Context Cushing's disease (CD) is a rare disorder with severe sequels and incompletely understood pathogenesis. The underlying corticotroph adenomas harbor frequently somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene. These mutations render USP8 hyperactive and prevent client proteins from degradation.Objective To investigate the impact of USP8 mutations on proteins deregulated in CD.Design 108 pituitary adenomas (75 corticotroph (58 USP8 wildtype (WT) and 17 USP8 mutated), 14 somatotroph and 19 non-functioning) were investigated by immunohistochemistry. All evaluated proteins (USP8, AVP receptor 1b & 2, CRH receptor, CREB, p27/kip1, cyclin E, HSP90, TR4, EGFR, HDAC2, GR, Cables1) were known to be deregulated in CD. Furthermore, AtT20 cells were transfected with USP8 to investigate the expression of possible downstream proteins by immunoblot.Results Whereas most of the investigated proteins were not differentially expressed, the cell cycle inhibitor p27 was significantly reduced in USP8 mutated corticotroph adenoma (H-score 2.0±1.0 vs 1.1±1.1 in wt adenomas; p=0.004). In contrast, the chaperone HSP90 was higher expressed (0.5±0.4 vs. 0.2±0.4; p=0.29) and the phosphorylation of the transcription factor CREB was increased in USP8 mutated adenomas (1.30.5±0.40.9 vs. 0.70.5±0.40.7; P=0.014).Accordingly, AtT20 cells transfected with USP8 P720R mutant had higher pCREB levels than WT transfected cells (1.3 ±0.14 vs 1 ±0.23; p=0.13). ConclusionsWe could demonstrate that USP8 mutations are associated with deregulation of p27/kip1, HSP90, and phosphorylated CREB. These findings suggest that these proteins are direct or indirect clients of USP8 and could therefore be potential targets for therapeutic approaches in patients with CD.

Background: Psoriasis is a chronic skin disease with a high mental burden. Well-known comorbidities include depression, anxiety, as well as alcohol and tobacco addiction, however, there is barely any evidence on other addictions. Objectives: The aim of this study was to estimate the prevalence of the six most common addictions among psoriasis patients in Germany and to determine associated clinical factors. Materials & Methods: Dermatologists working in four dermatological clinics and 32 practices across Germany recruited patients between September 2018 and November 2019. This cross-sectional study contained questionnaires on six addictions, depression, anxiety, and the Dermatology Life Quality Index (DLQI). In addition, scores for the Psoriasis Area and Severity Index (PASI) were obtained by physicians. Results: Overall, 502 patients (43.4% women; mean age: 49.7 ± 14.6 years) were included. Positive addictions were found in 30.3% for daily smoking, 8.6% for alcohol, 1.2% for gambling, 3.8% for internet use, 3.6% for food, and 6.0% for drugs. Younger age was associated with a higher probability of addiction except for alcohol dependency. The PASI was only significantly associated with smoking. Conclusion: Addictions seem to be common among psoriasis patients. Further research should include comprehensive data and control groups, furthermore, standardised screenings and early referrals could represent first steps to improve people-centred healthcare for patients with psoriasis.