A design principle for vascular beds: the effects of complex blood rheology

We propose a design principle that extends Murray's original optimization principle for vascular architecture to account for complex blood rheology. Minimization of an energy dissipation function enables us to determine how rheology affects the morphology of simple branching networks. The behavior of various physical quantities associated with the networks, such as the wall shear stress and the flow velocity, is also determined. Our results are shown to be qualitatively and quantitatively compatible with independent experimental observations and simulations

A mathematical model of the effects of hypoxia on the cell-cycle of normal and cancer cells

The evolution of the cell-cycle is known to be influenced by environmental conditions, including lack of extracellular oxygen (hypoxia). Notably, hypoxia appears to have different effects on normal and cancer cells. Whereas both experience hypoxia-induced arrest of the G1 phase of the cell-cycle (i.e. delay in the transition through the restriction point), experimental evidence suggests that only cancer cells undergo hypoxia-induced quiescence (i.e. the transition of the cell to a latent state in which most of the cell functions, including proliferation, are suspended). Here, we extend a model for the cell-cycle due to Tyson and Novak (J. Theor. Biol. 210 (2001) 249) to account for the action of the protein p27. This protein, whose expression is upregulated under hypoxia, inhibits the activation of the cyclin dependent kinases (CDKs), thus preventing DNA synthesis and delaying the normal progression through the cell-cycle. We use a combination of numerical and analytic techniques to study our model. We show that it reproduces many features of the response to hypoxia of normal and cancer cells, as well as generating experimentally testable predictions. For example our model predicts that cancer cells can undergo quiescence by increasing their levels of p27, whereas for normal cells p27 expression decreases when the cellular growth rate increases

Towards whole-organ modelling of tumour growth

Multiscale approaches to modelling biological phenomena are growing rapidly. We present here some recent results on the formulation of a theoretical framework which can be developed into a fully integrative model for cancer growth. The model takes account of vascular adaptation and cell-cycle dynamics. We explore the effects of spatial inhomogeneity induced by the blood flow through the vascular network and of the possible effects of p27 on the cell cycle. We show how the model may be used to investigate the efficiency of drug-delivery protocols

Cancer modelling: Getting to the heart of the problem

Paradoxically, improvements in healthcare that have enhanced the life expectancy of humans in the Western world have, indirectly, increased the prevalence of certain types of cancer such as prostate and breast. It remains unclear whether this phenomenon should be attributed to the ageing process itself or the cumulative effect of prolonged exposure to harmful environmental stimuli such as ultraviolet light, radiation and carcinogens (Franks and Teich, 1988). Equally, there is also compelling evidence that certain genetic abnormalities can predispose individuals to specific cancers (Ilyas et al., 1999). The variety of factors that have been implicated in the development of solid tumours stems, to a large extent, from the fact that ‘cancer’ is a generic term, often used to characterize a series of disorders that share common features. At this generic level of description, cancer may be viewed as a cellular disease in which controls that usually regulate growth and maintain homeostasis are disrupted. Cancer is typically initiated by genetic mutations that lead to enhanced mitosis of a cell lineage and the formation of an avascular tumour. Since it receives nutrients by diffusion from the surrounding tissue, the size of an avascular tumour is limited to several millimeters in diameter. Further growth relies on the tumour acquiring the ability to stimulate the ingrowth of a new, circulating blood supply from the host vasculature via a process termed angiogenesis (Folkman, 1974). Once vascularised, the tumour has access to a vast nutrient source and rapid growth ensues. Further, tumour fragments that break away from the primary tumour, on entering the vasculature, may be transported to other organs in which they may establish secondary tumours or metastases that further compromise the host. Invasion is another key feature of solid tumours whereby contact with the tissue stimulates the production of enzymes that digest the tissue, liberating space into which the tumour cells migrate. Thus, cancer is a complex, multiscale process. The spatial scales of interest range from the subcellular level, to the cellular and macroscopic (or tissue) levels while the timescales may vary from seconds (or less) for signal transduction pathways to months for tumour doubling times The variety of phenomena involved, the range of spatial and temporal scales over which they act and the complex way in which they are inter-related mean that the development of realistic theoretical models of solid tumour growth is extremely challenging. While there is now a large literature focused on modelling solid tumour growth (for a review, see, for example, Preziosi, 2003), existing models typically focus on a single spatial scale and, as a result, are unable to address the fundamental problem of how phenomena at different scales are coupled or to combine, in a systematic manner, data from the various scales. In this article, a theoretical framework will be presented that is capable of integrating a hierarchy of processes occurring at different scales into a detailed model of solid tumour growth (Alarcon et al., 2004). The model is formulated as a hybrid cellular automaton and contains interlinked elements that describe processes at each spatial scale: progress through the cell cycle and the production of proteins that stimulate angiogenesis are accounted for at the subcellular level; cell-cell interactions are treated at the cellular level; and, at the tissue scale, attention focuses on the vascular network whose structure adapts in response to blood flow and angiogenic factors produced at the subcellular level. Further coupling between the different spatial scales arises from the transport of blood-borne oxygen into the tissue and its uptake at the cellular level. Model simulations will be presented to illustrate the effect that spatial heterogeneity induced by blood flow through the vascular network has on the tumour’s growth dynamics and explain how the model may be used to compare the efficacy of different anti-cancer treatment protocols

A cellular automaton model for tumour growth in inhomogeneous environment

Most of the existing mathematical models for tumour growth and tumour-induced angiogenesis neglect blood flow. This is an important factor on which both nutrient and metabolite supply depend. In this paper we aim to address this shortcoming by developing a mathematical model which shows how blood flow and red blood cell heterogeneity influence the growth of systems of normal and cancerous cells. The model is developed in two stages. First we determine the distribution of oxygen in a native vascular network, incorporating into our model features of blood flow and vascular dynamics such as structural adaptation, complex rheology and red blood cell circulation. Once we have calculated the oxygen distribution, we then study the dynamics of a colony of normal and cancerous cells, placed in such a heterogeneous environment. During this second stage, we assume that the vascular network does not evolve and is independent of the dynamics of the surrounding tissue. The cells are considered as elements of a cellular automaton, whose evolution rules are inspired by the different behaviour of normal and cancer cells. Our aim is to show that blood flow and red blood cell heterogeneity play major roles in the development of such colonies, even when the red blood cells are flowing through the vasculature of normal, healthy tissue

Mathematical modelling of angiogenesis and vascular adaptation

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Integration of production and financial models to analyse the financial impact of livestock diseases: a case study of Schmallenberg virus disease on British and French dairy farms

AIMS AND OBJECTIVES: The aim of the study was to investigate and compare the financial impact of Schmallenberg disease for different dairy production types in the United Kingdom and France. MATERIALS AND METHODS: Integrated production and financial models for dairy cattle were developed and applied to Schmallenberg virus (SBV) disease in a British and French context. The five main production systems that prevail in these two countries were considered. Their respective gross margins measuring the holding's profitability were calculated based on public benchmarking, literature and expert opinion data. A partial budget analysis was performed within each production model to estimate the impact of SBV in the systems modelled. Two disease scenarios were simulated: low impact and high impact. RESULTS: The model gross margin obtained per cow space and year ranged from £1014 to £1484 for the UK and from £1037 to £1890 for France depending on the production system considered. In the UK, the net SBV disease costs in £/cow space/year for an average dairy farm with 100 milking spaces were estimated between £16.3 and £51.4 in the high-impact scenario and between £8.2 and £25.9 in the low-impact scenario. For France, the net SBV disease costs in £/cow space/year ranged from £19.6 to £48.6 in the high-impact scenario and £9.7 to £22.8 in the low-impact scenario, respectively. CONCLUSION: The study illustrates how the combination of production and financial models allows assessing disease impact taking into account differing management and husbandry practices and associated price structures in the dairy sector. It supports decision-making of farmers and veterinarians who are considering disease control measures as it provides an approach to estimate baseline disease impact in common dairy production systems in the UK and France

Development of a Standard Methodology for Documenting Processes in an Organization

The application of process management in our country has been extended throughout the last decade; improvement in management, high performance levels, reduction of operation times, optimization of resources and obtaining of quality certifications are among the main reasons why both public and private organizations seek to implement it. However, despite being an implicit activity within the change of management model to the process approach and even the improvement of the functional administrative model, the documentation of processes becomes an uncomfortable, complex and time-consuming task that often generates nervousness and distrust in workers. Diversity of criteria and the lack of an adequate methodology with effective tools makes it difficult to achieve the expected results. This article presents in detail the steps, their sequence and instruments used that allow an organization to raise the information of its processes and document them. As a result of different research projects developed over several years, the methodology of process mapping allowed for the documentation of all the activities of different administrative units of the Escuela Superior Politécnica de Chimborazo and not only to comply with the laws and regulations but also to improve their management. In the last application, it contributed to the development of the documentary structure of a quality management system that allowed an academic unit to achieve international quality certification. Keywords: management, processes, process documentation, process manual. Resumen Escuela Superior Politécnica de Chimborazo, Riobamba, Ecuador *E-mail: [email protected] La aplicación de la gestión de procesos en nuestro país se ha ido extendiendo a lo largo de la última década; mejoras en la gestión, altos niveles de rendimiento, reducción de tiempos de operaciones, optimización de recursos y obtenciones de certificaciones de calidad son entre otros los principales motivos por los cuales organizaciones tanto públicas como privadas buscan implementarla. Sin embargo y a pesar de ser una actividad implícita dentro del cambio de modelo de gestión hacia el enfoque de procesos e incluso del mejoramiento del modelo administrativo funcional, la documentación de los procesos se convierte en una labor incomoda, compleja y con un alto consumo de tiempo que suele generar nerviosismo y desconfianza en los trabajadores. Diversidad de criterios y la falta de una metodología adecuada con instrumentos eficaces complica cumplir los resultados esperados. El presente artículo presenta a detalle los pasos, su secuencia e instrumentos utilizados que le permiten a una organización levantar la información de sus procesos y documentarlos. Resultado de diferentes proyectos de investigación desarrollados a los largo de varios años, la metodología de levantamiento de procesos permitió documentar todas las actividades de distintas unidades administrativas de la Escuela Superior Politécnica de Chimborazo y no solo cumplir lo establecido el leyes y reglamentos sino también mejorar su gestión, en la última aplicación contribuyó a elaborar la estructura documental de un sistema de gestión de la calidad que logró que una unidad académica alcance una certificación internacional de calidad. Palabras claves: gestión, procesos, documentación de procesos, manual de procesos

The use of hybrid cellular automaton models for improving cancer therapy, In Proceedings, Cellular Automata: 6th International Conference on Cellular Automata for Research and Industry, ACRI 2004, Amsterdam, The Netherlands, eds P.M.A. Sloot, B. Chopard, A.G. Hoekstra

The Hybrid Cellular Automata (HCA) modelling framework can be an efficient approach to a number of biological problems, particularly those which involve the integration of multiple spatial and temporal scales. As such, HCA may become a key modelling tool in the development of the so-called intergrative biology. In this paper, we first discuss HCA on a general level and then present results obtained when this approach was implemented in cancer research

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