Transcriptional Profiling of the Dose Response: A More Powerful Approach for Characterizing Drug Activities

The dose response curve is the gold standard for measuring the effect of a drug treatment, but is rarely used in genomic scale transcriptional profiling due to perceived obstacles of cost and analysis. One barrier to examining transcriptional dose responses is that existing methods for microarray data analysis can identify patterns, but provide no quantitative pharmacological information. We developed analytical methods that identify transcripts responsive to dose, calculate classical pharmacological parameters such as the EC50, and enable an in-depth analysis of coordinated dose-dependent treatment effects. The approach was applied to a transcriptional profiling study that evaluated four kinase inhibitors (imatinib, nilotinib, dasatinib and PD0325901) across a six-logarithm dose range, using 12 arrays per compound. The transcript responses proved a powerful means to characterize and compare the compounds: the distribution of EC50 values for the transcriptome was linked to specific targets, dose-dependent effects on cellular processes were identified using automated pathway analysis, and a connection was seen between EC50s in standard cellular assays and transcriptional EC50s. Our approach greatly enriches the information that can be obtained from standard transcriptional profiling technology. Moreover, these methods are automated, robust to non-optimized assays, and could be applied to other sources of quantitative data

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic

The Sandpile Model: Optimal Stress and Hormesis

The sandpile model (developed by chaos theorists) is an elegant visual metaphor for the cumulative impact of environmental stressors on complex adaptive systems – an impact that is paradoxical by virtue of the fact that the grains of sand being steadily added to the gradually evolving sandpile are the occasion for both its disruption and its repair. As a result, complex adaptive systems are continuously refashioning themselves at ever-higher levels of complexity and integration – not just in spite of “stressful” input from the outside but by way of it. Stressful input is therefore inherently neither bad (“poison”) nor good (“medication”). Rather, it will be how well the system (be it sandpile or living system) is able to process, integrate, and adapt to the stressful input that will make of it either a growth-disrupting (sandpile-destabilizing) event or a growth-promoting (sandpile-restabilizing) opportunity. Too much stress – “traumatic stress” – will be too overwhelming for the system to manage, triggering instead devastating breakdown. Too little stress will provide too little impetus for transformation and growth, serving instead simply to reinforce the system’s status quo. But just the right amount of stress – “optimal stress” – will provoke recovery by activating the system’s innate capacity to heal itself