Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.

A multiscale orchestrated computational framework to reveal emergent phenomena in neuroblastoma.

Neuroblastoma is a complex and aggressive type of cancer that affects children. Current treatments involve a combination of surgery, chemotherapy, radiotherapy, and stem cell transplantation. However, treatment outcomes vary due to the heterogeneous nature of the disease. Computational models have been used to analyse data, simulate biological processes, and predict disease progression and treatment outcomes. While continuum cancer models capture the overall behaviour of tumours, and agent-based models represent the complex behaviour of individual cells, multiscale models represent interactions at different organisational levels, providing a more comprehensive understanding of the system. In 2018, the PRIMAGE consortium was formed to build a cloud-based decision support system for neuroblastoma, including a multi-scale model for patient-specific simulations of disease progression. In this work we have developed this multi-scale model that includes data such as patient's tumour geometry, cellularity, vascularization, genetics and type of chemotherapy treatment, and integrated it into an online platform that runs the simulations on a high-performance computation cluster using Onedata and Kubernetes technologies. This infrastructure will allow clinicians to optimise treatment regimens and reduce the number of costly and time-consuming clinical trials. This manuscript outlines the challenging framework's model architecture, data workflow, hypothesis, and resources employed in its development.