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Protein glycosylation profiling in lung adenocarcinoma and precursor lesions: analysis of FFPE tissue sections

Anal Bioanal Chem. 2026 Jul 27. doi: 10.1007/s00216-026-06702-z. Online ahead of print.

ABSTRACT

Protein glycosylation is a major post-translational modification that regulates tumor initiation and progression; however, its dynamic modeling during multistep evolution of lung adenocarcinoma (LUAD) remains poorly understood, particularly in clinically archived tissues. Here, we established an integrated multi-omics workflow combining global proteomes, N-glycans, and site-specific intact N-glycopeptides to comprehensively characterize glycosylation in formalin-fixed paraffin-embedded (FFPE) specimens spanning four pathological stages of LUAD progression: inflammatory nodules (IN), atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and invasive adenocarcinoma (IAC). Using optimized protein extraction, hydrophilic interaction liquid chromatography (HILIC)-based glycopeptide enrichment, and high-resolution LC-MS/MS, we achieved large-scale identification of proteins, N-glycans, and intact glycopeptides from archival clinical samples. Integrated analyses revealed progressive remodeling of site-specific N-glycosylation during malignant transformation, characterized by increased glycan branching, fucosylation, and sialylation during the transition from premalignant lesions to invasive cancer. Sialylated glycans reached their highest abundance in the premalignant AAH stage, whereas highly branched and fucosylated complex N-glycans predominated in invasive adenocarcinoma, indicating stage-dependent glycan remodeling throughout disease progression. Functional enrichment analyses linked these glycosylation alterations to extracellular matrix organization, neutrophil degranulation, and immune-associated pathways, while representative glycoproteins, including CEACAM6 and FGB, exhibited coordinated changes in protein abundance and site-specific glycoform micro-heterogeneity across pathological stages. Collectively, this study demonstrates the feasibility of deep glycoproteomic profiling using archived FFPE tissues and provides a comprehensive molecular atlas of glycosylation remodeling during LUAD progression. These findings establish a valuable resource for elucidating disease mechanisms and identifying stage-specific glycosylation biomarkers and potential glycan-targeted therapeutic candidates for early lung adenocarcinoma.

PMID:42509285 | DOI:10.1007/s00216-026-06702-z

The Model Says Walk: How Surface Heuristics Override Implicit Constraints in LLM Reasoning

arXiv:2603.29025v1 Announce Type: cross Abstract: Large language models systematically fail when a salient surface cue conflicts with an unstated feasibility constraint. We study this through a diagnose-measure-bridge-treat framework. Causal-behavioral analysis of the ``car wash problem'' across six models reveals approximately context-independent sigmoid heuristics: the distance cue exerts 8.7 to 38 times more influence than the goal, and token-level attribution shows patterns more consistent with keyword associations than compositional inference. The Heuristic Override Benchmark (HOB) -- 500 instances spanning 4 heuristic by 5 constraint families with minimal pairs and explicitness gradients -- demonstrates generality across 14 models: under strict evaluation (10/10 correct), no model exceeds 75%, and presence constraints are hardest (44%). A minimal hint (e.g., emphasizing the key object) recovers +15 pp on average, suggesting the failure lies in constraint inference rather than missing knowledge; 12/14 models perform worse when the constraint is removed (up to -39 pp), revealing conservative bias. Parametric probes confirm that the sigmoid pattern generalizes to cost, efficiency, and semantic-similarity heuristics; goal-decomposition prompting recovers +6 to 9 pp by forcing models to enumerate preconditions before answering. Together, these results characterize heuristic override as a systematic reasoning vulnerability and provide a benchmark for measuring progress toward resolving it.

Disentangling Reasoning in Large Audio-Language Models for Ambiguous Emotion Prediction

arXiv:2603.08230v1 Announce Type: cross Abstract: Speech emotion recognition plays an important role in various applications. However, most existing approaches predict a single emotion label, oversimplifying the inherently ambiguous nature of human emotional expression. Recent large audio-language models show promise in generating richer outputs, but their reasoning ability for ambiguous emotional understanding remains limited. In this work, we reformulate ambiguous emotion recognition as a distributional reasoning problem and present the first systematic study of ambiguity-aware reasoning in LALMs. Our framework comprises two complementary components: an ambiguity-aware objective that aligns predictions with human perceptual distributions, and a structured ambiguity-aware chain-of-thought supervision that guides reasoning over emotional cues. Experiments on IEMOCAP and CREMA-D demonstrate consistent improvements across SFT, DPO, and GRPO training strategies.

Agentic AI as a Cybersecurity Attack Surface: Threats, Exploits, and Defenses in Runtime Supply Chains

arXiv:2602.19555v1 Announce Type: cross Abstract: Agentic systems built on large language models (LLMs) extend beyond text generation to autonomously retrieve information and invoke tools. This runtime execution model shifts the attack surface from build-time artifacts to inference-time dependencies, exposing agents to manipulation through untrusted data and probabilistic capability resolution. While prior work has focused on model-level vulnerabilities, security risks emerging from cyclic and interdependent runtime behavior remain fragmented. We systematize these risks within a unified runtime framework, categorizing threats into data supply chain attacks (transient context injection and persistent memory poisoning) and tool supply chain attacks (discovery, implementation, and invocation). We further identify the Viral Agent Loop, in which agents act as vectors for self-propagating generative worms without exploiting code-level flaws. Finally, we advocate a Zero-Trust Runtime Architecture that treats context as untrusted control flow and constrains tool execution through cryptographic provenance rather than semantic inference.

LQA: A Lightweight Quantized-Adaptive Framework for Vision-Language Models on the Edge

arXiv:2602.07849v2 Announce Type: replace Abstract: Deploying Vision-Language Models (VLMs) on edge devices is challenged by resource constraints and performance degradation under distribution shifts. While test-time adaptation (TTA) can counteract such shifts, existing methods are too resource-intensive for on-device deployment. To address this challenge, we propose LQA, a lightweight, quantized-adaptive framework for VLMs that combines a modality-aware quantization strategy with gradient-free test-time adaptation. We introduce Selective Hybrid Quantization (SHQ) and a quantized, gradient-free adaptation mechanism to enable robust and efficient VLM deployment on resource-constrained hardware. Experiments across both synthetic and real-world distribution shifts show that LQA improves overall adaptation performance by 4.5\%, uses less memory than full-precision models, and significantly outperforms gradient-based TTA methods, achieving up to 19.9$\times$ lower memory usage across seven open-source datasets. These results demonstrate that LQA offers a practical pathway for robust, privacy-preserving, and efficient VLM deployment on edge devices.
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