Clinical and Translational Medicine最新文献

{"title":"Cell-free epigenomes enhanced fragmentomics-based model for early detection of lung cancer","authors":"Yadong Wang, Qiang Guo, Zhicheng Huang, Liyang Song, Fei Zhao, Tiantian Gu, Zhe Feng, Haibo Wang, Bowen Li, Daoyun Wang, Bin Zhou, Chao Guo, Yuan Xu, Yang Song, Zhibo Zheng, Zhongxing Bing, Haochen Li, Xiaoqing Yu, Ka Luk Fung, Heqing Xu, Jianhong Shi, Meng Chen, Shuai Hong, Haoxuan Jin, Shiyuan Tong, Sibo Zhu, Chen Zhu, Jinlei Song, Jing Liu, Shanqing Li, Hefei Li, Xueguang Sun, Naixin Liang","doi":"10.1002/ctm2.70225","DOIUrl":"https://doi.org/10.1002/ctm2.70225","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lung cancer is a leading cause of cancer mortality, highlighting the need for innovative non-invasive early detection methods. Although cell-free DNA (cfDNA) analysis shows promise, its sensitivity in early-stage lung cancer patients remains a challenge. This study aimed to integrate insights from epigenetic modifications and fragmentomic features of cfDNA using machine learning to develop a more accurate lung cancer detection model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To address this issue, a multi-centre prospective cohort study was conducted, with participants harbouring suspicious malignant lung nodules and healthy volunteers recruited from two clinical centres. Plasma cfDNA was analysed for its epigenetic and fragmentomic profiles using chromatin immunoprecipitation sequencing, reduced representation bisulphite sequencing and low-pass whole-genome sequencing. Machine learning algorithms were then employed to integrate the multi-omics data, aiding in the development of a precise lung cancer detection model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Cancer-related changes in cfDNA fragmentomics were significantly enriched in specific genes marked by cell-free epigenomes. A total of 609 genes were identified, and the corresponding cfDNA fragmentomic features were utilised to construct the ensemble model. This model achieved a sensitivity of 90.4% and a specificity of 83.1%, with an AUC of 0.94 in the independent validation set. Notably, the model demonstrated exceptional sensitivity for stage I lung cancer cases, achieving 95.1%. It also showed remarkable performance in detecting minimally invasive adenocarcinoma, with a sensitivity of 96.2%, highlighting its potential for early detection in clinical settings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>With feature selection guided by multiple epigenetic sequencing approaches, the cfDNA fragmentomics-based machine learning model demonstrated outstanding performance in the independent validation cohort. These findings highlight its potential as an effective non-invasive strategy for the early detection of lung cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Keypoints</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Our study elucidated the regulatory relationships between epigenetic modifications and their effects on fragmentomic features.</li>\u0000 \u0000 <li>Identifying epigeneticall","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248467","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":"Sodium pump subunit NKAα1 protects against diabetic endothelial dysfunction by inhibiting ferroptosis through the autophagy-lysosome degradation of ACSL4","authors":"Xue-Xue Zhu,&nbsp;Jia-Bao Su,&nbsp;Fang-Ming Wang,&nbsp;Xiao-Ying Chai,&nbsp;Guo Chen,&nbsp;An-Jing Xu,&nbsp;Xin-Yu Meng,&nbsp;Hong-Bo Qiu,&nbsp;Qing-Yi Sun,&nbsp;Yao Wang,&nbsp;Zhuo-Lin Lv,&nbsp;Yuan Zhang,&nbsp;Yao Liu,&nbsp;Zhi-Jun Han,&nbsp;Na Li,&nbsp;Hai-Jian Sun,&nbsp;Qing-Bo Lu","doi":"10.1002/ctm2.70221","DOIUrl":"https://doi.org/10.1002/ctm2.70221","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The sodium pump Na+/K+-ATPase (NKA), an enzyme ubiquitously expressed in various tissues and cells, is a critical player in maintaining cellular ion homeostasis. Dysregulation of α1 subunit of NKA (NKAα1) has been associated with cardiovascular and metabolic disorders, yet the exact role of NKAα1 in diabetes-induced endothelial malfunction remains incompletely understood. The NKAα1 expression and NKA activity were examined in high-glucose (HG)-exposed endothelial cells (ECs) and mouse aortae, as well as in high-fat-diet (HFD)-fed mice. Acetylcholine (Ach) was utilised to assess endothelium-dependent relaxation (EDR) in isolated mouse aortae. We found that both NKAα1 protein and mRNA levels were significantly downregulated in the aortae of HFD-fed mice, and HG-incubated mouse aortae and ECs. Gain- and loss-of-function experiments revealed that NKAα1 preserves EDR by mitigating oxidative/nitrative stresses in ECs. Overexpression of NKAα1 facilitated EC viability, migration, and angiogenesis by inhibiting the overproduction of superoxide and peroxynitrite. Mechanistically, dysfunctional NKAα1 impaired autophagy process, and prevented the transfer of acyl-CoA synthetase long-chain family member 4 (ACSL4) to the lysosome for degradation, thereby resulting in lipid peroxidation and ferroptosis in ECs. Induction of ferroptosis and inhibition of the autophagy-lysosome pathway blocked the protective effects of NKAα1 on EDR. Eventually, we identified Hamaudol as a potent activator of NKAα1 by restraining the phosphorylation and endocytosis of NKAα1, restoring EDR in obese diabetic mice. Overall, NKAα1 facilitates the autophagic degradation of ACSL4 via the lysosomal pathway, preventing ferroptosis and oxidative/nitrative stress in ECs. NKAα1 may serve as an attractive candidate for the management of vascular disorders associated with diabetes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>NKAα1 downregulation impairs endothelial function in diabetes by promoting oxidative/nitrative stress and ferroptosis.</li>\u0000 \u0000 <li>NKAα1 supports lysosomal degradation of ACSL4 via autophagy, preventing lipid peroxidation and ferroptosis.\u0000</li>\u0000 \u0000 <li>Hamaudol, an activator of NKAα1, restores endothelial relaxation in diabetic mice by inhibiting NKAα1 phosphorylation and endocytosis.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70221","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111844","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":"Monocyte–macrophage dynamics as key in disparate lung and peripheral immune responses in severe anti-melanoma differentiation-associated gene 5-positive dermatomyositis-related interstitial lung disease","authors":"Jia Shi,&nbsp;Xiaoya Pei,&nbsp;Jinmin Peng,&nbsp;Chanyuan Wu,&nbsp;Yulin Lv,&nbsp;Xiaoman Wang,&nbsp;Yangzhong Zhou,&nbsp;Xueting Yuan,&nbsp;Xingbei Dong,&nbsp;Shuang Zhou,&nbsp;Dong Xu,&nbsp;Jiuliang Zhao,&nbsp;Jun Liu,&nbsp;Jiao Huang,&nbsp;Bin Du,&nbsp;Chen Yao,&nbsp;Xiaofeng Zeng,&nbsp;Mengtao Li,&nbsp;Houzao Chen,&nbsp;Qian Wang","doi":"10.1002/ctm2.70226","DOIUrl":"https://doi.org/10.1002/ctm2.70226","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;Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5+ DM) is a rare inflammatory autoimmune disorder often complicated by life-threatening rapidly progressive interstitial lung disease (RP-ILD). The underlying mechanisms driving immune dysfunction and lung injury, however, remain poorly understood. The study aims to gain insights into the disrupted immune landscape in peripheral and pulmonary compartments of severe anti-MDA5+ DM and explore potential therapeutic targets.&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;We employed single-cell RNA sequencing to examine cellular constituents within five patients’ bronchoalveolar lavage fluid and paired peripheral blood mononuclear cells. Luminex assay and flow cytometry were further applied to validate the results.&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;Our analysis revealed starkly contrasting immune landscapes between the periphery and lungs, with peripheral immune suppression juxtaposed against pulmonary immune hyperactivation. Central to this dysregulation was the monocyte–macrophage lineage. Circulating monocytes exhibited an immunosuppressive phenotype, characterised by diminished cytokine production, reduced MHC II expression, and features resembling myeloid-derived suppressor cells. These monocytes were recruited to the lungs, where they differentiated into monocyte-derived alveolar macrophages (Mo-AMs) with robust proinflammatory and profibrotic activities. Mo-AMs drove cytokine storms and produced chemokines that amplified inflammatory cell recruitment and lung tissue remodelling. Additionally, peripheral T and NK cells exhibited increased cell death and active migration into the lungs, which may be the cause of lymphopenia.&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;Our study underscores the pivotal role of monocyte–macrophage dynamics in the immunopathogenesis of anti-MDA5+-associated RP-ILD, offering critical insights into compartment-specific immune dysregulation. These findings suggest potential therapeutic strategies targeting monocyte recruitment and macrophage activation to mitigate disease progression.&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;Peripheral immune suppression and pulmonary immune hyperactivation characterise the distinct immune landscapes in anti-MDA5+DM with RP-ILD.&lt;/li&gt;\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111849","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 transcriptomics and metabolomic analysis reveal adenosine-derived metabolites over-representation in pseudohypoxic neuroendocrine tumours","authors":"Yuval Kahan Yossef,&nbsp;Liav Sela Peremen,&nbsp;Alona Telerman,&nbsp;Gil Goldinger,&nbsp;Sergey Malitsky,&nbsp;Maxim Itkin,&nbsp;Reut Halperin,&nbsp;Naama Peshes Yaloz,&nbsp;Amit Tirosh","doi":"10.1002/ctm2.70159","DOIUrl":"https://doi.org/10.1002/ctm2.70159","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Von Hippel−Lindau protein (pVHL) is a critical factor in the cellular oxygen sensing apparatus. pVHL-deficient tumours are characterized by a pseudohypoxic state and a consequent metabolic shift towards anaerobic metabolism. Based on unbiased metabolic analysis, supported by single-cell transcriptomics analysis, we report a potential tumorigenic role of adenosine in pVHL-deficient pancreatic neuroendocrine tumors (vPNET).&lt;/p&gt;&lt;p&gt;VHL disease, caused by germline DNA pathogenic variants (PVs) in the &lt;i&gt;VHL&lt;/i&gt; gene,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; is associated with predisposition for pancreatic neuroendocrine tumours (PNETs); hemangioblastoma(s) of the cerebellum, spine and retina; pheochromocytoma and paraganglioma, and renal cell carcinoma of clear-cell type.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The pVHL serves as the recognition unit of the ubiquitin system and identifies hypoxia-inducible factor 1α (HIF1α) to promote its degradation.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; pVHL-deficient states lead to HIF1α accumulation and pseudohypoxia,&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; which promotes tumorigenesis and tumour progression and prompts a metabolic shift from oxidative pyruvate breakdown towards anaerobic glucose utilization.&lt;span&gt;&lt;sup&gt;2, 6, 7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Somatic &lt;i&gt;VHL&lt;/i&gt; PVs are exceedingly rare in sporadic PNET (sPNET).&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Hence, we hypothesized that &lt;i&gt;VHL&lt;/i&gt; PV alone is insufficient for developing vPNET, and metabolic changes drive tumorigenesis. To elucidate this, we conducted tumour metabolomic profiling, single-cell transcriptomic studies and tissue immunohistochemical characterization of vPNET and sPNET (please see full methods in the Supplementary Material).&lt;/p&gt;&lt;p&gt;The current work initiated with an unbiased metabolomic analysis to investigate the metabolic environment in patient-derived tissue samples of vPNET and sPNET. Our analysis led to the putative identification of 217 polar metabolites (Supplementary Material) that demonstrated distinct metabolomic signatures and separation of vPNET versus sPNET (Figure 1A). To identify the metabolites that contributed most to the distinction between the groups, we performed a Variable Importance in Projection analysis, in which adenosine monophosphate (AMP) was identified as a dominant metabolite (Figure 1B). As shown in the volcano plot (Figure 1C) and heatmap (Figure 1D), vPNET had a higher representation of AMP as compared with sPNET.&lt;/p&gt;&lt;p&gt;Other metabolites that were significantly differentially represented between the groups were less likely to be related to PNET tumorigenesis based on the literature review. To independently validate the metabolomics analysis findings, we performed an unbiased snRNA seq analysis. Single-nucleus RNA sequencing was chosen, as it allows single-cell transcriptomic analysis of frozen samples.&lt;/p&gt;&lt;p&gt;In the snRNA sequencing analysis, 25 982 high-quality cells from two vPNET and five sPNET were identified and analysed. Using canonical correlat","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70159","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111850","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-organ transcriptomic atlas reveals hallmarks of labour","authors":"Duan Ni,&nbsp;Ralph Nanan","doi":"10.1002/ctm2.70208","DOIUrl":"https://doi.org/10.1002/ctm2.70208","url":null,"abstract":"&lt;p&gt;We present a multi-organ transcriptomic atlas of labour for unprecedented comprehensive profiling of both organ-specific and systemic signalling changes associated with labour across maternal and fetal compartments. Labour signifies the concluding phase of pregnancy. While pregnancy is known to induce pronounced maternal and fetal reprogramming,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; specific alteration driven by labour remains elusive. In this context, previous studies have predominantly concentrated on individual organ systems,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; limited to gene-level analyses for specific marker gene identification,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; and more comprehensive overviews are lacking.&lt;/p&gt;&lt;p&gt;We surveyed Gene Expression Omnibus for all available transcriptomic datasets across both maternal and fetal compartments to collate a multi-organ transcriptomic atlas, cross-sectionally comparing labour versus non-labour (Supporting Information). The atlas contains 16 datasets, spanning six organ systems (maternal blood, subcutaneous fat, visceral fat, placenta, myometrium and cord blood mononuclear cells [CBMCs]), with 392 samples in total (Figure 1).&lt;/p&gt;&lt;p&gt;Extensive analyses like gene set enrichment analysis (GSEA) were run, focusing on pathway-level changes during labour. For each organ system, we compared the results from different datasets and compiled the most consistent changes. In maternal blood, labour was linked to upregulation of allograft rejection, tumour necrosis factor (TNF)-NFκB-related, and Myc-related signalling (Figure 1). Myc signals were also enhanced in maternal adipose tissues in labour, accompanied by pronounced metabolic changes like enhanced glycolysis, oxidative phosphorylation (OXPHOS) and fatty acid metabolism (FAM) in both visceral and subcutaneous fat (Figure 1).&lt;/p&gt;&lt;p&gt;We next probed the organs directly implicated in labour like myometrium and placenta (Figure 1). Similar to adipose tissues, myometrium exhibited increased glycolysis and Myc signalling. TNF and interleukin (IL)-6 signalling were higher, possibly induced by mTORC1 activation. These were consistent across seven myometrial datasets.&lt;/p&gt;&lt;p&gt;Labor-associated immune activation was also found in the placenta, as TNF signalling was consistently higher (Figure 1), aligned with a previous report.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; A published single-cell RNA-seq (scRNA-seq) dataset for placental tissues with/without labour was re-analyzed (Figure 1). As in the original study, eight different cell subsets were identified (endothelial cells, EC; decidual stromal cells, DSC; extravillous trophoblasts, EVT; smooth muscle cells, SMC; dendritic cells, DC; T cells, T; fibroblasts, FB; endometrial cells, EEC). EECs were excluded from downstream analysis due to low cellularity. GSEA found that all cell subsets upregulated the TNF signalling pathway in labour. They also generally displayed more active metabolic profiles, upregulating glycolysis, OXPHOS and FAM. An exception was EVTs, where the ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70208","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111920","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":"The utilisation of ctDNA approaches for residual disease detection during neoadjuvant and perioperative immunotherapy in oesophagogastric cancers","authors":"Ronan J. Kelly,&nbsp;Valsamo Anagnostou,&nbsp;Vincent K. Lam,&nbsp;Ali H. Zaidi","doi":"10.1002/ctm2.70223","DOIUrl":"https://doi.org/10.1002/ctm2.70223","url":null,"abstract":"&lt;p&gt;The optimal management of operable oesophageal/GEJ (E/GEJ) cancer has been the subject of much debate with the traditional trimodality approach of chemoradiotherapy followed by surgery as established by the CROSS trial&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; in 2012 being challenged by the recently presented results of the ESOPEC trial&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; which demonstrated superiority of the perioperative fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) chemotherapy regimen. Unfortunately, ESOPEC a phase III German led study that enrolled patients between 2016 and 2020 did not compare FLOT to the other standard of care which is chemoradiation followed by adjuvant nivolumab. CheckMate 577 a phase III international adjuvant study&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; published in 2021 investigated the efficacy of the PD-1 inhibitor nivolumab as a systemic agent in an attempt to overcome the challenges posed by utilising radiation sensitising low-dose chemotherapy used in the CROSS regimen. CheckMate 577 demonstrated a doubling in median disease-free survival (mDFS) from 11.0 to 22.4 months (HR 0.69) with the use of adjuvant nivolumab in tumours that had failed to attain a pathological complete response (pCR) post trimodality therapy. mDFS was the primary endpoint of the study but interestingly the secondary endpoint of median distant metastasis-free survival was also increased from 17.6 to 28.3 months (HR 0.74), indicating a systemic effect for PD-1 inhibition above and beyond loco-regional benefits. As is the norm in large adjuvant studies, overall survival (OS) has not been reported as yet requiring a number of years to meet predefined events but challenges in interpretation will exist given the widespread use of immune checkpoint inhibitors (ICIs) in the metastatic setting.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; The question therefore remains which is a better approach in operable E/GEJ cancers—perioperative FLOT or trimodality therapy followed by adjuvant nivolumab? In 2025, it may be the wrong question to ask whether chemotherapy or radiation is better, as the answer will vary depending on the biology of an individual's tumour. With the use of precision medicine, we would hope to be able to gain a more nuanced understanding and define an optimal way to select the most appropriate therapeutic options. This approach aims to ensure that patients achieve the best possible results while avoiding over- or under-treatment and undue toxicities.&lt;/p&gt;&lt;p&gt;The use of circulating tumour DNA (ctDNA) in detecting and tracking minimal residual disease (MRD) may improve upon the use of traditional ypTNM staging and pCR as surrogates for long-term survival.&lt;/p&gt;&lt;p&gt;In our study published in &lt;i&gt;Nature Medicine&lt;/i&gt; in April 2024,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; we sought to measure systemic tumour burden kinetics longitudinally using a tumour-agnostic, matched WBC DNA-informed deep sequencing approach coupled with a branched logic to assign variant cellular origin in the pre- and post-operative s","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70223","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111919","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":"Erratum for the “S100A7 as a potential diagnostic and prognostic biomarker of esophageal squamous cell carcinoma promotes M2 macrophage infiltration and angiogenesis” by Zhiliang Lu et al.","authors":"","doi":"10.1002/ctm2.70222","DOIUrl":"https://doi.org/10.1002/ctm2.70222","url":null,"abstract":"<p>Lu Z, Zheng S, Liu C, et al. S100A7 as a potential diagnostic andprognostic biomarker of esophageal squamous cellcarcinoma promotes M2 macrophage infiltrationand angiogenesis. <i>Clin Transl Med</i>. 2021;11:e459. doi: 10.1002/ctm2.459</p><p>The reason for the correction:</p><p>We proofread the entire article and found that the Western Blot band of the p65 protein in the S100A7 siRNA silencing group in Figure 3H on page 6 accidentally used the same band as the p65 protein in the S100A7 siRNA silencing group in Figure 3G during the editing process.</p><p>The western Blot band of p65 protein in the S100A7 siRNA silencing group in Figure 3H that needs errata is marked with a red block below.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70222","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111348","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":"Artificial metabzyme-driven metabolic reprogramming and precision oncology","authors":"Xi Hu,&nbsp;Daishun Ling","doi":"10.1002/ctm2.70215","DOIUrl":"10.1002/ctm2.70215","url":null,"abstract":"&lt;p&gt;Abnormal metabolism is a biological hallmark of cancer and represents critical targets for therapeutic intervention, as it unveils potential vulnerabilities for treatment.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; To sustain continuous proliferation and metastasis, tumour cells undergo several metabolic adaptations to cope with the nutrient-deficient microenvironment. Recent advancements have demonstrated the successful translation of identified metabolic dysregulations in cancer cells into FDA-approved metabolic inhibitors. Currently, several metabolic regulators are being developed or are undergoing clinical trials for the treatment of various cancers, such as nucleotide synthesis inhibitors (e.g. aminopterin, methotrexate and pemetrexed), indoleamine 2,3-dioxygenase 1 inhibitors (e.g. linrodostat and KHK2455), isocitrate dehydrogenases inhibitors (e.g. ivosidenib and enasidenib), glutaminase inhibitors (e.g. telaglenastat and telaglenastat), lactate efflux inhibitors (e.g. AZD3965), tyrosine mimetics (e.g. racemetyrosine), and so on.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; However, despite significant advancements in the development of drugs targeting cancer genomic alterations and the tumour microenvironment, the progress in targeting cancer metabolism—particularly non-nucleotide metabolism—remains in its nascent stages. A major challenge in targeting cancer metabolism for therapy lies in achieving effective antitumour effects while minimizing toxicity to normal cells, as many metabolic pathways essential for tumour cell survival are also shared by normal cells, resulting in a narrow therapeutic window and potential for significant toxicity.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Xanthine oxidoreductase (XOR), a key enzyme in purine catabolism containing redox-active molybdenum (Mo) and iron (Fe) centres, catalyses the oxidation of hypoxanthine to xanthine and xanthine to uric acid (UA).&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Its expression and activity are significantly reduced in tumour tissues from liver, breast, gastrointestinal, colorectal, ovarian and non-small cell lung cancers, with low XOR levels strongly associated with poor prognosis and recurrence.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; Moreover, the documented immunosuppressive properties of certain xanthine derivatives&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; and the notable role of UA in enhancing anti-tumour immunity&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; underscore the pivotal relevance of XOR in cancer research, suggesting its potential as both a therapeutic target and a mediator of immune responses. Leveraging this insight, we engineered FeMoO&lt;sub&gt;4&lt;/sub&gt; nanocatalysts, an artificial metabzyme graced with Fe&lt;sup&gt;2+&lt;/sup&gt; and tetrahedral Mo&lt;sup&gt;4+&lt;/sup&gt; active centres, to seamlessly simulate XOR's catalytic essence.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; Upon entering tumour cells with low XOR levels and elevated xanthine substrates, the FeMoO&lt;sub&gt;4&lt;/sub&gt; metabzyme efficiently catalyses the conversion of xanthine into excess UA. Interestingly, UA metabolite, in turn, trigger","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064018","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":"Histone methyltransferase KMT2A promotes pulmonary fibrogenesis via targeting pro-fibrotic factor PU.1 in fibroblasts","authors":"Wenting Lyu,&nbsp;Hui Wang,&nbsp;Tong Ji,&nbsp;Ling Liu,&nbsp;Haoran Chen,&nbsp;Li Fan,&nbsp;Guanning Zhong,&nbsp;Naihui Wan,&nbsp;Suwan Chen,&nbsp;Jingyu Chen,&nbsp;Hourong Cai,&nbsp;Hongyang Xu,&nbsp;Dongjin Wang,&nbsp;Jinghong Dai","doi":"10.1002/ctm2.70217","DOIUrl":"10.1002/ctm2.70217","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease driven by both environmental and genetic factors. Epigenetics refers to changes in gene expression or cellular phenotype that do not involve alterations to DNA sequence. KMT2A is a member of the SET family which catalyses H3K4 methylation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Through microarray and single-cell sequencing data, we discovered KMT2A-positive fibroblasts were increased in IPF lung tissues. KMT2A level was increased in IPF and bleomycin-induced pulmonary fibrosis mice lung tissues collected in our centre. Mice with AAV6-induced KMT2A knockdown in fibroblast showed attenuated pulmonary fibrosis after bleomycin treatment. Bioinformation also revealed that transcription factor PU.1 was a target of KMT2A. We demonstrated that PU.1 levels were increased in IPF tissues, bleomycin-induced mice lung tissues and primary fibrotic fibroblasts. KMT2A knockdown decreases PU.1 expression in vitro while KMT2A overexpression induces PU.1 activation. PU.1 fibroblast-specific knockout mice showed attenuated lung fibrosis induced by bleomycin. Furthermore, we demonstrated KMT2A up-regulated PU.1 in fibroblasts by catalysing H3K4me3 at the promoter of the PU.1 gene. The KMT2A transcription complex inhibitor mm102 treatment attenuated bleomycin-induced pulmonary fibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The current study indicated that histone modification participates in the pathogenesis of IPF and KMT2A may have the potential to be a therapeutic target of IPF treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>KMT2A plays a role in pulmonary fibrogenesis.</li>\u0000 \u0000 <li>KMT2A regulates PU.1 transcription in fibroblasts through H3K4me3 at promoter.</li>\u0000 \u0000 <li>KMT2A inhibitor attenuates pulmonary fibrosis in mice.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064021","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":"Oestrogen suppresses the adipogenesis of fibro/adipogenic progenitors through reactivating the METTL3–ESR1-mediated loop in post-menopausal females","authors":"Hao Zhou,&nbsp;Shujing Feng,&nbsp;Jinkui Cai,&nbsp;Xiexiang Shao,&nbsp;Siyuan Zhu,&nbsp;Han Zhou,&nbsp;Yongmin Cao,&nbsp;Ru Wang,&nbsp;Xingzuan Lin,&nbsp;Jianhua Wang","doi":"10.1002/ctm2.70206","DOIUrl":"10.1002/ctm2.70206","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;Post-menopausal women experience more severe muscular fatty infiltration, though the mechanisms remain unclear. The decline in estrogen levels is considered as a critical physiological alteration during post-menopause. Fibro/adipogenic progenitors (FAPs) are identified as major contributors to muscular fatty infiltration. This study aimed to investigate the detailed mechanism underlying the excessive muscular fatty infiltration in postmenopausal females.&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;Supraspinatus muscle samples were collected from female patients with or without menopause, and from mice with or without ovariectomy (OVX), to evaluate muscular fatty infiltration and isolated FAPs. The expressions of (estrogen receptor 1) ESR1, methyltransferase-like 3 (METTL3), and adipogenesis ability in FAPs from post-menopausal women and OVX mice were investigated. RNA sequencing (RNA-Seq) was performed to explore the gene expression profiles and potential mechanisms in FAPs from Pdgfrα-CreERT2; Esr1 knockout (Esr1 KO) mice and Esr1 flox/flox (Esr1 f/f) mice. The interplay of the METTL3-ESR1 mediated loop and its role in regulating adipogenesis in FAPs were investigated using dual luciferase reporter assays, chromatin immunoprecipitation (ChIP), and protein and RNA stability assays. The effects of estrogen supplementation on muscular fatty infiltration and locomotor function in OVX mice were evaluated by immunofluorescent staining and functional analysis.&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;Decreased expression of ESR1/METTL3 and increased adipogenesis ability in FAPs was found in post-menopausal female. METTL3-mediated m6A methylation promoted ESR1 mRNA stability at the post-transcriptional level in FAPs. METTL3-mediated m6A modification promoted ESR1 expression by stabilizing ESR1 mRNA, while ESR1 acted as a transcription factor that enhanced METTL3 transcription in turn. ESR1 also suppressed the transcription of the adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARγ), thereby inhibiting adipogenesis in FAPs. Reactivation of the METTL3-ESR1 mediated loop by estrogen alleviated excessive adipogenesis in FAPs from post-menopausal women, and it also reduced muscular fatty infiltration, and improved locomotor function in OVX mice.&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;Excessive muscular fatty infiltration in post-menopausal women arose from the disruption of the METTL3-ESR1 mediated loop of FAPs due to estrogen deficiency. Reactivation of the METTL3-ESR","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11774659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057966","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}