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From Efficiency to Adaptivity: A Deeper Look at Adaptive Reasoning in Large Language Models
SciTrust 2.0: A Comprehensive Framework for Evaluating Trustworthiness of Large Language Models in Scientific Applications
Multi-Agent Reinforcement Learning for Market Making: Competition without Collusion
Single-cell multi-omics analysis reveals cancer regulatory elements of transcriptional programs and clinical implications
Cell Death Dis. 2025 Oct 21;16(1):746. doi: 10.1038/s41419-025-08060-7.
ABSTRACT
The regulatory mechanisms governing transcriptional programs in the cancer genome remain elusive, particularly those concerning cell-type specificity. We carefully curated single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) data from eight distinct carcinoma tissues, including breast, skin, colon, endometrium, lung, ovary, liver, and kidney. Using single-cell multi-omics analysis, we identified extensive open chromatin regions and constructed peak-gene link networks, which can reveal distinct cancer gene regulation and genetic risks. We further explored conserved epigenetic regulation across cell types within cancer and elucidated their functional implications. Moreover, we identified cell-type-associated transcription factors (TFs) that regulate key cellular functions, such as the TEAD family of TFs, which widely control cancer-related signaling pathways in tumor cells. In colon cancer, we further identified tumor-specific TFs that are more highly activated in tumor cells than in normal epithelial cells, including CEBPG, LEF1, SOX4, TCF7, and TEAD4, which are pivotal in driving malignant transcriptional programs and represent potential therapeutic targets, as corroborated by single-cell sequencing data from multiple sources and in vitro experiments. Our findings provide a comprehensive understanding of the regulatory dynamics underlying carcinomas and offer valuable insights into potential therapeutic interventions.
PMID:41120274 | PMC:PMC12541060 | DOI:10.1038/s41419-025-08060-7
Using Large Language Models to Assess the Consistency of Randomized Controlled Trials on AI Interventions With CONSORT-AI: Cross-Sectional Survey
Decoding per- and polyfluoroalkyl substances (PFAS) in hepatocellular carcinoma: a multi-omics and computational toxicology approach
J Transl Med. 2025 May 2;23(1):504. doi: 10.1186/s12967-025-06517-z.
ABSTRACT
BACKGROUND: Per- and polyfluoroalkyl substances (PFAS), particularly perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), are synthetic chemicals known for their widespread use and environmental persistence. These compounds have been increasingly linked to hepatotoxicity and the development of hepatocellular carcinoma (HCC). However, the molecular mechanisms by which PFAS contribute to HCC remain underexplored.
METHODS: This study employs a multi-omics approach that combines network toxicology, integrated machine learning, single-cell RNA sequencing, spatial transcriptomics, experimental validation, and molecular docking simulations to uncover the mechanisms through which PFAS exposure drives HCC. We analyzed publicly available transcriptomic data from several HCC cohorts and used differential gene expression analysis to identify targets associated with both PFAS exposure and HCC. We constructed a protein-protein interaction (PPI) network and a survival risk model, the PFAS-related HCC signature (PFASRHSig), based on integrated machine learning to identify prognostic biomarkers, with the goal of identifying core targets of PFAS in HCC progression and prognosis. RT-qPCR and immunohistochemical (IHC) staining were used to validate the expression levels of the targets in both tumor and normal tissues. Molecular docking simulations were conducted to assess the binding affinities between PFAS compounds and selected target proteins.
RESULTS: Functional enrichment studies revealed that PFAS targets were associated with metabolic signaling pathways, which are actively involved in lipid, glucose, drug metabolism, etc. Through integrated machine learning and PPI network analysis, we identified six genes, APOA1, ESR1, IGF1, PPARGC1A, SERPINE1, and PON1, that serve as core targets of PFAS in both HCC progression and prognosis. These targets were further validated via bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomics, which revealed differential expression patterns across various cell types in the HCC tumor microenvironment. The results of RT-qPCR and IHC staining were consistent with the in silico findings. Molecular docking simulations revealed strong binding affinities between PFAS compounds and these core targets, supporting their potential roles in PFAS-induced hepatocarcinogenesis.
CONCLUSIONS: Our study highlights key molecular targets and pathways involved in PFAS-induced liver carcinogenesis and proposes a robust survival risk model (PFASRHSig) for HCC. These findings provide new insights into PFAS toxicity mechanisms and offer potential therapeutic targets for mitigating the health risks associated with PFAS exposure. Collectively, our findings help in advancing clinical applications by providing insights into disease mechanisms and potential therapeutic interventions.
PMID:40317014 | PMC:PMC12049027 | DOI:10.1186/s12967-025-06517-z
A deep learning framework for <em>in silico</em> screening of anticancer drugs at the single-cell level
Natl Sci Rev. 2024 Dec 10;12(2):nwae451. doi: 10.1093/nsr/nwae451. eCollection 2025 Feb.
ABSTRACT
Tumor heterogeneity plays a pivotal role in tumor progression and resistance to clinical treatment. Single-cell RNA sequencing (scRNA-seq) enables us to explore heterogeneity within a cell population and identify rare cell types, thereby improving our design of targeted therapeutic strategies. Here, we use a pan-cancer and pan-tissue single-cell transcriptional landscape to reveal heterogeneous expression patterns within malignant cells, precancerous cells, as well as cancer-associated stromal and endothelial cells. We introduce a deep learning framework named Shennong for in silico screening of anticancer drugs for targeting each of the landscape cell clusters. Utilizing Shennong, we could predict individual cell responses to pharmacologic compounds, evaluate drug candidates' tissue damaging effects, and investigate their corresponding action mechanisms. Prioritized compounds in Shennong's prediction results include FDA-approved drugs currently undergoing clinical trials for new indications, as well as drug candidates reporting anti-tumor activity. Furthermore, the tissue damaging effect prediction aligns with documented injuries and terminated discovery events. This robust and explainable framework has the potential to accelerate the drug discovery process and enhance the accuracy and efficiency of drug screening.
PMID:39872221 | PMC:PMC11771446 | DOI:10.1093/nsr/nwae451
The roles of intratumour heterogeneity in the biology and treatment of pancreatic ductal adenocarcinoma
Oncogene, Published online: 10 September 2022; doi:10.1038/s41388-022-02448-x
The roles of intratumour heterogeneity in the biology and treatment of pancreatic ductal adenocarcinoma