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Reduced melatonin levels may facilitate glioblastoma initiation in the subventricular zone 褪黑激素水平降低可能促进室下区胶质母细胞瘤的发生
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-05-16 DOI: 10.1017/erm.2022.15
Majid Ghareghani, K. Zibara, R. Reiter, S. Rivest
Abstract There is increasing evidence that glioblastoma, a highly aggressive brain tumour, originates from a neural stem cell (NSC) located in the subventricular zone (SVZ) of the lateral cerebral ventricle. Using the most advanced in vivo imaging techniques, Gengatharan and colleagues recently identified a day/night difference in the adult SVZ-NSC division. They reported that the circadian melatonin rhythm and its receptor control the day/night difference in NSC division with high mitotic activity during the day and low activity at night. Expression of melatonin and its receptor diminishes during ageing, which eliminates the regulatory effect of melatonin on NSC mitosis. Moreover, the circadian melatonin rhythm is dampened by light-at-night with the potential of altering the circadian mitotic cycle of NSC in the SVZ. Also, men with a lower melatonin amplitude than women exhibit a 60% higher rate of glioblastoma incidence. Given that ageing contributes significantly to glioblastoma initiation and progression, we suggest that the decline in circadian melatonin synthesis and release as well as its receptors in the SVZ, which also diminish with an ageing act in concert with other factors to facilitate glioblastoma initiation and growth.
越来越多的证据表明,胶质母细胞瘤是一种高度侵袭性的脑肿瘤,起源于位于侧脑室室下区(SVZ)的神经干细胞(NSC)。利用最先进的体内成像技术,Gengatharan和同事最近发现了成人SVZ-NSC区域的昼夜差异。他们报告说,褪黑素昼夜节律及其受体控制着NSC分裂的昼夜差异,白天有丝分裂活性高,晚上活性低。褪黑素及其受体的表达随着年龄的增长而减少,从而消除了褪黑素对NSC有丝分裂的调节作用。此外,昼夜褪黑激素节律受到夜间光线的抑制,有可能改变SVZ中NSC的昼夜有丝分裂周期。此外,褪黑素水平较低的男性患胶质母细胞瘤的几率比女性高60%。鉴于衰老对胶质母细胞瘤的发生和发展起着重要的作用,我们认为,随着年龄的增长,SVZ中昼夜褪黑激素的合成和释放以及受体的减少也会与其他因素一起减少,从而促进胶质母细胞瘤的发生和生长。
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引用次数: 3
Exploring hypoxic biology to improve radiotherapy outcomes 探索缺氧生物学改善放疗效果
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-04-27 DOI: 10.1017/erm.2022.14
Chun Li, Lucy Wiseman, Ene Okoh, Michael J Lind, R. Roy, A. Beavis, Isabel M. Pires
Abstract Ionising radiotherapy is a well-established, effective cancer treatment modality, whose efficacy has improved with the application of newer technological modalities. However, patient outcomes are governed and potentially limited by aspects of tumour biology that are associated with radioresistance. Patients also still endure treatment-associated toxicities owed to the action of ionising radiation in normoxic tissue adjacent to the tumour mass. Tumour hypoxia is recognised as a key component of the tumour microenvironment and is well established as leading to therapy resistance and poor prognosis. In this review, we outline the current understanding of hypoxia-mediated radiotherapy resistance, before exploring targeting tumour hypoxia for radiotherapy sensitisation to improve treatment outcomes and increase the therapeutic window. This includes increasing oxygen availability in solid tumours, the use of hypoxia-activated prodrugs, targeting of hypoxia-regulated or associated signalling pathways, as well as the use of high-LET radiotherapy modalities. Ultimately, targeting hypoxic radiobiology combined with precise radiotherapy delivery modalities and modelling should be associated with improvement to patient outcomes.
摘要电离放射治疗是一种公认的、有效的癌症治疗方式,其疗效随着新技术的应用而提高。然而,患者的预后受到肿瘤生物学与放射性耐药性相关的方面的控制,并可能受到限制。由于电离辐射在肿瘤块附近的常氧组织中的作用,患者仍会忍受与治疗相关的毒性。肿瘤缺氧被认为是肿瘤微环境的关键组成部分,并被公认为会导致治疗耐药性和不良预后。在这篇综述中,我们概述了目前对缺氧介导的放疗耐药性的理解,然后探索靶向肿瘤缺氧进行放疗增敏,以改善治疗结果并增加治疗窗口。这包括增加实体瘤的氧气供应,使用缺氧激活的前药,靶向缺氧调节或相关的信号通路,以及使用高LET放射治疗模式。最终,靶向低氧放射生物学与精确的放射治疗递送模式和建模相结合,应该与改善患者预后有关。
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引用次数: 4
Repositioning anticancer drugs as novel COVID-19 antivirals: targeting structural and functional similarities between viral proteins and cancer. 将抗癌药物重新定位为新的新冠肺炎抗病毒药物:靶向病毒蛋白和癌症之间的结构和功能相似性
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-04-22 DOI: 10.1017/erm.2022.11
Zheng Yao Low, Ashley Jia Wen Yip, Sunil Kumar Lal
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引用次数: 0
Immunopathogenesis of patients with COVID-19: from the perspective of immune system 'evolution' and 'revolution'. COVID-19患者的免疫发病机制:从免疫系统“进化”与“革命”的角度
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-04-12 DOI: 10.1017/erm.2022.12
Dan Lv, Bai Hu, Xingguang Lin, Renjie Wang, Di Wu, Rui Long, Mengzhou He, ShuJie Liao, Dongrui Deng

The pandemic caused by severe acute respiratory syndrome coronavirus 2 is sweeping the world, threatening millions of lives and drastically altering our ways of living. According to current studies, failure to either activate or eliminate inflammatory responses timely and properly at certain stages could result in the progression of the disease. In other words, robust immune responses to coronavirus disease 2019 (COVID-19) are critical. However, they do not theoretically present in some special groups of people, including the young, the aged, patients with autoimmunity or cancer. Differences also do occur between men and women. Our immune system evolves to ensure delicate coordination at different stages of life. The innate immune cells mainly consisted of myeloid lineage cells, including neutrophils, basophils, eosinophils, dendritic cells and mast cells; they possess phagocytic capacity to different degrees at different stages of life. They are firstly recruited upon infection and may activate the adaptive immunity when needed. The adaptive immune cells, on the other way, are comprised mainly of lymphoid lineages. As one grows up, the adaptive immunity matures and expands its memory repertoire, accompanied by an adjustment in quantity and quality. In this review, we would summarise and analyse the immunological characteristics of these groups from the perspective of the immune system 'evolution' as well as 'revolution' that has been studied and speculated so far, which would aid the comprehensive understanding of COVID-19 and personalised-treatment strategy.

由严重急性呼吸综合征冠状病毒引起的大流行正在席卷全球,威胁着数百万人的生命,并极大地改变了我们的生活方式。根据目前的研究,在某些阶段不能及时、适当地激活或消除炎症反应可能导致疾病的进展。换句话说,对2019冠状病毒病(COVID-19)的强大免疫反应至关重要。然而,从理论上讲,它们并不存在于某些特殊人群中,包括年轻人、老年人、自身免疫患者或癌症患者。男女之间也存在差异。我们的免疫系统不断进化,以确保生命不同阶段的微妙协调。先天免疫细胞主要由髓系细胞组成,包括中性粒细胞、嗜碱性粒细胞、嗜酸性粒细胞、树突状细胞和肥大细胞;它们在不同的生命阶段具有不同程度的吞噬能力。它们首先在感染时被招募,并在需要时激活适应性免疫。另一方面,适应性免疫细胞主要由淋巴系组成。随着一个人的成长,适应性免疫逐渐成熟并扩展其记忆库,同时伴随着数量和质量的调整。本文将从目前研究和推测的免疫系统“进化”和“革命”的角度对这些群体的免疫学特征进行总结和分析,有助于全面了解COVID-19和个性化治疗策略。
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引用次数: 3
Tumour-associated macrophages heterogeneity drives resistance to clinical therapy. 肿瘤相关巨噬细胞的异质性导致对临床治疗的耐药性。
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-04-11 DOI: 10.1017/erm.2022.8
Shuangshuang Guo, Xiaojing Chen, Chuhong Guo, Wei Wang

Tumour-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumour microenvironment (TME) that can account for up to 50% of solid tumours. TAMs heterogeneous are associated with different cancer types and stages, different stimulation of bioactive molecules and different TME, which are crucial drivers of tumour progression, metastasis and resistance to therapy. In this context, understanding the sources and regulatory mechanisms of TAM heterogeneity and searching for novel therapies targeting TAM subpopulations are essential for future studies. In this review, we discuss emerging evidence highlighting the redefinition of TAM heterogeneity from three different directions: origins, phenotypes and functions. We notably focus on the causes and consequences of TAM heterogeneity which have implications for the evolution of therapeutic strategies that targeted the subpopulations of TAMs.

肿瘤相关巨噬细胞(tam)构成肿瘤微环境(TME)的可塑性和异质性细胞群,可占实体肿瘤的50%。tam的异质性与不同的癌症类型和分期、不同的生物活性分子刺激和不同的TME相关,这是肿瘤进展、转移和治疗耐药的关键驱动因素。在此背景下,了解TAM异质性的来源和调控机制,寻找针对TAM亚群的新疗法对未来的研究至关重要。在这篇综述中,我们从三个不同的方向讨论了强调TAM异质性重新定义的新证据:起源、表型和功能。我们特别关注TAM异质性的原因和后果,这对针对TAM亚群的治疗策略的发展具有重要意义。
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引用次数: 9
Systematic review of preterm birth multi-omic biomarker studies. 早产儿多组学生物标志物研究的系统回顾。
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-04-05 DOI: 10.1017/erm.2022.13
Juhi K Gupta, Ana Alfirevic
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引用次数: 0
Cancer mutation profiles predict ICIs efficacy in patients with non-small cell lung cancer 癌症突变谱预测ICIs在非小细胞肺癌患者中的疗效
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-04-04 DOI: 10.1017/erm.2022.9
Liping Zhu, D. Ye, Tian-Run Lei, Jie Wu, Wei Wang, Bin Xu
Abstract Although immune checkpoint inhibitors (ICIs) have produced remarkable responses in non-small cell lung cancer (NSCLC) patients, receivers still have a relatively low response rate. Initial response assessment by conventional imaging and evaluation criteria is often unable to identify whether patients can achieve durable clinical benefit from ICIs. Overall, there are sparse effective biomarkers identified to screen NSCLC patients responding to this therapy. A lot of studies have reported that patients with specific gene mutations may benefit from or resist to immunotherapy. However, the single gene mutation may be not effective enough to predict the benefit from immunotherapy for patients. With the advancement in sequencing technology, further studies indicate that many mutations often co-occur and suggest a drastic transformation of tumour microenvironment phenotype. Moreover, co-mutation events have been reported to synergise to activate or suppress signalling pathways of anti-tumour immune response, which also indicates a potential target for combining intervention. Thus, the different mutation profile (especially co-mutation) of patients may be an important concern for predicting or promoting the efficacy of ICIs. However, there is a lack of comprehensive knowledge of this field until now. Therefore, in this study, we reviewed and elaborated the value of cancer mutation profile in predicting the efficacy of immunotherapy and analysed the underlying mechanisms, to provide an alternative way for screening dominant groups, and thereby, optimising individualised therapy for NSCLC patients.
尽管免疫检查点抑制剂(ICIs)在非小细胞肺癌(NSCLC)患者中产生了显著的应答,但受体的应答率仍然相对较低。通过常规影像学和评价标准进行的初始反应评估往往无法确定患者是否能从ici中获得持久的临床获益。总的来说,很少有有效的生物标志物被确定用于筛选对这种治疗有反应的NSCLC患者。许多研究报道,具有特定基因突变的患者可能受益于免疫治疗或抵抗免疫治疗。然而,单基因突变可能不足以预测患者从免疫治疗中获益。随着测序技术的进步,进一步的研究表明,许多突变经常同时发生,并提示肿瘤微环境表型的剧烈转变。此外,据报道,共突变事件协同激活或抑制抗肿瘤免疫反应的信号通路,这也表明了联合干预的潜在目标。因此,患者的不同突变谱(尤其是共突变)可能是预测或促进ICIs疗效的重要因素。然而,到目前为止,对这一领域还缺乏全面的认识。因此,在本研究中,我们回顾并阐述了癌症突变谱在预测免疫治疗疗效方面的价值,并分析了其潜在的机制,为筛选优势群体提供了一种替代方法,从而优化NSCLC患者的个体化治疗。
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引用次数: 1
Key biological mechanisms involved in high-LET radiation therapies with a focus on DNA damage and repair 高let放射治疗的关键生物学机制,重点是DNA损伤和修复
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-03-31 DOI: 10.1017/erm.2022.6
Z. Nikitaki, A. Velalopoulou, Vassiliki Zanni, Ioanna Tremi, S. Havaki, M. Kokkoris, V. Gorgoulis, C. Koumenis, A. Georgakilas
Abstract DNA damage and repair studies are at the core of the radiation biology field and represent also the fundamental principles informing radiation therapy (RT). DNA damage levels are a function of radiation dose, whereas the type of damage and biological effects such as DNA damage complexity, depend on radiation quality that is linear energy transfer (LET). Both levels and types of DNA damage determine cell fate, which can include necrosis, apoptosis, senescence or autophagy. Herein, we present an overview of current RT modalities in the light of DNA damage and repair with emphasis on medium to high-LET radiation. Proton radiation is discussed along with its new adaptation of FLASH RT. RT based on α-particles includes brachytherapy and nuclear-RT, that is proton-boron capture therapy (PBCT) and boron-neutron capture therapy (BNCT). We also discuss carbon ion therapy along with combinatorial immune-based therapies and high-LET RT. For each RT modality, we summarise relevant DNA damage studies. Finally, we provide an update of the role of DNA repair in high-LET RT and we explore the biological responses triggered by differential LET and dose.
DNA损伤与修复研究是放射生物学领域的核心,也是放射治疗的基本原理。DNA损伤水平是辐射剂量的函数,而损伤类型和生物效应(如DNA损伤复杂性)则取决于辐射质量,即线性能量转移(LET)。DNA损伤的水平和类型都决定细胞的命运,包括坏死、凋亡、衰老或自噬。在此,我们提出了当前的RT模式在DNA损伤和修复的光,重点是中至高let辐射的概述。基于α-粒子的质子放射治疗包括近距离放射治疗和核放射治疗,即质子-硼俘获治疗(PBCT)和硼-中子俘获治疗(BNCT)。我们还讨论了碳离子治疗以及组合免疫治疗和高let RT。对于每种RT方式,我们总结了相关的DNA损伤研究。最后,我们提供了DNA修复在高LET RT中的作用的最新进展,并探讨了不同LET和剂量引发的生物学反应。
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引用次数: 14
Importance of radiobiological studies for the advancement of boron neutron capture therapy (BNCT) 放射生物学研究对推进硼中子俘获治疗的重要性
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-03-31 DOI: 10.1017/erm.2022.7
A. Monti Hughes
Abstract Boron neutron capture therapy (BNCT) is a tumour selective particle radiotherapy, based on the administration of boron carriers incorporated preferentially by tumour cells, followed by irradiation with a thermal or epithermal neutron beam. BNCT clinical results to date show therapeutic efficacy, associated with an improvement in patient quality of life and prolonged survival. Translational research in adequate experimental models is necessary to optimise BNCT for different pathologies. This review recapitulates some examples of BNCT radiobiological studies for different pathologies and clinical scenarios, strategies to optimise boron targeting, enhance BNCT therapeutic effect and minimise radiotoxicity. It also describes the radiobiological mechanisms induced by BNCT, and the importance of the detection of biomarkers to monitor and predict the therapeutic efficacy and toxicity of BNCT alone or combined with other strategies. Besides, there is a brief comment on the introduction of accelerator-based neutron sources in BNCT. These sources would expand the clinical BNCT services to more patients, and would help to make BNCT a standard treatment modality for various types of cancer. Radiobiological BNCT studies have been of utmost importance to make progress in BNCT, being essential to design novel, safe and effective clinical BNCT protocols.
硼中子俘获疗法(BNCT)是一种肿瘤选择性粒子放射治疗,其基础是给予肿瘤细胞优先结合的硼载体,然后用热中子或超热中子束照射。迄今为止,BNCT的临床结果显示了治疗效果,与患者生活质量的改善和生存期的延长有关。在适当的实验模型的转化研究是必要的,以优化不同病理的BNCT。本文综述了不同病理和临床情况下BNCT放射生物学研究的一些例子,以及优化硼靶向,提高BNCT治疗效果和减少放射毒性的策略。本文还介绍了BNCT诱导的放射生物学机制,以及检测生物标志物对监测和预测BNCT单独或联合其他策略的治疗效果和毒性的重要性。此外,还对BNCT中基于加速器的中子源的引入作了简要评述。这些资源将使临床BNCT服务扩展到更多的患者,并有助于使BNCT成为各种类型癌症的标准治疗方式。放射生物学BNCT研究对于BNCT的发展至关重要,对于设计新颖、安全、有效的临床BNCT方案至关重要。
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引用次数: 12
Update on the role of extracellular vesicles in rheumatoid arthritis. 细胞外囊泡在类风湿关节炎中的作用的最新进展。
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-03-17 DOI: 10.1017/erm.2021.33
Hai-Bing Miao, Fang Wang, Shu Lin, Zhen Chen

Rheumatoid arthritis (RA) is a heterogeneous autoimmune disorder that leads to severe joint deformities, negatively affecting the patient's quality of life. Extracellular vesicles (EVs), which include exosomes and ectosomes, act as intercellular communication mediators in several physiological and pathological processes in various diseases including RA. In contrast, EVs secreted by mesenchymal stem cells perform an immunomodulatory function and stimulate cartilage repair, showing promising therapeutic results in animal models of RA. EVs from other sources, including dendritic cells, neutrophils and myeloid-derived suppressor cells, also influence the biological function of immune and joint cells. This review describes the role of EVs in the pathogenesis of RA and presents evidence supporting future studies on the therapeutic potential of EVs from different sources. This information will contribute to a better understanding of RA development, as well as a starting point for exploring cell-free-based therapies for RA.

类风湿性关节炎(RA)是一种异质性自身免疫性疾病,可导致严重的关节畸形,对患者的生活质量产生负面影响。细胞外囊泡(EVs)包括外泌体和外泌体,在包括RA在内的多种疾病的一些生理和病理过程中作为细胞间通讯介质。相反,间充质干细胞分泌的ev具有免疫调节功能,刺激软骨修复,在RA动物模型中显示出良好的治疗效果。其他来源的EVs,包括树突状细胞、中性粒细胞和髓源性抑制细胞,也会影响免疫细胞和关节细胞的生物学功能。本文综述了ev在RA发病机制中的作用,并提供了支持未来研究不同来源ev的治疗潜力的证据。这一信息将有助于更好地了解类风湿性关节炎的发展,以及探索无细胞治疗类风湿性关节炎的起点。
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引用次数: 13
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Expert Reviews in Molecular Medicine
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