No abstract

Proteasome inhibitors possess potent antitumor activity against a broad spectrum of human malignancies. However, the effects of these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effects of proteasome inhibitors on dendritic cells (DC), antigen‐presenting cells playing a key role in the initiation of immune responses. Exposure to the proteasome inhibitors bortezomib, MG132 or epoxomicin was found to promote apoptosis of human monocyte‐derived DC and to reduce the yield of viable DC when given to monocytes early during differentiation to DC. DC apoptosis via proteasome inhibition was accompanied by mitochondria disruption and subsequent activation of the caspase cascade. Up‐regulation and intracellular redistribution of Bcl‐2‐associated X protein (Bax), a pro‐apoptotic Bcl‐2 family protein, were observed in DC treated with these compounds and represent a suitable mechanism leading to activation of the intrinsic apoptotic pathway. Finally, active protein synthesis was found to represent an upstream prerequisite for DC apoptosis induced by proteasome inhibitors, since the translation inhibitor cycloheximide blocked all of the steps of the observed apoptotic response. In conclusion, induction of apoptosis in DC may represent a novel mechanism by which proteasome inhibitors affect the immune response at the antigen‐presenting cell level.

Background Attention-Deficit/ Hyperactivity Disorder (ADHD) is one of the most common childhood neurobehavioral conditions. Symptoms related to this disorder cause a significant impairment in school tasks and in the activities of children’s daily lives; an early diagnosis and appropriate treatment could almost certainly help improve their outcomes. The current study, part of the Models Of Child Health Appraised (MOCHA) project, aims to explore the age at which children experience the onset or diagnosis of ADHD in European countries. Methods A systematic review was done examining the studies reporting the age of onset/diagnosis (AO/AD) of ADHD in European countries (28 European Member States plus 2 European Economic Area countries), published between January 1, 2010 and December 31, 2019. Of the 2276 identified studies, 44 met all the predefined criteria and were included in the review. Results The lowest mean AO in the children diagnosed with ADHD alone was 2.25 years and the highest was 7.5 years. It was 15.3 years in the children with ADHD and disruptive behaviour disorder. The mean AD ranges between 6.2 and 18.1 years. Conclusions Our findings indicate that there is a wide variability in both the AO and AD of ADHD, and a too large distance between AO and AD. Since studies in the literature suggest that an early identification of ADHD symptoms may facilitate early referral and treatment, it would be important to understand the underlying reasons behind the wide variability found. Trial registration PROSPERO registration: CRD42017070631.