Alkynes in covalent enzyme inhibitors: down the kinetic rabbit hole

Drug candidates with a covalent binding mode have gained interest since the approval of multiple covalent anticancer drugs, but were long avoided due to concerns regarding promiscuous reactivity with off-target proteins. In this dissertation, the scope and versatility of the newly discovered in situ thiol–alkyne reaction is evaluated: the nonactivated alkynes exhibit an unprecedented target reactivity with excellent thiol selectivity, thus potentially outperforming currently used cysteine-reactive warheads. Chapter 1 starts with the history of (ir)reversible covalent inhibition, the reactivity of (non)activated alkynes, and the serendipitous discovery of the thiol–alkyne reaction. Established technologies for direct detection of covalent protein–drug adducts are reviewed in Chapter 2, and in Chapter 3 a detailed guide for the evaluation of (ir)reversible covalent inhibitors to obtain relevant kinetic parameters is provided, accompanied by kinetic simulations and step-wise protocols for enzymatic activity assays. In Chapter 4, the nitrile warhead in reversible CatK inhibitor odanacatib (ODN) is replaced with alkyne warheads to investigate whether it an irreversible covalent adduct is formed with cysteine protease cathepsin K (CatK) despite having a small recognition element. In Chapter 5, we evaluate if nonactivated alkynes can target noncatalytic cysteine residues by replacing the irreversible covalent acrylamide warhead in EGFR/HER2 inhibitor neratinib by an alkyne warhead. In Chapter 6, the impact of substituents on the alkyne warhead is explored using a panel of ubiquitin-based ABPs bearing substituents on the propargylamide warhead. Finally, the most important findings are summarized in Chapter 7, and placed in the context of covalent drug discovery. This work was financially supported by NWO VICI (724.013.002) and NWO Oncodrugs (731.014.205).LUMC / Geneeskund

Radiographic features of liver allograft rejection

The radiographic features of 19 transplanted patients with failure of the liver allograft were evaluated. These features were: poor filling, stretching, attenuation of intrahepatic biliary ducts documented by T-tube cholangiogram, attenuation of branches of the hepatic artery seen on angiogram as well as a decrease of blood flow through the liver seen on angiogram and nuclear medicine dynamic scintigram. These findings were secondary to swelling of the transplanted liver and were not specific for rejection; they may also be present in hepatic infarction or infection

Correlates of self-reported exposure to advertising of tobacco products and electronic cigarettes across 28 European Union member states.

BACKGROUND: Despite advertising bans in most European Union (EU) member states, outlets for promotion of tobacco products and especially e-cigarettes still exist. This study aimed to assess the correlates of self-reported exposure to tobacco products and e-cigarettee advertising in the EU. METHODS: We analysed data from wave 82.4 of the Eurobarometer survey (November-December 2014), collected through interviews in 28 EU member states (n=27 801 aged ≥15 years) and data on bans of tobacco advertising extracted from the Tobacco Control Scale (TCS, 2013). We used multilevel logistic regression to assess sociodemographic correlates of self-reported exposure to any tobacco and e-cigarette advertisements. RESULTS: 40% and 41.5% of the respondents reported having seen any e-cigarette and tobacco product advertisement respectively within the past year. Current smokers, males, younger respondents, those with financial difficulties, people who had tried e-cigarettes and daily internet users were more likely to report having seen an e-cigarette and a tobacco product advertisement. Respondents in countries with more comprehensive advertising bans were less likely to self-report exposure to any tobacco advertisements (OR 0.87; 95% CI 0.79 to 0.96 for one-unit increase in TCS advertising score), but not e-cigarette advertisements (OR 1.08; 95% CI 0.95 to 1.22). CONCLUSION: Ten years after ratification of the Framework Convention for Tobacco Control, self-reported exposure to tobacco and e-cigarette advertising in the EU is higher in e-cigarette and tobacco users, as well as those with internet access. The implementation of the Tobacco Products Directive may result in significant changes in e-cigarette advertising, therefore improved monitoring of advertising exposure is required in the coming years

Alignment of the UMLS semantic network with BioTop: Methodology and assessment

Motivation: For many years, the Unified Medical Language System (UMLS) semantic network (SN) has been used as an upper-level semantic framework for the categorization of terms from terminological resources in biomedicine. BioTop has recently been developed as an upper-level ontology for the biomedical domain. In contrast to the SN, it is founded upon strict ontological principles, using OWL DL as a formal representation language, which has become standard in the semantic Web. In order to make logic-based reasoning available for the resources annotated or categorized with the SN, a mapping ontology was developed aligning the SN with BioTop. Methods: The theoretical foundations and the practical realization of the alignment are being described, with a focus on the design decisions taken, the problems encountered and the adaptations of BioTop that became necessary. For evaluation purposes, UMLS concept pairs obtained from MEDLINE abstracts by a named entity recognition system were tested for possible semantic relationships. Furthermore, all semantic-type combinations that occur in the UMLS Metathesaurus were checked for satisfiability. Results: The effort-intensive alignment process required major design changes and enhancements of BioTop and brought up s

The use of foundational ontologies in biomedical research

Background: The FAIR principles recommend the use of controlled vocabularies, such as ontologies, to define data and metadata concepts. Ontologies are currently modelled following different approaches, sometimes describing conflicting definitions of the same concepts, which can affect interoperability. To cope with that, prior literature suggests organising ontologies in levels, where domain specific (low-level) ontologies are grounded in domain independent high-level ontologies (i.e., foundational ontologies). In this level-based organisation, foundational ontologies work as translators of intended meaning, thus improving interoperability. Despite their considerable acceptance in biomedical research, there are very few studies testing foundational ontologies. This paper describes a systematic literature mapping that was conducted to understand how foundational ontologies are used in biomedical research and to find empirical evidence supporting their claimed (dis)advantages. Results: From a set of 79 selected papers, we identified that foundational ontologies are used for several purposes: ontology construction, repair, mapping, and ontology-based data analysis. Foundational ontologies are claimed to improve interoperability, enhance reasoning, speed up ontology development and facilitate maintainability. The complexity of using foundational ontologies is the most commonly cited downside. Despite being used for several purposes, there were hardly any experiments (1 paper) testing the claims for or against the use of foundational ontologies. In the subset of 49 papers that describe the development of an ontology, it was observed a low adherence to ontology construction (16 papers) and ontology evaluation formal methods (4 papers). Conclusion: Our findings have two main implications. First, the lack of empirical evidence about the use of foundational ontologies indicates a need for evaluating the use of such artefacts in biomedical research. Second, the low adherence to formal methods illustrates how the field could benefit from a more systematic approach when dealing with the development and evaluation of ontologies. The understanding of how foundational ontologies are used in the biomedical field can drive future research towards the improvement of ontologies and, consequently, data FAIRness. The adoption of formal methods can impact the quality and sustainability of ontologies, and reusing these methods from other fields is encouraged.</p

FAIR Practices in Africa

This article investigates expansion of the Internet of FAIR Data and Services (IFDS) to Africa, through the three GO FAIR pillars: GO CHANGE, GO BUILD and GO TRAIN. Introduction of the IFDS in Africa has a focus on digital health. Two examples of introducing FAIR are compared: a regional initiative for digital health by governments in the East Africa Community (EAC) and an initiative by a local health provider (Solidarmed) in collaboration with Great Zimbabwe University in Zimbabwe. The obstacles to introducing FAIR are identified as underrepresentation of data from Africa in IFDS at this moment, the lack of explicit recognition of situational context of research in FAIR at present and the lack of acceptability of FAIR as a foreign and European invention which affects acceptance. It is envisaged that FAIR has an important contribution to solve fragmentation in digital health in Africa, and that any obstacles concerning African participation, context relevance and acceptance of IFDS need to be removed. This will require involvement of African researchers and ICT-developers so that it is driven by local ownership. Assessment of ecological validity in FAIR principles would ensure that the context specificity of research is reflected in the FAIR principles. This will help enhance the acceptance of the FAIR Guidelines in Africa and will help strengthen digital health research and services. Computer Systems, Imagery and Medi

Does previous abdominal surgery alter the outcome of pediatric patients subjected to orthotopic liver transplantation?

The medical, anesthesia, and surgical records of 89 consecutive pediatric patients who underwent an orthotopic hepatic transplantation procedure at the University of Pittsburgh from February 1981 to May 1984 were reviewed to evaluate the effect of prior abdominal surgery upon the morbidity and mortality of orthotopic liver transplantation in children. Fifty-seven children (group 1) had had prior abdominal surgery, whereas 32 (group 2) had not. The group 1 subjects were younger (p < 0.001), had better prothrombin times (p < 0.01), and better platelet counts (p < 0.02) than did those in group 2. No difference in the duration of anesthesia or intraoperative use of fresh frozen plasma or platelets was evident between the two groups. However, group 1 patients were given more red blood cells intraoperatively than were the group 2 patients (p < 0.01). The group 1 patients had more total postoperative infections (p < 0.05), which was due solely to a greater number of abdominal infections (p < 0.05), but similar total hospital and intensive care unit stays as did the group 2 patients. When those in group 1 were divided into those having a previous Kasai procedure versus those who did not, no differences between the two groups were apparent except for age. Based upon these data, we conclude that prior abdominal surgery does not affect mortality, the duration of hospital or intensive care unit stay, plasma or platelet requirements, and total anesthesia time required for orthotopic liver transplantation, but does enhance the number of red blood cell transfusions and infections, particularly abdominal infections, in children undergoing this procedure. © 1986

Social norms for e-cigarettes and smoking: associations with initiation of e-cigarette use, intentions to quit smoking and quit attempts: findings from the EUREST-PLUS ITC Europe Surveys

Background: Social norms have received little attention in relation to electronic cigarettes (EC). The current study examine social norms for EC use and smoking tobacco, and their associations with (i) initiation of EC use, (ii) intention to quit smoking and (iii) attempts to quit smoking. Methods: Cross-sectional and longitudinal data analysis from Waves 1 and 2 of the ITC 6 European Country Survey and corresponding waves from England (the ITC Four Country Smoking and Vaping Survey). Current smokers at baseline, who heard of ECs and provided data at both waves were included (n = 3702). Complex samples logistic regression examined associations between the outcomes and descriptive (seeing EC use in public, close friends using ECs/smoking) and injunctive (public approves of ECs/smoking) norms, adjusting for country, demographics, EC use and heaviness of smoking. Results: In longitudinal analyses, seeing EC use in public at least some days was the only social norm that predicted initiation of EC use between waves (OR = 1.66, 95%CI = 1.08–2.56). In the cross-sectional analysis, having an intention to quit was associated with seeing EC use in public (OR = 1.37, 95%CI = 1.04–1.81) and reporting fewer than three close friends smoke (OR = 0.59, 95%CI = 0.44–0.80). There was no association between any social norm and making a quit attempt between waves. Conclusions: Initiation of EC use is predicted by seeing EC use in public, which was also associated with greater intention to quit smoking. Friends’ smoking was associated with lower intention to quit. These findings may allay concerns that increased visibility of ECs is renormalizing smoking amongst current smokers

Natural and cultural heritage in mountain landscapes: towards an integrated valuation

Mountain areas of Europe have been managed by humans for a long time, leading to a prevalence of semi-natural habitats in mountain landscapes today. These landscapes contain both natural and cultural heritage; however, natural and cultural heritage are rarely considered together when valuing landscapes and developing management plans in protected areas. Here we present a case study of seven protected areas in the mountains of Great Britain and Norway. We take a long-term perspective on landscape and land-use change and propose an integrated model of landscape valuation on the basis of combined natural and cultural heritage. Our model plots indicators of natural and cultural heritage along a gradient of land-use intensity, allowing simultaneous assessment and highlighting how valuation depends on what type of heritage is considered. We show that while contemporary land-use changes follow similar trajectories in Norway and Britain, different land-use histories mean that the loss of heritage differs between the regions. The model presented here thus allows for the consolidation of valuation based on both cultural and natural heritage in landscapes.publishedVersio