Ants in a Labyrinth: A Statistical Mechanics Approach to the Division of Labour

Division of labour (DoL) is a fundamental organisational principle in human societies, within virtual and robotic swarms and at all levels of biological organisation. DoL reaches a pinnacle in the insect societies where the most widely used model is based on variation in response thresholds among individuals, and the assumption that individuals and stimuli are well-mixed. Here, we present a spatially explicit model of DoL. Our model is inspired by Pierre de Gennes' 'Ant in a Labyrinth' which laid the foundations of an entire new field in statistical mechanics. We demonstrate the emergence, even in a simplified one-dimensional model, of a spatial patterning of individuals and a right-skewed activity distribution, both of which are characteristics of division of labour in animal societies. We then show using a two-dimensional model that the work done by an individual within an activity bout is a sigmoidal function of its response threshold. Furthermore, there is an inverse relationship between the overall stimulus level and the skewness of the activity distribution. Therefore, the difference in the amount of work done by two individuals with different thresholds increases as the overall stimulus level decreases. Indeed, spatial fluctuations of task stimuli are minimised at these low stimulus levels. Hence, the more unequally labour is divided amongst individuals, the greater the ability of the colony to maintain homeostasis. Finally, we show that the non-random spatial distribution of individuals within biological and social systems could be caused by indirect (stigmergic) interactions, rather than direct agent-to-agent interactions. Our model links the principle of DoL with principles in the statistical mechanics and provides testable hypotheses for future experiments

The combination of circulating Ang1 and Tie2 levels predicts progression-free survival advantage in bevacizumab-treated patients with ovarian cancer

PURPOSE: Randomized ovarian cancer trials, including ICON7, have reported improved progression-free survival (PFS) when bevacizumab was added to conventional cytotoxic therapy. The improvement was modest prompting the search for predictive biomarkers for bevacizumab. EXPERIMENTAL DESIGN: Pre-treatment training (n = 91) and validation (n = 114) blood samples were provided by ICON7 patients. Plasma concentrations of 15 angio-associated factors were determined using validated multiplex ELISAs. Our statistical approach adopted PFS as the primary outcome measure and involved (i) searching for biomarkers with prognostic relevance or which related to between-individual variation in bevacizumab effect; (ii) unbiased determination of cut-offs for putative biomarker values; (iii) investigation of biologically meaningfully predictive combinations of putative biomarkers; and (iv) replicating the analysis on candidate biomarkers in the validation dataset. RESULTS: The combined values of circulating Ang1 and Tie2 concentrations predicted improved PFS in bevacizumab-treated patients in the training set. Using median concentrations as cut-offs, high Ang1/low Tie2 values were associated with significantly improved PFS for bevacizumab-treated patients in both data sets (median: 23.0 months versus 16.2, p=0.003 for the interaction of Ang1-Tie2-treatment in Cox regression analysis. The prognostic indices derived from the training set also distinguished high and low probability for progression in the validation set (p = 0.008), generating similar values for HR (0.21 versus 0.27) between treatment and control arms for patients with high Ang1 and low Tie2 values. CONCLUSIONS: The combined values of Ang1 and Tie2 are predictive biomarkers for improved PFS in bevacizumab-treated patients with ovarian cancer. These findings need to be validated in larger trials due to the limitation of sample size in this study

Plasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer.

Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi

A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker

BACKGROUND: Obtaining tissue for pancreatic carcinoma diagnosis and biomarker assessment to aid drug development is challenging. Circulating tumour cells (CTCs) may represent a potential biomarker to address these unmet needs. We compared prospectively the utility of two platforms for CTC enumeration and characterisation in pancreatic cancer patients in a pilot exploratory study. PATIENTS AND METHODS: Blood samples were obtained prospectively from 54 consenting patients and analysed by CellSearch and isolation by size of epithelial tumour cells (ISET). CellSearch exploits immunomagnetic capture of CTCs-expressing epithelial markers, whereas ISET is a marker independent, blood filtration device. Circulating tumour cell expression of epithelial and mesenchymal markers was assessed to explore any discrepancy in CTC number between the two platforms. RESULTS: ISET detected CTCs in more patients than CellSearch (93% vs 40%) and in higher numbers (median CTCs/7.5 ml, 9 (range 0–240) vs 0 (range 0–144)). Heterogeneity observed for epithelial cell adhesion molecule, pan-cytokeratin (CK), E-Cadherin, Vimentin and CK 7 expression in CTCs may account for discrepancy in CTC number between platforms. CONCLUSION: ISET detects more CTCs than CellSearch and offers flexible CTC characterisation with potential to investigate CTC biology and develop biomarkers for pancreatic cancer patient management