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Abstract Background To counteract the spread of new psychoactive substances (NPS) and to prevent the emergence of novel substances, specifically designed as a response to the legal control of individual substances, a new law was introduced in Germany in 2016: the New Psychoactive Substances Act (NpSG). The NpSG combines a generic approach with the waiver of criminal liability for the acquisition and possession of NPS for personal use, which is a novelty in German narcotics law. The present study aimed at exploring the impact of the introduction of the NpSG from three different perspectives—NPS users, staff of addiction care facilities, and members of law enforcement authorities—to better understand the dynamics surrounding such a change in legislation and to contribute to the body of international experience in dealing with NPS. Methods Semi-structured narrative interviews were conducted with a total of 193 representatives of the three different groups affected by the law. These interviews included questions on perceived changes associated with the introduction of the NpSG as well as questions on opinions regarding legal and criminal policy issues. The analysis was carried out using qualitative content analysis according to Mayring. Results Most interviewees welcomed the non-criminalisation approach of the NpSG but also noticed that, in practice, not much has changed for users. Nevertheless, the changes in legislation have had an impact on the market. For example, novel substances have emerged circumventing the new legislation. According to users, this has led some to reduce NPS use and others to adopt more hazardous consumption patterns. Overall, most respondents did not expect the introduction of the NpSG to bring any significant changes. Conclusions Although the idea of non-criminalisation inherent to the NpSG is appreciated and the generic approach has been well implemented in the law, thus covering a wide range of substances, the introduction of the law—perhaps for that very reason—has also had unintended and negative consequences, taking the cat-and-mouse game to the next level. To end the game, or at least to defuse the game situation, a combination of different strategies will be necessary, with legislation always playing a key role.

Background: Sensitivity to ionizing radiation differs between individuals, but there is a limited understanding of the biological mechanisms that account for these variations. One example of such mechanisms are the mutations in the ATM (mutated ataxia telangiectasia) gene, that cause the rare recessively inherited disease Ataxia telangiectasia (AT). Hallmark features include chromosomal instability and increased sensitivity to ionizing radiation (IR). Objectives: To deepen the molecular understanding of radiosensitivity and to identify potential new markers to predict it, human ATM-mutated and proficient cells were compared on a proteomic level. Design: In this study, we analyzed 3 cell lines from AT patients, with varying radiosensitivity, and 2 cell lines from healthy volunteers, 24 hours and 72 hours post-10 Gy irradiation Methods: We used label-free mass spectrometry to identify differences in signaling pathways after irradiation in normal and radiosensitive individuals. Cell viability was initially determined by water soluble tetrazolium (WST) assay and DNA damage response was analyzed with 53BP1 repair foci formation along with KRAB-associated protein 1 (KAP1) phosphorylation. Results: Proteomic analysis identified 4028 proteins, which were used in subsequent in silico pathway enrichment analysis to predict affected biological pathways post-IR. In AT cells, networks were heterogeneous at both time points with no common pathway identified. Mitotic cell cycle progress was the most prominent pathway altered after IR in cells from healthy donors. In particular, components of the chromosome passenger complex (INCENP and CDCA8) were significantly downregulated after 72 hours. This could also be verified at the mRNA level. Conclusion: Altogether, the most striking result was that proteins forming the chromosome passenger complex were downregulated after radiation exposure in healthy normosensitive control cells, but not in radiosensitive ATM-deficient cells. Thus, mitosis-associated proteins form an interesting compound to gain insights into the development and prediction of radiosensitivity.

ObjectiveHead and neck cancer (HNC) accounts for almost 890,000 new cases per year. Radiotherapy (RT) is used to treat the majority of these patients. A common side-effect of RT is the onset of oral mucositis, which decreases the quality of life and represents the major dose-limiting factor in RT. To understand the origin of oral mucositis, the biological mechanisms post-ionizing radiation (IR) need to be clarified. Such knowledge is valuable to develop new treatment targets for oral mucositis and markers for the early identification of “at-risk” patients.MethodsPrimary keratinocytes from healthy volunteers were biopsied, irradiated in vitro (0 and 6 Gy), and subjected to mass spectrometry-based analyses 96 h after irradiation. Web-based tools were used to predict triggered biological pathways. The results were validated in the OKF6 cell culture model. Immunoblotting and mRNA validation was performed and cytokines present in cell culture media post-IR were quantified.ResultsMass spectrometry-based proteomics identified 5879 proteins in primary keratinocytes and 4597 proteins in OKF6 cells. Amongst them, 212 proteins in primary keratinocytes and 169 proteins in OKF6 cells were differentially abundant 96 h after 6 Gy irradiation compared to sham-irradiated controls. In silico pathway enrichment analysis predicted interferon (IFN) response and DNA strand elongation pathways as mostly affected pathways in both cell systems. Immunoblot validations showed a decrease in minichromosome maintenance (MCM) complex proteins 2-7 and an increase in IFN-associated proteins STAT1 and ISG15. In line with affected IFN signalling, mRNA levels of IFNβ and interleukin 6 (IL-6) increased significantly following irradiation and also levels of secreted IL-1β, IL-6, IP-10, and ISG15 were elevated.ConclusionThis study has investigated biological mechanisms in keratinocytes post-in vitro ionizing radiation. A common radiation signature in keratinocytes was identified. The role of IFN response in keratinocytes along with increased levels of pro-inflammatory cytokines and proteins could hint towards a possible mechanism for oral mucositis.