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LcProt: Proteomics-based identification of plasma biomarkers for lung cancer multievent, a multicentre study LcProt:基于蛋白质组学的肺癌多事件血浆生物标志物鉴定,一项多中心研究。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-09 DOI: 10.1002/ctm2.70160
Hengrui Liang, Runchen Wang, Ran Cheng, Zhiming Ye, Na Zhao, Xiaohong Zhao, Ying Huang, Zhanpeng Jiang, Wangzhong Li, Jianqi Zheng, Hongsheng Deng, Yu Jiang, Yuechun Lin, Yun Yan, Lei Song, Jie Li, Xin Xu, Wenhua Liang, Jun Liu, Jianxing He
<div> <section> <h3> Background</h3> <p>Plasma protein has gained prominence in the non-invasive predicting of lung cancer. We utilised Zeolite Zotero NaY-based plasma proteomics to investigate its potential for multiple event predicting, including lung cancer diagnosis (task #1), lymph node metastasis detection (task #2) and tumour‒node‒metastasis (TNM) staging (task #3).</p> </section> <section> <h3> Methods</h3> <p>A total of 4703 plasma proteins were quantified from 241 participants based on a prospective cohort of 2757 participants. An additional 46 participants from external prospective cohort of 735 participants were used for validation. Feature selection was performed using differential expressed protein analysis, area under curve (AUC) evaluation and least absolute shrinkage and selection operator (LASSO) regression. Random forest was used for multitask model construction based on the key proteins. Feature importance was interpreted using Shapley additive explanations (SHAP) algorithm.</p> </section> <section> <h3> Results</h3> <p>For task #1, 10 proteins panel showed an AUC of .87 (.77‒.97) in the external validation. After integrating clinical factors, a significant increase diagnostic accuracy was observed with AUC of .91 (.85‒.98). For task #2, nine proteins panel achieved an AUC of .88 (.80‒.96), integration model showed an increase diagnostic accuracy with AUC of .90 (.85‒.97). For task #3, 10 proteins panel showed an AUC of .88 (.74‒.96) for stage I, .92 (.84‒.97) for stage II, .88 (.76‒.96) for stage III and .99 (.98‒.99) for stage IV in the integration model.</p> </section> <section> <h3> Conclusions</h3> <p>This study comprehensively profiled the NaY-based plasma proteome biomarker, laying the foundation for a high-performance blood test for predicting multiple events in lung cancer.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li> <p>Our study developed an innovative nanomaterial, Zeolite NaY, which addressed the masking effect and improved the depth of the proteome.</p> </li> <li> <p>The performance of NaY-based plasma proteomics as a preclinical diagnostic tool was validated through both internal and external cohort.</p> </li> <li> <p>Furthermore, we explore
背景:血浆蛋白在肺癌的无创预测中占有重要地位。我们利用基于Zeolite Zotero ny的血浆蛋白质组学来研究其在多事件预测方面的潜力,包括肺癌诊断(任务1)、淋巴结转移检测(任务2)和肿瘤淋巴结转移(TNM)分期(任务3)。方法:基于2757名参与者的前瞻性队列,对241名参与者的4703种血浆蛋白进行定量分析。另外从外部前瞻性队列735名参与者中选取46名参与者进行验证。使用差异表达蛋白分析、曲线下面积(AUC)评估和最小绝对收缩和选择算子(LASSO)回归进行特征选择。基于关键蛋白,采用随机森林方法构建多任务模型。特征重要性采用Shapley加性解释(SHAP)算法进行解释。结果:对于任务#1,10个蛋白面板在外部验证中显示AUC为0.87(0.77 - 0.97)。综合临床因素后,诊断准确率显著提高,AUC为0.91(0.85 - 0.98)。对于任务#2,9个蛋白质面板的AUC为0.88(0.80 - 0.96),整合模型显示诊断准确性提高至0.90(0.85 - 0.97)。对于任务#3,在整合模型中,10个蛋白质面板显示阶段I的AUC为0.88(0.74 - 0.96),阶段II的AUC为0.92(0.84 - 0.97),阶段III的AUC为0.88(0.76 - 0.96),阶段IV的AUC为0.99(0.98 - 0.99)。结论:本研究全面分析了基于nay的血浆蛋白质组生物标志物,为预测肺癌多种事件的高性能血液检测奠定了基础。我们的研究开发了一种创新的纳米材料,分子筛NaY,它解决了掩盖效应,提高了蛋白质组的深度。通过内部和外部队列验证了基于nay的血浆蛋白质组学作为临床前诊断工具的性能。此外,我们探索了肺癌进展过程中血浆蛋白的不同变化模式,并利用解释方法阐明了蛋白在多任务预测模型中的作用。
{"title":"LcProt: Proteomics-based identification of plasma biomarkers for lung cancer multievent, a multicentre study","authors":"Hengrui Liang,&nbsp;Runchen Wang,&nbsp;Ran Cheng,&nbsp;Zhiming Ye,&nbsp;Na Zhao,&nbsp;Xiaohong Zhao,&nbsp;Ying Huang,&nbsp;Zhanpeng Jiang,&nbsp;Wangzhong Li,&nbsp;Jianqi Zheng,&nbsp;Hongsheng Deng,&nbsp;Yu Jiang,&nbsp;Yuechun Lin,&nbsp;Yun Yan,&nbsp;Lei Song,&nbsp;Jie Li,&nbsp;Xin Xu,&nbsp;Wenhua Liang,&nbsp;Jun Liu,&nbsp;Jianxing He","doi":"10.1002/ctm2.70160","DOIUrl":"10.1002/ctm2.70160","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;Plasma protein has gained prominence in the non-invasive predicting of lung cancer. We utilised Zeolite Zotero NaY-based plasma proteomics to investigate its potential for multiple event predicting, including lung cancer diagnosis (task #1), lymph node metastasis detection (task #2) and tumour‒node‒metastasis (TNM) staging (task #3).&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;A total of 4703 plasma proteins were quantified from 241 participants based on a prospective cohort of 2757 participants. An additional 46 participants from external prospective cohort of 735 participants were used for validation. Feature selection was performed using differential expressed protein analysis, area under curve (AUC) evaluation and least absolute shrinkage and selection operator (LASSO) regression. Random forest was used for multitask model construction based on the key proteins. Feature importance was interpreted using Shapley additive explanations (SHAP) algorithm.&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;For task #1, 10 proteins panel showed an AUC of .87 (.77‒.97) in the external validation. After integrating clinical factors, a significant increase diagnostic accuracy was observed with AUC of .91 (.85‒.98). For task #2, nine proteins panel achieved an AUC of .88 (.80‒.96), integration model showed an increase diagnostic accuracy with AUC of .90 (.85‒.97). For task #3, 10 proteins panel showed an AUC of .88 (.74‒.96) for stage I, .92 (.84‒.97) for stage II, .88 (.76‒.96) for stage III and .99 (.98‒.99) for stage IV in the integration model.&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 comprehensively profiled the NaY-based plasma proteome biomarker, laying the foundation for a high-performance blood test for predicting multiple events in lung cancer.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;Our study developed an innovative nanomaterial, Zeolite NaY, which addressed the masking effect and improved the depth of the proteome.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;The performance of NaY-based plasma proteomics as a preclinical diagnostic tool was validated through both internal and external cohort.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;Furthermore, we explore","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11714244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945530","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
Nanopore adaptive sampling accurately detects nucleotide variants and improves the characterization of large-scale rearrangement for the diagnosis of cancer predisposition 纳米孔自适应采样准确地检测核苷酸变异,并提高了癌症易感性诊断的大规模重排特征。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-09 DOI: 10.1002/ctm2.70138
Sandy Chevrier, Corentin Richard, Marie Mille, Denis Bertrand, Romain Boidot

Background

Molecular diagnosis has become highly significant for patient management in oncology.

Methods

Here, 30 well-characterized clinical germline samples were studied with adaptive sampling to enrich the full sequence of 152 cancer predisposition genes. Sequencing was performed on Oxford Nanopore (ONT) R10.4.1 MinION flowcells with the Q20+ chemistry.

Results

In our cohort, 11 samples had large-scale rearrangements (LSR), which were all detected with ONT sequencing. In addition to perfectly detecting the locus of the LSR, we found a known MLPA amplification of exon 13 in the BRCA1 (NM_7294) gene corresponded to a duplication in tandem of both exons 12 and 13 of the reference NM_7300. Similarly, in another sample with a known total deletion of the BRCA1 gene, ONT sequencing highlighted this complete deletion was the consequence of a large deletion of almost 140 000 bp carrying over five different genes. ONT sequencing was also able to detect all pathogenic nucleotide variants present in 16 samples at low coverage. As we analyzed complete genes and more genes than with short-read sequencing, we detected novel unknown variants. We randomly selected six new variants with a coverage larger than 10× and an average quality higher than 14, and confirmed all of them by Sanger sequencing, suggesting that variants detected with ONT (coverage >10× and quality score >14) could be considered as real variants.

Conclusions

We showed that ONT adaptive sampling sequencing is suitable for the analysis of germline alterations, improves characterization of LSR, and detects single nucleotide variations even at low coverage.

Key points

  • Adaptive sampling is suitable for the analysis of germline alterations.
  • Improves the characterization of Large Scale Rearrangement and detects SNV at a minimum coverage of 10x.
  • Allows flexibility of sequencing.
背景:分子诊断在肿瘤患者管理中已经变得非常重要。方法:本研究采用自适应取样方法对30例具有良好特征的临床种系样本进行研究,以丰富152个癌症易感基因的全序列。采用Q20+化学方法对Oxford Nanopore (ONT) R10.4.1 MinION流式细胞进行测序。结果:在我们的队列中,11个样本存在大规模重排(LSR),均通过ONT测序检测到。除了完美地检测到LSR位点外,我们还发现BRCA1 (NM_7294)基因外显子13的已知MLPA扩增与参考基因NM_7300的外显子12和13的串联重复相对应。同样,在另一个已知BRCA1基因完全缺失的样本中,ONT测序强调了这种完全缺失是携带5种不同基因的近140,000 bp的大缺失的结果。ONT测序还能够在低覆盖率下检测到16个样本中存在的所有致病性核苷酸变异。当我们分析完整的基因和比短读测序更多的基因时,我们发现了新的未知变异。我们随机选择了6个覆盖率大于10倍、平均质量大于14的新变异,并通过Sanger测序对其进行了确认,表明ONT检测到的变异(覆盖率为10倍,质量评分为14分)可以被认为是真正的变异。结论:我们发现ONT自适应采样测序适用于种系改变的分析,提高了LSR的表征,即使在低覆盖率下也能检测到单核苷酸变异。重点:自适应取样适用于种系改变的分析。改进了大规模重排的特性,并在最小覆盖率为10倍的情况下检测SNV。允许排序的灵活性。
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引用次数: 0
Machine learning-based multi-omics models for diagnostic classification and risk stratification in diabetic kidney disease 基于机器学习的多组学模型用于糖尿病肾病的诊断分类和风险分层。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-08 DOI: 10.1002/ctm2.70133
Xian Shao, Suhua Gao, Pufei Bai, Qian Yang, Yao Lin, Mingzhen Pang, Weixi Wu, Lihua Wang, Ying Li, Saijun Zhou, Hongyan Liu, Pei Yu
<p>Dear Editor,</p><p>The global prevalence of chronic kidney disease (CKD) is about 10%.<span><sup>1</sup></span> Diabetic kidney disease (DKD) has emerged as the leading cause of end-stage renal failure.<span><sup>2</sup></span> Early identification of DKD is important for improving the survival rate and improving the quality of life. However, the preclinical stages of DKD may lack obvious symptoms and non-invasive biomarkers.<span><sup>3</sup></span> Through blood lipidomics, urine proteomics and metabolomics technologies, potential DKD markers are identified to establish an accurate early warning model for DKD. We aim to provide effective tools for the individualised prevention of DKD, and help to explain the associations between different molecules and their risk of DKD from multiple perspectives. The methods of study are shown in Appendix 1.</p><p>Figure 1 illustrates the overview of the common and unique changes in proteomics pathways observed at various stages of DKD. The pathways reflected the active biological processes closely related to multi-omics during the development of DKD. Potential proteomic biomarkers were identified through a multi-level screening process, with a comprehensive score used to assess their significance (Appendix 1). Finally, CD300LF, CST4, MMRN2, SERPINA14, L-glutamic acid dimethyl ester (DLG) and phosphatidylcholine (PC) were selected. The results of study are provided in Appendix 2.</p><p>The cross-sectional study included a total of 1500 patients (Figure S2 and Appendix 1). Patients were categorised into four groups: healthy control (HC, 30), type 2 diabetes mellitus (T2DM, 361), high-risk DKD (HR-DKD, 555) and DKD group (554). Baseline patient information is detailed in Appendix 2. The patients were categorised into two groups: a training and a test set (3:1). A total of seven prediction models for diagnosis classification were established, with the included indicators provided in Table S17 and Appendix 2. The integration of clinical indicators with multi-omics indicators resulted in a substantial accuracy improvement (Accuracy = .923 [.893, .947]; Figure 2A–G). This integrated model was the most effective, with improved performance across all metrics, including area under the curve (AUC), sensitivity, specificity and accuracy. Additionally, the study utilised a total of 12 machine learning algorithms, all of which achieved AUC values above .940 (Figure 2H).</p><p>The prospective cohort study involved 919 patients, with a median follow-up duration of 1.07 years. Based on the clinical and multi-omics indicators, three risk-prognostic prediction models were developed: the biomarker model (Model 1), clinical indicators model (Model 2) and integrated model (Model 3). The specific indicators used are detailed in Table S22 and Appendix 2. Figure 2I displays the AUC curves of these models, with Model 3 achieving the highest AUC of .813. A risk score was calculated using Model 3 (score cut-off = 1.06; Figure 2J). In
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引用次数: 0
Immunoregulatory programs in anti-N-methyl-D-aspartate receptor encephalitis identified by single-cell multi-omics analysis 单细胞多组学分析鉴定抗n -甲基- d -天冬氨酸受体脑炎的免疫调节程序。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-08 DOI: 10.1002/ctm2.70173
Xinhui Li, Yicong Xu, Weixing Zhang, Zihao Chen, Dongjie Peng, Wenxu Ren, Zhongjie Tang, Huilu Li, Jin Xu, Yaqing Shu
<div> <section> <h3> Background</h3> <p>Anti-<i>N</i>-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a prevalent type of autoimmune encephalitis caused by antibodies targeting the NMDAR's GluN1 subunit. While significant progress has been made in elucidating the pathophysiology of autoimmune diseases, the immunological mechanisms underlying anti-NMDARE remain elusive. This study aimed to characterize immune cell interactions and dysregulation in anti-NMDARE by leveraging single-cell multi-omics sequencing technologies.</p> </section> <section> <h3> Methods</h3> <p>Peripheral blood mononuclear cells (PBMCs) from patients in the acute phase of anti-NMDARE and healthy controls were sequenced using single-cell joint profiling of transcriptome and chromatin accessibility. Differential gene expression analysis, transcription factor activity profiling, and cell-cell communication modeling were performed to elucidate the immune mechanisms underlying the disease. In parallel, single-cell B cell receptor sequencing (scBCR-seq) and repertoire analysis were conducted to assess antigen-driven clonal expansion within the B cell population.</p> </section> <section> <h3> Results</h3> <p>The study revealed a significant clonal expansion of B cells, particularly plasma cells, in anti-NMDARE patients. The novel finding of type I interferon (IFN-I) pathway activation suggests a regulatory mechanism that may drive this expansion and enhance antibody secretion. Additionally, activation of Toll-like receptor 2 (TLR2) in myeloid cells was noted, which may connect to tumor necrosis factor-alpha (TNF-α) secretion. This cytokine may contribute to the activation of B and T cells, thereby perpetuating immune dysregulation.</p> </section> <section> <h3> Conclusions</h3> <p>This study presents a comprehensive single-cell multi-omics characterization of immune dysregulation in anti-NMDARE, highlighting the expansion of B cell and the activation of the IFN-I and TLR2 pathways. These findings provide deeper insights into the molecular mechanism driving the pathogenesis of anti-NMDARE and offer promising targets for future therapeutic intervention.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>Significant B cell clonal expansion, particularly in plasma cells, driven by antigen recognition.</li> <li>IFN-I pathway activation in plasma cells boosts their antibody production
背景:抗n -甲基- d -天冬氨酸受体脑炎(anti-NMDARE)是一种常见的自身免疫性脑炎,由靶向NMDAR的GluN1亚基的抗体引起。虽然在阐明自身免疫性疾病的病理生理方面取得了重大进展,但抗nmdare的免疫学机制仍然难以捉摸。本研究旨在利用单细胞多组学测序技术表征抗nmdare免疫细胞相互作用和失调。方法:采用单细胞联合转录组和染色质可及性分析对抗nmdare急性期患者和健康对照的外周血单个核细胞(PBMCs)进行测序。通过差异基因表达分析、转录因子活性分析和细胞间通讯模型来阐明该疾病的免疫机制。同时,进行了单细胞B细胞受体测序(scBCR-seq)和库分析,以评估B细胞群体中抗原驱动的克隆扩增。结果:研究显示抗nmdare患者的B细胞,特别是浆细胞有显著的克隆扩增。I型干扰素(IFN-I)通路激活的新发现提示了一种可能驱动这种扩展并增强抗体分泌的调节机制。此外,髓细胞中toll样受体2 (TLR2)的激活可能与肿瘤坏死因子α (TNF-α)的分泌有关。这种细胞因子可能有助于B细胞和T细胞的激活,从而使免疫失调永久化。结论:本研究对抗nmdare免疫失调进行了全面的单细胞多组学表征,强调了B细胞的扩增和IFN-I和TLR2通路的激活。这些发现为探究抗nmdare的分子机制提供了更深入的见解,并为未来的治疗干预提供了有希望的靶点。重点:在抗原识别驱动下,显著的B细胞克隆扩增,特别是在浆细胞中。血浆细胞中IFN-I通路的激活促进了它们的抗体产生,并可能加剧免疫失调。髓细胞中TLR2通路的激活有助于TNF-α的分泌,并可能影响适应性免疫反应。
{"title":"Immunoregulatory programs in anti-N-methyl-D-aspartate receptor encephalitis identified by single-cell multi-omics analysis","authors":"Xinhui Li,&nbsp;Yicong Xu,&nbsp;Weixing Zhang,&nbsp;Zihao Chen,&nbsp;Dongjie Peng,&nbsp;Wenxu Ren,&nbsp;Zhongjie Tang,&nbsp;Huilu Li,&nbsp;Jin Xu,&nbsp;Yaqing Shu","doi":"10.1002/ctm2.70173","DOIUrl":"10.1002/ctm2.70173","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;Anti-&lt;i&gt;N&lt;/i&gt;-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a prevalent type of autoimmune encephalitis caused by antibodies targeting the NMDAR's GluN1 subunit. While significant progress has been made in elucidating the pathophysiology of autoimmune diseases, the immunological mechanisms underlying anti-NMDARE remain elusive. This study aimed to characterize immune cell interactions and dysregulation in anti-NMDARE by leveraging single-cell multi-omics sequencing technologies.&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;Peripheral blood mononuclear cells (PBMCs) from patients in the acute phase of anti-NMDARE and healthy controls were sequenced using single-cell joint profiling of transcriptome and chromatin accessibility. Differential gene expression analysis, transcription factor activity profiling, and cell-cell communication modeling were performed to elucidate the immune mechanisms underlying the disease. In parallel, single-cell B cell receptor sequencing (scBCR-seq) and repertoire analysis were conducted to assess antigen-driven clonal expansion within the B cell population.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 &lt;p&gt;The study revealed a significant clonal expansion of B cells, particularly plasma cells, in anti-NMDARE patients. The novel finding of type I interferon (IFN-I) pathway activation suggests a regulatory mechanism that may drive this expansion and enhance antibody secretion. Additionally, activation of Toll-like receptor 2 (TLR2) in myeloid cells was noted, which may connect to tumor necrosis factor-alpha (TNF-α) secretion. This cytokine may contribute to the activation of B and T cells, thereby perpetuating immune dysregulation.&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 presents a comprehensive single-cell multi-omics characterization of immune dysregulation in anti-NMDARE, highlighting the expansion of B cell and the activation of the IFN-I and TLR2 pathways. These findings provide deeper insights into the molecular mechanism driving the pathogenesis of anti-NMDARE and offer promising targets for future therapeutic intervention.&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;Significant B cell clonal expansion, particularly in plasma cells, driven by antigen recognition.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;IFN-I pathway activation in plasma cells boosts their antibody production","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11710936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945241","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
Identification of CENPM as a key gene driving adrenocortical carcinoma metastasis via physical interaction with immune checkpoint ligand FGL1 通过与免疫检查点配体FGL1的物理相互作用,发现CENPM是驱动肾上腺皮质癌转移的关键基因。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-08 DOI: 10.1002/ctm2.70182
Cunru Zou, Yu Zhang, Chengyue Liu, Yaxin Li, Congjie Lin, Hao Chen, Jiangping Hou, Guojun Gao, Zheng Liu, Qiupeng Yan, Wenxia Su
<div> <section> <h3> Background</h3> <p>Distant metastasis occurs in the majority of adrenocortical carcinoma (ACC), leading to an extremely poor prognosis. However, the key genes driving ACC metastasis remain unclear.</p> </section> <section> <h3> Methods</h3> <p>Weighted gene co-expression network analysis (WGCNA) and functional enrichment analysis were conducted to identify ACC metastasis-related genes. Data from RNA-seq and microarray were analyzed to reveal correlations of the <i>CENPM</i> gene with cancer, metastasis, and survival in ACC. Immunohistochemistry was used to assess CENPM protein expression. The impact of CENPM on metastasis behaviour was verified in ACC (H295R and SW-13) cells and xenograft NPG mice. DIA quantitative proteomics analysis, western blot, immunofluorescence, and co-immunoprecipitation assay were performed to identify the downstream target of CENPM.</p> </section> <section> <h3> Results</h3> <p>Among the 12 035 analyzed genes, 363 genes were related to ACC metastasis and <i>CENPM</i> was identified as the hub gene. CENPM was upregulated in ACC samples and associated with metastasis and poor prognosis. Knockdown of <i>CENPM</i> inhibited proliferation, invasion, and migration of ACC cells and suppressed liver metastasis in xenograft NPG mice. Collagen-containing extracellular matrix signalling was primarily downregulated when <i>CENPM</i> was knocked down. FGL1, important components of ECM signalling and immune checkpoint ligand of LAG3, were downregulated following <i>CENPM</i> silence, overexpressed in human advanced ACC samples, and colocalized with CENPM. Physical interaction between CENPM and FGL1 was identified. Overexpression of <i>FGL1</i> rescued migration and invasion of <i>CENPM</i> knockdown ACC cells.</p> </section> <section> <h3> Conclusions</h3> <p><i>CENPM</i> is a key gene in driving ACC metastasis. CENPM promotes ACC metastasis through physical interaction with the immune checkpoint ligand FGL1. CENPM can be used as a new prognostic biomarker and therapeutic target for metastatic ACC.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li><i>CENPM</i> is the key gene that drives ACC metastasis, and a robust biomarker for ACC prognosis.</li> <li>Silencing <i>CENPM</i> impedes ACC metastasis in vitro and in vivo by physical interaction with immune checkpoint ligand FGL1.</li>
背景:肾上腺皮质癌(ACC)多发生远端转移,预后极差。然而,驱动ACC转移的关键基因仍不清楚。方法:采用加权基因共表达网络分析(Weighted gene co-expression network analysis, WGCNA)和功能富集分析鉴定ACC转移相关基因。我们分析了RNA-seq和微阵列数据,以揭示CENPM基因与ACC的癌症、转移和生存的相关性。免疫组化检测CENPM蛋白表达。在ACC (H295R和SW-13)细胞和异种移植物NPG小鼠中验证了CENPM对转移行为的影响。采用DIA定量蛋白质组学分析、western blot、免疫荧光、共免疫沉淀等方法鉴定CENPM下游靶点。结果:在分析的12035个基因中,有363个基因与ACC转移相关,以CENPM为中心基因。在ACC样本中,CENPM表达上调,并与转移和不良预后相关。敲低CENPM可抑制异种移植物NPG小鼠ACC细胞的增殖、侵袭和迁移,并抑制肝转移。当CENPM被敲除时,含胶原蛋白的细胞外基质信号主要下调。FGL1是ECM信号和LAG3免疫检查点配体的重要组成部分,在CENPM沉默后下调,在人类晚期ACC样品中过表达,并与CENPM共定位。确定了CENPM与FGL1之间的物理相互作用。FGL1的过表达挽救了CENPM敲低ACC细胞的迁移和侵袭。结论:CENPM是ACC转移的关键基因。CENPM通过与免疫检查点配体FGL1的物理相互作用促进ACC转移。CENPM可作为转移性ACC的新的预后生物标志物和治疗靶点。重点:CENPM是ACC转移的关键基因,也是ACC预后的一个强有力的生物标志物。沉默CENPM通过与免疫检查点配体FGL1的物理相互作用阻碍ACC在体外和体内的转移。FGL1在ACC中过表达并促进ACC转移。
{"title":"Identification of CENPM as a key gene driving adrenocortical carcinoma metastasis via physical interaction with immune checkpoint ligand FGL1","authors":"Cunru Zou,&nbsp;Yu Zhang,&nbsp;Chengyue Liu,&nbsp;Yaxin Li,&nbsp;Congjie Lin,&nbsp;Hao Chen,&nbsp;Jiangping Hou,&nbsp;Guojun Gao,&nbsp;Zheng Liu,&nbsp;Qiupeng Yan,&nbsp;Wenxia Su","doi":"10.1002/ctm2.70182","DOIUrl":"10.1002/ctm2.70182","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;Distant metastasis occurs in the majority of adrenocortical carcinoma (ACC), leading to an extremely poor prognosis. However, the key genes driving ACC metastasis 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;Weighted gene co-expression network analysis (WGCNA) and functional enrichment analysis were conducted to identify ACC metastasis-related genes. Data from RNA-seq and microarray were analyzed to reveal correlations of the &lt;i&gt;CENPM&lt;/i&gt; gene with cancer, metastasis, and survival in ACC. Immunohistochemistry was used to assess CENPM protein expression. The impact of CENPM on metastasis behaviour was verified in ACC (H295R and SW-13) cells and xenograft NPG mice. DIA quantitative proteomics analysis, western blot, immunofluorescence, and co-immunoprecipitation assay were performed to identify the downstream target of CENPM.&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;Among the 12 035 analyzed genes, 363 genes were related to ACC metastasis and &lt;i&gt;CENPM&lt;/i&gt; was identified as the hub gene. CENPM was upregulated in ACC samples and associated with metastasis and poor prognosis. Knockdown of &lt;i&gt;CENPM&lt;/i&gt; inhibited proliferation, invasion, and migration of ACC cells and suppressed liver metastasis in xenograft NPG mice. Collagen-containing extracellular matrix signalling was primarily downregulated when &lt;i&gt;CENPM&lt;/i&gt; was knocked down. FGL1, important components of ECM signalling and immune checkpoint ligand of LAG3, were downregulated following &lt;i&gt;CENPM&lt;/i&gt; silence, overexpressed in human advanced ACC samples, and colocalized with CENPM. Physical interaction between CENPM and FGL1 was identified. Overexpression of &lt;i&gt;FGL1&lt;/i&gt; rescued migration and invasion of &lt;i&gt;CENPM&lt;/i&gt; knockdown ACC cells.&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;&lt;i&gt;CENPM&lt;/i&gt; is a key gene in driving ACC metastasis. CENPM promotes ACC metastasis through physical interaction with the immune checkpoint ligand FGL1. CENPM can be used as a new prognostic biomarker and therapeutic target for metastatic ACC.&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;ul&gt;\u0000 \u0000 &lt;li&gt;&lt;i&gt;CENPM&lt;/i&gt; is the key gene that drives ACC metastasis, and a robust biomarker for ACC prognosis.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Silencing &lt;i&gt;CENPM&lt;/i&gt; impedes ACC metastasis in vitro and in vivo by physical interaction with immune checkpoint ligand FGL1.&lt;/li&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945719","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
iDICss robustly predicts melanoma immunotherapy response by synergizing genomic and transcriptomic knowledge via independent component analysis iDICss通过独立成分分析协同基因组和转录组学知识,强有力地预测黑色素瘤免疫治疗反应。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-08 DOI: 10.1002/ctm2.70183
Jiayue Qiu, Nana Jin, Lixin Cheng, Chen Huang
<p>Dear Editor,</p><p>Here, we present a tool named iDIC-based scoring system (iDICss) that is useful for predicting immunotherapy response and prognostic outcomes in melanoma patients. The core principle of the tool is that specific driver alterations affecting the immuno-related gene expression and functions,<span><sup>1</sup></span> may be indicative of high tumour mutation burden, a good predictor used to guide immunotherapy decisions in clinical,<span><sup>2</sup></span> and analysis of such interplays may provide novel strategies to improve prediction of immunotherapy response. This tool thereby builds on an immune driver independent components (iDICs) profile, which innovatively integrates the immunogenic properties into transcriptome using the independent component analysis (ICA), a popular matrix decomposition method. Optimized by comparison of multiple machine-learning models, an iDICss was established, which exhibits a superior performance of prognostic and immune response prediction compared with other published state-of-art biomarkers. Our study provides a novel strategy to improve the prediction of immunotherapy response for melanoma, which could be adaptable in numerous clinical prediction situations.</p><p>Melanoma is a highly aggressive skin cancer originating from melanocyte transformation, and its incidence has been increasing globally in recent years.<span><sup>3</sup></span> Immune checkpoint blocking immunotherapy is one of the most advanced treatment strategies and significantly improves the survival outcomes for melanoma sufferers. However, high genetic heterogeneity of melanoma results in immune responses occurring in only a small proportion of patients,<span><sup>4-6</sup></span> which motivates us to explore a robust biomarker to predict patients’ immunotherapy response and guide treatment decision. Accumulated studies demonstrate that oncogenic driver mutations shape tumor immune microenvironment (TIME), and cause impediments to immunotherapy.<span><sup>7-9</sup></span> Hence, the crosstalk between oncogene driver mutations and TIME-related gene expression alterations may reflect if a patient will respond to immunotherapy. Herein we started by integrating driver gene mutation and expression information via ICA by which we successfully figured out seven key TIME-driver iDICs, and then established an iDIC-based scoring system (iDICss) by a comparative analysis of multiple machine-learning methods. The main pipeline proceeded as follows: (1) independent component analysis, (2) independent component (IC) selection, (3) TIME-driver IC profile calculation, and (4) iDICss construction (Figure 1). The datasets involved in the study were summarized in Table S1.</p><p>Briefly, we collected the multi-omics data of 450 melanoma patients from the TCGA database, including gene expression, mutation as well as clinical information. ICA analysis was initially applied to the gene expression matrix <i>E</i>, resulting in an <i>S</i> matr
{"title":"iDICss robustly predicts melanoma immunotherapy response by synergizing genomic and transcriptomic knowledge via independent component analysis","authors":"Jiayue Qiu,&nbsp;Nana Jin,&nbsp;Lixin Cheng,&nbsp;Chen Huang","doi":"10.1002/ctm2.70183","DOIUrl":"10.1002/ctm2.70183","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Here, we present a tool named iDIC-based scoring system (iDICss) that is useful for predicting immunotherapy response and prognostic outcomes in melanoma patients. The core principle of the tool is that specific driver alterations affecting the immuno-related gene expression and functions,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; may be indicative of high tumour mutation burden, a good predictor used to guide immunotherapy decisions in clinical,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; and analysis of such interplays may provide novel strategies to improve prediction of immunotherapy response. This tool thereby builds on an immune driver independent components (iDICs) profile, which innovatively integrates the immunogenic properties into transcriptome using the independent component analysis (ICA), a popular matrix decomposition method. Optimized by comparison of multiple machine-learning models, an iDICss was established, which exhibits a superior performance of prognostic and immune response prediction compared with other published state-of-art biomarkers. Our study provides a novel strategy to improve the prediction of immunotherapy response for melanoma, which could be adaptable in numerous clinical prediction situations.&lt;/p&gt;&lt;p&gt;Melanoma is a highly aggressive skin cancer originating from melanocyte transformation, and its incidence has been increasing globally in recent years.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Immune checkpoint blocking immunotherapy is one of the most advanced treatment strategies and significantly improves the survival outcomes for melanoma sufferers. However, high genetic heterogeneity of melanoma results in immune responses occurring in only a small proportion of patients,&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt; which motivates us to explore a robust biomarker to predict patients’ immunotherapy response and guide treatment decision. Accumulated studies demonstrate that oncogenic driver mutations shape tumor immune microenvironment (TIME), and cause impediments to immunotherapy.&lt;span&gt;&lt;sup&gt;7-9&lt;/sup&gt;&lt;/span&gt; Hence, the crosstalk between oncogene driver mutations and TIME-related gene expression alterations may reflect if a patient will respond to immunotherapy. Herein we started by integrating driver gene mutation and expression information via ICA by which we successfully figured out seven key TIME-driver iDICs, and then established an iDIC-based scoring system (iDICss) by a comparative analysis of multiple machine-learning methods. The main pipeline proceeded as follows: (1) independent component analysis, (2) independent component (IC) selection, (3) TIME-driver IC profile calculation, and (4) iDICss construction (Figure 1). The datasets involved in the study were summarized in Table S1.&lt;/p&gt;&lt;p&gt;Briefly, we collected the multi-omics data of 450 melanoma patients from the TCGA database, including gene expression, mutation as well as clinical information. ICA analysis was initially applied to the gene expression matrix &lt;i&gt;E&lt;/i&gt;, resulting in an &lt;i&gt;S&lt;/i&gt; matr","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944908","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
Cannabinoid receptor 2 facilitates the Schwann cells-dependent peripheral nerve regeneration 大麻素受体2促进雪旺细胞依赖性周围神经再生。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-08 DOI: 10.1002/ctm2.70184
Heng Xu, Lu Wen, Yi Luo, Jiaying Zhou, Sheng Yao, Wei Ding, Jing Feng
<p>Dear Editor:</p><p>Here, we demonstrated that cannabinoid receptor 2 (CB2) plays a pivotal role in Schwann cells (SCs) by promoting the remyelination process following peripheral nerve injury (PNI). Selective activation of CB2 shows potential as a therapeutic approach to enhance nerve repair in these injuries.</p><p>Schwann cells form Büngner bands to guide axonal regeneration during PNI. However, the slow pace of axonal growth (∼1–3 mm/day) often leads to the degradation of these structures within 8 weeks, thereby disrupting the regenerative process.<span><sup>1, 2</sup></span> CB2 activation has been shown to promote remyelination and enhance nerve regeneration by modulating inflammatory responses and supporting cellular processes essential for nerve repair.<span><sup>3, 4</sup></span> However, the cellular mechanisms of CB2 function in remyelination remain unclear. This prompted the hypothesis that selective activation of CB2 could maintain Schwann cell function and create a more conducive environment for axonal regeneration.</p><p>To investigate this, we employed a mouse model of crush injury and treated the mice with delta-9-tetrahydrocannabinol (Δ<sup>9</sup>-THC, a partial agonist of both CB1 and CB2 receptors, for 16 consecutive days; Figure S1A). Interestingly, Δ<sup>9</sup>-THC treatment resulted in significantly increased growth rate of injured axons and improved behaviour in mice, including reflexive mechanical allodynia and walking parameters (Figure S1B–K). To exclude the possibility that Δ<sup>9</sup>-THC exerts its effect via CB1 activation, we used CB2-specific agonists. Although the agonist (GW842166X, EC50: ∼63 nM) did not improve mechanical pain (Figure S2A), the more efficient agonist, AM1241 (EC50: ∼3.4 nM), showed therapeutic efficacy. As expected, compared with vehicle treatment, daily administration of AM1241 significantly improved mechanical allodynia, gait abnormalities and motor function in mice. These improvements were further abolished when AM1241 was co-administered with the CB2 antagonist AM630 (Figure 1 and Figure S2B). Consistent with these behavioural data, immunofluorescence staining showed that while nerves in the control group began to extend along their original growth direction, this change appeared to be more pronounced after AM1241 treatment (Figure S3A–C). We also examined the mRNA expression of genes related to myelination in the sciatic nerve tissues using real-time quantitative PCR (RT-qPCR). In the presence of AM1241, pro-myelination-related genes including Sox10, Egr2 and Tprv4 were significantly upregulated, whereas AM630 blocked CB2-dependent gene upregulation. Trpv4 has been proved to delay the re-myelination after nerve injury.<span><sup>5, 6</sup></span> Interestingly, the expression of the SCs dedifferentiation-related genes Sox2 and c-Jun was not affected (Figure S3D). Moreover, Aniline Blue staining and electron microscopy demonstrated that CB2 stimulation significantly increased myelin t
{"title":"Cannabinoid receptor 2 facilitates the Schwann cells-dependent peripheral nerve regeneration","authors":"Heng Xu,&nbsp;Lu Wen,&nbsp;Yi Luo,&nbsp;Jiaying Zhou,&nbsp;Sheng Yao,&nbsp;Wei Ding,&nbsp;Jing Feng","doi":"10.1002/ctm2.70184","DOIUrl":"10.1002/ctm2.70184","url":null,"abstract":"&lt;p&gt;Dear Editor:&lt;/p&gt;&lt;p&gt;Here, we demonstrated that cannabinoid receptor 2 (CB2) plays a pivotal role in Schwann cells (SCs) by promoting the remyelination process following peripheral nerve injury (PNI). Selective activation of CB2 shows potential as a therapeutic approach to enhance nerve repair in these injuries.&lt;/p&gt;&lt;p&gt;Schwann cells form Büngner bands to guide axonal regeneration during PNI. However, the slow pace of axonal growth (∼1–3 mm/day) often leads to the degradation of these structures within 8 weeks, thereby disrupting the regenerative process.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; CB2 activation has been shown to promote remyelination and enhance nerve regeneration by modulating inflammatory responses and supporting cellular processes essential for nerve repair.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; However, the cellular mechanisms of CB2 function in remyelination remain unclear. This prompted the hypothesis that selective activation of CB2 could maintain Schwann cell function and create a more conducive environment for axonal regeneration.&lt;/p&gt;&lt;p&gt;To investigate this, we employed a mouse model of crush injury and treated the mice with delta-9-tetrahydrocannabinol (Δ&lt;sup&gt;9&lt;/sup&gt;-THC, a partial agonist of both CB1 and CB2 receptors, for 16 consecutive days; Figure S1A). Interestingly, Δ&lt;sup&gt;9&lt;/sup&gt;-THC treatment resulted in significantly increased growth rate of injured axons and improved behaviour in mice, including reflexive mechanical allodynia and walking parameters (Figure S1B–K). To exclude the possibility that Δ&lt;sup&gt;9&lt;/sup&gt;-THC exerts its effect via CB1 activation, we used CB2-specific agonists. Although the agonist (GW842166X, EC50: ∼63 nM) did not improve mechanical pain (Figure S2A), the more efficient agonist, AM1241 (EC50: ∼3.4 nM), showed therapeutic efficacy. As expected, compared with vehicle treatment, daily administration of AM1241 significantly improved mechanical allodynia, gait abnormalities and motor function in mice. These improvements were further abolished when AM1241 was co-administered with the CB2 antagonist AM630 (Figure 1 and Figure S2B). Consistent with these behavioural data, immunofluorescence staining showed that while nerves in the control group began to extend along their original growth direction, this change appeared to be more pronounced after AM1241 treatment (Figure S3A–C). We also examined the mRNA expression of genes related to myelination in the sciatic nerve tissues using real-time quantitative PCR (RT-qPCR). In the presence of AM1241, pro-myelination-related genes including Sox10, Egr2 and Tprv4 were significantly upregulated, whereas AM630 blocked CB2-dependent gene upregulation. Trpv4 has been proved to delay the re-myelination after nerve injury.&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; Interestingly, the expression of the SCs dedifferentiation-related genes Sox2 and c-Jun was not affected (Figure S3D). Moreover, Aniline Blue staining and electron microscopy demonstrated that CB2 stimulation significantly increased myelin t","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945714","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
Commentary: Molecular responses in pig heart to human xenotransplantation unveiled by longitudinal multi-omic profiling 评论:纵向多组学分析揭示了猪心脏对人类异种移植的分子反应。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-08 DOI: 10.1002/ctm2.70132
Brendan J. Keating, Eloi Schmauch, Michael P. Snyder, Jennifer D. Motter, Brian D. Piening
<p>Orthotopic heart transplantation is considered to be the best treatment for end-stage heart failure, with improved survival and quality of life for patients.<span><sup>1</sup></span> Despite the number of adult and pediatric heart transplants performed in the US having reached >4000 annually, the number of patients waiting for a heart allograft continues to exceed the available supply.<span><sup>2</sup></span> Xenotransplantation has emerged as a promising alternative to address the demand by providing a source of organs that is readily available and practically inexhaustible.<span><sup>3</sup></span> Given their anatomical and physiological similarity to humans, pigs are considered the most suitable donor species for xenotransplantation,<span><sup>4</sup></span> with immunologic barriers steadily being overcome through advances in targeted genetic engineering of the porcine genome and immunosuppression therapies.<span><sup>4, 5</sup></span> In 2022, two brain-dead human recipients “decedents” received 10-gene-edited porcine hearts. Over the two ∼3-day studies, there was sustained cardiac function, without evidence of acute-onset rejection or zoonotic transmission.<span><sup>6</sup></span> To better elucidate the molecular processes in the peripheral blood and pig heart xenograft tissues, Schmauch and colleagues recently reported in <i>Nature Medicine</i> the dynamic molecular interactions following these pig heart to human decedent xenotransplants using comprehensive, longitudinal multi-omic profiling.<span><sup>7</sup></span> This commentary dissects their key findings, emphasising the clinical translational implications and highlighting future research avenues in this evolving field.</p><p>Over the last decade, methodological and technical advances have led to the development of high-throughput, low-cost technologies where millions of biomolecules spanning nucleic acids, proteins, lipids and metabolites can be measured simultaneously.<span><sup>8</sup></span> This includes advances in high-throughput sequencing, with current platforms able to produce large high-quality human and pig whole genome sequencing (WGS), RNA-sequencing, epigenetic and genomic structure profiling e.g., bisulfite WGS and <span>A</span>ssay for <span>T</span>ransposase-<span>a</span>ccessible <span>c</span>hromatin with <span>seq</span>uencing (ATAC-seq), a technique that assesses chromatin accessibility across the genome. A number of these sequencing approaches can be performed in tissues as well as in cell-free fractions of DNA and RNA in peripheral fluids including blood and urine. Concomitantly, advances in biochemical preparation and mass spectrometry technologies have enabled the large-scale quantitative profiling of proteins (proteomics), metabolites (metabolomics) and lipids (lipidomics) in tissues and bodily fluids. Current advances have afforded the ability to perform a variety of assays at single cell resolution, for example, scRNA-seq and scATAC-seq, wh
{"title":"Commentary: Molecular responses in pig heart to human xenotransplantation unveiled by longitudinal multi-omic profiling","authors":"Brendan J. Keating,&nbsp;Eloi Schmauch,&nbsp;Michael P. Snyder,&nbsp;Jennifer D. Motter,&nbsp;Brian D. Piening","doi":"10.1002/ctm2.70132","DOIUrl":"10.1002/ctm2.70132","url":null,"abstract":"&lt;p&gt;Orthotopic heart transplantation is considered to be the best treatment for end-stage heart failure, with improved survival and quality of life for patients.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Despite the number of adult and pediatric heart transplants performed in the US having reached &gt;4000 annually, the number of patients waiting for a heart allograft continues to exceed the available supply.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Xenotransplantation has emerged as a promising alternative to address the demand by providing a source of organs that is readily available and practically inexhaustible.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Given their anatomical and physiological similarity to humans, pigs are considered the most suitable donor species for xenotransplantation,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; with immunologic barriers steadily being overcome through advances in targeted genetic engineering of the porcine genome and immunosuppression therapies.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; In 2022, two brain-dead human recipients “decedents” received 10-gene-edited porcine hearts. Over the two ∼3-day studies, there was sustained cardiac function, without evidence of acute-onset rejection or zoonotic transmission.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; To better elucidate the molecular processes in the peripheral blood and pig heart xenograft tissues, Schmauch and colleagues recently reported in &lt;i&gt;Nature Medicine&lt;/i&gt; the dynamic molecular interactions following these pig heart to human decedent xenotransplants using comprehensive, longitudinal multi-omic profiling.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; This commentary dissects their key findings, emphasising the clinical translational implications and highlighting future research avenues in this evolving field.&lt;/p&gt;&lt;p&gt;Over the last decade, methodological and technical advances have led to the development of high-throughput, low-cost technologies where millions of biomolecules spanning nucleic acids, proteins, lipids and metabolites can be measured simultaneously.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; This includes advances in high-throughput sequencing, with current platforms able to produce large high-quality human and pig whole genome sequencing (WGS), RNA-sequencing, epigenetic and genomic structure profiling e.g., bisulfite WGS and &lt;span&gt;A&lt;/span&gt;ssay for &lt;span&gt;T&lt;/span&gt;ransposase-&lt;span&gt;a&lt;/span&gt;ccessible &lt;span&gt;c&lt;/span&gt;hromatin with &lt;span&gt;seq&lt;/span&gt;uencing (ATAC-seq), a technique that assesses chromatin accessibility across the genome. A number of these sequencing approaches can be performed in tissues as well as in cell-free fractions of DNA and RNA in peripheral fluids including blood and urine. Concomitantly, advances in biochemical preparation and mass spectrometry technologies have enabled the large-scale quantitative profiling of proteins (proteomics), metabolites (metabolomics) and lipids (lipidomics) in tissues and bodily fluids. Current advances have afforded the ability to perform a variety of assays at single cell resolution, for example, scRNA-seq and scATAC-seq, wh","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945715","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
Somatic mutation correlation with lymph node metastasis and prognosis in T1/2 stage colorectal cancer patients: A propensity score matching analysis T1/2期结直肠癌患者的躯体突变与淋巴结转移和预后的相关性:倾向评分匹配分析。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-07 DOI: 10.1002/ctm2.70179
Junwei Tang, Yue Zhang, Dongjian Ji, Lu Wang, Han Zhuo, Yaping Wang, Yueming Sun
<p>Dear Editor,</p><p>Our study provides a comprehensive analysis of the correlation between specific somatic mutations and the lymph node metastasis in colorectal cancer (CRC) patients with T1/2 stage, addressing a significant gap in the early-stage prognosis and individualised treatment of CRC. By leveraging next-generation sequencing (NGS) and clinical data, we identified key mutations and pathological characteristics that can serve as robust predictors of lymph node metastasis, thereby enhancing clinicians' ability to stratify T1/2 CRC patients based on metastatic risk.</p><p>CRC remains a prevalent malignancy worldwide, with early-stage cases, particularly T1/2 stages, generally associated with favourable outcomes.<span><sup>1</sup></span> However, when lymph node metastasis is present, the prognosis worsens significantly.<span><sup>2</sup></span> Lymph node involvement in early-stage CRC is a strong indicator of potential distant metastasis and recurrence, highlighting the urgency of effective preoperative risk assessment in T1/2 patients.<span><sup>3</sup></span> Existing imaging techniques, such as enhanced computed tomography and magnetic resonance imaging, offer limited sensitivity and specificity for lymph node assessment, especially in early stages where inflammation or small metastatic nodes may escape detection.<span><sup>4, 5</sup></span> Therefore, identifying molecular markers that can predict lymph node involvement with high accuracy is paramount to guiding treatment decisions in early-stage CRC. Our study contributes to this goal by identifying specific genetic mutations and clinical features associated with metastatic risk, thus enabling a more refined preoperative evaluation of T1/2 stage CRC patients.</p><p>We conducted a retrospective cohort study including 212 T1/2 CRC patients (Figure S1), who were categorised based on lymph node involvement into T1/2N+ and T1/2N‒ groups and matched using propensity score analysis (Figure 1 and Table S1). Our NGS data showed that mutations in four genes (LRP1B, KMT2B, TSC2 and BRAF) were significantly more frequent in the T1/2N+ group (Figure 2), and the presence of any of these mutations correlated with reduced overall survival (Figure S2). Among the four, BRAF mutations have been widely recognised in literature as a poor prognostic factor in advanced CRC,<span><sup>6</sup></span> but their impact in early stages has remained largely unexplored until now. Additionally, LRP1B, KMT2B and TSC2 mutations appear to be novel findings in the context of early-stage lymph node metastasis in CRC, indicating that they could potentially be unique markers for predicting outcomes in T1/2 patients (Figure 3). Our analysis also showed that patients with LRP1B mutations had particularly poor survival outcomes, with a median survival of 22.2 months.</p><p>In addition to these molecular findings, there was no significant difference in the distribution of MSI status and TMB between the two groups; however,
{"title":"Somatic mutation correlation with lymph node metastasis and prognosis in T1/2 stage colorectal cancer patients: A propensity score matching analysis","authors":"Junwei Tang,&nbsp;Yue Zhang,&nbsp;Dongjian Ji,&nbsp;Lu Wang,&nbsp;Han Zhuo,&nbsp;Yaping Wang,&nbsp;Yueming Sun","doi":"10.1002/ctm2.70179","DOIUrl":"10.1002/ctm2.70179","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Our study provides a comprehensive analysis of the correlation between specific somatic mutations and the lymph node metastasis in colorectal cancer (CRC) patients with T1/2 stage, addressing a significant gap in the early-stage prognosis and individualised treatment of CRC. By leveraging next-generation sequencing (NGS) and clinical data, we identified key mutations and pathological characteristics that can serve as robust predictors of lymph node metastasis, thereby enhancing clinicians' ability to stratify T1/2 CRC patients based on metastatic risk.&lt;/p&gt;&lt;p&gt;CRC remains a prevalent malignancy worldwide, with early-stage cases, particularly T1/2 stages, generally associated with favourable outcomes.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; However, when lymph node metastasis is present, the prognosis worsens significantly.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Lymph node involvement in early-stage CRC is a strong indicator of potential distant metastasis and recurrence, highlighting the urgency of effective preoperative risk assessment in T1/2 patients.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Existing imaging techniques, such as enhanced computed tomography and magnetic resonance imaging, offer limited sensitivity and specificity for lymph node assessment, especially in early stages where inflammation or small metastatic nodes may escape detection.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; Therefore, identifying molecular markers that can predict lymph node involvement with high accuracy is paramount to guiding treatment decisions in early-stage CRC. Our study contributes to this goal by identifying specific genetic mutations and clinical features associated with metastatic risk, thus enabling a more refined preoperative evaluation of T1/2 stage CRC patients.&lt;/p&gt;&lt;p&gt;We conducted a retrospective cohort study including 212 T1/2 CRC patients (Figure S1), who were categorised based on lymph node involvement into T1/2N+ and T1/2N‒ groups and matched using propensity score analysis (Figure 1 and Table S1). Our NGS data showed that mutations in four genes (LRP1B, KMT2B, TSC2 and BRAF) were significantly more frequent in the T1/2N+ group (Figure 2), and the presence of any of these mutations correlated with reduced overall survival (Figure S2). Among the four, BRAF mutations have been widely recognised in literature as a poor prognostic factor in advanced CRC,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; but their impact in early stages has remained largely unexplored until now. Additionally, LRP1B, KMT2B and TSC2 mutations appear to be novel findings in the context of early-stage lymph node metastasis in CRC, indicating that they could potentially be unique markers for predicting outcomes in T1/2 patients (Figure 3). Our analysis also showed that patients with LRP1B mutations had particularly poor survival outcomes, with a median survival of 22.2 months.&lt;/p&gt;&lt;p&gt;In addition to these molecular findings, there was no significant difference in the distribution of MSI status and TMB between the two groups; however, ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945556","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
Integrating multi-omics features enables non-invasive early diagnosis and treatment response prediction of diffuse large B-cell lymphoma 整合多组学特征可实现弥漫性大b细胞淋巴瘤的无创早期诊断和治疗反应预测。
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-07 DOI: 10.1002/ctm2.70174
Weilong Zhang, Bangquan Ye, Yang Song, Ping Yang, Wenzhe Si, Hairong Jing, Fan Yang, Dan Yuan, Zhihong Wu, Jiahao Lyu, Kang Peng, Xu Zhang, Lingli Wang, Yan Li, Yan Liu, Chaoling Wu, Xiaoyu Hao, Yuqi Zhang, Wenxin Qi, Jing Wang, Fei Dong, Zijian Zhao, Hongmei Jing, Yanzhao Li

Background

Multi-omics features of cell-free DNA (cfDNA) can effectively improve the performance of non-invasive early diagnosis and prognosis of cancer. However, multimodal characterization of cfDNA remains technically challenging.

Methods

We developed a comprehensive multi-omics solution (COMOS) to specifically obtain an extensive fragmentomics landscape, presented by breakpoint characteristics of nucleosomes, CpG islands, DNase clusters and enhancers, besides typical methylation, copy number alteration of cfDNA. The COMOS was tested on 214 plasma samples of diffuse large B-cell lymphoma (DLBCL) and matched healthy controls.

Results

For early diagnosis, COMOS improved the area under the curve (AUC) value to .993 compared with the individual omics model, with a sensitivity of 95% at 98% specificity. Detection sensitivity achieved 91% at 99% specificity in early-stage patients, while the AUC values of the individual omics model were 0.942, 0.968, 0.989, 0.935, 0.921, 0.781 and 0.917, respectively, with lower sensitivity and specificity. In the treatment response cohort, COMOS yielded a superior sensitivity of 88% at 86% specificity (AUC, 0.903). COMOS has achieved excellent performance in early diagnosis and treatment response prediction.

Conclusions

Our study provides an effectively improved approach with high accuracy for the diagnosis and prognosis of DLBCL, showing great potential for future clinical application.

Key points

  • A comprehensive multi-omics solution to specifically obtain an extensive fragmentomics landscape, presented by breakpoint characteristics of nucleosomes, CpG islands, DNase clusters and enhancers, besides typical methylation, copy number alteration of cfDNA.
  • Integrated model of cfDNA multi-omics could be used for non-invasive early diagnosis of DLBCL.
  • Integrated model of cfDNA multi-omics could effectively evaluate the efficacy of R-CHOP before DLBCL treatment.
背景:游离DNA (cell-free DNA, cfDNA)的多组学特征可以有效提高肿瘤无创早期诊断和预后的效能。然而,cfDNA的多模态表征在技术上仍然具有挑战性。方法:我们开发了一个综合的多组学解决方案(COMOS),专门获得广泛的片段组学景观,除了典型的甲基化,cfDNA拷贝数改变外,还包括核小体,CpG岛,dna酶簇和增强子的断点特征。对214例弥漫性大b细胞淋巴瘤(DLBCL)和匹配的健康对照者的血浆样本进行了COMOS测试。结果:与个体组学模型相比,COMOS将早期诊断的曲线下面积(AUC)值提高到0.993,敏感性为95%,特异性为98%。早期患者的检测灵敏度为91%,特异性为99%,而个体组学模型的AUC值分别为0.942、0.968、0.989、0.935、0.921、0.781和0.917,敏感性和特异性较低。在治疗反应队列中,COMOS的敏感性为88%,特异性为86% (AUC, 0.903)。COMOS在早期诊断和治疗反应预测方面取得了优异的成绩。结论:本研究为DLBCL的诊断和预后提供了一种有效的改进方法,准确率高,具有很大的临床应用潜力。重点:一个全面的多组学解决方案,专门获得广泛的片段组学景观,包括核小体,CpG岛,dna酶簇和增强子的断点特征,以及典型的甲基化,cfDNA拷贝数改变。cfDNA多组学集成模型可用于DLBCL的无创早期诊断。cfDNA多组学综合模型可有效评价大细胞淋巴瘤治疗前R-CHOP的疗效。
{"title":"Integrating multi-omics features enables non-invasive early diagnosis and treatment response prediction of diffuse large B-cell lymphoma","authors":"Weilong Zhang,&nbsp;Bangquan Ye,&nbsp;Yang Song,&nbsp;Ping Yang,&nbsp;Wenzhe Si,&nbsp;Hairong Jing,&nbsp;Fan Yang,&nbsp;Dan Yuan,&nbsp;Zhihong Wu,&nbsp;Jiahao Lyu,&nbsp;Kang Peng,&nbsp;Xu Zhang,&nbsp;Lingli Wang,&nbsp;Yan Li,&nbsp;Yan Liu,&nbsp;Chaoling Wu,&nbsp;Xiaoyu Hao,&nbsp;Yuqi Zhang,&nbsp;Wenxin Qi,&nbsp;Jing Wang,&nbsp;Fei Dong,&nbsp;Zijian Zhao,&nbsp;Hongmei Jing,&nbsp;Yanzhao Li","doi":"10.1002/ctm2.70174","DOIUrl":"10.1002/ctm2.70174","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Multi-omics features of cell-free DNA (cfDNA) can effectively improve the performance of non-invasive early diagnosis and prognosis of cancer. However, multimodal characterization of cfDNA remains technically challenging.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We developed a comprehensive multi-omics solution (COMOS) to specifically obtain an extensive fragmentomics landscape, presented by breakpoint characteristics of nucleosomes, CpG islands, DNase clusters and enhancers, besides typical methylation, copy number alteration of cfDNA. The COMOS was tested on 214 plasma samples of diffuse large B-cell lymphoma (DLBCL) and matched healthy controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>For early diagnosis, COMOS improved the area under the curve (AUC) value to .993 compared with the individual omics model, with a sensitivity of 95% at 98% specificity. Detection sensitivity achieved 91% at 99% specificity in early-stage patients, while the AUC values of the individual omics model were 0.942, 0.968, 0.989, 0.935, 0.921, 0.781 and 0.917, respectively, with lower sensitivity and specificity. In the treatment response cohort, COMOS yielded a superior sensitivity of 88% at 86% specificity (AUC, 0.903). COMOS has achieved excellent performance in early diagnosis and treatment response prediction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study provides an effectively improved approach with high accuracy for the diagnosis and prognosis of DLBCL, showing great potential for future clinical application.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>A comprehensive multi-omics solution to specifically obtain an extensive fragmentomics landscape, presented by breakpoint characteristics of nucleosomes, CpG islands, DNase clusters and enhancers, besides typical methylation, copy number alteration of cfDNA.</li>\u0000 \u0000 <li>Integrated model of cfDNA multi-omics could be used for non-invasive early diagnosis of DLBCL.</li>\u0000 \u0000 <li>Integrated model of cfDNA multi-omics could effectively evaluate the efficacy of R-CHOP before DLBCL treatment.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945528","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
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Clinical and Translational Medicine
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