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Spatial omics accelerate the study of cancer-associated fibroblasts in non-small lung cancer 空间全息技术加速了对非小肺癌中癌症相关成纤维细胞的研究
Pub Date : 2024-03-15 DOI: 10.1002/ctd2.285
Haozhen Liu, Jixian Liu, Chao Chen

Tumour microenvironment (TME) is one of the important factors associated with cancer progression. TME is a multicellular system composed of fibroblasts, endothelial and immune cells, distributed in the extracellular matrix (ECM), and closely interacts with tumour cells to promote the occurrence and development of cancers. In TME, secreted products of various immune and non-immune cell types, such as cytokines and chemokines, as well as metabolites, hypoxia, angiogenesis and ECM remodelling drive chronic inflammation.1 Recent studies have shown that cancer-associated fibroblasts (CAFs) are important regulators of anti-tumour immune response. CAFs can reshape TME by secreting a variety of cytokines, thereby promoting immune escape. Therefore, targeting CAFs may improve the effectiveness of immunotherapy.2, 3 For example, NOX4 inhibitors can reverse the formation of CAFs, thereby restoring anti-tumor immunotherapy efficacy.3 However, due to the high heterogeneity of the CAF population, its origin and function remain unclear, and the lack of understanding of these issues greatly limits the clinical transformation of CAFs.4

The development of single-cell transcriptome sequencing (scRNA-seq) has brought fundamental advances in cancer research. The subpopulations and functions of CAFs in non-small-cell lung cancer (NSCLC) have been described in several studies using scRNA-seq.5-7 However, due to the loss of spatial information, most studies limited their research focus to immune cells in tumours. The emergence of spatial omics technology has made up for the shortcomings of single-cell sequencing, using spatial transcriptome technologies, it is expected to characterize the molecular characteristics and immune regulatory functions of CAFs in cancer.

In a recent study by Xu et al., a subpopulation of CAFs, POSTN+ CAFs were found to have a close localization with SPP1+ macrophages, and correlated with exhausted phenotypes and lower infiltration of T cells in NSCLC.8 Initially, the study identified diverse fibroblast subpopulations in NSCLC through the integration of fibroblasts in the Peking cohort (N = 1986) with fibroblasts in Samsung cohort6 (N = 3499) and Tongji cohort7 (N = 4497). Several iCAF subpopulations (clusters C01_CCL11, C05_IGF1 and C06_CCL2), adventitial fibroblasts (C03_PI16), alveolar fibroblasts (C04_COL13A1), as well as myCAF subgroups (C02_POSTN, C07_MKI67 and C09_MYH11) were identified. Specifically, they found that POSTN+ CAFs (C02_POSTN) were enriched in tumour/metastatic samples compared to normal samples. Gene Set Variation Analysis was performed and POSTN+ CAFs showed activities in several pro-invasive pathways such as “angiogenesis” and

肿瘤微环境(TME)是与癌症进展相关的重要因素之一。肿瘤微环境是一个由成纤维细胞、内皮细胞和免疫细胞组成的多细胞系统,分布在细胞外基质(ECM)中,与肿瘤细胞密切相互作用,促进癌症的发生和发展。在 TME 中,各种免疫和非免疫细胞类型的分泌产物,如细胞因子和趋化因子,以及代谢产物、缺氧、血管生成和 ECM 重塑,都是慢性炎症的驱动因素。CAFs 可通过分泌多种细胞因子重塑 TME,从而促进免疫逃逸。2, 3 例如,NOX4 抑制剂可以逆转 CAFs 的形成,从而恢复抗肿瘤免疫疗法的疗效。3 然而,由于 CAFs 群体的高度异质性,其起源和功能仍不清楚,对这些问题的不了解极大地限制了 CAFs 的临床转化。4 单细胞转录组测序(scRNA-seq)的发展为癌症研究带来了根本性的进步。5-7 然而,由于空间信息的缺失,大多数研究将研究重点局限于肿瘤中的免疫细胞。空间全息技术的出现弥补了单细胞测序的不足,利用空间转录组技术,有望描述癌症中 CAFs 的分子特征和免疫调节功能、8 最初,该研究通过将北京队列(N = 1986)中的成纤维细胞与三星队列6 (N = 3499)和同济队列7 (N = 4497)中的成纤维细胞进行整合,发现了 NSCLC 中多种多样的成纤维细胞亚群。结果发现了多个 iCAF 亚群(C01_CCL11、C05_IGF1 和 C06_CCL2 群)、临床成纤维细胞(C03_PI16)、肺泡成纤维细胞(C04_COL13A1)以及 myCAF 亚群(C02_POSTN、C07_MKI67 和 C09_MYH11)。具体而言,他们发现与正常样本相比,POSTN+ CAFs(C02_POSTN)在肿瘤/转移样本中富集。他们还进行了基因组变异分析,发现POSTN+ CAFs在 "血管生成 "和 "上皮-间质转化 "等几种促侵袭通路中表现出活性,这表明这些细胞具有促侵袭功能。此外,他们还采用了一种名为空间增强分辨率omics测序(stereo-seq)的新型空间RNA-seq方法来说明POSTN+ CAFs在5个肿瘤样本中的位置。立体测序利用 DNA 纳米球(DNBs)原位捕获 mRNA,其直径约为 220 nm,中心到中心的距离为 500 nm。9 采用 Seurat 方法将每个样本的空间基因表达分别聚类到 bin100 定义的单位(100 × 100 DNBs,即 5 ∼ 50 µm 的区域)。在 bin100 的分辨率下,空间聚类无法达到单细胞分辨率,但仍能反映不同类型细胞的空间接近性。有趣的是,五个样本中有四个样本显示 POSTN+ CAFs 和 SPP1+ 巨噬细胞相邻。研究发现了 POSTN+ CAFs 和 SPP1+ 巨噬细胞之间的几对配体-受体,如 COL4A1-ITGB1、Tenascin-C-整合素,它们可能通过调控各种靶基因来增强 SPP1+ 巨噬细胞的免疫调节活性和 POSTN+ CAFs 的表型。此外,scRNA-seq 数据表明,POSTN+ CAFs 与 T 细胞的低浸润和衰竭表型有关。为了验证他们的发现,Xu 等人分别使用 FFPE 肿瘤样本和癌症基因组图谱(TCGA)-NSCLC 样本进行了多重免疫组化染色和 CIBERSORTx 分析。此外,利用TCGA-NSCLC样本进行的临床分析表明,POSTN+ CAFs与癌症进展和不良临床预后有关。最近,Xu等人的发现揭示了POSTN+ CAFs的促肿瘤和免疫抑制作用,这可能是改善NSCLC中免疫检查点抑制剂反应的靶点。鉴于人们对单细胞和空间技术的兴趣,这是一项及时的研究,很可能会在该领域产生巨大的兴趣和影响。这项研究的目标意义重大,因为免疫疗法对 NSCLC 仍然无效,而表征 TME 是设计成功疗法的一种很有前景的方法。 然而,仍有几个问题有待解答:POSTN+ CAFs如何与其他细胞类型相互作用?POSTN+ CAFs与T细胞衰竭之间的关系及其背后的分子机制是什么?其他 CAF 亚群的功能和空间分布如何?最近,Li 等人的研究发现,POSTN+ CAFs 是肝细胞癌(HCC)病灶生态系统中的关键成分,通过病灶重编程过程促进 HCC 的进展。总之,这项研究是进一步研究 CAFs 作用的催化剂。进一步的研究有望揭示CAFs不同亚群在肿瘤中的分布趋势和分子特征,并阐明其在肿瘤组织器官中的广泛意义。刘继贤、陈超:文章的关键修改、编辑和最终版本的批准。作者声明无利益冲突。
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引用次数: 0
Roles of telocytes dominated cell–cell communication in fibroproliferative acute respiratory distress syndrome 纤维增生性急性呼吸窘迫综合征中端粒细胞主导细胞-细胞间通讯的作用
Pub Date : 2024-03-11 DOI: 10.1002/ctd2.277
Yonghua Zheng, Songshan Cai, Zongfeng Zhao, Xiangdong Wang, Lihua Dai, Dongli Song

Telocytes (TCs) are a new type of interstitial cell identified in multiple tissues of mammals, including the human lung, and mediate homocellular or heterocellular cell-cell communication. Acute respiratory distress syndrome (ARDS) is characterized by acute hypoxemia respiratory failure and combined with direct and indirect lung injury, which is induced by pneumonia, sepsis, burns, etc. Pulmonary fibrosis is a progressive lung disease that occurs due to increased fibrosis of lung tissue in response to chronic injury of the epithelium and gets more and more attention as a well-recognized sequela of ARDS or mechanical ventilation. However, the existing intervention measures could not prevent the progression of pulmonary fibrosis. Although the protective effect of TCs in acute lung injury had been demonstrated in both cellular and animal models in previous studies by our or other researchers, the roles of TCs mediated cell-cell communication in fibroproliferative ARDS is unclear. This review is aimed at integrating our understanding of TC-mediated cell–cell communication in lung diseases with pulmonary fibrosis after ARDS.

远端细胞(TC)是一种新型间质细胞,在包括人类肺部在内的多种哺乳动物组织中被发现,可介导同细胞或异细胞的细胞间通讯。急性呼吸窘迫综合征(ARDS)以急性低氧血症呼吸衰竭为特征,合并直接和间接肺损伤,由肺炎、败血症、烧伤等诱发。肺纤维化是一种渐进性肺部疾病,是由于上皮细胞慢性损伤导致肺组织纤维化加重而发生的,作为 ARDS 或机械通气的后遗症,肺纤维化已得到越来越多的关注。然而,现有的干预措施无法阻止肺纤维化的发展。虽然我们或其他研究人员在以前的研究中已在细胞和动物模型中证实了透明质酸对急性肺损伤的保护作用,但透明质酸介导的细胞-细胞通讯在纤维增生性 ARDS 中的作用尚不清楚。本综述旨在整合我们对 TC 介导的细胞-细胞通讯在 ARDS 后肺纤维化肺部疾病中的作用的认识。
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引用次数: 0
Nanomedicine: a frontier of the breast cancer treatment 纳米医学:乳腺癌治疗的前沿领域
Pub Date : 2024-03-11 DOI: 10.1002/ctd2.281
Swarup Sonar, Sidhanti Nyahatkar, Ketki Kalele, Manab Deb Adhikari

Cancer is an unsolved health crisis that affects a large number of world's population.1 Breast cancer is the most challenging problem in the current time and this cancer affects a huge female population every year.2 Several factors are involved in breast cancer such as age, genetic mutation, obesity, food habits, family history, etc. In this situation, we need an affordable, effective, and efficient theranostics approach. This global crisis is addressed via nanomedicine, which is an applied domain of nanotechnology (it is related to cancer diagnosis, sensor, and therapeutics development based on nanomaterials and nanotechnology).3 Nanoparticles based nanomedicine has dynamic application in cancer diagnostic tools development,  therapeutic approach development, and several biological molecules transports.4 It is also an effective and specific drug transport vehicle for breast cancer.4 The purpose of nanomedicine is to develop a strong immune response (cellular and humoral immune response together) against cancer. Nanovaccine (majorly based on nanoparticle modification for cellular transport) is more stable, biocompatible, and less toxic.5, 6 Immune response developmentary antigen protein-loaded particles are developed Treg (regulatory T-cells) cells mediated immune response.7 Nanomedicine becomes a promising solution for breast cancer. Nanomaterial size, surface charges, and chemical composition play principleroles in therapeutic release, cytotoxicity, and drug-uptake phenomena.8 The scientific investigation currently highlights that during cancer development and progression, extracellular vesicles (EVs) play a regulatory role in cancer.9 This type of invention introduces a new member of nanomedicine, called EVs. In breast cancer, exosomes (a subpopulation of EVs) regulate several stages of cancer development (cancer cell proliferation, angiogenesis, immune cells suppression, metastasis, and drug and therapeutic-resistance development).10-13 Exosomes cargo molecules are significantly influenced by breast cancer development.10 Blood-circulated exosomes carry signature breast cancer biomarkers (diagnostic and prognostic biomarkers).10, 13 In breast cancer, the most challenging part of early diagnosis. Exosomes-based liquid biopsy is the most efficient approach for screening cancer compared to tissue biopsy.14 The current development of nanomedicine indicates that single exosome profiling, exosome barcoding, exosome sensor, and multi-omic approaches are leading frontier combating for breast cancer.15, 16 Plant-source exosomes (tea leaf exosomes) based nanomedicine also (tea leaf exosomes) show breast cancer healing ac

1 乳腺癌是当前最具挑战性的问题,每年都有大量女性患上乳腺癌。2 乳腺癌与多种因素有关,如年龄、基因突变、肥胖、饮食习惯、家族史等。在这种情况下,我们需要一种经济、有效、高效的治疗方法。3 以纳米粒子为基础的纳米医学在癌症诊断工具开发、治疗方法开发和多种生物分子运输方面有着活跃的应用。4 它也是治疗乳腺癌的一种有效而特异的药物运输载体。纳米疫苗(主要基于纳米颗粒的细胞运输改性)更稳定、生物相容性更好、毒性更低。5, 6 免疫反应发育抗原蛋白负载颗粒可开发 Treg(调节性 T 细胞)细胞介导的免疫反应。纳米材料的尺寸、表面电荷和化学成分在治疗释放、细胞毒性和药物吸收现象中发挥着重要作用。8 目前的科学研究表明,在癌症的发展和恶化过程中,细胞外囊泡(EVs)在癌症中发挥着调节作用。在乳腺癌中,外泌体(EVs 的一个亚群)调控着癌症发展的几个阶段(癌细胞增殖、血管生成、免疫细胞抑制、转移以及药物和治疗抗性的发展)。与组织活检相比,基于外泌体的液体活检是筛查癌症最有效的方法。14 目前纳米医学的发展表明,单一外泌体分析、外泌体条形码、外泌体传感器和多组学方法是抗击乳腺癌的前沿技术、16 基于植物来源外泌体(茶叶外泌体)的纳米药物(茶叶外泌体)也显示出低毒性的乳腺癌治疗活性:Swarup Sonar:撰稿;Sidhanti Nyahatkar:撰稿;Ketki Kalele:审稿:审稿;Manab Deb Adhikari:作者声明无利益冲突。
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引用次数: 0
Investigating the biological effects of socioeconomic adversity in cancer 调查社会经济逆境对癌症的生物学影响
Pub Date : 2024-03-11 DOI: 10.1002/ctd2.284
David Füller

Numerous studies have demonstrated socioeconomic differences in cancer incidence and outcomes, including shorter cancer survival times in patients with lower educational attainment and income, which represent important indicators of lower socioeconomic status (SES). The hypothesis proposing that disparities in cancer outcomes and mortality linked to the social determinants of health (SDoH) can be accounted for by higher risk factor prevalences or the interrelation of various SDoH has been contradicted by current evidence and previous studies have introduced potential biological mechanisms of the SDoH which are summarised by the term ‘biology of socioeconomic adversity’. Socioeconomic inequalities in cancer risk and outcomes cannot be entirely attributed to differences in clinical, behavioural, and environmental risk factors in current clinical research. Hence, it is crucial to investigate various factors, including specific biomarkers and pathophysiological pathways affected by the SDoH.

For more than 30 years, numerous studies have demonstrated socioeconomic differences in cancer incidence and survival.1-3 In the first place, it was found that shorter survival times in solid cancers and lymphoma are associated with lower income and education levels, two important indicators of lower SES, and it was noted that this effect could not be accounted for by the stage of disease at initial presentation and that this association persisted after statistically adjusting for all known prognostic factors.4 Today, socioeconomic inequalities in cancer survival rates still persist in clinical trials despite access to protocol-directed care,5 implying that optimal equitable healthcare cannot resolve inequalities in outcomes. For these reasons, a multiplex approach to this global health problem is necessary.

The hypothesis proposing that disparities in premature and cancer mortality linked to the SDoH can be accounted for by higher risk factor prevalences, like smoking, as well as by the interrelation of various SDoH, such as low income and living in adverse neighbourhood physical and social environments which aggregate within an individual, thereby amplifying health effects, holds significant appeal. However, it has been estimated that only about half of the association between area-level SES, which includes factors such as income, education, and occupation at the neighbourhood level, and cancer mortality risk can be explained by higher rates of individual-level risk factors including smoking, diet, physical activity, participation in cancer screening programs, and obesity.6 Even more, current evidence contradicts the idea that differences in cancer-associated mortality based on educational attainment, an often used indicator of individual-level SES and a key SDoH, can be attributed to differences in conventional cancer risk factors or the interrelation

此外,还需要研究生物标志物水平变化背后的病理生理机制,以了解影响易感人群预后的生物学因素。最终,这些发现可能有助于为临床实践和卫生政策提供依据,从而实施有针对性的预防策略,降低癌症发病率和死亡率。
{"title":"Investigating the biological effects of socioeconomic adversity in cancer","authors":"David Füller","doi":"10.1002/ctd2.284","DOIUrl":"https://doi.org/10.1002/ctd2.284","url":null,"abstract":"<p>Numerous studies have demonstrated socioeconomic differences in cancer incidence and outcomes, including shorter cancer survival times in patients with lower educational attainment and income, which represent important indicators of lower socioeconomic status (SES). The hypothesis proposing that disparities in cancer outcomes and mortality linked to the social determinants of health (SDoH) can be accounted for by higher risk factor prevalences or the interrelation of various SDoH has been contradicted by current evidence and previous studies have introduced potential biological mechanisms of the SDoH which are summarised by the term ‘biology of socioeconomic adversity’. Socioeconomic inequalities in cancer risk and outcomes cannot be entirely attributed to differences in clinical, behavioural, and environmental risk factors in current clinical research. Hence, it is crucial to investigate various factors, including specific biomarkers and pathophysiological pathways affected by the SDoH.</p><p>For more than 30 years, numerous studies have demonstrated socioeconomic differences in cancer incidence and survival.<span><sup>1-3</sup></span> In the first place, it was found that shorter survival times in solid cancers and lymphoma are associated with lower income and education levels, two important indicators of lower SES, and it was noted that this effect could not be accounted for by the stage of disease at initial presentation and that this association persisted after statistically adjusting for all known prognostic factors.<span><sup>4</sup></span> Today, socioeconomic inequalities in cancer survival rates still persist in clinical trials despite access to protocol-directed care,<span><sup>5</sup></span> implying that optimal equitable healthcare cannot resolve inequalities in outcomes. For these reasons, a multiplex approach to this global health problem is necessary.</p><p>The hypothesis proposing that disparities in premature and cancer mortality linked to the SDoH can be accounted for by higher risk factor prevalences, like smoking, as well as by the interrelation of various SDoH, such as low income and living in adverse neighbourhood physical and social environments which aggregate within an individual, thereby amplifying health effects, holds significant appeal. However, it has been estimated that only about half of the association between area-level SES, which includes factors such as income, education, and occupation at the neighbourhood level, and cancer mortality risk can be explained by higher rates of individual-level risk factors including smoking, diet, physical activity, participation in cancer screening programs, and obesity.<span><sup>6</sup></span> Even more, current evidence contradicts the idea that differences in cancer-associated mortality based on educational attainment, an often used indicator of individual-level SES and a key SDoH, can be attributed to differences in conventional cancer risk factors or the interrelation","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.284","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140096698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multi-omic approaches for biomarker discovery in Moyamoya disease 发现莫亚莫亚病生物标志物的多组学方法
Pub Date : 2024-03-08 DOI: 10.1002/ctd2.270
Laura Gatti, Anna Bersano, Gemma Gorla, Giuliana Pollaci, Tatiana Carrozzini, Antonella Potenza

Moyamoya disease (MMD) is a rare cerebrovascular condition characterized by a chronic and progressive narrowing of the terminal portion of the bilateral internal carotid arteries, causing the formation of an abnormal vascular network. These compensatory brain vessels often prove insufficient, leading MMD patients to severe ischemic or hemorrhagic clinical manifestations. Surgical treatment, mainly based on direct and indirect revascularization, represents the preferred procedure for MMD patients until now, for improving cerebral hemodynamics and decreasing the pathological collateral network development. The specific mechanism underlying both the progressive arterial wall thickening and the spontaneous angiogenesis of the defective moyamoya vessels remains poorly understood. Moreover, the lack of reliable animal or cellular pre-clinical models and the heterogeneous data on MMD pathophysiology have hampered the clinical validation of powerful biomarkers, as well as the development of tailored therapeutic options.

The previous investigations aimed at biomarker discovery mainly addressed patients’ peripheral blood samples, which may not reflect the real pathological changes of MMD cerebral vessels. On the other hand, prior interesting studies involving cerebral artery specimens (e.g. middle cerebral artery [MCA]) were performed through RNA microarray techniques, which have several limitations as compared to high-throughput RNA sequencing (RNA-seq). As an example, the long noncoding RNA profile of MMD patients’ MCA provided data regarding antibacterial response, T-cell receptor signalling pathway and cytokine production.1 Interestingly, Xu et al. carried out an RNA-seq analysis of MMD patients’ MCA, as compared to atherosclerosis-associated intracranial artery stenosis/occlusion. The authors identified several differential expressed genes mainly involved in extracellular matrix organization and mitochondrial function, thus highlighting novel insights into disease pathogenesis.2

Since the challenging sampling of cerebral artery specimens for transcriptomic studies, other ultrasensitive techniques were recently carried out for molecular profiling of circulating biomarkers from cerebrospinal fluid (CSF) or blood. The study by Ota et al. through a next-generation sequencing (NGS) approach demonstrated that specific changes occurred in the expression levels of extracellular vesicle-derived microRNAs (miRNAs), extracted from intracranial CSF of MMD patients when compared to controls.3 The authors suggested that MMD has a specific regulatory mechanism for angiogenesis, different from that found in other ischemic disorders. Proteomic approaches towards MMD patients’ circulating fluids have already been reported. Tandem mass tag (TMT)-labelled proteome analysis was performed on serum-derived exosomes, extracted from pure ischemic or hemorrhagic MMD patients and healthy cont

莫亚莫亚病(MMD)是一种罕见的脑血管疾病,其特征是双侧颈内动脉末端部分慢性进行性狭窄,导致异常血管网络的形成。这些代偿性脑血管往往不足,导致 MMD 患者出现严重的缺血性或出血性临床表现。迄今为止,以直接和间接血管再通为主的手术治疗是 MMD 患者的首选治疗方法,可改善脑血流动力学,减少病理侧支网络的形成。人们对有缺陷的 moyamoya 血管的动脉壁逐渐增厚和自发性血管生成的具体机制仍然知之甚少。此外,由于缺乏可靠的动物或细胞临床前模型,以及有关MMD病理生理学的数据参差不齐,这都阻碍了强有力的生物标志物的临床验证,以及量身定制的治疗方案的开发。另一方面,之前涉及大脑动脉标本(如大脑中动脉[MCA])的有趣研究是通过 RNA 微阵列技术进行的,与高通量 RNA 测序(RNA-seq)相比,该技术存在一些局限性。例如,MMD 患者 MCA 的长非编码 RNA 图谱提供了有关抗菌反应、T 细胞受体信号通路和细胞因子产生的数据1。作者发现了几个主要涉及细胞外基质组织和线粒体功能的差异表达基因,从而凸显了对疾病发病机制的新见解。2 由于脑动脉标本的转录组学研究取样具有挑战性,最近又开展了其他超灵敏技术,对脑脊液(CSF)或血液中的循环生物标志物进行分子谱分析。Ota 等人通过新一代测序(NGS)方法进行的研究表明,与对照组相比,从 MMD 患者颅内 CSF 中提取的细胞外囊源性 microRNAs(miRNAs)的表达水平发生了特殊变化。目前已有关于 MMD 患者循环液蛋白质组学方法的报道。4 生物信息学分析显示,与对照组相比,MMD 患者的细胞生长/维持失调,肌动蛋白动力学紊乱,出血性 MMD 患者免疫功能失调。同样,利用 TMT 标记结合液相色谱-串联质谱法(LC-MS/MS)对血清蛋白进行了鉴定。5 在差异表达的蛋白中,选择并评估了载脂蛋白 E(APOE),以确定其作为 MMD 候选诊断标志物的可行性。He 及其同事最近开展的另一项研究调查了异常表达的血清蛋白在 MMD 发病机制中的潜在影响。6 作者采用数据无关的采集 MS 蛋白质组学方法,对大量 MMD 血清样本进行了检测,发现 MMD 亚组与对照组之间存在差异。有趣的是,定量分析显示,与对照组相比,所有 MMD 亚组中的丝胶素 A(FLNA)都明显上调。如果考虑到对 MMD 患者硬脑膜样本进行的全面、无标记、定量 MS 蛋白质组学表征所获得的结果,这些证据就显得尤为重要7 。事实上,FLNA 正是检测到的最丰富的蛋白质之一,并被认为是 MMD 发病机制中的第二个命中基因,能促进 MMD 样血管的形成。它是一种大型肌动蛋白结合蛋白,为多种细胞骨架蛋白提供支架,对细胞运动非常重要。尽管在蛋白质组学领域有大量发现,但人们对 MMD 的总体脂质组学或患者循环液中脂质成分的变化知之甚少。不过,最近有报道称,在 MMD 患者中发现的主要易感遗传因子(即环指蛋白 213)与脂质代谢有关。8 之前进行的一项非靶向脂质组学分析显示,与健康供体相比,MMD 患者血浆中的脂质资产累积消耗。
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引用次数: 0
Sculpting nursing resilience: Transforming lives, nurturing ethics in chimeric antigen receptor T-cell therapy 雕琢护理复原力:在嵌合抗原受体 T 细胞疗法中改变生命、培育伦理
Pub Date : 2024-03-08 DOI: 10.1002/ctd2.283
Pranay Bende

Revolutionizing cancer care, chimeric antigen receptor (CAR) T-cell therapy is an immunotherapy anticancer treatment that uses genetically modified T-cells to combat cancer. Nurses have a key role in fostering resilience in patients and caregivers undergoing this therapy, and in navigating ethical and legal issues and safeguarding their rights and interests. Unlike haematological malignancies, solid tumours have more diverse and heterogeneous tumour-associated antigens (TAAs), which can lead to off-target toxicity or antigen escape.1

Resilience enables the adversity to rebound from stress and trauma even amid faced with uncertainties risks and side effects including cytokine release syndrome, hypogammaglobulinemia, neurotoxicity, infection, prolonged cytopenias, and organ damage, and can lead to life-threatening in some cases (See Figure 1).

Mr. Bende contributed to preparing and collecting original literature and figures and writing and editing the manuscript.

The author declares no conflict of interest.

Not applicable.

嵌合抗原受体(CAR)T 细胞疗法是一种利用转基因 T 细胞抗击癌症的免疫抗癌疗法,它为癌症治疗带来了革命性的变化。护士在培养接受这种疗法的患者和护理人员的适应能力、处理伦理和法律问题以及维护他们的权益方面发挥着关键作用。与血液恶性肿瘤不同,实体瘤的肿瘤相关抗原(TAAs)更加多样化和异质性,这可能导致脱靶毒性或抗原逃逸。复原力使逆境中的人能够从压力和创伤中反弹,即使面临不确定的风险和副作用,包括细胞因子释放综合征、低丙种球蛋白血症、神经毒性、感染、长期细胞减少症和器官损伤,在某些情况下可能导致生命危险(见图1)。
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引用次数: 0
Cell-free DNA-associated multi-feature applications in cancer diagnosis and treatment 癌症诊断和治疗中的无细胞 DNA 相关多特征应用
Pub Date : 2024-03-07 DOI: 10.1002/ctd2.280
Xiaolu Zhang, Jingwei Li, Xun Lan, Jie Li

Malignant tumours pose significant challenges in terms of high morbidity and mortality rates, primarily due to the lack of large-scale applicable screening methods and efficient treatment strategies. However, the development of liquid biopsies, particularly circulating cell-free DNA (cfDNA), offers promising solutions characterised by their non-invasiveness and cost-effectiveness, providing comprehensive tumour information on a global scale. The release of cfDNA is predominantly associated with cell death and turnover, while its elimination occurs through nuclease digestion, renal excretion into the urine and uptake by the liver and spleen. Extensive research into the biological properties of cfDNA has led to the identification of novel applications, including non-invasive cancer screening, cancer subtype classification, tissue-of-origin detection and monitoring of treatment efficacy. Additionally, emerging fields such as methylation-omics, fragment-omics and nucleosome-omics show immense potential as tissue- and disease-specific markers. Therefore, this review aims to comprehensively introduce the latest detection techniques of cfDNA, along with detailed information on its characteristics and applications, providing valuable insights for cancer diagnosis and monitoring, which will assist us in purposefully enhancing relevant features for a more comprehensive application in clinical practice.

恶性肿瘤的发病率和死亡率居高不下,这主要是由于缺乏大规模适用的筛查方法和高效的治疗策略。然而,液体活检,特别是循环无细胞 DNA(cfDNA)的发展提供了前景广阔的解决方案,其特点是无创和成本效益高,可在全球范围内提供全面的肿瘤信息。cfDNA 的释放主要与细胞死亡和新陈代谢有关,而其排出则是通过核酸酶消化、肾脏排泄到尿液中以及肝脏和脾脏摄取。通过对 cfDNA 生物特性的广泛研究,人们发现了一些新型应用,包括无创癌症筛查、癌症亚型分类、原发组织检测和疗效监测。此外,甲基化组学、片段组学和核糖体组学等新兴领域也显示出作为组织和疾病特异性标记物的巨大潜力。因此,本综述旨在全面介绍 cfDNA 的最新检测技术,并详细介绍其特点和应用,为癌症诊断和监测提供有价值的见解,这将有助于我们有针对性地增强相关特点,以便更全面地应用于临床实践。
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引用次数: 0
Low-intensity pulsed ultrasound induces proliferation of human neural stem cells 低强度脉冲超声诱导人类神经干细胞增殖
Pub Date : 2024-02-29 DOI: 10.1002/ctd2.259
Arwa A. Al-Maswary, A. Damien Walmsley, Paul R. Cooper, Ben A. Scheven

Background

Low-intensity pulsed ultrasound (LIPUS) has been highlighted as a potential therapy for tissue repair and regeneration. However, little is known about LIPUS effects on neuromodulation. This research was conducted to study LIPUS effect on the proliferation of human neural stem cells.

Materials and methods

The human SH-SY5Y neuroblastoma cell line was used as a neural stem cell model. The well-documented SH-SY5Y neurogenic protocol, which involves treatment with all trans-retinoic acid (ATRA) for 5 days and then brain-derived neurotrophic factor (BDNF) for 7 days, was used to synchronise the growth cell cycle to G1 phase of the cell cycle before proliferation testing. Subsequently, the neural stem cells were then treated with single or triple 20-min LIPUS exposures (Intensity ISATA: 60 mW/cm2, frequency: 1.5 MHz, pulse repetition: 100 Hz, and duty cycle: 20%). Cell proliferation was analysed using cell counting of β-tubulin and neurofilament medium-positive neural stem cells, Ki67-cell proliferation marker and metabolic-based assays (cell counting kit-8 and alamarBlue). The involvement of ERK signalling was investigated by quantification of phospho-ERK1/2 levels and cell proliferation with and without MEK/ERK inhibitor (U0126).

Results

The results show that LIPUS exposure(s) induced cell proliferation, as evidenced by an increase in the numbers of neural stem cells. ERK signalling is involved in LIPUS-induced neural stem cell proliferation, as evidenced by concurrent inhibition of LIPUS-induced phospho-ERK levels and cell proliferation in the presence of the MEK/ERK inhibitor.

Conclusion

This study provides original evidence that LIPUS can stimulate neural stem/progenitor cell proliferation. LIPUS may be suggested as a sole or an adjunct therapeutic application to promote the neural stem cell pool in stem cell therapies and tissue engineering approaches for nerve repair and regeneration for the management of traumatic nerve injuries and regenerative endodontic treatment.

背景低强度脉冲超声(LIPUS)作为一种潜在的组织修复和再生疗法已受到重视。然而,人们对 LIPUS 对神经调节的影响知之甚少。本研究旨在研究 LIPUS 对人类神经干细胞增殖的影响。 材料与方法 以人类 SH-SY5Y 神经母细胞瘤细胞系作为神经干细胞模型。SH-SY5Y神经干细胞增殖试验采用的是有据可查的SH-SY5Y神经干细胞增殖方案,即用全反式维甲酸(ATRA)处理5天,然后用脑源性神经营养因子(BDNF)处理7天,在增殖试验前将生长细胞周期同步到细胞周期的G1期。随后,对神经干细胞进行单次或三次 20 分钟的 LIPUS 曝光(ISATA 强度:60 mW/cm2,频率:1.5 MHz,脉冲重复频率:100 Hz,占空比:1.5 MHz):100赫兹,占空比:20%)。细胞增殖分析采用了β-微管蛋白和神经丝介质阳性神经干细胞的细胞计数、Ki67-细胞增殖标记和基于代谢的检测方法(细胞计数试剂盒-8和α蓝)。在使用或不使用 MEK/ERK 抑制剂(U0126)的情况下,通过量化磷酸-ERK1/2 水平和细胞增殖来研究 ERK 信号的参与情况。 结果 结果表明,LIPUS 暴露可诱导细胞增殖,神经干细胞数量的增加就是证明。ERK信号参与了LIPUS诱导的神经干细胞增殖,在MEK/ERK抑制剂存在的情况下,LIPUS诱导的磷酸化ERK水平和细胞增殖同时受到抑制就证明了这一点。 结论 本研究提供了 LIPUS 可刺激神经干细胞/祖细胞增殖的原始证据。在干细胞疗法和组织工程方法中,LIPUS 可作为一种单独或辅助的治疗应用,促进神经干细胞池的神经修复和再生,以治疗创伤性神经损伤和牙髓再生治疗。
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引用次数: 0
Deubiquitination of Abelson tyrosine kinase: A novel regulatory mechanism targeting non-small cell lung cancer glycolysis Abelson酪氨酸激酶的去泛素化:针对非小细胞肺癌糖酵解的新型调控机制
Pub Date : 2024-02-24 DOI: 10.1002/ctd2.266
Tong Yu, Shuxia Jiang, Hongli Shan

In this commentary, we briefly introduce the importance of metabolic reprogramming in non-small celllung cancer (NSCLC) and the role of aberrant glycolysis processes intumorigenesis and metastasis. We further summarize the regulation of deubiquitylation modification on glycolysis-related kinases in this system. Andwe discusse the major discovery the research by He Yuanming et al. published in Clinical and Translational Medicine.Their study demonstrates targeting the USP7-c-Abl-HK2 axis represents a promising therapeutic strategt for NSCLC.

在这篇评论中,我们简要介绍了代谢重编程在非小细胞肺癌(NSCLC)中的重要性以及异常糖酵解过程在肿瘤发生和转移中的作用。我们进一步总结了该系统中去泛素化修饰对糖酵解相关激酶的调控。他们的研究表明,靶向 USP7-c-Abl-HK2 轴是一种治疗 NSCLC 的有前途的策略。
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引用次数: 0
CRISPR-based gene therapy for wet age-related macular degeneration in mouse model 基于 CRISPR 基因疗法的湿性老年黄斑变性小鼠模型
Pub Date : 2024-02-23 DOI: 10.1002/ctd2.278
Dongchun Xie, Yuxi Chen, Sihui Hu, Li Huang, Junjiu Huang

Wet age-related macular degeneration (AMD) is a common cause of vision loss in the elderly. It is characterised by choroidal neovascularisation (CNV), caused by overexpression of vascular endothelial growth factor (VEGF), resulting in abnormal vessel proliferation. Current clinical management predominantly relies on anti-VEGF agents, which require frequent and costly injections. Clustered regularly interspaced short palindromic repeats (CRISPR) technology has emerged as a promising strategy for permanently suppressing angiogenesis by targeting the VEGF-related pathway. Increased research suggests that disrupting this pathway holds potential for preventing CNV progression. This review provides an overview of the aetiology, classification and pathophysiology of wet AMD, followed by a concise summary of current gene editing research using the CRISPR/Cas system via viral vector delivery strategies to target ocular pro-angiogenic factors, including Hif-1α, VEGF and VEGFR. The importance of timely targeting of VEGFA is emphasised and the challenges associated with gene editing therapies are also highlighted.

湿性老年性黄斑变性(AMD)是老年人视力丧失的常见原因。它的特征是脉络膜新生血管(CNV),由血管内皮生长因子(VEGF)过度表达引起,导致血管异常增殖。目前的临床治疗主要依靠抗血管内皮生长因子药物,这种药物需要频繁注射,费用昂贵。针对血管内皮生长因子相关通路的成簇规则间隔短回文重复序列(CRISPR)技术已成为永久抑制血管生成的一种有前途的策略。越来越多的研究表明,破坏这一通路有可能预防 CNV 的发展。本综述概述了湿性黄斑变性的病因、分类和病理生理学,随后简要总结了目前通过病毒载体递送策略使用 CRISPR/Cas 系统靶向眼部促血管生成因子(包括 Hif-1α、VEGF 和 VEGFR)的基因编辑研究。报告强调了及时靶向血管内皮生长因子的重要性,并着重指出了与基因编辑疗法相关的挑战。
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引用次数: 0
期刊
Clinical and translational discovery
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