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Received — 26 March 2026 ⏭

RFC4 drives temozolomide resistance in glioblastoma by activating STK38-BECN1-dependent autophagy

✇(Multiomics OR Omics) AND (Lung OR gastric OR Hepatocellular)
By: Min Mao · Hang Ji · Wen-Qian Yu · Qu-Jing Gai · Qiang Sun · Qian Yan · Sen-Lin Xu · Meng-Li Zhu · Mei-Hua Qu · Han-Min Liu · Jean-Philipe Hugnot · Xi He · Xin Wang · Yan Wang
24 March 2026 at 18:00

Nat Commun. 2026 Mar 23. doi: 10.1038/s41467-026-70798-1. Online ahead of print.

ABSTRACT

Glioblastoma (GBM) remains a lethal brain tumor due to therapy resistance. While autophagy contributes to temozolomide (TMZ) resistance, its regulation is incompletely understood. This study investigates the role of replication factor RFC4, which is associated with poor prognosis and TMZ resistance in GBM. Multi-omics analyses and molecular experiments reveal that TMZ-induced chromatin accessibility enables transcription factor YY1 to bind the RFC4 promoter and upregulate its expression. RFC4, in turn, stabilizes the kinase STK38, which is essential for autophagosome formation. The RFC4-STK38 interaction facilitates BECN1 recruitment, thereby activating autophagy. Phosphorylation of STK38 at T444 stabilizes this complex, whereas a phospho-deficient mutant impairs autophagy. In vivo, RFC4 overexpression confers TMZ resistance, reversible by autophagy inhibition. Thus, our findings identify the RFC4-STK38-BECN1 axis as a mechanism underlying TMZ resistance and a potential target for precision therapy in GBM.

PMID:41872171 | DOI:10.1038/s41467-026-70798-1

Unannotated noncoding transcripts as a source of intratumor heterogeneity in malignant cell states

✇(Multiomics OR Omics) AND (Lung OR gastric OR Hepatocellular)
By: Xiaolan Zhou · Limin Lin · Yu Chen · Guangrui Yang · Ting Ni · Zhaozhao Zhao
23 March 2026 at 18:00

Sci China Life Sci. 2026 Mar 16. doi: 10.1007/s11427-025-3273-6. Online ahead of print.

ABSTRACT

Phenotypic diversity of malignant cells within a tumor underlies intratumor heterogeneity (ITH), a key determinant of cancer metastasis and treatment failure. However, the molecular mechanisms driving this heterogeneity are poorly understood. Here, we curated and analyzed a cohort of 3' tag-based single-cell RNA-seq covering 12 common cancer types. We identified thousands of poly(A) site (PAS) peaks representing the 3' ends of previously unannotated transcripts, whose expression is widely associated with diverse malignant cellular states. By integrating multi-omics data, we characterized the expression patterns and epigenetic landscape of these unannotated PAS peak-associated transcripts (UPTs). The expression heterogeneity of UPTs was supported by multi-region sampling bulk RNA-seq data and recapitulated within cancer cell lines. As proof of principle validation, functional experiments confirmed that two noncoding UPTs promoted the proliferation and migration of lung cancer cells. Our results suggest that epigenetic activation of unannotated noncoding transcripts might represent a previously unrecognized mechanism contributing to transcriptomic ITH.

PMID:41870780 | DOI:10.1007/s11427-025-3273-6

Unannotated noncoding transcripts as a source of intratumor heterogeneity in malignant cell states

✇Omics In Lung
By: Xiaolan Zhou · Limin Lin · Yu Chen · Guangrui Yang · Ting Ni · Zhaozhao Zhao
23 March 2026 at 18:00

Sci China Life Sci. 2026 Mar 16. doi: 10.1007/s11427-025-3273-6. Online ahead of print.

ABSTRACT

Phenotypic diversity of malignant cells within a tumor underlies intratumor heterogeneity (ITH), a key determinant of cancer metastasis and treatment failure. However, the molecular mechanisms driving this heterogeneity are poorly understood. Here, we curated and analyzed a cohort of 3' tag-based single-cell RNA-seq covering 12 common cancer types. We identified thousands of poly(A) site (PAS) peaks representing the 3' ends of previously unannotated transcripts, whose expression is widely associated with diverse malignant cellular states. By integrating multi-omics data, we characterized the expression patterns and epigenetic landscape of these unannotated PAS peak-associated transcripts (UPTs). The expression heterogeneity of UPTs was supported by multi-region sampling bulk RNA-seq data and recapitulated within cancer cell lines. As proof of principle validation, functional experiments confirmed that two noncoding UPTs promoted the proliferation and migration of lung cancer cells. Our results suggest that epigenetic activation of unannotated noncoding transcripts might represent a previously unrecognized mechanism contributing to transcriptomic ITH.

PMID:41870780 | DOI:10.1007/s11427-025-3273-6

Low-dose intestinal irradiation enhances the efficacy and prognosis of PD-1 blockade in metastatic non-small cell lung cancer

✇Omics In Lung
By: Baiyang Huang · Jiarui Zhao · Jingyu Zhu · Xingpeng Wang · Min Li · Jing Xu · Kaiyue Wang · Xiaohan Wang · Weiqing Wang · Cong Bo · Jinquan Yao · Menglin Bai · Bo Cheng · Jinming Yu · Guoxin Cai · Xue Meng
18 March 2026 at 18:00

Clin Cancer Res. 2026 Mar 18. doi: 10.1158/1078-0432.CCR-25-4153. Online ahead of print.

ABSTRACT

PURPOSE: Intestinal low-dose irradiation (ILDR) may enhance immunotherapy efficacy by modulating the gut microbiota and metabolism; however, its role in metastatic non-small cell lung cancer (mNSCLC), particularly in the first-line setting, remains unclear.

EXPERIMENTAL DESIGN: This multicenter retrospective and prospective study included mNSCLC patients receiving first- and second-line programmed cell death protein 1 (PD-1) inhibitors along with abdominopelvic radiotherapy between 2018 and 2025. Patients were stratified by the mean intestinal radiation dose into <1 Gy, 1-3 Gy, and >3 Gy groups and treatment outcomes were compared. The blood and fecal samples were subjected to multi-omics profiling.

RESULTS: g>309 patients were included in the retrospective analysis. Optimal efficacy was observed with a small intestinal mean radiation dose (SIMRD) of 1-3 Gy, showing longer progression-free survival (PFS, 10.2 months) and overall survival (OS, 22.8 months) (P < 0.01), which was consistent across subgroups. Compared with 1-3 Gy, SIMRD >3 Gy (Hazard ratio [HR] = 4.87, P < 0.001) and <1 Gy (HR = 1.85, P < 0.001) independently predicted worse OS. Prospective results confirmed the best disease control rate (P = 0.041) and PFS (P = 0.046) with SIMRD of 1-3 Gy. Responders were enriched in Bacillota, Clostridia, and indole derivatives, particularly indole-3-carboxylic acid. Moreover, the 1-3 Gy group exhibited increased circulating macrophage inflammatory protein-3α and reduced circulating α4β7+ regulatory T cells.

CONCLUSIONS: ILDR influences the efficacy of PD-1 blockade in patients with mNSCLC, particularly when SIMRD is maintained within the 1-3 Gy range, likely through modulation of the gut microbiota-metabolite-immune axis.

PMID:41849236 | DOI:10.1158/1078-0432.CCR-25-4153

Received — 17 March 2026 ⏭

Continual Learning in Large Language Models: Methods, Challenges, and Opportunities

✇cs.AI, q-bio.NC updates on arXiv.org
By: Hongyang Chen · Zhongwu Sun · Hongfei Ye · Kunchi Li · Xuemin Lin
16 March 2026 at 12:00
arXiv:2603.12658v1 Announce Type: cross Abstract: Continual learning (CL) has emerged as a pivotal paradigm to enable large language models (LLMs) to dynamically adapt to evolving knowledge and sequential tasks while mitigating catastrophic forgetting-a critical limitation of the static pre-training paradigm inherent to modern LLMs. This survey presents a comprehensive overview of CL methodologies tailored for LLMs, structured around three core training stages: continual pre-training, continual fine-tuning, and continual alignment.Beyond the canonical taxonomy of rehearsal-, regularization-, and architecture-based methods, we further subdivide each category by its distinct forgetting mitigation mechanisms and conduct a rigorous comparative analysis of the adaptability and critical improvements of traditional CL methods for LLMs. In doing so, we explicitly highlight core distinctions between LLM CL and traditional machine learning, particularly with respect to scale, parameter efficiency, and emergent capabilities. Our analysis covers essential evaluation metrics, including forgetting rates and knowledge transfer efficiency, along with emerging benchmarks for assessing CL performance. This survey reveals that while current methods demonstrate promising results in specific domains, fundamental challenges persist in achieving seamless knowledge integration across diverse tasks and temporal scales. This systematic review contributes to the growing body of knowledge on LLM adaptation, providing researchers and practitioners with a structured framework for understanding current achievements and future opportunities in lifelong learning for language models.

OffTopicEval: When Large Language Models Enter the Wrong Chat, Almost Always!

✇cs.AI, q-bio.NC updates on arXiv.org
By: Jingdi Lei · Varun Gumma · Rishabh Bhardwaj · Seok Min Lim · Chuan Li · Amir Zadeh · Soujanya Poria
16 March 2026 at 12:00
arXiv:2509.26495v3 Announce Type: replace Abstract: Large Language Model (LLM) safety is one of the most pressing challenges for enabling wide-scale deployment. While most studies and global discussions focus on generic harms, such as models assisting users in harming themselves or others, enterprises face a more fundamental concern: whether LLM-based agents are safe for their intended use case. To address this, we introduce operational safety, defined as an LLM's ability to appropriately accept or refuse user queries when tasked with a specific purpose. We further propose OffTopicEval, an evaluation suite and benchmark for measuring operational safety both in general and within specific agentic use cases. Our evaluations on six model families comprising 20 open-weight LLMs reveal that while performance varies across models, all of them remain highly operationally unsafe. Even the strongest models - Qwen-3 (235B) with 77.77% and Mistral (24B) with 79.96% - fall far short of reliable operational safety, while GPT models plateau in the 62-73% range, Phi achieves only mid-level scores (48-70%), and Gemma and Llama-3 collapse to 39.53% and 23.84%, respectively. While operational safety is a core model alignment issue, to suppress these failures, we propose prompt-based steering methods: query grounding (Q-ground) and system-prompt grounding (P-ground), which substantially improve OOD refusal. Q-ground provides consistent gains of up to 23%, while P-ground delivers even larger boosts, raising Llama-3.3 (70B) by 41% and Qwen-3 (30B) by 27%. These results highlight both the urgent need for operational safety interventions and the promise of prompt-based steering as a first step toward more reliable LLM-based agents.

SkillsBench: Benchmarking How Well Agent Skills Work Across Diverse Tasks

✇cs.AI, q-bio.NC updates on arXiv.org
By: Xiangyi Li · Wenbo Chen · Yimin Liu · Shenghan Zheng · Xiaokun Chen · Yifeng He · Yubo Li · Bingran You · Haotian Shen · Jiankai Sun · Shuyi Wang · Binxu Li · Qunhong Zeng · Di Wang · Xuandong Zhao · Yuanli Wang · Roey Ben Chaim · Zonglin Di · Yipeng Gao · Junwei He · Yizhuo He · Liqiang Jing · Luyang Kong · Xin Lan · Jiachen Li · Songlin Li · Yijiang Li · Yueqian Lin · Xinyi Liu · Xuanqing Liu · Haoran Lyu · Ze Ma · Bowei Wang · Runhui Wang · Tianyu Wang · Wengao Ye · Yue Zhang · Hanwen Xing · Yiqi Xue · Steven Dillmann · Han-chung Lee
16 March 2026 at 12:00
arXiv:2602.12670v3 Announce Type: replace Abstract: Agent Skills are structured packages of procedural knowledge that augment LLM agents at inference time. Despite rapid adoption, there is no standard way to measure whether they actually help. We present SkillsBench, a benchmark of 86 tasks across 11 domains paired with curated Skills and deterministic verifiers. Each task is evaluated under three conditions: no Skills, curated Skills, and self-generated Skills. We test 7 agent-model configurations over 7,308 trajectories. Curated Skills raise average pass rate by 16.2 percentage points(pp), but effects vary widely by domain (+4.5pp for Software Engineering to +51.9pp for Healthcare) and 16 of 84 tasks show negative deltas. Self-generated Skills provide no benefit on average, showing that models cannot reliably author the procedural knowledge they benefit from consuming. Focused Skills with 2--3 modules outperform comprehensive documentation, and smaller models with Skills can match larger models without them.
Received — 14 March 2026 ⏭
Received — 11 March 2026 ⏭

SkillsBench: Benchmarking How Well Agent Skills Work Across Diverse Tasks

✇cs.AI, q-bio.NC updates on arXiv.org
By: Xiangyi Li · Wenbo Chen · Yimin Liu · Shenghan Zheng · Xiaokun Chen · Yifeng He · Yubo Li · Bingran You · Haotian Shen · Jiankai Sun · Shuyi Wang · Binxu Li · Qunhong Zeng · Di Wang · Xuandong Zhao · Yuanli Wang · Roey Ben Chaim · Zonglin Di · Yipeng Gao · Junwei He · Yizhuo He · Liqiang Jing · Luyang Kong · Xin Lan · Jiachen Li · Songlin Li · Yijiang Li · Yueqian Lin · Xinyi Liu · Xuanqing Liu · Haoran Lyu · Ze Ma · Bowei Wang · Runhui Wang · Tianyu Wang · Wengao Ye · Yue Zhang · Hanwen Xing · Yiqi Xue · Steven Dillmann · Han-chung Lee
10 March 2026 at 12:00
arXiv:2602.12670v2 Announce Type: replace Abstract: Agent Skills are structured packages of procedural knowledge that augment LLM agents at inference time. Despite rapid adoption, there is no standard way to measure whether they actually help. We present SkillsBench, a benchmark of 86 tasks across 11 domains paired with curated Skills and deterministic verifiers. Each task is evaluated under three conditions: no Skills, curated Skills, and self-generated Skills. We test 7 agent-model configurations over 7,308 trajectories. Curated Skills raise average pass rate by 16.2 percentage points(pp), but effects vary widely by domain (+4.5pp for Software Engineering to +51.9pp for Healthcare) and 16 of 84 tasks show negative deltas. Self-generated Skills provide no benefit on average, showing that models cannot reliably author the procedural knowledge they benefit from consuming. Focused Skills with 2--3 modules outperform comprehensive documentation, and smaller models with Skills can match larger models without them.

Oscillatory shear stress-driven endothelial-to-mesenchymal transition: a critical mechanical signal transduction mechanism in atherosclerosis progression

✇Cell Death Discovery nature.com science feeds
By: Jie Li · Wenchao Xu · Jie Ju · Min Liu · Wenxu Wang · Min Cheng · Xiaoyun Zhang · Xiaodong Cui · Hao Chen
10 March 2026 at 08:00

Cell Death Discovery, Published online: 10 March 2026; doi:10.1038/s41420-026-03000-6

Oscillatory shear stress-driven endothelial-to-mesenchymal transition: a critical mechanical signal transduction mechanism in atherosclerosis progression
Received — 5 March 2026 ⏭

Intelligent Pathological Diagnosis of Gestational Trophoblastic Diseases via Visual-Language Deep Learning Model

✇cs.AI, q-bio.NC updates on arXiv.org
By: Yuhang Liu · Yueyang Cang · Wenge Que · Xinru Bai · Xingtong Wang · Kuisheng Chen · Jingya Li · Xiaoteng Zhang · Xinmin Li · Lixia Zhang · Pingge Hu · Qiaoting Xie · Peiyu Xu · Xianxu Zeng · Li Shi
4 March 2026 at 13:00
arXiv:2603.02704v1 Announce Type: cross Abstract: The pathological diagnosis of gestational trophoblastic disease(GTD) takes a long time, relies heavily on the experience of pathologists, and the consistency of initial diagnosis is low, which seriously threatens maternal health and reproductive outcomes. We developed an expert model for GTD pathological diagnosis, named GTDoctor. GTDoctor can perform pixel-based lesion segmentation on pathological slides, and output diagnostic conclusions and personalized pathological analysis results. We developed a software system, GTDiagnosis, based on this technology and conducted clinical trials. The retrospective results demonstrated that GTDiagnosis achieved a mean precision of over 0.91 for lesion detection in pathological slides (n=679 slides). In prospective studies, pathologists using GTDiagnosis attained a Positive Predictive Value of 95.59% (n=68 patients). The tool reduced average diagnostic time from 56 to 16 seconds per case (n=285 patients). GTDoctor and GTDiagnosis offer a novel solution for GTD pathological diagnosis, enhancing diagnostic performance and efficiency while maintaining clinical interpretability.
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