3D-Cultured Vascular-Like Networks Enable Validation of Vascular Disruption Properties of Drugs In Vitro

Vascular-disrupting agents are an interesting class of anticancer compounds because of their combined mode of action in preventing new blood vessel formation and disruption of already existing vasculature in the immediate microenvironment of solid tumors. The validation of vascular disruption properties of these drugs in vitro is rarely addressed due to the lack of proper in vitro angiogenesis models comprising mature and long-lived vascular-like networks. We herein report an indirect coculture model of human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts (HDFs) to form three-dimensional profuse vascular-like networks. HUVECs embedded and sandwiched in the collagen scaffold were cocultured with HDFs located outside the scaffold. The indirect coculture approach with the vascular endothelial growth factor (VEGF) producing HDFs triggered the formation of progressively maturing lumenized vascular-like networks of endothelial cells within less than 7 days, which have proven to be viably maintained in culture beyond day 21. Molecular weight-dependent Texas red-dextran permeability studies indicated high vascular barrier function of the generated networks. Their longevity allowed us to study the dose-dependent response upon treatment with the three known antiangiogenic and/or vascular disrupting agents brivanib, combretastatin A4 phosphate (CA4P), and 6´-sialylgalactose (SG) via semi-quantitative brightfield and qualitative confocal laser scanning microscopic (CLSM) image analysis. Compared to the reported data on in vivo efficacy of these drugs in terms of antiangiogenic and vascular disrupting effects, we observed similar trends with our 3D model, which are not reflected in conventional in vitro angiogenesis assays. High-vascular disruption under continuous treatment of the matured vascular-like network was observed at concentrations ≥3.5 ng·ml−1 for CA4P and ≥300 nM for brivanib. In contrast, SG failed to induce any significant vascular disruption in vitro. This advanced model of a 3D vascular-like network allows for testing single and combinational antiangiogenic and vascular disrupting effects with optimized dosing and may thus bridge the gap between the in vitro and in vivo experiments in validating hits from high-throughput screening. Moreover, the physiological 3D environment mimicking in vitro assay is not only highly relevant to in vivo studies linked to cancer but also to the field of tissue regeneration. Copyright © 2022 Yavvari, Laporte, Elomaa, Schraufstetter, Pacharzina, Daberkow, Hoppensack and Weinhart

Memory Efficient Adaptive Mesh Generation and Implementation of Multigrid Algorithms Using Sierpinski Curves

We will present both underlying ideas and concepts, and first results and experiencesgained within an ongoing project to implement a highly memory efficient version of thegrid generator amatos [BRH+05]. Our focus will be on algorithmic and implemen-tational approaches to realize multigrid algorithms on recursively structured adaptivetriangular grids. The key concept is to use a cell-oriented processing of the grids andspace-filling-curve techniques to get rid of the need to store neighbourship relations onadaptive grids

Memory efficient adaptive mesh generation and implementation of multigrid algorithms using Sierpinski curves

We will present an approach to numerical simulation on recursively structured adaptive discretisation grids. The respective grid generation process is based on recursive bisection of triangles along marked edges. The resulting refinement tree is sequentialised according to a Sierpinski space-filling curve, which leads to both minimal memory requirements and inherently cache-efficient processing schemes. The locality properties induced by the space-filling curve are even retained throughout adaptive refinement of the grid. We demonstrate the efficiency of the approach by implementing a multilevel-preconditioned conjugate gradient solver for a simple, yet adaptive, test problem: solving Poisson's equation on a re-entrant corner problem

3D-Cultured Vascular-Like Networks Enable Validation of Vascular Disruption Properties of Drugs In Vitro

Vascular-disrupting agents are an interesting class of anticancer compounds because of their combined mode of action in preventing new blood vessel formation and disruption of already existing vasculature in the immediate microenvironment of solid tumors. The validation of vascular disruption properties of these drugs in vitro is rarely addressed due to the lack of proper in vitro angiogenesis models comprising mature and long-lived vascular-like networks. We herein report an indirect coculture model of human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts (HDFs) to form three-dimensional profuse vascular-like networks. HUVECs embedded and sandwiched in the collagen scaffold were cocultured with HDFs located outside the scaffold. The indirect coculture approach with the vascular endothelial growth factor (VEGF) producing HDFs triggered the formation of progressively maturing lumenized vascular-like networks of endothelial cells within less than 7 days, which have proven to be viably maintained in culture beyond day 21. Molecular weight-dependent Texas red-dextran permeability studies indicated high vascular barrier function of the generated networks. Their longevity allowed us to study the dose-dependent response upon treatment with the three known antiangiogenic and/or vascular disrupting agents brivanib, combretastatin A4 phosphate (CA4P), and 6´-sialylgalactose (SG) via semi-quantitative brightfield and qualitative confocal laser scanning microscopic (CLSM) image analysis. Compared to the reported data on in vivo efficacy of these drugs in terms of antiangiogenic and vascular disrupting effects, we observed similar trends with our 3D model, which are not reflected in conventional in vitro angiogenesis assays. High-vascular disruption under continuous treatment of the matured vascular-like network was observed at concentrations ≥3.5 ng·ml−1 for CA4P and ≥300 nM for brivanib. In contrast, SG failed to induce any significant vascular disruption in vitro. This advanced model of a 3D vascular-like network allows for testing single and combinational antiangiogenic and vascular disrupting effects with optimized dosing and may thus bridge the gap between the in vitro and in vivo experiments in validating hits from high-throughput screening. Moreover, the physiological 3D environment mimicking in vitro assay is not only highly relevant to in vivo studies linked to cancer but also to the field of tissue regeneration

Option pricing with a direct adaptive sparse grid approach

AbstractWe present an adaptive sparse grid algorithm for the solution of the Black–Scholes equation for option pricing, using the finite element method. Sparse grids enable us to deal with higher-dimensional problems better than full grids. In contrast to common approaches that are based on the combination technique, which combines different solutions on anisotropic coarse full grids, the direct sparse grid approach allows for local adaptive refinement. When dealing with non-smooth payoff functions, this reduces the computational effort significantly. In this paper, we introduce the spatially adaptive discretization of the Black–Scholes equation with sparse grids and describe the algorithmic structure of the numerical solver. We present several strategies for adaptive refinement, evaluate them for different dimensionalities, and demonstrate their performance showing numerical results

An octree-based implementation of directional operators in a 3D Spatial Query Language for Building Information Models

In a current research project, our group is developing a 3D Spatial Query Language that enables the spatial analysis of Building Information Models and the extraction of partial models that fulfil certain spatial constraints. Among other features, the spatial language includes directional operators, i.e. operators that reflect the directional relationships between 3D spatial objects, such as northOf, southOf, eastOf, westOf, above and below. The paper presents in-depth definitions of the semantics of these operators by means of point set theory. It further gives an overview on the possible implementation of directional operators using a new space-partitioning data structure called slot-tree, which is derived from the objects’ octree representation. The slot-tree allows for the application of recursive algorithms that successively increase the discrete resolution of the spatial objects employed and thereby offer the possibility for a trade-off between computational effort and required accuracy

An

iterative, octree-based algorithm for distance computation between polyhedra with complex surfaces