ARAF suppresses ERBB3 expression and metastasis in a subset of lung cancers.

RAF kinases are highly conserved serine/threonine kinases, and among the three RAF isoforms (ARAF, BRAF, and CRAF), the pathophysiological relevance of ARAF is not well defined. Here, we show that patients with lung cancer exhibit low expression of ARAF, which is associated with lymph node metastasis and poor patient survival. We uncover that depletion of ARAF promotes anchorage-independent growth and metastasis through activation of AKT signaling in a subset of lung cancer cells.

Linking Complement C3 and B Cells in Nasal Polyposis.

Nasal polyposis often is characterized by a persistent inflammation of the sinonasal mucosa, disease recurrence after medical or surgical intervention, and asthma comorbidity. Dysregulated complement activation may contribute to immunologic alterations and disease. To date, there is only scattered knowledge on the source and regulation of the central complement factors in the pathogenesis of nasal polyps.

Zearalenone and ß-Zearalenol But Not Their Glucosides Inhibit Heat Shock Protein 90 ATPase Activity.

The mycotoxin zearalenone (ZEN) is produced by many plant pathogenic species. It is well known for its estrogenic activity in humans and animals, but whether ZEN has a role in plant-pathogen interaction and which process it is targeting was so far unclear. We found that treatment of seedlings with ZEN induced transcription of the gene.

Evaluation of the Performance of AmpliSeq and SureSelect Exome Sequencing Libraries for Ion Proton.

Library preparation for whole-exome sequencing is a critical step serving the enrichment of the regions of interest. For Ion Proton, there are only two exome library preparation methods available, AmpliSeq and SureSelect. Although of major interest, a comparison of the two methods is missing in the literature.

IgG4-Associated Adrenalitis-a Case Report.

A 67-year-old man was adrenalectomized due to a tumor measuring 100 mm. Specimens revealed an inflammation with slight fibrosis and moderate infiltrates of lymphocytes and plasmacytes with immunoreactivity for IgG and IgG4 resulting in the diagnosis of an active IgG4-associated adrenalitis. To our knowledge, this is the first reported active adrenalitis of this type.

Validation of "laboratory-supported" criteria for functional (psychogenic) tremor.

Background: In a small group of patients, we have previously shown that a combination of electrophysiological tests was able to distinguish functional (psychogenic) tremor and organic tremor with excellent sensitivity and specificity.

Objectives: This study aims to validate an electrophysiological test battery as a tool to diagnose patients with functional tremor with a "laboratory-supported" level of certainty.

Methods: For this prospective data collection study, we recruited 38 new patients with functional tremor (mean age 37.

Tremor associated with Klinefelter syndrome--a case series and review of the literature.

Background: Previous case series suggested a link between Klinefelter syndrome (KS) and essential tremor (ET) or an ET-like syndrome.

Methods: We investigated three KS-patients with tremor including tremor-analyzes and discuss our data in context to findings from a literature review. The clinical outcome after deep brain stimulation (DBS) is also reviewed.

Gender is an important determinant of the disposition of the loop diuretic torasemide.

Signals from pharmacovigilance studies indicate that women are at higher risk for adverse drug reactions (ADRs) due to diuretics. Despite the long-term use of torasemide, there are few studies investigating gender differences of torasemide pharmacokinetics in the hospital setting. Therefore, torasemide pharmacokinetics were investigated in 90 patients (45 women, 45 men) during steady-state conditions.

Effects of Leuzea carthamoides on human breast adenocarcinoma MCF-7 cells determined by gene expression profiling and functional assays.

Products derived from roots of Leuzea carthamoides (Maral root) are being promoted as dietary supplements with anti-aging, adaptogenic and anabolic activity, without much scientific evidence. We investigated the effects of a lipophilic Leuzea root extract and the major phytoecdysteroid, 20-hydroxyecdysone, in human breast adenocarcinoma MCF-7 cells. Cell proliferation was inhibited by the extract (IC50 = 30 microg/mL) but not by 20-hydroxyecdysone.

Determinants of steady-state torasemide pharmacokinetics: impact of pharmacogenetic factors, gender and angiotensin II receptor blockers.

Background: Torasemide is frequently used for the treatment of hypertension and heart failure. However, the determinants of torasemide pharmacokinetics in patients during steady-state conditions are largely unknown. We therefore explored the impact of genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and organic anion transporting polypeptide (OATP) 1B1 (SLCO1B1), gender, and the effects of losartan and irbesartan comedication on the interindividual variability of steady-state pharmacokinetics of torasemide.

Impact of enhanced external counterpulsation on peripheral circulation.

Enhanced external counterpulsation (EECP) is a noninvasive counterpulsation technique that reduces angina and improves exercise capacity in patients with coronary artery disease. Diastolic coronary perfusion is augmented by pneumatic compression of 3 sets of cuffs wrapped around the lower extremities. Although central hemodynamic changes are well investigated, almost no data exist about the changes of peripheral circulation during EECP.

Caffeine accelerates absorption and enhances the analgesic effect of acetaminophen.

The aim of this study was to determine the analgesic effect of acetaminophen compared to a combination of both caffeine and acetaminophen or caffeine alone using tonic and phasic pain stimulation. Twenty-four subjects were treated orally with 1000 mg acetaminophen, 130 mg caffeine, and a combination of both in a 4-way crossover, double-blind, placebo-controlled study. Pharmacokinetics and analgesic effects were assessed by means of an experimental pain model based on pain-related cortical potentials after phasic stimulation of the nasal mucosa with CO(2) and based on pain ratings after tonic stimulation with dry air.

Characterization of beta-adrenoceptor antagonists as substrates and inhibitors of the drug transporter P-glycoprotein.

Transporter proteins such as P-glycoprotein are major determinants of intracellular drug concentrations. Moreover, inhibition or induction of transporters is an important mechanism underlying drug interactions in humans. However, very little is known whether beta-adrenoceptor antagonists are substrates and/or inhibitors of P-glycoprotein.

Effect of selective cyclooxygenase-2 inhibitors on heart rate in healthy young men.

During an investigation of the possible pharmacokinetic interactions of cyclooxygenase-2 (COX-2) inhibitors with metoprolol, we observed that rofecoxib caused a significant reduction in heart rate in young healthy volunteers. The effect of valdecoxib did not reach significance. When these drugs were given together with metoprolol, the effect was continued.

Bioavailability of diclofenac potassium at low doses.

Aim: Diclofenac-K has been recently launched at low oral doses in different countries for over-the-counter use. However, given the considerable first-pass metabolism of diclofenac, the degree of absorption of diclofenac-K at low doses remained to be determined. The aim of this study was to determine the bioavailability of low-dose diclofenac-K.

Effect of amiodarone on the plasma levels of metoprolol.

On average, metoprolol plasma concentration is doubled after an amiodarone loading dose (1.2 g/day over a period of 6 days). However, the individual amount of this drug interaction depends on the CYP2D6 genotype.

A liquid chromatography-mass spectrometry method for the quantification of both etoricoxib and valdecoxib in human plasma.

A practicable and selective liquid chromatography-mass spectrometry assay for the determination of two cyclooxygenase-2 inhibitors, etoricoxib and valdecoxib, in human plasma is presented. The analytical technique is based on reversed-phase high-performance liquid chromatography (HPLC) coupled to atmospheric pressure chemical ionisation (APCI) mass spectrometry (Finnigan Mat LCQ ion trap). Mass analysis was performed in the positive ion mode.

Single-dose nimodipine normalizes impaired retinal circulation in normal tension glaucoma.

Purpose: Several studies indicate that calcium channel blockers improve the clinical course of normal tension glaucoma (NTG), whereas the underlying mechanism is not fully investigated. Hemodynamic improvement and neuroprotective effects are discussed. In this study, we measured the hemodynamic effects of nimodipine on retinal circulation.

Celecoxib modulates the expression of cyclooxygenase-2, ki67, apoptosis-related marker, and microvessel density in human cervical cancer: a pilot study.

Purpose: We investigated whether a short treatment with the cyclooxygenase-2 (COX-2) inhibitor celecoxib could modulate Ki67 antigen and the caspase cleavage product of keratin 18, recognized as a marker of early apoptosis. The activity of celecoxib on microvessel density (MVD) and angio-power Doppler sonography-derived indices of tumor vascularization was also assessed. Serum levels of squamous cell carcinoma antigen and the proliferative potential and subsets of peripheral T cells before and after celecoxib treatment were also analyzed.

Aceclofenac spares cyclooxygenase 1 as a result of limited but sustained biotransformation to diclofenac.

Objective: The mechanism of action of aceclofenac is currently unclear. This study investigated whether biotransformation to metabolites (4'-hydroxy-aceclofenac, diclofenac, 4'-hydroxy-diclofenac) contributes to inhibitory effects on the cyclooxygenase (COX) isozymes in vitro and ex vivo.

Methods: In vitro investigations were performed with human whole blood and human blood monocytes.

Celecoxib inhibits metabolism of cytochrome P450 2D6 substrate metoprolol in humans.

Objective: In vitro data have shown that celecoxib inhibits the metabolism of cytochrome P450 (CYP) 2D6 substrates. However, very limited data are available on the influence of cyclooxygenase 2 inhibitors on the disposition of CYP2D6 substrates in humans. Therefore the objective of this study was to examine the effect of celecoxib and rofecoxib on the pharmacokinetics of the clinically relevant CYP2D6 substrate metoprolol.

Simultaneous determination of aceclofenac and three of its metabolites in human plasma by high-performance liquid chromatography.

Aceclofenac [[2-(2',6'-dichlorophenyl)amino]phenylacetoxyacetic acid] is a phenylacetic acid derivative with potent analgesic and anti-inflammatory properties and an improved gastro-intestinal tolerance. In the present study, a liquid-liquid extraction-based reversed-phase HPLC method with UV detection was validated and applied for the analysis of aceclofenac and three of its metabolites (4'-hydroxy-aceclofenac, diclofenac, 4'-hydroxy-diclofenac) in human plasma. The analytes were separated using an acetonitrile-phosphate buffer gradient at a flow rate of 1 mL/min, and UV detection at 282 nm.

Steryl phenolic acid esters in cereals and their milling fractions.

The steryl ferulate contents of rye and wheat grains and their milling fractions were analyzed using a reversed-phase high-performance liquid chromatographic (HPLC) method. HPLC-mass spectrometry was used for identification. In addition, steryl ferulates of some selected milling byproducts were determined.

Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment.

The beta1 selective beta-blocker metoprolol is metabolized predominantly but not exclusively by CYP2D6. Due to the polymorphism of the CYP2D6 gene, CYP2D6 activity varies markedly between individuals. Consequently, after short-term administration metoprolol plasma concentrations were found to be several fold higher in poor metabolizers than in extensive metabolizers.