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Activation of the NLRP3-inflammasome pathway and production of the inflammatory cytokine IL-1B after cellular damage caused by infarct or infection is a key process in several diseases such as acute myocardial infarction and inflammatory bowel disease. However, while the molecular triggers of the NLRP3-pathway after cellular damage are well known, the mechanisms that sustain or confine its activity are currently under investigation. We present here an Ordinary Differential Equation-based model that investigates the mechanisms of inflammasome activation and regulation in monocytes to predict IL-1β activation kinetics upon a two-step activation by Damage-Associate-Molecular-Particles (DAMP) and extracellular ATP. Assuming both activation signals to be concomitantly present or present with a delay of 12h, the model predicted a transient IL-1β activation at different concentration levels dependent on signal synchronisation. Introducing a positive feedback loop mediated by active IL-1β resulted in a sustained IL-1β activation, hence arguing for a paracrine signalling between inflammatory cells to guarantee a temporally stable inflammatory response. We then investigate mechanisms that control termination of inflammation using two recently identified molecular intervention points in the inflammasome pathway. We found that a more upstream regulation, by attenuating production of the IL-1β-proform, was more potent in attenuating active IL-1β production than direct inhibition of the NLRP3-inflammasome. Interestingly, ablating this upstream negative feedback led to a high variability of IL-1β production in monocytes from different subjects, consistent with a recent pre-clinical study. We finally discuss the relevance and implications of our findings in disease models of acute myocardial infarction and spontaneous colitis., (Copyright © 2016. Published by Elsevier Ltd.)

In this communication, based upon the deterministic Gompertz law of cell growth, a stochastic model in tumour growth is proposed. This model takes account of both cell fission and mortality too. The corresponding density function of the size of the tumour cells obeys a functional Fokker--Planck equation which can be solved analytically. It is found that the density function exhibits an interesting "multi-peak" structure generated by cell fission as time evolves. Within this framework the action of therapy is also examined by simply incorporating a therapy term into the deterministic cell growth term.

The molecular mechanisms that drive mammalian cells to the development of cancer are the subject of intense biochemical, genetic and medical studies. But for the present, there is no comprehensive model that might serve as a general framework for the interpretation of experimental data. This paper is an attempt to create a conceptual model of the mechanism of the developing tumorigenic phenotype in mammalian cells, defined as having high genomic instability and proliferative activity. The basic statement in the model is that mutations acquired by tumor cells are not caused directly by external DNA damaging agents, but instead are produced by the cell itself as an output of a Mutator Response similar to the bacterial "SOS response" and characterized by the initiation of error-prone cell cycle progression and an elevated rate of mutation. This response may be induced in arrested mammalian cells by intracellular and extracellular proliferative signals combined with blocked apoptosis. The mutant cells originated by this response are subjected to natural selection via apoptosis and turnover. This selection process favors the survival of cells with high proliferative activity and the suppression of apoptosis resulting in the long run in the appearance of immortalized cells with high proliferative activity. Either a sustained stressful environment accompanied by continuing apoptotic cell death, or replicative senescence, provides conditions suitable for activation of the Mutator Response, namely the emergence of arrested cells with blocked apoptosis and the induction of proliferative signal. It also accelerates the selection process by providing continuing cell turnover. The proposed mechanism is described at the level of involved metabolic pathways and proteins and substantiated by the related experimental data available in the literature.

Complex multicellular organisms have evolved mechanisms to ensure that individual cells follow their proper developmental and somatic programs. Tumorigenesis, or uncontrolled cellular proliferation, is caused by somatic mutations to those genetic constraints that normally operate within a tissue. Genes involved in DNA repair and apoptosis are particularly instrumental in safeguarding cells against tumorigenesis. In this paper, we introduce a stochastic framework to analyse the somatic evolution of cancer initiation. Within this model, we study how apoptosis and DNA repair can maintain the transient stability of somatic cells and delay the onset of cancer. Focusing on individual cell lineages, we calculate the waiting time before tumorigenesis in the presence of varying degrees of apoptosis and DNA repair. We find that the loss of DNA repair or the loss of apoptosis both hasten tumorigenesis, but in characteristically different ways., (Copyright 2002 Elsevier Science Ltd.)

High-voltage electrical trauma frequently leads to extensive and selective destruction of muscle and nerve tissue. In this paper, the mechanism of plasma membrane disruption due to the large transmembrane potentials imposed during electrical trauma is used to explain the particular susceptibility of muscle and nerve cells to damage. It is proposed that this vulnerability is partially due to the relatively large size of these cells. A distributed-parameter electric cable model of an elongated cell is used to examine the alteration of the transmembrane potential caused by a 60 Hz electric field applied parallel to the long axis of the cell. The maximum predicted transmembrane potential occurs at the ends of the cell and is strongly cell-size dependent. Theories are discussed which illustrate how this could explain the predisposition of skeletal muscle to cell membrane breakdown and rupture. The predicted effect of either close-neighboring cells in a tissue or cell contact with cortical bone is even greater induced transmembrane potentials and increased probability of rupture. This is the first hypothesis which explains the clinically-observed pattern of tissue damage resulting from electrical trauma.