<div> <section> <h3> Background</h3> <p>Focal cortical dysplasia (FCD) is a heterogeneous group of cortical developmental malformations that constitute a common cause of medically intractable epilepsy. FCD type IIIa (FCD IIIa) refers to temporal neocortex alterations in architectural organisation or cytoarchitectural composition in the immediate vicinity of hippocampal sclerosis. Slight alterations in the temporal neocortex of FCD IIIa patients pose a challenge for the preoperative diagnosis and definition of the resection range.</p> </section> <section> <h3> Methods</h3> <p>We have performed multimodal integration of single-nucleus RNA sequencing and single-nucleus assay for transposase-accessible chromatin sequencing in the epileptogenic cortex of four patients with FCD IIIa, and three relatively normal temporal neocortex were chosen as controls.</p> </section> <section> <h3> Results</h3> <p>Our study revealed that the most significant dysregulation occurred in excitatory neurons (ENs) and oligodendrocyte precursor cells (OPCs) in the epileptogenic cortex of FCD IIIa patients. In ENs, we constructed a transcription factor (TF)-hub gene regulatory network and found <i>DAB1</i><sup>high</sup> ENs subpopulation mediates neuronal immunity characteristically in FCD IIIa. Western blotting and immunofluorescence were used to validate the changes in protein expression levels caused by some of the key genes. The OPCs were activated and exhibited aberrant phenotypes in FCD IIIa, and TFs regulating reconstructed pseudotime trajectory were identified. Finally, our results revealed aberrant intercellular communication between ENs and OPCs in FCD IIIa patients.</p> </section> <section> <h3> Conclusions</h3> <p>Our study revealed significant and intricate alterations in the transcriptomes and epigenomes in ENs and OPCs of FCD IIIa patients, shedding light on their cell type-specific regulation and potential pathogenic involvement in this disorder. This work will help evaluate the pathogenesis of cortical dysplasia and epilepsy and explore potential therapeutic targets.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li> <p>Paired snRNA-seq and snATAC-seq data were intergrated and analysed to identify crucial subpopulations of ENs and OPCs in the epileptogenic cortex of FCD IIIa patients and explore their possible pathogenic role in the disease.</p>
{"title":"Excitatory neurons and oligodendrocyte precursor cells are vulnerable to focal cortical dysplasia type IIIa as suggested by single-nucleus multiomics","authors":"Yingying Liu, Yinchao Li, Yaqian Zhang, Yubao Fang, Lei Lei, Jiabin Yu, Hongping Tan, Lisen Sui, Qiang Guo, Liemin Zhou","doi":"10.1002/ctm2.70072","DOIUrl":"10.1002/ctm2.70072","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Focal cortical dysplasia (FCD) is a heterogeneous group of cortical developmental malformations that constitute a common cause of medically intractable epilepsy. FCD type IIIa (FCD IIIa) refers to temporal neocortex alterations in architectural organisation or cytoarchitectural composition in the immediate vicinity of hippocampal sclerosis. Slight alterations in the temporal neocortex of FCD IIIa patients pose a challenge for the preoperative diagnosis and definition of the resection range.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We have performed multimodal integration of single-nucleus RNA sequencing and single-nucleus assay for transposase-accessible chromatin sequencing in the epileptogenic cortex of four patients with FCD IIIa, and three relatively normal temporal neocortex were chosen as controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our study revealed that the most significant dysregulation occurred in excitatory neurons (ENs) and oligodendrocyte precursor cells (OPCs) in the epileptogenic cortex of FCD IIIa patients. In ENs, we constructed a transcription factor (TF)-hub gene regulatory network and found <i>DAB1</i><sup>high</sup> ENs subpopulation mediates neuronal immunity characteristically in FCD IIIa. Western blotting and immunofluorescence were used to validate the changes in protein expression levels caused by some of the key genes. The OPCs were activated and exhibited aberrant phenotypes in FCD IIIa, and TFs regulating reconstructed pseudotime trajectory were identified. Finally, our results revealed aberrant intercellular communication between ENs and OPCs in FCD IIIa patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study revealed significant and intricate alterations in the transcriptomes and epigenomes in ENs and OPCs of FCD IIIa patients, shedding light on their cell type-specific regulation and potential pathogenic involvement in this disorder. This work will help evaluate the pathogenesis of cortical dysplasia and epilepsy and explore potential therapeutic targets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Paired snRNA-seq and snATAC-seq data were intergrated and analysed to identify crucial subpopulations of ENs and OPCs in the epileptogenic cortex of FCD IIIa patients and explore their possible pathogenic role in the disease.</p>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11497056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496130","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>Magnetic resonance imaging (MRI) technology has revolutionized the field of medical imaging by providing a non-invasive, non-ionizing and quantitative approach to visualizing different tissue types and assessing their structural and physiological integrity. Despite its importance and five decades of engineering development, the accessibility of MRI is low and extremely inhomogeneous around the world. This is due to the high cost and complex infrastructure requirements of existing high-field superconducting MRI scanners, which limit their availability in low and middle-income countries, and exclude their easy access in many healthcare facilities such as neurology clinics, trauma centres, surgical suites, neonatal/pediatric centres and community clinics. We and others have made intensive efforts in recent years to engineer low-cost and shielding-free MRI scanners for brain imaging at ultra-low-field (ULF) strengths (<0.1 T).<span><sup>1-5</sup></span> However, these developments are limited to brain and extremity imaging and their image quality is generally poor.</p><p>Recently we have developed a compact, low-power and highly simplified ULF MRI scanner that enables whole-body imaging with high image quality via computing.<span><sup>6</sup></span> In this work, we designed and prototyped a cost-effective whole-body 0.05 T MRI scanner that operates on a standard AC wall power outlet without any radiofrequency (RF) or magnetic shielding cages. The system utilized a compact 0.05 T permanent neodymium ferrite boron magnet with a double-plate structure and required no RF shielding cages (Figure 1A). To address electromagnetic interference (EMI) during scanning, we deployed active EMI sensing during scanning and deep learning direct signal prediction (Deep-DSP) strategy to retrospectively predict EMI-free MR signals prior to image reconstruction<span><sup>5, 7, 8</sup></span> (Figure 1B). We implemented and experimentally optimized the commonly used imaging protocols using phantoms and volunteers, keeping scan time at 8 min or less for each protocol. Our Deep-DSP strategy showed superior performance compared to other EMI reduction methods. Using traditional Fourier image reconstruction, we were able to image various anatomical structures with different MRI contrasts, including the brain, spine, abdomen, lung, extremities and heart (Figure 2A). We were also able to estimate cardiac function and visualize major vessels in the neck using time-of-flight magnetic resonance angiography without any exogenous contrast agent. However, these images exhibited a high level of noise and artefacts due to a drastically reduced MR signal at 0.05 T versus the standard 3 T. To address this challenge, we developed novel data-driven deep-learning image reconstruction methods to significantly advance ULF MRI image quality. We formulated a 3D partial Fourier super-resolution (PF-SR) strategy<span><sup>9, 10</sup></span> that integrates image reconstruction and super-res
磁共振成像（MRI）技术提供了一种非侵入性、非电离和定量的方法来观察不同类型的组织并评估其结构和生理完整性，从而彻底改变了医学成像领域。尽管核磁共振成像技术非常重要，而且经过了五十年的工程发展，但其普及率却很低，世界各地的普及程度也极不均衡。这是由于现有的高磁场超导核磁共振成像扫描仪成本高昂，基础设施要求复杂，限制了其在中低收入国家的可用性，而且许多医疗机构，如神经科诊所、创伤中心、手术室、新生儿/儿科中心和社区诊所都无法方便地使用。最近，我们开发了一种结构紧凑、低功耗、高度简化的超低场磁共振成像扫描仪，可通过计算实现全身成像，并具有较高的图像质量6。在这项工作中，我们设计并试制了一种经济高效的全身 0.05 T MRI 扫描仪，它可在标准交流壁式电源插座上运行，无需任何射频（RF）或磁屏蔽笼。该系统采用双板结构的紧凑型 0.05 T 永久钕铁硼磁铁，无需射频屏蔽罩（图 1A）。为了解决扫描过程中的电磁干扰（EMI）问题，我们在扫描过程中部署了主动 EMI 检测和深度学习直接信号预测（Deep-DSP）策略，以便在图像重建之前回溯预测无 EMI 的磁共振信号5、7、8（图 1B）。我们使用模型和志愿者实施并实验优化了常用的成像方案，将每个方案的扫描时间控制在 8 分钟以内。与其他减少电磁干扰的方法相比，我们的 Deep-DSP 策略表现出更优越的性能。利用传统的傅立叶图像重建技术，我们能够用不同的磁共振成像对比度对各种解剖结构进行成像，包括大脑、脊柱、腹部、肺部、四肢和心脏（图 2A）。我们还能在不使用任何外源性造影剂的情况下，利用飞行时间磁共振血管造影术估测心脏功能并观察颈部的主要血管。然而，与标准的 3 T 相比，0.05 T 的磁共振信号急剧下降，因此这些图像显示出高水平的噪声和伪影。为了应对这一挑战，我们开发了新颖的数据驱动深度学习图像重建方法，以显著提高超低频磁共振成像的质量。我们制定了一种三维部分傅立叶超分辨率（PF-SR）策略9、10，将图像重建和超分辨率融为一体。通过从高场 MRI 数据集中学习，PF-SR 重建方法抑制了伪影和噪声，提高了空间分辨率，从而改善了图像质量。PF-SR 方法提高了大脑、脊柱、腹部和膝关节的清晰度和可视化（图 2B）。这些 PF-SR 结果表明，深度学习 PF-SR 图像重建技术在推进超低频磁共振成像方面具有前所未有的能力。本研究中展示的由计算驱动的全身超低频磁共振成像技术具有补充现有高性能高场临床磁共振成像的潜力，提供了一种更经济实惠、更容易获得的选择。超低频磁共振成像具有几个明显的优势，包括开放的扫描环境、较低的声学噪声、对金属植入物的低敏感性、空气/组织界面的较少图像易感伪影以及极低的射频特异性吸收率。超低频磁共振成像还能为患者带来更舒适的体验，并在金属植入物或碎片存在时发挥优势。此外，由于纵向磁化恢复更快，横向磁化衰减更慢，因此超低频成像可实现更省时的数据采集方案5。5 超低频磁共振成像扫描仪本身价格低廉，操作简便，虽然在本研究中没有显示，但我们设想通过简单、智能的用户界面，如带有自动成像定位功能的单键扫描，可轻松实现扫描仪的自动化操作，用户无需接受专门培训。这种简化而智能的核磁共振成像技术尤其适用于中低收入国家和发达国家的医疗保健领域，可将核磁共振成像技术的使用范围扩大到传统放射科以外。通过提供低成本的筛查、诊断、监测和图像引导干预，医疗服务提供商可以让成像功能更贴近患者，最终提高患者护理水平和治疗效果。
{"title":"Reinventing magnetic resonance imaging for accessible healthcare: Whole-body imaging at 0.05 Tesla","authors":"Ed X. Wu, Xiaoyuan Feng","doi":"10.1002/ctm2.70071","DOIUrl":"10.1002/ctm2.70071","url":null,"abstract":"<p>Magnetic resonance imaging (MRI) technology has revolutionized the field of medical imaging by providing a non-invasive, non-ionizing and quantitative approach to visualizing different tissue types and assessing their structural and physiological integrity. Despite its importance and five decades of engineering development, the accessibility of MRI is low and extremely inhomogeneous around the world. This is due to the high cost and complex infrastructure requirements of existing high-field superconducting MRI scanners, which limit their availability in low and middle-income countries, and exclude their easy access in many healthcare facilities such as neurology clinics, trauma centres, surgical suites, neonatal/pediatric centres and community clinics. We and others have made intensive efforts in recent years to engineer low-cost and shielding-free MRI scanners for brain imaging at ultra-low-field (ULF) strengths (<0.1 T).<span><sup>1-5</sup></span> However, these developments are limited to brain and extremity imaging and their image quality is generally poor.</p><p>Recently we have developed a compact, low-power and highly simplified ULF MRI scanner that enables whole-body imaging with high image quality via computing.<span><sup>6</sup></span> In this work, we designed and prototyped a cost-effective whole-body 0.05 T MRI scanner that operates on a standard AC wall power outlet without any radiofrequency (RF) or magnetic shielding cages. The system utilized a compact 0.05 T permanent neodymium ferrite boron magnet with a double-plate structure and required no RF shielding cages (Figure 1A). To address electromagnetic interference (EMI) during scanning, we deployed active EMI sensing during scanning and deep learning direct signal prediction (Deep-DSP) strategy to retrospectively predict EMI-free MR signals prior to image reconstruction<span><sup>5, 7, 8</sup></span> (Figure 1B). We implemented and experimentally optimized the commonly used imaging protocols using phantoms and volunteers, keeping scan time at 8 min or less for each protocol. Our Deep-DSP strategy showed superior performance compared to other EMI reduction methods. Using traditional Fourier image reconstruction, we were able to image various anatomical structures with different MRI contrasts, including the brain, spine, abdomen, lung, extremities and heart (Figure 2A). We were also able to estimate cardiac function and visualize major vessels in the neck using time-of-flight magnetic resonance angiography without any exogenous contrast agent. However, these images exhibited a high level of noise and artefacts due to a drastically reduced MR signal at 0.05 T versus the standard 3 T. To address this challenge, we developed novel data-driven deep-learning image reconstruction methods to significantly advance ULF MRI image quality. We formulated a 3D partial Fourier super-resolution (PF-SR) strategy<span><sup>9, 10</sup></span> that integrates image reconstruction and super-res","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496131","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}
Yuan Wang, Maria-Filothei Lazaridou, Theresa Kordaß, Chiara Massa, Christoforos K. Vaxevanis, Stefan Eichmüller, Barbara Seliger
<p>Dear Editor,</p><p>The unconventional functional mechanisms of microRNA (miRNA)-mediated RNA or protein activation are complex and diverse,<span><sup>1</sup></span> like miRNA binding to AU-rich elements (ARE)<span><sup>2</sup></span> or competing with RNA-binding proteins.<span><sup>3</sup></span> Our own data demonstrated that miR-16 could bind to the coding sequence (CDS) of classical and non-classical human leukocyte antigen class I (HLA-I) molecules, thereby inducing their expression.<span><sup>4</sup></span> However, the interaction of silencers with miRNAs has not yet been investigated. Silencer features include a high GC content,<span><sup>5</sup></span> DNase hypersensitivity sites<span><sup>6</sup></span> and H3K27me3 regions.<span><sup>7</sup></span> Here we identified for the first time that miR-155-5p can directly bind a silencer in the 3′untranslated region (3′UTR) of TAP-binding protein (tpn) thereby increasing the HLA-I surface expression.</p><p>Using miRNA trapping by RNA in vitro affinity purification (miTRAP),<span><sup>8</sup></span> in silico analyses and molecular experiments, we identified miR-155-5p targeting of tpn 3′ UTR in melanoma cells affecting tpn and cell surface HLA-I expression, which has also clinical relevance. Interestingly, upon deletion of the predicted binding site within tpn 3´UTR (Figure 1A), luciferase (luc) reporter assays indicated higher relative luc activity of the wild type (wt) compared to the del 3′UTR in HEK293T cells (Figure 1B), which is opposite to the conventional function of miRNAs leading to a downregulation. Overexpression of miR-155-5p in three melanoma cell lines (Figure 1C) increased their tpn messenger RNA (mRNA) (Figure 1D) and protein levels (Figure 1E,F). This upregulation was specific for tpn since the mRNA of programmed death ligand 1 (PD-L1), another target of miR-155-5p,<span><sup>9</sup></span> was downregulated in the miR-155-5p-transfected MZ-Mel2 cell line (Figure 1G). Despite the overall expression levels of the HLA-I heavy chain (HC) were not altered in the miR-155-5p transfectants (Figure 1F,H), a tpn-mediated upregulation of the HLA-ABC and HLA-BC surface antigens was found on FM81 and MZ-Mel2 cells (Figure 1I,J), but not on FM3 cells, which might be probably due to the high HLA-I surface expression when compared to FM81 and MZ-Mel2 cells (Figure 1F). Actinomycin D treatment revealed a significant increase in the tpn mRNA half-life in FM81 miR-155-5p transfectants (Figure 1K). Using a CD107a degranulation assay, a reduced NK cell-mediated cytotoxicity against miR-155-5p transfected MZ-Mel2 cells expressing increased HLA-I surface antigens was shown by lower numbers of CD107a-positive NK cells (Figure 1L).</p><p>The overall survival (OS) analysis of 214 metastatic melanoma cases with patients’ outcomes demonstrated a positive correlation of miR-155 (miR-155HG) (Figure 2A), tpn (Figure 2B) and HLA-A (Figure 2C) expression levels with the OS of patients, thereby confirmi
{"title":"Unconventional microRNA role: Enhancing the human leukocyte antigen class I antigen processing pathway via interacting with a silencer","authors":"Yuan Wang, Maria-Filothei Lazaridou, Theresa Kordaß, Chiara Massa, Christoforos K. Vaxevanis, Stefan Eichmüller, Barbara Seliger","doi":"10.1002/ctm2.70010","DOIUrl":"10.1002/ctm2.70010","url":null,"abstract":"<p>Dear Editor,</p><p>The unconventional functional mechanisms of microRNA (miRNA)-mediated RNA or protein activation are complex and diverse,<span><sup>1</sup></span> like miRNA binding to AU-rich elements (ARE)<span><sup>2</sup></span> or competing with RNA-binding proteins.<span><sup>3</sup></span> Our own data demonstrated that miR-16 could bind to the coding sequence (CDS) of classical and non-classical human leukocyte antigen class I (HLA-I) molecules, thereby inducing their expression.<span><sup>4</sup></span> However, the interaction of silencers with miRNAs has not yet been investigated. Silencer features include a high GC content,<span><sup>5</sup></span> DNase hypersensitivity sites<span><sup>6</sup></span> and H3K27me3 regions.<span><sup>7</sup></span> Here we identified for the first time that miR-155-5p can directly bind a silencer in the 3′untranslated region (3′UTR) of TAP-binding protein (tpn) thereby increasing the HLA-I surface expression.</p><p>Using miRNA trapping by RNA in vitro affinity purification (miTRAP),<span><sup>8</sup></span> in silico analyses and molecular experiments, we identified miR-155-5p targeting of tpn 3′ UTR in melanoma cells affecting tpn and cell surface HLA-I expression, which has also clinical relevance. Interestingly, upon deletion of the predicted binding site within tpn 3´UTR (Figure 1A), luciferase (luc) reporter assays indicated higher relative luc activity of the wild type (wt) compared to the del 3′UTR in HEK293T cells (Figure 1B), which is opposite to the conventional function of miRNAs leading to a downregulation. Overexpression of miR-155-5p in three melanoma cell lines (Figure 1C) increased their tpn messenger RNA (mRNA) (Figure 1D) and protein levels (Figure 1E,F). This upregulation was specific for tpn since the mRNA of programmed death ligand 1 (PD-L1), another target of miR-155-5p,<span><sup>9</sup></span> was downregulated in the miR-155-5p-transfected MZ-Mel2 cell line (Figure 1G). Despite the overall expression levels of the HLA-I heavy chain (HC) were not altered in the miR-155-5p transfectants (Figure 1F,H), a tpn-mediated upregulation of the HLA-ABC and HLA-BC surface antigens was found on FM81 and MZ-Mel2 cells (Figure 1I,J), but not on FM3 cells, which might be probably due to the high HLA-I surface expression when compared to FM81 and MZ-Mel2 cells (Figure 1F). Actinomycin D treatment revealed a significant increase in the tpn mRNA half-life in FM81 miR-155-5p transfectants (Figure 1K). Using a CD107a degranulation assay, a reduced NK cell-mediated cytotoxicity against miR-155-5p transfected MZ-Mel2 cells expressing increased HLA-I surface antigens was shown by lower numbers of CD107a-positive NK cells (Figure 1L).</p><p>The overall survival (OS) analysis of 214 metastatic melanoma cases with patients’ outcomes demonstrated a positive correlation of miR-155 (miR-155HG) (Figure 2A), tpn (Figure 2B) and HLA-A (Figure 2C) expression levels with the OS of patients, thereby confirmi","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496133","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}
Circular RNAs (circRNAs) have been shown to play important roles in tumour development and tumour immunology. However, genome-wide characterisation of circRNAs and their roles in the immunology and immunotherapy of gallbladder carcinoma (GBC) has been lacking. We present a comprehensive characterisation of the circRNA landscape in GBC, revealing GBC-specific circRNAs. Our analysis found that circRNAs are significantly enriched in cell proliferation and are involved in cancer-related hallmarks. In particular, circAATF was upregulated in GBC, which was positively correlated with AATF mRNA expression, and promoted GBC cell growth. Through integrating computational and experimental approaches, we revealed that circAATF is positively associated with the CD4+ T cell abundance and PD-L1 level, and enhances the clinical benefits of anti-PD-L1 immunotherapy for GBC. We further demonstrate that circAATF elevates the PD-L1 level by activating phosphorylated AKT and acting as a sponge for miR-142-5p. CircAATF is positively associated with CD4+ T cells and PD-L1 levels and shows potential to aid anti-PD-L1 immunotherapy for GBC. Our study provides insights into roles of circAATF in the tumour development and immunology of GBC and accelerates the development of therapeutic strategies for GBC immunotherapy.
Highlights
We present a comprehensive characterisation of circRNA landscape in gallbladder carcinoma (GBC).
CircAATF is positively associated with CD4+ T cell abundance and PD-L1 expression and is shown to promote PD-L1 treatment in mouse model.
CircAATF can elevate PD-L1 level through phosphorylated AKT and linear AATF, which upregulates PD-L1 by acting as a sponge of miR-142-5p.
{"title":"CircRNome-wide characterisation reveals the promoting role of circAATF in anti-PD-L1 immunotherapy of gallbladder carcinoma","authors":"Yueqi Wang, Shengli Li, Xiaobo Bo, Yuan Li, Changcheng Wang, Lingxi Nan, Dexiang Zhang, Houbao Liu, Jiwei Zhang","doi":"10.1002/ctm2.70060","DOIUrl":"10.1002/ctm2.70060","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Circular RNAs (circRNAs) have been shown to play important roles in tumour development and tumour immunology. However, genome-wide characterisation of circRNAs and their roles in the immunology and immunotherapy of gallbladder carcinoma (GBC) has been lacking. We present a comprehensive characterisation of the circRNA landscape in GBC, revealing GBC-specific circRNAs. Our analysis found that circRNAs are significantly enriched in cell proliferation and are involved in cancer-related hallmarks. In particular, circAATF was upregulated in GBC, which was positively correlated with AATF mRNA expression, and promoted GBC cell growth. Through integrating computational and experimental approaches, we revealed that circAATF is positively associated with the CD4<sup>+</sup> T cell abundance and PD-L1 level, and enhances the clinical benefits of anti-PD-L1 immunotherapy for GBC. We further demonstrate that circAATF elevates the PD-L1 level by activating phosphorylated AKT and acting as a sponge for miR-142-5p. CircAATF is positively associated with CD4<sup>+</sup> T cells and PD-L1 levels and shows potential to aid anti-PD-L1 immunotherapy for GBC. Our study provides insights into roles of circAATF in the tumour development and immunology of GBC and accelerates the development of therapeutic strategies for GBC immunotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>We present a comprehensive characterisation of circRNA landscape in gallbladder carcinoma (GBC).</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>CircAATF is positively associated with CD4<sup>+</sup> T cell abundance and PD-L1 expression and is shown to promote PD-L1 treatment in mouse model.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>CircAATF can elevate PD-L1 level through phosphorylated AKT and linear AATF, which upregulates PD-L1 by acting as a sponge of miR-142-5p.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459357","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}
Tamara Vasilkovska, Marlies Verschuuren, Dorian Pustina, Monica van den Berg, Johan Van Audekerke, Isabel Pintelon, Roger Cachope, Winnok H. De Vos, Annemie Van der Linden, Mohit H. Adhikari, Marleen Verhoye
<div> <section> <h3> Background</h3> <p>Huntington's disease (HD) is marked by irreversible loss of neuronal function for which currently no availability for disease-modifying treatment exists. Advances in the understanding of disease progression can aid biomarker development, which in turn can accelerate therapeutic discovery.</p> </section> <section> <h3> Methods</h3> <p>We characterised the progression of altered dynamics of whole-brain network states in the zQ175DN mouse model of HD using a dynamic functional connectivity (FC) approach to resting-state fMRI and identified quasi-periodic patterns (QPPs) of brain activity constituting the most prominent resting-state networks.</p> </section> <section> <h3> Results</h3> <p>The occurrence of the normative QPPs, as observed in healthy controls, was reduced in the HD model as the phenotype progressed. This uncovered progressive cessation of synchronous brain activity with phenotypic progression, which is not observed with the conventional static FC approaches. To better understand the potential underlying cause of the observed changes in these brain states, we further assessed how mutant huntingtin (mHTT) protein deposition affects astrocytes and pericytes – one of the most important effectors of neurovascular coupling, along phenotypic progression. Increased cell-type dependent mHTT deposition was observed at the age of onset of motor anomalies, in the caudate putamen, somatosensory and motor cortex, regions that are prominently involved in HD pathology as seen in humans.</p> </section> <section> <h3> Conclusion</h3> <p>Our findings provide meaningful insights into the development and progression of altered functional brain dynamics in this HD model and open new avenues in assessing the dynamics of whole brain states, through QPPs, in clinical HD research.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Hyperactivity in the LCN-linked regions within short QPPs observed before motor impairment onset.</li> <li>DMLN QPP presents a progressive decrease in DMLN activity and occurrence along HD-like phenotype development.</li> <li>Breakdown of the LCN DMLN state flux at motor onset leads to a subsequent absence of the LCN DMLN QPP at an advanced HD-like stage.</li> </ul> </div> </section>
背景 亨廷顿舞蹈症（Huntington's disease，HD）以不可逆转的神经元功能丧失为特征，目前尚无可改变病情的治疗方法。对疾病进展的进一步了解有助于生物标志物的开发，进而加快治疗方法的发现。 方法 我们使用动态功能连接（FC）方法对静息态 fMRI 进行研究，确定了构成最突出静息态网络的大脑活动准周期模式（QPPs），从而描述了 zQ175DN HD 小鼠模型中全脑网络状态动态改变的进展。 结果 在健康对照组中观察到的标准 QPPs 在 HD 模型中随着表型的进展而减少。这揭示了随着表型的发展，大脑同步活动逐渐停止，而传统的静态 FC 方法却观察不到这一点。为了更好地了解观察到的这些大脑状态变化的潜在根本原因，我们进一步评估了突变型亨廷汀（mHTT）蛋白沉积如何随着表型进展影响星形胶质细胞和周细胞--神经血管耦合的最重要效应因子之一。在尾状核、躯体感觉皮层和运动皮层运动异常的发病年龄段，观察到了细胞类型依赖性 mHTT 沉积的增加，而这些区域正是人类 HD 病理学的主要涉及区域。 结论 我们的研究结果为了解这种 HD 模型中大脑功能动态变化的发展和进程提供了有意义的见解，并为在临床 HD 研究中通过 QPP 评估整个大脑状态的动态变化开辟了新的途径。 研究亮点 在运动障碍发生之前，在短QPP内观察到LCN连接区域的过度活跃。 DMLN QPP 随着 HD 类表型的发展，DMLN 活性和发生率逐渐降低。 在运动障碍发病时，LCN DMLN 状态通量的破坏导致随后在类似 HD 的晚期阶段 LCN DMLN QPP 的缺失。
{"title":"Evolution of aberrant brain-wide spatiotemporal dynamics of resting-state networks in a Huntington's disease mouse model","authors":"Tamara Vasilkovska, Marlies Verschuuren, Dorian Pustina, Monica van den Berg, Johan Van Audekerke, Isabel Pintelon, Roger Cachope, Winnok H. De Vos, Annemie Van der Linden, Mohit H. Adhikari, Marleen Verhoye","doi":"10.1002/ctm2.70055","DOIUrl":"https://doi.org/10.1002/ctm2.70055","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Huntington's disease (HD) is marked by irreversible loss of neuronal function for which currently no availability for disease-modifying treatment exists. Advances in the understanding of disease progression can aid biomarker development, which in turn can accelerate therapeutic discovery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We characterised the progression of altered dynamics of whole-brain network states in the zQ175DN mouse model of HD using a dynamic functional connectivity (FC) approach to resting-state fMRI and identified quasi-periodic patterns (QPPs) of brain activity constituting the most prominent resting-state networks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The occurrence of the normative QPPs, as observed in healthy controls, was reduced in the HD model as the phenotype progressed. This uncovered progressive cessation of synchronous brain activity with phenotypic progression, which is not observed with the conventional static FC approaches. To better understand the potential underlying cause of the observed changes in these brain states, we further assessed how mutant huntingtin (mHTT) protein deposition affects astrocytes and pericytes – one of the most important effectors of neurovascular coupling, along phenotypic progression. Increased cell-type dependent mHTT deposition was observed at the age of onset of motor anomalies, in the caudate putamen, somatosensory and motor cortex, regions that are prominently involved in HD pathology as seen in humans.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings provide meaningful insights into the development and progression of altered functional brain dynamics in this HD model and open new avenues in assessing the dynamics of whole brain states, through QPPs, in clinical HD research.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Hyperactivity in the LCN-linked regions within short QPPs observed before motor impairment onset.</li>\u0000 \u0000 <li>DMLN QPP presents a progressive decrease in DMLN activity and occurrence along HD-like phenotype development.</li>\u0000 \u0000 <li>Breakdown of the LCN DMLN state flux at motor onset leads to a subsequent absence of the LCN DMLN QPP at an advanced HD-like stage.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449207","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}
Haoxin Peng, Lei Jiang, Jiajia Yuan, Xiangrong Wu, Nan Chen, Dan Liu, Yueting Liang, Yi Xie, Keren Jia, Yanyan Li, Xujiao Feng, Jian Li, Xiaotian Zhang, Lin Shen, Yang Chen
<div> <section> <h3> Background</h3> <p>Gastric cancer patients with peritoneal metastasis (GCPM) experience a rapidly deteriorating clinical trajectory characterized by therapeutic resistance and dismal survival, particularly following the development of malignant ascites. However, the intricate dynamics within the peritoneal microenvironment (PME) during the treatment process remain largely unknown.</p> </section> <section> <h3> Methods</h3> <p>Matched samples from primary tumours (PT), peritoneal metastases (PM), and paired pre-treatment and post-chemo/immunotherapy (anti-PD-1/PD-L1) progression malignant ascites samples, were collected from 48 patients. These samples were subjected to single-cell RNA sequencing (<i>n</i> = 30), multiplex immunofluorescence (<i>n</i> = 30), and spatial transcriptomics (<i>n</i> = 3). Furthermore, post hoc analyses of a phase 1 clinical trial (<i>n</i> = 20, NCT03710265) and an in-house immunotherapy cohort (<i>n</i> = 499) were conducted to validate the findings.</p> </section> <section> <h3> Results</h3> <p>Tracing the evolutionary trajectory of epithelial cells unveiled the terminally differentially MUC1+ cancer cells with a high epithelial-to-mesenchymal transition potential, and they demonstrated spatial proximity with fibroblasts and endothelial cells, correlating with poor prognosis. A significant expansion of macrophage infiltrates, which exhibited the highest proangiogenic activity, was observed in the ascites compared with PT and PM. Besides, higher C1Q+ macrophage infiltrates correlated with significantly lower GZMA+ T-lymphocyte infiltrates in therapeutic failure cases, potentially mediated by the LGALS9-CD45 and SPP1-CD44 ligand–receptor interactions. In the chemoresistant group, intimate interactions between C1Q+ macrophages and fibroblasts through the complement activation pathway were found. In the group demonstrating immunoresistance, heightened TGF-β production activity was detected in MUC1+ cancer cells, and they were skewed to interplay with C1Q+ macrophages through the GDF15-TGF-βR2 axis. Ultimately, post hoc analyses indicated that co-targeting TGF-β and PDL1 pathways may confer superior clinical benefits than sole anti-PD-1/PD-L1 therapy for patients presenting with GCPM at the time of diagnosis.</p> </section> <section> <h3> Conclusions</h3> <p>Our findings elucidated the cellular differentiation trajectories and crucial drug resistance features within PME, facilitating the exploration of effective targets for GCPM treatment.</p> </section> <section>
{"title":"Single-cell characterization of differentiation trajectories and drug resistance features in gastric cancer with peritoneal metastasis","authors":"Haoxin Peng, Lei Jiang, Jiajia Yuan, Xiangrong Wu, Nan Chen, Dan Liu, Yueting Liang, Yi Xie, Keren Jia, Yanyan Li, Xujiao Feng, Jian Li, Xiaotian Zhang, Lin Shen, Yang Chen","doi":"10.1002/ctm2.70054","DOIUrl":"https://doi.org/10.1002/ctm2.70054","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Gastric cancer patients with peritoneal metastasis (GCPM) experience a rapidly deteriorating clinical trajectory characterized by therapeutic resistance and dismal survival, particularly following the development of malignant ascites. However, the intricate dynamics within the peritoneal microenvironment (PME) during the treatment process remain largely unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Matched samples from primary tumours (PT), peritoneal metastases (PM), and paired pre-treatment and post-chemo/immunotherapy (anti-PD-1/PD-L1) progression malignant ascites samples, were collected from 48 patients. These samples were subjected to single-cell RNA sequencing (<i>n</i> = 30), multiplex immunofluorescence (<i>n</i> = 30), and spatial transcriptomics (<i>n</i> = 3). Furthermore, post hoc analyses of a phase 1 clinical trial (<i>n</i> = 20, NCT03710265) and an in-house immunotherapy cohort (<i>n</i> = 499) were conducted to validate the findings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Tracing the evolutionary trajectory of epithelial cells unveiled the terminally differentially MUC1+ cancer cells with a high epithelial-to-mesenchymal transition potential, and they demonstrated spatial proximity with fibroblasts and endothelial cells, correlating with poor prognosis. A significant expansion of macrophage infiltrates, which exhibited the highest proangiogenic activity, was observed in the ascites compared with PT and PM. Besides, higher C1Q+ macrophage infiltrates correlated with significantly lower GZMA+ T-lymphocyte infiltrates in therapeutic failure cases, potentially mediated by the LGALS9-CD45 and SPP1-CD44 ligand–receptor interactions. In the chemoresistant group, intimate interactions between C1Q+ macrophages and fibroblasts through the complement activation pathway were found. In the group demonstrating immunoresistance, heightened TGF-β production activity was detected in MUC1+ cancer cells, and they were skewed to interplay with C1Q+ macrophages through the GDF15-TGF-βR2 axis. Ultimately, post hoc analyses indicated that co-targeting TGF-β and PDL1 pathways may confer superior clinical benefits than sole anti-PD-1/PD-L1 therapy for patients presenting with GCPM at the time of diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings elucidated the cellular differentiation trajectories and crucial drug resistance features within PME, facilitating the exploration of effective targets for GCPM treatment.</p>\u0000 </section>\u0000 \u0000 <section>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449142","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}
Qingqi Hong, Jingtao Zhu, Hexin Lin, Yinan Chen, Haoyu Bai, Linghua Yan, Li Xiao, Jun You
<p>Dear Editor,</p><p>Colorectal cancer (CRC) is a major global health issue with a 40% 5-year mortality rate,<span><sup>1</sup></span> and 30%−50% of patients still experience recurrence after curative resection.<span><sup>2, 3</sup></span> The clinical utility of molecular residual disease (MRD) detection in risk stratification and recurrence detection using circulating tumour DNA (ctDNA) noninvasively has attracted widespread attention but with limited studies.<span><sup>4-7</sup></span> We measured the value of tumour-agnostic ctDNA-guided MRD for recurrence prediction and monitoring, and explored the biological characteristics of ctDNA from MRD.</p><p>We included 104 patients with stage I-IV CRC (Figure S1), aged 26 to 82 years. Fourteen (13.5%) patients had positive landmark MRD, and thirty-two (30.8%) patients had positive longitudinal MRD (Table S1). The most frequently variant genes in tumour tissue were <i>TP53</i>, <i>KRAS</i> and <i>APC</i> (Figure S2A), while in ctDNA were <i>KRAS</i>, <i>EGFR</i> and <i>TP53</i> (Figure S2B).</p><p>Patients with negative landmark MRD had a lower recurrence percentage than positive cases (11.1% vs. 57.1%, <i>p</i> < .001), yielding a negative predictive value (NPV) of 88.9% (Figure 1A). The latter group had a significantly higher recurrence risk (hazard ratio [HR], 7.325; <i>p</i> < .001, Figure 1B). As for longitudinal MRD, the recurrence percentage was higher in positive-MRD compared to negative-MRD (43.8% vs. 5.6%, <i>p</i> < .001), yielding a high NPV (94.4%, Figure 1C). Positive longitudinal MRD was correlated with an elevated risk of recurrence (HR: 9.385; <i>p</i> < .001, Figure 1D). In multivariate analysis for disease-free survival (DFS), landmark and longitudinal MRD-positive were significantly associated with increased recurrence risks (Figure 1E). Furthermore, we explored the effect of longitudinal MRD status in patients receiving and not receiving neoadjuvant therapy (NAT). In both groups, longitudinal positive-MRD patients had higher recurrence risk than negative-MRD patients (NAT: HR, 12.509, <i>p</i> = .011; non-NAT: HR, 9.611, <i>p</i> < .001; Figure S3A and B). The recurrence risk was lower in those with negative landmark ctDNA and negative longitudinal ctDNA (Figure S4A–D). Although the NPV for ctDNA was slightly higher than that for MRD, the PPV for ctDNA was lower than that for MRD. The area under the curve (AUC) of 3-year DFS for landmark MRD was .678, longitudinal MRD was .895, and landmark and longitudinal MRD had higher AUCs than ctDNA (Figure S4E). Fourteen out of 18 cases with recurrence detected MRD at the postoperative time points (Figure 1F). And 85.7% (12/14) patients had positive MRD detection before computed tomography confirmed recurrence (median: 198.5 days, Figure 1G). For MRD-positive cases, actions such as initiating adjuvant therapies, more aggressive treatment, intensified monitoring, or early intervention before clinical relapse occurs, may be
{"title":"Comprehensive genomic analysis of molecular residual disease based on circulating tumour DNA in postoperative patients with colorectal cancer","authors":"Qingqi Hong, Jingtao Zhu, Hexin Lin, Yinan Chen, Haoyu Bai, Linghua Yan, Li Xiao, Jun You","doi":"10.1002/ctm2.70041","DOIUrl":"https://doi.org/10.1002/ctm2.70041","url":null,"abstract":"<p>Dear Editor,</p><p>Colorectal cancer (CRC) is a major global health issue with a 40% 5-year mortality rate,<span><sup>1</sup></span> and 30%−50% of patients still experience recurrence after curative resection.<span><sup>2, 3</sup></span> The clinical utility of molecular residual disease (MRD) detection in risk stratification and recurrence detection using circulating tumour DNA (ctDNA) noninvasively has attracted widespread attention but with limited studies.<span><sup>4-7</sup></span> We measured the value of tumour-agnostic ctDNA-guided MRD for recurrence prediction and monitoring, and explored the biological characteristics of ctDNA from MRD.</p><p>We included 104 patients with stage I-IV CRC (Figure S1), aged 26 to 82 years. Fourteen (13.5%) patients had positive landmark MRD, and thirty-two (30.8%) patients had positive longitudinal MRD (Table S1). The most frequently variant genes in tumour tissue were <i>TP53</i>, <i>KRAS</i> and <i>APC</i> (Figure S2A), while in ctDNA were <i>KRAS</i>, <i>EGFR</i> and <i>TP53</i> (Figure S2B).</p><p>Patients with negative landmark MRD had a lower recurrence percentage than positive cases (11.1% vs. 57.1%, <i>p</i> < .001), yielding a negative predictive value (NPV) of 88.9% (Figure 1A). The latter group had a significantly higher recurrence risk (hazard ratio [HR], 7.325; <i>p</i> < .001, Figure 1B). As for longitudinal MRD, the recurrence percentage was higher in positive-MRD compared to negative-MRD (43.8% vs. 5.6%, <i>p</i> < .001), yielding a high NPV (94.4%, Figure 1C). Positive longitudinal MRD was correlated with an elevated risk of recurrence (HR: 9.385; <i>p</i> < .001, Figure 1D). In multivariate analysis for disease-free survival (DFS), landmark and longitudinal MRD-positive were significantly associated with increased recurrence risks (Figure 1E). Furthermore, we explored the effect of longitudinal MRD status in patients receiving and not receiving neoadjuvant therapy (NAT). In both groups, longitudinal positive-MRD patients had higher recurrence risk than negative-MRD patients (NAT: HR, 12.509, <i>p</i> = .011; non-NAT: HR, 9.611, <i>p</i> < .001; Figure S3A and B). The recurrence risk was lower in those with negative landmark ctDNA and negative longitudinal ctDNA (Figure S4A–D). Although the NPV for ctDNA was slightly higher than that for MRD, the PPV for ctDNA was lower than that for MRD. The area under the curve (AUC) of 3-year DFS for landmark MRD was .678, longitudinal MRD was .895, and landmark and longitudinal MRD had higher AUCs than ctDNA (Figure S4E). Fourteen out of 18 cases with recurrence detected MRD at the postoperative time points (Figure 1F). And 85.7% (12/14) patients had positive MRD detection before computed tomography confirmed recurrence (median: 198.5 days, Figure 1G). For MRD-positive cases, actions such as initiating adjuvant therapies, more aggressive treatment, intensified monitoring, or early intervention before clinical relapse occurs, may be","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451203","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}
Peng Chen, Pingping Zhang, Jiangang Sun, Yangzhe Hou, Xianhu Liu
<p>The skin, as the largest organ of the human body, is often compromised by trauma, severe burns, ulcers and various other injuries.<span><sup>1, 2</sup></span> Such injuries not only precipitate pain and scarring but also significantly increase the risk of microbial infection. Consequently, there is an urgent imperative to develop effective treatment strategies to address these concerns. Wound dressings serve as crucial therapeutic tools that safeguard wounds, decrease the likelihood of contamination and infection, and promote tissue repair by absorbing exudates and maintaining a local moist environment. In recent years, a variety of functional polymer-based medical dressings have been developed – including polymer films.<span><sup>3, 4</sup></span> hydrogels.<span><sup>5, 6</sup></span> sponges and foams.<span><sup>7</sup></span>, <span><sup>8</sup></span> demonstrating excellent biocompatibility and significant potential for application in skin tissue engineering. These biocompatible dressings are characterised by antibacterial, antioxidant and controlled drug release properties. Additionally, they can function as flexible electrodes for electrotherapy and facilitate real-time monitoring of wound status, thereby enhancing their value in clinical applications.</p><p>Nevertheless, in the development of multifunctional wound dressings, it is imperative to emphasise their fundamental roles in wound protection and environmental regulation, particularly the regulation of wound temperature, which is of paramount importance.<span><sup>9-11</sup></span> Wounds are often accompanied by inflammation and increased localised temperature, while patients may also experience occasional exposure to direct sunlight and heat. Excessive heat can worsen tissue damage, raise the risk of infection, and slow healing. It may also promote fibroblast tissue overgrowth, increasing the likelihood of scarring. While conventional wound dressings are effective in protecting wounds and promoting healing, they still exhibit notable limitations in temperature regulation.<span><sup>12-14</sup></span></p><p>Passive radiative cooling (PRC) works by reflecting sunlight at wavelengths of 0.3 to 2.5 µm and utilising the atmospheric long-wave infrared transmission window (8 to 13 µm) to dissipate excess heat into outer space.<span><sup>15-17</sup></span> This process occurs without the need for mechanical equipment or energy consumption. Cooling materials with PRC properties can be engineered in various forms and structures to meet diverse application needs. Recent cooling research has also increasingly focused on biodegradable materials with improved biocompatibility.<span><sup>18, 19</sup></span> making the integration of PRC properties into medical wound dressings a highly promising development. This noninvasive approach optimises clinical treatment by utilising physical cooling mechanisms. It also serves as a carrier for slow-release medications, providing both bacteriostatic eff
{"title":"Cooling wound dressings: Prospects for clinical practice","authors":"Peng Chen, Pingping Zhang, Jiangang Sun, Yangzhe Hou, Xianhu Liu","doi":"10.1002/ctm2.70064","DOIUrl":"https://doi.org/10.1002/ctm2.70064","url":null,"abstract":"<p>The skin, as the largest organ of the human body, is often compromised by trauma, severe burns, ulcers and various other injuries.<span><sup>1, 2</sup></span> Such injuries not only precipitate pain and scarring but also significantly increase the risk of microbial infection. Consequently, there is an urgent imperative to develop effective treatment strategies to address these concerns. Wound dressings serve as crucial therapeutic tools that safeguard wounds, decrease the likelihood of contamination and infection, and promote tissue repair by absorbing exudates and maintaining a local moist environment. In recent years, a variety of functional polymer-based medical dressings have been developed – including polymer films.<span><sup>3, 4</sup></span> hydrogels.<span><sup>5, 6</sup></span> sponges and foams.<span><sup>7</sup></span>, <span><sup>8</sup></span> demonstrating excellent biocompatibility and significant potential for application in skin tissue engineering. These biocompatible dressings are characterised by antibacterial, antioxidant and controlled drug release properties. Additionally, they can function as flexible electrodes for electrotherapy and facilitate real-time monitoring of wound status, thereby enhancing their value in clinical applications.</p><p>Nevertheless, in the development of multifunctional wound dressings, it is imperative to emphasise their fundamental roles in wound protection and environmental regulation, particularly the regulation of wound temperature, which is of paramount importance.<span><sup>9-11</sup></span> Wounds are often accompanied by inflammation and increased localised temperature, while patients may also experience occasional exposure to direct sunlight and heat. Excessive heat can worsen tissue damage, raise the risk of infection, and slow healing. It may also promote fibroblast tissue overgrowth, increasing the likelihood of scarring. While conventional wound dressings are effective in protecting wounds and promoting healing, they still exhibit notable limitations in temperature regulation.<span><sup>12-14</sup></span></p><p>Passive radiative cooling (PRC) works by reflecting sunlight at wavelengths of 0.3 to 2.5 µm and utilising the atmospheric long-wave infrared transmission window (8 to 13 µm) to dissipate excess heat into outer space.<span><sup>15-17</sup></span> This process occurs without the need for mechanical equipment or energy consumption. Cooling materials with PRC properties can be engineered in various forms and structures to meet diverse application needs. Recent cooling research has also increasingly focused on biodegradable materials with improved biocompatibility.<span><sup>18, 19</sup></span> making the integration of PRC properties into medical wound dressings a highly promising development. This noninvasive approach optimises clinical treatment by utilising physical cooling mechanisms. It also serves as a carrier for slow-release medications, providing both bacteriostatic eff","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70064","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449102","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}
Haoyu Wang, Mu Xu, Tong Zhang, Jinkun Pan, Chaopu Li, Bei Pan, Linpeng Zhou, Yun Huang, Chenzi Gao, Mengping He, Yao Xue, Xuetao Ji, Xu Zhang, Ning Wang, Hongwen Zhou, Qian Wang, John Zhong Li
<div> <section> <h3> Background</h3> <p>Liver cancer (LC) is among the deadliest cancers worldwide, with existing treatments showing limited efficacy. This study aimed to elucidate the role and underlying mechanisms of pyrroline-5-carboxylate reductase 1 (PYCR1) as a potential therapeutic target in LC.</p> </section> <section> <h3> Methods</h3> <p>Immunohistochemistry and Western blot were used to analyse the expression of PYCR1 in LC cells and tissues. EdU assays, colony-forming assays, scratch wound healing assays, Transwell assays, nude mouse xenograft models and nude mouse lung metastasis models were used to detect the growth and metastasis abilities of LC cells. Transcriptome sequencing was used to search for downstream target genes regulated by PYCR1, and metabolomics was used to identify the downstream metabolites regulated by PYCR1. ChIP assays were used to analyse the enrichment of H3K18 lactylation in the IRS1 promoter region.</p> </section> <section> <h3> Results</h3> <p>We found that the expression of PYCR1 was significantly increased in HCC and that this high expression was associated with poor prognosis in HCC patients. Knockout or inhibition of PYCR1 inhibited HCC cell proliferation, migration and invasion both in vivo and in vitro. In addition, we revealed that knocking out or inhibiting PYCR1 could inhibit glycolysis in HCC cells and reduce H3K18 lactylation of the IRS1 histone, thereby inhibiting IRS1 expression.</p> </section> <section> <h3> Conclusions</h3> <p>Our findings identify PYCR1 as a pivotal regulator of LC progression that influences tumour cell metabolism and gene expression. By demonstrating the potential of targeting PYCR1 to inhibit LC cell proliferation and metastasis, this study identified PYCR1 as a promising therapeutic target for LC.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li> <p>Pyrroline-5-carboxylate reductase 1 (PYCR1) promotes the proliferation and metastasis of liver cancer (LC) cells.</p> </li> <li> <p>The expression of PYCR1 in LC is regulated by DNA methylation.</p> </li> <li> <p>Knocking down or inhibiting PYCR1 inhibits glycolysis as well as the PI3K/AKT/mTOR and MAPK/ERK pathways in LC cells.</p>
{"title":"PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification","authors":"Haoyu Wang, Mu Xu, Tong Zhang, Jinkun Pan, Chaopu Li, Bei Pan, Linpeng Zhou, Yun Huang, Chenzi Gao, Mengping He, Yao Xue, Xuetao Ji, Xu Zhang, Ning Wang, Hongwen Zhou, Qian Wang, John Zhong Li","doi":"10.1002/ctm2.70045","DOIUrl":"https://doi.org/10.1002/ctm2.70045","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Liver cancer (LC) is among the deadliest cancers worldwide, with existing treatments showing limited efficacy. This study aimed to elucidate the role and underlying mechanisms of pyrroline-5-carboxylate reductase 1 (PYCR1) as a potential therapeutic target in LC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Immunohistochemistry and Western blot were used to analyse the expression of PYCR1 in LC cells and tissues. EdU assays, colony-forming assays, scratch wound healing assays, Transwell assays, nude mouse xenograft models and nude mouse lung metastasis models were used to detect the growth and metastasis abilities of LC cells. Transcriptome sequencing was used to search for downstream target genes regulated by PYCR1, and metabolomics was used to identify the downstream metabolites regulated by PYCR1. ChIP assays were used to analyse the enrichment of H3K18 lactylation in the IRS1 promoter region.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that the expression of PYCR1 was significantly increased in HCC and that this high expression was associated with poor prognosis in HCC patients. Knockout or inhibition of PYCR1 inhibited HCC cell proliferation, migration and invasion both in vivo and in vitro. In addition, we revealed that knocking out or inhibiting PYCR1 could inhibit glycolysis in HCC cells and reduce H3K18 lactylation of the IRS1 histone, thereby inhibiting IRS1 expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings identify PYCR1 as a pivotal regulator of LC progression that influences tumour cell metabolism and gene expression. By demonstrating the potential of targeting PYCR1 to inhibit LC cell proliferation and metastasis, this study identified PYCR1 as a promising therapeutic target for LC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Pyrroline-5-carboxylate reductase 1 (PYCR1) promotes the proliferation and metastasis of liver cancer (LC) cells.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>The expression of PYCR1 in LC is regulated by DNA methylation.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Knocking down or inhibiting PYCR1 inhibits glycolysis as well as the PI3K/AKT/mTOR and MAPK/ERK pathways in LC cells.</p>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449076","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}
Julia E. Altman, Amy L. Olex, Emily K. Zboril, Carson J. Walker, David C. Boyd, Rachel K. Myrick, Nicole S. Hairr, Jennifer E. Koblinski, Madhavi Puchalapalli, Bin Hu, Mikhail G. Dozmorov, X. Steven Chen, Yunshun Chen, Charles M. Perou, Brian D. Lehmann, Jane E. Visvader, J. Chuck Harrell
<div> <section> <h3> Background</h3> <p>Breast cancer's complex transcriptional landscape requires an improved understanding of cellular diversity to identify effective treatments. The study of genetic variations among breast cancer subtypes at single-cell resolution has potential to deepen our insights into cancer progression.</p> </section> <section> <h3> Methods</h3> <p>In this study, we amalgamate single-cell RNA sequencing data from patient tumours and matched lymph metastasis, reduction mammoplasties, breast cancer patient-derived xenografts (PDXs), PDX-derived organoids (PDXOs), and cell lines resulting in a diverse dataset of 117 samples with 506 719 total cells. These samples encompass hormone receptor positive (HR+), human epidermal growth factor receptor 2 positive (HER2+), and triple-negative breast cancer (TNBC) subtypes, including isogenic model pairs. Herein, we delineated similarities and distinctions across models and patient samples and explore therapeutic drug efficacy based on subtype proportions.</p> </section> <section> <h3> Results</h3> <p>PDX models more closely resemble patient samples in terms of tumour heterogeneity and cell cycle characteristics when compared with TNBC cell lines. Acquired drug resistance was associated with an increase in basal-like cell proportions within TNBC PDX tumours as defined with SCSubtype and TNBCtype cell typing predictors. All patient samples contained a mixture of subtypes; compared to primary tumours HR+ lymph node metastases had lower proportions of HER2-Enriched cells. PDXOs exhibited differences in metabolic-related transcripts compared to PDX tumours. Correlative analyses of cytotoxic drugs on PDX cells identified therapeutic efficacy was based on subtype proportion.</p> </section> <section> <h3> Conclusions</h3> <p>We present a substantial multimodel dataset, a dynamic approach to cell-wise sample annotation, and a comprehensive interrogation of models within systems of human breast cancer. This analysis and reference will facilitate informed decision-making in preclinical research and therapeutic development through its elucidation of model limitations, subtype-specific insights and novel targetable pathways.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>Patient-derived xenografts models more closely resemble patient samples in tumour heterogeneity and cell cycle characteristics when compared with cell lines.
{"title":"Single-cell transcriptional atlas of human breast cancers and model systems","authors":"Julia E. Altman, Amy L. Olex, Emily K. Zboril, Carson J. Walker, David C. Boyd, Rachel K. Myrick, Nicole S. Hairr, Jennifer E. Koblinski, Madhavi Puchalapalli, Bin Hu, Mikhail G. Dozmorov, X. Steven Chen, Yunshun Chen, Charles M. Perou, Brian D. Lehmann, Jane E. Visvader, J. Chuck Harrell","doi":"10.1002/ctm2.70044","DOIUrl":"https://doi.org/10.1002/ctm2.70044","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Breast cancer's complex transcriptional landscape requires an improved understanding of cellular diversity to identify effective treatments. The study of genetic variations among breast cancer subtypes at single-cell resolution has potential to deepen our insights into cancer progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we amalgamate single-cell RNA sequencing data from patient tumours and matched lymph metastasis, reduction mammoplasties, breast cancer patient-derived xenografts (PDXs), PDX-derived organoids (PDXOs), and cell lines resulting in a diverse dataset of 117 samples with 506 719 total cells. These samples encompass hormone receptor positive (HR+), human epidermal growth factor receptor 2 positive (HER2+), and triple-negative breast cancer (TNBC) subtypes, including isogenic model pairs. Herein, we delineated similarities and distinctions across models and patient samples and explore therapeutic drug efficacy based on subtype proportions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PDX models more closely resemble patient samples in terms of tumour heterogeneity and cell cycle characteristics when compared with TNBC cell lines. Acquired drug resistance was associated with an increase in basal-like cell proportions within TNBC PDX tumours as defined with SCSubtype and TNBCtype cell typing predictors. All patient samples contained a mixture of subtypes; compared to primary tumours HR+ lymph node metastases had lower proportions of HER2-Enriched cells. PDXOs exhibited differences in metabolic-related transcripts compared to PDX tumours. Correlative analyses of cytotoxic drugs on PDX cells identified therapeutic efficacy was based on subtype proportion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We present a substantial multimodel dataset, a dynamic approach to cell-wise sample annotation, and a comprehensive interrogation of models within systems of human breast cancer. This analysis and reference will facilitate informed decision-making in preclinical research and therapeutic development through its elucidation of model limitations, subtype-specific insights and novel targetable pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Patient-derived xenografts models more closely resemble patient samples in tumour heterogeneity and cell cycle characteristics when compared with cell lines.","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447582","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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