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Spatial evolution of a cachexia-promoting microenvironment in pancreatic cancer

Cell. 2026 Sep 29:S0092-8674(26)01081-0. doi: 10.1016/j.cell.2026.09.012. Online ahead of print.

ABSTRACT

Cachexia is a major cause of morbidity in pancreatic cancer, but the cellular circuitry linking tumor progression to systemic wasting remains incompletely understood. Integrating single-cell RNA sequencing, Xenium spatial transcriptomics, multiplex immunohistochemistry, bulk transcriptomics, and functional studies across human non-cachexia, pre-cachexia, and cachexia samples, together with mouse models, we define a cachexia-associated microenvironmental niche composed of SEMA4A+ tumor cells, AQP9+ macrophages, and LOXL2+ cancer-associated fibroblasts. Mechanistically, SEMA4A-associated signaling promotes bone morphogenetic protein-2 (BMP2)-dependent acquisition of an AQP9-associated macrophage phenotype, and macrophage-derived CXCL8 activates LOXL2+ fibroblasts. LOXL2+ fibroblasts reciprocally enhance tumor cell FOSL1/SEMA4A signaling through exosomal N-glycosylated LOXL2. Spatial analyses demonstrate progressive enrichment of this niche with cachexia severity and association with postoperative development of cachexia in previously non-cachectic patients. These findings provide a framework linking local tumor ecosystem dynamics to cachexia progression.

PMID:42810340 | DOI:10.1016/j.cell.2026.09.012

CoSkill: Joint Reinforcement Learning of Reasoning and Meta-Skill Agents for Hierarchical Skill Evolution

arXiv:2609.04865v2 Announce Type: replace Abstract: Skill libraries improve the sample efficiency of agentic reinforcement learning (RL) by enabling large language model (LLM) agents to reuse procedural knowledge. Yet existing paradigms exhibit structural shortcomings: they either decouple skill evolution from policy optimization or instantiate meta-skills as fixed workflows. Both treat skills as passive objects to be managed, limiting the flexible evolution of skills and their co-adaptation with the reasoning agent. To address the limitations, we propose CoSkill, a unified multi-agent RL framework that recasts the static meta-skill workflow as a learnable Meta-Skill Agent and jointly trains it with a Reasoning Agent over a hierarchical skill library. By modeling the Reasoning and Meta-Skill Agents as a cooperative team sharing a single backbone, CoSkill enables end-to-end co-adaptation: the Reasoning Agent conditions its actions on a retrieved task skill and step skills selected from its child set, while its task performance guides the Meta-Skill Agent in refining those step skills. Experiments on ALFWorld and WebShop show that CoSkill substantially outperforms prior skill-based and RL baselines, achieving success rates of 98.4% and 90.6%, respectively (+3.5 and +6.2 pp). As shown in Figure 1, CoSkill achieves superior early-stage sample efficiency, asymptotic performance, and wall-clock efficiency. Our code is available at https://github.com/jinyuan-cookie/CoSkill.

OASES: Outcome-Aligned Search-Evaluation Co-Training for Agentic Search

arXiv:2604.03675v3 Announce Type: replace Abstract: Agentic search enables language models to solve knowledge-intensive tasks by adaptively acquiring external evidence over multiple steps. Reinforcement learning with verifiable rewards (RLVR) has emerged as a widely adopted training paradigm for search agents, yet outcome-only rewards are sparse and provide limited credit assignment for intermediate search actions. Existing process-reward methods therefore seek to densify supervision through proxy signals, external evaluators, or likelihood-based information gain. However, proxy rewards can deviate from the final outcome objective, while fixed evaluators can become stale as the search policy evolves, leading to unreliable process supervision. To address these challenges, we propose OASES, an Outcome-Aligned Search-Evaluation Supervision framework for agentic search. OASES derives outcome-aligned process rewards by evaluating how well each intermediate search state supports answering the original question. It further co-trains the search policy and the state evaluator on policy, allowing the evaluator to adapt to evolving search behavior and provide more reliable process rewards. Experiments on five multi-hop QA benchmarks show that OASES consistently outperforms strong RL baselines, with further analyses confirming the benefits of outcome-aligned process rewards and search-evaluation co-training.

PRAISE: Prefix-Based Rollout Reuse in Agentic Search Training

arXiv:2604.03675v1 Announce Type: new Abstract: In agentic search, large language models (LLMs) are trained to perform multi-turn retrieval and reasoning for complex tasks such as multi-hop question answering (QA). However, current search-based Reinforcement Learning (RL) methods suffer from two core limitations: expensive long-horizon rollouts are under-utilized during training, and supervision is typically available only at the final answer, resulting in severe reward sparsity. We present Prefix-based Rollout reuse for Agentic search with Intermediate Step rEwards (PRAISE), a framework for improving both data efficiency and credit assignment in agentic search training. Given a complete search trajectory, PRAISE extracts prefix states at different search turns, elicits intermediate answers from them, and uses these prefixes both to construct additional training trajectories and to derive step-level rewards from performance differences across prefixes. Our method uses a single shared model for both search policy learning and prefix answer evaluation, enabling joint optimization without extra human annotations or a separate reward model. Experiments on multi-hop QA benchmarks show that PRAISE consistently improves performance over strong baselines.

InferenceEvolve: Towards Automated Causal Effect Estimators through Self-Evolving AI

arXiv:2604.04274v1 Announce Type: new Abstract: Causal inference is central to scientific discovery, yet choosing appropriate methods remains challenging because of the complexity of both statistical methodology and real-world data. Inspired by the success of artificial intelligence in accelerating scientific discovery, we introduce InferenceEvolve, an evolutionary framework that uses large language models to discover and iteratively refine causal methods. Across widely used benchmarks, InferenceEvolve yields estimators that consistently outperform established baselines: against 58 human submissions in a recent community competition, our best evolved estimator lay on the Pareto frontier across two evaluation metrics. We also developed robust proxy objectives for settings without semi-synthetic outcomes, with competitive results. Analysis of the evolutionary trajectories shows that agents progressively discover sophisticated strategies tailored to unrevealed data-generating mechanisms. These findings suggest that language-model-guided evolution can optimize structured scientific programs such as causal inference, even when outcomes are only partially observed.

Boosted Distributional Reinforcement Learning: Analysis and Healthcare Applications

arXiv:2604.04334v1 Announce Type: cross Abstract: Researchers and practitioners are increasingly considering reinforcement learning to optimize decisions in complex domains like robotics and healthcare. To date, these efforts have largely utilized expectation-based learning. However, relying on expectation-focused objectives may be insufficient for making consistent decisions in highly uncertain situations involving multiple heterogeneous groups. While distributional reinforcement learning algorithms have been introduced to model the full distributions of outcomes, they can yield large discrepancies in realized benefits among comparable agents. This challenge is particularly acute in healthcare settings, where physicians (controllers) must manage multiple patients (subordinate agents) with uncertain disease progression and heterogeneous treatment responses. We propose a Boosted Distributional Reinforcement Learning (BDRL) algorithm that optimizes agent-specific outcome distributions while enforcing comparability among similar agents and analyze its convergence. To further stabilize learning, we incorporate a post-update projection step formulated as a constrained convex optimization problem, which efficiently aligns individual outcomes with a high-performing reference within a specified tolerance. We apply our algorithm to manage hypertension in a large subset of the US adult population by categorizing individuals into cardiovascular disease risk groups. Our approach modifies treatment plans for median and vulnerable patients by mimicking the behavior of high-performing references in each risk group. Furthermore, we find that BDRL improves the number and consistency of quality-adjusted life years compared with reinforcement learning baselines.

Towards AI Search Paradigm

arXiv:2506.17188v2 Announce Type: replace-cross Abstract: In this paper, we introduce the AI Search Paradigm, a comprehensive blueprint for next-generation search systems capable of emulating human information processing and decision-making. The paradigm employs a modular architecture of four LLM-powered agents (Master, Planner, Executor and Writer) that dynamically adapt to the full spectrum of information needs, from simple factual queries to complex multi-stage reasoning tasks. These agents collaborate dynamically through coordinated workflows to evaluate query complexity, decompose problems into executable plans, and orchestrate tool usage, task execution, and content synthesis. We systematically present key methodologies for realizing this paradigm, including task planning and tool integration, execution strategies, aligned and robust retrieval-augmented generation, and efficient LLM inference, spanning both algorithmic techniques and infrastructure-level optimizations. By providing an in-depth guide to these foundational components, this work aims to inform the development of trustworthy, adaptive, and scalable AI search systems.

Context-Aware Mapping of 2D Drawing Annotations to 3D CAD Features Using LLM-Assisted Reasoning for Manufacturing Automation

arXiv:2602.18296v1 Announce Type: cross Abstract: Manufacturing automation in process planning, inspection planning, and digital-thread integration depends on a unified specification that binds the geometric features of a 3D CAD model to the geometric dimensioning and tolerancing (GD&T) callouts, datum definitions, and surface requirements carried by the corresponding 2D engineering drawing. Although Model-Based Definition (MBD) allows such specifications to be embedded directly in 3D models, 2D drawings remain the primary carrier of manufacturing intent in automotive, aerospace, shipbuilding, and heavy-machinery industries. Correctly linking drawing annotations to the corresponding 3D features is difficult because of contextual ambiguity, repeated feature patterns, and the need for transparent and traceable decisions. This paper presents a deterministic-first, context-aware framework that maps 2D drawing entities to 3D CAD features to produce a unified manufacturing specification. Drawing callouts are first semantically enriched and then scored against candidate features using an interpretable metric that combines type compatibility, tolerance-aware dimensional agreement, and conservative context consistency, along with engineering-domain heuristics. When deterministic scoring cannot resolve an ambiguity, the system escalates to multimodal and constrained large-language-model reasoning, followed by a single human-in-the-loop (HITL) review step. Experiments on 20 real CAD-drawing pairs achieve a mean precision of 83.67%, recall of 90.46%, and F1 score of 86.29%. An ablation study shows that each pipeline component contributes to overall accuracy, with the full system outperforming all reduced variants. By prioritizing deterministic rules, clear decision tracking, and retaining unresolved cases for human review, the framework provides a practical foundation for downstream manufacturing automation in real-world industrial environments.
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