Clinical and Translational Medicine最新文献

{"title":"Multitemporal single-cell profiling uncovers alveolar IL1βhi neutrophils: A significant indicator of CARDS progression","authors":"Yingying Yang, Haochen Li, Peng Liu, Jinmeng Jia, Lei Wei, Xiangyu Chen, Ziqi Tan, Hantian Li, Qianlin Wang, Siyi Yuan, Liangyu Mi, Yuechuan Xue, Yi Chi, Shuaishuai Yang, Yanjie Zhao, Huaiwu He, Xuegong Zhang, Longxiang Su, Yun Long","doi":"10.1002/ctm2.70479","DOIUrl":"https://doi.org/10.1002/ctm2.70479","url":null,"abstract":"<p>Dear Editor</p><p>Acute respiratory distress syndrome (ARDS) is a complex life-threatening syndrome. Injury mechanisms behind ARDS rapid condition change and their association with treatment efficacy remain unclear. Using multitemporal single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid (BALF), we provided the first paired human lung immune cell atlas before and after ARDS condition change. We identified IL1β<sup>hi</sup> neutrophils as dominant in severe ARDS and linked to disease worsening. Neutrophil metabolic reprogramming and interactions with macrophages amplify inflammation, suggesting IL-1 blockade potential.</p><p>This study included eight severe ARDS patients, comprising four COVID-19-related ARDS (CARDS) and four non-CARDS patients (Table S1), with 23 public CARDS samples as controls. BALF samples were obtained upon admission (t1) and condition change (t2; Figure 1A). ScRNA-seq captured 87044 cells, labelled as major types<span><sup>1</sup></span> (Figure 1B,C). Compared to GSE145926 CARDS BALF data,<span><sup>1</sup></span> our CARDS patients exhibited significantly higher neutrophil proportions. Neutrophils were predominant in our results, followed by macrophages (Figure 1D). ΔMurray scores (MS) categorised patients into exacerbation (ΔMS ≥ +1) and remission groups, confirmed by computed tomography (CT; Figure 1E). In CARDS, after treatment, neutrophils significantly decreased and epithelial cells increased in remission groups, while no such change occurred in exacerbated patients (Figure 1F), suggesting neutrophils as important determinants of CARDS progression. In non-CARDS, we detected macrophages significantly increase in exacerbated patients, suggesting macrophages may have more impacts on non-CARDS progression (Figure 1G).</p><p>To identify neutrophil subtypes related to ARDS progression, we classified neutrophils into progenitor (CD63+), mature (IL1Β<sup>hi</sup>, S100A12+CXCR2+ and CCL4+), and hybrid neutrophils (CD74+)<span><sup>2</sup></span> (Figures 2A,B and S1A–F). Neutrophil evolution followed two trajectories: immature—S100A12+CXCR2+ neutrophils and immature—IL1β<sup>hi</sup>—S100A12+CXCR2+ neutrophils (Figures 2A and S1G,H). IL1β<sup>hi</sup> neutrophils significantly increased in exacerbated patients compared to baselines (Figure 2C,D), with upregulated inflammatory genes (<i>IL1B</i>, <i>ISG15</i>, and <i>PTGS2</i>) and interferon-related pathways (Figure 2E,F). These genes, like <i>PTGS2</i>, are identified as key genes in SARS-CoV-2 immunopathogenesis.<span><sup>3, 4</sup></span> IL1β<sup>hi</sup> neutrophil signatures and IL1B gene can also be used as prognostic indicators for CARDS (Area under curve [AUC]: .8693, Figure S1I). Comparing our neutrophils with neutrophils from CARDS peripheral blood<span><sup>5</sup></span> (Figure 2G), peripheral neutrophils rarely express IL1β<sup>hi</sup> neutrophil signatures, while cells with high expression nearly all come from BALF (Figure 2H). This demo","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70479","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135593","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":"Unravelling the distinct effects of VHL mutations and chromosome 3p loss in clear cell renal cell carcinoma: Implications for prognosis and treatment","authors":"Xiang Wang, Jian-Rong Li, Naail Raed Chowdhury, Lang Wu, Cheng Chao","doi":"10.1002/ctm2.70465","DOIUrl":"https://doi.org/10.1002/ctm2.70465","url":null,"abstract":"<p>Dear Editor,</p><p>In this study, we delineated the distinct transcriptomic effects of VHL mutation and chromosome 3p (chr3p) loss, revealing that chr3p loss is specifically associated with immune suppression in clear cell renal cell carcinoma (ccRCC). Furthermore, we developed driver genomic aberration (DGA) gene signatures that demonstrate superior performance in predicting both patient prognosis and treatment response compared to traditional mutation-based approaches.</p><p>Renal cell carcinoma (RCC) accounts for 80%–85% of all primary kidney cancers, with ccRCC being the most common subtype (∼75%).<span><sup>1</sup></span> In 2023, ∼82 000 new RCC cases and ∼15 000 deaths were reported in the U.S. Despite surgery being curative for localised disease, ∼33% of patients relapse, and those with metastatic disease (∼15%) have a poor prognosis.<span><sup>1</sup></span> Despite treatment advances, significant variability in outcomes highlights the need for reliable molecular biomarkers to guide the treatment. Large-scale genomic studies such as the Cancer Genome Atlas (TCGA) have shown that the VHL gene is frequently inactivated in ccRCC through mutation or chr3p deletion.<span><sup>2</sup></span> However, the prognostic and therapeutic relevance of VHL mutations and chr3p loss remains controversial.</p><p>We examined the most frequently mutated genes in the TCGA KIRC dataset.<span><sup>2</sup></span> The <i>VHL</i> gene exhibited the highest mutation rate (52%), followed by <i>PBRM1</i> (31%), <i>SETD2</i> (11%) and <i>BAP1</i> (5%) (Figure 1A). Copy number analysis revealed that chr3p loss occurred in 27% of patients, and most loss events, interestingly, encompassed these four genes. (Figure 1B). This genomic configuration is largely unique to ccRCC among TCGA cancer types (Figure S1A).</p><p>Mutation rates of these genes were consistent across tumour stages, indicating early tumourigenic roles (Figure S1B). To investigate the transcriptomic effects of <i>VHL</i> mutation and chr3p loss, we stratified TCGA-KIRC data by these aberrations and identified differentially expressed genes. In <i>VHL</i>-WT tumours, chr3p loss led to 1719 differentially expressed genes (DEGs; FDR < .05, |log<sub>2</sub>FC| > 1.5), while in tumours with intact chr3p, <i>VHL</i> mutation resulted in 1577 DEGs. However, in the presence of <i>VHL</i> mutation, chr3p loss still induced 442 DEGs, whereas <i>VHL</i> mutation had no significant transcriptomic impact in chr3p-loss tumours, indicating that chr3p loss exerts a dominant regulatory effect (Figure 1C). Notably, immune-related genes were significantly enriched in genes that were downregulated in chr3p-loss tumours (Figure 1D), and GSEA analysis confirmed the suppression of immune pathways (Figure S2).</p><p>Given that immune gene suppression associated with chr3p loss, we explored its impact on the tumour immune microenvironment (TIME). Using previously reported data,<span><sup>3</sup></span> we discovered that","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70465","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135594","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":"Confocal Raman microspectroscopy for spatially resolved tissue characterisation of disease-linked spectra-pathological signatures","authors":"Nektarios A. Valous,&nbsp;Inka Zörnig,&nbsp;Dirk Jäger","doi":"10.1002/ctm2.70487","DOIUrl":"https://doi.org/10.1002/ctm2.70487","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Raman spectroscopy is a versatile analytical technique for highly specific molecular characterisation of cells, biofluids and tissues. Confocal Raman microspectroscopy combines optical microscopy with Raman spectroscopy to spatially resolve biochemical changes in tissue samples. This work focuses on research articles that utilise confocal Raman microspectroscopy in human or murine tissue sections for identifying disease-linked spectra-pathological features. For scientists and clinicians who seek ideas in incorporating confocal Raman microspectroscopy into their experimental workflows, this piece provides a curated selection of studies (spanning cancer and cardiovascular diseases) that highlight key spectroscopic and biomedical insights. The lack of standardisation and the fragmentation of research protocols are major challenges that limit study reproducibility and prevent systematic cross-validation. Moving forward, confocal Raman microspectroscopy, coupled with robust computational approaches, will continue to detect disease-specific spatiotemporal biomolecular signatures, and integration with complementary imaging or omics methods will keep enhancing its ability to analyse complex biological systems and uncover disease progression mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Confocal Raman microspectroscopy enables spatially resolved tissue characterisation and reveals disease-linked spectra-pathological features.</li>\u0000 \u0000 <li>Key challenges limit clinical translation, for example, lack of standardisation and insufficient reference spectral databases.</li>\u0000 \u0000 <li>Future research progress depends on interdisciplinary collaboration, robust computational methods and integration with complementary imaging or omics technologies for enhanced disease characterisation.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70487","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135597","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 extracellular vesicles from cancer-associated fibroblasts drive oesophageal squamous cell carcinoma metastasis via the miR-193a-3p/PTEN/Akt pathway","authors":"Yechun Pang,&nbsp;Tiantian Guo,&nbsp;Yue Zhou,&nbsp;Shanshan Jiang,&nbsp;Yida Li,&nbsp;Jianjiao Ni,&nbsp;Xiao Chu,&nbsp;Li Chu,&nbsp;Fangyu Chen,&nbsp;Xi Yang,&nbsp;Zhengfei Zhu","doi":"10.1002/ctm2.70483","DOIUrl":"https://doi.org/10.1002/ctm2.70483","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;The recurrence and metastasis of oesophageal squamous cell cancer (ESCC) following radiation therapy are major treatment challenges. Cancer-associated fibroblasts (CAFs) are key in the ESCC microenvironment, yet their role in post-radiation recurrence remains unclear.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Materials and Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;KYSE150 ESCC cells were co-implanted with non-irradiated (0 Gy) or irradiated (8 Gy) CAFs in nude mice. CAF-derived extracellular vesicles (EVs) were isolated via differential centrifugation and analysed by electron microscopy and immunoblotting. Transwell assays evaluated EVs' effects on ESCC cell migration and invasion in vitro. RNA sequencing identified differentially expressed microRNAs, and functional experiments verified the role of miR-193a-3p. Plasma samples from 32 ESCC patients and tissue samples from 76 ESCC patients were analysed for miR-193a-3p expression.&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;Irradiated CAFs promoted the lung metastasis of ESCC cells in vivo, and their EVs enhanced ESCC cell invasion, migration and metastasis. Elevated miR-193a-3p levels in EVs from irradiated CAFs increased miR-193a-3p expression in ESCC cells. This effect was effectively attenuated by RNase and Triton X-100 (degrading microRNAs encapsulated in EVs), or GW4869 (inhibiting EVs biogenesis and secretion)—indicating that miR-193a-3p functions in an EV-dependent manner. Knockdown of miR-193a-3p diminished the invasion, migration and epithelial–mesenchymal transition (EMT)-promoting activities of CAF-derived EVs. Luciferase assays confirmed PTEN as a target of miR-193a-3p; miR-193a-3p overexpression decreased PTEN and increased p-Akt expression. In vivo, coinjection of miR-193a-3p-knockdown CAFs with KYSE150 ESCC cells resulted in smaller tumours, fewer lung metastases, increased PTEN and E-cadherin, and decreased p-Akt and Snail expression. Clinically, radiation increased plasma exosomal miR-193a-3p levels, and high miR-193a-3p expression was correlated with shorter survival, identifying miR-193a-3p as an independent predictor of poor prognosis in ESCC patients.&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;EVs from irradiated CAFs promote ESCC metastasis via the miR-193a-3p-mediated PTEN/Akt signalling pathway. Targeting this EVs-mediated interaction represents a promising strategy for improving ESCC radiotherapy outcomes.&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 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70483","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135595","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":"Genetic architecture of gastric adenocarcinoma in West Asia","authors":"Saeid Latifi-Navid,&nbsp;Esmat Abdi,&nbsp;Tianpei Wang,&nbsp;Farhad Pourfarzi,&nbsp;Abbas Yazdanbod,&nbsp;Seyed Alireza Salami,&nbsp;Reza Safaralizadeh,&nbsp;Omolbanin Amjadi,&nbsp;Hamid Latifi-Navid,&nbsp;Bahareh Safarnejad,&nbsp;Mahmoud Shokrabadi,&nbsp;Iradj Maleki,&nbsp;Vahid Hosseini,&nbsp;Seyed Mohammad Valizadeh,&nbsp;Mehdi Pourghasemian,&nbsp;Negin Abediasl,&nbsp;Arash Kazemi,&nbsp;Mohammad Eslami Jouybari,&nbsp;Zohreh Bari,&nbsp;Tarang Taghvaei,&nbsp;Caiwang Yan,&nbsp;Amir Taher Eftekhar Sadat,&nbsp;Seyed Yaghoub Moaddab,&nbsp;Ghasem Janbabaei,&nbsp;Mohammad Hossein Somi,&nbsp;Alireza Sadjadi,&nbsp;Ramin Shakeri,&nbsp;Farideh Siavoshi,&nbsp;Hafez Fakheri,&nbsp;Hossein Poustchi,&nbsp;Reza Malekzadeh,&nbsp;Guangfu Jin","doi":"10.1002/ctm2.70489","DOIUrl":"https://doi.org/10.1002/ctm2.70489","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Gastric cancer (GC) is a significant global health concern, with 968 000 new cases and 660 000 deaths in 2022, with male predominance.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Despite a declining trend, the absolute number of GC cases is anticipated to rise, particularly in East and West Asia.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Most genome-wide association studies (GWASs) have focused on East Asian populations,&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; leaving a gap in understanding the genetic contributions to GC risk in West Asia, particularly in countries like Iran, where GC incidence is notably high. Most of Iran's northern and northwestern regions are located in the GC belt of West Asia. &lt;i&gt;Helicobacter pylori&lt;/i&gt; infection, high salt intake, and smoking are major risk factors, along with gastroesophageal reflux disease, which contributes to higher cardia GC rates.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; This study presents a GWAS analysis of 4095 Iranian samples from high-risk areas, with subsequent replication in a large Chinese dataset of 21 168 samples, aiming to delineate susceptibility loci associated with GC.&lt;/p&gt;&lt;p&gt;The analysis strategy is thoroughly outlined in Figure 1A (Supporting Information Methods). Of 2061 patients, 1531 (74.3%) were male; among 2034 controls, 1503 (73.9%) were male. The average age (mean ± SD) was 65.8 ± 11.0 and 67.8 ± 10.9 years for the patients and controls, respectively (Table S1). After filtering and quality control, 3686 subjects (1880 cases and 1806 controls) with 9 159 468 genetic variants were retained in the GWAS dataset (Figure 1A). A quantile‒quantile plot did not show substantial evidence of an inflation rate, with &lt;i&gt;λ&lt;/i&gt; = 1.07 (Figure S1). Ethnicity and population structure were determined by the top two principal components for each study (Figure S2). Manhattan plots from the GWAS and multimarker analysis of the GenoMic Annotation (MAGMA) gene-based analyses&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; are shown in Figure 1B. Previous GWASs have identified a number of susceptibility loci (or common variants), including 1q22, 1p35.2, 2p11.2, 3q13.31, 5q14.3, 5p13.1, 6p22.1, 6p21.1, 8q24.3, 9q34.2, 10q23.33, 12q24.11–12, and 20q11.21.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; In the present study, three loci reached genome-wide significance (reported: 1q22 and 8q24.3; novel: 1p33; &lt;i&gt;p &lt;/i&gt;&lt; 5 × 10&lt;sup&gt;−8&lt;/sup&gt;). Compared with previous results, consistent associations were observed for single nucleotide polymorphisms (SNPs) in &lt;i&gt;MUC1&lt;/i&gt; at 1q22 (lead SNP: rs760077, OR = 1.39, 95% CI = 1.27–1.53; functional SNP: rs4072037, OR = 1.34, 95% CI = 1.22–1.47) and &lt;i&gt;PSCA&lt;/i&gt; at 8q24.3 (lead SNP: rs2717562, OR = 1.39, 95% CI = 1.27–1.53). At 1p33, the lead (intergenic) SNP rs498352 near &lt;i&gt;FOXD2&lt;/i&gt; was first found to be associated with GC risk (OR = 1.73, 95% CI = 1.43–2.10, &lt;i&gt;p &lt;/i&gt;= 2.26 × 10&lt;sup&gt;−8&lt;/sup&gt;; Table 1A; Figure 2A). FOXD2 binding reconfigures chromatin structure to suppress colorectal cancer by reprogramming enhancer interactions.&lt;span&gt;&lt;sup&gt;7&lt;/sup","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70489","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135596","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":"CD103+CD8+ tissue-resident memory T lymphocytes of melanoma boost anti-tumour immunity and predict immunotherapy outcomes","authors":"Tianyi Zhang,&nbsp;Junquan Song,&nbsp;Yinlam Li,&nbsp;Kangjie Shen,&nbsp;Jiangying Xuan,&nbsp;Yuan Gao,&nbsp;Lili Lu,&nbsp;Zhi Pang,&nbsp;Lu Wang,&nbsp;Yang Yang,&nbsp;Zixu Gao,&nbsp;Qianrong Hu,&nbsp;Yu Zhu,&nbsp;Chenlu Wei,&nbsp;Shaoluan Zheng,&nbsp;Rongkui Luo,&nbsp;Yingyong Hou,&nbsp;Yuhong Zhou,&nbsp;Chuanyuan Wei,&nbsp;Jianying Gu","doi":"10.1002/ctm2.70464","DOIUrl":"10.1002/ctm2.70464","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;Immunotherapy has revolutionised melanoma treatment, providing significant clinical benefits by reactivating the anti-tumour immune system. CD8&lt;sup&gt;+&lt;/sup&gt; tissue-resident memory T lymphocytes (CD8&lt;sup&gt;+&lt;/sup&gt; TRM) have emerged as crucial mediators of anti-tumour immunity, while their specific role in melanoma remains poorly understood.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Following CD8&lt;sup&gt;+&lt;/sup&gt;CD45.1&lt;sup&gt;+&lt;/sup&gt; OT-1 cell adoptive transfer into CD45.2&lt;sup&gt;+&lt;/sup&gt; mice, we employed magnetic separation to purify and analyse resident memory CD8&lt;sup&gt;+&lt;/sup&gt; T cells (TRM). We use multiple immunohistochemistry (mIHC) to evaluate the spatial distribution of CD8&lt;sup&gt;+&lt;/sup&gt; TRM in ZS melanoma cohort. Additionally, the biological function of CD8&lt;sup&gt;+&lt;/sup&gt; TRM and their impact on anti-tumour immunity are explored using scRNA sequencing and spatial transcriptomics, coupled with in vivo/in vitro experiments. Finally, CD8&lt;sup&gt;+&lt;/sup&gt; TRM utility as an immunotherapy response predictor is examined across several independent cohorts.&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;CD8&lt;sup&gt;+&lt;/sup&gt; TRM demonstrates potent tumour-killing capabilities in melanoma, with CD103 as a distinctive marker. High CD103&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt; TRM infiltration in tumour tissues strongly correlates with improved prognosis in melanoma patients. In vivo adoptive transfer of CD103&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt; TRM effectively inhibits melanoma progression. Mechanistically, CD103 activates the integrin-dependent PI3K/AKT signalling cascade, promoting both proliferation and anti-tumour effector functions of CD8&lt;sup&gt;+&lt;/sup&gt; TRM. Notably, CD103&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt; TRM preferentially localises within tertiary lymphoid structures (TLS), and its adoptive transfer promotes TLS formation. Clinically, CD103&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt; TRM is enriched in immunotherapy-responsive patients and serves as a strong predictor for immune checkpoint blockade (ICB) treatment outcomes.&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;CD103&lt;sup&gt;+&lt;/sup&gt; CD8&lt;sup&gt;+&lt;/sup&gt; TRM cells in melanoma play a key role in the anti-tumour immune process and can also be used as a reliable predictor of immunotherapy efficacy.&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;\u0000 &lt;p&gt;CD103 is a reliable marker of tissue-resident memory (TRM) CD8&lt;sup&gt;+&lt;/sup&gt; T cells in mel","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 9","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124314","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":"Stereo-cell: Advancing spatial single-cell biology towards clinical translation","authors":"Christian Baumgartner","doi":"10.1002/ctm2.70480","DOIUrl":"10.1002/ctm2.70480","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Stereo-cell is a newly developed platform for spatial single-cell sequencing that integrates morphology, transcriptomics, and proteomics in high resolution. By preserving spatial context while enabling multimodal profiling, it bridges the gap between advanced omics and traditional pathology, supporting the detection of rare cells and clinically interpretable diagnoses. This letter highlights the technical innovations of Stereo-cell, its positioning within the spatial omics landscape, and its potential for precision medicine. Important challenges in data integration, regulatory compliance, and digital modelling are discussed as essential steps on the path to clinical implementation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 9","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124331","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":"Extrachromosomal circular DNA expressing miRNA promotes ovarian cancer progression","authors":"Ning Wu,&nbsp;Ling Wei,&nbsp;Qiyu Liu,&nbsp;Tianhui He,&nbsp;Cuiyu Huang,&nbsp;Yunpeng Jiang,&nbsp;Kailong Li,&nbsp;Hongyan Guo,&nbsp;Fengbiao Mao,&nbsp;Xiaolu Zhao","doi":"10.1002/ctm2.70445","DOIUrl":"10.1002/ctm2.70445","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;Extrachromosomal circular DNA (eccDNA) has emerged as a critical driver of oncogenesis, yet its functional roles in high-grade serous ovarian cancer (HGSOC) remain poorly characterized. This highlights the need for comprehensive investigations into the abundance, biogenesis, and functional implications of eccDNA in HGSOC.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;To characterize eccDNA in HGSOC, we performed comprehensive Circle-seq analysis to assess eccDNA abundance and genomic annotation in HGSOC tissues compared to normal ovarian tissue. For mechanistic validation of eccDNA biogenesis pathways, targeted knockdown experiments of microhomology-mediated end-joining (MMEJ) dependent on LIG3 and POLQ were conducted. Functional characterization of HGSOC-specific eccDNA-harboring precursor microRNAs (eccMIRs) included in vitro assays using HGSOC cells and in vivo tumor growth experiments.&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;Circle-seq analysis revealed a 13-fold increase in eccDNA abundance in HGSOC compared to normal ovarian tissue, with significant enrichment in promoter and coding regions. The MMEJ pathway was identified as the predominant pathway for eccDNA biogenesis in HGSOC, supported by characteristic microhomologies at junction sites and validation via LIG3 and POLQ knockdown experiments. Notably, HGSOC-specific eccDNA frequently contained functional eccMIRs (eccMIR3661, eccMIR618, and eccMIR2277), which generate oncogenic miRNAs. These miRNAs promote tumor progression by downregulating tumor suppressor genes and activating key oncogenic pathways. Functional assays confirmed that these eccMIRs significantly enhanced HGSOC cell proliferation, migration, and invasion in vitro and promoted tumor growth in vivo.&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;These results underscore eccDNA as an oncogenic driver in HGSOC through non-coding RNA-mediated regulatory mechanisms, revealing novel therapeutic opportunities for targeting eccDNA biogenesis in this aggressive malignancy.&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;This study revealed a 13-fold increase of eccDNA in HGSOC compared to normal tissues, with significant enrichment in promoter and coding regions.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;eccDNA-derived miRNAs (eccMIRs) were shown to enhance cancer cell proliferation, invasion, and tumor","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 9","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124306","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":"Gene expression differences in differentially methylated sites associated with HIV status and cocaine use","authors":"Eric J. Earley,&nbsp;Bryan C. Quach,&nbsp;Fang Fang,&nbsp;Laura J. Bierut,&nbsp;M-J S. Milloy,&nbsp;Kanna Hayashi,&nbsp;Kora DeBeck,&nbsp;Dana B. Hancock,&nbsp;Bradley E. Aouizerat,&nbsp;Ke Xu,&nbsp;Eric Otto Johnson","doi":"10.1002/ctm2.70466","DOIUrl":"10.1002/ctm2.70466","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Advances in antiretroviral therapy (ART) have made HIV a chronic, manageable disease for people living with HIV (PLWH) with consistent ART access. However, HIV still increases risk of non-AIDS defining conditions such as cancer and impaired cognitive function.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; DNA methylation and gene expression dynamics appear to play a role in these comorbid disease-related processes.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Furthering a mechanistic understanding of the risk of non-AIDS defining conditions, this study is the first to demonstrate that many immune response genes, previously identified via epigenome-wide association studies (EWAS) of DNA methylation, also show consistently upregulated gene expression in PLWH, especially among those with detectable viral load despite ART and those who recently used cocaine.&lt;/p&gt;&lt;p&gt;HIV-1 infection is characterised by persistent immune activation and chronic inflammation.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; DNA methylation – particularly at CpG sites near immune-regulatory genes – has been linked to HIV acquisition, viral control, and comorbidities such as cancer and impaired cognitive function.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Recent EWAS have identified hypomethylation in key antiviral response genes such as &lt;i&gt;MX1&lt;/i&gt; and &lt;i&gt;NLRC5&lt;/i&gt;, and hypermethylation in genes linked to HIV progression including &lt;i&gt;CX3CR1&lt;/i&gt; and &lt;i&gt;TNF&lt;/i&gt;.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; However, it remains unclear whether such methylation changes translate into changes in gene expression. Moreover, cocaine use, common among PLWH and associated with faster disease progression, may further influence gene expression via epigenetic mechanisms.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;To investigate this, we analysed gene expression via RNAseq in whole blood from 588 individuals enrolled in the Vancouver People Who Inject Drugs Study (VPWIDS), including 227 PLWH (38.6%) with a mean age of 49.6 years (± 9.6 SD; Table 1).&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; All PLWH were on ART at the time of blood draw, 194 had undetectable viral load (&lt; 200 viral copies/mL), and 33 had detectable viral load (mean 18 850 viral copies/mL). The cohort had high prevalence of cocaine, opioid, and methamphetamine use. Focusing on cocaine use (crack and powder), 121 PLWH (47%) and 180 HIV-negative (50%) participants reported recent use.&lt;/p&gt;&lt;p&gt;A PubMed search using ‘HIV’ and ‘epigenome’ identified five in vivo human whole blood–based EWAS relevant to HIV acquisition or severity (Table S1). From these, we selected 18 genes for expression analyses based on stringent criteria: (1) harbouring CpG sites differentially methylated in association with HIV acquisition or severity that were independently replicated in at least one other study, or (2) containing CpG sites identified as significant mediators of cocaine's impact on HIV severity in prior mediation analyses. Expression differences by HIV status were assessed using negative binomial regression, adjusting for sex, age, RNA Integrity","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 9","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70466","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085294","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":"Neural mechanism of conscious perception for potential clinical applications","authors":"Yong Wang,&nbsp;Shouyang Yu,&nbsp;Yueqing Dong,&nbsp;Yuanyuan Dang,&nbsp;Hulin Zhao,&nbsp;Mingsha Zhang,&nbsp;Xiaoli Li","doi":"10.1002/ctm2.70387","DOIUrl":"10.1002/ctm2.70387","url":null,"abstract":"<p>The generation of consciousness has remained one of the most enduring scientific quests in human history. When a visual stimulus enters the eye, how does the brain transform it into the subjective experience of “I see”? Traditional theories posited the cerebral cortex as the epicenter of conscious perception, relegating the thalamus to a mere relay station for sensory signals. However, a groundbreaking study recently published in Science has overturned this paradigm, identifying the mediodorsal thalamic nuclei (MDm) and intralaminar nuclei (ILN) as the true “gatekeepers” of conscious perception.<span>¹</span> Through dynamic connectivity with the prefrontal cortex, these nuclei determine which sensory information gains access to the conscious perception. What groundbreaking clinical implications might this discovery yield?</p><p>Conscious perception, is one of the most complex issues in the field of cognitive science, meaning subjects convert external stimuli into subjective experiences through neural activity. Conscious perception involves the awareness and understanding of one's environment, internal stimuli, and cognitive processes. As a key capability for human cognition, it enables individuals to be aware of events, emotions, thoughts, and bodily states. From the perspective of neuroscience, conscious perception is a process that involves several brain regions, particularly the thalamus and the prefrontal cortex.<span>^{2, 3}</span> These regions synthesize information from sensory systems, such as vision, hearing, and touch, to construct a clear conscious experience.</p><p>Conscious perception is impaired in various medical conditions (see Figure 1). Neurodegenerative diseases, including Alzheimer's and Parkinson's, are linked to progressive deterioration in awareness and perception. Individuals with Alzheimer's disease often exhibit a decline in consciousness and self-awareness,<span>⁴</span> whereas those with Parkinson's may endure visual perception problems due to the loss of dopamine-producing cells in the retina.<span>⁵</span> Other conditions that affect conscious perception include epilepsy, which can cause sensory disturbances; and sleep disorders, which can lead to perceptual changes due to sleep deprivation or disrupted circadian rhythms (Figure 1).</p><p>This paradigm shift, from cortical-centric to thalamocortical network models of consciousness, calls for multidisciplinary collaboration. By integrating sEEG-guided neuromodulation, computational modeling of mesocircuit dynamics, and machine learning-based biomarker discovery, clinicians can develop precision therapies that bridge molecular mechanisms with systems-level network reorganization. These advances not only redefine our approach to DoC but also offer novel pathways for treating perceptual-cognitive deficits across neurological and psychiatric disorders.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 9","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70387","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085328","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}