10 research outputs found
Data from: Validation of the GARD skin assay for assessment of chemical skin sensitizers - ring trial results of predictive performance and reproducibility
Proactive identification of chemicals with skin sensitizing properties is a key toxicological endpoint within chemical safety assessment. In order to meet recent legislations and increase animal welfare, considerable efforts have been made to develop non-animal approaches to replace current animal testing. Genomic Allergen Rapid Detection (GARDâ˘) is a state-of-the-art technology platform, the most advanced application of which is the assay for assessment of skin sensitizing chemicals, GARDâ˘skin. The methodology is based on a dendritic cell (DC)-like cell line, thus mimicking the mechanistic events leading to initiation and modulation of downstream immunological responses. Induced transcriptional changes are measured following exposure to test chemicals, providing a detailed evaluation of cell activation. These changes are associated with the immunological decision-making role of DCs in vivo and include among other phenotypic modifications, up-regulation of co-stimulatory molecules, induction of cellular and oxidative stress pathways and xenobiotic responses. Here, results from an inter-laboratory ring trial of GARDâ˘skin, conducted in compliance with OECD guidance documents and comprising a blinded chemical test set of 28 chemicals, are summarized. The assay was found to be transferable to naĂŻve laboratories, with an inter-laboratory reproducibility of 92.0%. The within-laboratory reproducibility ranged between 82.1-88.9%, while the cumulated predictive accuracy across the three laboratories was 93.8%. Based on these and previously published data, it is concluded that GARDâ˘skin is a robust and reliable method for the identification of skin sensitizing chemicals and suitable for use as a stand-alone assay. These data form the basis for the regulatory validation of GARDâ˘skin
WITHDRAWN: Pre-operative skin traction in hip fractures may not be beneficial - Results from a meta-analysis
Fragment-Based Discovery of 6âArylindazole JAK Inhibitors
Janus kinase (JAK) inhibitors are
emerging as novel and efficacious
drugs for treating psoriasis and other inflammatory skin disorders,
but their full potential is hampered by systemic side effects. To
overcome this limitation, we set out to discover soft drug JAK inhibitors
for topical use. A fragment screen yielded an indazole hit that was
elaborated into a potent JAK inhibitor using structure-based design.
Growing the fragment by installing a phenol moiety in the 6-position
afforded a greatly improved potency. Fine-tuning the substituents
on the phenol and sulfonamide moieties afforded a set of compounds
with lead-like properties, but they were found to be phototoxic and
unstable in the presence of light
Violence at Work - The Emeregence of a Social Problem
This article analyses trends in violence at work on the basis of victim surveys, work-environment surveys, and press material. It proceeds from the two most common explanations of why violence at work appears to have increased over recent decades. These emphasize shifts in working conditions that have increased employees' victimization risk, and a broadened view of what is regarded as work-related violence. The empirical analyses provide support for both these explanations, and the various dimensions examinedâincreased reporting propensities, expanded definitions, a reduced tolerance of violence, and altered working conditionsâare linked to one another.Violence at work - the emergence, development and structure of a social problem (FAS
The GARDpotency Assay for Potency-Associated Subclassification of Chemical Skin SensitizersâRationale, Method Development, and Ring Trial Results of Predictive Performance and Reproducibility
Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases
A class
of potent, nonsteroidal, selective indazole ether-based
glucocorticoid receptor modulators (SGRMs) was developed for the inhaled
treatment of respiratory diseases. Starting from an orally available
compound with demonstrated anti-inflammatory activity in rat, a soft-drug
strategy was implemented to ensure rapid elimination of drug candidates
to minimize systemic GR activation. The first clinical candidate <b>1b</b> (AZD5423) displayed a potent inhibition of lung edema in
a rat model of allergic airway inflammation following dry powder inhalation
combined with a moderate systemic GR-effect, assessed as thymic involution.
Further optimization of inhaled drug properties provided a second,
equally potent, candidate, <b>15m</b> (AZD7594), that demonstrated
an improved therapeutic ratio over the benchmark inhaled corticosteroid <b>3</b> (fluticasone propionate) and prolonged the inhibition of
lung edema, indicating potential for once-daily treatment