Episodic, transient systemic acidosis delays evolution of the malignant phenotype: Possible mechanism for cancer prevention by increased physical activity

Background\ud \ud The transition from premalignant to invasive tumour growth is a prolonged multistep process governed by phenotypic adaptation to changing microenvironmental selection pressures. Cancer prevention strategies are required to interrupt or delay somatic evolution of the malignant invasive phenotype. Empirical studies have consistently demonstrated that increased physical activity is highly effective in reducing the risk of breast cancer but the mechanism is unknown.\ud \ud Results\ud \ud Here we propose the hypothesis that exercise-induced transient systemic acidosis will alter the in situ tumour microenvironment and delay tumour adaptation to regional hypoxia and acidosis in the later stages of carcinogenesis. We test this hypothesis using a hybrid cellular automaton approach. This model has been previously applied to somatic evolution on epithelial surfaces and demonstrated three phases of somatic evolution, with cancer cells escaping in turn from the constraints of limited space, nutrient supply and waste removal. In this paper we extend the model to test our hypothesis that transient systemic acidosis is sufficient to arrest, or at least delay, transition from in situ to invasive cancer.\ud \ud Conclusions\ud \ud Model simulations demonstrate that repeated episodes of transient systemic acidosis will interrupt critical evolutionary steps in the later stages of carcinogenesis resulting in substantial delay in the evolution to the invasive phenotype. Our results suggest transient systemic acidosis may mediate the observed reduction in cancer risk associated with increased physical activity

Mathematical modelling of tumour acidity

Acid-mediated tumour invasion is receiving increasing experimental and clinical attention. Previous models proposed to describe this phenomenon failed to capture key properties of the system, such as the existence of the benign steady state, or predicted incorrectly the size of the inter-tissue gap. Here we show that taking proper account of quiescence ameliorates these drawbacks as well as revealing novel behaviour. The simplicity of the model allows us to fully identify the key parameters controlling different aspects of behaviour

The role of acidity in solid tumour growth and invasion

Acidic pH is a common characteristic of human tumours. It has a significant impact on tumour progression and response to therapies. In this paper, we develop a simple model of three-dimensional tumour growth to examine the role of acidosis in the interaction between normal and tumour cell populations. Both vascular and avascular tumour dynamics are investigated, and a number of different behaviours are observed. Whilst an avascular tumour always proceeds to a benign steady state, a vascular tumour may display either benign or invasive dynamics, depending on the value of a critical parameter. Analysis of the model allows us to assess novel therapies directed towards changing the level of acidity within the tumour

Encoding monomorphic and polymorphic types

Most automatic theorem provers are restricted to untyped logics, and existing translations from typed logics are bulky or unsound. Recent research proposes monotonicity as a means to remove some clutter. Here we pursue this approach systematically, analysing formally a variety of encodings that further improve on efficiency while retaining soundness and completeness. We extend the approach to rank-1 polymorphism and present alternative schemes that lighten the translation of polymorphic symbols based on the novel notion of “cover”. The new encodings are implemented, and partly proved correct, in Isabelle/HOL. Our evaluation finds them vastly superior to previous schemes

Metabolic changes during carcinogenesis: Potential impact on invasiveness

Successful adaptation to varying microenvironmental constraints plays a crucial role during carcinogenesis. We develop a hybrid cellular automation approach to investigate the cell–microenvironmental interactions that mediate somatic evolution of cancer cells. This allows investigation of the hypothesis that regions of premalignant lesions develop a substrate-limited environment as proliferation carries cells away from blood vessels which remain separated by the intact basement membrane. We find that selective forces in tumoural regions furthest from the blood supply act to favour cells whose metabolism is best suited to respond to local changes in oxygen, glucose and pH levels. The model predicts three phases of somatic evolution. Initially, cell survival and proliferation is limited due to diminished oxygen levels. This promotes adaptation to a second phase of growth dominated by cells with constitutively up-regulated glycolysis, less reliant on oxygen for ATP production. Increased glycolysis induces acidification of the local environment, limiting proliferation and inducing cell death through necrosis and apoptosis. This promotes a third phase of cellular evolution, with emergence of phenotypes resistant to acid-induced toxicity. This emergent cellular phenotype has a significant proliferative advantage because it will consistently acidify the local environment in a way that is toxic to its competitors but harmless to itself. The model's results suggest this sequence is essential in the transition from self-limited premalignant growth to invasive cancer, and, therefore, that this transition may be delayed or prevented through novel strategies directed towards interrupting the hypoxia–glycolysis–acidosis cycle

Encoding monomorphic and polymorphic types

Many automatic theorem provers are restricted to untyped logics, and existing translations from typed logics are bulky or unsound. Recent research proposes monotonicity as a means to remove some clutter when translating monomorphic to un-typed first-order logic. Here we pursue this approach systematically, analysing formally a variety of encodings that further improve on efficiency while retaining soundness and completeness. We extend the approach to rank-1 polymorphism and present alternative schemes that lighten the translation of polymorphic symbols based on the novel notion of “cover”. The new encodings are implemented in Isabelle/HOL as part of the Sledgehammer tool. We include informal proofs of soundness and correctness, and have formalized the monomorphic part of this work in Isabelle/HOL. Our evaluation finds the new encodings vastly superior to previous schemes

Quiescience as a mechanism for cyclical hypoxia and acidosis

Tumour tissue characteristically experiences fluctuations in substrate supply. This unstable microenvironment drives constitutive metabolic changes within cellular populations and, ultimately, leads to a more aggressive phenotype. Previously, variations in substrate levels were assumed to occur through oscillations in the hæmodynamics of nearby and distant blood vessels. In this paper we examine an alternative hypothesis, that cycles of metabolite concentrations are also driven by cycles of cellular quiescence and proliferation. Using a mathematical modelling approach, we show that the interdependence between cell cycle and the microenvironment will induce typical cycles with the period of order hours in tumour acidity and oxygenation. As a corollary, this means that the standard assumption of metabolites entering diffusive equilibrium around the tumour is not valid; instead temporal dynamics must be considered

An integrated smart thermo-chemical energy network

Managing the intermittency of renewable sources together with transient (hourly to daily to seasonal) energy demands is one of the principal challenges of delivering a net-zero energy system. Smart multifunctional thermo-chemical energy networks represent an alternative energy network and storage system, a solution based on the distribution of energy via thermo-chemical material rather than thermal energy, gas, fuels or electricity– an option that has scope for integrated short- and long-term energy storage. This is the first research work to realise such a system and demonstrate how it might operate using smart control strategies and how thermo-chemical fluids (TCFs) can be used as a medium for timely energy storage and distribution. The experimental study also describes the effect of steady and variable heat sources on TCF regeneration performance and estimates the potential of thermo-chemical energy networks, which would be particularly beneficial in buildings with high energy consumption for humidity control. This research proves the practicality of the design idea for such a network, which would be governed by centralised control, regenerated by steady or transient heat loads and capable of supplying a variety of demands in an experimental setting. The energy and economic potential of the network were also assessed, identifying temperature and humidity control application scenarios with energy savings of more than 60% compared to conventional operation and payback periods of 6.6–9.7 years