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Progress in RAS-targeted therapeutic strategies: From small molecule inhibitors to proteolysis targeting chimeras ras靶向治疗策略的进展:从小分子抑制剂到靶向嵌合体的蛋白水解。
IF 13.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-11-27 DOI: 10.1002/med.21993
Xinchen Lu, Jinmei Jin, Ye Wu, Xiaoxia Liu, Xiaohui Liang, Jiayi Lin, Qingyan Sun, Jiangjiang Qin, Weidong Zhang, Xin Luan

As a widely considerable target in chemical biology and pharmacological research, rat sarcoma (RAS) gene mutations play a critical driving factor in several fatal cancers. Despite the great progress of RAS subtype-specific inhibitors, rapid acquired drug resistance could limit their further clinical applications. Proteolysis targeting chimera (PROTAC) has emerged as a powerful tool to handle “undruggable” targets and exhibited significant therapeutic benefit for the combat of drug resistance. Owing to unique molecular mechanism and binding kinetics, PROTAC is expected to become a feasible strategy to break the bottleneck of classical RAS inhibitors. This review aims to discuss the current advances of RAS inhibitors and especially focus on PROTAC strategy targeting RAS mutations and their downstream effectors for relevant cancer treatment.

大鼠肉瘤(rat sarcoma, RAS)基因突变在多种致死性癌症中起着重要的驱动作用,是化学生物学和药理学研究中广泛关注的靶点。尽管RAS亚型特异性抑制剂取得了很大进展,但快速获得性耐药可能限制其进一步的临床应用。蛋白水解靶向嵌合体(Proteolysis targeting chimera, PROTAC)已成为处理“不可药物”靶点的有力工具,并在对抗耐药性方面显示出显著的治疗效果。由于其独特的分子机制和结合动力学,PROTAC有望成为突破经典RAS抑制剂瓶颈的可行策略。本文综述了RAS抑制剂的研究进展,重点介绍了靶向RAS突变及其下游效应物的PROTAC策略在相关癌症治疗中的应用。
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引用次数: 0
COVID-19 cooling: Nanostrategies targeting cytokine storm for controlling severe and critical symptoms COVID-19降温:针对细胞因子风暴的纳米策略控制重症和危重症状。
IF 13.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-11-21 DOI: 10.1002/med.21997
Yu Zheng, Yuke Li, Mao Li, Rujing Wang, Yuhong Jiang, Mengnan Zhao, Jun Lu, Rui Li, Xiaofang Li, Sanjun Shi

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to wreak havoc worldwide, the “Cytokine Storm” (CS, also known as the inflammatory storm) or Cytokine Release Syndrome has reemerged in the public consciousness. CS is a significant contributor to the deterioration of infected individuals. Therefore, CS control is of great significance for the treatment of critically ill patients and the reduction of mortality rates. With the occurrence of variants, concerns regarding the efficacy of vaccines and antiviral drugs with a broad spectrum have grown. We should make an effort to modernize treatment strategies to address the challenges posed by mutations. Thus, in addition to the requirement for additional clinical data to monitor the long-term effects of vaccines and broad-spectrum antiviral drugs, we can use CS as an entry point and therapeutic target to alleviate the severity of the disease in patients. To effectively combat the mutation, new technologies for neutralizing or controlling CS must be developed. In recent years, nanotechnology has been widely applied in the biomedical field, opening up a plethora of opportunities for CS. Here, we put forward the view of cytokine storm as a therapeutic target can be used to treat critically ill patients by expounding the relationship between coronavirus disease 2019 (COVID-19) and CS and the mechanisms associated with CS. We pay special attention to the representative strategies of nanomaterials in current neutral and CS research, as well as their potential chemical design and principles. We hope that the nanostrategies described in this review provide attractive treatment options for severe and critical COVID-19 caused by CS.

随着严重急性呼吸系统综合征冠状病毒2 (SARS-CoV-2)变体在全球范围内持续肆虐,“细胞因子风暴”(CS,也称为炎症风暴)或细胞因子释放综合征重新出现在公众意识中。CS是导致感染者病情恶化的重要因素。因此,控制CS对救治危重患者,降低病死率具有重要意义。随着变异的发生,人们越来越关注广谱疫苗和抗病毒药物的功效。我们应该努力使治疗策略现代化,以应对突变带来的挑战。因此,除了需要额外的临床数据来监测疫苗和广谱抗病毒药物的长期效果外,我们还可以将CS作为切入点和治疗靶点,以减轻患者疾病的严重程度。为了有效地对抗突变,必须开发中和或控制CS的新技术。近年来,纳米技术在生物医学领域的广泛应用,为计算机科学提供了大量的发展机会。本文通过阐述2019冠状病毒病(COVID-19)与CS的关系及其相关机制,提出细胞因子风暴作为治疗靶点可用于治疗危重患者的观点。我们特别关注当前中性和CS研究中纳米材料的代表性策略,以及它们潜在的化学设计和原理。我们希望本综述中描述的纳米策略为CS引起的重症和危重型COVID-19提供有吸引力的治疗选择。
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引用次数: 0
B-cell lymphoma-2 family proteins in the crosshairs: Small molecule inhibitors and activators for cancer therapy b细胞淋巴瘤-2家族蛋白的十字准星:用于癌症治疗的小分子抑制剂和激活剂。
IF 13.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-11-20 DOI: 10.1002/med.21999
Qineng Gong, Haojie Wang, Mi Zhou, Lu Zhou, Renxiao Wang, Yan Li

The B-cell lymphoma-2 (BCL-2) family of proteins plays a crucial role in the regulation of apoptosis, offering a dual mechanism for its control. Numerous studies have established a strong association between gene disorders of these proteins and the proliferation of diverse cancer cell types. Consequently, the identification and development of drugs targeting BCL-2 family proteins have emerged as a prominent area in antitumor therapy. Over the last two decades, several small-molecules have been designed to modulate the protein–protein interactions between anti- and proapoptotic BCL-2 proteins, effectively suppressing tumor growth and metastasis in vivo. The primary focus of research has been on developing BCL-2 homology 3 (BH3) mimetics to target antiapoptotic BCL-2 proteins, thereby competitively releasing proapoptotic BCL-2 proteins and restoring the blocked intrinsic apoptotic program. Additionally, for proapoptotic BCL-2 proteins, exogenous small molecules have been explored to activate cell apoptosis by directly interacting with executioner proteins such as BCL-2-associated X protein (BAX) or BCL-2 homologous antagonist/killer protein (BAK). In this comprehensive review, we summarize the inhibitors and activators (sensitizers) of BCL-2 family proteins developed over the past decades, highlighting their discovery, optimization, preclinical and clinical status, and providing an overall landscape of drug development targeting these proteins for therapeutic purposes.

b细胞淋巴瘤-2 (BCL-2)蛋白家族在细胞凋亡的调控中起着至关重要的作用,为其调控提供了双重机制。大量的研究已经证实了这些蛋白的基因紊乱与不同类型癌细胞的增殖之间的密切联系。因此,靶向BCL-2家族蛋白的药物鉴定和开发已成为抗肿瘤治疗的一个突出领域。在过去的二十年里,一些小分子已经被设计用来调节抗和促凋亡BCL-2蛋白之间的蛋白质相互作用,有效地抑制肿瘤的生长和体内转移。目前研究的重点是开发BCL-2同源3 (BH3)模拟物,以靶向抗凋亡的BCL-2蛋白,从而竞争性地释放促凋亡的BCL-2蛋白,恢复被阻断的内在凋亡程序。此外,对于促凋亡的BCL-2蛋白,已经探索了外源小分子通过直接与刽子手蛋白(如BCL-2相关X蛋白(BAX)或BCL-2同源拮抗剂/杀伤蛋白(BAK))相互作用来激活细胞凋亡。在这篇全面的综述中,我们总结了过去几十年来开发的BCL-2家族蛋白的抑制剂和激活剂(敏化剂),重点介绍了它们的发现、优化、临床前和临床状态,并提供了针对这些蛋白进行治疗的药物开发的总体前景。
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引用次数: 0
Revisiting Aurora Kinase B: A promising therapeutic target for cancer therapy 重新审视极光激酶B:一个有希望的癌症治疗靶点。
IF 13.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-11-20 DOI: 10.1002/med.21994
Naga Rajiv Lakkaniga, Zhengyu Wang, Yao Xiao, Anupreet Kharbanda, Li Lan, Hong-yu Li

Cancer continues to be a major health concern globally, although the advent of targeted therapy has revolutionized treatment options. Aurora Kinase B is a serine-threonine kinase that has been explored as an oncology therapeutic target for more than two decades. Aurora Kinase B inhibitors show promising biological results in in-vitro and in-vivo experiments. However, there are no inhibitors approved yet for clinical use, primarily because of the side effects associated with Aurora B inhibitors. Several studies demonstrate that Aurora B inhibitors show excellent synergy with various chemotherapeutic agents, radiation therapy, and targeted therapies. This makes it an excellent choice as an adjuvant therapy to first-line therapies, which greatly improves the therapeutic window and side effect profile. Recent studies indicate the role of Aurora B in some deadly cancers with limited therapeutic options, like triple-negative breast cancer and glioblastoma. Herein, we review the latest developments in Aurora Kinase B targeted research, with emphasis on its potential as an adjuvant therapy and its role in some of the most difficult-to-treat cancers.

癌症仍然是全球主要的健康问题,尽管靶向治疗的出现已经彻底改变了治疗方案。极光激酶B是一种丝氨酸-苏氨酸激酶,作为肿瘤治疗靶点已经被探索了二十多年。极光激酶B抑制剂在体外和体内实验中显示出有希望的生物学结果。然而,目前还没有批准用于临床的抑制剂,主要是因为与Aurora B抑制剂相关的副作用。几项研究表明,Aurora B抑制剂与各种化疗药物、放射治疗和靶向治疗具有良好的协同作用。这使其成为一线治疗的辅助治疗的绝佳选择,大大改善了治疗窗口和副作用概况。最近的研究表明,极光B在一些治疗方案有限的致命癌症中发挥着作用,比如三阴性乳腺癌和胶质母细胞瘤。在此,我们回顾了极光激酶B靶向研究的最新进展,重点介绍了它作为辅助治疗的潜力及其在一些最难治疗的癌症中的作用。
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引用次数: 0
The new direction of drug development: Degradation of undruggable targets through targeting chimera technology 药物开发的新方向:通过靶向嵌合体技术降解不可药物靶标。
IF 13.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-11-20 DOI: 10.1002/med.21992
Xuewu Liang, Hairu Ren, Fengyang Han, Renwen Liang, Jiayan Zhao, Hong Liu

Imbalances in protein and noncoding RNA levels in vivo lead to the occurrence of many diseases. In addition to the use of small molecule inhibitors and agonists to restore these imbalances, recently emerged targeted degradation technologies provide a new direction for disease treatment. Targeted degradation technology directly degrades target proteins or RNA by utilizing the inherent degradation pathways, thereby eliminating the functions of pathogenic proteins (or RNA) to treat diseases. Compared with traditional therapies, targeted degradation technology which avoids the principle of traditional inhibitor occupation drive, has higher efficiency and selectivity, and widely expands the range of drug targets. It is one of the most promising and hottest areas for future drug development. Herein, we systematically introduced the in vivo degradation systems applied to degrader design: ubiquitin–proteasome system, lysosomal degradation system, and RNA degradation system. We summarized the development progress, structural characteristics, and limitations of novel chimeric design technologies based on different degradation systems. In addition, due to the lack of clear ligand-binding pockets, about 80% of disease-associated proteins cannot be effectively intervened with through traditional therapies. We deeply elucidated how to use targeted degradation technology to discover and design molecules for representative undruggable targets including transcription factors, small GTPases, and phosphatases. Overall, this review provides a comprehensive and systematic overview of targeted degradation technology-related research advances and a new guidance for the chimeric design of undruggable targets.

体内蛋白质和非编码RNA水平的失衡导致许多疾病的发生。除了使用小分子抑制剂和激动剂来恢复这些不平衡外,最近出现的靶向降解技术为疾病治疗提供了新的方向。靶向降解技术是利用固有的降解途径直接降解目标蛋白或RNA,从而消除致病蛋白(或RNA)治疗疾病的功能。与传统疗法相比,靶向降解技术避免了传统抑制剂占据驱动的原理,具有更高的效率和选择性,并广泛扩展了药物靶点范围。这是未来药物开发最有前途和最热门的领域之一。本文系统介绍了用于降解体设计的体内降解系统:泛素-蛋白酶体降解系统、溶酶体降解系统和RNA降解系统。综述了基于不同降解体系的新型嵌合设计技术的发展进展、结构特点和局限性。此外,由于缺乏明确的配体结合袋,约80%的疾病相关蛋白无法通过传统疗法进行有效干预。我们深入阐述了如何使用靶向降解技术来发现和设计具有代表性的不可药物靶标的分子,包括转录因子,小gtp酶和磷酸酶。综上所述,本文对靶向降解技术的相关研究进展进行了全面系统的综述,并为不可药物靶点的嵌合设计提供了新的指导。
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引用次数: 0
Revolutionizing the battle against locally advanced breast cancer: A comprehensive insight into neoadjuvant radiotherapy 革命性地对抗局部晚期癌症:新辅助放射治疗的全面见解。
IF 13.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-11-10 DOI: 10.1002/med.21998
Xiangyi Kong, Jiarui Song, Peng Gao, Ran Gao, Lin Zhang, Yi Fang, Yipeng Wang, Jidong Gao, Jing Wang

Breast cancer (BC) constitutes one of the most pervasive malignancies affecting the female population. Despite progressive improvements in diagnostic and therapeutic technologies, leading to an increased detection of early stage BCs, locally advanced breast cancer (LABC) persists as a significant clinical challenge. Owing to its poor overall survival (OS) rate, elevated recurrence rate, and high potential for distant metastasis, LABC prominently impacts the comprehensive efficacy of BC treatments. Radiotherapy, encompassing preoperative, intraoperative, and postoperative modalities, is acknowledged as an effective strategy for mitigating BC metastasis and enhancing survival rates among patients. Nevertheless, the domain of preoperative neoadjuvant radiotherapy (NART) remains conspicuously underexplored in clinical studies. Available research suggests that NART can induce tumor volume reduction, provoke fibrotic changes in tumor and adjacent normal tissues, thereby mitigating intraoperative cancer propagation and enhancing the quality of life for LABC patients. This manuscript seeks to provide a review of contemporary research pertaining to LABC and its preoperative radiotherapy.

癌症(BC)是影响女性最普遍的恶性肿瘤之一。尽管诊断和治疗技术不断进步,导致早期BCs的检测增加,但局部晚期癌症(LABC)仍然是一个重大的临床挑战。由于其总生存率低、复发率高和远处转移的可能性高,LABC显著影响BC治疗的综合疗效。放射治疗包括术前、术中和术后模式,被认为是减轻BC转移和提高患者生存率的有效策略。然而,术前新辅助放射治疗(NART)的领域在临床研究中仍明显未得到充分探索。现有研究表明,NART可以诱导肿瘤体积缩小,引起肿瘤和邻近正常组织的纤维化变化,从而减轻术中癌症的扩散,提高LABC患者的生活质量。本文旨在对LABC及其术前放疗的当代研究进行综述。
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引用次数: 0
Diverse biological functions of the renin-angiotensin system 肾素-血管紧张素系统的多种生物学功能。
IF 13.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-11-10 DOI: 10.1002/med.21996
Adithi Rao, Shabir A. Bhat, Tomohiro Shibata, Jorge F. Giani, Florian Rader, Kenneth E. Bernstein, Zakir Khan

The renin-angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS-inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.

众所周知,肾素-血管紧张素系统(RAS)是一种参与控制血压的循环内分泌系统。然而,RAS的成分被发现定位在身体中相当出乎意料的部位,包括肾脏、大脑、骨髓、免疫细胞和生殖系统。这些发现带来了稳定、越来越多的证据,证明身体某些部位存在独立的RAS组织。了解RAS是如何调节这些系统的,这一点很重要,原因多种多样:它能更好地全面了解人类生理,有助于理解和减轻RAS抑制或激活药物的意外后果,并为各种疾病的潜在新疗法奠定基础。这篇综述满足了对几种身体系统中局部组织RAS知识的更新概述的需求,包括其组成、功能和医学意义。
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引用次数: 0
FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid 用于MASH治疗的FXR激动剂:奥贝胆酸的经验教训和展望。
IF 13.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-10-30 DOI: 10.1002/med.21991
Kang Wang, Yuecan Zhang, Guangji Wang, Haiping Hao, Hong Wang

Nonalcoholic fatty liver disease, also called metabolic dysfunction-associated steatotic liver disease, is the most common liver disease worldwide and has no approved pharmacotherapy. Due to its beneficial effects on metabolic regulation, inflammation suppression, cell death prevention, and fibrogenesis inhibition, farnesoid X receptor (FXR) is widely accepted as a promising therapeutic target for nonalcoholic steatosis (NASH) or called metabolic dysfunction-associated steatohepatitis (MASH). Many FXR agonists have been developed for NASH/MASH therapy. Obeticholic acid (OCA) is the pioneering frontrunner FXR agonist and the first demonstrating success in clinical trials. Unfortunately, OCA did not receive regulatory approval as a NASH pharmacotherapy because its moderate benefits did not outweigh its safety risks, which may cast a shadow over FXR-based drug development for NASH/MASH. This review summarizes the milestones in the development of OCA for NASH/MASH and discuss its limitations, including moderate hepatoprotection and the undesirable side effects of dyslipidemia, pruritus, cholelithiasis, and liver toxicity risk, in depth. More importantly, we provide perspectives on FXR-based therapy for NASH/MASH, hoping to support a successful bench-to-clinic transition.

非酒精性脂肪肝,也称为代谢功能障碍相关脂肪变性肝病,是世界范围内最常见的肝病,目前尚未获得批准的药物治疗。由于其对代谢调节、炎症抑制、细胞死亡预防和纤维生成抑制的有益作用,法尼素X受体(FXR)被广泛认为是非酒精性脂肪变性(NASH)或代谢功能障碍相关脂肪性肝炎(MASH)的一个有前途的治疗靶点。许多FXR激动剂已被开发用于NASH/MASH治疗。奥贝胆酸(OCA)是FXR激动剂的先驱,也是首次在临床试验中取得成功。不幸的是,OCA没有作为NASH药物治疗获得监管部门的批准,因为其适度的益处并没有超过其安全风险,这可能会给基于FXR的NASH/MASH药物开发蒙上阴影。这篇综述总结了OCA治疗NASH/MASH的里程碑,并深入讨论了其局限性,包括适度的肝保护以及血脂异常、瘙痒、胆结石和肝毒性风险的不良副作用。更重要的是,我们提供了基于FXR的NASH/MASH治疗的观点,希望能支持成功的临床过渡。
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引用次数: 0
Front Cover Image, Volume 43, Issue 6 封面图片,第43卷第6期
IF 13.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-10-03 DOI: 10.1002/med.21911
Lijuan Xu, Chunlin Zhuang

The cover image is based on the Review Article Profiling of small-molecule necroptosis inhibitors based on the subpockets of kinase–ligand interactions by Lijuan Xu et al., https://doi.org/10.1002/med.21968.

封面图片基于Lijuan Xu等人的综述文章《基于激酶-配体相互作用亚包的小分子坏死抑制剂的概况》。,https://doi.org/10.1002/med.21968.
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引用次数: 0
The triangular relationship between traditional Chinese medicines, intestinal flora, and colorectal cancer 中药、肠道菌群与大肠癌之间的三角关系。
IF 13.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-09-03 DOI: 10.1002/med.21989
Yuqing Zou, Shuling Wang, Honghua Zhang, Yuxin Gu, Huijuan Chen, Zhihua Huang, Feifei Yang, Wenqi Li, Cheng Chen, Lianhui Men, Qingchang Tian, Tian Xie

Over the past decade, colorectal cancer has reported a higher incidence in younger adults and a lower mortality rate. Recently, the influence of the intestinal flora in the initiation, progression, and treatment of colorectal cancer has been extensively studied, as well as their positive therapeutic impact on inflammation and the cancer microenvironment. Historically, traditional Chinese medicine (TCM) has been widely used in the treatment of colorectal cancer via promoted cancer cell apoptosis, inhibited cancer metastasis, and reduced drug resistance and side effects. The present research is more on the effect of either herbal medicine or intestinal flora on colorectal cancer. The interactions between TCM and intestinal flora are bidirectional and the combined impacts of TCM and gut microbiota in the treatment of colon cancer should not be neglected. Therefore, this review discusses the role of intestinal bacteria in the progression and treatment of colorectal cancer by inhibiting carcinogenesis, participating in therapy, and assisting in healing. Then the complex anticolon cancer effects of different kinds of TCM monomers, TCM drug pairs, and traditional Chinese prescriptions embodied in apoptosis, metastasis, immune suppression, and drug resistance are summarized separately. In addition, the interaction between TCM and intestinal flora and the combined effect on cancer treatment were analyzed. This review provides a mechanistic reference for the application of TCM and intestinal flora in the clinical treatment of colorectal cancer and paves the way for the combined development and application of microbiome and TCM.

在过去十年中,结直肠癌在年轻人中的发病率越来越高,死亡率却越来越低。最近,人们广泛研究了肠道菌群在结直肠癌的发生、发展和治疗中的影响,以及它们对炎症和癌症微环境的积极治疗作用。传统中药通过促进癌细胞凋亡、抑制癌细胞转移、减少耐药性和副作用等作用被广泛应用于结直肠癌的治疗。目前的研究更侧重于中药或肠道菌群对结直肠癌的影响。中药与肠道菌群之间的相互作用是双向的,中药与肠道微生物群在结肠癌治疗中的综合影响不容忽视。因此,本综述探讨了肠道细菌在结直肠癌的发生发展和治疗中的作用,包括抑制癌变、参与治疗和协助愈合。然后,分别总结了不同种类的中药单体、中药配伍和中药方剂在细胞凋亡、转移、免疫抑制和耐药性等方面所体现的复杂抗大肠癌作用。此外,还分析了中药与肠道菌群的相互作用及其对癌症治疗的综合效应。本综述为中药与肠道菌群在结直肠癌临床治疗中的应用提供了机理参考,为微生物组与中药的联合开发与应用铺平了道路。
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引用次数: 0
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