Effects of paclitaxel on the viscoelastic properties of mouse sensory nerves.

Paclitaxel is an effective and widely used chemotherapeutic, but also causes debilitating peripheral sensory neuropathy. Due to its influence on microtubule stability, we and others have hypothesized that paclitaxel alters neuromechanical properties. A prior study suggested that paclitaxel increases the tensile moduli of rat sensory nerves. However, the effects of paclitaxel on tissue level viscoelasticity have not been tested. In this study, sural branches of C57BL/6J mouse sciatic nerves were bilaterally excised. One nerve was treated with Ringer's solution containing paclitaxel, and the contralateral nerve with Ringer's alone. Nerves were then subject to a passive loading protocol in which peak stress, relaxed stress, and stress-relaxation dynamics were monitored at increasing strain. Elastic and tangent tensile moduli were calculated from both peak and relaxed stress-strain curves as well as failure stress were significantly elevated in paclitaxel-treated nerves compared to controls. Double-exponential fits (with τm and τn indicating fast and slow time constants, respectively) were successfully applied to model stress-relaxation. Though no significant differences in the τm and τn were found between groups, paclitaxel treatment significantly increased the variability of τm, suggesting heterogeneous effects on nerve biomechanical properties. Our data establish that paclitaxel effects at the cellular level influence tensile viscoelastic properties of nerves at the tissue level. These results have implications for understanding biomechanical influences on the progression and physical rehabilitation of paclitaxel-induced neuropathy.

Harnessing public domain data to discover and validate therapeutic targets.

INTRODUCTION: Discovering, developing and validating new disease treatments is a challenging and time-consuming endeavor. Successful drug discovery hinges on selecting the best drug targets with relevance to human disease and evidence that modulating them will be beneficial for patients. Open data initiatives are increasingly placing such knowledge into the public domain. Areas covered: In this review, the authors discuss emerging resources such as Open Targets which integrate key information to prioritize target-disease connections. Researchers can use it, along with other resources, to select potential new therapeutic targets to initiate drug discovery projects. They also discuss public resources such as DrugBank and ChEMBL that offer potential tools to interrogate these targets. Expert opinion: In our opinion, publically available resources are democratizing and connecting information, enabling disease experts to access and prioritize targets of interest in ways that were not possible a few years ago. Moreover, there are several modalities in addition to small molecule perturbation to modulate a target's activity. Drug discovery scientists can now utilize these new resources to simultaneously evaluate a much larger number of targets than previously possible.