Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer

Conceptual models of carcinogenesis typically consist of an evolutionary sequence of heritable changes in genes controlling proliferation, apoptosis, and senescence. We propose that these steps are necessary but not sufficient to produce invasive breast cancer because intraductal tumour growth is also constrained by hypoxia and acidosis that develop as cells proliferate into the lumen and away from the underlying vessels. This requires evolution of glycolytic and acid-resistant phenotypes that, we hypothesise, is critical for emergence of invasive cancer. Mathematical models demonstrate severe hypoxia and acidosis in regions of intraductal tumours more than 100 m from the basement membrane. Subsequent evolution of glycolytic and acid-resistant phenotypes leads to invasive proliferation. Multicellular spheroids recapitulating ductal carcinoma in situ (DCIS) microenvironmental conditions demonstrate upregulated glucose transporter 1 (GLUT1) as adaptation to hypoxia followed by growth into normoxic regions in qualitative agreement with model predictions. Clinical specimens of DCIS exhibit periluminal distribution of GLUT-1 and Na+/H+ exchanger (NHE) indicating transcriptional activation by hypoxia and clusters of the same phenotype in the peripheral, presumably normoxic regions similar to the pattern predicted by the models and observed in spheroids. Upregulated GLUT-1 and NHE-1 were observed in microinvasive foci and adjacent intraductal cells. Adaptation to hypoxia and acidosis may represent key events in transition from in situ to invasive cancer

A Genetic Analysis of the Relationship Between Life-history Variation and Heat-shock Tolerance in Drosophila buzzatii

Although exposure to environmental stress is common in most populations, and the physiological effects of stress on individuals are well studied, the evolutionary importance of stress to populations is not well understood. To address multitrait responses to environmental change and potential constraints on character evolution, we analysed, in 100 isofemale lines of Drosophila buzzatii, the genetic relationships between resistance to a short heat shock and several life-history traits: survival in benign conditions, larval developmental time, fecundity and longevity. Estimates of heritability of larval thermotolerance were low, but significant, and all life-history traits varied significantly among isofemale lines. Several of these traits covaried significantly. Most correlations indicated positive life-history relationships, but males and females from lines where female fecundity was higher developed more slowly in the absence of stress, which is a negative life-history relationship. The stress reduced or negated many trait associations, and showed one additional relationship; more larvae from lines that developed fast at 25°C survived to adult after stress than did larvae from slow developing lines. These shifts in fitness relationships, when a single stress bout is applied, suggest that even small increases in environmental stress can have profound effects on evolutionary relationships among life-history traits

Improvements in the fossil record may largely resolve current conflicts between morphological and molecular estimates of mammal phylogeny

Phylogenies of mammals based on morphological data continue to show several major areas of conflict with the current consensus view of their relationships, which is based largely on molecular data. This raises doubts as to whether current morphological character sets are able to accurately resolve mammal relationships. We tested this under a hypothetical ‘best case scenario’ by using ancestral state reconstruction (under both maximum parsimony and maximum likelihood) to infer the morphologies of fossil ancestors for all clades present in a recent comprehensive DNA sequencebased phylogeny of mammals, and then seeing what effect the subsequent inclusion of these predicted ancestors had on unconstrained phylogenetic analyses of morphological data. We found that this resulted in topologies that are highly congruent with the current consensus phylogeny, at least when the predicted ancestors are assumed to be well preserved and densely sampled. Most strikingly, several analyses recovered the monophyly of clades that have never been found in previous morphology-only studies, such as Afrotheria and Laurasiatheria. Our results suggest that, at least in principle, improvements in the fossil record—specifically the discovery of fossil taxa that preserve the ancestral or near-ancestral morphologies of the nodes in the current consensus—may be sufficient to largely reconcile morphological and molecular estimates of mammal phylogeny, even using current morphological character set

Automated multi-objective calibration of biological agent-based simulations

Computational agent-based simulation (ABS) is increasingly used to complement laboratory techniques in advancing our understanding of biological systems. Calibration, the identification of parameter values that align simulation with biological behaviours, becomes challenging as increasingly complex biological domains are simulated. Complex domains cannot be characterized by single metrics alone, rendering simulation calibration a fundamentally multi-metric optimization problem that typical calibration techniques cannot handle. Yet calibration is an essential activity in simulation-based science; the baseline calibration forms a control for subsequent experimentation and hence is fundamental in the interpretation of results. Here, we develop and showcase a method, built around multi-objective optimization, for calibrating ABSs against complex target behaviours requiring several metrics (termed objectives) to characterize. Multi-objective calibration (MOC) delivers those sets of parameter values representing optimal trade-offs in simulation performance against each metric, in the form of a Pareto front. We use MOC to calibrate a well-understood immunological simulation against both established a priori and previously unestablished target behaviours. Furthermore, we show that simulation-borne conclusions are broadly, but not entirely, robust to adopting baseline parameter values from different extremes of the Pareto front, highlighting the importance of MOC's identification of numerous calibration solutions. We devise a method for detecting overfitting in a multi-objective context, not previously possible, used to save computational effort by terminating MOC when no improved solutions will be found. MOC can significantly impact biological simulation, adding rigour to and speeding up an otherwise time-consuming calibration process and highlighting inappropriate biological capture by simulations that cannot be well calibrated. As such, it produces more accurate simulations that generate more informative biological predictions

Regular breakfast consumption and type 2 diabetes risk markers in 9- to 10-year-old children in the child heart and health study in England (CHASE): a cross-sectional analysis.

BACKGROUND: Regular breakfast consumption may protect against type 2 diabetes risk in adults but little is known about its influence on type 2 diabetes risk markers in children. We investigated the associations between breakfast consumption (frequency and content) and risk markers for type 2 diabetes (particularly insulin resistance and glycaemia) and cardiovascular disease in children. METHODS AND FINDINGS: We conducted a cross-sectional study of 4,116 UK primary school children aged 9-10 years. Participants provided information on breakfast frequency, had measurements of body composition, and gave fasting blood samples for measurements of blood lipids, insulin, glucose, and glycated haemoglobin (HbA1c). A subgroup of 2,004 children also completed a 24-hour dietary recall. Among 4,116 children studied, 3,056 (74%) ate breakfast daily, 450 (11%) most days, 372 (9%) some days, and 238 (6%) not usually. Graded associations between breakfast frequency and risk markers were observed; children who reported not usually having breakfast had higher fasting insulin (percent difference 26.4%, 95% CI 16.6%-37.0%), insulin resistance (percent difference 26.7%, 95% CI 17.0%-37.2%), HbA1c (percent difference 1.2%, 95% CI 0.4%-2.0%), glucose (percent difference 1.0%, 95% CI 0.0%-2.0%), and urate (percent difference 6%, 95% CI 3%-10%) than those who reported having breakfast daily; these differences were little affected by adjustment for adiposity, socioeconomic status, and physical activity levels. When the higher levels of triglyceride, systolic blood pressure, and C-reactive protein for those who usually did not eat breakfast relative to those who ate breakfast daily were adjusted for adiposity, the differences were no longer significant. Children eating a high fibre cereal breakfast had lower insulin resistance than those eating other breakfast types (p for heterogeneity <0.01). Differences in nutrient intakes between breakfast frequency groups did not account for the differences in type 2 diabetes markers. CONCLUSIONS: Children who ate breakfast daily, particularly a high fibre cereal breakfast, had a more favourable type 2 diabetes risk profile. Trials are needed to quantify the protective effect of breakfast on emerging type 2 diabetes risk. Please see later in the article for the Editors' Summary

Evaluation of the Workplace Environment in the UK, and the Impact on Users’ Levels of Stimulation

The purpose of this study is to evaluate a number of recently completed workplaces in the UK. The first aim is to assess the impact of various aspects of the workplace environment on users’ levels of stimulation. The body of previous research undertaken into the workplace environment, identified the aspects to be investigated. Samples of employees from the sixteen businesses were surveyed to determine their perceptions of the workplaces. The results were entered into a regression analysis, and the most significant predictors of perceived stimulation identified. The data also revealed a dramatic reduction in staff arousal levels from mornings to afternoons. Thus, there is a second aim to determine whether changes to significant aspects of the workplace environment during the day can counteract the reduction in users’ stimulation. Two further workplaces were studied to enable changes to be made over a 12-week period. A sample of employees completed questionnaires, and semi-structured interviews revealed the reasons behind the results. It was found that provision of artwork, personal control of temperature and ventilation and regular breaks were the most significant contributions to increasing stimulation after lunch; while user choice of layout, and design and décor of workspaces and break areas, were the most significant aspects at design stage

Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: The Singapore Chinese Health Study

10.1038/sj.bjc.6601340British Journal of Cancer8991686-1692BJCA