Find the papers that actually matter

Mitochondria are essential for cancer cell survival, with the thioredoxin/thioredoxin reductase 2 (Trx/TrxR2) system acting as a key redox regulator. Steviol, an abundant natural ent-kaurane diterpenoid, exhibits negligible cytotoxicity, while most active ent-kaurane analogs depend on a reactive exo-methylene cyclopentanone moiety, raising selectivity and safety concerns. To address these limitations, 28 triphenylphosphonium (TPP)-conjugated steviol derivatives were synthesized to enhance mitochondrial accumulation and modulate mitochondrial signaling. SAR analysis revealed that dual functionalization at C-13 (TPP) and C-19 (esterification) markedly improved potency and selectivity. Conjugate 23d (C-13 TPP, C-19 benzyl ester) was the most potent (IC50 = 0.19 μM, SI = 15.42) and significantly suppressed Huh7 xenografts growth with favorable safety. Mechanistic studies demonstrated mitochondrial accumulation, TrxR2 inhibition, ROS elevation, and ASK1-mediated apoptosis. To our knowledge, 23d is the first non-electrophilic ent-kaurane derivative to combine mitochondrial targeting with TrxR2 inhibition and in vivo antitumor efficacy, highlighting dual modification as a promising strategy integrating biodistribution engineering with activity optimization for anticancer drug development.

Early diagnosis of liver cancer is crucial for developing clinical treatment strategies and improving patient survival rates. However, current diagnostic methods are often invasive, complex, and time-consuming, making them unsuitable for early screening in practical settings. Therefore, there is an urgent need to develop efficient and convenient non-invasive diagnostic techniques. This study presents a non-invasive optical diagnostic approach based on surface-enhanced Raman spectroscopy (SERS) and a deep learning algorithm for liver cancer staging identification and auxiliary screening. We systematically collected high-quality SERS spectral data from serum samples of patients with different stages of liver cancer (T1, T2, T3), hepatitis B (HBV), and healthy controls (Normal). Recursive feature elimination (RFE) was employed for feature selection, eliminating redundant spectral bands and retaining features highly relevant to classification, which significantly enhanced the model's discriminative ability. The selected features were input then into a gradient boosting decision tree (GBDT) model. Through residual iterative optimization, the model effectively captured nonlinear feature interactions, and key spectral bands were interpreted using the local interpretable model-agnostic explanations (LIME) algorithm. Compared to other commonly used classifiers such as logistic regression (LR) and random forest (RF), the RFE-GBDT model demonstrated superior performance in liver cancer staging tasks, achieving an accuracy of 92.68% in the five-class classification. The results indicate that the integration of SERS technology with the RFE-GBDT algorithm holds promise as an efficient and non-invasive auxiliary tool for the early diagnosis of liver cancer.

Medical experts often manually segment images to obtain diagnostic statistics and discard the resulting annotations. We aim to train segmentation models to alleviate this burden, but constrained to the retained summary statistics (e.g., the area of the annotated region). Empirical results suggest that statistics alone are insufficient for this task, but adding weak information in the form of a few pixels within the area of interest significantly improves performance. We use a novel loss function that combines terms for image reconstruction quality, matching to summary statistics, and overlap between the predicted foreground and the weak supervisory signal. Experiments on standard image, ultrasound (breast cancer), and Computed Tomography (CT) scan (kidney tumors) data demonstrate the utility and potential of the approach.

Accurate histological differentiation between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) is critical for personalized treatment in non-small cell lung cancer (NSCLC). While [$^{18}$F]FDG PET/CT is a standard tool for the clinical evaluation of lung cancer, its utility is often limited by high costs and radiation exposure. In this paper, we investigate the feasibility of "virtual scanning" as a feature-enhancement strategy by evaluating whether synthetic PET data can provide complementary feature representations to supplement anatomical CT scans in histological subtype classification. We propose a framework that leverages a 3D Pix2Pix Generative Adversarial Network (GAN), pretrained on the FDG-PET/CT Lesions dataset, to synthesize pseudo-PET volumes from anatomical CT scans. These synthetic volumes are integrated with structural CT data within the MINT framework, a multi-stage intermediate fusion architecture. Our experiments, conducted on a multi-center dataset of 714 subjects, demonstrate that the inclusion of synthetic metabolic features significantly improves classification performance over a CT-only baseline. The multimodal approach achieved a statistically significant increase in the Area Under the Curve (AUC) from 0.489 to 0.591 and improved the Geometric Mean (GMean) from 0.305 to 0.524. These results suggest that synthetic PET scans provide discriminatory metabolic cues that enable deep learning models to exploit complementary cross-modal information, offering a potential feature-enhancement strategy for clinical scenarios where physical PET scans are unavailable.

Predicting microsatellite instability (MSI) status from routine hematoxylin and eosin (H&E) whole slide images (WSIs) offers a practical alternative to molecular testing, but models trained at one institution tend to generalize poorly to slides acquired at a different site. Foundation model representations, despite their generality, still encode site-specific texture alongside the conserved biological morphology underlying MSI. We investigate whether tile-level spatial priors derived from known MSI histology can guide these representations toward more site-invariant features. We introduce a biologically motivated spatial prior based on peripheral distance encoding, reflecting the Crohn's-like peripheral lymphocytic reaction at the tumor invasive margin, and evaluate a secondary local immune neighborhood encoding reflecting the lymphocyte-to-tumor ratio in each tile's immediate spatial neighborhood. Both priors are injected into a TransMIL aggregator before self-attention, allowing the transformer to integrate spatial biological context with UNI2-h or Virchow2 features across all attention layers. We evaluate six foundation model and MIL aggregator combinations as a reference, then assess the effect of each spatial prior. Training on TCGA-COAD (137 slides) and evaluating externally on TCGA-READ (50 slides) without retraining, peripheral distance encoding achieves MSI AUC 0.959 +/- 0.012 on COAD and MSS specificity 1.000 on READ, compared to 0.957 and 0.939 for the strongest reference configuration. Local immune neighborhood encoding achieves comparable internal AUC but lower cross-site specificity, suggesting margin proximity encodes a more site-invariant biological signal than local immune density. Results suggest biologically grounded spatial priors act as regularizers that reduce reliance on site-specific imaging patterns.

The lack of analytical models describing diffusion time dependence at intermediate time scales in complex tissue microstructure limits the accurate quantification of extracellular diffusivity and tissue microstructure. We introduce TRACED, a biophysical model that incorporates diffusion time dependence in cell distributions to quantify pathologically-relevant properties in solid tumors. Neural networks were trained on Monte Carlo diffusion simulations using sphere distribution-based geometries to enable the rapid computation of time-dependent diffusion MRI signals in cell populations of variable cell size. Model sensitivity and fit performance were assessed via simulation. Diffusion data from eight mixed-grade glioma patients was fitted using the TRACED model. Data fitting was performed using a novel physics-informed transfer learning pipeline, Sim2PINN. In two patients, cell size measurements were compared directly with image-localized histology. Simulation results indicate improved parameter estimation compared to the simple two-compartment model. TRACED enabled the simultaneous in vivo quantification of intracellular volume fraction, cell size distribution, extracellular intrinsic diffusivity, and tortuosity in glioma patients. Neural network implementations of diffusion time-dependence and tortuosity showed behavior consistent with coarse-graining and effective medium theory, respectively. Future work will explore the clinical utility of TRACED parameters in additional patients.

Artificial intelligence (AI) is becoming a clinical tool for prostate pathology, but generalization across variations in sample preparation and preservation over prolonged time periods remains poorly understood. We evaluated GleasonAI, an end-to-end attention-based multiple instance learning model, on an independent validation cohort comprising 10,366 biopsy cores from 1,028 patients across 14 Swedish regions, using archival diagnostic specimens from the ProMort cohorts collected between 1998-2015. The model achieved an overall quadratic-weighted kappa of 0.86 for core-level ISUP grading, comparable to several experienced pathologists and consistent across geographic regions. Notably, performance remained stable across the 17-year collection period, demonstrating robustness to time-related variation in archival material, a property not consistently observed with foundation model-based approaches, with exploratory analysis demonstrating a significant prognostic gradient across AI-assigned grade groups for prostate cancer-specific mortality. These findings support the generalizability of the AI grading model and demonstrate the potential of pathology archives as a large-scale resource for AI development, validation, and retrospective prognostic research.

Chemotherapy dose optimization can be formulated as a dynamic treatment regime, requiring sequential decisions under uncertainty that must balance tumor suppression against toxicity. However, most reinforcement learning approaches assume full observability of the patient state, a condition rarely met in clinical practice. We investigate whether memory-augmented policies can improve chemotherapy control under partial observability. To this end, we employ a recurrent TD3-based approach with separate LSTM actor-critic networks and evaluate it on the AhnChemoEnv benchmark from DTR-Bench, considering both off-policy and on-policy recurrent architectures against feed-forward TD3 and Soft Actor-Critic. Pharmacokinetic and pharmacodynamic variability are held fixed to isolate hidden-state uncertainty and observation noise and to avoid confounding effects from inter-patient variability. Across ten random seeds, recurrence yields modest benefit under full observability but substantially stronger and more stable performance under partial observability, with more consistent tumor suppression and improved normal-cell preservation. These findings indicate that memory-based policies are particularly beneficial when clinically relevant state information is incomplete or noisy.

Tumor segmentation in whole-body PET/CT imaging is crucial for precise disease evaluation and treatment planning. However, it remains challenging due to variability in lesion size, contrast, and anatomical distribution. Relying on manual segmentation makes the process time-consuming and prone to intra- and inter-observer variability. This work presents a whole-body tumor segmentation method developed for the AutoPET III challenge, where the goal is to build models that generalize across tracers and multi-center data. We employ the nnU-Net framework with a ResNet-based encoder as our baseline and systematically investigate the impact of training strategies, including intensity normalization, batch dice optimization, and data augmentation using CraveMix. Our experiments show that these strategies significantly influence model performance, particularly in reducing false positives and improving robustness to lesion variability. The best-performing configuration achieves a Dice score of up to 0.80 on the preliminary test phase, and our method ranked third in the AutoPET III challenge. The code is publicly available here.

The widespread adoption of machine learning in critical applications demands techniques to mitigate high-consequence errors. Our method utilizes a dual-classifier GBDT pipeline to distinguish routine human-like errors from high-risk non-human misclassifications. Evaluated across three domains, animal breed classification, skin lesion diagnosis (ISIC 2018), and prostate histopathology (SICAPv2), our framework demonstrates robust safety improvements. To address real-world deployment concerns, our results confirm the pipeline introduces negligible inference latency (1.60% overhead for the animal dataset, 1.84% for ISIC, and 1.70% for SICAPv2) while outperforming traditional Maximum Class Probability (MCP) baselines in correction precision. Our conservative correction strategy successfully reduced dangerous non-human errors by 34.1% in ISIC and 12.57% in SICAPv2, improving super-class diagnostic safety to 90.41% and 92.13% respectively. This proves that safety-critical reliability can be substantially enhanced post-hoc without expensive model retraining. keywords: Error Analysis, Post-hoc Correction, Trustworthy AI.