AimsGenetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce.Methods and resultsRespirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration.ConclusionMitochondrial dysfunction is explained by cardiomyocyte architecture disruption and is linked to septal hypertrophy in genotype-negative HCM. Despite severe myocardial remodelling mitochondria were responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in HCM. Mitochondria-targeting therapy may particularly benefit genotype-negative patients with HCM, given the tight link between mitochondrial impairment and septal thickening in this subpopulation.
This historical review uncovers the institutionalisation and diffusion of the SWOTanalysis by assessing academic literature, seminar materials, proprietary research reports and interviews with experts from the virus theory perspective. We suggest that reviews of the SWOT analysis using the management fashion theory perspective are inadequate in explaining the diffusion and rejection of ideas born in practice. The virus theory perspective starts at an organizational level and reveals that predominantly practitioners were instrumental in spreading the ideas like participatory planning and distinguishing between short term and long range planning in order to resolve the planning paradox in provisional planning. Due to mutations in practice by consulting firms, the 2x2 matrix of SWOT became a cognitive artefact on its own. Theoretical roots of the original SWOT analysis stem from psychology and behavioural sciences.It is questionable if current strategy textbooks reflect these theoretical backgrounds.
Every year in the Netherlands around 10.000 people are diagnosed with non-small cell lung cancer, commonly at advanced stages. In 1 to 2% of patients, a chromosomal translocation of the ROS1 gene drives oncogenesis. Since a few years, ROS1+ cancer can be treated effectively by targeted therapy with the tyrosine kinase inhibitor (TKI) crizotinib, which binds to the ROS1 protein, impairs the kinase activity and thereby inhibits tumor growth. Despite the successful treatment with crizotinib, most patients eventually show disease progression due to development of resistance. The available TKI-drugs for ROS1+ lung cancer make it possible to sequentially change medication as the disease progresses, but this is largely a ‘trial and error’ approach. Patients and their doctors ask for better prediction which TKI will work best after resistance occurs. The ROS1 patient foundation ‘Stichting Merels Wereld’ raises awareness and brings researchers together to close the knowledge gap on ROS1-driven oncogenesis and increase the options for treatment. As ROS1+ lung cancer is rare, research into resistance mechanisms and the availability of cell line models are limited. Medical Life Sciences & Diagnostics can help to improve treatment by developing new models which mimic the situation in resistant tumor cells. In the current proposal we will develop novel TKI-resistant cell lines that allow screening for improved personalized treatment with TKIs. Knowledge of specific mutations occurring after resistance will help to predict more accurately what the next step in patient treatment could be. This project is part of a long-term collaboration between the ROS1 patient foundation ‘Stichting Merels Wereld’, the departments of Pulmonary Oncology and Pathology of the UMCG and the Institute for Life Science & Technology of the Hanzehogeschool. The company Vivomicx will join our consortium, adding expertise on drug screening in complex cell systems.
Logistics represents around 10-11% of global CO2 emissions, around 75% of which come from road freight transport. ‘The European Green Deal’ is calling for drastic CO2 reduction in this sector. This requires advanced and very expensive technological innovations; i.e. re-design of vehicle units, hybridization of powertrains and automatic vehicle technology. Another promising way to reach these environmental ambitions, without excessive technological investments, is the deployment of SUPER ECO COMBI’s (SEC). SEC is the umbrella name for multiple permutations of 32 meter, 70 tons, road-train combinations that can carry the payload-equivalent of 2 normal tractor-semitrailer combinations and even 3 rigid trucks. To fully deploy a SEC into the transport system the compliance with the existing infrastructure network and safety needs to be guaranteed; i.e. to deploy a specific SEC we should be able to determine which SEC-permutation is most optimal on specific routes with respect to regulations (a.o. damage to the pavement/bridges), the dimensions of specific infrastructures (roundabouts, slopes) and safety. The complexity of a SEC compared to a regular truck (double articulation, length) means that traditional optimisation methods are not applicable. The aim of this project is therefore to develop a first methodology enabling the deployment of the optimal SEC permutation. This will help transport companies (KIEM: Ewals) and trailer manufactures (KIEM: Emons) to invest in the most suitable designs for future SEC use. Additionally the methodology will help governments to be able to admit specific SEC’s to specific routes. The knowledge gained in this project will be combined with the knowledge of the broader project ENVELOPE (NWA-IDG). This will be the start of broader research into an overall methodology of deploying optimal vehicle combinations and a new regulatory framework. The knowledge will be used in master courses on vehicle dynamics.
