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Cell-free transcriptomic profiles and mechanism insights in female androgenetic alopecia 女性雄激素源性脱发的无细胞转录组谱和机制研究。
IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Clinical and Translational Medicine
Pub Date : 2025-11-14 DOI: 10.1002/ctm2.70471
Lingling Jia, Mingyang Lu, Siwei Deng, Yongcheng Jin, Changjiang Zhao, Ruiyu Luo, Yuan Zhu, Zihan Li, Zixuan An, Hua Jiang, Yufei Li
<p>Dear Editor,</p><p>Our study presents a novel predictive machine learning model that demonstrates the potential of plasma cell-free RNA (cfRNA) for diagnosing and prognosing female androgenetic alopecia (FAGA). We identified cell-free <i>DNAJB9</i> as significantly associated with FAGA through bioinformatic analysis and machine learning followed by RT-qPCR validation (Figure 1A).</p><p>FAGA manifests heterogeneously,<span><sup>1</sup></span> often as diffuse thinning of the crown and frontal scalp.<span><sup>2</sup></span> It's pathogenesis critically involves androgen-hair follicle interactions and WNT and JAK-STAT signalling.<span><sup>3</sup></span> The cfRNA in bodily fluids have shown diagnostic/prognostic potential for various diseases.<span><sup>4</sup></span> Machine learning is increasingly used to analyse complex cfRNA data.<span><sup>5</sup></span> However, the potential association between cfRNA and FAGA remains unclear.</p><p>For subsequent analyses comparing disease severity, we focused on the ‘upper’ group as patients in the top 25% of the FAGA-Index (scores > 5.53) and the ‘lower’ group as those in the bottom 25% (scores < 1.92). Blood test results (Figure S1 and Table S2) showed no significant differences in various haematological and biochemical indicators between the FAGA and control groups. However, testosterone exhibited a significantly lower level in the ‘upper’ group (Figure S5), supporting that the FAGA-Index effectively enhances the stratification of patients by severity and may facilitate identification of other potential biomarkers in FAGA progression. Greater variation in principal component analysis (PCA) of cfRNA expression profiles between upper and lower FAGA subgroups, compared to that between FAGA and control groups, also suggested increased heterogeneity or molecular diversity within FAGA subtypes (Figure 1C and D).</p><p>The RNA biotypes were categorised based on Ensembl classifications with minor adjustments (Figure 1E). Analysis of differentially expressed genes (DEGs) showed that <i>CYTB</i>, <i>RNY1</i>, and <i>TMSB4X</i> were notably upregulated in FAGA patients, whilst <i>EEF1A1</i> was significantly downregulated (Figure 2A; Table S5). Furthermore, genes including <i>ND2</i>, <i>ATP6, ND6</i>, and <i>PARLP1</i> exhibited significant expression changes across varying disease severities (Table S7), suggesting their potential association with FAGA progression (Figure 2B). Functional enrichment analysis of these DEGs implicated pathways related to sensory perception, nuclear division, chromosome segregation, and mitosis in FAGA (Figure 2C and D; Tables S6 and S8). Pathway activity analysis reinforced the potential importance of JAK-STAT and WNTs pathways in FAGA (Figure 3A–C; Tables S17–S19). A comparison of transcription factor (TF) activities between FAGA patients and controls (Figure 3D; Table S9) revealed significantly increased activity of <i>NCOA3</i> and <i>MAX</i>. However, no significant di
我们的研究提出了一种新的预测机器学习模型，该模型证明了无浆细胞RNA （cfRNA）在诊断和预测女性雄激素性脱发（FAGA）方面的潜力。我们通过生物信息学分析和机器学习以及RT-qPCR验证，鉴定了无细胞DNAJB9与FAGA显著相关（图1A）。FAGA的表现是不均匀的，常表现为冠部和额部弥漫性变薄它的发病机制主要涉及雄激素与毛囊的相互作用以及WNT和JAK-STAT信号体液中的cfRNA已显示出对多种疾病的诊断/预后潜力机器学习越来越多地用于分析复杂的cfRNA数据然而，cfRNA和FAGA之间的潜在关联尚不清楚。对于比较疾病严重程度的后续分析，我们将重点放在faga指数前25%的患者（得分&gt； 5.53）和最低25%的患者（得分&lt； 1.92）的“高”组和“低”组。血液检测结果（图S1和表S2）显示，FAGA组与对照组的各项血液学和生化指标均无显著差异。然而，睾酮在“高”组中表现出明显较低的水平（图S5），支持FAGA指数有效地增强了患者严重程度的分层，并可能有助于识别FAGA进展中的其他潜在生物标志物。与FAGA和对照组相比，上、下FAGA亚组之间cfRNA表达谱的主成分分析（PCA）差异更大，也表明FAGA亚型内异质性或分子多样性增加（图1C和D）。RNA生物型根据Ensembl分类进行分类，稍作调整（图1E）。差异表达基因（DEGs）分析显示，FAGA患者中CYTB、RNY1和TMSB4X显著上调，EEF1A1显著下调（图2A；表S5）。此外，包括ND2、ATP6、ND6和PARLP1在内的基因在不同疾病严重程度中表现出显著的表达变化（表S7），表明它们与FAGA进展的潜在关联（图2B）。这些deg的功能富集分析涉及FAGA中与感觉知觉、核分裂、染色体分离和有丝分裂相关的途径（图2C和D；表S6和S8）。通路活性分析强化了JAK-STAT和WNTs通路在FAGA中的潜在重要性（图3A-C；表S17-S19）。FAGA患者和对照组之间转录因子（TF）活性的比较（图3D；表S9）显示NCOA3和MAX活性显著增加。然而，faga高亚组和低亚组之间的TF活性没有显著差异（表S10）。至关重要的是，我们观察到无细胞DNAJB9表达与FAGA指数之间存在显著的负相关，这表明低DNAJB9表达可能与FAGA严重程度的增加有关（表S11）。蛋白-蛋白相互作用网络（PPI）分析进一步揭示，与对照组相比，在FAGA中，上调的基因驱动内分泌补偿和线粒体应激反应，而下调的基因抑制生长信号（MET/mTORC1）和RNA代谢（图S2）。比较上faga和下faga，线粒体/内分泌活动增加，同时翻译和钙稳态受损（图S3）。这些结果表明，随着FAGA进展，通路失调加剧（表S12-S15）。随后，我们利用机器学习开发了FAGA预测模型，采用GeneLLM下游分类框架，6这是一种最先进的cfRNA分类方法。在初始特征提取之后，进行深度特征挖掘，以发现FAGA基因表达谱中的潜在模式。cfRNA RPKM矩阵被分为训练集（40%）、验证集（40%）和测试集（40%）（图4A）。大的、完全固定的测试集提供了一个严格的内部验证模型对来自同一人口的未见数据的性能。为了确保稳健性，使用10倍交叉验证进行超参数优化。该模型的曲线下面积（AUC）为。707用于区分FAGA患者和对照组（图4B）。714用于区分高与低的FAGA-Index分数（图4C）。它鉴定了几个与FAGA相关的基因，包括VGLL3、CYP1A1、PDE7B的反义基因，尤其是DNAJB9（图4D）。与FAGA严重程度相关的特征，如长链非编码RNA ARL14EP-DT和假基因TJAP1P1也被突出显示（图4E）。我们对6种候选生物标志物的表达水平与各种血液参数进行了相关性分析（图S6；表S20）。 然而，相关系数显示只有弱到中等的相关性，这意味着生化诊断和分子诊断之间需要更多的验证。内部和外部队列的进一步RT-qPCR验证证实，无细胞VGLL3、PDE7B反义和DNAJB9在FAGA患者中显著下调，而lncRNA ARL14EP-DT和假基因TJAP1P1在FAGA上亚组中显著下调（图S4）。值得注意的是，DNAJB9是细胞应激反应所必需的DNAJ/HSP40热休克蛋白HSP40家族蛋白参与调节雄激素受体（AR）活性，通常使AR处于非活性状态。8,9 DNAJB9表达的减少可能会潜在地破坏毛囊中的AR信号，特别是在压力下。综上所述，作为首次将cfRNA生物信息学分析与机器学习相结合的研究，本研究为cfRNA在FAGA诊断和预后中的应用建立了关键的概念验证，解决了该领域的关键空白，并为未来的工作提供了坚实的基础。我们的探索性模型虽然预测能力中等，但证明了无细胞DNAJB9作为FAGA生物标志物和治疗干预的候选物是有效的，值得进一步研究。项目监督由H.J. Y.L. s.d.负责，y.j.、H.J.和Y.L.负责概念化。l.j., m.l.和Y.L.管理临床招募设计。Y.J.设计并进行了湿室实验。数据分析和解释由S.D.和z.a完成。主要的稿件撰写和修改工作由l.j.、m.l.、S.D.和Y.J.负责。人体样本和数据收集的协调工作由y.z.、l.j.、h.j.、m.l.、y.l.、Z.L、c.z.和R.L.负责。所有作者都参与了对结果的讨论并对稿件提供了反馈。没有竞争利益需要披露。所有数据预处理和下游分析使用标准生物信息学工具，在基于Linux CentOS 8的高性能计算（HPC）系统和R版本4.1.3上进行，由OxTium Technology Co. Ltd提供。这些工具的详细信息，包括它们的名称、版本和具体用法，将在方法部分中概述。除非另有说明，否则所有工具都采用默认参数。本研究中所有受试者均被充分告知研究目的、程序和可能存在的风险，并在参与前获得书面知情同意。此外，研究方案得到了上海东方医院伦理审查委员会（EC.D(BG).016.02.1）的伦理审查和批准。所有cfRNA测序数据已提交至NCBI SRA数据库，登录号为PRJNA1146172。
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Illuminating the genomic frontier of invasive non-typhoidal Salmonella infections 阐明侵袭性非伤寒沙门氏菌感染的基因组前沿。
IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Clinical and Translational Medicine
Pub Date : 2025-11-12 DOI: 10.1002/ctm2.70526
Hao Wang, Li Tang, Haiyang Zhou, Peilu Xie, Min Yue
<p>In October 2024, the World Health Organisation (WHO) designated non-typhoidal serovars of <i>Salmonella enterica</i> as a global high-risk agent for Public Health Emergency of International Concern (PHEIC), spotlighting this urgent threat to global public health.<span><sup>1</sup></span> Unlike non-invasive serovars, which typically cause gastroenteritis, the invasive non-typhoidal <i>Salmonella</i> (iNTS) ones drive severe extraintestinal infections, responsible for approximately 87,100 deaths annually, with mortality rates of 18.1%.<span><sup>3</sup></span> The burden is critically compounded by the escalating crisis of antimicrobial resistance (AMR).</p><p>While historically recognised as a major public health issue in Africa,<span><sup>4</sup></span> often associated with HIV and malaria co-infections,<span><sup>5</sup></span> its epidemiology and transmission dynamics in other regions remain poorly understood. To fill the gap, our group has reported several invasive non-typhodial <i>Salmonella</i> serovars (Goldcoast, Livingstone, Telelkebir and Uzaramo) circulating.<span><sup>6-9</sup></span> Most recently, our large-scale genomic epidemiology study in China,<span><sup>10</sup></span> combining whole-genome sequencing with advanced Bayesian analyses, has uncovered a disturbing evolutionary shift from serovar Choleraesuis to Enteritidis. Challenging the conventional understanding of iNTS as a zoonotic disease transmitted from animals, our genomic evidence, as well as the patient cohort, demonstrates that iNTS is adapting to humans and evolving toward sustained human-to-human transmission.<span><sup>10</sup></span> Growing recognition of the bacterium's pandemic potential demands an urgent revision of global surveillance and targeted interventions.</p><p>Analysing the whole-genome sequencing (WGS) data of iNTS collected over the past three decades in China, the recent study revealed a significant epidemiological shift in China: The predominant serovar has transitioned from <i>S</i>. Choleraesuis, traditionally associated with swine, to <i>S</i>. Enteritidis,<span><sup>10</sup></span> a serovar notorious for its global outbreak-prone and frequent association with poultry.<span><sup>11-13</sup></span> This change indicates possible adaptive evolution driven by environmental changes (e.g. surge of poultry consumption, targeted interventions) or host interactions (e.g. immune pressure). Alarmingly, the genomic analysis<span><sup>10</sup></span> highlights a surge of AMR—86.54% of the iNTS strains possessing quinolone resistance, either through genetic mutations (e.g. <i>gyrA</i> mutations) or acquired genes (e.g. <i>qnr</i> genes). Furthermore, 66% of the isolates were multidrug-resistant (MDR). Of particular concern is the annually increasing detection rate of <i>bla<sub>CTX-M</sub></i> genes, conferring resistance to third-generation cephalosporins. Genetic context and co-localisation analyses implicate mobile genetic elements (MGEs)—plasmid
2024年10月，世界卫生组织（世卫组织）将非伤寒沙门氏菌血清型指定为国际关注的突发公共卫生事件（PHEIC）的全球高风险病原体，突显了这一对全球公共卫生的紧迫威胁与通常引起肠胃炎的非侵入性血清型不同，侵入性非伤寒沙门氏菌（iNTS）引起严重的肠外感染，每年造成约87,100人死亡，死亡率为18.1% 3不断升级的抗菌素耐药性危机严重加重了这一负担。虽然历来被认为是非洲的一个重大公共卫生问题，4往往与艾滋病毒和疟疾合并感染有关5，但其在其他区域的流行病学和传播动态仍然知之甚少。为了填补这一空白，我们的小组报告了几种侵入性非伤寒沙门氏菌血清型（Goldcoast, Livingstone， Telelkebir和Uzaramo）的传播。最近，我们在中国进行的大规模基因组流行病学研究，将全基因组测序与先进的贝叶斯分析相结合，发现了从血清型霍乱到肠炎的令人不安的进化转变。我们的基因组证据以及患者队列挑战了将iNTS视为动物传播的人畜共患疾病的传统理解，表明iNTS正在适应人类，并朝着持续的人际传播发展人们日益认识到这种细菌的大流行潜力，需要紧急修订全球监测和有针对性的干预措施。最近的研究分析了过去三十年来在中国收集的iNTS全基因组测序（WGS）数据，揭示了中国的重大流行病学转变：主要的血清型已经从传统上与猪相关的霍乱沙门氏菌转变为肠炎沙门氏菌，后者是一种因其全球暴发易发且经常与家禽相关而臭名昭著的血清型。11-13这一变化表明，环境变化（如家禽消费激增、有针对性的干预措施）或宿主相互作用（如免疫压力）可能导致适应性进化。令人担忧的是，基因组分析10突出了amr的激增，86.54%的iNTS菌株具有喹诺酮类药物耐药性，要么是通过基因突变（如gyrA突变），要么是通过获得性基因（如qnr基因）。此外，66%的分离株具有多重耐药（MDR）。特别值得关注的是，blaCTX-M基因的检出率每年都在增加，这导致了对第三代头孢菌素的耐药性。遗传环境和共定位分析表明，移动遗传元件（MGEs）——质粒、转座子和整合子——是抗性基因传播的关键驱动因素。携带耐药决定因素的MGEs促进了细菌群体之间的水平基因转移，挑战了氟喹诺酮类药物和头孢菌素等一线治疗药物的疗效。为了应对肠杆菌科细菌耐药性上升的全球趋势，迫切需要加强对MGE动态的监测和有针对性的干预措施，以破坏MGE的传播。结合菌株特异性基因组数据和国家人口统计数据，一个新的风险指数模型评估了中国不同年龄和性别群体对iNTS感染的易感性。研究结果表明，一岁以下的婴儿感染iNTS的风险不成比例地高，其感染率是其他年龄组的15倍以上这一人群的高易感性可能归因于多种因素，包括不成熟的免疫系统和暴露风险，如受污染的人类食物或与病原体携带者密切接触。此外，该研究还揭示了显著的性别差异，男性感染iNTS的发生率明显高于女性这种基于性别的差异反映了在各种其他细菌感染中观察到的模式，表明潜在的生物因素（如激素对免疫反应的影响）或行为因素（如职业暴露）值得进一步调查。这些见解强调，迫切需要有针对性的公共卫生干预措施，如加强新生儿筛查和针对性别的风险缓解战略，以遏制非传染性疾病的发病率和死亡率。通过采用先进的贝叶斯时空模型和全面的全球系统基因组分析，我们将之前定义的肠炎沙门氏菌全球流行病进化支分解为三个不同的亚进化支：global -a（出现于1965-1975年）、global -b（1970-1981年）和global -c（2000-2004年）这一发现为理解全球流行病学和进化轨迹提供了一个完善的框架。 值得注意的是，Global-b在南非和中国的分布表明，可能通过国际旅行或贸易路线促进了病原体的洲际传播，例如从欧洲向亚洲出口家禽种禽。12 Global-c主要局限于中国，其特点是耐药性较高（耐多药率：Global-c， 97.56% &gt; Global-b, 22.36% &gt; Global-a, 2.07%）。10泛基因组分析进一步揭示，这支进化枝在控制一系列核心生物功能的基因上积累了明显的突变，包括代谢、信息处理和细胞信号，这将其与非洲进化枝（如C&amp；E谱系）区分开来遗传差异反映了由全球传播和区域特异性适应驱动的复杂进化史，这表明有必要进行支系特异性基因组监测，以监测iNTS的传播和适应。这项研究的范式转变发现是，人与人之间的传播在int的传播中占主导地位通过结合碱基替代率和时空相关性分析，我们确定单核苷酸多态性（SNP）距离为4或更少的对分离物表明最近发生了传播事件。通过对来自One Health的800多个肠炎沙门氏菌基因组的分析，包括动物、侵袭性人类病例和腹泻患者，该研究确定，导致侵袭性疾病的57.52%的传播事件可归因于人与人之间的直接接触值得注意的是，腹泻患者被认为是这一传播链中的关键媒介，可能通过密切接触或人为制备的食品污染，促进病原体在人群中传播。这一结论得到了人类和动物来源菌株之间显著的基因组差异的支持，如MGE分布、抗性基因谱和泛基因组数据所证明的那样，改变了传统的以牲畜为中心的传播模型，并与我们小组的初步证据一致这一发现强调迫切需要修订以人际接触网络为重点的公共卫生战略建议在基因组分析中使用≤4个SNP阈值来追踪疫情并进行早期干预10。迄今为止，还没有疫苗获得监管部门批准供人使用。为了应对全球范围内日益增加的人类适应传播的iNTS，我们提出了以下关键策略：(1)强制在血液感染的常规监测中进行iNTS，特别是在热点地区；(2)在医院和诊所实施严格的抗菌药物管理方案，特别是避免经验性使用氟喹诺酮类药物或第三代头孢菌素，除非有指示；(3)扩大One Health流行病学调查，结合人类病例数据、动物监测、食物链采样和WGS环境测试，确定主要宿主和具体传播途径；(4)针对非洲的鼠伤寒沙门氏菌ST313和中国的肠炎沙门氏菌等优势区域血清型/进化支开发疫苗，并针对保守的免疫参数进行优化。然而，从基因组发现到公共卫生干预的实施挑战仍然存在，特别是在资源有限的地区。由于不断增加的人际传播和加速的抗微生物药物耐药性的双重威胁，这场危机使我们迫切需要部署尖端技术。在公平的全球伙伴关系的支持下，人工智能增强监测、信使RNA疫苗平台、基于crispr的诊断和噬菌体治疗等创新至关重要。作为一种跨越人畜共患和人类领域的病原体，iNTS是持续威胁病原体的哨兵，要求采取积极主动、技术支持和全球协调的应对措施，这不仅是一种选择，而且是全球卫生安全的必要条件。MY， HW， LT共同撰写初稿，HZ和PX审阅稿件。作者声明无利益冲突。国家自然科学基金（no. 32573359）；国家重点研究项目（no. 32573359）；项目资助：2022YFC2604201)和欧盟地平线2020研究与创新计划（资助协议号861917 - SAFFI），浙江省自然科学基金（批准号：2022YFC2604201）。LZ24C180002)，中国科学院杭州高等研究院科研经费。资助者在研究设计、数据收集和分析、决定发表或准备手稿方面没有任何作用。不需要申报。
{"title":"Illuminating the genomic frontier of invasive non-typhoidal Salmonella infections","authors":"Hao Wang,&nbsp;Li Tang,&nbsp;Haiyang Zhou,&nbsp;Peilu Xie,&nbsp;Min Yue","doi":"10.1002/ctm2.70526","DOIUrl":"10.1002/ctm2.70526","url":null,"abstract":"&lt;p&gt;In October 2024, the World Health Organisation (WHO) designated non-typhoidal serovars of &lt;i&gt;Salmonella enterica&lt;/i&gt; as a global high-risk agent for Public Health Emergency of International Concern (PHEIC), spotlighting this urgent threat to global public health.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Unlike non-invasive serovars, which typically cause gastroenteritis, the invasive non-typhoidal &lt;i&gt;Salmonella&lt;/i&gt; (iNTS) ones drive severe extraintestinal infections, responsible for approximately 87,100 deaths annually, with mortality rates of 18.1%.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; The burden is critically compounded by the escalating crisis of antimicrobial resistance (AMR).&lt;/p&gt;&lt;p&gt;While historically recognised as a major public health issue in Africa,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; often associated with HIV and malaria co-infections,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; its epidemiology and transmission dynamics in other regions remain poorly understood. To fill the gap, our group has reported several invasive non-typhodial &lt;i&gt;Salmonella&lt;/i&gt; serovars (Goldcoast, Livingstone, Telelkebir and Uzaramo) circulating.&lt;span&gt;&lt;sup&gt;6-9&lt;/sup&gt;&lt;/span&gt; Most recently, our large-scale genomic epidemiology study in China,&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; combining whole-genome sequencing with advanced Bayesian analyses, has uncovered a disturbing evolutionary shift from serovar Choleraesuis to Enteritidis. Challenging the conventional understanding of iNTS as a zoonotic disease transmitted from animals, our genomic evidence, as well as the patient cohort, demonstrates that iNTS is adapting to humans and evolving toward sustained human-to-human transmission.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; Growing recognition of the bacterium's pandemic potential demands an urgent revision of global surveillance and targeted interventions.&lt;/p&gt;&lt;p&gt;Analysing the whole-genome sequencing (WGS) data of iNTS collected over the past three decades in China, the recent study revealed a significant epidemiological shift in China: The predominant serovar has transitioned from &lt;i&gt;S&lt;/i&gt;. Choleraesuis, traditionally associated with swine, to &lt;i&gt;S&lt;/i&gt;. Enteritidis,&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; a serovar notorious for its global outbreak-prone and frequent association with poultry.&lt;span&gt;&lt;sup&gt;11-13&lt;/sup&gt;&lt;/span&gt; This change indicates possible adaptive evolution driven by environmental changes (e.g. surge of poultry consumption, targeted interventions) or host interactions (e.g. immune pressure). Alarmingly, the genomic analysis&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; highlights a surge of AMR—86.54% of the iNTS strains possessing quinolone resistance, either through genetic mutations (e.g. &lt;i&gt;gyrA&lt;/i&gt; mutations) or acquired genes (e.g. &lt;i&gt;qnr&lt;/i&gt; genes). Furthermore, 66% of the isolates were multidrug-resistant (MDR). Of particular concern is the annually increasing detection rate of &lt;i&gt;bla&lt;sub&gt;CTX-M&lt;/sub&gt;&lt;/i&gt; genes, conferring resistance to third-generation cephalosporins. Genetic context and co-localisation analyses implicate mobile genetic elements (MGEs)—plasmid","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 11","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70526","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502393","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
m7G RNA methylation in cancer: Effect, mechanism and clinical application m7G RNA甲基化在肿瘤中的作用、机制及临床应用
IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Clinical and Translational Medicine
Pub Date : 2025-11-09 DOI: 10.1002/ctm2.70521
PengYuan Dang, KaiBo Li, ZhenQiang Sun

Background

RNA methylation has emerged as a pivotal layer of post-transcriptional regulation that shapes the biological behavior of cancer cells. Among the diverse chemical modifications identified—such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), 7-methylguanosine (m7G), 5-hydroxymethylcytosine (5hmC), and 2′-O-dimethyladenosine (m6Am)—the m7G modification has recently garnered increasing attention. Mounting evidence indicates that m7G methylation plays an essential role in RNA metabolism and profoundly influences cancer initiation and progression.

Main Topics

This Review synthesizes current advances in understanding the biological and clinical implications of m7G RNA methylation, with a particular focus on its key regulatory components, METTL1/WDR4 and eIF4E. We discuss how these enzymes and binding proteins orchestrate m7G deposition and recognition to modulate oncogenic processes, including cell growth, differentiation, metastasis, and therapeutic resistance. Furthermore, we highlight emerging evidence linking m7G-related pathways to broader signaling networks that govern cancer plasticity and tumor microenvironment remodeling.

Conclusions

m7G RNA methylation represents a rapidly evolving frontier in cancer epigenetics. The METTL1/WDR4 methyltransferase complex and eIF4E translation initiation factor have emerged as central nodes connecting RNA modification to oncogenic signaling. Targeting m7G-dependent pathways holds considerable promise for the development of novel diagnostic biomarkers and therapeutic strategies. Continued exploration of this modification may ultimately expand the landscape of RNA-based precision oncology.

Key points

  • m7G-driven selective regulation exerts context-dependent, two-sided effects on tumour progression.
  • m7G modulates therapeutic response, shaping chemosensitivity and resistance.
  • m7G holds substantial clinical promise as a diagnostic/prognostic biomarker and a therapeutic target.
背景：RNA甲基化已成为塑造癌细胞生物学行为的转录后调控的关键层。在已确定的各种化学修饰中，如n6 -甲基腺苷（m6A）、n1 -甲基腺苷（m1A）、5-甲基胞嘧啶（m5C）、7-甲基鸟苷（m7G）、5-羟甲基胞嘧啶（5hmC）和2'- o -二甲基腺苷（m6Am）， m7G修饰最近引起了越来越多的关注。越来越多的证据表明，m7G甲基化在RNA代谢中起重要作用，并深刻影响癌症的发生和进展。主要主题：本综述综合了m7G RNA甲基化的生物学和临床意义的最新进展，特别关注其关键调控成分METTL1/WDR4和eIF4E。我们讨论了这些酶和结合蛋白如何协调m7G沉积和识别来调节致癌过程，包括细胞生长、分化、转移和治疗耐药性。此外，我们强调了将m7g相关通路与控制癌症可塑性和肿瘤微环境重塑的更广泛的信号网络联系起来的新证据。结论：m7G RNA甲基化代表了癌症表观遗传学快速发展的前沿。METTL1/WDR4甲基转移酶复合物和eIF4E翻译起始因子已成为连接RNA修饰与致癌信号传导的中心节点。靶向m7g依赖性通路对于开发新的诊断生物标志物和治疗策略具有相当大的前景。继续探索这种修饰可能最终扩大基于rna的精确肿瘤学的前景。关键点：m7g驱动的选择性调控对肿瘤进展具有上下文依赖的双边效应。m7G调节治疗反应，形成化疗敏感性和耐药性。m7G作为诊断/预后生物标志物和治疗靶点具有巨大的临床前景。
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引用次数: 0
CORRECTION: “[Immune cell subset profiling and metabolic dysregulation define the divergent immune microenvironments in HIV immunological non-responders]” 更正：“[免疫细胞亚群分析和代谢失调定义了HIV免疫无应答者的不同免疫微环境]”。
IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Clinical and Translational Medicine
Pub Date : 2025-11-09 DOI: 10.1002/ctm2.70522

[Chu Q, Fang N, Chen H, et al. Immune cell subset profiling and metabolic dysregulation define the divergent immune microenvironments in HIV immunological non-responders. Clin Transl Med. 2025;15(10):e70498. doi:10.1002/ctm2.70498]

[1. Adjustment of institutional affiliation order

We noticed that the order of institutional affiliations in the published version differs from our original submission. For consistency and accuracy, we kindly request that the following order be restored:

‘’Immune cell subset profiling and metabolic dysregulation define the divergent immune microenvironments in HIV immunological non-responders

Qingfei Chu1,2,3†, Ningye Fang4†, Huanhuan Chen4, Abdur Rashid5,6, Xia Luo1, Jianjun Li4*, Kang Li1,2,5*

1 Department of Microbiology, School of Basic Medicine, Guangxi Medical University, Nanning, Guangxi, China.

2 Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, China

3 Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China

4 Guangxi Key Laboratory of Major Infectious Disease Prevention Control and Biosafety Emergency Response, Guangxi Center for Disease Control and Prevention, Nanning, China

5 National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Chinese Center for Disease Control and Prevention, Beijing, China

6 Division of Infectious Disease & International Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA

† These authors contributed equally to this work.

Corresponding authors:

E-mail: [email protected] (J. Li); [email protected] (K. Li).]

2. Correction to the Author Contributions section

During the proofing process, an oversight occurred regarding the Author Contributions statement. We sincerely apologize for this error. The corrected version should read as follows:

“Kang Li, Jianjun Li and Qingfei Chu conceived and designed the research. Qingfei Chu, Ningye Fang and Huanhuan Chen performed experiments. Abdur Rashid and Xia Luo assisted with the statistical analyses. Qingfei Chu and Ningye Fang wrote the first draft of the article. Qingfei Chu, Ningye Fang, Huanhuan Chen, Abdur Rashid, Xia Luo, Jianjun Li and Kang Li reviewed and edited the manuscript. All authors have read and agreed to the final version of the manuscript.”

We apologize for this error.

褚强，方宁，陈华，等。免疫细胞亚群分析和代谢失调定义了HIV免疫无应答者不同的免疫微环境。中华临床医学杂志，2015;15(10):e70498。doi: 10.1002 / ctm2.70498][1。机构归属顺序调整我们注意到发表版本中的机构归属顺序与我们最初提交的不同。为了保持一致性和准确性，我们要求恢复以下顺序：“免疫细胞亚群分析和代谢失调定义了HIV免疫无应答者的不同免疫微环境。楚庆飞1,2,3†，方宁晔4†，陈欢欢4，Abdur rashid5,6，罗霞1，李建军4*，李康1,2,5*1广西医科大学基础医学院微生物学系，广西南宁2广西艾滋病防治重点实验室，广西南宁市；广西医科大学公共卫生学院，南宁530021 3浙江大学医学院第二附属医院感染性疾病科，杭州310009 4广西疾病预防控制中心广西重大传染病预防控制与生物安全应急重点实验室，广西南宁5传染病智能跟踪与预测国家重点实验室，6南佛罗里达大学莫尔萨尼医学院感染性疾病与国际医学分科，Tampa, FL 33612， USA†作者对本文贡献相同。通讯作者：E-mail: [email protected] (J. Li)；[email protected] （K. Li）。对作者贡献部分的更正在校对过程中，出现了关于作者贡献声明的疏忽。我们真诚地为这个错误道歉。更正后的版本应该是：“李康、李建军、褚庆飞构思并设计了这项研究。褚庆飞、方宁业和陈欢欢进行了实验。Abdur Rashid和Xia Luo协助进行统计分析。这篇文章的初稿是由褚庆飞和方宁业撰写的。褚庆飞、方宁业、陈欢欢、Abdur Rashid、罗霞、李建军、李康对稿件进行了审编。所有作者都已经阅读并同意了手稿的最终版本。”我们为这个错误道歉。
{"title":"CORRECTION: “[Immune cell subset profiling and metabolic dysregulation define the divergent immune microenvironments in HIV immunological non-responders]”","authors":"","doi":"10.1002/ctm2.70522","DOIUrl":"10.1002/ctm2.70522","url":null,"abstract":"<p>[Chu Q, Fang N, Chen H, et al. Immune cell subset profiling and metabolic dysregulation define the divergent immune microenvironments in HIV immunological non-responders. <i>Clin Transl Med</i>. 2025;15(10):e70498. doi:10.1002/ctm2.70498]</p><p>[<b>1. Adjustment of institutional affiliation order</b></p><p>We noticed that the order of institutional affiliations in the published version differs from our original submission. For consistency and accuracy, we kindly request that the following order be restored:</p><p>‘’Immune cell subset profiling and metabolic dysregulation define the divergent immune microenvironments in HIV immunological non-responders</p><p>Qingfei Chu<sup>1,2,3†</sup>, Ningye Fang<sup>4†</sup>, Huanhuan Chen<sup>4</sup>, Abdur Rashid<sup>5,6</sup>, Xia Luo<sup>1</sup>, Jianjun Li<sup>4*</sup>, Kang Li<sup>1,2,5*</sup></p><p>1 Department of Microbiology, School of Basic Medicine, Guangxi Medical University, Nanning, Guangxi, China.</p><p>2 Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, China</p><p>3 Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China</p><p>4 Guangxi Key Laboratory of Major Infectious Disease Prevention Control and Biosafety Emergency Response, Guangxi Center for Disease Control and Prevention, Nanning, China</p><p>5 National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Chinese Center for Disease Control and Prevention, Beijing, China</p><p>6 Division of Infectious Disease &amp; International Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA</p><p>† These authors contributed equally to this work.</p><p>Corresponding authors:</p><p>E-mail: [email protected] (J. Li); [email protected] (K. Li).]</p><p><b>2. Correction to the Author Contributions section</b></p><p>During the proofing process, an oversight occurred regarding the Author Contributions statement. We sincerely apologize for this error. The corrected version should read as follows:</p><p>“Kang Li, Jianjun Li and Qingfei Chu conceived and designed the research. Qingfei Chu, Ningye Fang and Huanhuan Chen performed experiments. Abdur Rashid and Xia Luo assisted with the statistical analyses. Qingfei Chu and Ningye Fang wrote the first draft of the article. Qingfei Chu, Ningye Fang, Huanhuan Chen, Abdur Rashid, Xia Luo, Jianjun Li and Kang Li reviewed and edited the manuscript. All authors have read and agreed to the final version of the manuscript.”</p><p>We apologize for this error.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 11","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12596985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145480923","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
Altered nicotinamide adenine dinucleotide metabolism drives cartilage degeneration and osteoarthritis 改变烟酰胺腺嘌呤二核苷酸代谢驱动软骨变性和骨关节炎。
IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Clinical and Translational Medicine
Pub Date : 2025-11-06 DOI: 10.1002/ctm2.70513
Xiaoxin Wu, Xiwei Fan, Manuel Plan, Terra Stark, Tim McCubbin, Roberto A. Barrero, Maria Marinova, Michael J. Bertoldo, Dale M. Goss, Lindsay E. Wu, Ross Crawford, Xinzhan Mao, Indira Prasadam

Background

We previously conducted a comprehensive survey of energy metabolism in osteoarthritis (OA), revealing significant reductions of nicotinamide adenine dinucleotide (NAD+) levels in OA cartilage. This study aimed to test whether NAD+ deficiency present in OA plays a mechanistic role in disease development.

Methods

We conducted integrative analyses across human, murine, and rat OA models to examine NAD⁺ metabolism and its regulatory enzymes. The impact of pharmacological NAD⁺ augmentation (via nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR)) and genetic overexpression of the NAD⁺ biosynthetic enzyme NMN adenosyltransferase (NMNAT1) was tested in surgical and aging-related OA models. Expression and function of the NAD⁺-consuming enzyme poly (ADP-ribose) polymerase 14 (PARP14) were examined via siRNA knockdown in chondrocytes under inflammatory conditions, coupled with metabolic assays and extracellular matrix gene profiling.

Results

NAD+ levels were decreased in human and murine OA, accompanied by upregulation of both the NAD+ biosynthetic enzyme Nicotinamide phosphoribosyltransferase (NAMPT) and the NAD+ consuming enzyme PARP14. While NAMPT expression was elevated, its effect on total NAD⁺ may be offset by increased NAD⁺ consumption or substrate limitation under inflammatory conditions. Treatment with NAD+ precursors and transgenic overexpression of NMNAT1 suppressed cartilage disruption during in aging murine and surgical rat model of OA. Increased expression of PARP14 in OA cartilage contributed to NAD+ decline and promoted cartilage degeneration.

Conclusions

This study reveals that dysregulated NAD⁺ metabolism, driven by increased PARP14 consumption, constitutes a potential mechanism underlying OA pathogenesis. Our findings support the concept that enhancing NAD⁺ availability via precursors or biosynthetic pathway modulation may offer disease-modifying effects at the molecular and histological level. Further investigation is needed to determine the functional and translational implications of targeting this pathway.

Key points

  • PARP14 is upregulated in OA cartilage and contributes to NAD⁺ depletion
背景：我们之前对骨关节炎（OA）的能量代谢进行了全面调查，发现OA软骨中烟酰胺腺嘌呤二核苷酸（NAD+）水平显著降低。本研究旨在测试OA中存在的NAD+缺乏是否在疾病发展中起机制作用。方法：我们对人类、小鼠和大鼠OA模型进行了综合分析，以检测NAD⁺的代谢及其调节酶。在手术和衰老相关OA模型中测试了药理学NAD +增强（通过烟酰胺单核苷酸（NMN）和烟酰胺核苷（NR））和NAD +生物合成酶NMN腺苷转移酶（NMNAT1）基因过表达的影响。通过siRNA敲除炎症条件下软骨细胞中的NAD +消耗酶聚（adp -核糖）聚合酶14 （PARP14）的表达和功能，结合代谢测定和细胞外基质基因谱检测。结果：人和小鼠OA中NAD+水平降低，NAD+生物合成酶烟酰胺磷酸核糖基转移酶（NAMPT）和NAD+消耗酶PARP14均上调。虽然NAMPT表达升高，但其对NAD⁺总量的影响可能被炎症条件下NAD⁺消耗增加或底物限制所抵消。NAD+前体和转基因过表达NMNAT1可抑制衰老小鼠和OA手术大鼠模型的软骨破坏。PARP14在OA软骨中的表达增加导致NAD+下降，促进软骨退变。结论：该研究表明，由PARP14消耗增加驱动的NAD⁺代谢失调是OA发病的潜在机制。我们的研究结果支持通过前体或生物合成途径调节提高NAD⁺的可用性可能在分子和组织学水平上提供疾病修饰作用的概念。需要进一步的研究来确定靶向这一途径的功能和翻译意义。关键点：PARP14在OA软骨中表达上调，导致NAD⁺耗竭。PARP14沉默恢复NAD +水平，抑制oa相关的代谢和基质降解变化。NAD +前体处理和NMNAT1过表达可防止衰老和创伤后OA模型软骨变性。
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引用次数: 0
DNA damage response pathway is a promising therapeutic target for extrachromosomal DNA-positive tumours DNA损伤反应途径是染色体外DNA阳性肿瘤的治疗靶点。
IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Clinical and Translational Medicine
Pub Date : 2025-11-05 DOI: 10.1002/ctm2.70519
Congcong Tian, Haiyun Gan
<p>Circular extrachromosomal DNA (ecDNA) is acentric, mobile, large, and highly accessible circular DNA, which contains genes or regulatory regions. ecDNAs are present in nearly half of human cancers, but not in normal cells.<span><sup>1, 2</sup></span> ecDNA content varies widely between tumour types and between individual tumours.<span><sup>3</sup></span> Multiple ecDNA species and subspecies can co-exist within a tumour population.<span><sup>4</sup></span> Even in the same tumour cell, the sequencing and structure of ecDNA varies.<span><sup>5</sup></span> As a result of acentric, ecDNA segregating asymmetrically to daughter cells leads to tumour heterogeneity and confers adaptation advantages to some of the tumour cells.<span><sup>3, 4</sup></span> Different ecDNA species carrying oncogenes, enhancers, or immunoregulatory genes interact with each other and are coordinately inherited.<span><sup>5</sup></span> The heterogeneity is further extended along with the dynamic evolution of ecDNA caused by structural rearrangement, DNA damage and recurrent mutations.<span><sup>4</sup></span> Due to its ability to evade chemo-, or target-therapy and form an immune-cold status, ecDNA in patient tumours drives tumour evolution, drug resistance, therapeutic escape, and leads to poor outcomes.<span><sup>3, 6</sup></span></p><p>The formation, maintenance, amplification, integration and elimination of ecDNA are related to drug resistance of cancer cells. Double minutes (DM) with the <i>DHFR</i> gene are induced by higher doses and long duration of MTX treatment and promote MTX resistance in colon cancer HT29 cells.<span><sup>7</sup></span> After withdrawal of the drug, DM with the <i>DHFR</i> gene disappeared accompanied with drug sensitivity restoration. Similarly, MAPK inhibitors can select ecDNAs carrying resistance genes in melanoma patients.<span><sup>8</sup></span> The existence of ecDNA brings obstructs to target treatment as well. Attempts to target EGFR in glioblastoma (GBM) have had minimal success in comparison to other tumours. The failure is contributed by the variability of ecDNA. Target treatment with EGFR inhibitor erlotinib to GBM loading mice relieved most cancer initially accompanied by the copy number and expression of EGFRvIII ecDNA reduction.<span><sup>9</sup></span> However, EGFR ecDNAs re-emerged rapidly upon drug withdrawal, resulting in erlotinib resistance. Coincidentally, temporary removal of pemigatinib, which could reduce amplified <i>FGFR2</i> expression and <i>FGFR2</i> ecDNAs, resulted in recovery of <i>FGFR2</i> and its co-segregated <i>MYC</i> ecDNA copy numbers.<span><sup>5</sup></span> The complexity and variability of ecDNA restrict the therapeutic effects against specific elements within ecDNAs. Thus, identifying vulnerabilities generated by ecDNA is a critical priority for ecDNA-directed oncology treatments.<span><sup>3</sup></span></p><p>ecDNAs are highly accessible chromatin with an altered gene-regulatory architecture
环状染色体外DNA （ecDNA）是无中心的，可移动的，大的，高度可接近的环状DNA，它包含基因或调控区域。ecdna存在于近一半的人类癌症中，但不存在于正常细胞中。1,2 ecDNA含量在不同肿瘤类型和个体肿瘤之间差异很大多个ecDNA种和亚种可以在肿瘤种群中共存即使在同一个肿瘤细胞中，ecDNA的序列和结构也各不相同由于无中心，ecDNA不对称地分离到子细胞导致肿瘤异质性，并赋予一些肿瘤细胞适应优势。携带癌基因、增强子或免疫调节基因的不同ecDNA物种相互作用并协调遗传随着结构重排、DNA损伤和反复突变引起的ecDNA的动态演化，异质性进一步扩大由于其能够逃避化疗或靶向治疗并形成免疫冷状态，患者肿瘤中的ecDNA驱动肿瘤进化，耐药，治疗逃逸，并导致不良预后。3,6 ecDNA的形成、维持、扩增、整合和消除与癌细胞的耐药有关。高剂量和长时间的MTX治疗可诱导DHFR基因双分钟（Double minutes， DM），并促进MTX在结肠癌HT29细胞中的耐药停药后，伴有DHFR基因的DM消失，药敏恢复。同样，MAPK抑制剂可以选择黑色素瘤患者携带耐药基因的ecdnaecDNA的存在也给靶向治疗带来了障碍。与其他肿瘤相比，在胶质母细胞瘤（GBM）中靶向EGFR的尝试收效甚微。失败的原因是ecDNA的可变性。EGFR抑制剂厄洛替尼对GBM负荷小鼠的靶向治疗最初缓解了大多数癌症，并伴有EGFRvIII ecDNA拷贝数和表达的减少然而，EGFR ecdna在停药后迅速重新出现，导致厄洛替尼耐药。巧合的是，暂时去除可以减少扩增的FGFR2表达和FGFR2 ecDNA的pemigatinib，导致FGFR2及其共分离的MYC ecDNA拷贝数的恢复ecDNA的复杂性和可变性限制了针对ecDNA中特定元素的治疗效果。因此，识别由ecDNA产生的脆弱性是ecDNA导向肿瘤治疗的关键优先事项。3ecdna是一种高度可接近的染色质，由于其圆形结构而改变了基因调控结构，并且易于形成促进分子间合作的枢纽，产生高水平的致癌转录。ecDNA每个细胞周期复制一次，并在ecDNA+细胞中稳定维持。5,10由于ecDNA的高水平转录引起的转录-复制冲突诱导了ecDNA的复制应激。值得注意的是，与新生ecDNA相关的蛋白质在DNA修复途径中富集，表明DNA损伤反应（DDR）在ecDNA维持和复制中的重要作用拓扑异构酶（TOP1和TOP2B）消除了DNA转录和DNA复制过程中的拓扑应力，是ecDNA复制诱导的DNA双链断裂（DSBs）的重要来源，也是ecDNA诱导的DDR.10的关键调控因子，LIG3和其他与非同源末端连接（alt-NHEJ）途径相关的关键因子，而不是同源重组（HR）或NHEJ途径，对ecDNA的维持至关重要进一步对ecDNA±肿瘤细胞的细胞毒性分析表明，atm介导的DDR是治疗ecDNA+肿瘤的一个有希望的治疗靶点。敲低或抑制TOP1或TOP2B可显著降低ecDNA水平，增加HSR信号。10 .使用ATM抑制剂（ATMi）或检查点激酶蛋白抑制剂（CHKi）可以成功抑制ecDNA+细胞中的DDR通路，从而显著降低ecDNA的拷贝数令人鼓舞的是，尽管各种ecDNA+细胞中的ecDNA种类不同，但它们对靶向ATM、CHK2和TOP1的药物的敏感性都有广泛的提高同样，由于高复制应激，ecDNA+细胞对CHK1抑制也高度敏感简而言之，ecDNA的维持需要DDR，抑制DDR会损害ecDNA的循环，促进ecDNA+癌细胞的死亡。（参见图1）。值得注意的是，化疗和放疗导致多种形式的DNA损伤，随后激活多种DDR通路，进一步促进放射耐药和化疗耐药。12,13治疗诱导的DDR通路激活在ecDNA+肿瘤细胞中具有更深层次的生物学意义。 DDR不仅保证基因组复制，支持细胞周期和分裂，还负责ecDNA的维持和扩增，为处于绝境的癌细胞提供了更多的生存机会。ecDNA+细胞的DNA损伤程度与治疗诱导的相当。然而，ecDNA+细胞更倾向于出错的alt-NHEJ而不是HR或NHEJ来响应广泛的DNA损伤，使得修复过程不受细胞周期阶段的限制，形成更多的ecDNA亚种，进一步推动肿瘤的进化。多种DDR抑制剂已被证明在癌症治疗中是有益的，无论是单独治疗还是与化疗和放疗联合使用。12,13靶向DDR过程可诱导过度的DNA损伤，增强细胞毒治疗的效果，最终导致癌细胞死亡。12,13 ATMi， CHK1/2i已被证明通过损害DNA修复使癌细胞对化疗和放疗敏感，从而提高治疗效果TOP1和TOP2抑制剂通过扭转应力的积累，触发DDR通路和快速增殖癌细胞的凋亡，也被用于治疗实体瘤和血液系统恶性肿瘤的一线。14,15 TOP1抑制剂与DDR抑制剂合用可进一步增强抗肿瘤效果我们的研究结果表明，靶向atm介导的DDR（特别是alt-NHEJ）或拓扑异构酶（TOP1和TOP2B）对ecDNA+肿瘤细胞的治疗效果要好得多。不同的是，在ecDNA+癌细胞中，靶向DDR治疗降低了DNA损伤水平，而不是积累未修复的DNA。10 DNA损伤信号的减少可能是ecDNA整合和消除的继发作用，而不是靶向DDR药物的直接作用。患者选择对这些抑制剂的临床应用至关重要。我们的研究结果表明，在ATM、CHK1/2、TOP1/2B、LIG3和Polθ抑制剂的临床试验中，值得考虑纳入ecDNA患病率较高的肿瘤类型（如脂肪肉瘤、GBM、HER2+乳腺癌），这可能会产生意想不到的治疗效果。考虑到ecDNA的动态性质和异质性，靶向携带癌基因的ecDNA或其编码蛋白是具有挑战性的。然而，atm介导的DDR对于ecdna的维持和复制至关重要，这为ecdna驱动的癌症创造了治疗脆弱性。这些靶标提供了消除ecdna的机会，无论其来源、种类或在患者肿瘤中的分布如何。然而，当DDR抑制剂单独使用时，ecDNA整合或消除的趋势限制了其作为单一疗法的应用。靶向DDR通路可与其他靶向治疗、免疫治疗、化疗或放疗联合使用，是未来有希望的方向。10 .甘海云构思并设计了该项目。田聪聪写了手稿，画了示意图。作者声明无利益冲突。本文不涉及伦理问题。
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引用次数: 0
Progression significance for low-level aberrant B-lymphoblasts in chronic myeloid leukaemia patients 慢性髓性白血病患者低水平异常b淋巴细胞的进展意义。
IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Clinical and Translational Medicine
Pub Date : 2025-11-05 DOI: 10.1002/ctm2.70524
Haoren Wang, Huijun Wang, Yuanyuan Li, Bin Zheng, Qiuyun Fang, Yan Li, Yuntao Liu, Runxia Gu, Ying Wang, Yingchang Mi, Bingcheng Liu, Hui Wei, Jianxiang Wang
<p>Dear Editor,</p><p>Chronic myeloid leukaemia (CML) patients with progression events face limited treatment response and dismal survival.<span><sup>1</sup></span> However, the 2022 World Health Organization leaves an ambiguous threshold of the rate of lymphoblasts for blast crisis.<span><sup>2</sup></span> Otherwise, several studies reported conflicting outcomes for patients with low levels of aberrant B-lymphoblasts (ABLB), with El Rassi et al. and Vijayasekharan et al. reporting that low levels of ABLB associated with rapid progression to blast crisis,<span><sup>3, 4</sup></span> while Vrotsos et al. and Soma et al. observing sustained deep molecular responses under tyrosine kinase inhibitor (TKI) therapy.<span><sup>5, 6</sup></span> To explore the prognostic significance of low levels of ABLB, this study systematically evaluated the clinical characteristics and treatment response of 16 patients with low levels of ABLB and determined the cutoff value of ABLB associated with disease progression, providing a new risk factor for progression in CML patients and optimising risk-adapted therapeutic decisions.</p><p>Among 802 chronic phase-CML (CP-CML) patients who underwent flow cytometry (FCM) analysis at the time of diagnosis, 16 (2.0%) had a low level of ABLB, which was defined as <5%, in line with the 2022 International Consensus Classification (ICC) guideline that morphologically apparent lymphoblasts >5% should prompt consideration of lymphoblastic crisis.<span><sup>7</sup></span> The level of ABLB ranges from .01% to 4.69%, and 10 of them experienced progression events. Of these 16 patients, eight were male, and their ages ranged from 15 to 76 years. Only one patient (case 7), a 57-year-old male, was classified as high-risk according to Sokal and EUTOS long-term survival (ELTS) scores. No additional high-risk factors revealed for the drug resistance or progression occurring (Table S1). The immunophenotype of abnormal cells is shown in Table S2. Particular attention should be paid to B progenitors in FCM reports, as aberrant B lymphoblasts may exhibit immunophenotypic features closely resembling those of B progenitors, making them easily confused.</p><p>These 16 patients were included as a training group for the analysis of the cutoff value of ABLB associated with progression, and 18 patients from five reported studies<span><sup>3-6, 8</sup></span> were included as a validation group (ABLB levels range from .006% to 3.4%; Table S3). Among the total of 34 patients, those with progression events had higher levels of ABLB compared to those without progression events (<i>p </i>= .0225; Figure 1A). The area under the ROC curve was 86.4912 (Figure 1B), indicating a significant association between ABLB levels and the risk of progression. The cutoff value for ABLB was confirmed as .2% by the surv_cutpoint function. Patients with ≤.2% ABLB exhibited significantly longer progression-free survival than those with higher ABLB levels in the train
慢性髓性白血病（CML）进展事件患者面临有限的治疗反应和惨淡的生存然而，2022年世界卫生组织留下了一个模糊的淋巴母细胞率临界值此外，一些研究报告了低水平异常b淋巴细胞（ABLB）患者的相互矛盾的结果，El Rassi等人和Vijayasekharan等人报告说，低水平的异常b淋巴细胞与快速进展到原细胞危像有关，3,4而Vrotsos等人和Soma等人观察到酪氨酸激酶抑制剂（TKI）治疗下持续的深层分子反应。5,6为探讨低水平ABLB的预后意义，本研究系统评估了16例低水平ABLB患者的临床特征和治疗反应，确定了ABLB与疾病进展相关的临界值，为CML患者进展提供了新的危险因素，优化了风险适应的治疗决策。在诊断时接受流式细胞术（FCM）分析的802例慢性期cml （CP-CML）患者中，16例（2.0%）ABLB水平低，定义为5%，符合2022年国际共识分类（ICC）指南，即形态上明显的淋巴母细胞5%应提示考虑淋巴母细胞危象7ABLB的水平从。从1%到4.69%，其中10人经历了进展事件。16例患者中，男性8例，年龄15 ~ 76岁。根据Sokal和EUTOS长期生存（ELTS）评分，只有1例患者（病例7），57岁男性，被归为高风险。未发现其他导致耐药或进展的高危因素（表S1）。异常细胞的免疫表型见表S2。在流式细胞术报告中应特别注意B祖细胞，因为异常B淋巴细胞可能表现出与B祖细胞非常相似的免疫表型特征，使它们容易混淆。这16例患者被纳入训练组，用于分析ABLB与进展相关的临界值，来自5项已报道研究的18例患者被纳入验证组(ABLB水平范围从。006%至3.4%；表S3)。在34例患者中，有进展事件的患者的ABLB水平高于无进展事件的患者（p = 0.0225；图1A）。ROC曲线下面积为86.4912（图1B），表明ABLB水平与进展风险之间存在显著相关性。确认ABLB的截止值为。2%由surv_cutpoint函数。ABLB≤0.2%患者的无进展生存期分别明显长于训练组（p = 0.011，图1C）和验证组（p = 0.044，图1D）。考虑到TKI方案对解释ABLB的预后价值很重要，我们进一步进行了分层Cochran-Mantel-Haenszel分析，以解决治疗可能引起的混淆。经TKI治疗后，这种相关性仍然显著（Mantel-Haenszel χ2 = 9.312, p = 0.002）。层特异性优势比的同质性检验不显著（Breslow-Day检验，p = 0.176； Tarone检验，p = 0.188），表明本数据集中未观察到治疗对效果的影响。常见的Mantel-Haenszel优势比为24.238(95%可信区间2.803-209.575;p = 0.004)，表明ABLB患者的进展几率显著高于≤0.2%。ABLB与TKI方案分层进展之间的关系见表S4。进一步详细介绍我中心16例患者的治疗方案（表1）。在这些患者中，5例ABLB≤0.2%，均未发生进展事件。然而，其中两个遇到了失败事件。其中一个是ABLB。在尼罗替尼治疗第16个月时，12%的患者BCR::ABL1水平大于1%，其余患者ABLB为。到21个月时，2%的患者没有达到完全细胞遗传学缓解（CCyR），这表明对ABLB患者实现令人满意的治疗反应是具有挑战性的。在11例ABLB患者中，10例发生进展事件，其中3例死亡。爆发转化的中位时间为3个月，从检测到ABLB的时间范围为1-41个月（表2）。唯一无进展事件的患者ABLB为1.69%。由于CCyR的快速丧失，该患者改用Olverembatinib联合VP方案。在获得主要分子反应（MMR）后，患者接受了同种异体造血干细胞移植（alloo - hsct）并最终实现了长期无病生存。在这项研究中，所有的ABLB评估都是在基线进行的，大多数进展事件发生在第一个治疗分子里程碑之前（3个月）。 因此，我们将ABLB定位为基线风险标志物，但强化治疗似乎可以减轻。与ABLB水平较高的患者相比，ABLB≤0.2%的患者表现出较低的进展发生率，但仍存在有意义的失败风险；因此，第二代TKIs可能是实现快速疾病控制的最佳一线治疗。另一方面，ABLB患者对单药TKIs的反应有限。因此，我们推荐基于第二代TKIs的联合治疗，例如TKIs与VP方案联合使用。此外，应考虑采用同种异体造血干细胞移植来降低进展事件的风险（表2）。本研究受限于适度的队列规模，这限制了统计能力和调整分析的稳健性。虽然我们包括了一个外部队列的运输，总样本仍然不足以确定的推断。因此，需要进行多中心前瞻性研究来验证这些结论和建议。总的来说，诊断为ABLB的患者有很高的进展风险。因此，在诊断时用流式细胞仪检测ABLB对于识别高危进展为BP的个体和通过适当治疗改善患者预后是一个有价值的过程。形式分析、调查和写作——原稿：王浩仁。调查与数据管理：王慧军。验证：李媛媛，郑斌。调查：方秋云、李燕、刘云涛。调研及资金获取：顾润霞。验证与调查：王颖、米应昌。验证、撰稿编辑、监督：刘炳成。监督：慧伟。概念化、资金获取与监管：王建祥。本回顾性研究经血液学与血液病医院研究所伦理委员会批准（IIT2019004-EC-1）。
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引用次数: 0
Exploring the mechanisms of mutual influence between lactylation and macrophage polarization in the context of disease 探讨疾病背景下乳酸化与巨噬细胞极化相互影响的机制。
IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Clinical and Translational Medicine
Pub Date : 2025-11-05 DOI: 10.1002/ctm2.70499
Houhua Guo, Nannan Luan, Jian Gao, Xiaoao Pang, Jianlei Bi, Liancheng Zhu

Background

Lactylation, a post-translational alteration facilitated by lactic acidderived lactyl-CoA, has emerged as an epigenetic regulator that alters gene expression in macrophages. Emerging data situates lactylation at the nexus of metabolic flux and immune cell destiny, especially in tumor and inflammatory microenvironments.

Main text

Lactylation is significantly linked to tumor progression and the polarization of macrophages towards the M2 phenotype, a condition that exacerbates cancer and associated inflammation. Modulating lactylation levels can alter the M1/M2 balance, hence affecting the progression of cancer and inflammatory illnesses. These findings identify lactylation as aregulator that can either suppress or enhance tumor development and the related inflammatory response, contingent upon the context and degree of the change.

Conclusion

This review systematically elucidates the role of lactylation in directing macrophage polarization in the context of cancer and associated inflammation. The aggregated data suggest that targeting lactylation constitutes an innovative therapeutic strategy for regulating immune cell activity and managing the advancement of cancer and related inflammatory conditions.

Key points

  • The conversion of lactate to lactyl-CoA facilitates enzymatic histone lactylation, transforming glycolytic byproducts into an epigenetic regulatory mechanism for gene expression.
  • Lactylation modification influences macrophage polarization towards M1 or M2 phenotypes, affecting outcomes in infection, cancer, and fibrosis.
  • Targeting lactylation modifiers through pharmacological means introduces a novel metabolic-epigenetic approach for treating disorders.
背景：乳酸酰化是一种由乳酸衍生的乳酸辅酶a促进的翻译后改变，已成为巨噬细胞中改变基因表达的表观遗传调节剂。新出现的数据表明，乳酸化是代谢通量和免疫细胞命运的纽带，特别是在肿瘤和炎症微环境中。主要内容：乳酸化与肿瘤进展和巨噬细胞向M2表型的极化显著相关，而M2表型会加剧癌症和相关炎症。调节乳酸化水平可以改变M1/M2平衡，从而影响癌症和炎症性疾病的进展。这些发现确定了乳酸化作为一种调节因子，可以抑制或增强肿瘤的发展和相关的炎症反应，这取决于变化的背景和程度。结论：本综述系统地阐明了在癌症和相关炎症的背景下，乳酸化在指导巨噬细胞极化中的作用。综合数据表明，靶向乳酸化是调节免疫细胞活性和控制癌症及相关炎症进展的一种创新治疗策略。乳酸转化为乳酸辅酶a促进酶促组蛋白乳酸化，将糖酵解副产物转化为基因表达的表观遗传调控机制。乳酸化修饰影响巨噬细胞向M1或M2表型的极化，影响感染、癌症和纤维化的结果。通过药理学手段靶向乳酸化修饰剂引入了一种新的代谢-表观遗传学方法来治疗疾病。
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引用次数: 0
CLINICAL AND TRANSLATIONAL MEDICINE 临床和转化医学
IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Clinical and Translational Medicine
Pub Date : 2025-11-03 DOI: 10.1002/ctm2.70523
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引用次数: 0
Clinical application of single-cell RNA sequencing in disease and therapy 单细胞RNA测序在疾病和治疗中的临床应用
IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Clinical and Translational Medicine
Pub Date : 2025-10-31 DOI: 10.1002/ctm2.70512
Aisha Shigna Nadukkandy, Sowmiya Kalaiselvan, Lin Lin, Yonglun Luo

Background

The emergence of single-cell RNA sequencing (scRNA-seq) technology has revolutionized our capacity to study cell functions in complex tissue microenvironments. Traditional transcriptomic approaches, such as microarrays and bulk RNA sequencing, lacked the resolution to distinguish signals from heterogeneous cell populations or rare cell types, limiting their clinical utility. Since 2009, scRNA-seq has evolved as a new and powerful tool for revisiting somatic evolution and functions under physiological or pathological conditions.

Main Topics Covered

This review focus on elaborating on the clinical applications of scRNA-seq technology, with a particular emphasis on the application of scRNA-seq methods in revisiting the somatic cell evolution in human diseases. We further provide a snapshot of the scRNA-seq applications in biomarker discovery and drug development, current challenges associated with the technology, and future directions.

Conclusions

With the recent progresses in single cell and spatial transcriptome technologies, scRNA-seq enables a deeper understanding of the complexity of human diseases. The integration of AI and machine learning algorithms into big data analysis offers hope for overcoming these hurdles, potentially allowing scRNA-seq and multi-omics approaches to bridge the gap in our understanding of complex biological systems and advances the development of precision medicine.

Highlights

  • This review provides a systematic overview of the application of scRNA-seq technology in understanding of disease mechanisms.
  • We cover applications in respiratory diseases, metabolic disorders, cardiovascular diseases, cancers, autoimmune and auto-inflammatory diseases, neurodegenerative diseases, and infectious diseases.
  • This review also explores promises and challenges for the emerging application of scRNA-seq in drug discovery.
单细胞RNA测序（scRNA-seq）技术的出现彻底改变了我们在复杂组织微环境中研究细胞功能的能力。传统的转录组学方法，如微阵列和大量RNA测序，缺乏分辨异质细胞群或罕见细胞类型信号的分辨率，限制了它们的临床应用。自2009年以来，scRNA-seq已经发展成为一种新的强大工具，用于重新审视生理或病理条件下的体细胞进化和功能。本综述重点阐述了scRNA-seq技术的临床应用，特别强调了scRNA-seq方法在重新审视人类疾病中的体细胞进化中的应用。我们进一步提供了scRNA-seq在生物标志物发现和药物开发中的应用，与该技术相关的当前挑战和未来方向的快照。随着单细胞和空间转录组技术的发展，scRNA-seq技术使我们能够更深入地了解人类疾病的复杂性。将人工智能和机器学习算法集成到大数据分析中，为克服这些障碍提供了希望，有可能使scRNA-seq和多组学方法弥合我们对复杂生物系统理解的差距，并推动精准医学的发展。本综述系统综述了scRNA-seq技术在了解疾病机制中的应用。我们涵盖了呼吸系统疾病、代谢紊乱、心血管疾病、癌症、自身免疫性和自身炎症性疾病、神经退行性疾病和传染病的应用。本文还探讨了scRNA-seq在药物发现中的应用前景和挑战。
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