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CircPDIA3/miR-449a/XBP1 feedback loop curbs pyroptosis by inhibiting palmitoylation of the GSDME-C domain to induce chemoresistance of colorectal cancer CircPDIA3/miR-449a/XBP1反馈环路通过抑制GSDME-C结构域的棕榈酰化来抑制热蛋白沉积,从而诱导结直肠癌的化疗耐药性
IF 24.3 1区 医学 Q1 Medicine Pub Date : 2024-05-28 DOI: 10.1016/j.drup.2024.101097
Jiatong Lin , Zejian Lyu , Huolun Feng , Huajie Xie , Jingwen Peng , Weifu Zhang , Jun Zheng , Jiabin Zheng , Zihao Pan , Yong Li

Although oxaliplatin (OXA) is widely used in the frontline treatment of colorectal cancer (CRC), CRC recurrence is commonly observed due to OXA resistance. OXA resistance is associated with a number of factors, including abnormal regulation of pyroptosis. It is therefore important to elucidate the abnormal regulatory mechanism underlying pyroptosis. Here, we identified that the circular RNA circPDIA3 played an important role in chemoresistance in CRC. CircPDIA3 could induce chemoresistance in CRC by inhibiting pyroptosis both in vitro and in vivo. Mechanistically, RIP, RNA pull-down and co-IP assays revealed that circPDIA3 directly bonded to the GSDME-C domain, subsequently enhanced the autoinhibitory effect of the GSDME-C domain through blocking the GSDME-C domain palmitoylation by ZDHHC3 and ZDHHC17, thereby restraining pyroptosis. Additionally, it was found that the circPDIA3/miR-449a/XBP1 positive feedback loop increased the expression of circPDIA3 to induce chemoresistance. Furthermore, our clinical data and patient-derived tumor xenograft (PDX) models supported the positive association of circPDIA3 with development of chemoresistance in CRC patients. Taken together, our findings demonstrated that circPDIA3 could promote chemoresistance by amplifying the autoinhibitory effect of the GSDME-C domain through inhibition of the GSDME-C domain palmitoylation in CRC. This study provides novel insights into the mechanism of circRNA in regulating pyroptosis and providing a potential therapeutic target for reversing chemoresistance of CRC.

尽管奥沙利铂(OXA)被广泛应用于结直肠癌(CRC)的一线治疗,但由于对 OXA 产生耐药性,CRC 复发现象十分常见。OXA 耐药性与多种因素有关,包括热蛋白沉积的异常调控。因此,阐明热蛋白沉积的异常调控机制非常重要。在这里,我们发现环状 RNA circPDIA3 在 CRC 的化疗耐药性中发挥了重要作用。循环RNA circPDIA3可通过抑制体外和体内的热凋亡诱导CRC的化疗耐药性。从机理上讲,RIP、RNA pull-down和co-IP实验发现,circPDIA3直接与GSDME-C结构域结合,然后通过阻断ZDHHC3和ZDHHC17对GSDME-C结构域棕榈酰化,增强GSDME-C结构域的自身抑制作用,从而抑制热凋亡。此外,研究还发现,circPDIA3/miR-449a/XBP1正反馈回路增加了circPDIA3的表达,从而诱导化疗耐药。此外,我们的临床数据和患者来源的肿瘤异种移植(PDX)模型也支持 circPDIA3 与 CRC 患者化疗耐药性的发生呈正相关。综上所述,我们的研究结果表明,circPDIA3可通过抑制GSDME-C结构域棕榈酰化,放大GSDME-C结构域的自身抑制作用,从而促进CRC的化疗耐药性。这项研究为我们揭示circRNA调控化脓过程的机制提供了新的视角,并为逆转CRC的化疗耐药性提供了潜在的治疗靶点。
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引用次数: 0
KLF12 interacts with TRIM27 to affect cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma by regulating L1CAM expression KLF12与TRIM27相互作用,通过调节L1CAM的表达影响食管鳞状细胞癌的顺铂耐药性和癌症转移。
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-27 DOI: 10.1016/j.drup.2024.101096
Hao Zhang , Yujia Zheng , Zhen Wang , Lin Dong , Liyan Xue , Xiaolin Tian , Haiteng Deng , Qi Xue , Shugeng Gao , Yibo Gao , Chunxiang Li , Jie He

Krüppel-like factor 12 (KLF12) has been characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and natural killer (NK) cell proliferation. However, the contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma (ESCC). Mechanistically, KLF12 binds to the promoters of L1 Cell Adhesion Molecule (L1CAM) and represses its expression. Depletion of L1CAM abrogates cisplatin resistance and cancer metastasis caused by KLF12 loss. Moreover, the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC. Targeting these genes could be a promising approach for ESCC treatment.

Krüppel样因子12(KLF12)是一种转录抑制因子,先前的研究揭示了它在血管生成、神经管缺陷和自然杀伤(NK)细胞增殖中的作用。然而,KLF12 对癌症治疗的贡献仍未确定。在这里,我们发现 KLF12 在多种癌症类型中被下调,而 KLF12 的下调促进了食管鳞状细胞癌(ESCC)的顺铂耐药性和癌症转移。从机制上讲,KLF12 与 L1 细胞粘附分子(L1CAM)的启动子结合并抑制其表达。L1CAM的缺失会削弱顺铂抗性以及KLF12缺失导致的癌症转移。此外,E3 泛素连接酶含三方基序 27(TRIM27)与 KLF12 的 N 端区域结合,并通过 K33 链接的多泛素化在 K326 处泛素化 KLF12。值得注意的是,TRIM27 的缺失会增强 KLF12 的转录活性,从而抑制 L1CAM 的表达。总之,我们的研究阐明了一种涉及TRIM27、KLF12和L1CAM的新型调控机制,该机制在ESCC的顺铂耐药和癌症转移中发挥了重要作用。靶向这些基因可能是治疗 ESCC 的一种有前景的方法。
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引用次数: 0
FAT1 as a tumor mutation burden specific gene affects the immunotherapy effect in head and neck squamous cell cancer FAT1 作为肿瘤突变负荷特异性基因影响头颈部鳞状细胞癌的免疫治疗效果。
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-27 DOI: 10.1016/j.drup.2024.101095
Haotian Cao , Tianjun Lan , Shijia Kuang , Liansheng Wang , Jintao Li , Qunxin Li , Yanyan Li , Qiuping Xu , Qian Chen , Shuwei Ren , Chunhong Lan , Nengtai Ouyang , Jianwei Liao , Yongsheng Huang , Jinsong Li

Background

Response to immunotherapy is the main challenge of head and neck squamous cancer (HNSCC) treatment. Previous studies have indicated that tumor mutational burden (TMB) is associated with prognosis, but it is not always a precise index. Hence, investigating specific genetic mutations and tumor microenvironment (TME) changes in TMB-high patients is essential for precision therapy of HNSCC.

Methods

A total of 33 HNSCC patients were enrolled in this study. We calculated the TMB score based on next-generation sequencing (NGS) sequencing and grouped these patients based on TMB score. Then, we examined the immune microenvironment of HNSCC using assessments of the bulk transcriptome and the single-cell RNA sequence (scRNA-seq) focusing on the molecular nature of TMB and mutations in HNSCC from our cohort. The association of the mutation pattern and TMB was analyzed in The Cancer Genome Atlas (TCGA) and validated by our cohort.

Results

33 HNSCC patients were divided into three groups (TMB-low, -medium, and -high) based on TMB score. In the result of 520-gene panel sequencing data, we found that FAT1 and LRP1B mutations were highly prevalent in TMB-high patients. FAT1 mutations are associated with resistance to immunotherapy in HNSCC patients. This involves many metabolism-related pathways like RERE, AIRE, HOMER1, etc. In the scRNA-seq data, regulatory T cells (Tregs), monocytes, and DCs were found mainly enriched in TMB-high samples.

Conclusion

Our analysis unraveled the FAT1 gene as an assistant predictor when we use TMB as a biomarker of drug resistance in HNSCC. Tregs, monocytes, and dendritic cells (DCs) were found mainly enriched in TMB-high samples.

背景:对免疫疗法的反应是头颈部鳞癌(HNSCC)治疗的主要挑战。以往的研究表明,肿瘤突变负荷(TMB)与预后相关,但它并不总是一个精确的指标。因此,研究TMB高的患者的特定基因突变和肿瘤微环境(TME)变化对于HNSCC的精准治疗至关重要:本研究共纳入 33 例 HNSCC 患者。我们根据新一代测序(NGS)计算了TMB评分,并根据TMB评分对这些患者进行了分组。然后,我们利用大体转录组和单细胞 RNA 序列(scRNA-seq)的评估来研究 HNSCC 的免疫微环境,重点是我们队列中 HNSCC 中 TMB 和突变的分子性质。在癌症基因组图谱(TCGA)中分析了突变模式与TMB的关联,并通过我们的队列进行了验证:根据 TMB 评分,33 例 HNSCC 患者被分为三组(TMB 低、中、高)。在 520 个基因的测序结果中,我们发现 FAT1 和 LRP1B 突变在 TMB 高的患者中非常普遍。FAT1 突变与 HNSCC 患者对免疫疗法的耐药性有关。这涉及许多代谢相关通路,如 RERE、AIRE、HOMER1 等。在scRNA-seq数据中,调节性T细胞(Tregs)、单核细胞和DCs主要富集在TMB高的样本中:结论:我们的分析发现,当我们使用TMB作为HNSCC耐药性的生物标记时,FAT1基因是一个辅助预测因子。TMB高的样本中主要富集了Tregs、单核细胞和树突状细胞(DCs)。
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引用次数: 0
Characterization of NMCR-3, NMCR-4 and NMCR-5, three novel non-mobile colistin resistance determinants: Implications for MCR-3, MCR-7, and MCR-5 progenitors, respectively NMCR-3、NMCR-4 和 NMCR-5 这三种新型非移动性秋水仙素抗性决定因子的特征:分别对 MCR-3、MCR-7 和 MCR-5 祖细胞的影响
IF 24.3 1区 医学 Q1 Medicine Pub Date : 2024-04-26 DOI: 10.1016/j.drup.2024.101088
Yating Guo , Geng Zou , Anusak Kerdsin , Constance Schultsz , Can Hu , Weicheng Bei , Huanchun Chen , Jinquan Li , Yang Zhou

In this study, the progenitors of MCR-3, MCR-7 and MCR-5, namely NMCR-3, NMCR-4 and NMCR-5, were firstly discovered and indicating Aeromonas was a natural reservoir for MCR-3 and MCR-7. Furthermore, different evolutionary models for MCR-3, MCR-7 and MCR-5 were proposed.

本研究首次发现了MCR-3、MCR-7和MCR-5的祖先,即NMCR-3、NMCR-4和NMCR-5,并指出气单胞菌是MCR-3和MCR-7的天然储库。此外,还提出了 MCR-3、MCR-7 和 MCR-5 的不同进化模式。
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引用次数: 0
Spotlight on ideal target antigens and resistance in antibody-drug conjugates: Strategies for competitive advancement 聚焦抗体药物共轭物中的理想靶抗原和抗药性:提高竞争力的策略
IF 24.3 1区 医学 Q1 Medicine Pub Date : 2024-04-23 DOI: 10.1016/j.drup.2024.101086
Mingxia Jiang , Qiao Li , Binghe Xu

Antibody-drug conjugates (ADCs) represent a novel and promising approach in targeted therapy, uniting the specificity of antibodies that recognize specific antigens with payloads, all connected by the stable linker. These conjugates combine the best targeted and cytotoxic therapies, offering the killing effect of precisely targeting specific antigens and the potent cell-killing power of small molecule drugs. The targeted approach minimizes the off-target toxicities associated with the payloads and broadens the therapeutic window, enhancing the efficacy and safety profile of cancer treatments. Within precision oncology, ADCs have garnered significant attention as a cutting-edge research area and have been approved to treat a range of malignant tumors. Correspondingly, the issue of resistance to ADCs has gradually come to the fore. Any dysfunction in the steps leading to the ADCs' action within tumor cells can lead to the development of resistance. A deeper understanding of resistance mechanisms may be crucial for developing novel ADCs and exploring combination therapy strategies, which could further enhance the clinical efficacy of ADCs in cancer treatment. This review outlines the brief historical development and mechanism of ADCs and discusses the impact of their key components on the activity of ADCs. Furthermore, it provides a detailed account of the application of ADCs with various target antigens in cancer therapy, the categorization of potential resistance mechanisms, and the current state of combination therapies. Looking forward, breakthroughs in overcoming technical barriers, selecting differentiated target antigens, and enhancing resistance management and combination therapy strategies will broaden the therapeutic indications for ADCs. These progresses are anticipated to advance cancer treatment and yield benefits for patients.

抗体-药物共轭物(ADCs)是靶向治疗中一种新型且前景广阔的方法,它将识别特定抗原的特异性抗体与有效载荷结合在一起,所有载荷都由稳定的连接体连接。这些共轭物结合了最佳的靶向疗法和细胞毒疗法,既有精确靶向特定抗原的杀伤效果,又有小分子药物强大的细胞杀伤力。这种靶向方法最大限度地减少了有效载荷的脱靶毒性,扩大了治疗窗口,提高了癌症治疗的有效性和安全性。在精准肿瘤学领域,ADC 作为一个前沿研究领域备受关注,已被批准用于治疗一系列恶性肿瘤。相应地,ADCs 的耐药性问题也逐渐凸显出来。ADCs在肿瘤细胞内发挥作用的任何步骤出现功能障碍,都可能导致耐药性的产生。深入了解耐药机制可能对开发新型 ADC 和探索联合治疗策略至关重要,这将进一步提高 ADC 在癌症治疗中的临床疗效。本综述概述了 ADCs 的简要历史发展和机制,并讨论了其关键成分对 ADCs 活性的影响。此外,它还详细介绍了ADCs与各种靶抗原在癌症治疗中的应用、潜在耐药机制的分类以及联合疗法的现状。展望未来,在克服技术壁垒、选择差异化靶抗原、加强耐药性管理和联合治疗策略方面取得的突破将拓宽 ADCs 的治疗适应症。预计这些进展将推动癌症治疗,为患者带来益处。
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引用次数: 0
Heterogeneity of SOS response expression in clinical isolates of Escherichia coli influences adaptation to antimicrobial stress 临床分离的大肠埃希菌中 SOS 响应表达的异质性影响了对抗菌压力的适应性
IF 24.3 1区 医学 Q1 Medicine Pub Date : 2024-04-23 DOI: 10.1016/j.drup.2024.101087
Sara Diaz-Diaz , Andrea Garcia-Montaner , Roberta Vanni , Marina Murillo-Torres , Esther Recacha , Marina R. Pulido , Maria Romero-Muñoz , Fernando Docobo-Pérez , Alvaro Pascual , Jose Manuel Rodriguez-Martinez

In recent years, new evidence has shown that the SOS response plays an important role in the response to antimicrobials, with involvement in the generation of clinical resistance. Here we evaluate the impact of heterogeneous expression of the SOS response in clinical isolates of Escherichia coli on response to the fluoroquinolone, ciprofloxacin. In silico analysis of whole genome sequencing data showed remarkable sequence conservation of the SOS response regulators, RecA and LexA. Despite the genetic homogeneity, our results revealed a marked differential heterogeneity in SOS response activation, both at population and single-cell level, among clinical isolates of E. coli in the presence of subinhibitory concentrations of ciprofloxacin. Four main stages of SOS response activation were identified and correlated with cell filamentation. Interestingly, there was a correlation between clinical isolates with higher expression of the SOS response and further progression to resistance. This heterogeneity in response to DNA damage repair (mediated by the SOS response) and induced by antimicrobial agents could be a new factor with implications for bacterial evolution and survival contributing to the generation of antimicrobial resistance.

近年来,新的证据表明,SOS 反应在抗菌药物反应中发挥着重要作用,并参与了临床耐药性的产生。在此,我们评估了大肠埃希菌临床分离株中 SOS 反应异质性表达对氟喹诺酮类药物环丙沙星反应的影响。对全基因组测序数据的硅学分析表明,SOS 响应调节因子 RecA 和 LexA 的序列具有显著的保守性。尽管基因具有同质性,但我们的研究结果表明,在亚抑制浓度环丙沙星的作用下,临床分离的大肠杆菌在群体和单细胞水平上的 SOS 反应激活具有明显的差异性。确定了 SOS 反应激活的四个主要阶段,并将其与细胞丝状化相关联。有趣的是,SOS 反应表达较高的临床分离株与耐药性的进一步发展之间存在相关性。这种由抗菌剂诱导的 DNA 损伤修复反应(由 SOS 反应介导)的异质性可能是对细菌进化和生存产生影响的一个新因素,有助于抗菌剂耐药性的产生。
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引用次数: 0
Potential targets and therapeutics for cancer stem cell-based therapy against drug resistance in hepatocellular carcinoma 基于癌症干细胞的肝细胞癌抗药性治疗的潜在靶点和疗法
IF 24.3 1区 医学 Q1 Medicine Pub Date : 2024-04-16 DOI: 10.1016/j.drup.2024.101084
Hongxing Zhao , Yuhang Ling , Jie He , Jinling Dong , Qinliang Mo , Yao Wang , Ying Zhang , Hongbin Yu , Chengwu Tang

Hepatocellular carcinoma (HCC) is the most common digestive malignancyin the world, which is frequently diagnosed at late stage with a poor prognosis. For most patients with advanced HCC, the therapeutic options arelimiteddue to cancer occurrence of drug resistance. Hepatic cancer stem cells (CSCs) account for a small subset of tumor cells with the ability of self-renewal and differentiationin HCC. It is widely recognized that the presence of CSCs contributes to primary and acquired drug resistance. Therefore, hepatic CSCs-targeted therapy is considered as a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC. In this article, we review drug resistance in HCC and provide a summary of potential targets for CSCs-based therapy. In addition, the development of CSCs-targeted therapeuticsagainst drug resistance in HCC is summarized in both preclinical and clinical trials. The in-depth understanding of CSCs-related drug resistance in HCC will favor optimization of the current therapeutic strategies and gain encouraging therapeutic outcomes.

肝细胞癌(HCC)是世界上最常见的消化系统恶性肿瘤,常被诊断为晚期,预后较差。对于大多数晚期肝细胞癌患者来说,由于癌症出现耐药性,治疗方案十分有限。肝癌干细胞(CSCs)是 HCC 中一小部分具有自我更新和分化能力的肿瘤细胞。人们普遍认为,肝癌干细胞的存在会导致原发性和获得性耐药性。因此,肝脏 CSCs 靶向治疗被认为是克服 HCC 耐药性和改善治疗效果的一种有前途的策略。在本文中,我们回顾了 HCC 的耐药性,并总结了基于 CSCs 治疗的潜在靶点。此外,我们还总结了临床前和临床试验中针对 HCC 耐药性的 CSCs 靶向疗法的发展情况。深入了解 HCC 中与 CSCs 相关的耐药性将有利于优化当前的治疗策略,并获得令人鼓舞的治疗效果。
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引用次数: 0
Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy Syk依赖性同源重组激活促进癌症对DNA靶向疗法产生抗药性
IF 24.3 1区 医学 Q1 Medicine Pub Date : 2024-04-16 DOI: 10.1016/j.drup.2024.101085
Qin Zhou , Xinyi Tu , Xiaonan Hou , Jia Yu , Fei Zhao , Jinzhou Huang , Jake Kloeber , Anna Olson , Ming Gao , Kuntian Luo , Shouhai Zhu , Zheming Wu , Yong Zhang , Chenyu Sun , Xiangyu Zeng , Kenneth J. Schoolmeester , John S. Weroha , Xiwen Hu , Yanxia Jiang , Liewei Wang , Zhenkun Lou

Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase (PARP) inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase acknowledged for its regulatory roles in immune cell function, cell adhesion, and vascular development. This study presents evidence indicating that Syk expression in high-grade serous ovarian cancer and triple-negative breast cancers promotes DNA double-strand break resection, homologous recombination (HR), and subsequent therapeutic resistance. Our investigations reveal that Syk is activated by ATM following DNA damage and is recruited to DNA double-strand breaks by NBS1. Once localized to the break site, Syk phosphorylates CtIP, a pivotal mediator of resection and HR, at Thr-847 to promote repair activity, particularly in Syk-expressing cancer cells. Inhibition of Syk or its genetic deletion impedes CtIP Thr-847 phosphorylation and overcomes the resistant phenotype. Collectively, our findings suggest a model wherein Syk fosters therapeutic resistance by promoting DNA resection and HR through a hitherto uncharacterized ATM-Syk-CtIP pathway. Moreover, Syk emerges as a promising tumor-specific target to sensitize Syk-expressing tumors to PARP inhibitors, radiation and other DNA-targeted therapies.

DNA 修复能力的增强是 DNA 靶向疗法(包括聚 ADP 核糖聚合酶(PARP)抑制剂)固有和获得性抗药性的一个重要机制。脾脏相关酪氨酸激酶(Syk)是一种非受体酪氨酸激酶,在免疫细胞功能、细胞粘附和血管发育中发挥着公认的调节作用。本研究提供的证据表明,在高级别浆液性卵巢癌和三阴性乳腺癌中,Syk的表达会促进DNA双链断裂切除、同源重组(HR)以及随后的耐药性。我们的研究发现,DNA损伤后,Syk会被ATM激活,并被NBS1招募到DNA双链断裂处。一旦定位于断裂位点,Syk 就会在 Thr-847 处磷酸化 CtIP(切除和 HR 的关键介质),以促进修复活动,尤其是在表达 Syk 的癌细胞中。抑制 Syk 或基因缺失会阻碍 CtIP Thr-847 磷酸化,从而克服耐药表型。总之,我们的研究结果表明,Syk通过迄今尚未定性的ATM-Syk-CtIP途径促进DNA切除和HR,从而建立了一个促进治疗耐药性的模型。此外,Syk还是一个很有希望的肿瘤特异性靶点,可使Syk表达的肿瘤对PARP抑制剂、辐射和其他DNA靶向疗法敏感。
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引用次数: 0
Expansion and transmission dynamics of high risk carbapenem-resistant Klebsiella pneumoniae subclones in China: An epidemiological, spatial, genomic analysis 中国高风险耐碳青霉烯类肺炎克雷伯氏菌亚克隆的扩展和传播动态:流行病学、空间和基因组分析
IF 24.3 1区 医学 Q1 Medicine Pub Date : 2024-03-29 DOI: 10.1016/j.drup.2024.101083
Qi Wang , Ruobing Wang , Shuyi Wang , Anru Zhang , Qiaoyan Duan , Shijun Sun , Longyang Jin , Xiaojuan Wang , Yawei Zhang , Chunlei Wang , Haiquan Kang , Zhijie Zhang , Kang Liao , Yinghui Guo , Liang Jin , Zhiwu Liu , Chunxia Yang , Hui Wang , on behalf of the China Carbapenem-Resistant Enterobacterales (CRE) Network

Aims

Carbapenem-resistant Klebsiella pneumonia (CRKP) is a global threat that varies by region. The global distribution, evolution, and clinical implications of the ST11 CRKP clone remain obscure.

Methods

We conducted a multicenter molecular epidemiological survey using isolates obtained from 28 provinces and municipalities across China between 2011 and 2021. We integrated sequences from public databases and performed genetic epidemiology analysis of ST11 CRKP.

Results

Among ST11 CRKP, KL64 serotypes exhibited considerable expansion, increasing from 1.54% to 46.08% between 2011 and 2021. Combining our data with public databases, the phylogenetic and phylogeography analyses indicated that ST11 CRKP appeared in the Americas in 1996 and spread worldwide, with key clones progressing from China’s southeastern coast to the inland by 2010. Global phylogenetic analysis showed that ST11 KL64 CRKP has evolved to a virulent, resistant clade with notable regional spread. Single-nucleotide polymorphism (SNP) analysis identified BMPPS (bmr3, mltC, pyrB, ppsC, and sdaC) as a key marker for this clade. The BMPPS SNP clade is associated with high mortality and has strong anti-phagocytic and competitive traits in vitro.

Conclusions

The high-risk ST11 KL64 CRKP subclone showed strong expansion potential and survival advantages, probably owing to genetic factors.

目的耐碳青霉烯类肺炎克雷伯氏菌(CRKP)是一种全球性威胁,因地区而异。我们利用 2011 年至 2021 年期间从中国 28 个省市获得的分离株开展了一项多中心分子流行病学调查。结果在 ST11 CRKP 中,KL64 血清型表现出相当大的扩展性,从 2011 年的 1.54% 增加到 2021 年的 46.08%。结合我们的数据和公共数据库,系统发生学和系统地理学分析表明,ST11 CRKP于1996年出现在美洲,并向全球扩散,到2010年,主要克隆从中国东南沿海向内陆扩散。全球系统进化分析表明,ST11 KL64 CRKP 已经进化为一个具有明显区域性传播的毒性、抗性支系。单核苷酸多态性(SNP)分析发现,BMPPS(bmr3、mltC、PYRB、ppsC 和 sdaC)是该支系的关键标记。结论 高风险 ST11 KL64 CRKP 亚克隆显示出很强的扩增潜力和生存优势,这可能是遗传因素造成的。
{"title":"Expansion and transmission dynamics of high risk carbapenem-resistant Klebsiella pneumoniae subclones in China: An epidemiological, spatial, genomic analysis","authors":"Qi Wang ,&nbsp;Ruobing Wang ,&nbsp;Shuyi Wang ,&nbsp;Anru Zhang ,&nbsp;Qiaoyan Duan ,&nbsp;Shijun Sun ,&nbsp;Longyang Jin ,&nbsp;Xiaojuan Wang ,&nbsp;Yawei Zhang ,&nbsp;Chunlei Wang ,&nbsp;Haiquan Kang ,&nbsp;Zhijie Zhang ,&nbsp;Kang Liao ,&nbsp;Yinghui Guo ,&nbsp;Liang Jin ,&nbsp;Zhiwu Liu ,&nbsp;Chunxia Yang ,&nbsp;Hui Wang ,&nbsp;on behalf of the China Carbapenem-Resistant Enterobacterales (CRE) Network","doi":"10.1016/j.drup.2024.101083","DOIUrl":"10.1016/j.drup.2024.101083","url":null,"abstract":"<div><h3>Aims</h3><p>Carbapenem-resistant <em>Klebsiella pneumonia</em> (CRKP) is a global threat that varies by region. The global distribution, evolution, and clinical implications of the ST11 CRKP clone remain obscure.</p></div><div><h3>Methods</h3><p>We conducted a multicenter molecular epidemiological survey using isolates obtained from 28 provinces and municipalities across China between 2011 and 2021. We integrated sequences from public databases and performed genetic epidemiology analysis of ST11 CRKP.</p></div><div><h3>Results</h3><p>Among ST11 CRKP, KL64 serotypes exhibited considerable expansion, increasing from 1.54% to 46.08% between 2011 and 2021. Combining our data with public databases, the phylogenetic and phylogeography analyses indicated that ST11 CRKP appeared in the Americas in 1996 and spread worldwide, with key clones progressing from China’s southeastern coast to the inland by 2010. Global phylogenetic analysis showed that ST11 KL64 CRKP has evolved to a virulent, resistant clade with notable regional spread. Single-nucleotide polymorphism (SNP) analysis identified BMPPS (<em>bmr3, mltC, pyrB, ppsC,</em> and <em>sdaC</em>) as a key marker for this clade. The BMPPS SNP clade is associated with high mortality and has strong anti-phagocytic and competitive traits <em>in vitro</em>.</p></div><div><h3>Conclusions</h3><p>The high-risk ST11 KL64 CRKP subclone showed strong expansion potential and survival advantages, probably owing to genetic factors.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":24.3,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000414/pdfft?md5=19e3e9a36084d1d1417245bb9050b0d4&pid=1-s2.0-S1368764624000414-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140406228","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
Advances in molecular targeted drugs in combination with CAR-T cell therapy for hematologic malignancies 分子靶向药物结合 CAR-T 细胞疗法治疗血液系统恶性肿瘤的进展
IF 24.3 1区 医学 Q1 Medicine Pub Date : 2024-03-26 DOI: 10.1016/j.drup.2024.101082
Yuxian Huang , Yinjie Qin , Yingzhi He , Dezhi Qiu , Yeqin Zheng , Jiayue Wei , Lenghe Zhang , Dong‑Hua Yang , Yuhua Li

Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of treating hematologic malignancies. However, they face challenges such as drug resistance and recurrence after treatment. Combining molecular targeted drugs and CAR-T cells could regulate immunity, improve tumor microenvironment (TME), promote cell apoptosis, and enhance sensitivity to tumor cell killing. This approach might provide a dual coordinated attack on cancer cells, effectively eliminating minimal residual disease and overcoming therapy resistance. Moreover, molecular targeted drugs can directly or indirectly enhance the anti-tumor effect of CAR-T cells by inducing tumor target antigen expression, reversing CAR-T cell exhaustion, and reducing CAR-T cell associated toxic side effects. Therefore, combining molecular targeted drugs with CAR-T cells is a promising and novel tactic for treating hematologic malignancies. In this review article, we focus on analyzing the mechanism of therapy resistance and its reversal of CAR-T cell therapy resistance, as well as the synergistic mechanism, safety, and future challenges in CAR-T cell therapy in combination with molecular targeted drugs. We aim to explore the benefits of this combination therapy for patients with hematologic malignancies and provide a rationale for subsequent clinical studies.

分子靶向药物和嵌合抗原受体(CAR)T 细胞疗法是一种特殊的生物疗法,它们大大提高了治疗血液系统恶性肿瘤的疗效。然而,它们也面临着耐药性和治疗后复发等挑战。将分子靶向药物与 CAR-T 细胞相结合,可以调节免疫、改善肿瘤微环境(TME)、促进细胞凋亡,并提高对肿瘤细胞杀伤的敏感性。这种方法可对癌细胞进行双重协同攻击,有效消除微小残留病灶,克服耐药性。此外,分子靶向药物可通过诱导肿瘤靶抗原表达、逆转CAR-T细胞衰竭、减少CAR-T细胞相关毒副作用等方式,直接或间接增强CAR-T细胞的抗肿瘤效果。因此,将分子靶向药物与CAR-T细胞相结合是治疗血液系统恶性肿瘤的一种前景广阔的新策略。在这篇综述文章中,我们重点分析了CAR-T细胞治疗耐药的机制及其逆转,以及CAR-T细胞与分子靶向药物联合治疗的协同机制、安全性和未来的挑战。我们旨在探讨这种联合疗法对血液恶性肿瘤患者的益处,并为后续的临床研究提供理论依据。
{"title":"Advances in molecular targeted drugs in combination with CAR-T cell therapy for hematologic malignancies","authors":"Yuxian Huang ,&nbsp;Yinjie Qin ,&nbsp;Yingzhi He ,&nbsp;Dezhi Qiu ,&nbsp;Yeqin Zheng ,&nbsp;Jiayue Wei ,&nbsp;Lenghe Zhang ,&nbsp;Dong‑Hua Yang ,&nbsp;Yuhua Li","doi":"10.1016/j.drup.2024.101082","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101082","url":null,"abstract":"<div><p>Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of treating hematologic malignancies. However, they face challenges such as drug resistance and recurrence after treatment. Combining molecular targeted drugs and CAR-T cells could regulate immunity, improve tumor microenvironment (TME), promote cell apoptosis, and enhance sensitivity to tumor cell killing. This approach might provide a dual coordinated attack on cancer cells, effectively eliminating minimal residual disease and overcoming therapy resistance. Moreover, molecular targeted drugs can directly or indirectly enhance the anti-tumor effect of CAR-T cells by inducing tumor target antigen expression, reversing CAR-T cell exhaustion, and reducing CAR-T cell associated toxic side effects. Therefore, combining molecular targeted drugs with CAR-T cells is a promising and novel tactic for treating hematologic malignancies. In this review article, we focus on analyzing the mechanism of therapy resistance and its reversal of CAR-T cell therapy resistance, as well as the synergistic mechanism, safety, and future challenges in CAR-T cell therapy in combination with molecular targeted drugs. We aim to explore the benefits of this combination therapy for patients with hematologic malignancies and provide a rationale for subsequent clinical studies.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":24.3,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000402/pdfft?md5=af65de610b056964260cd200f4500120&pid=1-s2.0-S1368764624000402-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140342459","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}
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Drug Resistance Updates
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