These models excel in zero-shot and few-shot learning, enabling them to learn new tasks without parameter updates.

Quantitative imaging methods, such as magnetic resonance fingerprinting (MRF), aim to extract interpretable pathology biomarkers by estimating biophysical tissue parameters from signal evolutions. However, the pattern-matching algorithms or neural networks used in such inverse problems often lack principled uncertainty quantification, which limits the trustworthiness and transparency, required for clinical acceptance. Here, we describe a physics-structured variational autoencoder (PS-VAE) designed for rapid extraction of voxelwise multi-parameter posterior distributions. Our approach integrates a differentiable spin physics simulator with self-supervised learning, and provides a full covariance that captures the inter-parameter correlations of the latent biophysical space. The method was validated in a multi-proton pool chemical exchange saturation transfer (CEST) and semisolid magnetization transfer (MT) molecular MRF study, across in-vitro phantoms, tumor-bearing mice, healthy human volunteers, and a subject with glioblastoma. The resulting multi-parametric posteriors are in good agreement with those calculated using a brute-force Bayesian analysis, while providing an orders-of-magnitude acceleration in whole brain quantification. In addition, we demonstrate how monitoring the multi-parameter posterior dynamics across progressively acquired signals provides practical insights for protocol optimization and may facilitate real-time adaptive acquisition.

'Hope in a bottle' for a deadly cancer and the firefly gene that lit the way The first FDA-approved treatment for an incurable brain cancer gives the gift of time. On the road to the treatment's discovery, scientists used the illuminating luciferase gene, which gives fireflies their signature glow. Breakthroughs, discoveries, and DIY tips sent every weekday. It was as if his muscle memory had evaporated. Twenty-year-old Ethan White couldn't remember how to use the drumsticks.

Currently, there is a noticeable lack of AI in the medical field to support doctors in treating heterogenous brain tumors such as Glioblastoma Multiforme (GBM), the deadliest human cancer in the world with a five-year survival rate of just 5.1%. This project develops an AI system offering the only end-to-end solution by aiding doctors with both diagnosis and treatment planning. In the diagnosis phase, a sequential decision-making framework consisting of 4 classification models (Convolutional Neural Networks and Support Vector Machine) are used. Each model progressively classifies the patient's brain into increasingly specific categories, with the final step being named diagnosis. For treatment planning, an RL system consisting of 3 generative models is used. First, the resection model (diffusion model) analyzes the diagnosed GBM MRI and predicts a possible resection outcome. Second, the radiotherapy model (Spatio-Temporal Vision Transformer) generates an MRI of the brain's progression after a user-defined number of weeks. Third, the chemotherapy model (Diffusion Model) produces the post-treatment MRI. A survival rate calculator (Convolutional Neural Network) then checks if the generated post treatment MRI has a survival rate within 15% of the user defined target. If not, a feedback loop using proximal policy optimization iterates over this system until an optimal resection location is identified. When compared to existing solutions, this project found 3 key findings: (1) Using a sequential decision-making framework consisting of 4 small diagnostic models reduced computing costs by 22.28x, (2) Transformers regression capabilities decreased tumor progression inference time by 113 hours, and (3) Applying Augmentations resembling Real-life situations improved overall DICE scores by 2.9%. These results project to increase survival rates by 0.9%, potentially saving approximately 2,250 lives.

Glioblastoma (GBM) remains the most aggressive tumor, urgently requiring novel therapeutic strategies. Here, we present a dry-to-wet framework combining generative modeling and experimental validation to optimize peptides targeting ATP5A, a potential peptide-binding protein for GBM. Our framework introduces the first lead-conditioned generative model, which focuses exploration on geometrically relevant regions around lead peptides and mitigates the combinatorial complexity of de novo methods. Specifically, we propose POTFlow, a \underline{P}rior and \underline{O}ptimal \underline{T}ransport-based \underline{Flow}-matching model for peptide optimization. POTFlow employs secondary structure information (e.g., helix, sheet, loop) as geometric constraints, which are further refined by optimal transport to produce shorter flow paths. With this design, our method achieves state-of-the-art performance compared with five popular approaches. When applied to GBM, our method generates peptides that selectively inhibit cell viability and significantly prolong survival in a patient-derived xenograft (PDX) model. As the first lead peptide-conditioned flow matching model, POTFlow holds strong potential as a generalizable framework for therapeutic peptide design.

Frontier artificial intelligence (AI) models, such as OpenAI's GPT-5 and Meta's DINOv3, have advanced rapidly through training on internet-scale public data, yet such systems lack access to private clinical data. Neuroimaging, in particular, is underrepresented in the public domain due to identifiable facial features within MRI and CT scans, fundamentally restricting model performance in clinical medicine. Here, we show that frontier models underperform on neuroimaging tasks and that learning directly from uncurated data generated during routine clinical care at health systems, a paradigm we call health system learning, yields high-performance, generalist neuroimaging models. We introduce NeuroVFM, a visual foundation model trained on 5.24 million clinical MRI and CT volumes using a scalable volumetric joint-embedding predictive architecture. NeuroVFM learns comprehensive representations of brain anatomy and pathology, achieving state-of-the-art performance across multiple clinical tasks, including radiologic diagnosis and report generation. The model exhibits emergent neuroanatomic understanding and interpretable visual grounding of diagnostic findings. When paired with open-source language models through lightweight visual instruction tuning, NeuroVFM generates radiology reports that surpass frontier models in accuracy, clinical triage, and expert preference. Through clinically grounded visual understanding, NeuroVFM reduces hallucinated findings and critical errors, offering safer clinical decision support. These results establish health system learning as a paradigm for building generalist medical AI and provide a scalable framework for clinical foundation models.

Whole-genome sequencing (WGS) has revealed numerous non-coding short variants whose functional impacts remain poorly understood. Despite recent advances in deep-learning genomic approaches, accurately predicting and prioritizing clinically relevant mutations in gene regulatory regions remains a major challenge. Here we introduce Deep VRegulome, a deep-learning method for prediction and interpretation of functionally disruptive variants in the human regulome, which combines 700 DNABERT fine-tuned models, trained on vast amounts of ENCODE gene regulatory regions, with variant scoring, motif analysis, attention-based visualization, and survival analysis. We showcase its application on TCGA glioblastoma WGS dataset in prioritizing survival-associated mutations and regulatory regions. The analysis identified 572 splice-disrupting and 9,837 transcription-factor binding site altering mutations occurring in greater than 10% of glioblastoma samples. Survival analysis linked 1352 mutations and 563 disrupted regulatory regions to patient outcomes, enabling stratification via non-coding mutation signatures. All the code, fine-tuned models, and an interactive data portal are publicly available.

Glioblastoma (GBM) is the most common aggressive, fast-growing brain tumor, with a grim prognosis. Despite clinical diagnostic advancements, there have not been any substantial improvements to patient prognosis. Histopathological assessment of excised tumors is the first line of clinical diagnostic routine. We hypothesize that automated, robust, and accurate identification of distinct histological sub-regions within GBM could contribute to morphologically understanding this disease at scale. In this study, we designed a four-step deep learning approach to classify six (6) histopathological regions and quantitatively evaluated it on the BraTS-Path 2024 challenge dataset, which includes digitized Hematoxylin \& Eosin (H\&E) stained GBM tissue sections annotated for six distinct regions. We used the challenge's publicly available training dataset to develop and evaluate the effectiveness of several variants of EfficientNet architectures (i.e., B0, B1, B2, B3, B4). EfficientNet-B1 and EfficientNet-B4 achieved the best performance, achieving an F1 score of 0.98 in a 5-fold cross-validation configuration using the BraTS-Path training set. The quantitative performance evaluation of our proposed approach with EfficientNet-B1 on the BraTS-Path hold-out validation data and the final hidden testing data yielded F1 scores of 0.546 and 0.517, respectively, for the associated 6-class classification task. The difference in the performance on training, validation, and testing data highlights the challenge of developing models that generalize well to new data, which is crucial for clinical applications. The source code of the proposed approach can be found at the GitHub repository of Indiana University Division of Computational Pathology: https://github.com/IUCompPath/brats-path-2024-enet.

Glioblastoma (GBM) is an aggressive primary brain tumor with a median survival of approximately 15 months. In clinical practice, the Stupp protocol serves as the standard first-line treatment. However, patients exhibit highly heterogeneous therapeutic responses which required at least two months before first visual impact can be observed, typically with MRI. Early prediction treatment response is crucial for advancing personalized medicine. Disease Progression Modeling (DPM) aims to capture the trajectory of disease evolution, while Treatment Response Prediction (TRP) focuses on assessing the impact of therapeutic interventions. Whereas most TRP approaches primarly rely on time-series data, we consider the problem of early visual TRP as a slice-to-slice translation model generating post-treatment MRI from a pre-treatment MRI, thus reflecting the tumor evolution. To address this problem we propose a Latent Diffusion Model with a concatenation-based conditioning from the pre-treatment MRI and the tumor localization, and a classifier-free guidance to enhance generation quality using survival information, in particular post-treatment tumor evolution. Our model were trained and tested on a local dataset consisting of 140 GBM patients collected at Centre François Baclesse. For each patient we collected pre and post T1-Gd MRI, tumor localization manually delineated in the pre-treatment MRI by medical experts, and survival information.

These models excel in zero-shot and few-shot learning, enabling them to learn new tasks without parameter updates.