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"Clone-specific" antibody-drug conjugates: an innovative strategy in the treatment of T-cell cancers. "克隆特异性 "抗体药物共轭物:治疗 T 细胞癌症的创新策略。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1038/s41392-024-01945-7
Dennis Jungherz, Philipp Lückemeier, Marco Herling
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引用次数: 0
Sintilimab (anti-PD-1 antibody) combined with high-dose methotrexate, temozolomide, and rituximab (anti-CD20 antibody) in primary central nervous system lymphoma: a phase 2 study. 辛替利单抗(抗 PD-1 抗体)联合大剂量甲氨蝶呤、替莫唑胺和利妥昔单抗(抗 CD20 抗体)治疗原发性中枢神经系统淋巴瘤:一项 2 期研究。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1038/s41392-024-01941-x
Zhiyong Zeng, Apeng Yang, Jingke Yang, Sheng Zhang, Zhen Xing, Xingfu Wang, Wenzhong Mei, Changzhen Jiang, Junfang Lin, Xiyue Wu, Yihui Xue, Zanyi Wu, Lianghong Yu, Dengliang Wang, Jianwu Chen, Shufa Zheng, Qiaoxian Lin, Qingjiao Chen, Jinfeng Dong, Xiaoqiang Zheng, Jizhen Wang, Jinlong Huang, Zhenying Chen, Ping Chen, Meihong Zheng, Xiaofang Zhou, Youwen He, Yuanxiang Lin, Junmin Chen

Primary central nervous system lymphoma (PCNSL) is a rare and frequently fatal lymphoma subtype. The programmed death-1 (PD-1) pathway has emerged as a potential therapeutic target, but the effectiveness of PD-1 antibody sintilimab in combination with immunochemotherapy as a frontline treatment for PCNSL remains to be determined. In this phase 2 trial (ChiCTR1900027433) with a safety run-in, we included patients aged 18-70 with newly diagnosed PCNSL. Participants underwent six 21-day cycles of a SMTR regimen, which includes sintilimab (200 mg, Day 0), rituximab (375 mg/m2, Day 0), methotrexate (3.0 g/m2, Day 1 or 1.0 g/m2 for patients aged ≥65 years), and temozolomide (150 mg/m2/d, Days 1-5). Among 27 evaluable patients, the overall response rate (ORR) was 96.3% (95% confidence interval: 81-99.9%), with 25 complete responses. At a median follow-up of 24.4 months, the medians for duration of response, progression-free survival (PFS), and overall survival were not reached. The most common grade 3-4 treatment-related toxicities were increased levels of alanine aminotransferase (17.9%) and aspartate aminotransferase (14.3%). Additionally, baseline levels of interferon-α and the IL10/IL6 ratio in cerebrospinal fluid emerged as potential predictors of PFS, achieving areas under the curve of 0.88 and 0.84, respectively, at 2 years. Whole-exome sequencing revealed a higher prevalence of RTK-RAS and PI3K pathway mutations in the durable clinical benefit group, while a greater frequency of Notch and Hippo pathway mutations in the no durable benefit group. These findings suggest the SMTR regimen is highly efficacious and tolerable for newly diagnosed PCNSL, warranting further investigation.

原发性中枢神经系统淋巴瘤(PCNSL)是一种罕见且经常致命的淋巴瘤亚型。程序性死亡-1(PD-1)通路已成为潜在的治疗靶点,但PD-1抗体sintilimab联合免疫化疗作为PCNSL一线治疗的有效性仍有待确定。在这项具有安全性的 2 期试验(ChiCTR1900027433)中,我们纳入了 18-70 岁的新诊断 PCNSL 患者。参与者接受了 6 个 21 天周期的 SMTR 方案治疗,其中包括辛替利马(200 毫克,第 0 天)、利妥昔单抗(375 毫克/平方米,第 0 天)、甲氨蝶呤(3.0 克/平方米,第 1 天;年龄≥65 岁的患者为 1.0 克/平方米)和替莫唑胺(150 毫克/平方米/天,第 1-5 天)。在27例可评估的患者中,总反应率(ORR)为96.3%(95%置信区间:81-99.9%),其中25例为完全反应。在 24.4 个月的中位随访中,反应持续时间、无进展生存期(PFS)和总生存期的中位数均未达到。最常见的 3-4 级治疗相关毒性是丙氨酸氨基转移酶(17.9%)和天冬氨酸氨基转移酶(14.3%)水平升高。此外,干扰素-α基线水平和脑脊液中的IL10/IL6比值也是预测PFS的潜在指标,2年后的曲线下面积分别为0.88和0.84。全外显子组测序显示,持久临床获益组的RTK-RAS和PI3K通路突变发生率更高,而无持久获益组的Notch和Hippo通路突变发生率更高。这些研究结果表明,SMTR疗法对新诊断的PCNSL疗效显著且可耐受,值得进一步研究。
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引用次数: 0
Circulating tumor cells: from new biological insights to clinical practice. 循环肿瘤细胞:从生物学新见解到临床实践。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-02 DOI: 10.1038/s41392-024-01938-6
Xuyu Gu, Shiyou Wei, Xin Lv

The primary reason for high mortality rates among cancer patients is metastasis, where tumor cells migrate through the bloodstream from the original site to other parts of the body. Recent advancements in technology have significantly enhanced our comprehension of the mechanisms behind the bloodborne spread of circulating tumor cells (CTCs). One critical process, DNA methylation, regulates gene expression and chromosome stability, thus maintaining dynamic equilibrium in the body. Global hypomethylation and locus-specific hypermethylation are examples of changes in DNA methylation patterns that are pivotal to carcinogenesis. This comprehensive review first provides an overview of the various processes that contribute to the formation of CTCs, including epithelial-mesenchymal transition (EMT), immune surveillance, and colonization. We then conduct an in-depth analysis of how modifications in DNA methylation within CTCs impact each of these critical stages during CTC dissemination. Furthermore, we explored potential clinical implications of changes in DNA methylation in CTCs for patients with cancer. By understanding these epigenetic modifications, we can gain insights into the metastatic process and identify new biomarkers for early detection, prognosis, and targeted therapies. This review aims to bridge the gap between basic research and clinical application, highlighting the significance of DNA methylation in the context of cancer metastasis and offering new avenues for improving patient outcomes.

癌症患者死亡率高的主要原因是转移,即肿瘤细胞通过血液从原发部位转移到身体的其他部位。最近的技术进步大大提高了我们对循环肿瘤细胞(CTCs)血液传播背后机制的理解。其中一个关键过程是 DNA 甲基化,它能调节基因表达和染色体稳定性,从而维持体内的动态平衡。全局低甲基化和位点特异性高甲基化是 DNA 甲基化模式变化的例子,对致癌至关重要。本综述首先概述了导致 CTC 形成的各种过程,包括上皮-间质转化(EMT)、免疫监视和定植。然后,我们深入分析了 CTC 内 DNA 甲基化的改变如何影响 CTC 传播过程中的每个关键阶段。此外,我们还探讨了 CTC 中 DNA 甲基化变化对癌症患者的潜在临床意义。通过了解这些表观遗传修饰,我们可以深入了解转移过程,并确定用于早期检测、预后判断和靶向治疗的新生物标记物。本综述旨在弥合基础研究与临床应用之间的差距,强调 DNA 甲基化在癌症转移中的重要意义,并为改善患者预后提供新的途径。
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引用次数: 0
A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta (POLE/POLD1) mutation. 托利帕利单抗治疗聚合酶ε/聚合酶δ(POLE/POLD1)突变晚期实体瘤的II期临床试验。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-02 DOI: 10.1038/s41392-024-01939-5
Ying Jin, Run-Jie Huang, Wen-Long Guan, Zhi-Qiang Wang, Zong-Jiong Mai, Yu-Hong Li, Jian Xiao, Xing Zhang, Qi Zhao, Shi-Fu Chen, Ming Liu, Yan-Xia Shi, Feng Wang, Rui-Hua Xu

Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors. Yet, prospective trials exploring the efficacy in those with polymerase epsilon/polymerase delta mutations are still lacking. A phase II clinical trial was initiated to evaluate the efficacy of toripalimab, a humanized IgG4K monoclonal antibody to human PD-1, in patients with advanced solid tumors with unselected polymerase epsilon/polymerase delta mutations but without microsatellite instability-high. A total of 15 patients were enrolled, 14 of whom were assessed for treatment efficacy. There was a 21.4% overall response rate, with a disease control rate of 57.1%. The median overall survival and median progression-free survival were 17.9 (95% CI 13.5-not reach) months and 2.5 (95% CI 1.4-not reach) months, respectively. For patients with exonuclease domain mutations, the objective response rate was 66.7% (2/3), with a disease control rate of 66.7% (2/3). For those with non-exonuclease domain mutations, the rates were 9.1% (1/11) and 54.5% (6/11), respectively. Notably, patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0% (3/4). This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy, urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants.

携带聚合酶epsilon/聚合酶δ突变的患者对免疫检查点抑制剂产生了积极的反应。然而,探索聚合酶epsilon/聚合酶δ突变患者疗效的前瞻性试验仍然缺乏。我们启动了一项II期临床试验,评估人PD-1人源化IgG4K单克隆抗体托瑞帕利单抗(toripalimab)对未选择聚合酶ε/聚合酶δ突变但无微卫星不稳定性高的晚期实体瘤患者的疗效。共有15名患者入组,其中14人接受了疗效评估。总体反应率为21.4%,疾病控制率为57.1%。中位总生存期和中位无进展生存期分别为17.9个月(95% CI 13.5个月,未达标)和2.5个月(95% CI 1.4个月,未达标)。外切酶结构域突变患者的客观反应率为66.7%(2/3),疾病控制率为66.7%(2/3)。而非外切酶结构域突变患者的客观反应率分别为9.1%(1/11)和54.5%(6/11)。值得注意的是,PBRM1 基因突变患者对托瑞帕单抗的反应率很高,达到 75.0%(3/4)。这项研究表明,无论是外切酶结构域突变还是非外切酶结构域突变,都不能完全预测免疫疗法的疗效,因此需要进行更多研究,以明确聚合酶epsilon/聚合酶delta突变变体之间潜在的免疫敏感性差异。
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引用次数: 0
Mind-body control: a new perspective on motor neuron function 身心控制:运动神经元功能的新视角
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-30 DOI: 10.1038/s41392-024-01922-0
Maria-Luise Petrovic-Erfurth, Albena Jordanova
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引用次数: 0
Opioid receptors: single molecule studies shed light on mechanisms of efficacy 阿片受体:单分子研究揭示药效机制
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-30 DOI: 10.1038/s41392-024-01920-2
Cornelius Krasel, Moritz Bünemann
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引用次数: 0
Tertiary lymphoid structures in diseases: immune mechanisms and therapeutic advances 疾病中的三级淋巴结构:免疫机制与治疗进展
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1038/s41392-024-01947-5
Lianyu Zhao, Song Jin, Shengyao Wang, Zhe Zhang, Xuan Wang, Zhanwei Chen, Xiaohui Wang, Shengyun Huang, Dongsheng Zhang, Haiwei Wu

Tertiary lymphoid structures (TLSs) are defined as lymphoid aggregates formed in non-hematopoietic organs under pathological conditions. Similar to secondary lymphoid organs (SLOs), the formation of TLSs relies on the interaction between lymphoid tissue inducer (LTi) cells and lymphoid tissue organizer (LTo) cells, involving multiple cytokines. Heterogeneity is a distinguishing feature of TLSs, which may lead to differences in their functions. Growing evidence suggests that TLSs are associated with various diseases, such as cancers, autoimmune diseases, transplant rejection, chronic inflammation, infection, and even ageing. However, the detailed mechanisms behind these clinical associations are not yet fully understood. The mechanisms by which TLS maturation and localization affect immune function are also unclear. Therefore, it is necessary to enhance the understanding of TLS development and function at the cellular and molecular level, which may allow us to utilize them to improve the immune microenvironment. In this review, we delve into the composition, formation mechanism, associations with diseases, and potential therapeutic applications of TLSs. Furthermore, we discuss the therapeutic implications of TLSs, such as their role as markers of therapeutic response and prognosis. Finally, we summarize various methods for detecting and targeting TLSs. Overall, we provide a comprehensive understanding of TLSs and aim to develop more effective therapeutic strategies.

三级淋巴结构(TLS)是指非造血器官在病理条件下形成的淋巴聚集。与二级淋巴器官(SLOs)类似,三级淋巴结构的形成依赖于淋巴组织诱导细胞(LTi)和淋巴组织组织细胞(LTo)之间的相互作用,其中涉及多种细胞因子。异质性是TLS的一个显著特征,这可能导致其功能的差异。越来越多的证据表明,TLS 与癌症、自身免疫性疾病、移植排斥、慢性炎症、感染甚至衰老等多种疾病有关。然而,这些临床关联背后的详细机制尚未完全明了。TLS的成熟和定位影响免疫功能的机制也不清楚。因此,有必要在细胞和分子水平上加强对 TLS 发育和功能的了解,从而使我们能够利用它们来改善免疫微环境。在这篇综述中,我们将深入探讨 TLS 的组成、形成机制、与疾病的关联以及潜在的治疗应用。此外,我们还讨论了 TLS 的治疗意义,例如它们作为治疗反应和预后标志物的作用。最后,我们总结了检测和靶向 TLS 的各种方法。总之,我们提供了对 TLS 的全面了解,旨在开发更有效的治疗策略。
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引用次数: 0
Enhancing RBD exposure and S1 shedding by an extremely conserved SARS-CoV-2 NTD epitope. 通过极其保守的 SARS-CoV-2 NTD 表位增强 RBD 暴露和 S1 脱落。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1038/s41392-024-01940-y
Qianhui Zhu, Pan Liu, Shuo Liu, Can Yue, Xiangxi Wang
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引用次数: 0
Hyperuricemia and its related diseases: mechanisms and advances in therapy. 高尿酸血症及其相关疾病:治疗机制与进展。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1038/s41392-024-01916-y
Lin Du, Yao Zong, Haorui Li, Qiyue Wang, Lei Xie, Bo Yang, Yidan Pang, Changqing Zhang, Zhigang Zhong, Junjie Gao

Hyperuricemia, characterized by elevated levels of serum uric acid (SUA), is linked to a spectrum of commodities such as gout, cardiovascular diseases, renal disorders, metabolic syndrome, and diabetes, etc. Significantly impairing the quality of life for those affected, the prevalence of hyperuricemia is an upward trend globally, especially in most developed countries. UA possesses a multifaceted role, such as antioxidant, pro-oxidative, pro-inflammatory, nitric oxide modulating, anti-aging, and immune effects, which are significant in both physiological and pathological contexts. The equilibrium of circulating urate levels hinges on the interplay between production and excretion, a delicate balance orchestrated by urate transporter functions across various epithelial tissues and cell types. While existing research has identified hyperuricemia involvement in numerous biological processes and signaling pathways, the precise mechanisms connecting elevated UA levels to disease etiology remain to be fully elucidated. In addition, the influence of genetic susceptibilities and environmental determinants on hyperuricemia calls for a detailed and nuanced examination. This review compiles data from global epidemiological studies and clinical practices, exploring the physiological processes and the genetic foundations of urate transporters in depth. Furthermore, we uncover the complex mechanisms by which the UA induced inflammation influences metabolic processes in individuals with hyperuricemia and the association with its relative disease, offering a foundation for innovative therapeutic approaches and advanced pharmacological strategies.

高尿酸血症以血清尿酸(SUA)水平升高为特征,与痛风、心血管疾病、肾功能紊乱、代谢综合征和糖尿病等一系列疾病有关。高尿酸血症严重影响患者的生活质量,其发病率在全球呈上升趋势,尤其是在大多数发达国家。尿酸具有多方面的作用,如抗氧化、促氧化、促炎症、调节一氧化氮、抗衰老和免疫作用,这些作用在生理和病理情况下都非常重要。循环尿酸盐水平的平衡取决于尿酸盐生成和排泄之间的相互作用,而尿酸盐转运体的功能则在各种上皮组织和细胞类型中协调着这一微妙的平衡。虽然现有研究已发现高尿酸血症与许多生物过程和信号通路有关,但尿酸水平升高与疾病病因之间的确切机制仍有待全面阐明。此外,遗传易感性和环境决定因素对高尿酸血症的影响也需要细致入微的研究。本综述汇编了来自全球流行病学研究和临床实践的数据,深入探讨了尿酸盐转运体的生理过程和遗传基础。此外,我们还揭示了尿酸盐诱导的炎症影响高尿酸血症患者新陈代谢过程的复杂机制及其与相关疾病的关联,为创新治疗方法和先进药理策略奠定了基础。
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引用次数: 0
Predicting gastric cancer response to anti-HER2 therapy or anti-HER2 combined immunotherapy based on multi-modal data. 基于多模态数据预测胃癌对抗 HER2 治疗或抗 HER2 联合免疫疗法的反应。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-26 DOI: 10.1038/s41392-024-01932-y
Zifan Chen, Yang Chen, Yu Sun, Lei Tang, Li Zhang, Yajie Hu, Meng He, Zhiwei Li, Siyuan Cheng, Jiajia Yuan, Zhenghang Wang, Yakun Wang, Jie Zhao, Jifang Gong, Liying Zhao, Baoshan Cao, Guoxin Li, Xiaotian Zhang, Bin Dong, Lin Shen

The sole use of single modality data often fails to capture the complex heterogeneity among patients, including the variability in resistance to anti-HER2 therapy and outcomes of combined treatment regimens, for the treatment of HER2-positive gastric cancer (GC). This modality deficit has not been fully considered in many studies. Furthermore, the application of artificial intelligence in predicting the treatment response, particularly in complex diseases such as GC, is still in its infancy. Therefore, this study aimed to use a comprehensive analytic approach to accurately predict treatment responses to anti-HER2 therapy or anti-HER2 combined immunotherapy in patients with HER2-positive GC. We collected multi-modal data, comprising radiology, pathology, and clinical information from a cohort of 429 patients: 310 treated with anti-HER2 therapy and 119 treated with a combination of anti-HER2 and anti-PD-1/PD-L1 inhibitors immunotherapy. We introduced a deep learning model, called the Multi-Modal model (MuMo), that integrates these data to make precise treatment response predictions. MuMo achieved an area under the curve score of 0.821 for anti-HER2 therapy and 0.914 for combined immunotherapy. Moreover, patients classified as low-risk by MuMo exhibited significantly prolonged progression-free survival and overall survival (log-rank test, P < 0.05). These findings not only highlight the significance of multi-modal data analysis in enhancing treatment evaluation and personalized medicine for HER2-positive gastric cancer, but also the potential and clinical value of our model.

在治疗 HER2 阳性胃癌(GC)时,仅使用单一模式的数据往往无法捕捉到患者之间复杂的异质性,包括对抗 HER2 治疗的耐药性和联合治疗方案的疗效。许多研究都没有充分考虑到这种模式的缺陷。此外,人工智能在预测治疗反应方面的应用,尤其是在胃癌等复杂疾病中的应用,仍处于起步阶段。因此,本研究旨在使用一种综合分析方法来准确预测HER2阳性GC患者对抗HER2疗法或抗HER2联合免疫疗法的治疗反应。我们收集了 429 例患者的多模态数据,包括放射学、病理学和临床信息:其中310人接受了抗HER2疗法,119人接受了抗HER2和抗PD-1/PD-L1抑制剂联合免疫疗法。我们引入了一种名为多模态模型(MuMo)的深度学习模型,该模型整合了这些数据,可精确预测治疗反应。MuMo对抗HER2疗法的曲线下面积得分达到0.821,对联合免疫疗法的曲线下面积得分达到0.914。此外,被 MuMo 归类为低风险的患者的无进展生存期和总生存期明显延长(对数秩检验,P
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引用次数: 0
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Signal Transduction and Targeted Therapy
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