Clinical and Translational Medicine最新文献

{"title":"Neuro-associated SEMA3C+ tumour cells promote gastric cancer peritoneal metastasis via EBF2–FGF7–FGFR2-mediated tumour–endothelial crosstalk","authors":"Yajing Zhou, Chao Dong, Weikang Li, Minghao Sun, Qingyu Xie, Lixing Gu, Pengbo Wang, Chengxiang Xu, Tianzhan Gao, Caixin Zhu, Kaipeng Duan, Jin Zhou, Dongbao Li","doi":"10.1002/ctm2.70861","DOIUrl":"10.1002/ctm2.70861","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Recent studies have established that the nervous system is not merely a bystander in tumour progression but can actively remodel the tumour microenvironment through the neuro–tumour axis, thereby promoting tumour invasion, metastasis and survival. Semaphorin 3C (SEMA3C) has been reported to regulate tumour migration, angiogenesis and immune suppression, highlighting its potential role in tumour progression. Although the neuro–tumour axis has been identified in multiple cancer types, its role and underlying mechanisms in gastric cancer peritoneal metastasis (GCPM) remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed single-nucleus RNA sequencing (snRNA-seq) of GCPM tissues to profile tumour cell heterogeneity and identify tumour cell populations associated with neural-related signalling. Candidate tumour–microenvironmental interactions were further investigated using patient-derived organoids and co-culture models, and the identified signalling axis was validated using corresponding in vivo models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>SnRNA-seq identified a distinct subpopulation of poorly differentiated tumour cells with pronounced stem-like properties and high SEMA3C expression. This subpopulation was associated with neural-related features and interacted with tumour-associated endothelial cells, thereby contributing to remodelling of the metastatic microenvironment. Furthermore, these cells enhanced tumour–endothelial communication by activating the fibroblast growth factor receptor-associated signalling pathway. The transcription factor early B-cell factor 2 (EBF2) regulates the expression of FGF7 within this subpopulation, thereby strengthening FGF7–FGFR2 signalling and promoting tumour progression. Functional validation further demonstrated that SEMA3C depletion impaired organoid growth and tumour–endothelial interactions, whereas disruption of the SEMA3C–EBF2–FGF7–FGFR2 signalling axis attenuated tumour growth and peritoneal tumour burden in vivo. Additional experimental validation supported the potential involvement of neural-related signalling in the SEMA3C-associated tumour cell state.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings identify a SEMA3C<sup>+</sup> tumour cell subpopulation associated with neural-related signalling and suggest that SEMA3C promotes tumour–endothelial interactions through the EBF2–FGF7–FGFR2 signalling axis, providing a potential mechanistic link between neural regulation and microenvironmental remodelling in peritoneal metast","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70861","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Graph attention network-driven single-cell omics analysis reveals how B4GALNT1-mediated glycosylation remodelling of the ferroptosis–pyroptosis network promotes drug resistance in hepatocellular carcinoma","authors":"Lihan Bie, Biao Xu, Haitao Shen, Shuwen Ren, Xiaoyang Yao, Zhouhong Xiang, Zheng Xu","doi":"10.1002/ctm2.70873","DOIUrl":"10.1002/ctm2.70873","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Acquired resistance to sorafenib in hepatocellular carcinoma (HCC) is accompanied by coordinated changes in oxidative-stress handling and regulated cell-death pathways, yet how membrane organisation connects these adaptations is not fully resolved. We therefore examined whether B4GALNT1, a ganglioside biosynthetic glycosyltransferase, couples changes in ganglioside composition and lipid-raft architecture to ferroptosis regulation and caspase-1/GSDMD-associated signalling in sorafenib-resistant HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We combined TCGA-LIHC analysis, single-cell transcriptomics, pathway-level analyses, and graph attention network modelling with a treatment-annotated local cohort of 92 patients with HCC who received sorafenib. Functional experiments were conducted in Huh7/Huh7-SR cells and additional liver-tumour models using B4GALNT1 gain- and loss-of-function, an independent second-sgRNA knockout clone, GM1 rescue, and re-expression of either wild-type B4GALNT1 or the catalytic-loss D358A variant. Validation included ganglioside profiling, detergent-resistant membrane isolation, lipid-raft disruption/repletion, ferroptosis-directed pharmacology, cell-death measurements, and xenograft studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>B4GALNT1 was enriched in tumour-associated hepatocyte populations and was upregulated in Huh7-SR cells. In the local cohort, higher B4GALNT1 protein abundance tracked with less favourable response to sorafenib and poorer survival outcomes. Increasing B4GALNT1 shifted ganglioside abundance toward GM2/GM1/GD2 and increased GM1-enriched raft-associated fractions, whereas knockout produced reciprocal changes. B4GALNT1-high cells showed increased GPX4 and SLC7A11, reduced lipid peroxidation and labile Fe<sup>2</sup><sup>+</sup>, and lower ferroptotic injury. At the same time, caspase-1/GSDMD-associated signalling and IL-1β/IL-18 release increased without widespread terminal membrane lysis. Exogenous GM1 partially rescued knockout-associated changes, and wild-type B4GALNT1 restored the phenotype more effectively than the D358A mutant. Concordant directional effects were observed in additional cell models and in xenografts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The data are consistent with a model in which B4GALNT1 reshapes ganglioside composition and GM1-enriched membrane microdomains, thereby supporting a drug-adapted state that combines greater ferroptosis resistance with restricted caspase-1/GSDMD-associated membrane permeabilisation. This i","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70873","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A cortical pathway to sleep: Role of long-range inhibition","authors":"Geoffrey Terral, Renata Batista-Brito","doi":"10.1002/ctm2.70868","DOIUrl":"10.1002/ctm2.70868","url":null,"abstract":"<p>Identifying the brain regions that govern sleep–wake states has been one of the fundamental questions in neuroscience. For decades, models have emphasised subcortical structures, particularly brainstem, hypothalamus, basal forebrain and thalamus circuits, as central regulators of transitions between sleep and wakefulness.<span><sup>1</sup></span> In this framework, the neocortex has often been considered primarily a downstream recipient of global state signals. Yet, accumulating evidence indicates that cortical circuits themselves can influence sleep, sleep homeostasis and sleep-associated network dynamics.<span><sup>2-4</sup></span> Our recent study expands this emerging view by identifying a sparse population of long-range cortical inhibitory neurons (INs) that provides a cellular cortical pathway through which the neocortex can contribute to distributed sleep regulation.<span><sup>5</sup></span></p><p>The idea that the cortex can regulate sleep–wake states is particularly intriguing because cortical activity has traditionally been viewed primarily as a readout of these states. Indeed, electroencephalographic and local field potential recordings reveal stereotyped patterns of neocortical activity across sleep and wakefulness. Periods of low arousal, such as slow-wave sleep (SWS) or quiet immobility, are characterised by low-frequency fluctuations and coordinated cortical spiking and are termed synchronised states. These states alternate with desynchronised states, which occur during periods of high arousal and active behaviour and are characterised by the suppression of low-frequency cortical fluctuations. These observations raised the possibility that the cortex not only reflects sleep–wake states but also contributes to their regulation through specific neuronal populations. GABAergic INs have been repeatedly suggested as regulators of arousal state-dependent neocortical activity with fast-spiking parvalbumin-expressing INs demonstrated to promote desynchronised states. In contrast, little was known about the function of other INs in the control of synchronised states.</p><p>A small and distinct class of neocortical INs, characterised by the co-expression of somatostatin (<i>Ss</i>t) and chondrolectin (<i>Chodl</i>), together with neuronal nitric oxide synthase (<i>Nos1</i>) and the neurokinin-1 receptor (<i>Tacr1</i>), referred to as Sst-Chodl cells, has also long been proposed to contribute to sleep regulation.<span><sup>6</sup></span> Whereas most cortical neurons reduce their activity during sleep, previous ex vivo work suggested that Sst-Chodl cells may be active during sleep recovery,<span><sup>7</sup></span> pointing to a possible relationship between the activity of these cells, synchronised cortical states and behaviour. This raised three central questions: Are Sst-Chodl cells active during sleep in vivo? Do they causally promote synchronised cortical activity, sleep or both? And do they possess distinctive properties that enable ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70868","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATF6-mediated GTPase RHOQ promotes liver cancer progression via enhancing aerobic glycolysis through PAK1 phosphorylation","authors":"Yuange Zheng, Wei Li, Yuxin Guo, Xilin Zhu, Ying Liu, Xiaopan Wu","doi":"10.1002/ctm2.70871","DOIUrl":"10.1002/ctm2.70871","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) ranks among the most prevalent malignant tumours worldwide, accounting for approximately 90% of primary liver cancer cases, with the highest incidence observed in Asia. Activating Transcription Factor 6 (ATF6) is an endoplasmic reticulum stress-responsive transcription factor. Our previous studies have demonstrated that ATF6 contributes to HCC tumourigenesis and progression through signalling pathways such as ATF6–CTH–Keap1–mTORC1 and ATF6–PPM1H–RPS6KB1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>RNA sequencing identified ATF6 transcriptional targets, with Ras homolog family member Q (RHOQ) validation via chromatin immunoprecipitation and electrophoretic mobility shift assay. RHOQ expression and clinical significance were analysed in HCC cohorts. Functional assays assessed proliferation, migration, invasion and epithelial–mesenchymal transition (EMT). Tumour growth was evaluated in orthotopic (NOG mice) and subcutaneous (nude mice) models. Mechanistic analyses were performed to characterise RHOQ-mediated regulation of p21-activated kinase 1 (PAK1) signalling and metabolic remodelling. Furthermore, therapeutic synergy between PAK1 inhibitor IPA-3 and Glypican-3 (GPC3)–CAR T cells was tested.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified RHOQ as a direct transcriptional target of ATF6. Clinically, elevated RHOQ expression correlated with poorer progression-free survival (PFS) in patients with HCC. Functionally, RHOQ promoted the proliferation and metastasis of liver tumour cells. Correspondingly, RHOQ knockdown markedly suppressed tumour growth in xenograft models, with consistent results observed in a hydrodynamic tail vein injection(HTVi) model. Mechanistic investigations revealed that RHOQ directly bound to PAK1, promoted its phosphorylation and activation and thereby drove aerobic glycolysis in liver tumour cells. Furthermore, combined treatment with the PAK1-specific inhibitor IPA-3 and GPC3-targeted CAR T-cell therapy produced a significant synergistic anti-tumour effect.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In summary, this study systematically delineated the importance of the ATF6–RHOQ–PAK1 signalling cascade in driving liver cancer progression and provided a rationale for the design of targeted combination therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>RHOQ i","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70871","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond structure prediction: Translating D-I-TASSER models into functional and mechanistic hypotheses","authors":"Yujie Mo, Tianrui Jia, Yang Zhang","doi":"10.1002/ctm2.70879","DOIUrl":"10.1002/ctm2.70879","url":null,"abstract":"<p>Deep learning has revolutionised protein structure prediction, with AlphaFold demonstrating near-experimental accuracy for many targets and enabling structure prediction at proteome scale.<span><sup>1, 2</sup></span> This advance has expanded the role of predicted structures in functional annotation, mechanistic studies, and structure-guided experimental design. However, several significant challenges remain to be addressed. First, since many current AI models are trained on evolutionary profiles, proteins lacking detectable homologous sequences remain difficult to model.<span><sup>3</sup></span> In addition, for multidomain targets, accurate models of individual domains do not necessarily yield a correct full-length structure, because errors in their relative orientation can obscure interfaces and other functional relationships. Such errors are not merely geometric: they can change the inferred spatial relationships among ligand-binding regions, protein–protein interfaces and regulatory sites, and therefore alter the biological interpretation derived from a predicted structure. This distinction is particularly important in translational research, where structural models are increasingly used to formulate mechanistic hypotheses and guide subsequent experiments.</p><p>To address these challenges, we developed D-I-TASSER,<span><sup>4</sup></span> a hybrid framework that combines deep learning with physics-inspired conformational sampling for atomic-level protein structure prediction. Rather than accepting the output of a single neural network as the final structural prediction, D-I-TASSER uses replica-exchange Monte Carlo simulations to assemble structural models under a composite force field that integrates multiple complementary deep-learning-derived spatial restraints, threading-derived template information, and knowledge- and physics-based energy terms.<span><sup>5</sup></span> The resulting conformational ensemble is clustered to identify dominant structural states, which are expected to correspond to low-free-energy regions of the conformational landscape.<span><sup>6</sup></span> To enhance the collection of evolutionary information, D-I-TASSER utilises DeepMSA2 to construct deep multiple-sequence alignments (MSAs) through iterative searches of genomic and metagenomic databases, thereby improving both deep-learning-based restraint prediction and remote template identification.<span><sup>7</sup></span> For multidomain proteins, D-I-TASSER explicitly partitions the sequence into domains, generates domain-level MSAs, templates, and spatial restraints, and then recombines them to guide full-chain assembly. After model clustering and refinement, the resulting structures can be further analysed for structure-based protein function prediction, as summarised in Figure 1. This hybrid strategy therefore represents not simply another end-to-end neural network, but a complementary approach in which deep learning guides an explicit conformational sear","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70879","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics integration and machine learning identify an ACKR1+ endothelial cell-based lactate-immune signature associated with carotid plaque vulnerability and progression","authors":"Ji Zhang, Qijian Zhao, Yufei Wu, Keqiang Shu, Junye Chen, Kang Li, Yuyao Feng, Xu Zhang, Wenjian Liu, Zhichao Lai, Bao Liu","doi":"10.1002/ctm2.70856","DOIUrl":"10.1002/ctm2.70856","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Early identification of vulnerable carotid plaques is crucial for stroke prevention, but the upstream metabolic processes linked to endothelial transition and immune recruitment remain poorly defined. We characterised lactate metabolism in ACKR1<sup>+</sup> endothelial cells (ECs) in human carotid plaques and derived a machine-learning signature for discriminating plaque vulnerability.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Internal and external (GSE253903) single-cell datasets were integrated to identify endothelial subpopulations, and bulk transcriptomic (GSE163154) and in-house proteomic data were used to assess metabolism–immune correlations. Least absolute shrinkage and selection operator (LASSO) regression selected core features for a logistic model, which was locked and applied to three independent cohorts: GSE43292 (Stary stage ≥ IV vs. I–II), GSE28829 (early vs. advanced lesions) and GSE100927 (normal vs. atherosclerotic arteries). Key molecules were validated in situ by immunohistochemistry (IHC) and spatial transcriptomics in independent plaques (five stable, five unstable).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>An ACKR1<sup>+</sup> EC subpopulation linked to neovascularisation showed hyperactive glycolysis and enhanced lactate metabolism. Computational inference linked lactate accumulation to HIF-1α stability, CXCL12 release and CD8<sup>+</sup> T-cell infiltration via the CXCL12–CXCR4 axis, and the monocarboxylate transporters <i>SLC16A3</i> and <i>SLC16A4</i> emerged as quantitative readouts of this ‘lactate–immune’ state. In unstable plaques, IHC confirmed higher atypical chemokine receptor 1 (ACKR1; geometric mean ratio [GMR] = 6.82), CD8<sup>+</sup> T-cell density (GMR = 4.63), SLC16A3 (GMR = 4.74) and HIF-1α (GMR = 4.02; all <i>q</i> < .05), with lactylation elevated in the lipid core. A four-feature model (<i>ACKR1</i>, <i>SLC16A3</i>, <i>SLC16A4</i>, CD8<sup>+</sup> T-cell cytotoxicity score) performed well in training and retained discrimination in the progression-stratified cohorts, while in GSE100927 it showed high disease-identification performance across three arterial beds.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Lactate metabolic reprogramming under hypoxia is associated with ACKR1<sup>+</sup> EC-related CD8<sup>+</sup> T-cell recruitment and plaque instability. This chain is an association-based hypothesis requiring functional confirmation. The signature discriminates robustly at both the vulnerability-stratification and disease-identification levels, pro","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70856","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preventive governance for patient-centred medical AI","authors":"Linghua Yu","doi":"10.1002/ctm2.70872","DOIUrl":"10.1002/ctm2.70872","url":null,"abstract":"<p>Medical artificial intelligence (AI) is advancing from information provision and clinical assistance towards decision support and expanding clinical authority. Its reach now extends into diagnosis, treatment planning, monitoring, and patient management. Governance concerns have accordingly broadened from model performance alone to decision authority, accountability, meaningful human oversight, patient autonomy and health equity.<span><sup>1-3</sup></span> Recent work on AI-driven clinical consultations and autonomous agents indicates that these questions have shifted from hypothetical scenarios to emerging clinical realities.<span><sup>4, 5</sup></span></p><p>One question threads through these discussions: what happens when something goes wrong? Who made the decision, who should have intervened, and who is accountable? These questions remain essential.<span><sup>5, 6</sup></span> Autonomous systems, however, raise a complementary problem. What should be done before something goes wrong? Figure 1</p><p>Medical AI governance should therefore move beyond allocating responsibility after harm toward anticipating patient risk and preventing avoidable harm before it occurs.</p><p>Patient autonomy should be treated not only as an ethical principle at the point of consent, but as a potential safety mechanism throughout AI-mediated care. Growing recognition of patient rights over health data and AI governance reinforces the case for positioning patients more explicitly within the governance architecture.<span><sup>3, 7</sup></span></p><p>This places patient agency alongside technical performance, institutional accountability and human oversight as a component of clinical safety. It raises three practical questions. Can patients know that AI is involved in their care? Can they choose and contest its role? And can they reach meaningful human intervention when it matters most? These questions translate into three complementary safeguards.</p><p>These safeguards cannot be implemented through a single universal consent procedure. In life-threatening emergencies, extensive pre-procedure disclosure or choice may itself delay time-critical intervention. Governance must therefore consider risk-adaptive exceptions, rather than assuming that consent always precedes action or that clinical safety automatically overrides autonomy.</p><p>Decision-making capacity imposes a different constraint. Unconscious patients, people with cognitive impairment or delirium, and children may be unable to exercise these rights independently, and decisions may then involve interactions among patient preference, surrogate authority, and clinical necessity. In paediatric care, adolescents may be familiar with and receptive to AI while parents or guardians differ in their understanding or acceptance.</p><p>A further boundary condition concerns who is positioned to claim these rights. Disagreement may arise among patients, family members, clinicians, and institutions, and the operative q","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell multi-omics characterises transcriptional and chromatin accessibility heterogeneity of immune cells in allergic rhinitis","authors":"Yisha Wu,&nbsp;Zhihan Xu,&nbsp;Shikai Han,&nbsp;Zhongzhen Liu,&nbsp;Rui Dong,&nbsp;Chuanyu Liu,&nbsp;Jianhua Yin,&nbsp;Jinmei Xue","doi":"10.1002/ctm2.70854","DOIUrl":"10.1002/ctm2.70854","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Allergic rhinitis (AR) remains a global health challenge. However, the transcriptional and epigenetic features associated with seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR) relative to non-allergic rhinitis (NAR) remain poorly characterised at single-cell resolution.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed integrated single-cell transcriptomic and epigenomic profiling of nasal mucosal tissues from 22 patients, including NAR (<i>n</i> = 8), SAR (<i>n</i> = 6), and PAR (<i>n</i> = 8), to characterise transcriptional and epigenetic patterns associated with immune cell heterogeneity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified eight major immune cell types and 29 immune cell subsets across the nasal mucosa. Comparisons with NAR revealed distinct transcriptional and epigenetic features in SAR and PAR across both myeloid and T-cell compartments. In Macro_CCL3 cells, SAR showed enrichment of inflammation-associated programs, whereas PAR showed greater enrichment of antigen-presentation-related features. CD4_Tcm cells exhibited subtype-associated epigenetic differences, with IL-1β/IL-17-related features enriched in SAR and eosinophil- and Th2-associated programs enriched in PAR. CD8_Trm cells in both AR groups showed cytotoxicity-related features, including increased accessibility near <i>GZMB</i> and <i>PRF1</i>, while distinct inferred regulatory patterns were observed across the two AR groups. In addition, T-cell co-expression modules identified by hdWGCNA showed distinct associations with NAR, SAR, and PAR. sLDSC analysis revealed significant enrichment of pollinosis-associated heritability in CD8 T-cell open chromatin regions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study characterises distinct immune regulatory features associated with SAR and PAR relative to NAR across innate and adaptive immune compartments, providing a multi-omic framework for characterising AR heterogeneity and identifying subtype-associated molecular features for further investigation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Context-dependent TREM2 signalling in myeloid cells: Molecular mechanisms and immunotherapeutic divergence in neurodegeneration and cancer","authors":"Yaqing Lv,&nbsp;Mingpeng Shi,&nbsp;Yongfei Zhao,&nbsp;Yi Yu,&nbsp;Jiawei Lv,&nbsp;Hai Zhao","doi":"10.1002/ctm2.70863","DOIUrl":"10.1002/ctm2.70863","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Triggering receptor expressed on myeloid cells 2 (TREM2) is a pivotal lipid-sensing receptor that governs the functional plasticity and metabolic fitness of mononuclear phagocytes, including microglia, osteoclasts, dendritic cells and tissue-resident macrophages. While originally identified as a genetic risk factor for Alzheimer's disease (AD), TREM2 functions as a context-dependent immunometabolic checkpoint rather than a uniform phenotypic driver, exerting divergent biological outputs dictated by distinct tissue microenvironments and ligand repertoires.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Summary of key contents&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This review provides a comprehensive synthesis of TREM2 immunobiology, detailing how ligand engagement—including cell-surface phospholipids and apolipoprotein E (ApoE)—activates the DAP12/DAP10–SYK–PI3K–mTOR signalling axis. This coordinated intracellular cascade instructively drives myeloid adaptation towards metabolically competent disease-associated microglia (DAM) and lipid-associated macrophage (LAM) states, sustaining bioenergetics and debris clearance under pathological stress. Across neurodegenerative proteinopathies and acute cerebral ischemia, TREM2 signalling is predominantly neuroprotective by promoting aggregate compaction and mitigating secondary excitotoxicity, although chronic dysregulated activation may drive stage-dependent neuroinflammation. In peripheral inflammatory pathologies such as rheumatoid arthritis and sepsis, TREM2 fine-tunes macrophage efferocytosis and systemic metabolic thresholds. In oncology, TREM2 displays a complex, microenvironment-dependent divergence: in central nervous system malignancies such as glioblastoma (GBM), TREM2 exerts controversial, stage-dependent effects, spanning microglial tumour containment in early stages versus pro-tumoural myelin recycling and immunosuppression by monocyte-derived macrophages in post-treatment recurrence; conversely, in peripheral solid tumours, monocyte-derived TREM2+ tumour-associated macrophages (TAMs) predominantly orchestrate an immunosuppressive, nutrient-deprived niche that impairs cytotoxic T-cell function. Furthermore, we synthesise emerging paradigms along the bidirectional microbiome–gut–brain–tumour axis, elucidating how commensal and intra-tumoural microbial cues dynamically calibrate myeloid signalling tone and therapeutic susceptibility.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We address translation bottlenecks—including blood–brain barrier (BBB) shuttles, human trial scarcity and soluble TREM2 (sTREM2) biomarker harmonisation—outlining a biomarker-guided, context-tailored precision therapeutic fra","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radiation-induced AXL upregulation in CCR2+ monocytes promotes cardiac fibrosis","authors":"Ying-Yi Li,&nbsp;Jian-Qi Xiong,&nbsp;Zhi-Hui Zhang,&nbsp;Xin Liu,&nbsp;Yi-Xin Cheng,&nbsp;Yong-Xin Chi,&nbsp;Guan-Qiao Li,&nbsp;Wen-Huan Zhong,&nbsp;Shuang Chen,&nbsp;Zhen-Yu He","doi":"10.1002/ctm2.70852","DOIUrl":"10.1002/ctm2.70852","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Thoracic radiotherapy can cause delayed cardiac fibrosis, but the immune mechanisms linking radiation injury to fibroblast activation remain unclear. We investigated whether CCR2&lt;sup&gt;+&lt;/sup&gt; monocytes contribute to radiation-induced cardiac fibrosis and whether AXL regulates their fibroblast-activating activity.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods and materials&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;C57BL/6 mice received 20 Gy whole-thorax irradiation, and remodelling was assessed from IR_D0 to IR_D60. Bulk RNA sequencing was integrated with single-cell datasets and CIBERSORTx deconvolution, lineage tracing, and tissue staining. CCR2&lt;sup&gt;+&lt;/sup&gt; monocyte function was examined by CCR2 neutralisation, and circulating CCR2&lt;sup&gt;+&lt;/sup&gt;Ly6Cʰ&lt;sup&gt;i&lt;/sup&gt; monocytes were quantified by flow cytometry. AXL was investigated using inducible myeloid Axl deletion and bemcentinib (R428). MAPK signalling was assessed by transcriptomic analysis and immunoblotting of sorted CCR2&lt;sup&gt;+&lt;/sup&gt;Ly6Cʰ&lt;sup&gt;i&lt;/sup&gt; monocytes. Conditioned medium from sorted monocytes after Axl deletion, AXL inhibition with R428, or MEK1/2 inhibition with U0126 was applied to cardiac fibroblasts.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Cardiac fibrosis was established by IR_D30, while leukocyte infiltration and apoptotic signals remained above baseline. Transcriptomic analyses and lineage tracing showed increased cardiac accumulation of CCR2&lt;sup&gt;+&lt;/sup&gt; monocytes. CCR2 neutralisation reduced circulating CCR2&lt;sup&gt;+&lt;/sup&gt;Ly6Cʰ&lt;sup&gt;i&lt;/sup&gt; monocytes and attenuated interstitial collagen deposition and fibrotic marker expression. Axl was enriched in the CCR2&lt;sup&gt;+&lt;/sup&gt; monocyte compartment. Myeloid Axl deletion and R428 reduced cardiac fibrosis. Axl deletion suppressed MAPK-related transcriptional programs, whereas genetic or pharmacological AXL targeting reduced MEK and ERK phosphorylation in sorted monocytes. Conditioned medium from IR_D30 monocytes induced COL1A1 and α-SMA expression in fibroblasts, and this effect was reduced by Axl deletion, R428, or U0126 treatment of donor monocytes.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;AXL signalling contributes to the fibroblast-activating paracrine activity of cardiac CCR2&lt;sup&gt;+&lt;/sup&gt; monocytes after irradiation, at least in part through MEK/ERK signalling.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Radiation exposure induces cardiac fibrosis thr","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}