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Agrimol B induces autophagic death in TP53-mutant pancreatic cancer by targeting the S100A6-HDAC2-mutant p53 acetylation axis

Phytomedicine. 2026 Aug 26;161:158760. doi: 10.1016/j.phymed.2026.158760. Online ahead of print.

ABSTRACT

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) harbors TP53 mutations at high frequency, yet therapeutic strategies that specifically target mutant p53 remain limited.

PURPOSE: This study aimed to identify S100A6, a calcium-binding protein frequently upregulated in TP53-mutant PDAC, as a critical regulator of mutant p53 stability and tumor progression, and to explore potential S100A6-targeting agents for therapeutic intervention.

METHODS: We integrated computer-assisted drug screening with transcriptomics, acetylation omics, and molecular biology techniques to identify Agrimol B (AgrB), a bioactive compound derived from the traditional Chinese herb Agrimonia pilosa Ledeb., as a potential S100A6-targeting agent.

RESULTS: High S100A6 expression was closely associated with poor prognosis in patients with TP53-mutant PDAC, whereas S100A6 depletion markedly suppressed PDAC cell growth and metastatic potential. Mechanistically, AgrB enhanced the interaction between S100A6 and the deacetylase HDAC2, leading to reduced acetylation of mutant p53 at lysine 382. This disruption activated autophagy-dependent cell death and thereby inhibited PDAC progression.

CONCLUSION: Our findings reveal an S100A6-HDAC2-mutant p53 acetylation axis that regulates TP53-mutant pancreatic tumorigenesis, providing mechanistic evidence supporting S100A6 as a therapeutic vulnerability and highlighting AgrB as a promising natural-product-derived candidate for further development against this aggressive malignancy.

PMID:42700714 | DOI:10.1016/j.phymed.2026.158760

Contextual Rollout Bandits for Reinforcement Learning with Verifiable Rewards

arXiv:2602.08499v2 Announce Type: replace-cross Abstract: Reinforcement Learning with Verifiable Rewards (RLVR) is an effective paradigm for improving the reasoning capabilities of large language models. However, existing RLVR methods utilize rollouts in an indiscriminate and short-horizon manner: responses of heterogeneous quality within each prompt are treated uniformly, and historical rollouts are discarded after a single use. This leads to noisy supervision, poor sample efficiency, and suboptimal policy updates. We address these issues by formulating rollout scheduling in RLVR as a contextual bandit problem and proposing a unified neural scheduling framework that adaptively selects high-value rollouts throughout training. Each rollout is treated as an arm whose reward is defined by the induced performance gain between consecutive optimization steps. The resulting scheduler supports both noise-aware intra-group selection and adaptive global reuse of historical rollouts within a single principled framework. We provide theoretical justification by deriving sublinear regret bounds and showing that enlarging the rollout buffer improves the achievable performance upper bound. Experiments on six mathematical reasoning benchmarks demonstrate consistent gains in performance and training efficiency across multiple RLVR optimization methods.

CREST: Constraint-Release Execution for Multi-Robot Warehouse Shelf Rearrangement

arXiv:2603.28803v1 Announce Type: cross Abstract: Double-Deck Multi-Agent Pickup and Delivery (DD-MAPD) models the multi-robot shelf rearrangement problem in automated warehouses. MAPF-DECOMP is a recent framework that first computes collision-free shelf trajectories with a MAPF solver and then assigns agents to execute them. While efficient, it enforces strict trajectory dependencies, often leading to poor execution quality due to idle agents and unnecessary shelf switching. We introduce CREST, a new execution framework that achieves more continuous shelf carrying by proactively releasing trajectory constraints during execution. Experiments on diverse warehouse layouts show that CREST consistently outperforms MAPF-DECOMP, reducing metrics related to agent travel, makespan, and shelf switching by up to 40.5\%, 33.3\%, and 44.4\%, respectively, with even greater benefits under lift/place overhead. These results underscore the importance of execution-aware constraint release for scalable warehouse rearrangement. Code and data are available at https://github.com/ChristinaTan0704/CREST.

The 1000 Chinese Pangenome empowers medical and population genetics

Nature, Published online: 01 April 2026; doi:10.1038/s41586-026-10315-y

Development of the pangenome-informed genome assembly (PIGA) workflow enabled the generation of 1,116 diploid genome assemblies (55 de novo and 1,061 pangenome-informed), representing an extensive resource of medically relevant genic variations.
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