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Spatial, single-nucleus and pathological profiling of the invasive front in early hepatocellular carcinoma for characterizing specific leading-edge cell niche and improving recurrence modeling

Int J Biol Sci. 2026 Sep 10;22(14):8090-8118. doi: 10.7150/ijbs.137262. eCollection 2026.

ABSTRACT

The tumor leading edge (TLE) is a critical region where tumor cells interact with the microenvironment to drive invasion and metastasis; however, its cellular architecture in early hepatocellular carcinoma (HCC) remains poorly understood. Here, we integrated single-nucleus RNA-seq (snRNA-seq), spatial transcriptomics, and computational pathology to investigate TLE in early HCC. We annotated 35 cell subpopulations and identified STMN1-high tumor cells as a key malignant subset enriched at the invasive front, interacting with Treg, plasma B, LAMP3⁺ dendritic cells and SPP1⁺ macrophages. Spatial analysis revealed three co-localized cell pairs-(SPP1⁺ macrophages co-localized with Tip-like and inflammatory endothelial cells), (LAMP3⁺ DCs co-localized with naive T cells), and (plasma B cells co-localized with cancer-associated fibroblasts)-forming a leading-edge tumor microenvironment (L-TME) niche associated with early relapse. We developed an L-TME-related machine-learning benchmark framework incorporating 71 imaging features (65 deep-learning + 6 pathological) based on the snRNA-seq, spatial transcriptomics and pathomics. The pathology model achieved robust performance (mean C-index=0.77) and successfully predicted the recurrence of early HCC (log-rank p < 0.05) in TCGA (n=147) and an independent in-house cohort (n=123). This study delineates the TLE cellular ecosystem of early HCC, defines a spatially coordinated immunosuppressive L-TME niche, and provides a clinically applicable predictive tool for postoperative recurrence. Integrating multi-omics with computational pathology deepens our understanding of early HCC metastasis and offers insights into improved prognostication and therapeutic strategies.

PMID:42807944 | PMC:PMC13618224 | DOI:10.7150/ijbs.137262

Autoregression-Free Neural Operators for Time-Dependent PDEs

arXiv:2605.25413v1 Announce Type: cross Abstract: Neural operators learn mappings from function-dependent inputs to solutions, providing an effective framework for solving partial differential equations (PDEs). For time-dependent PDEs, existing methods typically perform long-horizon prediction through autoregressive rollout directly in high-dimensional physical field spaces, where each predicted state is recursively fed back as the input for the next step. Although effective for short-term prediction, this autoregressive rollout and the lack of continuous-time modeling lead to progressive error accumulation over long-horizon rollouts. In this work, we propose Autoregression-Free Neural Operators (AFNO), which map the time evolution of PDEs into a latent space and model continuous-time vector fields within it. AFNO uses flow matching to learn the latent vector field, thereby enabling continuous evolution over extended horizons, avoiding autoregressive rollout and capturing dynamics under varying parameter configurations through explicit conditioning on physical parameters. Theoretical analysis and extensive experiments on six PDEs demonstrate that AFNO improves long-horizon prediction stability and consistently reduces rollout errors compared with the baselines.

Mitigating Over-Refusal in Aligned Large Language Models via Inference-Time Activation Energy

arXiv:2510.08646v2 Announce Type: replace-cross Abstract: Safety alignment of large language models currently faces a central challenge: existing alignment techniques often prioritize mitigating responses to harmful prompts at the expense of overcautious behavior, leading models to incorrectly refuse benign requests. A key goal of safe alignment is therefore to improve safety while simultaneously minimizing false refusals. In this work, we introduce Energy Landscape Steering (ELS), a novel, fine-tuning free framework designed to resolve this challenge through dynamic, inference-time intervention. We train a lightweight external Energy-Based Model (EBM) to assign high energy to undesirable states (false refusal or jailbreak) and low energy to desirable states (helpful response or safe reject). During inference, the EBM maps the LLM's internal activations to an energy landscape, and we use the gradient of the energy function to steer the hidden states toward low-energy regions in real time. This dynamically guides the model toward desirable behavior without modifying its parameters. By decoupling behavioral control from the model's core knowledge, ELS provides a flexible and computationally efficient solution. Extensive experiments across diverse models demonstrate its effectiveness, raising compliance on the ORB-H benchmark from 57.3 percent to 82.6 percent while maintaining baseline safety performance. Our work establishes a promising paradigm for building LLMs that simultaneously achieve high safety and low false refusal rates.
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