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Highlights: [•] DHEA decreases CYP1A induction by 3-methylcholanthrene in primary human hepatocytes. [•] DHEA reduces CYP1A2 mRNA levels, but does not influence CYP1A1 and CYP1B1 expression. [•] DHEA post-transcriptionally modifies CYP1A2 induction. [•] Androgen receptor is involved in the increased degradation of CYP1A2 mRNA. [•] It accounts for the protection against chemically induced carcinogenesis by DHEA. [Copyright &y& Elsevier]

Background: Chinese hamster ovary (CHO) cells have become the host of choice for the production of recombinant proteins, due to their capacity for correct protein folding, assembly, and posttranslational modifications. The most widely used system for recombinant proteins is the gene amplification procedure that uses the CHO-Dhfr expression system. However, CHO cells are known to have a very unstable karyotype. This is due to chromosome rearrangements that can arise from translocations and homologous recombination, especially when cells with the CHO-Dhfr expression system are treated with methotrexate hydrate. The present method used in the industry for testing clones for their long-term stability of recombinant protein production is empirical, and it involves their cultivation over extended periods of time prior to the selection of the most suitable clone for further bioprocess development. The aim of the present study was the identification of marker genes that can predict stable expression of recombinant genes in particular clones early in the development stage. Results: The transcriptome profiles of CHO clones with stable and unstable recombinant protein production were investigated over 10-weeks of cultivation, using a DNA microarray. We identified 14 genes that were differentially expressed between the stable and unstable clones already at 2 weeks from the beginning of the cultivation. Their expression was validated by reverse-transcription quantitative real-time PCR (RT-qPCR). Furthermore, the k-nearest neighbour algorithm approach shows that the combination of the gene expression patterns of only five of these 14 genes is sufficient to predict stable recombinant protein production in clones in the early phases of cell-line development. Conclusions: The exact molecular mechanisms that cause unstable recombinant protein production are not fully understood. However, the expression profiles of some genes in clones with stable and unstable recombinant protein production allow prediction of such instability early in the cell-line development stage. We have thus developed a proof-of-concept for a novel approach to eliminate unstable clones in the CHO-Dhfr expression system, which saves time and labour-intensive work in cell-line development. [ABSTRACT FROM AUTHOR]

Examines the impact of computer-aided control system design on students. Advantage of virtual race; Description of the controller design solutions; Determination of the velocity of the surf regatta.

The efficacy of aripiprazole therapy and the risk of adverse reactions are influenced by substantial inter-individual variability in aripiprazole metabolizing capacity. In vitro studies assigned the potential role in aripiprazole metabolism to CYP2D6 and CYP3A enzymes; therefore, the association between the steady-state aripiprazole plasma concentrations and patients' CYP2D6 and CYP3A statuses (CYP2D6, CYP3A4, and CYP3A5 genotypes, and CYP3A4 expression) and/or co-medication with CYP function modifying medications has been investigated in 93 psychiatric patients on stable aripiprazole therapy. The patients' CYP2D6 genotype had a major effect on aripiprazole plasma concentrations, whereas contribution of CYP3A genotypes and CYP3A4 expression to aripiprazole clearance were considered to be minor or negligible. The role of CYP3A4 expression in aripiprazole metabolism did not predominate even in the patients with nonfunctional CYP2D6 alleles. Furthermore, dehydroaripiprazole exposure was also CYP2D6 genotype-dependent. Dehydroaripiprazole concentrations were comparable with aripiprazole levels in patients with functional CYP2D6 alleles, and 35% or 22% of aripiprazole concentrations in patients with one or two non-functional CYP2D6 alleles, respectively. The concomitant intake of CYP2D6 inhibitors, risperidone, metoprolol, or propranolol was found to increase aripiprazole concentrations in patients with at least one wild-type CYP2D6*1 allele. Risperidone and 9-hydroxy-risperidone inhibited both dehydrogenation and hydroxylation of aripiprazole, whereas metoprolol and propranolol blocked merely the formation of the active dehydroaripiprazole metabolite, switching towards the inactivation pathways. Patients' CYP2D6 genotype and co-medication with CYP2D6 inhibitors can be considered to be the major determinants of aripiprazole pharmacokinetics. Taking into account CYP2D6 genotype and co-medication with CYP2D6 inhibitors may improve the outcomes of aripiprazole therapy. [ABSTRACT FROM AUTHOR]

Background Incidence of drug–drug interactions (DDIs) increases with complexity of treatment and comorbidities, as in heart failure (HF). This randomized, double-blind study evaluated the intervention of the pharmacist on prevalence of clinically relevant DDIs ( NCT01855165 ). Methods Patients admitted with HF were screened for clinically relevant DDIs, and randomized to control or intervention. All attending physicians received standard advice about pharmacological therapy; those in the intervention group also received alerts about clinically relevant DDIs. Primary endpoint was DDI at discharge and secondary were re-hospitalization or death during follow-up. Results Of 213 patients, 51 (mean age, 79 ± 6 years; male, 47%) showed 66 clinically relevant DDIs and were randomized. For intervention (n = 26) versus control (n = 25), the number of patients with and the number of DDIs were significantly lower at discharge: 8 vs. 18 and 10 vs. 31; p = 0.003 and 0.0049, respectively. Over a 6 month follow-up period, 11 control and 9 intervention patients were re-hospitalized or died (p > 0.2 for all). No significant differences were seen between control and intervention for patients with eGFR < 60 mL/min/1.73 m 2 (78%) for re-hospitalization or death (10 vs. 7; p = 0.74). Conclusions Pharmacist intervention significantly reduces the number of patients with clinically relevant DDIs, but not clinical endpoints 6 months from discharge. [ABSTRACT FROM AUTHOR]

Current experimental methods for the study of reaching in the MRI environment do not exactly mimic actual reaching, due to constrains in movement which are imposed by the MRI machine itself. We tested a haptic robot (HR) as such a tool. Positive results would also be promising for combined use of fMRI and EEG to study reaching. Twenty right-handed subjects performed reaching tasks with their right hand with and without the HR. Reaction time, movement time (MT), accuracy, event-related potentials (ERPs) and event-related desynchronisation/synchronisation (ERD/ERS) were studied. Reaction times and accuracies did not differ significantly between the two tasks, while the MT was significantly longer in HR reaching (959 vs. 447 ms). We identified two positive and two negative ERP peaks across all leads in both tasks. The latencies of the P1 and N2 peaks were significantly longer in HR reaching, while there were no significant differences in the P3 and N4 latencies. ERD/ERS topographies were similar between tasks and similar to other reaching studies. Main difference was in ERS rebound which was observed only in actual reaching. Probable reason was significantly larger MT. We found that reaching with the HR engages similar neural structures as in actual reaching. Although there are some constrains, its use may be superior to other techniques used for reaching studies in the MRI environment, where freedom of movement is limited. [ABSTRACT FROM AUTHOR]