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G-protein coupled receptors (GPCRs) are transmembrane proteins that transmit signals from the extracellular environment to the inside of the cells. Their ability to adopt various conformational states, which influence their function, makes them crucial in pharmacoproteomic studies. While many drugs target specific GPCR states to exert their effects-thereby regulating the protein's activity-unraveling the activation pathway remains challenging due to the multitude of intermediate transformations occurring throughout this process, and intrinsically influencing the dynamics of the receptors. In this context, computational modeling, particularly molecular dynamics (MD) simulations, may offer valuable insights into the dynamics and energetics of GPCR transformations, especially when combined with machine learning (ML) methods and techniques for achieving model interpretability for knowledge generation. The current study builds upon previous work in which the layer relevance propagation (LRP) technique was employed to interpret the predictions in a multi-class classification problem concerning the conformational states of the β2- adrenergic (β2AR) receptor from MD simulations. Here, we address the challenges posed by class imbalance and extend previous analyses by evaluating the robustness and stability of deep learning (DL)-based predictions under different imbalance mitigation techniques. By meticulously evaluating explainability and imbalance strategies, we aim to produce reliable and robust insights.

Simple Summary: Within the rapidly evolving landscape of Machine Learning in the medical field, this paper focuses on the forefront advancements in neuro-oncological radiology. More specifically, it aims to provide the reader with an in-depth exploration of the latest advancements in employing Deep Learning methodologies for the classification of brain tumor radiological images. This review meticulously scrutinizes papers published from 2018 to 2023, unveiling ongoing topics of research while underscoring the main remaining challenges and potential avenues for future research identified by those studies. Beyond the review itself, the paper also underscores the importance of placing the image data modelling provided by Deep Learning techniques within the framework of analytical pipeline research. This means that data quality control and pre-processing should be correctly coupled with modelling itself, in a way that emphasizes the importance of responsible data utilization, as well as the critical need for transparency in data disclosure to ensure trustworthiness and reproducibility of findings. Machine Learning is entering a phase of maturity, but its medical applications still lag behind in terms of practical use. The field of oncological radiology (and neuro-oncology in particular) is at the forefront of these developments, now boosted by the success of Deep-Learning methods for the analysis of medical images. This paper reviews in detail some of the most recent advances in the use of Deep Learning in this field, from the broader topic of the development of Machine-Learning-based analytical pipelines to specific instantiations of the use of Deep Learning in neuro-oncology; the latter including its use in the groundbreaking field of ultra-low field magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

Simple Summary: Accurately grading gliomas, which are the most common and aggressive malignant brain tumors in adults, poses a significant challenge for radiologists. This study explores the application of Deep Learning techniques in assisting tumor grading using Magnetic Resonance Images (MRIs). By analyzing a glioma database sourced from multiple public datasets and comparing different settings, the aim of this study is to develop a robust and reliable grading system. The study demonstrates that by focusing on the tumor region of interest and augmenting the available data, there is a significant improvement in both the accuracy and confidence of tumor grade classifications. While successful in differentiating low-grade gliomas from high-grade gliomas, the accurate classification of grades 2, 3, and 4 remains challenging. The research findings have significant implications for advancing the development of a non-invasive, robust, and trustworthy data-driven system to support clinicians in the diagnosis and therapy planning of glioma patients. Glioma is the most common type of tumor in humans originating in the brain. According to the World Health Organization, gliomas can be graded on a four-stage scale, ranging from the most benign to the most malignant. The grading of these tumors from image information is a far from trivial task for radiologists and one in which they could be assisted by machine-learning-based decision support. However, the machine learning analytical pipeline is also fraught with perils stemming from different sources, such as inadvertent data leakage, adequacy of 2D image sampling, or classifier assessment biases. In this paper, we analyze a glioma database sourced from multiple datasets using a simple classifier, aiming to obtain a reliable tumor grading and, on the way, we provide a few guidelines to ensure such reliability. Our results reveal that by focusing on the tumor region of interest and using data augmentation techniques we significantly enhanced the accuracy and confidence in tumor classifications. Evaluation on an independent test set resulted in an AUC-ROC of 0.932 in the discrimination of low-grade gliomas from high-grade gliomas, and an AUC-ROC of 0.893 in the classification of grades 2, 3, and 4. The study also highlights the importance of providing, beyond generic classification performance, measures of how reliable and trustworthy the model's output is, thus assessing the model's certainty and robustness. [ABSTRACT FROM AUTHOR]

G-protein-coupled receptors (GPCRs) are cell membrane proteins of relevance as therapeutic targets, and are associated to the development of treatments for illnesses such as diabetes, Alzheimer's, or even cancer. Therefore, comprehending the underlying mechanisms of the receptor functional properties is of particular interest in pharmacoproteomics and in disease therapy at large. Their interaction with ligands elicits multiple molecular rearrangements all along their structure, inducing activation pathways that distinctly influence the cell response. In this work, we studied GPCR signaling pathways from molecular dynamics simulations as they provide rich information about the dynamic nature of the receptors. We focused on studying the molecular properties of the receptors using deep-learning-based methods. In particular, we designed and trained a one-dimensional convolution neural network and illustrated its use in a classification of conformational states: active, intermediate, or inactive, of the β 2 -adrenergic receptor when bound to the full agonist BI-167107. Through a novel explainability-oriented investigation of the prediction results, we were able to identify and assess the contribution of individual motifs (residues) influencing a particular activation pathway. Consequently, we contribute a methodology that assists in the elucidation of the underlying mechanisms of receptor activation–deactivation. [ABSTRACT FROM AUTHOR]