Clinical and Translational Medicine最新文献

{"title":"Aberrant DNA methylation of genes regulating CD4+ T cell HIV-1 reservoir in women with HIV","authors":"Ke Xu,&nbsp;Xinyu Zhang,&nbsp;Kesava Asam,&nbsp;Bryan C. Quach,&nbsp;Grier P. Page,&nbsp;Deborah Konkle-Parker,&nbsp;Claudia Martinez,&nbsp;Cecile D. Lahiri,&nbsp;Elizabeth F. Topper,&nbsp;Mardge H. Cohen,&nbsp;Seble G. Kassaye,&nbsp;Jack DeHovitz,&nbsp;Mark H. Kuniholm,&nbsp;Nancie M. Archin,&nbsp;Amir Valizadeh,&nbsp;Phyllis C. Tien,&nbsp;Vincent C. Marconi,&nbsp;Dana B. Hancock,&nbsp;Eric O. Johnson,&nbsp;Bradley E. Aouizerat","doi":"10.1002/ctm2.70267","DOIUrl":"https://doi.org/10.1002/ctm2.70267","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The HIV-1 reservoir in CD4+ T cells (HR_CD4) pose a major challenge to curing HIV, with many of its mechanisms still unclear. HIV-1 DNA integration and immune responses may alter the host's epigenetic landscape, potentially silencing HIV-1 replication.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study used bisulphite capture DNA methylation sequencing in CD4+ T cells from the blood of 427 virally suppressed women with HIV to identify differentially methylated sites and regions associated with HR_CD4.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The average total HR_CD4 size was 1409 copies per million cells, with most proviruses defective and only a small proportion intact. The study identified 245 differentially methylated CpG sites and 85 regions linked to HR_CD4 size, with 52% of significant sites in intronic regions. Genes associated with HR_CD4 were involved in viral replication, HIV-1 latency and cell growth and apoptosis. HR_CD4 size was inversely related to DNA methylation of interferon signalling genes and positively associated with methylation at known HIV-1 integration sites. HR_CD4-associated genes were enriched on the pathways related to immune defence, transcription repression and host–virus interactions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings suggest that HIV-1 reservoir is linked to aberrant DNA methylation in CD4+ T cells, offering new insights into epigenetic mechanisms of HIV-1 latency and potential molecular targets for eradication strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Study involved 427 women with HIV.</li>\u0000 \u0000 <li>Identified 245 aberrant DNA methylation sites and 85 methylation regions in CD4+ T cells linked to the HIV-1 reservoir.</li>\u0000 \u0000 <li>Highlighted genes are involved in viral replication, immune defence, and host genome integration.</li>\u0000 \u0000 <li>Findings suggest potential molecular targets for eradication strategies.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70267","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595347","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":"Integrated spatial multi-omics profiling of Fusobacterium nucleatum in breast cancer unveils its role in tumour microenvironment modulation and cancer progression","authors":"Feng Zhao,&nbsp;Rui An,&nbsp;Yilei Ma,&nbsp;Shaobo Yu,&nbsp;Yuzhen Gao,&nbsp;Yanzhong Wang,&nbsp;Haitao Yu,&nbsp;Xinyou Xie,&nbsp;Jun Zhang","doi":"10.1002/ctm2.70273","DOIUrl":"https://doi.org/10.1002/ctm2.70273","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;p&gt;Tumour-associated microbiota are integral components of the tumour microenvironment (TME). However, previous studies on intratumoral microbiota primarily rely on bulk tissue analysis, which may obscure their spatial distribution and localized effects. In this study, we applied in situ spatial-profiling technology to investigate the spatial distribution of intratumoral microbiota in breast cancer and their interactions with the local TME. Using 5R 16S rRNA gene sequencing and RNAscope FISH/CISH on patients’ tissue, we identified significant spatial heterogeneity in intratumoral microbiota, with &lt;i&gt;Fusobacterium nucleatum&lt;/i&gt; (&lt;i&gt;F. nucleatum&lt;/i&gt;) predominantly localized in tumour cell-rich areas. GeoMx digital spatial profiling (DSP) revealed that regions colonized by &lt;i&gt;F. nucleatum&lt;/i&gt; exhibit significant influence on the expression of RNAs and proteins involved in proliferation, migration and invasion. In vitro studies indicated that co-culture with &lt;i&gt;F. nucleatum&lt;/i&gt; significantly stimulates the proliferation and migration of breast cancer cells. Integrative spatial multi-omics and co-culture transcriptomic analyses highlighted the MAPK signalling pathways as key altered pathways. By intersecting these datasets, VEGFD and PAK1 emerged as critical upregulated proteins in &lt;i&gt;F. nucleatum&lt;/i&gt;-positive regions, showing strong positive correlations with MAPK pathway proteins. Moreover, the upregulation of VEGFD and PAK1 by &lt;i&gt;F. nucleatum&lt;/i&gt; was confirmed in co-culture experiments, and their knockdown significantly reduced &lt;i&gt;F. nucleatum&lt;/i&gt;-induced proliferation and migration. In conclusion, intratumoral microbiota in breast cancer exhibit significant spatial heterogeneity, with &lt;i&gt;F. nucleatum&lt;/i&gt; colonization markedly altering tumour cell protein expression to promote progression and migration. These findings provide novel perspectives on the role of microbiota in breast cancer, identify potential therapeutic targets, and lay the foundation for future cancer treatments.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;Intratumoral &lt;i&gt;Fusobacterium nucleatum&lt;/i&gt; exhibits significant spatial heterogeneity within breast cancer tissues.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;&lt;i&gt;F. nucleatum&lt;/i&gt; colonization alters the expression of key proteins involved in tumour progression and migration.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;The MAPK signalling pathway is a critical mediator of &lt;i&gt;F. nucleatum&lt;/i&gt;-induced breast cancer cell proliferation and migration.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70273","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143594895","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":"Exon junction complexes regulate osteoclast-induced bone resorption by influencing the NFATc1 m6A distribution through the “shield effect”","authors":"Bao Sun,&nbsp;Jin-Gang Yang,&nbsp;Zhe Wang,&nbsp;Zheng Wang,&nbsp;Wei Feng,&nbsp;Xing Li,&nbsp;Sheng-Nan Liu,&nbsp;Jiang Li,&nbsp;Ya-Qin Zhu,&nbsp;Ping Zhang,&nbsp;Wei Wang","doi":"10.1002/ctm2.70266","DOIUrl":"https://doi.org/10.1002/ctm2.70266","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The distribution of the m6A methylation modification on the transcriptome is highly regionally selective and is mainly concentrated in abnormally long exons and stop codons. However, in-depth research on the selective mechanism of m6A methylation is still lacking.&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;In this research, meRIP sequencing, mRNA sequencing, meRIP, luciferase reporter assays and CRISPR/Cas9 conditional knockout mice were used to elucidate the distribution characteristics of NFATc1 m6A.&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;METTL14 controls osteoclast-mediated bone resorption by means of the methylation (4249 A) of the NFATc1 gene during osteoclast differentiation. Exon junction complexes (EJCs) selectively protect the m6A methylation sites of the NFATc1 gene. When the methylation sites are located within short exon fragments (50–200 nt), EJCs prevent their hypermethylation and degradation through the “shield effect”; when the methylation sites are located in the 3′ UTR region or long exon fragments (greater than 300 nt), the “shield effect” disappears. Downstream, YTHDF2 induced the degradation of hypermethylation NFATc1 transcripts without site restriction.&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;EJCs act as “shields” to regulate the m6A region selectivity of the NFATc1 gene, thereby determining the characteristics of m6A distribution in the gene. Importantly, EJCs can raise the level of m6A methylation of NFATc1 and degrade its mRNA, thereby inhibiting osteoclast differentiation and preserving bone mass. These results will be helpful for identifying potential molecular targets for osteoporosis treatment.&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;METTL14 controls osteoclast-mediated bone resorption by means of the methylation (4249 A) of the NFATc1 gene during osteoclast differentiation.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Exon junction complexes (EJCs) protect the remaining methylation sites of the NFATc1 gene (located in the inner exon fragment of 50–200 nt) from hypermethylation and degradation.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The “shield effect” disappears when the exon fragment is extended to 300 nt. Downstream, YTHDF2 induced the degradation of hypermethylation NFATc1 transcripts without site restriction.&lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70266","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564891","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":"Id2 exacerbates the development of rheumatoid arthritis by increasing IFN-γ production in CD4+ T cells","authors":"Haoyang Sun,&nbsp;Jinlin Miao,&nbsp;Kui Zhang,&nbsp;Peiyan Zhang,&nbsp;Haomiao Shen,&nbsp;Jiawei Wang,&nbsp;Bei Zhang,&nbsp;Junfeng Jia,&nbsp;Zhaohui Zheng,&nbsp;Ping Zhu","doi":"10.1002/ctm2.70242","DOIUrl":"https://doi.org/10.1002/ctm2.70242","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Purpose&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This research investigates the role of inhibitor of differentiation 2 (Id2) in the synthesis of pro-inflammatory cytokines, specifically interferon-γ (IFN-γ) and interleukin-17 (IL-17), by various subsets of T cells, and its pathogenic role in rheumatoid arthritis (RA).&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;Flow cytometry was employed to assess T-cell activation and Id2 expression in 72 RA patients and 23 healthy controls. In vitro, peripheral blood mononuclear cells were treated with either an Id2 inhibitor or a T-cell co-stimulation inhibitor. An in vivo collagen-induced arthritis (CIA) model was established using T-cell-specific Id2 knockout mice. Additionally, follow-up observations were conducted among treated RA patients.&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;T-cell activation levels in RA synovial fluid were significantly elevated. A positive correlation was found between increased IFN-γ and Id2 expression. In vitro, antagonising Id2 reduced IFN-γ production after T-cell activation. T-cell-specific Id2 knockout mice exhibited a diminished occurrence and severity of CIA, along with a significant decrease in IFN-γ expression. Clinical monitoring indicated that Id2-induced circulating T-cell IFN-γ expression significantly decreased following treatment with the T-cell activation inhibitor abatacept.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The data suggest that high Id2 expression is a critical regulator of pro-inflammatory cytokine upregulation, particularly IFN-γ, by hyperactivated T cells in RA, potentially exacerbating the disease. Inhibiting Id2 expression or function may offer new therapeutic approaches for RA joint inflammation.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;Pro-inflammatory cytokines are significantly upregulated in the synovial fluid T cells in rheumatoid arthritis patients.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;The expression of pro-inflammatory cytokine interferon-γ (IFN-γ) positively correlates with the high expression of inhibitor of differentiation 2 (Id2).&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;The inhibition or ablation of Id2 can effectively suppress IFN-γ production and the onset and progression of arthritis.&lt;/p","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70242","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564892","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":"Ferroptosis of T cell in inflammation and tumour immunity","authors":"Xueli Xia,&nbsp;Haisheng Wu,&nbsp;Yuxuan Chen,&nbsp;Huiyong Peng,&nbsp;Shengjun Wang","doi":"10.1002/ctm2.70253","DOIUrl":"https://doi.org/10.1002/ctm2.70253","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Ferroptosis is an innovative concept defined as a distinct programmed cell death mode regulated by iron-dependent lipid peroxidation accumulation. This process is governed by numerous energy metabolites such as fatty acids, amino acids and glucose, as well as iron homeostasis. In recent years, increasing studies have been devoted to the crucial effects of ferroptosis in immune cells during the pathogenesis of diseases such as infections, tumours and autoimmune disorders. This review summarises the latest advancements in T-cell ferroptosis, addresses the key components and mechanism of ferroptosis in T cells during inflammatory conditions and tumour progression, and highlights the potential target for treating related diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Ferroptosis-related mechanisms significantly affect the biology of CD4⁺ T-cell subsets and are further involved in inflammatory diseases.</li>\u0000 \u0000 <li>Crosstalk between CD8⁺ T cells and tumour cells induces ferroptosis in the tumour microenvironment.</li>\u0000 \u0000 <li>Glutathione peroxidase 4 loss promotes regulatory T-cell ferroptosis to enhance anti-tumour immunity.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554475","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":"Fusobacterium nucleatum promotes anastomotic leakage by activating epithelial cells through the NOD1/RIPK2/ERK signalling pathway to drive IL-1β-induced neutrophil chemotaxis and collagen degradation","authors":"Zixian Wei,&nbsp;Liqing Bao,&nbsp;Bowen Li,&nbsp;Jinhua Yang,&nbsp;Jijiao Wang,&nbsp;Fangqi Xu,&nbsp;Hubin Wenren,&nbsp;Kunyu Zhang,&nbsp;Shang Shi,&nbsp;Liying Yan,&nbsp;Xin Tao,&nbsp;Tianqi Zhang,&nbsp;Zhiyue Wang,&nbsp;Yang Liu","doi":"10.1002/ctm2.70262","DOIUrl":"https://doi.org/10.1002/ctm2.70262","url":null,"abstract":"&lt;p&gt;Dear Editor:&lt;/p&gt;&lt;p&gt;We herein suggest that &lt;i&gt;Fusobacterium nucleatum&lt;/i&gt; (&lt;i&gt;F. nucleatum&lt;/i&gt;) disrupts anastomotic healing. It promotes the movement and activation of neutrophils, which increases MMPs production. These MMPs break down collagen, weakening the anastomosis and causing leakage.&lt;/p&gt;&lt;p&gt;Anastomotic leakage (AL) is a critical and potentially fatal complication that may arise following colorectal surgery.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Despite its clinical significance, no specific risk factors or surgical techniques have been identified that can effectively improve anastomotic healing.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Recent studies indicate a possible connection between gut microbiota imbalances and the occurrence of AL.&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt; We previously demonstrated an increased abundance of &lt;i&gt;F. nucleatum&lt;/i&gt; in patients who developed AL.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Inflammation has been implicated in anastomotic leakage (AL), with neutrophils (NEs) being the main inflammatory cells involved in acute colitis.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Matrix metalloproteinases (MMPs) play a crucial role in tissue damage associated with AL.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; Neutrophils contribute to tissue breakdown in AL by releasing MMPs.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; This study aims to investigate the impact of &lt;i&gt;F. nucleatum&lt;/i&gt; on AL, with a particular emphasis on the role of neutrophils in this process.&lt;/p&gt;&lt;p&gt;To establish that &lt;i&gt;F. nucleatum&lt;/i&gt; colonisation induces AL, we developed a colon anastomotic healing model in germ-free rederivation mice. Mice were inoculated via enema with &lt;i&gt;F. nucleatum&lt;/i&gt;, &lt;i&gt;E. coli&lt;/i&gt;, or PBS from the day of surgery (POD0) to POD3. All mice were sacrificed on POD7, and a laparotomy was performed to assess the gross anastomotic healing (Figure 1A). &lt;i&gt;F. nucleatum&lt;/i&gt; colonised both mucosal and submucosal layers (Figure 1B and C), leading to poor anastomotic healing, as evidenced by leakage, peritoneal contamination, and visible dehiscence (Figure 1D). The anastomotic healing scores were higher (poorer healing) in the &lt;i&gt;F. nucleatum&lt;/i&gt; group, with increased inflammatory cell infiltration (Figure 1E) and weak collagen deposition (Figure 1F). Neutrophil activation and enhanced MMP9 deposition were observed (Figure 1G), with gelatin zymography showing increased MMP9 and NGAL-MMP9 (Figures 1H and J). Collagenase activity was also elevated (Figure 1I), and multiplex immunofluorescence revealed co-localisation of &lt;i&gt;F. nucleatum&lt;/i&gt;, MMP9, and neutrophil markers, linked to reduced collagen deposition (Figure 1K). All these suggest that &lt;i&gt;F. nucleatum&lt;/i&gt; contribute to neutrophil activation and collagen degradation contribute to AL.&lt;/p&gt;&lt;p&gt;To evaluate the direct influence of &lt;i&gt;F. nucleatum&lt;/i&gt; on neutrophils, we infected neutrophils with &lt;i&gt;F. nucleatum&lt;/i&gt; in vitro. This led to neutrophil activation, as evidenced by an increase in reactive oxygen species (ROS) production (Figure S1F). The MMPs activity in neutrophil culture supern","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70262","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554533","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 novel GSDMD inhibitor GI-Y2 exerts antipyroptotic effects to reduce atherosclerosis","authors":"Xiaoxi Fan,&nbsp;Zhenfeng Cheng,&nbsp;Ruiyin Shao,&nbsp;Keke Ye,&nbsp;Xudong Chen,&nbsp;Xueli Cai,&nbsp;Shanshan Dai,&nbsp;Zhixuan Tang,&nbsp;Si Shi,&nbsp;Wenyuan Zheng,&nbsp;Weijian Huang,&nbsp;Jibo Han,&nbsp;Bozhi Ye","doi":"10.1002/ctm2.70263","DOIUrl":"https://doi.org/10.1002/ctm2.70263","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Introduction&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Gasdermin D (GSDMD) and the pyroptosis it mediates are importantly involved in cardiovascular diseases (CVDs). Identifying and developing new inhibitors of GSDMD could be a promising strategy for treating pyroptosis-mediated diseases, such as atherosclerosis.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objectives&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We aimed to develop new inhibitor of GSDMD in atherosclerosis, as well as clarify the mechanisms underlying this inhibiting effect.&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;Surface plasmon resonance and pull-down assay were used to identify the amino acid sites of GSDMD inhibited by GI-Y2. A mouse model of atherosclerosis was established by feeding a high-fat diet for 12 weeks. After treating mice with GI-Y2 (10 or 20 mg/kg, &lt;i&gt;i.g&lt;/i&gt;.), the lipid plaque area on the arterial intimal surface, lipid deposition, collagen deposition and pyroptosis levels in aortic root sections were evaluated. Additionally, further treatment of atherosclerotic mice with macrophage membrane-encapsulated GI-Y2 was conducted to enhance the targeting ability of GI-Y2 to atherosclerotic plaques.&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;In this study, we confirmed GI-Y2 as a novel inhibitor of GSDMD via structure-based virtual screening and pharmacological validation. Mechanistically, GI-Y2 directly interacts with the Arg10 residue of GSDMD and reduces the membrane binding of GSDMD-N. Functionally, we revealed that GI-Y2 inhibits the formation of atherosclerotic plaques by targeting GSDMD. Similarly, GI-Y2 reduces pyroptosis and macrophage infiltration in atherosclerosis. Furthermore, we constructed macrophage membrane-coated GI-Y2 nanoparticles to enhance the targeting of GI-Y2 to macrophages in atheromatous plaques and demonstrated its vascular protective effect in vivo.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This work demonstrated that GI-Y2 can potentially alleviate CVDs by targeting GSDMD and provided a new compound for the study of GSDMD-mediated pyroptosis.&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;We preliminarily confirmed GI-Y2 as a novel inhibitor of GSDMD via structure-based virtual screening and pharmacological validation.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;GI-Y2 directly interacts with GSDMD and reduc","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554476","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":"Chimeric antigen receptor T cell therapy based on stem cell-like memory T cells enhances anti-tumour effects in multiple myeloma","authors":"Zhaoyun Liu,&nbsp;Xintong Xu,&nbsp;Yihao Wang,&nbsp;Panpan Cao,&nbsp;Jia Song,&nbsp;Kai Ding,&nbsp;Hui Liu,&nbsp;Rong Fu","doi":"10.1002/ctm2.70264","DOIUrl":"https://doi.org/10.1002/ctm2.70264","url":null,"abstract":"&lt;p&gt;To the Editor,&lt;/p&gt;&lt;p&gt;Multiple myeloma (MM) is the second largest malignant tumour of the haematological system.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Nowadays, chimeric antigen receptor T-cell (CAR-T) therapy has become a revolutionary approach to the treatment of MM, significantly prolonging progression-free survival (PFS) and overall survival (OS) of MM patients.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; However, ultimately, most patients inevitably face the outcome of Relapse and drug resistance. Stem cell-like memory T cell (T&lt;sub&gt;SCM&lt;/sub&gt;) cells are a population of long-lived memory T cells with the capacity for self-renewal and differentiation.&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt; However, T&lt;sub&gt;SCM&lt;/sub&gt; cells are extremely low in proportion, and current technology still does not allow for easy access to sufficient quantities of T&lt;sub&gt;SCM&lt;/sub&gt; cells.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Currently, the therapeutic strategy of CAR-T&lt;sub&gt;SCM&lt;/sub&gt; has been actively pursued in solid tumours, but it is still rare in MM.&lt;/p&gt;&lt;p&gt;We first investigated the quantity and function of bone marrow T&lt;sub&gt;SCM&lt;/sub&gt; cells in MM patients with flow cytometry (FCM). We chose ‘CD3&lt;sup&gt;+&lt;/sup&gt;T&lt;sub&gt;SCM&lt;/sub&gt; events/CD3&lt;sup&gt;+&lt;/sup&gt;T events’ and ‘CD8&lt;sup&gt;+&lt;/sup&gt;T&lt;sub&gt;SCM&lt;/sub&gt; events/CD8&lt;sup&gt;+&lt;/sup&gt;T events’ to show the percentage of T&lt;sub&gt;SCM&lt;/sub&gt; and to ensure the comparability of the statistics results. The results revealed that the percentage of CD3&lt;sup&gt;+&lt;/sup&gt;T&lt;sub&gt;SCM&lt;/sub&gt; cells was significantly reduced in the newly diagnosed MM (NDMM) compared to both the health control (HC) (0.51 ± 0.31% vs. 0.98 ± 0.39%) and the complete response (CR) (0.51 ± 0.31% vs. 0.92 ± 0.54%) (&lt;i&gt;p &lt;/i&gt;&lt;  .0001, &lt;i&gt;p &lt;/i&gt;= .0005). The percentage of CD3&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T&lt;sub&gt;SCM&lt;/sub&gt; cells, which was reduced in the NDMM compared to both the HC (0.41 ± 0.28% vs. 0.97 ± 0.40%) and the CR (0.41 ± 0.28% vs. 0.61 ± 0.36%) (&lt;i&gt;p &lt;/i&gt;&lt;  .0001, &lt;i&gt;p &lt;/i&gt;= .0132) (Figure S1A,B).&lt;/p&gt;&lt;p&gt;Then, we found that the expression levels of Perforin and Granzyme B were significantly higher in CD3&lt;sup&gt;+&lt;/sup&gt;T&lt;sub&gt;SCM&lt;/sub&gt; cells compared to CD3&lt;sup&gt;+&lt;/sup&gt;T cells (42.26 ± 3.69% vs. 15.32 ± 2.75%, &lt;i&gt;p &lt;/i&gt;&lt;  .0001; 57.18 ± 6.38% vs. 21.56 ± 3.38%, &lt;i&gt;p &lt;/i&gt;&lt;  .0001); similarly, higher in CD3&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T&lt;sub&gt;SCM&lt;/sub&gt; cells than in CD3&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T cells (47.77 ± 3.18% vs. 18.37 ± 3.89%, &lt;i&gt;p &lt;/i&gt;&lt;  .0001; 50.30 ± 4.12% vs. 28.84 ± 3.49%, &lt;i&gt;p &lt;/i&gt;&lt;  .0001) (Figure S1C).&lt;/p&gt;&lt;p&gt;Afterwards, we took the bone marrow from MM patients who were candidates for B-cell maturation antigen (BCMA)-CART treatment. After aspiration, part of the bone marrow from these patients was used for their own clinical treatments and the rest was used in this experiment. Then we induced the expansion of T&lt;sub&gt;SCM&lt;/sub&gt; cells in vitro and FCM was used to detect the number and function of T&lt;sub&gt;SCM&lt;/sub&gt; cells (Figure 1A).&lt;/p&gt;&lt;p&gt;It has been demonstrated that MEK1/2 inhibition (MEKi) can be used to perform T&lt;sub&gt;SC","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70264","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554477","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":"Vascularised organoids: Recent advances and applications in cancer research","authors":"Rui Zhou,&nbsp;Dagmar Brislinger,&nbsp;Julia Fuchs,&nbsp;Alicia Lyons,&nbsp;Sonja Langthaler,&nbsp;Charlotte A. E. Hauser,&nbsp;Christian Baumgartner","doi":"10.1002/ctm2.70258","DOIUrl":"https://doi.org/10.1002/ctm2.70258","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;p&gt;Organoids are three-dimensional (3D) cellular models designed to replicate human tissues and organs while preserving their physiological complexity and functionality. Among these, vascularised organoids represent a groundbreaking advancement in 3D tissue engineering, incorporating vascular networks into engineered tissues to more accurately mimic the in vivo tumour microenvironment. These models offer significantly improved physiological relevance compared to conventional two-dimensional cultures or animal models, positioning them as invaluable tools in cancer research. Despite their potential, the rapid proliferation of techniques and materials for developing vascularised organoids presents challenges for researchers navigating this dynamic field. This systematic review provides a comprehensive examination of methodologies for fabricating vascularised organoids, with a focus on strategies that enhance vascularisation and support organoid growth. It critically evaluates the materials used, emphasising those that effectively mimic the extracellular matrix and facilitate vascular network formation. Key advancements in engineered organoids models are highlighted, emphasising their potential for studying interactions between vasculature and cancer cells, conducting drug screening, and understanding cytokine regulation. In summary, this review provides an in-depth overview of the current landscape of vascularised organoid fabrication and functionality, addressing challenges and opportunities within the field. A detailed understanding of the scope and future trajectories is essential for advancing organoid development and expanding their applications in both basic cancer research and clinical practice.&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;Comparative analysis: Evaluation of organoids, animal models, and 2D models, highlighting their respective strengths and limitations in replicating physiological conditions and studying disease processes.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Vascularisation techniques: Comparative evaluation of vascularised organoid fabrication methods, emphasising their efficiency, scalability and ability to replicate physiological vascular networks.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Material selection: Thorough evaluation of materials for vascularised organoid culture system, focusing on those that effectively mimic the extracellular matrix and support vascular network formation.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Applications: Overview of organoid applications in basic cancer research and clinical settings, with an emphasis on their potential in drug discovery, disease modelling and exploring complex biological p","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70258","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554478","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":"BRAFV600E-PROTAC versus inhibitors in melanoma cells: Deep transcriptomic characterisation","authors":"Solomon O. Alhassan,&nbsp;Zakaria Y. Abd Elmageed,&nbsp;Youssef Errami,&nbsp;Guangdi Wang,&nbsp;Joe A. Abi-Rached,&nbsp;Emad Kandil,&nbsp;Mourad Zerfaoui","doi":"10.1002/ctm2.70251","DOIUrl":"https://doi.org/10.1002/ctm2.70251","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>This study compares the suppression of Mitogen-activated protein kinase (MAPK) signalling and early resistance potential between a proteolysis-targeting chimera (PROTAC) and inhibitors targeting BRAF^V600E.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a detailed in silico analysis of the transcriptomic landscape of the A375 melanoma cell line treated with a PROTAC and BRAF^V600E inhibitors from RNA sequencing data. The study assessed gene dysregulation, MAPK and Phosphoinositide-3-kinase (PI3K/AKT) pathway inhibition, and cell survival. Key genes uniquely dysregulated by PROTAC treatment were validated by qPCR. Furthermore, analysis was performed to evaluate dedifferentiation and early resistance signatures to understand melanoma drug-induced plasticity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PROTAC-treated cells showed significantly lower MAPK pathway activity, strong cell cycle arrest and elevated apoptotic gene expression compared to inhibitor-treated cells, with no effect on the PI3K/AKT pathway. A high microphtalmia-associated transcription factor (MITF)/Tyrosine-Protein Kinase Receptor (AXL) ratio in PROTAC-treated cells indicated reduced early drug resistance. BRAF degradation induced a melanocytic-transitory phenotype. Although PROTAC and inhibitor treatments caused overlapping transcriptomic changes, key differences were observed. PROTAC treatment enriched processes such as epithelial‒mesenchymal transition, inflammatory responses, and Tumor necrosis factor-Alpha (TNF-α) and IL2/STAT5 signalling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>PROTAC-targeting BRAF^V600E demonstrates enhanced MAPK suppression, reduced early resistance and distinct transcriptional effects compared to traditional inhibitors. It represents a promising strategy for overcoming resistance in melanoma treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70251","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554488","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}