COX-2 specifické inhibitory byly vyvinuty ve snaze snížit výskyt nežádoucích vedlejších úího traktu pekávaným výsledkem jedné ze studií, která byla primárndoucích úýšený výskyt kardiovaskulárních pání s pacienty lého infarktu myokardu. O pasnjším jeví kardioprotektivní vliv naproxenu, který byl prokázán. Diskutuje se i otázka možného protektivního vlivu COX-2 selektivních inhibitorkardiovaskulárních příhod v souvislosti se známým protizánětlivým vlivem COX-2 selektivních inhibitorů. Metaanalýza studií provedených s meloxikamem neprokazuje zvýšení výskytu tromboembolických příhod v souvislosti s léčbou tímto COX-2 selektivním inhibitorem. Výsledky studie NUT-2 dokonce naznačují možný příznivý vliv meloxikamu na kardiovaskulární aterosklerotické příhody.

COX-2 selective inhibitors have been developed with intention to decrease an incidence of undesirable side effects in gastrointestinal tract with analgesic and anti-inflammatory effects maintained. One of studies, focused primarily to gastrointestinal undesirable effects detection (VIGOR), showed unexpected outcome - unpredicted elevation of cardiovascular attacks in patients treated with 50 mg of rofecoxib, compared to those with 2 × 500 mg of naproxen, particularly an incidence of minor (not fatal) myocardial infarction. The ground is a matter of debate, either cardioprotective effect of naproxen or prothrombotic effect of rofecoxib are possible. Presently a cardioprotective effect of naproxen, which has been proved, seems to be more likely. Question of possible protective effect of COX-2 selective inhibitors in prevention of thrombotic cardiovascular attacks is also being discussed in connection with their known anti-inflammatory effect. Meta-analysis of studies with meloxicam does not show increased incidence in thromboembolism connected to treatment with this COX-2 selective inhibitor. NUT-2 study shows even possible favourable action of meloxicam to cardiovascular atherosclerotic attacks.

• MeSH
• Anti-Inflammatory Agents, Non-Steroidal pharmacology   adverse effects   therapeutic use   MeSH
• Antirheumatic Agents antagonists & inhibitors   adverse effects   therapeutic use   MeSH
• Arteriosclerosis pathology   MeSH
• Drug Therapy methods   MeSH
• Drug Evaluation MeSH
• Cardiovascular System drug effects   MeSH
• Humans MeSH
• Drug-Related Side Effects and Adverse Reactions MeSH
• Thromboembolism prevention & control   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

• Keywords
• MELOCIKAM, NIMELISUD,
• MeSH
• Anti-Inflammatory Agents, Non-Steroidal adverse effects   therapeutic use   MeSH
• Duodenal Ulcer prevention & control   MeSH
• Gastrointestinal Tract drug effects   MeSH
• Cyclooxygenase Inhibitors metabolism   MeSH
• Misoprostol administration & dosage   therapeutic use   MeSH
• Nabumetone MeSH
• Peptic Ulcer prevention & control   MeSH
• Publication type
• Review MeSH

Survival analysis is commonly conducted in medical and public health research to assess the association of an exposure or intervention with a hard end outcome such as mortality. The Cox (proportional hazards) regression model is probably the most popular statistical tool used in this context. However, when the exposure includes compositional covariables (that is, variables representing a relative makeup such as a nutritional or physical activity behaviour composition), some basic assumptions of the Cox regression model and associated significance tests are violated. Compositional variables involve an intrinsic interplay between one another which precludes results and conclusions based on considering them in isolation as is ordinarily done. In this work, we introduce a formulation of the Cox regression model in terms of log-ratio coordinates which suitably deals with the constraints of compositional covariates, facilitates the use of common statistical inference methods, and allows for scientifically meaningful interpretations. We illustrate its practical application to a public health problem: the estimation of the mortality hazard associated with the composition of daily activity behaviour (physical activity, sitting time and sleep) using data from the U.S. National Health and Nutrition Examination Survey (NHANES).

• MeSH
• Exercise * MeSH
• Proportional Hazards Models MeSH
• Regression Analysis MeSH
• Nutrition Surveys MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

OBJECTIVES: Cyclooxygenase-2 (COX-2) and tumor suppressor p53 are molecules that are linked to the oncogenesis of pancreatic cancer. COX-2 represents a key modulatory molecule in inflammation and carcinogenesis, and is known to be implicated in the positive regulation of growth and tumorigenesis. Abnormal expression of p53 is common in many human neoplasms including pancreatic cancer. Recent studies demonstrated functional interactions between p53 and COX-2. The p53-dependent upregulation of COX-2 was proposed to be another mechanism by which p53 could abate its own growth-inhibitory and apoptotic effects. METHODS: In this study, we immunohistochemically analyzed the expression of COX-2 and p53 in 95 pancreatic resection specimens [adenocarcinomas, 95 lesions; pancreatic intraepithelial neoplasias (PanINs), 155; normal ducts, 70]. RESULTS: The expression of COX-2 increased progressively with the grade of ductal lesions (P<0.00001). A statistically significant difference of COX-2 expression between normal ducts and low-grade PanINs was revealed (P=0.0042). COX-2 overexpression was demonstrated in 82 PanINs (52.9%), and in 76 adenocarcinomas (80%). No significant correlation between the grade of adenocarcinoma and COX-2 expression was revealed (P=0.2). The expression of p53 again increased progressively with the grade of lesions (P<0.00001) with a significant increase in high-grade PanINs. A correlation between COX-2 and p53 expression levels in carcinomas was revealed (P=0.0002), and an accumulation of p53 was associated with COX-2 overexpression in premalignant and malignant ductal lesions. CONCLUSION: These findings confirmed the generally accepted pancreatic cancer progression model, and supported the concept of the interactive role of COX-2 and p53 in pancreatic cancer carcinogenesis, which offers opportunities for targeted therapy and chemoprevention of pancreatic cancer using COX-2 inhibitors.

• MeSH
• Adenocarcinoma metabolism   pathology   MeSH
• Cyclooxygenase 2 metabolism   MeSH
• Adult MeSH
• Carcinoma, Pancreatic Ductal metabolism   pathology   MeSH
• Financing, Organized MeSH
• Immunoenzyme Techniques MeSH
• Middle Aged MeSH
• Humans MeSH
• Tumor Suppressor Protein p53 metabolism   MeSH
• Pancreatic Neoplasms metabolism   pathology   MeSH
• Precancerous Conditions metabolism   pathology   MeSH
• Disease Progression MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Pancreatic Ducts metabolism   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH

• MeSH
• Sentinel Lymph Node Biopsy statistics & numerical data   utilization   MeSH
• Humans MeSH
• Breast Neoplasms diagnosis   therapy   MeSH
• Neoadjuvant Therapy methods   utilization   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Meta-Analysis MeSH

Selective cyclooxygenase (COX)-1 inhibitors can be employed as potential cardioprotective drugs. Moreover, COX-1 plays a key role in inflammatory processes and its activity is associated with some types of cancer. In this work, we designed and synthesized a set of compounds that structurally mimic the selective COX-1 inhibitors, SC-560 and mofezolac, the central cores of which were replaced either with triazole or benzene rings. The advantage of this approach is a relatively simple synthesis in comparison with the syntheses of parent compounds. The newly synthesized compounds exhibited remarkable activity and selectivity toward COX-1 in the enzymatic in vitro assay. The most potent compound, 10a (IC50 = 3 nM for COX-1 and 850 nM for COX-2), was as active as SC-560 (IC50 = 2.4 nM for COX-1 and 470 nM for COX-2) toward COX-1 and it was even more selective. The in vitro COX-1 enzymatic activity was further confirmed in the cell-based whole-blood antiplatelet assay, where three out of four selected compounds (10a,c,d, and 3b) exerted outstanding IC50 values in the nanomolar range (9-252 nM). Moreover, docking simulations were performed to reveal key interactions within the COX-1 binding pocket. Furthermore, the toxicity of the selected compounds was tested using the normal human kidney HK-2 cell line.

• MeSH
• Anti-Inflammatory Agents, Non-Steroidal * pharmacology   MeSH
• Cyclooxygenase 2 metabolism   MeSH
• Cyclooxygenase 2 Inhibitors * pharmacology   chemistry   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Project is focused on detailed analysis of modulation possibilities of the antineoplastic effect of retinoids (13-cis RA, ATRA) by combined application with LOX/COX inhibitors. Cell lines derived from neurogenic solid tumors in children (neuroblastoma, medulloblastoma) were chosen as model objects. Dynamics of intracellular metabolism of retinoids (detection of CRABP proteins) as well as relevant parameters of antineoplastic effect (differentiation, apoptosis, cell proliferation, growth factors relatedto the angiogenesis) will be evaluated during experiments. Resulting optimal combinations of the retionid and LOX/COX inhibitor will be subsequently evaluated using the same cell lines in additional combination with another antitumor drugs. Experimentalin vitro verification of the modulation of antineoplastic effect of the retinoids in selected solid childhood tumors would be a significant outcome with potentially important implications in clinical practice.

Projekt je zaměřen na analýzu možností modulace antineoplastického efektu retinoidů (13-cis RA, ATRA) jejich kombinovanou aplikací s LOX/COX inhibitory. Modelovým objektem budou linie neurogenních solidních nádorů dětského věku (neuroblastom, medulloblastom). V rámci experimentů bude hodnocena jednak dynamika intracelulárního metabolismu retinoidů (detekce CRABP proteinů), jednak příslušné parametry podmiňující antineoplastický efekt (diferenciace, apoptóza, proliferace, růstové faktory ovlivňující angiogenezi). Výsledné optimální kombinace příslušného retinoidu a LOX/COX inhibitoru budou dále testovány na stejných liniích v podmínkách in vitro v kombinaci s dalšími vybranými protinádorovými léčivy. Experimentální ověření způsobu modulace protinádorového efektu retinoidů na in vitro modelech uvedených solidních nádorů dětského věku by v tomto směru znamenalo důležitý výsledek s potenciálně významnými možnostmi pro klinickou praxi.

• MeSH
• Cell Differentiation MeSH
• Prostaglandin-Endoperoxide Synthases MeSH
• Child MeSH
• Angiogenesis Inhibitors MeSH
• Lipoxygenases MeSH
• Medulloblastoma MeSH
• Neuroblastoma MeSH
• Antibodies, Neoplasm MeSH
• Retinoids MeSH
• Check Tag
• Child MeSH

• Conspectus
• Biochemie. Molekulární biologie. Biofyzika
• NML Fields
• onkologie
• biologie
• pediatrie
• NML Publication type
• závěrečné zprávy o řešení grantu IGA MZ ČR

To define the soil properties for a given area or country including the level of pollution, soil survey and inventory programs are essential tools. Soil data transformations enable the expression of the original data on a new scale, more suitable for data analysis. In the computer-aided interactive analysis of large data files of soil characteristics containing outliers, the diagnostic plots of the exploratory data analysis (EDA) often find that the sample distribution is systematically skewed or reject sample homogeneity. Under such circumstances the original data should be transformed. The Box-Cox transformation improves sample symmetry and stabilizes spread. The logarithmic plot of a profile likelihood function enables the optimum transformation parameter to be found. Here, a proposed procedure for data transformation in univariate data analysis is illustrated on a determination of cadmium content in the plough zone of agricultural soils. A typical soil pollution survey concerns the determination of the elements Be (16 544 values available), Cd (40 317 values), Co (22 176 values), Cr (40 318 values), Hg (32 344 values), Ni (34 989 values), Pb (40 344 values), V (20 373 values) and Zn (36 123 values) in large samples.

• MeSH
• Financing, Government MeSH
• Data Interpretation, Statistical MeSH
• Cadmium analysis   MeSH
• Metals analysis   MeSH
• Soil Pollutants analysis   MeSH
• Environmental Monitoring methods   MeSH
• Likelihood Functions MeSH
• Agriculture MeSH
• Environmental Pollution analysis   MeSH

Relationships between conformation traits and functional longevity in Holstein cows were evaluated using survival analysis. Functional longevity was defined as the number of days between the first calving and culling; that is, length of productive life. The data set consisted of 116,369 Holstein cows that first calved from 2003 to 2008. All cows used in the analysis were scored for conformation between d 30 and d 210 of their first lactation. The data included 48% censored records. Analyses were done separately for 20 linear descriptive type traits, 6 composite traits, and height at sacrum measured in centimeters. Cox proportional hazard models were fitted to analyze data. The hazard function was described as the product of a baseline hazard function and the time-independent effects of age at first calving and sire (random), and the time-dependent effects of stage of lactation and lactation number, herd, year and season, herd size, and 305-d milk production. The strongest relationship between a composite trait and functional longevity was for dairy form, followed by udder and final score. Among the descriptive type traits, the strongest relationships with longevity were found for body condition score, angularity, traits related to udder attachment, and udder depth. Foot and leg traits showed substantially lower effect on functional longevity, and the effect of foot angle was minimal. Functional longevity declined with decreased body condition score of cows. Cows with deep udders had significantly lower functional survival compared with cows with shallow udders. In addition, weak central ligament was associated with significant reduction of cow longevity. For dairy form and angularity, cows classified as very good were the worst with respect to longevity, whereas cows classified as poor were the best. An intermediate optimum was evident for rear legs rear view and rear legs set (side view), whereas cows with sickled legs had lower longevity than cows with straighter legs.

• MeSH
• Biometry MeSH
• Longevity genetics   MeSH
• Quantitative Trait, Heritable MeSH
• Lactation genetics   MeSH
• Mammary Glands, Animal anatomy & histology   MeSH
• Proportional Hazards Models MeSH
• Cattle anatomy & histology   genetics   physiology   MeSH
• Animals MeSH
• Check Tag
• Cattle anatomy & histology   genetics   physiology   MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

Based on the significant anti-inflammatory activity of natural quinone primin (5a), series of 1,4-benzoquinones, hydroquinones, and related resorcinols were designed, synthesized, characterized and tested for their ability to inhibit the activity of cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) enzymes. Structural modifications resulted in the identification of two compounds 5b (2-methoxy-6-undecyl-1,4-benzoquinone) and 6b (2-methoxy-6-undecyl-1,4-hydroquinone) as potent dual COX/5-LOX inhibitors. The IC50 values evaluated in vitro using enzymatic assay were for compound 5b IC50 = 1.07, 0.57, and 0.34 μM and for compound 6b IC50 = 1.07, 0.55, and 0.28 μM for COX-1, COX-2, and 5-LOX enzyme, respectively. In addition, compound 6d was identified as the most potent 5-LOX inhibitor (IC50 = 0.14 μM; reference inhibitor zileuton IC50 = 0.66 μM) from the tested compounds while its inhibitory potential against COX enzymes (IC50 = 2.65 and 2.71 μM for COX-1 and COX-2, respectively) was comparable with the reference inhibitor ibuprofen (IC50 = 4.50 and 2.46 μM, respectively). The most important structural modification leading to increased inhibitory activity towards both COXs and 5-LOX was the elongation of alkyl chain in position 6 from 5 to 11 carbons. Moreover, the monoacetylation in ortho position of bromo-hydroquinone 13 led to the discovery of potent (IC50 = 0.17 μM) 5-LOX inhibitor 17 (2-bromo-6-methoxy-1,4-benzoquinone) while bromination stabilized the hydroquinone form. Docking analysis revealed the interaction of compounds with Tyr355 and Arg120 in the catalytic site of COX enzymes, while the hydrophobic parts of the molecules filled the hydrophobic substrate channel leading up to Tyr385. In the allosteric catalytic site of 5-LOX, compounds bound to Tyr142 and formed aromatic interactions with Arg138. Taken together, we identified optimal alkyl chain length for dual COX/5-LOX inhibition and investigated other structural modifications influencing COX and 5-LOX inhibitory activity.

• MeSH
• Benzoquinones chemistry   MeSH
• Cyclooxygenase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Lipoxygenase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Catalytic Domain MeSH
• Oxidation-Reduction MeSH
• Computer Simulation MeSH
• Resorcinols chemistry   MeSH
• Molecular Docking Simulation MeSH
• Spectrum Analysis methods   MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH