Fast and Efficient Discrimination of Traveling Salesperson Problem Stimulus Difficulty.

The Travelling Salesperson Problem (TSP) is a computationally difficult combinatorial optimization problem. In spite of its relative difficulty human solvers are able to generate close-to-optimal solutions in a close-to-linear time frame, and it has been suggested that this is due to the visual system’s inherent sensitivity to certain geometric properties of TSP stimuli. In the current study we employed a novel experimental paradigm in which we presented participants with sets of four TSP stimuli that varied in terms of their relative solution difficulty and asked them to indicate which of the four stimuli they would prefer to solve. The results indicated that the participants’ choice frequencies followed the same ordering as the stimuli’s empirical solution difficulty; i.e., easy-to-solve stimuli were chosen with a higher frequency than hard-to-solve stimuli. It is suggested that these results provide further evidence of the speed and efficiency of human processing of TSPs, and provide further evidence implicating the role of rapid visuo-perceptual organization in generating TSP solutions. An analysis of the geometric properties of the stimuli uncovered a number of factors that may have influenced the choice preferences of participants in the current experiment, and the performance quality of participants in previous experiments

Human Performance on Visually Presented Traveling Salesperson Problems with Varying Numbers of Nodes

We investigated the properties of the distribution of human solution times for Traveling Salesperson Problems (TSPs) with increasing numbers of nodes. New experimental data are presented that measure solution times for carefully chosen representative problems with 10, 20, . . . 120 nodes. We compared the solution times predicted by the convex hull procedure proposed by MacGregor and Ormerod (1996), the hierarchical approach of Graham, Joshi, and Pizlo (2000), and by five algorithms drawn from the artificial intelligence and operations research literature. The most likely polynomial model for describing the relationship between mean solution time and the size of a TSP is linear or near-linear over the range of problem sizes tested, supporting the earlier finding of Graham et al. (2000). We argue the properties of the solution time distributions place strong constraints on the development of detailed models of human performance for TSPs, and provide some evaluation of previously proposed models in light of our findings

Rapid activation of epithelial-mesenchymal transition drives PARP inhibitor resistance in Brca2-mutant mammary tumours

Tumours defective in the DNA homologous recombination repair pathway can be effectively treated with poly (ADP-ribose) polymerase (PARP) inhibitors; these have proven effective in clinical trials in patients with BRCA gene function-defective cancers. However, resistance observed in both pre-clinical and clinical studies is likely to impact on this treatment strategy. Over-expression of phosphoglycoprotein (P-gp) has been previously suggested as a mechanism of resistance to the PARP inhibitor olaparib in mouse models of Brca1/2-mutant breast cancer. Here, we report that in a Brca2 model treated with olaparib, P-gp upregulation is observed but is not sufficient to confer resistance. Furthermore, resistant/relapsed tumours do not show substantial changes in PK/PD of olaparib, do not downregulate PARP1 or re-establish double stranded DNA break repair by homologous recombination, all previously suggested as mechanisms of resistance. However, resistance is strongly associated with epithelial-mesenchymal transition (EMT) and treatment-naïve tumours given a single dose of olaparib upregulate EMT markers within one hour. Therefore, in this model, olaparib resistance is likely a product of an as-yet unidentified mechanism associated with rapid transition to the mesenchymal phenotype

RNA-Seq Differentiates Tumour and Host mRNA Expression Changes Induced by Treatment of Human Tumour Xenografts with the VEGFR Tyrosine Kinase Inhibitor Cediranib.

Pre-clinical models of tumour biology often rely on propagating human tumour cells in a mouse. In order to gain insight into the alignment of these models to human disease segments or investigate the effects of different therapeutics, approaches such as PCR or array based expression profiling are often employed despite suffering from biased transcript coverage, and a requirement for specialist experimental protocols to separate tumour and host signals. Here, we describe a computational strategy to profile transcript expression in both the tumour and host compartments of pre-clinical xenograft models from the same RNA sample using RNA-Seq. Key to this strategy is a species-specific mapping approach that removes the need for manipulation of the RNA population, customised sequencing protocols, or prior knowledge of the species component ratio. The method demonstrates comparable performance to species-specific RT-qPCR and a standard microarray platform, and allowed us to quantify gene expression changes in both the tumour and host tissue following treatment with cediranib, a potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, including the reduction of multiple murine transcripts associated with endothelium or vessels, and an increase in genes associated with the inflammatory response in response to cediranib. In the human compartment, we observed a robust induction of hypoxia genes and a reduction in cell cycle associated transcripts. In conclusion, the study establishes that RNA-Seq can be applied to pre-clinical models to gain deeper understanding of model characteristics and compound mechanism of action, and to identify both tumour and host biomarkers

Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors

Funder: AstraZenecaAbstract: BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-XL expression in melanoma biases the pro-survival pool towards MCL1. Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, driving profound tumour cell death that requires BAK/BAX, BIM and BMF, and inhibiting tumour growth in vivo. Combination of ERK1/2 pathway inhibitors with BCL2/BCL-w/BCL-XL inhibitors is stronger in CRC, correlating with a low MCL1:BCL-XL ratio; indeed the MCL1:BCL-XL ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL2/BCL-w/BCL-XL inhibitors. Finally, AZD5991 delays acquired BRAFi/MEKi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi + MEKi resistance. Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes

Dose-related effects of alcohol on cognitive functioning

We assessed the suitability of six applied tests of cognitive functioning to provide a single marker for dose-related alcohol intoxication. Numerous studies have demonstrated that alcohol has a deleterious effect on specific areas of cognitive processing but few have compared the effects of alcohol across a wide range of different cognitive processes. Adult participants (N = 56, 32 males, 24 females aged 18–45 years) were randomized to control or alcohol treatments within a mixed design experiment involving multiple-dosages at approximately one hour intervals (attained mean blood alcohol concentrations (BACs) of 0.00, 0.048, 0.082 and 0.10%), employing a battery of six psychometric tests; the Useful Field of View test (UFOV; processing speed together with directed attention); the Self-Ordered Pointing Task (SOPT; working memory); Inspection Time (IT; speed of processing independent from motor responding); the Traveling Salesperson Problem (TSP; strategic optimization); the Sustained Attention to Response Task (SART; vigilance, response inhibition and psychomotor function); and the Trail-Making Test(TMT; cognitive flexibility and psychomotor function). Results demonstrated that impairment is not uniform across different domains of cognitive processing and that both the size of the alcohol effect and the magnitude of effect change across different dose levels are quantitatively different for different cognitive processes. Only IT met the criteria for a marker for wide-spread application: reliable dose-related decline in a basic process as a function of rising BAC level and easy to use non-invasive task properties.Mathew J. Dry, Nicholas R. Burns, Ted Nettelbeck, Aaron L. Farquharson and Jason M. Whit

Clustering, Randomness, and Regularity: Spatial Distributions and Human Performance on the Traveling Salesperson Problem and Minimum Spanning Tree Problem

We investigated human performance on the Euclidean Traveling Salesperson Problem (TSP) and Euclidean Minimum Spanning Tree Problem (MST-P) in regards to a factor that has previously received little attention within the literature: the spatial distributions of TSP and MST-P stimuli. First, we describe a method for quantifying the relative degree of clustering, randomness or regularity within point distributions. We then review evidence suggesting this factor might influence human performance on the two problem types. Following this we report an experiment in which the participants were asked to solve TSP and MST-P test stimuli that had been generated to be either highly clustered, random, or highly regular. The results indicate that for both the TSP and MST-P the participants tended to produce better quality solutions when the stimuli were highly clustered compared to random, and similarly, better quality solutions for random compared to highly regular stimuli. It is suggested that these results provide support for the ideas that human solvers attend to salient clusters of nodes when solving these problems, and that a similar process (or series of processes) may underlie human performance on these two tasks