Investigating prostate cancer tumour-stroma interactions - clinical and biological insights from an evolutionary game

BACKGROUND: Tumours are made up of a mixed population of different types of cells that include normal structures as well as ones associated with the malignancy, and there are multiple interactions between the malignant cells and the local microenvironment. These intercellular interactions, modulated by the microenvironment, effect tumour progression and represent a largely under appreciated therapeutic target. We use observations of primary tumor biology from prostate cancer to extrapolate a mathematical model: specifically; it has been observed that in prostate cancer three disparate cellular outcomes predominate: (i) the tumour remains well differentiated and clinically indolent - in this case the local stromal cells may act to restrain the growth of the cancer; (ii) early in its genesis the tumour acquires a highly malignant phenotype, growing rapidly and displacing the original stromal population (often referred to as small cell prostate cancer) - these less common aggressive tumours are relatively independent of the local microenvironment; and, (iii) the tumour co-opts the local stroma - taking on a classic stromagenic phenotype where interactions with the local microenvironment are critical to the cancer growth. METHODS: We present an evolutionary game theoretical construct that models the influence of tumour-stroma interactions in driving these outcomes. We consider three characteristic and distinct cellular populations: stromal cells, tumour cells that are self-reliant in terms of microenvironmental factors and tumour cells that depend on the environment for resources but can also co-opt stroma. 
RESULTS: Using evolutionary game theory we explore a number of different scenarios that elucidate the impact of tumour-stromal interactions on the dynamics of prostate cancer growth and progression and how different treatments in the metastatic setting can affect different types of tumors.
CONCLUSIONS: The tumour microenvironment plays a crucial role selecting the traits of the tumour cells that will determine prostate cancer progression. Equally important, treatments like hormone therapy affect the selection of these cancer phenotypes making it very important to understand how they impact prostate cancer’s somatic evolution

Sex differences in plasma clozapine and norclozapine concentrations in clinical practice and in relation to body mass index and plasma glucose concentrations: a retrospective survey

Background Clozapine is widely prescribed and, although effective, can cause weight gain and dysglycemia. The dysmetabolic effects of clozapine are thought to be more prevalent in women with this gender on average attaining 17 % higher plasma clozapine concentrations than men. Methods We investigated the relationship between dose, body mass index (BMI), plasma glucose concentration, and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in 100 individuals with a severe enduring mental illness. Results Mean (10th/90th percentile) plasma clozapine concentrations were higher for women [0.49 (0.27–0.79) mg/L] compared with men [0.44 (0.26–0.70) mg/L] (F = 2.2; p = 0.035). There was no significant gender difference in the prescribed clozapine dose. BMI was significantly higher in women [mean (95 % CI) = 34.5 (26.0–45.3)] for females compared with 32.5 (25.2–41.0) for males. Overall, BMI increased by 0.7 kg/m 2 over a mean follow-up period of 210 days. A lower proportion, 41 % of women had a fasting blood glucose ≤6.0 mmol/L (<6.0 mmol/L is defined by the International Diabetes Federation as normal glucose handling), compared with 88 % of men (χ2  = 18.6, p < 0.0001). Conclusions We have shown that mean BMI and blood glucose concentrations are higher in women prescribed clozapine than in men. Women also tended to attain higher plasma clozapine concentrations than men. The higher BMI and blood glucose in women may relate to higher tissue exposure to clozapine, as a consequence of sex differences in drug metabolism

Rotational symmetry of self-similar solutions to the Ricci flow

Let (M,g) be a three-dimensional steady gradient Ricci soliton which is non-flat and \kappa-noncollapsed. We prove that (M,g) is isometric to the Bryant soliton up to scaling. This solves a problem mentioned in Perelman's first paper.Comment: Final version, to appear in Invent. Mat

Bariatric surgery and its impact on cardiovascular disease and mortality : A systematic review and meta-analysis

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.Peer reviewedPostprin

Fluid/solid transition in a hard-core system

We prove that a system of particles in the plane, interacting only with a certain hard-core constraint, undergoes a fluid/solid phase transition

Herbert Simon's decision-making approach: Investigation of cognitive processes in experts

This is a post print version of the article. The official published can be obtained from the links below - PsycINFO Database Record (c) 2010 APA, all rights reserved.Herbert Simon's research endeavor aimed to understand the processes that participate in human decision making. However, despite his effort to investigate this question, his work did not have the impact in the “decision making” community that it had in other fields. His rejection of the assumption of perfect rationality, made in mainstream economics, led him to develop the concept of bounded rationality. Simon's approach also emphasized the limitations of the cognitive system, the change of processes due to expertise, and the direct empirical study of cognitive processes involved in decision making. In this article, we argue that his subsequent research program in problem solving and expertise offered critical tools for studying decision-making processes that took into account his original notion of bounded rationality. Unfortunately, these tools were ignored by the main research paradigms in decision making, such as Tversky and Kahneman's biased rationality approach (also known as the heuristics and biases approach) and the ecological approach advanced by Gigerenzer and others. We make a proposal of how to integrate Simon's approach with the main current approaches to decision making. We argue that this would lead to better models of decision making that are more generalizable, have higher ecological validity, include specification of cognitive processes, and provide a better understanding of the interaction between the characteristics of the cognitive system and the contingencies of the environment

Power Law Distribution of Wealth in a Money-Based Model

A money-based model for the power law distribution (PLD) of wealth in an economically interacting population is introduced. The basic feature of our model is concentrating on the capital movements and avoiding the complexity of micro behaviors of individuals. It is proposed as an extension of the Equiluz and Zimmermann's (EZ) model for crowding and information transmission in financial markets. Still, we must emphasize that in EZ model the PLD without exponential correction is obtained only for a particular parameter, while our pattern will give it within a wide range. The Zipf exponent depends on the parameters in a nontrivial way and is exactly calculated in this paper.Comment: 5 pages and 4 figure

Zipf law in the popularity distribution of chess openings

We perform a quantitative analysis of extensive chess databases and show that the frequencies of opening moves are distributed according to a power-law with an exponent that increases linearly with the game depth, whereas the pooled distribution of all opening weights follows Zipf's law with universal exponent. We propose a simple stochastic process that is able to capture the observed playing statistics and show that the Zipf law arises from the self-similar nature of the game tree of chess. Thus, in the case of hierarchical fragmentation the scaling is truly universal and independent of a particular generating mechanism. Our findings are of relevance in general processes with composite decisions.Comment: 5 pages, 4 figure

Referral for specialist follow-up and its association with post-discharge mortality among patients with systolic heart failure (from the National Heart Failure Audit for England and Wales)

For patients admitted with worsening heart failure, early follow-up after discharge is recommended. Whether outcomes can be improved when follow-up is done by cardiologists is uncertain. We aimed to determine the association between cardiology follow-up and risk of death for patients with heart failure discharged from hospital. Using data from the National Heart Failure Audit (England & Wales), we investigated the effect of referral to cardiology follow-up on 30-day and one-year mortality in 68 772 patients with heart failure and a reduced left ventricular ejection fraction (HFREF) discharged from 185 hospitals between 2007 to 2013. The primary analyses used instrumental variable analysis complemented by hierarchical logistic and propensity matched models. At the hospital level, rates of referral to cardiologists varied from 6% to 96%. The median odds ratio (OR) for referral to cardiologist was 2.3 (95% confidence interval [CI] 2.1, 2.5), suggesting that, on average, the odds of a patient being referred for cardiologist follow-up after discharge differed approximately 2.3 times from one randomly selected hospital to another one. Based on the proportion of patients (per region) referred for cardiology follow-up, referral for cardiology follow-up was associated with lower 30-day (OR 0.70; CI 0.55, 0.89) and one-year mortality (OR 0.81; CI 0.68, 0.95) compared with no plans for cardiology follow-up (i.e., standard follow-up done by family doctors). Results from hierarchical logistic models and propensity matched models were consistent (30-day mortality OR 0.66; CI 0.61, 0.72 and 0.66; CI 0.58, 0.76 for hierarchical and propensity matched models, respectively). For patients with HFREF admitted to hospital with worsening symptoms, referral to cardiology services for follow-up after discharge is strongly associated with reduced mortality, both early and late

Towards the classification of static vacuum spacetimes with negative cosmological constant

We present a systematic study of static solutions of the vacuum Einstein equations with negative cosmological constant which asymptotically approach the generalized Kottler (``Schwarzschild--anti-de Sitter'') solution, within (mainly) a conformal framework. We show connectedness of conformal infinity for appropriately regular such space-times. We give an explicit expression for the Hamiltonian mass of the (not necessarily static) metrics within the class considered; in the static case we show that they have a finite and well defined Hawking mass. We prove inequalities relating the mass and the horizon area of the (static) metrics considered to those of appropriate reference generalized Kottler metrics. Those inequalities yield an inequality which is opposite to the conjectured generalized Penrose inequality. They can thus be used to prove a uniqueness theorem for the generalized Kottler black holes if the generalized Penrose inequality can be established.Comment: the discussion of our results includes now some solutions of Horowitz and Myers; typos corrected here and there; a shortened version of this version will appear in Journal of Mathematical Physic