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Hypoxia-induced nuclear localization of ubiquinol-cytochrome-c reductase complex assembly factor 3 (UQCC3) in hepatocellular carcinoma. 缺氧诱导肝细胞癌中泛醌-细胞色素-c还原酶复合物组装因子3(UQCC3)的核定位。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-29 DOI: 10.1038/s41392-024-01909-x
Yun Yang, Yinhao Wei, Yiying Sun, Yong Zhou, Hanshuo Yang
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引用次数: 0
Proximity-dependent protein (de)stabilization: screening the human ORFeome for protein degraders and stabilizers. 近距离依赖性蛋白质(去)稳定化:筛选人类 ORFeome 中的蛋白质降解剂和稳定剂。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-26 DOI: 10.1038/s41392-024-01884-3
Thomas Hermanns, Kay Hofmann
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引用次数: 0
CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation. 抑制 CDC7 可通过 MYC 降解抑制肺癌和前列腺癌的神经内分泌转化。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-26 DOI: 10.1038/s41392-024-01908-y
Alvaro Quintanal-Villalonga, Kenta Kawasaki, Esther Redin, Fathema Uddin, Swanand Rakhade, Vidushi Durani, Amin Sabet, Moniquetta Shafer, Wouter R Karthaus, Samir Zaidi, Yingqian A Zhan, Parvathy Manoj, Harsha Sridhar, Dennis Kinyua, Hong Zhong, Barbara P Mello, Metamia Ciampricotti, Umesh K Bhanot, Irina Linkov, Juan Qiu, Radhika A Patel, Colm Morrissey, Sanjoy Mehta, Jesse Barnes, Michael C Haffner, Nicholas D Socci, Richard P Koche, Elisa de Stanchina, Sonia Molina-Pinelo, Sohrab Salehi, Helena A Yu, Joseph M Chan, Charles M Rudin

Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.

神经内分泌(NE)转化是肺腺癌和前列腺癌对靶向治疗产生耐药性的一种机制,会导致不良预后。迄今为止,即使可以通过肿瘤中出现的肿瘤蛋白 P53(TP53)和视网膜母细胞瘤转录核心抑制因子 1(RB1)突变来识别高风险转化患者,也没有任何治疗策略可以预防或延缓组织学转化。在TP53/RB1共同失活后,细胞周期激酶细胞分裂周期7(CDC7)在肿瘤NE转化的初始阶段出现上调,导致肿瘤对CDC7抑制剂simurosertib敏感。在体内NE转化模型中,CDC7抑制剂通过诱导蛋白酶体介导的MYC原癌基因(MYC)降解,抑制了NE的转分化并延长了对靶向治疗的反应。异位过表达耐降解的MYC异构体可重建靶向治疗观察到的NE转化表型,即使在simurosertib存在的情况下也是如此。在肺癌和前列腺小细胞癌模型中,CDC7抑制也明显延长了对标准细胞毒性药物(顺铂、伊立替康)的反应。这些研究结果表明,CDC7抑制是一种治疗策略,可以限制细胞系的可塑性,并有效治疗新发或转化后的NE肿瘤。由于simurosertib的临床疗效试验正在进行中,这一概念可随时应用于有转化风险的患者。
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引用次数: 0
Sensory neurons: unveiling the symphony of wound healing. 感觉神经元:揭开伤口愈合交响乐的神秘面纱。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-24 DOI: 10.1038/s41392-024-01880-7
Dongsheng Jiang, Hans-Günther Machens, Yuval Rinkevich
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引用次数: 0
Targeting cytokine and chemokine signaling pathways for cancer therapy. 针对细胞因子和趋化因子信号通路进行癌症治疗。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-22 DOI: 10.1038/s41392-024-01868-3
Ming Yi, Tianye Li, Mengke Niu, Haoxiang Zhang, Yuze Wu, Kongming Wu, Zhijun Dai

Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and overcome resistance to conventional therapies. In this review, we summarized the current understanding and therapeutic implications of targeting cytokine and chemokine signaling pathways in cancer. By exploring the roles of these molecules in tumor biology and the immune response, we highlighted the development of novel therapeutic agents aimed at modulating these pathways to combat cancer. The review elaborated on the dual nature of cytokines as both promoters and suppressors of tumorigenesis, depending on the context, and discussed the challenges and opportunities this presents for therapeutic intervention. We also examined the latest advancements in targeted therapies, including monoclonal antibodies, bispecific antibodies, receptor inhibitors, fusion proteins, engineered cytokine variants, and their impact on tumor growth, metastasis, and the tumor microenvironment. Additionally, we evaluated the potential of combining these targeted therapies with other treatment modalities to overcome resistance and improve patient outcomes. Besides, we also focused on the ongoing research and clinical trials that are pivotal in advancing our understanding and application of cytokine- and chemokine-targeted therapies for cancer patients.

细胞因子是调节免疫反应和细胞行为的关键,在正常生理和癌症等疾病的病理过程中发挥着双重作用。这些分子包括白细胞介素、干扰素、肿瘤坏死因子、趋化因子以及 TGF-β、VEGF 和 EGF 等生长因子,它们可以促进或抑制肿瘤生长,影响肿瘤微环境,并影响癌症治疗的效果。针对这些通路的最新研究进展已显示出良好的治疗潜力,为调节免疫系统、抑制肿瘤进展和克服对传统疗法的耐药性提供了新策略。在这篇综述中,我们总结了目前对靶向癌症细胞因子和趋化因子信号通路的理解和治疗意义。通过探讨这些分子在肿瘤生物学和免疫反应中的作用,我们强调了旨在调节这些通路以抗击癌症的新型治疗药物的开发。综述阐述了细胞因子的双重性质,即根据具体情况,它们既是肿瘤发生的促进因素,也是肿瘤发生的抑制因素,并讨论了这给治疗干预带来的挑战和机遇。我们还研究了靶向疗法的最新进展,包括单克隆抗体、双特异性抗体、受体抑制剂、融合蛋白、工程细胞因子变体,以及它们对肿瘤生长、转移和肿瘤微环境的影响。此外,我们还评估了将这些靶向疗法与其他治疗方式相结合以克服耐药性和改善患者预后的潜力。此外,我们还关注正在进行的研究和临床试验,这些研究和临床试验对于加深我们对细胞因子和趋化因子靶向疗法的理解和应用于癌症患者至关重要。
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引用次数: 0
In vivo evaluation of guide-free Cas9-induced safety risks in a pig model. 在猪模型中对无向导 Cas9 诱导的安全风险进行体内评估。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-19 DOI: 10.1038/s41392-024-01905-1
Weikai Ge, Shixue Gou, Xiaozhu Zhao, Qin Jin, Zhenpeng Zhuang, Yu Zhao, Yanhui Liang, Zhen Ouyang, Xiaoyi Liu, Fangbing Chen, Hui Shi, Haizhao Yan, Han Wu, Liangxue Lai, Kepin Wang

The CRISPR/Cas9 system has shown great potential for treating human genetic diseases through gene therapy. However, there are concerns about the safety of this system, specifically related to the use of guide-free Cas9. Previous studies have shown that guide-free Cas9 can induce genomic instability in vitro. However, the in vivo safety risks associated with guide-free Cas9 have not been evaluated, which is necessary for the development of gene therapy in clinical settings. In this study, we used doxycycline-inducible Cas9-expressing pigs to evaluate the safety risks of guide-free Cas9 in vivo. Our findings demonstrated that expression of guide-free Cas9 could induce genomic damages and transcriptome changes in vivo. The severity of the genomic damages and transcriptome changes were correlate with the expression levels of Cas9 protein. Moreover, prolonged expression of Cas9 in pigs led to abnormal phenotypes, including a significant decrease in body weight, which may be attributable to genomic damage-induced nutritional absorption and metabolic dysfunction. Furthermore, we observed an increase in whole-genome and tumor driver gene mutations in pigs with long-term Cas9 expression, raising the risk of tumor occurrence. Our in vivo evaluation of guide-free Cas9 in pigs highlights the necessity of considering and monitoring the detrimental effects of Cas9 alone as genome editing via the CRISPR/Cas9 system is implemented in clinical gene therapy. This research emphasizes the importance of further study and implementation of safety measures to ensure the successful and safe application of the CRISPR/Cas9 system in clinical practice.

CRISPR/Cas9 系统已显示出通过基因疗法治疗人类遗传疾病的巨大潜力。然而,人们对该系统的安全性表示担忧,特别是与使用无向导 Cas9 有关的问题。先前的研究表明,无向导 Cas9 可在体外诱导基因组不稳定性。然而,与无向导 Cas9 相关的体内安全性风险尚未得到评估,而这是在临床环境中开发基因疗法所必需的。在这项研究中,我们使用强力霉素诱导的Cas9表达猪来评估无向导Cas9在体内的安全风险。我们的研究结果表明,无向导 Cas9 的表达可诱导体内基因组损伤和转录组变化。基因组损伤和转录组变化的严重程度与 Cas9 蛋白的表达水平相关。此外,在猪体内长时间表达 Cas9 会导致异常表型,包括体重显著下降,这可能是由于基因组损伤引起的营养吸收和代谢功能障碍。此外,我们观察到长期表达 Cas9 的猪的全基因组和肿瘤驱动基因突变增加,从而提高了肿瘤发生的风险。我们对猪体内无向导 Cas9 的体内评估突出表明,在临床基因治疗中通过 CRISPR/Cas9 系统实施基因组编辑时,有必要考虑和监测 Cas9 本身的有害影响。这项研究强调了进一步研究和实施安全措施的重要性,以确保在临床实践中成功、安全地应用CRISPR/Cas9系统。
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引用次数: 0
Heterogeneous hybrid immunity against Omicron variant JN.1 at 11 months following breakthrough infection. 突破性感染后 11 个月,针对 Omicron 变体 JN.1 的异质混合免疫。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-19 DOI: 10.1038/s41392-024-01898-x
Xuan He, Jingyou Yu, Jiajing Jiang, Jinyuan Liu, Qi Qi, Dan Liu, Weimin Li
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引用次数: 0
Bacterial persisters: molecular mechanisms and therapeutic development. 细菌宿主:分子机制和治疗方法的开发。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-17 DOI: 10.1038/s41392-024-01866-5
Hongxia Niu, Jiaying Gu, Ying Zhang

Persisters refer to genetically drug susceptible quiescent (non-growing or slow growing) bacteria that survive in stress environments such as antibiotic exposure, acidic and starvation conditions. These cells can regrow after stress removal and remain susceptible to the same stress. Persisters are underlying the problems of treating chronic and persistent infections and relapse infections after treatment, drug resistance development, and biofilm infections, and pose significant challenges for effective treatments. Understanding the characteristics and the exact mechanisms of persister formation, especially the key molecules that affect the formation and survival of the persisters is critical to more effective treatment of chronic and persistent infections. Currently, genes related to persister formation and survival are being discovered and confirmed, but the mechanisms by which bacteria form persisters are very complex, and there are still many unanswered questions. This article comprehensively summarizes the historical background of bacterial persisters, details their complex characteristics and their relationship with antibiotic tolerant and resistant bacteria, systematically elucidates the interplay between various bacterial biological processes and the formation of persister cells, as well as consolidates the diverse anti-persister compounds and treatments. We hope to provide theoretical background for in-depth research on mechanisms of persisters and suggest new ideas for choosing strategies for more effective treatment of persistent infections.

固着菌是指在抗生素暴露、酸性和饥饿条件等应激环境中存活的易受基因药物影响的静止(不生长或生长缓慢)细菌。这些细胞在压力消除后可以重新生长,并对相同的压力保持敏感。持续存在的细菌是治疗慢性和持续性感染、治疗后复发感染、耐药性产生和生物膜感染等问题的根源,对有效治疗构成重大挑战。要想更有效地治疗慢性和顽固性感染,就必须了解顽固菌形成的特点和确切机制,特别是影响顽固菌形成和存活的关键分子。目前,与宿主形成和存活有关的基因正在被发现和证实,但细菌形成宿主的机制非常复杂,仍有许多未解之谜。本文全面总结了细菌持久体的历史背景,详细阐述了细菌持久体的复杂特性及其与抗生素耐受性和耐药性细菌的关系,系统阐明了细菌各种生物学过程与持久体细胞形成之间的相互作用,并整合了多种抗持久体化合物和治疗方法。我们希望为深入研究顽固菌的机制提供理论背景,并为选择更有效治疗顽固性感染的策略提出新思路。
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引用次数: 0
Exploring treatment options in cancer: Tumor treatment strategies. 探索癌症治疗方案:肿瘤治疗策略。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-17 DOI: 10.1038/s41392-024-01856-7
Beilei Liu, Hongyu Zhou, Licheng Tan, Kin To Hugo Siu, Xin-Yuan Guan

Traditional therapeutic approaches such as chemotherapy and radiation therapy have burdened cancer patients with onerous physical and psychological challenges. Encouragingly, the landscape of tumor treatment has undergone a comprehensive and remarkable transformation. Emerging as fervently pursued modalities are small molecule targeted agents, antibody-drug conjugates (ADCs), cell-based therapies, and gene therapy. These cutting-edge treatment modalities not only afford personalized and precise tumor targeting, but also provide patients with enhanced therapeutic comfort and the potential to impede disease progression. Nonetheless, it is acknowledged that these therapeutic strategies still harbour untapped potential for further advancement. Gaining a comprehensive understanding of the merits and limitations of these treatment modalities holds the promise of offering novel perspectives for clinical practice and foundational research endeavours. In this review, we discussed the different treatment modalities, including small molecule targeted drugs, peptide drugs, antibody drugs, cell therapy, and gene therapy. It will provide a detailed explanation of each method, addressing their status of development, clinical challenges, and potential solutions. The aim is to assist clinicians and researchers in gaining a deeper understanding of these diverse treatment options, enabling them to carry out effective treatment and advance their research more efficiently.

化疗和放疗等传统治疗方法给癌症患者带来了沉重的生理和心理负担。令人鼓舞的是,肿瘤治疗的格局已经发生了全面而显著的转变。小分子靶向药物、抗体药物共轭物(ADC)、细胞疗法和基因疗法成为人们热衷追求的治疗方式。这些前沿治疗模式不仅能实现个性化和精确的肿瘤靶向治疗,还能为患者提供更舒适的治疗环境,并有可能阻碍疾病的进展。尽管如此,这些治疗策略仍然蕴藏着有待进一步开发的潜力。全面了解这些治疗方法的优点和局限性,有望为临床实践和基础研究工作提供新的视角。在这篇综述中,我们讨论了不同的治疗模式,包括小分子靶向药物、多肽药物、抗体药物、细胞疗法和基因疗法。它将对每种方法进行详细说明,探讨其发展现状、临床挑战和潜在的解决方案。目的是帮助临床医生和研究人员更深入地了解这些不同的治疗方案,使他们能够更有效地开展治疗和推进研究。
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引用次数: 0
The Ca2+-sensing receptor and the pocketome: comparing nature's complexity with human intervention in receptor modulation. Ca2+感应受体和口袋体:比较大自然的复杂性和人类对受体调节的干预。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-15 DOI: 10.1038/s41392-024-01863-8
Edda S F Matthees, Carsten Hoffmann
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引用次数: 0
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Signal Transduction and Targeted Therapy
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