首页 > 最新文献

Clinical and Translational Medicine最新文献

英文 中文
ATF3-mediated transactivation of CXCL14 in HSCs during liver fibrosis 肝纤维化过程中 ATF3 介导的造血干细胞中 CXCL14 的转录激活。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-02 DOI: 10.1002/ctm2.70040
Xinmiao Li, Lifan Lin, Yifei Li, Weizhi Zhang, Zhichao Lang, Jianjian Zheng

Background and aims

Myofibroblasts, the primary producers of extracellular matrix, primarily originate from hepatic stellate cells (HSCs), and their activation plays a pivotal role in liver fibrosis. This study aimed to investigate the function of CXC motif ligand 14 (CXCL14) in the progression of liver fibrosis.

Approach and results

CXCL14 knockdown significantly reduced the extent of liver fibrosis. Using Ingenuity pathway analysis and qRT-PCR, activating transcription factor 3 (ATF3) was identified as a key upstream regulator of CXCL14 expression. Mechanistically, ATF3 was shown to bind to the CXCL14 promoter, promoting its transactivation by TGF-β in HSCs. Notably, both global CXCL14 deletion (CXCL14−/−) and HSC/myofibroblast-specific CXCL14 knockdown significantly attenuated liver fibrosis in mice. RNA-seq comparisons between CXCL14−/− and WT mice highlighted Jak2 as the most significantly downregulated gene, implicating its role in the antifibrotic effects of CXCL14 suppression on HSC inactivation. Moreover, Jak2 overexpression reversed the inhibition of liver fibrosis caused by CXCL14 knockdown in vivo.

Conclusions

These findings unveil a novel ATF3/CXCL14/Jak2 signalling axis in liver fibrosis, presenting potential therapeutic targets for the disease.

背景和目的:肌成纤维细胞是细胞外基质的主要制造者,主要来源于肝星状细胞(HSCs),其活化在肝纤维化中起着关键作用。本研究旨在探讨CXC马达配体14(CXCL14)在肝纤维化进程中的功能:方法与结果:CXCL14基因敲除能明显减轻肝纤维化的程度。通过Ingenuity通路分析和qRT-PCR,活化转录因子3(ATF3)被确定为CXCL14表达的关键上游调节因子。从机制上看,ATF3 与 CXCL14 启动子结合,促进造血干细胞中 TGF-β 的转录激活。值得注意的是,全基因 CXCL14 缺失(CXCL14-/-)和造血干细胞/肌成纤维细胞特异性 CXCL14 基因敲除都能显著减轻小鼠肝纤维化。CXCL14-/-和WT小鼠的RNA-seq比较显示,Jak2是下调最明显的基因,这表明它在CXCL14抑制造血干细胞失活的抗纤维化作用中发挥了作用。此外,Jak2的过表达逆转了CXCL14敲除对体内肝纤维化的抑制作用:这些发现揭示了肝纤维化中一个新的 ATF3/CXCL14/Jak2 信号轴,为该疾病提供了潜在的治疗靶点。
{"title":"ATF3-mediated transactivation of CXCL14 in HSCs during liver fibrosis","authors":"Xinmiao Li,&nbsp;Lifan Lin,&nbsp;Yifei Li,&nbsp;Weizhi Zhang,&nbsp;Zhichao Lang,&nbsp;Jianjian Zheng","doi":"10.1002/ctm2.70040","DOIUrl":"10.1002/ctm2.70040","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and aims</h3>\u0000 \u0000 <p>Myofibroblasts, the primary producers of extracellular matrix, primarily originate from hepatic stellate cells (HSCs), and their activation plays a pivotal role in liver fibrosis. This study aimed to investigate the function of CXC motif ligand 14 (CXCL14) in the progression of liver fibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Approach and results</h3>\u0000 \u0000 <p>CXCL14 knockdown significantly reduced the extent of liver fibrosis. Using Ingenuity pathway analysis and qRT-PCR, activating transcription factor 3 (ATF3) was identified as a key upstream regulator of CXCL14 expression. Mechanistically, ATF3 was shown to bind to the CXCL14 promoter, promoting its transactivation by TGF-β in HSCs. Notably, both global CXCL14 deletion (<i>CXCL14<sup>−/−</sup></i>) and HSC/myofibroblast-specific CXCL14 knockdown significantly attenuated liver fibrosis in mice. RNA-seq comparisons between <i>CXCL14<sup>−/−</sup></i> and WT mice highlighted Jak2 as the most significantly downregulated gene, implicating its role in the antifibrotic effects of CXCL14 suppression on HSC inactivation. Moreover, Jak2 overexpression reversed the inhibition of liver fibrosis caused by CXCL14 knockdown in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings unveil a novel ATF3/CXCL14/Jak2 signalling axis in liver fibrosis, presenting potential therapeutic targets for the disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364598","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}
引用次数: 0
Single-cell and spatial omics unravel the spatiotemporal biology of tumour border invasion and haematogenous metastasis 单细胞和空间 omics 技术揭示了肿瘤边界侵袭和血源性转移的时空生物学特性。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-30 DOI: 10.1002/ctm2.70036
Xifu Cheng, Yuke Cao, Xiangyi Liu, Yuanheng Li, Qing Li, Dian Gao, Qiongfang Yu

Solid tumours exhibit a well-defined architecture, comprising a differentiated core and a dynamic border that interfaces with the surrounding tissue. This border, characterised by distinct cellular morphology and molecular composition, serves as a critical determinant of the tumour's invasive behaviour. Notably, the invasive border of the primary tumour represents the principal site for intravasation of metastatic cells. These cells, known as circulating tumour cells (CTCs), function as ‘seeds’ for distant dissemination and display remarkable heterogeneity. Advancements in spatial sequencing technology are progressively unveiling the spatial biological features of tumours. However, systematic investigations specifically targeting the characteristics of the tumour border remain scarce. In this comprehensive review, we illuminate key biological insights along the tumour body-border-haematogenous metastasis axis over the past five years. We delineate the distinctive landscape of tumour invasion boundaries and delve into the intricate heterogeneity and phenotype of CTCs, which orchestrate haematogenous metastasis. These insights have the potential to explain the basis of tumour invasion and distant metastasis, offering new perspectives for the development of more complex and precise clinical interventions and treatments.

实体瘤有明确的结构,包括分化的核心和与周围组织相接的动态边界。这种边界以独特的细胞形态和分子组成为特征,是决定肿瘤侵袭行为的关键因素。值得注意的是,原发肿瘤的侵袭边界是转移细胞内侵的主要部位。这些细胞被称为循环肿瘤细胞(CTC),是远处扩散的 "种子",具有显著的异质性。空间测序技术的进步正在逐步揭示肿瘤的空间生物学特征。然而,专门针对肿瘤边界特征的系统研究仍然很少。在这篇综合综述中,我们阐述了过去五年来沿着肿瘤体-边界-血行转移轴的关键生物学见解。我们描绘了肿瘤侵袭边界的独特景观,并深入探讨了协调血行转移的 CTCs 的复杂异质性和表型。这些见解有可能解释肿瘤侵袭和远处转移的基础,为开发更复杂、更精确的临床干预和治疗方法提供新的视角。
{"title":"Single-cell and spatial omics unravel the spatiotemporal biology of tumour border invasion and haematogenous metastasis","authors":"Xifu Cheng,&nbsp;Yuke Cao,&nbsp;Xiangyi Liu,&nbsp;Yuanheng Li,&nbsp;Qing Li,&nbsp;Dian Gao,&nbsp;Qiongfang Yu","doi":"10.1002/ctm2.70036","DOIUrl":"10.1002/ctm2.70036","url":null,"abstract":"<p>Solid tumours exhibit a well-defined architecture, comprising a differentiated core and a dynamic border that interfaces with the surrounding tissue. This border, characterised by distinct cellular morphology and molecular composition, serves as a critical determinant of the tumour's invasive behaviour. Notably, the invasive border of the primary tumour represents the principal site for intravasation of metastatic cells. These cells, known as circulating tumour cells (CTCs), function as ‘seeds’ for distant dissemination and display remarkable heterogeneity. Advancements in spatial sequencing technology are progressively unveiling the spatial biological features of tumours. However, systematic investigations specifically targeting the characteristics of the tumour border remain scarce. In this comprehensive review, we illuminate key biological insights along the tumour body-border-haematogenous metastasis axis over the past five years. We delineate the distinctive landscape of tumour invasion boundaries and delve into the intricate heterogeneity and phenotype of CTCs, which orchestrate haematogenous metastasis. These insights have the potential to explain the basis of tumour invasion and distant metastasis, offering new perspectives for the development of more complex and precise clinical interventions and treatments.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342703","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}
引用次数: 0
Adipose tissue-derived extracellular vesicles aggravate temporomandibular joint osteoarthritis associated with obesity 源自脂肪组织的细胞外囊泡会加重与肥胖有关的颞下颌关节骨关节炎。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-30 DOI: 10.1002/ctm2.70029
Baochao Li, Yuqin Jin, Bingqing Zhang, Tong Lu, Jialing Li, Jingzi Zhang, Yiwen Zhou, Yanyi Wang, Caixia Zhang, Yue Zhao, Huang Li
<div> <section> <h3> Introduction</h3> <p>Temporomandibular joint osteoarthritis (TMJ OA) is a major disease that affects maxillofacial health and is characterised by cartilage degeneration and subchondral bone remodelling. Obesity is associated with the exacerbation of pathological manifestations of TMJ OA. However, the underlying mechanism between adipose tissue and the TMJ axis remains limited.</p> </section> <section> <h3> Objectives</h3> <p>To evaluate the effects of obesity and the adipose tissue on the development of TMJ OA.</p> </section> <section> <h3> Methods</h3> <p>The obesity-related metabolic changes in TMJ OA patients were detected by physical signs and plasma metabolites. The effects of adipose tissue-derived EVs (Ad-EVs) on TMJ OA was investigated through histological and cytological experiments as well as gene editing technology. Alterations of Ad-EVs in obese state were identified by microRNA-seq analysis and the mechanism by which EVs affect TMJ OA was explored in vitro and in vivo.</p> </section> <section> <h3> Results</h3> <p>Obesity and the related metabolic changes were important influencing factors for TMJ OA. Ad-EVs from obese mice induced marked chondrocyte apoptosis, cartilage matrix degradation and subchondral bone remodelling, which exacerbated the development of TMJ OA. Depletion of Ad-EVs secretion by knocking out the geranylgeranyl diphosphate synthase (<i>Ggpps</i>) gene in adipose tissue significantly inhibited the obesity-induced aggravation of TMJ OA. MiR-3074-5p played an important role in this process .</p> </section> <section> <h3> Conclusions</h3> <p>Our work unveils an unknown link between obese adipose tissue and TMJ OA. Targeting the Ad-EVs and the miR-3074-5p may represent a promising therapeutic strategy for obesity-related TMJ OA.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>High-fat-diet-induced obesity aggravate the progression of TMJ OA in mice.</li> <li>Obese adipose tissue participates in cartilage damage through the altered miRNA in extracellular vesicles.</li> <li>Inhibition of miR-3074-5p/SMAD4 pathway in chondrocyte alleviated the effect of HFD-EVs on TMJ OA.</li> </ul> </div> </sect
导言:颞下颌关节骨关节炎(TMJ OA)是一种影响颌面部健康的主要疾病,其特点是软骨退化和软骨下骨重塑。肥胖与颞下颌关节炎的病理表现加剧有关。然而,脂肪组织与颞下颌关节轴之间的内在机制仍然有限:评估肥胖和脂肪组织对颞下颌关节 OA 发病的影响:方法:通过体征和血浆代谢物检测颞下颌关节OA患者与肥胖相关的代谢变化。方法:通过体征和血浆代谢物检测颞下颌关节OA患者与肥胖相关的代谢变化,通过组织学和细胞学实验以及基因编辑技术研究脂肪组织衍生的EVs(Ad-EVs)对颞下颌关节OA的影响。通过microRNA-seq分析确定了肥胖状态下Ad-EVs的变化,并在体外和体内探讨了EVs影响颞下颌关节OA的机制:结果:肥胖及相关代谢变化是颞下颌关节OA的重要影响因素。来自肥胖小鼠的Ad-EVs诱导了明显的软骨细胞凋亡、软骨基质降解和软骨下骨重塑,这加剧了颞下颌关节OA的发展。通过敲除脂肪组织中的香叶基二磷酸合成酶(Ggpps)基因来减少 Ad-EVs 的分泌,能显著抑制肥胖引起的颞下颌关节 OA 的恶化。MiR-3074-5p在这一过程中发挥了重要作用:我们的研究揭示了肥胖脂肪组织与颞下颌关节损伤之间的未知联系。针对 Ad-EVs 和 miR-3074-5p 可能是治疗肥胖相关颞下颌关节 OA 的一种有前景的策略:要点:高脂饮食诱导的肥胖会加剧小鼠颞下颌关节 OA 的进展。肥胖脂肪组织通过改变细胞外囊泡中的 miRNA 参与软骨损伤。抑制软骨细胞中的 miR-3074-5p/SMAD4 通路可减轻 HFD-EVs 对颞下颌关节 OA 的影响。
{"title":"Adipose tissue-derived extracellular vesicles aggravate temporomandibular joint osteoarthritis associated with obesity","authors":"Baochao Li,&nbsp;Yuqin Jin,&nbsp;Bingqing Zhang,&nbsp;Tong Lu,&nbsp;Jialing Li,&nbsp;Jingzi Zhang,&nbsp;Yiwen Zhou,&nbsp;Yanyi Wang,&nbsp;Caixia Zhang,&nbsp;Yue Zhao,&nbsp;Huang Li","doi":"10.1002/ctm2.70029","DOIUrl":"10.1002/ctm2.70029","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Introduction&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Temporomandibular joint osteoarthritis (TMJ OA) is a major disease that affects maxillofacial health and is characterised by cartilage degeneration and subchondral bone remodelling. Obesity is associated with the exacerbation of pathological manifestations of TMJ OA. However, the underlying mechanism between adipose tissue and the TMJ axis remains limited.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objectives&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;To evaluate the effects of obesity and the adipose tissue on the development of TMJ OA.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The obesity-related metabolic changes in TMJ OA patients were detected by physical signs and plasma metabolites. The effects of adipose tissue-derived EVs (Ad-EVs) on TMJ OA was investigated through histological and cytological experiments as well as gene editing technology. Alterations of Ad-EVs in obese state were identified by microRNA-seq analysis and the mechanism by which EVs affect TMJ OA was explored in vitro and in vivo.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Obesity and the related metabolic changes were important influencing factors for TMJ OA. Ad-EVs from obese mice induced marked chondrocyte apoptosis, cartilage matrix degradation and subchondral bone remodelling, which exacerbated the development of TMJ OA. Depletion of Ad-EVs secretion by knocking out the geranylgeranyl diphosphate synthase (&lt;i&gt;Ggpps&lt;/i&gt;) gene in adipose tissue significantly inhibited the obesity-induced aggravation of TMJ OA. MiR-3074-5p played an important role in this process .&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our work unveils an unknown link between obese adipose tissue and TMJ OA. Targeting the Ad-EVs and the miR-3074-5p may represent a promising therapeutic strategy for obesity-related TMJ OA.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;High-fat-diet-induced obesity aggravate the progression of TMJ OA in mice.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Obese adipose tissue participates in cartilage damage through the altered miRNA in extracellular vesicles.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Inhibition of miR-3074-5p/SMAD4 pathway in chondrocyte alleviated the effect of HFD-EVs on TMJ OA.&lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 &lt;/div&gt;\u0000 &lt;/sect","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342702","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}
引用次数: 0
Trem2 acts as a non-classical receptor of interleukin-4 to promote diabetic wound healing Trem2 作为白细胞介素-4 的非经典受体,可促进糖尿病伤口愈合。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-30 DOI: 10.1002/ctm2.70026
Xinlin Zhu, Chao Zhang, Weiwei Jiang, Zhaoxiang Zeng, Keming Zhang, Mingwei Du, Juan Chen, Qian Wu, Wanqing Liao, Youming Chen, Wenjie Fang, Weihua Pan

Background

The immunoglobulin superfamily protein Trem2 (triggering receptor expressed on myeloid cells 2) is primarily expressed on myeloid cells where it functions to regulate macrophage-related immune response induction. While macrophages are essential mediators of diabetic wound healing, the specific regulatory role that Trem2 plays in this setting remains to be established.

Objective

This study was developed to explore the potential importance of Trem2 signalling in diabetic wound healing and to clarify the underlying mechanisms through which it functions.

Methods and results

Following wound induction, diabetic model mice exhibited pronounced upregulation of Trem2 expression, which was primarily evident in macrophages. No cutaneous defects were evident in mice bearing a macrophage-specific knockout of Trem2 (T2-cKO), but they induced more pronounced inflammatory responses and failed to effectively repair cutaneous wounds, with lower levels of neovascularization, slower rates of wound closure, decreased collagen deposition following wounding. Mechanistically, we showed that interleukin (IL)-4 binds directly to Trem2, inactivating MAPK/AP-1 signalling to suppress the expression of inflammatory and chemoattractant factors. Co-culture of fibroblasts and macrophages showed that macrophages from T2-cKO mice suppressed the in vitro activation and proliferation of dermal fibroblasts through upregulation of leukaemia inhibitory factor (Lif). Injecting soluble Trem2 in vivo was also sufficient to significantly curtail inflammatory responses and to promote diabetic wound healing.

Conclusions

These analyses offer novel insight into the role of IL-4/Trem2 signalling as a mediator of myeloid cell-fibroblast crosstalk that may represent a viable therapeutic target for efforts to enhance diabetic wound healing.

背景:免疫球蛋白超家族蛋白 Trem2(髓样细胞上表达的触发受体 2)主要在髓样细胞上表达,其功能是调节与巨噬细胞相关的免疫反应诱导。虽然巨噬细胞是糖尿病伤口愈合的重要介质,但 Trem2 在这种情况下发挥的特定调节作用仍有待确定:本研究旨在探索 Trem2 信号在糖尿病伤口愈合中的潜在重要性,并阐明其发挥作用的基本机制:在诱导伤口愈合后,糖尿病模型小鼠表现出明显的 Trem2 表达上调,这主要体现在巨噬细胞中。巨噬细胞特异性敲除Trem2(T2-cKO)的小鼠没有明显的皮肤缺陷,但它们会诱发更明显的炎症反应,而且不能有效修复皮肤伤口,新生血管水平较低,伤口闭合速度较慢,伤口后胶原沉积减少。从机理上讲,我们发现白细胞介素(IL)-4可直接与Trem2结合,使MAPK/AP-1信号失活,从而抑制炎症因子和趋化因子的表达。成纤维细胞和巨噬细胞的共培养显示,T2-cKO 小鼠的巨噬细胞通过上调白血病抑制因子(Lif)抑制了真皮成纤维细胞的体外活化和增殖。在体内注射可溶性Trem2也足以显著抑制炎症反应并促进糖尿病伤口愈合:这些分析提供了有关 IL-4/Trem2 信号作为髓系细胞-成纤维细胞串联的介质的作用的新见解,它可能是促进糖尿病伤口愈合的一个可行的治疗靶点。
{"title":"Trem2 acts as a non-classical receptor of interleukin-4 to promote diabetic wound healing","authors":"Xinlin Zhu,&nbsp;Chao Zhang,&nbsp;Weiwei Jiang,&nbsp;Zhaoxiang Zeng,&nbsp;Keming Zhang,&nbsp;Mingwei Du,&nbsp;Juan Chen,&nbsp;Qian Wu,&nbsp;Wanqing Liao,&nbsp;Youming Chen,&nbsp;Wenjie Fang,&nbsp;Weihua Pan","doi":"10.1002/ctm2.70026","DOIUrl":"10.1002/ctm2.70026","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The immunoglobulin superfamily protein Trem2 (triggering receptor expressed on myeloid cells 2) is primarily expressed on myeloid cells where it functions to regulate macrophage-related immune response induction. While macrophages are essential mediators of diabetic wound healing, the specific regulatory role that Trem2 plays in this setting remains to be established.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study was developed to explore the potential importance of Trem2 signalling in diabetic wound healing and to clarify the underlying mechanisms through which it functions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and results</h3>\u0000 \u0000 <p>Following wound induction, diabetic model mice exhibited pronounced upregulation of Trem2 expression, which was primarily evident in macrophages. No cutaneous defects were evident in mice bearing a macrophage-specific knockout of Trem2 (T2-cKO), but they induced more pronounced inflammatory responses and failed to effectively repair cutaneous wounds, with lower levels of neovascularization, slower rates of wound closure, decreased collagen deposition following wounding. Mechanistically, we showed that interleukin (IL)-4 binds directly to Trem2, inactivating MAPK/AP-1 signalling to suppress the expression of inflammatory and chemoattractant factors. Co-culture of fibroblasts and macrophages showed that macrophages from T2-cKO mice suppressed the in vitro activation and proliferation of dermal fibroblasts through upregulation of leukaemia inhibitory factor (Lif). Injecting soluble Trem2 in vivo was also sufficient to significantly curtail inflammatory responses and to promote diabetic wound healing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These analyses offer novel insight into the role of IL-4/Trem2 signalling as a mediator of myeloid cell-fibroblast crosstalk that may represent a viable therapeutic target for efforts to enhance diabetic wound healing.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342704","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}
引用次数: 0
Corrigendum to ‘Adipocyte-specific FAK deletion promotes pancreatic β-cell apoptosis via adipose inflammatory response to exacerbate diabetes mellitus’ 脂肪细胞特异性FAK缺失通过脂肪炎症反应促进胰腺β细胞凋亡从而加剧糖尿病》的更正
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-24 DOI: 10.1002/ctm2.70033

In this article, we have just realized the wrong usage of flow cytometry chart in the FAK siRNA group in Figure S7B of Supplementary Material.

The wrong Figure S7 is as follows.

The corrected Figure S7 is as follows.

在本文中,我们刚刚意识到补充材料图 S7B 中 FAK siRNA 组流式细胞仪图的错误用法。
{"title":"Corrigendum to ‘Adipocyte-specific FAK deletion promotes pancreatic β-cell apoptosis via adipose inflammatory response to exacerbate diabetes mellitus’","authors":"","doi":"10.1002/ctm2.70033","DOIUrl":"10.1002/ctm2.70033","url":null,"abstract":"<p>In this article, we have just realized the wrong usage of flow cytometry chart in the FAK siRNA group in Figure S7B of Supplementary Material.</p><p>The wrong Figure S7 is as follows.</p><p></p><p>The corrected Figure S7 is as follows.</p><p></p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307231","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}
引用次数: 0
RETRACTION: The Novel Role of Circular RNA ST3GAL6 on Blocking Gastric Cancer Malignant Behaviours Through Autophagy Regulated by the FOXP2/MET/Mtor Axis 回归:环状 RNA ST3GAL6 在 FOXP2/MET/Mtor 轴调控下通过自噬阻断胃癌恶性行为的新作用
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-24 DOI: 10.1002/ctm2.70025

RETRACTION: P. Xu, X. Zhang, J. Cao, J. Yang, Z. Chen, W. Wang, S. Wang, L. Zhang, L. Xie, L. Fang, Y. Xia, Z. Xuan, J. Lv, H. Xu, and Z. Xu, “The Novel Role of Circular RNA ST3GAL6 on Blocking Gastric Cancer Malignant Behaviours Through Autophagy Regulated by the FOXP2/MET/Mtor Axis,” Clinical and Translational Medicine 12, no.1 (2022): e707, https://doi.org/10.1002/ctm2.707.

The above article, published online on 21 January 2022 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Xiangdong Wang; the Shanghai Institute of Clinical Bioinformatics; and John Wiley & Sons Australia, Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed inappropriate duplications of image panels within the article (Figures 6H and 7J) and between this article (Figures 2D, 7B, 7K, 8E and 8J) and another article previously published elsewhere by an overlapping group of authors in a different scientific context. The authors were unable to provide a satisfactory explanation and the raw data they supplied could not explain the identified issues. In addition, the cell line SGC-7901 used in this study has been reported as contaminated with HeLa cells, making it a problematic model for gastric cancer [1,2]. Given the extent of the identified issues, the editors have lost confidence in the data presented and the article's conclusions can no longer be considered reliable.

References

[1] F. Ye, C. Chen, J. Qin, J. Liu, and C. Zheng, “Genetic Profiling Reveals an Alarming Rate of Cross-Contamination Among Human Cell Lines Used in China,” The FASEB Journal 29, no. 10 (2015):4268–4272, https://doi.org/10.1096/fj.14-266718.

[2] X. Bian, Z. Yang, H. Feng, H. Sun, and Y. Liu, “A Combination of Species Identification and STR Profiling Identifies Cross-contaminated Cells from 482 Human Tumor Cell Lines,” Scientific Reports 7, no. 1 (2017):9774, https://doi.org/10.1038/s41598-017-09660-w.

撤回:P. Xu, X. Zhang, J. Cao, J. Yang, Z. Chen, W. Wang, S. Wang, L. Zhang, L. Xie, L. Fang, Y. Xia, Z. Xuan, J. Lv, H. Xu, and Z. Xu, "Novel Role of Circular RNA ST3GAL6 on Blocking Gastric Cancer Malignhaviours Through Autophagy Regulated by FOXP2/ MGM, the Journal of Journal of Clinical Research, 2009.Xu, "The Novel Role of Circular RNA ST3GAL6 on Blocking Gastric Cancer Malignant Behaviours Through Autophagy Regulated by the FOXP2/MET/Mtor Axis," Clinical and Translational Medicine 12, no.(2022): e707, https://doi.org/10.1002/ctm2.707。上述文章于 2022 年 1 月 21 日在线发表于 Wiley Online Library (wileyonlinelibrary.com),经杂志主编王向东、上海临床生物信息研究所和 John Wiley & Sons Australia, Ltd.(澳大利亚约翰威利父子公司)协商,现予以撤稿。在对第三方提出的疑虑进行调查后,我们同意撤稿。调查显示,文章(图 6H 和 7J)中的图像面板与本文(图 2D、7B、7K、8E 和 8J)中的图像面板存在不恰当的重复,而这篇文章与之前由一组相同作者在不同科学背景下发表的另一篇文章之间也存在不恰当的重复。作者无法提供令人满意的解释,他们提供的原始数据也无法解释发现的问题。此外,这项研究中使用的细胞系 SGC-7901 已被报道受到 HeLa 细胞的污染,使其成为一个有问题的胃癌模型[1,2]。鉴于所发现问题的严重性,编辑对所提供的数据失去了信心,文章的结论也不再可靠。参考文献 [1] F. Ye, C. Chen, J. Qin, J. Liu, and C. Zheng, "Genetic Profiling Reveals an Alarming Rate of Cross-Contamination Among Human Cell Lines Used in China," The FASEB Journal 29, no. 10 (2015):4268-4272, https://doi.org/10.1096/fj.14-266718.[2] X. Bian, Z. Yang, H. Feng, H. Sun, and Y. Liu, "A Combination of Species Identification and STR Profiling Identifies Cross-contaminated Cells from 482 Human Tumor Cell Lines," Scientific Reports 7, no. 1 (2017):9774, https://doi.org/10.1038/s41598-017-09660-w.
{"title":"RETRACTION: The Novel Role of Circular RNA ST3GAL6 on Blocking Gastric Cancer Malignant Behaviours Through Autophagy Regulated by the FOXP2/MET/Mtor Axis","authors":"","doi":"10.1002/ctm2.70025","DOIUrl":"10.1002/ctm2.70025","url":null,"abstract":"<p><b>RETRACTION</b>: P. Xu, X. Zhang, J. Cao, J. Yang, Z. Chen, W. Wang, S. Wang, L. Zhang, L. Xie, L. Fang, Y. Xia, Z. Xuan, J. Lv, H. Xu, and Z. Xu, “The Novel Role of Circular RNA ST3GAL6 on Blocking Gastric Cancer Malignant Behaviours Through Autophagy Regulated by the FOXP2/MET/Mtor Axis,” <i>Clinical and Translational Medicine</i> 12, no.1 (2022): e707, https://doi.org/10.1002/ctm2.707.</p><p>The above article, published online on 21 January 2022 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Xiangdong Wang; the Shanghai Institute of Clinical Bioinformatics; and John Wiley &amp; Sons Australia, Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed inappropriate duplications of image panels within the article (Figures 6H and 7J) and between this article (Figures 2D, 7B, 7K, 8E and 8J) and another article previously published elsewhere by an overlapping group of authors in a different scientific context. The authors were unable to provide a satisfactory explanation and the raw data they supplied could not explain the identified issues. In addition, the cell line SGC-7901 used in this study has been reported as contaminated with HeLa cells, making it a problematic model for gastric cancer [1,2]. Given the extent of the identified issues, the editors have lost confidence in the data presented and the article's conclusions can no longer be considered reliable.</p><p><b>References</b></p><p>[1] F. Ye, C. Chen, J. Qin, J. Liu, and C. Zheng, “Genetic Profiling Reveals an Alarming Rate of Cross-Contamination Among Human Cell Lines Used in China,” <i>The FASEB Journal</i> 29, no. 10 (2015):4268–4272, https://doi.org/10.1096/fj.14-266718.</p><p>[2] X. Bian, Z. Yang, H. Feng, H. Sun, and Y. Liu, “A Combination of Species Identification and STR Profiling Identifies Cross-contaminated Cells from 482 Human Tumor Cell Lines,” <i>Scientific Reports</i> 7, no. 1 (2017):9774, https://doi.org/10.1038/s41598-017-09660-w.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307234","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}
引用次数: 0
Rapid, portable Epstein‒Barr virus DNA detection using enzymatic recombinase amplification combined with the CRISPR–Cas12a system 利用酶重组酶扩增结合 CRISPR-Cas12a 系统进行快速、便携式 Epstein-Barr 病毒 DNA 检测。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-23 DOI: 10.1002/ctm2.70028
Jia Li, Hao Cheng, Xiaojun Wang, Ning Chen, Liujie Chen, Lili Duan, Fenghua Tan, Kai Li, Duanfang Liao, Zheng Hu
<p>Dear Editor,</p><p>Nasopharyngeal carcinoma (NPC), a malignancy affecting the head and neck region, is prevalent in the southern and southeastern coastal regions of China. The primary cause of NPC is the Epstein−Barr virus (EBV).<span><sup>1</sup></span> EBV DNA detection is crucial for the screening and monitoring of NPC and other EBV infection-related diseases. Plasma EBV DNA is considered an important indicator for early NPC screening,<span><sup>2</sup></span> as well as monitoring NPC prognosis and treatment efficacy.<span><sup>3</sup></span> However, the clinical diagnostic method involves quantitative polymerase chain reaction (qPCR), the application of which is limited by its time, cost and convenience.<span><sup>4</sup></span> Recently, rapid detection techniques that combine the CRISPR-Cas system with isothermal amplification technique (for instance recombinase polymerase amplification [RPA], rolling circle amplification [RCA] and loop-mediated isothermal amplification [LAMP]) have been increasingly developed and used for identifying various pathogens, (e.g. SARS-CoV-2,<span><sup>5</sup></span> HPV16/18,<span><sup>6</sup></span> HIV<span><sup>7</sup></span>). Enzymatic recombination amplification (ERA) is an advanced version of isothermal amplification technology,<span><sup>8</sup></span> building on RPA technology. Given its efficiency, adaptability and robustness, ERA is a promising method for enhancing the sensitivity of CRISPR-based pathogen detection.<span><sup>9</sup></span> In this study, we developed a rapid, portable method for detecting EBV nucleic acids by ERA combined with CRISPR–Cas12a (ERA–Cas12a).</p><p>Firstly, we tested the enhanced effect of ERA amplification to CRISPR–Cas12a detection of EB DNA by CRISPR–Cas12a-mediated fluorescence cleavage assay. EBV DNA samples that were not pre-amplified by ERA showed no notable alteration of fluorescence intensity contrast to the negative control (Figure S1). On the other hand, employing ERA amplification significantly improved the sensitivity of EBV DNA detection using the CRISPR‒Cas12a system (Figure S1).</p><p>Secondly, the reaction conditions of ERA (such as primer, volume) were optimized to improve the system of ERA–Cas12a sensitivity and specificity.</p><p>Primer design is crucial for ERA. LMP2A transcripts are relatively stable and can be detected persistently in NPC and other EBV-related malignant tumours. In total, we designed and tested 18 ERA primer pairs targeting the LMP-2A gene of EBV. Of them, 12 primer pairs were tested for LMP1 fragments, with the most efficient amplification achieved using LMP1-F2+R3 and LMP1-F3+R3 (Figure S2A). Moreover, six primer pairs were tested for LMP2 fragments, with the most efficient amplification achieved using LMP2-F3+R1 and LMP2-F3+R2 (Figure S2B). The real-time fluorescence curve demonstrated that LMP1-F3+R3 and LMP2-F3+R1 reached a plateau phase rapidly. Consequently, the primer pairs LMP1-F3+R3 and LMP2-F3+R1 were identified as
亲爱的编辑,鼻咽癌(Nasopharyngeal carcinoma,NPC)是一种影响头颈部的恶性肿瘤,流行于中国南部和东南沿海地区。1 EBV DNA 检测对于鼻咽癌和其他 EBV 感染相关疾病的筛查和监测至关重要。血浆 EBV DNA 被认为是早期鼻咽癌筛查2 以及监测鼻咽癌预后和疗效的重要指标。3 然而,临床诊断方法涉及定量聚合酶链反应(qPCR),其应用受到时间、成本和便利性的限制。近来,结合 CRISPR-Cas 系统和等温扩增技术(如重组酶聚合酶扩增法 [RPA]、滚动圈扩增法 [RCA] 和环介导等温扩增法 [LAMP])的快速检测技术得到了越来越多的开发和应用,用于鉴定各种病原体(如 SARS-CoV-2、5 HPV16/18、6 HIV7)。酶重组扩增(ERA)是等温扩增技术8 的高级版本,以 RPA 技术为基础。首先,我们通过 CRISPR-Cas12a 介导的荧光裂解实验检测了 ERA 扩增对 CRISPR-Cas12a 检测 EB DNA 的增强效果。与阴性对照相比,未经ERA预扩增的EBV DNA样本的荧光强度没有明显变化(图S1)。另一方面,ERA扩增显著提高了CRISPR-Cas12a系统检测EBV DNA的灵敏度(图S1)。其次,ERA反应条件(如引物、体积)的优化提高了ERA-Cas12a系统的灵敏度和特异性。LMP2A 转录本相对稳定,可在鼻咽癌和其他 EBV 相关恶性肿瘤中持续检测到。我们总共设计并测试了 18 对针对 EBV LMP-2A 基因的ERA 引物。其中12对引物对LMP1片段进行了测试,LMP1-F2+R3和LMP1-F3+R3的扩增效率最高(图S2A)。此外,有 6 对引物对 LMP2 片段进行了测试,其中 LMP2-F3+R1 和 LMP2-F3+R2 的扩增效率最高(图 S2B)。实时荧光曲线显示,LMP1-F3+R3 和 LMP2-F3+R1 很快就达到了高原期。因此,引物对 LMP1-F3+R3 和 LMP2-F3+R1 分别被确定为 LMP1 和 LMP2 的最佳选择(图 1A,B)。引物浓度为 200 nM(图 1C)、活化剂体积为 1.5 µL(图 1D)、模板体积为 8 µL(图 1E)时,荧光值最高。最佳ERA时间为20分钟(图1F)。随后的实验均使用了这些量。这些结果表明,基于荧光的ERA检测的检测限(LOD)为2×102拷贝/微升(图1G)。然而,仅靠ERA无法检测到四份临床EBV核酸样本(图S3)。EBV 是一种双链 DNA 病毒。Cas12a 有能力在有 crRNA 的情况下识别目标 DNA。在介导靶点序列特异性裂解的同时,Cas12a 还具有非特异性单链 DNA(ssDNA)消化活性,一旦形成 Cas12a/crRNA/靶 DNA 聚合物,就会触发附近的 ssDNA 荧光探针或其他信号探针的裂解(称为附带裂解特性)。接下来,我们对 CRISPR-Cas12a 系统(浓度、缓冲液和探针)进行了优化。筛选出特异性强、效率高的 crRNA 对于进一步测试至关重要。在这些候选crRNA中,我们选择了荧光信号最强的LMP1 crRNA3和LMP2 crRNA1,因为它们在CRISPR-Cas12a/crRNA反应中的裂解效率最高(图2A和S4A,B)。为了建立最佳反应条件,我们调整了各种因素,如 Cas12a 浓度、缓冲液类型、缓冲液浓度以及 F-Q 和 F-B 探针浓度。我们选择了模板体积(6 µL)(图 2B)、Cas12a 浓度(50 nM)(图 2C)和 crRNA 浓度(180 nM)(图 2D)、反应缓冲液系统 NEBuffer 2.1(图 2E)。本研究测试了三种缓冲液浓度(1×、2× 和 4×)。在 NEBuffer 2.1 中,Cas12a 的活性在 1× 缓冲液浓度下达到峰值(图 S5)。
{"title":"Rapid, portable Epstein‒Barr virus DNA detection using enzymatic recombinase amplification combined with the CRISPR–Cas12a system","authors":"Jia Li,&nbsp;Hao Cheng,&nbsp;Xiaojun Wang,&nbsp;Ning Chen,&nbsp;Liujie Chen,&nbsp;Lili Duan,&nbsp;Fenghua Tan,&nbsp;Kai Li,&nbsp;Duanfang Liao,&nbsp;Zheng Hu","doi":"10.1002/ctm2.70028","DOIUrl":"10.1002/ctm2.70028","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Nasopharyngeal carcinoma (NPC), a malignancy affecting the head and neck region, is prevalent in the southern and southeastern coastal regions of China. The primary cause of NPC is the Epstein−Barr virus (EBV).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; EBV DNA detection is crucial for the screening and monitoring of NPC and other EBV infection-related diseases. Plasma EBV DNA is considered an important indicator for early NPC screening,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; as well as monitoring NPC prognosis and treatment efficacy.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; However, the clinical diagnostic method involves quantitative polymerase chain reaction (qPCR), the application of which is limited by its time, cost and convenience.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Recently, rapid detection techniques that combine the CRISPR-Cas system with isothermal amplification technique (for instance recombinase polymerase amplification [RPA], rolling circle amplification [RCA] and loop-mediated isothermal amplification [LAMP]) have been increasingly developed and used for identifying various pathogens, (e.g. SARS-CoV-2,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; HPV16/18,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; HIV&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;). Enzymatic recombination amplification (ERA) is an advanced version of isothermal amplification technology,&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; building on RPA technology. Given its efficiency, adaptability and robustness, ERA is a promising method for enhancing the sensitivity of CRISPR-based pathogen detection.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; In this study, we developed a rapid, portable method for detecting EBV nucleic acids by ERA combined with CRISPR–Cas12a (ERA–Cas12a).&lt;/p&gt;&lt;p&gt;Firstly, we tested the enhanced effect of ERA amplification to CRISPR–Cas12a detection of EB DNA by CRISPR–Cas12a-mediated fluorescence cleavage assay. EBV DNA samples that were not pre-amplified by ERA showed no notable alteration of fluorescence intensity contrast to the negative control (Figure S1). On the other hand, employing ERA amplification significantly improved the sensitivity of EBV DNA detection using the CRISPR‒Cas12a system (Figure S1).&lt;/p&gt;&lt;p&gt;Secondly, the reaction conditions of ERA (such as primer, volume) were optimized to improve the system of ERA–Cas12a sensitivity and specificity.&lt;/p&gt;&lt;p&gt;Primer design is crucial for ERA. LMP2A transcripts are relatively stable and can be detected persistently in NPC and other EBV-related malignant tumours. In total, we designed and tested 18 ERA primer pairs targeting the LMP-2A gene of EBV. Of them, 12 primer pairs were tested for LMP1 fragments, with the most efficient amplification achieved using LMP1-F2+R3 and LMP1-F3+R3 (Figure S2A). Moreover, six primer pairs were tested for LMP2 fragments, with the most efficient amplification achieved using LMP2-F3+R1 and LMP2-F3+R2 (Figure S2B). The real-time fluorescence curve demonstrated that LMP1-F3+R3 and LMP2-F3+R1 reached a plateau phase rapidly. Consequently, the primer pairs LMP1-F3+R3 and LMP2-F3+R1 were identified as","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307233","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}
引用次数: 0
IBR1, a novel endogenous IFIH1-binding dsRNA, governs IFIH1 activation and M1 macrophage polarisation in ARDS IBR1是一种新型内源性IFIH1结合dsRNA,它在ARDS中控制着IFIH1的激活和M1巨噬细胞的极化。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-23 DOI: 10.1002/ctm2.70027
Shi Zhang, Wei Huang, Xueling Wu, Hanbing Chen, Lu Wang, Jie Chao, Jianfeng Xie, Haibo Qiu
<div> <section> <h3> Background</h3> <p>Uncontrolled inflammation caused by macrophages and monocytes plays a crucial role in worsening acute respiratory distress syndrome (ARDS). Previous studies have highlighted the importance of IFIH1 in regulating macrophage polarisation in ARDS triggered by pneumonia. However, the mechanisms by which IFIH1 is activated in ARDS remain unclear.</p> </section> <section> <h3> Methods</h3> <p>In this study, we utilised multiomics sequencing and molecular interaction experiments to explore the molecular mechanisms underlying IFIH1 activation in ARDS. Through the use of conditional gene knockout mice and primary cells, we demonstrated the significant role of these mechanisms in the development of ARDS. Additionally, we validated the associations between these mechanisms and ARDS by quantitative PCR analysis of CD14<sup>+</sup> cells obtained from the peripheral blood of 140 ARDS patients.</p> </section> <section> <h3> Results</h3> <p>Our investigation revealed that lipopolysaccharide, a critical component derived from Gram-negative bacteria, activated IFIH1 by upregulating a novel transcript known as IFIH1-binding RNA1 (IBR1) in monocytes and macrophages. Specifically, as an endogenous double-stranded RNA, IBR1 bind to the helicase domain of IFIH1 because of its unique double-stranded structure. Deletion of IBR1 significantly reduced the activation of IFIH1, M1 polarisation of macrophages, and inflammatory lung injury in ARDS. Moreover, IBR1 directly induced M1 polarisation of macrophages and ARDS, whereas deletion of IFIH1 inhibited IBR1-induced macrophage M1 polarisation and inflammatory lung injury. Importantly, we observed a notable increase in IBR1 expression in ARDS patients with pneumonia caused by Gram-negative bacteria. Furthermore, we demonstrated that the delivery of IFIH1 mutants through exosomes effectively counteracted IBR1, thereby reducing pulmonary inflammation and alleviating lung injury.</p> </section> <section> <h3> Conclusions</h3> <p>This study revealed a novel mechanism involving IBR1, an endogenous double-stranded RNA (dsRNA) that binds to IFIH1, shedding light on the complex process of macrophage polarisation in ARDS. The administration of IFIH1 variants has the potential to eliminate pulmonary dsRNA and alleviate inflammatory lung injury in ARDS.</p> </section> <section> <h3> Highlights</h3> <div> <ol> <li>
背景:巨噬细胞和单核细胞引起的不受控制的炎症在急性呼吸窘迫综合征(ARDS)恶化中起着至关重要的作用。先前的研究强调了 IFIH1 在调节肺炎引发的 ARDS 中巨噬细胞极化的重要性。然而,IFIH1在ARDS中被激活的机制仍不清楚:在这项研究中,我们利用多组学测序和分子相互作用实验来探索 ARDS 中 IFIH1 激活的分子机制。通过使用条件基因敲除小鼠和原代细胞,我们证明了这些机制在 ARDS 的发生发展中的重要作用。此外,我们还通过对140名ARDS患者外周血中的CD14+细胞进行定量PCR分析,验证了这些机制与ARDS之间的关联:我们的研究发现,脂多糖(一种来自革兰氏阴性细菌的重要成分)通过上调单核细胞和巨噬细胞中一种名为 IFIH1 结合 RNA1(IBR1)的新转录本激活了 IFIH1。具体来说,作为一种内源性双链 RNA,IBR1 因其独特的双链结构而与 IFIH1 的螺旋酶结构域结合。缺失 IBR1 能显著减少 IFIH1 的激活、巨噬细胞的 M1 极化以及 ARDS 中的炎性肺损伤。此外,IBR1 直接诱导巨噬细胞的 M1 极化和 ARDS,而 IFIH1 的缺失则抑制了 IBR1 诱导的巨噬细胞 M1 极化和炎性肺损伤。重要的是,我们观察到,在革兰氏阴性菌引起肺炎的 ARDS 患者中,IBR1 的表达明显增加。此外,我们还证明,通过外泌体递送 IFIH1 突变体可有效抵消 IBR1,从而减轻肺部炎症并缓解肺损伤:这项研究揭示了一种涉及 IBR1 的新机制,IBR1 是一种与 IFIH1 结合的内源性双链 RNA(dsRNA),它揭示了 ARDS 中巨噬细胞极化的复杂过程。服用IFIH1变体有可能消除肺部dsRNA,减轻ARDS的炎性肺损伤:在单核细胞和巨噬细胞中,内源性双链 RNA IFIH1-binding RNA 1(IBR1)因其独特的双链结构而与 IFIH1 的螺旋酶结构域结合。IBR1 在巨噬细胞极化和由革兰氏阴性细菌或脂多糖(LPS)诱发的急性呼吸窘迫综合征(ARDS)的发展过程中发挥着重要作用。服用 IFIH1 变体有可能消除肺 IBR1,减轻 ARDS 患者的肺部炎症损伤。
{"title":"IBR1, a novel endogenous IFIH1-binding dsRNA, governs IFIH1 activation and M1 macrophage polarisation in ARDS","authors":"Shi Zhang,&nbsp;Wei Huang,&nbsp;Xueling Wu,&nbsp;Hanbing Chen,&nbsp;Lu Wang,&nbsp;Jie Chao,&nbsp;Jianfeng Xie,&nbsp;Haibo Qiu","doi":"10.1002/ctm2.70027","DOIUrl":"10.1002/ctm2.70027","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Uncontrolled inflammation caused by macrophages and monocytes plays a crucial role in worsening acute respiratory distress syndrome (ARDS). Previous studies have highlighted the importance of IFIH1 in regulating macrophage polarisation in ARDS triggered by pneumonia. However, the mechanisms by which IFIH1 is activated in ARDS remain unclear.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In this study, we utilised multiomics sequencing and molecular interaction experiments to explore the molecular mechanisms underlying IFIH1 activation in ARDS. Through the use of conditional gene knockout mice and primary cells, we demonstrated the significant role of these mechanisms in the development of ARDS. Additionally, we validated the associations between these mechanisms and ARDS by quantitative PCR analysis of CD14&lt;sup&gt;+&lt;/sup&gt; cells obtained from the peripheral blood of 140 ARDS patients.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our investigation revealed that lipopolysaccharide, a critical component derived from Gram-negative bacteria, activated IFIH1 by upregulating a novel transcript known as IFIH1-binding RNA1 (IBR1) in monocytes and macrophages. Specifically, as an endogenous double-stranded RNA, IBR1 bind to the helicase domain of IFIH1 because of its unique double-stranded structure. Deletion of IBR1 significantly reduced the activation of IFIH1, M1 polarisation of macrophages, and inflammatory lung injury in ARDS. Moreover, IBR1 directly induced M1 polarisation of macrophages and ARDS, whereas deletion of IFIH1 inhibited IBR1-induced macrophage M1 polarisation and inflammatory lung injury. Importantly, we observed a notable increase in IBR1 expression in ARDS patients with pneumonia caused by Gram-negative bacteria. Furthermore, we demonstrated that the delivery of IFIH1 mutants through exosomes effectively counteracted IBR1, thereby reducing pulmonary inflammation and alleviating lung injury.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study revealed a novel mechanism involving IBR1, an endogenous double-stranded RNA (dsRNA) that binds to IFIH1, shedding light on the complex process of macrophage polarisation in ARDS. The administration of IFIH1 variants has the potential to eliminate pulmonary dsRNA and alleviate inflammatory lung injury in ARDS.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ol&gt;\u0000 \u0000 &lt;li&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307232","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}
引用次数: 0
Clinical and translational mode of single-cell measurements: An artificial intelligent single-cell 单细胞测量的临床和转化模式:人工智能单细胞
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-22 DOI: 10.1002/ctm2.1818
Xiangdong Wang, Charles A. Powell, Qin Ma, Jia Fan

With rapid development and mature of single-cell measurements, single-cell biology and pathology become an emerging discipline to understand the disease. However, it is important to address concerns raised by clinicians as to how to apply single-cell measurements for clinical practice, translate the signals of single-cell systems biology into determination of clinical phenotype, and predict patient response to therapies. The present Perspective proposes a new system coined as the clinical artificial intelligent single-cell (caiSC) with the dynamic generator of clinical single-cell informatics, artificial intelligent analyzers, molecular multimodal reference boxes, clinical inputs and outs, and AI-based computerization. This system provides reliable and rapid information for impacting clinical diagnoses, monitoring, and prediction of the disease at the single-cell level. The caiSC represents an important step and milestone to translate the single-cell measurement into clinical application, assist clinicians’ decision-making, and improve the quality of medical services. There is increasing evidence to support the possibility of the caiSC proposal, since the corresponding biotechnologies associated with caiSCs are rapidly developed. Therefore, we call the special attention and efforts from various scientists and clinicians on the caiSCs and believe that the appearance of the caiSCs can shed light on the future of clinical molecular medicine.

随着单细胞测量技术的迅速发展和成熟,单细胞生物学和病理学已成为一门了解疾病的新兴学科。然而,如何将单细胞测量应用于临床实践,将单细胞系统生物学信号转化为临床表型的判断,以及预测病人对疗法的反应,是临床医生所关心的问题。本视角提出了一种新的系统,被称为临床人工智能单细胞(caiSC),它由临床单细胞信息学、人工智能分析仪、分子多模态参考盒、临床输入和输出以及基于人工智能的计算机化动态生成器组成。该系统可提供可靠、快速的信息,在单细胞水平上影响临床诊断、监测和预测疾病。caiSC 是将单细胞测量转化为临床应用、辅助临床医生决策和提高医疗服务质量的重要步骤和里程碑。由于与 caiSCs 相关的生物技术发展迅速,越来越多的证据支持 caiSC 提议的可能性。因此,我们呼吁各位科学家和临床医生对 caiSCs 给予特别的关注和努力,并相信 caiSCs 的出现能为临床分子医学的未来带来曙光。
{"title":"Clinical and translational mode of single-cell measurements: An artificial intelligent single-cell","authors":"Xiangdong Wang,&nbsp;Charles A. Powell,&nbsp;Qin Ma,&nbsp;Jia Fan","doi":"10.1002/ctm2.1818","DOIUrl":"10.1002/ctm2.1818","url":null,"abstract":"<p>With rapid development and mature of single-cell measurements, single-cell biology and pathology become an emerging discipline to understand the disease. However, it is important to address concerns raised by clinicians as to how to apply single-cell measurements for clinical practice, translate the signals of single-cell systems biology into determination of clinical phenotype, and predict patient response to therapies. The present Perspective proposes a new system coined as the clinical artificial intelligent single-cell (caiSC) with the dynamic generator of clinical single-cell informatics, artificial intelligent analyzers, molecular multimodal reference boxes, clinical inputs and outs, and AI-based computerization. This system provides reliable and rapid information for impacting clinical diagnoses, monitoring, and prediction of the disease at the single-cell level. The caiSC represents an important step and milestone to translate the single-cell measurement into clinical application, assist clinicians’ decision-making, and improve the quality of medical services. There is increasing evidence to support the possibility of the caiSC proposal, since the corresponding biotechnologies associated with caiSCs are rapidly developed. Therefore, we call the special attention and efforts from various scientists and clinicians on the caiSCs and believe that the appearance of the caiSCs can shed light on the future of clinical molecular medicine.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1818","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281189","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}
引用次数: 0
Distinct discrepancy in breast cancer organoids recapitulation among molecular subtypes revealed by single-cell transcriptomes analysis 单细胞转录组分析揭示乳腺癌器官组织分子亚型再现的差异
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-21 DOI: 10.1002/ctm2.70023
Ziqi Jia, Hengyi Xu, Yaru Zhang, Heng Cao, Chunyu Deng, Longchen Xu, Yuning Sun, Jiayi Li, Yansong Huang, Pengming Pu, Tongxuan Shang, Xiang Wang, Jianzhong Su, Jiaqi Liu
<p>Dear Editor,</p><p>Breast cancer organoids (BCOs) are increasingly recognised as crucial tools in personalised medicine,<span><sup>1</sup></span> yet a significant gap remains between the need for precise drug sensitivity assessments and the biological disparities observed between BCOs and primary breast cancer (PBC) tissues.<span><sup>2, 3</sup></span> Our extensive analysis of paired single-cell RNA sequencing data has revealed a substantial preservation of molecular characteristics in hormone receptor-positive (HR-positive) and HER2-positive breast cancers. However, in triple-negative breast cancer (TNBC), we observed marked variability in cell subpopulations, likely influenced by oxygen-enriched culture conditions.</p><p>To investigate the preservation of characteristics across different molecular subtypes of breast cancer, we cultured six BCOs representing three subtypes: two HR-positive, two HER2-positive, and two TNBCs derived from surgical samples without prior adjuvant treatments (for study design, see Figure S1; for images of successfully established organoids, see Figure S2; patient clinical characteristics are detailed in the Supplementary Table). Following establishment, single-cell RNA sequencing was performed on matched PBCs and BCOs, yielding 66,920 quality-controlled cells (Figure 1A; for contributions of samples, molecular subtypes, and sample sources, see Figure S3). Our analysis of cell type composition revealed a significant reduction in immune and stromal cells in BCOs compared to PBCs (adjusted <i>p</i> < 0.001; Figure 1B), while epithelial cells proportions nearly doubled (<i>p</i> = 0.031, median fold change = 0.96, IQR = 0.94-1.78, Figure 1C). This suggests that organoid culture better preserves epithelial cells, and co-culture systems are required for the preservation of the tumour microenvironment (TME).<span><sup>4</sup></span> Further analyses demonstrated reductions in both the proportions and functionality of all immune and stromal cell subpopulations (Figure 1D-F). Notably, both malignant and non-malignant epithelial cells were amplified in BCOs while maintaining key functional characteristics (Figure 1G-I; see Methods section in Supplementary Materials for malignancy determination). Thus, despite the observed differences in cell type distribution, these findings did not diminish the value of organoids as robust in vitro models for studying epithelial components of tumours.</p><p>To assess genomic concordance in PDOs,<sup>5</sup> we analysed copy number variation (CNV) as a genomic marker between BCOs and PBCs using both paired and unpaired comparisons. Our findings revealed that BCOs effectively preserved cellular-level CNVs from PBCs in five out of six cases (Figure 2A), with an average retention rate of 71.6%. This preservation was particularly robust in HR-positive breast cancer at 88.2%, though it was less pronounced in TNBC at 62.4% (Figure 2B and C). Moreover, BCOs demonstrated the ability to amplify
亲爱的编辑,乳腺癌有机体(BCOs)越来越被认为是个性化医疗的重要工具1,但在精确药物敏感性评估的需求与BCOs和原发性乳腺癌(PBC)组织之间观察到的生物学差异之间仍存在巨大差距2, 3。我们对配对单细胞RNA测序数据的广泛分析表明,激素受体阳性(HR阳性)和HER2阳性乳腺癌的分子特征得到了很大程度的保留。为了研究不同分子亚型乳腺癌的特征保留情况,我们培养了代表三种亚型的六种 BCOs:两种 HR 阳性、两种 HER2 阳性和两种 TNBCs,它们都来自事先未接受辅助治疗的手术样本(研究设计见图 S1;成功建立的有机体图像见图 S2;患者临床特征详见附表)。建立后,对匹配的PBC和BCO进行了单细胞RNA测序,得到了66,920个质控细胞(图1A;样本贡献、分子亚型和样本来源见图S3)。我们对细胞类型组成的分析表明,与 PBCs 相比,BCOs 中的免疫细胞和基质细胞显著减少(调整后 p &lt; 0.001;图 1B),而上皮细胞的比例几乎翻了一番(p = 0.031,中位折叠变化 = 0.96,IQR = 0.94-1.78,图 1C)。4 进一步的分析表明,所有免疫细胞和基质细胞亚群的比例和功能都有所下降(图 1D-F)。值得注意的是,BCOs 中的恶性和非恶性上皮细胞均有扩增,同时保持了关键的功能特征(图 1G-I;恶性程度的测定方法见补充材料中的方法部分)。因此,尽管观察到细胞类型分布存在差异,但这些发现并没有降低有机体作为研究肿瘤上皮成分的强大体外模型的价值。为了评估 PDOs 的基因组一致性,5 我们使用配对和非配对比较的方法分析了 BCOs 和 PBCs 之间作为基因组标记的拷贝数变异(CNV)。我们的研究结果表明,在六个病例中,有五个病例的 BCO 有效保留了 PBC 的细胞级 CNV(图 2A),平均保留率为 71.6%。这种保留在 HR 阳性乳腺癌中尤为明显,保留率高达 88.2%,但在 TNBC 中的保留率较低,仅为 62.4%(图 2B 和 C)。此外,BCOs 还能扩增 CNV 的大小和比例,包括关键致癌基因,如 8q 染色体上的 MYC 和其他肿瘤驱动基因,从而导致扩增或删除 CNV 的细胞水平和比例增加(图 S4)。在P06患者身上观察到的CNV保存率较低,这与TNBC亚型有关,凸显了在此类病例中加强质量控制的必要性。虽然之前的研究记录了BCO中不同的DNA拷贝数保留情况,但我们的数据进一步证实,虽然不同分子亚型的保留模式各不相同,但器官组织显示出更强更清晰的CNV信号。PAM50 检测证实,BCOs 准确地保留了原始样本的分子亚型(图 2D)6。然而,在 HR 阳性乳腺癌中,与 PBCs 相比,BCOs 中 ESR1 的表达和 ESR1 高表达细胞的比例都显著降低(p &lt; 0.001,图 S5)。对于HER2阳性乳腺癌,PBCs和BCOs中99.5%的细胞都表现出ERBB2/HER2表达升高,但PBCs中的表达水平更高(p &lt; 0.05,图S5)。为了评估不同分子亚型 BCOs 中的细胞异质性和关键细胞群的保留情况,我们采用 Seurat 将细胞聚类为 11 个功能亚群(图 2E)。7 对分子亚型和这些亚群起源的分析表明,在 HR 阳性乳腺癌中占主导地位的雌激素受体反应亚群和在 HER2 阳性乳腺癌中占突出地位的代谢亚群在有机体中得到了高度保留。
{"title":"Distinct discrepancy in breast cancer organoids recapitulation among molecular subtypes revealed by single-cell transcriptomes analysis","authors":"Ziqi Jia,&nbsp;Hengyi Xu,&nbsp;Yaru Zhang,&nbsp;Heng Cao,&nbsp;Chunyu Deng,&nbsp;Longchen Xu,&nbsp;Yuning Sun,&nbsp;Jiayi Li,&nbsp;Yansong Huang,&nbsp;Pengming Pu,&nbsp;Tongxuan Shang,&nbsp;Xiang Wang,&nbsp;Jianzhong Su,&nbsp;Jiaqi Liu","doi":"10.1002/ctm2.70023","DOIUrl":"https://doi.org/10.1002/ctm2.70023","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Breast cancer organoids (BCOs) are increasingly recognised as crucial tools in personalised medicine,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; yet a significant gap remains between the need for precise drug sensitivity assessments and the biological disparities observed between BCOs and primary breast cancer (PBC) tissues.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; Our extensive analysis of paired single-cell RNA sequencing data has revealed a substantial preservation of molecular characteristics in hormone receptor-positive (HR-positive) and HER2-positive breast cancers. However, in triple-negative breast cancer (TNBC), we observed marked variability in cell subpopulations, likely influenced by oxygen-enriched culture conditions.&lt;/p&gt;&lt;p&gt;To investigate the preservation of characteristics across different molecular subtypes of breast cancer, we cultured six BCOs representing three subtypes: two HR-positive, two HER2-positive, and two TNBCs derived from surgical samples without prior adjuvant treatments (for study design, see Figure S1; for images of successfully established organoids, see Figure S2; patient clinical characteristics are detailed in the Supplementary Table). Following establishment, single-cell RNA sequencing was performed on matched PBCs and BCOs, yielding 66,920 quality-controlled cells (Figure 1A; for contributions of samples, molecular subtypes, and sample sources, see Figure S3). Our analysis of cell type composition revealed a significant reduction in immune and stromal cells in BCOs compared to PBCs (adjusted &lt;i&gt;p&lt;/i&gt; &lt; 0.001; Figure 1B), while epithelial cells proportions nearly doubled (&lt;i&gt;p&lt;/i&gt; = 0.031, median fold change = 0.96, IQR = 0.94-1.78, Figure 1C). This suggests that organoid culture better preserves epithelial cells, and co-culture systems are required for the preservation of the tumour microenvironment (TME).&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Further analyses demonstrated reductions in both the proportions and functionality of all immune and stromal cell subpopulations (Figure 1D-F). Notably, both malignant and non-malignant epithelial cells were amplified in BCOs while maintaining key functional characteristics (Figure 1G-I; see Methods section in Supplementary Materials for malignancy determination). Thus, despite the observed differences in cell type distribution, these findings did not diminish the value of organoids as robust in vitro models for studying epithelial components of tumours.&lt;/p&gt;&lt;p&gt;To assess genomic concordance in PDOs,&lt;sup&gt;5&lt;/sup&gt; we analysed copy number variation (CNV) as a genomic marker between BCOs and PBCs using both paired and unpaired comparisons. Our findings revealed that BCOs effectively preserved cellular-level CNVs from PBCs in five out of six cases (Figure 2A), with an average retention rate of 71.6%. This preservation was particularly robust in HR-positive breast cancer at 88.2%, though it was less pronounced in TNBC at 62.4% (Figure 2B and C). Moreover, BCOs demonstrated the ability to amplify ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276619","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}
引用次数: 0
期刊
Clinical and Translational Medicine
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1