Elevated lactate is associated with vascular endothelial dysfunction, a factor that can contribute to organ failure in sepsis. However, the specific mechanisms involved have yet to be fully elucidated. Here, we investigated the role of enolase 1 (ENO1) lactylation in modulating the functions of endothelial cells (ECs) in sepsis pathogenesis.
Methods
The septic mouse model was established using two methods: cecal ligation and puncture (CLP) and intraperitoneal injection of LPS. AAV-ENO1 shRNA was administered to ablate ENO1 in vascular endothelial cells of mice. Tail vein injection of .5% Evans Blue Dye (EBD) was utilised to assess microvascular permeability in septic mice. Post-translational modification (PTM) mass spectrometry was employed to detect key proteins undergoing lactylation in endothelial cells. Additionally, CCK-8 assay, Transwell assay, and scratch wound healing assay were performed to evaluate the fundamental functions of ECs. Further investigations were conducted through Western blotting, Co-immunoprecipitation (CO-IP), RT-qPCR, RNA immunoprecipitation (RIP) and RNA sequencing to examine genes/proteins involved in vascular endothelial injury and their interactions.
Results
We found that elevated lactate in sepsis promoted the lactylation of ENO1 at the K71 residue, facilitated by the increased activity of the lactyltransferase P300. This modification reduced the binding of TRIM21 mRNA to ENO1, thereby preventing its degradation by limiting the recruitment of CNOT6. Consequently, the stability and expression of TRIM21 mRNA were enhanced. Elevated TRIM21 subsequently binds to vascular endothelial-cadherin (VE-Cadherin), promoting its ubiquitination and degradation, disrupting endothelial adherens junctions (AJs) and increasing endothelial permeability. Targeting the lactylation of ENO1 at K71 with a specific inhibitory peptide alleviated endothelial injury and improved survival rates in septic mice.
Conclusions
These findings suggest that ENO1 lactylation plays a pivotal role in vascular endothelial dysfunction during sepsis. Inhibiting lactylation may offer a therapeutic strategy for sepsis treatment.
{"title":"Targeting the lactylation of ENO1 alleviates endothelial dysfunction in sepsis","authors":"Xueru Xie, Tingyan Liu, Caiyan Zhang, Ye Cheng, Yajing Gao, Wenfeng Xiao, Haiyan Guo, Yutong Zhou, Yawei Yu, Kexin Wang, Yinghong Lin, Lisheng Xiao, Yingying Zhang, Weiguo Yang, Gangfeng Yan, Guoping Lu, Yufeng Zhou","doi":"10.1002/ctm2.70597","DOIUrl":"10.1002/ctm2.70597","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Elevated lactate is associated with vascular endothelial dysfunction, a factor that can contribute to organ failure in sepsis. However, the specific mechanisms involved have yet to be fully elucidated. Here, we investigated the role of enolase 1 (ENO1) lactylation in modulating the functions of endothelial cells (ECs) in sepsis pathogenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The septic mouse model was established using two methods: cecal ligation and puncture (CLP) and intraperitoneal injection of LPS. AAV-ENO1 shRNA was administered to ablate ENO1 in vascular endothelial cells of mice. Tail vein injection of .5% Evans Blue Dye (EBD) was utilised to assess microvascular permeability in septic mice. Post-translational modification (PTM) mass spectrometry was employed to detect key proteins undergoing lactylation in endothelial cells. Additionally, CCK-8 assay, Transwell assay, and scratch wound healing assay were performed to evaluate the fundamental functions of ECs. Further investigations were conducted through Western blotting, Co-immunoprecipitation (CO-IP), RT-qPCR, RNA immunoprecipitation (RIP) and RNA sequencing to examine genes/proteins involved in vascular endothelial injury and their interactions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that elevated lactate in sepsis promoted the lactylation of ENO1 at the K71 residue, facilitated by the increased activity of the lactyltransferase P300. This modification reduced the binding of <i>TRIM21</i> mRNA to ENO1, thereby preventing its degradation by limiting the recruitment of CNOT6. Consequently, the stability and expression of <i>TRIM21</i> mRNA were enhanced. Elevated TRIM21 subsequently binds to vascular endothelial-cadherin (VE-Cadherin), promoting its ubiquitination and degradation, disrupting endothelial adherens junctions (AJs) and increasing endothelial permeability. Targeting the lactylation of ENO1 at K71 with a specific inhibitory peptide alleviated endothelial injury and improved survival rates in septic mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings suggest that ENO1 lactylation plays a pivotal role in vascular endothelial dysfunction during sepsis. Inhibiting lactylation may offer a therapeutic strategy for sepsis treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12801394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145965234","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}
In colorectal cancer (CRC), innate lymphoid cells (ILCs) play a vital role in preserving and modulating immune homeostasis within the intestinal environment. However, the origins and diverse functions of ILCs in CRC remain poorly understood, making it difficult to clarify how these cells contribute to disease progression and influence therapeutic efficacy.
Methods
Single-cell RNA sequencing (scRNA-seq) generated an atlas of ILCs from multiple tissues (bone marrow, blood, and intestine), revealing their origins, heterogeneity, and plasticity. Spatial transcriptomics (ST) and immunofluorescence (IF) defined their specific cellular neighbourhoods within the tumour microenvironment. In vitro co-culture assays were performed to validate the regulatory role of ILC2s in B cell maturation. Bulk RNA sequencing and flow cytometry were employed to assess the survival and therapeutic response potential of ILCs.
Results
Intestinal ILCs have two distinct origins: ILC3-CD83 cells derived from the fetal gut, which persist into adulthood; and ILC2 and ILC3-S100A4 cells that might originate from the bone marrow and migrate through the circulation to colonise intestinal tissues. The tissue-resident ILC3 subsets exhibited diverse functional roles in CRC. Specifically, trajectory analysis showed that ILC3s differentiated into either stress-responsive ILC3-HSPA1B cells or cytotoxic ILC1/NK cells in CRC. Additionally, by using spatial transcriptomics analysis combined with functional assays, we found that bone marrow-derived ILC2s preferentially localise in tertiary lymphoid structures (TLSs), where they likely support B cell maturation. Notably, higher ILC2 abundance correlated with better clinical outcomes and greater therapeutic benefit.
Conclusions
This study reveals the distinct origins and functional heterogeneity of intestinal ILC subsets in CRC. The enrichment of bone marrow-derived ILC2s in TLSs, where they likely support B cell maturation, is associated with improved prognosis and favourable immunotherapy response, which may serve as biomarkers for survival and therapeutic efficacy in CRC.
{"title":"Decoding innate lymphoid cell heterogeneity and plasticity in colorectal cancer","authors":"Shuomin Zhang, Qingfeng Fu, Zhengyang Xu, Sijun Wang, Guoju You, Xiaoyu Su, Xiaotong Yuan, Chao Liu, Chen Liu, Chaojun Zhang, Bing Liu, Yandong Gong","doi":"10.1002/ctm2.70593","DOIUrl":"10.1002/ctm2.70593","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>In colorectal cancer (CRC), innate lymphoid cells (ILCs) play a vital role in preserving and modulating immune homeostasis within the intestinal environment. However, the origins and diverse functions of ILCs in CRC remain poorly understood, making it difficult to clarify how these cells contribute to disease progression and influence therapeutic efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Single-cell RNA sequencing (scRNA-seq) generated an atlas of ILCs from multiple tissues (bone marrow, blood, and intestine), revealing their origins, heterogeneity, and plasticity. Spatial transcriptomics (ST) and immunofluorescence (IF) defined their specific cellular neighbourhoods within the tumour microenvironment. In <i>vitro</i> co-culture assays were performed to validate the regulatory role of ILC2s in B cell maturation. Bulk RNA sequencing and flow cytometry were employed to assess the survival and therapeutic response potential of ILCs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Intestinal ILCs have two distinct origins: ILC3-CD83 cells derived from the fetal gut, which persist into adulthood; and ILC2 and ILC3-S100A4 cells that might originate from the bone marrow and migrate through the circulation to colonise intestinal tissues. The tissue-resident ILC3 subsets exhibited diverse functional roles in CRC. Specifically, trajectory analysis showed that ILC3s differentiated into either stress-responsive ILC3-HSPA1B cells or cytotoxic ILC1/NK cells in CRC. Additionally, by using spatial transcriptomics analysis combined with functional assays, we found that bone marrow-derived ILC2s preferentially localise in tertiary lymphoid structures (TLSs), where they likely support B cell maturation. Notably, higher ILC2 abundance correlated with better clinical outcomes and greater therapeutic benefit.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study reveals the distinct origins and functional heterogeneity of intestinal ILC subsets in CRC. The enrichment of bone marrow-derived ILC2s in TLSs, where they likely support B cell maturation, is associated with improved prognosis and favourable immunotherapy response, which may serve as biomarkers for survival and therapeutic efficacy in CRC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12796840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959094","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>Long non-coding RNAs (<i>lncRNAs</i>) regulate macrophage inflammation and atherosclerotic plaque stability, but mechanisms need comprehensive investigations.</p> </section> <section> <h3> Methods</h3> <p>Whole-transcriptome sequencing was used to identify a novel human-specific lncRNA, <i>lncAPAT</i> (atherosclerotic plaque instability-associated transcript), in the peripheral blood of patients with coronary artery disease (CAD; <i>n</i> = 5) with mixed plaques on coronary computed tomography angiography (CCTA). <i>LncAPAT</i> was quantified using quantitative real-time polymerase chain reaction in the discovery cohort and independently validated in patients with coronary mixed plaques by CCTA (<i>n</i> = 22) and in patients with acute ST-segment elevation myocardial infarction (STEMI; <i>n</i> = 22). Myeloid cell-specific <i>lncAPAT</i> knock-in mice were generated and injected with recombinant adeno-associated virus of murine proprotein convertase subtilisin/kexin type 9 to induce atherosclerosis and explore the effects of <i>lncAPAT</i> on inflammation and plaque instability. Macrophages were cultured to evaluate <i>lncAPAT</i> function in vitro. Chromatin isolation by RNA purification and sequencing and RNA immunoprecipitation assays were used to identify potential targets of <i>lncAPAT</i>.</p> </section> <section> <h3> Results</h3> <p><i>LncAPAT</i> expression was highly expressed in the peripheral blood of CAD and STEMI patients compared with the control individuals. Mice with myeloid cell-specific <i>lncAPAT</i> knock-in showed an increased plaque burden (2.7-fold), elevated macrophage counts (2.4-fold), and higher matrix metalloproteinase (MMP) expression (3.3-fold for MMP9, 2.0-fold for MMP2) in thoracic aortic plaques. In vitro, <i>lncAPAT</i> significantly promoted the inflammatory responses, adhesive capacity and cholesterol accumulation of macrophages, and decreased the cholesterol efflux ratio. <i>LncAPAT</i> interacted with the promoter of the ribosomal protein L22 gene (<i>RPL22</i>) and inhibited <i>RPL22</i> transcription. <i>RPL22</i> inhibition significantly increased the expression of inflammatory cytokines. The RPL22 protein directly interacted with monocyte chemoattractant protein-1 (<i>MCP-1</i>) mRNA and decreased <i>MCP-1</i> expression. Furthermore, <i>RPL22</i> expression in the peripheral blood was lower in CAD and STEMI patients than in control individuals.</p> </section> <section> <h3> Conclusions</h3> <p><i>LncAPAT</i> promoted the macrophage inflammatory response by inhibiti
背景：长链非编码rna （lncRNAs）调节巨噬细胞炎症和动脉粥样硬化斑块稳定性，但机制需要全面研究。方法：采用全转录组测序技术，在冠状动脉ct血管造影（CCTA）显示有混合斑块的冠状动脉疾病（CAD; n = 5）患者的外周血中鉴定一种新的人类特异性lncRNA， lncAPAT（动脉粥样硬化斑块不稳定性相关转录本）。LncAPAT在发现队列中采用实时定量聚合酶链反应进行量化，并在冠状动脉混合斑块患者（n = 22）和急性st段抬高型心肌梗死患者（n = 22）中通过CCTA独立验证。制备髓细胞特异性lncAPAT敲入小鼠，注射重组鼠蛋白转化酶subtilisin/ keexin type 9腺相关病毒诱导动脉粥样硬化，探讨lncAPAT对炎症和斑块不稳定的影响。体外培养巨噬细胞评价lncAPAT的功能。利用RNA纯化分离染色质、测序和RNA免疫沉淀法鉴定lncAPAT的潜在靶点。结果：与对照组相比，冠心病和STEMI患者外周血中LncAPAT表达高。骨髓细胞特异性lncAPAT敲入小鼠显示胸主动脉斑块斑块负荷增加（2.7倍），巨噬细胞计数增加（2.4倍），基质金属蛋白酶（MMP）表达增加（MMP9 3.3倍，MMP2 2.0倍）。在体外实验中，lncAPAT显著促进巨噬细胞的炎症反应、黏附能力和胆固醇积累，降低胆固醇外排比。LncAPAT与核糖体蛋白L22基因（RPL22）启动子相互作用，抑制RPL22的转录。RPL22抑制显著增加炎症细胞因子的表达。RPL22蛋白直接与单核细胞趋化蛋白-1 (MCP-1) mRNA相互作用，降低MCP-1的表达。此外，CAD和STEMI患者外周血中RPL22的表达低于对照组。结论：LncAPAT通过抑制RPL22转录活性促进巨噬细胞炎症反应，促进斑块不稳定。重点：一种新的人类特异性长链非编码RNA (lncRNA)，命名为lncAPAT，在冠状动脉混合斑块患者的外周血中高表达。LncAPAT增加胸主动脉斑块不稳定性，促进巨噬细胞炎症反应。LncAPAT直接与RPL22的启动子区相互作用，抑制RPL22的转录活性，增加MCP-1的表达，从而导致斑块不稳定。
{"title":"Long non-coding RNA lncAPAT promotes atherosclerotic plaque instability by targeting ribosomal protein L22","authors":"Rongxia Li, Qiyue Zhang, Yu Chen, Shuting Wang, Shuang Han, Adalaiti Kamili, Yixuan Zhong, Shujun Yang, Weili Zhang","doi":"10.1002/ctm2.70564","DOIUrl":"10.1002/ctm2.70564","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Long non-coding RNAs (<i>lncRNAs</i>) regulate macrophage inflammation and atherosclerotic plaque stability, but mechanisms need comprehensive investigations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Whole-transcriptome sequencing was used to identify a novel human-specific lncRNA, <i>lncAPAT</i> (atherosclerotic plaque instability-associated transcript), in the peripheral blood of patients with coronary artery disease (CAD; <i>n</i> = 5) with mixed plaques on coronary computed tomography angiography (CCTA). <i>LncAPAT</i> was quantified using quantitative real-time polymerase chain reaction in the discovery cohort and independently validated in patients with coronary mixed plaques by CCTA (<i>n</i> = 22) and in patients with acute ST-segment elevation myocardial infarction (STEMI; <i>n</i> = 22). Myeloid cell-specific <i>lncAPAT</i> knock-in mice were generated and injected with recombinant adeno-associated virus of murine proprotein convertase subtilisin/kexin type 9 to induce atherosclerosis and explore the effects of <i>lncAPAT</i> on inflammation and plaque instability. Macrophages were cultured to evaluate <i>lncAPAT</i> function in vitro. Chromatin isolation by RNA purification and sequencing and RNA immunoprecipitation assays were used to identify potential targets of <i>lncAPAT</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>LncAPAT</i> expression was highly expressed in the peripheral blood of CAD and STEMI patients compared with the control individuals. Mice with myeloid cell-specific <i>lncAPAT</i> knock-in showed an increased plaque burden (2.7-fold), elevated macrophage counts (2.4-fold), and higher matrix metalloproteinase (MMP) expression (3.3-fold for MMP9, 2.0-fold for MMP2) in thoracic aortic plaques. In vitro, <i>lncAPAT</i> significantly promoted the inflammatory responses, adhesive capacity and cholesterol accumulation of macrophages, and decreased the cholesterol efflux ratio. <i>LncAPAT</i> interacted with the promoter of the ribosomal protein L22 gene (<i>RPL22</i>) and inhibited <i>RPL22</i> transcription. <i>RPL22</i> inhibition significantly increased the expression of inflammatory cytokines. The RPL22 protein directly interacted with monocyte chemoattractant protein-1 (<i>MCP-1</i>) mRNA and decreased <i>MCP-1</i> expression. Furthermore, <i>RPL22</i> expression in the peripheral blood was lower in CAD and STEMI patients than in control individuals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p><i>LncAPAT</i> promoted the macrophage inflammatory response by inhibiti","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12796838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959088","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}
Angiogenesis, driven by the vascular endothelial growth factor (VEGF)/VEGFR signalling axis under hypoxic conditions, is one of the hallmarks of ovarian cancer (OC), contributing to tumour progression, metastatic dissemination and immune evasion. Hypoxia-induced angiogenic signalling sustains tumour growth and shapes an immunosuppressive tumour microenvironment, while homologous recombination deficiency (HRD) has been associated with increased tumour hypoxia and pro-angiogenic signalling. Conversely, VEGF pathway inhibition may exacerbate DNA damage and modulate immune cell trafficking, providing a strong biological rationale for synergy between anti-angiogenic agents, PARP inhibitors (PARPi), and immune checkpoint inhibitors. Bevacizumab, a humanised monoclonal antibody targeting VEGF-A, represents a pivotal therapeutic agent in OC management by inhibiting tumour angiogenesis and inducing transient vascular normalisation. Its clinical efficacy has been demonstrated as maintenance therapy in the first-line setting, alone or in combination with PARPi for HRD-positive disease, and in the recurrent setting both in platinum-sensitive and platinum-resistant disease. Despite these benefits, variability in patient response highlights the unmet need for validated predictive biomarkers. Circulating, tissue-based and molecular biomarkers have been investigated, including angiogenic factors (Tie2/Ang1 axis, interleukin-6 [IL-6] and chitinase-3-like protein [YKL-40]), VEGF-A isoforms, microvessel density, EGFR/ADAM17 signalling, angiomiRs and transcriptional subtypes with mesenchymal and proliferative phenotypes showing greater sensitivity to anti-angiogenic strategies. Although HRD status holds prognostic relevance and selected microRNAs show emerging potential, no biomarker has yet been validated to predict benefit from bevacizumab in clinical practice. Translational analyses from the MITO16A/MaNGO OV-2 program, highlight challenges such as assay standardisation, multiplicity correction and external validation, while identifying tumour immune infiltration patterns, TP53 mutation classes and composite HRD assessments as areas of further investigation. In conclusion, bevacizumab remains an integral component of OC treatment. Future progress will depend on biomarker-driven, prospectively designed clinical trials and the integration of multi-omic data and machine learning approaches to enable precision application of anti-angiogenic strategies, maximising clinical benefit while minimising toxicity.
{"title":"Bevacizumab in ovarian cancer: Clinical data and predictive and prognostic biomarkers","authors":"Maria Rosaria Lamia, Erica Perri, Gustavo Baldassarre, Sandro Pignata, Chiara D'Alessio, Davide Limongello, Francesca Basso-Valentina","doi":"10.1002/ctm2.70591","DOIUrl":"10.1002/ctm2.70591","url":null,"abstract":"<p>Angiogenesis, driven by the vascular endothelial growth factor (VEGF)/VEGFR signalling axis under hypoxic conditions, is one of the hallmarks of ovarian cancer (OC), contributing to tumour progression, metastatic dissemination and immune evasion. Hypoxia-induced angiogenic signalling sustains tumour growth and shapes an immunosuppressive tumour microenvironment, while homologous recombination deficiency (HRD) has been associated with increased tumour hypoxia and pro-angiogenic signalling. Conversely, VEGF pathway inhibition may exacerbate DNA damage and modulate immune cell trafficking, providing a strong biological rationale for synergy between anti-angiogenic agents, PARP inhibitors (PARPi), and immune checkpoint inhibitors. Bevacizumab, a humanised monoclonal antibody targeting VEGF-A, represents a pivotal therapeutic agent in OC management by inhibiting tumour angiogenesis and inducing transient vascular normalisation. Its clinical efficacy has been demonstrated as maintenance therapy in the first-line setting, alone or in combination with PARPi for HRD-positive disease, and in the recurrent setting both in platinum-sensitive and platinum-resistant disease. Despite these benefits, variability in patient response highlights the unmet need for validated predictive biomarkers. Circulating, tissue-based and molecular biomarkers have been investigated, including angiogenic factors (Tie2/Ang1 axis, interleukin-6 [IL-6] and chitinase-3-like protein [YKL-40]), VEGF-A isoforms, microvessel density, EGFR/ADAM17 signalling, angiomiRs and transcriptional subtypes with mesenchymal and proliferative phenotypes showing greater sensitivity to anti-angiogenic strategies. Although HRD status holds prognostic relevance and selected microRNAs show emerging potential, no biomarker has yet been validated to predict benefit from bevacizumab in clinical practice. Translational analyses from the MITO16A/MaNGO OV-2 program, highlight challenges such as assay standardisation, multiplicity correction and external validation, while identifying tumour immune infiltration patterns, TP53 mutation classes and composite HRD assessments as areas of further investigation. In conclusion, bevacizumab remains an integral component of OC treatment. Future progress will depend on biomarker-driven, prospectively designed clinical trials and the integration of multi-omic data and machine learning approaches to enable precision application of anti-angiogenic strategies, maximising clinical benefit while minimising toxicity.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12789898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942729","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}
Rachel N. Grisham, Elizabeth Hopp, Kathryn Pennington, Robert Holloway, Robert M. Wenham, Pawel Blecharz, Lauren Dockery, Koji Matsuo, Ritu Salani, Mariusz Bidzinski, Patricia Braly, Paul Celano, Thomas Reid, Shelly Seward, Jocelyn Lewis, Mark Johnson, Robert DuBose, Sarah Ahn, Shinta Cheng, Carmelita Alvero, Panagiotis A. Konstantinopoulos
<div> <section> <h3> Background</h3> <p>Adult ovarian granulosa cell tumours (GCT) are the most common subtype of ovarian sex cord-stromal tumours. Forkhead transcription factor <i>FOXL2</i> is required for development and function of normal granulosa cells, including proliferation and ovarian hormone synthesis. A single somatic missense mutation in <i>FOXL2</i>, c.402C > G (p.Cys134Trp), has previously been identified in the majority of GCT and is a pathognomonic marker for this tumour type. NOTCH activation contributes to GCT survival in preclinical models, and <i>NOTCH2</i> and <i>NOTCH3</i> are critical for embryonic development of the ovary and function of the ovarian follicle. Nirogacestat is a potent, selective, noncompetitive inhibitor of gamma secretase, which inhibits NOTCH pathway signalling. Treatment of GCT with nirogacestat was predicted to inhibit granulosa cell survival.</p> </section> <section> <h3> Methods</h3> <p>A Phase II clinical trial was conducted to assess antitumour activity of nirogacestat in adult patients with relapsed/refractory ovarian GCT (NCT05348356). This study enrolled 53 patients; all were evaluable for efficacy and safety. Endpoints included objective response rate by Response Evaluation Criteria in Solid Tumors v1.1 and 6-month progression-free survival (PFS6). Fresh or archival tumour samples were analysed for mutational profiling.</p> </section> <section> <h3> Results</h3> <p>Patients received a median of 5 prior lines of therapy (range, 1–13) and a median of 3.7 months of treatment (range, 0–20 months). A decrease in tumour burden was seen in 16 (30%) patients; however, there were no confirmed objective responses. Thirty-one (58%) patients had stable disease; 18 (34%) had progressive disease. Eleven (21%) patients achieved PFS6. No correlations with disease stability were found with baseline clinical characteristics. All 3 patients who had an activating <i>NOTCH1</i> mutation achieved PFS6.</p> </section> <section> <h3> Conclusions</h3> <p>In patients with heavily pretreated GCT, nirogacestat treatment resulted in durable disease stabilisation of at least 7 weeks for 58% of patients, with 21% achieving PFS6, including the 3 patients whose tumours had an activating <i>NOTCH1</i> mutation.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li> <p>This Phase II clinical trial of a rare tumour achieved its enrolment t
{"title":"Phase II clinical trial of nirogacestat in patients with relapsed ovarian granulosa cell tumours","authors":"Rachel N. Grisham, Elizabeth Hopp, Kathryn Pennington, Robert Holloway, Robert M. Wenham, Pawel Blecharz, Lauren Dockery, Koji Matsuo, Ritu Salani, Mariusz Bidzinski, Patricia Braly, Paul Celano, Thomas Reid, Shelly Seward, Jocelyn Lewis, Mark Johnson, Robert DuBose, Sarah Ahn, Shinta Cheng, Carmelita Alvero, Panagiotis A. Konstantinopoulos","doi":"10.1002/ctm2.70568","DOIUrl":"10.1002/ctm2.70568","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Adult ovarian granulosa cell tumours (GCT) are the most common subtype of ovarian sex cord-stromal tumours. Forkhead transcription factor <i>FOXL2</i> is required for development and function of normal granulosa cells, including proliferation and ovarian hormone synthesis. A single somatic missense mutation in <i>FOXL2</i>, c.402C > G (p.Cys134Trp), has previously been identified in the majority of GCT and is a pathognomonic marker for this tumour type. NOTCH activation contributes to GCT survival in preclinical models, and <i>NOTCH2</i> and <i>NOTCH3</i> are critical for embryonic development of the ovary and function of the ovarian follicle. Nirogacestat is a potent, selective, noncompetitive inhibitor of gamma secretase, which inhibits NOTCH pathway signalling. Treatment of GCT with nirogacestat was predicted to inhibit granulosa cell survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A Phase II clinical trial was conducted to assess antitumour activity of nirogacestat in adult patients with relapsed/refractory ovarian GCT (NCT05348356). This study enrolled 53 patients; all were evaluable for efficacy and safety. Endpoints included objective response rate by Response Evaluation Criteria in Solid Tumors v1.1 and 6-month progression-free survival (PFS6). Fresh or archival tumour samples were analysed for mutational profiling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patients received a median of 5 prior lines of therapy (range, 1–13) and a median of 3.7 months of treatment (range, 0–20 months). A decrease in tumour burden was seen in 16 (30%) patients; however, there were no confirmed objective responses. Thirty-one (58%) patients had stable disease; 18 (34%) had progressive disease. Eleven (21%) patients achieved PFS6. No correlations with disease stability were found with baseline clinical characteristics. All 3 patients who had an activating <i>NOTCH1</i> mutation achieved PFS6.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In patients with heavily pretreated GCT, nirogacestat treatment resulted in durable disease stabilisation of at least 7 weeks for 58% of patients, with 21% achieving PFS6, including the 3 patients whose tumours had an activating <i>NOTCH1</i> mutation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>This Phase II clinical trial of a rare tumour achieved its enrolment t","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12789897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942687","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}
BRD7 has been confirmed to be lowly expressed in nasopharyngeal carcinoma (NPC) tissues and exerts tumour suppressive roles. However, the molecular mechanism of the downregulation of BRD7 expression and whether the strategy of activating BRD7 expression plays anti-tumour effects still needs to be clarified.
Methods
Methylation-specific polymerase chain reaction (PCR) was used to identify the methylation levels of BRD7 promoter. In vitro experiments were used to evaluate the effects of BRD7-targeted demethylation system on the malignant progression of NPC cells. Chromatin immunoprecipitation (ChIP)-qPCR experiment was employed to examine the regulatory mechanisms underlying the demethylation system. Xenograft tumour models were used to assess impact of this demethylation system on tumour growth in vivo and the anti-tumour effects of the lentivirus-mediated demethylation system in NPC.
Results
There was hypermethylation modification in BRD7 promoter, which was negatively correlated with BRD7 expression. Next, we constructed a LentiCRISPRv2/dCas9-TET1CD-sgRNAs system targeting specific methylation sites of BRD7 promoter based on five sgRNAs, and confirmed that all five sgRNA-guided CRISPR/dCas9 systems could activate BRD7 and inhibit cell proliferation to varying degrees, among which sgRNA2&sgRNA5 were the most significant. Further, we constructed NPC cell lines stably transfected with LentiCRISPRv2/dCas9-TET1CD-sgRNA2&5, and confirmed that both sgRNA2&sgRNA5 could promote the transcriptional activation by reducing its methylation, and inhibit the cell proliferation, migration, invasion and tumour growth in vivo of NPC, and the combination of them has a more significant demethylation, transcriptional activation and anti-tumour effect. In addition, BRD7 had hypermethylation modification in its promoter and decreased expression in NPC tissues, and both of them were negatively correlated, making it a potential diagnostic marker for NPC diagnosis.
Conclusions
The hypermethylation modification of BRD7 is an important mechanism leading to the inactivation of BRD7, and targeting demethylation of BRD7 inhibits the malignant progression of NPC, which might be a promising targeted therapeutic approach for treating NPC.
{"title":"Targeted demethylation of the BRD7 promoter based on CRISPR/dCas9 system inhibits the malignant progression of nasopharyngeal carcinoma","authors":"Jianxia Wei, Yumei Duan, Changning Xue, Lemei Zheng, Qingqing Wei, Zubing Wu, Huizhen Xin, Ting Zeng, Hongyu Deng, Songqing Fan, Wei Xiong, Zhaoyang Zeng, Mengna Li, Ming Zhou","doi":"10.1002/ctm2.70583","DOIUrl":"10.1002/ctm2.70583","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>BRD7 has been confirmed to be lowly expressed in nasopharyngeal carcinoma (NPC) tissues and exerts tumour suppressive roles. However, the molecular mechanism of the downregulation of BRD7 expression and whether the strategy of activating BRD7 expression plays anti-tumour effects still needs to be clarified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Methylation-specific polymerase chain reaction (PCR) was used to identify the methylation levels of BRD7 promoter. In vitro experiments were used to evaluate the effects of BRD7-targeted demethylation system on the malignant progression of NPC cells. Chromatin immunoprecipitation (ChIP)-qPCR experiment was employed to examine the regulatory mechanisms underlying the demethylation system. Xenograft tumour models were used to assess impact of this demethylation system on tumour growth in vivo and the anti-tumour effects of the lentivirus-mediated demethylation system in NPC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There was hypermethylation modification in BRD7 promoter, which was negatively correlated with BRD7 expression. Next, we constructed a LentiCRISPRv2/dCas9-TET1CD-sgRNAs system targeting specific methylation sites of BRD7 promoter based on five sgRNAs, and confirmed that all five sgRNA-guided CRISPR/dCas9 systems could activate BRD7 and inhibit cell proliferation to varying degrees, among which sgRNA2&sgRNA5 were the most significant. Further, we constructed NPC cell lines stably transfected with LentiCRISPRv2/dCas9-TET1CD-sgRNA2&5, and confirmed that both sgRNA2&sgRNA5 could promote the transcriptional activation by reducing its methylation, and inhibit the cell proliferation, migration, invasion and tumour growth in vivo of NPC, and the combination of them has a more significant demethylation, transcriptional activation and anti-tumour effect. In addition, BRD7 had hypermethylation modification in its promoter and decreased expression in NPC tissues, and both of them were negatively correlated, making it a potential diagnostic marker for NPC diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The hypermethylation modification of BRD7 is an important mechanism leading to the inactivation of BRD7, and targeting demethylation of BRD7 inhibits the malignant progression of NPC, which might be a promising targeted therapeutic approach for treating NPC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932333","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}
Sepideh Iranfar, Sophie Bagur, Chloé Felgerolle, Maxence Cornille, Najate Benamer, Hélène Le Ribeuz, Marie Giorgi, Sara Jamali, Amel Saoudi, Marie-José Lecomte, Vincent Michel, Brice Bathellier, Saaid Safieddine
<div> <section> <h3> Background</h3> <p>DFNB16, the second most common genetic cause of hearing loss, is caused by mutations of the <i>STRC</i> gene encoding stereocilin, a protein essential for the effective functioning of outer hair cells (OHCs) as cochlear amplifiers. <i>Strc</i><sup>−/−</sup> mice, which lack stereocilin, display severe to profound deafness and constitute a relevant preclinical model for DFNB16.</p> </section> <section> <h3> Methods</h3> <p>Using Strc<sup>−</sup>/<sup>−</sup> mice, we developed a gene therapy strategy based on the use of dual AAV9-PHP.eB vectors to deliver the full-length <i>Strc</i> cDNA. Therapeutic efficacy was assessed by evaluating stereocilin expression, OHC bundle architecture, and their attachment to the tectorial membrane, together with functional recovery using distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABR) measurements and Go/No-Go behavioral testing with psychometric analysis.</p> </section> <section> <h3> Results</h3> <p>Dual-AAV–mediated Strc gene delivery restored stereocilin expression, OHC bundle architecture and their attachment to the tectorial membrane, leading to the recovery of cochlear amplification and hearing to near normal thresholds, as confirmed by distortion product otoacoustic emission (DPOAE) and auditory brainstem response measurements. Behavioural assessment showed that treated <i>Strc</i><sup>−/−</sup> mice regained normal frequency discrimination, indicating a restoration of higher-order auditory processing, up to 100 days post-treatment.</p> </section> <section> <h3> Conclusion</h3> <p>These findings provide the first proof-of-principle that peripheral gene therapy can restore OHC function, cochlear amplification and central auditory perception in a DFNB16 model.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>Dual AAV-mediated gene delivery restored peripheral hearing in a DFNB16 preclinical mouse model.</li> <li>The same treatment also restored central auditory processing.</li> <li>AAV-mediated gene therapy represents a promising curative strategy for DFNB16.</li> <li>These results reinforce the translational potential for treating human genetic deafness.</li> </ul> </div> </section>
{"title":"Dual AAV gene therapy achieves recovery of hearing and auditory processing in a DFNB16 mouse model","authors":"Sepideh Iranfar, Sophie Bagur, Chloé Felgerolle, Maxence Cornille, Najate Benamer, Hélène Le Ribeuz, Marie Giorgi, Sara Jamali, Amel Saoudi, Marie-José Lecomte, Vincent Michel, Brice Bathellier, Saaid Safieddine","doi":"10.1002/ctm2.70571","DOIUrl":"10.1002/ctm2.70571","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>DFNB16, the second most common genetic cause of hearing loss, is caused by mutations of the <i>STRC</i> gene encoding stereocilin, a protein essential for the effective functioning of outer hair cells (OHCs) as cochlear amplifiers. <i>Strc</i><sup>−/−</sup> mice, which lack stereocilin, display severe to profound deafness and constitute a relevant preclinical model for DFNB16.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using Strc<sup>−</sup>/<sup>−</sup> mice, we developed a gene therapy strategy based on the use of dual AAV9-PHP.eB vectors to deliver the full-length <i>Strc</i> cDNA. Therapeutic efficacy was assessed by evaluating stereocilin expression, OHC bundle architecture, and their attachment to the tectorial membrane, together with functional recovery using distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABR) measurements and Go/No-Go behavioral testing with psychometric analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Dual-AAV–mediated Strc gene delivery restored stereocilin expression, OHC bundle architecture and their attachment to the tectorial membrane, leading to the recovery of cochlear amplification and hearing to near normal thresholds, as confirmed by distortion product otoacoustic emission (DPOAE) and auditory brainstem response measurements. Behavioural assessment showed that treated <i>Strc</i><sup>−/−</sup> mice regained normal frequency discrimination, indicating a restoration of higher-order auditory processing, up to 100 days post-treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings provide the first proof-of-principle that peripheral gene therapy can restore OHC function, cochlear amplification and central auditory perception in a DFNB16 model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Dual AAV-mediated gene delivery restored peripheral hearing in a DFNB16 preclinical mouse model.</li>\u0000 \u0000 <li>The same treatment also restored central auditory processing.</li>\u0000 \u0000 <li>AAV-mediated gene therapy represents a promising curative strategy for DFNB16.</li>\u0000 \u0000 <li>These results reinforce the translational potential for treating human genetic deafness.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932235","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}
Weijuan Xin, Junjie Zhang, Dan Wu, Yiying Cai, Xue Ding, Lu Zhou, Na Liu, Yue Wang, Zhiling Zhu, Keqin Hua
<div> <section> <h3> Backgroud</h3> <p>Persistent infection with high-risk human papillomavirus type 16 (HPV16) is a principal etiological factor in cervical cancer. Nevertheless, the molecular events linking HPV16-associated lesion progression to malignant transformation remain insufficiently characterized, particularly those involving vesicular trafficking and autophagy regulation.</p> </section> <section> <h3> Methods</h3> <p>Proteomic analysis was conducted across five stages of HPV16-associated cervical lesion progression to identify differentially expressed proteins. The expression of vesicle-associated membrane protein 7 (VAMP7) was validated in cervical tissue specimens and cellular models. Gain- and loss-of-function approaches were employed to assess the effects of VAMP7 on cellular proliferation, migration, invasion, and apoptosis. Autophagic activity was evaluated by LC3 lipidation, autophagosome accumulation, and analysis of SNARE complexrelated proteins. The in vivo effects of VAMP7 were examined using xenograft tumor models.</p> </section> <section> <h3> Results</h3> <p>VAMP7 demonstrated dynamic expression changes during cervical lesion progression, characterized by decreased expression in HPV16-positive non-malignant tissues and a gradual increase with disease severity, reaching the highest levels in advanced cervical cancer. Functionally, VAMP7 enhanced proliferation, migration, and invasion while inhibiting apoptosis in cervical cancer cells, whereas distinct effects were observed in non-tumor cervical epithelial cells. Mechanistically, VAMP7 regulated autophagic flux through modulation of SNARE-mediated vesicle fusion, resulting in altered autophagosome accumulation and autophagy-related signaling. In xenograft models, VAMP7 overexpression significantly promoted tumor growth and increased the expression of autophagy-associated markers.</p> </section> <section> <h3> Conclusion</h3> <p>These data indicate that dysregulation of VAMP7-mediated autophagy contributes to cervical carcinogenesis in an HPV16-associated context. VAMP7 may represent a potential therapeutic target for the treatment of cervical cancer.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>VAMP7 displays dynamic expression changes during HPV16-associated cervical lesion progression.</li> <li>VAMP7 promotes malignant phenotypes of cervical cancer cells
背景：持续感染高危16型人乳头瘤病毒（HPV16）是宫颈癌的主要病因。然而，将hpv16相关病变进展与恶性转化联系起来的分子事件仍然没有得到充分的表征，特别是那些涉及囊泡运输和自噬调节的分子事件。方法：对hpv16相关宫颈病变进展的五个阶段进行蛋白质组学分析，以鉴定差异表达蛋白。vesicle-associated membrane protein 7 （VAMP7）的表达在宫颈组织标本和细胞模型中得到验证。采用功能增益和功能丧失方法来评估VAMP7对细胞增殖、迁移、侵袭和凋亡的影响。通过LC3脂化、自噬体积累和SNARE复合物相关蛋白分析来评估自噬活性。采用异种移植肿瘤模型检测VAMP7的体内作用。结果：VAMP7在宫颈病变进展过程中表现为动态表达变化，在hpv16阳性的非恶性组织中表达降低，随病情严重程度逐渐升高，在晚期宫颈癌中达到最高水平。在功能上，VAMP7增强宫颈癌细胞的增殖、迁移和侵袭，同时抑制凋亡，而在非肿瘤宫颈上皮细胞中观察到明显的作用。在机制上，VAMP7通过调节snare介导的囊泡融合来调节自噬通量，导致自噬体积累和自噬相关信号的改变。在异种移植物模型中，VAMP7过表达显著促进肿瘤生长并增加自噬相关标志物的表达。结论：这些数据表明，在hpv16相关的背景下，vamp7介导的自噬失调有助于宫颈癌的发生。VAMP7可能是宫颈癌治疗的潜在靶点。关键点：VAMP7在hpv16相关宫颈病变进展过程中呈现动态表达变化。VAMP7通过snare介导的囊泡融合调节自噬通量，从而促进宫颈癌细胞的恶性表型。在hpv16相关背景下，失调的vamp7介导的自噬有助于宫颈癌的发生。
{"title":"VAMP7-mediated autophagy regulates cervical cancer progression associated with persistent HPV16 infection","authors":"Weijuan Xin, Junjie Zhang, Dan Wu, Yiying Cai, Xue Ding, Lu Zhou, Na Liu, Yue Wang, Zhiling Zhu, Keqin Hua","doi":"10.1002/ctm2.70590","DOIUrl":"10.1002/ctm2.70590","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Backgroud</h3>\u0000 \u0000 <p>Persistent infection with high-risk human papillomavirus type 16 (HPV16) is a principal etiological factor in cervical cancer. Nevertheless, the molecular events linking HPV16-associated lesion progression to malignant transformation remain insufficiently characterized, particularly those involving vesicular trafficking and autophagy regulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Proteomic analysis was conducted across five stages of HPV16-associated cervical lesion progression to identify differentially expressed proteins. The expression of vesicle-associated membrane protein 7 (VAMP7) was validated in cervical tissue specimens and cellular models. Gain- and loss-of-function approaches were employed to assess the effects of VAMP7 on cellular proliferation, migration, invasion, and apoptosis. Autophagic activity was evaluated by LC3 lipidation, autophagosome accumulation, and analysis of SNARE complexrelated proteins. The in vivo effects of VAMP7 were examined using xenograft tumor models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>VAMP7 demonstrated dynamic expression changes during cervical lesion progression, characterized by decreased expression in HPV16-positive non-malignant tissues and a gradual increase with disease severity, reaching the highest levels in advanced cervical cancer. Functionally, VAMP7 enhanced proliferation, migration, and invasion while inhibiting apoptosis in cervical cancer cells, whereas distinct effects were observed in non-tumor cervical epithelial cells. Mechanistically, VAMP7 regulated autophagic flux through modulation of SNARE-mediated vesicle fusion, resulting in altered autophagosome accumulation and autophagy-related signaling. In xenograft models, VAMP7 overexpression significantly promoted tumor growth and increased the expression of autophagy-associated markers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These data indicate that dysregulation of VAMP7-mediated autophagy contributes to cervical carcinogenesis in an HPV16-associated context. VAMP7 may represent a potential therapeutic target for the treatment of cervical cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>VAMP7 displays dynamic expression changes during HPV16-associated cervical lesion progression.</li>\u0000 \u0000 <li>VAMP7 promotes malignant phenotypes of cervical cancer cells","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12783914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932316","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>The key findings suggest an association between DNA methylation variability and aberrant balance of Th17/Treg cells and T-cell differentiation in children with aplastic anaemia (AA), which may be related to activation of the JAK/STAT signalling pathway. The CAMK4 subtype in CD4+ naïve T cells provided potential evidence that supports the ‘locust’ theory in the progression of pediatric AA and possibly novel targets for immunotherapy in the future.</p><p>AA is considered as an immune-mediated bone marrow failure syndrome and exhibits an inexplicable peak of age distribution in children.<span><sup>1, 2</sup></span> The incidence in East Asia is two to three times that of Western countries, suggesting significant differences in genetic background.<span><sup>3</sup></span> T-cell differentiation, which plays a critical role in disease pathogenesis, is governed by both genetic and epigenetic programs.<span><sup>4</sup></span> So far, the role of DNA methylation in pediatric AA and its crosstalk with aberrant T- cell differentiation remains unexplored.</p><p>We recruited 83 patients with acquired AA and 22 controls (<18 years) between January 2016 and October 2024. Methods were detailed in the Supporting Information. This study was approved by the institutional review board of Shanghai Children's Medical Center and conducted in accordance with the Declaration of Helsinki.</p><p>We performed flow cytometry in 76 pediatric AA patients and 20 healthy controls to detect the populations of T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells and their subtypes (Figure 1, Table S1, Figure S1a). The average age was 8.3 years for both AA patients (range 2–17) and controls (range 5–12; Table S2). Among the patients, 23 (30%) had very severe AA (VSAA), 20 (26%) had severe AA (SAA), and the remaining 33 (43%) had non-severe AA (NSAA).</p><p>The percentage of T cells in lymphocytes was 78.6% ± 7.8% versus 74.0% ± 5.4% in pediatric AA patients versus the controls (<i>p</i> = .015) and showed a trend of increase with disease severity (Figure 2A). The absolute T-cell count did not differ in the two cohorts (Figure S1b). The percentage and absolute NK cell count were lower in AA patients than in controls (percentage: 7.1% ± 5.0% vs. 11.6% ± 4.8%, <i>p</i> = .0004; absolute count: 100 ± 87 × 10<sup>6</sup>/L vs. 198 ± 115 × 10<sup>6</sup>/L, <i>p</i> < .0001; Figure 2B,C). The percentage and absolute count in B cells and DCs did not differ between the two cohorts (Figure S1c,d and Figure 2D). The Th17/Treg ratio was 1.2 ± 1.2 versus.8 ± .3 in patients and controls, respectively (<i>p</i> = .022) and showed a trend of decrease with disease severity (Figure 2F and Figure S1e). There was no significant difference in CD4/CD8 ratio and percentages of naïve T cells (TN), central memory T cells (TCM), effector memory T cells (TEM), and effector T cells (Teff) subsets between patients and controls (Figure S1f,g).</p><p>We performed
{"title":"DNA methylation variability in pediatric aplastic anaemia contributes to T-cell differentiation","authors":"Junchen Lai, Fangli Chen, Yan Miao, Manpin Zhang, Hua Zhu, Huanhuan Liang, Liting Yang, Yingwen Zhang, Dabin Tang, Chengjuan Luo, Changying Luo, Yanxin Li, Xiaodong Wang, Yu Liu, Jing Chen, Xia Qin, Xinan Wang","doi":"10.1002/ctm2.70588","DOIUrl":"10.1002/ctm2.70588","url":null,"abstract":"<p>Dear Editor,</p><p>The key findings suggest an association between DNA methylation variability and aberrant balance of Th17/Treg cells and T-cell differentiation in children with aplastic anaemia (AA), which may be related to activation of the JAK/STAT signalling pathway. The CAMK4 subtype in CD4+ naïve T cells provided potential evidence that supports the ‘locust’ theory in the progression of pediatric AA and possibly novel targets for immunotherapy in the future.</p><p>AA is considered as an immune-mediated bone marrow failure syndrome and exhibits an inexplicable peak of age distribution in children.<span><sup>1, 2</sup></span> The incidence in East Asia is two to three times that of Western countries, suggesting significant differences in genetic background.<span><sup>3</sup></span> T-cell differentiation, which plays a critical role in disease pathogenesis, is governed by both genetic and epigenetic programs.<span><sup>4</sup></span> So far, the role of DNA methylation in pediatric AA and its crosstalk with aberrant T- cell differentiation remains unexplored.</p><p>We recruited 83 patients with acquired AA and 22 controls (<18 years) between January 2016 and October 2024. Methods were detailed in the Supporting Information. This study was approved by the institutional review board of Shanghai Children's Medical Center and conducted in accordance with the Declaration of Helsinki.</p><p>We performed flow cytometry in 76 pediatric AA patients and 20 healthy controls to detect the populations of T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells and their subtypes (Figure 1, Table S1, Figure S1a). The average age was 8.3 years for both AA patients (range 2–17) and controls (range 5–12; Table S2). Among the patients, 23 (30%) had very severe AA (VSAA), 20 (26%) had severe AA (SAA), and the remaining 33 (43%) had non-severe AA (NSAA).</p><p>The percentage of T cells in lymphocytes was 78.6% ± 7.8% versus 74.0% ± 5.4% in pediatric AA patients versus the controls (<i>p</i> = .015) and showed a trend of increase with disease severity (Figure 2A). The absolute T-cell count did not differ in the two cohorts (Figure S1b). The percentage and absolute NK cell count were lower in AA patients than in controls (percentage: 7.1% ± 5.0% vs. 11.6% ± 4.8%, <i>p</i> = .0004; absolute count: 100 ± 87 × 10<sup>6</sup>/L vs. 198 ± 115 × 10<sup>6</sup>/L, <i>p</i> < .0001; Figure 2B,C). The percentage and absolute count in B cells and DCs did not differ between the two cohorts (Figure S1c,d and Figure 2D). The Th17/Treg ratio was 1.2 ± 1.2 versus.8 ± .3 in patients and controls, respectively (<i>p</i> = .022) and showed a trend of decrease with disease severity (Figure 2F and Figure S1e). There was no significant difference in CD4/CD8 ratio and percentages of naïve T cells (TN), central memory T cells (TCM), effector memory T cells (TEM), and effector T cells (Teff) subsets between patients and controls (Figure S1f,g).</p><p>We performed ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12783688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932243","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>The triglyceride-glucose index (TyG), a novel marker of insulin resistance, is recognised as a risk factor for multiple cardiovascular diseases. The link between its risk and aortic dissection and aortic aneurysm (AD/AA) is not well-defined. This research seeks to explore the relationship.</p> </section> <section> <h3> Methods</h3> <p>This study analysed 386 063 participants from the UK Biobank, a large prospective cohort, all initially free of AD/AA. The main focus was on the occurrence rate of AD/AA. Multivariate Cox regression models were used to analyse the association between the TyG index, its related parameters, and the risk of AD/AA. Association was further validated using a real-world clinical cohort from Central China Fuwai Hospital. A two-sample Mendelian randomisation (MR) analysis utilising the inverse variance weighting method was conducted to investigate the causal link between TyG and AD/AA.</p> </section> <section> <h3> Result</h3> <p>Among the 386 063 participants in the UK Biobank cohort, 3805 cases of AD/AA were reported. After controlling for covariates, a higher TyG index and its related parameters were associated with an increased incidence of AD/AA. The hazard ratios (HRs) were as follows: TyG (HR = 1.14, 95% CI: 1.07–1.22, <i>p</i> <.001), TyG-WHR (HR = 1.17, 95% CI: 1.12–1.22, <i>p</i> <.001), and TyG-WHtR (HR = 1.11, 95% CI: 1.06–1.16, <i>p</i> <.001). Association between TyG and the risk of aortic diseases was also replicated in the single-centre cohort. Two-sample MR analysis indicated strong evidence of a causal relationship between genetically predicted TyG levels and AA (OR = 1.97, 95% CI: 1.37–2.84, <i>p</i> <.001), while no significant association was observed with AD (OR = 0.79, 95% CI: 0.31–1.99, <i>p</i> = .61).</p> </section> <section> <h3> Conclusion</h3> <p>Through complementary epidemiological, clinical, and genetic approaches, our findings indicate that elevated TyG index represents a robust and potentially causal risk factor for aortic diseases (especially AA). These results highlight the importance of metabolic risk assessment in aortic disease prevention and emphasise the need for further mechanistic studies to understand the differential links between TyG and specific aortic phenotypes.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Higher TyG index and related ratios are linked
{"title":"Insulin resistance indicators in aortic disease: A large cohort study","authors":"Zehua Shao, Zhongyuan Lu, Wanxin Duan, Lingchen Huang, Yangxue Sun, Lixi Gan, Yue Gu, Hongwei Guo","doi":"10.1002/ctm2.70570","DOIUrl":"10.1002/ctm2.70570","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The triglyceride-glucose index (TyG), a novel marker of insulin resistance, is recognised as a risk factor for multiple cardiovascular diseases. The link between its risk and aortic dissection and aortic aneurysm (AD/AA) is not well-defined. This research seeks to explore the relationship.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study analysed 386 063 participants from the UK Biobank, a large prospective cohort, all initially free of AD/AA. The main focus was on the occurrence rate of AD/AA. Multivariate Cox regression models were used to analyse the association between the TyG index, its related parameters, and the risk of AD/AA. Association was further validated using a real-world clinical cohort from Central China Fuwai Hospital. A two-sample Mendelian randomisation (MR) analysis utilising the inverse variance weighting method was conducted to investigate the causal link between TyG and AD/AA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>Among the 386 063 participants in the UK Biobank cohort, 3805 cases of AD/AA were reported. After controlling for covariates, a higher TyG index and its related parameters were associated with an increased incidence of AD/AA. The hazard ratios (HRs) were as follows: TyG (HR = 1.14, 95% CI: 1.07–1.22, <i>p</i> <.001), TyG-WHR (HR = 1.17, 95% CI: 1.12–1.22, <i>p</i> <.001), and TyG-WHtR (HR = 1.11, 95% CI: 1.06–1.16, <i>p</i> <.001). Association between TyG and the risk of aortic diseases was also replicated in the single-centre cohort. Two-sample MR analysis indicated strong evidence of a causal relationship between genetically predicted TyG levels and AA (OR = 1.97, 95% CI: 1.37–2.84, <i>p</i> <.001), while no significant association was observed with AD (OR = 0.79, 95% CI: 0.31–1.99, <i>p</i> = .61).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Through complementary epidemiological, clinical, and genetic approaches, our findings indicate that elevated TyG index represents a robust and potentially causal risk factor for aortic diseases (especially AA). These results highlight the importance of metabolic risk assessment in aortic disease prevention and emphasise the need for further mechanistic studies to understand the differential links between TyG and specific aortic phenotypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Higher TyG index and related ratios are linked","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12778938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917153","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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