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Checkpoint blockade therapy in Hodgkin lymphoma: improved response through combination with JAK inhibition 霍奇金淋巴瘤的检查点阻断疗法:与 JAK 抑制剂联合使用可改善反应
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 DOI: 10.1038/s41392-024-01968-0
Marc A. Weniger, Ralf Küppers
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引用次数: 0
Spliceosomal repression: unleashing human cell totipotency 剪接体抑制:释放人类细胞的全能性
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 DOI: 10.1038/s41392-024-01966-2
Felipe F. Lüttmann, Kee-Pyo Kim, Johnny Kim
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引用次数: 0
Pyroptosis in health and disease: mechanisms, regulation and clinical perspective. 健康和疾病中的裂解酶:机制、调节和临床视角。
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-20 DOI: 10.1038/s41392-024-01958-2
Yifan Liu,Renjie Pan,Yuzhen Ouyang,Wangning Gu,Tengfei Xiao,Hongmin Yang,Ling Tang,Hui Wang,Bo Xiang,Pan Chen
Pyroptosis is a type of programmed cell death characterized by cell swelling and osmotic lysis, resulting in cytomembrane rupture and release of immunostimulatory components, which play a role in several pathological processes. Significant cellular responses to various stimuli involve the formation of inflammasomes, maturation of inflammatory caspases, and caspase-mediated cleavage of gasdermin. The function of pyroptosis in disease is complex but not a simple angelic or demonic role. While inflammatory diseases such as sepsis are associated with uncontrollable pyroptosis, the potent immune response induced by pyroptosis can be exploited as a therapeutic target for anti-tumor therapy. Thus, a comprehensive review of the role of pyroptosis in disease is crucial for further research and clinical translation from bench to bedside. In this review, we summarize the recent advancements in understanding the role of pyroptosis in disease, covering the related development history, molecular mechanisms including canonical, non-canonical, caspase 3/8, and granzyme-mediated pathways, and its regulatory function in health and multiple diseases. Moreover, this review also provides updates on promising therapeutic strategies by applying novel small molecule inhibitors and traditional medicines to regulate pyroptosis. The present dilemmas and future directions in the landscape of pyroptosis are also discussed from a clinical perspective, providing clues for scientists to develop novel drugs targeting pyroptosis.
裂解是一种程序性细胞死亡,其特点是细胞肿胀和渗透性裂解,导致细胞膜破裂并释放免疫刺激成分,这些成分在多个病理过程中发挥作用。细胞对各种刺激的重要反应包括炎性体的形成、炎性卡巴酶的成熟以及卡巴酶介导的气体蛋白的裂解。炎症蛋白酶在疾病中的功能很复杂,但并不是一个简单的天使或魔鬼角色。脓毒症等炎症性疾病与无法控制的热蛋白沉积有关,而热蛋白沉积诱导的强效免疫反应则可作为抗肿瘤疗法的治疗靶点加以利用。因此,全面回顾热蛋白沉积在疾病中的作用对于进一步研究和从实验室到临床的转化至关重要。在这篇综述中,我们总结了最近在了解热蛋白变性在疾病中的作用方面取得的进展,涵盖了相关的发展历史、分子机制(包括规范、非规范、caspase 3/8 和颗粒酶介导的途径)以及它在健康和多种疾病中的调控功能。此外,本综述还介绍了通过应用新型小分子抑制剂和传统药物来调控裂解酶的最新治疗策略。本综述还从临床角度探讨了热蛋白沉积症目前的困境和未来的发展方向,为科学家开发针对热蛋白沉积症的新型药物提供了线索。
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引用次数: 0
Neutrophil extracellular traps in homeostasis and disease. 平衡与疾病中的中性粒细胞胞外捕获器
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-20 DOI: 10.1038/s41392-024-01933-x
Han Wang,Susan J Kim,Yu Lei,Shuhui Wang,Hui Wang,Hai Huang,Hongji Zhang,Allan Tsung
Neutrophil extracellular traps (NETs), crucial in immune defense mechanisms, are renowned for their propensity to expel decondensed chromatin embedded with inflammatory proteins. Our comprehension of NETs in pathogen clearance, immune regulation and disease pathogenesis, has grown significantly in recent years. NETs are not only pivotal in the context of infections but also exhibit significant involvement in sterile inflammation. Evidence suggests that excessive accumulation of NETs can result in vessel occlusion, tissue damage, and prolonged inflammatory responses, thereby contributing to the progression and exacerbation of various pathological states. Nevertheless, NETs exhibit dual functionalities in certain pathological contexts. While NETs may act as autoantigens, aggregated NET complexes can function as inflammatory mediators by degrading proinflammatory cytokines and chemokines. The delineation of molecules and signaling pathways governing NET formation aids in refining our appreciation of NETs' role in immune homeostasis, inflammation, autoimmune diseases, metabolic dysregulation, and cancer. In this comprehensive review, we delve into the multifaceted roles of NETs in both homeostasis and disease, whilst discussing their potential as therapeutic targets. Our aim is to enhance the understanding of the intricate functions of NETs across the spectrum from physiology to pathology.
中性粒细胞胞外捕获物(NET)在免疫防御机制中至关重要,因其倾向于排出含有炎症蛋白的解聚染色质而闻名。近年来,我们对 NETs 在病原体清除、免疫调节和疾病发病机制中的作用有了更深入的了解。NET 不仅在感染中起着关键作用,在无菌性炎症中也表现出重要作用。有证据表明,NET 的过度积聚会导致血管闭塞、组织损伤和炎症反应延长,从而导致各种病理状态的发展和恶化。然而,NET 在某些病理情况下具有双重功能。NET 可充当自身抗原,而聚集的 NET 复合物则可通过降解促炎细胞因子和趋化因子充当炎症介质。对支配 NET 形成的分子和信号通路的描述有助于我们更好地理解 NET 在免疫平衡、炎症、自身免疫性疾病、代谢失调和癌症中的作用。在这篇综述中,我们深入探讨了 NET 在体内平衡和疾病中的多方面作用,同时讨论了它们作为治疗靶点的潜力。我们的目的是加深人们对 NETs 从生理到病理的复杂功能的理解。
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引用次数: 0
The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma p-MYH9/USP22/HIF-1α轴促进肝细胞癌中的来伐替尼耐药性和癌症干性
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1038/s41392-024-01963-5
Qiaonan Shan, Lu Yin, Qifan Zhan, Jiongjie Yu, Sheng Pan, Jianyong Zhuo, Wei Zhou, Jiaqi Bao, Lincheng Zhang, Jiachen Hong, Jianan Xiang, Qingyang Que, Kangchen Chen, Shengjun Xu, Jingrui Wang, Yangbo Zhu, Bin He, Jingbang Wu, Haiyang Xie, Shusen Zheng, Tingting Feng, Sunbin Ling, Xiao Xu

Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance. We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α (HIF-1α) pathway activation is responsible for acquired LR in HCC. Phosphorylated non-muscle myosin heavy chain 9 (MYH9) at Ser1943, p-MYH9 (Ser1943), could recruit ubiquitin-specific protease 22 (USP22) to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC. Clinically, p-MYH9 (Ser1943) expression was upregulated in HCC samples, which predicted poor prognosis and LR. A casein kinase-2 (CK2) inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro. Therefore, the p-MYH9 (Ser1943)/USP22/HIF-1α axis is critical for LR and cancer stemness. For the diagnosis and treatment of LR in HCC, p-MYH9 (Ser1943), USP22, and HIF-1α might be valuable as novel biomarkers and targets.

来伐替尼是一种用于肝细胞癌(HCC)一线治疗的靶向药物。目前亟需深入了解HCC对伦伐替尼的耐药机制。在本研究中,我们旨在剖析来伐替尼耐药(LR)的内在机制,并提供有效的治疗策略。我们建立了获得性来伐替尼耐药的HCC模型。通过细胞计数、迁移、自我更新能力、化疗耐药性和干性基因的表达来检测HCC细胞的干性。采用分子和生化策略,如RNA测序、免疫沉淀、质谱分析和泛素化检测,来探索其潜在机制。患者衍生的 HCC 模型和患者的 HCC 样本被用来证明其临床意义。我们发现,由缺氧诱导因子-1α(HIF-1α)通路激活驱动的癌症干性增强是导致HCC获得性LR的原因。在来伐替尼耐药的HCC中,Ser1943处磷酸化的非肌球蛋白重链9(MYH9)(p-MYH9 (Ser1943))可招募泛素特异性蛋白酶22(USP22)去泛素化并稳定HIF-1α。临床上,p-MYH9(Ser1943)在HCC样本中表达上调,这预示着预后不良和LR。酪蛋白激酶-2(CK2)抑制剂和USP22抑制剂能有效逆转体内和体外的LR。因此,p-MYH9(Ser1943)/USP22/HIF-1α轴对LR和癌症干性至关重要。对于 HCC 中 LR 的诊断和治疗,p-MYH9 (Ser1943)、USP22 和 HIF-1α 可能是有价值的新型生物标记物和靶点。
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引用次数: 0
Irinotecan hydrochloride liposome HR070803 in combination with 5-fluorouracil and leucovorin in locally advanced or metastatic pancreatic ductal adenocarcinoma following prior gemcitabine-based therapy (PAN-HEROIC-1): a phase 3 trial 盐酸伊立替康脂质体 HR070803 联合 5-氟尿嘧啶和白血病素治疗既往接受过吉西他滨治疗的局部晚期或转移性胰腺导管腺癌(PAN-HEROIC-1):3 期试验
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1038/s41392-024-01948-4
Jiujie Cui, Shukui Qin, Yuhong Zhou, Shuang Zhang, Xiaofeng Sun, Mingjun Zhang, Jiuwei Cui, Weijia Fang, Kangsheng Gu, Zhihua Li, Jufeng Wang, Xiaobing Chen, Jun Yao, Jun Zhou, Gang Wang, Yuxian Bai, Juxiang Xiao, Wensheng Qiu, Bangmao Wang, Tao Xia, Chunyue Wang, Li Kong, Jiajun Yin, Tao Zhang, Xionghu Shen, Deliang Fu, Chuntao Gao, Huan Wang, Quanren Wang, Liwei Wang

Liposomal irinotecan has shown promising antitumor activity in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) who have undergone prior gemcitabine-based therapies. This randomized, double-blind, parallel-controlled, multicenter phase 3 study (NCT05074589) assessed the efficacy and safety of liposomal irinotecan HR070803 combined with 5-fluorouracil (5-FU) and leucovorin (LV) in this patient population. Patients with unresectable, locally advanced, or metastatic PDAC who had previously received gemcitabine-based therapies were randomized 1:1 to receive either HR070803 (60 mg/m2 anhydrous irinotecan hydrochloride, equal to 56.5 mg/m2 free base) or placebo, both in combination with 5-FU (2000 mg/m2) and LV (200 mg/m2), all given intravenously every two weeks. The primary endpoint of the study was overall survival (OS). A total of 298 patients were enrolled and received HR070803 plus 5-FU/LV (HR070803 group, n = 149) or placebo plus 5-FU/LV (placebo group, n = 149). Median OS was significantly improved in the HR070803 group compared to the placebo group (7.4 months [95% CI 6.1–8.4] versus 5.0 months [95% CI 4.3–6.0]; HR 0.63 [95% CI 0.48–0.84]; two-sided p = 0.0019). The most common grade ≥ 3 adverse events in the HR070803 group were increased gamma-glutamyltransferase (19.0% versus 11.6% in placebo group) and decreased neutrophil count (12.9% versus 0 in placebo group). No treatment-related deaths occurred in the HR070803 group, while the placebo group reported one treatment-related death (abdominal infection). HR070803 in combination with 5-FU/LV has shown promising efficacy and manageable safety in advanced or metastatic PDAC in the second-line setting, representing a potential option in this patient population.

脂质体伊立替康在既往接受过吉西他滨疗法的晚期或转移性胰腺导管腺癌(PDAC)患者中显示出良好的抗肿瘤活性。这项随机、双盲、平行对照、多中心3期研究(NCT05074589)评估了脂质体伊立替康HR070803联合5-氟尿嘧啶(5-FU)和亮菌素(LV)在该患者群体中的疗效和安全性。既往接受过吉西他滨疗法的不可切除、局部晚期或转移性PDAC患者按1:1比例随机接受HR070803(60毫克/平方米无水盐酸伊立替康,相当于56.5毫克/平方米游离碱)或安慰剂,两者均与5-FU(2000毫克/平方米)和LV(200毫克/平方米)联合使用,每两周静脉给药一次。研究的主要终点是总生存期(OS)。共有298名患者接受了HR070803加5-FU/LV(HR070803组,n=149)或安慰剂加5-FU/LV(安慰剂组,n=149)治疗。与安慰剂组相比,HR070803组的中位OS明显改善(7.4个月[95% CI 6.1-8.4]对5.0个月[95% CI 4.3-6.0];HR 0.63 [95% CI 0.48-0.84];双侧P = 0.0019)。HR070803组最常见的≥3级不良事件是γ-谷氨酰转移酶升高(19.0%,安慰剂组为11.6%)和中性粒细胞计数减少(12.9%,安慰剂组为0)。HR070803组未发生治疗相关死亡病例,而安慰剂组有一例治疗相关死亡病例(腹部感染)。HR070803联合5-FU/LV在二线治疗晚期或转移性PDAC方面显示出良好的疗效和可控的安全性,是该患者群体的一个潜在选择。
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引用次数: 0
Glucagon-like peptide-1 receptor: mechanisms and advances in therapy 胰高血糖素样肽-1 受体:治疗机制与进展
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-18 DOI: 10.1038/s41392-024-01931-z
Zhikai Zheng, Yao Zong, Yiyang Ma, Yucheng Tian, Yidan Pang, Changqing Zhang, Junjie Gao

The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and is found primarily on the surfaces of various cell types within the human body. This receptor specifically interacts with GLP-1, a key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and several other crucial biological functions. In recent years, GLP-1 medications have become a focal point in the medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, and broad development prospects. This article thoroughly traces the developmental milestones of GLP-1 drugs, from their initial discovery to their clinical application, detailing the evolution of diverse GLP-1 medications along with their distinct pharmacological properties. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. It provides an in-depth assessment of the effectiveness of GLP-1RAs across multiple body systems-including the nervous, cardiovascular, musculoskeletal, and digestive systems. This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms. The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases, such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases, musculoskeletal inflammation, and various forms of cancer. The ongoing development of new indications for GLP-1 drugs offers promising prospects for further expanding therapeutic interventions, showcasing their significant potential in the medical field.

胰高血糖素样肽-1(GLP-1)受体,即 GLP-1R,是 G 蛋白偶联受体(GPCR)家族的重要组成部分,主要存在于人体内各种细胞的表面。这种受体专门与 GLP-1 相互作用,GLP-1 是一种关键的激素,在调节血糖水平、脂质代谢和其他一些重要的生物功能方面发挥着不可或缺的作用。近年来,GLP-1 药物因其创新的治疗机制、显著的疗效和广阔的发展前景而成为医学界的焦点。本文全面回顾了 GLP-1 药物从最初发现到临床应用的发展里程碑,详细介绍了各种 GLP-1 药物的演变过程及其独特的药理特性。此外,本文还探讨了 GLP-1 受体激动剂 (GLP-1RA) 在神经保护、抗感染措施、减轻各种炎症和增强心血管功能等领域的潜在应用。该书深入评估了 GLP-1RA 在多个身体系统中的有效性,包括神经、心血管、肌肉骨骼和消化系统。这包括整合最新的临床试验数据,深入探讨潜在的信号传导途径和药理机制。本文的主要目的是强调使用 GLP-1RA 治疗肥胖症、心血管疾病、非酒精性脂肪肝、神经退行性疾病、肌肉骨骼炎症和各种癌症等多种疾病的广泛益处。GLP-1 药物新适应症的不断开发为进一步扩大治疗干预提供了广阔前景,展示了其在医疗领域的巨大潜力。
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引用次数: 0
Characterization of ACTN4 as a novel antiviral target against SARS-CoV-2 ACTN4 作为抗击 SARS-CoV-2 的新型抗病毒靶点的特征描述
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-18 DOI: 10.1038/s41392-024-01956-4
Miao Zhu, Fang Huang, Huize Sun, Kunpeng Liu, Zhen Chen, Baocheng Yu, Haojie Hao, Haizhou Liu, Shuang Ding, Xueyan Zhang, Lishi Liu, Kui Zhang, Jierao Ren, Yi Liu, Haibin Liu, Chao Shan, Wuxiang Guan

The various mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pose a substantial challenge in mitigating the viral infectivity. The identification of novel host factors influencing SARS-CoV-2 replication holds potential for discovering new targets for broad-spectrum antiviral drugs that can combat future viral mutations. In this study, potential host factors regulated by SARS-CoV-2 infection were screened through different high-throughput sequencing techniques and further identified in cells. Subsequent analysis and experiments showed that the reduction of m6A modification level on ACTN4 (Alpha-actinin-4) mRNA leads to a decrease in mRNA stability and translation efficiency, ultimately inhibiting ACTN4 expression. In addition, ACTN4 was demonstrated to target nsp12 for binding and characterized as a competitor for SARS-CoV-2 RNA and the RNA-dependent RNA polymerase complex, thereby impeding viral replication. Furthermore, two ACTN4 agonists, YS-49 and demethyl-coclaurine, were found to dose-dependently inhibit SARS-CoV-2 infection in both Huh7 cells and K18-hACE2 transgenic mice. Collectively, this study unveils the pivotal role of ACTN4 in SARS-CoV-2 infection, offering novel insights into the intricate interplay between the virus and host cells, and reveals two potential candidates for future anti-SARS-CoV-2 drug development.

严重急性呼吸系统综合症冠状病毒 2(SARS-CoV-2)的各种变异对降低病毒传染性构成了巨大挑战。确定影响 SARS-CoV-2 复制的新型宿主因素,有可能为广谱抗病毒药物发现新的靶点,以应对未来的病毒变异。本研究通过不同的高通量测序技术筛选出受 SARS-CoV-2 感染调控的潜在宿主因子,并在细胞中进行了进一步鉴定。随后的分析和实验表明,ACTN4(α-肌动蛋白-4)mRNA上的m6A修饰水平降低会导致mRNA稳定性和翻译效率下降,最终抑制ACTN4的表达。此外,研究还证明 ACTN4 可与 nsp12 结合,成为 SARS-CoV-2 RNA 和 RNA 依赖性 RNA 聚合酶复合物的竞争者,从而阻碍病毒复制。此外,研究还发现两种 ACTN4 激动剂 YS-49 和去甲基可可碱对 Huh7 细胞和 K18-hACE2 转基因小鼠的 SARS-CoV-2 感染具有剂量依赖性抑制作用。总之,这项研究揭示了 ACTN4 在 SARS-CoV-2 感染中的关键作用,为病毒与宿主细胞之间错综复杂的相互作用提供了新的见解,并揭示了未来抗 SARS-CoV-2 药物开发的两种潜在候选药物。
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引用次数: 0
Sintilimab combined with anlotinib and chemotherapy as second-line or later therapy in extensive-stage small cell lung cancer: a phase II clinical trial 辛替利单抗联合安罗替尼和化疗作为广泛期小细胞肺癌的二线或后期治疗:II 期临床试验
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 DOI: 10.1038/s41392-024-01957-3
Xiao Han, Jun Guo, Lingyu Li, Yong Huang, Xue Meng, Linlin Wang, Hui Zhu, Xiangjiao Meng, Qian Shao, Xing Li, Yan Zhang, Jin Wang, Yanhua Chen, Yingjie Zhang, Yiru Chen, Changbin Zhu, Zhehai Wang

Treatment options for patients with relapsed extensive-stage small cell lung cancer (ES-SCLC) remain scarce. This study aims to evaluate the efficacy and safety of combining anlotinib and sintilimab plus chemotherapy as a second line or later therapy for ES-SCLC patients. This is a phase II clinical trial (ChiCTR2100049390) conducting at Shandong Cancer Hospital. Patients with ES-SCLC and received at least one prior systemic treatment were enrolled. The trial design involved a combination therapy (sintilimab, anlotinib, and nab-paclitaxel) administered over six 21-day cycles, followed by maintenance sintilimab therapy. The primary endpoint was objective response rate (ORR). Circulating tumor DNA sequencing was employed for exploratory analysis. From July 2021 to April 2023, 25 eligible patients were enrolled. The confirmed ORR was 60% (95% CI: 38.7–78.9%) and the DCR was 76% (95% CI: 54.9–90.6%). The mPFS was 6.0 months (95% CI: 5.4–9.7), and the 6-month PFS rate was 49.2%. The mOS was 13.4 months (95% CI: 11.8-NR), with a 12-month survival rate of 62.2%. Treatment-related adverse events (TRAEs) of any grade occurred in 80% of patients, with the most common being fatigue (40%) and nausea (32%). TRAEs of Grade 3 or higher were reported in 12% of patients. ctDNA analysis indicated that low on-treatment blood tumor mutation burden was associated with longer PFS and OS and a potential role of KMT2D mutation in treatment resistance. This combination therapy shows promising efficacy and a manageable safety profile as a second-line or later treatment for ES-SCLC, with genomic insights providing potential biomarkers for treatment response.

复发的广泛期小细胞肺癌(ES-SCLC)患者的治疗方案仍然很少。本研究旨在评估安罗替尼和辛替利单抗联合化疗作为ES-SCLC患者二线或后期治疗的有效性和安全性。这是山东省肿瘤医院开展的一项II期临床试验(ChiCTR2100049390)。ES-SCLC患者既往至少接受过一次系统治疗。试验设计包括6个21天周期的联合治疗(辛替利单抗、安罗替尼和纳伯-紫杉醇),随后是辛替利单抗的维持治疗。主要终点是客观反应率(ORR)。循环肿瘤DNA测序用于探索性分析。从2021年7月到2023年4月,共有25名符合条件的患者入组。确诊ORR为60%(95% CI:38.7-78.9%),DCR为76%(95% CI:54.9-90.6%)。mPFS为6.0个月(95% CI:5.4-9.7),6个月PFS率为49.2%。mOS为13.4个月(95% CI:11.8-NR),12个月生存率为62.2%。80%的患者发生了任何级别的治疗相关不良事件(TRAEs),最常见的是疲劳(40%)和恶心(32%)。ctDNA分析表明,低治疗时血液肿瘤突变负荷与较长的PFS和OS有关,KMT2D突变在耐药中可能起作用。这种联合疗法作为ES-SCLC的二线或后期治疗,显示出良好的疗效和可控的安全性,其基因组学见解为治疗反应提供了潜在的生物标志物。
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引用次数: 0
Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases 跨越表观遗传学前沿:新型组蛋白修饰与疾病的交汇点
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 DOI: 10.1038/s41392-024-01918-w
Weiyi Yao, Xinting Hu, Xin Wang

Histone post-translational modifications (HPTMs), as one of the core mechanisms of epigenetic regulation, are garnering increasing attention due to their close association with the onset and progression of diseases and their potential as targeted therapeutic agents. Advances in high-throughput molecular tools and the abundance of bioinformatics data have led to the discovery of novel HPTMs which similarly affect gene expression, metabolism, and chromatin structure. Furthermore, a growing body of research has demonstrated that novel histone modifications also play crucial roles in the development and progression of various diseases, including various cancers, cardiovascular diseases, infectious diseases, psychiatric disorders, and reproductive system diseases. This review defines nine novel histone modifications: lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butyrylation, 2-hydroxyisobutyrylation, and 2-hydroxybutyrylation. It comprehensively introduces the modification processes of these nine novel HPTMs, their roles in transcription, replication, DNA repair and recombination, metabolism, and chromatin structure, as well as their involvement in promoting the occurrence and development of various diseases and their clinical applications as therapeutic targets and potential biomarkers. Moreover, this review provides a detailed overview of novel HPTM inhibitors targeting various targets and their emerging strategies in the treatment of multiple diseases while offering insights into their future development prospects and challenges. Additionally, we briefly introduce novel epigenetic research techniques and their applications in the field of novel HPTM research.

组蛋白翻译后修饰(HPTMs)是表观遗传调控的核心机制之一,由于其与疾病的发生和发展密切相关,并具有作为靶向治疗药物的潜力,因此正受到越来越多的关注。高通量分子工具的进步和生物信息学数据的丰富导致了新型 HPTMs 的发现,这些 HPTMs 同样会影响基因表达、新陈代谢和染色质结构。此外,越来越多的研究表明,新型组蛋白修饰在各种疾病(包括各种癌症、心血管疾病、传染病、精神疾病和生殖系统疾病)的发生和发展过程中也起着至关重要的作用。本综述定义了九种新型组蛋白修饰:乳酰化、瓜氨酸化、巴豆酰化、琥珀酰化、SUMO酰化、丙酰化、丁酰化、2-羟基异丁酰化和 2-羟基丁酰化。综述全面介绍了这九种新型 HPTMs 的修饰过程,它们在转录、复制、DNA 修复和重组、新陈代谢和染色质结构中的作用,以及它们在促进各种疾病的发生和发展中的参与和作为治疗靶点和潜在生物标记物的临床应用。此外,本综述还详细概述了针对各种靶点的新型 HPTM 抑制剂及其在治疗多种疾病方面的新兴策略,同时对其未来的发展前景和挑战提出了见解。此外,我们还简要介绍了新型表观遗传学研究技术及其在新型 HPTM 研究领域的应用。
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Signal Transduction and Targeted Therapy
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