<div> <section> <h3> Background</h3> <p>Although RANK-LRANK interaction is essential for osteoclastogenesis, the mechanisms by which cancer cells invade bone tissues and initiate osteolytic metastasis remain unclear. Here, we show that the hyperactivation of RelB fosters prostate cancer (PCa) osteolytic metastasis by coordinating interleukin-8 (IL-8) and calcium-binging protein A4 (S100A4).</p> </section> <section> <h3> Methods</h3> <p>The factors promoting PCa bone metastasis were investigated in sera from PCa patients and tumour tissues derived from nude mice using immunohistochemical analysis and enzyme-linked immunosorbent assays (ELISA). Cell mobility and mineralization were quantified using BioStation CT and Osteolmage assay. The relative cistrome was investigated in advanced PCa cells by standard transcriptional analyses, including the luciferase reporter response, site-directed mutagenesis, and chromatin immunoprecipitation (ChIP) assay. PCa cell-initiated tumour formation, expansion, and bone metastasis were validated in mice using multiple approaches, including orthotopic, intraskeletal, and caudal arterial implantation models.</p> </section> <section> <h3> Results</h3> <p>IL-8 and S100A4 correlated with patient Gleason scores and bone metastasis. RelB upregulated IL-8, facilitating androgen receptor (AR)-independent growth. RelB-Sp1 interaction enhanced epithelial-mesenchymal transition (EMT) by activating Snail and Twist. RelB-NFAT1c super-enhancer upregulated S100A4 in the organization of the cytoskeleton and bone metastasis. The RelB-IL-8-S100A4 signalling axis was confirmed to promote osteolytic metastasis in nude mice.</p> </section> <section> <h3> Conclusion</h3> <p>RelB-IL-8 reciprocally promoted EMT by activating inflammatory signalling and inactivating AR signalling. IL-8 is essential for provoking PCa metastasis but insufficient to drive bone metastasis. IL-8-S100A4 cooperation was necessary for metastatic cells to target the bone.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>RelB activates inflammatory signalling by upregulating IL-8 and suppressing AR.</li> <li>RelB upregulates S100A4 by cooperating with NFATC1.</li> <li>IL-8 boosts EMT by activating Snail 1 and Twist 1, and S100A4 exacerbates osteolytic metastasis via calcium consumption.</li>
{"title":"Insight into prostate cancer osteolytic metastasis by RelB coordination of IL-8 and S100A4","authors":"Wenbo Sun, Kenny Xu, Xiao Li, Peipei Qian, Fan Xu, Yanyan Zhang, Xiumei Wang, Zhi Xu, Jiaji Ding, Xinyu Xu, Xiaowei Wei, Qin Jiang, Yong Xu","doi":"10.1002/ctm2.70058","DOIUrl":"https://doi.org/10.1002/ctm2.70058","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Although RANK-LRANK interaction is essential for osteoclastogenesis, the mechanisms by which cancer cells invade bone tissues and initiate osteolytic metastasis remain unclear. Here, we show that the hyperactivation of RelB fosters prostate cancer (PCa) osteolytic metastasis by coordinating interleukin-8 (IL-8) and calcium-binging protein A4 (S100A4).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The factors promoting PCa bone metastasis were investigated in sera from PCa patients and tumour tissues derived from nude mice using immunohistochemical analysis and enzyme-linked immunosorbent assays (ELISA). Cell mobility and mineralization were quantified using BioStation CT and Osteolmage assay. The relative cistrome was investigated in advanced PCa cells by standard transcriptional analyses, including the luciferase reporter response, site-directed mutagenesis, and chromatin immunoprecipitation (ChIP) assay. PCa cell-initiated tumour formation, expansion, and bone metastasis were validated in mice using multiple approaches, including orthotopic, intraskeletal, and caudal arterial implantation models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>IL-8 and S100A4 correlated with patient Gleason scores and bone metastasis. RelB upregulated IL-8, facilitating androgen receptor (AR)-independent growth. RelB-Sp1 interaction enhanced epithelial-mesenchymal transition (EMT) by activating Snail and Twist. RelB-NFAT1c super-enhancer upregulated S100A4 in the organization of the cytoskeleton and bone metastasis. The RelB-IL-8-S100A4 signalling axis was confirmed to promote osteolytic metastasis in nude mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>RelB-IL-8 reciprocally promoted EMT by activating inflammatory signalling and inactivating AR signalling. IL-8 is essential for provoking PCa metastasis but insufficient to drive bone metastasis. IL-8-S100A4 cooperation was necessary for metastatic cells to target the bone.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>RelB activates inflammatory signalling by upregulating IL-8 and suppressing AR.</li>\u0000 \u0000 <li>RelB upregulates S100A4 by cooperating with NFATC1.</li>\u0000 \u0000 <li>IL-8 boosts EMT by activating Snail 1 and Twist 1, and S100A4 exacerbates osteolytic metastasis via calcium consumption.</li>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70058","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447698","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}
<div> <section> <h3> Background</h3> <p>Combinatory therapeutic strategy containing immunochemotherapy as part of induction therapy components is one of the current trends in the treatment of high-risk metastatic locally advanced nasopharyngeal carcinoma (NPC). However, the mechanism underlying the heterogeneity of response at the single-cell level has not been underexplored.</p> </section> <section> <h3> Methods</h3> <p>18 bulks and 11 single-cell RNA sequencing from paired before-treatment and on-treatment samples in patients with treatment-naive high-risk metastatic locally advanced NPCs were obtained. Following quality control, a total of 87 191 cells were included in the subsequence bioinformatics analysis.</p> </section> <section> <h3> Results</h3> <p>Immunochemotherapy was associated with on-treatment tumour microenvironment (TME) remodelling, including upregulation of anti-TMEs signatures, downregulation of pro-TMEs signatures, reversing CD8<sup>+</sup> T exhaustion, and repolarizing proinflammatory TAMs. For the patients achieving a complete response, the cytotoxic activity of CD8<sup>+</sup> T cells was stimulated and more interferon-gamma was provided, which would be the key for TAMs proinflammatory repolarization and eventually promote the CD8<sup>+</sup> T cells maturation in turn. Among patients who did not reach complete response, differentiation and hypoxia signatures for endothelial cells were elevated after therapy. These patients exhibited higher levels of immune checkpoint genes in malignant cells at the baseline (before treatment), and decreased tumour antigen presentation activity, which may underlie the resistance mechanism to therapy.</p> </section> <section> <h3> Conclusions</h3> <p>This study pictures a map of TME modulation following immunochemotherapy-based combination induction therapy and provides potential future approaches.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Immunochemotherapy remodeled T cell phenotypes.</li> <li>For the patients achieving complete response, more interferon gamma was provided by CD8<sup>+</sup> T cells after therapy, which would be the key for TAMs pro-inflammatory repolarization and eventually promote the CD8<sup>+</sup> T cells maturation in turns.</li> <li>Among patients who did not reach complete response, malignant cells exh
背景 含有免疫化疗作为诱导治疗组成部分的联合治疗策略是目前治疗高风险转移性局部晚期鼻咽癌（NPC）的趋势之一。然而，单细胞水平反应异质性的机制尚未得到充分探索。 方法 从未经治疗的高危转移性局部晚期鼻咽癌患者治疗前和治疗中的配对样本中获得了 18 个批次和 11 个单细胞 RNA 测序。经过质量控制后，共有 87 191 个细胞被纳入后续生物信息学分析。 结果 免疫化疗与治疗中的肿瘤微环境（TME）重塑有关，包括抗TMEs特征的上调、促TMEs特征的下调、CD8+ T衰竭的逆转以及促炎TAMs的再极化。对于获得完全应答的患者，CD8+ T 细胞的细胞毒性活性得到了激发，干扰素-γ 的供应量增加，这将成为 TAMs 促炎性极化的关键，并最终反过来促进 CD8+ T 细胞的成熟。在未达到完全应答的患者中，内皮细胞的分化和缺氧特征在治疗后升高。这些患者的基线（治疗前）恶性细胞中免疫检查点基因水平较高，肿瘤抗原呈递活性降低，这可能是治疗耐药机制的基础。 结论 本研究描绘了基于免疫化疗的联合诱导疗法后的TME调控图，并提供了潜在的未来方法。 亮点 免疫化疗重塑了T细胞表型。 对于获得完全应答的患者，治疗后 CD8+ T 细胞提供了更多的γ干扰素，这将是 TAMs 促炎症复极的关键，并最终促进 CD8+ T 细胞的成熟。 在未达到完全应答的患者中，恶性细胞在治疗前表现出更高水平的免疫检查点基因，肿瘤抗原递呈活性降低，这可能是治疗耐药机制的基础。
{"title":"Single-cell transcriptome analysis reveals evolving tumour microenvironment induced by immunochemotherapy in nasopharyngeal carcinoma","authors":"Yaofei Jiang, Weixin Bei, Wangzhong Li, Ying Huang, Shuiqing He, Xiaobin Zhu, Lisheng Zheng, Weixiong Xia, Shuhui Dong, Qin Liu, Chuanrun Zhang, Shuhui Lv, Changqing Xie, Yanqun Xiang, Guoying Liu","doi":"10.1002/ctm2.70061","DOIUrl":"https://doi.org/10.1002/ctm2.70061","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Combinatory therapeutic strategy containing immunochemotherapy as part of induction therapy components is one of the current trends in the treatment of high-risk metastatic locally advanced nasopharyngeal carcinoma (NPC). However, the mechanism underlying the heterogeneity of response at the single-cell level has not been underexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>18 bulks and 11 single-cell RNA sequencing from paired before-treatment and on-treatment samples in patients with treatment-naive high-risk metastatic locally advanced NPCs were obtained. Following quality control, a total of 87 191 cells were included in the subsequence bioinformatics analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Immunochemotherapy was associated with on-treatment tumour microenvironment (TME) remodelling, including upregulation of anti-TMEs signatures, downregulation of pro-TMEs signatures, reversing CD8<sup>+</sup> T exhaustion, and repolarizing proinflammatory TAMs. For the patients achieving a complete response, the cytotoxic activity of CD8<sup>+</sup> T cells was stimulated and more interferon-gamma was provided, which would be the key for TAMs proinflammatory repolarization and eventually promote the CD8<sup>+</sup> T cells maturation in turn. Among patients who did not reach complete response, differentiation and hypoxia signatures for endothelial cells were elevated after therapy. These patients exhibited higher levels of immune checkpoint genes in malignant cells at the baseline (before treatment), and decreased tumour antigen presentation activity, which may underlie the resistance mechanism to therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study pictures a map of TME modulation following immunochemotherapy-based combination induction therapy and provides potential future approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Immunochemotherapy remodeled T cell phenotypes.</li>\u0000 \u0000 <li>For the patients achieving complete response, more interferon gamma was provided by CD8<sup>+</sup> T cells after therapy, which would be the key for TAMs pro-inflammatory repolarization and eventually promote the CD8<sup>+</sup> T cells maturation in turns.</li>\u0000 \u0000 <li>Among patients who did not reach complete response, malignant cells exh","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447605","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}
Mengmeng Xiao, Da Qin, Xiangji Li, Fanqin Bu, Shixiang Ma, Xiaobing Chen, Yu Zhao, Chenghua Luo, Li Min
<p>Dear Editor,</p><p>Retroperitoneal liposarcoma (RPLS) is an extremely rare malignant tumour.<span><sup>1</sup></span> It is largely understudied with unknown risk factors and limited treatment options. The rapid development of next-generation sequencing technology has brought the diagnosis and treatment of neoplastic diseases to the era of precision medicine.<span><sup>2</sup></span> It provided detailed RNA-seq information for the prognosis and prediction of different therapies and guided the crucial clinical decision-making processes throughout the treatment.<span><sup>3</sup></span> Here, we aim to develop prognosis-oriented molecular subtyping of RPLS and further provide novel treatment strategies for RPLS patients (Figure 1A). This work fundamentally differs from our previous reports.<span><sup>4</sup></span> It focuses on prognostic genes rather than differential genes, employing Weighted Gene Network Analysis and nonnegative matrix factorization (NMF) algorithms to achieve a more refined molecular classification of RPLS. By selecting and validating representative molecular biomarkers for each subtype, we have further streamlined the classification system for clinical application. Additionally, this classification system elucidates how the molecular biological characteristics of the different subtypes influence distinct clinical prognoses.</p><p>To construct prognosis-oriented RPLS molecular subtypes, we first identify the prognostic genes in our training cohort based on univariate cox regression (<i>N</i> = 80, Table 1; Tables S1 and S2). The regression analysis pipeline was conducted with the R package “survival” (Supporting Information Material and methods). A total of 3550 genes were associated with OS and DFS (<i>p </i>< .05; Figure 1B), and the top 10 genes of HR > 1 and HR < 1 were shown in Figure 1C. Functional annotation revealed these genes were enriched in the cell cycle, TGFβ-signalling pathway, angiopoietin, and cellular senescence (Figure 1D–F). We then functionally clustered 3550 prognostic genes by WGCNA (Figure S1) and selected the top 20 genes in each module for NMF grouping. Three RPLS subtypes were significantly distinguished (Figure 1G–H). Log-rank analysis showed that subtype 2 (S2) had the best prognostic outcomes (including OS, <i>p</i> < .0046; DFS, <i>p</i> < .0001) compared with subtype 1 (S1) and subtype 3 (S3), while S3 had the worst prognostic outcomes among them (Figure 2A,B). Functional annotation of characteristic genes showed that “Obesity”, “Overnutrition”, and “<i>PPAR</i> signaling pathway” were mainly enrichment terms of S2 (Figure S2).</p><p>Hallmark gene set of cancer well represents the specific biological processes and states of tumours. We previously revealed the differences in the functional annotation among subtypes. To verify them, hallmark gene sets were scored on patients of each subtype by ssGSEA. We found that metabolism-related pathways, including “adipogenesis” and “bile
{"title":"Prognosis-oriented molecular subtypes of retroperitoneal liposarcoma","authors":"Mengmeng Xiao, Da Qin, Xiangji Li, Fanqin Bu, Shixiang Ma, Xiaobing Chen, Yu Zhao, Chenghua Luo, Li Min","doi":"10.1002/ctm2.70050","DOIUrl":"https://doi.org/10.1002/ctm2.70050","url":null,"abstract":"<p>Dear Editor,</p><p>Retroperitoneal liposarcoma (RPLS) is an extremely rare malignant tumour.<span><sup>1</sup></span> It is largely understudied with unknown risk factors and limited treatment options. The rapid development of next-generation sequencing technology has brought the diagnosis and treatment of neoplastic diseases to the era of precision medicine.<span><sup>2</sup></span> It provided detailed RNA-seq information for the prognosis and prediction of different therapies and guided the crucial clinical decision-making processes throughout the treatment.<span><sup>3</sup></span> Here, we aim to develop prognosis-oriented molecular subtyping of RPLS and further provide novel treatment strategies for RPLS patients (Figure 1A). This work fundamentally differs from our previous reports.<span><sup>4</sup></span> It focuses on prognostic genes rather than differential genes, employing Weighted Gene Network Analysis and nonnegative matrix factorization (NMF) algorithms to achieve a more refined molecular classification of RPLS. By selecting and validating representative molecular biomarkers for each subtype, we have further streamlined the classification system for clinical application. Additionally, this classification system elucidates how the molecular biological characteristics of the different subtypes influence distinct clinical prognoses.</p><p>To construct prognosis-oriented RPLS molecular subtypes, we first identify the prognostic genes in our training cohort based on univariate cox regression (<i>N</i> = 80, Table 1; Tables S1 and S2). The regression analysis pipeline was conducted with the R package “survival” (Supporting Information Material and methods). A total of 3550 genes were associated with OS and DFS (<i>p </i>< .05; Figure 1B), and the top 10 genes of HR > 1 and HR < 1 were shown in Figure 1C. Functional annotation revealed these genes were enriched in the cell cycle, TGFβ-signalling pathway, angiopoietin, and cellular senescence (Figure 1D–F). We then functionally clustered 3550 prognostic genes by WGCNA (Figure S1) and selected the top 20 genes in each module for NMF grouping. Three RPLS subtypes were significantly distinguished (Figure 1G–H). Log-rank analysis showed that subtype 2 (S2) had the best prognostic outcomes (including OS, <i>p</i> < .0046; DFS, <i>p</i> < .0001) compared with subtype 1 (S1) and subtype 3 (S3), while S3 had the worst prognostic outcomes among them (Figure 2A,B). Functional annotation of characteristic genes showed that “Obesity”, “Overnutrition”, and “<i>PPAR</i> signaling pathway” were mainly enrichment terms of S2 (Figure S2).</p><p>Hallmark gene set of cancer well represents the specific biological processes and states of tumours. We previously revealed the differences in the functional annotation among subtypes. To verify them, hallmark gene sets were scored on patients of each subtype by ssGSEA. We found that metabolism-related pathways, including “adipogenesis” and “bile ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443379","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}
Yongbing Qian, Xiaoning Hong, Yang Yu, Cong Du, Jing Li, Jiaying Yu, Wenjun Xiao, Chen Chen, Defa Huang, Tianyu Zhong, Jiang Li, Xi Xiang, Zhigang Li
<p>Extrachromosomal circular DNA (eccDNA) is a mobile, circular DNA molecule that originates from but exists independently of linear chromosomes.<span><sup>1</sup></span> Its characteristics and potential function in liver failure remain elusive. Herein, we established a reliable workflow for purifying the internal eccDNAs harboured by plasma-derived extracellular vesicles (EVs) and characterization of these EVs-eccDNAs in liver failure. Additionally, the impact of liver failure-specific circulating EVs-eccDNAs on the hepatocytes was evaluated by synthetic eccDNAs transfection and RNAseq analysis.</p><p>This study recruited 22 participants, including 13 patients with liver failure and nine healthy individuals. Detailed information is provided in Table S1 and Material S1. Patients were diagnosed with liver failure using established criteria, and their hepatic function was matched accordingly.<span><sup>2-4</sup></span> Subsequently, we isolated plasma-derived EVs from both healthy control individuals and liver failure.<span><sup>5, 6</sup></span> Electron microscopy images showed that both healthy control EVs (HCEVs) and liver failure patient EVs (LFEVs) exhibited the typical “cup-shaped” morphology with similar average diameters around 100 nm (Figure 1A). Nano-flow cytometry indicated that the concentration of LFEVs was significantly higher than that of HCEVs, but no significant difference in size was found (Figure 1B). Western blot analysis confirmed small EV markers CD9, CD81 and TSG101 were present, while the negative marker Mitofilin was absent (Figure 1C). Notably, LFEVs had a higher level of CD9 than HCEVs. Our data revealed an increased presence of EVs in the peripheral circulation of liver failure patients.</p><p>We then isolated eccDNA from HCEVs and LFEVs using the process illustrated in Figure 2A. Specifically, eccDNAs with > 75 bp overlap of a certain gene were defined as “eccGenes” in the study.<span><sup>7</sup></span> The read sizes for HCEVs and LFEVs were similar (Figure 2B and Table S2). We then identified that LFEVs had a significantly higher number of eccDNAs compared to HCEVs (Figure 2C and Table S2). The normalized eccDNA count per million mapped reads (EPM) was significantly higher in LFEVs (Figure 2D). Additionally, the GC content and flanking regions of eccDNAs from LFEVs were higher than those from HCEVs (Figure 2E,F). The percentage of EPM across all chromosomes was similar for both LFEVs and HCEVs (Figure 2G, Figure S1A and Material S2). Overall, these data indicate that LFEVs carry a higher abundance of eccDNAs than HCEVs.</p><p>We then analyzed the eccDNA lengths in HCEVs and LFEVs. Figure 3A shows five enriched peaks in LFEVs at 370, 566, 751, 946 and 1124 bp, with a noticeably higher density of eccDNAs in LFEVs compared to HCEVs. We calculated the cumulative frequency of HCEVs and LFEVs containing eccDNAs and found that eccDNA lengths in LFEVs were much shorter than those in HCEVs (Figure 3B). Additionally, we f
{"title":"Characterization and functional analysis of extrachromosomal circular DNA discovered from circulating extracellular vesicles in liver failure","authors":"Yongbing Qian, Xiaoning Hong, Yang Yu, Cong Du, Jing Li, Jiaying Yu, Wenjun Xiao, Chen Chen, Defa Huang, Tianyu Zhong, Jiang Li, Xi Xiang, Zhigang Li","doi":"10.1002/ctm2.70059","DOIUrl":"https://doi.org/10.1002/ctm2.70059","url":null,"abstract":"<p>Extrachromosomal circular DNA (eccDNA) is a mobile, circular DNA molecule that originates from but exists independently of linear chromosomes.<span><sup>1</sup></span> Its characteristics and potential function in liver failure remain elusive. Herein, we established a reliable workflow for purifying the internal eccDNAs harboured by plasma-derived extracellular vesicles (EVs) and characterization of these EVs-eccDNAs in liver failure. Additionally, the impact of liver failure-specific circulating EVs-eccDNAs on the hepatocytes was evaluated by synthetic eccDNAs transfection and RNAseq analysis.</p><p>This study recruited 22 participants, including 13 patients with liver failure and nine healthy individuals. Detailed information is provided in Table S1 and Material S1. Patients were diagnosed with liver failure using established criteria, and their hepatic function was matched accordingly.<span><sup>2-4</sup></span> Subsequently, we isolated plasma-derived EVs from both healthy control individuals and liver failure.<span><sup>5, 6</sup></span> Electron microscopy images showed that both healthy control EVs (HCEVs) and liver failure patient EVs (LFEVs) exhibited the typical “cup-shaped” morphology with similar average diameters around 100 nm (Figure 1A). Nano-flow cytometry indicated that the concentration of LFEVs was significantly higher than that of HCEVs, but no significant difference in size was found (Figure 1B). Western blot analysis confirmed small EV markers CD9, CD81 and TSG101 were present, while the negative marker Mitofilin was absent (Figure 1C). Notably, LFEVs had a higher level of CD9 than HCEVs. Our data revealed an increased presence of EVs in the peripheral circulation of liver failure patients.</p><p>We then isolated eccDNA from HCEVs and LFEVs using the process illustrated in Figure 2A. Specifically, eccDNAs with > 75 bp overlap of a certain gene were defined as “eccGenes” in the study.<span><sup>7</sup></span> The read sizes for HCEVs and LFEVs were similar (Figure 2B and Table S2). We then identified that LFEVs had a significantly higher number of eccDNAs compared to HCEVs (Figure 2C and Table S2). The normalized eccDNA count per million mapped reads (EPM) was significantly higher in LFEVs (Figure 2D). Additionally, the GC content and flanking regions of eccDNAs from LFEVs were higher than those from HCEVs (Figure 2E,F). The percentage of EPM across all chromosomes was similar for both LFEVs and HCEVs (Figure 2G, Figure S1A and Material S2). Overall, these data indicate that LFEVs carry a higher abundance of eccDNAs than HCEVs.</p><p>We then analyzed the eccDNA lengths in HCEVs and LFEVs. Figure 3A shows five enriched peaks in LFEVs at 370, 566, 751, 946 and 1124 bp, with a noticeably higher density of eccDNAs in LFEVs compared to HCEVs. We calculated the cumulative frequency of HCEVs and LFEVs containing eccDNAs and found that eccDNA lengths in LFEVs were much shorter than those in HCEVs (Figure 3B). Additionally, we f","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443421","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}
Antoine Desilets, Matteo Repetto, Alexander Drilon
The ROS1 proto-oncogene encodes a receptor tyrosine kinase with structural homology to other oncogenic drivers, including ALK and TRKA-B-C. The FDA-approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion-positive NSCLC. However, limitations such as poor blood-brain barrier penetration and acquired resistance, particularly the ROS1 G2032R solvent-front mutation, hinder treatment durability. Repotrectinib, a next-generation macrocyclic TKI, was rationally designed to overcome on-target resistance mutations and improve brain distribution through its low molecular weight. In the TRIDENT-1 clinical trial, repotrectinib demonstrated significant efficacy in both TKI-naïve and TKI-pretreated patients with ROS1-rearranged NSCLC, including those with CNS metastases and G2032R resistance mutations. In the TKI-naïve cohort (n = 71), 79% of patients achieved an objective response, with a median progression-free survival (PFS) of 35.7 months, surpassing all previously approved ROS1 TKIs. In patients who had received one prior ROS1 TKI but were chemotherapy-naïve (n = 56), objective responses were observed in 38%, and median PFS was 9.0 months. The safety profile of repotrectinib was consistent with earlier-generation ROS1 TKIs and common adverse events included anemia, neurotoxicity, increased creatine kinase levels, and weight gain. These findings underscore the potential of repotrectinib to address unmet needs in ROS1-rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next-generation, selective ROS1 inhibitors to reduce Trk-mediated toxicities and improve treatment tolerance.
{"title":"Repotrectinib: Redefining the therapeutic landscape for patients with ROS1 fusion-driven non-small cell lung cancer","authors":"Antoine Desilets, Matteo Repetto, Alexander Drilon","doi":"10.1002/ctm2.70017","DOIUrl":"https://doi.org/10.1002/ctm2.70017","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The ROS1 proto-oncogene encodes a receptor tyrosine kinase with structural homology to other oncogenic drivers, including ALK and TRKA-B-C. The FDA-approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion-positive NSCLC. However, limitations such as poor blood-brain barrier penetration and acquired resistance, particularly the ROS1 G2032R solvent-front mutation, hinder treatment durability. Repotrectinib, a next-generation macrocyclic TKI, was rationally designed to overcome on-target resistance mutations and improve brain distribution through its low molecular weight. In the TRIDENT-1 clinical trial, repotrectinib demonstrated significant efficacy in both TKI-naïve and TKI-pretreated patients with ROS1-rearranged NSCLC, including those with CNS metastases and G2032R resistance mutations. In the TKI-naïve cohort (<i>n</i> = 71), 79% of patients achieved an objective response, with a median progression-free survival (PFS) of 35.7 months, surpassing all previously approved ROS1 TKIs. In patients who had received one prior ROS1 TKI but were chemotherapy-naïve (<i>n</i> = 56), objective responses were observed in 38%, and median PFS was 9.0 months. The safety profile of repotrectinib was consistent with earlier-generation ROS1 TKIs and common adverse events included anemia, neurotoxicity, increased creatine kinase levels, and weight gain. These findings underscore the potential of repotrectinib to address unmet needs in ROS1-rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next-generation, selective ROS1 inhibitors to reduce Trk-mediated toxicities and improve treatment tolerance.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435320","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}
Shujin Li, Jun Wang, Lin Qiu, Gaohui Fu, Yang Li, Qiang Su, Yiheng Zhu, Feilong Zhao, Jinglin Tian, Jinyong Huang, Yanqin Niu, Kang Kang, Deming Gou
<p>The incidence of colorectal cancer (CRC) is increasing, especially among younger populations, underscoring the necessity for a thorough examination of biomarkers.<span><sup>1, 2</sup></span> This study explores the clinical and functional roles of circRNAs in CRC using a stage-stratified, integrated multiomics approach. The identified circRNA panel holds promise for CRC diagnosis.<span><sup>3, 4</sup></span></p><p>Utilising whole transcriptome sequencing on tumour, normal, and paracancer tissues from 30 CRC patients, circRNA alterations were investigated (Table S1). CircRNAs were identified with CIRI2 and DCC software (Table S2).<span><sup>5, 6</sup></span> Increased sequencing depth correlated with a higher number of identified circRNAs (Figure S1A–D). Tumour tissues exhibited a lower abundance of circRNAs compared to normal and paracancer tissues (Figure S1 E–H), indicating changes in circRNA expression during CRC pathogenesis.<span><sup>3</sup></span> To minimise variability, we focused on circRNAs detectable in at least half of the patients (Figure 1A and B), which revealed more distinct tissue-specific differences in circRNA numbers (Figures 1C and S1I); further analysis revealed high consistency between cirRNAs identified by CIRI2 and DCC (Figure 1D–F). In subsequent analysis, only circRNAs detected by both software were considered (Figure S1J–L). Our investigation showed that most circRNAs corresponded to a single host gene and were predominantly exon-type (Figure 1G and H). Despite the reduced number of circRNAs in tumours, their chromosomal distribution was similar to those in normal and paracancer tissues (Figure S2A and B). Annotation of the circRNAs using circBase supports the reliability of our identification process (Figure 1I).</p><p>We further identified 67 and 71 differentially expressed circRNAs (DEcircRNAs) in tumour versus normal (N vs. T) and paracancer versus tumour (P vs. T), respectively (Figure S2C and D). Notably, no DEcircRNAs were found in the normal versus paracancer comparisons (N vs. P) (Figure S2E). Focusing on the 55 DEcircRNAs in tumour tissues (Figure 2A and Table S3), these circRNAs effectively distinguished tumour from normal or paracancer tissues in both heatmap, and principal component analysis (PCA) (Figures 2B and S2F and G), outperforming the top 50 highly expressed circRNAs. Although these circRNAs did not show specific chromosomal enrichment, they significantly overlapped with known CRC-sensitive mutagenic segments (Figure 2C), suggesting a potential association with mRNA imbalance in these regions. Positive correlations between circRNA expression changes and their host genes comparisons support the hypothesis of host gene-driven circRNA changes (Figures 2D and E and S2H).</p><p>Applying WGCNA to the circRNA dataset (Figure S3A–C), we identified two co-expression modules significantly linked to CRC, which further helped to identify tumour tissue-specific circRNAs (Figure 2F and Table S4). Investigati
{"title":"Comprehensive circular RNA profiling provides insight into colorectal cancer pathogenesis and reveals diagnostically relevant biomarkers","authors":"Shujin Li, Jun Wang, Lin Qiu, Gaohui Fu, Yang Li, Qiang Su, Yiheng Zhu, Feilong Zhao, Jinglin Tian, Jinyong Huang, Yanqin Niu, Kang Kang, Deming Gou","doi":"10.1002/ctm2.70049","DOIUrl":"https://doi.org/10.1002/ctm2.70049","url":null,"abstract":"<p>The incidence of colorectal cancer (CRC) is increasing, especially among younger populations, underscoring the necessity for a thorough examination of biomarkers.<span><sup>1, 2</sup></span> This study explores the clinical and functional roles of circRNAs in CRC using a stage-stratified, integrated multiomics approach. The identified circRNA panel holds promise for CRC diagnosis.<span><sup>3, 4</sup></span></p><p>Utilising whole transcriptome sequencing on tumour, normal, and paracancer tissues from 30 CRC patients, circRNA alterations were investigated (Table S1). CircRNAs were identified with CIRI2 and DCC software (Table S2).<span><sup>5, 6</sup></span> Increased sequencing depth correlated with a higher number of identified circRNAs (Figure S1A–D). Tumour tissues exhibited a lower abundance of circRNAs compared to normal and paracancer tissues (Figure S1 E–H), indicating changes in circRNA expression during CRC pathogenesis.<span><sup>3</sup></span> To minimise variability, we focused on circRNAs detectable in at least half of the patients (Figure 1A and B), which revealed more distinct tissue-specific differences in circRNA numbers (Figures 1C and S1I); further analysis revealed high consistency between cirRNAs identified by CIRI2 and DCC (Figure 1D–F). In subsequent analysis, only circRNAs detected by both software were considered (Figure S1J–L). Our investigation showed that most circRNAs corresponded to a single host gene and were predominantly exon-type (Figure 1G and H). Despite the reduced number of circRNAs in tumours, their chromosomal distribution was similar to those in normal and paracancer tissues (Figure S2A and B). Annotation of the circRNAs using circBase supports the reliability of our identification process (Figure 1I).</p><p>We further identified 67 and 71 differentially expressed circRNAs (DEcircRNAs) in tumour versus normal (N vs. T) and paracancer versus tumour (P vs. T), respectively (Figure S2C and D). Notably, no DEcircRNAs were found in the normal versus paracancer comparisons (N vs. P) (Figure S2E). Focusing on the 55 DEcircRNAs in tumour tissues (Figure 2A and Table S3), these circRNAs effectively distinguished tumour from normal or paracancer tissues in both heatmap, and principal component analysis (PCA) (Figures 2B and S2F and G), outperforming the top 50 highly expressed circRNAs. Although these circRNAs did not show specific chromosomal enrichment, they significantly overlapped with known CRC-sensitive mutagenic segments (Figure 2C), suggesting a potential association with mRNA imbalance in these regions. Positive correlations between circRNA expression changes and their host genes comparisons support the hypothesis of host gene-driven circRNA changes (Figures 2D and E and S2H).</p><p>Applying WGCNA to the circRNA dataset (Figure S3A–C), we identified two co-expression modules significantly linked to CRC, which further helped to identify tumour tissue-specific circRNAs (Figure 2F and Table S4). Investigati","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435286","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}
Dietary fibres consist of a heterogeneous group of carbohydrate polymers which resist digestion by human gastrointestinal enzymes. Consumption of dietary fibre has been linked with innumerable health benefits encompassing the foundational pillars of metabolic health from obesity to hypertension, dyslipidaemia, and type 2 diabetes mellitus (T2DM), with many of these benefits linked with metabolites produced by the fermentation of fibre by gut microbes [1]. The potential of dietary fibre to provide a safe and effective nonpharmacologic complementary tool with which to combat the evolving consequences of the obesity epidemic has recently garnered tremendous attention in both medical literature and lay media alike.
Highlights
Consumption of dietary fibre has been linked with innumerable health benefits encompassing the foundational pillars of metabolic health with many of these benefits linked with metabolites produced by the fermentation of fibre by gut microbes
At the present time clinicians are faced with an impossible task in which there is rapidly mounting evidence for dietary fibres advancing metabolic health, but little practical options for healthcare providers other than to simply recommend patients consume more fibre.
Benefits of fibre intake may perhaps be maximised in an individual by matching specific fibre consumption with existing microbial functional characteristics
If dietary fibres could be demonstrated to act as successful adjuncts to sustain or improve standard of care therapies or even alleviate common gastrointestinal side effects associated with current treatments, they would be an invaluable tool in our metabolic health armamentarium. Neither Dr. Madsen or I have any financial conflicts of interest pertinent to the contents of this manuscript.
{"title":"Dietary fibre and metabolic health: A clinical primer","authors":"Valentin Mocanu, Karen L Madsen","doi":"10.1002/ctm2.70018","DOIUrl":"https://doi.org/10.1002/ctm2.70018","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Dietary fibres consist of a heterogeneous group of carbohydrate polymers which resist digestion by human gastrointestinal enzymes. Consumption of dietary fibre has been linked with innumerable health benefits encompassing the foundational pillars of metabolic health from obesity to hypertension, dyslipidaemia, and type 2 diabetes mellitus (T2DM), with many of these benefits linked with metabolites produced by the fermentation of fibre by gut microbes [1]. The potential of dietary fibre to provide a safe and effective nonpharmacologic complementary tool with which to combat the evolving consequences of the obesity epidemic has recently garnered tremendous attention in both medical literature and lay media alike.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ol>\u0000 \u0000 <li>\u0000 <p>Consumption of dietary fibre has been linked with innumerable health benefits encompassing the foundational pillars of metabolic health with many of these benefits linked with metabolites produced by the fermentation of fibre by gut microbes</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>At the present time clinicians are faced with an impossible task in which there is rapidly mounting evidence for dietary fibres advancing metabolic health, but little practical options for healthcare providers other than to simply recommend patients consume more fibre.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Benefits of fibre intake may perhaps be maximised in an individual by matching specific fibre consumption with existing microbial functional characteristics</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>If dietary fibres could be demonstrated to act as successful adjuncts to sustain or improve standard of care therapies or even alleviate common gastrointestinal side effects associated with current treatments, they would be an invaluable tool in our metabolic health armamentarium. Neither Dr. Madsen or I have any financial conflicts of interest pertinent to the contents of this manuscript.</p>\u0000 </li>\u0000 </ol>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435293","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}
Qingxia Huang, Mingxia Wu, Lu Ding, Chen Guo, Yisa Wang, Zhuo Man, Hang Su, Jing Li, Jinjin Chen, Yao Yao, Zeyu Wang, Daqing Zhao, Linhua Zhao, Xiaolin Tong, Xiangyan Li
<p>Dear Editor,</p><p>In this study, we unveiled the bioactive compounds and molecular mechanisms of ShenFuShanYuRou decoction (SFSY) against hemorrhagic shock/resuscitation (HS/R) injury via the promotion of regulatory T (Treg) cell function. Our work offers new therapeutic strategies for circumventing HS/R-induced injury.</p><p>HS is a substantial global problem with more than 1.9 million deaths per year worldwide.<span><sup>1</sup></span> While advances in resuscitation strategies have circumvented early mortality from HS, still ∼30% of patients experience multiple organ dysfunction (MOD).<span><sup>2</sup></span> Treg cells play a vital role in maintaining innate immune homeostasis to foster tissue repair.<span><sup>3</sup></span> Thus, multitarget regulation of Treg cell function offers a new therapeutic intervention to minimize HS/R injury. SFSY is a famous Traditional Chinese Medicine formula, widely used in the supplementary therapy of patients with shock in China. However, the bioactive compounds and molecular mechanisms of SFSY against HS/R injury have not yet been elucidated.</p><p>A total of 263 chemical compounds and 39 prototype compounds in the plasma of SFSY were characterized (Figure S1–S3, Tables S1–S3). To clarify the effect of SFSY treatment on Treg cell function, the function and frequency of Th, Ts, Th1, Th2, Th17, and Treg cells were detected in the well-established rodent model of HS/R (Figure S4A) and a naïve Treg cell model. As shown in Figure 1A, SFSY treatment did not affect the transcripts of Tbx21, Gata3, and Rorc, but increased FOXP3 transcript in response to HS/R. We also found that SFSY increased the proportion of Treg cells in both peripheral blood mononuclear cells (PBMCs) and lungs (Figure 1B,C; Figures S4B and S5). Furthermore, the incubation with SFSY increased the localization of FOXP3 to the nuclei of Treg cells (Figure 1D; Figure S6). These results indicate that SFSY treatment augments FOXP3 expression, thereby promoting Treg cell function both in in vitro and in vivo.</p><p>Additionally, SFSY treatment increased the blood pressure and heart rate (Figure 2A,B; Figure S7A). The HS/R-induced metabolic disorders, lymphocyte depletion, and MOD (lungs, liver, kidneys, and intestine) injury were also ameliorated by SFSY treatment (Figure 2C–F; Figures S7B–S11). To explore the molecular mechanisms underlying the SFSY-mediated Treg cell function, CD4<sup>+</sup>CD25<sup>+</sup> Treg cells were purified from PBMCs, and transcriptomic sequencing was performed. The results of principal component and volcano map analyses showed significant differences in mRNA expression among the Sham, HS/R, and HS/R + SFSY groups (Figure 2G,H; Figure S12). SFSY significantly reduced the HS/R-induced activation of immune-related pathways in Treg cells (Figure 2I; Figure S13A). Further validation studies in Treg cells and lungs demonstrated that the enhancement of Treg cell function by SFSY against HS/R-induced injury was Stat1-, Ebi3-
{"title":"Bioactive compounds from ShenFuShanYuRou decoction enhance Treg cell function against hemorrhagic shock injury via Stat1- and Gbp5-dependent FOXP3 induction","authors":"Qingxia Huang, Mingxia Wu, Lu Ding, Chen Guo, Yisa Wang, Zhuo Man, Hang Su, Jing Li, Jinjin Chen, Yao Yao, Zeyu Wang, Daqing Zhao, Linhua Zhao, Xiaolin Tong, Xiangyan Li","doi":"10.1002/ctm2.70047","DOIUrl":"10.1002/ctm2.70047","url":null,"abstract":"<p>Dear Editor,</p><p>In this study, we unveiled the bioactive compounds and molecular mechanisms of ShenFuShanYuRou decoction (SFSY) against hemorrhagic shock/resuscitation (HS/R) injury via the promotion of regulatory T (Treg) cell function. Our work offers new therapeutic strategies for circumventing HS/R-induced injury.</p><p>HS is a substantial global problem with more than 1.9 million deaths per year worldwide.<span><sup>1</sup></span> While advances in resuscitation strategies have circumvented early mortality from HS, still ∼30% of patients experience multiple organ dysfunction (MOD).<span><sup>2</sup></span> Treg cells play a vital role in maintaining innate immune homeostasis to foster tissue repair.<span><sup>3</sup></span> Thus, multitarget regulation of Treg cell function offers a new therapeutic intervention to minimize HS/R injury. SFSY is a famous Traditional Chinese Medicine formula, widely used in the supplementary therapy of patients with shock in China. However, the bioactive compounds and molecular mechanisms of SFSY against HS/R injury have not yet been elucidated.</p><p>A total of 263 chemical compounds and 39 prototype compounds in the plasma of SFSY were characterized (Figure S1–S3, Tables S1–S3). To clarify the effect of SFSY treatment on Treg cell function, the function and frequency of Th, Ts, Th1, Th2, Th17, and Treg cells were detected in the well-established rodent model of HS/R (Figure S4A) and a naïve Treg cell model. As shown in Figure 1A, SFSY treatment did not affect the transcripts of Tbx21, Gata3, and Rorc, but increased FOXP3 transcript in response to HS/R. We also found that SFSY increased the proportion of Treg cells in both peripheral blood mononuclear cells (PBMCs) and lungs (Figure 1B,C; Figures S4B and S5). Furthermore, the incubation with SFSY increased the localization of FOXP3 to the nuclei of Treg cells (Figure 1D; Figure S6). These results indicate that SFSY treatment augments FOXP3 expression, thereby promoting Treg cell function both in in vitro and in vivo.</p><p>Additionally, SFSY treatment increased the blood pressure and heart rate (Figure 2A,B; Figure S7A). The HS/R-induced metabolic disorders, lymphocyte depletion, and MOD (lungs, liver, kidneys, and intestine) injury were also ameliorated by SFSY treatment (Figure 2C–F; Figures S7B–S11). To explore the molecular mechanisms underlying the SFSY-mediated Treg cell function, CD4<sup>+</sup>CD25<sup>+</sup> Treg cells were purified from PBMCs, and transcriptomic sequencing was performed. The results of principal component and volcano map analyses showed significant differences in mRNA expression among the Sham, HS/R, and HS/R + SFSY groups (Figure 2G,H; Figure S12). SFSY significantly reduced the HS/R-induced activation of immune-related pathways in Treg cells (Figure 2I; Figure S13A). Further validation studies in Treg cells and lungs demonstrated that the enhancement of Treg cell function by SFSY against HS/R-induced injury was Stat1-, Ebi3-","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406191","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}
<p>Dear Editor,</p><p>This study emphasises the potential of utilising early postoperative plasma circulating tumour DNA (ctDNA) to predict tumour relapse in patients with resectable non-small cell lung cancer (NSCLC) while considering region-specific susceptibility within a real-world study cohort.</p><p>Lung cancer remains the predominant cause of cancer-associated mortality, with NSCLC constituting nearly 85% of cases. Standard treatment for operable NSCLC typically involves curative-intent surgery, but the high risk of recurrence necessitates further exploration of effective biomarkers for monitoring and personalised treatment. Advances in detecting ultra-low-frequency somatic genomic alterations in plasma ctDNA have shown potential for identifying patients at higher risk of tumour relapse in NSCLC.<span><sup>1, 2</sup></span> Nonetheless, the prognostic value of ctDNA-based molecular residue disease (MRD), especially concerning regional variations in lung cancer risk, remains unexplored. Xuanwei, a city in Yunnan province, China, offers an opportunity to investigate genetic attributes influencing lung cancer due to its exceptionally high incidence linked to indoor air pollution from smoky coal combustion.<span><sup>3</sup></span></p><p>Here, we retrospectively analysed targeted next-generation sequencing data of primary tumours from 226 stage I–III patients with resectable NSCLC, including 31 from the Xuanwei region (Figure S1). Adenocarcinoma was the predominant histological subtype, and most patients presented with stage I disease (Table 1). Notably, Xuanwei patients exhibited a higher incidence of multifocal lesions and tumours with high TMB (Figure 1A–C). Frequently mutated genes included <i>EGFR</i> (62%), <i>TP53</i> (32%), <i>KRAS</i> (18%), and <i>LRP1B</i> (12%), while additional mutations were identified in oncogenes or tumour suppressor genes, such as <i>ALK</i>, <i>RB1</i>, <i>ERBB2</i>, <i>PIK3CA</i>, <i>BRAF</i>, <i>NTRK1</i>, and <i>ARID1A</i>. Furthermore, Xuanwei patients showed more uncommon <i>EGFR</i> mutations associated with US Food and Drug Administration (FDA)-approved treatments (<i>p </i>< .001)<span><sup>4</sup></span> and fewer common mutations like p.L858R and exon 19 deletions (19del), but higher p.G719X and p.S768I frequencies (Figure 1D and E). This distinct distribution of <i>EGFR</i> variants was confirmed using the MSKCC and OncoSG cohorts and was consistent with previous studies (Figure 1F).<span><sup>5</sup></span> Gene enrichment analysis revealed six genes with higher mutational frequencies in Xuanwei, among which <i>KRAS</i> and <i>PIK3CA</i> mutations might provide insights due to their clinical actionability (Figure 1G). Here, we showed that KRAS p.G12C (51.1%, 23/45) and PIK3CA p.E545K (20%, 3/15) mutations were predominant, with mutations like KRAS p.G12A, p.Q61E, and PIK3CA p.G106V, p.P471H exclusive to Xuanwei patients (Figures 1H and I and S2).</p><p>Mutational signature analysis revealed hig
{"title":"Early postoperative plasma circulating tumour DNA for molecular residue disease detection and recurrence risk evaluation in surgical non-small cell lung cancer","authors":"Jie Tang, Yingsong Tian, Song Wang, Yong Liu, Manjun Chen, Xudong Yang, Xinghe Tong, Mengtian Wang, Yunping Zhao, Jiaohui Pang, Qiuxiang Ou, Xiaobo Chen","doi":"10.1002/ctm2.70056","DOIUrl":"10.1002/ctm2.70056","url":null,"abstract":"<p>Dear Editor,</p><p>This study emphasises the potential of utilising early postoperative plasma circulating tumour DNA (ctDNA) to predict tumour relapse in patients with resectable non-small cell lung cancer (NSCLC) while considering region-specific susceptibility within a real-world study cohort.</p><p>Lung cancer remains the predominant cause of cancer-associated mortality, with NSCLC constituting nearly 85% of cases. Standard treatment for operable NSCLC typically involves curative-intent surgery, but the high risk of recurrence necessitates further exploration of effective biomarkers for monitoring and personalised treatment. Advances in detecting ultra-low-frequency somatic genomic alterations in plasma ctDNA have shown potential for identifying patients at higher risk of tumour relapse in NSCLC.<span><sup>1, 2</sup></span> Nonetheless, the prognostic value of ctDNA-based molecular residue disease (MRD), especially concerning regional variations in lung cancer risk, remains unexplored. Xuanwei, a city in Yunnan province, China, offers an opportunity to investigate genetic attributes influencing lung cancer due to its exceptionally high incidence linked to indoor air pollution from smoky coal combustion.<span><sup>3</sup></span></p><p>Here, we retrospectively analysed targeted next-generation sequencing data of primary tumours from 226 stage I–III patients with resectable NSCLC, including 31 from the Xuanwei region (Figure S1). Adenocarcinoma was the predominant histological subtype, and most patients presented with stage I disease (Table 1). Notably, Xuanwei patients exhibited a higher incidence of multifocal lesions and tumours with high TMB (Figure 1A–C). Frequently mutated genes included <i>EGFR</i> (62%), <i>TP53</i> (32%), <i>KRAS</i> (18%), and <i>LRP1B</i> (12%), while additional mutations were identified in oncogenes or tumour suppressor genes, such as <i>ALK</i>, <i>RB1</i>, <i>ERBB2</i>, <i>PIK3CA</i>, <i>BRAF</i>, <i>NTRK1</i>, and <i>ARID1A</i>. Furthermore, Xuanwei patients showed more uncommon <i>EGFR</i> mutations associated with US Food and Drug Administration (FDA)-approved treatments (<i>p </i>< .001)<span><sup>4</sup></span> and fewer common mutations like p.L858R and exon 19 deletions (19del), but higher p.G719X and p.S768I frequencies (Figure 1D and E). This distinct distribution of <i>EGFR</i> variants was confirmed using the MSKCC and OncoSG cohorts and was consistent with previous studies (Figure 1F).<span><sup>5</sup></span> Gene enrichment analysis revealed six genes with higher mutational frequencies in Xuanwei, among which <i>KRAS</i> and <i>PIK3CA</i> mutations might provide insights due to their clinical actionability (Figure 1G). Here, we showed that KRAS p.G12C (51.1%, 23/45) and PIK3CA p.E545K (20%, 3/15) mutations were predominant, with mutations like KRAS p.G12A, p.Q61E, and PIK3CA p.G106V, p.P471H exclusive to Xuanwei patients (Figures 1H and I and S2).</p><p>Mutational signature analysis revealed hig","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406192","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}
Chae-Min Ryu, YongHwan Kim, Jung-Hyun Shin, Seungun Lee, Hyein Ju, Yun Ji Nam, Hyungu Kwon, Min-Young Jo, Jinah Lee, Hyun Jun Im, Min Gi Jang, Ki-Sung Hong, Hyung-Min Chung, Sang Hoon Song, Myung-Soo Choo, Seong Who Kim, Juhyun Park, Dong-Myung Shin
<p>Dear Editor,</p><p>Diabetic cystopathy, particularly when it progresses to detrusor underactivity (DUA), poses significant clinical management challenges and affects a substantial number of individuals with diabetes mellitus (DM).<span><sup>1</sup></span> Despite its prevalence, the etiology of diabetic DUA is poorly understood, and effective treatments are lacking. Our study addressed these gaps by investigating the mechanisms, tumorigenic risks, and optimal protocols of mesenchymal stem cell (MSC)<span><sup>2</sup></span> transplantation in a preclinical model of diabetic DUA. Molecular signature of the transplanted cells in the pathological micro-environments was characterised by single-cell transcriptome analysis,<span><sup>3</sup></span> emphasising the importance of the hepatocyte growth factor (HGF)–mesenchymal-epithelial transition factor (MET) pathway and PD-L1 in the mechanism for muscle regeneration and immunomodulation.</p><p>We reported the first clinical study of multipotent-MSCs (M-MSCs) derived from human embryonic stem cells (hESCs) for treating Hunner-type interstitial cystitis, characterised by defective urothelium integrity and chronic inflammation.<span><sup>4</sup></span> The hESC-derived M-MSCs were effective in a streptozotocin (STZ)-induced diabetic DUA (STZ-DUA) rat model.<span><sup>5</sup></span> Transcriptomes of these preclinical samples were analysed to gain molecular insight into the pathogenesis of DM-associated DUA and the mechanism of the MSC therapy (Figure 1A). Transcriptomes of STZ-DUA bladders were distinct from those of sham-operated bladders and also from those of STZ-DUA rats administered M-MSCs (Figure 1B), with 525 and 112 differentially expressed genes in the STZ-DUA group relative to the sham and M-MSC groups, respectively (Figure S1A–C).</p><p>Gene networks/pathways analysis by MetaCore indicated altered expression of genes involved in oxidative-stress, inflammatory, and immune responses in the STZ-DUA group (Figures 1C and S1D–F). Gene-set enrichment analysis (GSEA) supported the significance of glutathione (GSH) metabolism and inflammatory responses in the pathogenesis of DM-associated DUA, with gene-sets related to muscle contraction and cardiomyopathy being downregulated in the STZ-DUA group (Figure 1D and Table S1). Four gene clusters were observed in transcriptome changes following the M-MSC therapy (Figure 1E,F). Cluster-3 (131) genes were upregulated in diabetic DUA, but their expression was normalised by the M-MSC therapy. The cluster-3 genes predominantly involved in GSH-related metabolic processes (Figures 1G and S1G–I).</p><p>For biomarkers from gene-network (MetaCore) and leading-edge (GSEA) analyses by comparing STZ-DUA with M-MSC groups, the M-MSC therapy effectively coordinated the regulation of genes associated with GSH synthesis and metabolism (<i>Gclc</i> and <i>Gpx2</i>), activation of NADPH oxidase (<i>Noxa1</i>, <i>Noxo1</i>, and <i>Nox3</i>), nitric oxide synthesis (<i>Nos2</
{"title":"Mesenchymal stem cells with an enhanced antioxidant capacity integrate as smooth muscle cells in a model of diabetic detrusor underactivity","authors":"Chae-Min Ryu, YongHwan Kim, Jung-Hyun Shin, Seungun Lee, Hyein Ju, Yun Ji Nam, Hyungu Kwon, Min-Young Jo, Jinah Lee, Hyun Jun Im, Min Gi Jang, Ki-Sung Hong, Hyung-Min Chung, Sang Hoon Song, Myung-Soo Choo, Seong Who Kim, Juhyun Park, Dong-Myung Shin","doi":"10.1002/ctm2.70052","DOIUrl":"10.1002/ctm2.70052","url":null,"abstract":"<p>Dear Editor,</p><p>Diabetic cystopathy, particularly when it progresses to detrusor underactivity (DUA), poses significant clinical management challenges and affects a substantial number of individuals with diabetes mellitus (DM).<span><sup>1</sup></span> Despite its prevalence, the etiology of diabetic DUA is poorly understood, and effective treatments are lacking. Our study addressed these gaps by investigating the mechanisms, tumorigenic risks, and optimal protocols of mesenchymal stem cell (MSC)<span><sup>2</sup></span> transplantation in a preclinical model of diabetic DUA. Molecular signature of the transplanted cells in the pathological micro-environments was characterised by single-cell transcriptome analysis,<span><sup>3</sup></span> emphasising the importance of the hepatocyte growth factor (HGF)–mesenchymal-epithelial transition factor (MET) pathway and PD-L1 in the mechanism for muscle regeneration and immunomodulation.</p><p>We reported the first clinical study of multipotent-MSCs (M-MSCs) derived from human embryonic stem cells (hESCs) for treating Hunner-type interstitial cystitis, characterised by defective urothelium integrity and chronic inflammation.<span><sup>4</sup></span> The hESC-derived M-MSCs were effective in a streptozotocin (STZ)-induced diabetic DUA (STZ-DUA) rat model.<span><sup>5</sup></span> Transcriptomes of these preclinical samples were analysed to gain molecular insight into the pathogenesis of DM-associated DUA and the mechanism of the MSC therapy (Figure 1A). Transcriptomes of STZ-DUA bladders were distinct from those of sham-operated bladders and also from those of STZ-DUA rats administered M-MSCs (Figure 1B), with 525 and 112 differentially expressed genes in the STZ-DUA group relative to the sham and M-MSC groups, respectively (Figure S1A–C).</p><p>Gene networks/pathways analysis by MetaCore indicated altered expression of genes involved in oxidative-stress, inflammatory, and immune responses in the STZ-DUA group (Figures 1C and S1D–F). Gene-set enrichment analysis (GSEA) supported the significance of glutathione (GSH) metabolism and inflammatory responses in the pathogenesis of DM-associated DUA, with gene-sets related to muscle contraction and cardiomyopathy being downregulated in the STZ-DUA group (Figure 1D and Table S1). Four gene clusters were observed in transcriptome changes following the M-MSC therapy (Figure 1E,F). Cluster-3 (131) genes were upregulated in diabetic DUA, but their expression was normalised by the M-MSC therapy. The cluster-3 genes predominantly involved in GSH-related metabolic processes (Figures 1G and S1G–I).</p><p>For biomarkers from gene-network (MetaCore) and leading-edge (GSEA) analyses by comparing STZ-DUA with M-MSC groups, the M-MSC therapy effectively coordinated the regulation of genes associated with GSH synthesis and metabolism (<i>Gclc</i> and <i>Gpx2</i>), activation of NADPH oxidase (<i>Noxa1</i>, <i>Noxo1</i>, and <i>Nox3</i>), nitric oxide synthesis (<i>Nos2</","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399568","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}
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