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Spatial and multi-omics transcriptomic dissects platinum resistance in lung adenocarcinoma: a five-gene predictive model with tumor microenvironment dynamics
Chem Biol Interact. 2026 Feb 7:111952. doi: 10.1016/j.cbi.2026.111952. Online ahead of print.
ABSTRACT
The scarcity of reliable biomarkers and predictive models for platinum resistance in lung adenocarcinoma (LUAD) poses a significant clinical challenge. This study endeavors to identify molecular subtypes related to platinum resistance and construct a robust predictive model through multi-omics techniques. We performed integrative analysis of public datasets using advanced bioinformatics strategies, including spatial transcriptome deconvolution and consensus clustering. Bulk RNA deconvolution analysis was conducted to characterize tumor microenvironment heterogeneity. Feature selection was performed using the Supervised Principal Component (SuperPC) algorithm, followed by diagnostic model construction validated through receiver operating characteristic (ROC) analysis. Functional validation was performed through cytological experiments measuring cisplatin IC50 alterations following gene manipulation in LUAD cell lines. Consensus clustering revealed distinct LUAD subtypes, with Cluster1 demonstrating significant platinum resistance. We first subtyped the patients in the bulk transcriptome data based on consistency clustering, and then analyzed the differences between different platinum-resistant subtypes (Cluster 1 and Cluster 2), so as to screen 333 isotype-specific differentially expressed genes and 15 platinum resistance-related (PRR) genes were selected through machine learning. A refined 5-gene signature (ANKRD29/CACNA2D2/DSP/HSD17B6/SPP1) achieved exceptional predictive performance (AUC=0.9639). Spatial transcriptomics demonstrated compartmentalized expression patterns: SPP1/DSP localized to tumor niches, HSD17B6/CACNA2D2 to epithelial regions, and ANKRD29 depletion in stromal areas. Cellular colocalization analysis revealed malignant epithelial PH proximity to myeloid and mast cells. Functional validation confirmed that ANKRD29/CACNA2D2 overexpression sensitized A549/DDP cells to cisplatin, while DSP/SPP1/HSD17B6 overexpression induced resistance. Experiments in nude mice have shown that these genes are closely related to cisplatin resistance in LUAD. This study identifies the Cluster1 subtype and malignant epithelial PH as crucial determinants of platinum resistance in LUAD. Our innovative 5-gene predictive model exhibits clinical-grade diagnostic accuracy, and spatial transcriptomic characterization offers mechanistic insights into the dynamics of the tumor microenvironment.
PMID:41662930 | DOI:10.1016/j.cbi.2026.111952
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Reliability of LLMs as medical assistants for the general public: a randomized preregistered study
Nature Medicine, Published online: 09 February 2026; doi:10.1038/s41591-025-04074-y
In a randomized controlled study involving 1,298 participants from a general sample, performance of humans when assisted by a large language model (LLM) was sensibly inferior to that of the LLM alone when assessing ten medical scenarios leading to disease identification and recommendations for treatment.EcDNA-borne structural variants drive oncogenic fusion transcript amplification
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Extrachromosomal DNA drives molecular and clinical heterogeneity in hepatocellular carcinoma: a multi-omics analysis and prognostic model development
Hum Genomics. 2026 Feb 3. doi: 10.1186/s40246-026-00927-w. Online ahead of print.
ABSTRACT
BACKGROUND: Extrachromosomal DNA (ecDNA) is an emerging hallmark of cancer that promotes tumor evolution and heterogeneity. However, the molecular characteristics and clinical significance of ecDNA in hepatocellular carcinoma (HCC) remain incompletely understood.
METHODS: The clinical outcomes, genomics, transcriptomics, proteomics, tumor microenvironment, and drug target landscapes of ecDNA-negative and ecDNA-positive HCC in the Cancer Genome Atlas (TCGA) were compared. Next, the least absolute shrinkage and selection operator (LASSO) and random survival forest (RSF) algorithms were used to screen the ecDNA gene signature. A nomogram was constructed and evaluated based on the risk score and clinicopathological features. Finally, the role of DNASE1L3 was validated through in vitro experiments.
RESULTS: EcDNA-positive tumors showed increased vascular invasion, higher AFP levels, and more TP53 mutations. These tumors displayed unique activation of proliferation pathways, decreased stromal infiltration, and heightened immune activation. Our validated six-gene signature (RNF186, BMP6, AOC1, FBLL1, MYBL2, and DNASE1L3) demonstrated strong prognostic value when combined with tumor stage in the nomogram. Notably, DNASE1L3 was downregulated in HCC, showed endothelial cell-specific expression, and suppressed the proliferation and migration of Hep3B2.1-7 cells.
CONCLUSION: Our study characterizes the molecular and clinical distinctions between ecDNA-negative and ecDNA-positive HCC and establishes a clinically applicable gene signature for patient prognosis. These findings advance our understanding of ecDNA-driven tumor heterogeneity and provide potential strategies for personalized HCC management.
PMID:41634868 | DOI:10.1186/s40246-026-00927-w
Integrative proteogenomics maps multifactorial aetiology, progression and therapeutic vulnerabilities in gastric cancer
Gut. 2026 Jan 30:gutjnl-2025-337247. doi: 10.1136/gutjnl-2025-337247. Online ahead of print.
ABSTRACT
BACKGROUND: Gastric cancer, with disproportionately higher incidence in East Asia, arises from complex host-microbiome-environment interactions beyond Helicobacter pylori (HP) infection. However, the molecular architecture linking environmental carcinogens, microbial succession and host response remains unclear.
OBJECTIVE: To delineate multifactorial aetiologies and clinically actionable subtypes/biomarkers of gastric cancer through integrative proteogenomic, microbial and environmental exposure profiling.
DESIGN: We established a multiomics atlas of paired tumour, adjacent mucosa tissues and blood from 154 treatment-naïve Taiwanese patients, integrating whole-exome sequencing, RNA-seq, proteome and phosphoproteome profiling with carcinogen signatures, HP status, microbiome composition and refined anatomical mapping. Cell-based functional assays tested carcinogen effects. Microbial subtype was assessed in an independent cohort.
RESULTS: A polycyclic-aromatic-hydrocarbon signature, dibenz[a,h]acridine, emerged as a high-risk exposure promoting invasion, immune suppression and poor survival, significantly exceeding nitrosamine-linked risk in this cohort. Multilayer integration defined three initiation ecologies: HP-driven inflammatory, non-HP microbiome-enriched immune-silent and HP-free microbially depleted states. Among HP-negative tumours, a Streptococcus-enriched subtype associated with tight-junction (CLDN18.2/ZO-1/OCLN) disruption and epithelial-mesenchymal transition, whereas a subset of clinically aggressive cases retained CLDN18.2-high epithelial-stable subtype for therapeutic accessibility. An independent cohort revealed gastric juice-derived Streptococcus anginosus abundance inversely correlated with tight-junction proteins. Anatomical mapping reveals location-specific, sex-specific, subtype-specific oncogenic networks and kinase activity, including CDK4 activation in clinical biomarker-negative tumours. Decision-tree models combining exposure and proteome-immune states refined recurrence and survival prediction beyond stage.
CONCLUSION: This proteogenomic framework defines exposure-informed and microbiome-informed gastric cancer subtypes, providing a molecular schema for patient stratification, prevention and actionable therapeutic vulnerabilities.
PMID:41617485 | DOI:10.1136/gutjnl-2025-337247
Publisher Correction: Best practice recommendations and considerations for designing and electronically implementing event-driven diaries in clinical trials
npj Digital Medicine, Published online: 27 January 2026; doi:10.1038/s41746-026-02396-w
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Multimodal digital biopsy for preoperative prediction of occult peritoneal metastasis in gastric cancer
npj Digital Medicine, Published online: 26 January 2026; doi:10.1038/s41746-025-02268-9
Multimodal digital biopsy for preoperative prediction of occult peritoneal metastasis in gastric cancerPyHealth 2.0: A Comprehensive Open-Source Toolkit for Accessible and Reproducible Clinical Deep Learning
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An artificial intelligence-powered learning health system to improve sepsis detection and quality of care: a before-and-after study
npj Digital Medicine, Published online: 20 January 2026; doi:10.1038/s41746-025-02180-2
An artificial intelligence-powered learning health system to improve sepsis detection and quality of care: a before-and-after studyLLM-driven collaborative framework for knowledge-enhanced cancer pain assessment and management
npj Digital Medicine, Published online: 19 January 2026; doi:10.1038/s41746-026-02362-6
LLM-driven collaborative framework for knowledge-enhanced cancer pain assessment and management