Clinical and Translational Medicine最新文献

{"title":"RNF31 induces paclitaxel resistance by sustaining ALYREF cytoplasmic–nuclear shuttling in human triple-negative breast cancer","authors":"Shumei Huang, Dongni Shi, Shuqin Dai, Xingyu Jiang, Rui Wang, Muwen Yang, Boyu Chen, Xuwei Chen, Lingzhi Kong, Lixin He, Pinwei Deng, Xiangfu Chen, Chuyong Lin, Yue Li, Jun Li, Libing Song, Yawei Shi, Weidong Wei","doi":"10.1002/ctm2.70203","DOIUrl":"https://doi.org/10.1002/ctm2.70203","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Resistance to paclitaxel-based chemotherapy is the major obstacle in triple-negative breast cancer (TNBC) treatment. However, overcoming paclitaxel resistance remains an unsolved problem. The present study aimed to determine whether paclitaxel treatment impairs Aly/REF export factor (ALYREF) cytoplasmic–nuclear shuttling, its mechanism, and the role of ubiquitinated ALYREF in paclitaxel resistance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The subcellular proportion of ALYREF was detected in samples from patients with TNBC using immunohistochemistry to analyze the relationship between ALYREF distribution and paclitaxel response. Cell viability assays, immunofluorescence assays, quantitative real-time reverse transcription PCR assays, western blotting, and terminal deoxynucleotidyl transferase nick-end-labelling assays were conducted to measure the biological function of the subcellular proportion of ALYREF and E3 ligase ring finger protein 31 (RNF31) on paclitaxel sensitivity in TNBC. The synergistic effects of an RNF31 inhibitor plus paclitaxel on TNBC were evaluated. Cox regression models were adopted to assess the prognostic role of RNF31 in TNBC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Herein, we showed that regulation of ALYREF cytoplasmic–nuclear shuttling is associated with the paclitaxel response in TNBC. In paclitaxel-sensitive TNBC, ALYREF was trapped in the cytoplasm by paclitaxel, while in paclitaxel-resistant TNBC, ALYREF was efficiently transported into the nucleus to exert its function, allowing the export of the mRNAs encoding paclitaxel-resistance-related factors, including tubulin beta 3 class III (TUBB3), stathmin 1 (STMN1), and microtubule-associated protein Tau (TAU), ultimately inducing paclitaxel resistance in TNBC. Mechanistically, we found that RNF31 interacts with and ubiquitinates ALYREF, which facilitates ALYREF nuclear transportation via importin 13 (IPO13) under paclitaxel treatment. Notably, the RNF31 inhibitor and paclitaxel synergistically repressed tumour growth in vivo and in TNBC patient-derived organoids. In addition, analysis of patients with TNBC showed that elevated RNF31 levels correlated with poor prognosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These data indicated that RNF31-mediated ALYREF ubiquitylation could represent a potent target to reverse paclitaxel resistance in TNBC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362668","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":"HSPG2 could promote normal haematopoiesis in acute myeloid leukaemia patients after complete remission by repairing bone marrow endothelial progenitor cells","authors":"Chen-Yuan Li, Zhen-Kun Wang, Tong Xing, Meng-Zhu Shen, Xin-Yan Zhang, Dan-Dan Chen, Yu Wang, Hao Jiang, Qian Jiang, Xiao-Jun Huang, Yuan Kong","doi":"10.1002/ctm2.70220","DOIUrl":"https://doi.org/10.1002/ctm2.70220","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Even after achieving complete remission (CR), many acute myeloid leukaemia (AML) patients suffer from poor haematopoietic recovery after chemotherapy. Previous studies have shown that the damage of bone marrow endothelial progenitor cell (BM EPC) hinders haematopoietic recovery after chemotherapy in mice. Therefore, elucidation of the mechanism and repair strategy of chemotherapy-induced BM EPC damage is urgent needed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The prospective case–control study enrolled 40 AML patients after CR (CR patients), who received idarubicin and cytarabine (IA) regimen (<i>n</i> = 20), or homoharringtonine, aclarubicin and cytarabine (HAA) regimen (<i>n</i> = 20) as induction chemotherapy, and their age-matched healthy controls (HCs, <i>n</i> = 20). The HSPG2 expression level in BM EPCs and BM plasma were determined via flow cytometry and enzyme-linked immunosorbent assays. The BM EPC's functions were evaluated by apoptosis, reactive oxygen species (ROS) level, migration and tube formation assays. The haematopoiesis-supporting ability and leukaemia cell-supporting ability of BM EPCs were assessed through coculture assay. Moreover, RNA sequencing and qPCR were performed to further explore the underlying mechanism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>HSPG2 levels decreased in both the BM plasma and BM EPCs of CR patients after IA and HAA induction chemotherapy. Moreover, the BM EPC's functions of CR patients were reduced. In vitro experiments demonstrated that the <i>HSPG2</i> gene knockdown or cytosine arabinoside treatment led to BM EPC dysfunction, whereas the HSPG2 treatment promoted repair of the BM EPC function in vitro. In addition, we found that the HSPG2 treatment restored the BM EPC function from CR patients without affecting their leukaemia cell-supporting ability. Mechanistically, BM EPC functions and haematopoietic regulation-related genes were significantly decreased after the <i>HSPG2</i> gene knockdown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings demonstrate a significant role of HSPG2 in BM EPC functions. This discovery uncovers that HSPG2 is a potential therapeutic target for promoting the BM EPC function of AML-CR patients after chemotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>The HSPG2 level in the BM EPCs of AML-CR patien","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362669","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":"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}