Application of the adverse outcome pathway framework to genotoxic modes of action

In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114–134, 2020. © 2019 Wiley Periodicals, Inc.     

Isokinetic flexion strength recovery after ACL reconstruction: a comparison between all inside graft-link technique and full tibial tunnel technique

Introduction: Recently, a new minimally invasive single bundle technique for anatomic ACL reconstruction has been described, called the ‘All-Inside graft-link technique’. One of the advantages of this procedure is the reduced morbidity at the donor site as the graft choice is the quadrupled semitendinosus, thus sparing the gracilis tendon. The aim of this study was to evaluate isokinetic flexion strength recovery in patients who underwent a gracilis sparing technique compared to those with a full-tibial tunnel technique using a doubled gracilis and semitendinosus tendons (DGST) graft.

Methods: Patients were divided into two groups: Group A (22 patients) who underwent ACL reconstruction performed with an All-Inside graft-link technique; Group B (22 patients) who underwent ACL reconstruction with an Out-In technique and DGST graft. At a mean follow-up of 13 months, quadriceps and hamstring isokinetic peak torque deficits were recorded.

Results: In group A, the mean side to side peak torque flexion difference between the operated and non-operated limbs was ?3% and the mean torque at 30° was ?7.5% at high angular velocity (180°/sec); the mean peak flexion torque was 7.2% and the mean torque at 30° was 3.1% at low angular velocity (60°/sec).

In group B, the mean side to side peak flexion torque was ?3.5% and the mean torque at 30° was ?7.6% at high angular velocity (180°/sec); the mean peak flexion torque was ?7.2% and the mean torque at 30° was ?11% at low angular velocity (60°/sec).

A statistically significant difference was found between the two groups at lower angular velocity both for the mean peak flexion torque and the mean torque at 30° (p = 0.009), with better results in the study group.

Discussion/conclusion: Gracilis sparing technique is a minimally invasive technique for ACL reconstruction and yielded a significantly better flexion strength recovery at lower angular velocity compared to a full tibial tunnel technique with DGST for ACL reconstruction.     

Same-Day Yttrium-90 Radioembolization: Feasibility with Resin Microspheres

Purpose

To evaluate the feasibility of a same-day yttrium-90 (⁹⁰Y) radioembolization protocol with resin microspheres (including pretreatment angiography, lung shunt fraction [LSF] determination, and radioembolization) for the treatment of hepatocellular carcinoma (HCC) and liver metastases.