Metoclopramide treatment blocks CD93-signaling-mediated self-renewal of chronic myeloid leukemia stem cells.

Self-renewal is a key characteristic of leukemia stem cells (LSCs) responsible for the development and maintenance of leukemia. In this study, we identify CD93 as an important regulator of self-renewal and proliferation of murine and human LSCs, but not hematopoietic stem cells (HSCs). The intracellular domain of CD93 promotes gene transcription via the transcriptional regulator SCY1-like pseudokinase 1 independently of ligation of the extracellular domain. In a drug library screen, we identify the anti-emetic agent metoclopramide as an efficient blocker of CD93 signaling. Metoclopramide treatment reduces murine and human LSCs in vitro and prolongs survival of chronic myeloid leukemia (CML) mice through downregulation of pathways related to stemness and proliferation in LSCs. Overall, these results identify CD93 signaling as an LSC-specific regulator of self-renewal and proliferation and a targetable pathway to eliminate LSCs in CML.

25-Hydroxyvitamin-D3 serum modulation after use of sunbeds compliant with European Union standards: A randomized open observational controlled trial.

BACKGROUND: Regular use of sunbed exposure has been reported to increase 25-hydroxyvitamin-D3 [25(OH)D] serum levels. However, the influence of sunbeds compliant with the recent European Union standard EN-60335-2-27 on 25(OH)D serum levels is unknown. OBJECTIVE: We investigated the impact of standard sunbed use compliant with the European Union standard on 25(OH)D serum modulation and well-being. METHODS: In a randomized controlled study, 25(OH)D serum levels were measured at enrollment, after 1 week, and after completion of the 12-week period of sunbed use with twice weekly exposure and compared with the control group without any sunbed exposure. RESULTS: In the sunbed intervention group (N = 31), a 27% increase of mean 25(OH)D levels was noted 1 week after starting sunbed use (P < .01). However, after 12 weeks, mean 25(OH)D levels had declined and were no longer different from baseline (P = .06). After 12 weeks, 25(OH)D levels did not differ between the intervention and control group (P = .36). Also the 5-item World Health Organization Well-Being Index score did not differ between the sunbed and control groups (P = .19). LIMITATIONS: For ethical reasons recruitment was limited to persons actively seeking sunbed exposure. CONCLUSIONS: Standard use of sunbeds compliant with the European Union standard induced a transient increase of 25(OH)D levels, whereas no change in well-being was observed.