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Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis. ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18–80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6–24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed. Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI –0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (–0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI –0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and –0·03 (–0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group. Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug. Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases". [ABSTRACT FROM AUTHOR]

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 546% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells., Author(s): Helena Kilpinen [1]; Angela Goncalves [2]; Andreas Leha [2]; Vackar Afzal [3]; Kaur Alasoo [2]; Sofie Ashford [4]; Sendu Bala [2]; Dalila Bensaddek [3]; Francesco Paolo Casale [1]; Oliver [...]

Immunotherapies using checkpoint blockade and BRAF/MEK therapies have improved overall survival (OS) in patients with unresectable melanoma metastases. In this retrospective study, we aimed to demonstrate the resulting increase in melanoma‐specific survival (MSS) and OS after the excision of primary melanomas (≥1 mm thick) and sentinel lymph node (SN) biopsy (SNB). Using Kaplan‐Meier estimates and Cox models, we compared two consecutive cohorts. Patients in cohort 1 (N = 518) underwent SNB between 1998 and 2009, and patients in cohort 2 (N = 460) between 2010 and 2017, when checkpoint blockade and BRAF/(MEK) inhibition became available for the treatment of unresectable relapses. The median follow‐up times were 120 and 73 months, respectively. While recurrence‐free and distant metastasis‐free survival rates remained very similar, MSS and OS increased in favor of cohort 2. The estimated 5‐year OS rate of SN‐positive patients increased by 14.3% (78.5% vs 64.2%, logrank test: P =.005). The MSS benefit was significant even with low SN tumor burden (metastasis diameter < 1 mm). On multivariate analyses, the risk‐reduction in favor of cohort 2 was significant in the total population and in the SN‐negative and SN‐positive subgroups. In SN‐positive patients, besides the availability of modern therapies, SN metastasis diameter and ulceration were independent factors of MSS and OS. Treatment of unresectable melanoma recurrences with modern drug therapies results in significantly higher survival rates in a population with SNB. The survival benefit measured from primary melanoma affects both the SN‐positive and SN‐negative subpopulations. [ABSTRACT FROM AUTHOR]

The relationship of food comminution and individual age in Tupaia belangeri is investigated. It is hypothesized that with increasing age the performance of the molar dentition decreases due to progressive tooth wear. While this relationship is well-documented for herbivores, age-related test series are largely lacking for insectivorous mammals. 15 individuals of Tupaia belangeri were fed exclusively with mealworms, and their faeces were analyzed for the number and size of chitin particles. The exoskeleton of a mealworm is resistant to digestive fluids in the gastrointestinal tract, and the size of individual chitin particles indicates the effectiveness of mechanical comminution that occurs in the oral cavity during mastication. It is hypothesized that a more precise occlusion of the dentition results in smaller particle size. Although individuals of all ages (juvenile, adult, and senile) were able to effectively process mealworms with their dentition prior to digestion, a larger area of very large chitin particles (98% quantile of all particles in senile animals as compared to in the same quantile in adults) in the feces of senile animals was detected. Even though the particle size of indigestible material is irrelevant for the digestive process, these findings either document somatic senescence in the functionality of the teeth, or alternatively a change in chewing behaviour with age. [ABSTRACT FROM AUTHOR]