OBJECTIVES: The aim of this study was to evaluate the association of fibroblast growth factor (FGF)-23 with clinical and laboratory findings, the prognostic value of FGF-23, and the relationship between angiotensin-converting enzyme inhibitor (ACEi) therapy, FGF-23 levels, and outcomes in patients with chronic systolic heart failure (HF). BACKGROUND: FGF-23 is a bone-derived hormone regulating mineral metabolism. Higher FGF-23 levels are associated with an increased risk of cardiovascular mortality or HF development. Mechanisms leading to increased FGF-23 and its prognostic value have not been thoroughly studied in HF. METHODS: FGF-23 was measured in 369 patients (mean age 59 ± 11 years, 84% male) with systolic HF. Patients were followed for adverse events (e.g., death, urgent heart transplantation, ventricular assist device implantation). RESULTS: Tricuspid regurgitation severity, chronic kidney disease (CKD), alkaline phosphatase concentrations, inferior vena cava dilation, and absence of ACEi therapy were independently associated with FGF-23. FGF-23 was independently associated with outcomes in patients without CKD (hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.14 to 1.78), but not in CKD patients (HR: 1.12, 95% CI: 0.87 to 1.45). In patients without CKD and with FGF-23 in the highest tertile, ACEi therapy was associated with a lower risk of adverse events (HR: 0.42, 95% CI: 0.21 to 0.81), whereas no association was seen in the remaining patients (HR: 1.18, 95% CI: 0.52 to 2.70). CONCLUSIONS: In systolic HF, elevated FGF-23 is an independent predictor of adverse events, particularly in patients with preserved renal function. The association of FGF-23 with adverse events likely reflects early alterations of renal hemodynamics and renin-angiotensin system activation. Increased FGF-23 may identify a subset of HF patients benefiting from ACEi therapy.

• MeSH
• absorpční fotometrie metody   MeSH
• analýza přežití MeSH
• biologické markery MeSH
• chronická nemoc MeSH
• chronické selhání ledvin etiologie   mortalita   patofyziologie   MeSH
• dopplerovská echokardiografie MeSH
• fibroblastové růstové faktory krev   MeSH
• hodnocení rizik MeSH
• inhibitory ACE terapeutické užití   MeSH
• Kaplanův-Meierův odhad MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• multivariační analýza MeSH
• prediktivní hodnota testů MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• systolické srdeční selhání krev   komplikace   farmakoterapie   mortalita   MeSH
• vyšetření funkce ledvin MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

Background.  To investigate the relationship between hemagglutinin-inhibition (HI) antibody levels to the risk of influenza disease, we conducted a correlate of protection analysis using pooled data from previously published randomized trials. Methods.  Data on the occurrence of laboratory-confirmed influenza and HI levels pre- and postvaccination were analyzed from 4 datasets: 3 datasets included subjects aged <65 years who received inactivated trivalent influenza vaccine (TIV) or placebo, and 1 dataset included subjects aged ≥65 years who received AS03-adjuvanted TIV (AS03-TIV) or TIV. A logistic model was used to evaluate the relationship between the postvaccination titer of A/H3N2 HI antibodies and occurrence of A/H3N2 disease. We then built a receiver-operating characteristic curve to identify a potential cutoff titer between protection and no protection. Results.  The baseline odds ratio of A/H3N2 disease was higher for subjects aged ≥65 years than <65 years and higher in seasons of strong epidemic intensity than moderate or low intensity. Including age and epidemic intensity as covariates, a 4-fold increase in titer was associated with a 2-fold decrease in the risk of A/H3N2 disease. Conclusions.  The modeling exercise confirmed a relationship between A/H3N2 disease and HI responses, but it did not allow an evaluation of the predictive power of the HI response.

• Publikační typ
• časopisecké články MeSH

AIMS: Delcasertib is a selective inhibitor of delta-protein kinase C (delta-PKC), which reduced infarct size during ischaemia/reperfusion in animal models and diminished myocardial necrosis and improved reperfusion in a pilot study during primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI). METHODS AND RESULTS: A multicentre, double-blind trial was performed in patients presenting within 6 h and undergoing primary PCI for anterior (the primary analysis cohort, n = 1010 patients) or inferior (an exploratory cohort, capped at 166 patients) STEMI. Patients with anterior STEMI were randomized to placebo or one of three doses of delcasertib (50, 150, or 450 mg/h) by intravenous infusion initiated before PCI and continued for ∼2.5 h. There were no differences between treatment groups in the primary efficacy endpoint of infarct size measured by creatine kinase MB fraction area under the curve (AUC) (median 5156, 5043, 4419, and 5253 ng h/mL in the placebo, delcasertib 50, 150, and 450 mg/mL groups, respectively) in the anterior STEMI cohort. No treatment-related differences were seen in secondary endpoints of infarct size, electrocardiographic ST-segment recovery AUC or time to stable ST recovery, or left ventricular ejection fraction at 3 months. No differences in rates of adjudicated clinical endpoints (death, heart failure, or serious ventricular arrhythmias) were observed. CONCLUSIONS: Selective inhibition of delta-PKC with intravenous infusion of delcasertib during PCI for acute STEMI in a population of patients treated according to contemporary standard of care did not reduce biomarkers of myocardial injury.

• MeSH
• adjuvantní chemoterapie MeSH
• biologické markery metabolismus   MeSH
• dvojitá slepá metoda MeSH
• infarkt myokardu terapie   MeSH
• inhibitory proteinkinas aplikace a dávkování   MeSH
• intravenózní infuze MeSH
• koronární angioplastika metody   MeSH
• kreatinkinasa, forma MB metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• peptidy aplikace a dávkování   MeSH
• pilotní projekty MeSH
• plocha pod křivkou MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• troponin I metabolismus   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

The equilibrium dissociation constant of competitive antagonists represents the affinity of the receptor-ligand interaction, and it is a key characteristic of many therapeutic drugs or toxic compounds. Two commonly used methods by which the affinity of the antagonist can be estimated are Schild analysis and the Cheng-Prusoff method. However, both methods yield different results when applied to systems with slopes not equal to one. The Gaddum equation, which is fundamental for both methods, should be extended to incorporate the slope parameter of the dose-response curves and this extension should diminish the differences between the Schild and Cheng-Prusoff methods. In this study, we derived a novel form of the Gaddum equation with a slope parameter (Hill coefficient) of agonist dose-response curve. We also derived the subsequent equations for Schild and Cheng-Prusoff analysis and we validated the proposed model by the measurement of several known estrogen receptor competitive antagonists. Standardized in vitro yeast reporter gene assay (BMAEREluc/ERα) has been used for the measurements and the range of used antagonist concentrations was 1.37-46.03 μM. By applying our mathematical model, both Schild and Cheng-Prusoff methods provide more similar values of antagonist affinity than the original mathematical approach. The correctness of the model has also been demonstrated by the measurement of a partial agonist with a known receptor affinity. The presented mathematical model significantly reduces the differences in values calculated by the Cheng-Prusoff and Schild methods and yields more accurate estimations of antagonist affinity.

• MeSH
• alfa receptor estrogenů antagonisté a inhibitory   metabolismus   MeSH
• antagonisté estrogenového receptoru metabolismus   farmakologie   MeSH
• benzhydrylové sloučeniny metabolismus   toxicita   MeSH
• biologické modely * MeSH
• endokrinní disruptory metabolismus   toxicita   MeSH
• estradiol metabolismus   farmakologie   MeSH
• estrogeny metabolismus   farmakologie   MeSH
• fenoly metabolismus   toxicita   MeSH
• kompetitivní vazba MeSH
• lidé MeSH
• ligandy MeSH
• parciální agonismus léků MeSH
• reprodukovatelnost výsledků MeSH
• vazba proteinů MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Background: In recent years, significant resistance of microorganisms to antibiotics has been observed. A biofilm is a structure that significantly aids the survival of the microbial population and also significantly affects its resistance. Methods: Thyme and clove essential oils (EOs) were subjected to chemical analysis using gas chromatography coupled to mass spectrometry (GC-MS) and gas chromatography with a flame ionization detector (GC-FID). Furthermore, the antimicrobial effect of these EOs was tested in both the liquid and vapor phases using the volatilization method. The effect of the EOs on growth parameters was monitored using an RTS-8 bioreactor. However, the effect of the EOs on the biofilm formation of commonly occurring bacteria with pathogenic potential was also monitored, but for less described and yet clinically important strains of Arcobacter spp. Results: In total, 37 and 28 compounds were identified in the thyme and clove EO samples, respectively. The most common were terpenes and also derivatives of phenolic substances. Both EOs exhibited antimicrobial activity in the liquid and/or vapor phase against at least some strains. The determined antimicrobial activity of thyme and clove oil was in the range of 32-1024 μg/mL in the liquid phase and 512-1024 μg/mL in the vapor phase, respectively. The results of the antimicrobial effect are also supported by similar conclusions from monitoring growth curves using the RTS bioreactor. The effect of EOs on biofilm formation differed between strains. Biofilm formation of Pseudomonas aeruginosa was completely suppressed in an environment with a thyme EO concentration of 1024 μg/mL. On the other hand, increased biofilm formation was found, e.g., in an environment of low concentration (1-32 μg/mL). Conclusions: The potential of using natural matrices as antimicrobials or preservatives is evident. The effect of these EOs on biofilm formation, especially Arcobacter strains, is described for the first time.

• Publikační typ
• časopisecké články MeSH

PURPOSE: MicroRNA-21 (miR-21) is one of the miRNAs that are frequently and highly overexpressed in tumor tissue of colorectal cancer (CRC) patients; however, only a little is known about its functional role in CRC. METHODS: We examined the expression level of miR-21 in 44 paired samples of tumoral and non-tumoral colon tissues diagnosed for CRC using TaqMan real-time PCR method. Furthermore, we used miR-21 inhibitor (anti-miR-21) to transient knockdown of miR-21 in DLD-1 colon cancer cells and examined the effects of miR-21 silencing on viability, apoptosis, chemosensitivity, cell cycle, and migration of DLD1 cells. RESULTS: The expression levels of miR-21 were significantly increased in CRC tumor tissue (P < 0.0001). Significant differences in miR-21 levels were observed also between CRC tissues of patients with CRC in different clinical stages: I vs. II (P = 0.033) and I vs. IV (P = 0.021). Kaplan-Meier analysis proved that the miR-21 expression levels are correlated to shorter overall survival of CRC patients (P = 0.0341). MiR-21 silencing in DLD1 cell line had no effect on the cell viability; however, when combined with chemotherapeutics (5-FU, L-OHP, and SN38), it contributed to the decrease of cell viability. Suppression of miR-21 decreased cell migration ability of DLD-1 cells by nearly 30 % (P = 0.016). CONCLUSION: We have confirmed the overexpression of miR-21 in CRC samples and its correlation with advanced disease and shorter overall survival. These findings could be described in part by the fact that CRC cells with increased expression of miR-21 have higher migration ability.

• MeSH
• apoptóza účinky léků   genetika   MeSH
• buněčný cyklus účinky léků   genetika   MeSH
• Kaplanův-Meierův odhad MeSH
• kolorektální nádory farmakoterapie   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA antagonisté a inhibitory   genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory tračníku genetika   patologie   MeSH
• pohyb buněk účinky léků   genetika   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• viabilita buněk účinky léků   genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. METHODS AND RESULTS: We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B-type natriuretic peptide and troponin) versus enalapril. CONCLUSIONS: Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

• MeSH
• aminobutyráty terapeutické užití   MeSH
• antagonisté receptorů pro angiotenzin terapeutické užití   MeSH
• biologické markery krev   MeSH
• dvojitá slepá metoda MeSH
• enalapril terapeutické užití   MeSH
• inhibitory ACE terapeutické užití   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé MeSH
• natriuretický peptid typu B krev   MeSH
• neprilysin antagonisté a inhibitory   MeSH
• peptidové fragmenty krev   MeSH
• přežívající MeSH
• progrese nemoci * MeSH
• rizikové faktory MeSH
• srdeční selhání krev   farmakoterapie   patofyziologie   MeSH
• tepový objem fyziologie   MeSH
• tetrazoly terapeutické užití   MeSH
• troponin krev   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor used in first-line combination antiretroviral therapy (cART). It is usually administered with nucleoside reverse transcriptase inhibitors (NRTI), many of which are substrates of OCT uptake solute carriers (SLC22A) and MATE (SLC47A), P-gp (MDR1, ABCB1), BCRP (ABCG2), or MRP2 (ABCC2) efflux transporters. The aim of this study was to evaluate the inhibitory potential of efavirenz towards these transporters and investigate its effects on the pharmacokinetics and tissue distribution of a known Oct/Mate substrate, lamivudine, in rats. Accumulation and transport assays showed that efavirenz inhibits the uptake of metformin by OCT1-, OCT2- and MATE1-expressing MDCK cells and reduces transcellular transport of lamivudine across OCT1/OCT2- and MATE1-expressing MDCK monolayers. Only negligible inhibition of MATE2-K was observed in HEK-MATE2-K cells. Efavirenz also reduced the efflux of calcein from MDCK-MRP2 cells, but had a rather weak inhibitory effect on Hoechst 33342 accumulation in MDCK-MDR1 and MDCK-BCRP cells. An in vivo pharmacokinetic interaction study in male Wistar rats revealed that intravenous injection of efavirenz or the control Oct/Mate inhibitor cimetidine significantly reduced the recovery of lamivudine in urine and greatly increased lamivudine retention in the renal tissue. Co-administration with efavirenz or cimetidine also increased the AUC0-∞ value and reduced total body clearance of lamivudine. These data suggest that efavirenz is a potent inhibitor of OCT/Oct and MATE/Mate transporters. Consequently, it can engage in drug-drug interactions that reduce renal excretion of co-administered substrates and enhance their retention in the kidneys, potentially compromising therapeutic safety.

• MeSH
• benzoxaziny farmakologie   MeSH
• buňky MDCK MeSH
• cimetidin farmakologie   MeSH
• eliminace ledvinami MeSH
• HEK293 buňky MeSH
• inhibitory reverzní transkriptasy farmakokinetika   farmakologie   moč   MeSH
• krysa rodu rattus MeSH
• lamivudin farmakokinetika   farmakologie   moč   MeSH
• ledviny metabolismus   MeSH
• lidé MeSH
• metformin metabolismus   farmakologie   MeSH
• plocha pod křivkou MeSH
• poločas MeSH
• potkani Wistar MeSH
• proteiny přenášející organické kationty antagonisté a inhibitory   metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům antagonisté a inhibitory   metabolismus   MeSH
• psi MeSH
• ROC křivka MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: MiR150-5p has been reported to be involved in generalized myasthenia gravis, in which different cytokines play critical roles. The regulatory network of cytokines in generalized myasthenia gravis has not been fully elucidated. Our study aimed to investigate the interactions between miR150-5p and different cytokines in generalized myasthenia gravis. MATERIALS AND METHOD: Serum levels of miR150-5p and different cytokines including IL-2, IL-17, IL-10, IL-19, IL-20 and IL-35 were detected by qRT-PCR and ELISA, respectively. ROC curve analysis was performed to evaluate the diagnostic value of miR150-5p for generalized myasthenia gravis. Correlation between serum levels of miR150-5p and different cytokines were analyzed by Pearson correlation coefficient. RESULTS: Compared with healthy controls, decreased serum levels of IL-2 and IL-17 and increased serum levels of miR150-5p, IL-10, IL-19, IL-20 and IL-35 were observed in patients with generalized myasthenia gravis. Serum levels of miR150-5p were positively correlated with IL-10 and negatively correlated with IL-17. After treatments, serum levels of miR150-5p and IL-10 decreased, while serum levels of IL-2 and IL-17 increased. CONCLUSION: Upregulation of miR150-5p is involved in generalized myasthenia gravis patients and is associated with decreased serum levels of IL-17 as well as increased serum levels of IL-10.

• MeSH
• dospělí MeSH
• interleukin-10 krev   MeSH
• interleukin-17 krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• mladý dospělý MeSH
• myasthenia gravis krev   genetika   MeSH
• ROC křivka MeSH
• studie případů a kontrol MeSH
• upregulace MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The poor prognosis of colorectal cancer (CRC) contributes to a yearly increase in CRC mortality, while microRNAs (miRNAs) were found to play a regulatory function in diversiform cancers, including CRC. The objective of this research was to evaluate the clinical value and possible regulatory mechanisms of miR-767-5p in CRC. The expression level of miR-767-5p in CRC tissues and cells was examined. The Kaplan-Meier curve was utilized to analyse the function of miR-767-5p in CRC prognosis. The independent prognostic factors in CRC were assessed by a multivariate COX regression analysis. Additionally, the regulatory mechanism of miR-767-5p in CRC was determined through an in vitro cell experiment. The miR-767-5p expression was down-regulated in CRC tumour tissues and CRC cells. Indicators such as tumour differentiation, TNM, LNM and miR-767-5p were identified as independent prognostic factors for a poor CRC prognosis. The regulatory relationship between miR-767-5p and nuclear factor I A (NFIA) was verified by the dual-luciferase reporter assay, and the NFIA expression level was significantly suppressed by over-expressed miR-767-5p. The proliferation, migration and invasion of CRC cells were inhibited by over-expressing miR-767-5p, while the inhibition effect could be reversed by over-expressing NFIA. The over-expressed miR-767-5p could serve as a tumour suppressor to inhibit the progression of CRC by suppressing the expression level of NFIA.

• MeSH
• invazivní růst nádoru MeSH
• Kaplanův-Meierův odhad MeSH
• kolorektální nádory * genetika   patologie   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA * genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• pohyb buněk genetika   MeSH
• prognóza MeSH
• proliferace buněk genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• senioři MeSH
• transkripční faktory NFI metabolismus   genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH