A conditionally replicating adenovirus with strict selectivity in killing cells expressing epidermal growth factor receptor

AbstractVirotherapy of cancer using oncolytic adenoviruses has shown promise in both preclinical and clinical settings. One important challenge to reach the full therapeutic potential of oncolytic adenoviruses is accomplishing efficient infection of cancer cells and avoiding uptake by normal tissue through tropism modification. Towards this goal, we constructed and characterized an oncolytic adenovirus, carrying mutated capsid proteins to abolish the promiscuous adenovirus native tropism and encoding a bispecific adapter molecule to target the virus to the epidermal growth factor receptor (EGFR). The new virus displayed a highly selective targeting profile, with reduced infection of EGFR-negative cells and efficient killing of EGFR-positive cancer cells including primary EGFR-positive osteosarcoma cells that are refractory to infection by conventional adenoviruses. Our method to modify adenovirus tropism might thus be useful to design new oncolytic adenoviruses for more effective treatment of cancer

Extreme radio flares and associated X-ray variability from young stellar objects in the Orion Nebula Cluster

Jan Forbrich, et al, ‘Extreme Radio Flares and Associated XRay Variability from Young Stellar Objects in the Orion Nebula Cluster’, The Astrophysical Journal, Vol. 844 (2), July 2017. DOI: https://doi.org/10.3847/1538-4357/aa7aa4. © 2017 The American Astronomical Society. All Rights Reserved.Young stellar objects are known to exhibit strong radio variability on timescales of weeks to months, and a few reports have documented extreme radio flares with at least an order of magnitude change in flux density on timescales of hours to days. However, there have been few constraints on the occurrence rate of such radio flares or on the correlation with pre-main sequence X-ray flares, although such correlations are known for the Sun and nearby active stars. Here we report simultaneous deep VLA radio and Chandra X-ray observations of the Orion Nebula Cluster, targeting hundreds of sources to look for the occurrence rate of extreme radio variability and potential correlation with the most extreme X-ray variability. We identify 13 radio sources with extreme radio variability, with some showing an order of magnitude change in flux density in less than 30 minutes. All of these sources show X-ray emission and variability, but we find clear correlations with extreme radio flaring only on timescales <1 hr. Strong X-ray variability does not predict the extreme radio sources and vice versa. Radio flares thus provide us with a new perspective on high-energy processes in YSOs and the irradiation of their protoplanetary disks. Finally, our results highlight implications for interferometric imaging of sources violating the constant-sky assumption.Peer reviewedFinal Published versio

The CHIP-Family study to improve the psychosocial wellbeing of young children with congenital heart disease and their families: design of a randomized controlled trial

Background: Children with congenital heart disease (CHD) are at increased risk for behavioral, emotional, and cognitive problems. They often have reduced exercise capacity and participate less in sports, which is associated with a lower quality of life. Starting school may present more challenges for children with CHD and their families than for families with healthy children. Moreover, parents of children with CHD are at risk for psychosocial problems. Therefore, a family-centered psychosocial intervention for children with CHD when starting school is needed. Until now, the 'Congenital Heart Disease Intervention Program (CHIP) - School' is the only evidence-based intervention in this field. However, CHIP-School targeted parents only and resulted in non-significant, though positive, effects as to child psychosocial wellbeing. Hence, we expanded CHIP by adding a specific child module and including siblings, creating the CHIP-Family intervention. The CHIP-Family study aims to (1) test the effects of CHIP-Family on parental mental health and psychosocial wellbeing of CHD-children and to (2) identify baseline psychosocial and medical predictors for the e

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets

Multisurface interface model for analysis of masonry structures

The performance of an interface elastoplastic constitutive model for the analysis of unreinforced masonry structures is evaluated. Both masonry components are discretized aiming at a rational unit-joint model able to describe cracking, slip, and crushing of the material. The model is formulated in the spirit of softening plasticity for tension, shear and compression, with consistent treatment of the intersections defined by these modes. The numerical implementation is based on modern algorithmic concepts such as local and global Newton-Raphson methods, implicit integration of the rate equations and consistent tangent stiffness matrices. The parameters necessary to define the model are derived from microexperiments in units, joints, and small masonry samples. The model is used to analyze masonry shear-walls and is capable of predicting the experimental collapse load and behaviour accurately. Detailed comparisons between experimental and numerical results permit a clear understanding of the walls structural behavior, flow of internal forces and redistribution of stresses both in the pre- and post-peak regime.(undefined)info:eu-repo/semantics/publishedVersio

Multisurface interface model for analysis of masonry structures

The performance of an interface elastoplastic constitutive model for the analysis of unreinforced masonry structures is evaluated. Both masonry components are discretized aiming at a rational unit-joint model able to describe cracking, slip, and crushing of the material. The model is formulated in the spirit of softening plasticity for tension, shear and compression, with consistent treatment of the intersections defined by these modes. The numerical implementation is based on modern algorithmic concepts such as local and global Newton-Raphson methods, implicit integration of the rate equations and consistent tangent stiffness matrices. The parameters necessary to define the model are derived from microexperiments in units, joints, and small masonry samples. The model is used to analyze masonry shear-walls and is capable of predicting the experimental collapse load and behaviour accurately. Detailed comparisons between experimental and numerical results permit a clear understanding of the walls structural behavior, flow of internal forces and redistribution of stresses both in the pre- and post-peak regime.(undefined)info:eu-repo/semantics/publishedVersio

Non-proportional loading in sequentially linear solution procedures for quasi-brittle fracture: A comparison and perspective on the mechanism of stress redistribution

Sequentially linear solution procedures provide a robust alternative to their traditional incremental-iterative counterparts for finite element simulation of quasi-brittle materials. Sequentially linear analysis (SLA), one such non-incremental (total) approach, has been extended to non-proportional loading situations in the past few years. Although the process of damage propagation and localisation is often dynamic in nature, the simulation being quasi-static poses a fundamental problem. This article gives an overview of the different approaches to address non-proportional loading in SLA and other sequentially linear methods, and their corresponding redistribution methodologies to address the dynamic phenomenon. Furthermore, the inherent differences between two such methods: SLA (total) and the Force-Release method (incremental), and their suitability to structural continuum models involving non-proportional loading, are illustrated using real-life concrete and masonry experimental benchmarks tested up to and beyond brittle collapse. In each illustration, SLA is shown to enforce equilibrium during dynamic failure by load reduction, using the intermittent proportional loading, while allowing for active damage propagation resulting in a relaxed failure mechanism which manifests as snap-back(s). Contrarily, the Force-Release method is shown to describe the collapse through states of disequilibrium