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CircRHBDD1(4,5) drives malignant progression of oral squamous cell carcinoma by enhancing DKK1 mRNA stability through facilitating m<sup>6</sup>A-dependent IGF2BP2 binding

Oncogene, Published online: 11 September 2026; doi:10.1038/s41388-026-03986-4

CircRHBDD1(4,5) drives malignant progression of oral squamous cell carcinoma by enhancing DKK1 mRNA stability through facilitating m6A-dependent IGF2BP2 binding

XAI-Refine: An Automated Explanation-Knowledge Loop for Brain-Age Prediction

arXiv:2609.09388v1 Announce Type: cross Abstract: Brain-age prediction models are commonly evaluated by predictive accuracy, yet accurate predictions alone do not establish that a model relies on reproducible or neurobiologically supported mechanisms. Post-hoc explanation methods can expose these mechanisms, but existing workflows typically stop at diagnosis or require correction targets to be specified before model analysis. We propose XAI-Refine, an automated explanation-knowledge loop for brain-age prediction from resting-state functional connectivity. At each iteration, XAI-Refine consolidates complementary post-hoc analyses across repeated training runs into reliable, structured model explanations. It converts each reliable explanation into a neutral neurobiological question, retrieves and verifies relevant literature, and compiles the verified evidence into an admissible set in the same typed explanation space. The target for refinement is defined as the minimal projection of the current model explanation onto the admissible set induced by applicable verified knowledge. This revised explanation is then translated into a differentiable constraint while preserving the originating model variable, measurement operator, and applicable scope. Candidate updates are promoted only when multi-seed validation confirms target-directed explanatory movement, predictive performance remains within a prespecified guardrail, and non-target explanatory drift remains bounded. Experiments on functional-connectivity-based brain-age prediction evaluate predictive performance, explanation reliability, literature alignment, and target-specific model revision, illustrating a structured route from post-hoc analysis to evidence-guided model refinement.

Spatial multi-omics unveils the monoclonal origin, neuroendocrine plasticity, and microenvironment niches in combined small-cell lung cancer

Cell Rep Med. 2026 Apr 10:102741. doi: 10.1016/j.xcrm.2026.102741. Online ahead of print.

ABSTRACT

Combined small-cell lung cancer (cSCLC) is an aggressive subtype of SCLC with mixed histologic components. Despite heterogeneity and poorer prognosis than de novo SCLC, cSCLC is managed as SCLC because molecular insight into biology, lineage plasticity, and tumor microenvironment (TME) is limited. We perform spatial whole-exome sequencing, spatial transcriptomics, and single-nucleus RNA sequencing across 19 treatment-naive cSCLC tumors. Different histologic components share a monoclonal origin, whereas divergence associates with distinct mutation and copy-number alteration patterns. Our results define spatially exclusive or interspersed tumor domains with distinct TME and immune landscapes; fibroblast-rich boundaries enriched for an aggressive fibroblast subtype may shape TME and treatment responses. We identify lineage plasticity, including adenocarcinoma-to-SCLC transdifferentiation and SCLC-subtype coexistence, and develop cSCLC Detector, a sensitive mutation-based assay improving cSCLC detection in tissue and liquid biopsies. These findings illuminate cSCLC evolution and heterogeneity, underscoring the need for tailored diagnostic and therapeutic strategies for this aggressive subtype.

PMID:41966692 | DOI:10.1016/j.xcrm.2026.102741

Spatial multi-omics unveils the monoclonal origin, neuroendocrine plasticity, and microenvironment niches in combined small-cell lung cancer

Cell Rep Med. 2026 Apr 10:102741. doi: 10.1016/j.xcrm.2026.102741. Online ahead of print.

ABSTRACT

Combined small-cell lung cancer (cSCLC) is an aggressive subtype of SCLC with mixed histologic components. Despite heterogeneity and poorer prognosis than de novo SCLC, cSCLC is managed as SCLC because molecular insight into biology, lineage plasticity, and tumor microenvironment (TME) is limited. We perform spatial whole-exome sequencing, spatial transcriptomics, and single-nucleus RNA sequencing across 19 treatment-naive cSCLC tumors. Different histologic components share a monoclonal origin, whereas divergence associates with distinct mutation and copy-number alteration patterns. Our results define spatially exclusive or interspersed tumor domains with distinct TME and immune landscapes; fibroblast-rich boundaries enriched for an aggressive fibroblast subtype may shape TME and treatment responses. We identify lineage plasticity, including adenocarcinoma-to-SCLC transdifferentiation and SCLC-subtype coexistence, and develop cSCLC Detector, a sensitive mutation-based assay improving cSCLC detection in tissue and liquid biopsies. These findings illuminate cSCLC evolution and heterogeneity, underscoring the need for tailored diagnostic and therapeutic strategies for this aggressive subtype.

PMID:41966692 | DOI:10.1016/j.xcrm.2026.102741

Talk to Right Specialists: Iterative Routing in Multi-agent Systems for Question Answering

arXiv:2501.07813v2 Announce Type: replace-cross Abstract: Retrieval-augmented generation (RAG) agents are increasingly deployed to answer questions over local knowledge bases that cannot be centralized due to knowledge-sovereignty constraints. This results in two recurring failures in production: users do not know which agent to consult, and complex questions require evidence distributed across multiple agents. To overcome these challenges, we propose RIRS, a training-free orchestration framework to enable a multi-agent system for question answering. In detail, RIRS summarizes each agent's local corpus in an embedding space, enabling a user-facing server to route queries only to the most relevant agents, reducing latency and avoiding noisy "broadcast-to-all" contexts. For complicated questions, the server can iteratively aggregate responses to derive intermediate results and refine the question to bridge the gap toward a comprehensive answer. Extensive experiments demonstrate the effectiveness of RIRS, including its ability to precisely select agents and provide accurate responses to single-hop queries, and its use of an iterative strategy to achieve accurate, multi-step resolutions for complex queries.

Temporal-Aware Heterogeneous Graph Reasoning with Multi-View Fusion for Temporal Question Answering

arXiv:2602.19569v1 Announce Type: cross Abstract: Question Answering over Temporal Knowledge Graphs (TKGQA) has attracted growing interest for handling time-sensitive queries. However, existing methods still struggle with: 1) weak incorporation of temporal constraints in question representation, causing biased reasoning; 2) limited ability to perform explicit multi-hop reasoning; and 3) suboptimal fusion of language and graph representations. We propose a novel framework with temporal-aware question encoding, multi-hop graph reasoning, and multi-view heterogeneous information fusion. Specifically, our approach introduces: 1) a constraint-aware question representation that combines semantic cues from language models with temporal entity dynamics; 2) a temporal-aware graph neural network for explicit multi-hop reasoning via time-aware message passing; and 3) a multi-view attention mechanism for more effective fusion of question context and temporal graph knowledge. Experiments on multiple TKGQA benchmarks demonstrate consistent improvements over multiple baselines.

Reinforcement Learning with Promising Tokens for Large Language Models

arXiv:2602.03195v2 Announce Type: replace-cross Abstract: Reinforcement learning (RL) has emerged as a key paradigm for aligning and optimizing large language models (LLMs). Standard approaches treat the LLM as the policy and apply RL directly over the full vocabulary space. However, this formulation includes the massive tail of contextually irrelevant tokens in the action space, which could distract the policy from focusing on decision-making among the truly reasonable tokens. In this work, we verify that valid reasoning paths could inherently concentrate within a low-rank subspace. Based on this insight, we introduce Reinforcement Learning with Promising Tokens (RLPT), a framework that mitigates the action space issue by decoupling strategic decision-making from token generation. Specifically, RLPT leverages the semantic priors of the base model to identify a dynamic set of promising tokens and constrains policy optimization exclusively to this refined subset via masking. Theoretical analysis and empirical results demonstrate that RLPT effectively reduces gradient variance, stabilizes the training process, and improves sample efficiency. Experiment results on math, coding, and telecom reasoning show that RLPT outperforms standard RL baselines and integrates effectively across various model sizes (4B and 8B) and RL algorithms (GRPO and DAPO).
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