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Multi-Omics and Single-Cell Mendelian Randomization Reveal a Potential Role of VNN2 in Lung Adenocarcinoma in Resting Natural Killer Cells

13 March 2026 at 18:00

World J Oncol. 2026 Mar 5;17(2):247-255. doi: 10.14740/wjon2689. eCollection 2026 Apr.

ABSTRACT

BACKGROUND: We aimed to evaluate the potential association between genetically predicted vanin-2 (VNN2) expression and lung adenocarcinoma (LUAD) risk, and to explore the immune cell subtype that may underlie this relationship.

METHODS: We integrated whole-blood expression quantitative trait loci (eQTL) data from eQTLGen, plasma protein quantitative trait loci (pQTL) data from deCODE, and LUAD genome-wide association study (GWAS) data from European-ancestry cohorts, together with differential expression analysis using GEPIA2, to identify candidate genes for subsequent single-cell eQTL (sc-eQTL) Mendelian randomization (MR) analysis. For the sc-eQTL analysis, VNN2-associated eQTLs from 14 immune cell types profiled in the OneK1K single-cell eQTL resource were tested for associations with LUAD risk.

RESULTS: Bulk-level MR analysis showed that genetically predicted increases in VNN2 expression and protein levels were significantly associated with a reduced risk of LUAD (eQTL-MR: odds ratio (OR) = 0.964, 95% confidence interval (95% CI), 0.934-0.995; P = 0.024; pQTL-MR: OR = 0.946, 95% CI, 0.921-0.970; P = 2.87 Γ— 10-5). Transcriptomic analyses confirmed significant downregulation of VNN2 in LUAD tumors compared with normal lung tissues. sc-eQTL MR identified the strongest association in resting natural killer (rNK) cells (OR = 0.896, 95% CI, 0.829-0.967; P = 0.005).

CONCLUSIONS: Multi-omics and sc-eQTL MR analyses indicated that genetically predicted increases in VNN2 expression were associated with a reduced risk of LUAD, with the most pronounced effect observed in rNK cells. These findings suggest a potential cell type-specific role of VNN2 in LUAD susceptibility and warrant further studies to validate its biological relevance and clinical implications.

PMID:41822323 | PMC:PMC12978397 | DOI:10.14740/wjon2689

Isotonic Layer: A Universal Framework for Generic Recommendation Debiasing

arXiv:2603.06589v1 Announce Type: cross Abstract: Model calibration and debiasing are fundamental to the reliability and fairness of large scale recommendation systems. We introduce the Isotonic Layer, a novel, differentiable framework that integrates piecewise linear fitting directly into neural architectures. By partitioning the feature space into discrete segments and optimizing non negative slopes via a constrained dot product mechanism, we enforce a global monotonic inductive bias. This ensures model outputs remain logically consistent with critical features such as latent relevance, recency, or quality scores. We further generalize this architecture by parameterizing segment wise slopes as learnable embeddings. This enables the model to adaptively capture context specific distortions, such as position based CTR bias through specialized isotonic profiles. Our approach utilizes a dual task formulation that decouples the recommendation objective into latent relevance estimation and bias aware calibration. A major contribution of this work is the ability to perform highly granular, customized calibration for arbitrary combinations of context features, a level of control difficult to achieve with traditional non parametric methods. We also extend this to Multi Task Learning environments with dedicated embeddings for distinct objectives. Extensive empirical evaluations on real world datasets and production AB tests demonstrate that the Isotonic Layer effectively mitigates systematic bias and enhances calibration fidelity, significantly outperforming production baselines in both predictive accuracy and ranking consistency.

Beyond In-Domain Detection: SpikeScore for Cross-Domain Hallucination Detection

arXiv:2601.19245v4 Announce Type: replace Abstract: Hallucination detection is critical for deploying large language models (LLMs) in real-world applications. Existing hallucination detection methods achieve strong performance when the training and test data come from the same domain, but they suffer from poor cross-domain generalization. In this paper, we study an important yet overlooked problem, termed generalizable hallucination detection (GHD), which aims to train hallucination detectors on data from a single domain while ensuring robust performance across diverse related domains. In studying GHD, we simulate multi-turn dialogues following LLMs' initial response and observe an interesting phenomenon: hallucination-initiated multi-turn dialogues universally exhibit larger uncertainty fluctuations than factual ones across different domains. Based on the phenomenon, we propose a new score SpikeScore, which quantifies abrupt fluctuations in multi-turn dialogues. Through both theoretical analysis and empirical validation, we demonstrate that SpikeScore achieves strong cross-domain separability between hallucinated and non-hallucinated responses. Experiments across multiple LLMs and benchmarks demonstrate that the SpikeScore-based detection method outperforms representative baselines in cross-domain generalization and surpasses advanced generalization-oriented methods, verifying the effectiveness of our method in cross-domain hallucination detection.
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