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 (GARD™) is a state-of-the-art technology platform, the most advanced application of which is the assay for assessment of skin sensitizing chemicals, GARD™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 GARD™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 naïve 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 GARD™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 GARD™skin

Supplementary Material S3 revised

Historical data

Supplementary Material S2

Results calculation spreadsheat

Supplementary Material S1

GARD SOP v.05.0

Fragment-Based Discovery of 6‑Arylindazole 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

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Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases

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