❌

Reading view

Can LLMs Time Travel? Enhancing Temporal Consistency in Legal Agentic Search through Reinforcement Learning

arXiv:2605.25920v1 Announce Type: cross Abstract: While large language models (LLMs) augmented with agentic search capabilities show promise for legal reasoning, they overlook a fundamental constraint that applicable law must match the temporal context of each case, as retroactive application of statutes violates core legal principles and leads to erroneous conclusions. Our observations reveal that current legal LLMs suffer from temporal bias anchored to their training cutoff, while search agents rarely incorporate temporal constraints into queries, and that web search alone cannot provide the precise statute and precedent citations that legal reasoning demands. To address these challenges, we propose LegalSearch-R1, an end-to-end reinforcement learning framework that pairs local statute RAG for precise article matching with online web search for broader legal knowledge, trained on temporally-indexed data spanning multiple amendment periods to enforce temporal consistency. Extensive experiments on our benchmark covering 13 legal tasks demonstrate that our 7B-parameter agent outperforms state-of-the-art deep research frameworks and specialized legal LLMs by 12.9% to 29.8%, surpasses baselines by 57.7% to 80.3% on temporal consistency, and exhibits robust out-of-domain generalization. The code and data are available at https://github.com/AlexFanw/LegalSearch-R1.
  •  

Multi-omics integration and Mendelian randomization elucidate the PARP16-UPR axis driving chemoresistancein gastric cancer

Front Oncol. 2026 May 1;16:1785100. doi: 10.3389/fonc.2026.1785100. eCollection 2026.

ABSTRACT

BACKGROUND: Acquired resistance to cisplatin-based chemotherapy is common in patients with gastric cancer (GC) and significantly limits treatment efficacy. The aim of this study was to investigate molecular features associated with GC chemoresistance using an integrative multi-level analytical framework combined with Mendelian randomization (MR), followed by cellular validation of key candidates.

METHODS: Transcriptome datasets GSE14210 and GSE31811 were obtained from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to explore potential pathways. A total of 113 machine learning model combinations were applied for feature selection. MR analysis integrating expression quantitative trait loci (eQTLs) and genome-wide association study (GWAS) data was conducted to assess causal relationships between candidate genes and chemoresistance. The single-cell dataset GSE183904 was used to examine cell-type-specific expression patterns. Cisplatin-resistant NCI-N87/DDP cells were then established in vitro, and qRT-PCR, Western blotting, and drug sensitivity assays were performed to evaluate gene expression and function. Pathway inhibitors were applied to test the reversal of resistance.

RESULTS: A total of 827 DEGs were identified, mainly enriched in immune response, ECM interactions, metabolic reprogramming, and signaling pathways such as PI3K-Akt and MAPK. Among the machine learning models, the Stepglm[both] + Random Forest (RF) model achieved the best performance [area under the curve (AUC) = 0.865] and identified several core candidate genes. MR analysis supported potential risk associations for TRABD, RXRA, DEFA4, PARP16, SLC12A9, and TMEM132A, with PARP16 consistently highlighted across transcriptomic, machine learning, and MR analyses. In vitro experiments showed that PARP16 expression was elevated by approximately 3.1-fold in NCI-N87/DDP cells, accompanied by activation of the unfolded protein response (UPR) and suppression of apoptosis, and an elevated cisplatin IC50 of 11.82 ΞΌg/mL. Inhibition of the PARP16-UPR axis significantly reduced the IC50 to 4.67 ΞΌg/mL and restored DNA damage and apoptosis, demonstrating synergistic effects.

CONCLUSIONS: PARP16 emerged as a key candidate associated with chemoresistance in GC. Its elevated expression in stem-like cell populations and resistant cell models was associated with UPR activation, and targeting the PARP16-UPR axis restored cisplatin sensitivity. Targeting the PARP16-UPR axis effectively reverses resistance, providing new insights and potential therapeutic strategies for overcoming chemoresistance in GC.

PMID:42147232 | PMC:PMC13175845 | DOI:10.3389/fonc.2026.1785100

  •  

GPNMB Drives Brain Metastasis by Sculpting a Pathological Endothelial-Immune Interactome

Cancer Discov. 2026 Apr 15. doi: 10.1158/2159-8290.CD-25-1663. Online ahead of print.

ABSTRACT

Brain metastases (BM) remain a devastating disease with dismal prognosis. How circulating tumor cells (CTCs) penetrate the blood brain barrier (BBB) and reprogram the brain microenvironment remain unclear. Using spatially resolved multi-omic profiling of CTCs and brain metastases, integrated with experimental and clinical analyses, we identified Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) as a CTC-secreted driver of vascular disruption and brain colonization. CBX3 upregulation induced GPNMB expression, which bound endothelial EGFR, triggering CBL-mediated ubiquitination and degradation. Attenuated EGFR signaling suppressed FTO and disrupted endothelial junctions via YTHDF2-dependent TJP1 m6A methylation. Remarkably, GPNMB-induced BBB remodeling promoted immune infiltration via CXCL12-CXCR4 axis, and induced time course-dependent T cell exhaustion within the brain microenvironment. Clinically, elevated CBX3⁺GPNMB⁺ CTCs and plasma CXCL12 were significantly associated with BM progression in lung cancer and melanoma. Therapeutically, dual blockade of GPNMB and PD1 enhanced anti-BM efficacy in mice, unveiling GPNMB as a promising target for precision immunotherapy.

PMID:41973996 | DOI:10.1158/2159-8290.CD-25-1663

  •  
❌