ID diet during pregnancy and lactation. The effects of marginal ID on long-term potentiation (LTP) were investigated in the hippocampal CA1 region. To study the development of dendritic spines in pyramidal cells, Golgi-Cox staining was conducted on postnatal day (PN) 7, PN14, PN21, and PN28. The activation of Rac1 signaling pathway, which is essential for dendritic spine development by regulating actin cytoskeleton, was also investigated. Our results showed that marginal ID slightly reduced the field-excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Besides, the density of dendritic spines during the critical period of rat postnatal development was mildly decreased, and we found no significant change of spine morphology in marginal ID group. We also observed decreased activation of the Rac1 signaling pathway in pups subjected to maternal marginal ID. Our study may support the hypothesis that decreased T 4 induced by marginal ID results in slight impairments of LTP and leads to mild damage of dendritic spine development, which may be due to abnormal regulation of Rac1 signaling pathway on cytoskeleton.

Cox-2 inhibitory effects of naturally occurring and modified fatty acids.

PubMed

Ringbom, T; Huss, U; Stenholm , A; Flock, S; Skattebøl, L; Perera, P; Bohlin, L

2001-06-01

In the search for new cyclooxygenase-2 (COX-2) selective inhibitors, the inhibitory effects of naturally occurring fatty acids and some of their structural derivatives on COX-2-catalyzed prostaglandin biosynthesis were investigated. Among these fatty acids, linoleic acid (LA), alpha-linolenic acid (alpha-LNA), myristic acid, and palmitic acid were isolated from a CH(2)Cl(2) extract of the plant Plantago major by bioassay-guided fractionation. Inhibitory effects of other natural, structurally related fatty acids were also investigated: stearic acid, oleic acid, pentadecanoic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further, the inhibitory effects of these compounds on COX-2- and COX-1-catalyzed prostaglandin biosynthesis was compared with the inhibition of some synthesized analogues of EPA and DHA with ether or thioether functions. The most potent COX-2-catalyzed prostaglandin biosynthesis inhibitor was all-(Z)-5-thia-8,11,14,17-eicosatetraenoic acid (2), followed by EPA, DHA, alpha-LNA, LA, (7E,11Z,14Z,17Z)-5-thiaeicosa-7,11,14,17-tetraenoic acid, all-(Z)-3-thia-6,9,12,15-octadecatetraenoic acid, and (5E,9Z,12Z,15Z,18Z)-3-oxaheneicosa-5,9,12,15,18-pentaenoic acid, with IC(50) values ranging from 3.9 to180 microM. The modified compound 2 and alpha-LNA were most selective toward COX-2, with COX-2/COX-1 ratios of 0.2 and 0.1, respectively. This study shows that several of the natural fatty acids as well as all of the semisynthetic thioether-containing fatty acids inhibited COX-2-catalyzed prostaglandin biosynthesis, where alpha-LNA and compound 2 showed selectivity toward COX-2.

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

PubMed

Wolfensberger, M

1992-01-01

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

Reappraisal of the Therapeutic Role of Celecoxib in Cholangiocarcinoma

PubMed Central

Juang, Horng-Heng; S. Pang, Jong-Hwei; Yu, Chung-Shan; Lin, Kun-Ju; Yeh, Ta-Sen; Jan, Yi-Yin

2013-01-01

Cholangiocarcinoma (CCA), a lethal disease, affects many thousands worldwide yearly. Surgical resection provides the best chance for a cure; however, only one-third of CCA patients present with a resectable tumour at the time of diagnosis. Currently, no effective chemotherapy is available for advanced CCA. Cyclooxygenase-2 (COX-2) is a potential oncogene expressing in human CCA tissues and represents a candidate target for treatment; however, COX-2 inhibitors increase the risk of negative cardiovascular events as application for chemoprevention aim. Here, we re-evaluated the effectiveness and safety of celecoxib, one widely used COX-2 inhibitor, in treating CCA. We demonstrated that celecoxib exhibited an anti-proliferative effect on CGCCA cells via cell cycle arrest at G2 phase and apoptosis induction. Treatment for 5 weeks high dose celecoxib (160 mg/kg) significantly repressed thioacetamide-induced CCA tumour growth in rats as monitored by animal positron emission tomography through apoptosis induction. No obviously observable side effects were noted during the therapeutic period. As retrospectively reviewing 78 intrahepatic mass-forming CCA patients, their survival was strongly and negatively associated with a positive resection margin and high COX-2 expression. Based on our result, we concluded that short-term high dose celecoxib may be a promising therapeutic regimen for CCA. Yet its clinical application still needs more studies to prove its safety. PMID:23922859

Incidence of HIV infection in Young Gay, Bisexual, and other YMSM: The P18 Cohort Study

PubMed Central

Kapadia, Farzana; Ompad, Danielle

2015-01-01

Content HIV infections continue to rise in a new generation of young, gay, bisexual and other men who have sex with men (YMSM) despite three decades of HIV prevention and recent biomedical technologies to deter infection. Objectives To examine the incidence of HIV and the demographics, behavioral, and structural factors associated with incident infections. Design Cohort study. Participants 600 YMSM who were ages 18-19 at baseline. Results At baseline 6 prevalent cases of HIV were detected. Over the course of 36 months and six additional waves of data collection, we identified 43 (7.2%) incident cases of HIV. Incident infections were marginally higher among those residing in neighborhoods with higher rates of HIV prevalence. Using Cox proportional hazards models we detected that hazard ratios for time to HIV seroconversion were significantly higher for Black YMSM (HR = 7.46) and Mixed/Other race YMSM (HR = 7.99), and older age at sexual debut with another man was associated with a lower risk of HIV seroconversion (HR = 0.50), while low perceived familial SES was marginally associated with an increased risk for HIV seroconversion (HR = 2.45). Conclusions These findings support the disparities for HIV that exist within the population of sexual minority men and suggest that we attend to behavioral, structural and social conditions to effectively tailor HIV prevention for a new generation of YMSM with a keen eyes to the conditions faced by racial and ethnic minority YMSM which heightened their risk for acquiring HIV. PMID:26115438

Cytochrome oxidase assembly does not require catalytically active cytochrome C.

PubMed

Barrientos, Antoni; Pierre, Danielle; Lee, Johnson; Tzagoloff, Alexander

2003-03-14

Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the transfer of electrons from reduced cytochrome c to molecular oxygen. COX assembly requires the coming together of nuclear- and mitochondrial-encoded subunits and the assistance of a large number of nuclear gene products acting at different stages of maturation of the enzyme. In Saccharomyces cerevisiae, expression of cytochrome c, encoded by CYC1 and CYC7, is required not only for electron transfer but also for COX assembly through a still unknown mechanism. We have attempted to distinguish between a functional and structural requirement of cytochrome c in COX assembly. A cyc1/cyc7 double null mutant strain was transformed with the cyc1-166 mutant gene (Schweingruber, M. E., Stewart, J. W., and Sherman, F. (1979) J. Biol. Chem. 254, 4132-4143) that expresses stable but catalytically inactive iso-1-cytochrome c. The COX content of the cyc1/cyc7 double mutant strain harboring non-functional iso-1-cytochrome c has been characterized spectrally, functionally, and immunochemically. The results of these studies demonstrate that cytochrome c plays a structural rather than functional role in assembly of cytochrome c oxidase. In addition to its requirement for COX assembly, cytochrome c also affects turnover of the enzyme. Mutants containing wild type apocytochrome c in mitochondria lack COX, suggesting that only the folded and mature protein is able to promote COX assembly.

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

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

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

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

Crystal structure of rofecoxib bound to human cyclooxygenase-2

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

Orlando, Benjamin J.; Malkowski, Michael G.

2016-10-26

Rofecoxib (Vioxx) was one of the first selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) to be approved for use in humans. Within five years after its release to the public, Vioxx was withdrawn from the market owing to the adverse cardiovascular effects of the drug. Despite the widespread knowledge of the development and withdrawal of Vioxx, relatively little is known at the molecular level about how the inhibitor binds to COX-2. Vioxx is unique in that the inhibitor contains a methyl sulfone moiety in place of the sulfonamide moiety found in other coxibs such as celecoxib and valdecoxib. Here, new crystallization conditionsmore » were identified that allowed the structural determination of human COX-2 in complex with Vioxx and the structure was subsequently determined to 2.7- Å resolution. The crystal structure provides the first atomic level details of the binding of Vioxx to COX-2. As anticipated, Vioxx binds with its methyl sulfone moiety located in the side pocket of the cyclooxygenase channel, providing support for the isoform selectivity of this drug.« less

Long-term outcomes of dental implants placed in elderly patients: a retrospective clinical and radiographic analysis.

PubMed

Park, Jung-Chul; Baek, Won-Sun; Choi, Seong-Ho; Cho, Kyoo-Sung; Jung, Ui-Won

2017-02-01

The aim of this retrospective study was to determine the clinical and the radiographic outcomes of dental implants placed in elderly people older than 65 years. In total, 902 implants in 346 patients (age: 65-89 years) were followed up for 2-17 years following the implant surgery. The survival rate of these implants was recorded and analyzed. Changes in marginal bone levels were also analyzed in serial radiographs, and Cox regression analysis for implant loss was performed. The survival rates were 95.39% and 99.98% in the implant- and patient-based analyses, respectively (involving a total of 29 implant failures), and the marginal bone loss at the implants was 0.17 ± 0.71 mm (mean ± SD). The number of failures was greatest in patients aged 65-69 years. The Cox regression with shared frailty analysis showed that implant loss was significantly greater in those aged 65-69 years than in those aged 70-74 years (P < 0.05), and it varied between specific implant systems. Within the limitations of this retrospective study, it was concluded that implant therapy can be successfully provided to elderly patients and that age alone does not seem to affect the implant survival rate. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Missense mutations in SURF1 associated with deficient cytochrome c oxidase assembly in Leigh syndrome patients.

PubMed

Poyau, A; Buchet, K; Bouzidi, M F; Zabot, M T; Echenne, B; Yao, J; Shoubridge, E A; Godinot, C

2000-02-01

We have studied the fibroblasts of three patients suffering from Leigh syndrome associated with cytochrome c oxidase deficiency (LS-COX-). Their mitochondrial DNA was functional and all nuclear COX subunits had a normal sequence. The expression of transcripts encoding mitochondrial and nuclear COX subunits was normal or slightly increased. Similarly, the OXA1 transcript coding for a protein involved in COX assembly was increased. However, several COX-protein subunits were severely depressed, indicating deficient COX assembly. Surf1, a factor involved in COX biogenesis, was recently reported as mutated in LS-COX- patients, all mutations predicting a truncated protein. Sequence analysis of SURF1 gene in our three patients revealed seven heterozygous mutations, six of which were new : an insertion, a nonsense mutation, a splicing mutation of intron 7 in addition to three missense mutations. The mutation G385 A (Gly124-->Glu) changes a Gly that is strictly conserved in Surfl homologs of 12 species. The substitution G618 C (Asp202-->His), changing an Asp that is conserved only in mammals, appears to be a polymorphism. The mutation T751 C changes Ile246 to Thr, a position at which a hydrophobic amino acid is conserved in all eukaryotic and some bacterial species. Replacing Ile246 by Thr disrupts a predicted beta sheet structure present in all higher eukaryotes. COX activity could be restored in fibroblasts of the three patients by complementation with a retroviral vector containing normal SURF1 cDNA. These mutations identify domains essential to Surf1 protein structure and/or function.

Immunohistochemical analysis of an ectopic endometriosis in the uterine round ligament.

PubMed

Terada, Shinichi; Miyata, Yachiyo; Nakazawa, Hiroaki; Higashimori, Takamitsu; Arai, Takanari; Kikuchi, Yuji; Nozaki, Motohiro

2006-09-09

A rare case of the inguinal endometriosis was reported with immunohistochemical analysis. A 28-year-old woman had a thumb-sized tumor in the right groin for two years with a gradual increase in size and pain. An operation revealed an elastic hard tumor with an unclear margin and adhesion to the uterine round ligament. The histology showed irregular proliferation of the endometrial glands and stroma. The glandular epithelium stained weakly positive against CD125 antibody and the stromal matrix stained strongly positive against CD10 antibody. The nucleus in both the epithelial and stromal cells stained strongly positive against progesterone and estrogen receptor antibodies, and the cytoplasm in both types of cells stained moderately positive against COX-2 (cyclooxygenase-2) antibody. In conclusion, the combination of estrogen or progesterone receptor antibody for the nucleus and CD10 or COX-2 antibody for the cytoplasm could enhance the accuracy of diagnosis for ectopic endometriosis.

Factors affecting surgical margin recurrence after hepatectomy for colorectal liver metastases.

PubMed

Akyuz, Muhammet; Aucejo, Federico; Quintini, Cristiano; Miller, Charles; Fung, John; Berber, Eren

2016-06-01

Hepatic recurrence after resection of colorectal liver metastasis (CLM) occurs in 50% of patients during follow-up, with 2.8% to 13.9% presenting with surgical margin recurrence (SMR). The aim of this study is to analyze factors that related to SMR in patients with CLM undergoing hepatectomy. Demographics, clinical and survival data of patients who underwent hepatectomy were identified from a prospectively maintained, institutional review board (IRB)-approved database between 2000 and 2012. Statistical analysis was performed using univariate Kaplan Meier and Cox proportional hazard model. There were 85 female and 121 male patients who underwent liver resection for CLM. An R0 resection was performed in 157 (76%) patients and R1 resection in 49. SMR was detected in 32 patients (15.5%) followed up for a median of 29 months (range, 3-121 months). A half of these patients had undergone R1 (n=16) and another half R0 resection (n=16). Tumor size, preoperative carcinoembryonic antigen (CEA) level and margin status were associated with SMR on univariate analysis. On multivariate analysis, a positive surgical margin was the only independent predictor of SMR. The receipt of adjuvant chemotherapy did not affect margin recurrence. SMR was an independent risk factor associated with worse disease-free (DFS) and overall survival (OS). This study shows that SMR, which can be detected in up to 15.5% of patients after liver resection for CLM, adversely affects DFS and OS. The fact that a positive surgical margin was the only predictive factor for SMR in these patients underscores the importance of achieving negative margins during hepatectomy.

Surface plasmon resonance studies and biochemical evaluation of a potent peptide inhibitor against cyclooxygenase-2 as an anti-inflammatory agent.

PubMed

Somvanshi, Rishi K; Kumar, Ashwini; Kant, Shashi; Gupta, Deepti; Singh, S Bhaskar; Das, Utpal; Srinivasan, Alagiri; Singh, Tej P; Dey, Sharmistha

2007-09-14

Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are mediators of inflammation [D.L. Dewitt, W.L. Smith, Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence, Proc. Natl. Acad. Sci. USA 85 (1988) 1412-1416, 1]. It exists mainly in two isoforms COX-1 and COX-2 [A. Raz, A. Wyche, N. Siegel, P. Needleman, Regulation of fibroblast cyclooxygenase synthesis by interleukin-1, J. Biol. Chem. 263 (1988) 3022-3028, 2]. The conventional non-steroidal anti-inflammatory drugs (NSAIDs) have adverse gastrointestinal side-effects, because they inhibit both isoforms [T.D. Warner, F. Guiliano, I. Vojnovic, A. Bukasa, J.A. Mitchell, J.P. Vane, Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis, Proc. Natl. Acad. Sci. USA 96 (1999) 7563-7568, 3; L.J. Marnett, A.S. Kalgutkar, Cyclooxygenase 2 inhibitors: discovery, selectivity and the future, Trends Pharmacol. Sci. 20 (1999) 465-469, 4; J.R. Vane, NSAIDs, Cox-2 inhibitors, and the gut, Lancet 346 (1995) 1105-1106, 5]. Therefore drugs which selectively inhibit COX-2, known as coxibs were developed. Recent reports on the harmful cardiovascular and renovascular side-effects of the anti-inflammatory drugs have led to the quest for a novel class of COX-2 selective inhibitors. Keeping this in mind, we have used the X-ray crystal structures of the complexes of the COX-1 and COX-2 with the known inhibitors for a rational, structure based approach to design a small peptide, which is potent inhibitor for COX-2. The peptides have been checked experimentally by in-vitro kinetic studies using surface plasmon resonance (SPR) and other biochemical methods. We have identified a tripeptide inhibitor which is a potential lead for a new class of COX-2 inhibitor. The dissociation constant (K(D)) determined for COX-2 with peptide WCS is 1.90x10(-10)M, the kinetic constant (K(i)) determined by spectrophotometry is 4.85x10(-9)M and the IC(50) value is 1.5x10(-8)M by ELISA test.

Margin to tumor thickness ratio - A predictor of local recurrence and survival in oral squamous cell carcinoma.

PubMed

Heiduschka, Gregor; Virk, Sohaib A; Palme, Carsten E; Ch'ng, Sydney; Elliot, Michael; Gupta, Ruta; Clark, Jonathan

2016-04-01

To assess whether small oral squamous cell carcinomas (OSCC) require the same margin clearance as large tumors. We evaluated the association between the ratio of the closest margin to tumor size (MSR) and tumor thickness (MTR) with local control and survival. The clinicopathologic and follow up data were obtained for 501 OSCC patients who had surgical resection with curative intent at our institution. MTR and MSR were computed and their associations with local control and survival were assessed using multivariable Cox-regression model. Survival curves were generated using the Kaplan-Meier method. MTR was a better predictor of disease control than MSR. MTR was a predictor of local failure (p=0.033) and disease specific death (p=0.038) after adjusting for perineural invasion, lymphovascular involvement, nodal status, and radiotherapy. A threshold MTR value of 0.3 was identified, above which the risk of local recurrence was low. The ratio of margin to tumor thickness was an independent predictor for local recurrence and disease specific death in this cohort. A MTR>0.3 can serve as a useful tool for adjuvant therapy planning as it combines tumor thickness and margin clearance, two well established prognostic factors. The minimum safe margin can be calculated by multiplying the tumor thickness by 0.3. Further prospective studies in other institutions are warranted to confirm the prognostic utility of MTR and assess the generalizability of our threshold values. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed Central

2015-01-01

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

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

Signaling of Prostaglandin E Receptors, EP3 and EP4 Facilitates Wound Healing and Lymphangiogenesis with Enhanced Recruitment of M2 Macrophages in Mice.

PubMed

Hosono, Kanako; Isonaka, Risa; Kawakami, Tadashi; Narumiya, Shuh; Majima, Masataka

2016-01-01

Lymphangiogenesis plays an important role in homeostasis, metabolism, and immunity, and also occurs during wound-healing. Here, we examined the roles of prostaglandin E2 (PGE2) receptor (EP) signaling in enhancement of lymphangiogenesis in wound healing processes. The hole-punch was made in the ears of male C57BL/6 mice using a metal ear punch. Healing process and lymphangiogenesis together with macrophage recruitment were analyzed in EP knockout mice. Lymphangiogenesis was up-regulated in the granulation tissues at the margins of punched-hole wounds in mouse ears, and this increase was accompanied by increased expression levels of COX-2 and microsomal prostaglandin E synthase-1. Administration of celecoxib, a COX-2 inhibitor, suppressed lymphangiogenesis in the granulation tissues and reduced the induction of the pro-lymphangiogenic factors, vascular endothelial growth factor (VEGF) -C and VEGF-D. Topical applications of selective EP receptor agonists enhanced the expressions of lymphatic vessel endothelial hyaluronan receptor-1 and VEGF receptor-3. The wound-healing processes and recruitment of CD11b-positive macrophages, which produced VEGF-C and VEGF-D, were suppressed under COX-2 inhibition. Mice lacking either EP3 or EP4 exhibited reduced wound-healing, lymphangiogenesis and recruitment of M2 macrophages, compared with wild type mice. Proliferation of cultured human lymphatic endothelial cells was not detected under PGE2 stimulation. Lymphangiogenesis and recruitment of M2 macrophages that produced VEGF-C/D were suppressed in mice treated with a COX-2 inhibitor or lacking either EP3 or EP4 during wound healing. COX-2 and EP3/EP4 signaling may be novel targets to control lymphangiogenesis in vivo.

Statistical modelling for recurrent events: an application to sports injuries

PubMed Central

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

2014-01-01

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

Phylogeographic heterogeneity of the brown macroalga Sargassum horneri (Fucaceae) in the northwestern Pacific in relation to late Pleistocene glaciation and tectonic configurations.

PubMed

Hu, Zi-Min; Uwai, Shinya; Yu, Shen-Hui; Komatsu, Teruhisa; Ajisaka, Tetsuro; Duan, De-Lin

2011-09-01

Pleistocene glacial oscillations and associated tectonic processes are believed to have influenced the historical abundances and distribution of organisms in the Asia Northwest Pacific (ANP). Accumulating evidence indicates that factors shaping tempospatial population dynamics and distribution patterns of marine taxa vary with biogeographical latitude, pelagic behaviour and oceanographic regimes. To detect what kinds of historical and contemporary factors affected genetic connectivity, phylogeographic profiles of littoral macroalga Sargassum horneri in the ANP were analysed based on mitochondrial (Cox3) and chloroplast (rbcL) data sets. Five distinct clades were recovered. A strong signature of biogeographical structure was revealed (Φ(CT) = 0.487, P < 0.0001) derived from remarkable differentiation in clade distribution, as clade I is restricted to Chinese marginal seas (Yellow-Bohai Sea, East China Sea and South China Sea), whereas clades II-V are discontinuously scattered around the main Islands of Japan. Furthermore, two secondary contact regions were identified along the south Japan-Pacific coastline. This significant differentiation between the two basins may reflect historical glacial isolation in the northwestern Pacific, which is congruent with the estimates of clade divergence and demographic expansion during the late Quaternary low sea levels. Analysis of molecular variance and the population-pair statistic F(ST) also revealed significant genetic structural differences between Chinese marginal seas and the Japanese basin. This exceptional phylogeographic architecture in S. horneri, initially shaped by historical geographic isolation during the late Pleistocene ice age and physical biogeographical barriers, can be complicated by oceanographic regimes (ocean surface currents) and relocating behaviour such as oceanic drifting. © 2011 Blackwell Publishing Ltd.

Colon Cancer Survival With Herbal Medicine and Vitamins Combined With Standard Therapy in a Whole-Systems Approach: Ten-Year Follow-up Data Analyzed With Marginal Structural Models and Propensity Score Methods

PubMed Central

McCulloch, Michael; Broffman, Michael; van der Laan, Mark; Hubbard, Alan; Kushi, Lawrence; Abrams, Donald I.; Gao, Jin; Colford, John M.

2014-01-01

Although localized colon cancer is often successfully treated with surgery, advanced disease requires aggressive systemic therapy that has lower effectiveness. Approximately 30% to 75% of patients with colon cancer use complementary and alternative medicine (CAM), but there is limited formal evidence of survival efficacy. In a consecutive case series with 10-year follow-up of all colon cancer patients (n = 193) presenting at a San Francisco Bay-Area center for Chinese medicine (Pine Street Clinic, San Anselmo, CA), the authors compared survival in patients choosing short-term treatment lasting the duration of chemotherapy/radiotherapy with those continuing long-term. To put these data into the context of treatment responses seen in conventional medical practice, they also compared survival with Pan-Asian medicine + vitamins (PAM+V) with that of concurrent external controls from Kaiser Permanente Northern California and California Cancer Registries. Kaplan-Meier, traditional Cox regression, and more modern methods were used for causal inference—namely, propensity score and marginal structural models (MSMs), which have not been used before in studies of cancer survival and Chinese herbal medicine. PAM+V combined with conventional therapy, compared with conventional therapy alone, reduced the risk of death in stage I by 95%, stage II by 64%, stage III by 29%, and stage IV by 75%. There was no significant difference between short-term and long-term PAM+V. Combining PAM+V with conventional therapy improved survival, compared with conventional therapy alone, suggesting that prospective trials combining PAM+V with conventional therapy are justified. PMID:21964510

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

PubMed

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

2014-10-01

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

Arylhydrazone derivatives of naproxen as new analgesic and anti-inflammatory agents: Design, synthesis and molecular docking studies.

PubMed

Azizian, Homa; Mousavi, Zahra; Faraji, Hamidreza; Tajik, Mohammad; Bagherzadeh, Kowsar; Bayat, Peyman; Shafiee, Abbas; Almasirad, Ali

2016-06-01

A series of new arylidenehydrazone derivatives of naproxen were synthesized and evaluated for their analgesic and anti-inflammatory activities. Some of the synthesized analogues showed comparable activities when compared against naproxen for their analgesic and anti-inflammatory properties. 2-(6-methoxy-2-naphthyl)-N'-[(pyridine-4-yl)methylene]propanoic acid hydrazide 4j was found to be the most active analgesic agent. 2-(6-methoxy-2-naphthyl)-N'-[4-nitrobenzylidene]propanoic acid hydrazide 4g showed highest anti-inflammatory activity in comparison to the naproxen. Molecular modeling study of the synthesized compounds suggested that the designed molecules were well located and bound to the COX-1 and COX-2 active sites. Compound 4g showed the highest selectivity for COX-2 (RCOX-2/COX-1=1.94) and higher affinity rather than naproxen in COX-2 active site (RCOX-2/naproxen=1.28). Moreover, the structural analyses confirmed that the E-ap rotamer is the preferred structure for the arylidenehydrazone derivatives. Copyright © 2016 Elsevier Inc. All rights reserved.

New carboxamide derivatives bearing benzenesulphonamide as a selective COX-II inhibitor: Design, synthesis and structure-activity relationship

PubMed Central

Okoro, Uchechukwu Chris; Ahmad, Hilal

2017-01-01

Sixteen new carboxamide derivatives bearing substituted benzenesulphonamide moiety (7a-p) were synthesized by boric acid mediated amidation of appropriate benzenesulphonamide with 2-amino-4-picoline and tested for anti-inflammatory activity. One compound 7c showed more potent anti-inflammatory activity than celecoxib at 3 h in carrageenan-induced rat paw edema bioassay. Compounds 7g and 7k also showed good anti-inflammatory activity comparable to celecoxib. Compound 7c appeared selectivity index (COX-2/COX-1) better than celecoxib. Compound 7k appeared selectivity index (COX-2/COX-1) a little higher than the half of celecoxib while compound 7g is non-selective for COX-2. The LD50 of compounds 7c, 7g and 7k were comparable to celecoxib. PMID:28922386

Factors affecting surgical margin recurrence after hepatectomy for colorectal liver metastases

PubMed Central

Akyuz, Muhammet; Aucejo, Federico; Quintini, Cristiano; Miller, Charles; Fung, John

2016-01-01

Background Hepatic recurrence after resection of colorectal liver metastasis (CLM) occurs in 50% of patients during follow-up, with 2.8% to 13.9% presenting with surgical margin recurrence (SMR). The aim of this study is to analyze factors that related to SMR in patients with CLM undergoing hepatectomy. Methods Demographics, clinical and survival data of patients who underwent hepatectomy were identified from a prospectively maintained, institutional review board (IRB)-approved database between 2000 and 2012. Statistical analysis was performed using univariate Kaplan Meier and Cox proportional hazard model. Results There were 85 female and 121 male patients who underwent liver resection for CLM. An R0 resection was performed in 157 (76%) patients and R1 resection in 49. SMR was detected in 32 patients (15.5%) followed up for a median of 29 months (range, 3–121 months). A half of these patients had undergone R1 (n=16) and another half R0 resection (n=16). Tumor size, preoperative carcinoembryonic antigen (CEA) level and margin status were associated with SMR on univariate analysis. On multivariate analysis, a positive surgical margin was the only independent predictor of SMR. The receipt of adjuvant chemotherapy did not affect margin recurrence. SMR was an independent risk factor associated with worse disease-free (DFS) and overall survival (OS). Conclusions This study shows that SMR, which can be detected in up to 15.5% of patients after liver resection for CLM, adversely affects DFS and OS. The fact that a positive surgical margin was the only predictive factor for SMR in these patients underscores the importance of achieving negative margins during hepatectomy. PMID:27294032

Medical and Social Determinants of Subsequent Labour Market Marginalization in Young Hospitalized Suicide Attempters.

PubMed

Niederkrotenthaler, Thomas; Tinghög, Petter; Goldman-Mellor, Sidra; Wilcox, Holly C; Gould, Madelyn; Mittendorfer-Rutz, Ellenor

2016-01-01

Individuals with a history of suicide attempt have a high risk for subsequent labour market marginalization. This study aimed at assessing the effect of individual and parental factors on different measures of marginalization. Prospective cohort study based on register linkage of 5 649 individuals who in 1994 were 16-30 years old, lived in Sweden and were treated in inpatient care for suicide attempt during 1992-1994. Hazard ratios (HRs) for labour market marginalization defined as long-term unemployment (>180 days), sickness absence (>90 days), or disability pension in 1995-2010 were calculated with Cox regression. Medical risk factors, particularly any earlier diagnosed specific mental disorders (e.g., schizophrenia: HR 5.4 (95% CI: 4.2, 7.0), personality disorders: HR 3.9, 95% CI: 3.1, 4.9), repetitive suicide attempts (HR 1.6, 95% CI: 1.4, 1.9) were associated with a higher relative risk of disability pension. Individual medical factors were of smaller importance for long-term sickness absence, and of only marginal relevance to long-term unemployment. Country of birth outside Europe had an opposite effect on disability pension (HR 0.6, 95% CI: 0.4, 0.8) and long-term unemployment (HR 1.5, 95% CI: 1.3, 1.8). Female sex was positively correlated with long-term sickness absence (HR 1.6, 95% CI: 1.4, 1.7), and negatively associated with long-term unemployment (HR: 0.8, 95% CI: 0.7, 0.9). As compared to disability pension, long-term sickness absence and unemployment was more strongly related to socio-economic variables. Marginalization pathways seemed to vary with migration status and sex. These findings may contribute to the development of intervention strategies which take the individual risk for marginalization into account.

Carbonic anhydrase inhibition: insight into non-COX-2 pharmacological effect of some coxibs.

PubMed

Dogné, Jean-Michel; Thiry, Anne; Supuran, Claudiu T

2008-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent the most commonly used medications for the treatment of pain and inflammation, but numerous well-described adverse drug reactions (ADRs) limit their use. These drugs act via the inhibition of cyclooxygenase (COX) enzyme of which at least two isoforms were described: COX-1 which plays important roles in homeostatic processes such as thrombogenesis and homeostasis of the gastrointestinal tract and kidneys and COX-2 expressed in pathological conditions such as inflammation or cancer proliferation. Selective COX-2 inhibitors or "coxibs" were initially developed as a therapeutic strategy to avoid not only the gastrointestinal but also the renal and cardiovascular side effects of non specific NSAIDs. However, this class of drug did not fulfill all their promises. Indeed, numerous unexpected side effects have limited their use and some of them have been withdrawn or suspended from the market for different safety reasons including cardiovascular, hepatic and skin adverse reactions. For instance, cardiovascular warnings have been applied to the whole class of coxibs and more recently for all classical NSAIDs as well. However, differences in the chemical structures should be taken into consideration in order to discriminate between coxibs and the development of some ADRs of which renal events and hypertension. The aim of this paper is to focus on the differences in chemical structures of all marketed COX-2 inhibitors and their unexpected effects on carbonic anhydrase in order to provide non-COX-2 mechanistic insights into some of the differences observed between coxibs.

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

PubMed

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

2013-01-01

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

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

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

Ghezali, Lamia; Leger, David Yannick; Limami, Youness

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 effectmore » 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.« less

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.

2,3,5-Substituted tetrahydrofurans: COX-2 inhibitory activities of 5-hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols.

PubMed

Singh, Palwinder; Mittal, Anu; Kaur, Satwinderjeet; Kumar, Subodh

2008-12-01

5-Hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols have been investigated for their COX-1 and COX-2 inhibitory activities. Compounds 17, 18 and 20 have been identified as showing appreciable COX-2 inhibition and selectivity. The group present at C-5 of tetrahydrofuran and the substituents at the two phenyl rings, through their interactions with active site amino acid residues, significantly affect the activities of these molecules. The quantitative structure-activity relationship studies indicate the role of logP, TPSA, molecular connectivity and valence connectivity towards the activities of these molecules.

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

NASA Astrophysics Data System (ADS)

Kavitha, T.; Velraj, G.

2017-08-01

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

Molecular docking, molecular modeling, and molecular dynamics studies of azaisoflavone as dual COX-2 inhibitors and TP receptor antagonists.

PubMed

Hadianawala, Murtuza; Mahapatra, Amarjyoti Das; Yadav, Jitender K; Datta, Bhaskar

2018-02-26

Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques. Flavonoids were selected as a starting point based on their known COX-2 inhibitory and TP receptor antagonist activity. Iterative design and docking studies resulted in the evolution of a new class scaffold replacing the benzopyran-4-one ring of flavonoids with quinolin-4-one. The docking and binding parameters of these new compounds are found to be promising in comparison to those of selective COX-2 inhibitors, such as SC-558 and celecoxib. Owing to the lack of structural information, a model for the TP receptor was generated using a threading base alignment method with loop optimization performed using an ab initio method. The model generated was validated against known antagonists for TP receptor using docking/MMGBSA. Finally, the molecules that were designed for selective COX-2 inhibition were docked into the active site of the TP receptor. Iterative structural modifications and docking on these molecules generated a series which displays optimum docking scores and binding interaction for both targets. Molecular dynamics studies on a known TP receptor antagonist and a designed molecule show that both molecules remain in contact with protein throughout the simulation and interact in similar binding modes. Graphical abstract ᅟ.

The structure of DSM-IV-TR personality disorder diagnoses in NESARC: a reanalysis.

PubMed

Trull, Timothy J; Vergés, Alvaro; Wood, Phillip K; Sher, Kenneth J

2013-12-01

Cox, Clara, Worobec, and Grant (2012) recently presented results from a series of analyses aimed at identifying the factor structure underlying the DSM-IV-TR (APA, 2000) personality diagnoses assessed in the large NESARC study. Cox et al. (2012) concluded that the best fitting model was one that modeled three lower-order factors (the three clusters of PDs as outlined by DSM-IV-TR), which in turn loaded on a single PD higher-order factor. Our reanalyses of the NESARC Wave 1 and Wave 2 data for personality disorder diagnoses revealed that the best fitting model was that of a general PD factor that spans each of the ten DSM-IV PD diagnoses, and our reanalyses do not support the three-cluster hierarchical structure outlined by Cox et al. (2012) and DSM-IV-TR. Finally, we note the importance of modeling the Wave 2 assessment method factor in analyses of NESARC PD data.

Effect of cobalt doping on the structural, magnetic and abnormal thermal expansion properties of NaZn13-type La(Fe1-xCox)11.4Al1.6 compounds.

PubMed

Zhao, Yuqiang; Huang, Rongjin; Li, Shaopeng; Wang, Wei; Jiang, Xingxing; Lin, Zheshuai; Li, Jiangtao; Li, Laifeng

2016-07-27

Cubic NaZn13-type La(Fe1-xCox)11.4Al1.6 compounds were synthesized and extensively explored through crystal structure and magnetization analyses. By optimizing the chemical composition, the isotropic abnormal properties of excellent zero and giant negative thermal expansion in a pure form were both found at different temperature ranges through room temperature. Moreover, the temperature regions with the remarkable abnormal thermal expansion (ATE) properties have been broadened which are controlled by the dM/dT. The present study demonstrates that the ATE behavior mainly depends on special structural and magnetic properties. These diverse properties suggest the high potential of La(Fe1-xCox)11.4Al1.6 for the development of abnormal expansion materials.

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

NASA Astrophysics Data System (ADS)

Kavitha, T.; Velraj, G.

2018-03-01

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

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

PubMed Central

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

2018-01-01

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

Effects of pro-inflammatory cytokines, lipopolysaccharide and COX-2 mediators on human colonic neuromuscular function and epithelial permeability.

PubMed

Safdari, B K; Sia, T C; Wattchow, D A; Smid, S D

2016-07-01

Chronic colitis is associated with decreased colonic muscle contraction and loss of mucosal barrier function. Pro-inflammatory cytokines and bacterial lipopolysaccharide (LPS) are important in the generation and maintenance of inflammation. While colitis is associated with upregulated COX-2 -derived prostanoids and nitric oxide (NO), the direct activity of pro-inflammatory cytokines on human colonic neuromuscular function is less clear. This study investigated the effects of IBD-associated pro-inflammatory cytokines IL-17, TNF-α, IL-1β and LPS on human colonic muscle strip contractility, alone and following inhibition of COX-2 or nitric oxide production. In addition, human colonic epithelial Caco-2 cell monolayers were treated with LPS or COX-2 mediators including prostaglandins (PGE2, PGF2α) or their corresponding ethanolamides (PGE2-EA or PGF2α-EA) over 48h and trans-epithelial electrical resistance used to record permeability changes. Longitudinal muscle strips were obtained from healthy colonic resection margins and mounted in organ baths following IL-17, TNF-α, IL-1β and bacterial LPS incubations in an explant setting over 20h. Contraction in response to acetylcholine (ACh) was then measured, before and after either COX-2 inhibition (nimesulide; 10(-5)M) or nitric oxide synthase (NOS) inhibition (l-NNA; 10(-4)M). None of the cytokine or LPS explant incubations affected the potency or maximum cholinergic contraction in vitro, and subsequent COX-2 blockade with nimesulide revealed a significant but similar decrease in potency of ACh-evoked contraction in control, LPS and cytokine-incubated muscle strips. Pre-treatment with l-NNA provided no functional differences in the potency or maximum contractile responses to ACh in cytokine or LPS-incubated colonic longitudinal smooth muscle. Only PGE2 transiently increased Caco-2 monolayer permeability at 24h, while LPS (10μg/ml) increased permeability over 24-48h. These findings indicate that cholinergic contractility in the human colon can be decreased by the blockade of COX-2 generated excitatory prostanoids, but major pro-inflammatory cytokines or LPS do not alter the sensitivity or amplitude of this contraction ex vivo. While PGE2 transiently increase epithelial permeability, LPS generates a significant and sustained increase in permeability indicative of an important role on barrier function at the mucosal interface. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Cyclooxygenase inhibitory natural products: current status.

PubMed

Jachak, Sanjay M

2006-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are of huge therapeutic benefit in the treatment of rheumatoid arthritis and various types of inflammatory conditions. The target for these drugs is cyclooxygenase (COX), a rate-limiting enzyme involved in the conversion of arachidonic acid into inflammatory prostaglandins. COX-2 selective inhibitors are believed to have the same anti-inflammatory, anti-pyretic and analgesic activities as that of nonselective inhibitor NSAIDs with little or none of the gastrointestinal side effects. Thus, in the last 6-7 years several selective COX-2 inhibitors including coxibs were discovered and introduced into clinic. Recent reports evidence that selective COX-2 inhibitor such as rofecoxib, can lead to thrombotic cardiovascular events through inhibition of prostacyclin formation in the infracted heart. This has resulted in withdrawal of rofecoxib from the clinic in September 2004. Moreover, the COX-2/COX-1 selectivity ratio is vital in the design of COX-2 inhibitory drugs, as it is clear from rofecoxib, which is more than 50-fold COX-2 selective. After looking at all above mentioned facts, natural product-based compounds seem better as these compounds are generally supposed to be devoid of severe side effects. The literature indicates that natural product-based compounds are mainly COX-1 selective. Through minor semi-synthetic changes in the structures, their selectivity towards COX-2 can be increased. The present review article addresses natural product COX inhibitors of plant and marine origin, reported during last ten years and their advantages, possible leads for further development and current status. In addition we describe our experience in the characterization, design and synthesis of potential natural COX inhibitors.

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.

Structure-based design, synthesis, molecular docking study and biological evaluation of 1,2,4-triazine derivatives acting as COX/15-LOX inhibitors with anti-oxidant activities.

PubMed

Khoshneviszadeh, Mehdi; Shahraki, Omolbanin; Khoshneviszadeh, Mahsima; Foroumadi, Alireza; Firuzi, Omidreza; Edraki, Najmeh; Nadri, Hamid; Moradi, Alireza; Shafiee, Abbas; Miri, Ramin

2016-12-01

A set of 1,2,4-triazine derivatives were designed as cyclooxygenase-2 (COX-2) inhibitors. These compounds were synthesized and screened for inhibition of cyclooxygenases (COX-1 and COX-2) based on a cellular assay using human whole blood (HWB) and lipoxygenase (LOX-15) that are key enzymes in inflammation. The results showed that 3-(2-(benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (G11) was identified as the most potent COX-2 inhibitor (78%) relative to COX-1 (50%). Ferric reducing anti-oxidant power (FRAP) assay revealed that compound G10 possesses the highest anti-oxidant activity. The compound G3 with IC50 value of 124 μM was the most potent compound in LOX inhibitory assay. Molecular docking was performed and a good agreement was observed between computational and experimental results.

Accuracy of Seattle Heart Failure Model and HeartMate II Risk Score in Non-Inotrope-Dependent Advanced Heart Failure Patients: Insights From the ROADMAP Study (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients).

PubMed

Lanfear, David E; Levy, Wayne C; Stehlik, Josef; Estep, Jerry D; Rogers, Joseph G; Shah, Keyur B; Boyle, Andrew J; Chuang, Joyce; Farrar, David J; Starling, Randall C

2017-05-01

Timing of left ventricular assist device (LVAD) implantation in advanced heart failure patients not on inotropes is unclear. Relevant prediction models exist (SHFM [Seattle Heart Failure Model] and HMRS [HeartMate II Risk Score]), but use in this group is not established. ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients) is a prospective, multicenter, nonrandomized study of 200 advanced heart failure patients not on inotropes who met indications for LVAD implantation, comparing the effectiveness of HeartMate II support versus optimal medical management. We compared SHFM-predicted versus observed survival (overall survival and LVAD-free survival) in the optimal medical management arm (n=103) and HMRS-predicted versus observed survival in all LVAD patients (n=111) using Cox modeling, receiver-operator characteristic (ROC) curves, and calibration plots. In the optimal medical management cohort, the SHFM was a significant predictor of survival (hazard ratio=2.98; P <0.001; ROC area under the curve=0.71; P <0.001) but not LVAD-free survival (hazard ratio=1.41; P =0.097; ROC area under the curve=0.56; P =0.314). SHFM showed adequate calibration for survival but overestimated LVAD-free survival. In the LVAD cohort, the HMRS had marginal discrimination at 3 (Cox P =0.23; ROC area under the curve=0.71; P =0.026) and 12 months (Cox P =0.036; ROC area under the curve=0.62; P =0.122), but calibration was poor, underestimating survival across time and risk subgroups. In non-inotrope-dependent advanced heart failure patients receiving optimal medical management, the SHFM was predictive of overall survival but underestimated the risk of clinical worsening and LVAD implantation. Among LVAD patients, the HMRS had marginal discrimination and underestimated survival post-LVAD implantation. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01452802. © 2017 American Heart Association, Inc.

Geomorphology and Neogene tectonic evolution of the Palomares continental margin (Western Mediterranean)

NASA Astrophysics Data System (ADS)

Gómez de la Peña, Laura; Gràcia, Eulàlia; Muñoz, Araceli; Acosta, Juan; Gómez-Ballesteros, María; R. Ranero, César; Uchupi, Elazar

2016-10-01

The Palomares continental margin is located in the southeastern part of Spain. The margin main structure was formed during Miocene times, and it is currently part of the wide deformation zone characterizing the region between the Iberian and African plates, where no well-defined plate boundary occurs. The convergence between these two plates is here accommodated by several structures, including the left lateral strike-slip Palomares Fault. The region is characterized by sparse, low to moderate magnitude (Mw < 5.2) shallow instrumental earthquakes, although large historical events have also occurred. To understand the recent tectonic history of the margin we analyze new high-resolution multibeam bathymetry data and re-processed three multichannel seismic reflection profiles crossing the main structures. The analysis of seafloor morphology and associated subsurface structure provides new insights of the active tectonic features of the area. In contrast to other segments of the southeastern Iberian margin, the Palomares margin contains numerous large and comparatively closely spaced canyons with heads that reach near the coast. The margin relief is also characterized by the presence of three prominent igneous submarine ridges that include the Aguilas, Abubacer and Maimonides highs. Erosive processes evidenced by a number of scars, slope failures, gullies and canyon incisions shape the present-day relief of the Palomares margin. Seismic images reveal the deep structure distinguishing between Miocene structures related to the formation of the margin and currently active features, some of which may reactivate inherited structures. The structure of the margin started with an extensional phase accompanied by volcanic accretion during the Serravallian, followed by a compressional pulse that started during the Latemost Tortonian. Nowadays, tectonic activity offshore is subdued and limited to few, minor faults, in comparison with the activity recorded onshore. The deep Algero-Balearic Basin is affected by surficial processes, associated to halokinesis of Messinian evaporites.

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

PubMed

Banting, Graham S; Glerum, D Moira

2006-03-01

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

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

PubMed

Hollenbeak, Christopher S

2005-10-15

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

Northeastern Brazilian margin: Regional tectonic evolution based on integrated analysis of seismic reflection and potential field data and modelling

NASA Astrophysics Data System (ADS)

Blaich, Olav A.; Tsikalas, Filippos; Faleide, Jan Inge

2008-10-01

Integration of regional seismic reflection and potential field data along the northeastern Brazilian margin, complemented by crustal-scale gravity modelling, is used to reveal and illustrate onshore-offshore crustal structure correlation, the character of the continent-ocean boundary, and the relationship of crustal structure to regional variation of potential field anomalies. The study reveals distinct along-margin structural and magmatic changes that are spatially related to a number of conjugate Brazil-West Africa transfer systems, governing the margin segmentation and evolution. Several conceptual tectonic models are invoked to explain the structural evolution of the different margin segments in a conjugate margin context. Furthermore, the constructed transects, the observed and modelled Moho relief, and the potential field anomalies indicate that the Recôncavo, Tucano and Jatobá rift system may reflect a polyphase deformation rifting-mode associated with a complex time-dependent thermal structure of the lithosphere. The constructed transects and available seismic reflection profiles, indicate that the northern part of the study area lacks major breakup-related magmatic activity, suggesting a rifted non-volcanic margin affinity. In contrast, the southern part of the study area is characterized by abrupt crustal thinning and evidence for breakup magmatic activity, suggesting that this region evolved, partially, with a rifted volcanic margin affinity and character.

Role of Adjuvant Therapy for Node-Negative Lung Cancer Invading the Chest Wall.

PubMed

Gao, Sarah J; Corso, Christopher D; Blasberg, Justin D; Detterbeck, Frank C; Boffa, Daniel J; Decker, Roy H; Kim, Anthony W

2017-03-01

The present study investigated the effect of adjuvant chemotherapy and radiation on survival among patients undergoing chest wall resection for T3N0 non-small cell lung cancer (NSCLC). Patients with T3N0 NSCLC who underwent chest wall resection were identified in the National Cancer Data Base in 2004 to 2012. The cohort was divided into patients who had received adjuvant chemotherapy, radiation therapy, chemoradiation therapy, or no adjuvant treatment. Kaplan-Meier and log-rank tests were used to compare overall survival, and a bootstrapped Cox proportional hazards model was used to determine the significant contributors to survival. A subset analysis was performed with stratification by margin status and tumor size. Of 759 patients identified, 42.0% underwent surgery alone, 23.3% underwent surgery followed by chemotherapy, 22.3% underwent surgery followed by chemoradiation therapy, and 12.3% underwent surgery followed by radiotherapy alone. Tumors > 4 cm benefited from adjuvant chemotherapy and radiation therapy in the multivariable analysis, and those ≤ 4 cm benefited only from adjuvant chemotherapy. The subgroup analysis by margin status identified that margin-positive patients with tumors > 4 cm benefited significantly from either adjuvant chemoradiation therapy or radiation therapy alone. T3N0 NSCLC with chest wall invasion requires unique management compared with other stage IIB tumors. An important determinant of management is tumor size, with tumors ≤ 4 cm benefiting from adjuvant chemotherapy and tumors > 4 cm benefiting from adjuvant chemotherapy if margin negative and adjuvant chemoradiation therapy or radiotherapy if margin positive. Copyright © 2016 Elsevier Inc. All rights reserved.

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

PubMed

Hanley, James A

2008-01-01

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

Evolution of structure and superconductivity in Ba(Ni 1 -xCox)2As2

NASA Astrophysics Data System (ADS)

Eckberg, Chris; Wang, Limin; Hodovanets, Halyna; Kim, Hyunsoo; Campbell, Daniel J.; Zavalij, Peter; Piccoli, Philip; Paglione, Johnpierre

2018-06-01

The effects of Co substitution on Ba (Ni1-xCox) 2As2 (0 ≤x ≤0.251 ) single crystals grown out of Pb flux are investigated via transport, magnetic, and thermodynamic measurements. BaNi2As2 exhibits a first-order tetragonal to triclinic structural phase transition at Ts=137 K upon cooling, and enters a superconducting phase below Tc=0.7 K. The structural phase transition is sensitive to cobalt content and is suppressed completely by x ≥0.133 . The superconducting critical temperature, Tc, increases continuously with x , reaching a maximum of Tc=2.3 K at x =0.083 and then decreases monotonically until superconductivity is no longer observable well into the tetragonal phase. In contrast to similar BaNi2As2 substitutional studies, which show an abrupt change in Tc at the triclinic-tetragonal boundary that extends far into the tetragonal phase, Ba (Ni1-xCox) 2As2 exhibits a domelike phase diagram centered around the zero-temperature tetragonal-triclinic boundary. Together with an anomalously large heat capacity jump Δ Ce/γ T ˜2.2 near optimal doping, the smooth evolution of Tc in the Ba (Ni1-xCox) 2As2 system suggests a mechanism for pairing enhancement other than phonon softening.

Structure Evolution and Multiferroic Properties in Cobalt Doped Bi4NdTi3Fe1-xCoxO15-Bi3NdTi2Fe1-xCoxO12-δ Intergrowth Aurivillius Compounds

PubMed Central

Zhang, D. L.; Huang, W. C.; Chen, Z. W.; Zhao, W. B.; Feng, L.; Li, M.; Yin, Y. W.; Dong, S. N.; Li, X. G.

2017-01-01

Here, we report the structure evolution, magnetic and ferroelectric properties in Co-doped 4- and 3-layered intergrowth Aurivillius compounds Bi4NdTi3Fe1-xCoxO15-Bi3NdTi2Fe1-xCoxO12-δ. The compounds suffer a structure evolution from the parent 4-layered phase (Bi4NdTi3FeO15) to 3-layered phase (Bi3NdTi2CoO12-δ) with increasing cobalt doping level from 0 to 1. Meanwhile the remanent magnetization and polarization show opposite variation tendencies against the doping level, and the sample with x = 0.3 has the largest remanent magnetization and the smallest polarization. It is believed that the Co concentration dependent magnetic properties are related to the population of the Fe3+ -O-Co3+ bonds, while the suppressed ferroelectric polarization is due to the enhanced leakage current caused by the increasing Co concentration. Furthermore, the samples (x = 0.1–0.7) with ferromagnetism show magnetoelectric coupling effects at room temperature. The results indicate that it is an effective method to create new multiferroic materials through modifying natural superlattices. PMID:28272495

Development of Antioxidant COX-2 Inhibitors as Radioprotective Agents for Radiation Therapy—A Hypothesis-Driven Review

PubMed Central

Laube, Markus; Kniess, Torsten; Pietzsch, Jens

2016-01-01

Radiation therapy (RT) evolved to be a primary treatment modality for cancer patients. Unfortunately, the cure or relief of symptoms is still accompanied by radiation-induced side effects with severe acute and late pathophysiological consequences. Inhibitors of cyclooxygenase-2 (COX-2) are potentially useful in this regard because radioprotection of normal tissue and/or radiosensitizing effects on tumor tissue have been described for several compounds of this structurally diverse class. This review aims to substantiate the hypothesis that antioxidant COX-2 inhibitors are promising radioprotectants because of intercepting radiation-induced oxidative stress and inflammation in normal tissue, especially the vascular system. For this, literature reporting on COX inhibitors exerting radioprotective and/or radiosensitizing action as well as on antioxidant COX inhibitors will be reviewed comprehensively with the aim to find cross-points of both and, by that, stimulate further research in the field of radioprotective agents. PMID:27104573

Stereotactic Radiosurgery of the Postoperative Resection Cavity for Brain Metastases: Prospective Evaluation of Target Margin on Tumor Control

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

Choi, Clara Y.H.; Chang, Steven D.; Gibbs, Iris C.

2012-10-01

Purpose: Given the neurocognitive toxicity associated with whole-brain irradiation (WBRT), approaches to defer or avoid WBRT after surgical resection of brain metastases are desirable. Our initial experience with stereotactic radiosurgery (SRS) targeting the resection cavity showed promising results. We examined the outcomes of postoperative resection cavity SRS to determine the effect of adding a 2-mm margin around the resection cavity on local failure (LF) and toxicity. Patients and Methods: We retrospectively evaluated 120 cavities in 112 patients treated from 1998-2009. Factors associated with LF and distant brain failure (DF) were analyzed using competing risks analysis, with death as a competingmore » risk. The overall survival (OS) rate was calculated by the Kaplan-Meier product-limit method; variables associated with OS were evaluated using the Cox proportional hazards and log rank tests. Results: The 12-month cumulative incidence rates of LF and DF, with death as a competing risk, were 9.5% and 54%, respectively. On univariate analysis, expansion of the cavity with a 2-mm margin was associated with decreased LF; the 12-month cumulative incidence rates of LF with and without margin were 3% and 16%, respectively (P=.042). The 12-month toxicity rates with and without margin were 3% and 8%, respectively (P=.27). On multivariate analysis, melanoma histology (P=.038) and number of brain metastases (P=.0097) were associated with higher DF. The median OS time was 17 months (range, 2-114 months), with a 12-month OS rate of 62%. Overall, WBRT was avoided in 72% of the patients. Conclusion: Adjuvant SRS targeting the resection cavity of brain metastases results in excellent local control and allows WBRT to be avoided in a majority of patients. A 2-mm margin around the resection cavity improved local control without increasing toxicity compared with our prior technique with no margin.« less

Medical and Social Determinants of Subsequent Labour Market Marginalization in Young Hospitalized Suicide Attempters

PubMed Central

Niederkrotenthaler, Thomas; Tinghög, Petter; Goldman-Mellor, Sidra; Wilcox, Holly C.; Gould, Madelyn; Mittendorfer-Rutz, Ellenor

2016-01-01

Background Individuals with a history of suicide attempt have a high risk for subsequent labour market marginalization. This study aimed at assessing the effect of individual and parental factors on different measures of marginalization. Methods Prospective cohort study based on register linkage of 5 649 individuals who in 1994 were 16–30 years old, lived in Sweden and were treated in inpatient care for suicide attempt during 1992–1994. Hazard ratios (HRs) for labour market marginalization defined as long-term unemployment (>180 days), sickness absence (>90 days), or disability pension in 1995–2010 were calculated with Cox regression. Results Medical risk factors, particularly any earlier diagnosed specific mental disorders (e.g., schizophrenia: HR 5.4 (95% CI: 4.2, 7.0), personality disorders: HR 3.9, 95% CI: 3.1, 4.9), repetitive suicide attempts (HR 1.6, 95% CI: 1.4, 1.9) were associated with a higher relative risk of disability pension. Individual medical factors were of smaller importance for long-term sickness absence, and of only marginal relevance to long-term unemployment. Country of birth outside Europe had an opposite effect on disability pension (HR 0.6, 95% CI: 0.4, 0.8) and long-term unemployment (HR 1.5, 95% CI: 1.3, 1.8). Female sex was positively correlated with long-term sickness absence (HR 1.6, 95% CI: 1.4, 1.7), and negatively associated with long-term unemployment (HR: 0.8, 95% CI: 0.7, 0.9). Conclusions As compared to disability pension, long-term sickness absence and unemployment was more strongly related to socio-economic variables. Marginalization pathways seemed to vary with migration status and sex. These findings may contribute to the development of intervention strategies which take the individual risk for marginalization into account. PMID:26784886

Role of Adjuvant Treatment in Esophageal Cancer With Incidental Pathologic Node Positivity.

PubMed

Gao, Sarah J; Park, Henry S; Corso, Christopher D; Rutter, Charles E; Kim, Anthony W; Johung, Kimberly L

2017-07-01

The optimal adjuvant treatment for cT1-2 N0 esophageal cancer patients found to have pathologic nodal involvement after an upfront operation is unclear. This study investigated the effects of postoperative chemotherapy and chemoradiation therapy on overall survival in cT1-2 N0 patients with incidental pN + disease stratified by margin status. We identified cT1-2 N0 M0 esophageal carcinoma patients from 2004 to 2012 from the National Cancer Data Base. Patients were categorized as having received surgical resection alone, surgical resection followed by chemotherapy (S+CT), and surgical resection followed by concurrent chemoradiation therapy (S+CRT). Subset analyses were conducted on margin-negative and margin-positive patients. Overall survival was compared by Kaplan-Meier estimation, the log-rank test, and multivariable Cox regression analysis. Among 443 patients, 52.6% received surgical resection alone, 18.7% received S+CT, and 28.6% received S+CRT. Significantly more adenocarcinoma patients received adjuvant treatment (50.8%) than squamous cell carcinoma patients (27.7%, p = 0.001). On multivariable analysis, S+CT (hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; p = 0.014) and S+CRT (hazard ratio, 0.73; 95% confidence interval,. 0.55 to 0.98; p = 0.038) both were associated with significantly increased overall survival. These findings persisted among margin-negative patients. However, in margin-positive patients, S+CRT (hazard ratio, 0.29; p = 0.002) was the only treatment arm that was associated with significantly improved survival compared with surgical resection alone. Among cT1-2 N0 pN + esophageal cancer patients, adjuvant chemotherapy may be sufficient for margin-negative patients, whereas adjuvant chemoradiation therapy appears necessary for margin-positive patients. Further prospective studies are needed to confirm the results. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

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

PubMed Central

2011-01-01

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

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

PubMed

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

2011-08-19

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

A sequential Cox approach for estimating the causal effect of treatment in the presence of time-dependent confounding applied to data from the Swiss HIV Cohort Study.

PubMed

Gran, Jon Michael; Røysland, Kjetil; Wolbers, Marcel; Didelez, Vanessa; Sterne, Jonathan A C; Ledergerber, Bruno; Furrer, Hansjakob; von Wyl, Viktor; Aalen, Odd O

2010-11-20

When estimating the effect of treatment on HIV using data from observational studies, standard methods may produce biased estimates due to the presence of time-dependent confounders. Such confounding can be present when a covariate, affected by past exposure, is both a predictor of the future exposure and the outcome. One example is the CD4 cell count, being a marker for disease progression for HIV patients, but also a marker for treatment initiation and influenced by treatment. Fitting a marginal structural model (MSM) using inverse probability weights is one way to give appropriate adjustment for this type of confounding. In this paper we study a simple and intuitive approach to estimate similar treatment effects, using observational data to mimic several randomized controlled trials. Each 'trial' is constructed based on individuals starting treatment in a certain time interval. An overall effect estimate for all such trials is found using composite likelihood inference. The method offers an alternative to the use of inverse probability of treatment weights, which is unstable in certain situations. The estimated parameter is not identical to the one of an MSM, it is conditioned on covariate values at the start of each mimicked trial. This allows the study of questions that are not that easily addressed fitting an MSM. The analysis can be performed as a stratified weighted Cox analysis on the joint data set of all the constructed trials, where each trial is one stratum. The model is applied to data from the Swiss HIV cohort study. Copyright © 2010 John Wiley & Sons, Ltd.

Renin-angiotensin II-aldosterone system blockers and time to renal replacement therapy in children with CKD.

PubMed

Abraham, Alison G; Betoko, Aisha; Fadrowski, Jeffrey J; Pierce, Christopher; Furth, Susan L; Warady, Bradley A; Muñoz, Alvaro

2017-04-01

Clinical care decisions to treat chronic kidney disease (CKD) in a growing child must often be made without the benefit of evidence from clinical trials. We used observational data from the Chronic Kidney Disease in Children cohort to estimate the effectiveness of renin-angiotensin II-aldosterone system blockade (RAAS) to delay renal replacement therapy (RRT) in children with CKD. A total of 851 participants (median age: 11 years, median glomerular filtration rate [GFR]: 52 ml/min/1.73 m 2 , median urine protein to creatinine ratio: 0.35 mg/mg) were included. RAAS use was reported at annual study visits. Both Cox proportional hazards models with time-varying RAAS exposure and Cox marginal structural models (MSM) were used to evaluate the effect of RAAS use on time to RRT. Analyses were adjusted or weighted to control for age, male sex, glomerular diagnosis, GFR, nephrotic range proteinuria, anemia, elevated blood pressure, acidosis, elevated phosphate and elevated potassium. There were 217 RRT events over a 4.1-year median follow-up. At baseline, 472 children (55 %) were prevalent RAAS users, who were more likely to be older, have a glomerular etiology, have higher urine protein, be anemic, have elevated serum phosphate and potassium, take more medications, but less likely to have elevated blood pressure, compared with non-users. RAAS use was found to reduce the risk of RRT by 21 % (hazard ratio: 0.79) to 37 % (hazard ratio: 0.63) from standard regression adjustment and MSM models, respectively. These results support inferences from adult studies of a substantial benefit of RAAS use in pediatric CKD patients.

Statin Treatment and Clinical Outcomes of Heart Failure Among Africans: An Inverse Probability Treatment Weighted Analysis.

PubMed

Bonsu, Kwadwo Osei; Owusu, Isaac Kofi; Buabeng, Kwame Ohene; Reidpath, Daniel D; Kadirvelu, Amudha

2017-04-01

Randomized control trials of statins have not demonstrated significant benefits in outcomes of heart failure (HF). However, randomized control trials may not always be generalizable. The aim was to determine whether statin and statin type-lipophilic or -hydrophilic improve long-term outcomes in Africans with HF. This was a retrospective longitudinal study of HF patients aged ≥18 years hospitalized at a tertiary healthcare center between January 1, 2009 and December 31, 2013 in Ghana. Patients were eligible if they were discharged from first admission for HF (index admission) and followed up to time of all-cause, cardiovascular, and HF mortality or end of study. Multivariable time-dependent Cox model and inverse-probability-of-treatment weighting of marginal structural model were used to estimate associations between statin treatment and outcomes. Adjusted hazard ratios were also estimated for lipophilic and hydrophilic statin compared with no statin use. The study included 1488 patients (mean age 60.3±14.2 years) with 9306 person-years of observation. Using the time-dependent Cox model, the 5-year adjusted hazard ratios with 95% CI for statin treatment on all-cause, cardiovascular, and HF mortality were 0.68 (0.55-0.83), 0.67 (0.54-0.82), and 0.63 (0.51-0.79), respectively. Use of inverse-probability-of-treatment weighting resulted in estimates of 0.79 (0.65-0.96), 0.77 (0.63-0.96), and 0.77 (0.61-0.95) for statin treatment on all-cause, cardiovascular, and HF mortality, respectively, compared with no statin use. Among Africans with HF, statin treatment was associated with significant reduction in mortality. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Low levels of the AhR in chronic obstructive pulmonary disease (COPD)-derived lung cells increases COX-2 protein by altering mRNA stability

PubMed Central

Zago, Michela; Sheridan, Jared A.; Traboulsi, Hussein; Hecht, Emelia; Zhang, Yelu; Guerrina, Necola; Matthews, Jason; Nair, Parameswaran; Eidelman, David H.; Hamid, Qutayba

2017-01-01

Heightened inflammation, including expression of COX-2, is associated with chronic obstructive pulmonary disease (COPD) pathogenesis. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is reduced in COPD-derived lung fibroblasts. The AhR also suppresses COX-2 in response to cigarette smoke, the main risk factor for COPD, by destabilizing the Cox-2 transcript by mechanisms that may involve the regulation of microRNA (miRNA). Whether reduced AhR expression is responsible for heightened COX-2 in COPD is not known. Here, we investigated the expression of COX-2 as well as the expression of miR-146a, a miRNA known to regulate COX-2 levels, in primary lung fibroblasts derived from non-smokers (Normal) and smokers (At Risk) with and without COPD. To confirm the involvement of the AhR, AhR knock-down via siRNA in Normal lung fibroblasts and MLE-12 cells was employed as were A549-AhRko cells. Basal expression of COX-2 protein was higher in COPD lung fibroblasts compared to Normal or Smoker fibroblasts but there was no difference in Cox-2 mRNA. Knockdown of AhR in lung structural cells increased COX-2 protein by stabilizing the Cox-2 transcript. There was less induction of miR-146a in COPD-derived lung fibroblasts but this was not due to the AhR. Instead, we found that RelB, an NF-κB protein, was required for transcriptional induction of both Cox-2 and miR-146a. Therefore, we conclude that the AhR controls COX-2 protein via mRNA stability by a mechanism independent of miR-146a. Low levels of the AhR may therefore contribute to the heightened inflammation common in COPD patients. PMID:28749959

Low levels of the AhR in chronic obstructive pulmonary disease (COPD)-derived lung cells increases COX-2 protein by altering mRNA stability.

PubMed

Zago, Michela; Sheridan, Jared A; Traboulsi, Hussein; Hecht, Emelia; Zhang, Yelu; Guerrina, Necola; Matthews, Jason; Nair, Parameswaran; Eidelman, David H; Hamid, Qutayba; Baglole, Carolyn J

2017-01-01

Heightened inflammation, including expression of COX-2, is associated with chronic obstructive pulmonary disease (COPD) pathogenesis. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is reduced in COPD-derived lung fibroblasts. The AhR also suppresses COX-2 in response to cigarette smoke, the main risk factor for COPD, by destabilizing the Cox-2 transcript by mechanisms that may involve the regulation of microRNA (miRNA). Whether reduced AhR expression is responsible for heightened COX-2 in COPD is not known. Here, we investigated the expression of COX-2 as well as the expression of miR-146a, a miRNA known to regulate COX-2 levels, in primary lung fibroblasts derived from non-smokers (Normal) and smokers (At Risk) with and without COPD. To confirm the involvement of the AhR, AhR knock-down via siRNA in Normal lung fibroblasts and MLE-12 cells was employed as were A549-AhRko cells. Basal expression of COX-2 protein was higher in COPD lung fibroblasts compared to Normal or Smoker fibroblasts but there was no difference in Cox-2 mRNA. Knockdown of AhR in lung structural cells increased COX-2 protein by stabilizing the Cox-2 transcript. There was less induction of miR-146a in COPD-derived lung fibroblasts but this was not due to the AhR. Instead, we found that RelB, an NF-κB protein, was required for transcriptional induction of both Cox-2 and miR-146a. Therefore, we conclude that the AhR controls COX-2 protein via mRNA stability by a mechanism independent of miR-146a. Low levels of the AhR may therefore contribute to the heightened inflammation common in COPD patients.

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

PubMed

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

2005-04-15

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

Local geometric and electronic structures and origin of magnetism in Co-doped BaTiO3 multiferroics

NASA Astrophysics Data System (ADS)

Phan, The-Long; Thang, P. D.; Ho, T. A.; Manh, T. V.; Thanh, Tran Dang; Lam, V. D.; Dang, N. T.; Yu, S. C.

2015-05-01

We have prepared polycrystalline samples BaTi1-xCoxO3 (x = 0-0.1) by solid-state reaction. X-ray diffraction and Raman-scattering studies reveal the phase separation in crystal structure as changing Co-doping content (x). The samples with x = 0-0.01 are single phase in a tetragonal structure. At higher doping contents (x > 0.01), there is the formation and development of a secondary hexagonal phase. Magnetization measurements at room temperature indicate a coexistence of paramagnetic and weak-ferromagnetic behaviors in BaTi1-xCoxO3 samples with x > 0, while pure BaTiO3 is diamagnetic. Both these properties increase with increasing x. Analyses of X-ray absorption spectra recorded from BaTi1-xCoxO3 for the Co and Ti K-edges indicate the presence of Co2+ and Co3+ ions. They locate in the Ti4+ site of the tetragonal and hexagonal BaTiO3 structures. Particularly, there is a shift of oxidation state from Co2+ to Co3+ when Co-doping content increases. We believe that the paramagnetic nature in BaTi1-xCoxO3 samples is due to isolated Co2+ and Co3+ centers. The addition of Co3+ ions enhances the paramagnetic behavior. Meanwhile, the origin of ferromagnetism is due to lattice defects, which is less influenced by the changes caused by the variation in concentration of Co2+ and Co3+ ions.

Structure and evolution of the eastern Gulf of Aden conjugate margins from seismic reflection data

NASA Astrophysics Data System (ADS)

d'Acremont, Elia; Leroy, Sylvie; Beslier, Marie-Odile; Bellahsen, Nicolas; Fournier, Marc; Robin, Cécile; Maia, Marcia; Gente, Pascal

2005-03-01

The Gulf of Aden is a young and narrow oceanic basin formed in Oligo-Miocene time between the rifted margins of the Arabian and Somalian plates. Its mean orientation, N75°E, strikes obliquely (50°) to the N25°E opening direction. The western conjugate margins are masked by Oligo-Miocene lavas from the Afar Plume. This paper concerns the eastern margins, where the 19-35 Ma breakup structures are well exposed onshore and within the sediment-starved marine shelf. Those passive margins, about 200 km distant, are non-volcanic. Offshore, during the Encens-Sheba cruise we gathered swath bathymetry, single-channel seismic reflection, gravity and magnetism data, in order to compare the structure of the two conjugate margins and to reconstruct the evolution of the thinned continental crust from rifting to the onset of oceanic spreading. Between the Alula-Fartak and Socotra major fracture zones, two accommodation zones trending N25°E separate the margins into three N110°E-trending segments. The margins are asymmetric: offshore, the northern margin is narrower and steeper than the southern one. Including the onshore domain, the southern rifted margin is about twice the breadth of the northern one. We relate this asymmetry to inherited Jurassic/Cretaceous rifts. The rifting obliquity also influenced the syn-rift structural pattern responsible for the normal faults trending from N70°E to N110°E. The N110°E fault pattern could be explained by the decrease of the influence of rift obliquity towards the central rift, and/or by structural inheritance. The transition between the thinned continental crust and the oceanic crust is characterized by a 40 km wide zone. Our data suggest that its basement is made up of thinned continental crust along the southern margin and of thinned continental crust or exhumed mantle, more or less intruded by magmatic rocks, along the northern margin.

Continental transform margins : state of art and future milestones

NASA Astrophysics Data System (ADS)

Basile, Christophe

2010-05-01

Transform faults were defined 45 years ago as ‘a new class of fault' (Wilson, 1965), and transform margins were consequently individualized as a new class of continental margins. While transform margins represent 20 to 25 % of the total length of continent-ocean transitions, they were poorly studied, especially when compared with the amount of data, interpretations, models and conceptual progress accumulated on divergent or convergent continental margins. The best studied examples of transform margins are located in the northern part of Norway, south of South Africa, in the gulf of California and on both sides of the Equatorial Atlantic. Here is located the Côte d'Ivoire - Ghana margin, where the more complete data set was acquired, based on numerous geological and geophysical cruises, including ODP Leg 159. The first models that encompassed the structure and evolution of transform margins were mainly driven by plate kinematic reconstructions, and evidenced the diachronic end of tectonic activity and the non-cylindrical character of these margins, with a decreasing strike-slip deformation from the convex to the concave divergent-transform intersections. Further thermo-mechanical models were more specifically designed to explain the vertical displacements along transform margins, and especially the occurrence of high-standing marginal ridges. These thermo-mechanical models involved either heat transfer from oceanic to continental lithospheres across the transform faults or tectonically- or gravity-driven mass transfer in the upper crust. These models were far from fully fit observations, and were frequently dedicated to specific example, and not easily generalizable. Future work on transform continental margins may be expected to fill some scientific gaps, and the definition of working directions can benefit from the studies dedicated to other types of margins. At regional scale the structural and sedimentological variability of transform continental margins has to be emphasized. There is not only one type of transform margins, but as for divergent margins huge changes from one margin to another in both structure and evolution. Multiple types have to be evidenced together with the various parameters that should control the variability. As for divergent margins, special attention should be paid to conjugated transform margins as a tool to assess symmetrical / asymmetrical processes in the oceanic opening. Attention should also be focused on the three-dimensional structure of the intersections between transform and divergent margins, such as the one where the giant oil field Jubilee was recently discovered. There is almost no 3D data available in these area, and their structures still have to be described. An other key point to develop is the mechanical behavior of the lithosphere in and in the vicinity of transform margins. The classical behaviors (isostasy, elastic flexure) have be tested extensively. The localization of the deformation by the transform fault, and the coupling of continental and oceanic lithosphere across the transform fault have to be adressed to understand the evolution of these margins. Again as for divergent margins, new concepts are needed to explain the variations in the post-rift and post-transform subsidence, that can not always be explained by classical subsidence models. But the most remarkable advance in our understanding of transform margins may be related to the study of interactions between the lithosphere and adjacent envelops : deep interactions with the mantle, as underplating, tectonic erosion, or possible lateral crustal flow ; surficial interactions between structural evolution, erosion and sedimentation processes in transform margins may affect the topography and bathymetry, thus the oceanic circulation with possible effects on regional and global climate.

Prognostic scores after surgical treatment for cervical intraepithelial neoplasia: a proposed model and possible implications for post-operative follow-up.

PubMed

Andrade, Carlos E M C; Scapulatempo-Neto, Cristovam; Longatto-Filho, Adhemar; Vieira, Marcelo A; Tsunoda, Audrey T; Da Silva, Ismael D C G; Fregnani, José Humberto T G

2014-09-01

To develop a prognostic model for women who underwent surgical treatment for cervical intraepithelial neoplasia. Cohort study. Patient inclusion and follow-up occurred retrospectively and prospectively. Barretos Cancer Hospital, Barretos, São Paulo, Brazil. Women (n = 242) diagnosed with cervical intraepithelial neoplasia who were submitted to conization. Immediately prior to surgical treatment, a cervical cytology sample was collected from each individual included in the study by endocervical brushing and stored in a preservative solution with methanol. A human papilloma virus-DNA test was conducted using an aliquot of the endocervical brushings. The surgical specimens were subjected to immunohistochemical analysis of p16 (immunohistochemical analysis 4a) protein expression. Two-year disease-free survival rates calculated for each study variable. Identified variables in the multivariate Cox model were used for elaboration of prognostic scores. Variables associated with outcome included age (p = 0.033), tobacco use (p < 0.001), final histopathological diagnosis (p = 0.007), surgical margins (p < 0.001), high-risk human papilloma virus status (p = 0.008), human papilloma virus-16 status (p < 0.001) and immunoexpression of p16 in the cytoplasm (p = 0.049). By the Cox model, independent risk factors for disease recurrence/persistence were: tobacco use (hazard risk = 3.0; 95% confidence interval 1.6-5.6), positive surgical margins (hazard risk = 3.2; 95% confidence interval 1.6-6.1), human papilloma virus-16 (hazard risk = 3.3; 95% confidence interval 1.6-6.9) and age over 45 years (hazard risk = 2.7; 95% confidence interval 1.1-6.6). Establishment of a prognostic score can represent a valuable tool for determining the risk of cervical intraepithelial neoplasia recurrence after conization. The use of clinical (age and tobacco use), pathological (surgical margins) and molecular (human papilloma virus-16 genotyping) factors can facilitate more appropriate patient follow up according to risk stratification. © 2014 Nordic Federation of Societies of Obstetrics and Gynecology.

Lithosphere structure and subsidence evolution of the conjugate S-African and Argentine margins

NASA Astrophysics Data System (ADS)

Dressel, Ingo; Scheck-Wenderoth, Magdalena; Cacace, Mauro; Götze, Hans-Jürgen; Franke, Dieter

2016-04-01

The bathymetric evolution of the South Atlantic passive continental margins is a matter of debate. Though it is commonly accepted that passive margins experience thermal subsidence as a result of lithospheric cooling as well as load induced subsidence in response to sediment deposition it is disputed if the South Atlantic passive margins were affected by additional processes affecting the subsidence history after continental breakup. We present a subsidence analysis along the SW African margin and offshore Argentina and restore paleobathymetries to assess the subsidence evolution of the margin. These results are discussed with respect to mechanisms behind margin evolution. Therefore, we use available information about the lithosphere-scale present-day structural configuration of these margins as a starting point for the subsidence analysis. A multi 1D backward modelling method is applied to separate individual subsidence components such as the thermal- as well as the load induced subsidence and to restore paleobathymetries for the conjugate margins. The comparison of the restored paleobathymetries shows that the conjugate margins evolve differently: Continuous subsidence is obtained offshore Argentina whereas the subsidence history of the SW African margin is interrupted by phases of uplift. This differing results for both margins correlate also with different structural configurations of the subcrustal mantle. In the light of these results we discuss possible implications for uplift mechanisms.

Structure of the North American Atlantic Continental Margin.

ERIC Educational Resources Information Center

Klitgord, K. K.; Schlee, J. S.

1986-01-01

Offers explanations on the origin of the North American Atlantic continental margin. Provides an analysis and illustrations of structural and strategraphic elements of cross sections of the Atlantic continental margin. Also explains the operations and applications of seismic-relection profiles in studying ocean areas. (ML)

Preclinical Alzheimer's disease and longitudinal driving decline.

PubMed

Roe, Catherine M; Babulal, Ganesh M; Head, Denise M; Stout, Sarah H; Vernon, Elizabeth K; Ghoshal, Nupur; Garland, Brad; Barco, Peggy P; Williams, Monique M; Johnson, Ann; Fierberg, Rebecca; Fague, M Scot; Xiong, Chengjie; Mormino, Elizabeth; Grant, Elizabeth A; Holtzman, David M; Benzinger, Tammie L S; Fagan, Anne M; Ott, Brian R; Carr, David B; Morris, John C

2017-01-01

Links between preclinical AD and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs. 104 OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries and self-reported their driving habits. Higher values of CSF tau/Aβ 42 and ptau 181 /Aβ 42 ratios, but not uptake on PIB amyloid imaging (p=.12), predicted time to a rating of Marginal or Fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70-19.53), p=.005 for CSF tau/Aβ 42 ; 6.19 (1.75-21.88) and p=.005 for CSF ptau 181 /Aβ 42 . Preclinical AD predicted time to receiving a Marginal or Fail rating on an on-road driving test. Driving performance shows promise as a functional outcome in AD prevention trials.

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

PubMed

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

2017-07-10

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

Structural, optical and enhanced power filtering application of PEG capped Zn1-xCoxS quantum dots

NASA Astrophysics Data System (ADS)

Vineeshkumar, T. V.; Prasanth, S.; Pragash, R.; Unnikrishnan, N. V.; Sudarsanakumar, C.

2018-04-01

Zn1-xCoxS (x= 0.05, 0.1, 0.15 and 0.2) quantum dots were synthesized successfully using co precipitation technique in polyethylene glycol (PEG) matrix. The PEG acted as a capping agent as well as a reducing agent. The structural and optical properties of the samples were studied by x-ray diffraction (XRD), TEM analysis and UV-Visible absorption. Nonlinear optical properties were measured using open aperture z-scan technique, employing frequency doubled (532 nm) pumping sources.

Synthesis and pharmacological evaluation of N-substituted 2-(2-oxo-2H-chromen-4-yloxy)propanamide as cyclooxygenase inhibitors.

PubMed

Rambabu, D; Mulakayala, Naveen; Ismail; Kumar, K Ravi; Kumar, G Pavan; Mulakayala, Chaitanya; Kumar, Chitta Suresh; Kalle, Arunasree M; Rao, M V Basaveswara; Oruganti, Srinivas; Pal, Manojit

2012-11-01

A series of novel N-substituted 2-(2-oxo-2H-chromen-4-yloxy)propanamide derivatives were synthesized via converting the readily available 4-hydroxy coumarin to the corresponding ethyl 2-(2-oxo-2H-chromen-4-yloxy)propanoate followed by hydrolysis and then reacting with different substituted amines. The molecular structures of two representative compounds, that is, 3 and 5l were confirmed by single crystal X-ray diffraction study. All the compounds synthesized were evaluated for their cyclooxygenase (COX) inhibiting properties in vitro. The compound 5i showed balanced selectivity towards COX-2 over COX-1 inhibition and good docking scores when docked into the COX-2 protein. Copyright © 2012 Elsevier Ltd. All rights reserved.

Crustal-Scale Fault Interaction at Rifted Margins and the Formation of Domain-Bounding Breakaway Complexes: Insights From Offshore Norway

NASA Astrophysics Data System (ADS)

Osmundsen, P. T.; Péron-Pinvidic, G.

2018-03-01

The large-magnitude faults that control crustal thinning and excision at rifted margins combine into laterally persistent structural boundaries that separate margin domains of contrasting morphology and structure. We term them breakaway complexes. At the Mid-Norwegian margin, we identify five principal breakaway complexes that separate the proximal, necking, distal, and outer margin domains. Downdip and lateral interactions between the faults that constitute breakaway complexes became fundamental to the evolution of the 3-D margin architecture. Different types of fault interaction are observed along and between these faults, but simple models for fault growth will not fully describe their evolution. These structures operate on the crustal scale, cut large thicknesses of heterogeneously layered lithosphere, and facilitate fundamental margin processes such as deformation coupling and exhumation. Variations in large-magnitude fault geometry, erosional footwall incision, and subsequent differential subsidence along the main breakaway complexes likely record the variable efficiency of these processes.

Mitochondrial-nuclear interactions and accelerated compensatory evolution: evidence from the primate cytochrome C oxidase complex.

PubMed

Osada, Naoki; Akashi, Hiroshi

2012-01-01

Accelerated rates of mitochondrial protein evolution have been proposed to reflect Darwinian coadaptation for efficient energy production for mammalian flight and brain activity. However, several features of mammalian mtDNA (absence of recombination, small effective population size, and high mutation rate) promote genome degradation through the accumulation of weakly deleterious mutations. Here, we present evidence for "compensatory" adaptive substitutions in nuclear DNA- (nDNA) encoded mitochondrial proteins to prevent fitness decline in primate mitochondrial protein complexes. We show that high mutation rate and small effective population size, key features of primate mitochondrial genomes, can accelerate compensatory adaptive evolution in nDNA-encoded genes. We combine phylogenetic information and the 3D structure of the cytochrome c oxidase (COX) complex to test for accelerated compensatory changes among interacting sites. Physical interactions among mtDNA- and nDNA-encoded components are critical in COX evolution; amino acids in close physical proximity in the 3D structure show a strong tendency for correlated evolution among lineages. Only nuclear-encoded components of COX show evidence for positive selection and adaptive nDNA-encoded changes tend to follow mtDNA-encoded amino acid changes at nearby sites in the 3D structure. This bias in the temporal order of substitutions supports compensatory weak selection as a major factor in accelerated primate COX evolution.

LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

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

Sun Haipeng; Xu Beibei; Sheveleva, Elena

2008-10-01

Glucocorticoids induce COX-2 expression in rat cardiomyocytes. While investigating whether phosphatidylinositol 3 kinase (PI3K) plays a role in corticosterone (CT)-induced COX-2, we found that LY294002 (LY29) but not wortmannin (WM) attenuates CT from inducing COX-2 gene expression. Expression of a dominant-negative mutant of p85 subunit of PI3K failed to inhibit CT from inducing COX-2 expression. CT did not activate PI3K/AKT signaling pathway whereas LY29 and WM decreased the activity of PI3K. LY303511 (LY30), a structural analogue and a negative control for PI3K inhibitory activity of LY29, also suppressed COX-2 induction. These data suggest PI3K-independent mechanisms in regulating CT-induced COX-2 expression.more » LY29 and LY30 do not inhibit glucocorticoid receptor transactivity. Both compounds have been reported to inhibit Casein Kinase 2 activity and modulate potassium and calcium levels independent of PI3K, while LY29 has been reported to inhibit mammalian Target of Rapamycin (mTOR), and DNA-dependent Protein Kinase (DNA-PK). Inhibitor of Casein Kinase 2 (CK2), mTOR or DNA-PK failed to prevent CT from inducing COX-2 expression. Tetraethylammonium (TEA), a potassium channel blocker, and nimodipine, a calcium channel blocker, both attenuated CT from inducing COX-2 gene expression. CT was found to increase intracellular Ca{sup 2+} concentration, which can be inhibited by LY29, TEA or nimodipine. These data suggest a possible role of calcium instead of PI3K in CT-induced COX-2 expression in cardiomyocytes.« less

A fast identification algorithm for Box-Cox transformation based radial basis function neural network.

PubMed

Hong, Xia

2006-07-01

In this letter, a Box-Cox transformation-based radial basis function (RBF) neural network is introduced using the RBF neural network to represent the transformed system output. Initially a fixed and moderate sized RBF model base is derived based on a rank revealing orthogonal matrix triangularization (QR decomposition). Then a new fast identification algorithm is introduced using Gauss-Newton algorithm to derive the required Box-Cox transformation, based on a maximum likelihood estimator. The main contribution of this letter is to explore the special structure of the proposed RBF neural network for computational efficiency by utilizing the inverse of matrix block decomposition lemma. Finally, the Box-Cox transformation-based RBF neural network, with good generalization and sparsity, is identified based on the derived optimal Box-Cox transformation and a D-optimality-based orthogonal forward regression algorithm. The proposed algorithm and its efficacy are demonstrated with an illustrative example in comparison with support vector machine regression.

The characterisation of atomic structure and glass-forming ability of the Zr-Cu-Co metallic glasses studied by molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Celtek, M.; Sengul, S.

2018-03-01

In the present work, the glass formation process and structural properties of Zr50Cu50-xCox (0 ≤ x ≤ 50) bulk metallic glasses were investigated by a molecular dynamics simulation with the many body tight-binding potentials. The evolution of structure and glass formation process with temperature were discussed using the coordination number, the radial distribution functions, the volume-temperature curve, icosahedral short-range order, glass transition temperature, Voronoi analysis, Honeycutt-Andersen pair analysis technique and the distribution of bond-angles. Results indicate that adding Co causes similar responses on the nature of the Zr50Cu50-xCox (0 ≤ x ≤ 50) alloys except for higher glass transition temperature and ideal icosahedral type ordered local atomic environment. Also, the differences of the atomic radii play the key role in influencing the atomic structure of these alloys. Both Cu and Co atoms play a significant role in deciding the chemical and topological short-range orders of the Zr50Cu50-xCox ternary liquids and amorphous alloys. The glass-forming ability of these alloys is supported by the experimental observations reported in the literature up to now.

Factors associated with Iowa rural hospitals' decision to convert to critical access hospital status.

PubMed

Li, Pengxiang; Ward, Marcia M; Schneider, John E

2009-01-01

The Balanced Budget Act (BBA) of 1997 allowed some rural hospitals meeting certain requirements to convert to Critical Access Hospitals (CAHs) and changed their Medicare reimbursement from prospective to cost-based. Some subsequent CAH-related laws reduced restrictions and increased payments, and the number of CAHs grew rapidly. To examine factors related to hospitals' decisions to convert and time to CAH conversion. Eighty-nine rural hospitals in Iowa were characterized and observed from 1998 to 2005. Cox proportional hazards models were used to identify the determinants of time to CAH conversion. T-test and one-covariate Cox regression indicated that, in 1998, Iowa rural hospitals with more staffed beds, discharges, and acute inpatient days, higher operating margin, lower skilled swing bed days relative to acute days, and located in relatively high density counties were more likely to convert later or not convert before 2006. Multiple Cox regression with baseline covariates indicated that lower number of discharges and average length of stay (ALOS) were significant after controlling all other covariates. Iowa rural hospitals' decisions regarding CAH conversion were influenced by hospital size, financial condition, skilled swing bed days relative to acute days, length of stay, proportion of Medicare acute days, and geographic factors. Although financial concerns are often cited in surveys as the main reason for conversion, lower number of discharges and ALOS are the most prominent factors affecting rural hospitals' decision on when to convert.

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

PubMed

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

2010-05-01

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

Endothelin ETA receptor/lipid peroxides/COX-2/TGF-β1 signalling underlies aggravated nephrotoxicity caused by cyclosporine plus indomethacin in rats.

PubMed

Helmy, Maged W; El-Gowelli, Hanan M; Ali, Rabab M; El-Mas, Mahmoud M

2015-09-01

Cyclosporine (CSA) and non-steroidal anti-inflammatory drugs (NSAIDs) are co-prescribed for some arthritic conditions. We tested the hypothesis that this combined regimen elicits exaggerated nephrotoxicity in rats via the up-regulation of endothelin (ET) receptor signalling. The effects of a 10 day treatment with CSA (20 mg · kg(-1) · day(-1)), indomethacin (5 mg · kg(-1) · day(-1)) or their combination on renal biochemical, inflammatory, oxidative and structural profiles were assessed. The roles of ETA receptor and COX-2 pathways in the interaction were evaluated. Oral treatment with CSA or indomethacin elevated serum urea and creatinine, caused renal tubular atrophy and interstitial fibrosis, increased renal TGF-β1, and reduced immunohistochemical expressions of ETA receptors and COX-2. CSA, but not indomethacin, increased renal ET-1, the lipid peroxidation product malondialdehyde (MDA) and GSH activity. Compared with individual treatments, simultaneous CSA/indomethacin exposure caused: (i) greater elevations in serum creatinine and renal MDA; (ii) loss of the compensatory increase in GSH; (iii) renal infiltration of inflammatory cells and worsening of fibrotic and necrotic profiles; and (iv) increased renal ET-1 and decreased ETA receptor and COX-2 expressions. Blockade of ETA receptors by atrasentan ameliorated the biochemical, structural, inflammatory and oxidative abnormalities caused by the CSA/indomethacin regimen. Furthermore, atrasentan partly reversed the CSA/indomethacin-evoked reductions in the expression of ETA receptor and COX-2 protein. The exaggerated oxidative insult and associated dysregulation of the ETA receptor/COX-2/TGF-β1 signalling might account for the aggravated nephrotoxicity caused by the CSA/indomethacin regimen. The potential renoprotective effect of ETA receptor antagonism might be exploited therapeutically. © 2015 The British Pharmacological Society.

Structure and degree of magmatism of North and South Atlantic rifted margins

NASA Astrophysics Data System (ADS)

Faleide, Jan Inge; Breivik, Asbjørn J.; Blaich, Olav A.; Tsikalas, Filippos; Planke, Sverre; Mansour Abdelmalak, Mohamed; Mjelde, Rolf; Myklebust, Reidun

2014-05-01

The structure and evolution of conjugate rifted margins in the South and North Atlantic have been studied mainly based on seismic reflection and refraction profiles, complemented by potential field data and plate reconstructions. All margins exhibit distinct along-margin structural and magmatic changes reflecting both structural inheritance extending back to a complex pre-breakup geological history and the final breakup processes. The sedimentary basins at the conjugate margins developed as a result of multiple phases of rifting, associated with complex time-dependent thermal structure of the lithosphere. A series of conjugate crustal transects reveal tectonomagmatic asymmetry, both along-strike and across the conjugate margin systems. The continent-ocean transitional domain along the magma-dominated margin segments is characterized by a large volume of flood basalts and high-velocity/high-density lower crust emplaced during and after continental breakup. Both the volume and duration of excess magmatism varies. The extrusive and intrusive complexes make it difficult to pin down a COB to be used in plate reconstructions. The continent-ocean transition is usually well defined as a rapid increase of P-wave velocities at mid- to lower crustal levels. The transition is further constrained by comparing the mean P-wave velocity to the thickness of the crystalline crust. By this comparison we can also address the magmatic processes associated with breakup, whether they are convection dominated or temperature dominated. In the NE Atlantic there is a strong correlation between magma productivity and early plate spreading rate, suggesting a common cause. A model for the breakup-related magmatism should be able to explain this correlation, but also the magma production peak at breakup, the along-margin magmatic segmentation, and the active mantle upwelling. It is likely that mantle plumes (Iceland in the NE Atlantic, Tristan da Cunha in the South Atlantic) may have influenced the volume of magmatism but they did not necessarily alter the process of rifted margin formation, implying that parts of the margins may have much in common with more magma-poor margins. Conjugate margin segments from the North and South Atlantic will be compared and discussed with particular focus on the tectonomagmatic processes associated with continental breakup.

Impact of margin status and lymphadenectomy on clinical outcomes in resected pancreatic adenocarcinoma: implications for adjuvant radiotherapy.

PubMed

Osipov, Arsen; Naziri, Jason; Hendifar, Andrew; Dhall, Deepti; Rutgers, Joanne K; Chopra, Shefali; Li, Quanlin; Tighiouart, Mourad; Annamalai, Alagappan; Nissen, Nicholas N; Tuli, Richard

2016-04-01

Adjuvant chemoradiotherapy (CRT) in the treatment of pancreatic ductal adenocarcinoma (PDA) is controversial. Minimal data exists regarding the clinical significance of margin clearance distance and lymph node (LN) parameters, such as extent of dissection and LN ratio. We assessed the impact of these variables on clinical outcomes to more clearly define the subset of patients who may benefit from adjuvant radiotherapy (RT). We identified 106 patients with resected stage 1-3 PDA from 2007-2013. Resection margins were categorized as positive (tumor at ink), ≤1, or >1 mm. LN evaluation included total number examined (NE), number of positive nodes (NP), ratio of NP to NE (NR), extent of dissection, and positive periportal LNs. The impact of these variables was assessed on disease-free survival (DFS) and overall survival (OS) using multivariate cox proportional hazards modeling. In patients receiving adjuvant chemotherapy (CT) alone, greater margin clearance led to improved DFS (P=0.0412, HR =0.51). Range of NE was 4-37, with a mean of 19. NE was not associated with DFS or OS, yet absolute NP of 5 or more was associated with a significantly worse DFS (P=0.005). Whereas periportal lymphadenectomy did not result in improved DFS or OS, patients with positive periportal LN had worse clinical outcomes (DFS, P=0.0052; OS, P=0.023). The use of adjuvant CRT was associated with improved OS (P=0.049; HR=0.29). In patients receiving adjuvant CT alone, there was a clinically significant benefit to clearing the surgical margin beyond tumor at ink. Having ≥5 NP and positive periportal LN led to significantly worse clinical outcomes. The addition of adjuvant RT to CT in resected PDA improved OS. A comprehensive evaluation of resection margin distance and LN parameters may identify more patients at risk for locoregional failure who may benefit from adjuvant CRT.

Impact of margin status and lymphadenectomy on clinical outcomes in resected pancreatic adenocarcinoma: implications for adjuvant radiotherapy

PubMed Central

Osipov, Arsen; Naziri, Jason; Hendifar, Andrew; Dhall, Deepti; Rutgers, Joanne K.; Chopra, Shefali; Li, Quanlin; Tighiouart, Mourad; Annamalai, Alagappan; Nissen, Nicholas N.

2016-01-01

Background Adjuvant chemoradiotherapy (CRT) in the treatment of pancreatic ductal adenocarcinoma (PDA) is controversial. Minimal data exists regarding the clinical significance of margin clearance distance and lymph node (LN) parameters, such as extent of dissection and LN ratio. We assessed the impact of these variables on clinical outcomes to more clearly define the subset of patients who may benefit from adjuvant radiotherapy (RT). Methods We identified 106 patients with resected stage 1-3 PDA from 2007-2013. Resection margins were categorized as positive (tumor at ink), ≤1, or >1 mm. LN evaluation included total number examined (NE), number of positive nodes (NP), ratio of NP to NE (NR), extent of dissection, and positive periportal LNs. The impact of these variables was assessed on disease-free survival (DFS) and overall survival (OS) using multivariate cox proportional hazards modeling. Results In patients receiving adjuvant chemotherapy (CT) alone, greater margin clearance led to improved DFS (P=0.0412, HR =0.51). Range of NE was 4-37, with a mean of 19. NE was not associated with DFS or OS, yet absolute NP of 5 or more was associated with a significantly worse DFS (P=0.005). Whereas periportal lymphadenectomy did not result in improved DFS or OS, patients with positive periportal LN had worse clinical outcomes (DFS, P=0.0052; OS, P=0.023). The use of adjuvant CRT was associated with improved OS (P=0.049; HR=0.29). Conclusions In patients receiving adjuvant CT alone, there was a clinically significant benefit to clearing the surgical margin beyond tumor at ink. Having ≥5 NP and positive periportal LN led to significantly worse clinical outcomes. The addition of adjuvant RT to CT in resected PDA improved OS. A comprehensive evaluation of resection margin distance and LN parameters may identify more patients at risk for locoregional failure who may benefit from adjuvant CRT. PMID:27034792

Colorado Basin Structure and Rifting, Argentine passive margin

NASA Astrophysics Data System (ADS)

Autin, Julia; Scheck-Wenderoth, Magdalena; Loegering, Markus; Anka, Zahie; Vallejo, Eduardo; Rodriguez, Jorge; Marchal, Denis; Reichert, Christian; di Primio, Rolando

2010-05-01

The Argentine margin presents a strong segmentation with considerable strike-slip movements along the fracture zones. We focus on the volcanic segment (between the Salado and Colorado transfer zones), which is characterized by seaward dipping reflectors (SDR) all along the ocean-continent transition [e.g. Franke et al., 2006; Gladczenko et al., 1997; Hinz et al., 1999]. The segment is structured by E-W trending basins, which differs from the South African margin basins and cannot be explained by classical models of rifting. Thus the study of the relationship between the basins and the Argentine margin itself will allow the understanding of their contemporary development. Moreover the comparison of the conjugate margins suggests a particular evolution of rifting and break-up. We firstly focus on the Colorado Basin, which is thought to be the conjugate of the well studied Orange Basin [Hirsch et al., 2009] at the South African margin [e.g. Franke et al., 2006]. This work presents results of a combined approach using seismic interpretation and structural, isostatic and thermal modelling highlighting the structure of the crust. The seismic interpretation shows two rift-related discordances: one intra syn-rift and the break-up unconformity. The overlying sediments of the sag phase are less deformed (no sedimentary wedges) and accumulated before the generation of oceanic crust. The axis of the Colorado Basin trends E-W in the western part, where the deepest pre-rift series are preserved. In contrast, the basin axis turns to a NW-SE direction in its eastern part, where mainly post-rift sediments accumulated. The most distal part reaches the margin slope and opens into the oceanic basin. The general basin direction is almost orthogonal to the present-day margin trend. The most frequent hypothesis explaining this geometry is that the Colorado Basin is an aborted rift resulting from a previous RRR triple junction [e.g. Franke et al., 2002]. The structural interpretation partly supports this hypothesis and shows two main directions of faulting: margin-parallel faults (~N30°) and rift-parallel faults (~N125°). A specific distribution of the two fault sets is observed: margin-parallel faults are restrained to the most distal part of the margin. Starting with a 3D structural model of the basin fill based on seismic and well data the deeper structure of the crust beneath the Colorado Basin can be evaluate using isostatic and thermal modelling. Franke, D., et al. (2002), Deep Crustal Structure Of The Argentine Continental Margin From Seismic Wide-Angle And Multichannel Reflection Seismic Data, paper presented at AAPG Hedberg Conference "Hydrocarbon Habitat of Volcanic Rifted Passive Margins", Stavanger, Norway Franke, D., et al. (2006), Crustal structure across the Colorado Basin, offshore Argentina Geophysical Journal International 165, 850-864. Gladczenko, T. P., et al. (1997), South Atlantic volcanic margins Journal of the Geological Society, London 154, 465-470. Hinz, K., et al. (1999), The Argentine continental margin north of 48°S: sedimentary successions, volcanic activity during breakup Marine and Petroleum Geology 16(1-25). Hirsch, K. K., et al. (2009), Tectonic subsidence history and thermal evolution of the Orange Basin, Marine and Petroleum Geology, in press, doi:10.1016/j.marpetgeo.2009.1006.1009

Microbial communities in methane seep sediments along US Atlantic Margin are structured by organic matter and seepage dynamics

NASA Astrophysics Data System (ADS)

Graw, M. F.; Pohlman, J.; Treude, T.; Ruppel, C. D.; Colwell, F. S.

2016-12-01

Methane seeps are dynamic environments on continental margins where subsurface methane reaches the ocean. Microbial communities play a critical role in carbon cycling within seep sediments via organic carbon degradation, methane production, and anaerobic oxidation of methane (AOM), which consumes 20-80% of methane in seep sediments. However, biogeochemical controls on microbial community structure at seeps on a margin-wide scale remain unclear. The passive US Atlantic Margin (USAM) has been identified as a region of active methane seepage. Passive margin seeps have traditionally been understudied relative to seeps on active margins. Passive margins exhibit large cross-margin variability in organic carbon deposition and are anticipated to have divergent seep dynamics from active margins. Thus, the USAM offers a unique opportunity to investigate controls on microbial communities in seep sediments. We undertook analysis of microbial communities inhabiting seep sediments at 6 biogeochemically distinct sites along the USAM. Microbiological samples were co-located with measurements of sediment geochemistry and AOM and sulfate reduction rates. Illumina sequencing of the 16S rRNA gene, using both universal (83 samples) and archaeal-specific (64 samples) primers, and the mcrA gene (18 samples) identified 44 bacterial phyla and 7 archaeal phyla. Seeps in canyons and on open slope, likely representing high and low organic content sediments, hosted distinct communities; the former was dominated by ammonia-oxidizing Marine Group I Thaumarchaeota and the latter by mixotrophic Hadesarchaeota. Seep stability also impacted microbial community structure, and in particular the establishment of an AOM community rather than a Bathyarchaeota-dominated community. These findings contribute to understanding how microbial communities are structured within methane seep sediments and pave the way for investigating broad differences in carbon cycling between seeps on passive and active margins.

Voices of the poor from the margins of Bengal: structural inequities and health.

PubMed

Dutta, Mohan J; Dutta, Uttaran

2013-01-01

In opposition to the traditional approaches to health communication that treat the subaltern sectors as passive recipients of messages of enlightenment configured in top-down interventions, the culture-centered approach foregrounds the importance of listening to subaltern communities at the margins through dialogue. We build on earlier culture-centered projects in rural communities of West Bengal, India, to develop participatory research strategies for understanding the local processes through which the structural marginalization of the poor plays out in rural Bengal. Study results point toward the marginalization of the poor both communicatively and economically, attending to the ways in which communicative marginalization lies at the heart of economic oppressions. Through locally articulated concepts of "health as shortage" and "communication as shortage," community members put forth alternative rationalities of health that highlight structural resources at the heart of health. These local articulations of shortage offer an alternative rationality for organizing health promotion efforts in the rural margins of Bengal through the foregrounding of discourses of shortage.

The importance of structural softening for the evolution and architecture of passive margins

PubMed Central

Duretz, T.; Petri, B.; Mohn, G.; Schmalholz, S. M.; Schenker, F. L.; Müntener, O.

2016-01-01

Lithospheric extension can generate passive margins that bound oceans worldwide. Detailed geological and geophysical studies in present and fossil passive margins have highlighted the complexity of their architecture and their multi-stage deformation history. Previous modeling studies have shown the significant impact of coarse mechanical layering of the lithosphere (2 to 4 layer crust and mantle) on passive margin formation. We built upon these studies and design high-resolution (~100–300 m) thermo-mechanical numerical models that incorporate finer mechanical layering (kilometer scale) mimicking tectonically inherited heterogeneities. During lithospheric extension a variety of extensional structures arises naturally due to (1) structural softening caused by necking of mechanically strong layers and (2) the establishment of a network of weak layers across the deforming multi-layered lithosphere. We argue that structural softening in a multi-layered lithosphere is the main cause for the observed multi-stage evolution and architecture of magma-poor passive margins. PMID:27929057

State policy change: Revenue decoupling in the electricity market

NASA Astrophysics Data System (ADS)

McNeil, Kytson L.

The study seeks to answer the question, why are states adopting revenue decoupling in the electricity market, by investigating the relationship between policy adoption and attributes of the electricity market, the structure of the state utility commissions, and the political climate of the state. The study examines the period 1978-2008. Two econometric models, the marginal risk set model and the conditional risk set model, are estimated to predict the influence of covariates on the probability of the state adopting revenue decoupling in the electricity market. The models are both variants of the Cox proportional hazard model and use different underlying assumptions about the nature of adoption of revenue decoupling and when the states are considered to be at risk of adoption. Results suggest that market attributes, such as the source of electricity generation in the state, state energy intensity, and the distribution of non-public and public utilities, significantly influence the adoption of the policy. Also, the method of selecting commissioners and the party affiliation of elected officials in the state are important factors. The study concludes by suggestions to improve the implementation and evaluation of revenue decoupling in the electricity markets.

Local Recurrence After Uveal Melanoma Proton Beam Therapy: Recurrence Types and Prognostic Consequences

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

Caujolle, Jean-Pierre, E-mail: ncaujolle@aol.com; Paoli, Vincent; Chamorey, Emmanuel

Purpose: To study the prognosis of the different types of uveal melanoma recurrences treated by proton beam therapy (PBT). Methods and Materials: This retrospective study analyzed 61 cases of uveal melanoma local recurrences on a total of 1102 patients treated by PBT between June 1991 and December 2010. Survival rates have been determined by using Kaplan-Meier curves. Prognostic factors have been evaluated by using log-rank test or Cox model. Results: Our local recurrence rate was 6.1% at 5 years. These recurrences were divided into 25 patients with marginal recurrences, 18 global recurrences, 12 distant recurrences, and 6 extrascleral extensions. Fivemore » factors have been identified as statistically significant risk factors of local recurrence in the univariate analysis: large tumoral diameter, small tumoral volume, low ratio of tumoral volume over eyeball volume, iris root involvement, and safety margin inferior to 1 mm. In the local recurrence-free population, the overall survival rate was 68.7% at 10 years and the specific survival rate was 83.6% at 10 years. In the local recurrence population, the overall survival rate was 43.1% at 10 years and the specific survival rate was 55% at 10 years. The multivariate analysis of death risk factors has shown a better prognosis for marginal recurrences. Conclusion: Survival rate of marginal recurrences is superior to that of the other recurrences. The type of recurrence is a clinical prognostic value to take into account. The influence of local recurrence retreatment by proton beam therapy should be evaluated by novel studies.« less

A comparison of the left thoracoabdominal and Ivor-Lewis esophagectomy.

PubMed

Davies, A R; Zylstra, J; Baker, C R; Gossage, J A; Dellaportas, D; Lagergren, J; Findlay, J M; Puccetti, F; El Lakis, M; Drummond, R J; Dutta, S; Mera, A; Van Hemelrijck, M; Forshaw, M J; Maynard, N D; Allum, W H; Low, D; Mason, R C

2018-03-01

The purpose of this study was to assess the oncological outcomes of a large multicenter series of left thoracoabdominal esophagectomies, and compare these to the more widely utilized Ivor-Lewis esophagectomy. With ethics approval and an established study protocol, anonymized data from five centers were merged into a structured database. The study exposure was operative approach (ILE or LTE). The primary outcome measure was time to death. Secondary outcome measures included time to tumor recurrence, positive surgical resection margins, lymph node yield, postoperative death, and hospital length of stay. Cox proportional hazards models provided hazard ratios (HR) with 95% confidence intervals (CI) adjusting for age, pathological tumor stage, tumor grade, lymphovascular invasion, and neoadjuvant treatment. Among 1228 patients (598 ILE; 630 LTE), most (86%) had adenocarcinoma (AC) and were male (81%). Comparing ILE and LTE for AC patients, no difference was seen in terms of time to death (HR 0.904 95%CI 0.749-1.1090) or time to recurrence (HR 0.973 95%CI 0.768-1.232). The risk of a positive resection margin was also similar (OR 1.022 95%CI 0.731-1.429). Median lymph node yield did not differ between approaches (LTE 21; ILE 21; P = 0.426). In-hospital mortality was 2.4%, significantly lower in the LTE group (LTE 1.3%; ILE 3.6%; P = 0.004). Median hospital stay was 11 days in the LTE group and 14 days in the ILE group (P < 0.0001). In conclusion, this is the largest series of left thoracoabdominal esophagectomies to be submitted for publication and the only one to compare two different transthoracic esophagectomy strategies. It demonstrates oncological equivalence between operative approaches but possible short- term advantages to the left thoracoabdominal esophagectomy.

Mesozoic evolution of the northeast African shelf margin, Libya and Egypt

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

Aadland, R.K.; Schamel, S.

1988-08-01

The present tectonic features of the northeast African shelf margin between the Nile delta and the Gulf of Sirte are products of (1) precursory late Paleozoic basement arches, (2) early Mesozoic rifting and plate separation, and (3) Late Cretaceous structural inversion. Isopach and structural maps, cross sections, and sediment accumulation (geohistory) curves constructed from 89 wells in the Western Desert and 27 wells in northeastern Libya depict the structural and stratigraphic development of the northeast African shelf margin.

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

PubMed

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

1991-07-01

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

Redox and non-redox mechanism of in vitro cyclooxygenase inhibition by natural quinones.

PubMed

Landa, Premysl; Kutil, Zsofia; Temml, Veronika; Vuorinen, Anna; Malik, Jan; Dvorakova, Marcela; Marsik, Petr; Kokoska, Ladislav; Pribylova, Marie; Schuster, Daniela; Vanek, Tomas

2012-03-01

In this study, ten anthra-, nine naphtho-, and five benzoquinone compounds of natural origin and five synthetic naphthoquinones were assessed, using an enzymatic in vitro assay, for their potential to inhibit cyclooxygenase-1 and -2 (COX-1 and COX-2), the key enzymes of the arachidonic acid cascade. IC₅₀ values comparable with COX reference inhibitor indomethacin were recorded for several quinones (primin, alkannin, diospyrin, juglone, 7-methyljuglone, and shikonin). For some of the compounds, we suggest the redox potential of quinones as the mechanism responsible for in vitro COX inhibition because of the quantitative correlation with their pro-oxidant effect. Structure-relationship activity studies revealed that the substitutions at positions 2 and 5 play the key roles in the COX inhibitory and pro-oxidant actions of naphthoquinones. In contrast, the redox mechanism alone could not explain the activity of primin, embelin, alkannin, and diospyrin. For these four quinones, molecular modeling suggested similar binding modes as for conventional nonsteroidal anti-inflammatory drugs (NSAIDs). © Georg Thieme Verlag KG Stuttgart · New York.

Adsorption of hydrogen gas and redox processes in clays.

PubMed

Didier, Mathilde; Leone, Laura; Greneche, Jean-Marc; Giffaut, Eric; Charlet, Laurent

2012-03-20

In order to assess the adsorption properties of hydrogen gas and reactivity of adsorbed hydrogen, we measured H(2)(g) adsorption on Na synthetic montmorillonite-type clays and Callovo-Oxfordian (COx) clayrock using gas chromatography. Synthetic montmorillonites with increasing structural Fe(III) substitution (0 wt %, 3.2 wt %, and 6.4 wt % Fe) were used. Fe in the synthetic montmorillonites is principally present as structural Fe(III) ions. We studied the concomitant reduction of structural Fe(III) in the clays using (57)Fe Mössbauer spectrometry. The COx, which mainly contains smectite/illite and calcite minerals, is also studied together with the pure clay fraction of this clayrock. Experiments were performed with dry clay samples which were reacted with hydrogen gas at 90 and 120 °C for 30 to 45 days at a hydrogen partial pressure close to 0.45 bar. Results indicate that up to 0.11 wt % of hydrogen is adsorbed on the clays at 90 °C under 0.45 bar of relative pressure. (57)Fe Mössbauer spectrometry shows that up to 6% of the total structural Fe(III) initially present in these synthetic clays is reduced upon adsorption of hydrogen gas. No reduction is observed with the COx sample in the present experimental conditions.

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

PubMed

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

2014-01-01

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

Targeted Maximum Likelihood Estimation for Dynamic and Static Longitudinal Marginal Structural Working Models

PubMed Central

Schwab, Joshua; Gruber, Susan; Blaser, Nello; Schomaker, Michael; van der Laan, Mark

2015-01-01

This paper describes a targeted maximum likelihood estimator (TMLE) for the parameters of longitudinal static and dynamic marginal structural models. We consider a longitudinal data structure consisting of baseline covariates, time-dependent intervention nodes, intermediate time-dependent covariates, and a possibly time-dependent outcome. The intervention nodes at each time point can include a binary treatment as well as a right-censoring indicator. Given a class of dynamic or static interventions, a marginal structural model is used to model the mean of the intervention-specific counterfactual outcome as a function of the intervention, time point, and possibly a subset of baseline covariates. Because the true shape of this function is rarely known, the marginal structural model is used as a working model. The causal quantity of interest is defined as the projection of the true function onto this working model. Iterated conditional expectation double robust estimators for marginal structural model parameters were previously proposed by Robins (2000, 2002) and Bang and Robins (2005). Here we build on this work and present a pooled TMLE for the parameters of marginal structural working models. We compare this pooled estimator to a stratified TMLE (Schnitzer et al. 2014) that is based on estimating the intervention-specific mean separately for each intervention of interest. The performance of the pooled TMLE is compared to the performance of the stratified TMLE and the performance of inverse probability weighted (IPW) estimators using simulations. Concepts are illustrated using an example in which the aim is to estimate the causal effect of delayed switch following immunological failure of first line antiretroviral therapy among HIV-infected patients. Data from the International Epidemiological Databases to Evaluate AIDS, Southern Africa are analyzed to investigate this question using both TML and IPW estimators. Our results demonstrate practical advantages of the pooled TMLE over an IPW estimator for working marginal structural models for survival, as well as cases in which the pooled TMLE is superior to its stratified counterpart. PMID:25909047

Brazed Joints Design and Allowables: Discuss Margins of Safety in Critical Brazed Structures

NASA Technical Reports Server (NTRS)

FLom, Yury

2009-01-01

This slide presentation tutorial discusses margins of safety in critical brazed structures. It reviews: (1) the present situation (2) definition of strength (3) margins of safety (4) design allowables (5) mechanical testing (6) failure criteria (7) design flowchart (8) braze gap (9) residual stresses and (10) delayed failures. This presentation addresses the strength of the brazed joints, the methods of mechanical testing, and our ability to evaluate the margins of safety of the brazed joints as it applies to the design of critical and expensive brazed assemblies.

Integration host factor is necessary for lysogenization of Escherichia coli by bacteriophage P2.

PubMed

Saha, S; Haggård-Ljungquist, E; Nordström, K

1990-01-01

Whether infection by bacteriophage P2 results in lysogenization of the host or vegetative growth of the phage depends upon a race between transcription from the repressor promoter Pc and the early promoter Pe; transcription from these promoters is mutually exclusive, since the Pc repressor Cox is formed from the Pe transcript and the Pe repressor C from the Pc transcript. The involvement of integration host factor (IHF) in the lysogenization of Escherichia coli K12 by P2 was tested by comparing wild-type and IHF-deficient (himA and himD) mutants. No lysogenic clones were formed following infection of the mutant bacteria. A switch plasmid that contains Pc-C-cat and Pe-cox-kan was used to test the choice for expression of Pc versus Pe. In the wild-type K12 bacteria, 20% of the clones expressed Pe transcription and 80% Pc transcription, whereas all transformed IHF-defective clones expressed transcription from Pe only. The effects of IHF on the in vivo expression of the Pe and Pc promoters were only marginal. The IHF protein was found to bind upstream of the Pe promoter, where a potential ihf sequence is located.

Ethyl caffeate suppresses NF-kappaB activation and its downstream inflammatory mediators, iNOS, COX-2, and PGE2 in vitro or in mouse skin.

PubMed

Chiang, Yi-Ming; Lo, Chiu-Ping; Chen, Yi-Ping; Wang, Sheng-Yang; Yang, Ning-Sun; Kuo, Yueh-Hsiung; Shyur, Lie-Fen

2005-10-01

Ethyl caffeate, a natural phenolic compound, was isolated from Bidens pilosa, a medicinal plant popularly used for treating certain inflammatory syndromes. The purpose of this study was to investigate the structural activity, and the anti-inflammatory functions and mechanism(s) of ethyl caffeate. Ethyl caffeate was found to markedly suppress the lipopolysaccharide (LPS)-induced nitric oxide (NO) production (IC(50) = 5.5 microg ml(-1)), mRNA and protein expressions of inducible nitric oxide synthase (iNOS), and prostaglandin E(2) (PGE(2)) production in RAW 264.7 macrophages. Transient gene expression assays using human cox-2 promoter construct revealed that ethyl caffeate exerted an inhibitory effect on cox-2 transcriptional activity in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated MCF-7 cells. Immunohistochemical studies of mouse skin demonstrated that TPA-induced COX-2 expression was significantly inhibited by ethyl caffeate with a superior effect to that of celecoxib, a nonsteroidal anti-inflammatory drug. The phosphorylation and degradation of inhibitor kappaB (IkappaB) and the translocation of nuclear transcription factor-kappaB (NF-kappaB) into the nucleus, as well as the activation of mitogen-activated protein kinases (MAPKs) induced by LPS in macrophages, were not affected by ethyl caffeate. Ethyl caffeate, however, could inhibit NF-kappaB activation by impairing the binding of NF-kappaB to its cis-acting element. These results suggest that ethyl caffeate suppresses iNOS and COX-2 expressions partly through the inhibition of the NF-kappaB.DNA complex formation. Structure-activity relationship analyses suggested that the catechol moiety and alpha,beta-unsaturated ester group in ethyl caffeate are important and essential structural features for preventing NF-kappaB.DNA complex formation. This study provides an insight into the probable mechanism(s) underlying the anti-inflammatory and therapeutic properties of ethyl caffeate.

A receptor-grounded approach to teaching nonsteroidal antiinflammatory drug chemistry and structure-activity relationships.

PubMed

Roche, Victoria F

2009-12-17

To describe a receptor-based approach to promote learning about nonsteroidal anti-inflammatory drug (NSAID) chemistry, structure-activity relationships, and therapeutic decision-making. Three lessons on cyclooxygenase (COX) and NSAID chemistry, and NSAID therapeutic utility, were developed using text-based resources and primary medicinal chemistry and pharmacy practice literature. Learning tools were developed to assist students in content mastery. Student learning was evaluated via performance on quizzes and examinations that measured understanding of COX and NSAID chemistry, and the application of that knowledge to therapeutic problem solving. Student performance on NSAID-focused quizzes and examinations documented the success of this approach.

N, P-codoped Mesoporous Carbon Supported PtCox Nanoparticles and Their Superior Electrochemical toward Methanol Oxidation

NASA Astrophysics Data System (ADS)

Cui, Hangjun; Li, Yueming; Liu, Shimin

2018-03-01

In this report, a novel strategy by using the N, P co-doped mesoporous carbon structure as catalyst support to enhance the electrochemical catalytic activity of Pt-based catalysts is proposed. The as-synthesized PtCox@N, P-doped mesoporous carbon nanocomposties have been studied as an anode catalyst toward methanol oxidation, exhibiting greatly improved electrochemical activity and stability compared with Pt@mesoporous carbon. The synergistic effects of N, P dual-doping and porous carbon structure help to achieve better electron transport at the electrode surface, which eventually leads to greatly enhanced catalytic activity compared to the pristine Pt/mesoporous carbon.…

Gaussianization for fast and accurate inference from cosmological data

NASA Astrophysics Data System (ADS)

Schuhmann, Robert L.; Joachimi, Benjamin; Peiris, Hiranya V.

2016-06-01

We present a method to transform multivariate unimodal non-Gaussian posterior probability densities into approximately Gaussian ones via non-linear mappings, such as Box-Cox transformations and generalizations thereof. This permits an analytical reconstruction of the posterior from a point sample, like a Markov chain, and simplifies the subsequent joint analysis with other experiments. This way, a multivariate posterior density can be reported efficiently, by compressing the information contained in Markov Chain Monte Carlo samples. Further, the model evidence integral (I.e. the marginal likelihood) can be computed analytically. This method is analogous to the search for normal parameters in the cosmic microwave background, but is more general. The search for the optimally Gaussianizing transformation is performed computationally through a maximum-likelihood formalism; its quality can be judged by how well the credible regions of the posterior are reproduced. We demonstrate that our method outperforms kernel density estimates in this objective. Further, we select marginal posterior samples from Planck data with several distinct strongly non-Gaussian features, and verify the reproduction of the marginal contours. To demonstrate evidence computation, we Gaussianize the joint distribution of data from weak lensing and baryon acoustic oscillations, for different cosmological models, and find a preference for flat Λcold dark matter. Comparing to values computed with the Savage-Dickey density ratio, and Population Monte Carlo, we find good agreement of our method within the spread of the other two.

Preoperative radiation therapy in the surgical management of gastric and junctional adenocarcinoma: Should lymph node retrieval guidelines be altered?

PubMed

Lane, Whitney O; Nussbaum, Daniel P; Sun, Zhifei; Blazer, Dan G

2018-05-25

Although surgery remains the cornerstone of gastric cancer therapy, the use of radiation therapy (RT) is increasingly being employed to optimize outcomes. We sought to assess outcomes following use of RT for the treatment of gastric adenocarcinoma. Using the National Cancer Data Base (NCDB) from 1998 to 2012, all patients with resected gastric adenocarcinoma were identified. Patients were stratified into four groups based on preoperative therapy: RT alone, chemotherapy only, chemoradiotherapy (CRT), and no preoperative therapy. Overall survival was estimated using multivariate Cox proportional hazards model. Adjusted secondary outcomes include margin positivity, lymph node harvest, LOS, 30-day readmission and mortality. A total of 10 019 patients met study criteria. In the unadjusted analysis, patients undergoing CRT compared to chemotherapy alone had fewer positive margins (7.9% vs 15.9%; P < 0.001), increased negative LNs (54.6% vs 37.7%; P < 0.001) with reduced LN retrieval (mean: 13.5 vs 19.6; P < 0.01). After multivariate adjustment, there was no survival benefit to any preoperative therapy; however, preoperative RT/CRT remained associated with decreased LN retrieval. The results support previous reports on preoperative RT resulting in decreased margin positivity. This study highlights the need to reconsider practice guidelines regarding appropriate lymphadenectomy in the setting of preoperative RT given reduced LN retrieval. © 2018 Wiley Periodicals, Inc.

Structural design/margin assessment

NASA Technical Reports Server (NTRS)

Ryan, R. S.

1993-01-01

Determining structural design inputs and the structural margins following design completion is one of the major activities in space exploration. The end result is a statement of these margins as stability, safety factors on ultimate and yield stresses, fracture limits (fracture control), fatigue lifetime, reuse criteria, operational criteria and procedures, stability factors, deflections, clearance, handling criteria, etc. The process is normally called a load cycle and is time consuming, very complex, and involves much more than structures. The key to successful structural design is the proper implementation of the process. It depends on many factors: leadership and management of the process, adequate analysis and testing tools, data basing, communications, people skills, and training. This process and the various factors involved are discussed.

Morphology and deformational history of Tellus Regio, Venus: Evidence for assembly and collision

NASA Astrophysics Data System (ADS)

Gilmore, M. S.; Head, J. W.

2018-05-01

Tessera terrain is the oldest stratigraphic unit on Venus, but its origin and evolution are inadequately understood. Here we have performed detailed mapping of Tellus Regio, the third largest tessera plateau on Venus. Tellus Regio is shown to have distinct marginal and interior facies. The east and west margins of Tellus rise up to 2 km above the interior and include ridges and troughs ∼5-20 km across, oriented parallel to the present plains-tessera boundary. Structures characteristic of the interior of Tellus are found within the eastern and western margins and are deformed by the margin-parallel ridges indicating their presence during the time of the formation of the current margins. These relationships suggest that the margins formed by the application of external horizontal compressional stresses at the edges of an already-existing tessera interior. Structural and stratigraphic relationships in southwest Tellus show the assembly of three structurally distinct tessera regions and intervening plains that are consistent with the collision of the southwest margin into the plateau interior. This requires that tessera terrain was formed regionally and collected into the present day Tellus plateau. The latest stages of activity in Tellus include volcanism and pervasive, distributed, 1-2 km wide graben, which may have been formed due to large-scale gravitational relaxation of the plateau topography. A large intratessera plains unit may have formed via crustal delamination. The collisional oroclinal deformation of the margins are most consistent with models that invoke mantle downwelling for the origin of Tellus Regio and other tessera plateaus with similar structural relationships.

Structure of the North American Atlantic Continental Margin

USGS Publications Warehouse

Schlee, J.S.; Klitgord, K.K.

1986-01-01

Off E N America, where the structure of the continental margin is essentially constructional, seismic profiles have approximated geologic cross sections up to 10-15km below the sea floor and revealed major structural and stratigraphic features that have regional hydrocarbon potential. These features include a) a block-faulted basement hinge zone; b) a deep, broad, rifted basement filled with clastic sediment and salt; and c) a buried paleoshelf-edge complex that has many forms. The mapping of seismostratigraphic units over the continental shelf, slope, and rise has shown that the margin's developmental state included infilling of a rifted margin, buildup of a carbonate platform, and construction of an onlapping continental-rise wedge that was accompanied by erosion of the slope. -from Authors

Pleiotropic mechanisms facilitated by resveratrol and its metabolites

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

Calamini, Barbara; Ratia, Kiira; Malkowski, Michael G.

2010-07-01

Resveratrol has demonstrated cancer chemopreventive activity in animal models and some clinical trials are underway. In addition, resveratrol was shown to promote cell survival, increase lifespan and mimic caloric restriction, thereby improving health and survival of mice on high-calorie diet. All of these effects are potentially mediated by the pleiotropic interactions of resveratrol with different enzyme targets including COX-1 (cyclo-oxygenase-1) and COX-2, NAD{sup +}-dependent histone deacetylase SIRT1 (sirtuin 1) and QR2 (quinone reductase 2). Nonetheless, the health benefits elicited by resveratrol as a direct result of these interactions with molecular targets have been questioned, since it is rapidly and extensivelymore » metabolized to sulfate and glucuronide conjugates, resulting in low plasma concentrations. To help resolve these issues, we tested the ability of resveratrol and its metabolites to modulate the function of some known targets in vitro. In the present study, we have shown that COX-1, COX-2 and QR2 are potently inhibited by resveratrol, and that COX-1 and COX-2 are also inhibited by the resveratrol 4{prime}-O-sulfate metabolite. We determined the X-ray structure of resveratrol bound to COX-1 and demonstrate that it occupies the COX active site similar to other NSAIDs (non-steroidal anti-inflammatory drugs). Finally, we have observed that resveratrol 3- and 4?-O-sulfate metabolites activate SIRT1 equipotently to resveratrol, but that activation is probably a substrate-dependent phenomenon with little in vivo relevance. Overall, the results of this study suggest that in vivo an interplay between resveratrol and its metabolites with different molecular targets may be responsible for the overall beneficial health effects previously attributed only to resveratrol itself.« less

Analysis of the Mitochondrial Genome in Hypomyces aurantius Reveals a Novel Twintron Complex in Fungi.

PubMed

Deng, Youjin; Zhang, Qihui; Ming, Ray; Lin, Longji; Lin, Xiangzhi; Lin, Yiying; Li, Xiao; Xie, Baogui; Wen, Zhiqiang

2016-06-30

Hypomyces aurantius is a mycoparasite that causes cobweb disease, a most serious disease of cultivated mushrooms. Intra-species identification is vital for disease control, however the lack of genomic data makes development of molecular markers challenging. Small size, high copy number, and high mutation rate of fungal mitochondrial genome makes it a good candidate for intra and inter species differentiation. In this study, the mitochondrial genome of H. H.a0001 was determined from genomic DNA using Illumina sequencing. The roughly 72 kb genome shows all major features found in other Hypocreales: 14 common protein genes, large and small subunit rRNAs genes and 27 tRNAs genes. Gene arrangement comparison showed conserved gene orders in Hypocreales mitochondria are relatively conserved, with the exception of Acremonium chrysogenum and Acremonium implicatum. Mitochondrial genome comparison also revealed that intron length primarily contributes to mitogenome size variation. Seventeen introns were detected in six conserved genes: five in cox1, four in rnl, three in cob, two each in atp6 and cox3, and one in cox2. Four introns were found to contain two introns or open reading frames: cox3-i2 is a twintron containing two group IA type introns; cox2-i1 is a group IB intron encoding two homing endonucleases; and cox1-i4 and cox1-i3 both contain two open reading frame (ORFs). Analyses combining secondary intronic structures, insertion sites, and similarities of homing endonuclease genes reveal two group IA introns arranged side by side within cox3-i2. Mitochondrial data for H. aurantius provides the basis for further studies relating to population genetics and species identification.

Analysis of the Mitochondrial Genome in Hypomyces aurantius Reveals a Novel Twintron Complex in Fungi

PubMed Central

Deng, Youjin; Zhang, Qihui; Ming, Ray; Lin, Longji; Lin, Xiangzhi; Lin, Yiying; Li, Xiao; Xie, Baogui; Wen, Zhiqiang

2016-01-01

Hypomyces aurantius is a mycoparasite that causes cobweb disease, a most serious disease of cultivated mushrooms. Intra-species identification is vital for disease control, however the lack of genomic data makes development of molecular markers challenging. Small size, high copy number, and high mutation rate of fungal mitochondrial genome makes it a good candidate for intra and inter species differentiation. In this study, the mitochondrial genome of H. H.a0001 was determined from genomic DNA using Illumina sequencing. The roughly 72 kb genome shows all major features found in other Hypocreales: 14 common protein genes, large and small subunit rRNAs genes and 27 tRNAs genes. Gene arrangement comparison showed conserved gene orders in Hypocreales mitochondria are relatively conserved, with the exception of Acremonium chrysogenum and Acremonium implicatum. Mitochondrial genome comparison also revealed that intron length primarily contributes to mitogenome size variation. Seventeen introns were detected in six conserved genes: five in cox1, four in rnl, three in cob, two each in atp6 and cox3, and one in cox2. Four introns were found to contain two introns or open reading frames: cox3-i2 is a twintron containing two group IA type introns; cox2-i1 is a group IB intron encoding two homing endonucleases; and cox1-i4 and cox1-i3 both contain two open reading frame (ORFs). Analyses combining secondary intronic structures, insertion sites, and similarities of homing endonuclease genes reveal two group IA introns arranged side by side within cox3-i2. Mitochondrial data for H. aurantius provides the basis for further studies relating to population genetics and species identification. PMID:27376282

Late Results of Cox Maze III Procedure in Patients with Atrial Fibrillation Associated with Structural Heart Disease

PubMed Central

Gomes, Gustavo Gir; Gali, Wagner Luis; Sarabanda, Alvaro Valentim Lima; da Cunha, Claudio Ribeiro; Kessler, Iruena Moraes; Atik, Fernando Antibas

2017-01-01

Background Cox-Maze III procedure is one of the surgical techniques used in the surgical treatment of atrial fibrillation (AF). Objectives To determine late results of Cox-Maze III in terms of maintenance of sinus rhythm, and mortality and stroke rates. Methods Between January 2006 and January 2013, 93 patients were submitted to the cut-and-sew Cox-Maze III procedure in combination with structural heart disease repair. Heart rhythm was determined by 24-hour Holter monitoring. Procedural success rates were determined by longitudinal methods and recurrence predictors by multivariate Cox regression models. Results Thirteen patients that obtained hospital discharge alive were excluded due to lost follow-up. The remaining 80 patients were aged 49.9 ± 12 years and 47 (58.7%) of them were female. Involvement of mitral valve and rheumatic heart disease were found in 67 (83.7%) and 63 (78.7%) patients, respectively. Seventy patients (87.5%) had persistent or long-standing persistent AF. Mean follow-up with Holter monitoring was 27.5 months. There were no hospital deaths. Sinus rhythm maintenance rates were 88%, 85.1% and 80.6% at 6 months, 24 months and 36 months, respectively. Predictors of late recurrence of AF were female gender (HR 3.52; 95% CI 1.21-10.25; p = 0.02), coronary artery disease (HR 4.73 95% CI 1.37-16.36; p = 0.01) and greater left atrium diameter (HR 1.05; 95% CI 1.01-1.09; p = 0.02). Actuarial survival was 98.5% at 12, 24 and 48 months and actuarial freedom from stroke was 100%, 100% and 97.5% in the same time frames. Conclusions The Cox-Maze III procedure, in our experience, is efficacious for sinus rhythm maintenance, with very low late mortality and stroke rates. PMID:28678926

New Coumarin Derivatives as Potent Selective COX-2 Inhibitors: Synthesis, Anti-Inflammatory, QSAR, and Molecular Modeling Studies.

PubMed

Dawood, Dina H; Batran, Rasha Z; Farghaly, Thoraya A; Khedr, Mohammed A; Abdulla, Mohamed M

2015-12-01

Two new series of coumarin derivatives incorporating thiazoline and thiazolidinone moieties were designed, synthesized, and investigated in vivo for their anti-inflammatory activities using the carrageenan-induced rat paw edema model and in vitro for their inhibitory activities against the human cyclooxygenase (COX)-1 and COX-2 isoforms. Most of the synthesized compounds demonstrated exceptionally high in vivo anti-inflammatory activity and displayed superior GI safety profiles (0-7% ulceration) as compared to indomethacin. All the bioactive compounds showed in vitro high affinity and selectivity toward the COX-2 isoenzyme, compared to the reference celecoxib with IC50 values ranging from 0.31 to 0.78 μM. The ethyl thiosemicarbazone 2b, thiazoline derivatives 3a, 3b, 5b, 6a, and 7f, and the thiazolidinone compounds 8b and 9a showed the highest in vivo and in vitro anti-inflammatory activities with remarkable COX-2 selectivity. Quantitative structure-activity relationship study (QSAR) was done and resulted in a highly predictive power R(2) (0.908). A molecular docking study revealed a relationship between the docking affinity and the biological results. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Short (≤ 1 mm) positive surgical margin and risk of biochemical recurrence after radical prostatectomy.

PubMed

Shikanov, Sergey; Marchetti, Pablo; Desai, Vikas; Razmaria, Aria; Antic, Tatjana; Al-Ahmadie, Hikmat; Zagaja, Gregory; Eggener, Scott; Brendler, Charles; Shalhav, Arieh

2013-04-01

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: It has been suggested that a very short positive margin does not confer additional risk of BCR after radical prostatectomy. This study shows that even very short PSM is associated with increased risk of BCR. To re-evaluate, in a larger cohort with longer follow-up, our previously reported finding that a positive surgical margin (PSM) ≤ 1 mm may not confer an additional risk for biochemical recurrence (BCR) compared with a negative surgical margin (NSM). Margin status and length were evaluated in 2866 men treated with radical prostatectomy (RP) for clinically localized prostate cancer at our institution from 1994 to 2009. We compared the BCR-free survival probability of men with NSMs, a PSM ≤ 1 mm, and a PSM < 1 mm using the Kaplan-Meier method and a Cox regression model adjusted for preoperative prostate-specific antigen (PSA) level, age, pathological stage and pathological Gleason score (GS). Compared with a NSM, a PSM ≤ 1 mm was associated with 17% lower 3-year BCR-free survival for men with pT3 and GS ≥ 7 tumours and a 6% lower 3-year BCR-free survival for men with pT2 and GS ≤ 6 tumours (log-rank P < 0.001 for all). In the multivariate model, a PSM ≤ 1 mm was associated with a probability of BCR twice as high as that for a NSM (hazard ratio [HR] 2.2), as were a higher PSA level (HR 1.04), higher pathological stage (HR 2.7) and higher pathological GS (HR 3.7 [all P < 0.001]). In men with non-organ-confined or high grade prostate cancer, a PSM ≤ 1 mm has a significant adverse impact on BCR rates. © 2012 The Authors. BJU International © 2012 BJU International.

O-desmethylquinine as a cyclooxygenase-2 (COX-2) inhibitors using AutoDock Vina

NASA Astrophysics Data System (ADS)

Damayanti, Sophi; Mahardhika, Andhika Bintang; Ibrahim, Slamet; Chong, Wei Lim; Lee, Vannajan Sanghiran; Tjahjono, Daryono Hadi

2014-10-01

Computational approach was employed to evaluate the biological activity of novel cyclooxygenase-2 COX-2 inhibitor, O-desmethylquinine, in comparison to quinine as common inhibitor which can also be used an agent of antipyretic, antimalaria, analgesic and antiinflamation. The molecular models of the compound were constructed and optimized with the density function theory with at the B3LYP/6-31G (d,p) level using Gaussian 09 program. Molecular docking studies of the compounds were done to obtain the COX-2 complex structures and their binding energies were analyzed using the AutoDock Vina. The results of docking of the two ligands were comparable and cannot be differentiated from the energy scoring function with AutoDock Vina.

Microwave absorption enhancement, magnetic coupling and ab initio electronic structure of monodispersed (Mn1-xCox)3O4 nanoparticles

NASA Astrophysics Data System (ADS)

Zhao, Pengfei; Liang, Chongyun; Gong, Xiwen; Gao, Ran; Liu, Jiwei; Wang, Min; Che, Renchao

2013-08-01

Monodispersed manganese oxide (Mn1-xCox)3O4 (0 <= x <= 0.5) nanoparticles, less than 10 nm size, are respectively synthesized via a facile thermolysis method at a rather low temperature, ranging from 90 to 100 °C, without any inertia gas for protection. The influences of the Co dopant content on the critical reaction temperature required for the nanoparticle formation, electronic band structures, magnetic properties, and the microwave absorption capability of (Mn1-xCox)3O4 are comprehensively investigated by means of both experimental and theoretical approaches including powder X-ray diffraction (XRD), electron energy loss spectroscopy (EELS), super conductivity quantum interference device (SQUID) examination, and first-principle simulations. Co is successfully doped into the Mn atomic sites of the (Mn1-xCox)3O4 lattice, which is further confirmed by EELS data acquired from one individual nanoparticle. Therefore, continuous solid solutions of well-crystallized (Mn1-xCox)3O4 products are achieved without any impurity phase or phase separation. With increases in the Co dopant concentration x from 0 to 0.5, the lattice parameters change systemically, where the overall saturation magnetization at 30 K increases due to the more intense coupling of the 3d electrons between Mn and Co, as revealed by simulations. The microwave absorption properties of the (Mn1-xCox)3O4 nanoparticles are examined between 2 and 18 GHz. The maximum absorption peak -11.0 dB of the x = 0 sample is enhanced to -11.5 dB for x = 0.2, -12.7 dB for x = 0.25, -15.6 dB for x = 0.33, and -24.0 dB for x = 0.5 respectively, suggesting the Co doping effects. Our results might provide novel insights into the understanding of the influences of metallic ion doping on the electromagnetic properties of metallic oxide nanomaterials.Monodispersed manganese oxide (Mn1-xCox)3O4 (0 <= x <= 0.5) nanoparticles, less than 10 nm size, are respectively synthesized via a facile thermolysis method at a rather low temperature, ranging from 90 to 100 °C, without any inertia gas for protection. The influences of the Co dopant content on the critical reaction temperature required for the nanoparticle formation, electronic band structures, magnetic properties, and the microwave absorption capability of (Mn1-xCox)3O4 are comprehensively investigated by means of both experimental and theoretical approaches including powder X-ray diffraction (XRD), electron energy loss spectroscopy (EELS), super conductivity quantum interference device (SQUID) examination, and first-principle simulations. Co is successfully doped into the Mn atomic sites of the (Mn1-xCox)3O4 lattice, which is further confirmed by EELS data acquired from one individual nanoparticle. Therefore, continuous solid solutions of well-crystallized (Mn1-xCox)3O4 products are achieved without any impurity phase or phase separation. With increases in the Co dopant concentration x from 0 to 0.5, the lattice parameters change systemically, where the overall saturation magnetization at 30 K increases due to the more intense coupling of the 3d electrons between Mn and Co, as revealed by simulations. The microwave absorption properties of the (Mn1-xCox)3O4 nanoparticles are examined between 2 and 18 GHz. The maximum absorption peak -11.0 dB of the x = 0 sample is enhanced to -11.5 dB for x = 0.2, -12.7 dB for x = 0.25, -15.6 dB for x = 0.33, and -24.0 dB for x = 0.5 respectively, suggesting the Co doping effects. Our results might provide novel insights into the understanding of the influences of metallic ion doping on the electromagnetic properties of metallic oxide nanomaterials. Electronic supplementary information (ESI) available: Fig. S1. A digital photo showing the large-scale synthesis of our monodispersed (Mn1-xCox)3O4 Fig. S2. Microwave absorption measurements; Fig. S3. Schematic diagram of the microwave absorption mechanism of the (Mn1-xCox)3O4. See DOI: 10.1039/c3nr02287k

The Reliability and Validity of the Power-Load-Margin Inventory: A Rasch Analysis.

PubMed

Hardigan, Patrick C; Cohen, Stanley R; Hagen, Kathleen P

2015-01-01

Margin is a function of the relationship of stress to strength. The greater the margin, the more likely students are able to successfully navigate academic structures. This study examined the psychometric properties of a newly created instrument designed to measure margin - the Power-Load-Margin Inventory (PLMI). The PLMI was created using eight domains: (A) Student's aptitude and ability, (B) Course structure, (C) External motivation, (D) Student health, (E) Instructor style, (F) Internal motivation, (G) Life opportunities, and (H) University support structure. A three-point response scale was used to measure the domains: (1) stress, (2) neither stress nor strength, and (3) strength. The PLMI was administered to 586 medical, dental, and pharmacy students. A Rasch rating scale model was used to examine the psychometric properties of the PLMI. The PLMI demonstrated acceptable psychometric properties for use with pharmacy, dental, and medical students. The PLMI's primary weakness was with the subscales' reliability. We attribute this to the small number of items per subscale.

Evolution of Devonian carbonate-shelf margin, Nevada

USGS Publications Warehouse

Morrow, J.R.; Sandberg, C.A.

2008-01-01

The north-trending, 550-km-long Nevada segment of the Devonian carbonate-shelf margin, which fringed western North America, evidences the complex interaction of paleotectonics, eustasy, biotic changes, and bolide impact-related influences. Margin reconstruction is complicated by mid-Paleozoic to Paleogene compressional tectonics and younger extensional and strike-slip faulting. Reports published during the past three decades identify 12 important events that influenced development of shelf-margin settings; in chronological order, these are: (1) Early Devonian inheritance of Silurian stable shelf inargin, (2) formation of Early to early Middle 'Devonian shelf-margin basins, (3) propradation of later Middle Devonian shelf margin, (4) late Middle Devonian Taghanic ondap and continuing long-term Frasnian transgression, (5) initiation of latest Middle Devonian to early Frasnian proto-Antler orogenic forebulge, (6) mid-Frasnian Alamo Impact, (7) accelerated development of proto-Antler forebulge and backbulge Pilot basin, (8) global late Frasnian sentichatovae sea-level rise, (9) end-Frasnian sea-level fluctuations and ensuing mass extinction, (10) long-term Famennian regression and continept-wide erosion, (11) late Famennian emergence: of Ahtler orogenic highlands, and (12) end-Devonian eustatic sea-level fall. Although of considerable value for understanding facies relationships and geometries, existing standard carbonate platform-margin models developed for passive settings else-where do not adequately describe the diverse depositional and, structural settings along the Nevada Devonian platform margin. Recent structural and geochemical studies suggest that the Early to Middle Devonian-shelf-margin basins may have been fault-bound and controlled by inherited Precambrian structure. Subsequently, the migrating latest Middle to Late Devonian Antler orogenic forebulge exerted a dominant control on shelf-margin position, morphology, and sedimentation. ??Geological Society of America.

Quantitative calculation and numerical modeling of the conjugate margins of the South China Sea

NASA Astrophysics Data System (ADS)

Dong, D.; Pérez-Gussinyé, M.; Wang, W.; Bai, Y.

2017-12-01

South China margin rifted on the tectonic setting of the early active continental margin since Cenozoic. The present South China Sea (SCS) opened at 32 Ma and showed propagation from east to west, with different crustal and sedimentary structures at the conjugate continental margins. Based on the latest high-quality multi-channel seismic data, bathymetric data, and other obtained seismic profiles, the asymmetric characteristics between the conjugate margins of the SCS are revealed. Spatial variation of morphology, basement structure and marginal faults are discovered among the SCS margin profiles. We calculate the lithospheric stretching factors and analyze the anomalous post-rift subsidence from two typical seismic profiles in the conjugate margins of the SCS, with integrated method of 2D forward and inversion based on flexural-cantilever model. We propose a differential extension model to explain the spatial differences in the SCS margins and emphasize the role of detachment fault in evolutionary process. Numerical modeling has a great advantage in studying the rifted margin formation mechanism. Dynamic modeling for the formation of asymmetric conjugate margins of the SCS is carried out by solving the thermal-mechanical equation, based on the viscoelastic-plastic model. The results show that the width and symmetry of the margin are controlled by the crustal rheological structure and sedimentation rate. Crust with lower strength is prone to distributed and persistent faulting instead of strain localization, which results in the wider margin. On the contrary, the stronger crust would generate large faults and lead to strain localization in a small amount of them, easier to form narrow continental margin. Large sediment loading is favorable for the development of large faults, meanwhile, the subsequent thermal effect reduces the crustal viscosity. A sudden transition zone of sedimentation rate is prone to strain localization and accelerates the crust rift, which may affect the future break-up. The numerical modeling with full dynamics in SCS needs a further investigation. Acknowledge: This study was supported by the National Natural Science Foundation of China (No. 41476042, 41506055 )

Future risk of labour market marginalization in young suicide attempters--a population-based prospective cohort study.

PubMed

Niederkrotenthaler, Thomas; Tinghög, Petter; Alexanderson, Kristina; Dahlin, Marie; Wang, Mo; Beckman, Karin; Gould, Madeleine; Mittendorfer-Rutz, Ellenor

2014-10-01

Research on future labour market marginalization following suicide attempt at young age is scarce. We investigated the effects of suicide attempts on three labour market outcomes: unemployment, sickness absence and disability pension. We conducted a prospective cohort study based on register linkage of 1,613,816 individuals who in 1994 were 16-30 years old and lived in Sweden. Suicide attempters treated in inpatient care during the 3 years preceding study entry, i.e. 1992-94 (N=5649) were compared with the general population of the same age without suicide attempt between 1973 and 2010 (n=1,608,167). Hazard ratios (HRs) for long-term unemployment (>180 days), sickness absence (>90 days) and disability pension in 1995-2010 were calculated by Cox regression models, adjusted for a number of parental and individual risk markers, and stratified for previous psychiatric inpatient care not due to suicide attempt. The risks for unemployment [HR 1.58; 95% confidence interval (CI) 1.52-1.64], sickness absence (HR 2.16; 2.08-2.24) and disability pension (HR 4.57; 4.34-4.81) were considerably increased among suicide attempters. There was a dose-response relationship between number of suicide attempts and the risk of disability pension, for individuals both with or without previous psychiatric hospitalizations not due to suicide attempts. No such relationship was present with regard to unemployment. This study highlights the strong association of suicide attempts with future marginalization from the labour market, particularly for outcomes that are based on a medical assessment. Studies that focus only on unemployment may largely underestimate the true detrimental impact of suicide attempt on labour market marginalization. © The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Spatial working memory in Wistar rats: brain sex differences in metabolic activity.

PubMed

Méndez-López, Magdalena; Méndez, Marta; López, Laudino; Arias, Jorge L

2009-05-29

Several works have shown that males and females differ in the ability to learn spatial locations in mazes. In this study, we used the Morris water maze to assess the acquisition of a spatial working memory (WM) task in adult male and female Wistar rats. The task consisted of a paired sample procedure made up of two daily identical trials, sample and retention. To study the oxidative metabolic activity of some brain limbic system regions after the WM task, we applied the cytochrome oxidase (COx) histochemistry. In addition to the experimental groups, free swimming control groups and untrained naïve groups were added to explore the COx changes not specific to the learning process. Similar spatial performances were found between sexes as only one more sample and retention trials were needed in males to reduce the escape latencies significantly. Males showed decreased COx activity as compared to control groups in the medial prefrontal cortex (prelimbic and infralimbic regions) as well as in the lateral septum and dentate gyrus. Regarding females, an increase in COx activity was found in nucleus accumbens, ventral tegmental area and supramammillary region in relation to control groups. Overall, these findings suggest that the acquisition of the spatial WM task is mediated by different subsystems in a sex-dependent manner that points to the hippocampus as the central structure in males whereas other structures would be central in females.

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

PubMed Central

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

2013-01-01

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

A Receptor-Grounded Approach to Teaching Nonsteroidal Antiinflammatory Drug Chemistry and Structure-Activity Relationships

PubMed Central

2009-01-01

Objective To describe a receptor-based approach to promote learning about nonsteroidal anti-inflammatory drug (NSAID) chemistry, structure-activity relationships, and therapeutic decision-making. Design Three lessons on cyclooxygenase (COX) and NSAID chemistry, and NSAID therapeutic utility, were developed using text-based resources and primary medicinal chemistry and pharmacy practice literature. Learning tools were developed to assist students in content mastery. Assessment Student learning was evaluated via performance on quizzes and examinations that measured understanding of COX and NSAID chemistry, and the application of that knowledge to therapeutic problem solving. Conclusion Student performance on NSAID-focused quizzes and examinations documented the success of this approach. PMID:20221336

The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: The second clinical candidate having a shorter and favorable human half-life

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

Wang, Jane L.; Limburg, David; Graneto, Matthew J.

2012-05-29

In this Letter, we provide the structure-activity relationships, optimization of design, testing criteria, and human half-life data for a series of selective COX-2 inhibitors. During the course of our structure-based drug design efforts, we discovered two distinct binding modes within the COX-2 active site for differently substituted members of this class. The challenge of a undesirably long human half-life for the first clinical candidate 1t{sub 1/2} = 360 h was addressed by multiple strategies, leading to the discovery of 29b-(S) (SC-75416) with t{sub 1/2} = 34 h.

Effusanin E suppresses nasopharyngeal carcinoma cell growth by inhibiting NF-κB and COX-2 signaling.

PubMed

Zhuang, Mingzhu; Zhao, Mouming; Qiu, Huijuan; Shi, Dingbo; Wang, Jingshu; Tian, Yun; Lin, Lianzhu; Deng, Wuguo

2014-01-01

Rabdosia serra is well known for its antibacterial, anti-inflammatory and antitumor activities, but no information has been available for the active compounds derived from this plant in inhibiting human nasopharyngeal carcinoma (NPC) cell growth. In this study, we isolated and purified a natural diterpenoid from Rabdosia serra and identified its chemical structure as effusanin E and elucidated its underlying mechanism of action in inhibiting NPC cell growth. Effusanin E significantly inhibited cell proliferation and induced apoptosis in NPC cells. Effusanin E also induced the cleavage of PARP, caspase-3 and -9 proteins and inhibited the nuclear translocation of p65 NF-κB proteins. Moreover, effusanin E abrogated the binding of NF-κB to the COX-2 promoter, thereby inhibiting the expression and promoter activity of COX-2. Pretreatment with a COX-2 or NF-κB-selective inhibitor (celecoxib or ammonium pyrrolidinedithiocarbamate) had an additive effect on the effusanin E-mediated inhibition of proliferation, while pretreatment with an activator of NF-κB/COX-2 (lipopolysaccharides) abrogated the effusanin E-mediated inhibition of proliferation. Effusanin E also significantly suppressed tumor growth in a xenograft mouse model without obvious toxicity, furthermore, the expression of p50 NF-κB and COX-2 were down-regulated in the tumors of nude mice. These data suggest that effusanin E suppresses p50/p65 proteins to down-regulate COX-2 expression, thereby inhibiting NPC cell growth. Our findings provide new insights into exploring effusanin E as a potential therapeutic compound for the treatment of human nasopharyngeal carcinoma.

Stratal stacking patterns and tectono-sedimentary evolution of hyperextended magma-poor rifted margins

NASA Astrophysics Data System (ADS)

Ribes, C.; Gillard, M.; Epin, M. E.; Ghienne, J. F.; Manatschal, G.; Karner, G. D.; Johnson, C. A.

2016-12-01

Research on the formation and evolution of deep-water rifted margins has undergone a major paradigm shift in recent years. An increasing number of studies of present-day and fossil rifted margins allow us to identify and characterize the structural architecture of the most distal parts of rifted margins, the so-called hyperextended, magma-poor rifted margins. However, at present, little is known about the depositional environments, sedimentary facies, stacking patterns, subsidence and thermal history within these domains. In this context, characterizing the stratal stacking patterns and understanding their spatial and temporal evolution is a new challenge. The major difficulty comes from the fact that the observed stratigraphic geometries and facies relationships are a result of the complex interplay between sediment supply and available accommodation, which is controlled by not only the regional generation of accommodation, but also by local tectono-magmatic processes. These parameters are poorly constrained or even sufficiently known in these tectonic settings. Indeed, the complex structural evolution of hyperextended magma-poor rifted margins, including the development of poly-phase in-sequence and out of sequence extensional detachment faults and associated mantle exhumation and magmatic activity, can generate complex accommodation patterns over a highly structured top basement. The presentation summarizes early results concerning the controlling parameters on ultra-deep water stratigraphic stacking patterns and to provide a conceptual framework. This observation-driven approach combines fieldwork from fossil Alpine Tethys margins exposed in the Alps and the analysis of seismic reflection data from present-day deep water rifted margins such as the Australian-Antarctic, East India and Iberia-Newfoundland margins.

[Impact of Gleason score on biochemical recurrence free survival after radical prostatectomy with positive surgical margins].

PubMed

Roux, V; Eyraud, R; Brureau, L; Gourtaud, G; Senechal, C; Fofana, M; Blanchet, P

Research of predictive factors of biochemical recurrence to guide the establishment of an adjuvant treatment after radical prostatectomy for cancer with positive surgical margins. A retrospective cohort of 1577 afro-caribbean patients undergoing radical prostatectomy operated between 1st January 2000 and 1st July 2013 was analyzed. In this cohort, 406 patients had positive surgical margin, we excluded 11 patients who received adjuvant therapy (radiotherapy, hormonotherapy, radio-hormonotherapy) and 2 patients for whom histological analysis of the surgical specimen was for a pT4 pathological stage. After a descriptive analysis, we used a Cox model to look for predictors of survival without biochemical recurrence then, depending on the significant variables, we separated our population into six groups: stage pT2 with Gleason score≤3+4 (group 1), stage pT2 with a score of Gleason≥4+3 (group 2), stage pT3a with a Gleason core≤3+4 (group 3), pT3a stage with a score of Gleason≥4+3 (group 4), stage pT3b with a Gleason score≤3+4 (group 5) and stage pT3b Gleason≥with a score of 4+3 (group 6) and compared survival without biochemical recurrence using a log rank test. After radical prostatectomy with surgical margins with an anatomopathological stage≤pT3b, a Gleason score≥4+3 had a pejorative survival without biochemical recurrence than pathological stage (P<0.001). In multivariate analysis, predictors of survival without biochemical recurrence after radical prostatectomy with positive surgical margins were the majority Gleason postoperative (P<0.0001), pathological stage (P=0.049) adjusted preoperative PSA (P=0.826), with the body mass index (BMI) (P=0.59) and tumor volume (P=0.95). A high postoperatively Gleason score (≥4+3) has a better predictive value of biochemical recurrence than pathological stage pT2 or pT3 at the patients having been treated for prostate cancer by radical prostatectomy with positive surgical margins. 4. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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

PubMed Central

Sundar, Durai; Thorat, Sunil S.

2014-01-01

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

[Spatio-temporal distribution of carabids and spiders between semi-natural field margin and the adjacent crop fields in agricultural landscape].

PubMed

Zhang, Xu Zhu; Han, Yin; Yu, Zhen Rong; Liu, Yun Hui

2017-06-18

This study was conducted before and after harvesting of wheat and maize in a typical agricultural landscape of the North China Plain. We investigated the diversity of two important natural enemy groups, carabids and spiders, using pitfall traps at crop field margin with different vegetation structures and their neighboring crop field. Throughout the comparison of the spatial and temporal distribution of the diversity of carabids and spiders in field margin and neighboring field, and the investigation of the relationship between arthropod communities and vegetation structure, this study aimed to understand the role of semi-natural field margin in biodiversity conservation of different natural enemy taxa. Results showed that the abundance of spiders was significantly higher in field margin than in neighboring fields over the entire period. No significant difference of the diversity of carabids in field margin and crop field was observed, but the community composition was different. Number of spider families increased in field margin but deceased in crop field after harvesting, indicating a migration activity between field and field margin. Vegetation structure in the field margin had different association with carabids than with spiders, with diversity of dominant carabid species positively associated with herb coverage and negatively with wood coverage, while the diversity of spider family Linyphiidae was positively associated with herb coverage only. Semi-natural habitat benefited the conservation of the diversity of arthropod natural enemies in crop field via promoting their dispersal to crop field, while such impacts differed from different vegetation structures and varied from target beneficial natural enemy communities. Future studies should focus on in-depth understanding of the food and habitat source requirement of different natural enemy taxa, and hence to design suitable semi-natural habitats to maintain a high diversity of natural enemy communities.

MARGATS cruise: investigation of the deep internal structure and the heterogeneous margins of the Demerara plateau reveals a polyphased volcanic history

NASA Astrophysics Data System (ADS)

Graindorge, D.; Museur, T.; Roest, W. R.; Klingelhoefer, F.; Loncke, L.; Basile, C.; Poetisi, E.; Deverchere, J.; Heuret, A.; Jean-Frederic, L.; Perrot, J.

2017-12-01

The MARGATS scientific cruise was carried out from October 20th to November 16th 2016 on board the R/V L'Atalante, offshore Suriname and French Guiana. This cruise is part of a program dedicated to the geological investigation of the continental margin, including the Demerara plateau, following the GUYAPLAC (2003), IGUANES (2013) and DRADEM (2016) cruises. The aim of MARGATS was to image the internal structure of the Demerara plateau and its different margins using coincident deep penetrating wide angle refraction and multi channel reflection seismic (MCS) methods. During the MARGATS experiment 171 OBS deployments were distributed along 4 wide-angle lines. Along each wide-angle line we also recorded coincident MCS data using a 3 km long 480 channel streamer. The dataset was completed by three MCS lines along the eastern part of the Demerara plateau. MCS MAR007 line which is coincident with line OBS MAR-3 was extended on land by 13 land stations deployed along the Maroni River. This line, together with MCS MAR001 and the coincident OBS MAR-1 line reveal the highly homogeneous deep structure of the internal part of the plateau. MCS MAR005 line, which is coincident with OBS MAR-2, MCS MAR006 line coincident with OBS MAR-4, MCS MAR002, MCS MAR003 and MCS MAR004 helps to elucidate the structural complexity of the northern transform margin and the eastern divergent margin of the plateau. These new datasets are highly complementary to the DRADEM dredge results which provide evidence for mid Jurassic volcanic rocks along the plateau and significant vertical displacements along the transform margin. These results allow to interpret the plateau as the remains of a huge jurassic volcanic divergent margin along the Central Atlantic ocean to the west, possibly remobilized during the cretaceous opening of the Equatorial Atlantic ocean as an highly oblique margin to the north and a divergent margin to the east in persistent presence of volcanism. This AGU session will be a great opportunity to present the exceptional quality of the seismic data, after the initial processing steps and how these data are conditioning a new understanding of the Demarara plateau and its margins which implies the hypothetic role of a new hot spot shaping the complex polyphased history of the structure.

Tectonic evolution and extension at the Møre Margin - Offshore mid-Norway

NASA Astrophysics Data System (ADS)

Theissen-Krah, S.; Zastrozhnov, D.; Abdelmalak, M. M.; Schmid, D. W.; Faleide, J. I.; Gernigon, L.

2017-11-01

Lithospheric stretching is the key process in forming extensional sedimentary basins at passive rifted margins. This study explores the stretching factors, resulting extension, and structural evolution of the Møre segment on the Mid-Norwegian continental margin. Based on the interpretation of new and reprocessed high-quality seismic, we present updated structural maps of the Møre margin that show very thick post-rift sediments in the central Møre Basin and extensive sill intrusion into the Cretaceous sediments. A major shift in subsidence and deposition occurred during mid-Cretaceous. One transect across the Møre continental margin from the Slørebotn Subbasin to the continent-ocean boundary is reconstructed using the basin modelling software TecMod. We test different initial crustal configurations and rifting events and compare our structural reconstruction results to stretching factors derived both from crustal thinning and the classical backstripping/decompaction approach. Seismic interpretation in combination with structural reconstruction modelling does not support the lower crustal bodies as exhumed and serpentinised mantle. Our extension estimate along this transect is 188 ± 28 km for initial crustal thickness varying between 30 and 40 km.

Apixaban Plus Mono Versus Dual Antiplatelet Therapy in Acute Coronary Syndromes: Insights From the APPRAISE-2 Trial.

PubMed

Hess, Connie N; James, Stefan; Lopes, Renato D; Wojdyla, Daniel M; Neely, Megan L; Liaw, Danny; Hagstrom, Emil; Bhatt, Deepak L; Husted, Steen; Goodman, Shaun G; Lewis, Basil S; Verheugt, Freek W A; De Caterina, Raffaele; Ogawa, Hisao; Wallentin, Lars; Alexander, John H

2015-08-18

Bleeding limits anticoagulant treatment in patients with acute coronary syndromes (ACS). We investigated whether background concomitant antiplatelet therapy influences the effects of apixaban after ACS. This study examined high-risk ACS patients who were treated with aspirin or aspirin plus clopidogrel and who were randomized to apixaban 5 mg twice daily or placebo. In a post-hoc analysis, we assessed whether the effect of apixaban on efficacy and safety outcomes varied by the concomitant antiplatelet regimen by using simple Cox modeling and marginal structural models with propensity scores and antiplatelet therapy as a time-dependent covariate. At baseline, of 7,364 patients, 16.3% (n = 1,202) were on aspirin alone, and 79.0% (n = 5,814) were on aspirin plus clopidogrel. A total of 19.2% (n = 1,415) switched antiplatelet therapy during follow-up. No differential effect of apixaban versus placebo was observed for the composite endpoint of cardiovascular death, myocardial infarction, and ischemic stroke in patients taking aspirin (12.21 per 100 patient-years vs. 13.21 per 100 patient-years; adjusted hazard ratio [HR]: 0.91; 95% confidence interval [CI]: 0.62 to 1.32) or aspirin plus clopidogrel (13.22 vs. 14.24; adjusted HR: 0.95; 95% CI: 0.78 to 1.14; p(interaction)= 0.84). Compared with placebo, apixaban increased Thrombolysis In Myocardial Infarction major bleeding in patients taking aspirin (1.48 vs. 0.25; adjusted HR: 6.62; 95% CI: 0.75 to 51.73) and in patients taking aspirin plus clopidogrel (2.58 vs. 1.02; adjusted HR: 2.44; 95% CI: 1.34 to 4.45; p(interaction)= 0.41). Similar results were obtained with marginal structural models and in patients treated with and without percutaneous coronary intervention. Post-ACS treatment with apixaban versus placebo showed no efficacy, but it increased bleeding regardless of concomitant therapy with aspirin alone or aspirin plus clopidogrel. (Apixaban for Prevention of Acute Ischemic Events 2 [APPRAISE-2]; NCT00831441). Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Post-processing of multi-model ensemble river discharge forecasts using censored EMOS

NASA Astrophysics Data System (ADS)

Hemri, Stephan; Lisniak, Dmytro; Klein, Bastian

2014-05-01

When forecasting water levels and river discharge, ensemble weather forecasts are used as meteorological input to hydrologic process models. As hydrologic models are imperfect and the input ensembles tend to be biased and underdispersed, the output ensemble forecasts for river runoff typically are biased and underdispersed, too. Thus, statistical post-processing is required in order to achieve calibrated and sharp predictions. Standard post-processing methods such as Ensemble Model Output Statistics (EMOS) that have their origins in meteorological forecasting are now increasingly being used in hydrologic applications. Here we consider two sub-catchments of River Rhine, for which the forecasting system of the Federal Institute of Hydrology (BfG) uses runoff data that are censored below predefined thresholds. To address this methodological challenge, we develop a censored EMOS method that is tailored to such data. The censored EMOS forecast distribution can be understood as a mixture of a point mass at the censoring threshold and a continuous part based on a truncated normal distribution. Parameter estimates of the censored EMOS model are obtained by minimizing the Continuous Ranked Probability Score (CRPS) over the training dataset. Model fitting on Box-Cox transformed data allows us to take account of the positive skewness of river discharge distributions. In order to achieve realistic forecast scenarios over an entire range of lead-times, there is a need for multivariate extensions. To this end, we smooth the marginal parameter estimates over lead-times. In order to obtain realistic scenarios of discharge evolution over time, the marginal distributions have to be linked with each other. To this end, the multivariate dependence structure can either be adopted from the raw ensemble like in Ensemble Copula Coupling (ECC), or be estimated from observations in a training period. The censored EMOS model has been applied to multi-model ensemble forecasts issued on a daily basis over a period of three years. For the two catchments considered, this resulted in well calibrated and sharp forecast distributions over all lead-times from 1 to 114 h. Training observations tended to be better indicators for the dependence structure than the raw ensemble.

Influence of Fe/Co ratio on structural and magnetic properties of (Fe100-xCox)84.5Nb5B8.5P2 alloy

NASA Astrophysics Data System (ADS)

Gehlot, K.; Kane, S. N.; Sinha, A. K.; Ghodke, N.; Varga, L. K.

2018-05-01

Structural and magnetic properties of a series of (Fe100-xCox)84.5Nb5B8.5P2 (x = 20, 40, 60) have been investigated respectively by using synchrotron x-ray diffraction and magnetic measurements. Results show that Fe/Co ratio: i) affects stability of the alloy against crystallization, ii) shows evidence for ordering, which has considerable effect on magnetic properties, iii) influences the grain diameter and volume fraction of the formed nano-grains range between 4.8 - 9.5 nm and 1.5 - 9 %, affects magnetic properties considerably. An empirical relation is obtained, which shows linear relationship between interatomic distances for 1st, 2nd co-ordination shell, suggests strong correlation between structural, magnetic properties.

Investigations on the electronic, structural, magnetic properties related to shape-memory behavior in Ti{sub 2}CoX (X=Al, Ga, In)

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

Wei, Xiao-Ping, E-mail: weixp2008@gmail.com; Chu, Yan-Dong; Sun, Xiao-Wei

2015-02-15

Highlights: • The analysis of phase stability trend is studied for Ti{sub 2}CoX(X = Al, Ga, In). • Ti{sub 2}CoGa is more suitable as shape memory alloy. • Total magnetic moments disappear with a increase of c/a ratio for all systems. • Density of states at the Fermi level are also shown. - Abstract: Using the full-potential local orbital minimum-basis method, we have performed a systematic investigations on the electronic, structural, and magnetic properties related to shape memory applications for Ti{sub 2}CoX (X=Al, Ga, In) alloys. Our results confirm that these alloys are half-metallic ferromagnets with total magnetic moment ofmore » 2μ{sub B} per formula unit in austenite phase, and undergo a martensitic transformation at low temperatures. The relative stabilities of the martensitic phases differ considerably between Ti{sub 2}CoX (X=Al, Ga, In). Details of the electronic structures suggest that the differences in hybridizations between the magnetic components are responsible for trends of phase. Quantitative estimates for the energetics and the magnetizations indicate that Ti{sub 2}CoGa is a promising candidate for shape memory applications.« less

Flower-like morphology of blue and greenish-gray ZnCoxAl2-xO4 nanopigments

NASA Astrophysics Data System (ADS)

Wahba, Adel Maher; Imam, N. G.; Mohamed, Mohamed Bakr

2016-02-01

In the present work, ZnCoxAl2 - xO4 (x = 0.00-1.50) nanosized pigments were synthesized for the first time by citrate-precursor autocombustion method and heat treatment at 900 °C. In this new nanopigment system the vacancies participate in the spinel structure since the divalent cobalt ions substitute the trivalent Al ions. Structural, microstructural and optical properties were investigated using XRD, FTIR, TEM, HRSEM, XRF, and PL techniques. XRD and FTIR spectra proved the formation of a pure cubic spinel phase. Size of the synthesized nano-crystals ranges from 15 to 60 nm, which is further confirmed with TEM micrographs. HRSEM confirms the microporous nature with flower-like morphology of the prepared nanopigments. Cation distribution has been suggested for the whole samples that matches quite well with XRD and IR experimental data. PL results show that the ZnCoxAl2 - xO4 pigments have good potential for use as a yellow-orange phosphor for displays and/or white light-emitting diodes.

OESbathy version 1.0: a method for reconstructing ocean bathymetry with generalized continental shelf-slope-rise structures

NASA Astrophysics Data System (ADS)

Goswami, A.; Olson, P. L.; Hinnov, L. A.; Gnanadesikan, A.

2015-09-01

We present a method for reconstructing global ocean bathymetry that combines a standard plate cooling model for the oceanic lithosphere based on the age of the oceanic crust, global oceanic sediment thicknesses, plus generalized shelf-slope-rise structures calibrated at modern active and passive continental margins. Our motivation is to develop a methodology for reconstructing ocean bathymetry in the geologic past that includes heterogeneous continental margins in addition to abyssal ocean floor. First, the plate cooling model is applied to maps of ocean crustal age to calculate depth to basement. To the depth to basement we add an isostatically adjusted, multicomponent sediment layer constrained by sediment thickness in the modern oceans and marginal seas. A three-parameter continental shelf-slope-rise structure completes the bathymetry reconstruction, extending from the ocean crust to the coastlines. Parameters of the shelf-slope-rise structures at active and passive margins are determined from modern ocean bathymetry at locations where a complete history of seafloor spreading is preserved. This includes the coastal regions of the North, South, and central Atlantic, the Southern Ocean between Australia and Antarctica, and the Pacific Ocean off the west coast of South America. The final products are global maps at 0.1° × 0.1° resolution of depth to basement, ocean bathymetry with an isostatically adjusted multicomponent sediment layer, and ocean bathymetry with reconstructed continental shelf-slope-rise structures. Our reconstructed bathymetry agrees with the measured ETOPO1 bathymetry at most passive margins, including the east coast of North America, north coast of the Arabian Sea, and northeast and southeast coasts of South America. There is disagreement at margins with anomalous continental shelf-slope-rise structures, such as around the Arctic Ocean, the Falkland Islands, and Indonesia.

Investigations of the Origin of the Magnetic Remanence in Late Pleistocene Lacustrine Sediments in the Mono Basin, CA

NASA Astrophysics Data System (ADS)

Vasquez, N.; Corley, A. D.

2015-12-01

In the Mono Basin, CA, fine sand, silt, and volcanic ash deposited in Pleistocene Lake Russell is exposed on the margin of Mono Lake, and on Paoha Island in the lake. The silt records the Mono Lake Excursion (MLE: Denham and Cox, 1971) and several tens of thousands of years of paleomagnetic secular variation (PSV: Denham and Cox, 1971; Liddicoat, 1976; Lund et al., 1988). The sediment is believed to be an accurate recorder of PSV because the MLE has the same signal at widely separated localities in the basin (Denham, 1974; Liddicoat and Coe, 1979; Liddicoat, 1992) with the exception at wave-cut cliffs on the southeast side of the lake (Coe and Liddicoat, 1994). Magnetite, titanomagnetite, and titanomaghemite are present in the sediment (Denham and Cox, 1971; Liddicoat, 1976; Liddicoat and Coe, 1979), which is glacial flour from the adjacent Sierra Nevada (Lajoie, 1968). X-rays of the sediment and lineation measurements show patterns of normal bedding with layers aligned such that the minimum axes are within 5-10 degrees of normal bedding, with 10 percent foliation and 1 percent lineation (Coe and Liddicoat, 1994). We explore reasons for the difference in part of the PSV record at the wave-cut cliffs beyond the interpretation of Coe and Liddicoat (1994) that paleomagnetic field strength is a controlling factor. Possibilities include the sedimentation rate - at localities on the margin of Mono Lake the rate is about 60 percent less than at the wave-cut cliffs - and lithology of the sediment. At Mill Creek on the northwest side of Mono Lake, the non-magnetic sediment fraction is coarser-grained than at the wave-cut cliffs by a factor of about two, and there is a similar difference in the total inorganic carbon (TIC) percentage by weight for the two localities. (Spokowski et al., 2011) Studies of the sediment at two localities in the basin where the Hilina Pali Excursion (Teanby et al., 2002) might be recorded (Wilson Creek and South Shore Cliffs; Liddicoat and Coe, 2013) and at an extension of the PSV record of Lund et al. (1988) show a similar pattern to the grain size distribution and TIC percentage described above. Additional measurements of the TIC in the sediments from both sides of Mono Lake for the intervals recording the possible HPE and PSV extension of Lund et al. (1988) are in progress and will be presented.

Effects of electroacupuncture on luteal regression and steroidogenesis in ovarian hyperstimulation syndrome model rat.

PubMed

Huang, Xuan; Chen, Li; Xia, You-Bing; Xie, Min; Sun, Qin; Yao, Bing

2018-03-15

Electroacupuncture (EA) is an effective and safe therapeutic method widely used for treating clinical diseases. Previously, we found that EA could decrease serum hormones and reduce ovarian size in ovarian hyperstimulation syndrome (OHSS) rat model. Nevertheless, the mechanisms that contribute to these improvements remain unclear. HE staining was used to count the number of corpora lutea (CL) and follicles. Immunohistochemical and ELISA were applied to examine luteal functional and structural regression. Immunoprecipitation was used for analyzing the interaction between NPY (neuropeptide Y) and COX-2; western blotting and qRT-PCR were used to evaluate the expressions of steroidogenic enzymes and PKA/CREB pathway. EA treatment significantly reduced the ovarian weight and the number of CL, also decreased ovarian and serum levels of PGE2 and COX-2 expression; increased ovarian PGF2α levels and PGF2α/PGE2 ratio; decreased PCNA expression and distribution; and increased cyclin regulatory inhibitor p27 expression to have further effect on the luteal formation, and promote luteal functional and structural regression. Moreover, expression of COX-2 in ovaries was possessed interactivity increased expression of NPY. Furthermore, EA treatment lowered the serum hormone levels, inhibited PKA/CREB pathway and decreased the expressions of steroidogenic enzymes. Hence, interaction with COX-2, NPY may affect the levels of PGF2α and PGE2 as well as impact the proliferation of granulosa cells in ovaries, thus further reducing the luteal formation, and promoting luteal structural and functional regression, as well as the ovarian steroidogenesis following EA treatment. EA treatment could be an option for preventing OHSS in ART. Copyright © 2018 Elsevier Inc. All rights reserved.

Population structure analysis of the neglected parasite Thelazia callipaeda revealed high genetic diversity in Eastern Asia isolates.

PubMed

Zhang, Xi; Shi, Ya Li; Han, Lu Lu; Xiong, Chen; Yi, Shi Qi; Jiang, Peng; Wang, Zeng Xian; Shen, Ji Long; Cui, Jing; Wang, Zhong Quan

2018-01-01

Thelazia callipaeda is the causative agent of thelaziasis in canids, felids and humans. However, the population genetic structure regarding this parasite remains unclear. In this study, we first explored the genetic variation of 32 T. callipaeda clinical isolates using the following multi-molecular markers: cox1, cytb, 12S rDNA, ITS1 and 18S rDNA. The isolates were collected from 13 patients from 11 geographical locations in China. Next, the population structure of T. callipaeda from Europe and other Asian countries was analyzed using the cox1 sequences collected during this study and from the GenBank database. In general, the Chinese clinical isolates of T. callipaeda expressed high genetic diversity. Based on the cox1 gene, a total of 21 haplotypes were identified. One only circulated in European countries (Hap1), while the other 20 haplotypes were dispersed in Korea, Japan and China. There were five nucleotide positions in the cox1 sequences that were confirmed as invariable among individuals from Europe and Asia, but the sequences were distinct between these two regions. Population differences between Europe and Asian countries were greater than those among China, Korea and Japan. The T. callipaeda populations from Europe and Asia should be divided into two separate sub-populations. These two groups started to diverge during the middle Pleistocene. Neutrality tests, mismatch distribution and Bayesian skyline plot (BSP) analysis all rejected possible population expansion of T. callipaeda. The Asian population of T. callipaeda has a high level of genetic diversity, but further studies should be performed to explore the biology, ecology and epidemiology of T. callipaeda.

Population structure analysis of the neglected parasite Thelazia callipaeda revealed high genetic diversity in Eastern Asia isolates

PubMed Central

Zhang, Xi; Shi, Ya Li; Han, Lu Lu; Xiong, Chen; Yi, Shi Qi; Jiang, Peng; Wang, Zeng Xian; Shen, Ji Long; Wang, Zhong Quan

2018-01-01

Background Thelazia callipaeda is the causative agent of thelaziasis in canids, felids and humans. However, the population genetic structure regarding this parasite remains unclear. Methodology/principal findings In this study, we first explored the genetic variation of 32 T. callipaeda clinical isolates using the following multi-molecular markers: cox1, cytb, 12S rDNA, ITS1 and 18S rDNA. The isolates were collected from 13 patients from 11 geographical locations in China. Next, the population structure of T. callipaeda from Europe and other Asian countries was analyzed using the cox1 sequences collected during this study and from the GenBank database. In general, the Chinese clinical isolates of T. callipaeda expressed high genetic diversity. Based on the cox1 gene, a total of 21 haplotypes were identified. One only circulated in European countries (Hap1), while the other 20 haplotypes were dispersed in Korea, Japan and China. There were five nucleotide positions in the cox1 sequences that were confirmed as invariable among individuals from Europe and Asia, but the sequences were distinct between these two regions. Population differences between Europe and Asian countries were greater than those among China, Korea and Japan. The T. callipaeda populations from Europe and Asia should be divided into two separate sub-populations. These two groups started to diverge during the middle Pleistocene. Neutrality tests, mismatch distribution and Bayesian skyline plot (BSP) analysis all rejected possible population expansion of T. callipaeda. Conclusions The Asian population of T. callipaeda has a high level of genetic diversity, but further studies should be performed to explore the biology, ecology and epidemiology of T. callipaeda. PMID:29324738

Measuring Institutional Quality in Head and Neck Surgery Using Hospital-Level Data: Negative Margin Rates and Neck Dissection Yield.

PubMed

Schoppy, David W; Rhoads, Kim F; Ma, Yifei; Chen, Michelle M; Nussenbaum, Brian; Orosco, Ryan K; Rosenthal, Eben L; Divi, Vasu

2017-11-01

Negative margins and lymph node yields (LNY) of 18 or more from neck dissections in patients with head and neck squamous cell carcinomas (HNSCC) have been associated with improved patient survival. It is unclear whether these metrics can be used to identify hospitals with improved outcomes. To determine whether 2 patient-level metrics would predict outcomes at the hospital level. A retrospective review of records from the National Cancer Database (NCDB) was used to identify patients who underwent primary surgery and concurrent neck dissection for HNSCC between 2004 and 2013. The percentage of patients at each hospital with negative margins on primary resection and an LNY 18 or more from a neck dissection was quantified. Cox proportional hazard models were used to define the association between hospital performance on these metrics and overall survival. Margin status and lymph node yield at hospital level. Overall survival (OS). We identified 1008 hospitals in the NCDB where 64 738 patients met inclusion criteria. Of the 64 738 participants, 45 170 (69.8%) were men and 19 568 (30.2%) were women. The mean SD age of included patients was 60.5 (12.0) years. Patients treated at hospitals attaining the combined metric of a 90% or higher negative margin rate and 80% or more of cases with LNYs of 18 or more experienced a significant reduction in mortality (hazard ratio [HR] 0.93; 95% CI, 0.89-0.98). This benefit in survival was independent of the patient-level improvement associated with negative margins (HR, 0.73; 95% CI, 0.71-0.76) and LNY of 18 or more (HR, 0.85; 95% CI, 0.83-0.88). Including these metrics in the model neutralized the association of traditional measures of hospital quality (volume and teaching status). Treatment at hospitals that attain a high rate of negative margins and LNY of 18 or more is associated with improved survival in patients undergoing surgery for HNSCC. These surgical outcome measures predicted outcomes independent of traditional, but generally nonmodifiable characteristics. Tracking of these metrics may help identify high-quality centers and provide guidance for institution-level quality improvement.

Geodynamic models of the Wilson Cycle: From rifts to mountains to rifts

NASA Astrophysics Data System (ADS)

Buiter, Susanne; Tetreault, Joya; Torsvik, Trond

2015-04-01

The Wilson Cycle theory that oceans close and reopen along the former suture is a fundamental concept in plate tectonics. The theory suggests that subduction initiates at a passive margin, closing the ocean, and that future continental extension localises at the ensuing collision zone. Each stage of the Wilson Cycle will therefore be characterised by inherited structural and thermal heterogeneities. Here we investigate the role of Wilson Cycle inheritance by considering the influence of (1) passive margin structure on continental collision and (2) collision zones on passive margin formation. Passive margins may be preferred locations for subduction initiation because inherited faults and areas of exhumed serpentinized mantle may weaken a margin enough to localise shortening. If subduction initiates at a passive margin, the shape and structure of the passive margins will affect future continental collision. Our review of present-day passive margins along the Atlantic and Indian Oceans reveals that most passive margins are located on former collision zones. Continental break-up occurs on relatively young sutures, such as Morocco-Nova Scotia, and on very old sutures, such as the Greenland-Labrador and East Antarctica-Australia systems. This implies that it is not always post-collisional collapse that initiates the extensional phase of a Wilson Cycle. We highlight the impact of collision zone inheritance on continental extension and rifted margin architecture. We show numerical experiments of one Wilson Cycle of subduction, collision, and extension. Subduction initiates at a tapered passive margin. Closure of a 60 Ma ocean leads to continental collision and slab break-off, followed by some tens of kilometres of slab eduction. Mantle flow above the sinking detached slab enhances deformation in the rift area. The resulting rift exposes not only continental crust, but also subduction-related sediments and oceanic crust remnants. Renewed subduction in the post-collision phase is enabled by lithosphere delamination and slab rollback, leading to back-arc extension in a style similar to the Tyrrhenian Sea.

Deep structure of the continental margin and basin off Greater Kabylia, Algeria - New insights from wide-angle seismic data modeling and multichannel seismic interpretation

NASA Astrophysics Data System (ADS)

Aïdi, Chafik; Beslier, Marie-Odile; Yelles-Chaouche, Abdel Karim; Klingelhoefer, Frauke; Bracene, Rabah; Galve, Audrey; Bounif, Abdallah; Schenini, Laure; Hamai, Lamine; Schnurle, Philippe; Djellit, Hamou; Sage, Françoise; Charvis, Philippe; Déverchère, Jacques

2018-03-01

During the Algerian-French SPIRAL survey aimed at investigating the deep structure of the Algerian margin and basin, two coincident wide-angle and reflection seismic profiles were acquired in central Algeria, offshore Greater Kabylia, together with gravimetric, bathymetric and magnetic data. This 260 km-long offshore-onshore profile spans the Balearic basin, the central Algerian margin and the Greater Kabylia block up to the southward limit of the internal zones onshore. Results are obtained from modeling and interpretation of the combined data sets. The Algerian basin offshore Greater Kabylia is floored by a thin oceanic crust ( 4 km) with P-wave velocities ranging between 5.2 and 6.8 km/s. In the northern Hannibal High region, the atypical 3-layer crustal structure is interpreted as volcanic products stacked over a thin crust similar to that bordering the margin and related to Miocene post-accretion volcanism. These results support a two-step back-arc opening of the west-Algerian basin, comprising oceanic crust accretion during the first southward stage, and a magmatic and probably tectonic reworking of this young oceanic basement during the second, westward, opening phase. The structure of the central Algerian margin is that of a narrow ( 70 km), magma-poor rifted margin, with a wider zone of distal thinned continental crust than on the other margin segments. There is no evidence for mantle exhumation in the sharp ocean-continent transition, but transcurrent movements during the second opening phase may have changed its initial geometry. The Plio-Quaternary inversion of the margin related to ongoing convergence between Africa and Eurasia is expressed by a blind thrust system under the margin rising toward the surface at the slope toe, and by an isostatic disequilibrium resulting from opposite flexures of two plates decoupled at the continental slope. This disequilibrium is likely responsible for the peculiar asymmetrical shape of the crustal neck that may thus be a characteristic feature of inverted rifted margins.

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

PubMed Central

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

2012-01-01

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

An appraisal of statistical procedures used in derivation of reference intervals.

PubMed

Ichihara, Kiyoshi; Boyd, James C

2010-11-01

When conducting studies to derive reference intervals (RIs), various statistical procedures are commonly applied at each step, from the planning stages to final computation of RIs. Determination of the necessary sample size is an important consideration, and evaluation of at least 400 individuals in each subgroup has been recommended to establish reliable common RIs in multicenter studies. Multiple regression analysis allows identification of the most important factors contributing to variation in test results, while accounting for possible confounding relationships among these factors. Of the various approaches proposed for judging the necessity of partitioning reference values, nested analysis of variance (ANOVA) is the likely method of choice owing to its ability to handle multiple groups and being able to adjust for multiple factors. Box-Cox power transformation often has been used to transform data to a Gaussian distribution for parametric computation of RIs. However, this transformation occasionally fails. Therefore, the non-parametric method based on determination of the 2.5 and 97.5 percentiles following sorting of the data, has been recommended for general use. The performance of the Box-Cox transformation can be improved by introducing an additional parameter representing the origin of transformation. In simulations, the confidence intervals (CIs) of reference limits (RLs) calculated by the parametric method were narrower than those calculated by the non-parametric approach. However, the margin of difference was rather small owing to additional variability in parametrically-determined RLs introduced by estimation of parameters for the Box-Cox transformation. The parametric calculation method may have an advantage over the non-parametric method in allowing identification and exclusion of extreme values during RI computation.

Aspirin Does Not Increase Heart Failure Events in Heart Failure Patients: From the WARCEF Trial.

PubMed

Teerlink, John R; Qian, Min; Bello, Natalie A; Freudenberger, Ronald S; Levin, Bruce; Di Tullio, Marco R; Graham, Susan; Mann, Douglas L; Sacco, Ralph L; Mohr, J P; Lip, Gregory Y H; Labovitz, Arthur J; Lee, Seitetz C; Ponikowski, Piotr; Lok, Dirk J; Anker, Stefan D; Thompson, John L P; Homma, Shunichi

2017-08-01

The aim of this study was to determine whether aspirin increases heart failure (HF) hospitalization or death in patients with HF with reduced ejection fraction receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Because of its cyclooxygenase inhibiting properties, aspirin has been postulated to increase HF events in patients treated with ACE inhibitors or ARBs. However, no large randomized trial has addressed the clinical relevance of this issue. We compared aspirin and warfarin for HF events (hospitalization, death, or both) in the 2,305 patients enrolled in the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial (98.6% on ACE inhibitor or ARB treatment), using conventional Cox models for time to first event (489 events). In addition, to examine multiple HF hospitalizations, we used 2 extended Cox models, a conditional model and a total time marginal model, in time to recurrent event analyses (1,078 events). After adjustment for baseline covariates, aspirin- and warfarin-treated patients did not differ in time to first HF event (adjusted hazard ratio: 0.87; 95% confidence interval: 0.72 to 1.04; p = 0.117) or first hospitalization alone (adjusted hazard ratio: 0.88; 95% confidence interval: 0.73 to 1.06; p = 0.168). The extended Cox models also found no significant differences in all HF events or in HF hospitalizations alone after adjustment for covariates. Among patients with HF with reduced ejection fraction in the WARCEF trial, there was no significant difference in risk of HF events between the aspirin and warfarin-treated patients. (Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction trial [WARCEF]; NCT00041938). Copyright © 2017 American College of Cardiology Foundation. All rights reserved.

Neogene to recent contraction and basin inversion along the Nubia-Iberia boundary in SW Iberia

NASA Astrophysics Data System (ADS)

Ramos, Adrià; Fernández, Oscar; Terrinha, Pedro; Muñoz, Josep Anton

2017-02-01

The SW of Iberia is currently undergoing compression related to the convergence between Nubia and Iberia. Multiple compressive structures, and their related seismic activity, have been documented along the diffuse Nubia-Iberia plate boundary, including the Gorringe bank west of the Gulf of Cadiz, and the Betic-Rif orogen to the east. Despite seismic activity indicating a dominant compressive stress along the Algarve margin in the Gulf of Cadiz, the structures at the origin of this seismicity remain elusive. This paper documents the contractional structures that provide linkage across the Gulf of Cadiz and play a major role in defining the present-day seismicity and bathymetry of this area. The structures described in this paper caused the Neogene inversion of the Jurassic oblique passive margin that formed between the central Atlantic and the Ligurian Tethys. This example of a partially inverted margin provides insights into the factors that condition the inversion of passive margins.

"In situ preparation": new surgical procedure indicated for soft-tissue sarcoma of a lower limb in close proximity to major neurovascular structures.

PubMed

Matsumoto, Seiichi; Kawaguchi, Noriyoshi; Manabe, Jun; Matsushita, Yasushi

2002-02-01

When soft-tissue sarcomas occur near neurovascular structures, preoperative images cannot always reveal the accurate relationship between the tumor and these structures. Therefore, in some patients, neurovascular structures are sacrificed unnecessarily. In other patients, neurovascular structures are preserved with an inappropriate margin, followed by local recurrence. The objective of this study was to evaluate a new surgical method, "in situ preparation" (ISP), which enables the preparation of neurovascular bundles and the intraoperative evaluation of the surgical margin without contamination by tumor cells. With this method, additional procedures, including pasteurization, alcohol soaking, and distilled water soaking of the preserved neurovascular bundle can also be performed to preserve the continuity of vessels. Between April 1992 and December 1998, 18 patients with soft-tissue sarcoma were operated on using ISP. The tumor and neurovascular structure were lifted en bloc from the surgical bed and separated from the field by the use of a vinyl sheet. The consistency of the neurovascular structures was preserved. The tissue block could be freely turned around and the neurovascular structure was separated from the block through the nearest approach. The margin between the tumor and neurovascular structure was evaluated, and an additional procedure, such as pasteurization, alcohol soaking or distilled water soaking, was performed, according to the safety of the surgical margin. Only one patient showed recurrence after ISP. Complications after ISP were arterial occlusion in two patients and nerve palsy in three patients. The main cause of these complications was the long period of pasteurization; modified additional procedures could prevent such complications. ISP is a useful method with which to ensure a safe surgical margin and good functional results.

Structural style and tectonic evolution of the easternmost Gulf of Aden conjugate margins (Socotra - Southern Oman)

NASA Astrophysics Data System (ADS)

Nonn, Chloe; Leroy, Sylvie; Castilla, Raymi; de Clarens, Philippe; Lescanne, Marc

2016-04-01

Observations from distal rifted margins in present day magma-poor rifted margins led to the discovery of hyperextended crust and exhumed sub-continental mantle. This finding allowed to better figure out how thinning process are accommodate by tectonic structures, forming various crustal domains, as the deformation localized towards the future area of breakup. However, some of the current challenges are about clarifying how factors as oblique kinematic, pre-existing structures and volcanism can control the 3D geometry and crustal architecture of the passive margins? A key to better understand the rifting evolution in its entirety is to study conjugate margins. The gulf of Aden is a young oceanic basin (with a global trend about N75°E) oblique to the divergence (about 30°N), separating Arabia from Somalia of less than 800 km. Thanks to its immerged margins and its thin post-rift sediment cover, the gulf of Aden basin is a natural laboratory to investigate conjugate margins and strain localisation throughout the rift history. In this contribution, we focus our interest on offshore Socotra Island (Yemen) and its conjugate in Southeastern Oman. This area extends from Socotra-Hadbeen (SHFZ) and the eastern Gulf of Aden fault zones (EGAFZ). In the easternmost part of the gulf of Aden, we provide new insights into crustal deformation and emplacement of the new oceanic crust thanks to bathymetric, magnetic, gravimetric data and single-, multi-channel, high speed seismic reflection data collected during Encens-Sheba (2000), Encens (2006) and the more recent Marges-Aden (2012) cruises respectively. The results obtained after compilation of these data, previous geological (field works) and geophysical (receiver functions, Pn-tomography, magnetic anomalies, heat flow) studies on the focused area, allowed us to provide new structural mapping and stratigraphic correlation between onshore and offshore parts of Socotra and Oman margins. We precisely defined and map crustal domains, syn-tectonic structures and oblique accommodation zones to highlighted asymmetrical margins, characterized by strong lateral variability of crustal domains along and across strike. From external to internal domains of the margins and in between SHFZ and EGAFZ (first-order segment), this study details sharp necking domain and complex transition from hyperextended to oceanic crust characterized by: (i) hyperextended crust affected by volcanic extrusions; (ii) detachment faulting in the distal part of the margins allowing exhumation; (iii) volcanic constructions in the exhumation domain; (iv) a complex proto-oceanic crust. We highlight a significant second-order segmentation characterized by six N20°E trending transfer zones, limiting seven 25 - 60 km length segments and affecting necking domain as well as the ocean-continent transition. Based on interpretative cross-sections and detailed stratigraphic analysis, we discuss the complex temporal and spatial evolution of conjugate margins: (i) the margins segmentation and the relationship with structural inheritance (ii) the set-up of a long-offset detachment fault and the nature of the exhumed basement (iv) the origin and timing of magmatic events and the onset of proto-oceanic crust.

Robust Flutter Margin Analysis that Incorporates Flight Data

NASA Technical Reports Server (NTRS)

Lind, Rick; Brenner, Martin J.

1998-01-01

An approach for computing worst-case flutter margins has been formulated in a robust stability framework. Uncertainty operators are included with a linear model to describe modeling errors and flight variations. The structured singular value, mu, computes a stability margin that directly accounts for these uncertainties. This approach introduces a new method of computing flutter margins and an associated new parameter for describing these margins. The mu margins are robust margins that indicate worst-case stability estimates with respect to the defined uncertainty. Worst-case flutter margins are computed for the F/A-18 Systems Research Aircraft using uncertainty sets generated by flight data analysis. The robust margins demonstrate flight conditions for flutter may lie closer to the flight envelope than previously estimated by p-k analysis.

Complete mitochondrial genome of Chocolate Pansy, Junonia iphita (Lepidoptera: Nymphalidae: Nymphalinae).

PubMed

Vanlalruati, Catherine; Mandal, Surajit De; Gurusubramanian, Guruswami; Senthil Kumar, Nachimuthu

2016-07-01

The complete mitochondrial genome of Junonia iphita was determined to be 15,433 bp in length, including 37 typical mitochondrial genes and an AT-rich region. All the protein coding genes (PCGs) are initiated by typical ATN codons, except cox1 gene that is by CGA codon. Eight genes use complete termination codon (TAA), whereas the cox1, cox2 and nad5 genes end with single T; nad4 and nad1 ends with stop codon TA. All the tRNA show secondary cloverleaf structures except trnS1 (AGN). The A + T rich region is 546 bp in length containing ATAGA motif followed by a 18 bp poly-T stretch, two microsatellite-like (TA)9 elements and 8 bp poly-A stretch immediately upstream of trnM gene.

Tectonostratigraphy of the Passive Continental Margin Offshore Indus Pakistan

NASA Astrophysics Data System (ADS)

Aslam, K.; Khan, M.; Liu, Y.; Farid, A.

2017-12-01

The tectonic evolution and structural complexities are poorly understood in the passive continental margin of the Offshore Indus of Pakistan. In the present study, an attempt has been made to interpret the structural trends and seismic stratigraphic framework in relation to the tectonics of the region. Seismic reflection data revealed tectonically controlled, distinct episodes of normal faulting representing rifting at different ages and transpression in the Late Eocene time. This transpression has resulted in the reactivation of the Pre-Cambrian basement structures. The movement of these basement structures has considerably affected the younger sedimentary succession resulting in push up structures resembling anticlines. The structural growth of the push-up structures was computed. The most remarkable tectonic setting in the region is represented by the normal faulting and by the basement uplift which divides the rifting and transpression stages. Ten mappable seismic sequences have been identified on the seismic records. A Jurassic aged paleo-shelf has also been identified on all regional seismic profiles which is indicative of Indian-African Plates separation during the Jurassic time. Furthermore, the backstripping technique was applied which has been proved to be a powerful technique to quantify subsidence/uplift history of rift-type passive continental margins. The back strip curves suggest that transition from an extensional rifted margin to transpression occurred during Eocene time (50-30 Ma). The backstripping curves show uplift had happened in the area. We infer that the uplift has occurred due to the movement of basement structures by the transpression movements of Arabian and Indian Plates. The present study suggests that the structural styles and stratigraphy of the Offshore Indus Pakistan were significantly affected by the tectonic activities during the separation of Gondwanaland in the Mesozoic and northward movement of the Indian Plate, post-rifting, and sedimentations along its western margin during the Middle Cenozoic. The present comprehensive interpretation can help in understanding the structural complexities and stratigraphy associated with tectonics in other parts of the passive continental margins worldwide dominated by rifting and drifting tectonics.

Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.

PubMed

Hallmann, Kerstin; Kudin, Alexei P; Zsurka, Gábor; Kornblum, Cornelia; Reimann, Jens; Stüve, Burkhard; Waltz, Stephan; Hattingen, Elke; Thiele, Holger; Nürnberg, Peter; Rüb, Cornelia; Voos, Wolfgang; Kopatz, Jens; Neumann, Harald; Kunz, Wolfram S

2016-02-01

Isolated cytochrome c oxidase (complex IV) deficiency is one of the most frequent respiratory chain defects in humans and is usually caused by mutations in proteins required for assembly of the complex. Mutations in nuclear-encoded structural subunits are very rare. In a patient with Leigh-like syndrome presenting with leukodystrophy and severe epilepsy, we identified a homozygous splice site mutation in COX8A, which codes for the ubiquitously expressed isoform of subunit VIII, the smallest nuclear-encoded subunit of complex IV. The mutation, affecting the last nucleotide of intron 1, leads to aberrant splicing, a frame-shift in the highly conserved exon 2, and decreased amount of the COX8A transcript. The loss of the wild-type COX8A protein severely impairs the stability of the entire cytochrome c oxidase enzyme complex and manifests in isolated complex IV deficiency in skeletal muscle and fibroblasts, similar to the frequent c.845_846delCT mutation in the assembly factor SURF1 gene. Stability and activity of complex IV could be rescued in the patient's fibroblasts by lentiviral expression of wild-type COX8A. Our findings demonstrate that COX8A is indispensable for function of human complex IV and its mutation causes human disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Drugs to Treat Systemic Lupus Erythematosus: Relationship between Current Use and Cardiovascular Risk Factors

PubMed Central

Rho, Young Hee; Oeser, Annette; Chung, Cecilia P; Morrow, Jason D; Stein, C Michael

2008-01-01

Objectives Cardiovascular risk is increased in patients with systemic lupus erythematosus (SLE). Drugs used to treat SLE can modify traditional cardiovascular risk factors. We examined the effect of selected drugs used in the treatment of SLE on cardiovascular risk factors. Methods We compared systolic and diastolic blood pressure, serum lipid concentrations, glucose, homocysteine, and urinary F2-isoprostane concentrations in 99 patients with lupus who were either current users or non-users of systemic corticosteroids, antimalarials, non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 selective NSAIDs, azathioprine, and methotrexate. Multivariable adjustment was done with linear regression modeling using sex, age and disease activity (SLEDAI) as controlling variables. Results Serum triglyceride concentrations were higher (135.1 ± 61.4 vs. 95.3 ± 47.5 mg/dL, adjusted P = 0.003) in patients receiving corticosteroids. Homocysteine concentrations were marginally higher in patients receiving methotrexate (adjusted P = 0.08). Current use of either NSAIDs or COX-2 inhibitors was not associated with increased cardiovascular risk factors. Current hydroxychloroquine use was not associated with significant alterations in lipid profiles. Conclusions In a non-random sample of patients with SLE, current corticosteroid use was associated with increased triglyceride concentrations, but other drugs had little effect on traditional cardiovascular risk factors. PMID:20157365

Identification and isolation of the cyclooxygenase-2 inhibitory principle in Isatis tinctoria.

PubMed

Danz, H; Stoyanova, S; Wippich, P; Brattström, A; Hamburger, M

2001-07-01

Various extracts prepared from the traditional dye and medicinal plant Isatis tinctoria L. were submitted to a broad in vitro screening against 16 anti-inflammatory targets. Dichloromethane (DCM) extracts from dried leaves showed a marked cyclooxygenase (COX) inhibitory activity with a preferential effect on COX-2 catalysed prostaglandin synthesis. A supercritical fluid extraction (SFE) procedure employing CO2-modifier mixtures was developed by which the bioactivity profile and chromatographic fingerprint of the DCM extract could be reproduced. High-resolution activity directed on-line identification of the COX-2 inhibitory principle, using a combination of LC-DAD-MS with a microtitre-based bioassay, led to the identification of tryptanthrin (1) as the constituent responsible for essentially all COX-2 inhibitory activity in the crude extract. Following on-line identification, 1 was isolated at preparative scale and its structure confirmed by comparison with synthetic tryptanthrin. In an assay with lipopolysaccharide stimulated Mono Mac 6 cells, tryptanthrin (1) was of comparable potency (IC50 = 64 nM) than the preferential COX-2 inhibitors nimesulide (IC50 = 39 nM) and NS 398 (IC50 = 2 nM). The SFE extract and 1 showed no cytotoxicity in Mono Mac 6 and RAW 264.7 cells when tested at 100 microg/ml and 10 microM, respectively.

The complete mitochondrial genome of the pink stem borer, Sesamia inferens, in comparison with four other Noctuid moths.

PubMed

Chai, Huan-Na; Du, Yu-Zhou

2012-01-01

The complete 15,413-bp mitochondrial genome (mitogenome) of Sesamia inferens (Walker) (Lepidoptera: Noctuidae) was sequenced and compared with those of four other noctuid moths. All of the mitogenomes analyzed displayed similar characteristics with respect to gene content, genome organization, nucleotide comparison, and codon usages. Twelve-one protein-coding genes (PCGs) utilized the standard ATN, but the cox1 gene used CGA as the initiation codon; cox1, cox2, and nad4 genes had the truncated termination codon T in the S. inferens mitogenome. All of the tRNA genes had typical cloverleaf secondary structures except for trnS1(AGN), in which the dihydrouridine (DHU) arm did not form a stable stem-loop structure. Both the secondary structures of rrnL and rrnS genes inferred from the S. inferens mitogenome closely resembled those of other noctuid moths. In the A+T-rich region, the conserved motif "ATAGA" followed by a long T-stretch was observed in all noctuid moths, but other specific tandem-repeat elements were more variable. Additionally, the S. inferens mitogenome contained a potential stem-loop structure, a duplicated 17-bp repeat element, a decuplicated segment, and a microsatellite "(AT)(7)", without a poly-A element upstream of the trnM in the A+T-rich region. Finally, the phylogenetic relationships were reconstructed based on amino acid sequences of mitochondrial 13 PCGs, which support the traditional morphologically based view of relationships within the Noctuidae.

The Complete Mitochondrial Genome of the Pink Stem Borer, Sesamia inferens, in Comparison with Four Other Noctuid Moths

PubMed Central

Chai, Huan-Na; Du, Yu-Zhou

2012-01-01

The complete 15,413-bp mitochondrial genome (mitogenome) of Sesamia inferens (Walker) (Lepidoptera: Noctuidae) was sequenced and compared with those of four other noctuid moths. All of the mitogenomes analyzed displayed similar characteristics with respect to gene content, genome organization, nucleotide comparison, and codon usages. Twelve-one protein-coding genes (PCGs) utilized the standard ATN, but the cox1 gene used CGA as the initiation codon; cox1, cox2, and nad4 genes had the truncated termination codon T in the S. inferens mitogenome. All of the tRNA genes had typical cloverleaf secondary structures except for trnS1(AGN), in which the dihydrouridine (DHU) arm did not form a stable stem-loop structure. Both the secondary structures of rrnL and rrnS genes inferred from the S. inferens mitogenome closely resembled those of other noctuid moths. In the A+T-rich region, the conserved motif “ATAGA” followed by a long T-stretch was observed in all noctuid moths, but other specific tandem-repeat elements were more variable. Additionally, the S. inferens mitogenome contained a potential stem-loop structure, a duplicated 17-bp repeat element, a decuplicated segment, and a microsatellite “(AT)7”, without a poly-A element upstream of the trnM in the A+T-rich region. Finally, the phylogenetic relationships were reconstructed based on amino acid sequences of mitochondrial 13 PCGs, which support the traditional morphologically based view of relationships within the Noctuidae. PMID:22949858

Tangeretin suppresses IL-1beta-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells.

PubMed

Chen, Kuan-Hung; Weng, Meng-Shih; Lin, Jen-Kun

2007-01-15

Tangeretin (5,6,7,8,4'-pentamethoxyflavone) is a polymethoxylated flavonoid concentrated in the peel of citrus fruits. Recent studies have shown that tangeretin exhibits anti-proliferative, anti-invasive, anti-metastatic, and antioxidant activities. However, the anti-inflammatory properties of tangeretin are unclear. In this study, we examine the effects of tangeretin and its structure-related compound, nobiletin, on the expression of cyclooxygenases-2 (COX-2) in human lung epithelial carcinoma cells, A549, and human non-small cell lung carcinoma cells, H1299. Tangeretin exerts a much better inhibitory activity than nobiletin against IL-1beta-induced production of COX-2 in A549 cells, and it effectively represses the constitutively expressed COX-2 in H1299. RT-PCR was used to investigate the transcriptional inhibition of COX-2 by tangeretin. COX-2 mRNA was rapidly induced by IL-1beta in 3h and markedly suppressed by tangeretin. IL-1beta-induced the activation of ERK, p38 MAPK, JNK, and AKT in A549 cells. COX-2 expression in response to IL-1beta was attenuated by pretreatment with SB203580, SP600125, and LY294002, but not with PD98059, suggesting the involvement of p38 MAPK, JNK, and PI3K in this response. Pretreatment of cells with tangeretin inhibited IL-1beta-induced p38 MAPK, JNK, and AKT phosphorylation and the downstream activation of NF-kappaB. These results may reveal that the tangeretin inhibition of IL-1beta-induced COX-2 expression in A549 cells is, at least in part, mediated through suppression of NF-kappaB transcription factor as well as through suppression of the signaling proteins of p38 MAPK, JNK, and PI3K, but not of ERK.

Unified framework to evaluate panmixia and migration direction among multiple sampling locations.

PubMed

Beerli, Peter; Palczewski, Michal

2010-05-01

For many biological investigations, groups of individuals are genetically sampled from several geographic locations. These sampling locations often do not reflect the genetic population structure. We describe a framework using marginal likelihoods to compare and order structured population models, such as testing whether the sampling locations belong to the same randomly mating population or comparing unidirectional and multidirectional gene flow models. In the context of inferences employing Markov chain Monte Carlo methods, the accuracy of the marginal likelihoods depends heavily on the approximation method used to calculate the marginal likelihood. Two methods, modified thermodynamic integration and a stabilized harmonic mean estimator, are compared. With finite Markov chain Monte Carlo run lengths, the harmonic mean estimator may not be consistent. Thermodynamic integration, in contrast, delivers considerably better estimates of the marginal likelihood. The choice of prior distributions does not influence the order and choice of the better models when the marginal likelihood is estimated using thermodynamic integration, whereas with the harmonic mean estimator the influence of the prior is pronounced and the order of the models changes. The approximation of marginal likelihood using thermodynamic integration in MIGRATE allows the evaluation of complex population genetic models, not only of whether sampling locations belong to a single panmictic population, but also of competing complex structured population models.

Worst-Case Flutter Margins from F/A-18 Aircraft Aeroelastic Data

NASA Technical Reports Server (NTRS)

Lind, Rick; Brenner, Marty

1997-01-01

An approach for computing worst-case flutter margins has been formulated in a robust stability framework. Uncertainty operators are included with a linear model to describe modeling errors and flight variations. The structured singular value, micron, computes a stability margin which directly accounts for these uncertainties. This approach introduces a new method of computing flutter margins and an associated new parameter for describing these margins. The micron margins are robust margins which indicate worst-case stability estimates with respect to the defined uncertainty. Worst-case flutter margins are computed for the F/A-18 SRA using uncertainty sets generated by flight data analysis. The robust margins demonstrate flight conditions for flutter may lie closer to the flight envelope than previously estimated by p-k analysis.

Absence of genetic structure in Baylisascaris schroederi populations, a giant panda parasite, determined by mitochondrial sequencing.

PubMed

Xie, Yue; Zhou, Xuan; Zhang, Zhihe; Wang, Chengdong; Sun, Yun; Liu, Tianyu; Gu, Xiaobin; Wang, Tao; Peng, Xuerong; Yang, Guangyou

2014-12-23

Infection with the parasitic nematode, Baylisascaris schroederi (Ascaridida: Nematoda), is one of the most important causes of death in giant pandas, and was responsible for half of deaths between 2001 and 2005. Mitochondrial (mt) DNA sequences of parasites can unveil their genetic diversity and depict their likely dynamic evolution and therefore may provide insights into parasite survival and responses to host changes, as well as parasite control. Based on previous studies, the present study further annotated the genetic variability and structure of B. schroederi populations by combining two different mtDNA markers, ATPase subunit 6 (atp6) and cytochrome c oxidase subunit I (cox1). Both sequences were completely amplified and genetically analyzed among 57 B. schroederi isolates, which were individually collected from ten geographical regions located in three important giant panda habitats in China (Minshan, Qionglai and Qinling mountain ranges). For the DNA dataset, we identified 20 haplotypes of atp6, 24 haplotypes of cox1, and 39 haplotypes of atp6 + cox1. Further haplotype network and phylogenetic analyses demonstrated that B. schroederi populations were predominantly driven by three common haplotypes, atp6 A1, cox1 C10, and atp6 + cox1 H11. However, due to low rates of gene differentiation between the three populations, both the atp6 and cox1 genes appeared not to be significantly associated with geographical divisions. In addition, high gene flow was detected among the B. schroederi populations, consistent with previous studies, suggesting that this parasite may be essentially homogenous across endemic areas. Finally, neutrality tests and mismatch analysis indicated that B. schroederi had undergone earlier demographic expansion. These results confirmed that B. schroederi populations do not follow a pattern of isolation by distance, further revealing the possible existence of physical connections before geographic separation. This study should also contribute to an improved understanding of the population genetics and evolutionary biology of B. schroederi and assist in the control of baylisascariasis in giant pandas.

Orogenic structural inheritance and rifted passive margin formation

NASA Astrophysics Data System (ADS)

Salazar Mora, Claudio A.; Huismans, Ritske S.

2016-04-01

Structural inheritance is related to mechanical weaknesses in the lithosphere due to previous tectonic events, e.g. rifting, subduction and collision. The North and South Atlantic rifted passive margins that formed during the breakup of Western Gondwana, are parallel to the older Caledonide and the Brasiliano-Pan-African orogenic belts. In the South Atlantic, 'old' mantle lithospheric fabric resulting from crystallographic preferred orientation of olivine is suggested to play a role during rifted margin formation (Tommasi and Vauchez, 2001). Magnetometric and gravimetric mapping of onshore structures in the Camamu and Almada basins suggest that extensional faults are controlled by two different directions of inherited older Brasiliano structures in the upper lithosphere (Ferreira et al., 2009). In the South Atlantic Campos Basin, 3D seismic data indicate that inherited basement structures provide a first order control on basin structure (Fetter, 2009). Here we investigate the role of structural inheritance on the formation of rifted passive margins with high-resolution 2D thermo-mechanical numerical experiments. The numerical domain is 1200 km long and 600 km deep and represents the lithosphere and the sublithospheric mantle. Model experiments were carried out by creating self-consistent orogenic inheritance where a first phase of orogen formation is followed by extension. We focus in particular on the role of varying amount of orogenic shortening, crustal rheology, contrasting styles of orogen formation on rifted margin style, and the time delay between orogeny and subsequent rifted passive formation. Model results are compared to contrasting structural styles of rifted passive margin formation as observed in the South Atlantic. Ferreira, T.S., Caixeta, J.M., Lima, F.D., 2009. Basement control in Camamu and Almada rift basins. Boletim de Geociências da Petrobrás 17, 69-88. Fetter, M., 2009. The role of basement tectonic reactivation on the structural evolution of Campos Basin, offshore Brazil: Evidence from 3D seismic analysis and section restoration. Marine and Petroleum Geology 26, 873-886. Tommasi, A., Vauchez, A., 2001. Continental rifting parallel to ancient collisional belts: An effect of the mechanical anisotropy of the lithospheric mantle. Earth and Planetary Science Letters 185, 199-210.

The Red Sea structural architecture assessment based on yield strength spatial variations and Arabian margin preexisting structures

NASA Astrophysics Data System (ADS)

Alotaibi, T.; Furlong, K. P.

2016-12-01

Rift initiation and localization might reflect spatial changes in the lithospheric yield strength. However, this does not appear to be the case in the Red Sea extensional system where fission track analysis shows no significant changes in the geothermal gradient prior to the Red Sea rift onset. In contrast, though the whole Red Sea rift initiated 25 Ma ago, its extensional architecture changes dramatically along strike from narrow localized spreading in the south to asymmetrical diffuse extension north of 21° latitude. This onset of diffuse extension has been recorded in the north-western Arabian margin as old as 33 Ma. Such diversity in the extensional style might reflect along strike yield strength variations as a consequence of the geological setting in the Arabian margin. The north-western Arabian basin, which is part of the Arabian margin, bounded by Qiba high from the east, the Arabian shield from the south and the west and Syrian plateau from the north. The basin accommodates part of the Red Sea diffuse extension and has a preexisting structural architecture represented in the Cenozoic failed rift that called Sarhan graben. Our goal is to analyze the current lithospheric yield strength spatial variations along the Red Sea rift and emphasize their relationship with the Arabian margin structural architecture. We hypothesize that the north-western Arabian margin's lithospheric weakness and structural diversity are playing an important role in producing region of diffuse extension by their interaction with the forces applied by far field stresses represented by the New Tethys slab pull. On the other hand, the south-western Arabian margin interacts with the far field stresses as a single strong block in which led to localize the extension in the southern Red Sea. Our work may improve the scientific community understanding for how rifts initiate and evolve over time.

Realistic sampling of anisotropic correlogram parameters for conditional simulation of daily rainfields

NASA Astrophysics Data System (ADS)

Gyasi-Agyei, Yeboah

2018-01-01

This paper has established a link between the spatial structure of radar rainfall, which more robustly describes the spatial structure, and gauge rainfall for improved daily rainfield simulation conditioned on the limited gauged data for regions with or without radar records. A two-dimensional anisotropic exponential function that has parameters of major and minor axes lengths, and direction, is used to describe the correlogram (spatial structure) of daily rainfall in the Gaussian domain. The link is a copula-based joint distribution of the radar-derived correlogram parameters that uses the gauge-derived correlogram parameters and maximum daily temperature as covariates of the Box-Cox power exponential margins and Gumbel copula. While the gauge-derived, radar-derived and the copula-derived correlogram parameters reproduced the mean estimates similarly using leave-one-out cross-validation of ordinary kriging, the gauge-derived parameters yielded higher standard deviation (SD) of the Gaussian quantile which reflects uncertainty in over 90% of cases. However, the distribution of the SD generated by the radar-derived and the copula-derived parameters could not be distinguished. For the validation case, the percentage of cases of higher SD by the gauge-derived parameter sets decreased to 81.2% and 86.6% for the non-calibration and the calibration periods, respectively. It has been observed that 1% reduction in the Gaussian quantile SD can cause over 39% reduction in the SD of the median rainfall estimate, actual reduction being dependent on the distribution of rainfall of the day. Hence the main advantage of using the most correct radar correlogram parameters is to reduce the uncertainty associated with conditional simulations that rely on SD through kriging.

The continent-ocean transition at the mid-northern margin of the South China Sea

NASA Astrophysics Data System (ADS)

Gao, Jinwei; Wu, Shiguo; McIntosh, Kirk; Mi, Lijun; Yao, Bochu; Chen, Zeman; Jia, Liankai

2015-07-01

The northern margin of the South China Sea (SCS) has particular structural and stratigraphic characteristics that are somewhat different from those described in typical passive margin models. The differences are attributable to poly-phase tectonic movements and magmatic activity resulting from the interaction among the Eurasian, Philippine Sea and Indo-Australian plates. Based on several crustal-scale multi-channel seismic reflection profiles and satellite gravity data across the northern SCS margin, this paper analyzes the structures, volcanoes and deep crust of the continent-ocean transition zone (COT) at the mid-northern margin of the SCS to study the patterns and model of extension there. The results indicate that the COT is limited landward by basin-bounding faults near Baiyun sag and is bounded by seaward-dipping normal faults near the oceanic basin in our seismic lines. The shallow anatomy of the COT is characterized by rift depression, structural highs with igneous rock and/or a volcanic zone or a zone of tilted fault blocks at the distal edge. Gravity modeling revealed that a high velocity layer (HVL) with a 0.8-6-km thickness is frequently present in the slope below the lower crust. Our study shows that the HVL is only located in the eastern portion of the northern SCS margin based on the available geophysical data. We infer from this that the presence of an HVL is not required in the COT at the northern SCS margin. The magmatic intrusions and HVL may be related to partial melting caused by the decompression of a passive, upwelling asthenosphere, which resulted primarily in post-rifting underplating and magmatic emplacement or modification of the crust. Based on this study, we propose that an intermediate mode of rifting was active in the mid-northern margin of the SCS with characteristics that are closer to those of the magma-poor margins than those of volcanic margins.

First images of the crustal structure across the eastern Algerian margin, from deep penetrating seismic data.

NASA Astrophysics Data System (ADS)

Bouyahiaoui, Boualem; Abtout, Abdeslam; Sage, Françoise; Klingelhoeffer, Frauke; Collot, Jean-yves; Yelles-chaouche, Abdelkarim; Marok, Abbas; Djellit, Hamou; Galves, Audrey; Bracène, Rabah; Schnurle, Philippe; Graindorge, David; party, Scientific

2013-04-01

The Algerian continental margin North Africa presents one of only a few examples of a passive continental margin formed in a back-arc environment, which undergoes current compression and is proposed to be reactivated today. In the framework of the Algerian - French SPIRAL research program (Sismique Profonde et Investigation Regionale du nord de l'ALgérie), a seismic cruise was conducted on the R/V Atalante from September to November 2009. During the cruise, deep penetrating low frequency multichannel and wide-angle seismic data were acquired in order to study the deep structure of the Algerian margin. In this work, we present the preliminary results from wide-angle modeling of the North-east Algerian margin in the region of Annaba along a N-S transect using a data set of 42 OBS (ocean bottom seismometers) along a profile extending 117km, and 13 broadband seismological stations along a profile of 80 km length. Travel-time tomography and forward modeling were undertaken to model the velocity structure in this region. The resulting velocity models image the thickness of the sedimentary layers, which varies between a few hundred meters on the continental margin of more than 4 km in the basin. The crust is about 6 km thick in the basin, and thickens to 7-8 km between 40 and 60km distance from the margin toe. Crustal thickness increases to about 22 km at the continental slope over a distance of ~ 90 km. The nature of the crust was determined to be thin oceanic with abnormal velocity gradient in the basin, and thinned continental from around 30 km distance from the coast landward. Integration of the wide-angle seismic data with multichannel seismic, gravity and magnetic data will help to better understand the structure of the Algerian margin and the adjacent oceanic basin in the Annaba region, and to discuss the numerous cinematic models proposed in literature regarding the formation of the north-Algerian basin.

Influence of the Kingak Shale ultimate shelf margin on frontal structures of the Brooks Range in the National Petroleum Reserve in Alaska

USGS Publications Warehouse

Stier, Natalie E.; Connors, Christopher D.; Houseknecht, David W.

2014-01-01

The Jurassic–Lower Cretaceous Kingak Shale in the National Petroleum Reserve in Alaska (NPRA) includes several southward-offlapping depositional sequences that culminate in an ultimate shelf margin, which preserves the depositional profile in southern NPRA. The Kingak Shale thins abruptly southward across the ultimate shelf margin and grades into condensed shale, which is intercalated with underlying condensed shale and chert of the Upper Triassic Shublik Formation and overlying condensed shale of the Lower Cretaceous pebble shale unit and the gamma-ray zone (GRZ) of the Hue Shale. This composite of condensed shale forms a thin (≈300-meter) and mechanically weak section between much thicker and mechanically stronger units, including the Sadlerochit and Lisburne Groups below and the sandstone-prone foredeep wedge of the Torok Formation above. Seismic interpretation indicates that the composite condensed section acted as the major detachment during an Early Tertiary phase of deformation in the northern foothills of the Brooks Range and that thrust faults step up northward to the top of the Kingak, or to other surfaces within the Kingak or the overlying Torok. The main structural style is imbricate fault-bend folding, although fault-propagation folding is evident locally, and large-displacement thrust faults incorporate backthrusting to form structural wedges. The Kingak ultimate shelf margin served as a ramp to localize several thrust faults, and the spatial relationship between the ultimate shelf margin and thrust vergence is inferred to have controlled many structures in southern NPRA. For example, the obliqueness of the Carbon Creek anticline relative to other structures in the foothills is the result of northward-verging thrust faults impinging obliquely on the Kingak ultimate shelf margin in southwestern NPRA.

Drug repurposing of novel quinoline acetohydrazide derivatives as potent COX-2 inhibitors and anti-cancer agents

NASA Astrophysics Data System (ADS)

Manohar, Chelli Sai; Manikandan, A.; Sridhar, P.; Sivakumar, A.; Siva Kumar, B.; Reddy, Sabbasani Rajasekhara

2018-02-01

Novel QuinolineAcetohydrazide (QAh) derivatives (9a-n) were firstly evaluated in silico to determine their anti-inflammatory and anti-cancer efficacy via the mechanisms of COX1 and COX2 inhibition, and NF-ĸB, HDAC and Human Topoisomerase I pathways respectively. In the studied set, the trifluoro substituted QAh derivatives: (E)-N'-(4-(trifluoro methyl) benzylidene)-2-(7-fluoro-2-methoxy quinolin-8-yl) acetohydrazid and (E)-N'-(3-(trifluoro methyl) benzylidene)-2-(7-fluoro-2-methoxy quinolin-8-yl) acetohydrazide are determined to be potential leads, indicated from their best docked scores, relative ligand efficiency, and significant structural attributes evaluated by ab initio simulations. The only setback being their partition co-efficient that retrieved a red flag in the evaluation of their Lipinski parameters. The experimental in vitro studies confirmed the significant enhancement as COX-2 inhibitors and appreciable enhancement in MTT assay of breast and skin cancer cell lines. Significantly, trifluoro substituent in the quinoline scaffold can be reasoned to note the excellent binding affinity to all the evaluated drug targets.

Pharmacological and Toxicological Screening of Novel Benzimidazole-Morpholine Derivatives as Dual-Acting Inhibitors.

PubMed

Can, Nafiz Öncü; Çevik, Ulviye Acar; Sağlık, Begüm Nurpelin; Özkay, Yusuf; Atlı, Özlem; Baysal, Merve; Özkay, Ümide Demir; Can, Özgür Devrim

2017-08-19

The aim of this study was to investigate acetylcholinesterase (AChE), monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme inhibitory, and antimicrobial activities of a new series of 2-(4-substituted phenyl)-1-[2-(morpholin-4-yl)ethyl]-1 H -benzimidazole derivatives, for their possible use as multi-action therapeutic agents. Target compounds ( n = 15) were synthesized under microwave irradiation conditions in two steps, and their structures were elucidated by FT-IR, ¹H-NMR, 13 C-NMR and high resolution mass spectroscopic analyses. Pharmacological screening studies revealed that two of the compounds ( 2b and 2j ) have inhibitory potential on both COX-1 and COX-2 enzymes. In addition, cytotoxic and genotoxic properties of the compounds 2b , 2j and 2m were investigated via the well-known MTT and Ames tests, which revealed that the mentioned compounds are non-cytotoxic and non-genotoxic. As a concise conclusion, two novel compounds were characterized as potential candidates for treatment of frequently encountered inflammatory diseases.

Soft-sediment deformation structures from an ice-marginal storm-tide interactive system, Permo-Carboniferous Talchir Formation, Talchir Coalbasin, India

NASA Astrophysics Data System (ADS)

Bhattacharya, H. N.; Bhattacharya, Biplab

2010-01-01

Permo-Carboniferous Talchir Formation, Talchir Coalbasin, India, records sedimentation during a phase of climatic amelioration in an ice-marginal storm-affected shelf. Evidences of subtidal processes are preserved only under thick mud drapes deposited during waning storm phases. Various soft-sediment deformation structures in some sandstone/siltstone-mudstone interbeds, like syn-sedimentary faults, deformed laminations, sand-silt flows, convolute laminations and various flame structures, suggest liquefaction and fluidization of the beds due to passage of syn-depositional seismic shocks. In the Late Paleozoic ice-marginal shelf, such earthquake tremors could be generated by crustal movements in response to glacioisostatic adjustments of the basin floor.

Geology of continental margins

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

Not Available

With continued high interest in offshore petroleum exploration, the 1977 AAPG Short Course presents the latest interpretations of new data bearing on the geology and geophysics of continental margins. Seven well-known earth scientists have organized an integrated program covering major topics involved in the development of ocean basins and continental margins with emphasis on the slopes and rises. The discussion of plate tectonics and evolution of continental margins is followed by presentations on the stratigraphy and structure of pull-apart and compressional margins. Prospective petroleum source rocks, their organic content, rate of burial, and distribution on slopes and rises of differentmore » margin types is covered. Prospective reservoir rock patterns are related to depositional processes and to the sedimentary and structural histories for different types of continental margins. Finally, the seismic recognition of depositional facies on slopes and rises for different margin types with varying rates of sediment supply during eustatic sea-level changes are discussed. The course with this syllabus offers an invaluable opportunity for explorationists to refresh their understanding of the geology associated with an important petroleum frontier. In addition, the course sets forth a technical frame of reference for the case-histoy papers to be presented later in the AAPG Research Symposium on the Petroleum Potential of Slopes, Rises, and Plateaus.« less

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

ERIC Educational Resources Information Center

Terrell, Cassidy R.; Listenberger, Laura L.

2017-01-01

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

Capacity fade of LiNi(1-x-y)CoxAlyO2 cathode for lithium-ion batteries during accelerated calendar and cycle life test. I. Comparison analysis between LiNi(1-x-y)CoxAlyO2 and LiCoO2 cathodes in cylindrical lithium-ion cells during long term storage test

NASA Astrophysics Data System (ADS)

Watanabe, Shoichiro; Kinoshita, Masahiro; Nakura, Kensuke

2014-02-01

Ni-based LiNi(1-x-y)CoxAlyO2 (NCA) and LiCoO2 (LCO) cathode materials taken out of lithium-ion cells after storage for 2 years at 45 °C were analyzed by various spectroscopic techniques. X-ray photoelectron spectroscopy exhibited that there was no difference between NCA and LCO. On the other hand, scanning transmission electron microscopy-electron energy-loss spectroscopy demonstrated there was a remarkably large difference between the two cathode materials. Ni-L2,3 energy-loss near-edge structure (ELNES) spectra of the NCA showed a peak at about 856.5 eV, which was assigned to trivalent nickel, was maintained even after storage, indicating that the NCA had no significant change in its surface structure during storage. On the other hand, in the Co-L2,3 ELNES spectra of the LCO a peak at about 782.5 eV, which was assigned to trivalent cobalt, significantly shifted to the lower energies after storage. These results suggest that crystal structure change of the active material surface is a predominant reason of deterioration during the storage test.

Assessing Mediation Using Marginal Structural Models in the Presence of Confounding and Moderation

ERIC Educational Resources Information Center

Coffman, Donna L.; Zhong, Wei

2012-01-01

This article presents marginal structural models with inverse propensity weighting (IPW) for assessing mediation. Generally, individuals are not randomly assigned to levels of the mediator. Therefore, confounders of the mediator and outcome may exist that limit causal inferences, a goal of mediation analysis. Either regression adjustment or IPW…

Meroterpenoids from the fruiting bodies of Ganoderma theaecolum.

PubMed

Luo, Qi; Tu, Zheng-Chao; Yang, Zhu-Liang; Cheng, Yong-Xian

2018-03-01

A series of new terminal cyclohexane-type meroterpenoids, ganotheaecoloids A-N (1-6, 8-13, 15, and 16), along with three known ones (7, 14, and 17), were isolated from the dried fruiting bodies of Ganoderma theaecolum. Their chemical structures were identified by using spectroscopic data and computational methods. Biological activity of all the new meroterpenoids against COX-2 was evaluated in vitro, only ganotheaecoloid J (11) was found to have COX-2 inhibitory activity with IC 50 value of 9.96μM. Copyright © 2018 Elsevier B.V. All rights reserved.

SU-F-J-17: Patient Localization Using MRI-Guided Soft Tissue for Head-And-Neck Radiotherapy: Indication for Margin Reduction and Its Feasibility

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

Qi, X; Yang, Y; Jack, N

Purpose: On-board MRI provides superior soft-tissue contrast, allowing patient alignment using tumor or nearby critical structures. This study aims to study H&N MRI-guided IGRT to analyze inter-fraction patient setup variations using soft-tissue targets and design appropriate CTV-to-PTV margin and clinical implication. Methods: 282 MR images for 10 H&N IMRT patients treated on a ViewRay system were retrospectively analyzed. Patients were immobilized using a thermoplastic mask on a customized headrest fitted in a radiofrequency coil and positioned to soft-tissue targets. The inter-fraction patient displacements were recorded to compute the PTV margins using the recipe: 2.5∑+0.7σ. New IMRT plans optimized on themore » revised PTVs were generated to evaluate the delivered dose distributions. An in-house dose deformation registration tool was used to assess the resulting dosimetric consequences when margin adaption is performed based on weekly MR images. The cumulative doses were compared to the reduced margin plans for targets and critical structures. Results: The inter-fraction displacements (and standard deviations), ∑ and σ were tabulated for MRI and compared to kVCBCT. The computed CTV-to-PTV margin was 3.5mm for soft-tissue based registration. There were minimal differences between the planned and delivered doses when comparing clinical and the PTV reduced margin plans: the paired t-tests yielded p=0.38 and 0.66 between the planned and delivered doses for the adapted margin plans for the maximum cord and mean parotid dose, respectively. Target V95 received comparable doses as planned for the reduced margin plans. Conclusion: The 0.35T MRI offers acceptable soft-tissue contrast and good spatial resolution for patient alignment and target visualization. Better tumor conspicuity from MRI allows soft-tissue based alignments with potentially improved accuracy, suggesting a benefit of margin reduction for H&N radiotherapy. The reduced margin plans (i.e., 2 mm) resulted in improved normal structure sparing and accurate dose delivery to achieve intended treatment goal under MR guidance.« less

Constraints Imposed by Rift Inheritance on the Compressional Reactivation of a Hyperextended Margin: Mapping Rift Domains in the North Iberian Margin and in the Cantabrian Mountains

NASA Astrophysics Data System (ADS)

Cadenas, P.; Fernández-Viejo, G.; Pulgar, J. A.; Tugend, J.; Manatschal, G.; Minshull, T. A.

2018-03-01

The Alpine Pyrenean-Cantabrian orogen developed along the plate boundary between Iberia and Europe, involving the inversion of Mesozoic hyperextended basins along the southern Biscay margin. Thus, this margin represents a natural laboratory to analyze the control of structural rift inheritance on the compressional reactivation of a continental margin. With the aim to identify former rift domains and investigate their role during the subsequent compression, we performed a structural analysis of the central and western North Iberian margin, based on the interpretation of seismic reflection profiles and local constraints from drill-hole data. Seismic interpretations and published seismic velocity models enabled the development of crustal thickness maps that helped to constrain further the offshore and onshore segmentation. Based on all these constraints, we present a rift domain map across the central and western North Iberian margin, as far as the adjacent western Cantabrian Mountains. Furthermore, we provide a first-order description of the margin segmentation resulting from its polyphase tectonic evolution. The most striking result is the presence of a hyperthinned domain (e.g., Asturian Basin) along the central continental platform that is bounded to the north by the Le Danois High, interpreted as a rift-related continental block separating two distinctive hyperextended domains. From the analysis of the rift domain map and the distribution of reactivation structures, we conclude that the landward limit of the necking domain and the hyperextended domains, respectively, guide and localize the compressional overprint. The Le Danois block acted as a local buttress, conditioning the inversion of the Asturian Basin.

Elucidating the role of Cyclooxygenase-2 in the pathogenesis of oral lichen planus - an immunohistochemical study with supportive histochemical analysis.

PubMed

Singh, Pratyush; Grover, Jasleen; Byatnal, Aditi Amit; Guddattu, Vasudeva; Radhakrishnan, Raghu; Solomon, Monica Charlotte

2017-05-01

Oral lichen planus (OLP) is a chronic, inflammatory disorder that affects the oral mucous membrane. During an inflammatory response, several chemokines and cytokines are released by the cells of the immune system. Activation of MMPs, along with mast cell-derived chymase and tryptase, degrades the basement membrane structural proteins, resulting in basement membrane breaks. To investigate the association between the COX-2 expressions, presence of intact or degranulating mast cells within the connective tissue and the extent of basement membrane discontinuity in OLP cases. This study included a total of 50 formalin-fixed paraffin-embedded specimens (FFPE) of histologically confirmed cases of idiopathic oral lichen planus. A retrospective cross-sectional analysis was carried out by immunohistochemistry to study the epithelial expression of COX-2 and by the use of special stains such as toluidine blue and periodic acid-Schiff (PAS) to study the mast cell count and basement membrane changes in the oral mucosal tissue, respectively. There was a significant (P = 0.03) association between the COX-2 expressions and mast cell count. As the intensity of COX-2 expression increased from mild to moderate or severe, the number of mast cell count almost doubled. Interaction between upregulation of COX-2, mast cell and basement membrane sets a vicious cycle which relates to the chronic nature of the disease. Inhibitors of COX-2 may reduce the inflammatory process preceding the immune dysregulation in OLP. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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. © 2016, The International Biometric Society.

Mechanisms underlying the organizer formation in Bufo arenarum embryos.

PubMed

Manes, M E; Nieto, O L

1989-06-01

In the early gastrula of Bufo arenarum the prospective mesoderm was previously identified as a marginal belt of grey cells. To analyze their differentiation capacity explants of these cells were cultured within ectodermal vesicles, in isolation and in combination with vegetal components. When cultured in isolation, dorsal and ventral fragments from the deep marginal zone behaved differently. Whilst ventral explants produced blood cells, dorsal explants failed to differentiate, remaining as masses of yolk-laden cells. On the other hand, both cultures were drastically modified when associated with superficial cells from the blastoporal zone, which caused the following effects: a) Promotion of differentiation in dorsal marginal explants, able now to produce notochordal and somitic structures, in addition to mesenchymatic cells. b) Promotion of dorsalization in ventral marginal explants, which changed their expected destiny developing axial components, similar to those furnished by "activated" dorso marginal explants. On the contrary, combined cultures of animal and vegetal pieces were unable to generate mesodermal structures. These studies suggest that the axial mesoderm, identified as the "organizer", develops from a marginal substrate of genuine mesodermal cells through a dorsalizing inductive stimulus originated in superficial periblastoporal cells.

Upper mantle structure at Walvis Ridge from Pn tomography

NASA Astrophysics Data System (ADS)

Ryberg, Trond; Braeuer, Benjamin; Weber, Michael

2017-10-01

Passive continental margins offer the unique opportunity to study the processes involved in continental extension and break-up. Within the LISPWAL (LIthospheric Structure of the Namibian continental Passive margin at the intersection with the Walvis Ridge from amphibious seismic investigations) project, combined on- and offshore seismic experiments were designed to characterize the Southern African passive margin at the Walvis Ridge in northern Namibia. In addition to extensive analysis of the crustal structures, we carried out seismic investigations targeting the velocity structure of the upper mantle in the landfall region of the Walvis Ridge with the Namibian coast. Upper mantle Pn travel time tomography from controlled source, amphibious seismic data was used to investigate the sub-Moho upper mantle seismic velocity. We succeeded in imaging upper mantle structures potentially associated with continental break-up and/or the Tristan da Cunha hotspot track. We found mostly coast-parallel sub-Moho velocity anomalies, interpreted as structures which were created during Gondwana break-up.

Drug Targets for Cardiovascular-Safe Anti-Inflammatory: In Silico Rational Drug Studies

PubMed Central

Shahbazi, Sajad; Sahrawat, Tammanna R.; Ray, Monalisa; Dash, Swagatika; Kar, Dattatreya; Singh, Shikha

2016-01-01

Cyclooxygenase-2 (COX-2) plays an important role in memory consolidation and synaptic activity, the most fundamental functions of the brain. It converts arachidonic acid to prostaglandin endoperoxide H2. In contrast, if over-expressed, it causes inflammation in response to cytokine, pro-inflammatory molecule, and growth factor. Anti-inflammatory agents, by allosteric or competitive inhibition of COX-2, alleviate the symptoms of inflammation. Coxib family drugs, particularly celecoxib, are the most famous anti-inflammatory agents available in the market showing significant inhibitory effect on COX-2 activity. Due to high cardiovascular risk of this drug group, recent researches are focused on the investigation of new safer drugs for anti-inflammatory diseases. Natural compounds, particularly, phytochemicals are found to be good candidates for drug designing and discovery. In the present study, we performed in silico studies to quantitatively scrutinize the molecular interaction of curcumin and its structural analogs with COX-2, COX-1, FXa and integrin αIIbβIII to investigate their therapeutic potential as a cardiovascular-safe anti-inflammatory medicine (CVSAIM). The results of both ADMET and docking study indicated that out of all the 39 compounds studied, caffeic acid had remarkable interaction with proteins involved in inflammatory response. It was also found to inhibit the proteins that are involved in thrombosis, thereby, having the potential to be developed as therapeutic agent. PMID:27258084

The crustal structure of the southern Argentine margin

NASA Astrophysics Data System (ADS)

Becker, Katharina; Franke, Dieter; Schnabel, Michael; Schreckenberger, Bernd; Heyde, Ingo; Krawczyk, Charlotte M.

2012-06-01

Multichannel reflection seismic profiles, combined with gravimetric and magnetic data provide insight into the crustal structure of the southernmost Argentine margin, at the transition from a rifted to a transform margin and outline the extent of the North Falkland Graben. Based on these data, we establish a regional stratigraphic model for the post-rift sediments, comprising six marker horizons with a new formation in the Barremian/Lower Cretaceous. Our observations support that a N-S trending subsidiary branch of the North Falkland Graben continues along the continental shelf and slope to the Argentine basin. During the rift phase, a wide shelf area was affected by the E-W extension, subsequently forming the North Falkland Graben and the subsidiary branch along which finally breakup occurred. We propose the division of the margin in two segments: a N-S trending rifted margin and an E-W trending transform margin. This is further underpinned by crustal scale gravity modelling. Three different tectono-dynamic processes shaped the study area. (1) The Triassic/Early Jurassic extensional phase resulting in the formation of the North Falkland Graben and additional narrower rift grabens ended synchronously with the breakup of the South Atlantic in the early Valanginian. (2) Extensional phase related to the opening of the South Atlantic. (3) The transform margin was active in the study area from about Hauterivian times and activity lasted until late Cretaceous/early Cenozoic. Both, the rifted margin and the transform margin are magma-poor. Very limited structures may have a volcanic origin but are suggested to be post-rift. The oceanic crust was found to be unusually thin, indicating a deficit in magma supply during formation. These findings in combination with the proposed breakup age in the early Valanginian that considerably predates the formation of the Paraná-Etendeka continental flood basalt provinces in Brazil and Namibia question the influence of the Tristan da Cunha hotspot during the initial formation of the South Atlantic.

The Colorado front range: anatomy of a Laramide uplift

USGS Publications Warehouse

Kellogg, Karl; Bryant, Bruce; Reed, John C.

2004-01-01

Along a transect across the Front Range from Denver to the Blue River valley near Dillon, the trip explores the geologic framework and Laramide (Late Cretaceous to early Eocene) uplift history of this basement-cored mountain range. Specific items for discussion at various stops are (1) the sedimentary and structural record along the upturned eastern margin of the range, which contains several discontinuous, east-directed reverse faults; (2) the western structural margin of the range, which contains a minimum of 9 km of thrust overhang and is significantly different in structural style from the eastern margin; (3) mid- to late-Tertiary modifications to the western margin of the range from extensional faulting along the northern Rio Grande rift trend; (4) the thermal and uplift history of the range as revealed by apatite fission track analysis; (5) the Proterozoic basement of the range, including the significance of northeast-trending shear zones; and (6) the geologic setting of the Colorado mineral belt, formed during Laramide and mid-Tertiary igneous activity.

Crustal structure and inferred extension mode in the northern margin of the South China Sea

NASA Astrophysics Data System (ADS)

Gao, J.; Wu, S.; McIntosh, K. D.; Mi, L.; Spence, G.

2016-12-01

Combining multi-channel seismic reflection and satellite gravity data, this study has investigated the crustal structure and magmatic activities of the northern South China Sea (SCS) margin. Results show that a broad continent-ocean transition zone (COT) with more than 140 km wide is characterized by extensive igneous intrusion/extrusion and hyper-extended continental crust in the northeastern SCS margin, a broader COT with 220-265 km wide is characterized by crustal thinning, rift depression, structural highs with igneous rock and perhaps a volcanic zone or a zone of tilted fault blocks at the distal edge in the mid-northern SCS margin, and a narrow COT with 65 km wide bounded seawards by a volcanic buried seamount is characterized by extremely hyper-extended continental crust in the northwestern SCS margin, where the remnant crust with less than 3 km thick is bounded by basin-bounding faults corresponding to an aborted rift below the Xisha Trough with a sub-parallel fossil ridge in the adjacent Northwest Sub-basin. Results from gravity modeling and seismic refraction data show that a high velocity layer (HVL) is present in the outer shelf and slope below extended continental crust in the eastern portion of the northern SCS margin and is thickest (up to 10 km) in the Dongsha Uplift where the HVL gradually thins to east and west below the lower slope and finally terminates at the Manila Trench and Baiyun sag of the Pearl River Mouth Basin. The magmatic intrusions/extrusions and HVL may be related to partial melting caused by decompression of passive, upwelling asthenosphere which resulted primarily in post-rifting underplating and magmatic emplacement or modification of the crust. The northern SCS margin is closer to those of the magma-poor margins than those of volcanic margins, but the aborted rift near the northwestern continental margin shows that there may be no obvious detachment fault like that in the Iberia-Newfoundland type margin. The symmetric aborted rift, broad hyper-extended continental crust, locally distributed HVL, and hotter mantle materials indicate that continental crust underwent stretching phase (pure-shear deformation), thinning phase and breakup followed by onset of seafloor spreading and the mantle-lithosphere may break up before crustal-necking in the northern South China Sea margin.

First images of the crustal structure across the central Algerian margin, off Tipaza (West Algiers) from deep penetrating seismic data: new information to constrain the opening of the Algerian basin

NASA Astrophysics Data System (ADS)

Leprêtre, A.; Deverchere, J.; Klingelhoefer, F.; Graindorge, D.; Schnurle, P.; Yelles, K.; Bracene, R.

2011-12-01

The origin of the Algerian margin remains one of the key questions still unresolved in the Western Mediterranean sea. This is related to the unknown nature and kinematics of this Neogene basin. Whereas the westernmost margin is generally assumed to have been shaped as a STEP-fault (Subduction-Transform Edge Propagator, transcurrent) margin by the westward displacement of the Alboran block, the central Algerian margin is believed to have involved a NW-SE basin opening related to a southward slab rollback. This work sheds insight on this issue, using data acquired in the context of the Algerian-French program SPIRAL (Sismique Profonde et Investigation Régionale en Algérie): a cruise conducted on the 'R/V L'Atalante' in October-November 2009. It has provided 5 new combined onshore-offshore wide-angle seismic profiles and an extensive multi-channel seismic dataset spread along the margin, from Oran to Annaba. In this work, the available structural information on the ~N-S wide-angle transect of Tipaza is presented, where the margin broadens due to the presence of a bathymetric high (the Khayr-Al-Din bank) which is assumed to represent a remaining titled block of the passive margin. Along the transect, 39 OBS and 13 landstations recorded 751 low frequency airgun shots. Travel-time tomography and forward modelling were computed using the software developed by Zelt and Barton (1998) and Zelt and Smith (1992), to obtain the velocity structure in the region. A set of multi-channel seismic reflection profiles including two coincident profiles with the wide-angle data allows a combined interpretation and extend the deep structure in the Bou Ismail Bay. MCS data outline the sedimentary sequence filling the Algerian basin depicting an intensive salt tectonic associated with the Messinan Salinity Crisis and allowing to image locally below the salt layer. The deep penetrating data SPIRAL allow to image the sedimentary sequence in the Algerian basin off Tipaza (West Algiers) and the crustal structure at the continent-ocean boundary. In the Algerian basin off Tipaza, the Moho discontinuity is identified using wide-angle modelling at 11-12 km depth which corresponds in two-way travel-time to 7-8 s. Wide-angle seismic modelling imaged a major thinning of the crust from more of 15 km in the upper margin (KADB) to only 5-6 km in the deep basin. This thinning also marks the rapid transition from a thinned continental crust at the Khayr-al-Din bank to an oceanic crust in the Algerian Basin, revealing a narrow transition zone (20-30 km) between the two domains. This work presents the deep structure of the margin West of Algiers from wide-angle and multichannel seismic data in order to discuss models of opening for the Algerian basin.

OCT structure, COB location and magmatic type of the SE Brazilian & S Angolan margins from integrated quantitative analysis of deep seismic reflection and gravity anomaly data

NASA Astrophysics Data System (ADS)

Cowie, L.; Kusznir, N. J.; Horn, B.

2013-12-01

Knowledge of ocean-continent transition (OCT) structure, continent-ocean boundary (COB) location and magmatic type are of critical importance for understanding rifted continental margin formation processes and in evaluating petroleum systems in deep-water frontier oil and gas exploration. The OCT structure, COB location and magmatic type of the SE Brazilian and S Angolan rifted continental margins are much debated; exhumed and serpentinised mantle have been reported at these margins. Integrated quantitative analysis using deep seismic reflection data and gravity inversion have been used to determine OCT structure, COB location and magmatic type for the SE Brazilian and S Angolan margins. Gravity inversion has been used to determine Moho depth, crustal basement thickness and continental lithosphere thinning. Residual Depth Anomaly (RDA) analysis has been used to investigate OCT bathymetric anomalies with respect to expected oceanic bathymetries and subsidence analysis has been used to determine the distribution of continental lithosphere thinning. These techniques have been validated on the Iberian margin for profiles IAM9 and ISE-01. In addition a joint inversion technique using deep seismic reflection and gravity anomaly data has been applied to the ION-GXT BS1-575 SE Brazil and ION-GXT CS1-2400 S Angola. The joint inversion method solves for coincident seismic and gravity Moho in the time domain and calculates the lateral variations in crustal basement densities and velocities along profile. Gravity inversion, RDA and subsidence analysis along the S Angolan ION-GXT CS1-2400 profile has been used to determine OCT structure and COB location. Analysis suggests that exhumed mantle, corresponding to a magma poor margin, is absent beneath the allochthonous salt. The thickness of earliest oceanic crust, derived from gravity and deep seismic reflection data is approximately 7km. The joint inversion predicts crustal basement densities and seismic velocities which are slightly less than expected for 'normal' oceanic crust. The difference between the sediment corrected RDA and that predicted from gravity inversion crustal thickness variation implies that this margin is experiencing ~300m of anomalous uplift attributed to mantle dynamic uplift. Gravity inversion, RDA and subsidence analysis have also been used to determine OCT structure and COB location along the ION-GXT BS1-575 profile, crossing the Sao Paulo Plateau and Florianopolis Ridge of the SE Brazilian margin. Gravity inversion, RDA and subsidence analysis predict the COB to be located SE of the Florianopolis Ridge. Analysis shows no evidence for exhumed mantle on this margin profile. The joint inversion technique predicts normal oceanic basement seismic velocities and densities and beneath the Sao Paulo Plateau and Florianopolis Ridge predicts crustal basement thicknesses between 10-15km. The Sao Paulo Plateau and Florianopolis Ridge are separated by a thin region of crustal basement beneath the salt interpreted as a regional transtensional structure. Sediment corrected RDAs and gravity derived 'synthetic' RDAs are of a similar magnitude on oceanic crust, implying negligible mantle dynamic topography.

The dinoflagellates Durinskia baltica and Kryptoperidinium foliaceum retain functionally overlapping mitochondria from two evolutionarily distinct lineages

PubMed Central

Imanian, Behzad; Keeling, Patrick J

2007-01-01

Background The dinoflagellates Durinskia baltica and Kryptoperidinium foliaceum are distinguished by the presence of a tertiary plastid derived from a diatom endosymbiont. The diatom is fully integrated with the host cell cycle and is so altered in structure as to be difficult to recognize it as a diatom, and yet it retains a number of features normally lost in tertiary and secondary endosymbionts, most notably mitochondria. The dinoflagellate host is also reported to retain mitochondrion-like structures, making these cells unique in retaining two evolutionarily distinct mitochondria. This redundancy raises the question of whether the organelles share any functions in common or have distributed functions between them. Results We show that both host and endosymbiont mitochondrial genomes encode genes for electron transport proteins. We have characterized cytochrome c oxidase 1 (cox1), cytochrome oxidase 2 (cox2), cytochrome oxidase 3 (cox3), cytochrome b (cob), and large subunit of ribosomal RNA (LSUrRNA) of endosymbiont mitochondrial ancestry, and cox1 and cob of host mitochondrial ancestry. We show that all genes are transcribed and that those ascribed to the host mitochondrial genome are extensively edited at the RNA level, as expected for a dinoflagellate mitochondrion-encoded gene. We also found evidence for extensive recombination in the host mitochondrial genes and that recombination products are also transcribed, as expected for a dinoflagellate. Conclusion Durinskia baltica and K. foliaceum retain two mitochondria from evolutionarily distinct lineages, and the functions of these organelles are at least partially overlapping, since both express genes for proteins in electron transport. PMID:17892581

Biological Activity of Japanese Quince Extract and Its Interactions with Lipids, Erythrocyte Membrane, and Human Albumin.

PubMed

Strugała, Paulina; Cyboran-Mikołajczyk, Sylwia; Dudra, Anna; Mizgier, Paulina; Kucharska, Alicja Z; Olejniczak, Teresa; Gabrielska, Janina

2016-06-01

The aim of the study was to determine in vitro biological activity of fruit ethanol extract from Chaenomeles speciosa (Sweet) Nakai (Japanese quince, JQ) and its important constituents (-)-epicatechin (EC) and chlorogenic acid (CA). The study also investigated the structural changes in phosphatidylcholine (PC) liposomes, dipalmitoylphosphatidylcholine liposomes, and erythrocyte membranes (RBC) induced by the extract. It was found that the extract effectively inhibits oxidation of RBC, induced by 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH), and PC liposomes, induced by UVB radiation and AAPH. Furthermore, JQ extract to a significant degree inhibited the activity of the enzymes COX-1 and COX-2, involved in inflammatory reactions. The extract has more than 2 times greater activity in relation to COX-2 than COX-1 (selectivity ratio 0.48). JQ extract stimulated growth of the beneficial intestinal bacteria Lactobacillus casei and Lactobacillus plantarum. In the fluorimetric method by means of the probes Laurdan, DPH and TMA-DPH, and (1)H-NMR, we examined the structural changes induced by JQ and its EC and CA components. The results show that JQ and its components induce a considerable increase of the packing order of the polar heads of lipids with a slight decrease in mobility of the acyl chains. Lipid membrane rigidification could hinder the diffusion of free radicals, resulting in inhibition of oxidative damage induced by physicochemical agents. JQ extract has the ability to quench the intrinsic fluorescence of human serum albumin through static quenching. This report thus could be of huge significance in the food industry, pharmacology, and clinical medicine.

Influence of Co doping on structural, optical and magnetic properties of BiFeO3 films deposited on quartz substrates by sol-gel method

NASA Astrophysics Data System (ADS)

Peng, Lin; Deng, Hongmei; Tian, Jianjun; Ren, Qing; Peng, Cheng; Huang, Zhipeng; Yang, Pingxiong; Chu, Junhao

2013-03-01

Multiferroic BiFe1-xCoxO3 (x = 0, 0.03, 0.05, 0.1) thin films have been prepared on quartz substrates using a sol-gel technique. X-ray diffraction data confirms that Co atoms have been successfully incorporated into the host lattice. The scanning electron microscopy (SEM) exhibits that the surface morphologies of BiFe0.97Co0.03O3 and BiFe0.95Co0.05O3 thin films become more compact and uniform. With increasing Co dopant, the position of A1-1 and E-4 modes shift towards the lower wavenumber indicates that Co doping induces structural distortion of BiFeO3. With increasing Co composition, the fundamental absorption edges of BiFe1-xCoxO3 films show red shift. Furthermore, transmittance spectra demonstrates that the optical band gap of BiFe1-xCoxO3 films decreases from 2.66 eV to 2.53 eV with the increase of Co from x = 0 to 0.1. At the wavelength of 720 nm, the refractive index decreases and the extinction coefficient increases with increasing the amount of Co. Optical properties reveal that Co doping in BiFeO3 provides preliminary research for optoelectronic devices and infrared detectors. Compared with BiFeO3 prepared under similar conditions, the remanent magnetization Mr of BiFe1-xCoxO3 (x = 0.03, 0.05, 0.1) thin films significantly enhanced, which provides potential applications in information storage.

International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study.

PubMed

Pagès, Franck; Mlecnik, Bernhard; Marliot, Florence; Bindea, Gabriela; Ou, Fang-Shu; Bifulco, Carlo; Lugli, Alessandro; Zlobec, Inti; Rau, Tilman T; Berger, Martin D; Nagtegaal, Iris D; Vink-Börger, Elisa; Hartmann, Arndt; Geppert, Carol; Kolwelter, Julie; Merkel, Susanne; Grützmann, Robert; Van den Eynde, Marc; Jouret-Mourin, Anne; Kartheuser, Alex; Léonard, Daniel; Remue, Christophe; Wang, Julia Y; Bavi, Prashant; Roehrl, Michael H A; Ohashi, Pamela S; Nguyen, Linh T; Han, SeongJun; MacGregor, Heather L; Hafezi-Bakhtiari, Sara; Wouters, Bradly G; Masucci, Giuseppe V; Andersson, Emilia K; Zavadova, Eva; Vocka, Michal; Spacek, Jan; Petruzelka, Lubos; Konopasek, Bohuslav; Dundr, Pavel; Skalova, Helena; Nemejcova, Kristyna; Botti, Gerardo; Tatangelo, Fabiana; Delrio, Paolo; Ciliberto, Gennaro; Maio, Michele; Laghi, Luigi; Grizzi, Fabio; Fredriksen, Tessa; Buttard, Bénédicte; Angelova, Mihaela; Vasaturo, Angela; Maby, Pauline; Church, Sarah E; Angell, Helen K; Lafontaine, Lucie; Bruni, Daniela; El Sissy, Carine; Haicheur, Nacilla; Kirilovsky, Amos; Berger, Anne; Lagorce, Christine; Meyers, Jeffrey P; Paustian, Christopher; Feng, Zipei; Ballesteros-Merino, Carmen; Dijkstra, Jeroen; van de Water, Carlijn; van Lent-van Vliet, Shannon; Knijn, Nikki; Mușină, Ana-Maria; Scripcariu, Dragos-Viorel; Popivanova, Boryana; Xu, Mingli; Fujita, Tomonobu; Hazama, Shoichi; Suzuki, Nobuaki; Nagano, Hiroaki; Okuno, Kiyotaka; Torigoe, Toshihiko; Sato, Noriyuki; Furuhata, Tomohisa; Takemasa, Ichiro; Itoh, Kyogo; Patel, Prabhu S; Vora, Hemangini H; Shah, Birva; Patel, Jayendrakumar B; Rajvik, Kruti N; Pandya, Shashank J; Shukla, Shilin N; Wang, Yili; Zhang, Guanjun; Kawakami, Yutaka; Marincola, Francesco M; Ascierto, Paolo A; Sargent, Daniel J; Fox, Bernard A; Galon, Jérôme

2018-05-26

The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system. The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer. French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer. Copyright © 2018 Elsevier Ltd. All rights reserved.

Mapping rift domains within an inverted hyperextended rift system: The role of rift inheritance in controlling the present-day structure of the North Iberian margin (Bay of Biscay)

NASA Astrophysics Data System (ADS)

Cadenas, Patricia; Fernández-Viejo, Gabriela; Álvarez-Pulgar, Javier; Tugend, Julie; Manatschal, Gianreto; Minshull, Tim

2017-04-01

This study presents a new rift domain map in the central and western North Iberian margin, in the southern Bay of Biscay. This margin was structured during polyphase Triassic to Lower Cretaceous rifting events which led to hyperextension and exhumation and the formation of oceanic crust during a short-lived seafloor spreading period. Extension was halted due to the Alpine convergence between the Iberian and the European plates which led to the formation of the Cantabrian-Pyrenean orogen during the Cenozoic. In the Bay of Biscay, while the northern Biscay margin was slightly inverted, the North Iberian margin, which is at present-day part of the western branch of the Alpine belt together with the Cantabrian Mountains, exhibits several degrees of compressional reactivation. This makes this area a natural laboratory to study the influence of rift inheritance into the inversion of a passive margin. Relying on the interpretation of geological and geophysical data and the integration of wide-angle results, we have mapped five rift domains, corresponding to the proximal, necking, hyperthinned, exhumed mantle, and oceanic domains. One of the main outcomes of this work is the identification of the Asturian Basin as part of a hyperthinned domain bounded to the north by the Le Danois basement high. We interpret Le Danois High as a rift-related crustal block inherited from the margin structure. Our results suggest that the inherited rift architecture controlled the subsequent compressional reactivation. The hyperextended domains within the abyssal plain focused most of the compression resulting in the development of an accretionary wedge and the underthrusting of part of these distal domains beneath the margin. The presence of the Le Danois continental block added complexity, conditioning the inversion undergone by the Asturian Basin. This residual block of less thinned continental crust acted as a local buttress hampering further compressional reactivation within the platform and the inner basin, which were only slightly inverted and uplifted passively due to the underthrusting of the hyperextended domains beneath Le Danois High. The new inverted rift domain map adds some constraints to support kinematic reconstructions and confine palinspatic restorations of the inverted rifted margin. Furthermore, it provides more insights to comprehend the strain partitioning within the Bay of Biscay-Pyrenean inverted hyperextended rift and the broad structural variability observed in such a reduced area, arising from the strong segmentation and the obliquity between the NW-SE and WNW-ESE trending rift structures and the E-W compressional front.

Prognostic Value of National Comprehensive Cancer Network Lung Cancer Resection Quality Parameters

PubMed Central

Osarogiagbon, Raymond U.; Ray, Meredith A.; Faris, Nicholas R.; Div, M.; Smeltzer, Matthew P.; Stat, M.; Fehnel, Carrie; Houston-Harris, Cheryl; Signore, Raymond S.; McHugh, Laura M.; Levy, Paul; Wiggins, Lynn; Sachdev, Vishal; Robbins, Edward T.

2017-01-01

Background The National Comprehensive Cancer Network (NCCN) surgical resection guidelines for non-small-cell lung cancer (NSCLC) recommend anatomic resection, negative margins, examination of hilar/intrapulmonary lymph nodes, and examination of 3 or more mediastinal nodal stations. We examined the survival impact of these guidelines. Methods Population-based observational study using patient-level data from all curative-intent NSCLC resections from 2004–2013 at 11 institutions in 4 contiguous Dartmouth Hospital Referral Regions in 3 US states. We used an adjusted Cox proportional hazards model to assess the overall survival impact of attaining NCCN guidelines. Results Of 2,429 eligible resections,91% were anatomic, 94% had negative margins, 51% sampled hilar nodes, and 26% examined three or more mediastinal nodal stations. Only 17% of resections met all four criteria, however there was a significant increasing trend from 2% in 2004 to 39% in 2013 (p<0.001). Compared to patients whose surgery missed one or more parameters, the hazard ratio for patients whose surgery met all four criteria was 0.71 (95% confidence interval: 0.59–0.86, p<0.001). Margin status and the nodal staging parameters were most strongly linked with survival. Conclusions Attainment of NCCN surgical quality guidelines was low, but improving, over the past decade in this cohort from a high lung cancer mortality region of the US. The NCCN quality criteria, especially the nodal examination criteria, were strongly associated with survival. The quality of nodal examination should be a focus of quality improvement in NSCLC care. PMID:28366464

Structure and magnetism in Co/X, Fe/Si, and Fe/(FeSi) multilayers

NASA Astrophysics Data System (ADS)

Franklin, Michael Ray

Previous studies have shown that magnetic behavior in multilayers formed by repeating a bilayer unit comprised of a ferromagnetic layer and a non-magnetic spacer layer can be affected by small structural differences. For example, a macroscopic property such as giant magnetoresistance (GMR) is believed to depend significantly upon interfacial roughness. In this study, several complimentary structural probes were used to carefully characterize the structure of several sputtered multilayer systems-Co/Ag, Co/Cu, Co/Mo, Fe/Si, and Fe//[FeSi/]. X-ray diffraction (XRD) studies were used to examine the long-range structural order of the multilayers perpendicular to the plane of the layers. Transmission electron diffraction (TED) studies were used to probe the long-range order parallel to the layer plane. X-ray Absorption Fine Structure (XAFS) studies were used to determine the average local structural environment of the ferromagnetic atoms. For the Co/X systems, a simple correlation between crystal structure and saturation magnetization is discovered for the Co/Mo system. For the Fe/X systems, direct evidence of an Fe-silicide is found for the /[FeSi/] spacer layer but not for the Si spacer layer. Additionally, differences were observed in the magnetic behavior between the Fe in the nominally pure Fe layer and the Fe contained in the /[FeSi/] spacer layers.

Synthesis, evaluation and modeling of some triazolothienopyrimidinones as anti-inflammatory and antimicrobial agents.

PubMed

Bekhit, Adnan A; Farghaly, Ahmed M; Shafik, Ragab M; Elsemary, Mona Ma; El-Shoukrofy, Mai S; Bekhit, Alaa El-Din A; Ibrahim, Tamer M

2017-06-01

New triazolotetrahydrobenzothienopyrimidinone derivatives were synthesized. Their structures were confirmed, and their anti-inflammatory, antimicrobial activities and ulcerogenic potentials were evaluated. Compounds 7a, 10a and 11a showed minimal ulcerogenic effect and high selectivity toward human recombinant COX-2 over COX-1 enzyme with IC 50 values of 1.39, 1.22 and 0.56 μM, respectively. Their docking outcome correlated with their biological activity and confirmed the high selectivity binding toward COX-2. Compound 12b displayed antimicrobial activity comparable to that of ampicillin against Escherichia coli while compounds 6 and 11c were similar to ampicillin against Staphylococcus aureus. In addition, compounds 7a, 9a, 10b and 11c showed dual anti-inflammatory/antimicrobial activities. This work represents a promising matrix for developing new potential anti-inflammatory, antimicrobial and dual antimicrobial/anti-inflammatory candidates. [Formula: see text].

Structure and rheology of the lithosphere below southeastern margin of India and Sri Lanka, and its conjugate segment of the east Antarctica: Implications on early breakup history and margin formation

NASA Astrophysics Data System (ADS)

Rao Gangumalla, Srinivasa; Radhakrishna, Munukutla

2014-05-01

The eastern continental margin of India has evolved as a consequence of rifting and breakup between India and east Antarctica during the early Cretaceous. Plate reconstruction models for the breakup of eastern Gondwanaland by many earlier workers have unambiguously placed the southeast margin of Sri Lanka and India together as a conjugate segment with the east Antarctica margin that extends from Gunnerus Ridge in the west to western Enderby basin in the east. In this study, we present results of integrated analysis of gravity, geoid, magnetic and seismic data from these two conjugate portions in order to examine the lithosphere structure and early seafloor spreading, style of breakup, continent-ocean boundary (COB) and rheological characteristics at these margins. The interpreted COB lies at a distance of 55-140 km on the side of southeast margin of Sri Lanka and India, whereas, it lies at a distance of 190-550 km on the side of east Antarctica margin. The seismic profiles and the constrained potential field models across these two segments do not show the existence of seaward dipping reflector sequences or magmatic underplating suggesting that these segments have not encountered major magmatic activity. While, significant crustal thinning/stretching is observed at the east Antarctic margin, the Cauvery offshore had experienced limited stretching with faulted Moho interface. Further, the conspicuous residual geoid low in the Cauvery offshore basin is inferred to be due to a continental crustal block. The modelled Lithosphere-Astenosphere Boundary (LAB) in these two margins is located around 110-120 km depth with slightly thicker lithosphere at the east Antarctica margin. In addition, the interpretation of magnetic anomalies provided structure of the oceanic crust generated through seafloor spreading processes with age and magnetization data constrained from the identified magnetic anomalies in the respective margins. Using the Bouguer coherence method, we computed spatial variations in effective elastic thickness (Te) at these margin segments. The estimated Te values at the Indian margin ranges between 5-8 km in the southeast of Sri Lanka to around 10-12 km in the Cauvery offshore which decrease further north to < 5 km in the Cauvery-Palar basin. Along the east Antarctic margin, the Te values ranges between 5-10 km in the Gunnerus ridge region, 35-40 km in the western Enderby basin which decrease further towards the central Enderby basin up to 20 km. In this study, the above results have been analyzed in terms of early breakup mechanism and subsequent evolution of these two conjugate segments.

Negative Stress Margins - Are They Real?

NASA Technical Reports Server (NTRS)

Raju, Ivatury S.; Lee, Darlene S.; Mohaghegh, Michael

2011-01-01

Advances in modeling and simulation, new finite element software, modeling engines and powerful computers are providing opportunities to interrogate designs in a very different manner and in a more detailed approach than ever before. Margins of safety are also often evaluated using local stresses for various design concepts and design parameters quickly once analysis models are defined and developed. This paper suggests that not all the negative margins of safety evaluated are real. The structural areas where negative margins are frequently encountered are often near stress concentrations, point loads and load discontinuities, near locations of stress singularities, in areas having large gradients but with insufficient mesh density, in areas with modeling issues and modeling errors, and in areas with connections and interfaces, in two-dimensional (2D) and three-dimensional (3D) transitions, bolts and bolt modeling, and boundary conditions. Now, more than ever, structural analysts need to examine and interrogate their analysis results and perform basic sanity checks to determine if these negative margins are real.

Improved Nazca slab structure from teleseismic P-wave tomography along the Andean margin

NASA Astrophysics Data System (ADS)

Portner, D. E.; Beck, S. L.; Scire, A. C.; Zandt, G.

2017-12-01

South America marks the longest continuous ocean-continent subduction zone. As such, there is significant along-strike variability in the subducting Nazca slab structure and the tectonics of the South American margin. Most notably two gaps in the otherwise continuous volcanic arc are correlated with regions of flat slab subduction, indicating that the structure of the Nazca slab plays a controlling role in South American tectonics. Traditionally in subduction zones, our knowledge of slab structure is defined by Wadati-Benioff zone earthquakes. While this method allows for the determination of large-scale variations in Nazca slab structure such as regions of flat slab subduction, a scarcity of intermediate-depth earthquakes hinders our ability to observe the smaller-scale structural variations in the slab that may be critical to our understanding of the geologic record. We use an updated, larger dataset for finite-frequency teleseismic P-wave tomography including relative arrival times from >700 seismic stations along the Andean margin to image the detailed Nazca slab structure throughout the upper mantle and uppermost lower mantle between latitudes 5°S and 45°S. Our results show prominent variations in slab character along the margin. Slab dip varies significantly, from sub-vertical inboard of the Peruvian flat slab segment to 30° dip south of the Pampean flat slab, while the slab's velocity anomaly amplitude changes dramatically near the Pampean flat slab region. High slab velocities north of the Pampean region relative to the south indicate variable slab thermal structures that correspond roughly with the locations of deep (>500 km depth) earthquakes that also occur exclusively north of the Pampean region. Additionally, a wider regional footprint increases our sampling of the upper-lower mantle boundary, improving constraints on the slab's interaction with the 660 km discontinuity along strike. We see that the Nazca slab appears to penetrate into the lower mantle along the majority of the margin.

Contrast of lithospheric dynamics across the southern and eastern margins of the Tibetan Plateau: a numerical study

NASA Astrophysics Data System (ADS)

Sun, Yujun; Fan, Taoyuan; Wu, Zhonghai

2018-05-01

Both of the southern and eastern margins of the Tibetan Plateau are bounded by the cratonic blocks (Indian plate and Sichuan basin). However, there are many differences in tectonic deformation, lithospheric structure and surface heat flow between these two margins. What dynamics cause these differences? With the constraints of the lithospheric structure and surface heat flow across the southern and eastern margins of Tibetan Plateau, we constructed 2-D thermal-mechanical finite-element models to investigate the dynamics across these two margins. The results show that the delamination of mantle lithosphere beneath the Lhasa terrane in Oligocene and the rheological contrast between the Indian and Tibetan crust are the two main factors that control the subduction of the Indian plate. The dynamics across the eastern margin of the Tibetan Plateau are different from the southern margin. During the lateral expansion of the Tibetan Plateau, pure shear thickening is the main deformation characteristic for the Songpan-Ganzi lithosphere. This thickening results in the reduction of geothermal gradient and surface heat flow. From this study, it can be seen that the delamination of the mantle lithosphere and the rheological contrast between the Tibetan Plateau and its bounding blocks are the two main factors that control the lithospheric deformation and surface heat flow.

Final stress analysis report ultraviolet spectrometer S169

NASA Technical Reports Server (NTRS)

Cooper, S.

1971-01-01

The stress analysis report verifies the structural integrity of the Apollo S-169 UV-spectrometer experiment. The methods by which the various members were analyzed are described. A detailed summary of results for the individual structural elements appears in the form of a table of minimum margins of safety. No negative margins of safety were experienced. It is concluded that the component structure is more than adequate to withstand the environmental load conditions given in the design criteria.

First results on the crustal structure of the Natal Valley from combined wide-angle and reflection seismic data (MOZ3/5 cruise), South Mozambique Margin.

NASA Astrophysics Data System (ADS)

Leprêtre, Angélique; Verrier, Fanny; Evain, Mikael; Schnurle, Philippe; Watremez, Louise; Aslanian, Daniel; de Clarens, Philippe; Dias, Nuno; Afilhado, Alexandra; Leroy, Sylvie; d'Acremont, Elia; Castilla, Raymi; Moulin, Maryline

2017-04-01

The Natal valley (South Mozambique margin) is a key area for the understanding of the SW Indian Ocean history since the Gondwana break-up, and widely, the structure of a margin system at the transition between divergent and strike-slip segments. As one part of the PAMELA project (PAssive Margins Exploration Laboratories), conducted by TOTAL, IFREMER, in collaboration with Université de Bretagne Occidentale, Université Rennes 1, Université Pierre and Marie Curie, CNRS et IFPEN, the Natal Valley and the East Limpopo margin have been explored during the MOZ3/5 cruise (2016), conducted onboard the R/V Pourquoi Pas?, through the acquisition of 7 wide-angle profiles and coincident marine multichannel (720 traces) seismic as well as potential field data. Simultaneously, land seismometers were deployed in the Mozambique coastal plains, extending six of those profiles on land for about 100 km in order to provide information on the onshore-offshore transition. Wide-angle seismic data are of major importance as they can provide constrains on the crustal structure of the margin and the position of the continent-ocean boundary in an area where the crustal nature is poorly known and largely controversial. The aim of this work is to present the first results on the crustal structure from P-waves velocity modeling along two perpendicular MZ1 & MZ7 wide-angle profiles crossing the Natal Valley in an E-W and NNW-SSE direction respectively, which reveal a crust up to 30 km thick below the Natal Valley and thus raises questions of a purely oceanic origin of the Valley. The post-doc of Angélique Leprêtre is co-funded by TOTAL and IFREMER as part of the PAMELA (Passive Margin Exploration Laboratories) scientific project.

Geophysical reassessment of the role of ancient crustal structures on the development of western Laurentia and Selwyn Basin, Yukon and Northwest Territories, Canada.

NASA Astrophysics Data System (ADS)

Hayward, N.

2017-12-01

The structure of the western margin of the North American craton (Laurentia) in the northern Canadian Cordillera and its role in the development of the Neoproterozoic-Early Paleozoic Selwyn Basin are reassessed through 3D inversion of a new compilation of aeromagnetic data and archival Bouguer gravity data. The region's tectonic history is obscured by partial burial beneath Selwyn Basin, and a tectonic overprint that includes terrane accretion, regional plutonism, and strike-slip faults with displacements of 100s and perhaps 1000s of kilometers. Despite the implied complexity, preliminary geological and geophysical based interpretations of the structure of the western margin of Laurentia, have been adopted with few refinements in over two decades. Regionally continuous, NE-trending, crustal lineaments, including the Fort Norman line and Leith Ridge fault, were interpreted as having had long-standing influence on the craton development, its western margin, and overlapping sedimentary basin. New results reveal limited evidence for the regional continuity of the NE-trending lineaments. Instead, models suggest that the structure of the Laurentian margin is characterised by segmentation on numerous shorter structures of varied strike. The western margin of the craton and its structures are bound by a NW-trending structure that connects with the Richardson Trough to the north and may have been active during rifting of the Misty Creek embayment. This boundary also marks the easternmost limit of both granitic intrusions in Selwyn Basin, which gravity models suggest are of greater extent than reflected on geological maps, and SEDEX occurrences. An ENE-trending structure beneath northern Selwyn Basin is interpreted as marking the southern edge of a previously unidentified cratonic promontory, akin to the Liard line that marks a transfer fault that bounds the promontory of the Macdonald Platform, south of Selwyn Basin. The ENE-trending structure is traced from the Tintina fault in the west to near to the Great Bear magmatic zone. The structure's regional continuity also limits the interpretation of a post-Cretaceous structure, inboard of the Tintina fault that could be responsible for 1000's km of dextral strike-slip ascribed to the Baja-BC terrane translation model.

COX16 promotes COX2 metallation and assembly during respiratory complex IV biogenesis

PubMed Central

Aich, Abhishek; Wang, Cong; Chowdhury, Arpita; Ronsör, Christin; Pacheu-Grau, David; Richter-Dennerlein, Ricarda; Dennerlein, Sven

2018-01-01

Cytochrome c oxidase of the mitochondrial oxidative phosphorylation system reduces molecular oxygen with redox equivalent-derived electrons. The conserved mitochondrial-encoded COX1- and COX2-subunits are the heme- and copper-center containing core subunits that catalyze water formation. COX1 and COX2 initially follow independent biogenesis pathways creating assembly modules with subunit-specific, chaperone-like assembly factors that assist in redox centers formation. Here, we find that COX16, a protein required for cytochrome c oxidase assembly, interacts specifically with newly synthesized COX2 and its copper center-forming metallochaperones SCO1, SCO2, and COA6. The recruitment of SCO1 to the COX2-module is COX16- dependent and patient-mimicking mutations in SCO1 affect interaction with COX16. These findings implicate COX16 in CuA-site formation. Surprisingly, COX16 is also found in COX1-containing assembly intermediates and COX2 recruitment to COX1. We conclude that COX16 participates in merging the COX1 and COX2 assembly lines. PMID:29381136

ROCOPT: A user friendly interactive code to optimize rocket structural components

NASA Technical Reports Server (NTRS)

Rule, William K.

1989-01-01

ROCOPT is a user-friendly, graphically-interfaced, microcomputer-based computer program (IBM compatible) that optimizes rocket components by minimizing the structural weight. The rocket components considered are ring stiffened truncated cones and cylinders. The applied loading is static, and can consist of any combination of internal or external pressure, axial force, bending moment, and torque. Stress margins are calculated by means of simple closed form strength of material type equations. Stability margins are determined by approximate, orthotropic-shell, closed-form equations. A modified form of Powell's method, in conjunction with a modified form of the external penalty method, is used to determine the minimum weight of the structure subject to stress and stability margin constraints, as well as user input constraints on the structural dimensions. The graphical interface guides the user through the required data prompts, explains program options and graphically displays results for easy interpretation.

Polaronic transport and thermoelectricity in Fe1 -xCoxSb2S4 (x =0 , 0.1, and 0.2)

NASA Astrophysics Data System (ADS)

Liu, Yu; Kang, Chang-Jong; Stavitski, Eli; Du, Qianheng; Attenkofer, Klaus; Kotliar, G.; Petrovic, C.

2018-04-01

We report a study of Co-doped berthierite Fe1 -xCoxSb2S4 (x =0 , 0.1, and 0.2). The alloy series of Fe1 -xCoxSb2S4 crystallize in an orthorhombic structure with the Pnma space group, similar to FeSb2, and show semiconducting behavior. The large discrepancy between activation energy for conductivity, Eρ (146 ˜270 meV ), and thermopower, ES (47 ˜108 meV ), indicates the polaronic transport mechanism. Bulk magnetization and heat-capacity measurements of pure FeSb2S4 (x =0 ) exhibit a broad antiferromagnetic transition (TN=46 K ) followed by an additional weak transition (T*=50 K ). Transition temperatures (TN and T*) slightly decrease with increasing Co content x . This is also reflected in the thermal conductivity measurement, indicating strong spin-lattice coupling. Fe1 -xCoxSb2S4 shows relatively high value of thermopower (up to ˜624 μ V K-1 at 300 K) and thermal conductivity much lower when compared to FeSb2, a feature desired for potential applications based on FeSb2 materials.

Cyclooxygenase inhibitory compounds from Gymnosporia heterophylla aerial parts.

PubMed

Ochieng, Charles O; Opiyo, Sylvia A; Mureka, Edward W; Ishola, Ismail O

2017-06-01

Gymnosporia heterophylla (Celastraceae) is an African medicinal plants used to treat painful and inflammatory diseases with partial scientific validation. Solvent extractions followed by repeated chromatographic purification of the G. heterophylla aerial parts led to the isolation of one new β-dihydroagarofuran sesquiterpene alkaloid (1), and two triterpenes (2-3). In addition, eight known compounds including one β-dihydroagarofuran sesquiterpene alkaloid (4), and six triterpenes (5-10) were isolated. All structures were determined through extensive analysis of the NMR an MS data as well as by comparison with literature data. These compounds were evaluated for the anti-inflammatory activities against COX-1 and -2 inhibitory potentials. Most of the compound isolated showed non selective COX inhibitions except for 3-Acetoxy-1β-hydroxyLupe-20(29)-ene (5), Lup-20(29)-ene-1β,3β-diol (6) which showed COX-2 selective inhibition at 0.54 (1.85), and 0.45 (2.22) IC 50 , in mM (Selective Index), respectively. The results confirmed the presence of anti-inflammatory compounds in G. heterophylla which are important indicators for development of complementary medicine for inflammatory reactions; however, few could be useful as selective COX-2 inhibitor. Copyright © 2017 Elsevier B.V. All rights reserved.

Vitual screening and binding mode elucidation of curcumin analogues on Cyclooxygenase-2 using AYO_COX2_V1.1 protocol

NASA Astrophysics Data System (ADS)

Mulatsari, E.; Mumpuni, E.; Herfian, A.

2017-05-01

Curcumin is yellow colored phenolic compounds contained in Curcuma longa. Curcumin is known to have biological activities as anti-inflammatory, antiviral, antioxidant, and anti-infective agent [1]. Synthesis of curcumin analogue compounds has been done and some of them had biological activity like curcumin. In this research, the virtual screening of curcumin analogue compounds has been conducted. The purpose of this research was to determine the activity of these compounds as selective Cyclooxygenase-2inhibitors in in-silico. Binding mode elucidation was made by active and inactive representative compounds to see the interaction of the amino acids in the binding site of the compounds. This research used AYO_COX2_V.1.1, a structure-based virtual screening protocol (SBVS) that has been validated by Mumpuni E et al, 2014 [2]. AYO_COX2_V.1.1 protocol using a variety of integrated applications such as SPORES, PLANTS, BKchem, OpenBabel and PyMOL. The results of virtual screening conducted on 49 curcumin analogue compounds obtained 8 compounds with 4 active amino acid residues (GLY340, ILE503, PHE343, and PHE367) that were considered active as COX-2 inhibitor.

First principles investigations of Fe2CrSi Heusler alloys by substitution of Co at Fe site

NASA Astrophysics Data System (ADS)

Jain, Rakesh; Lakshmi, N.; Jain, Vivek Kumar; Chandra, Aarti R.

2018-04-01

Electronic structure and magnetic properties of Fe2-xCoxCrSi Heusler alloys have been investigated by varying Co concentration from x = 0 to 2. On increasing Co concentration, lattice constant and magnetic moment of Fe2-xCoxCrSi alloys increase. These alloys show true half metallic Ferromagnetic behavior with 100% spin polarization. Band gap of the alloys also increase from 0.54 eV to 0.85 eV on increasing Co concentration making these alloys promising materials for spintronics based device applications.

The tapeworm Atractolytocestus tenuicollis (Cestoda: Caryophyllidea)--a sister species or ancestor of an invasive A. huronensis?

PubMed

Králová-Hromadová, Ivica; Štefka, Jan; Bazsalovicsová, Eva; Bokorová, Silvia; Oros, Mikuláš

2013-10-01

Atractolytocestus tenuicollis (Li, 1964) Xi, Wang, Wu, Gao et Nie, 2009 is a monozoic, non-segmented tapeworm of the order Caryophyllidea, parasitizing exclusively common carp (Cyprinus carpio L.). In the current work, the first molecular data, in particular complete ribosomal internal transcribed spacer 2 (ITS2) and partial mitochondrial cytochrome c oxidase subunit I (cox1) on A. tenuicollis from Niushan Lake, Wuhan, China, are provided. In order to evaluate molecular interrelationships within Atractolytocestus, the data on A. tenuicollis were compared with relevant data on two other congeners, Atractolytocestus huronensis and Atractolytocestus sagittatus. Divergent intragenomic copies (ITS2 paralogues) were detected in the ITS2 ribosomal spacer of A. tenuicollis; the same phenomenon has previously been observed also in two other congeners. ITS2 structure of A. tenuicollis was very similar to that of A. huronensis from Slovakia, USA and UK; overall pairwise sequence identity was 91.7-95.2%. On the other hand, values of sequence identity between A. tenuicollis and A. sagittatus were lower, 69.7-70.9%. Cox1 sequence, analysed in five A. tenuicollis individuals, were 100 % identical and no intraspecific variation was observed. Comparison of A. tenuicollis cox1 with respective sequences of two other Atractolytocestus species showed that the mitochondrial haplotype found in Chinese A. tenuicollis is structurally specific (haplotype 4; Ha4) and differs from all so far determined Atractolytocestus haplotypes (Ha1 and Ha2 for A. huronensis; Ha3 for A. sagittatus). Pairwise sequence identity between A. tenuicollis cox1 haplotype and remaining three haplotypes followed the same pattern as in ITS2. The nucleotide and amino acide (aa) sequence comparison with A. huronensis Ha1 and Ha2 revealed higher sequence identity, 90.3-90.8% (96.9% in aa), while lower values were achieved between A. tenuicollis haplotype and Ha3 of Japanese A. sagittatus-75.2 % (81.9 % in aa). The phylogenetic analyses using cox1, ITS2 and combined cox1 + ITS2 sequences revealed close genetic interrelationship between A. tenuicollis and A. huronensis. Independently of a type of analysis and DNA region used, the topology of obtained trees was always identical; A. tenuicollis formed separate clade with A. huronensis forming a closely related sister group.

A discussion on the origin of quantum probabilities

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

Holik, Federico, E-mail: olentiev2@gmail.com; Departamento de Matemática - Ciclo Básico Común, Universidad de Buenos Aires - Pabellón III, Ciudad Universitaria, Buenos Aires; Sáenz, Manuel

We study the origin of quantum probabilities as arising from non-Boolean propositional-operational structures. We apply the method developed by Cox to non distributive lattices and develop an alternative formulation of non-Kolmogorovian probability measures for quantum mechanics. By generalizing the method presented in previous works, we outline a general framework for the deduction of probabilities in general propositional structures represented by lattices (including the non-distributive case). -- Highlights: •Several recent works use a derivation similar to that of R.T. Cox to obtain quantum probabilities. •We apply Cox’s method to the lattice of subspaces of the Hilbert space. •We obtain a derivationmore » of quantum probabilities which includes mixed states. •The method presented in this work is susceptible to generalization. •It includes quantum mechanics and classical mechanics as particular cases.« less

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

PubMed

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

2005-06-30

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

The Cascadia Subduction Zone: two contrasting models of lithospheric structure

USGS Publications Warehouse

Romanyuk, T.V.; Blakely, R.; Mooney, W.D.

1998-01-01

The Pacific margin of North America is one of the most complicated regions in the world in terms of its structure and present day geodynamic regime. The aim of this work is to develop a better understanding of lithospheric structure of the Pacific Northwest, in particular the Cascadia subduction zone of Southwest Canada and Northwest USA. The goal is to compare and contrast the lithospheric density structure along two profiles across the subduction zone and to interpet the differences in terms of active processes. The subduction of the Juan de Fuca plate beneath North America changes markedly along the length of the subduction zone, notably in the angle of subduction, distribution of earthquakes and volcanism, goelogic and seismic structure of the upper plate, and regional horizontal stress. To investigate these characteristics, we conducted detailed density modeling of the crust and mantle along two transects across the Cascadia subduction zone. One crosses Vancouver Island and the Canadian margin, the other crosses the margin of central Oregon.

Cordilleran hingeline: Late Precambrian rifted margin of the North American craton and its impact on the depositional and structural history, Utah and Nevada

NASA Astrophysics Data System (ADS)

Picha, Frank; Gibson, Richard I.

1985-07-01

The structural pattern set by late Precambrian rifting and fragmentation of the North American continent is apparent in both sedimentary and tectonic trends in western Utah and eastern Nevada. The late Precambrian cratonic margin (Cordilleran hingeline) displays several prominent structural features, such as the Wasatch and Ancient Ephraim faults, Fillmore arch and northeast-trending lineaments, which were repeatedly reactivated as structural uplifts, ramps, strike-slip faults, and extensional detachments. The renewed activity affected, among others, the geometry of the late Paleozoic Ancestral Rocky Mountain uplifts and basins, the extent of the Jurassic Arapien basin, the sedimentary pattern of the Cretaceous foreland basin, the geometry of the Sevier orogenic belt, and the extent and type of Basin-and-Range extensional tectonics. The rifted cratonic margin has thus remained a major influence on regional structures long after rifting has ceased. *Present address: Everest Geotech, 10101 Southwest Freeway, Houston, Texas 77074

Late Jurassic - Early Cretaceous convergent margins of Northeastern Asia with Northwestern Pacific and Proto-Arctic oceans

NASA Astrophysics Data System (ADS)

Sokolov, Sergey; Luchitskaya, Marina; Tuchkova, Marianna; Moiseev, Artem; Ledneva, Galina

2013-04-01

Continental margin of Northeastern Asia includes many island arc terranes that differ in age and tectonic position. Two convergent margins are reconstructed for Late Jurassic - Early Cretaceous time: Uda-Murgal and Alazeya - Oloy island arc systems. A long tectonic zone composed of Upper Jurassic to Lower Cretaceous volcanic and sedimentary rocks is recognized along the Asian continent margin from the Mongol-Okhotsk thrust-fold belt on the south to the Chukotka Peninsula on the north. This belt represents the Uda-Murgal arc, which was developed along the convergent margin between Northeastern Asia and Northwestern Meso-Pacific. Several segments are identified in this arc based upon the volcanic and sedimentary rock assemblages, their respective compositions and basement structures. The southern and central parts of the Uda-Murgal island arc system were a continental margin belt with heterogeneous basement represented by metamorphic rocks of the Siberian craton, the Verkhoyansk terrigenous complex of Siberian passive margin and the Koni-Taigonos late Paleozoic to early Mesozoic island arc with accreted oceanic terranes. At the present day latitude of the Pekulney and Chukotka segments there was an ensimatic island arc with relicts of the South Anyui oceanic basin in backarc basin. Alazeya-Oloy island arc systems consists of Paleozoic and Mesozoic complexes that belong to the convergent margin between Northeastern Asia and Proto-Artic Ocean. It separated structures of the North American and Siberian continents. The Siberian margin was active whereas the North American margin was passive. The Late Jurassic was characterized by termination of a spreading in the Proto-Arctic Ocean and transformation of the latter into the closing South Anyui turbidite basin. In the beginning the oceanic lithosphere and then the Chukotka microcontinent had been subducted beneath the Alazeya-Oloy volcanic belt

3-D Structure and Morphology of the S-reflector Detachment Fault, Offshore Galicia, Spain

NASA Astrophysics Data System (ADS)

Schuba, C. N.; Sawyer, D. S.; Gray, G. G.; Morgan, J.; Bull, J.; Shillington, D. J.; Jordan, B.; Reston, T. J.

2017-12-01

The crustal architecture of passive continental margins provides valuable clues for understanding rift initiation and evolution. The Galicia margin is an archetypal magma-poor margin displaying exhumed serpentinized mantle, and is an optimal setting in which to examine rift-related processes. A new 3-D seismic reflection volume images this margin in great detail. The S-reflector detachment fault, one of the most prominent structural features associated with the Galicia margin, is imaged as a continuous interface over an area of 600 km2. The top and base of the fault zone can be mapped independently, which enables seismic attribute analysis of this significant structure. RMS amplitude maps extracted from this interface show localized patches of high amplitude stripes that coincide with thickness variations of the fault zone and undulations in the bounding surfaces of the fault. These variations bear similarities to grooves on the fault surface such as slickensides, and appear to have developed as the fault zone evolved. These features thus represent good indicators of the kinematics of the fault system. In general, there is good correlation between S-reflector morphology and the overriding fault intersections; however this relationship does not appear to be present with the fault gouge thickness.

GLORIA mosaic of the Gulf of Alaska and the British Columbia margin: Deep-sea channels, margin deformation, and the Queen Charlotte fault

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

Bruns, T.R.; Carlson, P.R.; Stevenson, A.J.

1990-05-01

GLORIA images collected from 1986 to 1989 show sea-floor morphology from the shelf break seaward to 400 km in the Gulf of Alaska and a 70-km-wide swath along British Columbia. Along the Aleutian convergent margin sediment is dominantly trapped in mid-slope basins, where few canyons reach the trench. Accretionary wedge structures range from highly discontinuous to long and continuous. The Yakutat transition margin is either extensively cut by dendritic drainages or, at sea-valley mouths, covered by glacially derived sediment. Young structures underlie the slope from Middleton Island to Pamplona Spur, but are absent from Pamplona Spur to Cross Sound. Alongmore » the southeast Alaska transform margin the Queen Charlotte fault is imaged as a narrow linear feature. The fault steps westward at Tuzo Wilson Knolls, which likely is a spreading ridge segment. Large anticlines lie seaward of and trend parallel to the fault. On the abyssal plain off the Shumagin margin inherited structural and bathymetric features trend parallel to magnetic anomalies, and trench parallel features reflect faulting as the ocean plate bends into the trench. To the north, three turbidite systems drain the margin. The Surveyor system begins between Pamplona Spur and Alsek Canyon and empties into the Aleutian Trench. The Chirikof system arises near Cross Sound and ends in turbidite fans south of the Kodiak-Bowie Seamount chain, a relic Chirikov channel that once carried sediment westward to the Aleutian Trench. The Mukluk and Horizon channels start along southeast Alaska and end 1,000 km away on the Tufts abyssal plain.« less

Passive recording of an active transform, an example from the Levant continental margin and the Dead Sea Fault

NASA Astrophysics Data System (ADS)

Lang, Guy; Lazar, Michael; Schattner, Uri

2017-04-01

Transform faults accommodate lateral motion between two adjacent plates. Records of plate motion and consequent boundary development on land is, at times, scarce and limited to structures along the fault axis. Investigation of a passive continental margin adjacent to the plate boundary might broaden the scope and provide estimates for its structural development. To examine this hypothesis, we analyzed depth and time migrated 3D seismic data together with four boreholes located along the southern Levant continental margin, ca. 100 Km from the continental Dead Sea fault (DSF). The analysis focus on the Plio-Pleistocene sequence, a key period in the development of the DSF. It includes formation of structural maps, stacking pattern investigation and calculation of sedimentation rates based on decompacted 3D depth data. These, in turn, enabled the reconstruction of margin development. This includes Messinian-earliest Zanclean NNE-SSW sinistral strike-slip faulting followed by Zanclean-Late Gelasian syn-depositional folding striking in the same direction. Abrupt change is marked by the Top Gelasian surface that shows indications of regional mass slumping. Successive Mid-Late Pleistocene progradation marks a basinward shift of the depocenter. Progradation controls margin sedimentation rates during the mid-late Pleistocene. These were found to increase throughout the whole Plio-Pleistocene, in contrast to reported sediment discharge from the Nile, which was shown to decrease after the Gelasian. Correlations to onshore findings, suggest that the continental margin records strain localization on the DSF during the Pliocene-Gelasian. This trend peaked at 1.8 Ma when short wavelength strain ceased along the margin, and differential subsidence commenced basinwards. This is attributed to consequent deepening of the DSF plate boundary.

Structural Margins Assessment Approach

NASA Technical Reports Server (NTRS)

Ryan, Robert S.

1988-01-01

A general approach to the structural design and verification used to determine the structural margins of the space vehicle elements under Marshall Space Flight Center (MSFC) management is described. The Space Shuttle results and organization will be used as illustrations for techniques discussed. Given also are: (1) the system analyses performed or to be performed by, and (2) element analyses performed by MSFC and its contractors. Analysis approaches and their verification will be addressed. The Shuttle procedures are general in nature and apply to other than Shuttle space vehicles.

Influence of the site of origin on the outcome of squamous cell carcinoma of the maxilla-oral versus sinus.

PubMed

Bobinskas, A M; Wiesenfeld, D; Chandu, A

2014-02-01

The maxilla may be affected by squamous cell carcinoma (SCC) from both oral and sinus sites. We sought to determine whether the site of origin of the maxillary tumour, oral as compared to sinus, influences survival. Univariate Kaplan-Meier and multivariate Cox proportional hazard models analysis of 58 patients with SCC involving the maxilla, treated with curative intent, was conducted. The overall 5-year disease-free survival for the group was 41.7%. Five-year disease-free survival for oral subsite SCC was 56.8%, while for sinus subsite was only 21.6%. Univariate analysis found SCC of sinus origin to be associated with a poorer prognosis, however this was not confirmed on multivariate analysis. T-stage and positive margins were found to be the only independent risk factors. For SCC of the maxilla, sinus origin of the tumour per se does not confer a poorer prognosis; however, as a result of the complex anatomy of the midface, these tumours can present at an advanced stage, while surgical control of the disease can be more difficult, especially posteriorly. Tumour size and positive margins were the determinants of a poor prognosis in this group of patients with maxillary SCC. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Engineering the Electronic Structure of 2D WS2 Nanosheets Using Co Incorporation as Cox W(1- x ) S2 for Conspicuously Enhanced Hydrogen Generation.

PubMed

Shifa, Tofik Ahmed; Wang, Fengmei; Liu, Kaili; Xu, Kai; Wang, Zhenxing; Zhan, Xueying; Jiang, Chao; He, Jun

2016-07-01

Transition metal dichalcogenides (TMDs), as one of potential electrocatalysts for hydrogen evolution reaction (HER), have been extensively studied. Such TMD-based ternary materials are believed to engender optimization of hydrogen adsorption free energy to thermoneutral value. Theoretically, cobalt is predicted to actively promote the catalytic activity of WS2 . However, experimentally it requires systematic approach to form Cox W(1- x ) S2 without any concomitant side phases that are detrimental for the intended purpose. This study reports a rational method to synthesize pure ternary Cox W(1- x ) S2 nanosheets for efficiently catalyzing HER. Benefiting from the modification in the electronic structure, the resultant material requires overpotential of 121 mV versus reversible hydrogen electrode (RHE) to achieve current density of 10 mA cm(-2) and shows Tafel slope of 67 mV dec(-1) . Furthermore, negligible loss of activity is observed over continues electrolysis of up to 2 h demonstrating its fair stability. The finding provides noticeable experimental support for other computational reports and paves the way for further works in the area of HER catalysis based on ternary materials. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

THERMAL AND ELECTRICAL PROPERTIES OF Ba0.5Sr0.5CoxFe1-x-yNiyO3-δ (x = 0.4, 0 ≤ y ≤ 0.25) AS CATHODE MATERIAL FOR IT-SOFCs

NASA Astrophysics Data System (ADS)

Burnwal, Suman Kumar; Kistaiah, P.

2015-03-01

Ba0.5Sr0.5CoxFe1-x-yNiyO3-δ (BSCFNi; x = 0.4, 0 ≤ y ≤ 0.25) were studied in relation to their potential use as intermediate temperature solid oxide fuel cell (IT-SOFC) cathode. An emphasis is made on the effect of Ni-doping on crystal structure, thermal expansion coefficient (TEC) and dc electrical conductivity. A cubic perovskite structure was observed in the X-ray diffraction (XRD) measurement. The TEC of BSCFNi obtained for 0 ≤ y ≤ 0.25, varies in the range of (12.38-18.81) × 10-6 K-1, measured in the temperature range of 30°C to 800°C. The electrical conductivity which is a major defect of Ba0.5Sr0.5CoxFe1-xO3-δ (BSCF) was improved by Ni-doping. The compound with y = 0.20 and 0.25 demonstrated a conductivity of σ = 62.59 S-cm-1 and 72.64 S-cm-1 at 400°C and 77.01 S-cm-1 and 89.68 S-cm-1 at 500°C.

A preliminary investigation into the genetic variation and population structure of Taenia hydatigena from Sardinia, Italy.

PubMed

Boufana, Belgees; Scala, Antonio; Lahmar, Samia; Pointing, Steve; Craig, Philip S; Dessì, Giorgia; Zidda, Antonella; Pipia, Anna Paola; Varcasia, Antonio

2015-11-30

Cysticercosis caused by the metacestode stage of Taenia hydatigena is endemic in Sardinia. Information on the genetic variation of this parasite is important for epidemiological studies and implementation of control programs. Using two mitochondrial genes, the cytochrome c oxidase subunit 1 (cox1) and the NADH dehydrogenase subunit 1 (ND1) we investigated the genetic variation and population structure of Cysticercus tenuicollis from Sardinian intermediate hosts and compared it to that from other hosts from various geographical regions. The parsimony cox1 network analysis indicated the existence of a common lineage for T. hydatigena and the overall diversity and neutrality indices indicated demographic expansion. Using the cox1 sequences, low pairwise fixation index (Fst) values were recorded for Sardinian, Iranian and Palestinian sheep C. tenuicollis which suggested the absence of genetic differentiation. Using the ND1 sequences, C. tenuicollis from Sardinian sheep appeared to be differentiated from those of goat and pig origin. In addition, goat C. tenuicollis were genetically different from adult T. hydatigena as indicated by the statistically significant Fst value. Our results are consistent with biochemical and morphological studies that suggest the existence of variants of T. hydatigena. Copyright © 2015 Elsevier B.V. All rights reserved.

The composition and structure of volcanic rifted continental margins in the North Atlantic: Further insight from shear waves

NASA Astrophysics Data System (ADS)

Eccles, Jennifer D.; White, Robert S.; Christie, Philip A. F.

2011-07-01

Imaging challenges caused by highly attenuative flood basalt sequences have resulted in the understanding of volcanic rifted continental margins lagging behind that of non-volcanic rifted and convergent margins. Massive volcanism occurred during break-up at 70% of the passive margins bordering the Atlantic Ocean, the causes and dynamics of which are still debated. This paper shows results from traveltime tomography of compressional and converted shear wave arrivals recorded on 170 four-component ocean bottom seismometers along two North Atlantic continental margin profiles. This traveltime tomography was performed using two different approaches. The first, a flexible layer-based parameterisation, enables the quality control of traveltime picks and investigation of the crustal structure. The second, with a regularised grid-based parameterisation, requires correction of converted shear wave traveltimes to effective symmetric raypaths and allows exploration of the model space via Monte Carlo analyses. The velocity models indicate high lower-crustal velocities and sharp transitions in both velocity and Vp/Vs ratios across the continent-ocean transition. The velocities are consistent with established mixing trends between felsic continental crust and high magnesium mafic rock on both margins. Interpretation of the high quality seismic reflection profile on the Faroes margin confirms that this mixing is through crustal intrusion. Converted shear wave data also provide constraints on the sub-basalt lithology on the Faroes margin, which is interpreted as a pre-break-up Mesozoic to Paleocene sedimentary system intruded by sills.

NRC Continental Margins Workshop

NASA Astrophysics Data System (ADS)

Katsouros, Mary Hope

The Ocean Studies Board of the National Research Council is organizing a workshop, “Continental Margins: Evolution of Passive Continental Margins and Active Marginal Processes,” to stimulate discussion and longterm planning in the scientific community about the evolution of all types of continental margins. We want to coordinate academic, industry, and government agency efforts in this field, and to enhance communication between sea-based and land-based research programs.The continental margins constitute the only available record of the long-term dynamic interaction of oceanic and continental lithosphere. Of great interest are the unique structures and thick sedimentary sequences associated with this interaction. A major focus of the workshop will be to define strategies for exploring and understanding the continental margins in three dimensions and through geologic time. The workshop will be divided into 7 working groups, each concentrating on a major issue in continental margins research. A background document is being prepared summarizing recent research in specific continental margin fields and identifying key scientific and technical issues.

Asymmetric rifting, breakup and magmatism across conjugate margin pairs: insights from Newfoundland to Ireland

NASA Astrophysics Data System (ADS)

Peace, Alexander L.; Welford, J. Kim; Foulger, Gillian R.; McCaffrey, Ken J. W.

2017-04-01

Continental extension, subsequent rifting and eventual breakup result in the development of passive margins with transitional crust between extended continental crust and newly created oceanic crust. Globally, passive margins are typically classified as either magma-rich or magma-poor. Despite this simple classification, magma-poor margins like the West Orphan Basin, offshore Newfoundland, do exhibit some evidence of localized magmatism, as magmatism to some extent invariably accompanies all continental breakup. For example, on the Newfoundland margin, a small volcanic province has been interpreted near the termination of the Charlie Gibbs Fracture Zone, whereas on the conjugate Irish margin within the Rockall Basin, magmatism appears to be more widespread and has been documented both in the north and in the south. The broader region over which volcanism has been identified on the Irish margin is suggestive of magmatic asymmetry across this conjugate margin pair and this may have direct implications for the mechanisms governing the nature of rifting and breakup. Possible causes of the magmatic asymmetry include asymmetric rifting (simple shear), post-breakup thermal anomalies in the mantle, or pre-existing compositional zones in the crust that predispose one of the margins to more melting than its conjugate. A greater understanding of the mechanisms leading to conjugate margin asymmetry will enhance our fundamental understanding of rifting processes and will also reduce hydrocarbon exploration risk by better characterizing the structural and thermal evolution of hydrocarbon bearing basins on magma-poor margins where evidence of localized magmatism exists. Here, the latest results of a conjugate margin study of the Newfoundland-Ireland pair utilizing seismic interpretation integrated with other geological and geophysical datasets are presented. Our analysis has begun to reveal the nature and timing of rift-related magmatism and the degree to which magmatic asymmetry exists between these conjugate margins. The main implications from this work are that different processes may have operated during and after rifting on these conjugate margins. This concept should be carried forward when conducting conjugate margin studies elsewhere, particularly when exploring for hydrocarbons as prospectivity on one margin may not be predictive for its conjugate as different thermal and structural regimes may have been in operation during conjugate basin evolution.

Association Between Unprotected Ultraviolet Radiation Exposure and Recurrence of Ocular Herpes Simplex Virus

PubMed Central

Ludema, Christina; Cole, Stephen R.; Poole, Charles; Smith, Jennifer S.; Schoenbach, Victor J.; Wilhelmus, Kirk R.

2014-01-01

Studies have suggested that exposure to ultraviolet (UV) light may increase risk of herpes simplex virus (HSV) recurrence. Between 1993 and 1997, the Herpetic Eye Disease Study (HEDS) randomized 703 participants with ocular HSV to receipt of acyclovir or placebo for prevention of ocular HSV recurrence. Of these, 308 HEDS participants (48% female and 85% white; median age, 49 years) were included in a nested study of exposures thought to cause recurrence and were followed for up to 15 months. We matched weekly UV index values from the National Oceanic and Atmospheric Administration to each participant's study center and used marginal structural Cox models to account for time-varying psychological stress and contact lens use and selection bias from dropout. There were 44 recurrences of ocular HSV, yielding an incidence of 4.3 events per 1,000 person-weeks. Weighted hazard ratios comparing persons with ≥8 hours of time outdoors to those with less exposure were 0.84 (95% confidence interval (CI): 0.27, 2.63) and 3.10 (95% CI: 1.14, 8.48) for weeks with a UV index of <4 and ≥4, respectively (ratio of hazard ratios = 3.68, 95% CI: 0.43, 31.4). Though results were imprecise, when the UV index was higher (i.e., ≥4), spending 8 or more hours per week outdoors was associated with increased risk of ocular HSV recurrence. PMID:24142918

The Association Between Renin-Angiotensin System Blockade and Long-term Outcomes in Renal Transplant Recipients: The Wisconsin Allograft Recipient Database (WisARD).

PubMed

Shin, Jung-Im; Palta, Mari; Djamali, Arjang; Kaufman, Dixon B; Astor, Brad C

2016-07-01

Renin-angiotensin system (RAS) blockade reduces mortality in the general population and among non-dialysis-dependent patients with chronic kidney disease. The RAS blockade also decreases proteinuria and protects renal function in non-transplant patients with chronic kidney disease. It remains controversial, however, whether this translates to improved patient or graft survival among transplant recipients. We analyzed 2684 primary kidney transplant recipients at the University of Wisconsin in 1994 to 2010 who had a functioning graft at 6 months after transplantation. We assessed the association of RAS blockade with patient and graft survival using time-dependent Cox and marginal structural models. Three hundred seventy-seven deaths and 329 graft failures before death (638 total graft losses) occurred during a median of 5.4 years of follow-up. The RAS blockade was associated with an adjusted-hazard ratio of 0.63 (95% confidence interval, 0.53-0.75) for total graft loss, 0.69 (0.55-0.86) for death, and 0.62 (0.49-0.78) for death-censored graft failure. The associations of RAS blockade with a lower risk of total graft loss and mortality were stronger with more severe proteinuria. The RAS blockade was associated with a 2-fold higher risk of hyperkalemia. Our findings suggest RAS blockade is associated with better patient and graft survival in renal transplant recipients.

Effect of cobalt doping on crystallinity, stability, magnetic and optical properties of magnetic iron oxide nano-particles

NASA Astrophysics Data System (ADS)

Anjum, Safia; Tufail, Rabia; Rashid, Khalid; Zia, Rehana; Riaz, S.

2017-06-01

This paper is dedicated to investigate the effect of Co2+ ions in magnetite Fe3O4 nano-particles with stoichiometric formula CoxFe3-xO4 where (x = 0, 0.05, 0.1 and 0.15) prepared by co-precipitation method. The structural, thermal, morphological, magnetic and optical properties of magnetite and Co2+ doped magnetite nanoparticles have been carried out using X-ray Diffractometer, Fourier Transform Infrared Spectroscopy, Themogravimetric Analysis, Scanning Electron Microscopy, Vibrating Sample Magnetometer (VSM) and UV-Vis Spectrometer (UV-Vis) respectively. Structural analysis verified the formation of single phase inverse spinel cubic structure with decrease in lattice parameters due to increase in cobalt content. FTIR analysis confirms the single phase of CoxFe3-xO4 nanoparticles with the major band at 887 cm-1, which might be due to the stretching vibrations of metal-oxide bond. The DSC results corroborate the finding of an increase in the maghemite to hematite phase transition temperature with increase in Co2+ content. The decrease in enthalpy with increase in Co2+ concentration attributed to the fact that the degree of conversion from maghemite to hematite decrease which shows that the stability increases with increasing Co2+ content in B-site of Fe3O4 structure. SEM analysis demonstrated the formation of spherical shaped nanoparticles with least agglomeration. The magnetic measurements enlighten that the coercivity and anisotropy of CoxFe3-xO4 nanoparticles are significantly increased. From UV-Vis analysis it is revealed that band gap energy increases with decreasing particle size. This result has a great interest for magnetic fluid hyperthermia application (MPH).

Rebamipide Promotes the Regeneration of Aspirin-Induced Small-Intestine Mucosal Injury through Accumulation of β-Catenin.

PubMed

Lai, Yu; Zhong, Wa; Yu, Tao; Xia, Zhong-Sheng; Li, Jie-Yao; Ouyang, Hui; Shan, Ti-Dong; Yang, Hong-Sheng; Chen, Qi-Kui

2015-01-01

The effect of rebamipide on repairing intestinal mucosal damage induced by nonsteroidal anti-inflammatory drugs and its mechanism remain unclear. In this study, we sought to explore the mechanism whereby rebamipide could promote the regeneration of aspirin-induced intestinal mucosal damage. BALB/c mice were administered aspirin (200 mg/kg/d) for 5 days to induce acute small intestinal injury (SII). Subsequently, SII mice were treated with rebamipide (320 mg/kg/d) for 5 days. The structure of intestinal barrier was observed with transmission electron microscope, and Zo-1 and occludin expressions were detected. The proliferative index was indicated by the percentage of proliferating cell nuclear antigen positive cells. The prostaglandin E2 (PGE2) levels in the small intestine tissues were measured by an enzyme immunoassay. The mRNA and protein expression levels of cyclooxygenase (COX) and β-catenin signal were detected in the small intestine using quantitative PCR and Western blot, respectively. COX expression was significantly down-regulated in aspirin induced SII (P < 0.05). In SII mice treated with rebamipide, histopathological findings of aspirin-induced intestinal inflammation were significantly milder and tight junctions between intestinal epithelial cells were improved significantly. The proliferative index increased after rebamipide treatment when compared with that in the control mice. The expressions of COX-2, β-catenin, and c-myc and the PGE2 concentrations in small intestinal tissues were significantly increased in mice with rebamipide treatments (P < 0.05). Rebamipide administration in aspirin-induced SII mice could improve the intestinal barrier structure and promote the regeneration of small intestinal epithelial injury through up-regulating COX-2 expression and the accumulation of β-catenin.

Rebamipide Promotes the Regeneration of Aspirin-Induced Small-Intestine Mucosal Injury through Accumulation of β-Catenin

PubMed Central

Yu, Tao; Xia, Zhong-Sheng; Li, Jie-Yao; Ouyang, Hui; Shan, Ti-Dong; Yang, Hong-Sheng; Chen, Qi-Kui

2015-01-01

Background The effect of rebamipide on repairing intestinal mucosal damage induced by nonsteroidal anti-inflammatory drugs and its mechanism remain unclear. In this study, we sought to explore the mechanism whereby rebamipide could promote the regeneration of aspirin-induced intestinal mucosal damage. Methods BALB/c mice were administered aspirin (200 mg/kg/d) for 5 days to induce acute small intestinal injury (SII). Subsequently, SII mice were treated with rebamipide (320 mg/kg/d) for 5 days. The structure of intestinal barrier was observed with transmission electron microscope, and Zo-1 and occludin expressions were detected. The proliferative index was indicated by the percentage of proliferating cell nuclear antigen positive cells. The prostaglandin E2 (PGE2) levels in the small intestine tissues were measured by an enzyme immunoassay. The mRNA and protein expression levels of cyclooxygenase (COX) and β-catenin signal were detected in the small intestine using quantitative PCR and Western blot, respectively. Results COX expression was significantly down-regulated in aspirin induced SII (P < 0.05). In SII mice treated with rebamipide, histopathological findings of aspirin-induced intestinal inflammation were significantly milder and tight junctions between intestinal epithelial cells were improved significantly. The proliferative index increased after rebamipide treatment when compared with that in the control mice. The expressions of COX-2, β-catenin, and c-myc and the PGE2 concentrations in small intestinal tissues were significantly increased in mice with rebamipide treatments (P < 0.05). Conclusion Rebamipide administration in aspirin-induced SII mice could improve the intestinal barrier structure and promote the regeneration of small intestinal epithelial injury through up-regulating COX-2 expression and the accumulation of β-catenin. PMID:26135128

How the structural architecture of the Eurasian continental margin affects the structure, seismicity, and topography of the south central Taiwan fold-and-thrust belt

NASA Astrophysics Data System (ADS)

Brown, Dennis; Alvarez-Marron, Joaquina; Biete, Cristina; Kuo-Chen, Hao; Camanni, Giovanni; Ho, Chun-Wei

2017-07-01

Studies of mountain belts worldwide show that along-strike changes are common in their foreland fold-and-thrust belts. These are typically caused by processes related to fault reactivation and/or fault focusing along changes in sedimentary sequences. The study of active orogens, like Taiwan, can also provide insights into how these processes influence transient features such as seismicity and topography. In this paper, we trace regional-scale features from the Eurasian continental margin in the Taiwan Strait into the south central Taiwan fold-and-thrust belt. We then present newly mapped surface geology, P wave velocity maps and sections, seismicity, and topography data to test the hypothesis of whether or not these regional-scale features of the margin are contributing to along-strike changes in structural style, and the distribution of seismicity and topography in this part of the Taiwan fold-and-thrust belt. These data show that the most important along-strike change takes place at the eastward prolongation of the upper part of the margin necking zone, where there is a causal link between fault reactivation, involvement of basement in the thrusting, concentration of seismicity, and the formation of high topography. On the area correlated with the necking zone, the strike-slip reactivation of east northeast striking extensional faults is causing sigmoidal offset of structures and topography along two main zones. Here basement is not involved in the thrusting; there is weak focusing of seismicity and localized development of topography. We also show that there are important differences in structure, seismicity, and topography between the margin shelf and its necking zone.

Gigapixel surface imaging of radical prostatectomy specimens for comprehensive detection of cancer-positive surgical margins using structured illumination microscopy

PubMed Central

Wang, Mei; Tulman, David B.; Sholl, Andrew B.; Kimbrell, Hillary Z.; Mandava, Sree H.; Elfer, Katherine N.; Luethy, Samuel; Maddox, Michael M.; Lai, Weil; Lee, Benjamin R.; Brown, J. Quincy

2016-01-01

Achieving cancer-free surgical margins in oncologic surgery is critical to reduce the need for additional adjuvant treatments and minimize tumor recurrence; however, there is a delicate balance between completeness of tumor removal and preservation of adjacent tissues critical for normal post-operative function. We sought to establish the feasibility of video-rate structured illumination microscopy (VR-SIM) of the intact removed tumor surface as a practical and non-destructive alternative to intra-operative frozen section pathology, using prostate cancer as an initial target. We present the first images of the intact human prostate surface obtained with pathologically-relevant contrast and subcellular detail, obtained in 24 radical prostatectomy specimens immediately after excision. We demonstrate that it is feasible to routinely image the full prostate circumference, generating gigapixel panorama images of the surface that are readily interpreted by pathologists. VR-SIM confirmed detection of positive surgical margins in 3 out of 4 prostates with pathology-confirmed adenocarcinoma at the circumferential surgical margin, and furthermore detected extensive residual cancer at the circumferential margin in a case post-operatively classified by histopathology as having negative surgical margins. Our results suggest that the increased surface coverage of VR-SIM could also provide added value for detection and characterization of positive surgical margins over traditional histopathology. PMID:27257084

Transition from magma dominant to magma poor rifting along the Nova Scotia Continental Margin

NASA Astrophysics Data System (ADS)

Lau, K. H.; Louden, K. E.; Nedimović, M. R.; Whitehead, M.; Farkas, A.; Watremez, L.; Dehler, S. A.

2011-12-01

Passive margins have been characterized as magma-dominant (volcanic) or magma-poor (non-volcanic). However, the conditions under which margins might switch states are not well understood as they typically have been studied as end member examples in isolation to each other. The Nova Scotia (NS) continental margin, however, offers an opportunity to study the nature of such a transition between the magma-dominant US East Coast margin to the south and the magma-poor Newfoundland margin to the north within a single rift segment. This transition is evidenced by a clear along-strike reduction in features characteristic of syn-rift volcanism from south-to-north along the NS margin, such as the weakening of the East Coast Magnetic Anomaly (ECMA) and the coincident disappearance of seaward dipping reflector sequences (SDRS) on multichannel seismic (MCS) reflection profiles. Results from recent industry MCS profiles along and across the margin suggest a potentially narrow magma-dominant to magma-poor along-strike transition between the southern and the central NS margin. Such a transition is broadly consistent with results of several widely-spaced, across-strike ocean bottom seismometer (OBS) wide-angle profiles. In the southern region, the crustal structure exhibits a narrow (~120-km wide) ocean-continent transition (OCT) with a high velocity (7.2 km/s) lower crust, interpreted as a gabbro-rich underplated melt, beneath the SDRS and the ECMA, similar to crustal models across the US East Coast. In contrast, profiles across the central and northern margin contain a much wider OCT (150-200-km wide) underlain by a low velocity mantle layer (7.3-7.9 km/s), interpreted as partially serpentinized olivine, which is similar to the magma-poor Newfoundland margin to the north. However, the central-to-northern OBS profiles also exhibit significant variations within the OCT and the along-strike continuity of these OCT structures is not yet clear. In November 2010, we acquired, in the OCTOPUS survey, wide-angle seismic data along a 240-km-long margin parallel profile extending from the central to the northern margin segments along an existing industry MCS profile (Ion/GX Technology NovaSPAN 5100). Twenty OBSs at 10-km spacing were analysed. A preliminary p-wave velocity model along the profile indicates that the cross-strike structures are continuous within the OCT. However, a substantial anisotropy in velocity (~8% lower parallel to the margin) is observed within the OCT. This result is consistent with an interpretation of partially serpentinized mantle that flowed perpendicular to the margin during its extension. In addition, along strike variations are also observed along the profile, which suggest a higher degree of volcanism and a thinner layer of serpentinized mantle to the southwest. These results provide a framework for future studies to the southwest to further investigate the transition to a magma-dominant regime towards the US East Coast.

Extensional fault geometry and its flexural isostatic response during the formation of the Iberia - Newfoundland conjugate rifted margins

NASA Astrophysics Data System (ADS)

Gómez-Romeu, Júlia; Kusznir, Nick; Manatschal, Gianreto; Roberts, Alan

2017-04-01

Despite magma-poor rifted margins having been extensively studied for the last 20 years, the evolution of extensional fault geometry and the flexural isostatic response to faulting remain still debated topics. We investigate how the flexural isostatic response to faulting controls the structural development of the distal part of rifted margins in the hyper-extended domain and the resulting sedimentary record. In particular we address an important question concerning the geometry and evolution of extensional faults within distal hyper-extended continental crust; are the seismically observed extensional fault blocks in this region allochthons from the upper plate or are they autochthons of the lower plate? In order to achieve our aim we focus on the west Iberian rifted continental margin along the TGS and LG12 seismic profiles. Our strategy is to use a kinematic forward model (RIFTER) to model the tectonic and stratigraphic development of the west Iberia margin along TGS-LG12 and quantitatively test and calibrate the model against breakup paleo-bathymetry, crustal basement thickness and well data. RIFTER incorporates the flexural isostatic response to extensional faulting, crustal thinning, lithosphere thermal loads, sedimentation and erosion. The model predicts the structural and stratigraphic consequences of recursive sequential faulting and sedimentation. The target data used to constrain model predictions consists of two components: (i) gravity anomaly inversion is used to determine Moho depth, crustal basement thickness and continental lithosphere thinning and (ii) reverse post-rift subsidence modelling consisting of flexural backstripping, decompaction and reverse post-rift thermal subsidence modelling is used to give paleo-bathymetry at breakup time. We show that successful modelling of the structural and stratigraphic development of the TGS-LG12 Iberian margin transect also requires the simultaneous modelling of the Newfoundland conjugate margin, which we constrain using target data from the SCREECH 2 seismic profile. We also show that for the successful modelling and quantitative validation of the lithosphere hyper-extension stage it is necessary to first have a good calibrated model of the necking phase. Not surprisingly the evolution of a rifted continental margin cannot be modelled without modelling and calibration of its conjugate margin.

Unified theory for stochastic modelling of hydroclimatic processes: Preserving marginal distributions, correlation structures, and intermittency

NASA Astrophysics Data System (ADS)

Papalexiou, Simon Michael

2018-05-01

Hydroclimatic processes come in all "shapes and sizes". They are characterized by different spatiotemporal correlation structures and probability distributions that can be continuous, mixed-type, discrete or even binary. Simulating such processes by reproducing precisely their marginal distribution and linear correlation structure, including features like intermittency, can greatly improve hydrological analysis and design. Traditionally, modelling schemes are case specific and typically attempt to preserve few statistical moments providing inadequate and potentially risky distribution approximations. Here, a single framework is proposed that unifies, extends, and improves a general-purpose modelling strategy, based on the assumption that any process can emerge by transforming a specific "parent" Gaussian process. A novel mathematical representation of this scheme, introducing parametric correlation transformation functions, enables straightforward estimation of the parent-Gaussian process yielding the target process after the marginal back transformation, while it provides a general description that supersedes previous specific parameterizations, offering a simple, fast and efficient simulation procedure for every stationary process at any spatiotemporal scale. This framework, also applicable for cyclostationary and multivariate modelling, is augmented with flexible parametric correlation structures that parsimoniously describe observed correlations. Real-world simulations of various hydroclimatic processes with different correlation structures and marginals, such as precipitation, river discharge, wind speed, humidity, extreme events per year, etc., as well as a multivariate example, highlight the flexibility, advantages, and complete generality of the method.

[Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle].

PubMed

Balashov, Iu S; Grigor'eva, L A; Leonovich, S A

2009-01-01

A method of visual estimation of the biological age of living hungry tick females by visible changes in the depth of marginal groove and the structure of the alloscutum cuticle during natural ageing is developed. In recently activated individuals, the body is convex and the marginal groove is exposed, demonstrating distinctly visible cuticular microfolds (Figs 1-4). In attenuated ticks, the body is flattened and marginal fold overlays the marginal groove, concealing cuticular microfolds (Figs 5-8).

Albian salt-tectonics in Central Tunisia: Evidences for an Atlantic-type passive margin

NASA Astrophysics Data System (ADS)

Jaillard, Etienne; Bouillin, Jean-Pierre; Ouali, Jamel; Dumont, Thierry; Latil, Jean-Louis; Chihaoui, Abir

2017-11-01

Tunisia is part of the south-Tethyan margin, which comprises Triassic evaporites and a thick series of Jurassic and Cretaceous, mainly marine deposits, related to the Tethyan rifting evolution. A survey of various Cretaceous outcrops of central Tunisia (Kasserine-El Kef area), combined with literature descriptions, shows that the style of Albian deformation changes from the proximal (South) to the distal part (North) of the margin. The southern part is dominated by tilted blocks and growth faults, which evolve to the north to turtle-back and roll-over structures. Farther North, deformation is dominated by the extrusion of diapirs and salt walls. Such a distribution of deformation strongly suggests that the whole sedimentary cover glided northward on the Triassic evaporites during Albian times, as described for the Atlantic passive margin or for the Gulf of Mexico. Subsequently, these halokinetic structures have been folded during Alpine compressional tectonics.

Multidisciplinary scientific program of investigation of the structure and evolution of the Demerara marginal plateau

NASA Astrophysics Data System (ADS)

Loncke, Lies; Basile, Christophe; Roest, Walter; Graindorge, David; Mercier de Lépinay, Marion; Klinghelhoefer, Frauke; Heuret, Arnauld; Pattier, France; Tallobre, Cedric; Lebrun, Jean-Frédéric; Poetisi, Ewald; Loubrieu, Benoît; Iguanes, Dradem, Margats Scientific Parties, Plus

2017-04-01

Mercier de Lépinay et al. published in 2016 an updated inventory of transform passive margins in the world. This inventory shows that those margins represent 30% of continental passive margins and a cumulative length of 16% of non-convergent margins. It also highlights the fact that many submarine plateaus prolong transform continental margins, systematically at the junction of oceanic domains of different ages. In the world, we identified twenty of those continental submarine plateaus (Falklands, Voring, Demerara, Tasman, etc). Those marginal plateaus systematically experiment two phases of deformation: a first extensional phase and a second transform phase that allows the individualization of those submarine reliefs appearing on bathymetry as seaward continental-like salients. The understanding of the origin, nature, evolution of those marginal plateaus has many scientific and economic issues. The Demerara marginal plateau located off French Guiana and Surinam belongs to this category of submarine provinces. The French part of this plateau has been the locus of a first investigation in 2003 in the framework of the GUYAPLAC cruise dedicated to support French submissions about extension of the limit of the continental shelf beyond 200 nautical miles. This cruise was the starting point of a scientific program dedicated to geological investigations of the Demerara plateau that was sustained by different cruises and collaborations (1) IGUANES (2013) that completed the mapping of this plateau including off Surinam, allowed to better understand the segmentation of the Northern edge of this plateau, and to evidence the combined importance of contourite and mass-wasting processes in the recent sedimentary evolution of this domain, (2) Collaboration with TOTAL (Mercier de Lépinay's PhD thesis) that allowed to better qualify the two main phases of structural evolution of the plateau respectively during Jurassic times for its Western border, Cretaceous times for its Northern and Eastern border (2) DRADEM (2016) (see poster session) that better mapped the continental slope domain of the transform margin north of the Demerara plateau and was dedicated to the dredging of rocks outcropping on the continental slope, suspected to be Cretaceous in age and older, (3) MARGATS (2016) (see poster session) that was dedicated to the better understanding of the internal structure of the plateau and its different margins using multi-channels seismic and refraction methods. The combination of all those experiments allow us to paint an integrated portrait of the Demerara marginal plateau - that may be very useful in understanding the processes involved (1) in the individualization of such plateaus (volcanism, heritages, kinematics, …) (2) in their evolution (subsidence, mass-wasting processes, domains of deep-sea current acceleration). In the future, those scientific advances may allow to better define the natural resources associated with such marginal domains.

Mesozoic evolution of northeast African shelf margin, Libya and Egypt

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

Aadland, R.K.; Schamel, S.

1989-03-01

The present tectonic features of the northeast African shelf margin between the Nile delta and the Gulf of Sirte are products of (1) precursory late Paleozoic basement arches, (2) early Mesozoic rifting and plate separation, and (3) Late Cretaceous structural inversion. The 250 km-wide and highly differentiated Mesozoic passive margin in the Western Desert region of Egypt is developed above a broad northwest-trending Late Carboniferous basement arch. In northeastern Libya, in contrast, the passive margin is restricted to just the northernmost Cyrenaica platform, where subsidence was extremely rapid in the Jurassic and Early Cretaceous. The boundary between the Western Desertmore » basin and the Cyrenaica platform is controlled by the western flank of the basement arch. In the middle Cretaceous (100-90 Ma), subsidence accelerated over large areas of the Western desert, further enhancing a pattern of east-west-trending subbasins. This phase of rapid subsidence was abruptly ended about 80 Ma by the onset of structural inversion that uplifted the northern Cyrenaica shelf margin and further differentiated the Western Desert subbasin along a northeasterly trend.« less

Local Telephone Costs and the Design of Rate Structures,

DTIC Science & Technology

1981-05-01

guide the setting of prices for the multi-product regulated firm. Economic effi- ciency can be increased by designing rate structures that incorporate the... basic principles developed from this theory. These principles call for provisionally pricing each of the firm’s outputs at its marginal cost, testing...rule--prices are increased above marginal costs in inverse proportion to the individual price elasticities of demand. This paper applies ratemaking

Evaluation and comparison of the marginal adaptation of two different substructure materials.

PubMed

Karaman, Tahir; Ulku, Sabiha Zelal; Zengingul, Ali Ihsan; Guven, Sedat; Eratilla, Veysel; Sumer, Ebru

2015-06-01

In this study, we aimed to evaluate the amount of marginal gap with two different substructure materials using identical margin preparations. Twenty stainless steel models with a chamfer were prepared with a CNC device. Marginal gap measurements of the galvano copings on these stainless steel models and Co-Cr copings obtained by a laser-sintering method were made with a stereomicroscope device before and after the cementation process and surface properties were evaluated by scanning electron microscopy (SEM). A dependent t-test was used to compare the mean of the two groups for normally distributed data, and two-way variance analysis was used for more than two data sets. Pearson's correlation analysis was also performed to assess relationships between variables. According to the results obtained, the marginal gap in the galvano copings before cementation was measured as, on average, 24.47 ± 5.82 µm before and 35.11 ± 6.52 µm after cementation; in the laser-sintered Co-Cr structure, it was, on average, 60.45 ± 8.87 µm before and 69.33 ± 9.03 µm after cementation. A highly significant difference (P<.001) was found in marginal gap measurements of galvano copings and a significant difference (P<.05) was found in marginal gap measurements of the laser-sintered Co-Cr copings. According to the SEM examination, surface properties of laser sintered Co-Cr copings showed rougher structure than galvano copings. The galvano copings showed a very smooth surface. Marginal gaps values of both groups before and after cementation were within the clinically acceptable level. The smallest marginal gaps occurred with the use of galvano copings.

Evaluation and comparison of the marginal adaptation of two different substructure materials

PubMed Central

Karaman, Tahir; Ulku, Sabiha Zelal; Zengingul, Ali Ihsan; Eratilla, Veysel; Sumer, Ebru

2015-01-01

PURPOSE In this study, we aimed to evaluate the amount of marginal gap with two different substructure materials using identical margin preparations. MATERIALS AND METHODS Twenty stainless steel models with a chamfer were prepared with a CNC device. Marginal gap measurements of the galvano copings on these stainless steel models and Co-Cr copings obtained by a laser-sintering method were made with a stereomicroscope device before and after the cementation process and surface properties were evaluated by scanning electron microscopy (SEM). A dependent t-test was used to compare the mean of the two groups for normally distributed data, and two-way variance analysis was used for more than two data sets. Pearson's correlation analysis was also performed to assess relationships between variables. RESULTS According to the results obtained, the marginal gap in the galvano copings before cementation was measured as, on average, 24.47 ± 5.82 µm before and 35.11 ± 6.52 µm after cementation; in the laser-sintered Co-Cr structure, it was, on average, 60.45 ± 8.87 µm before and 69.33 ± 9.03 µm after cementation. A highly significant difference (P<.001) was found in marginal gap measurements of galvano copings and a significant difference (P<.05) was found in marginal gap measurements of the laser-sintered Co-Cr copings. According to the SEM examination, surface properties of laser sintered Co-Cr copings showed rougher structure than galvano copings. The galvano copings showed a very smooth surface. CONCLUSION Marginal gaps values of both groups before and after cementation were within the clinically acceptable level. The smallest marginal gaps occurred with the use of galvano copings. PMID:26140178

Arabian Plate Deformation: The role of inherited structures in the localization of strain in the Red Sea extensional system

NASA Astrophysics Data System (ADS)

Aldaajani, T.; Furlong, K.; Malservisi, R.

2017-12-01

The Red Sea rift structural architecture changes dramatically along strike from narrow localized spreading (with creation of new oceanic crust) in the south to asymmetrical diffuse extension north of 21 ° latitude. The region of diffuse extension falls within a triangle that is bounded to the east by the Sarhan graben, (a Cenozoic failed rift), to the west by the northern Red Sea Rift, and to the south by the Makkah-Madinah-Nafud (MMN) volcanic line. Geological observations appear to show that tectonic stresses acting on inherited structures within the NW Arabian margin are associated with the region of diffuse extension. In contrast, in the southern Red Sea, a single strong block within the SW Arabian margin led to localize the extension there. Using current velocities from more than 30 GNSS stations distributed within the Arabian plate, we are able to map its rigidity and the distribution of strain along the plate margin. The data show that the transition between the two styles of extension within the Red Sea (crustal accretion vs crustal extension) corresponds with a transition between rigid behavior and diffuse extension within the Arabian Plate. This suggests that the preexisting structures within the Arabian plate play a significant role in the style of extension along the Red Sea margin.

Briaviolides K–N, New Briarane-Type Diterpenoids from Cultured Octocoral Briareum violaceum

PubMed Central

Xu, Jing-Hao; Lai, Kuei-Hung; Su, Yin-Di; Chang, Yu-Chia; Peng, Bo-Rong; Wen, Zhi-Hong

2018-01-01

Four new briarane diterpenoids, briaviolides K–N (1–4), have been obtained from the cultured-type octocoral Briareum violaceum. Using a spectroscopic approach, the structures of briaranes 1–4 were identified. This study employed an in vitro model of lipopolysaccharide (LPS)-induced inflammation in the murine macrophage RAW 264.7 cell line, and found that among the four briaranes, briarane 2 possessed anti-inflammatory activity against inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expressions in cells. In addition, principal component analysis using the chemical global positioning system (ChemGPS) for natural products (ChemGPS-NP) was employed in order to analyze the structure-activity relationship (SAR), and the results indicated that the ring conformation of the compound has a leading role in suppressing the expressions of pro-inflammatory iNOS and COX-2 proteins in macrophages. PMID:29495481

Magnetic properties of CeFe11-xCoxTi with ThMn12 structure

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

Zhou, C; Pinkerton, FE; Herbst, JF

2014-05-07

A series of novel alloys CeFe11-xCoxTi (0 <= x <= 11) with ThMn12 structure has been successfully prepared by melt-spinning. The Curie temperature T-c increases with Co content x, reaching a maximum of 689 degrees C at x = 9 and declining to 664 degrees C at complete Co filling (x = 11). The room temperature saturation magnetization 4 pi M-s and magnetocrystalline anisotropy H-a have been estimated by fitting the first quadrant demagnetization curve with the Stoner-Wohlfarth model. 4 pi M-s first increases with increasing Co up to x = 3, then decrease. H-a has a complex dependence onmore » Co content, which is indicative of a change in the easy magnetization direction from axis to plane and back as the Co content increases. (C) 2014 AIP Publishing LLC.« less

Multilayer Disk Reduced Interlayer Crosstalk with Wide Disk-Fabrication Margin

NASA Astrophysics Data System (ADS)

Hirotsune, Akemi; Miyauchi, Yasushi; Endo, Nobumasa; Onuma, Tsuyoshi; Anzai, Yumiko; Kurokawa, Takahiro; Ushiyama, Junko; Shintani, Toshimichi; Sugiyama, Toshinori; Miyamoto, Harukazu

2008-07-01

To reduce interlayer crosstalk caused by the ghost spot which appears in a multilayer optical disk with more than three information layers, a multilayer disk structure which reduces interlayer crosstalk with a wide disk-fabrication margin was proposed in which the backward reflectivity of the information layers is sufficiently low. It was confirmed that the interlayer crosstalk caused by the ghost spot was reduced to less than the crosstalk from the adjacent layer by controlling backward reflectivity. The wide disk-fabrication margin of the proposed disk structure was indicated by experimentally confirming that the tolerance of the maximum deviation of the spacer-layer thickness is four times larger than that in the previous multilayer disk.

78 FR 2200 - Establishment of VOR Federal Airway V-629; Las Vegas, NV

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-10

... existing routes structure for aircraft navigating in an area of marginal radar coverage. This action... navigating in an area of marginal radar coverage. VOR Federal airways are published in paragraph 6010(a) of...

Clustered marginalization of minorities during social transitions induced by co-evolution of behaviour and network structure

NASA Astrophysics Data System (ADS)

Schleussner, Carl-Friedrich; Donges, Jonathan F.; Engemann, Denis A.; Levermann, Anders

2016-08-01

Large-scale transitions in societies are associated with both individual behavioural change and restructuring of the social network. These two factors have often been considered independently, yet recent advances in social network research challenge this view. Here we show that common features of societal marginalization and clustering emerge naturally during transitions in a co-evolutionary adaptive network model. This is achieved by explicitly considering the interplay between individual interaction and a dynamic network structure in behavioural selection. We exemplify this mechanism by simulating how smoking behaviour and the network structure get reconfigured by changing social norms. Our results are consistent with empirical findings: The prevalence of smoking was reduced, remaining smokers were preferentially connected among each other and formed increasingly marginalized clusters. We propose that self-amplifying feedbacks between individual behaviour and dynamic restructuring of the network are main drivers of the transition. This generative mechanism for co-evolution of individual behaviour and social network structure may apply to a wide range of examples beyond smoking.

Clustered marginalization of minorities during social transitions induced by co-evolution of behaviour and network structure.

PubMed

Schleussner, Carl-Friedrich; Donges, Jonathan F; Engemann, Denis A; Levermann, Anders

2016-08-11

Large-scale transitions in societies are associated with both individual behavioural change and restructuring of the social network. These two factors have often been considered independently, yet recent advances in social network research challenge this view. Here we show that common features of societal marginalization and clustering emerge naturally during transitions in a co-evolutionary adaptive network model. This is achieved by explicitly considering the interplay between individual interaction and a dynamic network structure in behavioural selection. We exemplify this mechanism by simulating how smoking behaviour and the network structure get reconfigured by changing social norms. Our results are consistent with empirical findings: The prevalence of smoking was reduced, remaining smokers were preferentially connected among each other and formed increasingly marginalized clusters. We propose that self-amplifying feedbacks between individual behaviour and dynamic restructuring of the network are main drivers of the transition. This generative mechanism for co-evolution of individual behaviour and social network structure may apply to a wide range of examples beyond smoking.

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

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

PubMed

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

2009-02-01

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 x 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.

Early return of continence in patients undergoing robot-assisted laparoscopic prostatectomy using modified maximal urethral length preservation technique.

PubMed

Hamada, Alaa; Razdan, Shirin; Etafy, Mohamed H; Fagin, Randy; Razdan, Sanjay

2014-08-01

To evaluate the impact of maximal urethral length preservation (MULP) technique in comparison with posterior urethral reconstruction and anterior bladder suspension (PRAS) technique on the continence rates (CR), time to achieve continence among patients with prostate cancer (PCa) undergoing robot-assisted laparoscopic prostatectomy (RALP). We prospectively analyzed the CR, time to achieve continence, pre- and postoperative prostate-specific antigen (PSA) levels, rates of positive margins among three groups of continent men with PCa undergoing RALP from whom consent was obtained. Each group consisted of 30 patients: PRAS was performed in group A, combined MULP and PRAS in group B, and MULP in group C. Continence was measured by patient self-reporting of the number of pads/24 h. No differences were detected in the age, preoperative PSA levels, biochemical recurrence, prostate volume, and positive margins for the three groups. Men in groups B and C had marked improvement in CR 1, 3, and 6 months after catheter removal vs group A (50% and 70% vs 10%, 90% and 96.66% vs 23.3% and 100%, 100% vs 53.3%, respectively, P<0.0001). The average and median times to continence were significantly shorter in group B (5.4 and 4 weeks) and C (3.8 and 3 weeks) vs group A (27.4 and 22.5 weeks), P<0.00001. Using Cox regression analysis, only MULP and MULP+PRAS techniques were significantly correlated with continence outcomes 1, 3, and 6 months after catheter removal. MULP rather than PRAS confers higher postoperative CR and shorter time to achieve continence among patients with PCa who underwent RALP without increasing risk of positive margin.

Oncologic outcomes following robot-assisted radical cystectomy with minimum 5-year follow-up: the Roswell Park cancer institute experience.

PubMed

Raza, Syed Johar; Al-Daghmin, Ali; Zhuo, Sharon; Mehboob, Zayn; Wang, Katy; Wilding, Gregory; Kauffman, Eric; Guru, Khurshid A

2014-11-01

Long-term oncologic outcomes following robot-assisted radical cystectomy (RARC) remain scarce. To report long-term oncologic outcomes following RARC at a single institution. Retrospective review of 99 patients who underwent RARC for urothelial carcinoma of bladder between 2005 and 2009. RARC was performed. Primary outcomes included recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS), measured by the Kaplan-Meier method. The association between primary outcomes and perioperative and pathologic factors was assessed using a multivariable Cox proportional hazards model. Fifty-one (52%) patients had stage pT3 or higher disease. Eight (8%) patients had positive margins and 30 (30%) had positive lymph nodes (LNs), with a median of 21 LNs removed. Median follow-up for patients alive was 74 mo. The 5-yr RFS, CSS, and OS rates were 52.5%, 67.8%, and 42.4%, respectively. Tumor stage, LN stage, and margin status were each significantly associated with RFS, CSS, and OS. On multivariable analysis, tumor and LN stage were independent predictors of RFS, CSS, and OS, while positive margin status and Charlson comorbidity index predicted worse OS and CSS. Adjuvant chemotherapy predicted RFS only. Retrospective design and lack of open comparison are main limitations of this study. Long-term oncologic outcomes following RARC demonstrate RFS and CSS estimates similar to those reported in literature for open radical cystectomy. Randomized controlled trials can better define outcomes of any alternative technique. Survival data 5 yr after RARC for bladder cancer demonstrate that survival outcomes are dependent on the same oncologic parameters as previously reported for open surgery. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Prognosis of Primary and Recurrent Chondrosarcoma of the Rib.

PubMed

Roos, Eva; van Coevorden, Frits; Verhoef, Cornelis; Wouters, Michel W; Kroon, Herman M; Hogendoorn, Pancras C W; van Houdt, Winan J

2016-03-01

Chondrosarcoma of the rib is a rare disease. Although surgery is the only curative treatment option, rib resection with an adequate margin can be challenging and local recurrence is a frequent problem. In this study, the prognosis of primary and recurrent chondrosarcoma of the rib is reported. Retrospective analysis was performed of patients treated for chondrosarcoma of the rib between 1984 and 2014 in three major tertiary referral centers in The Netherlands. Clinical and histopathological features were analyzed for their prognostic value using Kaplan-Meier and Cox proportional hazard analysis. Endpoints were set at local recurrent disease, metastasis rate, or death. Overall, 76 patients underwent a resection for a primary chondrosarcoma, and 26 patients underwent a resection for a recurrent chondrosarcoma. Five-year overall survival in the primary group was 90%, local recurrence rate was 17%, and metastasis rate was 12%. The 5-year outcome after recurrent chondrosarcoma was lower, with an overall survival of 65%, local recurrence rate of 27%, and metastasis rate of 27%. For primary chondrosarcoma, tumor size >5 cm and a positive resection margin were correlated with worse overall survival [hazard ratio (HR) 3.28, 95% confidence interval (CI) 1.03-10.44; HR 2.92, 95% CI 1.03-8.25). A higher histological grade was correlated with a higher local recurrence and metastasis rate (HR 5.92, 95% CI 1.11-31.65; HR 6.96, 95% CI 1.15-42.60). Surgical resection of both primary and recurrent chondrosarcoma of the rib is an effective treatment strategy. The oncological outcome after surgery is worse in tumors >5 cm, in tumors with positive resection margins and grade 3 chondrosarcoma.

Corneal inflammatory events with daily silicone hydrogel lens wear.

PubMed

Szczotka-Flynn, Loretta; Jiang, Ying; Raghupathy, Sangeetha; Bielefeld, Roger A; Garvey, Matthew T; Jacobs, Michael R; Kern, Jami; Debanne, Sara M

2014-01-01

This study aimed to determine the probability and risk factors for developing a corneal inflammatory event (CIE) during daily wear of lotrafilcon A silicone hydrogel contact lenses. Eligible participants (n = 218) were fit with lotrafilcon A lenses for daily wear and followed up for 12 months. Participants were randomized to either a polyhexamethylene biguanide-preserved multipurpose solution or a one-step peroxide disinfection system. The main exposures of interest were bacterial contamination of lenses, cases, lid margins, and ocular surface. Kaplan-Meier (KM) plots were used to estimate the cumulative unadjusted probability of remaining free from a CIE, and multivariate Cox proportional hazards regression was used to model the hazard of experiencing a CIE. The KM unadjusted cumulative probability of remaining free from a CIE for both lens care groups combined was 92.3% (95% confidence interval [CI], 88.1 to 96.5%). There was one participant with microbial keratitis, five participants with asymptomatic infiltrates, and seven participants with contact lens peripheral ulcers, providing KM survival estimates of 92.8% (95% CI, 88.6 to 96.9%) and 98.1% (95% CI, 95.8 to 100.0%) for remaining free from noninfectious and symptomatic CIEs, respectively. The presence of substantial (>100 colony-forming units) coagulase-negative staphylococci bioburden on lid margins was associated with about a five-fold increased risk for the development of a CIE (p = 0.04). The probability of experiencing a CIE during daily wear of lotrafilcon A contact lenses is low, and symptomatic CIEs are rare. Patient factors, such as high levels of bacterial bioburden on lid margins, contribute to the development of noninfectious CIEs during daily wear of silicone hydrogel lenses.

Repeating platinum/bevacizumab in recurrent or progressive cervical cancer yields marginal survival benefits.

PubMed

Zamorano, Abigail S; Wan, Leping; Powell, Matthew A; Massad, L Stewart

2017-11-01

Our objective was to assess overall survival of cervical cancer patients following prior platinum/bevacizumab chemotherapy, comparing retreatment with platinum/bevacizumab with alternative therapies. A retrospective analysis was performed of women who received platinum/bevacizumab (PB) chemotherapy for cervical cancer at Washington University between July 1, 2005 and December 31, 2015. Wilcoxon rank-sum exact test and Fisher's exact test were used to compare the treatment groups, and Kaplan Meier curves were generated. Cox regression analyses were performed, with treatment free interval and prior therapy response included as covariates. Of 84 patients who received PB chemotherapy, 59 (70%) received no second line chemotherapy, as they did not recur, progressed without further chemotherapy, were lost to follow up, or expired. Of the remaining 25 patients, 9 were retreated with the combination of platinum/bevacizumab (PB), 6 were retreated with a platinum regimen without bevacizumab (P), and 10 were retreated with neither (not-P). The only long-term survivor was in the not-P group and was treated with an immunotherapy agent. Median overall survival of all patients was 7.1 months. There was a marginal difference in survival between women in the PB and not-PB groups (11.8 versus 5.7 months; HR 3.02, 95% CI, 0.98-9.28). There was no difference in survival based on platinum interval (HR 0.81; 95% CI, 0.27-2.45). Outcomes are grim for women retreated after platinum/bevacizumab therapy and are only marginally improved by retreatment with a platinum/bevacizumab regimen. Rather than additional PB therapy, women with cervical cancer who recur after platinum/bevacizumab should consider supportive care or clinical trials.

Patterns of Local Recurrence and Dose Fractionation of Adjuvant Radiation Therapy in 462 Patients With Soft Tissue Sarcoma of Extremity and Trunk Wall

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

Jebsen, Nina L., E-mail: nina.louise.jebsen@helse-bergen.no; Department of Oncology, Haukeland University Hospital, Bergen; Engellau, Jacob

2013-08-01

Purpose: To study the impact of dose fractionation of adjuvant radiation therapy (RT) on local recurrence (LR) and the relation of LR to radiation fields. Methods and Materials: LR rates were analyzed in 462 adult patients with soft tissue sarcoma who underwent surgical excision and adjuvant RT at five Scandinavian sarcoma centers from 1998 to 2009. Medical records were reviewed for dose fractionation parameters and to determine the location of the LR relative to the radiation portals. Results: Fifty-five of 462 patients developed a LR (11.9%). Negative prognostic factors included intralesional surgical margin (hazard ratio [HR]: 7.83, 95% confidence intervalmore » [CI]: 3.08-20.0), high malignancy grade (HR: 5.82, 95% CI: 1.31-25.8), age at diagnosis (HR per 10 years: 1.27, 95% CI: 1.03-1.56), and malignant peripheral nerve sheath tumor histological subtype (HR: 6.66, 95% CI: 2.56-17.3). RT dose was tailored to margin status. No correlation between RT dose and LR rate was found in multiple Cox regression analysis. The majority (65%) of LRs occurred within the primary RT volume. Conclusions: No significant dose–response effect of adjuvant RT was demonstrated. Interestingly, patients given 45-Gy accelerated RT (1.8 Gy twice daily/2.5 weeks) had the best local outcome. A total dose of 50 Gy in 25 fractions seemed adequate following wide margin surgery. The risk of LR was associated with histopathologic subtype, which should be included in the treatment algorithm of adjuvant RT in soft tissue sarcoma.« less

Oncologic outcomes of patients with positive surgical margin after partial nephrectomy: a 25-year single institution experience.

PubMed

Petros, Firas G; Metcalfe, Michael J; Yu, Kai-Jie; Keskin, Sarp K; Fellman, Bryan M; Chang, Courtney M; Gu, Cindy; Tamboli, Pheroze; Matin, Surena F; Karam, Jose A; Wood, Christopher G

2018-07-01

To evaluate oncologic outcomes and management of patients with microscopic positive surgical margin (PSM) after partial nephrectomy (PN) for renal cell carcinoma (RCC). We reviewed our database to identify patients who underwent PN between 1990 and 2015 for RCC and had PSM on final pathology. A 1:3 matching was performed to a negative surgical margin (NSM) cohort. Kaplan-Meier method and log-rank test were used to estimate survival and differences in outcomes, respectively. Cox proportional hazards models were conducted to estimate the Hazards ratio. A total of 2297 patients underwent PN at our institution, of which 1863 (81%) had RCC. Microscopic PSM was found in 34 (1.8%) RCC patients who were matched to 100 patients with NSM. Of these 34 patients, local recurrence (n = 4), distant kidney recurrences (n = 4), and metastases (n = 5) developed during a median follow-up of 62 months. Bilateral tumors/tumors in a solitary kidney (n = 12/13, 92%), and multifocal tumors (n = 7/13, 54%) were found in patients who developed recurrence/metastasis. PSM patients were at a higher risk of shorter overall survival (p = 0.001), local recurrence-free survival (p = 0.003), distant recurrence-free survival (p = 0.032) and metastasis-free survival (p = 0.018). There was statistically significant association between PSM and bilateral tumors, prior treated RCC at presentation and higher nephrometry score in multivariable model. There was a low rate of microscopic PSM in our large cohort of patients undergoing PN despite tumor complexity. Higher nephrometry score, bilateral tumors, and prior treated RCC independently predicted PSM which showed worse survival, recurrence and metastasis compared to patients with NSM.

Local-regional recurrence after surgery without postoperative irradiation for carcinomas of the major salivary glands: Implications for adjuvant therapy

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

Chen, Allen M.; Granchi, Phillip J.; Garcia, Joaquin

2007-03-15

Purpose: To determine factors predictive of local-regional recurrence (LRR) after surgery alone for carcinomas of the major salivary glands in an attempt to evaluate the potential role of postoperative radiation therapy. Methods and Materials: Between 1960 and 2004, 207 patients with carcinomas of the major salivary glands were treated with definitive surgery without postoperative radiation therapy. Histology was: 67 mucoepidermoid (32%), 50 adenoid cystic (24%), 34 acinic cell (16%), 23 malignant mixed (11%), 16 adenocarcinoma (8%), 6 oncocytic (3%), 6 myoepithelial (3%), and 5 other (2%). Distribution of pathologic T-stage was: 54 T1 (26%), 83 T2 (40%), 46 T3 (22%),more » and 24 T4 (12%). Sixty patients (29%) had microscopically positive margins. Median follow-up was 6.1 years (range, 0.5-18.7 years). Results: The 5-year and 10-year estimates of local-regional control were 86% and 74%, respectively. A Cox proportional hazard model identified pathologic lymph node metastasis (hazard ratio [HR], 4.8; p = 0.001), high histologic grade (HR, 4.2; p = 0.003), positive margins (HR, 2.6; p = 0.03), and T3-4 disease (HR, 2.0; p = 0.04) as independent predictors of LRR. The presence of any one of these factors was associated with 10-year local-regional control rates of 37% to 63%. Conclusion: Lymph node metastasis, high tumor grade, positive margins, and T3-4 stage predict for significant rates of LRR after surgery for carcinomas of the major salivary glands. Postoperative radiation therapy should be considered for patients with these disease characteristics.« less

Clinicopathological review and survival characteristics of adenoid cystic carcinoma.

PubMed

Binesh, Fariba; Akhavan, Ali; Masumi, Omid; Mirvakili, Abbas; Behniafard, Nasim

2015-03-01

To study the clinical characters, the outcomes of treatments and the factors affecting treatment results of adenoid cystic carcinomas at Shahid Sadoughi Hospital and Shahid Ramazanzadeh radiotherapy center, Yazd, Iran. The clinical data of 31 patients with adenoid cystic carcinoma of any anatomic site diagnosed over an 8 year period (2004-2012), were investigated retrospectively. Data regarding patients' characteristics, pathological features and follow-up were obtained from patients records. Survival rate, local recurrence and distant metastasis were analyzed using Kaplan-Meier method. Prognosis factors were analyzed by Log-rank test and Cox regression. The study included31 patients with adenoid cystic carcinoma. The mean age at presentation was 50.2 ± 24.8 years. There were 11 (35.5 %) males and 20 (64.5 %) females with a female predilection (M:F = 0.55:1). Parotid gland was the most common site (8/31, 25.7 %) followed by submandibular gland (7/31, 22.6 %). Perineural invasion was detected in 67.7 % of the cases. Positive surgical status was reported in 48.4 % of the specimens. Metastasis was detected in 25.8 % of the patients and the most common site of distant metastasis was lung. Overall survival rates at 2, 5, and 7 years were 95, 75, and 57 % respectively. Margin status showed significant effect on survival (P value = 0.01). Positive surgical margin is an important factor affecting the prognosis of the patients with adenoid cystic carcinoma. Surgery with negative surgical margin is the first choice of treatment for the patients with adenoid cystic carcinoma. Our findings show that the prognosis of patients with adenoid cystic carcinoma in our center is fair.

Development of continental margins of the Atlantic Ocean and successive breakup of the Pangaea-3 supercontinent

NASA Astrophysics Data System (ADS)

Melankholina, E. N.; Sushchevskaya, N. M.

2017-01-01

Comparative tectonic analysis of passive margins of the Atlantic Ocean has been performed. Tectonotypes of both volcanic and nonvolcanic margins are described, and their comparison with other passive Atlantic margins is given. The structural features of margins, peculiarities of magmatism, its sources and reasons for geochemical enrichment of melts are discussed. The important role of melting of the continental lithosphere in the development of magmatism is demonstrated. Enriched EM I and EM II sources are determined for the lower parts of the volcanic section, and a depleted or poorly enriched source is determined for the upper parts of the volcanic section based on isotope data. The conclusions of the paper relate to tectonic settings of the initial occurrence of magmatism and rifting and breakup during the period of opening of the Mesozoic Ocean. It was found out that breakup and magmatism at proximal margins led only to insignificant structural transformations and reduction of the thickness of the ancient continental crust, while very important magmatic events happened later in the distal zone. New growth of magmatic crust at the stage of continental breakup is determined as a typical feature of distal zones of the margins under study. The relationship of development of margins with the impact of deep plumes as the source of magmatic material or a heat source only is discussed. Progradation of the zone of extension and breakup into the areas of cold lithosphere of the Atlantic and the formation of a single tectonomagmatic system of the ocean are under consideration.

Group I intron-mediated trans-splicing in mitochondria of Gigaspora rosea and a robust phylogenetic affiliation of arbuscular mycorrhizal fungi with Mortierellales.

PubMed

Nadimi, Maryam; Beaudet, Denis; Forget, Lise; Hijri, Mohamed; Lang, B Franz

2012-09-01

Gigaspora rosea is a member of the arbuscular mycorrhizal fungi (AMF; Glomeromycota) and a distant relative of Glomus species that are beneficial to plant growth. To allow for a better understanding of Glomeromycota, we have sequenced the mitochondrial DNA of G. rosea. A comparison with Glomus mitochondrial genomes reveals that Glomeromycota undergo insertion and loss of mitochondrial plasmid-related sequences and exhibit considerable variation in introns. The gene order between the two species is almost completely reshuffled. Furthermore, Gigaspora has fragmented cox1 and rns genes, and an unorthodox initiator tRNA that is tailored to decoding frequent UUG initiation codons. For the fragmented cox1 gene, we provide evidence that its RNA is joined via group I-mediated trans-splicing, whereas rns RNA remains in pieces. According to our model, the two cox1 precursor RNA pieces are brought together by flanking cox1 exon sequences that form a group I intron structure, potentially in conjunction with the nad5 intron 3 sequence. Finally, we present analyses that address the controversial phylogenetic association of Glomeromycota within fungi. According to our results, Glomeromycota are not a separate group of paraphyletic zygomycetes but branch together with Mortierellales, potentially also Harpellales.

OESbathy version 1.0: a method for reconstructing ocean bathymetry with realistic continental shelf-slope-rise structures

NASA Astrophysics Data System (ADS)

Goswami, A.; Olson, P. L.; Hinnov, L. A.; Gnanadesikan, A.

2015-04-01

We present a method for reconstructing global ocean bathymetry that uses a plate cooling model for the oceanic lithosphere, the age distribution of the oceanic crust, global oceanic sediment thicknesses, plus shelf-slope-rise structures calibrated at modern active and passive continental margins. Our motivation is to reconstruct realistic ocean bathymetry based on parameterized relationships of present-day variables that can be applied to global oceans in the geologic past, and to isolate locations where anomalous processes such as mantle convection may affect bathymetry. Parameters of the plate cooling model are combined with ocean crustal age to calculate depth-to-basement. To the depth-to-basement we add an isostatically adjusted, multicomponent sediment layer, constrained by sediment thickness in the modern oceans and marginal seas. A continental shelf-slope-rise structure completes the bathymetry reconstruction, extending from the ocean crust to the coastlines. Shelf-slope-rise structures at active and passive margins are parameterized using modern ocean bathymetry at locations where a complete history of seafloor spreading is preserved. This includes the coastal regions of the North, South, and Central Atlantic Ocean, the Southern Ocean between Australia and Antarctica, and the Pacific Ocean off the west coast of South America. The final products are global maps at 0.1° × 0.1° resolution of depth-to-basement, ocean bathymetry with an isostatically adjusted, multicomponent sediment layer, and ocean bathymetry with reconstructed continental shelf-slope-rise structures. Our reconstructed bathymetry agrees with the measured ETOPO1 bathymetry at most passive margins, including the east coast of North America, north coast of the Arabian Sea, and northeast and southeast coasts of South America. There is disagreement at margins with anomalous continental shelf-slope-rise structures, such as around the Arctic Ocean, the Falkland Islands, and Indonesia.

Bidirectional interactions between indomethacin and the murine intestinal microbiota

PubMed Central

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

2015-01-01

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

Universality of the helimagnetic transition in cubic chiral magnets: Small angle neutron scattering and neutron spin echo spectroscopy studies of FeCoSi

NASA Astrophysics Data System (ADS)

Bannenberg, L. J.; Kakurai, K.; Falus, P.; Lelièvre-Berna, E.; Dalgliesh, R.; Dewhurst, C. D.; Qian, F.; Onose, Y.; Endoh, Y.; Tokura, Y.; Pappas, C.

2017-04-01

We present a comprehensive small angle neutron scattering and neutron spin echo spectroscopy study of the structural and dynamical aspects of the helimagnetic transition in Fe1 -xCoxSi with x =0.30 . In contrast to the sharp transition observed in the archetype chiral magnet MnSi, the transition in Fe1 -xCoxSi is gradual, and long-range helimagnetic ordering coexists with short-range correlations over a wide temperature range. The dynamics are more complex than in MnSi and involve long relaxation times with a stretched exponential relaxation which persists even under magnetic field. These results in conjunction with an analysis of the hierarchy of the relevant length scales show that the helimagnetic transition in Fe1 -xCoxSi differs substantially from the transition in MnSi and question the validity of a universal approach to the helimagnetic transition in chiral magnets.

A study on magneto-optic properties of CoxMg1-xFe2O4 nanoferrofluids

NASA Astrophysics Data System (ADS)

Karthick, R.; Ramachandran, K.; Srinivasan, R.

2018-04-01

Nanoparticles of CoxMg1-xFe2O4 (x = 0.1, 0.5, 0.9) were synthesized using chemical co-precipitation method. Characterization by X-ray diffraction technique confirmed the formation of cubic crystalline structure and the crystallite size of the samples obtained using Debye-Scherrer approximation were found to increase with increasing cobalt substitution. Surface morphology and the Chemical composition of the samples were visualized using scanning electron microscope (SEM) with energy dispersive analysis of X-rays (EDAX). Room temperature magnetic parameters of the nanoparticles by vibrating sample magnetometer (VSM) revealed the magnetic properties such as Saturation magnetization (Ms), Remanent magnetization (Mr) and Coercive field (Hc) found to increase with increasing cobalt substitution. Faraday rotation measurements on CoxMg1-xFe2O4 ferrofluids exhibited increase in rotation with cobalt substitution. Further, there is an increase in Faraday rotation with increasing magnetic field for all the samples.

Potency and selectivity of carprofen enantiomers for inhibition of bovine cyclooxygenase in whole blood assays.

PubMed

Brentnall, Claire; Cheng, Zhangrui; McKellar, Quintin A; Lees, Peter

2012-12-01

Whole blood in vitro assays were used to determine the potency and selectivity of carprofen enantiomers for inhibition of the isoforms of cyclooxygenase (COX), COX-1 and COX-2, in the calf. S(+)-carprofen possessed preferential activity for COX-2 inhibition but, because the slopes of inhibition curves differed, the COX-1:COX-2 inhibition ratio decreased from 9.04:1 for inhibitory concentration (IC)10 to 1.84:1 for IC95. R(-) carprofen inhibited COX-2 preferentially only for low inhibition of the COX isoforms (IC10 COX-1:COX-2=6.63:1), whereas inhibition was preferential for COX-1 for a high level of inhibition (IC95 COX-1:COX-2=0.20:1). S(+) carprofen was the more potent inhibitor of COX isoforms; potency ratios S(+):R(-) carprofen were 11.6:1 for IC10 and 218:1 for IC90. Based on serum concentrations of carprofen enantiomers obtained after administration of a therapeutic dose of 1.4 mg/kg to calves subcutaneously, S(+)-carprofen concentrations exceeded the in vitro IC80 COX-2 value for 32 h and the IC20 for COX-1 for 33 h. The findings are discussed in relation to efficacy and safety of carprofen in calves. Copyright © 2012 Elsevier Ltd. All rights reserved.

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 new insight into bone physiology; namely, that COX-2 is constitutively expressed in osteoblasts in the dynamic bone growth area, which facilitates osteoblast proliferation via PTEN/Akt/p27(Kip1) signaling. Copyright © 2010 Elsevier Inc. All rights reserved.

The marginal band system in nymphalid butterfly wings.

PubMed

Taira, Wataru; Kinjo, Seira; Otaki, Joji M

2015-01-01

Butterfly wing color patterns are highly complex and diverse, but they are believed to be derived from the nymphalid groundplan, which is composed of several color pattern systems. Among these pattern systems, the marginal band system, including marginal and submarginal bands, has rarely been studied. Here, we examined the color pattern diversity of the marginal band system among nymphalid butterflies. Marginal and submarginal bands are usually expressed as a pair of linear bands aligned with the wing margin. However, a submarginal band can be expressed as a broken band, an elongated oval, or a single dot. The marginal focus, usually a white dot at the middle of a wing compartment along the wing edge, corresponds to the pupal edge spot, one of the pupal cuticle spots that signify the locations of color pattern organizing centers. A marginal band can be expressed as a semicircle, an elongated oval, or a pair of eyespot-like structures, which suggest the organizing activity of the marginal focus. Physical damage at the pupal edge spot leads to distal dislocation of the submarginal band in Junonia almana and in Vanessa indica, suggesting that the marginal focus functions as an organizing center for the marginal band system. Taken together, we conclude that the marginal band system is developmentally equivalent to other symmetry systems. Additionally, the marginal band is likely a core element and the submarginal band a paracore element of the marginal band system, and both bands are primarily specified by the marginal focus organizing center.

Modelling of Continental Lithosphere Breakup and Rifted Margin Formation in Response to an Upwelling Divergent Flow Field Incorporating a Temperature Dependent Rheology

NASA Astrophysics Data System (ADS)

Tymms, V. J.; Kusznir, N. J.

2005-05-01

We numerically model continental lithosphere deformation leading to breakup and sea floor spreading initiation in response to an imposed upwelling and divergent flow field applied to continental lithosphere and asthenosphere. The model is used to predict rifted continental margin lithosphere thinning and temperature structure. Model predictions are compared with observed rifted margin structure for four diverse case studies. Prior to application of the upwelling divergent flow field the continental lithosphere is undeformed with a uniform temperature gradient. The upwelling divergent flow field is defined kinematically using boundary conditions consisting of the upwelling velocity Vz at the divergence axis and the half divergence rate Vx . The resultant velocity field throughout the continuum is computed using finite element (FE) code incorporating a Newtonian temperature dependent rheology. The flow field is used to advect the continental lithosphere material and lithospheric and asthenospheric temperatures. Viscosity structure is hence modified and the velocities change correspondingly in a feedback loop. We find the kinematic boundary conditions Vz and Vx to be of first order importance. A high Vz/Vx (greater than10), corresponding to buoyancy assisted flow, leads to minimal mantle exhumation and a well defined continent ocean transition consistent with observations at volcanic margins. For Vz/Vx near unity, corresponding to plate boundary driven divergence, mantle exhumation over widths of up to 100 km is predicted which is consistent with observations at non-volcanic margins. The FE method allows the upwelling velocity Vz to be propagated upwards from the top of the asthenosphere to the Earth's surface without the requirement of imposing Vx. When continental breakup is achieved the half divergence velocity Vx can be applied at the lithosphere surface and the upwelling velocity Vz left free. We find this time and space dependent set of boundary conditions is more plausible than a constant corner flow type solution and predicts levels of depth dependent stretching and continent ocean transitions consistent with observation. Depth dependent lithosphere stretching, which is observed at rifted continental margins, is predicted to occur before continental breakup and sea-floor spreading initiation. The model may be used to predict surface heat flow and bathymetry, and to provide estimates of melt production rates and cumulative thickness. We compare model predictions with observed margin structure for four diverse rifted margins: the Lofoten Margin (a mature volcanic margin), Goban Spur (a mature non-volcanic margin), the Woodlark Basin (a neotectonic young ocean basin) and the Faroe-Shetland Basin (a failed attempt at continental breakup). This work forms part of the NERC Margins iSIMM project. iSIMM investigators are from Liverpool and Cambridge Universities, Badley Geoscience & Schlumberger Cambridge Research supported by the NERC, the DTI, Agip UK, BP, Amerada Hess Ltd, Anadarko, Conoco¬Phillips, Shell, Statoil and WesternGeco. The iSIMM team comprises NJ Kusznir, RS White, AM Roberts, PAF Christie, A Chappell, J Eccles, R Fletcher, D Healy, N Hurst, ZC Lunnon, CJ Parkin, AW Roberts, LK Smith, V Tymms & R Spitzer.

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

PubMed

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

2016-01-01

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

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

PubMed Central

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

2016-01-01

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

Deciphering amphibian diversity through DNA barcoding: chances and challenges.

PubMed

Vences, Miguel; Thomas, Meike; Bonett, Ronald M; Vieites, David R

2005-10-29

Amphibians globally are in decline, yet there is still a tremendous amount of unrecognized diversity, calling for an acceleration of taxonomic exploration. This process will be greatly facilitated by a DNA barcoding system; however, the mitochondrial population structure of many amphibian species presents numerous challenges to such a standardized, single locus, approach. Here we analyse intra- and interspecific patterns of mitochondrial variation in two distantly related groups of amphibians, mantellid frogs and salamanders, to determine the promise of DNA barcoding with cytochrome oxidase subunit I (cox1) sequences in this taxon. High intraspecific cox1 divergences of 7-14% were observed (18% in one case) within the whole set of amphibian sequences analysed. These high values are not caused by particularly high substitution rates of this gene but by generally deep mitochondrial divergences within and among amphibian species. Despite these high divergences, cox1 sequences were able to correctly identify species including disparate geographic variants. The main problems with cox1 barcoding of amphibians are (i) the high variability of priming sites that hinder the application of universal primers to all species and (ii) the observed distinct overlap of intraspecific and interspecific divergence values, which implies difficulties in the definition of threshold values to identify candidate species. Common discordances between geographical signatures of mitochondrial and nuclear markers in amphibians indicate that a single-locus approach can be problematic when high accuracy of DNA barcoding is required. We suggest that a number of mitochondrial and nuclear genes may be used as DNA barcoding markers to complement cox1.

High genetic diversities between isolates of the fish parasite Cryptocaryon irritans (Ciliophora) suggest multiple cryptic species.

PubMed

Chi, Hongshu; Taik, Patricia; Foley, Emily J; Racicot, Alycia C; Gray, Hilary M; Guzzetta, Katherine E; Lin, Hsin-Yun; Song, Yen-Ling; Tung, Che-Huang; Zenke, Kosuke; Yoshinaga, Tomoyoshi; Cheng, Chao-Yin; Chang, Wei-Jen; Gong, Hui

2017-07-01

The ciliate protozoan Cryptocaryon irritans parasitizes marine fish and causes lethal white spot disease. Sporadic infections as well as large-scale outbreaks have been reported globally and the parasite's broad host range poses particular threat to the aquaculture and ornamental fish markets. In order to better understand C. irritans' population structure, we sequenced and compared mitochondrial cox-1, SSU rRNA, and ITS-1 sequences from 8 new isolates of C. irritans collected in China, Japan, and Taiwan. We detected two SSU rRNA haplotypes, which differ at three positions, separating the isolates into two main groups (I and II). Cox-1 sequences also support the division into two groups, and the cox-1 divergence between these two groups is unexpectedly high (9.28% for 1582 nucleotide positions). The divergence is much greater than that detected in Ichthyophthirius multifiliis, the ciliate protozoan causing freshwater white spot disease in fish, where intraspecies divergence on cox-1 sequence is only 1.95%. ITS-1 sequences derived from these eight isolates and from all other C. irritans isolates (deposited in the GenBank) not only support the two groups, but further suggest the presence of a third group with even greater sequence divergence. Finally, a small Ka/Ks ratio estimated from cox-1 sequences suggests that this gene in C. irritans remains under strong purifying selection. Taken together, the C. irritans species may consists of many subspecies and/or syngens. Further work is needed to determine if there is reproductive isolation between the groups we have defined. Copyright © 2017 Elsevier Inc. All rights reserved.

Models and analysis for multivariate failure time data

NASA Astrophysics Data System (ADS)

Shih, Joanna Huang

The goal of this research is to develop and investigate models and analytic methods for multivariate failure time data. We compare models in terms of direct modeling of the margins, flexibility of dependency structure, local vs. global measures of association, and ease of implementation. In particular, we study copula models, and models produced by right neutral cumulative hazard functions and right neutral hazard functions. We examine the changes of association over time for families of bivariate distributions induced from these models by displaying their density contour plots, conditional density plots, correlation curves of Doksum et al, and local cross ratios of Oakes. We know that bivariate distributions with same margins might exhibit quite different dependency structures. In addition to modeling, we study estimation procedures. For copula models, we investigate three estimation procedures. the first procedure is full maximum likelihood. The second procedure is two-stage maximum likelihood. At stage 1, we estimate the parameters in the margins by maximizing the marginal likelihood. At stage 2, we estimate the dependency structure by fixing the margins at the estimated ones. The third procedure is two-stage partially parametric maximum likelihood. It is similar to the second procedure, but we estimate the margins by the Kaplan-Meier estimate. We derive asymptotic properties for these three estimation procedures and compare their efficiency by Monte-Carlo simulations and direct computations. For models produced by right neutral cumulative hazards and right neutral hazards, we derive the likelihood and investigate the properties of the maximum likelihood estimates. Finally, we develop goodness of fit tests for the dependency structure in the copula models. We derive a test statistic and its asymptotic properties based on the test of homogeneity of Zelterman and Chen (1988), and a graphical diagnostic procedure based on the empirical Bayes approach. We study the performance of these two methods using actual and computer generated data.

Marginal inherited structures impact on the oblique convergent N American Plate/ Central Caribbean plate-boundary in the Northern Caribbean. The tectonic evolution since Miocene times based on Haiti data acquired onshore and offshore since 2012- a step toward an ADP Drilling Proposal (Haiti-DRILL).

NASA Astrophysics Data System (ADS)

Ellouz, N.; Hamon, Y.; Deschamps, R.; Battani, A.; Wessels, R.; Boisson, D.; Prepetit, C.; Momplaisir, R.

2017-12-01

Since Early Paleogene times, the North Caribbean plate is colliding obliquely with the south continental part of the old N. American Margins, which is represented by various segments from West to East, inherited from Jurassic times. Location, amount of displacement, rotation and the structural deformation of these margin segments, resulting from the dislocation of the continental N American margin, are not clearly yet established. At present, the plate limits are marked either by two left lateral faults west and inside Haiti (OSF in the North and EPGF in the South), oblique collision front (further west in Cuba), oblique subducted segments (to the East, Porto-Rico). From our recent works operated both offshore (Haiti-SIS and Haiti-BGF surveys 2012-2015) and onshore (field campaigns 2013-2017) in Haitian zone, the position of the present-day and paleo major limits have been redefined. These paleolimits have been reconstructed up to early Miocene times, based on: restoration of regional structural cross-sections, sedimentology and on paleoenvironement studies. In a preliminary way, we analyzed the complexity of the tectonic heritage with possible nature, heterogeneity of the crustal fragments and associated margins close to Haiti (age, structure, environment, location of the dislocated blocks through times) which profoundly impact the partitioning of the deformation along this complex transformed margin. The change in the structure wavelength, decollement level variations are primary constraints in the restoration of the main units and do impose a deep connection along specific segments either related to strike-slip or to splay faults. The asymmetry on the repartition of the fault activity tend to prove that the past motion related to "EPGF transfer zone" is mainly partitioned in Haiti to the North of the present-day EPGF position. At present, these results are still coherent with the distribution of the aftershoks registered after 2010, and with the present-day seismicity during the last years.

The influence of cyclooxygenase-1 expression on the efficacy of cyclooxygenase-2 inhibition in head and neck squamous cell carcinoma cell lines.

PubMed

Park, Seok-Woo; Kim, Hyo-Sun; Choi, Myung-Sun; Kim, Ji-Eun; Jeong, Woo-Jin; Heo, Dae-Seog; Sung, Myung-Whun

2011-06-01

We have previously observed that cyclooxygenase-2 (COX-2) inhibition blocked the production of vascular endothelial growth factor (VEGF) in some head and neck squamous cell carcinoma (HNSCC) cells. However, as some HNSCC cells showed little response to COX-2 inhibition, although they highly expressed COX-2 and prostaglandin E2, we set out to elucidate what made this difference between them and focused on the possibility of the differential expression of COX-1. In western blotting, we found that COX-1 was expressed in SNU-1041 and SNU-1066, but not in SNU-1076 and PCI-50. Only in those cell lines without expression of COX-1 was VEGF production blocked meaningfully by small interfering RNA of COX-2. However, by cotreating with small interfering RNAs of COX-2 and COX-1, VEGF synthesis and prostaglandin E2 were inhibited in SNU-1041 and SNU-1066, similarly in SNU-1076 and PCI-50 with high expression of only COX-2. We also found that there was no difference in the pattern of prostaglandin synthesis between COX-2 and COX-1 through enzyme-linked immunosorbent assay for various prostaglandins. Our study suggests that, as COX-1 and COX-2 express and affect VEGF synthesis in HNSCC cells, we should check COX-1 expression in investigations on cancer treatment by inhibiting COX-2-induced prostaglandins.

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

PubMed

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

2000-01-01

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

A unifying framework for marginalized random intercept models of correlated binary outcomes

PubMed Central

Swihart, Bruce J.; Caffo, Brian S.; Crainiceanu, Ciprian M.

2013-01-01

We demonstrate that many current approaches for marginal modeling of correlated binary outcomes produce likelihoods that are equivalent to the copula-based models herein. These general copula models of underlying latent threshold random variables yield likelihood-based models for marginal fixed effects estimation and interpretation in the analysis of correlated binary data with exchangeable correlation structures. Moreover, we propose a nomenclature and set of model relationships that substantially elucidates the complex area of marginalized random intercept models for binary data. A diverse collection of didactic mathematical and numerical examples are given to illustrate concepts. PMID:25342871

Effects of Supervised Structured Aerobic Exercise Training Program on Interleukin-6, Nitric Oxide Synthase-1, and Cyclooxygenase-2 in Type 2 Diabetes Mellitus.

PubMed

Karimi, Hossein; Rehman, Syed Shakil Ur; Gillani, Syed Amir

2017-06-01

To determine the effects of supervised structured aerobic exercise training (SSAET) program on interleukin-6 (IL-6), nitric oxide synthase 1 (NOS-1), and cyclooxygenase-2 (COX-2) in type 2 diabetes mellitus (T2DM). Randomized controlled trial. Riphah Rehabilitation and Research Centre, Railways General Hospital, Rawalpindi, from January 2015 to June 2016. Patients of either gender of minimum one year history of T2DM ranging from 40-70 years of age were included. Those with chronic systemic diseases, history of regular exercise, smoking, and those on dietary plan were excluded. Atotal of 195 patients were screened; 120 were selected and 102 agreed to participate in the study. They were randomly placed into experimental and control groups. SSAETprogram, routine medication, and dietary plan were applied in experimental group; whereas, control group was managed with routine medication and dietary plan for 25 weeks. IL-6, NOS-1, and COX-2 were assessed at baseline and 25 weeks. SSAET program, routine medication and dietary plan showed significantly improved IL-6 (pre-mean=0.25 ±0.11ng/ml, post-mean=0.19 ±0.04 ng/ml), NOS-1 (pre-median=4.65 ng/ml, IQ range=1.04 ng/ml), (post-median=2.72 ng/ml, IQ range=1.60 ng/ml), and COX-2 (pre-mean=18.72 ±4.42 ng/ml, post-mean=15.18 ±2.63 ng/ml) in experimental group, as compared with control group managed by routine medication and dietary plan, where deterioration was noted in IL-6 (pre-mean=0.23 ±0.08 ng/ml, post-mean=0.27 ±0.08 ng/ml) and COX-2 (pre-mean=18.49 ±4.56 ng/ml, postmean=19.10 ±4.76 ng/ml), while NOS-1 slight improvement (pre-mean=4.99 ng/ml, IQ range=2.67 ng/ml), (postmean=4.56 ng/ml, IQ range=3.85 ng/ml). Statistically at the baseline the p-values were not significant (p>0.05) in both experimental and control groups for IL-6, COX-2 and NOS-1; while after 25 weeks of intervention, the experimental group showed significant improvement (p<0.05) in comparison with the control group. SSAET program, routine medication, and dietary plan had positive effect on IL-6, NOS-1, and COX-2 in T2DM patients.

The Positive and Negative Syndrome Scale (PANSS): A Three-Factor Model of Psychopathology in Marginally Housed Persons with Substance Dependence and Psychiatric Illness.

PubMed

Giesbrecht, Chantelle J; O'Rourke, Norm; Leonova, Olga; Strehlau, Verena; Paquet, Karine; Vila-Rodriguez, Fidel; Panenka, William J; MacEwan, G William; Smith, Geoffrey N; Thornton, Allen E; Honer, William G

2016-01-01

Rates of psychopathology are elevated in marginalized and unstably housed persons, underscoring the need for applicable clinical measures for these populations. The Positive and Negative Syndrome Scale (PANSS) is a clinical instrument principally developed for use in schizophrenia to identify the presence and severity of psychopathology symptoms. The current study investigates whether a reliable and valid PANSS factor structure emerges in a marginally housed, heterogeneous sample recruited from the Downtown Eastside of Vancouver where substance use disorders and psychiatric illness are pervasive. Participants (n = 270) underwent structured clinical assessments including the PANSS and then were randomly assigned to either exploratory (EFA) or confirmatory factor analytic (CFA) subsamples. EFA pointed to a novel three factor PANSS. This solution was supported by CFA. All retained items (28 out of 30) load significantly upon hypothesized factors and model goodness of fit analyses are in the acceptable to good range. Each of the three first-order factor constructs, labeled Psychosis/Disorganized, Negative Symptoms/Hostility, and Insight/Awareness, contributed significantly to measurement of a higher-order psychopathology construct. Further, the latent structure of this 3-factor solution appears temporally consistent over one-year. This PANSS factor structure appears valid and reliable for use in persons with multimorbidity, including substance use disorders. The structure is somewhat distinct from existing solutions likely due to the unique characteristics of this marginally housed sample.

The Positive and Negative Syndrome Scale (PANSS): A Three-Factor Model of Psychopathology in Marginally Housed Persons with Substance Dependence and Psychiatric Illness

PubMed Central

Giesbrecht, Chantelle J.; O’Rourke, Norm; Leonova, Olga; Strehlau, Verena; Paquet, Karine; Vila-Rodriguez, Fidel; Panenka, William J.; MacEwan, G. William; Smith, Geoffrey N.; Thornton, Allen E.; Honer, William G.

2016-01-01

Rates of psychopathology are elevated in marginalized and unstably housed persons, underscoring the need for applicable clinical measures for these populations. The Positive and Negative Syndrome Scale (PANSS) is a clinical instrument principally developed for use in schizophrenia to identify the presence and severity of psychopathology symptoms. The current study investigates whether a reliable and valid PANSS factor structure emerges in a marginally housed, heterogeneous sample recruited from the Downtown Eastside of Vancouver where substance use disorders and psychiatric illness are pervasive. Participants (n = 270) underwent structured clinical assessments including the PANSS and then were randomly assigned to either exploratory (EFA) or confirmatory factor analytic (CFA) subsamples. EFA pointed to a novel three factor PANSS. This solution was supported by CFA. All retained items (28 out of 30) load significantly upon hypothesized factors and model goodness of fit analyses are in the acceptable to good range. Each of the three first-order factor constructs, labeled Psychosis/Disorganized, Negative Symptoms/Hostility, and Insight/Awareness, contributed significantly to measurement of a higher-order psychopathology construct. Further, the latent structure of this 3-factor solution appears temporally consistent over one-year. This PANSS factor structure appears valid and reliable for use in persons with multimorbidity, including substance use disorders. The structure is somewhat distinct from existing solutions likely due to the unique characteristics of this marginally housed sample. PMID:26999280

Automated design and optimization of flexible booster autopilots via linear programming. Volume 2: User's manual

NASA Technical Reports Server (NTRS)

Hauser, F. D.; Szollosi, G. D.; Lakin, W. S.

1972-01-01

COEBRA, the Computerized Optimization of Elastic Booster Autopilots, is an autopilot design program. The bulk of the design criteria is presented in the form of minimum allowed gain/phase stability margins. COEBRA has two optimization phases: (1) a phase to maximize stability margins; and (2) a phase to optimize structural bending moment load relief capability in the presence of minimum requirements on gain/phase stability margins.

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

PubMed Central

Herschman, Harvey

2014-01-01

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

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

PubMed

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

2014-06-01

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

Genetic diversity and population structure in Bactrocera correcta (Diptera: Tephritidae) inferred from mtDNA cox1 and microsatellite markers

PubMed Central

Qin, Yu-Jia; Buahom, Nopparat; Krosch, Matthew N.; Du, Yu; Wu, Yi; Malacrida, Anna R.; Deng, Yu-Liang; Liu, Jia-Qi; Jiang, Xiao-Long; Li, Zhi-Hong

2016-01-01

Bactrocera correcta is one of the most destructive pests of horticultural crops in tropical and subtropical regions. Despite the economic risk, the population genetics of this pest have remained relatively unexplored. This study explores population genetic structure and contemporary gene flow in B. correcta in Chinese Yunnan Province and attempts to place observed patterns within the broader geographical context of the species’ total range. Based on combined data from mtDNA cox1 sequences and 12 microsatellite loci obtained from 793 individuals located in 7 countries, overall genetic structuring was low. The expansion history of this species, including likely human-mediated dispersal, may have played a role in shaping the observed weak structure. The study suggested a close relationship between Yunnan Province and adjacent countries, with evidence for Western and/or Southern Yunnan as the invasive origin of B. correcta within Yunnan Province. The information gleaned from this analysis of gene flow and population structure has broad implications for quarantine, trade and management of this pest, especially in China where it is expanding northward. Future studies should concentrate effort on sampling South Asian populations, which would enable better inferences of the ancestral location of B. correcta and its invasion history into and throughout Asia. PMID:27929126

Neutron scattering study of the interplay between structure and magnetism in Ba(Fe1-xCox)2As2

NASA Astrophysics Data System (ADS)

Lester, C.; Chu, Jiun-Haw; Analytis, J. G.; Capelli, S. C.; Erickson, A. S.; Condron, C. L.; Toney, M. F.; Fisher, I. R.; Hayden, S. M.

2009-04-01

Single-crystal neutron diffraction is used to investigate the magnetic and structural phase diagrams of the electron-doped superconductor Ba(Fe1-xCox)2As2 . Heat-capacity and resistivity measurements have demonstrated that Co doping this system splits the combined antiferromagnetic and structural transition present in BaFe2As2 into two distinct transitions. For x=0.025 , we find that the upper transition is between the high-temperature tetragonal and low-temperature orthorhombic structures with (TTO=99±0.5K) and the antiferromagnetic transition occurs at TAF=93±0.5K . We find that doping rapidly suppresses the antiferromagnetism, with antiferromagnetic order disappearing at x≈0.055 . However, there is a region of coexistence of antiferromagnetism and signatures of superconductivity obtained from thermodynamic and transport properties. For all the compositions studied, we find two anomalies in the temperature dependence of the structural Bragg peaks from both neutron scattering and x-ray diffraction at the same temperatures where anomalies in the heat capacity and resistivity have been previously identified. Thus for x=0.025 , where we have shown that the lower anomaly occurs at TAF , we infer that there is strong coupling between the antiferromagnetism and the crystal lattice which may persist to larger x .

Differential cyclooxygenase-2 expression in squamous cell carcinoma and adenocarcinoma of the uterine cervix.

PubMed

Kim, Yong Bae; Kim, Gwi Eon; Pyo, Hong Ryull; Cho, Nam Hoon; Keum, Ki Chang; Lee, Chang Geol; Seong, Jinsil; Suh, Chang Ok; Park, Tchan Kyu

2004-11-01

To determine the differential expression of cyclooxygenase-2 (COX-2) in patients with squamous cell carcinoma (SCC) and adenocarcinoma (ADC) of the uterine cervix and the prognostic significance of COX-2 expression in these histologic types. A total of 105 International Federation of Gynecology and Obstetrics Stage IIB uterine cervical cancer patients were screened for COX-2 expression immunohistochemically. COX-2 expression was determined in invasive cervical SCC (n = 84) and invasive cervical ADC (n = 21). To determine the clinical significance of COX-2 expression by histologic type, the patients were arbitrarily divided into four groups: SCC/COX-2 negative (n = 64); SCC/COX-2 positive (n = 20); ADC/COX-2 negative (n = 9); and ADC/COX-2 positive (n = 12). The clinical response to treatment, patterns of treatment failure, and survival data by COX-2 expression were compared for these two major histologic types. Univariate and multivariate analyses were performed to identify the prognostic factors influencing survival. Immunohistochemical examination showed that COX-2 expression was more frequently observed in ADC than in SCC (57% vs. 24%, p = 0.007). Moreover, COX-2 expression was an important predictor of treatment response, irrespective of the histologic type. All COX-2-negative patients achieved complete remission after initial treatment; 17% of SCC patients and 33% of ADC patients with COX-2 expression did not have complete remission after the initial treatment. The incidence of local failure for those with COX-2 expression was significantly greater than for COX-2-negative patients, regardless of histologic type. With a minimal follow-up of 60 months, the overall 5-year actuarial survival rate for SCC and ADC patients was 79% and 62%, respectively (p = 0.05). The 5-year disease-free survival rate for SCC and ADC patients was 73% and 56%, respectively (p = 0.13). Irrespective of the pathologic type, COX-2-positive patients had an unfavorable prognosis. The overall 5-year actuarial survival rate was 57% for COX-2-positive patients and 83% for COX-2-negative patients (p = 0.001). When patients were stratified into the four groups according to histologic type and COX-2 expression status, ADC/COX-2-positive patients had the worst prognosis, with an overall 5-year actuarial survival rate of 49% compared with 78% for ADC/COX-2-negative patients, 62% for SCC/COX-2-positive, and 84% for SCC/COX-2-negative patients (p = 0.007, log-rank test). Irrespective of histologic type, COX-2 expression was an independent prognostic factor by univariate and multivariate analyses. In uterine cervical cancer, COX-2 was expressed in a greater proportion of ADC patients than SCC patients. COX-2 expression was also identified as a major determiner of a poor response to treatment and of an unfavorable prognosis, irrespective of the histologic type, reflecting the importance of the COX-2 protein in the acquisition of biologic aggressiveness and more malignant phenotype or increased resistance to the standard chemotherapy and radiotherapy in both histologic types. Given these observations, we believe that that ADC/COX-2-positive patients might be appropriate candidates for future trials of selective COX-2 inhibitor adjunctive therapy.

Chapter 34: Geology and petroleum potential of the rifted margins of the Canada Basin

USGS Publications Warehouse

Houseknecht, D.W.; Bird, K.J.

2011-01-01

Three sides of the Canada Basin are bordered by high-standing, conjugate rift shoulders of the Chukchi Borderland, Alaska and Canada. The Alaska and Canada margins are mantled with thick, growth-faulted sediment prisms, and the Chukchi Borderland contains only a thin veneer of sediment. The rift-margin strata of Alaska and Canada reflect the tectonics and sediment dispersal systems of adjacent continental regions whereas the Chukchi Borderland was tectonically isolated from these sediment dispersal systems. Along the eastern Alaska-southern Canada margin, termed herein the 'Canning-Mackenzie deformed margin', the rifted margin is deformed by ongoing Brooks Range tectonism. Additional contractional structures occur in a gravity fold belt that may be present along the entire Alaska and Canada margins of the Canada Basin. Source-rock data inboard of the rift shoulders and regional palaeogeographic reconstructions suggest three potential source-rock intervals: Lower Cretaceous (Hauterivian-Albian), Upper Cretaceous (mostly Turonian) and Lower Palaeogene. Burial history modelling indicates favourable timing for generation from all three intervals beneath the Alaska and Canada passive margins, and an active petroleum system has been documented in the Canning-Mackenzie deformed margin. Assessment of undiscovered petroleum resources indicates the greatest potential in the Canning-Mackenzie deformed margin and significant potential in the Canada and Alaska passive margins. ?? 2011 The Geological Society of London.

Platelet cyclooxygenase expression in normal dogs.

PubMed

Thomason, J; Lunsford, K; Mullins, K; Stokes, J; Pinchuk, L; Wills, R; McLaughlin, R; Langston, C; Pruett, S; Mackin, A

2011-01-01

Human platelets express both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Variation in COX-2 expression could be a mechanism for variable response to aspirin. The hypotheses were that circulating canine platelets express COX-1 and COX-2, and that aspirin alters COX expression. The objective was to identify changes in platelet COX expression and in platelet function caused by aspirin administration to dogs. Eight female, intact hounds. A single population, repeated measures design was used to evaluate platelet COX-1 and COX-2 expression by flow cytometry before and after aspirin (10 mg/kg Q12h for 10 days). Platelet function was analyzed via PFA-100(®) (collagen/epinephrine), and urine 11-dehydro-thromboxane B(2) (11-dTXB(2)) was measured and normalized to urinary creatinine. Differences in COX expression, PFA-100(®) closure times, and urine 11-dTXB(2 ): creatinine ratio were analyzed before and after aspirin administration. Both COX-1 and COX-2 were expressed in canine platelets. COX-1 mean fluorescent intensity (MFI) increased in all dogs, by 250% (range 63-476%), while COX-2 expression did not change significantly (P = 0.124) after aspirin exposure, with large interindividual variation. PFA-100(®) closure times were prolonged and urine 11-dTXB(2) concentration decreased in all dogs after aspirin administration. Canine platelets express both COX isoforms. After aspirin exposure, COX-1 expression increased despite impairment of platelet function, while COX-2 expression varied markedly among dogs. Variability in platelet COX-2 expression should be explored as a potential mechanism for, or marker of, variable aspirin responsiveness. Copyright © 2011 by the American College of Veterinary Internal Medicine.

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

PubMed

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

2014-08-01

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

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

PubMed Central

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

2014-01-01

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

Magma-poor vs. magma-rich continental rifting and breakup in the Labrador Sea

NASA Astrophysics Data System (ADS)

Gouiza, M.; Paton, D.

2017-12-01

Magma-poor and magma-rich rifted margins show distinct structural and stratigraphic geometries during the rift to breakup period. In magma-poor margins, crustal stretching is accommodated mainly by brittle faulting and the formation of wide rift basins shaped by numerous graben and half-graben structures. Continental breakup and oceanic crust accretion are often preceded by a localised phase of (hyper-) extension where the upper mantle is embrittled, serpentinized, and exhumed to the surface. In magma-rich margins, the rift basin is narrow and extension is accompanied by a large magmatic supply. Continental breakup and oceanic crust accretion is preceded by the emplacement of a thick volcanic crust juxtaposing and underplating a moderately thinned continental crust. Both magma-poor and magma-rich rifting occur in response to lithospheric extension but the driving forces and processes are believed to be different. In the former extension is assumed to be driven by plate boundary forces, while in the latter extension is supposed to be controlled by sublithospheric mantle dynamics. However, this view fails in explaining observations from many Atlantic conjugate margins where magma-poor and magma-rich segments alternate in a relatively abrupt fashion. This is the case of the Labrador margin where the northern segment shows major magmatic supply during most of the syn-rift phase which culminate in the emplacement of a thick volcanic crust in the transitional domain along with high density bodies underplating the thinned continental crust; while the southern segment is characterized mainly by brittle extension, mantle seprentinization and exhumation prior to continental breakup. In this work, we use seismic and potential field data to describe the crustal and structural architectures of the Labrador margin, and investigate the tectonic and mechanical processes of rifting that may have controlled the magmatic supply in the different segments of the margin.

Tectonic Inversion Along the Algerian and Ligurian Margins: On the Insight Provided By Latest Seismic Processing Techniques Applied to Recent and Vintage 2D Offshore Multichannel Seismic Data

NASA Astrophysics Data System (ADS)

Schenini, L.; Beslier, M. O.; Sage, F.; Badji, R.; Galibert, P. Y.; Lepretre, A.; Dessa, J. X.; Aidi, C.; Watremez, L.

2014-12-01

Recent studies on the Algerian and the North-Ligurian margins in the Western Mediterranean have evidenced inversion-related superficial structures, such as folds and asymmetric sedimentary perched basins whose geometry hints at deep compressive structures dipping towards the continent. Deep seismic imaging of these margins is difficult due to steep slope and superficial multiples, and, in the Mediterranean context, to the highly diffractive Messinian evaporitic series in the basin. During the Algerian-French SPIRAL survey (2009, R/V Atalante), 2D marine multi-channel seismic (MCS) reflection data were collected along the Algerian Margin using a 4.5 km, 360 channel digital streamer and a 3040 cu. in. air-gun array. An advanced processing workflow has been laid out using Geocluster CGG software, which includes noise attenuation, 2D SRME multiple attenuation, surface consistent deconvolution, Kirchhoff pre-stack time migration. This processing produces satisfactory seismic images of the whole sedimentary cover, and of southward dipping reflectors in the acoustic basement along the central part of the margin offshore Great Kabylia, that are interpreted as inversion-related blind thrusts as part of flat-ramp systems. We applied this successful processing workflow to old 2D marine MCS data acquired on the North-Ligurian Margin (Malis survey, 1995, R/V Le Nadir), using a 2.5 km, 96 channel streamer and a 1140 cu. in. air-gun array. Particular attention was paid to multiple attenuation in adapting our workflow. The resulting reprocessed seismic images, interpreted with a coincident velocity model obtained by wide-angle data tomography, provide (1) enhanced imaging of the sedimentary cover down to the top of the acoustic basement, including the base of the Messinian evaporites and the sub-salt Miocene series, which appear to be tectonized as far as in the mid-basin, and (2) new evidence of deep crustal structures in the margin which the initial processing had failed to reveal.

The role of tectonic inheritance in the morphostructural evolution of the Galicia continental margin and adjacent abyssal plains from digital bathymetric model (DBM) analysis (NW Spain)

NASA Astrophysics Data System (ADS)

Maestro, A.; Jané, G.; Llave, E.; López-Martínez, J.; Bohoyo, F.; Druet, M.

2018-06-01

The identification of recent major tectonic structures in the Galicia continental margin and adjacent abyssal plains was carried out by means of a quantitative analysis of the linear structures having bathymetric expression on the seabed. It was possible to identify about 5800 lineaments throughout the entire study area, of approximately 271,500 km2. Most lineaments are located in the Charcot and Coruña highs, in the western sector of the Galicia Bank, in the area of the Marginal Platforms and in the northern sector of the margin. Analysis of the lineament orientations shows a predominant NE-SW direction and three relative maximum directions: NW-SE, E-W and N-S. The total length of the lineaments identified is over 44,000 km, with a mode around 5000 m and an average length of about 7800 m. In light of different tectonic studies undertaken in the northwestern margin of the Iberian Peninsula, we establish that the lineaments obtained from analysis of the digital bathymetric model of the Galicia continental margin and adjacent abyssal plains would correspond to fracture systems. In general, the orientation of lineaments corresponds to main faults, tectonic structures following the directions of ancient faults that resulted from late stages of the Variscan orogeny and Mesozoic extension phases related to Triassic rifting and Upper Jurassic to Early Cretaceous opening of the North Atlantic Ocean. The N-S convergence between Eurasian and African plates since Palaeogene times until the Miocene, and NW-SE convergence from Neogene to present, reactivated the Variscan and Mesozoic fault systems and related physiography.

Domestic violence at the intersections of race, class, and gender: challenges and contributions to understanding violence against marginalized women in diverse communities.

PubMed

Sokoloff, Natalie J; Dupont, Ida

2005-01-01

This article provides a comprehensive review of the emerging domestic violence literature using a race, class, gender, sexual orientation intersectional analysis and structural framework fostered by women of color and their allies to understand the experiences and contexts of domestic violence for marginalized women in U.S. society. The first half of the article lays out a series of challenges that an intersectional analysis grounded in a structural framework provides for understanding the role of culture in domestic violence. The second half of the article points to major contributions of such an approach to feminist methods and practices in working with battered women on the margins of society.

Flight-determined stability analysis of multiple-input-multiple-output control systems

NASA Technical Reports Server (NTRS)

Burken, John J.

1992-01-01

Singular value analysis can give conservative stability margin results. Applying structure to the uncertainty can reduce this conservatism. This paper presents flight-determined stability margins for the X-29A lateral-directional, multiloop control system. These margins are compared with the predicted unscaled singular values and scaled structured singular values. The algorithm was further evaluated with flight data by changing the roll-rate-to-aileron command-feedback gain by +/- 20 percent. Minimum eigenvalues of the return difference matrix which bound the singular values are also presented. Extracting multiloop singular values from flight data and analyzing the feedback gain variations validates this technique as a measure of robustness. This analysis can be used for near-real-time flight monitoring and safety testing.

Flight-determined stability analysis of multiple-input-multiple-output control systems

NASA Technical Reports Server (NTRS)

Burken, John J.

1992-01-01

Singular value analysis can give conservative stability margin results. Applying structure to the uncertainty can reduce this conservatism. This paper presents flight-determined stability margins for the X-29A lateral-directional, multiloop control system. These margins are compared with the predicted unscaled singular values and scaled structured singular values. The algorithm was further evaluated with flight data by changing the roll-rate-to-aileron-command-feedback gain by +/- 20 percent. Also presented are the minimum eigenvalues of the return difference matrix which bound the singular values. Extracting multiloop singular values from flight data and analyzing the feedback gain variations validates this technique as a measure of robustness. This analysis can be used for near-real-time flight monitoring and safety testing.

Multiple imputation to account for measurement error in marginal structural models

PubMed Central

Edwards, Jessie K.; Cole, Stephen R.; Westreich, Daniel; Crane, Heidi; Eron, Joseph J.; Mathews, W. Christopher; Moore, Richard; Boswell, Stephen L.; Lesko, Catherine R.; Mugavero, Michael J.

2015-01-01

Background Marginal structural models are an important tool for observational studies. These models typically assume that variables are measured without error. We describe a method to account for differential and non-differential measurement error in a marginal structural model. Methods We illustrate the method estimating the joint effects of antiretroviral therapy initiation and current smoking on all-cause mortality in a United States cohort of 12,290 patients with HIV followed for up to 5 years between 1998 and 2011. Smoking status was likely measured with error, but a subset of 3686 patients who reported smoking status on separate questionnaires composed an internal validation subgroup. We compared a standard joint marginal structural model fit using inverse probability weights to a model that also accounted for misclassification of smoking status using multiple imputation. Results In the standard analysis, current smoking was not associated with increased risk of mortality. After accounting for misclassification, current smoking without therapy was associated with increased mortality [hazard ratio (HR): 1.2 (95% CI: 0.6, 2.3)]. The HR for current smoking and therapy (0.4 (95% CI: 0.2, 0.7)) was similar to the HR for no smoking and therapy (0.4; 95% CI: 0.2, 0.6). Conclusions Multiple imputation can be used to account for measurement error in concert with methods for causal inference to strengthen results from observational studies. PMID:26214338

Ensemble learning of inverse probability weights for marginal structural modeling in large observational datasets.

PubMed

Gruber, Susan; Logan, Roger W; Jarrín, Inmaculada; Monge, Susana; Hernán, Miguel A

2015-01-15

Inverse probability weights used to fit marginal structural models are typically estimated using logistic regression. However, a data-adaptive procedure may be able to better exploit information available in measured covariates. By combining predictions from multiple algorithms, ensemble learning offers an alternative to logistic regression modeling to further reduce bias in estimated marginal structural model parameters. We describe the application of two ensemble learning approaches to estimating stabilized weights: super learning (SL), an ensemble machine learning approach that relies on V-fold cross validation, and an ensemble learner (EL) that creates a single partition of the data into training and validation sets. Longitudinal data from two multicenter cohort studies in Spain (CoRIS and CoRIS-MD) were analyzed to estimate the mortality hazard ratio for initiation versus no initiation of combined antiretroviral therapy among HIV positive subjects. Both ensemble approaches produced hazard ratio estimates further away from the null, and with tighter confidence intervals, than logistic regression modeling. Computation time for EL was less than half that of SL. We conclude that ensemble learning using a library of diverse candidate algorithms offers an alternative to parametric modeling of inverse probability weights when fitting marginal structural models. With large datasets, EL provides a rich search over the solution space in less time than SL with comparable results. Copyright © 2014 John Wiley & Sons, Ltd.

Ensemble learning of inverse probability weights for marginal structural modeling in large observational datasets

PubMed Central

Gruber, Susan; Logan, Roger W.; Jarrín, Inmaculada; Monge, Susana; Hernán, Miguel A.

2014-01-01

Inverse probability weights used to fit marginal structural models are typically estimated using logistic regression. However a data-adaptive procedure may be able to better exploit information available in measured covariates. By combining predictions from multiple algorithms, ensemble learning offers an alternative to logistic regression modeling to further reduce bias in estimated marginal structural model parameters. We describe the application of two ensemble learning approaches to estimating stabilized weights: super learning (SL), an ensemble machine learning approach that relies on V -fold cross validation, and an ensemble learner (EL) that creates a single partition of the data into training and validation sets. Longitudinal data from two multicenter cohort studies in Spain (CoRIS and CoRIS-MD) were analyzed to estimate the mortality hazard ratio for initiation versus no initiation of combined antiretroviral therapy among HIV positive subjects. Both ensemble approaches produced hazard ratio estimates further away from the null, and with tighter confidence intervals, than logistic regression modeling. Computation time for EL was less than half that of SL. We conclude that ensemble learning using a library of diverse candidate algorithms offers an alternative to parametric modeling of inverse probability weights when fitting marginal structural models. With large datasets, EL provides a rich search over the solution space in less time than SL with comparable results. PMID:25316152

Addressing the knowledge gap in clinical recommendations for management and complete excision of clinically atypical nevi/dysplastic nevi: Pigmented Lesion Subcommittee consensus statement.

PubMed

Kim, Caroline C; Swetter, Susan M; Curiel-Lewandrowski, Clara; Grichnik, James M; Grossman, Douglas; Halpern, Allan C; Kirkwood, John M; Leachman, Sancy A; Marghoob, Ashfaq A; Ming, Michael E; Nelson, Kelly C; Veledar, Emir; Venna, Suraj S; Chen, Suephy C

2015-02-01

The management of clinically atypical nevi/dysplastic nevi (CAN/DN) is controversial, with few data to guide the process. Management recommendations for DN with positive histologic margins were developed by the Delphi method to achieve consensus among members of the Pigmented Lesion Subcommittee (PLS) of the Melanoma Prevention Working Group (MPWG) after reviewing the current evidence. To outline key issues related to the management of CAN/DN: (1) biopsies of CAN and how positive margins arise, (2) whether incompletely excised DN evolve into melanoma, (3) current data on the outcomes of DN with positive histologic margins, (4) consensus recommendations, and (5) a proposal for future studies, including a large-scale study to help guide the management of DN with positive margins. The literature, including recent studies examining management and outcomes of DN with positive margins between 2009 to 2014, was reviewed. A consensus statement by the PLS of the MPWG following review of the literature, group discussions, and a structured Delphi method consensus. This consensus statement reviews the complexities of management of CAN/DN. A review of the literature and 2 rounds of a structured Delphi consensus resulted in the following recommendations: (1) mildly and moderately DN with clear margins do not need to be reexcised, (2) mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than reexcised, and (3) observation may be a reasonable option for management of moderately DN with positive histologic margins without clinically apparent residual pigmentation; however, more data are needed to make definitive recommendations in this clinical scenario.

Spreading and slope instability at the continental margin offshore Mt Etna, imaged by high-resolution 2D seismic data

NASA Astrophysics Data System (ADS)

Gross, Felix; Krastel, Sebastian; Behrmann, Jan-Hinrich; Papenberg, Cord; Geersen, Jacob; Ridente, Domenico; Latino Chiocci, Francesco; Urlaub, Morelia; Bialas, Jörg; Micallef, Aaron

2015-04-01

Mount Etna is the largest active volcano in Europe. Its volcano edifice is located on top of continental crust close to the Ionian shore in east Sicily. Instability of the eastern flank of the volcano edifice is well documented onshore. The continental margin is supposed to deform as well. Little, however, is known about the offshore extension of the eastern volcano flank and its adjacent continental margin, which is a serious shortcoming in stability models. In order to better constrain the active tectonics of the continental margin offshore the eastern flank of the volcano, we acquired and processed a new marine high-resolution seismic and hydro-acoustic dataset. The data provide new detailed insights into the heterogeneous geology and tectonics of shallow continental margin structures offshore Mt Etna. In a similiar manner as observed onshore, the submarine realm is characterized by different blocks, which are controlled by local- and regional tectonics. We image a compressional regime at the toe of the continental margin, which is bound to an asymmetric basin system confining the eastward movement of the flank. In addition, we constrain the proposed southern boundary of the moving flank, which is identified as a right lateral oblique fault movement north of Catania Canyon. From our findings, we consider a major coupled volcano edifice instability and continental margin gravitational collapse and spreading to be present at Mt Etna, as we see a clear link between on- and offshore tectonic structures across the entire eastern flank. The new findings will help to evaluate hazards and risks accompanied by Mt Etna's slope- and continental margin instability and will be used as a base for future investigations in this region.

Insights into crustal structure of the Eastern North American Margin from community multichannel seismic and potential field data

NASA Astrophysics Data System (ADS)

Davis, J. K.; Becel, A.; Shillington, D. J.; Buck, W. R.

2017-12-01

In the fall of 2014, the R/V Marcus Langseth collected gravity, magnetic, and reflection seismic data as part of the Eastern North American Margin Community Seismic Experiment. The dataset covers a 500 km wide section of the Mid-Atlantic passive margin offshore North Carolina, which formed after the Mesozoic breakup of the supercontinent Pangaea. Using these seismic and potential field data, we present observations and interpretations along two cross margin and one along-margin profiles. Analyses and interpretations are conducted using pre-stack depth migrated reflection seismic profiles in conjunction with forward modeling of shipboard gravity and magnetic anomalies. Preliminary interpretations of the data reveal variations in basement character and structure across the entire transition between continental and oceanic domains. These interpretations help provide insight into the origin and nature of the prominent East Coast and Blake Spur magnetic anomalies, as well as the Inner Magnetic Quiet Zone which occupies the domain between the anomalies. Collectively, these observations can aid in deciphering the rift-to-drift transition during the breakup of North America and West Africa and formation of the Central Atlantic.

Geomorphological and sedimentary processes of the glacially influenced northwestern Iberian continental margin and abyssal plains

NASA Astrophysics Data System (ADS)

Llave, Estefanía; Jané, Gloria; Maestro, Adolfo; López-Martínez, Jerónimo; Hernández-Molina, F. Javier; Mink, Sandra

2018-07-01

The offshore region of northwestern Iberia offers an opportunity to study the impacts of along-slope processes on the morphology of a glacially influenced continental margin, which has traditionally been conceptually characterised by predominant down-slope sedimentary processes. High-resolution multibeam bathymetry, acoustic backscatter and ultrahigh-resolution seismic reflection profile data are integrated and analysed to describe the present-day and recent geomorphological features and to interpret their associated sedimentary processes. Seventeen large-scale seafloor morphologies and sixteen individual echo types, interpreted as structural features (escarpments, marginal platforms and related fluid escape structures) and depositional and erosional bedforms developed either by the influence of bottom currents (moats, abraded surfaces, sediment waves, contourite drifts and ridges) or by gravitational features (gullies, canyons, slides, channel-levee complexes and submarine fans), are identified for the first time in the study area (spanning 90,000 km2 and water depths of 300 m to 5 km). Different types of slope failures and turbidity currents are mainly observed on the upper and lower slopes and along submarine canyons and deep-sea channels. The middle slope morphologies are mostly determined by the actions of bottom currents (North Atlantic Central Water, Mediterranean Outflow Water, Labrador Sea Water and North Atlantic Deep Water), which thereby define the margin morphologies and favour the reworking and deposition of sediments. The abyssal plains (Biscay and Iberian) are characterised by pelagic deposits and channel-lobe systems (the Cantabrian and Charcot), although several contourite features are also observed at the foot of the slope due to the influence of the deepest water masses (i.e., the North Atlantic Deep Water and Lower Deep Water). This work shows that the study area is the result of Mesozoic to present-day tectonics (e.g. the marginal platforms and structural highs). Therefore, tectonism constitutes a long-term controlling factor, whereas the climate, sediment supply and bottom currents play key roles in the recent short-term architecture and dynamics. Moreover, the recent predominant along-slope sedimentary processes observed in the studied northwestern Iberian Margin represent snapshots of the progressive stages and mixed deep-water system developments of the marginal platforms on passive margins and may provide information for a predictive model of the evolution of other similar margins.

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

PubMed

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

2016-10-07

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

The Continental Margins of the Western North Atlantic.

ERIC Educational Resources Information Center

Schlee, John S.; And Others

1979-01-01

Presents an interpretation of geological and geophysical data, which provides a summary of the structural and sedimentary history of the United States Atlantic Margin. The importance of an understanding of the development of the outer continental shelf to future hydrocarbon exploration is detailed. (BT)

Betwixt and Between: Academic Developers in the Margins

ERIC Educational Resources Information Center

Little, Deandra; Green, David A.

2012-01-01

Previously, the authors developed a theoretical framework drawing on an early sociological study of migration to explore how marginality--being between cultures--might account for academic developers' "hybrid" academic identities and help them navigate institutional power dynamics. Based on data from semi-structured interviews, this…

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.

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

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

Rimon, Gilad; Sidhu, Ranjinder S.; Lauver, D. Adam

Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A{sub 2} formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we reportmore » the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.« less

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

PubMed

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

2017-06-01

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

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

PubMed Central

Dewi, Lestari

2016-01-01

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

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

PubMed

Dewi, Lestari

2016-06-01

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

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

Mascle, J.; Blarez, E.

The authors present a marine study of the eastern Ivory Coast-Ghana continental margins which they consider one of the most spectacular extinct transform margins. This margin has been created during Early-Lower Cretaceous time and has not been submitted to any major geodynamic reactivation since its fabric. Based on this example, they propose to consider during the evolution of the transform margin four main and successive stages. Shearing contact is first active between two probably thick continental crusts and then between progressively thinning continental crusts. This leads to the creation of specific geological structures such as pull-apart graben, elongated fault lineaments,more » major fault scarps, shear folds, and marginal ridges. After the final continental breakup, a hot center (the mid-oceanic ridge axis) is progressively drifting along the newly created margin. The contact between two lithospheres of different nature should necessarily induce, by thermal exchanges, vertical crustal readjustments. Finally, the transform margin remains directly adjacent to a hot but cooling oceanic lithosphere; its subsidence behavior should then progressively be comparable to the thermal subsidence of classic rifted margins.« less

Studies in Public Welfare. Paper No. 12 (Part II): The Family, Poverty and Welfare Programs--Household Patterns and Government Policies.

ERIC Educational Resources Information Center

Joint Economic Committee, Washington, DC.

The papers in this volume deal with patterns of household composition and income sharing among low-income families as well as current and proposed Government policies directly related to family structure. Government policies relevant to family structure make up one set of topics. Irene Cox describes how public income transfer benefits and…

Impacts of Co-doping on the superconductivity and the orbital ordering state in Fe1-xCoxSe single crystal studied by the electrical transport.

NASA Astrophysics Data System (ADS)

Urata, Takahiro; Tanabe, Yoichi; Heguri, Satoshi; Tanigaki, Katsumi

2015-03-01

In the FeSe with the simplest crystal structure in the Fe-based superconductor families, although both the superconductivity and the orbital ordering states are investigated, the relation between them is still unclear. Here, we report Co doping effects on the superconductivity and the orbital ordering state in Fe1-xCoxSe single crystals. The electrical transport measurements demonstrated that the superconductivity vanishes at 4 % Co doping while the orbital ordering state may be robust against Co doping. Present results suggest that the orbital ordering state is not related to the emergence of the superconductivity in FeSe.

Is Ki67 prognostic for aggressive prostate cancer? A multicenter real-world study.

PubMed

Fantony, Joseph J; Howard, Lauren E; Csizmadi, Ilona; Armstrong, Andrew J; Lark, Amy L; Galet, Colette; Aronson, William J; Freedland, Stephen J

2018-06-15

To test if Ki67 expression is prognostic for biochemical recurrence (BCR) after radical prostatectomy (RP). Ki67 immunohistochemistry was performed on tissue microarrays constructed from specimens obtained from 464 men undergoing RP at the Durham and West LA Veterans Affairs Hospitals. Hazard ratios (HR) for Ki67 expression and time to BCR were estimated using Cox regression. Ki67 was associated with more recent surgery year (p < 0.001), positive margins (p = 0.001) and extracapsular extension (p < 0.001). In center-stratified analyses, the adjusted HR for Ki67 expression and BCR approached statistical significance for west LA (HR: 1.54; p = 0.06), but not Durham (HR: 1.10; p = 0.74). This multi-institutional 'real-world' study provides limited evidence for the prognostic role of Ki67 in predicting outcome after RP.

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

PubMed

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

2013-07-01

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

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

PubMed

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

2008-07-01

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

Heat flow anomalies on the Western Mediterranean margins: first results from the WestMedFlux-2016 cruise

NASA Astrophysics Data System (ADS)

Poort, Jeffrey; Lucazeau, Francis; Le Gal, Virginie; Rabineau, Marina; Dal Cin, Michela; Bouzid, Abderrezak; Palomino, Desirée; Leroux, Estelle; Akhmanov, Grigory; Battani, Anne; Bachir, Roza Si; Khlystov, Oleg; Koptev, Aleksandre

2017-04-01

While there is now a large consensus that Western Mediterranean basins developed in a Miocene back-arc setting due to slab roll-back and that some of its domains are floored by oceanic crust, there is still a lot of speculation on the configuration, nature and evolution of its margins and the ocean-continent transitions (OCT). A thick Messinian layer of evaporites in the deep basin obscures deep seismic reflectors, and only recently seismic refraction and wide-angle studies revealed a confident picture of basement configuration. In order to further constrain models of crustal structure and margin evolution, heat flow is one of the key parameters needed. Recent heat flow studies on other margins have shown the existence of a persistent thermal anomaly under rifted margins that urges to reconsider the classical models of its evolution. The young age of OCT and ceased oceanic formation in the Western Mediterranean make it an interesting test case for a thermo-mechanical study of its margins. The presence of halokinetic structuring and salt diapirs urges the need of close spaced heat flow measurement to evaluate heat refraction and advective heat transfer by fluid migration. During the WestMedFlux cruise on the research vessel L'Atalante, we collected a total of 150 new heat flow measurement (123 in pogo mode, 27 with a sediment corer) in the deep basin of the Western Mediterranean where heat flow data were sparse. Preliminary analysis of the heat flow data confirms two regional trends: in the southern Provencal basin an overall increase from west to east (from about 60 mW/m2 at the Golf of Lion towards 75 mW/m2 at the West-Sardinia margin), while in the northern part of the Algero-Balearic basin heat flow increases from east to west (from about 80 to 100 mW/m2). On this regional trends, several local anomalies are clearly differentiated. In the deep oceanic basin, strong anomalies seem to be merely associated to salt diapiric structures. On the OCT and on the rifted continent, both strongly reduced and elevated heat flow are observed and suggest other heat sink and sources. We will discuss on the different processes that might have affected the surface heat flow (e.g., bottom water currents, slope instabilities and focused fluid migrations) and try to link the large scale heat flow patterns with crustal nature, structuring of the margins and mantle dynamics.

Late Results of Cox Maze III Procedure in Patients with Atrial Fibrillation Associated with Structural Heart Disease.

PubMed

Gomes, Gustavo Gir; Gali, Wagner Luis; Sarabanda, Alvaro Valentim Lima; Cunha, Claudio Ribeiro da; Kessler, Iruena Moraes; Atik, Fernando Antibas

2017-07-01

Cox-Maze III procedure is one of the surgical techniques used in the surgical treatment of atrial fibrillation (AF). To determine late results of Cox-Maze III in terms of maintenance of sinus rhythm, and mortality and stroke rates. Between January 2006 and January 2013, 93 patients were submitted to the cut-and-sew Cox-Maze III procedure in combination with structural heart disease repair. Heart rhythm was determined by 24-hour Holter monitoring. Procedural success rates were determined by longitudinal methods and recurrence predictors by multivariate Cox regression models. Thirteen patients that obtained hospital discharge alive were excluded due to lost follow-up. The remaining 80 patients were aged 49.9 ± 12 years and 47 (58.7%) of them were female. Involvement of mitral valve and rheumatic heart disease were found in 67 (83.7%) and 63 (78.7%) patients, respectively. Seventy patients (87.5%) had persistent or long-standing persistent AF. Mean follow-up with Holter monitoring was 27.5 months. There were no hospital deaths. Sinus rhythm maintenance rates were 88%, 85.1% and 80.6% at 6 months, 24 months and 36 months, respectively. Predictors of late recurrence of AF were female gender (HR 3.52; 95% CI 1.21-10.25; p = 0.02), coronary artery disease (HR 4.73 95% CI 1.37-16.36; p = 0.01) and greater left atrium diameter (HR 1.05; 95% CI 1.01-1.09; p = 0.02). Actuarial survival was 98.5% at 12, 24 and 48 months and actuarial freedom from stroke was 100%, 100% and 97.5% in the same time frames. The Cox-Maze III procedure, in our experience, is efficacious for sinus rhythm maintenance, with very low late mortality and stroke rates. A operação de Cox-Maze III é uma das variantes técnicas no tratamento cirúrgico da fibrilação atrial (FA). Estudar os resultados tardios da operação de Cox-Maze III, quanto à eficácia na manutenção de ritmo sinusal e taxas de mortalidade e acidente vascular cerebral (AVC). Entre janeiro de 2006 a janeiro de 2013, 93 pacientes foram submetidos a operação de Cox-Maze III por corte e sutura associada a correção de cardiopatias estruturais. Avaliação do ritmo cardíaco ocorreu por Holter 24 horas. Taxas de sucesso da operação foram estudadas por métodos longitudinais e os preditores de recorrência por análise de regressão de Cox multivariada. Foram excluídos 13 pacientes sobreviventes ao período intra-hospitalar cujo seguimento tardio não foi possível. Os 80 pacientes restantes tinham idade média de 49,9 ± 12 anos e 47 (58,75%) eram do sexo feminino. Acometimento da valva mitral ocorreu em 67 pacientes (83,7%). Valvopatia reumática ocorreu em 63 (78,7%). Setenta pacientes (87,5%) tinham fibrilação atrial persistente ou persistente de longa duração. O tempo médio de seguimento clínico com avaliação de Holter foi de 27,5 meses. Não houve óbitos intra-hospitalares. As taxas de manutenção de ritmo sinusal foram 88%, 85,1% e 80,6% aos 6 meses, 24 meses e 36 meses, respectivamente. Os preditores de recorrência tardia foram sexo feminino (RR 3,52; IC 95% 1,21-10,25; p = 0,02), doença arterial coronária (RR 4,73; IC 95% 1,37-16,36; p = 0,01) e maior diâmetro de átrio esquerdo (RR 1,05; IC 95% 1,01-1,09; p = 0,02). A sobrevida atuarial aos 12, 24 e 48 meses foi de 98,5% e as taxas atuariais livres de AVC nos mesmos períodos de 100%, 100% e 97,5%. A operação de Cox-Maze III, na nossa experiência, é eficaz na manutenção do ritmo sinusal, com baixíssimos índices de mortalidade e de AVC tardios.

Clustered marginalization of minorities during social transitions induced by co-evolution of behaviour and network structure

PubMed Central

Schleussner, Carl-Friedrich; Donges, Jonathan F.; Engemann, Denis A.; Levermann, Anders

2016-01-01

Large-scale transitions in societies are associated with both individual behavioural change and restructuring of the social network. These two factors have often been considered independently, yet recent advances in social network research challenge this view. Here we show that common features of societal marginalization and clustering emerge naturally during transitions in a co-evolutionary adaptive network model. This is achieved by explicitly considering the interplay between individual interaction and a dynamic network structure in behavioural selection. We exemplify this mechanism by simulating how smoking behaviour and the network structure get reconfigured by changing social norms. Our results are consistent with empirical findings: The prevalence of smoking was reduced, remaining smokers were preferentially connected among each other and formed increasingly marginalized clusters. We propose that self-amplifying feedbacks between individual behaviour and dynamic restructuring of the network are main drivers of the transition. This generative mechanism for co-evolution of individual behaviour and social network structure may apply to a wide range of examples beyond smoking. PMID:27510641

Geophysical evidence for a transform margin in Northwestern Algeria: possible vestige of a Subduction-Transform Edge Propagator

NASA Astrophysics Data System (ADS)

Badji, R.; Charvis, P.; Bracene, R.; Galve, A.; Badsi, M.; Ribodetti, A.; Benaissa, Z.; Klingelhoefer, F.; Medaouri, M.; Beslier, M.

2013-12-01

This work is part of the Algerian-French SPIRAL program (Sismique Profonde et Investigation Régionale du Nord de l'Algérie) which provides unprecedented images of the deep structure of the western Algerian Margin based on several wide-angle and multichannel seismic data shot across the Algerian Margin. One of the different hypotheses for the opening of the western Mediterranean Sea, we are testing is that the western part of the Algerian margin was possibly part of the southern edge of the Alboran continental block during its westward migration related to the rollback of the Betic-Rif-Alboran subduction zone. A tomographic inversion of the first arrival traveltimes along a 100-km long wide-angle seismic profile shot over 40 Ocean Bottom Seismometers, across the Margin offshore Mostaganem (Northwestern Algerian Margin) was conducted. The final model reveals striking feature in the deep structure of the margin from north to south: 1- the oceanic crust is as thin as 4-km, with velocities ranging from 5.0 to 7.1 km/s, covered by a 3.3 km thick sedimentary pile (seismic velocities from 1.5 to 5.0 km/s) characterized by an intense diapiric activity of the Messinian salt layer. 2- a sharp transition zone, less than 10 km wide, with seismic velocities intermediate between oceanic seismic velocities (observed northward) and continental seismic velocities (observed southward). This zone coincides with narrow and elongated pull apart basins imaged by multichannel seismic data. No evidence of volcanism nor of exhumed serpentinized upper mantle as described along many extensional continental margins are observed along this segment of the margin. 3- a thinned continental crust coincident with a rapid variation of the Moho depth imaged from 12 to ~20 km with a dip up to 50%. The seafloor bathymetry is showing a steep continental slope (>20%). Either normal or inverse faults are observed along MCS lines shot in the dip direction but they do not present large vertical displacement and could be related primarily to strike slip motion. These results support the hypothesis, that the margin offshore Mostaganem is not an extensional margin but rather a transform margin. There is little evidence of tectonic inversion as described eastward along the Kabylian Margin. Possibly strike slip motion affected the thinned continental crust and the transition zone suggesting that this margin is a vestige of the Subduction-Transform Edge Propagator (STEP) related to the westward migration of the Alboran block.

Kinematic Reconstruction of the Costa Rican Margin: Evidence for Discontinuities in Deformation Across the Margin

NASA Astrophysics Data System (ADS)

Gose, B.; Bangs, N. L.; McIntosh, K. D.

2016-12-01

Recently acquired 3D seismic reflection data shows that both in-sequence and out-of sequence faults makeup the interior structure of the Costa Rican convergent margin. Recent studies have found evidence for a phase of accretion that led to the formation of a series of thrust-bounded folds that are easily observable within the margin-wedge fabric. Along a primary 2D transect through the center of the 3D survey, faults partition the outer 23km of the margin into 8 fault-bounded segments that can be divided into two characteristic zones, those closest to the trench (S1-S3) and those furthest (S4-S8) separated by a slope break 10 km from the trench (Fig 1). To better understand the observed structure, each segment was characterized as a fault-propagation fold and geometrically modeled using Paradigm's Geosec 2D software. Kinematic flexural slip modules were applied in order to perform bed-length balancing and generate a geologic reconstruction of the margin. Results show the section of the margin spanning from 3-23km from the deformation front has experienced 27.5% shortening, assuming the interpreted horizons were initially flat and continuous. The individual values for percent shortening are not consistent across the margin but distributed into two zones each with progressively increasing strain in the landward direction. Zone 2 (landward) begins with a percent shortening for S8 at 22% and linearly decreases to 2% shortening as you move seaward to S4. The Zone 1-2 boundary is marked by a slope break coinciding with an increase in percent shortening (S3,15%) followed by less shortening seaward (9%, 8%). Shortening and the associated strain is focused at the landward side of the two zones, within S3 and S8. We conclude that the Costa Rican margin has some degree of mechanical partitioning, with a notable discontinuity in strain patterns occurring 10 km from the trench.

Deepwater Fold-and-Thrust Belt Along New Caledonia's Western Margin: Relation to Post-obduction Vertical Motions

NASA Astrophysics Data System (ADS)

Collot, J.; Patriat, M.; Etienne, S.; Rouillard, P.; Soetaert, F.; Juan, C.; Marcaillou, B.; Palazzin, G.; Clerc, C.; Maurizot, P.; Pattier, F.; Tournadour, E.; Sevin, B.; Privat, A.

2017-10-01

Classically, deepwater fold-and-thrust belts are classified in two main types, depending if they result from near- or far-field stresses and the understanding of their driving and triggering mechanism is poorly known. We present a geophysical data set off the western margin of New Caledonia (SW Pacific) that reveals deformed structures of a deepwater fold-and-thrust belt that we interpret as a near-field gravity-driven system, which is not located at a rifted passive margin. The main factor triggering deformation is inferred to be oversteepening of the margin slope by postobduction isostatic rebound. Onshore erosion of abnormally dense obducted material, combined with sediment loading in the adjacent basin, has induced vertical motions that have caused oversteepening of the margin. Detailed morphobathymetric, seismic stratigraphic, and structural analysis reveals that the fold-and-thrust belt extends 200 km along the margin, and 50 km into the New Caledonia Trough. Deformation is rooted at depths greater than 5 km beneath the seafloor, affects an area of 3,500 km2, and involves a sediment volume of approximately 13,000 km3. This deformed belt is organized into an imbricate fan system of faults, and one out-of-sequence thrust fault affects the seabed. The thrust faults are deeply rooted in the basin along a low-angle floor thrust and connected to New Caledonia Island along a major detachment. This study not only provides a better knowledge of the New Caledonia margin but also provides new insight into the mechanisms that trigger deepwater fold-and-thrust belts.

Molecular characterization of Atractolytocestus sagittatus (Cestoda: Caryophyllidea), monozoic parasite of common carp, and its differentiation from the invasive species Atractolytocestus huronensis.

PubMed

Bazsalovicsová, Eva; Králová-Hromadová, Ivica; Stefka, Jan; Scholz, Tomáš

2012-05-01

Sequence structure of complete internal transcribed spacer 1 and 2 (ITS1 and ITS2) of the ribosomal DNA region and partial mitochondrial cytochrome c oxidase subunit I (cox1) gene sequences were studied in the monozoic tapeworm Atractolytocestus sagittatus (Kulakovskaya et Akhmerov, 1965) (Cestoda: Caryophyllidea), a parasite of common carp (Cyprinus carpio carpio L.). Intraindividual sequence diversity was observed in both ribosomal spacers. In ITS1, a total number of 19 recombinant clones yielded eight different sequence types (pairwise sequence identity, 99.7-100%) which, however, did not resemble the structure typical for divergent intragenomic ITS copies (paralogues). Polymorphism was displayed by several single nucleotide mutations present exclusively in single clones, but variation in the number of short repetitive motifs was not observed. In ITS2, a total of 21 recombinant clones yielded ten different sequence types (pairwise sequence identity, 97.5-100%). They were mostly characterized by a varying number of (TCGT)(n) repeats resulting in assortment of ITS2 sequences into two sequence variants, which reflected the structure specific for ITS paralogues. The third DNA region analysed, mitochondrial cox1 gene (669 bp) was detected to be 100% identical in all studied A. sagittatus individuals. Comparison of molecular data on A. sagittatus with those on Atractolytocestus huronensis Anthony, 1958, an invasive parasite of common carp, has shown that interspecific differences significantly exceeded intraspecific variation in both ribosomal spacers (81.4-82.5% in ITS1, 74.4-75.2% in ITS2) as well as in mitochondrial cox1, which confirms validity of both congeneric tapeworms parasitic in the same fish host.

Dynamic regime marginal structural mean models for estimation of optimal dynamic treatment regimes, Part II: proofs of results.

PubMed

Orellana, Liliana; Rotnitzky, Andrea; Robins, James M

2010-03-03

In this companion article to "Dynamic Regime Marginal Structural Mean Models for Estimation of Optimal Dynamic Treatment Regimes, Part I: Main Content" [Orellana, Rotnitzky and Robins (2010), IJB, Vol. 6, Iss. 2, Art. 7] we present (i) proofs of the claims in that paper, (ii) a proposal for the computation of a confidence set for the optimal index when this lies in a finite set, and (iii) an example to aid the interpretation of the positivity assumption.

Free radical scavenging and COX-2 inhibition by simple colon metabolites of polyphenols: A theoretical approach.

PubMed

Amić, Ana; Marković, Zoran; Marković, Jasmina M Dimitrić; Jeremić, Svetlana; Lučić, Bono; Amić, Dragan

2016-12-01

Free radical scavenging and inhibitory potency against cyclooxygenase-2 (COX-2) by two abundant colon metabolites of polyphenols, i.e., 3-hydroxyphenylacetic acid (3-HPAA) and 4-hydroxyphenylpropionic acid (4-HPPA) were theoretically studied. Different free radical scavenging mechanisms are investigated in water and pentyl ethanoate as a solvent. By considering electronic properties of scavenged free radicals, hydrogen atom transfer (HAT) and sequential proton loss electron transfer (SPLET) mechanisms are found to be thermodynamically probable and competitive processes in both media. The Gibbs free energy change for reaction of inactivation of free radicals indicates 3-HPAA and 4-HPPA as potent scavengers. Their reactivity toward free radicals was predicted to decrease as follows: hydroxyl>alkoxyls>phenoxyl≈peroxyls>superoxide. Shown free radical scavenging potency of 3-HPAA and 4-HPPA along with their high μM concentration produced by microbial colon degradation of polyphenols could enable at least in situ inactivation of free radicals. Docking analysis with structural forms of 3-HPAA and 4-HPPA indicates dianionic ligands as potent inhibitors of COX-2, an inducible enzyme involved in colon carcinogenesis. Obtained results suggest that suppressing levels of free radicals and COX-2 could be achieved by 3-HPAA and 4-HPPA indicating that these compounds may contribute to reduced risk of colon cancer development. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed Central

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

2014-01-01

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

[Right extremities pain caused by a malacia lesion in the left putamen:a resting functional magnetic resonance imaging of the marginal division of the human brain].

PubMed

Chen, Zhi-Ye; Ma, Lin

2014-04-01

To explore the role of marginal division of the human brain in the pain modulation. Resting functional magnetic resonance imaging was applied in a patient with right extremities pain caused by a malacia lesion in the left putamen and in 8 healthy volunteers. Marginal division was defined using manual drawing on structure images, and was applied to the computation of fuctional connectivity maps. The functional connectivities in the left marginal division showed an evident decrease in the patient when compared with healthy controls. These connectivities were mainly located in the bilateral head of caudate nucleus, putamen, and left globus pallidus. The marginal division may be involved in the pain modulation.

Deep structure of the Algerian margin offshore Great Kabylie: Preliminary results of an offshore-onshore seismic profile (SPIRAL campaign)

NASA Astrophysics Data System (ADS)

Chafik, Aidi; Abd el Karim, Yelles; Marie-Odile, Beslier; Frauke, Klingelhoefer; Philippe, Schnurle; Rabah, Bracene; Hamou, Djellit; Audrey, Galve; Laure, Schenini; Françoise, Sage; Abdallah, Bounif Mohand ou; Philippe, Charvis

2013-04-01

In October-November 2009 the Algerian-French SPIRAL research program (Sismique Profonde et Investigation Régionale du Nord de l'ALgérie) was conducted onboard the R/V Atalante in order to understand the deep structure and tectonic history of the Algerian Margin using multichannel and wide-angle seismic data. An extensive dataset was acquired along five regional transects off Algeria, from Arzew Bay to the west, to Annaba to the east. The profiles range from 80 to 180 km long and around 40 ocean-bottom seismometers were deployed on each profile. All profiles were extended on land up to 125 km by land-stations to better constrain the structure of the margin and the nature of the ocean-continent transition zone. We present the preliminary results from modeling of deep and superficial structures in the central Algerian margin, more precisely in the region of the Great Kabylie where a N-S transect of combined wide-angle data using a set of 40 OBS (ocean bottom seismometer) and 24 on-land seismological stations and reflection seismic data was acquired. The profile with a total length of about 260 km (140 km offshore and approximately 124 km onshore), crosses from the north to south the Algeria-Provence Basin, the central Algerian Margin and onshore the geological unit of the Great Kabylie that represents the Kabylides block and the transitional zone between the internal zone (Kabylides) and the external zone in the central Algeria. The network (OBS and seismological stations), recorded 1031 low frequency air gun shots in order to ensure good penetration in the crust. Travel time tomography of first arrivals time of OBS data has yielded a preliminary model of P wave velocities along the profile. In the oceanic domain, a relatively thin crust of about 5 km thickness was imaged overlying a mantle characterized by seismic velocities of about 8 km/s, and covered by a thin sedimentary layer of about 2 km thickness. For the study of the sedimentary cover near the margin several MCS profiles were acquired in this region during the Spiral survey and previously by the Maradja cruise. This data sets allows to image reactivation of the Algerian Margin in this region.

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

Shim, Su Jung; Yang, Woo-Ick; Shin, Eunah

Purpose: To determine whether there are any differences in therapeutic response, patterns of systemic recurrence, and prognosis of patients with extranodal natural killer (NK)/T-cell lymphoma, nasal type, by the cyclooxygenase-2 (COX-2) expression. Patients and Methods: Thirty-four patients with Ann Arbor Stage I and II extranodal NK/T-cell lymphoma who underwent chemotherapy or radiotherapy, or both, were retrospectively reviewed. These patients were divided into two groups according to their immunohistochemical staining for COX-2 expressions: a COX-2-negative group (n = 10 patients) and a COX-2-positive group (n = 24 patients). The treatment response, patterns of treatment failure, and survival data for the patientsmore » were compared between the COX-2-positive and negative groups. Results: There was no significant difference in the clinical profiles between the COX-2-negative and COX-2-positive groups. All patients (100%) in the COX-2-negative group achieved complete response after initial treatment, whereas only 14 patients (58%) in the COX-2-positive group achieved complete response (p = 0.03). Compared with the patients in the COX-2-negative group, those in the COX-2-positive group had a significantly lower 2-year systemic recurrence-free survival rate (100% for the COX-2-negative group vs. 54% for the COX-2-positive group) (p = 0.02) and a decreased 5-year overall survival rate (70% for the COX-2-negative group vs. 32% for the COX-2-positive group) (p = 0.06). Conclusion: Cyclooxygenase-2 expression can serve as a predictive factor for poor treatment response, higher systemic recurrence, and unfavorable prognosis in patients with extranodal NK/T-cell lymphoma, nasal type.« less

Farm Household Survival Strategies and Diversification on Marginal Farms

ERIC Educational Resources Information Center

Meert, H.; Van Huylenbroeck, G.; Vernimmen, T.; Bourgeois, M.; van Hecke, E.

2005-01-01

On marginal farms, and in agriculture in general, sustainability is largely guaranteed by a broad range of survival strategies, closely interlinked and embedded in the household structure of typical family farms. This paper reports results of a socio-economic study carried out among Belgian farmers, focusing specifically on the opportunities…

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Science.gov Websites

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Effect of tuberculosis on the survival of HIV-infected men in a country with low TB incidence

PubMed Central

López-Gatell, H; Cole, SR; Margolick, JB; Witt, MD; Martinson, J; Phair, JP; Jacobson, LP

2010-01-01

Evidence regarding the effect of tuberculosis disease (TB) on HIV disease progression at the population level remains inconclusive. We estimated the effect of incident TB on time to acquired immunodeficiency syndrome (AIDS)-related death, using a marginal structural Cox model. Between 1984 and 2005, 2,882 HIV-infected men in the Multicenter AIDS Cohort Study contributed 21,914 person-years while followed for a median of 5.4 years. At study entry, the median CD4 cell count and HIV-1 RNA viral load were 533 cells/mm3 (interquartile range [IQR], 365 – 737) and 12,953 copies/ml (IQR, 2,453 – 48,540), respectively. This study was performed in a setting with a modest exposure to HAART; 8,295 of 23,801 (35%) person-years were followed during the HAART era. Fifteen men incurred incident TB, yielding a TB incidence of 7 (95% confidence interval [CI]: 4, 14) per 10,000 person-years, and 1,072 died of AIDS-related causes. Accounting for potential confounders, including CD4 cell count and viral load, the hazard of AIDS-related death was 2.4 times larger for the person-time with TB, compared to the person-time without TB (95% CI: 1.2, 4.7). Results underscore the importance of avoiding TB by using preventive interventions, such as treatment of latent TB infection, particularly in populations with a large prevalence of HIV/TB co-infected individuals. PMID:18753866

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

PubMed Central

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

2008-01-01

Previous studies suggest that cyclooxygenase-2 (COX-2) expression may predict survival among patients with non-small cell lung cancer. COX-2 may interact with epidermal growth factor receptor (EGFR), suggesting that combined COX-2/EGFR expression may provide predictive value. The extent to which their independent or combined expression is associated with prognosis in women with adenocarcinoma of the lung is unknown. In the present study, we examined relationships between COX-2 expression (n = 238), EGFR expression (n = 158) and dual COX-2/EGFR expression (n = 157) and survival among women with adenocarcinoma of the lung. Overall survival was estimated by constructing Cox proportional hazards models adjusting for other significant variables and stratifying by stage at diagnosis and race. Clinical or demographic parameters were not associated with either COX-2 or EGFR expression. Patients with COX-2-positive tumors tended to have poorer prognosis than did patients with COX-2-negative tumors [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.01–2.78]. African-Americans with COX-2-positive tumors had a statistically non-significant higher risk of death than African-Americans with COX-2-negative tumors (HR 5.58, 95% CI 0.64–48.37). No association between COX-2 expression and survival was observed among Caucasians (HR 1.29, 95% CI 0.72–2.30). EGFR expression was associated with a 44% reduction in the risk of death (HR 0.56, 95% CI 0.32–0.98). COX-2−/EGFR+ tumor expression, but not COX-2+/EGFR+ tumor expression, was associated with survival when compared with other combined expression results. In conclusion, COX-2 and EGFR expression, but not combined COX-2+/EGFR+ expression, independently predict survival of women with adenocarcinoma of the lung. PMID:18453539

Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine prehepatic portal hypertension

PubMed Central

Skill, N. J.; Theodorakis, N. G.; Wang, Y. N.; Wu, J. M.; Redmond, E. M.; Sitzmann, J. V.

2008-01-01

Portal hypertension (PHT) is a common complication of liver cirrhosis and significantly increases morbidity and mortality. Abrogation of PHT using NSAIDs has demonstrated that prostacyclin (PGI2), a direct downstream metabolic product of cyclooxygenase (COX) activity, is an important mediator in the development of experimental and clinical PHT. However, the role of COX isoforms in PGI2 biosynthesis and PHT is not fully understood. Prehepatic PHT was induced by portal vein ligation (PVL) in wild-type, COX-1−/−, and COX-2−/− mice treated with and without COX-2 (NS398) or COX-1 (SC560) inhibitors. Hemodynamic measurements and PGI2 biosynthesis were determined 1–7 days after PVL or sham surgery. Gene deletion or pharmacological inhibition of COX-1 or COX-2 attenuated but did not ameliorate PGI2 biosynthesis after PVL or prevent PHT. In contrast, treatment of COX-1−/− mice with NS398 or COX-2−/− mice with SC560 restricted PGI2 biosynthesis and abrogated the development of PHT following PVL. In conclusion, either COX-1 or COX-2 can mediate elevated PGI2 biosynthesis and the development of experimental prehepatic PHT. Consequently, PGI2 rather then COX-selective drugs are indicated in the treatment of PHT. Identification of additional target sites downstream of COX may benefit the >27,000 patients whom die annually from cirrhosis in the United States alone. PMID:18772366

5-(1-Aryl-3-(thiophen-2-yl)-1H-pyrazol-4-yl)-1H-tetrazoles: Synthesis, structural characterization, Hirshfeld analysis, anti-inflammatory and anti-bacterial studies

NASA Astrophysics Data System (ADS)

Kumbar, Mahadev N.; Kamble, Ravindra R.; Dasappa, Jagadeesh Prasad; Bayannavar, Praveen K.; Khamees, Hussien Ahmed; Mahendra, M.; Joshi, Shrinivas D.; Dodamani, Suneel; Rasal, V. P.; Jalalpure, Sunil

2018-05-01

A series of novel 5-(1-aryl-3-(thiophen-2-yl)-1H-pyrazol-4-yl)-1H-tetrazoles 7(h-s) were designed and synthesized. Structural characterization was done by spectral and single crystal X-ray studies. The intermolecular interactions of compound 7n were quantified and visualized using Hirshfeld surface analysis. Structures of newly synthesized compounds were docked into active site of COX-2 enzyme PDB:

Low Divergence of Clonorchis sinensis in China Based on Multilocus Analysis

PubMed Central

Sun, Jiufeng; Huang, Yan; Huang, Huaiqiu; Liang, Pei; Wang, Xiaoyun; Mao, Qiang; Men, Jingtao; Chen, Wenjun; Deng, Chuanhuan; Zhou, Chenhui; Lv, Xiaoli; Zhou, Juanjuan; Zhang, Fan; Li, Ran; Tian, Yanli; Lei, Huali; Liang, Chi; Hu, Xuchu; Xu, Jin; Li, Xuerong; XinbingYu

2013-01-01

Clonorchis sinensis, an ancient parasite that infects a number of piscivorous mammals, attracts significant public health interest due to zoonotic exposure risks in Asia. The available studies are insufficient to reflect the prevalence, geographic distribution, and intraspecific genetic diversity of C. sinensis in endemic areas. Here, a multilocus analysis based on eight genes (ITS1, act, tub, ef-1a, cox1, cox3, nad4 and nad5 [4.986 kb]) was employed to explore the intra-species genetic construction of C. sinensis in China. Two hundred and fifty-six C. sinensis isolates were obtained from environmental reservoirs from 17 provinces of China. A total of 254 recognized Multilocus Types (MSTs) showed high diversity among these isolates using multilocus analysis. The comparison analysis of nuclear and mitochondrial phylogeny supports separate clusters in a nuclear dendrogram. Genetic differentiation analysis of three clusters (A, B, and C) showed low divergence within populations. Most isolates from clusters B and C are geographically limited to central China, while cluster A is extraordinarily genetically diverse. Further genetic analyses between different geographic distributions, water bodies and hosts support the low population divergence. The latter haplotype analyses were consistent with the phylogenetic and genetic differentiation results. A recombination network based on concatenated sequences showed a concentrated linkage recombination population in cox1, cox3, nad4 and nad5, with spatial structuring in ITS1. Coupled with the history record and archaeological evidence of C. sinensis infection in mummified desiccated feces, these data point to an ancient origin of C. sinensis in China. In conclusion, we present a likely phylogenetic structure of the C. sinensis population in mainland China, highlighting its possible tendency for biogeographic expansion. Meanwhile, ITS1 was found to be an effective marker for tracking C. sinensis infection worldwide. Thus, the present study improves our understanding of the global epidemiology and evolution of C. sinensis. PMID:23825605

Increasing Safety of a Robotic System for Inner Ear Surgery Using Probabilistic Error Modeling Near Vital Anatomy

PubMed Central

Dillon, Neal P.; Siebold, Michael A.; Mitchell, Jason E.; Blachon, Gregoire S.; Balachandran, Ramya; Fitzpatrick, J. Michael; Webster, Robert J.

2017-01-01

Safe and effective planning for robotic surgery that involves cutting or ablation of tissue must consider all potential sources of error when determining how close the tool may come to vital anatomy. A pre-operative plan that does not adequately consider potential deviations from ideal system behavior may lead to patient injury. Conversely, a plan that is overly conservative may result in ineffective or incomplete performance of the task. Thus, enforcing simple, uniform-thickness safety margins around vital anatomy is insufficient in the presence of spatially varying, anisotropic error. Prior work has used registration error to determine a variable-thickness safety margin around vital structures that must be approached during mastoidectomy but ultimately preserved. In this paper, these methods are extended to incorporate image distortion and physical robot errors, including kinematic errors and deflections of the robot. These additional sources of error are discussed and stochastic models for a bone-attached robot for otologic surgery are developed. An algorithm for generating appropriate safety margins based on a desired probability of preserving the underlying anatomical structure is presented. Simulations are performed on a CT scan of a cadaver head and safety margins are calculated around several critical structures for planning of a robotic mastoidectomy. PMID:29200595

Increasing safety of a robotic system for inner ear surgery using probabilistic error modeling near vital anatomy

NASA Astrophysics Data System (ADS)

Dillon, Neal P.; Siebold, Michael A.; Mitchell, Jason E.; Blachon, Gregoire S.; Balachandran, Ramya; Fitzpatrick, J. Michael; Webster, Robert J.

2016-03-01

Safe and effective planning for robotic surgery that involves cutting or ablation of tissue must consider all potential sources of error when determining how close the tool may come to vital anatomy. A pre-operative plan that does not adequately consider potential deviations from ideal system behavior may lead to patient injury. Conversely, a plan that is overly conservative may result in ineffective or incomplete performance of the task. Thus, enforcing simple, uniform-thickness safety margins around vital anatomy is insufficient in the presence of spatially varying, anisotropic error. Prior work has used registration error to determine a variable-thickness safety margin around vital structures that must be approached during mastoidectomy but ultimately preserved. In this paper, these methods are extended to incorporate image distortion and physical robot errors, including kinematic errors and deflections of the robot. These additional sources of error are discussed and stochastic models for a bone-attached robot for otologic surgery are developed. An algorithm for generating appropriate safety margins based on a desired probability of preserving the underlying anatomical structure is presented. Simulations are performed on a CT scan of a cadaver head and safety margins are calculated around several critical structures for planning of a robotic mastoidectomy.

Asperpyrone-Type Bis-Naphtho-γ-Pyrones with COX-2-Inhibitory Activities from Marine-Derived Fungus Aspergillus niger.

PubMed

Fang, Wei; Lin, Xiuping; Wang, Jianjiao; Liu, Yonghong; Tao, Huaming; Zhou, Xuefeng

2016-07-20

Bis-naphtho-γ-pyrones (BNPs) are an important group of aromatic polyketides derived from fungi, and asperpyrone-type BNPs are produced primarily by Aspergillus species. The fungal strain Aspergillus niger SCSIO Jcsw6F30, isolated from a marine alga, Sargassum sp., and identified according to its morphological traits and the internal transcribed spacer (ITS) region sequence, was studied for BNPs secondary metabolisms. After HPLC/MS analysis of crude extract of the fermentation broth, 11 asperpyrone-type BNPs were obtained directly and quickly by chromatographic separation in the extract, and those isolated asperpyrone-type BNPs were structurally identified by NMR and MS analyses. All of the BNPs showed weak cytotoxicities against 10 human tumor cells (IC50 > 30 μM). However, three of them, aurasperone F (3), aurasperone C (6) and asperpyrone A (8), exhibited obvious COX-2-inhibitory activities, with the IC50 values being 11.1, 4.2, and 6.4 μM, respectively. This is the first time the COX-2-inhibitory activities of BNPs have been reported.

Design Strategy of Multi-electron Transfer Catalysts Based on a Bioinformatic Analysis of Oxygen Evolution and Reduction Enzymes.

PubMed

Ooka, Hideshi; Hashimoto, Kazuhito; Nakamura, Ryuhei

2018-05-14

Understanding the design strategy of photosynthetic and respiratory enzymes is important to develop efficient artificial catalysts for oxygen evolution and reduction reactions. Here, based on a bioinformatic analysis of cyanobacterial oxygen evolution and reduction enzymes (photosystem II: PS II and cytochrome c oxidase: COX, respectively), the gene encoding the catalytic D1 subunit of PS II was found to be expressed individually across 38 phylogenetically diverse strains, which is in contrast to the operon structure of the genes encoding major COX subunits. Selective synthesis of the D1 subunit minimizes the repair cost of PS II, which allows compensation for its instability by lowering the turnover number required to generate a net positive energy yield. The different bioenergetics observed between PS II and COX suggest that in addition to the catalytic activity rationalized by the Sabatier principle, stability factors have also provided a major influence on the design strategy of biological multi-electron transfer enzymes. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Control of Co content and SOFC cathode performance in Y1-ySr2+yCu3-xCoxO7+δ

NASA Astrophysics Data System (ADS)

Šimo, F.; Payne, J. L.; Demont, A.; Sayers, R.; Li, Ming; Collins, C. M.; Pitcher, M. J.; Claridge, J. B.; Rosseinsky, M. J.

2014-11-01

The electrochemical performance of the layered perovskite YSr2Cu3-xCoxO7+δ, a potential solid oxide fuel cell (SOFC) cathode, is improved by increasing the Co content from x = 1.00 to a maximum of x = 1.30. Single phase samples with x > 1.00 are obtained by tuning the Y/Sr ratio, yielding the composition Y1-ySr2+yCu3-xCoxO7+δ (where y ≤ 0.05). The high temperature structure of Y0.95Sr2.05Cu1.7Co1.3O7+δ at 740 °C is characterised by powder neutron diffraction and the potential of this Co-enriched material as a SOFC cathode is investigated by combining AC impedance spectroscopy, four-probe DC conductivity and powder XRD measurements to determine its electrochemical properties along with its thermal stability and compatibility with a range of commercially available electrolytes. The material is shown to be compatible with doped ceria electrolytes at 900 °C.

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

PubMed Central

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

2011-01-01

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

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

PubMed

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

2010-10-01

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

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

PubMed

Mozaffari, Elahe; Doosti, Abbas; Arshi, Asghar; Faghani, Mostafa

2016-12-01

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. 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. 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). 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.

Redox and Reactive Oxygen Species Regulation of Mitochondrial Cytochrome c Oxidase Biogenesis

PubMed Central

Bourens, Myriam; Fontanesi, Flavia; Soto, Iliana C.; Liu, Jingjing

2013-01-01

Abstract Significance: Cytochrome c oxidase (COX), the last enzyme of the mitochondrial respiratory chain, is the major oxygen consumer enzyme in the cell. COX biogenesis involves several redox-regulated steps. The process is highly regulated to prevent the formation of pro-oxidant intermediates. Recent Advances: Regulation of COX assembly involves several reactive oxygen species and redox-regulated steps. These include: (i) Intricate redox-controlled machineries coordinate the expression of COX isoenzymes depending on the environmental oxygen concentration. (ii) COX is a heme A-copper metalloenzyme. COX copper metallation involves the copper chaperone Cox17 and several other recently described cysteine-rich proteins, which are oxidatively folded in the mitochondrial intermembrane space. Copper transfer to COX subunits 1 and 2 requires concomitant transfer of redox power. (iii) To avoid the accumulation of reactive assembly intermediates, COX is regulated at the translational level to minimize synthesis of the heme A-containing Cox1 subunit when assembly is impaired. Critical Issues: An increasing number of regulatory pathways converge to facilitate efficient COX assembly, thus preventing oxidative stress. Future Directions: Here we will review on the redox-regulated COX biogenesis steps and will discuss their physiological relevance. Forthcoming insights into the precise regulation of mitochondrial COX biogenesis in normal and stress conditions will likely open future perspectives for understanding mitochondrial redox regulation and prevention of oxidative stress. Antioxid. Redox Signal. 19, 1940–1952. PMID:22937827

Spillover stabilization and decentralized modal control of large space structures

NASA Technical Reports Server (NTRS)

Czajkowski, Eva A.; Preumont, Andre

1987-01-01

The stabilization of the neglected dynamics of the higher modes of vibration in large space structures is studied, and the influence of the structure of the plant noise intensity matrix of the Kalman-Bucy filter on the stability margin of the residual modes is shown. An optimization procedure uses information on the residual modes to minimize spillover of known residual modes while preserving robustness with respect to the unknown dynamics, and the optimum plant noise intensity matrix is selected to maximize the stability margins of the residual modes and to properly place the observer poles. Examples for both centralized and decentralized control are considered.

Intracellular gene transfer in action: Dual transcription and multiple silencings of nuclear and mitochondrial cox2 genes in legumes

PubMed Central

Adams, Keith L.; Song, Keming; Roessler, Philip G.; Nugent, Jacqueline M.; Doyle, Jane L.; Doyle, Jeff J.; Palmer, Jeffrey D.

1999-01-01

The respiratory gene cox2, normally present in the mitochondrion, was previously shown to have been functionally transferred to the nucleus during flowering plant evolution, possibly during the diversification of legumes. To search for novel intermediate stages in the process of intracellular gene transfer and to assess the evolutionary timing and frequency of cox2 transfer, activation, and inactivation, we examined nuclear and mitochondrial (mt) cox2 presence and expression in over 25 legume genera and mt cox2 presence in 392 genera. Transfer and activation of cox2 appear to have occurred during recent legume evolution, more recently than previously inferred. Many intermediate stages of the gene transfer process are represented by cox2 genes in the studied legumes. Nine legumes contain intact copies of both nuclear and mt cox2, although transcripts could not be detected for some of these genes. Both cox2 genes are transcribed in seven legumes that are phylogenetically interspersed with species displaying only nuclear or mt cox2 expression. Inactivation of cox2 in each genome has taken place multiple times and in a variety of ways, including loss of detectable transcripts or transcript editing and partial to complete gene loss. Phylogenetic evidence shows about the same number (3–5) of separate inactivations of nuclear and mt cox2, suggesting that there is no selective advantage for a mt vs. nuclear location of cox2 in plants. The current distribution of cox2 presence and expression between the nucleus and mitochondrion in the studied legumes is probably the result of chance mutations silencing either cox2 gene. PMID:10570164

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

PubMed Central

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

2013-01-01

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

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

PubMed Central

2014-01-01

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

The relationship between cyclooxygenase-2 expression and characteristics of malignant transformation in human colorectal adenomas.

PubMed

Sheehan, Katherine M; O'Connell, Fionnuala; O'Grady, Anthony; Conroy, Ronan M; Leader, Mary B; Byrne, Michael F; Murray, Frank E; Kay, Elaine W

2004-06-01

Cyclooxygenase 2 (COX-2) is a target of aspirin and other non-steroidal anti-inflammatory drugs and is implicated in the pathogenesis of colorectal cancer. The objective of this study was to evaluate the extent of COX-2 in pre-malignant colorectal polyps and to assess the relationship between COX-2 and the level of dysplasia in these lesions. Whole polypectomy specimens were retrieved from 123 patients by endoscopic or surgical resection. Following formalin fixation and paraffin embedding, the polyps were evaluated histologically for size, type and grade of dysplasia. The extent of COX-2 expression was measured by the avidin-biotin immunohistochemical technique using a monoclonal COX-2 antibody. The extent of COX-2 expression was graded according to percentage epithelial COX-2 expression. The polyps were of the following histological types: 10 hyperplastic, 35 tubular adenomas, 61 tubulovillous adenomas and 17 villous adenomas. Twenty showed mild dysplasia, 65 moderate dysplasia, and 28 focal or severe dysplasia (including eight with focal invasion). The average polyp size was 1.7 cm. Nine hyperplastic polyps were COX-2-negative and one was COX-2-positive. COX-2 expression was more extensive in larger polyps and in polyps with a higher villous component. There was a significant increase in the extent of COX-2 protein with increasing severity of dysplasia. Within a polyp, there was a focal corresponding increase in COX-2 expression within epithelium showing a higher grade of dysplasia. COX-2 expression is related directly to colorectal adenomatous polyp size, type and grade of dysplasia. This suggests that the role of COX-2 in colorectal cancer may be at an early stage in the adenoma-to-carcinoma sequence and supports the suggestion that inhibition of COX-2 may be useful chemoprevention for this disease.

Direct and irreversible inhibition of cyclooxygenase-1 by nitroaspirin (NCX 4016).

PubMed

Corazzi, Teresa; Leone, Mario; Maucci, Raffaella; Corazzi, Lanfranco; Gresele, Paolo

2005-12-01

Benzoic acid, 2-(acetyl-oxy)-3-[(nitrooxy)methyl]phenyl ester (NCX 4016), a new drug made by an aspirin molecule linked, through a spacer, to a nitric oxide (NO)-donating moiety, is now under clinical testing for the treatment of atherothrombotic conditions. Aspirin exerts its antithrombotic activity by irreversibly inactivating platelet cyclooxygenase (COX)-1. NCX 4016 in vivo undergoes metabolism into deacetylated and/or denitrated metabolites, and it is not known whether NCX 4016 needs to liberate aspirin to inhibit COX-1, or whether it can block it as a whole molecule. The aim of our study was to evaluate the effects of NCX 4016 and its analog or metabolites on platelet COX-1 and whole blood COX-2 and on purified ovine COX (oCOX)-1 and oCOX-2. In particular, we have compared the mechanism by which NCX 4016 inhibits purified oCOX enzymes with that of aspirin using a spectrophotometric assay. All the NCX 4016 derivatives containing acetylsalicylic acid inhibited the activity of oCOX-1 and oCOX-2, whereas the deacetylated metabolites and the nitric oxide-donating moiety were inactive. Dialysis experiments showed that oCOX-1 inhibition by NCX 4016, similar to aspirin, is irreversible. Reversible COX inhibitors (indomethacin) or salicylic acid incubated with the enzyme before NCX 4016 prevent the irreversible inhibition of oCOX-1 by NCX 4016 as well as by aspirin. In conclusion, our data show that NCX 4016 acts as a direct and irreversible inhibitor of COX-1 and that the presence of a spacer and NO-donating moiety in the molecule slows the kinetics of COX-1 inhibition by NCX 4016, compared with aspirin.

Outcomes for Spine Stereotactic Body Radiation Therapy and an Analysis of Predictors of Local Recurrence

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

Bishop, Andrew J.; Tao, Randa; Rebueno, Neal C.

Purpose: To investigate local control, survival outcomes, and predictors of local relapse for patients treated with spine stereotactic body radiation therapy. Methods and Materials: We reviewed the records of 332 spinal metastases consecutively treated with stereotactic body radiation therapy between 2002 and 2012. The median follow-up for all living patients was 33 months (range, 0-111 months). Endpoints were overall survival and local control (LC); recurrences were classified as either in-field or marginal. Results: The 1-year actuarial LC and overall survival rates were 88% and 64%, respectively. Patients with local relapses had poorer dosimetric coverage of the gross tumor volume (GTV) compared withmore » patients without recurrence (minimum dose [Dmin] biologically equivalent dose [BED] 23.9 vs 35.1 Gy, P<.001; D98 BED 41.8 vs 48.1 Gy, P=.001; D95 BED 47.2 vs 50.5 Gy, P=.004). Furthermore, patients with marginal recurrences had poorer prescription coverage of the GTV (86% vs 93%, P=.01) compared with those with in-field recurrences, potentially because of more upfront spinal canal disease (78% vs 24%, P=.001). Using a Cox regression univariate analysis, patients with a GTV BED Dmin ≥33.4 Gy (median dose) (equivalent to 14 Gy in 1 fraction) had a significantly higher 1-year LC rate (94% vs 80%, P=.001) compared with patients with a lower GTV BED Dmin; this factor was the only significant variable on multivariate Cox analysis associated with LC (P=.001, hazard ratio 0.29, 95% confidence interval 0.14-0.60) and also was the only variable significant in a separate competing risk multivariate model (P=.001, hazard ratio 0.30, 95% confidence interval 0.15-0.62). Conclusions: Stereotactic body radiation therapy offers durable control for spinal metastases, but there is a subset of patients that recur locally. Patients with local relapse had significantly poorer tumor coverage, which was likely attributable to treatment planning directives that prioritized the spinal cord constraints over tumor coverage. When possible, we recommend maintaining a GTV Dmin above 14 Gy in 1 fraction and 21 Gy in 3 fractions.« less

Crustal structure of the basin in the Southwest Subbasin, South China Sea

NASA Astrophysics Data System (ADS)

Yu, Z.; Li, J.; Ding, W.; Zhang, J.; Ruan, A.; Niu, X.; Yin, J.

2016-12-01

Using two-dimensional seismic tomography, we reported a detailed P-wave velocity model of the basin area and the northern margin in the southwest SWSB. We used two OBS profiles (OBS973-1 and OBS973-3), and 12 OBSs were involved into forward modeling and inversion. The whole profile is approximately 311-km-long. The average thickness of the crust beneath the basin is 5.33 km, and the Moho interface is about 10-12 km. No High Velocity Bodies (HVBs) are observed, and only two thin high-velocity structures ( 7.3 km/s) in the layer 3 are identified beneath the northern continent-ocean transition (COT) and the extinct spreading center. It is suggested that the basin area is a typical oceanic crust. Combined with other refraction profiles in the SWSB, the thickness of crust became thinner from the east to the west, indicating a decreasing magma supply. Besides, the continental block shows asymmetric crustal thickness: the southern margin represents thicker crust than the northern margin, which may be related to the large scale of detachment fault systems developed in the southern margin. Revealed from the multi-channel seismic (MCS) profile, the profile here shows asymmetric structural characteristics between the north and south section of the spreading center, which may be controlled by detachment faults. The initial rifting is likely to occur in the south of our study area.KEY WORDS crustal structure; South China Sea; Southwest Sub-basin Extinct spreading center, Asymmetric extension; Thinned crust

Late Cenozoic flexural deformation of the middle U.S. Atlantic passive margin

NASA Technical Reports Server (NTRS)

Pazzaglia, Frank J.; Gardner, Thomas, W.

1994-01-01

Despite the century-long recognition of regional epeirogeny along the middle Atlantic passive margin, relatively few studies have focused on understanding postrift uplift mechanisms. Here, we demonstrate that epeirogenic uplift of the central Appalachian Piedmont and subsidence of the Salisbury Embayment represent first-order, flexural isostatic processes driven by continental denudation and offshore deposition. Our results show that regional epeirogenic processes, present on all Atlantic-type passive margins, are best resolved by specific stratigraphic and geomorphic relationships, rather than topography. A simple one-dimensional geodynamic model, constrained by well-dated Baltimore Canyon trough, Coastal Plain, and lower Susquehanna River (piedmont) stratigraphy, simulates flexural deforamtion of the U.S. Atlantic margin. The model represents the passive margin lithosphree as a uniformly thick elastic plate, without horizontal compressive stresses, that deforms flexurally under the stress of strike-averaged, vertically applied line loads. Model results illustrate a complex interaction among margin stratigraphy and geomorphology, the isostatic repsonse to denudational and depositional processes, and the modulating influence of exogenic forces such as eustasy. The current elevation, with respect to modern sea level, of fluvial terraces and correlateive Coastal Plain deposits or unconformities is successfully predicted through the synthesis of paleotopography, eustatic change, and margin flexure. Results suggest that the middle U.S. Atlantic margin landward of East Coast Magnetic Anomaly is underlain by lithoshpere with an average elastic thickness of 40 km (flexural rigidity, D = 4 X 10(exp 23) N m), the margin experience an average, long-term denudation rate of approximately 10m/m.y., and the Piedmont has been flexurally upwaped between 35 and 130 meters in the last 15 m.y. Long term isostatic continental uplift resulting rom denudation and basin subsidence resulting rom sediment loading are accomodated primately by a convex-up flexural hinge, physiographically represented by the Fall Zone. Our results elucidate an inherent danger in using topography alone to constrain late-stage passive margin deformation mechanisms. Only through careful synthesis of field stratigraphic and geomorphic elements such as fluvial terraces, Coastal Plain deposits, and offshore stratigraphy can age control be extended from the offshore depositional setting to the erosionally dominated continent. This sudy demonstrates that despite a relatively subdued topography, the middle U.S. Atlantic margin experiences progressive flexural isostatic deformation similar to that proposed for high-relief margins characterized by great escarpments. Thus margin topographic diversity remains a function of other factors, such as lithospheric composition and/or structure, supracrustal stratigraphy and structure, degree of drainage integration, drainage divide migration and climate.

Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

PubMed Central

Majed, Batoule H.

2012-01-01

Prostacyclin (PGI2) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A2, cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI2 is produced by endothelial cells and influences many cardiovascular processes. PGI2 acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI2 analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI2/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca2+]i, and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI2 intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI2 counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A2 (TXA2), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI2/TXA2 balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI2/TXA2 ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI2 activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI2 analogs in the management of pregnancy-associated and neonatal vascular disorders. The use of aspirin to decrease TXA2 synthesis has shown little benefit in preeclampsia, whereas indomethacin and ibuprofen are used effectively to close PDA in the premature newborn. PGI2 analogs have been used effectively in primary pulmonary hypertension in adults and have shown promise in PPHN. Careful examination of PGI2 metabolism and the complex interplay with other prostanoids will help design specific modulators of the PGI2-dependent pathways for the management of pregnancy-related and neonatal vascular disorders. PMID:22679221

Molecular mechanisms regulating the vascular prostacyclin pathways and their adaptation during pregnancy and in the newborn.

PubMed

Majed, Batoule H; Khalil, Raouf A

2012-07-01

Prostacyclin (PGI(2)) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A(2), cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI(2) is produced by endothelial cells and influences many cardiovascular processes. PGI(2) acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI(2) analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI(2)/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca(2+)](i), and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI(2) intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI(2) counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A(2) (TXA(2)), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI(2)/TXA(2) balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI(2)/TXA(2) ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI(2) activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI(2) analogs in the management of pregnancy-associated and neonatal vascular disorders. The use of aspirin to decrease TXA(2) synthesis has shown little benefit in preeclampsia, whereas indomethacin and ibuprofen are used effectively to close PDA in the premature newborn. PGI(2) analogs have been used effectively in primary pulmonary hypertension in adults and have shown promise in PPHN. Careful examination of PGI(2) metabolism and the complex interplay with other prostanoids will help design specific modulators of the PGI(2)-dependent pathways for the management of pregnancy-related and neonatal vascular disorders.

Expression of cyclooxygenase-2 in transitional cell carcinoma of the urinary bladder in dogs.

PubMed

Khan, K N; Knapp, D W; Denicola, D B; Harris, R K

2000-05-01

To evaluate expression of cyclooxygenase (COX)-1 and COX-2 in the urinary bladder epithelium of clinically normal dogs and in transitional cell carcinoma cells of dogs. 21 dogs with transitional cell carcinoma of the urinary bladder and 8 dogs with clinically normal urinary bladders. COX-1 and COX-2 were evaluated by use of isoform-specific antibodies with standard immunohistochemical methods. COX-1, but not COX-2, was constitutively expressed in normal urinary bladder epithelium; however, COX-2 was expressed in neoplastic epithelium in primary tumors and in metastatic lesions of all 21 dogs and in new proliferating blood vessels in 3 dogs. Also, COX-1 was expressed in the neoplastic cells. Lack of expression of COX-2 in normal bladder epithelium and its substantial expression in transitional cell carcinoma cells suggest that this isoform may be involved in tumor cell growth. Inhibition of COX-2 is a likely mechanism of the antineoplastic effects of non steroidal antiinflammatory drugs.

An assay of optimal cytochrome c oxidase activity in fish gills.

PubMed

Hu, Yau-Chung; Chung, Meng-Han; Lee, Tsung-Han

2018-07-15

Cytochrome c oxidase (COX) catalyzes the terminal oxidation reaction in the electron transport chain (ETC) of aerobic respiratory systems. COX activity is an important indicator for the evaluation of energy production by aerobic respiration in various tissues. On the basis of the respiratory characteristics of muscle, we established an optimal method for the measurement of maximal COX activity. To validate the measurement of cytochrome c absorbance, different ionic buffer concentrations and tissue homogenate protein concentrations were used to investigate COX activity. The results showed that optimal COX activity is achieved when using 50-100 μg fish gill homogenate in conjunction with 75-100 mM potassium phosphate buffer. Furthermore, we compared branchial COX activities among three species of euryhaline teleost (Chanos chanos, Oreochromis mossambicus, and Oryzias dancena) to investigate differences in aerobic respiration of osmoregulatory organs. COX activities in the gills of these three euryhaline species were compared with COX subunit 4 (COX4) protein levels. COX4 protein abundance and COX activity patterns in the three species occurring in environments with various salinities increased when fish encountered salinity challenges. This COX activity assay therefore provides an effective and accurate means of assessing aerobic metabolism in fish. Copyright © 2018 Elsevier Inc. All rights reserved.

Crustal structure and extension mode in the northwestern margin of the South China Sea

NASA Astrophysics Data System (ADS)

Gao, Jinwei; Wu, Shiguo; McIntosh, Kirk; Mi, Lijun; Liu, Zheng; Spence, George

2016-06-01

Combining multi-channel seismic reflection and gravity modeling, this study has investigated the crustal structure of the northwestern South China Sea margin. These data constrain a hyper-extended crustal area bounded by basin-bounding faults corresponding to an aborted rift below the Xisha Trough with a subparallel fossil ridge in the adjacent Northwest Sub-basin. The thinnest crust is located in the Xisha Trough, where it is remnant lower crust with a thickness of less than 3 km. Gravity modeling also revealed a hyper-extended crust across the Xisha Trough. The postrift magmatism is well developed and more active in the Xisha Trough and farther southeast than on the northwestern continental margin of the South China Sea; and the magmatic intrusion/extrusion was relatively active during the rifting of Xisha Trough and the Northwest Sub-basin. A narrow continent-ocean transition zone with a width of ˜65 km bounded seaward by a volcanic buried seamount is characterized by crustal thinning, rift depression, low gravity anomaly and the termination of the break-up unconformity seismic reflection. The aborted rift near the continental margin means that there may be no obvious detachment fault like that in the Iberia-Newfoundland type margin. The symmetric rift, extreme hyper-extended continental crust and hotter mantle materials indicate that continental crust underwent stretching phase (pure-shear deformation), thinning phase and breakup followed by onset of seafloor spreading and the mantle-lithosphere may break up before crustal-necking in the northwestern South China Sea margin.

Effect on Bone Architecture of Marginal Grooves in Dental Implants Under Occlusal Loaded Conditions in Beagle Dogs.

PubMed

Kato, Hatsumi; Kuroshima, Shinichiro; Inaba, Nao; Uto, Yusuke; Sawase, Takashi

2018-02-01

The aim of this study was to clarify whether marginal grooves on dental implants affect osseointegration, bone structure, and the alignment of collagen fibers to determine bone quality under loaded conditions. Anodized Ti-6Al-4V alloy dental implants, with and without marginal grooves (test and control implants, respectively), were used (3.7 × 8.0 mm). Fourth premolars and first molars of 6 beagle mandibles were extracted. Two control and test implants were placed in randomly selected healed sites at 12 weeks after tooth extraction. Screw-retained single crowns for first molars were fabricated. Euthanasia was performed at 8 weeks after the application of occlusal forces. Implant marginal bone level, bone to implant contact (BIC), bone structure around dental implants, and the alignment of collagen fibers determining bone quality were analyzed. The marginal bone level in test implants was significantly higher than that in control implants. Occlusal forces significantly increased BIC in test implants ( P = .007), whereas BIC did not change in control implants, irrespective of occlusal forces ( P = .303). Moreover, occlusal forces significantly increased BIC in test implants compared with control implants ( P = .032). Additionally, occlusal forces preferentially aligned collagen fibers in test implants, but not control implants. Hence, marginal grooves on dental implants have positive effects on increased osseointegration and adapted bone quality based on the preferential alignment of collagen fibers around dental implants under loaded conditions.

Red (anthocyanic) leaf margins do not correspond to increased phenolic content in New Zealand Veronica spp.

PubMed Central

Hughes, Nicole M.; Smith, William K.; Gould, Kevin S.

2010-01-01

Background and Aims Red or purple coloration of leaf margins is common in angiosperms, and is found in approx. 25 % of New Zealand Veronica species. However, the functional significance of margin coloration is unknown. We hypothesized that anthocyanins in leaf margins correspond with increased phenolic content in leaf margins and/or the leaf entire, signalling low palatability or leaf quality to edge-feeding insects. Methods Five species of Veronica with red leaf margins, and six species without, were examined in a common garden. Phenolic content in leaf margins and interior lamina regions of juvenile and fully expanded leaves was quantified using the Folin–Ciocalteu assay. Proportions of leaf margins eaten and average lengths of continuous bites were used as a proxy for palatability. Key Results Phenolic content was consistently higher in leaf margins compared with leaf interiors in all species; however, neither leaf margins nor more interior tissues differed significantly in phenolic content with respects to margin colour. Mean phenolic content was inversely correlated with the mean length of continuous bites, suggesting effective deterrence of grazing. However, there was no difference in herbivore consumption of red and green margins, and the plant species with the longest continuous grazing patterns were both red-margined. Conclusions Red margin coloration was not an accurate indicator of total phenolic content in leaf margins or interior lamina tissue in New Zealand Veronica. Red coloration was also ineffective in deterring herbivory on the leaf margin, though studies controlling for variations in leaf structure and biochemistry (e.g. intra-specific studies) are needed before more precise conclusions can be drawn. It is also recommended that future studies focus on the relationship between anthocyanin and specific defence compounds (rather than general phenolic pools), and evaluate possible alternative functions of red margins in leaves (e.g. antioxidants, osmotic adjustment). PMID:20145003

Margin based ontology sparse vector learning algorithm and applied in biology science.

PubMed

Gao, Wei; Qudair Baig, Abdul; Ali, Haidar; Sajjad, Wasim; Reza Farahani, Mohammad

2017-01-01

In biology field, the ontology application relates to a large amount of genetic information and chemical information of molecular structure, which makes knowledge of ontology concepts convey much information. Therefore, in mathematical notation, the dimension of vector which corresponds to the ontology concept is often very large, and thus improves the higher requirements of ontology algorithm. Under this background, we consider the designing of ontology sparse vector algorithm and application in biology. In this paper, using knowledge of marginal likelihood and marginal distribution, the optimized strategy of marginal based ontology sparse vector learning algorithm is presented. Finally, the new algorithm is applied to gene ontology and plant ontology to verify its efficiency.

A Worst-Case Approach for On-Line Flutter Prediction

NASA Technical Reports Server (NTRS)

Lind, Rick C.; Brenner, Martin J.

1998-01-01

Worst-case flutter margins may be computed for a linear model with respect to a set of uncertainty operators using the structured singular value. This paper considers an on-line implementation to compute these robust margins in a flight test program. Uncertainty descriptions are updated at test points to account for unmodeled time-varying dynamics of the airplane by ensuring the robust model is not invalidated by measured flight data. Robust margins computed with respect to this uncertainty remain conservative to the changing dynamics throughout the flight. A simulation clearly demonstrates this method can improve the efficiency of flight testing by accurately predicting the flutter margin to improve safety while reducing the necessary flight time.

Sedimentary masses and concepts about tectonic processes at underthrust ocean margins ( subduction).

USGS Publications Warehouse

Scholl, D. W.; von Huene, Roland E.; Vallier, T.L.; Howell, D.G.

1980-01-01

Tectonic processes associated with subduction of oceanic crust, but unrelated to the collision of thick crustal masses or microplates, are presumed by many geologists to significantly affect the formation and deformation of large sedimentary bodies at underthrust ocean margins. More geologists are familiar with the concept of subduction accretion than with other noncollision processes - for example, sediment subduction, subduction erosion, and subduction kneading. In our opinion, no single subduction-related tectonic process is the dominant or typical one that forges the geologic framework of modern underthrust ocean margins. It is likely, therefore, that the rock records of ancient underthrust margins are preserved in a multitude of structural and stratigraphic forms.-from Authors

Evolution of Northeast Atlantic Magmatic Continental Margins from an Ethiopian-Afar Perspective

NASA Astrophysics Data System (ADS)

England, R. W.; Cornwell, D. G.; Ramsden, A. M.

2014-12-01

One of the major problems interpreting the evolution of magmatic continental margins is that the structure which should record the pre-magmatic evolution of the rift and which potentially influences the character of the rifting process is partially or completely obscured by thick basalt lava flows and sills. A limited number of deep reflection seismic profiles acquired with tuned seismic sources have penetrated the basalts and provide an image of the pre-magmatic structure, otherwise the principle data are lower resolution wide-angle/refraction profiles and potential field models which have greater uncertainties associated with them. In order to sidestep the imaging constraints we have examined the Ethiopian - Afar rift system to try to understand the rifting process. The Main Ethiopian rift contains an embryonic magmatic passive margin dominated by faulting at the margins of the rift and en-echelon magmatic zones at the centre. Further north toward Afar the rift becomes in-filled with extensive lava flows fed from fissure systems in the widening rift zone. This rift system provides, along its length, a series of 'snapshots' into the possible tectonic evolution of a magmatic continental margin. Deep seismic profiles crossing the NE Atlantic margins reveal ocean dipping reflector sequences (ODRS) overlying extended crust and lower crustal sill complexes of intruded igneous rock, which extend back beneath the continental margin. The ODRS frequently occur in fault bounded rift structures along the margins. We suggest, by analogy to the observations that can be made in the Ethiopia-Afar rift that these fault bounded basins largely form at the embryonic rift stage and are then partially or completely filled with lavas fed from fissures which are now observed as the ODRS. Also in the seismic profiles we identify volcanic constructs on the ODRS which we interpret as the equivalent of the present day fissure eruptions seen in Afar. The ocean ward dip on the ODRS is predominantly the result of post-eruption differential subsidence, as opposed to syn-eruption extension. The timing of intrusion of the lower crustal sill complexes remains unclear but they are most likely to have been emplaced as the supply of magma increased, which implies they are a late stage addition.

NSAIDs: the Emperor’s new dogma?

PubMed Central

Bjarnason, I; Takeuchi, K; Simpson, R

2003-01-01

The spectacular marketing success of the selective cyclooxygenase 2 (COX-2) inhibitors is largely based on efficacy comparable with conventional non-steroidal anti-inflammatory drugs (NSAIDs) with vastly improved gastrointestinal safety. The additional key to the marketing success is the purity and simplicity of the message—that is, COX-1 inhibition causes the gastrointestinal side effects of NSAIDs (COX-1 dogma) while COX-2 blocking confers the therapeutic benefits (COX-2 dogma). Adherence to the COX dogmas with development of COX-2 selective agents has undoubtedly benefited many patients, but ironically their scientific basis is now seriously challenged by experimentation. PMID:12912873

Isolation of (S)-(+)-naproxene from Musa acuminata. Inhibitory effect of naproxene and its 7-methoxy isomer on constitutive COX-1 and inducible COX-2.

PubMed

Abad, T; McNaughton-Smith, G; Fletcher, W Q; Echeverri, F; Diaz-Peñate, R; Tabraue, C; Ruiz de Galarreta, C M; López-Blanco, F; Luis, J G

2000-06-01

The isolation and characterisation of (S)-(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid, a well known synthetic non-steroidal anti-inflammatory drug (naproxene), from a natural source is described for the first time. We evaluated the ability of naproxene and its 7-methoxy isomer to abrogate constitutive COX-1 and inducible COX-2 activity in human A549 cells. Naproxene inhibited COX-1 (IC50 = 3.42 microM) and COX-2 (IC50 = 1.53 microM), whereas the 7-methoxy isomer had no appreciable effect on COX-1 (IC50 > 100 microM) but also abrogated the activity of COX-2 enzyme (IC50 = 14.42 microM).

Cyclooxygenase-2 inhibitors: promise or peril?

PubMed Central

Mengle-Gaw, Laurel J; Schwartz, Benjamin D

2002-01-01

The discovery of two isoforms of the cyclooxygenase enzyme, COX-1 and COX-2, and the development of COX-2-specific inhibitors as anti-inflammatories and analgesics have offered great promise that the therapeutic benefits of NSAIDs could be optimized through inhibition of COX-2, while minimizing their adverse side effect profile associated with inhibition of COX-1. While COX-2 specific inhibitors have proven to be efficacious in a variety of inflammatory conditions, exposure of large numbers of patients to these drugs in postmarketing studies have uncovered potential safety concerns that raise questions about the benefit/risk ratio of COX-2-specific NSAIDs compared to conventional NSAIDs. This article reviews the efficacy and safety profiles of COX-2-specific inhibitors, comparing them with conventional NSDAIDs. PMID:12467519

Nonparametric Inference of Doubly Stochastic Poisson Process Data via the Kernel Method

PubMed Central

Zhang, Tingting; Kou, S. C.

2010-01-01

Doubly stochastic Poisson processes, also known as the Cox processes, frequently occur in various scientific fields. In this article, motivated primarily by analyzing Cox process data in biophysics, we propose a nonparametric kernel-based inference method. We conduct a detailed study, including an asymptotic analysis, of the proposed method, and provide guidelines for its practical use, introducing a fast and stable regression method for bandwidth selection. We apply our method to real photon arrival data from recent single-molecule biophysical experiments, investigating proteins' conformational dynamics. Our result shows that conformational fluctuation is widely present in protein systems, and that the fluctuation covers a broad range of time scales, highlighting the dynamic and complex nature of proteins' structure. PMID:21258615

Stability of half-metallic behavior with lattice variation for Fe2-xCoxMnAl Heusler alloy

NASA Astrophysics Data System (ADS)

Jain, Vivek Kumar; Lakshmi, N.; Jain, Rakesh

2018-04-01

The electronic structure and magnetic properties with variation of lattice constant for Fe2-xCoxMnAl Heusler alloys have been studied. Total magnetic moments predicted by the Slater Pauling rule is maintained over a wide range of lattice variation for the series. Half metallic ferromagnetic nature with 100% spin polarization is observed for a lattice range from 5.40-5.70 Å, 5.35-5.55 Å, 5.30-5.60 Å and 5.25-5.55 Å respectively for x = 0.5, 1.0 1.5, 2.0. Due to the stability of half metallic character for a wide range of lattice parameters, these alloys are promising, robust materials suitable for spintronics device applications.

Nonparametric Inference of Doubly Stochastic Poisson Process Data via the Kernel Method.

PubMed

Zhang, Tingting; Kou, S C

2010-01-01

Doubly stochastic Poisson processes, also known as the Cox processes, frequently occur in various scientific fields. In this article, motivated primarily by analyzing Cox process data in biophysics, we propose a nonparametric kernel-based inference method. We conduct a detailed study, including an asymptotic analysis, of the proposed method, and provide guidelines for its practical use, introducing a fast and stable regression method for bandwidth selection. We apply our method to real photon arrival data from recent single-molecule biophysical experiments, investigating proteins' conformational dynamics. Our result shows that conformational fluctuation is widely present in protein systems, and that the fluctuation covers a broad range of time scales, highlighting the dynamic and complex nature of proteins' structure.

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

PubMed

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

2014-02-01

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

Pharmacology of a selective cyclooxygenase-2 inhibitor, HN-56249: a novel compound exhibiting a marked preference for the human enzyme in intact cells.

PubMed

Berg, J; Fellier, H; Christoph, T; Kremminger, P; Hartmann, M; Blaschke, H; Rovensky, F; Towart, R; Stimmeder, D

2000-04-01

HN-56249 (3-(2,4-dichlorothiophenoxy)-4-methylsulfonylamino-benzenesu lfonamide), a highly selective cyclooxygenase (COX)-2 inhibitor, is the prototype of a novel series of COX inhibitors comprising bicyclic arylethersulfonamides; of this series HN-56249 is the most potent and selective human COX-2 inhibitor. HN-56249 inhibited platelet aggregation as a measure of COX-1 activity only moderately (IC50 26.5+/-1.7 microM). In LPS-stimulated monocytic cells the release of prostaglandin (PG) F1alpha as a measure of COX-2 was markedly inhibited (IC50 0.027+/-0.001 microM). Thus, HN-56249 showed an approximately 1000-fold selectivity for COX-2 in intact cells. In whole blood assays HN-56249 showed a potent inhibitory activity for COX-2 (IC50 0.78+/-0.37 microM) only. COX-1 was only weakly inhibited (IC50 867+/-181 microM). Hence, HN-56249 exhibited a greater than 1000-fold selectivity for whole blood COX-2. HN-56249 surpassed the COX-2 selectivities of the COX-2 selective inhibitors 3-cyclohexyloxy-4-methylsulfonylamino-nitrobenzene (NS-398) and 6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanone (flosulide) in the intact cell assays by eight- and threefold, respectively, and in the whole blood assays by approximately 40-fold. Following i.v. administration HN-56249 inhibited carrageenan-induced rat paw oedema only moderately (ID50 26.2+/-5.7 mg/kg, mean +/- SEM), approximately tenfold less potent than indomethacin (ID50 2.1+/-0.2 mg/kg, mean +/- SEM). After oral administration HN-56249 reversed thermal hyperalgesia in the carrageenan-induced rat paw oedema test, however, some 30-fold less potently than diclofenac. Comparing the inhibitory potency of HN-56249 against human COX-2 with that against murine COX-2 in intact cells revealed a 300-fold selectivity for the human enzyme. Similar effects were observed with other COX-2-selective arylethersulfonamides. In contrast, non-COX-2-selective arylethersulfonamides, including a highly selective COX-1 inhibitor, inhibited human and murine COX-2 approximately equipotently. In conclusion, HN-56249 is a novel potent and highly selective COX-2 inhibitor with a marked preference for the human COX-2 enzyme in vitro. Despite excellent bioavailability and the long plasma half-life of HN-56249, anti-inflammatory effects in rodents were only moderate. We suggest these differing in vitro-in vivo effects observed could be due to significant inflammatory prostaglandin synthesis by COX-1, or to the genetic differences between human and rodent COX-2, or to both.

Post-breakup faulting of the outer Vøring Margin

NASA Astrophysics Data System (ADS)

Planke, S.; Millett, J.; Jerram, D. A.; Maharjan, D.; Hafeez, A.; Abdelmalak, M. M.; Zastrozhnov, D.; Faleide, J. I.

2017-12-01

Tectonic activity on passive margins may continue for a long time after the main phase of continental breakup. On the southern Vøring Margin, offshore Norway, new high-quality 3D seismic data reveal the presence of extensive normal faults offsetting the Top basalt horizon, along with overlying lower Eocene age sediments. We have completed a detailed seismic interpretation of the new data using a combination of conventional seismic horizon interpretation and igneous seismic geomorphological techniques. The seismic data have been tied to scientific and industry wells to constrain the age of the interpreted horizons and the age and duration of the faulting. The Top basalt horizon displays a dominantly subaerial lava field, on the Vøring Marginal High, with well-defined lava flow morphologies including inflated flow lobes and surface pressure ridges. The prominent kilometer-high Vøring Escarpment was developed when landward flowing lava met the ocean, developing an extensive foreset bedded hyaloclastite delta. Later, a pitted surface was developed in the west during lava emplacement in a wet environment during subsidence of the central rift valley. Earliest Eocene sediments were subsequently deposited on the marginal high. Well-defined northeast trending faults are imaged on the marginal high, cutting across the escarpment. Spacing of the faults is ca. 400-500 m, and offsets are typically of ca. 30-50 m, often defining graben structures. The faults further offset the overlying earliest Eocene sequences in a number of examples. Based on the well ties, faulting mainly took place 5-10 m.y. after continental breakup near the Paleocene-Eocene boundary. Our hypothesis is that the faulting is related to strain partitioning across the developing Vøring Transform Margin. Plate tectonic constraints show that there was an active continent-continent transform in this region also for 10-15 m.y. after breakup. The transform margin is a linear, northwest trending structure, with a well-developed transform marginal high, the Mimir High, along its central part. The transform margin extends into the southwestern segment of the Jan Mayen Fracture Zone to the northwest. We speculate that the ocean basin separating the Vøring Spur from the Vøring Marginal High was formed by a rift propagation event during the same time period.

Controls of tectonics and sediment source locations on along-strike variations in transgressive deposits on the northern California margin

USGS Publications Warehouse

Spinelli, G.A.; Field, M.E.

2003-01-01

We identify two surfaces in the shallow subsurface on the Eel River margin offshore northern California, a lowstand erosion surface, likely formed during the last glacial maximum, and an overlying surface likely formed during the most recent transgression of the shoreline. The lowstand erosion surface, which extends from the inner shelf to near the shelfbreak and from the Eel River to Trinidad Head (???80 km), truncates underlying strata on the shelf. Above the surface, inferred transgressive coastal and estuarine sedimentary units separate it from the transgressive surface on the shelf. Early in the transgression, Eel River sediment was likely both transported down the Eel Canyon and dispersed on the slope, allowing transgressive coastal sediment from the smaller Mad River to accumulate in a recognizable deposit on the shelf. The location of coastal Mad River sediment accumulation was controlled by the location of the paleo-Mad River. Throughout the remainder of the transgression, dispersed sediment from the Eel River accumulated an average of 20 m of onlapping shelf deposits. The distribution and thickness of these transgressive marine units was strongly modified by northwest-southeast trending folds. Thick sediment packages accumulated over structural lows in the lowstand surface. The thinnest sediment accumulations (0-10 m) were deposited over structural highs along faults and uplifting anticlines. The Eel margin, an active margin with steep, high sediment-load streams, has developed a thick transgressive systems tract. On this margin sediment accumulates as rapidly as the processes of uplift and downwarp locally create and destroy accommodation space. Sequence stratigraphic models of tectonically active margins should account for variations in accommodation space along margins as well as across them. ?? 2003 Elsevier Science B.V. All rights reserved.

Joint geophysical and petrological models for the lithosphere structure of the Antarctic Peninsula continental margin

NASA Astrophysics Data System (ADS)

Yegorova, Tamara; Bakhmutov, Vladimir; Janik, Tomasz; Grad, Marek

2011-01-01

The Antarctic Peninsula (AP) is a composite magmatic arc terrane formed at the Pacific margin of Gondwana. Through the late Mesozoic and Cenozoic subduction has stopped progressively from southwest to northeast as a result of a series of ridge trench collisions. Subduction may be active today in the northern part of the AP adjacent to the South Shetland Islands. The subduction system is confined by the Shackleton and Hero fracture zones. The magmatic arc of the AP continental margin is marked by high-amplitude gravity and magnetic anomaly belts reaching highest amplitudes in the region of the South Shetland Islands and trench. The sources for these anomalies are highly magnetic and dense batholiths of mafic bulk composition, which were intruded in the Cretaceous, due to partial melting of upper-mantle and lower-crustal rocks. 2-D gravity and magnetic models provide new insights into crustal and upper-mantle structure of the active and passive margin segments of the northern AP. Our models incorporate seismic refraction constraints and physical property data. This enables us to better constrain both Moho geometry and petrological interpretations in the crust and upper mantle. Model along the DSS-12 profile crosses the AP margin near the Anvers Island and shows typical features of a passive continental margin. The second model along the DSS-17 profile extends from the Drake Passage through the South Shetland Trench/Islands system and Bransfield Strait to the AP and indicates an active continental margin linked to slow subduction and on-going continental rifting in the backarc region. Continental rifting beneath the Bransfield Strait is associated with an upward of hot upper mantle rocks and with extensive magmatic underplating.

Breakup magmatism on the Vøring Margin, mid-Norway: New insight from interpretation of high-quality 2D and 3D seismic reflection data

NASA Astrophysics Data System (ADS)

Abdelmalak, M. M.; Planke, S.; Millett, J.; Jerram, D. A.; Maharjan, D.; Zastrozhnov, D.; Schmid, D. W.; Faleide, J. I.; Svensen, H.; Myklebust, R.

2017-12-01

The Vøring Margin offshore mid-Norway is a classic volcanic rifted margin, characterized by voluminous Paleogene igneous rocks present on both sides of the continent-ocean boundary. The margin displays (1) thickened transitional crust with a well-defined lower crustal high-velocity body and prominent deep crustal reflections, the so-called T-Reflection, (2) seaward dipping reflector (SDR) wedges and a prominent northeast-trending escarpment on the Vøring Marginal High, and (3) extensive sill complexes in the adjacent Cretaceous Vøring Basin. During the last decade, new 2D and 3D industry seismic data along with improved processing techniques, such as broadband processing and noise reduction processing sequences, have made it possible to image and map the breakup igneous complex in much greater detail than previously possible. Our interpretation includes a combination of (1) seismic horizon picking, (2) integrated seismic-gravity-magnetic (SGM) interpretation, (3) seismic volcanostratigraphy, and (4) igneous seismic geomorphology. The results are integrated with published wide-angle seismic data, re-analyzed borehole data including new geochronology, and new geodynamic modeling of the effects of magmatism on the thermal history and subsidence of the margin. The extensive sill complexes and associated hydrothermal vent complexes in the Vøring Basin have a Paleocene-Eocene boundary age based on high-precision U/Pb dating combined with seismic mapping constraints. On the marginal high, our results show a highly variable crustal structure, with a pre-breakup configuration consisting of large-scale structural highs and sedimentary basins. These structures were in-filled and covered by basalt flows and volcanogenic sediments during the early stages of continental breakup in the earliest Eocene. Subsequently, rift basins developed along the continent-ocean boundary and where infilled by up to ca. 6 km thick basalt sequences, currently imaged as SDRs fed by a dike swarm imaged on seismic data. The addition of magma within the crust had a prominent effect on the thermal history and hydrocarbon maturation of the sedimentary basin, causing uplift, delayed subsidence, and possibly contributing to the triggering of global warming during the Paleocene-Eocene Thermal Maximum (PETM).

Counterspaces for Women of Color in STEM Higher Education: Marginal and Central Spaces for Persistence and Success

ERIC Educational Resources Information Center

Ong, Maria; Smith, Janet M.; Ko, Lily T.

2018-01-01

Counterspaces in science, technology, engineering, and mathematics (STEM) are often considered "safe spaces" at the margins for groups outside the mainstream of STEM education. The prevailing culture and structural manifestations in STEM have traditionally privileged norms of success that favor competitive, individualistic, and solitary…

OCT structure, COB location and magmatic type of the S Angolan & SE Brazilian margins from integrated quantitative analysis of deep seismic reflection and gravity anomaly data

NASA Astrophysics Data System (ADS)

Cowie, Leanne; Kusznir, Nick; Horn, Brian

2014-05-01

Integrated quantitative analysis using deep seismic reflection data and gravity inversion have been applied to the S Angolan and SE Brazilian margins to determine OCT structure, COB location and magmatic type. Knowledge of these margin parameters are of critical importance for understanding rifted continental margin formation processes and in evaluating petroleum systems in deep-water frontier oil and gas exploration. The OCT structure, COB location and magmatic type of the S Angolan and SE Brazilian rifted continental margins are much debated; exhumed and serpentinised mantle have been reported at these margins. Gravity anomaly inversion, incorporating a lithosphere thermal gravity anomaly correction, has been used to determine Moho depth, crustal basement thickness and continental lithosphere thinning. Residual Depth Anomaly (RDA) analysis has been used to investigate OCT bathymetric anomalies with respect to expected oceanic bathymetries and subsidence analysis has been used to determine the distribution of continental lithosphere thinning. These techniques have been validated for profiles Lusigal 12 and ISE-01 on the Iberian margin. In addition a joint inversion technique using deep seismic reflection and gravity anomaly data has been applied to the ION-GXT BS1-575 SE Brazil and ION-GXT CS1-2400 S Angola deep seismic reflection lines. The joint inversion method solves for coincident seismic and gravity Moho in the time domain and calculates the lateral variations in crustal basement densities and velocities along the seismic profiles. Gravity inversion, RDA and subsidence analysis along the ION-GXT BS1-575 profile, which crosses the Sao Paulo Plateau and Florianopolis Ridge of the SE Brazilian margin, predict the COB to be located SE of the Florianopolis Ridge. Integrated quantitative analysis shows no evidence for exhumed mantle on this margin profile. The joint inversion technique predicts oceanic crustal thicknesses of between 7 and 8 km thickness with normal oceanic basement seismic velocities and densities. Beneath the Sao Paulo Plateau and Florianopolis Ridge, joint inversion predicts crustal basement thicknesses between 10-15km with high values of basement density and seismic velocities under the Sao Paulo Plateau which are interpreted as indicating a significant magmatic component within the crustal basement. The Sao Paulo Plateau and Florianopolis Ridge are separated by a thin region of crustal basement beneath the salt interpreted as a regional transtensional structure. Sediment corrected RDAs and gravity derived "synthetic" RDAs are of a similar magnitude on oceanic crust, implying negligible mantle dynamic topography. Gravity inversion, RDA and subsidence analysis along the S Angolan ION-GXT CS1-2400 profile suggests that exhumed mantle, corresponding to a magma poor margin, is absent..The thickness of earliest oceanic crust, derived from gravity and deep seismic reflection data, is approximately 7km consistent with the global average oceanic crustal thicknesses. The joint inversion predicts a small difference between oceanic and continental crustal basement density and seismic velocity, with the change in basement density and velocity corresponding to the COB independently determined from RDA and subsidence analysis. The difference between the sediment corrected RDA and that predicted from gravity inversion crustal thickness variation implies that this margin is experiencing approximately 500m of anomalous uplift attributed to mantle dynamic uplift.

Nurture Versus Nature: Accounting for the Differences Between the Taiwan and Timor active arc-continent collisions

NASA Astrophysics Data System (ADS)

Harris, R. A.

2011-12-01

The active Banda arc/continent collision of the Timor region provides many important contrasts to what is observed in Taiwan, which is mostly a function of differences in the nature of the subducting plate. One of the most important differences is the thermal state of the respective continental margins: 30 Ma China passive margin versus 160 Ma NW Australian continental margin. The subduction of the cold and strong NW Australian passive margin beneath the Banda trench provides many new constraints for resolving longstanding issues about the formative stages of collision and accretion of continental crust. Some of these issues include evidence for slab rollback and subduction erosion, deep continental subduction, emplacement or demise of forearc basement, relative amounts of uplift from crustal vs. lithospheric processes, influence of inherited structure, partitioning of strain away from the thrust front, extent of mélange development, metamorphic conditions and exhumation mechanisms, continental contamination and accretion of volcanic arcs, does the slab tear, and does subduction polarity reverse? Most of these issues link to the profound control of lower plate crustal heterogeneity, thermal state and inherited structure. The thermomechanical characteristics of subducting an old continental margin allow for extensive underthrusting of lower plate cover units beneath the forearc and emplacement and uplift of extensive nappes of forearc basement. It also promotes subduction of continental crust to deep enough levels to experience high pressure metamorphism (not found in Taiwan) and extensive contamination of the volcanic arc. Seismic tomography confirms subduction of continental lithosphere beneath the Banda Arc to at least 400 km with no evidence for slab tear. Slab rollback during this process results in massive subduction erosion and extension of the upper plate. Other differences in the nature of the subducting plates in Taiwan in Timor are differences in the lateral continuity of the continental margins. The northern Australian continental margin is highly irregular with many rift basins subducting parallel to their axes. This feature gives rise to irregularities in the uplift pattern of the collision and its continental margin parallel structural grain. Another major difference between Taiwan and Timor is the mechanical stratigraphy entering the trench. The Australian continental margin bears a carbonate rich pre and post rift sequence that is separated by a 1000 m thick, over pressured mudstone unit that acts as major detachment and promotes extensive mud diapirism. The post breakup Australian Passive Margin Sequence is incorporated into the orogenic wedge by frontal accretion and forms a classic imbricate thrust stack near the front of the Banda forearc. The pre breakup Gondwana Sequence below the detachment continues at least to depth of 30 km in the subduction channel beneath the Banda forearc upper plate and stacks up into a duplex zone that forms structural culminations throughout Timor. The upper plate of both collisions is similar in nature but is deformed in different ways due to the strong influence of the lower plate. However, both have extensive subduction erosion and demise of the forearc and systematic accretion of the arc.

Fostering marginalized youths' political participation: longitudinal roles of parental political socialization and youth sociopolitical development.

PubMed

Diemer, Matthew A

2012-09-01

This study examines the roles of parental political socialization and the moral commitment to change social inequalities in predicting marginalized youths' (defined here as lower-SES youth of color) political participation. These issues are examined by applying structural equation modeling to a longitudinal panel of youth. Because tests of measurement invariance suggested racial/ethnic heterogeneity, the structural model was fit separately for three racial/ethnic groups. For each group, parental political socialization: discussion predicted youths' commitment to produce social change and for two groups, longitudinally predicted political participation. This study contributes to the literature by examining civic/political participation among disparate racial/ethnic groups, addresses an open scholarly question (whether youths' commitment to create social change predicts their "traditional" participation), and emphasizes parents' role in fostering marginalized youths' civic and political participation.

The marginal cost of public funds with an aging population.

PubMed

Wildasin, D E

1991-05-01

"As populations in the United States and other advanced economies grow older, the burden of social security and health care financing is expected to rise markedly. Payroll, income, and other taxes on working populations are projected to rise accordingly. The marginal welfare cost to workers of social security and other public expenditures is analyzed within the context of a two-period life cycle model. By relaxing separability assumptions that have become common in the literature, the theoretical structure properly incorporates the effect of these public expenditures on labor supply. Comparative statics results indicate that changing age structure is likely to raise the marginal welfare to workers of social security, education, and other public expenditures. Illustrative calculations for the United States confirm this result, suggesting that the cost to workers of incremental social security benefits may easily double by 2025-2050." excerpt

Pathogenesis of NSAID-induced gastric damage: Importance of cyclooxygenase inhibition and gastric hypermotility

PubMed Central

Takeuchi, Koji

2012-01-01

This article reviews the pathogenic mechanism of non-steroidal anti-inflammatory drug (NSAID)-induced gastric damage, focusing on the relation between cyclooxygenase (COX) inhibition and various functional events. NSAIDs, such as indomethacin, at a dose that inhibits prostaglandin (PG) production, enhance gastric motility, resulting in an increase in mucosal permeability, neutrophil infiltration and oxyradical production, and eventually producing gastric lesions. These lesions are prevented by pretreatment with PGE2 and antisecretory drugs, and also via an atropine-sensitive mechanism, not related to antisecretory action. Although neither rofecoxib (a selective COX-2 inhibitor) nor SC-560 (a selective COX-1 inhibitor) alone damages the stomach, the combined administration of these drugs provokes gastric lesions. SC-560, but not rofecoxib, decreases prostaglandin E2 (PGE2) production and causes gastric hypermotility and an increase in mucosal permeability. COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib. The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility. In addition, selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions, including adrenalectomy, arthritis, and Helicobacter pylori-infection. In summary, gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage, and the response, causally related with PG deficiency due to COX-1 inhibition, occurs prior to other pathogenic events such as increased mucosal permeability; and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition. PMID:22611307

Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPARβ/δ-Dependent Vasodilator Pathway.

PubMed

Kirkby, Nicholas S; Sampaio, Walkyria; Etelvino, Gisele; Alves, Daniele T; Anders, Katie L; Temponi, Rafael; Shala, Fisnik; Nair, Anitha S; Ahmetaj-Shala, Blerina; Jiao, Jing; Herschman, Harvey R; Xiaomeng, Wang; Wahli, Walter; Santos, Robson A; Mitchell, Jane A

2018-02-01

Cyclooxygenase-2 (COX-2) is an inducible enzyme expressed in inflammation and cancer targeted by nonsteroidal anti-inflammatory drugs. COX-2 is also expressed constitutively in discreet locations where its inhibition drives gastrointestinal and cardiovascular/renal side effects. Constitutive COX-2 expression in the kidney regulates renal function and blood flow; however, the global relevance of the kidney versus other tissues to COX-2-dependent blood flow regulation is not known. Here, we used a microsphere deposition technique and pharmacological COX-2 inhibition to map the contribution of COX-2 to regional blood flow in mice and compared this to COX-2 expression patterns using luciferase reporter mice. Across all tissues studied, COX-2 inhibition altered blood flow predominantly in the kidney, with some effects also seen in the spleen, adipose, and testes. Of these sites, only the kidney displayed appreciable local COX-2 expression. As the main site where COX-2 regulates blood flow, we next analyzed the pathways involved in kidney vascular responses using a novel technique of video imaging small arteries in living tissue slices. We found that the protective effect of COX-2 on renal vascular function was associated with prostacyclin signaling through PPARβ/δ (peroxisome proliferator-activated receptor-β/δ). These data demonstrate the kidney as the principle site in the body where local COX-2 controls blood flow and identifies a previously unreported PPARβ/δ-mediated renal vasodilator pathway as the mechanism. These findings have direct relevance to the renal and cardiovascular side effects of drugs that inhibit COX-2, as well as the potential of the COX-2/prostacyclin/PPARβ/δ axis as a therapeutic target in renal disease. © 2018 The Authors.

Dynamic Regime Marginal Structural Mean Models for Estimation of Optimal Dynamic Treatment Regimes, Part II: Proofs of Results*

PubMed Central

Orellana, Liliana; Rotnitzky, Andrea; Robins, James M.

2010-01-01

In this companion article to “Dynamic Regime Marginal Structural Mean Models for Estimation of Optimal Dynamic Treatment Regimes, Part I: Main Content” [Orellana, Rotnitzky and Robins (2010), IJB, Vol. 6, Iss. 2, Art. 7] we present (i) proofs of the claims in that paper, (ii) a proposal for the computation of a confidence set for the optimal index when this lies in a finite set, and (iii) an example to aid the interpretation of the positivity assumption. PMID:20405047

Specific trans-acting proteins interact with auxiliary RNA polyadenylation elements in the COX-2 3′-UTR

PubMed Central

Hall-Pogar, Tyra; Liang, Songchun; Hague, Lisa K.; Lutz, Carol S.

2007-01-01

Two cyclooxygenase (COX) enzymes, COX-1 and COX-2, are present in human cells. While COX-1 is constitutively expressed, COX-2 is inducible and up-regulated in response to many signals. Since increased transcriptional activity accounts for only part of COX-2 up-regulation, we chose to explore other RNA processing mechanisms in the regulation of this gene. Previously, we showed that COX-2 is regulated by alternative polyadenylation, and that the COX-2 proximal polyadenylation signal contains auxiliary upstream sequence elements (USEs) that are very important in efficient polyadenylation. To explore trans-acting protein factors interacting with these cis-acting RNA elements, we performed pull-down assays with HeLa nuclear extract and biotinylated RNA oligonucleotides representing COX-2 USEs. We identified PSF, p54nrb, PTB, and U1A as proteins specifically bound to the COX-2 USEs. We further explored their participation in polyadenylation using MS2 phage coat protein-MS2 RNA binding site tethering assays, and found that tethering any of these four proteins to the COX-2 USE mutant RNA can compensate for these cis-acting elements. Finally, we suggest that these proteins (p54nrb, PTB, PSF, and U1A) may interact as a complex since immunoprecipitations of the transfected MS2 fusion proteins coprecipitate the other proteins. PMID:17507659

Synthesis and biological evaluation of loxoprofen derivatives.

PubMed

Yamakawa, Naoki; Suemasu, Shintaro; Matoyama, Masaaki; Tanaka, Ken-Ichiro; Katsu, Takashi; Miyata, Keishi; Okamoto, Yoshinari; Otsuka, Masami; Mizushima, Tohru

2011-06-01

Non-steroidal anti-inflammatory drugs (NSAIDs) achieve their anti-inflammatory actions through an inhibitory effect on cyclooxygenase (COX). Two COX subtypes, COX-1 and COX-2, are responsible for the majority of COX activity at the gastrointestinal mucosa and in tissues with inflammation, respectively. We previously suggested that both gastric mucosal cell death due to the membrane permeabilization activity of NSAIDs and COX-inhibition at the gastric mucosa are involved in NSAID-induced gastric lesions. We have also reported that loxoprofen has the lowest membrane permeabilization activity among the NSAIDs we tested. In this study, we synthesized a series of loxoprofen derivatives and examined their membrane permeabilization activities and inhibitory effects on COX-1 and COX-2. Among these derivatives, 2-{4'-hydroxy-5-[(2-oxocyclopentyl)methyl]biphenyl-2-yl}propanoate 31 has a specificity for COX-2 over COX-1. Compared to loxoprofen, oral administration of 31 to rats produced fewer gastric lesions but showed an equivalent anti-inflammatory effect. These results suggest that 31 is likely to be a therapeutically beneficial and safer NSAID. Copyright © 2011. Published by Elsevier Ltd.

The crustal structure of the north-eastern Gulf of Aden continental margin: insights from wide-angle seismic data

NASA Astrophysics Data System (ADS)

Watremez, L.; Leroy, S.; Rouzo, S.; D'Acremont, E.; Unternehr, P.; Ebinger, C.; Lucazeau, F.; Al-Lazki, A.

2011-02-01

The wide-angle seismic (WAS) and gravity data of the Encens survey allow us to determine the deep crustal structure of the north-eastern Gulf of Aden non-volcanic passive margin. The Gulf of Aden is a young oceanic basin that began to open at least 17.6 Ma ago. Its current geometry shows first- and second-order segmentation: our study focusses on the Ashawq-Salalah second-order segment, between Alula-Fartak and Socotra-Hadbeen fracture zones. Modelling of the WAS and gravity data (three profiles across and three along the margin) gives insights into the first- and second-order structures. (1) Continental thinning is abrupt (15-20 km thinning across 50-100 km distance). It is accommodated by several tilted blocks. (2) The ocean-continent transition (OCT) is narrow (15 km wide). The velocity modelling provides indications on its geometry: oceanic-type upper-crust (4.5 km s-1) and continental-type lower crust (>6.5 km s-1). (3) The thickness of the oceanic crust decreases from West (10 km) to the East (5.5 km). This pattern is probably linked to a variation of magma supply along the nascent slow-spreading ridge axis. (4) A 5 km thick intermediate velocity body (7.6 to 7.8 km s-1) exists at the crust-mantle interface below the thinned margin, the OCT and the oceanic crust. We interpret it as an underplated mafic body, or partly intruded mafic material emplaced during a `post-rift' event, according to the presence of a young volcano evidenced by heat-flow measurement (Encens-Flux survey) and multichannel seismic reflection (Encens survey). We propose that the non-volcanic passive margin is affected by post-rift volcanism suggesting that post-rift melting anomalies may influence the late evolution of non-volcanic passive margins.

Ductile extension of syn-magmatic lower crusts, with application to volcanic passive margins: the Ivrea Zone (Southern Alps, Italy)

NASA Astrophysics Data System (ADS)

Bidault, Marie; Geoffroy, Laurent; Arbaret, Laurent; Aubourg, Charles

2017-04-01

Deep seismic reflection profiles of present-day volcanic passive margins often show a 2-layered lower crust, from top to bottom: an apparently ductile 12 km-thick middle-lower layer (LC1) of strong folded reflectors and a 4 km-thick supra-Moho layer (LC2) of horizontal and parallel reflectors. Those layers appear to be structurally disconnected and to develop at the early stages of margins evolution. A magmatic origin has been suggested by several studies to explain those strong reflectors, favoring mafic sills intrusion hypothesis. Overlying mafic and acidic extrusives (Seaward Dipping Reflectors sequences) are bounded by continentward-dipping detachment faults rooting in, and co-structurated with, the ductile part of the lower crust (LC1). Consequently the syn-rift to post-rift evolution of volcanic passive margins (and passive margins in general) largely depends on the nature and the properties of the lower crust, yet poorly understood. We propose to investigate the properties and rheology of a magma-injected extensional lower crust with a field analogue, the Ivrea Zone (Southern Alps, Italy). The Ivrea Zone displays a complete back-thrusted section of a Variscan continental lower crust that first underwent gravitational collapse, and then lithospheric extension. This Late Paleozoic extension was apparently associated with the continuous intrusion of a large volume of mafic to acid magma. Both the magma timing and volume, and the structure of the Ivrea lower crust suggest that this section represents an adequate analogue of a syn-magmatic in-extension mafic rift zone which aborted at the end of the Permian. Notably, we may recognize the 2 layers LC1 and LC2. From a number of tectonic observations, we reconstitute the whole tectonic history of the area, focusing on the strain field evolution with time, in connection with mafic magma injection. We compare those results with available data from extensional mafic lower crusts at rifts and margins.

Marginalization and social change processes among lesbian, gay, bisexual and transgender persons in Swaziland: implications for HIV prevention.

PubMed

H Logie, Carmen; Perez-Brumer, Amaya; Jenkinson, Jesse; Madau, Veli; Nhlengethwa, Winnie; Baral, Stefan

2018-05-30

Swaziland has among the highest national adult HIV prevalence globally. There is limited knowledge of HIV vulnerabilities and prevention engagement among lesbian, gay, bisexual and transgender (LGBT) persons in the context of Swaziland's criminalization of consensual same-sex practices. This study explored social processes of marginalization to assess how they could potentiate HIV vulnerabilities and limit engagement in HIV prevention services. Additionally, we assessed positive change to better understand existing strategies employed by LGBT persons to challenge these HIV prevention barriers. Guided by community-based research methodology and conducted in Mbabane and Manzini, Swaziland, data were collected by LGBT peer-research assistants (PRA) in collaboration with an LGBT community organization in Manzini. Semi-structured interviews were conducted by trained PRAs and explored HIV prevention, including experiences of stigma and coping. Audio files were transcribed verbatim, translated to English, and analyzed using thematic techniques. Among participants (n = 51; mean age: 26.47, SD: 4.68), 40 self-identifed as gay or lesbian (78.4%), 11 bisexual (22.6%), and 12 (23.5%) identified as transgender. Findings highlighted three primary processes of marginalization and positive change in structural, community, and internal domains. First, structural marginalization, which included criminalization, healthcare discrimination, and a scarcity of LGBT tailored HIV prevention resources was challenged by grassroots networks created to access and share specific HIV resources with LGBT persons and the Ministry of Health. Second, community marginalization included stigma and multi-dimensional forms of violence, however, this was met with LGBT persons providing mutual peer support, including for accessing HIV testing services. Thirdly, internal marginalization comprised of self-stigma and associated sexual risk practices was contrasted with coping strategies focused on self-acceptance, stemming from social support and leading to healthcare utilization. Jointly, these findings can inform the implementation of community-based and rights affirming HIV prevention and care cascade strategies that improve coverage of services with LGBT persons in Swaziland.

Mesozoic architecture of a tract of the European-Iberian continental margin: Insights from preserved submarine palaeotopography in the Longobucco Basin (Calabria, Southern Italy)

NASA Astrophysics Data System (ADS)

Santantonio, Massimo; Fabbi, Simone; Aldega, Luca

2016-01-01

The sedimentary successions exposed in northeast Calabria document the Jurassic-Early Cretaceous tectonic-sedimentary evolution of a former segment of the European-Iberian continental margin. They are juxtaposed today to units representing the deformation of the African and Adriatic plates margins as a product of Apenninic crustal shortening. A complex pattern of unconformities reveals a multi-stage tectonic evolution during the Early Jurassic, which affected the facies and geometries of siliciclastic and carbonate successions deposited in syn- and post-rift environments ranging from fluvial to deep marine. Late Sinemurian/Early Pliensbachian normal faulting resulted in exposure of the Hercynian basement at the sea-floor, which was onlapped by marine basin-fill units. Shallow-water carbonate aprons and reefs developed in response to the production of new accommodation space, fringing the newborn islands which represent structural highs made of Paleozoic crystalline and metamorphic rock. Their drowning and fragmentation in the Toarcian led to the development of thin caps of Rosso Ammonitico facies. Coeval to these deposits, a thick (> 1 km) hemipelagic/siliciclastic succession was sedimented in neighboring hanging wall basins, which would ultimately merge with the structural high successions. Footwall blocks of the Early Jurassic rift, made of Paleozoic basement and basin-margin border faults with their onlapping basin-fill formations, are found today at the hanging wall of Miocene thrusts, overlying younger (Middle/Late Jurassic to Late Paleogene) folded basinal sediments. This paper makes use of selected case examples to describe the richly diverse set of features, ranging from paleontology to sedimentology, to structural geology, which are associated with the field identification of basin-margin unconformities. Our data provide key constraints for restoring the pre-orogenic architecture of a continental margin facing a branch of the Liguria-Piedmont ocean in the Western Tethys, and for estimating displacements and slip rates along synsedimentary faults.

Effects of coffee management on deforestation rates and forest integrity.

PubMed

Hylander, Kristoffer; Nemomissa, Sileshi; Delrue, Josefien; Enkosa, Woldeyohannes

2013-10-01

Knowledge about how forest margins are utilized can be crucial for a general understanding of changes in forest cover, forest structure, and biodiversity across landscapes. We studied forest-agriculture transitions in southwestern Ethiopia and hypothesized that the presence of coffee (Coffea arabica)decreases deforestation rates because of coffee's importance to local economies and its widespread occurrence in forests and forest margins. Using satellite images and elevation data, we compared changes in forest cover over 37 years (1973-2010) across elevations in 2 forest-agriculture mosaic landscapes (1100 km(2) around Bonga and 3000 km(2) in Goma-Gera). In the field in the Bonga area, we determined coffee cover and forest structure in 40 forest margins that differed in time since deforestation. Both the absolute and relative deforestation rates were lower at coffee-growing elevations compared with at higher elevations (-10/20% vs. -40/50% comparing relative rates at 1800 m asl and 2300-2500 m asl, respectively). Within the coffee-growing elevation, the proportion of sites with high coffee cover (>20%) was significantly higher in stable margins (42% of sites that had been in the same location for the entire period) than in recently changed margins (0% of sites where expansion of annual crops had changed the margin). Disturbance level and forest structure did not differ between sites with 30% or 3% coffee. However, a growing body of literature on gradients of coffee management in Ethiopia reports coffee's negative effects on abundances of forest-specialist species. Even if the presence of coffee slows down the conversion of forest to annual-crop agriculture, there is a risk that an intensification of coffee management will still threaten forest biodiversity, including the genetic diversity of wild coffee. Conservation policy for Ethiopian forests thus needs to develop strategies that acknowledge that forests without coffee production may have higher deforestation risks than forests with coffee production and that forests with coffee production often have lower biodiversity value. © 2013 Society for Conservation Biology.

Linkage between mantle and crustal structures and its bearing on inherited structures in northwestern Scotland

USGS Publications Warehouse

Snyder, D.B.; England, R.W.; McBride, J.H.

1997-01-01

Deep seismic reflection profiles in Scotland reveal mantle structures beneath a crust with a polyphase tectonic history that resulted in several generations of structures. Continuum mechanics suggests that coeval mantle and crustal structures must be kinematically linked. Inherited structures imply relative ages for the reflectors, ages that can be placed into the context of the geological history of the near-surface rocks of northern Scotland. Thus, some mantle reflectors are assigned Triassic ages related to the opening of the West Orkney and related marginal basins of the Atlantic Ocean. Other mantle reflectors are cut by late Caledonian structures associated with the Great Glen Fault Zone and therefore older than c. 400 Ma. Many of these structures also track the late Precambrian margin of Laurentia and may be related to either the opening (900-600 Ma) or closing (500-400 Ma) of the Iapetus Ocean. Some reflective structures may also be attributed to 1800-1700 Ma Laxfordian deformation that was part of a global-scale orogenic belt.

Non-Steroidal Anti-Inflammatory Drugs and Cardiovascular Outcomes in Women: Results from the Women’s Health Initiative

PubMed Central

Bavry, Anthony A.; Thomas, Fridtjof; Allison, Matthew; Johnson, Karen C.; Howard, Barbara V.; Hlatky, Mark; Manson, JoAnn E.; Limacher, Marian C.

2014-01-01

Background Conclusive data regarding cardiovascular (CV) toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) are sparse. We hypothesized that regular NSAID use is associated with increased risk for CV events in post-menopausal women, and that this association is stronger with greater cyclooxygenase (cox)-2 compared with cox-1 inhibition. Methods and Results Post-menopausal women enrolled in the Women’s Health Initiative (WHI) were classified as regular users or non-users of non-aspirin NSAIDs. Cox regression examined NSAID use as a time-varying covariate and its association with the primary outcome of total CV disease defined as CV death, nonfatal myocardial infarction, or nonfatal stroke. Secondary analyses considered the association of selective cox-2 inhibitors (e.g., celecoxib), non-selective agents with cox-2>cox-1 inhibition (e.g., naproxen), and non-selective agents with cox-1>cox-2 inhibition (e.g., ibuprofen) with the primary outcome. Overall, 160,801 participants were available for analysis (mean follow-up 11.2 years). Regular NSAID use at some point in time was reported by 53,142 participants. Regular NSAID use was associated with an increased hazard for CV events versus no NSAID use (HR=1.10[95% CI 1.06–1.15], Pitalic>0.001). Selective cox-2 inhibitors were associated with a modest increased hazard for CV events (HR=1.13[1.04–1.23], P=0.004; celecoxib only HR=1.13[1.01–1.27], P=0.031). Among aspirin users, concomitant selective cox-2 inhibitor use was no longer associated with increased hazard for CV events. There was an increased risk for agents with cox-2>cox-1 inhibition (HR=1.17[1.10–1.24], Pbold>0.001; naproxen only HR=1.22[1.12–1.34], P<0.001). This harmful association remained among concomitant aspirin users. We did not observe a risk elevation for agents with cox-1>cox-2 inhibition (HR=1.01[0.95–1.07], P=0.884; ibuprofen only HR=1.00[0.93–1.07], P=0.996). Conclusions Regular use of selective cox-2 inhibitors and non-selective NSAIDs with cox-2>cox-1 inhibition showed a modestly increased hazard for CV events. Non-selective agents with cox-1>cox-2 inhibition were not associated with increased CV risk. Clinical Trial Registration www.clinicaltrials.gov NCT00000611 PMID:25006185

Tectonic development of passive continental margins of the southern and central Red Sea with a comparison to Wilkes Land, Antarctica

USGS Publications Warehouse

Bohannon, R.G.; Eittreim, S.L.

1991-01-01

The continental margins of the southern and central Red Sea and most of Wilkes Land, Antarctica have bulk crustal configurations and detailed structures that are best explained by a prolonged history of magmatic expansion that followed a brief, but intense period of mechanical extension. Extension on the Red Sea margins was spatially confined to a rift that was 20-30 km in width. The rifting phase along the Arabian margin of the central and southern Red Sea occurred 25-32 Ma ago, primarily by detachment faulting at upper crustal levels and ductile uniform stretching at depth. Rifting was followed by an early magmatic phase during which the margin was invaded by dikes and plutons, primarily of gabbro and diorite, at 20-24 Ma, after the crust was mechanically thinned from 40 km to ??? 20 km. We infer continued spreading after that in which broad shelves were formed by a process of magmatic expansion, because the offshore crust is only 8-15 km thick, including sediment, and seismic reflection data do not depict horst and graben or half graben structures from which mechanical extension might be inferred. The Wilkes Land margin is similar to the Arabian example. The margin is about 150 km in width, the amount of upper crustal extension is too low to explain the change in sub-sediment crustal thickness from ??? 35 km on the mainland to < 10 km beneath the margin and reflectors in the deepest seismic sequence are nearly flat lying. Our model requires large volumes of melt in the early stages of continental rifting. The voluminous melt might be partly a product of nearby hot spots, such as Afar and partly the result of an initial period of partial fusion in the deep continental lithosphere under lower temperatures than ordinarily required by dry solidus conditions. ?? 1991.

Structural Test Laboratory | Water Power | NREL

Science.gov Websites

Structural Test Laboratory Structural Test Laboratory NREL engineers design and configure structural components can validate models, demonstrate system reliability, inform design margins, and assess , including mass and center of gravity, to ensure compliance with design goals Dynamic Characterization Use

The cytochrome oxidase subunit I and subunit III genes in Oenothera mitochondria are transcribed from identical promoter sequences

PubMed Central

Hiesel, Rudolf; Schobel, Werner; Schuster, Wolfgang; Brennicke, Axel

1987-01-01

Two loci encoding subunit III of the cytochrome oxidase (COX) in Oenothera mitochondria have been identified from a cDNA library of mitochondrial transcripts. A 657-bp sequence block upstream from the open reading frame is also present in the two copies of the COX subunit I gene and is presumably involved in homologous sequence rearrangement. The proximal points of sequence rearrangements are located 3 bp upstream from the COX I and 1139 bp upstream from the COX III initiation codons. The 5'-termini of both COX I and COX III mRNAs have been mapped in this common sequence confining the promoter region for the Oenothera mitochondrial COX I and COX III genes to the homologous sequence block. ImagesFig. 5. PMID:15981332

MAPK/ERK signal pathway involved expression of COX-2 and VEGF by IL-1β induced in human endometriosis stromal cells in vitro

PubMed Central

Huang, Fengying; Cao, Jing; Liu, Qiuhong; Zou, Ying; Li, Hongyun; Yin, Tuanfang

2013-01-01

Objective: Now there are more and more evidences that Cyclooxygenase-2 (COX-2) plays an important role in angiogenesis of endometriosis (EMs). Vascular endothelial growth factor (VEGF) has a potent angiogenic activity. However, it is worth studying about the regulating mechanism of COX-2/COX-1 and VEGF in the development of human endometriosis in vitro. The current study was designed to investigate the effect of 4 cytokines on COX-2/COX-1 expression and the effect of IL-1β on VEGF release in human endometriosis stromal cells (ESC), and to explore the related signaling pathways involved in vitro. Methods: Isolation, culture and identification of ESC. Cells were treated with 4 cytokines, and the inhibitor mitogen-activated protein-Erk (MEK) and the inhibitor p38 mitogen-activated protein kinase (MAPK) prior to adding cytokine IL-1β. COX-2 protein expression was measured by western blot and VEGF secretion was determined by ELISA. Results: Among four kinds of cytokines, IL-1β treatment increased COX-2 protein expression and VEGF release in three ESC, and TNF-α had the same effect on COX-2 protein level as IL-1β only in ectopic and eutopic ESC, and MCSF had only slight effect on ectopic ESC. In contrast, cytokines had no effect on COX-1 expression. We also demonstrated that MAPK reduced the synthesis of COX-2 by IL-1β induced. COX-2 inhibitor reduced VEGF release by IL-1β induced. Conclusions: i) In human ESC in vitro, IL-1β up-regulated the COX-2 expression through the activation of p38 MAPK pathway, and not to COX-1. ii) Up-regulation of VEGF level by IL-1β treatment was found in human endometriosis stromal cell and COX-2 inhibitor was involved in this process. PMID:24133591

Nucleotide sequence of the COX1 gene in Kluyveromyces lactis mitochondrial DNA: evidence for recent horizontal transfer of a group II intron.

PubMed

Hardy, C M; Clark-Walker, G D

1991-07-01

The cytochrome oxidase subunit 1 gene (COX1) in K. lactis K8 mtDNA spans 8,826 bp and contains five exons (termed E1-E5) totalling 1,602 bp that show 88% nucleotide base matching and 91% amino acid homology to the equivalent gene in S. cerevisiae. The four introns (termed K1 cox1.1-1.4) contain open reading frames encoding proteins of 786, 333, 319 and 395 amino acids respectively that potentially encode maturase enzymes. The first intron belongs to group II whereas the remaining three are group I type B. Introns K1 cox1.1, 1.3, and 1.4 are found at identical locations to introns Sc cox1.2, 1.5 a, and 1.5 b respectively from S. cerevisiae. Horizontal transfer of an intron between recent progenitors of K. lactis and S. cerevisiae is suggested by the observation that K1 cox1.1 and Sc cox1.2 show 96% base matching. Sequence comparisons between K1 cox1.3/Sc cox1.5 a and K1 cox1.4/Sc cox1.5 b suggest that these introns are likely to have been present in the ancestral COX1 gene of these yeasts. Intron K1 cox1.2 is not found in S. cerevisiae and appears at an unique location in K. lactis. A feature of the DNA sequences of the group I introns K1 cox1.2, 1.3, and 1.4 is the presence of 11 GC-rich clusters inserted into both coding and noncoding regions. Immediately downstream of the COX1 gene is the ATPase subunit 8 gene (A8) that shows 82.6% base matching to its counterpart in S. cerevisiae mtDNA.

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

PubMed

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

2015-03-01

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

Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage.

PubMed

Liu, Dan; Wang, Dongsheng; Xu, Zhenbiao; Gao, Jing; Liu, Min; Liu, Yanxin; Jiang, Minghong; Zheng, Dexian

2015-10-01

Aging is the natural process of decline in physiological structure and function of various molecules, cells, tissues, and organs. Growing evidence indicates that increased immune genetic diversity and dysfunction of immune system cause aging-related pathophysiological process with the growth of age. In the present study, we observed that LPS-induced higher activation of cyclooxygenase (COX)-2 promoter is associated with the upregulated binding activity of nuclear factor kappa B (NF-κB) in peritoneal macrophages of aged mice than young ones. Additionally, COX-2 is a direct target of miR-101b and miR-26b in the macrophages. Significant upregulation of miR-101b and miR-26b effectively prevented LPS-induced excessive expression of COX-2 in the young mice. Because these negative regulatory factors were unresponsive to LPS stimulation, the levels of COX-2 were markedly higher in the macrophages of aged mice. Further study showed that NF-κB activation contributed to the increase in the expression of miR-101b and miR-26b in the LPS-stimulated macrophages of young mice, but not aged ones. Moreover, histone deacetylase (HDAC) inhibitor trichostatin A (TSA) upregulated expression of miR-101b and miR-26b in the aged mouse macrophages only, but not the young cells. This demonstrated that HDAC suppressed the expression of miR-101b and miR-26b in the LPS-treated macrophages of aged mice and contributed to the aging process. TSA-induced increased expression of miR-101b and miR-26b could further suppress COX-2 expression. These findings provide novel evidence on the regulation of immune senescence and miR-101b and miR-26b, which might be promising targets in treating aged-related inflammatory diseases. Epigenetic regulation of the microRNAs (miRNAs) provides an important evidence for the treatment of innate inflammatory disease with HDAC inhibitors in elderly.

Comparison of the tectonics and geophysics of the major structural belts between the northern and southern continental margins of the South China Sea

NASA Astrophysics Data System (ADS)

Xia, Kan-yuan; Huang, Ci-liu; Jiang, Shao-ren; Zhang, Yi-xiang; Su, Da-quan; Xia, Si-gao; Chen, Zhong-rong

1994-07-01

A comparison of the tectonics and geophysics of the major structural belts of the northern and the southern continental margins of South China Sea has been made, on the basis of measured geophysical data obtained by ourselves over a period of 8 years (1984-1991). This confirmed that the northern margin is a divergent one and the southern margin is characterized by clearly convergent features. The main extensional structures of the northern margin are, from north to south: (1) The Littoral Fault Belt, a tectonic boundary between the continental crust and a transitional zone, along the coast of the provinces of Guangdong and Fujian in South China. It is characterised by earthquake activities, high magnetic anomalies and a rapid change in crustal thickness. (2) The Northern and Southern Depression zones (i.e., the Pearl River Mouth Basin), this strikes NE-ENE and is a very large Cenozoic depression which extends from offshore Shantou westwards to Hainan Island. (3) The Central Uplift Zone. This includes the Dongsha Uplift, Shenhu Uplift and may be linked with the Penghu uplift and Taiwan shoals to the east, forming a large NE-striking uplift zone along the northern continental slope. It is characterized by high magnetic anomalies. (4) Southern Boundary Fault Belt of the transitional crust. This has positive gravity anomalies on the land side and negative ones on the sea side. (5) The Magnetic Quiet Zone. This is located south of the southern Boundary Fault Belt and between the continental margin and the Central Basin of the South China Sea. Magnetic anomalies in this belt are of small amplitude and low gradient. We consider the Magnetic Quiet Zone to be a very important tectonic zone. The major structures of southern continental margin southwards are: (1) The Northern Fault Belt of the Nansha Block. This extends along the continental slope north of the Liyue shoal (Reed Bank) and Zhongye reef, and is a tectonic boundary between oceanic crust and the Nansha Block continental crust. (2) The Nansha Block Uplift Zone. Due to the development of reefs and shoals, there are many channels and valleys. Our long-distance multichannel seismic profiles indicated that there are thick Paleogene sediments and thin Neogene sediments all over the central part of the block. (3) The Nansha Trough, a nappe structure formed by the southeastward drifting of Nansha Block and northwestward overthrusting of Palawan-northwest Borneo. (4) Zengmu Shoal Basin, southwest of the Nansha Block; the maximum thickness of Cenozoic strata is over 9 km in this important petroliferous basin.

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

PubMed

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

2012-01-01

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

Cytochrome c oxidase is activated by the oncoprotein Ras and is required for A549 lung adenocarcinoma growth

PubMed Central

2012-01-01

Background Constitutive activation of Ras in immortalized bronchial epithelial cells increases electron transport chain activity, oxygen consumption and tricarboxylic acid cycling through unknown mechanisms. We hypothesized that members of the Ras family may stimulate respiration by enhancing the expression of the Vb regulatory subunit of cytochrome c oxidase (COX). Results We found that the introduction of activated H-RasV12 into immortalized human bronchial epithelial cells increased eIF4E-dependent COX Vb protein expression simultaneously with an increase in COX activity and oxygen consumption. In support of the regulation of COX Vb expression by the Ras family, we also found that selective siRNA-mediated inhibition of K-Ras expression in A549 lung adenocarcinoma cells reduced COX Vb protein expression, COX activity, oxygen consumption and the steady-state concentration of ATP. We postulated that COX Vb-mediated activation of COX activity may be required for the anchorage-independent growth of A549 cells as soft agar colonies or as lung xenografts. We transfected the A549 cells with COX Vb small interfering or shRNA and observed a significant reduction of their COX activity, oxygen consumption, ATP and ability to grow in soft agar and as poorly differentiated tumors in athymic mice. Conclusion Taken together, our findings indicate that the activation of Ras increases COX activity and mitochondrial respiration in part via up-regulation of COX Vb and that this regulatory subunit of COX may have utility as a Ras effector target for the development of anti-neoplastic agents. PMID:22917272

Genetic variability and haplotypes of Echinococcus isolates from Tunisia.

PubMed

Boufana, Belgees; Lahmar, Samia; Rebaï, Waël; Ben Safta, Zoubeir; Jebabli, Leïla; Ammar, Adel; Kachti, Mahmoud; Aouadi, Soufia; Craig, Philip S

2014-11-01

The species/genotypes of Echinococcus infecting a range of intermediate, canid and human hosts were examined as well as the intraspecific variation and population structure of Echinococcus granulosus sensu lato (s.l.) within these hosts. A total of 174 Echinococcus isolates from humans and ungulate intermediate hosts and adult tapeworms from dogs and jackals were used. Genomic DNA was used to amplify a fragment within a mitochondrial gene and a nuclear gene, coding for cytochrome c oxidase subunit 1 (cox1; 828 bp) and elongation factor 1-alpha (ef1a; 656 bp), respectively. E. granulosus sensu stricto was identified from all host species examined, E. canadensis (G6) in a camel and, for the first time, fertile cysts of E. granulosus (s.s.) and E. equinus in equids (donkeys) and E. granulosus (s.s.) from wild boars and goats. Considerable genetic variation was seen only for the cox1 sequences of E. granulosus (s.s.). The pairwise fixation index (Fst) for cox1 E. granulosus (s.s.) sequences from donkeys was high and was statistically significant compared with that of E. granulosus populations from other intermediate hosts. A single haplotype (EqTu01) was identified for the cox1 nucleotide sequences of E. equinus. The role of donkeys in the epidemiology of echinococcosis in Tunisia requires further investigation. © The Author 2014. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Changes in mitochondrial electron transport chain activity during insect metamorphosis.

PubMed

Chamberlin, M E

2007-02-01

The midgut of the tobacco hornworm (Manduca sexta) is a highly aerobic tissue that is destroyed by programmed cell death during larval-pupal metamorphosis. The death of the epithelium begins after commitment to pupation, and the oxygen consumption of isolated midgut mitochondria decreases soon after commitment. To assess the role of the electron transport chain in this decline in mitochondrial function, the maximal activities of complexes I-IV of the respiratory chain were measured in isolated midgut mitochondria. Whereas there were no developmental changes in the activity of complex I or III, activities of complexes II and IV [cytochrome c oxidase (COX)] were higher in mitochondria from precommitment than postcommitment larvae. This finding is consistent with a higher rate of succinate oxidation in mitochondria isolated from precommitment larvae and reveals that the metamorphic decline in mitochondrial respiration is due to the targeted destruction or inactivation of specific sites within the mitochondria, rather than the indiscriminate destruction of the organelles. The COX turnover number (e- x s(-1) x cytochrome aa3(-1)) was greater for the enzyme from precommitment than postcommitment larvae, indicating a change in the enzyme structure and/or its lipid environment during the early stages of metamorphosis. The turnover number of COX in the intact mitochondria (in organello COX) was also lower in postcommitment larvae. In addition to changes in the protein or membrane phospholipids, the metamorphic decline in this rate constant may be a result of the observed loss of endogenous cytochrome c.

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

PubMed

Woo, Kyung Jin; Kwon, Taeg Kyu

2007-12-15

Sulforaphane is a natural, biologically active compound extracted from cruciferous vegetables such as broccoli and cabbage. It possesses potent anti-inflammation and anti-cancer properties. The mechanism by which sulforaphane suppresses COX-2 expression remains poorly understood. In the present report, we investigated the effect of sulforaphane on the expression of COX-2 in lipopolysaccharide (LPS)-activated Raw 264.7 cells. Sulforaphane significantly suppressed the LPS-induced COX-2 protein and mRNA expression in a dose-dependent manner. The ability of sulforaphane to suppress the expression of the COX-2 was investigated using luciferase reporters controlled by various cis-elements in COX-2 promoter region. Electrophoretic mobility shift assay (EMSA) verified that NF-kappaB, C/EBP, CREB and AP-1 were identified as responsible for the sulforaphane-mediated COX-2 down-regulation. In addition, we demonstrated the signal transduction pathway of mitogen-activated protein kinase (MAP kinase) in LPS-induced COX-2 expression. Taken together, these results demonstrate that sulforaphane effectively suppressed the LPS-induced COX-2 protein via modulation of multiple core promoter elements (NF-kappaB, C/EBP, CREB and AP-1) in the COX-2 transcriptional regulation. These results will provide new insights into the anti-inflammatory and anti-carcinogenic properties of sulforaphane.

Preliminary results from combined wide-angle and reflection seismic data in the Natal Valley, South Mozambique margin across the Almirante Leite volcanic ridge : MZ2 profile (MOZ3/5 cruise).

NASA Astrophysics Data System (ADS)

Verrier, Fanny; Leprêtre, Angélique; Evain, Mikael; Schnurle, Philippe; Watremez, Louise; Aslanian, Daniel; De Clarens, Philippe; Afonso Dias, Nuno; Afilhado, Alexandra; Leroy, Sylvie; d'Acremont, Elia; Castilla, Raymi; Moulin, Maryline

2017-04-01

The study of South Mozambique passive margin is essential to understand its rifting evolution and better constrain kinematic reconstructions model of the Indian Ocean. MOZ3-5 oceanographic cruises (2016) is part of the PAMELA project (PAssive Margin Exploration LAboratory), conducted by TOTAL, IFREMER, in collaboration with Université de Bretagne Occidentale, Université Rennes 1, Université Pierre and Marie Curie, CNRS et IFPEN. These campaigns allowed the acquisition of wide-angle and multichannel seismic data as well as high resolution bathymetric data, dredges, magnetic and gravimetric data. This work focuses on the deep structure of the northern segment of the Natal Valley which was investigated along a 300 km long E-W seismic transect cross-cutting the Almirante Leite volcanic ridge (MZ2 profile). The wide-angle data set is composed of 23 OBS (Ocean Bottom Seismometers) and 19 LSS (Land Seismic Station) spaced by about 12 km and 4-5 km respectively. Forward modelling of the wide-angle data led to a preliminary 2D P-waves velocity model revealing the sedimentary architecture, crustal and lithospherical structures and shallow high velocity material at the volcanic ridge. The aim of this work is to present the first results on the crustal structure from P-waves velocity modeling along the profile MZ2, in order to discuss the sedimentary sequences, the geometry and nature of the crust (oceanic or continental) as well as structures associated with volcanism, and to better understand the margin's evolution. The post-doc of Fanny Verrier is co-funded by TOTAL and IFREMER as part of the PAMELA (Passive Margin Exploration Laboratories) scientific project. Moulin, M., Aslanian, D., 2016. PAMELA-MOZ03 cruise, RV Pourquoi pas ?, http://dx.doi.org/10.17600/16001600 Moulin, M., Evain, M., 2016. PAMELA-MOZ05 cruise, RV Pourquoi pas ?, http://dx.doi.org/10.17600/16009500

"We don't exist": a qualitative study of marginalization experienced by HIV-positive lesbian, bisexual, queer and transgender women in Toronto, Canada.

PubMed

Logie, Carmen H; James, Llana; Tharao, Wangari; Loutfy, Mona R

2012-09-07

Lesbian, bisexual, queer and transgender (LBQT) women living with HIV have been described as invisible and understudied. Yet, social and structural contexts of violence and discrimination exacerbate the risk of HIV infection among LBQT women. The study objective was to explore challenges in daily life and experiences of accessing HIV services among HIV-positive LBQT women in Toronto, Canada. We used a community-based qualitative approach guided by an intersectional theoretical framework. We conducted two focus groups; one focus group was conducted with HIV-positive lesbian, bisexual and queer women (n = 7) and the second with HIV-positive transgender women (n = 16). Participants were recruited using purposive sampling. Focus groups were digitally recorded and transcribed verbatim. Thematic analysis was used for analyzing data to enhance understanding of factors that influence the wellbeing of HIV-positive LBQT women. Participant narratives revealed a trajectory of marginalization. Structural factors such as social exclusion and violence elevated the risk for HIV infection; this risk was exacerbated by inadequate HIV prevention information. Participants described multiple barriers to HIV care and support, including pervasive HIV-related stigma, heteronormative assumptions in HIV-positive women's services and discriminatory and incompetent treatment by health professionals. Underrepresentation of LBQT women in HIV research further contributed to marginalization and exclusion. Participants expressed a willingness to participate in HIV research that would be translated into action. Structural factors elevate HIV risk among LBQT women, limit access to HIV prevention and present barriers to HIV care and support. This study's conceptualization of a trajectory of marginalization enriches the discussion of structural factors implicated in the wellbeing of LBQT women and highlights the necessity of addressing LBQT women's needs in HIV prevention, care and research. Interventions that address intersecting forms of marginalization (e.g. sexual stigma, transphobia, HIV-related stigma) in community and social norms, HIV programming and research are required to promote health equity among LBQT women.

“We don't exist”: a qualitative study of marginalization experienced by HIV-positive lesbian, bisexual, queer and transgender women in Toronto, Canada

PubMed Central

Logie, Carmen H; James, LLana; Tharao, Wangari; Loutfy, Mona R

2012-01-01

Background Lesbian, bisexual, queer and transgender (LBQT) women living with HIV have been described as invisible and understudied. Yet, social and structural contexts of violence and discrimination exacerbate the risk of HIV infection among LBQT women. The study objective was to explore challenges in daily life and experiences of accessing HIV services among HIV-positive LBQT women in Toronto, Canada. Methods We used a community-based qualitative approach guided by an intersectional theoretical framework. We conducted two focus groups; one focus group was conducted with HIV-positive lesbian, bisexual and queer women (n=7) and the second with HIV-positive transgender women (n=16). Participants were recruited using purposive sampling. Focus groups were digitally recorded and transcribed verbatim. Thematic analysis was used for analyzing data to enhance understanding of factors that influence the wellbeing of HIV-positive LBQT women. Results Participant narratives revealed a trajectory of marginalization. Structural factors such as social exclusion and violence elevated the risk for HIV infection; this risk was exacerbated by inadequate HIV prevention information. Participants described multiple barriers to HIV care and support, including pervasive HIV-related stigma, heteronormative assumptions in HIV-positive women's services and discriminatory and incompetent treatment by health professionals. Underrepresentation of LBQT women in HIV research further contributed to marginalization and exclusion. Participants expressed a willingness to participate in HIV research that would be translated into action. Conclusions Structural factors elevate HIV risk among LBQT women, limit access to HIV prevention and present barriers to HIV care and support. This study's conceptualization of a trajectory of marginalization enriches the discussion of structural factors implicated in the wellbeing of LBQT women and highlights the necessity of addressing LBQT women's needs in HIV prevention, care and research. Interventions that address intersecting forms of marginalization (e.g. sexual stigma, transphobia, HIV-related stigma) in community and social norms, HIV programming and research are required to promote health equity among LBQT women. PMID:22989529

IL-1β Stimulates COX-2 Dependent PGE2 Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells

PubMed Central

Neeb, Lars; Hellen, Peter; Boehnke, Carsten; Hoffmann, Jan; Schuh-Hofer, Sigrid; Dirnagl, Ulrich; Reuter, Uwe

2011-01-01

Objective Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX) inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified. Methods and Results 1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1β can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1β caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE2) release 4 hours after stimulation with IL-1β, which could be aborted by a selective COX-2 (parecoxib) and a non-selective COX-inhibitor (indomethacin). 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE2 and 24 hours after IL-1β stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1β induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect. Conclusion We identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-β leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE2 (by COX-2) in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2 and CGRP. The results could help to explain the mechanism of action of COX-2 inhibitors in migraine. PMID:21394197

Structure of marginally jammed polydisperse packings of frictionless spheres

NASA Astrophysics Data System (ADS)

Zhang, Chi; O'Donovan, Cathal B.; Corwin, Eric I.; Cardinaux, Frédéric; Mason, Thomas G.; Möbius, Matthias E.; Scheffold, Frank

2015-03-01

We model the packing structure of a marginally jammed bulk ensemble of polydisperse spheres. To this end we expand on the granocentric model [Clusel et al., Nature (London) 460, 611 (2009), 10.1038/nature08158], explicitly taking into account rattlers. This leads to a relationship between the characteristic parameters of the packing, such as the mean number of neighbors and the fraction of rattlers, and the radial distribution function g (r ) . We find excellent agreement between the model predictions for g (r ) and packing simulations, as well as experiments on jammed emulsion droplets. The observed quantitative agreement opens the path towards a full structural characterization of jammed particle systems for imaging and scattering experiments.

Synthesis, biological evaluation and molecular docking studies of stellatin derivatives as cyclooxygenase (COX-1, COX-2) inhibitors and anti-inflammatory agents.

PubMed

Gautam, Raju; Jachak, Sanjay M; Kumar, Vivek; Mohan, C Gopi

2011-03-15

Stellatin (4), isolated from Dysophylla stellata is a cyclooxygenase (COX) inhibitor. The present study reports the synthesis and biological evaluation of new stellatin derivatives for COX-1, COX-2 inhibitory and anti-inflammatory activities. Eight derivatives showed more pronounced COX-2 inhibition than stellatin and, 17 and 21 exhibited the highest COX-2 inhibition. They also exhibited the significant anti-inflammatory activity in TPA-induced mouse ear edema assay and their anti-inflammatory effects were more than that of stellatin and indomethacin at 0.5mg/ear. The derivatives were further evaluated for antioxidant activity wherein 16 and 17 showed potent free radical scavenging activity against DPPH and ABTS radicals. Molecular docking study revealed the binding orientations of stellatin and its derivatives into the active sites of COX-1 and COX-2 and thereby helps to design the potent inhibitors. Copyright © 2011 Elsevier Ltd. All rights reserved.

New Ferrocene Compounds as Selective Cyclooxygenase (COX-2) Inhibitors: Design, Synthesis, Cytotoxicity and Enzyme-inhibitory Activity.

PubMed

Farzaneh, Shabnam; Zeinalzadeh, Elnaz; Daraei, Bahram; Shahhosseini, Soraya; Zarghi, Afshin

2018-01-01

Due to the astonishing properties of ferrocene and its derivatives, it has a broad application in diverse areas. Numerous ferrocene derivatives demonstrated anti-proliferative activity. Also COX-2, as a key isoenzyme for production of prostaglandins, is frequently overexpressed in various cancers. It is now recognized that COX-2 over expression promotes tumorigenic functions which can be suppressed by COX-2 inhibitors, a phenomenon useful for the preventing of tumor progression. The combination of COX-2 inhibitors with other anti-cancer or cancer prevention drugs may reduce their side effects in future cancer prevention and treatment. Owing to high anticancer potential of ferrocene derivatives and considerable COX-2 inhibitory and cytotoxicity effects of our previously synthesized chalcones, we decided to incorporate the ferrocenyl moiety into appropriate COX-2 inhibitor chalcone based scaffold, to evaluate COX-2 inhibitory activity as well as anticancer activities. Chalcones were synthesized via clasien-schmidt condensation of methylsulfonyl aldehyde and acetyl ferrocene. Further different amines with solvent free and ultra sound condition were reacted with chalcones to have different 1-ferrocenyl-3-amino carbonyl compounds. Docking study was carried out with Auto Dock vina software. All the newly-synthesized compounds were evaluated for their cyclooxygenase-2 (COX-2) inhibitory activity using chemiluminescent enzyme assays as well as cytotoxicity activity against MCF-7 and T47D and fibroblast cell lines by MTT assay. In vitro COX-1/COX-2 inhibition studies demonstrated that all compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the highly potent 0.05-0.12 µM range, and COX-2 selectivity indexes (SI) in the 148.3-313.7 range. These results indicated that either potency or selectivity of COX-2 inhibitory activity was affected by the nature and size of the substituents on C-3 of propane-1-one. Also anti-proliferative and toxicity activities of synthesized compounds against breast cancer cell lines MCF-7 and T47D and fibroblast cell lines showed that the synthesized compounds had mild to moderate cytotoxicity against MCT7 and T47D breast cancer cell lines at 10 µM concentration. In vitro COX-1/COX-2 inhibition studies and anticancer activity against MCF-7, identified 1-ferrocenyl-3-(4-methylsulfonylphenyl) propen-1-one as a potent compound (IC50 COX-2 = 0.05 µM, MCF-7: % inhibition (at concentration of 10 µM) = 32.7%), and also 1-ferrocenyl-3- (propan-1-amine)-3-(4-methylsulfonylphenyl) propan-1-one showed the most selectivity on COX-2 inhibition (selectivity index= 313.7). A novel group of ferrocene compounds, possessing a methyl sulfonyl COX-2 pharmacophore were synthesized to investigate the effect of different substituents on selectivity and potency of COX-2 inhibitory activity and their cytotoxicity effects. This study indicates that 1-ferrocenyl-3-amino carbonyl compounds having ferrocene motif and methyl sulfonyl COX-2 pharmacophore is a suitable scaffold to design COX-2 inhibitors and anti-cancer agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Bounded Linear Stability Analysis - A Time Delay Margin Estimation Approach for Adaptive Control

NASA Technical Reports Server (NTRS)

Nguyen, Nhan T.; Ishihara, Abraham K.; Krishnakumar, Kalmanje Srinlvas; Bakhtiari-Nejad, Maryam

2009-01-01

This paper presents a method for estimating time delay margin for model-reference adaptive control of systems with almost linear structured uncertainty. The bounded linear stability analysis method seeks to represent the conventional model-reference adaptive law by a locally bounded linear approximation within a small time window using the comparison lemma. The locally bounded linear approximation of the combined adaptive system is cast in a form of an input-time-delay differential equation over a small time window. The time delay margin of this system represents a local stability measure and is computed analytically by a matrix measure method, which provides a simple analytical technique for estimating an upper bound of time delay margin. Based on simulation results for a scalar model-reference adaptive control system, both the bounded linear stability method and the matrix measure method are seen to provide a reasonably accurate and yet not too conservative time delay margin estimation.

Opening of the Central Atlantic Ocean: Implications for Geometric Rifting and Asymmetric Initial Seafloor Spreading after Continental Breakup

NASA Astrophysics Data System (ADS)

Klingelhoefer, F.; Biari, Y.; Sahabi, M.; Funck, T.; Benabdellouahed, M.; Schnabel, M.; Reichert, C. J.; Gutscher, M. A.; Bronner, A.; Austin, J. A., Jr.

2017-12-01

The structure of conjugate passive margins provides information about rifting styles, the initial phases of the opening of an ocean and the formation of its associated sedimentary basins. The study of the deep structure of conjugate passive continental margins combined with precise plate kinematic reconstructions can provide constraints on the mechanisms of rifting and formation of initial oceanic crust. In this study the Central Atlantic conjugate margins are compared, based on compilation of wide-angle seismic profiles from the NW-Africa Nova Scotian and US passive margins. Plate cinematic reconstructions were used to place the profiles in the position at opening and at the M25 magnetic anomaly. The patterns of volcanism, crustal thickness, geometry, and seismic velocities in the transition zone. suggest symmetric rifting followed by asymmetric oceanic crustal accretion. Conjugate profiles in the southern Central Atlantic image differences in the continental crustal thickness. While profiles on the eastern US margin are characterized by thick layers of magmatic underplating, no such underplate was imaged along the NW-African continental margin. It has been proposed that these volcanic products form part of the CAMP (Central Atlantic Magmatic Province). In the north, two wide-angle seismic profiles acquired in exactly conjugate positions show that the crustal geometry of the unthinned continental crust and the necking zone are nearly symmetric. A region including seismic velocities too high to be explained by either continental or oceanic crust is imaged along the Nova Scotia margin off Eastern Canada, corresponding on the African side to an oceanic crust with slightly elevated velocities. These might result from asymmetric spreading creating seafloor by faulting the existing lithosphere on the Canadian side and the emplacement of magmatic oceanic crust including pockets of serpentinite on the Moroccan margin. A slightly elevated crustal thickness along the African margin can be explained by the influence of the Canary hotspot between 60 and 30 Ma in the study region. After isochron M25, a large-scale plate reorganization may then have led to an increase in spreading velocity and the production of a more typical but thin magmatic crust on both sides.

K-feldspar megacryst accumulations formed by mechanical instabilities in magma chamber margins, Asha pluton, NW Argentina

NASA Astrophysics Data System (ADS)

Rocher, Sebastián; Alasino, Pablo H.; Grande, Marcos Macchioli; Larrovere, Mariano A.; Paterson, Scott R.

2018-07-01

The Asha pluton, the oldest unit of the San Blas intrusive complex (Early Carboniferous), exhibits impressive examples of magmatic structures formed by accumulation of K-feldspar megacrysts, enclaves, and schlieren. Almost all recognized structures are meter-scale, vertically elongate bodies of variable shapes defined as fingers, trails, drips, and blobs. They preferentially developed near the external margin of the Asha pluton and generally are superimposed by chamber-wide magmatic fabrics. They mostly have circular or sub-circular transverse sections with an internal fabric defined by margin-parallel, inward-dipping concentric foliation and steeply plunging lineation at upper parts and flat foliation at lower parts. The concentration of megacrysts usually grades from upper sections, where they appear in a proportion similar to the host granite, to highly packed accumulations of K-feldspar along with grouped flattened enclaves at lower ends. These features suggest an origin by downward localized multiphase magmatic flow, narrowing and 'log jamming', and gravitational sinking of grouped crystals and enclaves, with compaction and filter pressing as main mechanisms of melt removal. Crystal size distribution analysis supports field observations arguing for a mechanical origin of accumulations. The magmatic structures of the Asha pluton represent mechanical instabilities generated by thermal and compositional convection, probably owing to cooling and crystallization near the pluton margins during early stages of construction of the intrusive complex.

Characterization of Free Radicals Formed from COX-Catalyzed DGLA Peroxidation

PubMed Central

Xiao, Ying; Gu, Yan; Purwaha, Preeti; Ni, Kunyi; Law, Benedict; Mallik, Sanku; Qian, Steven Y.

2011-01-01

Like arachidonic acid (AA), dihomo-γ-linolenic acid (DGLA) is a 20-carbon ω-6 polyunsaturated fatty acid and a substrate of cyclooxygenase (COX). Through free radical reactions, COX metabolizes DGLA and AA to form well-known bioactive metabolites, namely, the 1- and 2-series of prostaglandins (PGs1 and PGs2), respectively. Unlike PGs2, which are viewed as pro-inflammatory, PGs1 possess anti-inflammatory and anticancer activities. However, the mechanisms linking the PGs to their bioactivities are still unclear, and radicals generated in COX-DGLA have not been detected. In order to better understand PGs biology and determine whether different reactions occur in COX-DGLA than in COX-AA, we have used LC/ESR/MS with a spin trap, α-[4-pyridyl-1-oxide]-N-tert-butyl nitrone (POBN), to characterize the carbon-centered radicals formed from COX-DGLA in vitro, including cellular peroxidation. A total of five types of DGLA-derived radicals were characterized as POBN adducts: m/z 266, m/z 296 and m/z 550 (same as and/or similar to COX-AA), and m/z 324 and m/z 354 (exclusively from COX-DGLA). Our results suggested that C-15 oxygenation to form PGGs occurs in both COX-DGLA and COX-AA; however, C-8 oxygenation occurs exclusively in COX-DGLA. This new finding will be further investigated for its association with different bioactivities of PGs, with potential implications for inflammatory diseases. PMID:21310230

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

PubMed

Thomas, David M; Kuhn, Donald M

2005-05-01

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

Curriculum as Post-Intentional Phenomenological Text: Working along the Edges and Margins of Phenomenology Using Post-Structuralist Ideas

ERIC Educational Resources Information Center

Vagle, Mark D.

2015-01-01

In this article, I experiment along the edges and margins of the phenomenological notion of intentionality using the Deleuzoguattarian concepts of multiplicity and line of flight. Working from Pinar et al.'s anticipation that phenomenology would undergo discursive shifts tending towards the post-structural, I theorize curriculum as…

Unraveling the Complexity of Critical Consciousness, Political Efficacy, and Political Action among Marginalized Adolescents

ERIC Educational Resources Information Center

Diemer, Matthew A.; Rapa, Luke J.

2016-01-01

This research examines the complex patterns by which distinct dimensions of critical consciousness may lead marginalized adolescents toward distinct forms of political action. Structural equation modeling was applied to nationally representative data from the Civic Education Study (2,811 ninth graders; M[subscript age] = 14.6), first establishing…

How One Exceptional Teacher Navigated Her Working Environment as the Teacher of a Marginal Subject

ERIC Educational Resources Information Center

Lux, Karen; McCullick, Bryan A.

2011-01-01

The purpose of this study was to analyze how one exceptional elementary physical education teacher navigated her working environment as the teacher of a marginal subject. Structuration Theory (Giddens, 1984) was used to make meaning of how the teacher functioned within her school community allowing her to remain motivated and effective. Data…

Flutter Sensitivity to Boundary Layer Thickness, Structural Damping, and Static Pressure Differential for a Shuttle Tile Overlay Repair Concept

NASA Technical Reports Server (NTRS)

Scott, Robert C.; Bartels, Robert E.

2009-01-01

This paper examines the aeroelastic stability of an on-orbit installable Space Shuttle patch panel. CFD flutter solutions were obtained for thick and thin boundary layers at a free stream Mach number of 2.0 and several Mach numbers near sonic speed. The effect of structural damping on these flutter solutions was also examined, and the effect of structural nonlinearities associated with in-plane forces in the panel was considered on the worst case linear flutter solution. The results of the study indicated that adequate flutter margins exist for the panel at the Mach numbers examined. The addition of structural damping improved flutter margins as did the inclusion of nonlinear effects associated with a static pressure difference across the panel.

Stable structures of coalitions in competitive and altruistic military teams

NASA Astrophysics Data System (ADS)

Aurangzeb, M.; Mikulski, D.; Hudas, G.; Lewis, F. L.; Gu, Edward

2013-05-01

In heterogeneous battlefield teams, the balance between team and individual objectives forms the basis for the internal topological structure of teams. The stability of team structure is studied by presenting a graphical coalitional game (GCG) with Positional Advantage (PA). PA is Shapley value strengthened by the Axioms of value. The notion of team and individual objectives is studied by defining altruistic and competitive contribution made by an individual; altruistic and competitive contributions made by an agent are components of its total or marginal contribution. Moreover, the paper examines dynamic team effects by defining three online sequential decision games based on marginal, competitive and altruistic contributions of the individuals towards team. The stable graphs under these sequential decision games are studied and found to be structurally connected, complete, or tree respectively.

Inferring Multiple Refugia and Phylogeographical Patterns in Pinus massoniana Based on Nucleotide Sequence Variation and DNA Fingerprinting

PubMed Central

Lin, Chung-Jian; Huang, Chi-Chung; Huang, Chao-Ching; Chiang, Yu-Chung; Chiang, Tzen-Yuh

2012-01-01

Background Pinus massoniana, an ecologically and economically important conifer, is widespread across central and southern mainland China and Taiwan. In this study, we tested the central–marginal paradigm that predicts that the marginal populations tend to be less polymorphic than the central ones in their genetic composition, and examined a founders' effect in the island population. Methodology/Principal Findings We examined the phylogeography and population structuring of the P. massoniana based on nucleotide sequences of cpDNA atpB-rbcL intergenic spacer, intron regions of the AdhC2 locus, and microsatellite fingerprints. SAMOVA analysis of nucleotide sequences indicated that most genetic variants resided among geographical regions. High levels of genetic diversity in the marginal populations in the south region, a pattern seemingly contradicting the central–marginal paradigm, and the fixation of private haplotypes in most populations indicate that multiple refugia may have existed over the glacial maxima. STRUCTURE analyses on microsatellites revealed that genetic structure of mainland populations was mediated with recent genetic exchanges mostly via pollen flow, and that the genetic composition in east region was intermixed between south and west regions, a pattern likely shaped by gene introgression and maintenance of ancestral polymorphisms. As expected, the small island population in Taiwan was genetically differentiated from mainland populations. Conclusions/Significance The marginal populations in south region possessed divergent gene pools, suggesting that the past glaciations might have low impacts on these populations at low latitudes. Estimates of ancestral population sizes interestingly reflect a recent expansion in mainland from a rather smaller population, a pattern that seemingly agrees with the pollen record. PMID:22952747

Cyclooxygenase and lipoxygenase gene expression in the inflammogenesis of breast cancer.

PubMed

Kennedy, Brian M; Harris, Randall E

2018-05-07

We examined the expression of major inflammatory genes, cyclooxygenase-1 and 2 (COX1, COX2) and arachidonate 5-lipoxygenase (ALOX5) in 1090 tumor samples of invasive breast cancer from The Cancer Genome Atlas (TCGA). Mean cyclooxygenase expression (COX1 + COX2) ranked in the upper 99th percentile of all 20,531 genes and surprisingly, the mean expression of COX1 was more than tenfold higher than COX2. Highly significant correlations were observed between COX2 with eight tumor-promoting genes (EGR2, IL6, RGS2, B3GNT5, SGK1, SLC2A3, SFRP1 and ETS2) and between ALOX5 and ten tumor promoter genes (CD33, MYOF1, NLRP1, GAB3, CD4, IFR8, CYTH4, BTK, FGR, CD37). Expression of CYP19A1 (aromatase) was significantly correlated with COX2, but only in tumors positive for ER, PR and HER2. Tumor-promoting genes correlated with the expression of COX1, COX2, and ALOX5 are known to effectively increase mitogenesis, mutagenesis, angiogenesis, cell survival, immunosuppression and metastasis in the pathogenesis of breast cancer.

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

PubMed

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

2014-11-01

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

Cyclooxygenase-2 regulated by the nuclear factor-κB pathway plays an important role in endometrial breakdown in a female mouse menstrual-like model.

PubMed

Xu, Xiangbo; Chen, Xihua; Li, Yunfeng; Cao, Huizi; Shi, Cuige; Guan, Shuo; Zhang, Shucheng; He, Bin; Wang, Jiedong

2013-08-01

The role of prostaglandins (PGs) in menstruation has long been proposed. Although evidence from studies on human and nonhuman primates supports the involvement of PGs in menstruation, whether PGs play an obligatory role in the process remains unclear. Although cyclooxygenase (COX) inhibitors have been used in the treatment of irregular uterine bleeding, the mechanism involved has not been elucidated. In this study, we used a recently established mouse menstrual-like model for investigating the role of COX in endometrial breakdown and its regulation. Administration of the nonspecific COX inhibitor indomethacin and the COX-2 selective inhibitor DuP-697 led to inhibition of the menstrual-like process. Furthermore, immunostaining analysis showed that the nuclear factor (NF)κB proteins P50, P65, and COX-2 colocalized in the outer decidual stroma at 12 to 16 hours after progesterone withdrawal. Chromatin immunoprecipitation analysis showed that NFκB binding to the Cox-2 promoter increased at 12 hours after progesterone withdrawal in vivo, and real-time PCR analysis showed that the NFκB inhibitors pyrrolidine dithiocarbamate and MG-132 inhibited Cox-2 mRNA expression in vivo and in vitro, respectively. Furthermore, COX-2 and NFκB inhibitors similarly reduced endometrial breakdown, suggesting that NFκB/COX-2-derived PGs play a critical role in this process. In addition, the CD45(+) leukocyte numbers were sharply reduced following indomethacin (COX-1 and COX-2 inhibitor), DuP-697 (COX-2 inhibitor), and pyrrolidine dithiocarbamate (NFκB inhibitor) treatment. Collectively, these data indicate that NFκB/COX-2-induced PGs regulate leukocyte influx, leading to endometrial breakdown.

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

PubMed Central

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

2011-01-01

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

Back-arc basin opening and closure along the southern margin of the Sea of Japan

NASA Astrophysics Data System (ADS)

Sato, Hiroshi; Claringbould, Johan; Ishiyama, Tatsuya; Kato, Naoko; Abe, Susumu; Kawasaki, Shinji

2016-04-01

Following the tsunami disaster produced by 2001 Off-Tohoku earthquake (M9) along the Pacific coast of Japan, the Japanese government started an intense evaluation of tsunami hazards. This evaluation spanned along the full Japanese coast, including the Sea of Japan coast on the western side of the Japan arc. In the Sea of Japan, tsunamis are produced by crustal faults. As the longer interval of faulting activity, the historical records of tsunamis in the Sea of Japan are not enough for the evaluation of tsunami height. Thus, the evaluation is carried out based on structural analyses of the margin of the Sea of Japan. To get better understanding of the present-day structural geometry and develop a source-fault model in this region, intense seismic reflection profiling has been carried out since 2013. We introduce the results of the seismic reflection profiles and discuss the structural evolution of the southern margin of the Sea of Japan. 2D seismic reflection profiles were acquired using 1950 cu. in. air-gun and 2100 m streamer cable. The seismic profiles provide the image image up to 3 seconds TWT. The southern margin of the Sea of Japan was produced by back-arc opening and post-rift deformation, and the structural evolution of this area is divided into several stages: rifting (25 - 14 Ma), post-rift compression (14 - 5 Ma), weak thrusting (5 - 1 Ma), and strike-slip deformation (1 Ma to present). During the rifting stage that is associated with the fan-shaped opening of the Sea of Japan, grabens and half-grabens were formed trending parallel to the extension of SW-Japan arc. These grabens were filled by syn-rift sediments, and the maximum thickness of basin fill is observed along the southern margin of the rifted crust. The opening of the Sea of Japan ceased as a result of the collision of Izu-Bonin-Mariana arc system at the Izu collision zone on the central part of Honshu, Japan. Soon after the this event, the young Shikoku basin within the Philippine Sea plate (PHS) moved northward towards the Nankai trough on the southeastern side of the SW-Japan arc. Due to the high thermal regime of the Shikoku basin, the resistance along the Nankai trough was so large that shortening deformation occurred along in the failed marginal rift zone that was developed previously along the southern margin of the Sea of Japan. This resulted in the Shinji fold belt. After the start of the subduction of the Shikoku basin along the Nankai trough, the rate of shortening in the Shinji fold belt was decreased and the folded strata were covered by sub-horizontal Pliocene sediments. Reverse faulting of the arc-parallel faults from Pliocene to early Pleistocene along the small number of faults suggests that the compression from the Nankai trough still has been continued in this stage. A change in the direction of the motion of PHS at 1 Ma produced major change in stress regime from NS compression to EW compression in the back-arc. Following the change of stress regime, the former reverse faults reactivated as strike-slip faults. The structural evolution and inherited structure presented here provide essential information for constructing the tsunami source-fault model along southern margin of the Sea of Japan.

Application of fermionic marginal constraints to hybrid quantum algorithms

NASA Astrophysics Data System (ADS)

Rubin, Nicholas C.; Babbush, Ryan; McClean, Jarrod

2018-05-01

Many quantum algorithms, including recently proposed hybrid classical/quantum algorithms, make use of restricted tomography of the quantum state that measures the reduced density matrices, or marginals, of the full state. The most straightforward approach to this algorithmic step estimates each component of the marginal independently without making use of the algebraic and geometric structure of the marginals. Within the field of quantum chemistry, this structure is termed the fermionic n-representability conditions, and is supported by a vast amount of literature on both theoretical and practical results related to their approximations. In this work, we introduce these conditions in the language of quantum computation, and utilize them to develop several techniques to accelerate and improve practical applications for quantum chemistry on quantum computers. As a general result, we demonstrate how these marginals concentrate to diagonal quantities when measured on random quantum states. We also show that one can use fermionic n-representability conditions to reduce the total number of measurements required by more than an order of magnitude for medium sized systems in chemistry. As a practical demonstration, we simulate an efficient restoration of the physicality of energy curves for the dilation of a four qubit diatomic hydrogen system in the presence of three distinct one qubit error channels, providing evidence these techniques are useful for pre-fault tolerant quantum chemistry experiments.

Fracture modes in human teeth.

PubMed

Lee, J J-W; Kwon, J-Y; Chai, H; Lucas, P W; Thompson, V P; Lawn, B R

2009-03-01

The structural integrity of teeth under stress is vital to functional longevity. We tested the hypothesis that this integrity is limited by fracture of the enamel. Experiments were conducted on molar teeth, with a metal rod loaded onto individual cusps. Fracture during testing was tracked with a video camera. Two longitudinal modes of cracking were observed: median cracking from the contact zone, and margin cracking along side walls. Median cracks initiated from plastic damage at the contact site, at first growing slowly and then accelerating to the tooth margin. Margin cracks appeared to originate from the cemento-enamel junction, and traversed the tooth wall adjacent to the loaded cusp from the gingival to the occlusal surface. All cracks remained confined within the enamel shell up to about 550 N. At higher loads, additional crack modes--such as enamel chipping and delamination--began to manifest themselves, leading to more comprehensive failure of the tooth structure.

A New Era in the Surgical Treatment of Atrial Fibrillation

PubMed Central

Melby, Spencer J.; Zierer, Andreas; Bailey, Marci S.; Cox, James L.; Lawton, Jennifer S.; Munfakh, Nabil; Crabtree, Traves D.; Moazami, Nader; Huddleston, Charles B.; Moon, Marc R.; Damiano, Ralph J.

2006-01-01

Background/Objective: While the Cox-Maze procedure remains the gold standard for the surgical treatment of atrial fibrillation (AF), the use of ablation technology has revolutionized the field. To simplify the procedure, our group has replaced most of the incisions with bipolar radiofrequency ablation lines. The purpose of this study was to examine results using bipolar radiofrequency in 130 patients undergoing a full Cox-Maze procedure, a limited Cox-Maze procedure, or pulmonary vein isolation alone. Methods: A retrospective review was performed of patients who underwent a Cox-Maze procedure (n = 100), utilizing bipolar radiofrequency ablation, a limited Cox-Maze procedure (n = 7), or pulmonary vein isolation alone (n = 23). Follow-up was available on 129 of 130 patients (99%). Results: Pulmonary vein isolation was confirmed by intraoperative pacing in all patients. Cross-clamp time in the lone Cox-Maze procedure patients was 44 ± 21 minutes, and 104 ± 42 minutes for the Cox-Maze procedure with a concomitant procedure, which was shortened considerably from our traditional cut-and-sew Cox-Maze procedure times (P < 0.05). There were 4 postoperative deaths in the Cox-Maze procedure group and 1 in the pulmonary vein isolation group. The mean follow-up was 13 ± 10, 23 ± 15, and 9 ± 10 months for the Cox-Maze IV, the pulmonary vein isolation, and the limited Cox-Maze procedure groups, respectively. At last follow-up, freedom from AF was 90% (85 of 94), 86% (6 of 7), and 59% (10 of 17) in the in the Cox-Maze procedure group, limited Cox-Maze procedure group, and pulmonary vein isolation alone group, respectively. Conclusions: The use of bipolar radiofrequency ablation to replace Cox-Maze incisions was safe and effective at controlling AF. Pulmonary vein isolation alone was much less effective, and should be used cautiously in this population. PMID:16998367

Cyclooxygenase-2 mediates the febrile response of mice to interleukin-1beta.

PubMed

Li, S; Ballou, L R; Morham, S G; Blatteis, C M

2001-08-10

Various lines of evidence have implicated cyclooxygenase (COX)-2 as a modulator of the fever induced by the exogenous pyrogen lipopolysaccharide (LPS). Thus, treatment with specific inhibitors of COX-2 suppresses the febrile response without affecting basal body (core) temperature (T(c)). Furthermore, COX-2 gene-ablated mice are unable to develop a febrile response to intraperitoneal (i.p.) LPS, whereas their COX-1-deficient counterparts produce fevers not different from their wild-type (WT) controls. To extend the apparently critical role of COX-2 for LPS-induced fevers to fevers produced by endogenous pyrogens, we studied the thermal responses of COX-1- and COX-2 congenitally deficient mice to i.p. and intracerebroventricular (i.c.v.) injections of recombinant murine (rm) interleukin (IL)-1beta. We also assessed the effects of one selective COX-1 inhibitor, SC-560, and two selective COX-2 inhibitors, nimesulide (NIM) and dimethylfuranone (DFU), on the febrile responses of WT and COX-1(-/-) mice to LPS and rmIL-1beta, i.p. Finally, we verified the integrity of the animals' responses to PGE2, i.c.v. I.p. and i.c.v. rmIL-1beta induced similar fevers in WT and COX-1 knockout mice, but provoked no rise in the T(c)s of COX-2 null mutants. The fever produced in WT mice by i.p. LPS was not affected by SC-560, but it was attenuated and abolished by NIM and DFU, respectively, while that caused by i.p. rmIL-1beta was converted into a T(c) fall by DFU. There were no differences in the responses to i.c.v. PGE2 among the WT and COX knockout mice. These results, therefore, further support the notion that the production of PGE2 in response to pyrogens is critically dependent on COX-2 expression.

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

PubMed

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

2011-10-01

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

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

PubMed

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

2017-03-20

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

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

PubMed Central

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

2015-01-01

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

The transcription factor c-Fos coordinates with histone lysine-specific demethylase 2A to activate the expression of cyclooxygenase-2

PubMed Central

Du, Yipeng; Cao, Lin-lin; Li, Meiting; Shen, Changchun; Hou, Tianyun; Zhao, Ying; Wang, Haiying; Deng, Dajun; Wang, Lina; He, Qihua; Zhu, Wei-Guo

2015-01-01

Cyclooxygenase-2 (COX-2) is overexpressed in a variety of human epithelial cancers, including lung cancer, and is highly associated with a poor prognosis and a low survival rate. Understanding how COX-2 is regulated in response to carcinogens will offer insight into designing anti-cancer strategies and preventing cancer development. Here, we analyzed COX-2 expression in several human lung cancer cell lines and found that COX-2 expression was absent in the H719 and H460 cell lines by a DNA methylation-independent mechanism. The re-expression of COX-2 was observed after 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment in both cell lines. Further investigation found that H3K36 dimethylation was significantly reduced near the COX-2 promoter because histone demethylase 2A (KDM2A) was recruited to the COX-2 promoter after TPA treatment. In addition, the transcription factor c-Fos was found to be required to recruit KDM2A to the COX-2 promoter for reactivation of COX-2 in response to TPA treatment in both the H719 and H460 cell lines. Together, our data reveal a novel mechanism by which the carcinogen TPA activates COX-2 expression by regulating H3K36 dimethylation near the COX-2 promoter. PMID:26430963

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

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

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

2006-09-10

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

What Is the Influence of Both Risk Donor and Risk Receiver on Simultaneous Pancreas-Kidney Transplantation?

PubMed

Sánchez-Hidalgo, J M; Salamanca-Bustos, J J; Arjona-Sánchez, Á; Campos-Hernández, J P; Ruiz Rabelo, J; Rodríguez-Benot, A; Requena-Tapia, M J; Briceño-Delgado, J

2018-03-01

Some factors affect the pancreas of a marginal donor, and although their influence on graft survival has been determined, there is an increasing consensus to accept marginal organs in a controlled manner to increase the pool of organs. Certain factors related to the recipient have also been proposed as having negative influence on graft prognosis. The objective of this study was to analyze the influence of these factors on the results of our simultaneous pancreas-kidney (SPK) transplantation series. Retrospective analysis of 126 SPK transplants. Donors and recipients were stratified in an optimal group (<2 expanded donor criteria) and a risk group (≥2 criteria). A pancreatic graft survival analysis was performed using a Kaplan-Meier test and log-rank test. Prognostic variables on graft survival were studied by Cox regression. Postoperative complications (graded by Clavien classification) were compared by χ 2 test or Fisher test. Median survival of pancreas was 66 months, with no significant difference between groups (P > .05). Multivariate analysis showed risk factors to be donor age, cold ischemia time, donor body mass index, receipt body mass index, and receipt panel-reactive antibody. In our series, the use of pancreatic grafts from donors with expanded criteria is safe and has increased the pool of grafts. Different variables, both donor and recipient, influence the survival of the pancreatic graft and should be taken into account in organ distribution systems. Copyright © 2017 Elsevier Inc. All rights reserved.

Significance and outcome of nuclear anaplasia and mitotic index in prostatic adenocarcinomas.

PubMed

Kır, Gozde; Sarbay, Billur Cosan; Gumus, Eyup

2016-10-01

The Gleason grading system measures architectural differentiation and disregards nuclear atypia and the cell proliferation index. Several studies have reported that nuclear grade and mitotic index (MI) are prognostically useful. This study included 232 radical prostatectomy specimens. Nuclear anaplasia (NA) was determined on the basis of nucleomegali (at least 20µm); vesicular chromatin; eosinophilic macronucleoli, nuclear lobulation, and irregular thickened nuclear membranei. The proportion of area of NA was recorded in each tumor in 10% increments. The MI was defined as the number of mitotic figures in 10 consecutive high-power fields (HPF). In univariate analysis, significant differences included associations between biochemical prostate-specific antigen recurrence (BCR) and Gleason score, extraprostatic extension, positive surgical margin, the presence of high-pathologic stage, NA≥10% of tumor area, MI≥3/10 HPF, and preoperative prostate-specific antigen. In a stepwise Cox regression model, a positive surgical margin, the presence of a NA≥10% of tumor area, and a MI of≥3/10 HPF were independent predictors of BCR after radical prostatectomy. NA≥10% of tumor area appeared to have a stronger association with outcome than MI≥3/10 HPF, as still associated with BCR when Gleason score was in the model. The results of our study showed that, in addition to the conventional Gleason grading system, NA, and MI are useful prognostic parameters while evaluating long-term prognosis in prostatic adenocarcinoma. Copyright © 2016 Elsevier Inc. All rights reserved.

Adjuvant Gemcitabine and Gemcitabine-based Chemoradiotherapy Versus Gemcitabine Alone After Pancreatic Cancer Resection: The Indiana University Experience.

PubMed

Khawaja, Muhammad R; Kleyman, Svetlana; Yu, Zhangsheng; Howard, Thomas; Burns, Matthew; Nakeeb, Attila; Loehrer, Patrick J; Cardenes, Higinia R; Chiorean, Elena Gabriela

2017-02-01

Adjuvant therapy after surgical resection is the current standard for pancreatic adenocarcinoma; however, the role of chemoradiotherapy (CRT) remains unclear. This study was conducted to compare the efficacy outcomes with adjuvant gemcitabine and gemcitabine-based CRT (CT-CRT) versus gemcitabine chemotherapy (CT) alone after pancreaticoduodenectomy. Among 165 patients who underwent surgical resection for pancreatic cancer at Indiana University Medical Center between 2004 and 2008, we retrospectively identified 53 consecutive patients who received adjuvant therapy (CT-CRT=34 patients; CT=19 patients) and had adequate follow-up medical records. The median follow-up was 19.1 months. Median disease-free (DFS) and overall survival (OS) were determined using Kaplan-Meier method, and a Cox-regression model was used to compare survival outcomes after adjusting for age, status of resection margins, and lymph node involvement. The OS for the CT-CRT group was significantly higher compared with the CT group (median, 20.4 vs. 16.6 mo; hazard ratio, 2.42; 95% CI, 1.17-5.01). The median DFS for the CT-CRT group was 13.7 versus 11.1 months for the CT group (hazard ratio, 2.88; 95% CI, 1.37-6.06). On subgroup analyses, significantly superior OS and DFS were observed among patients younger than 65 years, T3/T4 tumor stage, negative resection margins, and positive lymph node involvement. Gemcitabine plus gemcitabine-based CRT compared with gemcitabine alone leads to superior DFS and OS for patients with resected pancreatic cancer.

A study comparing two consecutive historical periods in breast cancer with a focus on surgical treatment, loco-regional recurrence, distant metastases and mortality.

PubMed

García-Fernández, A; Chabrera, C; García-Font, M; Fraile, M; Barco, I; González, S; Cirera, L; Lain, J M; González, C; Veloso, E; Codina, L; Piqueras, M; Pessarrodona, A; Gimenez, N

2015-04-01

Recent introduction of breast units, mass-screening programmes (SP) and sentinel node biopsy (SNB) has impacted on the clinical care of breast cancer patients (BC), resulting in a significant increase of breast-conserving surgery with the goal of achieving completely free margins and good cosmetic outcome, along with significantly less axillary morbidity. In order to ascertain the combined impact of SP and SNB on BC patients, we have reviewed the primary therapeutic approach of patients diagnosed with invasive breast carcinoma in our centre, both before and after implementation of the two new procedures. 1,942 patients operated for BC between 1997 and 2013 in two clinical centres. Two historical periods were considered: before and after the advent of the Breast Unit in our institutions and the concurrent implementation of SP and SNB (September 2002). Rates of breast-conserving surgery and re-operations improved in the second period. Intraoperative margin re-excision increased in the second period. Breast-conserving surgery decreased in parallel to stage: from 79 % for stage I to 31 % for stage III. The Cox analysis, including stage as adjusted for all significant variables, showed statistically significant differences in favour of the initial stages but only for specific mortality, not overall mortality. Combined implementation of breast units, SP, and SNB have resulted in a significant improvement of BC treatment leading to increased rates of breast-conserving surgery and decreased disease recurrence and mortality.

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

PubMed Central

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

2010-01-01

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

Bcr-Abl-independent mechanism of resistance to imatinib in K562 cells: Induction of cyclooxygenase-2 (COX-2) by histone deacetylases (HDACs).

PubMed

Kalle, Arunasree M; Sachchidanand, Sachchidanand; Pallu, Reddanna

2010-09-01

Our previous studies have shown that overexpression of MDR1 and cyclooygenase-2 (COX-2) resulted in resistance development to imatinib in chronic myelogenous leukemia (CML) K562 (IR-K562) cells. In the present study, the regulatory mechanism of MDR1 induction by COX-2 was investigated. A gradual overexpression of MDR1 and COX-2 during the process of development was observed. Furthermore, down regulation of MDR1 upon COX-2 knockdown by siRNA showed a decrease in the PKC levels and activation of PKC by addition of PGE(2) to K562 cells, suggesting a role for PKC in the COX-2 mediated induction of MDR1. The present study demonstrates COX-2 induction by HDACs and MDR1 induction by COX-2 via PGE(2)-cAMP-PKC-mediated pathway. Copyright 2010 Elsevier Ltd. All rights reserved.

COX-2 expression and outcome in canine nasal carcinomas treated with hypofractionated radiotherapy.

PubMed

Belshaw, Z; Constantio-Casas, F; Brearley, M J; Dunning, M D; Holmes, M A; Dobson, J M

2011-06-01

The expression of cyclooxygenase isoform 2 (COX-2) in canine nasal carcinomas has been well documented. COX-2 expression has proven to be a prognostic factor in several human tumours. The aims of this study were to assess the correlation between immunohistochemical COX-2 expression and prognosis using rhinoscopic biopsies from 42 dogs with nasal carcinomas treated with hypofractionated radiotherapy, and to establish a replicable COX-2 scoring system. Ninety per cent of sections evaluated were COX-2 positive with a mean score of 6.6 (median 8.0; range 0-12). Neither COX-2 expression nor tumour type had a significant correlation with survival. There are likely to be many as yet unidentified variants which contribute to length of survival in dogs with nasal carcinomas. Immunohistochemical COX-2 expression appears unlikely to be of prognostic significance for canine nasal carcinoma. © 2010 Blackwell Publishing Ltd.

The role of adjuvant therapy in the management of head and neck merkel cell carcinoma: an analysis of 4815 patients.

PubMed

Chen, Michelle M; Roman, Sanziana A; Sosa, Julie A; Judson, Benjamin L

2015-02-01

Merkel cell carcinoma (MCC) is a rare neuroendocrine malignant neoplasm that most commonly occurs in the head and neck and is rapidly increasing in incidence. The role of adjuvant chemoradiotherapy (CRT) in the management of head and neck MCC remains controversial. To evaluate the association between different adjuvant therapies and survival in head and neck MCC. Retrospective review of adult patients with head and neck MCC who had surgery recorded in the National Cancer Data Base from 1998 to 2011. Surgical excision, adjuvant radiation therapy (RT), or adjuvant CRT. Our main outcome was overall survival (OS). Statistical analysis included χ2, t tests, Kaplan-Meier survival analysis, and Cox proportional hazards regression analysis. We identified 4815 patients; 92.0% underwent standard surgical excision, and 8.0% underwent Mohs surgery. On multivariate analysis, age at least 75 years (hazard ratio [HR], 2.83 [95% CI, 1.82-4.41]), larger tumor size, positive margins (HR, 1.52 [95% CI, 1.25-1.85]), and metastatic lymph nodes (HR, 2.29 [95% CI, 1.84-2.85]) were independently associated with decreased OS. Postoperative CRT (HR, 0.62 [95% CI, 0.47-0.81]) and RT (HR, 0.80 [95% CI, 0.70-0.92]) provided a survival benefit over surgery alone. Adjuvant CRT was associated with improved OS over adjuvant RT in patients with positive margins (HR, 0.48 [95% CI, 0.25-0.93]), tumor size at least 3 cm (HR, 0.52 [95% CI, 0.30-0.90]), and male sex (HR, 0.69 [95% CI, 0.50-0.94]). To our knowledge, this the first study examining the role of adjuvant CRT in head and neck MCC. Results suggest that adjuvant CRT may help improve survival in high-risk patients, such as males and those with positive margins and larger tumors.