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NFATC2::NUTM2 Fusion Defines a Novel Primary Pulmonary Epithelial Tumor With a Distinctive Immunophenotype

Am J Surg Pathol. 2026 Jun 1;50(6):695-704. doi: 10.1097/PAS.0000000000002533. Epub 2026 Mar 13.

ABSTRACT

With the application of molecular techniques in pathologic diagnosis, several novel primary pulmonary epithelial tumors have been continuously discovered and classified under the WHO classification of thoracic tumors. Recently, a pulmonary tumor with NFATC2 :: NUTM2B fusion was first documented, but the spectrum of NFATC2::NUTM2 fusion variants and their associated pathologic features remains incompletely characterized. Coincidentally, we also found and described 6 primary pulmonary tumors harboring recurrent NFATC2::NUTM2A/E fusions through integrated genomic analysis. These patients, including 4 females and 2 males, with a median age of 53 years, presented with incidentally detected peripheral lung nodules composed of monotonous epithelioid cells arranged in cords, nests, and trabeculae within a prominent desmoplastic stroma. All tumors exhibited a consistent immunophenotype: CK5/6+/GATA3+/calponin+/EMA+/DOG1 (perinuclear dot-like staining)/p63-. High-throughput chromosome conformation capture (Hi-C) analysis showed the structural variation of NFATC2::NUTM2E in all 6 cases, whereas RNA sequencing detected the fusion transcripts in 5 cases ( NFATC2::NUTM2A , n=2; NFATC2::NUTM2E , n=3). Ultrastructural examination of 1 case suggested epithelial differentiation. All patients remained disease-free after complete resection (median follow-up: 24 mo; range: 9 to 41 mo). These findings define a novel primary pulmonary tumor entity driven by NFATC2::NUTM2 fusions, and characterized by a distinctive immunophenotype, expanding the spectrum of NUTM2 -associated neoplasms. Our study underscores the utility of multiomics approaches for characterizing rare neoplasms and provides a diagnostic framework for this entity.

PMID:41821426 | DOI:10.1097/PAS.0000000000002533

Targeting the OXNAD1-PTGS2 axis with resveratrol overcomes ferroptosis Inhibition and reverses 5-FU resistance in gastric cancer

Gastric Cancer. 2026 Mar 13. doi: 10.1007/s10120-026-01718-x. Online ahead of print.

ABSTRACT

BACKGROUND: 5-Fluorouracil (5-FU) remains a cornerstone of first-line chemotherapy for gastric cancer, yet the emergence of resistance severely compromises its clinical efficacy. Although ferroptosis suppression has been recognized as a pivotal mechanism of chemoresistance, the mitochondrial regulatory processes involved remain poorly understood.

METHODS: We integrated clinical specimen analysis, in vitro and in vivo functional assays, multi-omics profiling, and molecular docking to delineate the role of the mitochondrial oxidoreductase OXNAD1 in mediating 5-FU resistance in gastric cancer, and to assess the therapeutic potential of the natural polyphenol resveratrol as a chemosensitizing agent.

RESULTS: OXNAD1 was found to be significantly overexpressed in gastric cancer tissues and cell lines, correlating with unfavorable prognosis and enhanced 5-FU resistance. Mechanistically, OXNAD1 directly bound to and suppressed the ferroptosis driver PTGS2, thereby attenuating lipid peroxidation and mitochondrial damage, ultimately restraining ferroptosis and promoting drug resistance. Notably, resveratrol disrupted the OXNAD1-PTGS2 interaction by directly binding OXNAD1, reinstating ferroptotic activity, markedly enhancing the cytotoxic effect of 5-FU in resistant cells, and potentiating the antitumor efficacy of 5-FU in xenograft models.

CONCLUSION: The OXNAD1-PTGS2 axis constitutes a critical metabolic-cell death cross-regulatory pathway underlying 5-FU resistance in gastric cancer. Targeting this axis with resveratrol provides a promising combinatorial strategy to overcome chemoresistance.

PMID:41824193 | DOI:10.1007/s10120-026-01718-x

NFATC2::NUTM2 Fusion Defines a Novel Primary Pulmonary Epithelial Tumor With a Distinctive Immunophenotype

Am J Surg Pathol. 2026 Mar 13. doi: 10.1097/PAS.0000000000002533. Online ahead of print.

ABSTRACT

With the application of molecular techniques in pathologic diagnosis, several novel primary pulmonary epithelial tumors have been continuously discovered and classified under the WHO classification of thoracic tumors. Recently, a pulmonary tumor with NFATC2::NUTM2B fusion was first documented, but the spectrum of NFATC2::NUTM2 fusion variants and their associated pathologic features remains incompletely characterized. Coincidentally, we also found and described 6 primary pulmonary tumors harboring recurrent NFATC2::NUTM2A/E fusions through integrated genomic analysis. These patients, including 4 females and 2 males, with a median age of 53 years, presented with incidentally detected peripheral lung nodules composed of monotonous epithelioid cells arranged in cords, nests, and trabeculae within a prominent desmoplastic stroma. All tumors exhibited a consistent immunophenotype: CK5/6+/GATA3+/calponin+/EMA+/DOG1 (perinuclear dot-like staining)/p63-. High-throughput chromosome conformation capture (Hi-C) analysis showed the structural variation of NFATC2::NUTM2E in all 6 cases, whereas RNA sequencing detected the fusion transcripts in 5 cases (NFATC2::NUTM2A, n=2; NFATC2::NUTM2E, n=3). Ultrastructural examination of 1 case suggested epithelial differentiation. All patients remained disease-free after complete resection (median follow-up: 24 mo; range: 9 to 41 mo). These findings define a novel primary pulmonary tumor entity driven by NFATC2::NUTM2 fusions, and characterized by a distinctive immunophenotype, expanding the spectrum of NUTM2-associated neoplasms. Our study underscores the utility of multiomics approaches for characterizing rare neoplasms and provides a diagnostic framework for this entity.

PMID:41821426 | DOI:10.1097/PAS.0000000000002533

FNDC1 Competitively Binds Gbeta2 to Suppress the beta-Catenin-Destruction Complex and Promote Gastric Cancer Malignancy

FASEB J. 2026 Mar 31;40(6):e71634. doi: 10.1096/fj.202503587R.

ABSTRACT

Gastric cancer (GC) is a leading cause of cancer-related deaths and has high recurrence rate. Although fibronectin domain-containing protein 1 (FNDC1) is implicated in GC progression, its molecular mechanisms remain unclear. Multi-omics analyses (TCGA, GEO datasets) were used to assess FNDC1 expression and clinical correlation. In vitro (cell proliferation, invasion, EMT markers) and in vivo (xenograft) experiments, combined with molecular assays (Co-IP, WB, ChIP), explored FNDC1's function and mechanism. FNDC1 was significantly upregulated in GC, correlating with advanced clinicopathological features and poor prognosis. Knockdown of FNDC1 suppressed GC cell proliferation, invasion, and metastasis by inhibiting EMT and Wnt/β-catenin signaling. Mechanistically, FNDC1 competitively bound the WD5 domain (residues 224-254) of Gβ2, disrupting Gβγ-Dvl1 interaction. This prevented Dvl1 degradation, promoted Axin1 ubiquitination, and destabilized the β-catenin-destruction complex (GSK3 β-APC-Axin1), leading to β-catenin accumulation and Wnt pathway activation. FNDC1 drives GC malignancy by targeting the Gβ2-Dvl1 axis to activate Wnt/β-catenin signaling, suggesting FNDC1 as a novel prognostic biomarker and therapeutic target.

PMID:41808415 | PMC:PMC12976582 | DOI:10.1096/fj.202503587R

Adaptive Collaboration with Humans: Metacognitive Policy Optimization for Multi-Agent LLMs with Continual Learning

arXiv:2603.07972v1 Announce Type: new Abstract: While scaling individual Large Language Models (LLMs) has delivered remarkable progress, the next frontier lies in scaling collaboration through multi-agent systems (MAS). However, purely autonomous MAS remain ''closed-world'' systems, constrained by the static knowledge horizon of pre-trained models. This limitation makes them brittle on tasks requiring knowledge beyond training data, often leading to collective failure under novel challenges. To address this, we propose the Human-In-the-Loop Multi-Agent Collaboration (HILA) framework, a principled paradigm for human--agent collaboration. HILA trains agents to learn a metacognitive policy that governs when to solve problems autonomously and when to defer to a human expert. To operationalize this policy, we introduce Dual-Loop Policy Optimization, which disentangles immediate decision-making from long-term capability growth. The inner loop applies Group Relative Policy Optimization (GRPO) with a cost-aware reward to optimize deferral decisions, while the outer loop implements continual learning, transforming expert feedback into high-quality supervised signals that strengthen the agent's reasoning ability. Experiments on challenging mathematical and problem-solving benchmarks show that HILA, equipped with Dual-Loop Policy Optimization, consistently outperforms advanced MAS, establishing a principled foundation for collaborative and continually improving agentic systems.

ARLArena: A Unified Framework for Stable Agentic Reinforcement Learning

arXiv:2602.21534v2 Announce Type: replace Abstract: Agentic reinforcement learning (ARL) has rapidly gained attention as a promising paradigm for training agents to solve complex, multi-step interactive tasks. Despite encouraging early results, ARL remains highly unstable, often leading to training collapse. This instability limits scalability to larger environments and longer interaction horizons, and constrains systematic exploration of algorithmic design choices. In this paper, we first propose ARLArena, a stable training recipe and systematic analysis framework that examines training stability in a controlled and reproducible setting. ARLArena first constructs a clean and standardized testbed. Then, we decompose policy gradient into four core design dimensions and assess the performance and stability of each dimension. Through this fine-grained analysis, we distill a unified perspective on ARL and propose SAMPO, a stable agentic policy optimization method designed to mitigate the dominant sources of instability in ARL. Empirically, SAMPO achieves consistently stable training and strong performance across diverse agentic tasks. Overall, this study provides a unifying policy gradient perspective for ARL and offers practical guidance for building stable and reproducible LLM-based agent training pipelines.

C-Jun-activated S100A10 promotes malignant progression via in diminishing ubiquitin-dependent degradation of vimentin in gastric cancer

Oncogene, Published online: 06 March 2026; doi:10.1038/s41388-026-03720-0

C-Jun-activated S100A10 promotes malignant progression via in diminishing ubiquitin-dependent degradation of vimentin in gastric cancer

PROSPECT: Unified Streaming Vision-Language Navigation via Semantic--Spatial Fusion and Latent Predictive Representation

arXiv:2603.03739v1 Announce Type: cross Abstract: Multimodal large language models (MLLMs) have advanced zero-shot end-to-end Vision-Language Navigation (VLN), yet robust navigation requires not only semantic understanding but also predictive modeling of environment dynamics and spatial structure. We propose PROSPECT, a unified streaming navigation agent that couples a streaming Vision-Language-Action (VLA) policy with latent predictive representation learning. PROSPECT uses CUT3R as a streaming 3D foundation spatial encoder to produce long-context, absolute-scale spatial features, and fuses them with SigLIP semantic features via cross-attention. During training, we introduce learnable stream query tokens that query the streaming context and predict next-step 2D and 3D latent features (rather than pixels or explicit modalities), supervised in the latent spaces of frozen SigLIP and CUT3R teachers. The predictive branch shapes internal representations without inference overhead. Experiments on VLN-CE benchmarks and real-robot deployment demonstrate state-of-the-art performance and improved long-horizon robustness under diverse lighting. We will release code for the community soon.

EnECG: Efficient Ensemble Learning for Electrocardiogram Multi-task Foundation Model

arXiv:2511.22935v2 Announce Type: replace-cross Abstract: Electrocardiogram (ECG) analysis plays a vital role in the early detection, monitoring, and management of various cardiovascular conditions. While existing models have achieved notable success in ECG interpretation, they fail to leverage the interrelated nature of various cardiac abnormalities. Conversely, developing a specific model capable of extracting all relevant features for multiple ECG tasks remains a significant challenge. Large-scale foundation models, though powerful, are not typically pretrained on ECG data, making full re-training or fine-tuning computationally expensive. To address these challenges, we propose EnECG(Mixture of Experts-based Ensemble Learning for ECG Multi-tasks), an ensemble-based framework that integrates multiple specialized foundation models, each excelling in different aspects of ECG interpretation. Instead of relying on a single model or single task, EnECG leverages the strengths of multiple specialized models to tackle a variety of ECG-based tasks. To mitigate the high computational cost of full re-training or fine-tuning, we introduce a lightweight adaptation strategy: attaching dedicated output layers to each foundation model and applying Low-Rank Adaptation (LoRA) only to these newly added parameters. We then adopt a Mixture of Experts (MoE) mechanism to learn ensemble weights, effectively combining the complementary expertise of individual models. Our experimental results demonstrate that by minimizing the scope of fine-tuning, EnECG can help reduce computational and memory costs while maintaining the strong representational power of foundation models. This framework not only enhances feature extraction and predictive performance but also ensures practical efficiency for real-world clinical applications. The code is available at https://github.com/yuhaoxu99/EnECG.git.

Nano-EmoX: Unifying Multimodal Emotional Intelligence from Perception to Empathy

arXiv:2603.02123v2 Announce Type: replace Abstract: The development of affective multimodal language models (MLMs) has long been constrained by a gap between low-level perception and high-level interaction, leading to fragmented affective capabilities and limited generalization. To bridge this gap, we propose a cognitively inspired three-level hierarchy that organizes affective tasks according to their cognitive depth-perception, understanding, and interaction-and provides a unified conceptual foundation for advancing affective modeling. Guided by this hierarchy, we introduce Nano-EmoX, a small-scale multitask MLM, and P2E (Perception-to-Empathy), a curriculum-based training framework. Nano-EmoX integrates a suite of omni-modal encoders, including an enhanced facial encoder and a fusion encoder, to capture key multimodal affective cues and improve cross-task transferability. The outputs are projected into a unified language space via heterogeneous adapters, empowering a lightweight language model to tackle diverse affective tasks. Concurrently, P2E progressively cultivates emotional intelligence by aligning rapid perception with chain-of-thought-driven empathy. To the best of our knowledge, Nano-EmoX is the first compact MLM (2.2B) to unify six core affective tasks across all three hierarchy levels, achieving state-of-the-art or highly competitive performance across multiple benchmarks, demonstrating excellent efficiency and generalization.

UniWeTok: An Unified Binary Tokenizer with Codebook Size $\mathit{2^{128}}$ for Unified Multimodal Large Language Model

arXiv:2602.14178v1 Announce Type: cross Abstract: Unified Multimodal Large Language Models (MLLMs) require a visual representation that simultaneously supports high-fidelity reconstruction, complex semantic extraction, and generative suitability. However, existing visual tokenizers typically struggle to satisfy these conflicting objectives within a single framework. In this paper, we introduce UniWeTok, a unified discrete tokenizer designed to bridge this gap using a massive binary codebook ($\mathit{2^{128}}$). For training framework, we introduce Pre-Post Distillation and a Generative-Aware Prior to enhance the semantic extraction and generative prior of the discrete tokens. In terms of model architecture, we propose a convolution-attention hybrid architecture with the SigLu activation function. SigLu activation not only bounds the encoder output and stabilizes the semantic distillation process but also effectively addresses the optimization conflict between token entropy loss and commitment loss. We further propose a three-stage training framework designed to enhance UniWeTok's adaptability cross various image resolutions and perception-sensitive scenarios, such as those involving human faces and textual content. On ImageNet, UniWeTok achieves state-of-the-art image generation performance (FID: UniWeTok 1.38 vs. REPA 1.42) while requiring a remarkably low training compute (Training Tokens: UniWeTok 33B vs. REPA 262B). On general-domain, UniWeTok demonstrates highly competitive capabilities across a broad range of tasks, including multimodal understanding, image generation (DPG Score: UniWeTok 86.63 vs. FLUX.1 [Dev] 83.84), and editing (GEdit Overall Score: UniWeTok 5.09 vs. OmniGen 5.06). We release code and models to facilitate community exploration of unified tokenizer and MLLM.

ShallowJail: Steering Jailbreaks against Large Language Models

arXiv:2602.07107v2 Announce Type: replace-cross Abstract: Large Language Models(LLMs) have been successful in numerous fields. Alignment has usually been applied to prevent them from harmful purposes. However, aligned LLMs remain vulnerable to jailbreak attacks that deliberately mislead them into producing harmful outputs. Existing jailbreaks are either black-box, using carefully crafted, unstealthy prompts, or white-box, requiring resource-intensive computation. In light of these challenges, we introduce ShallowJail, a novel attack that exploits shallow alignment in LLMs. ShallowJail can misguide LLMs' responses by manipulating the initial tokens during inference. Through extensive experiments, we demonstrate the effectiveness of ShallowJail, which substantially degrades the safety of state-of-the-art LLM responses. Our code is available at https://github.com/liuup/ShallowJail.
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