Abstract.Drug-induced kidney injury is often observed in the clinics and can lead to longterm organ failure. In this work, we evaluated a novel in vitro system that aims at detecting whether compounds can cause renal proximal tubule damage in man. For this, we implemented organotypic cultures of human conditionally immortalized proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1) in a threechannel OrganoPlate under microfluidic conditions. Cells were exposed to four known nephrotoxicants (cisplatin, tenofovir, cyclosporine A, and tobramycin). The effect on cell viability and NAG release into the medium was determined. A novel panel of four miRNAs (mir-21, mir-29a, mir-34a, and mir-192) was selected as potential biomarkers of proximal tubule damage. After nephrotoxicant treatment, miRNA levels in culture medium were earlier indicators than cell viability (WST-8 assay) and outperformed NAG for proximal tubule damage. In particular, mir-29a, mir-34a, and mir-192 were highly reproducible between experiments and across compounds, whereas mir-21 showed more variability. Moreover, similar data were obtained in two different laboratories, underlining the reproducibility and technical transferability of the results, a key requirement for the implementation of novel biomarkers. In conclusion, the selected miRNAs behaved like sensitive biomarkers of damage to tubular epithelial cells caused by several nephrotoxicity mechanisms. This biomarker panel, in combination with the 3D cultures of ciPTEC-OAT1 in the OrganoPlate, represents a novel tool for in vitro nephrotoxicity detection. These results pave the way for the application of miRNAs in longitudinal, time-course in vitro toxicity studies.
Agile frameworks such as Scrum contribute to a flexible product development process. In a scaled agile modular design development environment at TRUMPF Group, research shows that not all committed Backlog-Items are completed by the end of the sprint. By applying the Design Research Methodology by BLESSING and CHAKRABARTI, factors that influence the reliability of sprint commitment were identified. Furthermore, support was developed for two influencing factors, "quality of estimation" and "awareness of the advantages of reliable sprint commitments". Firstly, the usability of the User Story Mapping method to increase the quality of estimation was tested. Secondly, a workshop concept that aims to draw attention to the importance of the topic was tested in one Scrum team, resulting in higher awareness.
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