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Ryanodine receptor type I-related myopathies (RYR1-RMs) are a common group of childhood muscle diseases associated with severe disabilities and early mortality for which there are no available treatments. The goal of this study is to identify new therapeutic targets for RYR1-RMs. To accomplish this, we developed a discovery pipeline using nematode, zebrafish, and mammalian cell models. We first performed large-scale drug screens in C. elegans which uncovered 74 hits. Targeted testing in zebrafish yielded positive results for two p38 inhibitors. Using mouse myotubes, we found that either pharmacological inhibition or siRNA silencing of p38 impaired caffeine-induced Ca2+ release from wild type cells while promoting intracellular Ca2+ release in Ryr1 knockout cells. Lastly, we demonstrated that p38 inhibition blunts the aberrant temperature-dependent increase in resting Ca2+ in myotubes from an RYR1-RM mouse model. This unique platform for RYR1-RM therapy development is potentially applicable to a broad range of neuromuscular disorders.

Aim: To evaluate the progression of wound healing of standardized palatal defects in groups using three different collagen‐based wound dressings and a control group, in terms of wound closure, pain perception and descriptive histology. Materials and Methods: Twenty participants were enrolled in this experimental study, in whom four palatal defects were created. The defects (6 mm diameter, 3 mm depth) were randomly assigned to one of four treatment modalities: C (control), MG (Mucograft®), MD (mucoderm®) and FG (Fibro‐Gide®). Photographs were taken, and pain assessment was performed before and after treatment and at 5, 7, 9, 12, 14 and 16 days after surgery. All participants wore a palatal splint for a duration of 16 days. Results: All groups achieved complete wound closure at 14 days. The percentage of the remaining open wound on day 7 amounted to 49.3% (C; interquartile range [IQR]: 22.6), 70.1% (FG; IQR: 20.7), 56.8% (MD; IQR: 26.3) and 62.2% (MG; IQR: 34.4). Statistically significant differences were found between FG and C (p =.01) and between MD and FG (p =.04). None of the participants rated pain higher than 4 out of 10 during the entire study period. Conclusions: Collagen‐based wound dressings provide coverage of open defects, albeit without acceleration of wound closure or reduction of pain. FG (which is not intended for open oral wounds) showed slower wound closure compared to C and MD. [ABSTRACT FROM AUTHOR]

Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERB[alpha] as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV- ERB[alpha] and its paralog REV-ERB[beta] in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERB[alpha] plays the dominant role, as deletion of REV-ERB[beta] alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERB[alpha] protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERB[alpha] protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV- ERB[alpha] in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERB[alpha] protein couple the core clock to innate immunity., Introduction Protection of pulmonary mucosal surfaces from infection requires complex interplay between the airway epithelial cells and mono-nuclear phagocyte populations both resident within the lung (1). Airway macrophages function as [...]

Abstract Background Beyond survival of nowadays >80%, modern childhood cancer treatment strives to preserve long-term health and quality of life. However, the majority of today’s survivors suffer from short- and long-term adverse effects such as cardiovascular and pulmonary diseases, obesity, osteoporosis, fatigue, depression, and reduced physical fitness and quality of life. Regular exercise can play a major role to mitigate or prevent such late-effects. Despite this, there are no data on the effects of regular exercise in childhood cancer survivors from randomized controlled trials (RCTs). Primary outcome of the current RCT is therefore the effect of a 12-months exercise program on a composite cardiovascular disease risk score in childhood cancer survivors. Secondary outcomes are single cardiovascular disease risk factors, glycaemic control, bone health, body composition, physical fitness, physical activity, quality of life, mental health, fatigue and adverse events (safety). Methods A total of 150 childhood cancer survivors aged ≥16 years and diagnosed ≥5 years prior to the study are recruited from Swiss paediatric oncology clinics. Following the baseline assessments patients are randomized 1:1 into an intervention and control group. Thereafter, they are seen at month 3, 6 and 12 for follow-up assessments. The intervention group is asked to add ≥2.5 h of intense physical activity/week, including 30 min of strength building and 2 h of aerobic exercises. In addition, they are told to reduce screen time by 25%. Regular consulting by physiotherapists, individual web-based activity diaries, and pedometer devices are used as motivational tools for the intervention group. The control group is asked to keep their physical activity levels constant. Discussion The results of this study will show whether a partially supervised exercise intervention can improve cardiovascular disease risk factors, bone health, body composition, physical activity and fitness, fatigue, mental health and quality of life in childhood cancer survivors. If the program will be effective, all relevant information of the SURfit physical activity intervention will be made available to interested clinics that treat and follow-up childhood cancer patients to promote exercise in their patients. Trial registration Prospectively registered in clinicaltrials.gov [ NCT02730767 ], registration date: 10.12.2015.

Abstract Background The increasing prevalence of diabetes is leading to a rise of eye diseases, augmenting the risk of sight-threatening complications. The aim of this study was to evaluate prevalence, awareness and practices regarding eye diseases among patients with diabetes in the canton of Vaud, Switzerland. Methods A cohort of 323 patients with diabetes completed a self-administered questionnaire assessing prevalence, awareness and practices regarding eye diseases, besides health status and quality of care measures. Descriptive analyses followed by exploratory subgroup analyses and linear regressions were performed to investigate factors associated with awareness and practices. Results While diabetic retinopathy was reported by 40.9% of patients with type 1 diabetes and 9.8% of patients with type 2 diabetes, 35.8% and 12.6% of all participants reported cataract and glaucoma, respectively. Awareness that diabetes could damage the eyes was reported by almost all participants; the majority was also aware of the importance of glycemic control and regular eye examination in preventing eye diseases. In contrast, only 70.5% of participants underwent an eye examination by an ophthalmologist during the past year. Eye examination was associated with better patients’ awareness. Barriers mentioned by patients revealed a lack of knowledge about screening guidelines, in particular regarding the preventive nature of eye examinations. Conclusions Despite high levels of awareness regarding diabetic eye diseases, a significant proportion of patients with diabetes did not report annual eye examination. Both healthcare strategic efforts targeting the promotion of regular eye examination and initiatives aiming at improving knowledge of screening guidelines should be encouraged. Trial registration ClinicalTrials.gov on 9th July 2013, identifier NCT01902043 (retrospectively registered).

Abstract The human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes and linked to a variety of tumors. However, understanding the cellular role of VRKs and establishing their potential use as targets for therapeutic intervention has been limited by the lack of tool compounds that can specifically modulate the activity of these kinases in cells. Here we identified BI-D1870, a dihydropteridine inhibitor of RSK kinases, as a promising starting point for the development of chemical probes targeting the active VRKs. We solved co-crystal structures of both VRK1 and VRK2 bound to BI-D1870 and of VRK1 bound to two broad-spectrum inhibitors. These structures revealed that both VRKs can adopt a P-loop folded conformation, which is stabilized by different mechanisms on each protein. Based on these structures, we suggest modifications to the dihydropteridine scaffold that can be explored to produce potent and specific inhibitors towards VRK1 and VRK2.