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Immunogenic relationship mapping supports a minimal-set trivalent vaccine strategy for broad sarbecovirus protection 免疫原性关系图谱支持广泛保护sarbecvirus的最小集三价疫苗策略
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-09 DOI: 10.1038/s41392-025-02565-5
Yeqing Sun, Ziqi Cheng, Xi Wu, Yunbo Bai, Lina Zhao, Hongyu Xiang, Weijin Huang, Jianhui Nie
Major outbreaks of severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19), together with the continuous risk of zoonotic spillover of animal sarbecoviruses, underscore the urgent need for vaccines that confer broad protection across the sarbecovirus subgenus. Current immunogen selection strategies for pansarbecovirus vaccine development predominantly rely on phylogenetic or spike sequence conservation analyses, which often fail to accurately predict the breadth of cross-neutralization. To overcome this limitation, we systematically evaluated cross-neutralization profiles among 25 representative sarbecoviruses from clades 1 and 3 via guinea pig antisera individually raised against full-length spike proteins in pseudovirus neutralization assays while excluding clade 2 viruses lacking known receptor usage. Neutralization profiling revealed four distinct immunogenic clusters that diverged from traditional phylogenetic relationships. Antisera induced by the palm civet–derived SARS-CoV-1 strain SZ1 broadly neutralized all clade 1a viruses, whereas full coverage of clade 1b viruses required at least two distinct immunogens. Remarkably, sera elicited by multiple clade 1 immunogens also neutralized clade 3 viruses despite no prior exposure to clade 3 antigens. Guided by these findings, we proposed a minimal trivalent immunogen combination—SZ1, SARS-CoV-2, and PCoV-GX—that elicited broad neutralization against both clade 1 and clade 3. This rational approach eliminates the need for additional clade 3–specific antigens and provides a preclinical framework for developing next-generation pansarbecovirus vaccines.
严重急性呼吸系统综合症(SARS)和2019年冠状病毒病(COVID-19)的重大暴发,以及动物sarbecovirus人畜共患外溢的持续风险,突显出迫切需要对整个sarbecovirus亚属提供广泛保护的疫苗。目前用于泛虫病毒疫苗开发的免疫原选择策略主要依赖于系统发育或刺突序列保守分析,这往往不能准确预测交叉中和的广度。为了克服这一局限性,我们通过在假病毒中和试验中分别针对全长刺突蛋白培养的豚鼠抗血清,系统地评估了来自进化支系1和3的25种代表性sarbecovirus的交叉中和谱,同时排除了缺乏已知受体使用的进化支系2病毒。中和分析揭示了四个不同的免疫原性集群,偏离了传统的系统发育关系。由棕榈果子狸衍生的SARS-CoV-1株SZ1诱导的抗血清可广泛中和所有1a进化支病毒,而完全覆盖1b进化支病毒则需要至少两种不同的免疫原。值得注意的是,由多个进化支1免疫原诱导的血清也能中和进化支3病毒,尽管之前没有暴露于进化支3抗原。在这些发现的指导下,我们提出了一种最小的三价免疫原组合- sz1, SARS-CoV-2和pcov - gx,可引起对进化枝1和进化枝3的广泛中和。这种合理的方法消除了额外的进化支3特异性抗原的需要,并为开发下一代泛sarbecvirus疫苗提供了临床前框架。
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引用次数: 0
Spatial dynamics in health and disease: from neurodevelopment to therapeutic target identification for inflammatory diseases 健康与疾病的空间动力学:从神经发育到炎性疾病的治疗靶点识别
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-09 DOI: 10.1038/s41392-026-02589-5
Matteo Barberis, Jinkun Xie
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引用次数: 0
Aromaticity-driven laser photo-responses and binding efficiency in IAF-conjugated natural products for neurodegenerative disease targets. 芳香驱动的激光光响应和iaf偶联天然产物对神经退行性疾病靶点的结合效率。
IF 52.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-06 DOI: 10.1038/s41392-025-02560-w
Nik Humaidi Nik Zulkarnine, Vahid Faramarzi, Michael Taeyoung Hwang
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引用次数: 0
It’s a kind of MAGIC: uncovering the origins of chromosomal instability 揭示染色体不稳定性的起源是一种魔力
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-05 DOI: 10.1038/s41392-026-02588-6
David Gómez-Peregrina, César Serrano
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引用次数: 0
Oncolytic viruses: advanced strategies in cancer therapy 溶瘤病毒:癌症治疗的先进策略
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-05 DOI: 10.1038/s41392-025-02343-3
Danli Xiao, Huarong Zhang, Ye Liu, Yan Li, Gongchu Li, Yunshan Ning
Oncolytic viruses (OVs) represent a promising strategy in cancer immunotherapy, as they selectively infect and lyse tumor cells while simultaneously triggering robust antitumor immune responses. By inducing immunogenic cell death, OVs enhance tumor antigen presentation and initiate a systemic immune response, effectively transforming the tumor microenvironment from an immune-suppressive state to an immune-permissive state. In addition to exerting direct oncolytic effects, OVs modulate key tumor-associated biological processes, including tumor angiogenesis and extracellular matrix remodeling, disrupting tumor progression and metastasis. Notably, recent advances have highlighted the therapeutic potential of combining OVs with conventional and emerging cancer treatments, such as chemotherapy, radiotherapy, immune checkpoint inhibitors, adoptive cell therapy, and epigenetic-targeted drugs. These combination strategies demonstrate synergistic effects by improving tumor selectivity, increasing antitumor immunity, and overcoming treatment resistance. Nevertheless, persistent challenges, such as viral dissemination dynamics, therapy resistance, and regulatory complexities, impede the broad clinical implementation of oncolytic virus therapy (OVT). In this Review, we illustrate recent advancements and innovative therapeutic strategies in OVT within the context of contemporary cancer treatment paradigms. First, we outline the historical evolution and key milestones in OVT development. We then discuss the classification of OVs and their multimodal mechanisms that target tumorigenesis, metastasis, disease recurrence, and therapy resistance. Finally, we evaluate the clinical research progress of OVT applications, focusing on their integration with other therapies, analyze the translational barriers hindering clinical implementation, and propose evidence-based future directions for optimizing cancer treatment.
溶瘤病毒(OVs)是一种很有前途的癌症免疫治疗策略,因为它们可以选择性地感染和溶解肿瘤细胞,同时引发强大的抗肿瘤免疫反应。通过诱导免疫原性细胞死亡,OVs增强肿瘤抗原呈递并启动全身免疫应答,有效地将肿瘤微环境从免疫抑制状态转变为免疫允许状态。除了发挥直接的溶瘤作用外,OVs还调节肿瘤相关的关键生物过程,包括肿瘤血管生成和细胞外基质重塑,破坏肿瘤的进展和转移。值得注意的是,最近的进展突出了OVs与传统和新兴癌症治疗方法(如化疗、放疗、免疫检查点抑制剂、过继细胞治疗和表观遗传靶向药物)相结合的治疗潜力。这些联合策略通过提高肿瘤选择性、增强抗肿瘤免疫和克服治疗耐药性显示出协同效应。然而,持续存在的挑战,如病毒传播动力学、治疗耐药性和监管复杂性,阻碍了溶瘤病毒治疗(OVT)的广泛临床实施。在这篇综述中,我们阐述了在当代癌症治疗范式背景下OVT的最新进展和创新治疗策略。首先,我们概述了OVT发展的历史演变和关键里程碑。然后,我们讨论了OVs的分类及其针对肿瘤发生、转移、疾病复发和治疗抵抗的多模式机制。最后,我们评估了OVT应用的临床研究进展,重点关注其与其他疗法的整合,分析了阻碍临床实施的转化障碍,并提出了基于证据的优化癌症治疗的未来方向。
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引用次数: 0
Cyclic di-GMP suppresses cancer metastasis by targeting proteasome 26S subunit non-ATPase 3 independently of STING. 环二gmp通过独立于STING的靶向蛋白酶体26S亚基非atp酶3来抑制癌症转移。
IF 52.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-04 DOI: 10.1038/s41392-025-02553-9
Jieqiong Wang, Alexander Mrozek, Kewen Hu, Hanyu You, Sarah E Traverse, Hyemin Lee, Shelya X Zeng, Xiufeng Pang, Heewon Park, Hua Lu

Cancer metastasis is the primary cause of cancer-related mortality, yet effective treatments remain limited. There is an urgent need to develop novel therapeutic strategies to combat metastasis. In this study, we demonstrate that the bacterial intracellular signaling molecule cyclic di-GMP (c-di-GMP, or cdG) exerts a potent inhibitory effect on cancer metastasis, particularly in metastatic breast cancer, via both in vitro and in vivo models, with little toxicity to mice. Interestingly, this antimetastatic function is achieved by suppressing the NF-κB signaling pathway, which is important for cancer progression and metastasis, but independent of STING, a previously identified c-di-GMP sensor and NF-κB regulator in mammalian cells. Surprisingly, c-di-GMP inhibits NF-κB activity (p-p65) by directly binding to the proteasome 26S subunit non-ATPase 3 (PSMD3) that we identified as a new TBK1-binding activator, and disrupting the interaction between PSMD3 and TBK1. This PSMD3-TBK1 interaction boosts the phosphorylation and activation of TBK1, representing a noncanonical function of PSMD3 distinct from its established role in proteasomal degradation. Significantly, PSMD3 is highly expressed in malignant and metastatic breast cancers, particularly triple-negative breast cancer. The compelling evidence strongly suggests PSMD3 as a promising target for developing a therapy against metastatic breast cancer. These findings underscore the high potential of c-di-GMP as a safe and effective therapeutic agent for metastatic cancers by targeting the PSMD3-TBK1-NF-κB pathway.

癌症转移是癌症相关死亡的主要原因,但有效的治疗方法仍然有限。迫切需要开发新的治疗策略来对抗转移。在这项研究中,我们通过体外和体内模型证明了细菌细胞内信号分子环二gmp (c-二gmp,或cdG)对癌症转移,特别是转移性乳腺癌具有有效的抑制作用,对小鼠几乎没有毒性。有趣的是,这种抗转移功能是通过抑制NF-κB信号通路实现的,而NF-κB信号通路对癌症的进展和转移很重要,但独立于STING(一种先前在哺乳动物细胞中发现的c-di-GMP传感器和NF-κB调节剂)。令人惊讶的是,c-di-GMP通过直接结合蛋白酶体26S亚基非atp酶3 (PSMD3)抑制NF-κB活性(p-p65),我们确定PSMD3是一种新的TBK1结合激活剂,并破坏PSMD3和TBK1之间的相互作用。这种PSMD3-TBK1相互作用促进了TBK1的磷酸化和激活,代表了PSMD3的非规范功能,不同于其在蛋白酶体降解中的既定作用。值得注意的是,PSMD3在恶性和转移性乳腺癌,特别是三阴性乳腺癌中高度表达。令人信服的证据强烈表明,PSMD3是开发一种治疗转移性乳腺癌的有希望的靶点。这些发现强调了c-di-GMP通过靶向PSMD3-TBK1-NF-κB通路作为转移性癌症安全有效的治疗药物的巨大潜力。
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引用次数: 0
Region-resolved proteomic map of the human brain: functional interconnections and neurological implications. 人类大脑的区域分辨蛋白质组图:功能互连和神经学意义。
IF 52.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-04 DOI: 10.1038/s41392-025-02554-8
Pei-Pei Zhang, Man-Sheng Li, Jia Zhou, Chu-Hong Zhu, Rui Tang, Zhi-Cheng He, Xiao-Hong Yao, Yi-Fang Ping, Dong-Fang Xiang, Le-Yong Tan, Yu-Jie Wang, Shuai Wang, Si-Si Li, Jie Ma, Yun-Ping Zhu, Xiu-Wu Bian, Ling Leng

While progress has been made in transcriptomic profiling of the human brain, functional characterization of brain regions and their interactions on the basis of regional protein expression remains limited. Here, we constructed a proteomic map from thirteen anatomical brain regions of eight cadaver donors to elucidate region-specific protein expression patterns and their implications for brain function. The results underscore the interconnectivity of the four cerebral lobes, suggesting facilitated information integration through large-scale neural networks. We propose a three-module framework (cortical integration module [frontal lobe, temporal lobe, parietal lobe, occipital lobe], limbic-relay network [amygdaloid nucleus, hippocampus, thalamus/hypothalamus], and midline regulatory axis [thalamus/hypothalamus, corpus callosum, ventricles, optic chiasm]) and provide molecular evidence supporting the potential involvement of the midline regulatory axis, brainstem, and cerebellum in higher-order cognitive functions. The midline regulatory axis may play a critical but underexplored role in neurodevelopment, interregional signaling, and structural homeostasis, potentially through efficient synaptic function, energy metabolism, and extracellular matrix integrity. This analysis may enhance the understanding of brain physiology and highlight the need to integrate proteomic and transcriptomic approaches in the study of brain function and neurological disorders.

虽然人类大脑的转录组学分析取得了进展,但基于区域蛋白表达的大脑区域功能表征及其相互作用仍然有限。在这里,我们从8具尸体供体的13个解剖脑区域构建了蛋白质组学图,以阐明区域特异性蛋白质表达模式及其对脑功能的影响。研究结果强调了四个脑叶的互联性,表明通过大规模神经网络促进了信息整合。我们提出了一个三模块框架(皮质整合模块[额叶、颞叶、顶叶、枕叶]、边缘-中转网络[杏仁核、海马、丘脑/下丘脑]和中线调节轴[丘脑/下丘脑、胼胝体、脑室、视交叉]),并提供了支持中线调节轴、脑干和小脑参与高阶认知功能的分子证据。中线调节轴可能在神经发育、区域间信号传导和结构稳态中发挥关键作用,但尚未得到充分研究,可能通过有效的突触功能、能量代谢和细胞外基质完整性发挥作用。这一分析可能会增强对脑生理学的理解,并强调在脑功能和神经系统疾病研究中整合蛋白质组学和转录组学方法的必要性。
{"title":"Region-resolved proteomic map of the human brain: functional interconnections and neurological implications.","authors":"Pei-Pei Zhang, Man-Sheng Li, Jia Zhou, Chu-Hong Zhu, Rui Tang, Zhi-Cheng He, Xiao-Hong Yao, Yi-Fang Ping, Dong-Fang Xiang, Le-Yong Tan, Yu-Jie Wang, Shuai Wang, Si-Si Li, Jie Ma, Yun-Ping Zhu, Xiu-Wu Bian, Ling Leng","doi":"10.1038/s41392-025-02554-8","DOIUrl":"10.1038/s41392-025-02554-8","url":null,"abstract":"<p><p>While progress has been made in transcriptomic profiling of the human brain, functional characterization of brain regions and their interactions on the basis of regional protein expression remains limited. Here, we constructed a proteomic map from thirteen anatomical brain regions of eight cadaver donors to elucidate region-specific protein expression patterns and their implications for brain function. The results underscore the interconnectivity of the four cerebral lobes, suggesting facilitated information integration through large-scale neural networks. We propose a three-module framework (cortical integration module [frontal lobe, temporal lobe, parietal lobe, occipital lobe], limbic-relay network [amygdaloid nucleus, hippocampus, thalamus/hypothalamus], and midline regulatory axis [thalamus/hypothalamus, corpus callosum, ventricles, optic chiasm]) and provide molecular evidence supporting the potential involvement of the midline regulatory axis, brainstem, and cerebellum in higher-order cognitive functions. The midline regulatory axis may play a critical but underexplored role in neurodevelopment, interregional signaling, and structural homeostasis, potentially through efficient synaptic function, energy metabolism, and extracellular matrix integrity. This analysis may enhance the understanding of brain physiology and highlight the need to integrate proteomic and transcriptomic approaches in the study of brain function and neurological disorders.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":"43"},"PeriodicalIF":52.7,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12868004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146114133","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
Inducible CD147 up-regulation boosts extended SARS-CoV-2 infection triggering severe COVID-19 independent of ACE2. 诱导性CD147上调可促进SARS-CoV-2延长感染,引发不依赖ACE2的严重COVID-19。
IF 52.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-03 DOI: 10.1038/s41392-025-02551-x
Ke Wang, Peng Lin, Ruo Chen, Qiang Huang, Yizhen Zhao, Lei Zhang, Yongxiang Zhao, Liping Zhong, Ke Xu, Linlin Bao, Youchun Wang, Chuan Qin, Guizhen Wu, Hai Zhang, Jiejie Geng, Zheng Zhang, Ding Wei, Xiaochun Chen, Hao Tang, Liu Yang, Xu Yang, Xiuxuan Sun, Rui Yao, Ye Zhao, Weijun Qin, Zhiwei Yang, Liang Chen, Huijie Bian, Zhi-Nan Chen, Ping Zhu

The high mortality caused by severe COVID-19 poses great challenges to the public health. However, the underlying pathogenesis of severe cases remains unclear. Here, we find that SARS-CoV-2 infection boosts CD147 inducible up-regulation in the lung tissues of virus-infected rhesus macaques coupled with down-regulated membrane-bound ACE2, which conduces to extended virus infection and severe pathological lesions. Specifically, SARS-CoV-2 infection enhances the expression of transcriptional factor aryl hydrocarbon receptor and facilitates its nucleus translocation, which causes CD147 gene transcription and its up-regulation in protein level, thereby leading to virus susceptibility of the hosts and extended virus infection. Meanwhile, SARS-CoV-2 infection triggers immune imbalance of lung tissues by promoting cell death of CD4 + T cells and B cells and mediating abnormal cell-cell communications, especially for M2 macrophages. Meplazumab, a humanized anti-CD147 antibody, effectively inhibits virus entry and cytokine level, and restores immune balance in the lung tissues of virus-infected rhesus macaque model. Importantly, we further present the cryo-EM structure of CD147-spike complex, and identify five pairs of functional residues for their interaction, which could be interrupted by Meplazumab via steric hindrance effect. Our findings provide direct evidence for CD147-SARS-CoV-2 spike interaction and uncover the pathogenesis of severe COVID-19 caused by CD147-mediated extended virus infection.

COVID-19严重疫情造成的高死亡率给公共卫生带来了巨大挑战。然而,严重病例的潜在发病机制尚不清楚。本研究发现,SARS-CoV-2感染可促进病毒感染恒河猴肺组织中CD147诱导的上调,并伴随膜结合ACE2的下调,从而导致病毒感染的延长和严重的病理病变。具体而言,SARS-CoV-2感染可增强转录因子芳烃受体的表达,促进其核易位,导致CD147基因转录并在蛋白水平上上调,从而导致宿主的病毒易感性和病毒感染的延长。同时,SARS-CoV-2感染通过促进CD4 + T细胞和B细胞的细胞死亡,介导细胞间通信异常,尤其是M2巨噬细胞,引发肺组织免疫失衡。Meplazumab是一种人源抗cd147抗体,可有效抑制病毒进入和细胞因子水平,恢复病毒感染恒河猴模型肺组织的免疫平衡。重要的是,我们进一步展示了CD147-spike复合物的冷冻电镜结构,并鉴定了它们相互作用的5对功能残基,这些残基可以通过位阻效应被Meplazumab打断。我们的研究结果为CD147-SARS-CoV-2刺突相互作用提供了直接证据,并揭示了cd147介导的扩展病毒感染引起的严重COVID-19的发病机制。
{"title":"Inducible CD147 up-regulation boosts extended SARS-CoV-2 infection triggering severe COVID-19 independent of ACE2.","authors":"Ke Wang, Peng Lin, Ruo Chen, Qiang Huang, Yizhen Zhao, Lei Zhang, Yongxiang Zhao, Liping Zhong, Ke Xu, Linlin Bao, Youchun Wang, Chuan Qin, Guizhen Wu, Hai Zhang, Jiejie Geng, Zheng Zhang, Ding Wei, Xiaochun Chen, Hao Tang, Liu Yang, Xu Yang, Xiuxuan Sun, Rui Yao, Ye Zhao, Weijun Qin, Zhiwei Yang, Liang Chen, Huijie Bian, Zhi-Nan Chen, Ping Zhu","doi":"10.1038/s41392-025-02551-x","DOIUrl":"10.1038/s41392-025-02551-x","url":null,"abstract":"<p><p>The high mortality caused by severe COVID-19 poses great challenges to the public health. However, the underlying pathogenesis of severe cases remains unclear. Here, we find that SARS-CoV-2 infection boosts CD147 inducible up-regulation in the lung tissues of virus-infected rhesus macaques coupled with down-regulated membrane-bound ACE2, which conduces to extended virus infection and severe pathological lesions. Specifically, SARS-CoV-2 infection enhances the expression of transcriptional factor aryl hydrocarbon receptor and facilitates its nucleus translocation, which causes CD147 gene transcription and its up-regulation in protein level, thereby leading to virus susceptibility of the hosts and extended virus infection. Meanwhile, SARS-CoV-2 infection triggers immune imbalance of lung tissues by promoting cell death of CD4 + T cells and B cells and mediating abnormal cell-cell communications, especially for M2 macrophages. Meplazumab, a humanized anti-CD147 antibody, effectively inhibits virus entry and cytokine level, and restores immune balance in the lung tissues of virus-infected rhesus macaque model. Importantly, we further present the cryo-EM structure of CD147-spike complex, and identify five pairs of functional residues for their interaction, which could be interrupted by Meplazumab via steric hindrance effect. Our findings provide direct evidence for CD147-SARS-CoV-2 spike interaction and uncover the pathogenesis of severe COVID-19 caused by CD147-mediated extended virus infection.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":"42"},"PeriodicalIF":52.7,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12864993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146107040","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
First-line Aumolertinib (EGFR tyrosine kinase inhibitor) plus apatinib (VEGFR inhibitor) versus aumolertinib in EGFR-mutant non-small cell lung cancer patients: a randomized, multicenter, phase II trial. 一线奥莫替尼(EGFR酪氨酸激酶抑制剂)加阿帕替尼(VEGFR抑制剂)与奥莫替尼治疗EGFR突变的非小细胞肺癌患者:一项随机、多中心、II期试验
IF 52.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-02 DOI: 10.1038/s41392-025-02550-y
Fan Zhang, Zhendong Zheng, Hongmei Zhang, Xiaolong Yan, Zhefeng Liu, Fan Yang, Juyi Wen, Xin Gan, Lin Wu, Shundong Cang, Hongmei Wang, Jun Zhao, Liang Peng, Xiaosong Li, Zaiwen Fan, Ge Shen, Qiong Zhou, Jinjing Zou, Yu Xu, Lei Zhang, Mingfang Zhao, Shangli Cai, Yi Hu

Inactivating vascular endothelial growth factor receptor (VEGFR) may improve the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). The ATTENTION study (phase II, open-label, randomized, multicenter trial (Registration number: ChiCTR2100047453), evaluated the efficacy and safety of aumolertinib plus apatinib vs. aumolertinib alone in untreated, EGFR-mutant, advanced NSCLC. The primary endpoint was the 18-month PFS rate. Across 18 centers in China, 104 patients were enrolled to receive aumolertinib alone (n = 51) or with apatinib (n = 53). At a median follow-up duration of 19.4 months, aumolertinib plus apatinib outperformed aumolertinib alone in terms of the 18-month progression-free survival (PFS) rate (74% vs. 50%, P = 0.036), median PFS (not reached [NR] vs. 20.1 months, hazard ratio [HR] = 0.41, P = 0.017), and objective response rate (79% vs. 59%, P = 0.024). No grade 4/5 treatment-related adverse effects (TRAEs) were observed, whereas grade 3 TRAEs occurred in 38% vs. 27% of patients, with hypertension (11%) and platelet count decrease (9%) being most common in the combination arm. Exploratory analysis revealed that PFS benefits from aumolertinib plus apatinib predominantly in those with TP53 mutations. As an infusion-free option, aumolertinib plus apatinib demonstrated PFS benefits with manageable safety in patients with untreated, EGFR-mutant, advanced NSCLC.

灭活血管内皮生长因子受体(VEGFR)可能会提高表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKIs)在EGFR突变型非小细胞肺癌(NSCLC)中的疗效。ATTENTION研究(II期,开放标签,随机,多中心试验(注册号:ChiCTR2100047453),评估了奥莫替尼联合阿帕替尼与单独奥莫替尼治疗未经治疗的egfr突变晚期NSCLC的疗效和安全性。主要终点是18个月的PFS率。在中国的18个中心,104名患者入组接受单独奥莫替尼(n = 51)或阿帕替尼(n = 53)。在中位随访时间为19.4个月时,奥莫替尼联合阿帕替尼在18个月无进展生存(PFS)率(74% vs 50%, P = 0.036)、中位PFS(未达到[NR] vs. 20.1个月,风险比[HR] = 0.41, P = 0.017)和客观缓解率(79% vs. 59%, P = 0.024)方面优于奥莫替尼单独治疗。未观察到4/5级治疗相关不良反应(TRAEs),而3级TRAEs发生率分别为38%和27%,其中高血压(11%)和血小板计数下降(9%)在联合治疗组中最常见。探索性分析显示,奥莫替尼加阿帕替尼对PFS的益处主要发生在TP53突变的患者身上。作为一种无输注的选择,aumolertinib + apatinib在未经治疗的egfr突变的晚期NSCLC患者中显示出PFS的益处和可控的安全性。
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引用次数: 0
Wnt-associated DKK3 in keratinocytes mediates radiation-induced hyperplasia, dermatitis and skin fibrosis. 角化细胞中wnt相关的DKK3介导辐射诱导的增生、皮炎和皮肤纤维化。
IF 52.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-02 DOI: 10.1038/s41392-025-02541-z
Li Li, Ramon Lopez Perez, Khuram Shehzad, Richard Jennemann, Claudia Schmidt, Thomas Walle, Alexandra Tietz-Dahlfuß, Elisabeth Grimm, Joscha A Kraske, Peter Häring, Uladzimir Barayeu, Tobias P Dick, Luxi Ye, Stephan A Braun, Michael Hertl, Thomas Worzfeld, Thorsten Wiech, Huihui Ji, Jing Su, Jonathan M Schneeweiss, Muzi Liu, Katharina Kommoss, Matthias Heikenwälder, Bingwen Zou, Sabrina Mücklich, Kerstin Steinbrink, Verena K Raker, Wenjun Wu, Elfriede Noessner, Hermann-Josef Gröne, Peter J Nelson, Roger Sandhoff, Peter E Huber

Radiotherapy remains a mainstay of cancer treatment. However, radiotherapy can also elicit acute and chronic adverse effects, including dermal inflammation and skin fibrosis. A comprehensive understanding of the underlying fibrotic processes remains elusive, and currently, no established treatment options exist. Canonical Wnt signaling has emerged as a significant player in fibrotic conditions. The Dickkopf (DKK) protein family comprises key modulators of Wnt signaling. To define the function of DKK3 in radiation-induced skin damage, we combined complementary in vivo and in vitro approaches, including a 3D human skin model, mice with cell-type-specific Dkk3 deletions, and irradiated human skin specimens. Our study revealed the pivotal role of DKK3 in regulating the response of the skin to radiation, with diminished DKK3 significantly mitigating radiation-induced skin damage. We found that radiation increases DKK3 expression in basal keratinocytes, leading to elevated ROS levels, TGF-β-mediated Wnt activation, epidermal hyperplasia, and subsequent skin fibrosis. Increased keratinocyte expression of DKK3 also drives macrophage polarization toward a CD163highCD206high profibrotic M2 phenotype, activating myofibroblasts and leading to fibrosis. Notably, DKK3 deficiency in keratinocytes markedly reduces radiation-induced dermal hyperplasia and fibrosis, identifying DKK3 as a key regulator of cutaneous radiation responses. These findings position DKK3 as a promising upstream modulator of TGF-β signaling for mitigating radiation-induced dermatitis and fibrosis, with potential relevance to other fibrotic diseases.

放射治疗仍然是癌症治疗的主要手段。然而,放射治疗也可引起急性和慢性不良反应,包括皮肤炎症和皮肤纤维化。对潜在纤维化过程的全面了解仍然难以捉摸,目前,没有确定的治疗方案存在。典型Wnt信号已成为纤维化条件下的重要参与者。Dickkopf (DKK)蛋白家族包括Wnt信号的关键调节因子。为了确定DKK3在辐射诱导的皮肤损伤中的功能,我们结合了互补的体内和体外方法,包括3D人体皮肤模型,具有细胞类型特异性DKK3缺失的小鼠和辐照的人体皮肤标本。我们的研究揭示了DKK3在调节皮肤对辐射的反应中的关键作用,DKK3的减少显著减轻了辐射引起的皮肤损伤。我们发现,辐射增加基底角化细胞中DKK3的表达,导致ROS水平升高,TGF-β介导的Wnt激活,表皮增生和随后的皮肤纤维化。角化细胞DKK3表达的增加也驱动巨噬细胞向cd163high - cd206high - profibrosis M2表型极化,激活肌成纤维细胞并导致纤维化。值得注意的是,角化细胞中DKK3的缺乏显著减少了辐射诱导的皮肤增生和纤维化,这表明DKK3是皮肤辐射反应的关键调节因子。这些发现表明,DKK3是一种有希望的TGF-β信号上游调节剂,可缓解辐射诱导的皮炎和纤维化,并可能与其他纤维化疾病相关。
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引用次数: 0
期刊
Signal Transduction and Targeted Therapy
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