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Mechanism exploration and model construction for small cell transformation in EGFR-mutant lung adenocarcinomas. 表皮生长因子受体突变肺腺癌小细胞转化的机制探索与模型构建。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-02 DOI: 10.1038/s41392-024-01981-3
Yan Li, Tongji Xie, Shouzheng Wang, Lin Yang, Xuezhi Hao, Yan Wang, Xingsheng Hu, Lin Wang, Junling Li, Jianming Ying, Puyuan Xing

Small-cell lung cancer (SCLC) transformation accounts for 3-14% of resistance in EGFR-TKI relapsed lung adenocarcinomas (LUADs), with unknown molecular mechanisms and optimal treatment strategies. We performed transcriptomic analyses (including bulk and spatial transcriptomics) and multiplex immunofluorescence on pre-treated samples from LUADs without transformation after EGFR-TKI treatment (LUAD-NT), primary SCLCs (SCLC-P) and LUADs with transformation after EGFR-TKI treatment (before transformation: LUAD-BT; after transformation: SCLC-AT). Our study found that LUAD-BT exhibited potential transcriptomic characteristics for transformation compared with LUAD-NT. We identified several pathways that shifted during transformation, and the transformation might be promoted by epigenetic alterations (such as HDAC10, HDAC1, DNMT3A) within the tumor cells instead of within the tumor microenvironment. For druggable pathways, transformed-SCLC were proved to be less dependent on EGF signaling but more relied on FGF signaling, while VEGF-VEGFR pathway remained active, indicating potential treatments after transformation. We also found transformed-SCLC showed an immuno-exhausted status which was associated with the duration of EGFR-TKI before transformation. Besides, SCLC-AT exhibited distinct molecular subtypes from SCLC-P. Moreover, we constructed an ideal 4-marker model based on transcriptomic and IHC data to predict SCLC transformation, which obtained a sensitivity of 100% and 87.5%, a specificity of 95.7% and 100% in the training and test cohorts, respectively. We provided insights into the molecular mechanisms of SCLC transformation and the differences between SCLC-AT and SCLC-P, which might shed light on prevention strategies and subsequent therapeutic strategies for SCLC transformation in the future.

小细胞肺癌(SCLC)转化占表皮生长因子受体-TKI复发肺腺癌(LUADs)耐药性的3-14%,其分子机制和最佳治疗策略尚不清楚。我们对经 EGFR-TKI 治疗后未发生转化的 LUAD(LUAD-NT)、原发性 SCLC(SCLC-P)和经 EGFR-TKI 治疗后发生转化的 LUAD(转化前:LUAD-BT;转化后:SCLC-AT)的预处理样本进行了转录组学分析(包括批量和空间转录组学)和多重免疫荧光分析。我们的研究发现,与 LUAD-NT 相比,LUAD-BT 表现出潜在的转化转录组特征。我们发现了一些在转化过程中发生转变的通路,而肿瘤细胞内的表观遗传学改变(如 HDAC10、HDAC1、DNMT3A)可能会促进转化,而不是肿瘤微环境中的表观遗传学改变。在可用药途径方面,转化后的SCLC对EGF信号的依赖性降低,但对FGF信号的依赖性增加,而VEGF-VEGFR通路仍然活跃,这表明转化后的SCLC具有治疗潜力。我们还发现,转化后的 SCLC 表现出免疫耗竭状态,这与转化前使用 EGFR-TKI 的时间长短有关。此外,SCLC-AT 与 SCLC-P 表现出不同的分子亚型。此外,我们基于转录组和IHC数据构建了一个理想的4标记物模型来预测SCLC转化,该模型在训练组和测试组中的灵敏度分别为100%和87.5%,特异性分别为95.7%和100%。我们深入了解了SCLC转化的分子机制以及SCLC-AT和SCLC-P之间的差异,这或许能为今后SCLC转化的预防策略和后续治疗策略提供启示。
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引用次数: 0
Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy. 成人 2 型糖尿病:发病机制、预防和治疗。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-02 DOI: 10.1038/s41392-024-01951-9
Xi Lu, Qingxing Xie, Xiaohui Pan, Ruining Zhang, Xinyi Zhang, Ge Peng, Yuwei Zhang, Sumin Shen, Nanwei Tong

Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet β cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and β cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet β cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. There is currently no cure for T2D, but it can be prevented or in remission by lifestyle intervention and/or some medication. If prevention fails, holistic and personalized management should be taken as soon as possible through timely detection and diagnosis, considering target organ protection, comorbidities, treatment goals, and other factors in reality. T2D is often accompanied by other components of MDS, such as preobesity/obesity, metabolic dysfunction associated steatotic liver disease, dyslipidemia, which usually occurs before it, and they are considered as the upstream diseases of T2D. It is more appropriate to call "diabetic complications" as "MDS-related target organ damage (TOD)", since their development involves not only hyperglycemia but also other metabolic disorders of MDS, promoting an up-to-date management philosophy. In this review, we aim to summarize the underlying mechanism, screening, diagnosis, prevention, and treatment of T2D, especially regarding the personalized selection of hypoglycemic agents and holistic management based on the concept of "MDS-related TOD".

2 型糖尿病(T2D)是一种以胰岛β细胞胰岛素分泌异质性进行性丧失为特征的疾病,通常发生在胰岛素抵抗(IR)之后,是代谢综合征(MS)的组成部分之一,我们将其命名为代谢功能障碍综合征(MDS)。T2D 的发病机制尚未完全明了,IR 和 β 细胞功能障碍在其病理生理学中起着核心作用。血脂异常、高血糖以及其他代谢紊乱通过一些共同的途径,如炎症、内质网应激(ERS)、氧化应激和异位脂质沉积,导致红外和/或胰岛β细胞功能障碍。目前还没有根治 T2D 的方法,但可以通过生活方式干预和/或一些药物来预防或缓解 T2D。如果预防失败,应尽快通过及时发现和诊断,考虑靶器官保护、合并症、治疗目标和其他现实因素,采取整体和个性化的管理。T2D 常伴有 MDS 的其他组成部分,如肥胖前期/肥胖、代谢功能障碍伴脂肪性肝病、血脂异常等,这些疾病通常发生在 T2D 之前,被认为是 T2D 的上游疾病。将 "糖尿病并发症 "称为 "MDS 相关靶器官损害(TOD)"更为恰当,因为其发生不仅涉及高血糖,还涉及 MDS 的其他代谢紊乱,从而促进了最新的管理理念。本综述旨在总结 T2D 的基本机制、筛查、诊断、预防和治疗,尤其是基于 "MDS 相关 TOD "概念的个性化降糖药物选择和整体管理。
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引用次数: 0
Correction: M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity. 更正:M2 巨噬细胞(而非 M1 巨噬细胞)通过上调 PI3K-AKT 通路活性支持巨核细胞生成。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-12 DOI: 10.1038/s41392-024-01965-3
Hong-Yan Zhao, Yuan-Yuan Zhang, Tong Xing, Shu-Qian Tang, Qi Wen, Zhong-Shi Lyu, Meng Lv, Yu Wang, Lan-Ping Xu, Xiao-Hui Zhang, Yuan Kong, Xiao-Jun Huang
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引用次数: 0
Anti-PD-L1 antibody ASC22 in combination with a histone deacetylase inhibitor chidamide as a "shock and kill" strategy for ART-free virological control: a phase II single-arm study. 抗PD-L1抗体ASC22与组蛋白去乙酰化酶抑制剂千达酰胺联用作为无抗病毒疗法病毒学控制的 "冲击和杀伤 "策略:一项II期单臂研究。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-09 DOI: 10.1038/s41392-024-01943-9
Luling Wu, Zhihang Zheng, Jingna Xun, Li Liu, Jiangrong Wang, Xinyu Zhang, Yueming Shao, Yinzhong Shen, Renfang Zhang, Min Zhang, Meiyan Sun, Tangkai Qi, Zhenyan Wang, Shuibao Xu, Wei Song, Yang Tang, Bihe Zhao, Zichen Song, Jean-Pierre Routy, Hongzhou Lu, Jun Chen

The combination of ASC22, an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide, a HIV latency reversal agent, may serve as a strategy for antiretroviral therapy-free virological control for HIV. People living with HIV, having achieved virological suppression, were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy. Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8+ T cells (NCT05129189). 15 participants completed the study. At week 8, CA HIV RNA levels showed a significant increase from baseline, and the values returned to baseline after discontinuing ASC22 and chidamide. The total HIV DNA was only transiently increased at week 4 (P = 0.014). In contrast, integrated HIV DNA did not significantly differ from baseline. Increases in the proportions of effector memory CD4+ and CD8+ T cells (TEM) were observed from baseline to week 24 (P = 0.034 and P = 0.002, respectively). The combination treatment did not succeed in enhancing the function of HIV Gag/Pol- specific CD8+ T cells. Nevertheless, at week 8, a negative correlation was identified between the proportions of HIV Gag-specific TEM cells and alterations in integrated DNA in the T cell function improved group (P = 0.042 and P = 0.034, respectively). Nine adverse events were solicited, all of which were graded 1 and resolved spontaneously. The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs. Further investigations are warranted in the context of analytic treatment interruption.

ASC22是一种抗PD-L1抗体,有可能增强艾滋病病毒的特异性免疫力,而chidamide是一种艾滋病病毒潜伏逆转剂,两者结合可作为一种策略,在抗逆转录病毒治疗的同时控制艾滋病病毒。已达到病毒学抑制的艾滋病病毒感染者在接受抗逆转录病毒疗法的同时,还接受了 ASC22 和 chidamide 治疗。对参与者进行为期 24 周的监测,以测量病毒动态变化和 HIV 特异性 CD8+ T 细胞的功能(NCT05129189)。15 名参与者完成了研究。第 8 周时,CA HIV RNA 水平较基线有显著上升,停用 ASC22 和氯达酰胺后,其值恢复至基线。在第 4 周时,HIV DNA 总量仅短暂增加(P = 0.014)。相比之下,整合 HIV DNA 与基线相比没有明显差异。从基线到第 24 周,观察到效应记忆 CD4+ 和 CD8+ T 细胞(TEM)的比例增加(P = 0.034 和 P = 0.002)。联合治疗未能成功增强 HIV Gag/Pol 特异性 CD8+ T 细胞的功能。不过,在第 8 周时,T 细胞功能改善组中 HIV Gag 特异性 TEM 细胞的比例与整合 DNA 的改变之间出现了负相关(分别为 P = 0.042 和 P = 0.034)。共征集到 9 例不良反应,所有不良反应均为 1 级,并可自行缓解。ASC22和氯达酰胺联合治疗的耐受性良好,并能有效激活潜伏的HIV储库。在分析治疗中断的情况下,有必要进行进一步研究。
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引用次数: 0
Metabolic inflexibility of mitochondria: beneficial for the fitness of regenerating liver cells. 线粒体的代谢不灵活性:有利于再生肝细胞的健康。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-09 DOI: 10.1038/s41392-024-01959-1
Josef Ecker, Sarah Brunner, Klaus-Peter Janssen
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引用次数: 0
A new paradigm for generating high-quality cardiac pacemaker cells from mouse pluripotent stem cells. 从小鼠多能干细胞生成高质量心脏起搏器细胞的新范例。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-06 DOI: 10.1038/s41392-024-01942-w
Zheyi Lin, Bowen Lin, Chengwen Hang, Renhong Lu, Hui Xiong, Junyang Liu, Siyu Wang, Zheng Gong, Mingshuai Zhang, Desheng Li, Guojian Fang, Jie Ding, Xuling Su, Huixin Guo, Dan Shi, Duanyang Xie, Yi Liu, Dandan Liang, Jian Yang, Yi-Han Chen

Cardiac biological pacing (BP) is one of the future directions for bradyarrhythmias intervention. Currently, cardiac pacemaker cells (PCs) used for cardiac BP are mainly derived from pluripotent stem cells (PSCs). However, the production of high-quality cardiac PCs from PSCs remains a challenge. Here, we developed a cardiac PC differentiation strategy by adopting dual PC markers and simulating the developmental route of PCs. First, two PC markers, Shox2 and Hcn4, were selected to establish Shox2:EGFP; Hcn4:mCherry mouse PSC reporter line. Then, by stepwise guiding naïve PSCs to cardiac PCs following naïve to formative pluripotency transition and manipulating signaling pathways during cardiac PCs differentiation, we designed the FSK method that increased the yield of SHOX2+; HCN4+ cells with typical PC characteristics, which was 12 and 42 folds higher than that of the embryoid body (EB) and the monolayer M10 methods respectively. In addition, the in vitro cardiac PCs differentiation trajectory was mapped by single-cell RNA sequencing (scRNA-seq), which resembled in vivo PCs development, and ZFP503 was verified as a key regulator of cardiac PCs differentiation. These PSC-derived cardiac PCs have the potential to drive advances in cardiac BP technology, help with the understanding of PCs (patho)physiology, and benefit drug discovery for PC-related diseases as well.

心脏生物起搏(BP)是缓性心律失常干预的未来发展方向之一。目前,用于心脏生物起搏的心脏起搏器细胞(PCs)主要来自多能干细胞(PSCs)。然而,如何从多能干细胞制备高质量的心脏起搏器细胞仍是一项挑战。在这里,我们通过采用双PC标记物和模拟PC的发育路线,开发了一种心脏PC分化策略。首先,我们选择了Shox2和Hcn4这两个PC标记物,建立了Shox2:EGFP; Hcn4:mCherry小鼠PSC报告基因系。然后,我们设计了FSK方法,该方法能提高具有典型PC特征的SHOX2+; HCN4+细胞的产量,比类胚体(EB)和单层M10方法分别高出12倍和42倍。此外,通过单细胞RNA测序(scRNA-seq)绘制的体外心脏多核细胞分化轨迹与体内多核细胞发育相似,ZFP503被证实是心脏多核细胞分化的关键调控因子。这些来源于造血干细胞的心脏多核细胞有望推动心脏BP技术的进步,有助于了解多核细胞的(病)生理学,并有利于多核细胞相关疾病的药物研发。
{"title":"A new paradigm for generating high-quality cardiac pacemaker cells from mouse pluripotent stem cells.","authors":"Zheyi Lin, Bowen Lin, Chengwen Hang, Renhong Lu, Hui Xiong, Junyang Liu, Siyu Wang, Zheng Gong, Mingshuai Zhang, Desheng Li, Guojian Fang, Jie Ding, Xuling Su, Huixin Guo, Dan Shi, Duanyang Xie, Yi Liu, Dandan Liang, Jian Yang, Yi-Han Chen","doi":"10.1038/s41392-024-01942-w","DOIUrl":"10.1038/s41392-024-01942-w","url":null,"abstract":"<p><p>Cardiac biological pacing (BP) is one of the future directions for bradyarrhythmias intervention. Currently, cardiac pacemaker cells (PCs) used for cardiac BP are mainly derived from pluripotent stem cells (PSCs). However, the production of high-quality cardiac PCs from PSCs remains a challenge. Here, we developed a cardiac PC differentiation strategy by adopting dual PC markers and simulating the developmental route of PCs. First, two PC markers, Shox2 and Hcn4, were selected to establish Shox2:EGFP; Hcn4:mCherry mouse PSC reporter line. Then, by stepwise guiding naïve PSCs to cardiac PCs following naïve to formative pluripotency transition and manipulating signaling pathways during cardiac PCs differentiation, we designed the FSK method that increased the yield of SHOX2<sup>+</sup>; HCN4<sup>+</sup> cells with typical PC characteristics, which was 12 and 42 folds higher than that of the embryoid body (EB) and the monolayer M10 methods respectively. In addition, the in vitro cardiac PCs differentiation trajectory was mapped by single-cell RNA sequencing (scRNA-seq), which resembled in vivo PCs development, and ZFP503 was verified as a key regulator of cardiac PCs differentiation. These PSC-derived cardiac PCs have the potential to drive advances in cardiac BP technology, help with the understanding of PCs (patho)physiology, and benefit drug discovery for PC-related diseases as well.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":"230"},"PeriodicalIF":40.8,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141016","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
Elimination of mutant SWI/SNF complexes by protein quality control: new opportunities targeting aggressive rhabdoid tumours. 通过蛋白质质量控制消除突变的 SWI/SNF 复合物:针对侵袭性横纹肌瘤的新机遇。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-06 DOI: 10.1038/s41392-024-01935-9
Andreas Krämer, Stefan Knapp
{"title":"Elimination of mutant SWI/SNF complexes by protein quality control: new opportunities targeting aggressive rhabdoid tumours.","authors":"Andreas Krämer, Stefan Knapp","doi":"10.1038/s41392-024-01935-9","DOIUrl":"10.1038/s41392-024-01935-9","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":"224"},"PeriodicalIF":40.8,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141017","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
"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
{"title":"\"Clone-specific\" antibody-drug conjugates: an innovative strategy in the treatment of T-cell cancers.","authors":"Dennis Jungherz, Philipp Lückemeier, Marco Herling","doi":"10.1038/s41392-024-01945-7","DOIUrl":"10.1038/s41392-024-01945-7","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":"228"},"PeriodicalIF":40.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126627","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
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
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Signal Transduction and Targeted Therapy
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