Multiscale modelling of tumour growth and therapy: the influence of vessel normalisation on chemotherapy

Following the poor clinical results of antiangiogenic drugs, particularly when applied in isolation, tumour biologists and clinicians are now turning to combinations of therapies in order to obtain better results. One of these involves vessel normalisation strategies. In this paper, we investigate the effects on tumour growth of combinations of antiangiogenic and standard cytotoxic drugs, taking into account vessel normalisation. An existing multiscale framework is extended to include new elements such as tumour-induced vessel dematuration. Detailed simulations of our multiscale framework allow us to suggest one possible mechanism for the observed vessel normalisation-induced improvement in the efficacy of cytotoxic drugs: vessel dematuration produces extensive regions occupied by quiescent (oxygen-starved) cells which the cytotoxic drug fails to kill. Vessel normalisation reduces the size of these regions, thereby allowing the chemotherapeutic agent to act on a greater number of cells

On-lattice agent-based simulation of populations of cells within the open-source chaste framework

Over the years, agent-based models have been developed that combine cell division and reinforced random walks of cells on a regular lattice, reaction-diffusion equations for nutrients and growth factors and ordinary differential equations (ODEs) for the subcellular networks regulating the cell cycle. When linked to a vascular layer, this multiple scale model framework has been applied to tumour growth and therapy. Here we report on the creation of an agent-based multiscale environment amalgamating the characteristics of these models within a Virtual Pysiological Human (VPH) Exemplar Project. This project enables re-use, integration, expansion and sharing of the model and relevant data. The agent-based and reactiondiffusion parts of the multiscale model have been implemented and are available for download as part of the latest public release of Chaste (“Cancer, Heart and Soft Tissue Environment”), (http://www.cs.ox.ac.uk/chaste/) version 3.1, part of the VPH Toolkit (http://toolkit.vph-noe.eu/). The environment functionalities are verified against the original models, in addition to extra validation of all aspects of the code. In this work, we present the details of the implementation of the agent-based environment, including the system description, the conceptual model, the development of the simulation model and the processes of verification and validation of the simulation results. We explore the potential use of the environment by presenting exemplar applications of the “what if” scenarios that can easily be studied in the environment. These examples relate to tumour growth, cellular competition for resources and tumour responses to hypoxia. We conclude our work by summarising the future steps for the expansion of the current system

Pathways for Nutrient Loss to Water; Slurry and Fertilizer Spreading

End of project reportThere are almost 150,000 farms in Ireland and these contribute substantial quantities of N and P to inland and coastal waters. Some of these nutrients are carried from wet soils by overland flow and by leaching from dry soils. Farm practice can reduce the loss from farms by judicious management of nutrients. Improvements are required to diminish export of nutrients without impairing operations on the farm. Literature regarding nutrient loss from agriculture was reviewed in this project and maps were prepared to predict best slurry spreading times around Ireland. Two further maps were prepared to show slurry storage requirement on farms

Nitrous Oxide Emissions

End of project reportNitrous oxide (N2O) is one of the three most important greenhouse gases (GHG). Nitrous oxide emissions currently account for approximately one third of GHG emissions from agriculture in Ireland. Emissions of N2O arise naturally from soil sources and from the application of nitrogen (N) in the form of N fertilizers and N in dung and urine deposition by grazing animals at pasture. Nitrous oxide emission measurements were conducted at three different scales. Firstly, a large-scale field experiment was undertaken to compare emission rates from a pasture receiving three different rates of N fertilizer application and to identify the effects of controlling variables over a two-year period. Variation in emission rates was large both within and between years. Two contrasting climatic years were identified. The cooler and wetter conditions in year 1 gave rise to considerably lower emission levels than the warmer and drier year 2. However, in both years, peak emissions were associated with fertilizer N applications coincident with rainfall events in the summer months. A small-plot study was conducted to identify the individual and combined effects of fertilizer, dung and urine applications to grassland. Treatment effects were however, difficult to obtain due to the overriding effects of environmental variables. Thirdly, through the use of a small-scale mini-lysimeter study, the diurnal nature of N2O emission rates was identified for two distinct periods during the year. The occurrence of a diurnal pattern has important implications for the identification of a measurement period during the day which is representative of the true daily flux. The research presented aims to identify the nature and magnitude of N2O emissions and the factors which affect emission rates from a grassland in Ireland. Further work is required to integrate the effects of different soil types and contrasting climatic regimes across soil types on N2O emissions.Environmental Protection Agenc

Modelling the response of vascular tumours to chemotherapy: A multiscale approach

An existing multiscale model is extended to study the response of a vascularised tumour to treatment with chemotherapeutic drugs which target proliferating cells. The underlying hybrid cellular automaton model couples tissue-level processes (e.g. blood flow, vascular adaptation, oxygen and drug transport) with cellular and subcellular phenomena (e.g. competition for space, progress through the cell cycle, natural cell death and drug-induced cell kill and the expression of angiogenic factors). New simulations suggest that, in the absence of therapy, vascular adaptation induced by angiogenic factors can stimulate spatio-temporal oscillations in the tumour's composition.\ud \ud Numerical simulations are presented and show that, depending on the choice of model parameters, when a drug which kills proliferating cells is continuously infused through the vasculature, three cases may arise: the tumour is eliminated by the drug; the tumour continues to expand into the normal tissue; or, the tumour undergoes spatio-temporal oscillations, with regions of high vascular and tumour cell density alternating with regions of low vascular and tumour cell density. The implications of these results and possible directions for future research are also discussed

The impact of cell crowding and active cell movement on vascular tumour growth

A multiscale model for vascular tumour growth is presented which includes systems of ordinary differential equations for the cell cycle and regulation of apoptosis in individual cells, coupled to partial differential equations for the spatio-temporal dynamics of nutrient and key signalling chemicals. Furthermore, these subcellular and tissue layers are incorporated into a cellular automaton framework for cancerous and normal tissue with an embedded vascular network. The model is the extension of previous work and includes novel features such as cell movement and contact inhibition. We presented a detailed simulation study of the effects of these additions on the invasive behaviour of tumour cells and the tumour's response to chemotherapy. In particular, we find that cell movement alone increases the rate of tumour growth and expansion, but that increasing the tumour cell carrying capacity leads to the formation of less invasive dense hypoxic tumours containing fewer tumour cells. However, when an increased carrying capacity is combined with significant tumour cell movement, the tumour grows and spreads more rapidly, accompanied by large spatio-temporal fluctuations in hypoxia, and hence in the number of quiescent cells. Since, in the model, hypoxic/quiescent cells produce VEGF which stimulates vascular adaptation, such fluctuations can dramatically affect drug delivery and the degree of success of chemotherapy

miR-375 gene dosage in pancreatic β-cells: implications for regulation of β-cell mass and biomarker development

MicroRNAs play a crucial role in the regulation of cell growth and differentiation. Mice with genetic deletion of miR-375 exhibit impaired glycemic control due to decreased β-cell and increased α-cell mass and function. The relative importance of these processes for the overall phenotype of miR-375KO mice is unknown. Here, we show that mice overexpressing miR-375 exhibit normal β-cell mass and function. Selective re-expression of miR-375 in β-cells of miR-375KO mice normalizes both, α- and β-cell phenotypes as well as glucose metabolism. Using this model, we also analyzed the contribution of β-cells to the total plasma miR-375 levels. Only a small proportion (≈1 %) of circulating miR-375 originates from β-cells. Furthermore, acute and profound β-cell destruction is sufficient to detect elevations of miR-375 levels in the blood. These findings are supported by higher miR-375 levels in the circulation of type 1 diabetes (T1D) subjects but not mature onset diabetes of the young (MODY) and type 2 diabetes (T2D) patients. Together, our data support an essential role for miR-375 in the maintenance of β-cell mass and provide in vivo evidence for release of miRNAs from pancreatic β-cells. The small contribution of β-cells to total plasma miR-375 levels make this miRNA an unlikely biomarker for β-cell function but suggests a utility for the detection of acute β-cell death for autoimmune diabetes

High-frequency high-voltage high-power DC-to-DC converters

The current and voltage waveshapes associated with the power transitor and the power diode in an example current-or-voltage step-up (buck-boost) converter were analyzed to highlight the problems and possible tradeoffs involved in the design of high voltage high power converters operating at switching frequencies in the range of 100 Khz. Although the fast switching speeds of currently available power diodes and transistors permit converter operation at high switching frequencies, the resulting time rates of changes of current coupled with parasitic inductances in series with the semiconductor switches, produce large repetitive voltage transients across the semiconductor switches, potentially far in excess of the device voltage ratings. The need is established for semiconductor switch protection circuitry to control the peak voltages appearing across the semiconductor switches, as well as to provide the waveshaping action require for a given semiconductor device. The possible tradeoffs, as well as the factors affecting the tradeoffs that must be considered in order to maximize the efficiency of the converters are enumerated

Analysis of transistor and snubber turn-off dynamics in high-frequency high-voltage high-power converters

Dc to dc converters which operate reliably and efficiently at switching frequencies high enough to effect substantial reductions in the size and weight of converter energy storage elements are studied. A two winding current or voltage stepup (buck boost) dc-to-dc converter power stage submodule designed to operate in the 2.5-kW range, with an input voltage range of 110 to 180 V dc, and an output voltage of 250 V dc is emphasized. In order to assess the limitations of present day component and circuit technologies, a design goal switching frequency of 10 kHz was maintained. The converter design requirements represent a unique combination of high frequency, high voltage, and high power operation. The turn off dynamics of the primary circuit power switching transistor and its associated turn off snubber circuitry are investigated

A dc model for power switching transistors suitable for computer-aided design and analysis

A model for bipolar junction power switching transistors whose parameters can be readily obtained by the circuit design engineer, and which can be conveniently incorporated into standard computer-based circuit analysis programs is presented. This formulation results from measurements which may be made with standard laboratory equipment. Measurement procedures, as well as a comparison between actual and computed results, are presented