CT Coronary Angiography to Detect Coronary Artery Disease: low dose radiation in high risk individuals

Coronary atherosclerosis is a frequently encountered chronic disease of the arteries of the heart with very high mortality rates worldwide. It occurs predominantly in individuals with acquired risk factors and a genetic predisposition. Progression of atherosclerosis develops from early asymptomatic stages to advanced stages that may cause cardiac symptoms already starting in the 2nd or 3rd decades in life. In the last one and a half decades Computed Tomography Coronary Angiography (CTCA) has emerged as modality for imaging of the coronary arteries of the heart. A non-enhanced scan shows the total amount of coronary calcium; while a contrast-enhanced CT coronary angiography permits evaluation of narrowing of the vessel lumen as well as detection of both calcified and non-calcified atherosclerotic plaques. Radiation exposure for the patient is inherent to CT technique and the related risk of cancer is of major concern. The average radiation dose of a CTCA has decreased over the years from 20-30 mSv to <3 mSv which is below the dose of nuclear cardiac imaging techniques or conventional invasive coronary angiography Several studies acknowledge the high diagnostic accuracy of CTCA compared to the gold standard invasive coronary angiography. CTCA reliably detects, and especially rules out significant stenosis in stable patients with a low or intermediate pre-test probability of having coronary artery disease (CAD). Besides these direct diagnostic purposes, CTCA has incremental prognostic value over traditional risk factors (i.e. hypertension, diabetes mellitus, smoking, cholesterol blood values etc.) to predict adverse cardiac events in symptomatic patients. Nevertheless clinical guidelines only recommend CTCA as first choice diagnostic modality in a limited number of specified symptomatic patients. Further lowering of radiation dose and improvement of the diagnostic performance of CTCA will probably expand the number of appropriate indications for CTCA. This might even include screening of high risk individuals when supported by extended research in the future

Into the Intracellular Logistics of Cross-Presentation

The induction of cytotoxic CD8+ T cell responses requires the presentation of antigenic peptides by MHC class I molecules (MHC I). MHC I usually present peptides derived from endogenous proteins. However, some subtypes of dendritic cells have developed the ability to efficiently present peptides derived from exogenous antigens on MHC I via a process called cross-presentation. Cross-presentation is intimately linked to the induction of anti-viral, -bacterial, and -tumor cytotoxic T cell (CTL) responses, as well as a wide variety of CTL-mediated diseases and transplant rejections. The molecular and cellular mechanisms underlying cross-presentation have been studied intensively since its original description, yet understanding of this process is incomplete and on the forefront of immunological research. Numerous pathways and models, some of them conflicting, have been described so far. Here, we review the various pathways reported as involved in cross-presentation, highlighting the complexity of this process. We also discuss in detail the different intracellular steps required, from antigen capture and routing, to processing, and finally peptide loading, emphasizing the need for a better understanding of the cell biology of this phenomenon

A Role for Estrogen Receptor Phosphorylation in the Resistance to Tamoxifen

About two thirds of all human breast cancer cases are estrogen receptor positive. The drug of first choice for these patients is tamoxifen. However, about half of the recurrences after removal of the primary tumor are or become resistant to this drug. While many mechanisms have been identified for tamoxifen resistance in the lab, at present only a few have been translated to the clinic. This paper highlights the role in tamoxifen resistance of phosphorylation by different kinases on different sites of the estrogen receptor. We will discuss the molecular pathways and kinases that are involved in phosphorylation of ERα and how these affect tamoxifen resistance. Finally, we will elaborate on the clinical translation of these observations and the possibility to predict tamoxifen responses in patient tumor samples before treatment onset. The findings made originally on the bench may translate into a better and personalized treatment of breast cancer patients using an old and safe anticancer drug: tamoxifen

Modeling approaches for atmospheric ion-dipole collisions : all-atom trajectory simulations and central field methods

Ion-dipole collisions can facilitate the formation of atmospheric aerosol particles and play an important role in their detection in chemical ionization mass spectrometers. Conventionally, analytical models, or simple parametrizations, have been used to calculate the rate coefficients of ion-dipole collisions in the gas phase. Such models, however, neglect the atomistic structure and charge distribution of the collision partners. To determine the accuracy and applicability of these approaches under atmospheric conditions, we calculated collision cross sections and rate coefficients from all-atom molecular dynamics collision trajectories, sampling the relevant range of impact parameters and relative velocities, and from a central field model using an effective attractive interaction fitted to the long-range potential of mean force between the collision partners. We considered collisions between various atmospherically relevant molecular ions and dipoles and charged and neutral dipolar clusters. Based on the good agreement between collision cross sections and rate coefficients obtained from molecular dynamics trajectories and a generalized central field model, we conclude that the effective interactions between the collision partners are isotropic to a high degree, and the model is able to capture the relevant physicochemical properties of the systems. In addition, when the potential of mean force is recalculated at the respective temperatures, the central field model exhibits the correct temperature dependence of the collision process. The classical parametrization by Su and Chesnavich (1982), which combines a central field model with simplified trajectory simulations, is able to predict the collision rate coefficients and their temperature dependence quite well for molecular systems, but the agreement worsens for systems containing clusters. Based on our results, we propose the combination of potential of mean force calculation and a central field model as a viable and elegant alternative to the brute force sampling of individual collision trajectories over a large range of impact parameters and relative velocities.Peer reviewe

Ubiquitin-based probes prepared by total synthesis to profile the activity of deubiquitinating enzymes

Epitope-tagged active-site-directed probes are widely used to visualize the activity of deubiquitinases (DUBs) in cell extracts, to investigate the specificity and potency of small-molecule DUB inhibitors, and to isolate and identify DUBs by mass spectrometry. With DUBs arising as novel potential drug targets, probes are required that can be produced in sufficient amounts and to meet the specific needs of a given experiment. The established method for the generation of DUB probes makes use of labor-intensive intein-based methods that have inherent limitations concerning the incorporation of unnatural amino acids and the amount of material that can be obtained. Here, we describe the total chemical synthesis of active-site-directed probes and their application to activity-based profiling and identification of functional DUBs. This synthetic methodology allowed the easy incorporation of desired tags for specific applications, for example, fluorescent reporters, handles for immunoprecipitation or affinity pull-down, and cleavable linkers. Additionally, the synthetic method can be scaled up to provide significant amounts of probe. Fluorescent ubiquitin probes allowed faster, in-gel detection of active DUBs, as compared to (immuno)blotting procedures. A biotinylated probe holding a photocleavable linker enabled the affinity pull-down and subsequent mild, photorelease of DUBs. Also, DUB activity levels were monitored in response to overexpression or knockdown, and to inhibition by small molecules. Furthermore, fluorescent probes revealed differential DUB activity profiles in a panel of lung and prostate cancer cells

Leren van toezicht

Toezicht staat onder immer toenemende belangstelling, of het nu gaat om het toezicht op financiële instellingen, de veiligheid van het vliegverkeer of de gezondheidszorg. De oorzaken hiervan zijn divers maar kunnen deels gevonden worden in het terugtreden van de overheid als uitvoerder van publieke diensten. Om controle te kunnen houden op die diensten zijn de afgelopen decennia grote toezichthoudende organen opgericht, die inmiddels een flink deel van de economie beslaan; volgens sommige berekeningen werken momenteel ongeveer een miljoen mensen in de ‘toezichtsindustrie’ (van Waarden 2006). Daarnaast dringt steeds meer het besef door dat we leven in een ‘risicomaatschappij’ (Beck 1992) die, hoe paradoxaal ook, aanleiding heeft gegeven tot een ‘veiligheidsutopie’ (Boutelier 2002). Risico’s worden steeds minder geaccepteerd en overheden en toezichthouders worden daar in toenemende mate op aangesproken. Deze trend brengt met zich mee dat onderzoek naar het functioneren van toezichthouders sterk in maatschappelijk belang heeft gewonnen. De afgelopen jaren is dan ook internationaal te constateren dat dit onderzoek een hoge vlucht heeft genomen. Ook de inspecties zelf hebben inmiddels onderzoeksprogramma’s opgezet. Dit geldt ook voor de Inspectie voor de Gezondheidszorg (IGZ). Het voorliggende rapport is een verslag van onderzoek naar de effectiviteit van een van de belangrijke toezichtsinstrumenten van de IGZ, het zogeheten Thematisch Toezicht. Middels casestudie onderzoek beoogt dit rapport de vraag te beantwoorden op welke manier het thematisch toezicht effectief kan zijn en voor welk type risicoproblemen deze vorm van toezicht het meest geschikt is. Hiermee probeert het rapport een zowel conceptuele als empirische bijdrage te leveren aan de discussie over het toezicht in algemene zin, en in het bijzonder over het toezicht op en in de gezondheidszorg