Genetic and environmental determinants of O6-methylguanine DNA-methyltransferase (MGMT) gene methylation: a 10-year longitudinal study of Danish twins

Background: Epigenetic inactivation of O6-methylguanine DNA-methyltransferase (MGMT) is associated with increased sensitivity to alkylating chemotherapeutic agents in glioblastoma patients. The genetic background underlying MGMT gene methylation may explain individual differences in treatment response and provide a clue to a personalized treatment strategy. Making use of the longitudinal twin design, we aimed, for the first time, to estimate the genetic contributions to MGMT methylation in a Danish twin cohort. Methods: DNA-methylation from whole blood (18 monozygotic (MZ) and 25 dizygotic (DZ) twin pairs) repeated 10 years apart from the Longitudinal Study of Aging Danish Twins (LSADT) were used to search for genetic and environmental contributions to DNA-methylation at 170 CpG sites of across the MGMT gene. Both univariate and bivariate twin models were applied. The intraclass correlations, performed on cross-sectional data (246 MZ twin pairs) from an independent study population, the Middle-Aged Danish Twins (MADT), were used to assess the genetic influence at each CpG site of MGMT for replication. Results: Univariate twin model revealed twelve CpG sites showing significantly high heritability at intake (wave 1, h2 > 0.43), and seven CpG sites with significant heritability estimates at end of follow-up (wave 2, h2 > 0.5). There were six significant CpG sites, located at the gene body region, that overlapped among the two waves (h2 > 0.5), of which five remained significant in the bivariate twin model, which was applied to both waves. Within MZ pair correlation in these six CpGs from MADT demarks top level of genetic influence. There were 11 CpGs constantly have substantial common environmental component over the 10 years. Conclusions: We have identified 6 CpG sites linked to the MGMT gene with strong and persistent genetic control based on their DNA methylation levels. The genetic basis of MGMT gene methylation could help to explain individual differences in glioblastoma treatment response and most importantly, provide references for mapping the methylation Quantitative Trait Loci (meQTL) underlying the genetic regulation.Peer reviewe

Beyond the security paradox:Ten criteria for a socially informed security policy

This article is based on a research that has been funded by the EU project “SurPriSe: Surveillance, Privacy and Security: A large scale participatory assessment of criteria and factors determining acceptability and acceptance of security technologies in Europe”, which received funding from the FP7 program, under the grant number: 285492.This article investigates the normative and procedural criteria adopted by European citizens to assess the acceptability of surveillance-oriented security technologies. It draws on qualitative data gathered at 12 citizen summits in nine European countries. The analysis identifies 10 criteria, generated by citizens themselves, for a socially informed security policy. These criteria not only reveal the conditions, purposes and operation rules that would make current European security policies and technologies more consistent with citizens’ priorities. They also cast light on an interesting paradox: although people feel safe in their daily lives, they believe security could, and should, be improved.PostprintPeer reviewe

Anticoagulants and the Propagation Phase of Thrombin Generation

The view that clot time-based assays do not provide a sufficient assessment of an individual's hemostatic competence, especially in the context of anticoagulant therapy, has provoked a search for new metrics, with significant focus directed at techniques that define the propagation phase of thrombin generation. Here we use our deterministic mathematical model of tissue-factor initiated thrombin generation in combination with reconstructions using purified protein components to characterize how the interplay between anticoagulant mechanisms and variable composition of the coagulation proteome result in differential regulation of the propagation phase of thrombin generation. Thrombin parameters were extracted from computationally derived thrombin generation profiles generated using coagulation proteome factor data from warfarin-treated individuals (N = 54) and matching groups of control individuals (N = 37). A computational clot time prolongation value (cINR) was devised that correlated with their actual International Normalized Ratio (INR) values, with differences between individual INR and cINR values shown to derive from the insensitivity of the INR to tissue factor pathway inhibitor (TFPI). The analysis suggests that normal range variation in TFPI levels could be an important contributor to the failure of the INR to adequately reflect the anticoagulated state in some individuals. Warfarin-induced changes in thrombin propagation phase parameters were then compared to those induced by unfractionated heparin, fondaparinux, rivaroxaban, and a reversible thrombin inhibitor. Anticoagulants were assessed at concentrations yielding equivalent cINR values, with each anticoagulant evaluated using 32 unique coagulation proteome compositions. The analyses showed that no anticoagulant recapitulated all features of warfarin propagation phase dynamics; differences in propagation phase effects suggest that anticoagulants that selectively target fXa or thrombin may provoke fewer bleeding episodes. More generally, the study shows that computational modeling of the response of core elements of the coagulation proteome to a physiologically relevant tissue factor stimulus may improve the monitoring of a broad range of anticoagulants

Global Citizen Deliberation on Genome Editing

status: publishe

Antithrombin-S195A factor Xa-heparin structure reveals the allosteric mechanism of antithrombin activation.

Regulation of blood coagulation is critical for maintaining blood flow, while preventing excessive bleeding or thrombosis. One of the principal regulatory mechanisms involves heparin activation of the serpin antithrombin (AT). Inhibition of several coagulation proteases is accelerated by up to 10 000-fold by heparin, either through bridging AT and the protease or by inducing allosteric changes in the properties of AT. The anticoagulant effect of short heparin chains, including the minimal AT-specific pentasaccharide, is mediated exclusively through the allosteric activation of AT towards efficient inhibition of coagulation factors (f) IXa and Xa. Here we present the crystallographic structure of the recognition (Michaelis) complex between heparin-activated AT and S195A fXa, revealing the extensive exosite contacts that confer specificity. The heparin-induced conformational change in AT is required to allow simultaneous contacts within the active site and two distinct exosites of fXa (36-loop and the autolysis loop). This structure explains the molecular basis of protease recognition by AT, and the mechanism of action of the important therapeutic low-molecular-weight heparins