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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

SARE: Sample-wise Adaptive Reasoning for Training-free Fine-grained Visual Recognition

arXiv:2603.17729v2 Announce Type: replace-cross Abstract: Recent advances in Large Vision-Language Models (LVLMs) have enabled training-free Fine-Grained Visual Recognition (FGVR). However, effectively exploiting LVLMs for FGVR remains challenging due to the inherent visual ambiguity of subordinate-level categories. Existing methods predominantly adopt either retrieval-oriented or reasoning-oriented paradigms to tackle this challenge, but both are constrained by two fundamental limitations:(1) They apply the same inference pipeline to all samples without accounting for uneven recognition difficulty, thereby leading to suboptimal accuracy and efficiency; (2) The lack of mechanisms to consolidate and reuse error-specific experience causes repeated failures on similar challenging cases. To address these limitations, we propose SARE, a Sample-wise Adaptive textbfREasoning framework for training-free FGVR. Specifically, SARE adopts a cascaded design that combines fast candidate retrieval with fine-grained reasoning, invoking the latter only when necessary. In the reasoning process, SARE incorporates a self-reflective experience mechanism that leverages past failures to provide transferable discriminative guidance during inference, without any parameter updates. Extensive experiments across 14 datasets substantiate that SARE achieves state-of-the-art performance while substantially reducing computational overhead.

Evaluation Faking: Unveiling Observer Effects in Safety Evaluation of Frontier AI Systems

arXiv:2505.17815v2 Announce Type: replace Abstract: As foundation models grow increasingly more intelligent, reliable and trustworthy safety evaluation becomes more indispensable than ever. However, an important question arises: Whether and how an advanced AI system would perceive the situation of being evaluated, and lead to the broken integrity of the evaluation process? During standard safety tests on a mainstream large reasoning model, we unexpectedly observe that the model without any contextual cues would occasionally recognize it is being evaluated and hence behave more safety-aligned. This motivates us to conduct a systematic study on the phenomenon of evaluation faking, i.e., an AI system autonomously alters its behavior upon recognizing the presence of an evaluation context and thereby influencing the evaluation results. Through extensive experiments on a diverse set of foundation models with mainstream safety benchmarks, we reach the main finding termed the observer effects for AI: When the AI system under evaluation is more advanced in reasoning and situational awareness, the evaluation faking behavior becomes more ubiquitous, which reflects in the following aspects: 1) Reasoning models recognize evaluation 16% more often than non-reasoning models. 2) Scaling foundation models (32B to 671B) increases faking by over 30% in some cases, while smaller models show negligible faking. 3) AI with basic memory is 2.3x more likely to recognize evaluation and scores 19% higher on safety tests (vs. no memory). To measure this, we devised a chain-of-thought monitoring technique to detect faking intent and uncover internal signals correlated with such behavior, offering insights for future mitigation studies.
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