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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 Q1 BIOCHEMISTRY & 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 Q1 BIOCHEMISTRY & 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 Q1 BIOCHEMISTRY & 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
IL-1β in breast cancer bone metastasis 白细胞介素1β在乳腺癌症骨转移中的作用
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-03-01 DOI: 10.1017/erm.2022.4
Jiabao Zhou, C. Tulotta, P. Ottewell
Abstract Bone is the most common site for advanced breast cancer to metastasise. The proinflammatory cytokine, interleukin-1β (IL-1β) plays a complex and contradictory role in this process. Recent studies have demonstrated that breast cancer patients whose primary tumours express IL-1β are more likely to experience relapse in bone or other organs. Importantly, IL-1β affects different stages of the metastatic process including growth of the primary tumour, epithelial to mesenchymal transition (EMT), dissemination of tumour cells into the blood stream, tumour cell homing to the bone microenvironment and, once in bone, this cytokine participates in the interaction between cancer cells and bone cells, promoting metastatic outgrowth at this site. Interestingly, although inhibition of IL-1β signalling has been shown to have potent anti-metastatic effects, inhibition of the activity of this cytokine has contradictory effects on primary tumours, sometimes reducing but often promoting their growth. In this review, we focus on the complex roles of IL-1β on breast cancer bone metastasis: specifically, we discuss the distinct effects of IL-1β derived from tumour cells and/or microenvironment on inhibition/induction of primary breast tumour growth, induction of the metastatic process through the EMT, promotion of tumour cell dissemination into the bone metastatic niche and formation of overt metastases.
摘要骨是晚期癌症转移最常见的部位。促炎细胞因子白细胞介素-1β(IL-1β)在这一过程中发挥着复杂而矛盾的作用。最近的研究表明,原发肿瘤表达IL-1β的癌症患者更有可能在骨骼或其他器官复发。重要的是,IL-1β影响转移过程的不同阶段,包括原发肿瘤的生长、上皮-间充质转化(EMT)、肿瘤细胞向血流中的扩散、肿瘤细胞归位到骨微环境,一旦进入骨,这种细胞因子参与癌症细胞和骨细胞之间的相互作用,促进该部位的转移性生长。有趣的是,尽管抑制IL-1β信号传导已被证明具有强大的抗转移作用,但抑制这种细胞因子的活性对原发性肿瘤的影响是矛盾的,有时会减少但往往会促进其生长。在这篇综述中,我们重点讨论了IL-1β在乳腺癌症骨转移中的复杂作用:特别是,我们讨论了来源于肿瘤细胞和/或微环境的IL-1β对抑制/诱导原发性乳腺肿瘤生长、通过EMT诱导转移过程、,促进肿瘤细胞向骨转移生态位的扩散和明显转移的形成。
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引用次数: 11
In vitro assays for investigating the FLASH effect. 研究FLASH效应的体外实验。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-02-28 DOI: 10.1017/erm.2022.5
Gabriel Adrian, Jia-Ling Ruan, Salomé Paillas, Christian R Cooper, Kristoffer Petersson

FLASH radiotherapy is a novel technique that has been shown in numerous preclinical in vivo studies to have the potential to be the next important improvement in cancer treatment. However, the biological mechanisms responsible for the selective FLASH sparing effect of normal tissues are not yet known. An optimal translation of FLASH radiotherapy into the clinic would require a good understanding of the specific beam parameters that induces a FLASH effect, environmental conditions affecting the response, and the radiobiological mechanisms involved. Even though the FLASH effect has generally been considered as an in vivo effect, studies finding these answers would be difficult and ethically challenging to carry out solely in animals. Hence, suitable in vitro studies aimed towards finding these answers are needed. In this review, we describe and summarise several in vitro assays that have been used or could be used to finally elucidate the mechanisms behind the FLASH effect.

FLASH放射治疗是一项新技术,已在许多临床前体内研究中被证明有潜力成为癌症治疗的下一个重要改进。然而,正常组织的选择性FLASH保留效应的生物学机制尚不清楚。将FLASH放射治疗最佳地转化为临床将需要很好地理解引起FLASH效应的特定光束参数、影响反应的环境条件以及所涉及的放射生物学机制。尽管FLASH效应通常被认为是一种体内效应,但寻找这些答案的研究将是困难的,并且在伦理上具有挑战性,只能在动物身上进行。因此,需要合适的体外研究来寻找这些答案。在这篇综述中,我们描述和总结了几种已经使用或可能用于最终阐明FLASH效应背后机制的体外试验。
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引用次数: 8
Reproductive and developmental toxicities of 5-fluorouracil in model organisms and humans. 5-氟尿嘧啶对模式生物和人类的生殖和发育毒性。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-01-31 DOI: 10.1017/erm.2022.3
Gerile Naren, Jiaojiao Guo, Qiujuan Bai, Na Fan, Buhe Nashun

Chemotherapy, as an important clinical treatment, has greatly enhanced survival in cancer patients, but the side effects and long-term sequelae bother both patients and clinicians. 5-Fluorouracil (5-FU) has been widely used as a chemotherapeutic agent in the clinical treatment of various cancers, but several studies showed its adverse effects on reproduction. Reproductive toxicity of 5-FU often associates with developmental block, malformation and ovarian damage in the females. In males, 5-FU administration alters the morphology of sexual organs, the levels of reproductive endocrine hormones and the progression of spermatogenesis, ultimately reducing sperm numbers. Mechanistically, 5-FU exerts its effect through incorporating the active metabolites into nucleic acids directly, or inhibiting thymidylate synthase to disrupt the function of DNA and RNA, leading to profound effects on cellular metabolism and viability. However, some studies suggested that the toxicity of 5-FU on reproduction is reversible and certain drugs used in combination with 5-FU during chemotherapy could protect reproductive systems from 5-FU damage both in females and males. Herein, we summarise the recent findings and discuss underlying mechanisms of the 5-FU-induced reproductive toxicity, providing a reference for future research and clinical treatments.

化疗作为一种重要的临床治疗手段,大大提高了癌症患者的生存,但其副作用和长期后遗症困扰着患者和临床医生。5-氟尿嘧啶(5-FU)作为一种化疗药物被广泛应用于临床治疗各种癌症,但多项研究表明其对生殖有不良影响。5-FU的生殖毒性通常与雌性发育障碍、畸形和卵巢损伤有关。在男性中,施用5-FU会改变性器官的形态、生殖内分泌激素的水平和精子发生的进程,最终减少精子数量。机制上,5-FU通过将活性代谢物直接掺入核酸,或抑制胸苷酸合成酶破坏DNA和RNA的功能来发挥作用,从而对细胞代谢和活力产生深远影响。然而,一些研究表明5-FU对生殖的毒性是可逆的,在化疗期间与5-FU联合使用的某些药物可以保护雌性和雄性生殖系统免受5-FU的损害。在此,我们总结了最近的研究结果,并讨论了5- fu诱导生殖毒性的潜在机制,为今后的研究和临床治疗提供参考。
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引用次数: 6
Chimeric antigen receptor engineered T cells and their application in the immunotherapy of solid tumours. 嵌合抗原受体工程 T 细胞及其在实体瘤免疫疗法中的应用。
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-01-28 DOI: 10.1017/erm.2021.32
Rui Mao, Mohamed S Hussein, Yukai He

In this article, we reviewed the current literature studies and our understanding of the parameters that affect the chimeric antigen receptor T cells (CAR-T's) activation, effector function, in vivo persistence, and antitumour effects. These factors include T cell subsets and their differentiation stages, the components of chimeric antigen receptors (CAR) design, the expression promoters and delivery vectors, and the CAR-T production process. The CAR signalling and CAR-T activation were also studied in comparison to TCR. The last section of the review gave special consideration of CAR design for solid tumours, focusing on strategies to improve CAR-T tumour infiltration and survival in the hostile tumour microenvironment. With several hundred clinical trials undergoing worldwide, the pace of CAR-T immunotherapy moves from bench to bedside is unprecedented. We hope that the article will provide readers a clear and comprehensive view of this rapidly evolving field and will help scientists and physician to design effective CAR-Ts immunotherapy for solid tumours.

在本文中,我们回顾了目前的文献研究,以及我们对影响嵌合抗原受体 T 细胞(CAR-T)活化、效应功能、体内持久性和抗肿瘤效果的参数的理解。这些因素包括 T 细胞亚群及其分化阶段、嵌合抗原受体(CAR)设计成分、表达启动子和传递载体以及 CAR-T 生产过程。此外,还对 CAR 信号和 CAR-T 激活进行了研究,并与 TCR 进行了比较。综述的最后一部分特别考虑了针对实体瘤的 CAR 设计,重点是改善 CAR-T 肿瘤浸润和在恶劣肿瘤微环境中存活的策略。目前全球正在进行数百项临床试验,CAR-T 免疫疗法从实验室走向临床的速度是前所未有的。我们希望这篇文章能让读者对这一快速发展的领域有一个清晰而全面的认识,并帮助科学家和医生设计出有效的CAR-T实体瘤免疫疗法。
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引用次数: 0
Cell death mechanisms in head and neck cancer cells in response to low and high-LET radiation 头颈部癌症细胞对低和高LET辐射反应的细胞死亡机制
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-01-12 DOI: 10.1017/erm.2021.31
Maria Rita Fabbrizi, J. Parsons
Head and neck squamous cell carcinoma (HNSCC) is a common malignancy that develops in or around the throat, larynx, nose, sinuses and mouth, and is mostly treated with a combination of chemo- and radiotherapy (RT). The main goal of RT is to kill enough of the cancer cell population, whilst preserving the surrounding normal and healthy tissue. The mechanisms by which conventional photon RT achieves this have been extensively studied over several decades, but little is known about the cell death pathways that are activated in response to RT of increasing linear energy transfer (LET), including proton beam therapy and heavy ions. Here, we provide an up-to-date review on the observed radiobiological effects of low- versus high-LET RT in HNSCC cell models, particularly in the context of specific cell death mechanisms, including apoptosis, necrosis, autophagy, senescence and mitotic death. We also detail some of the current therapeutic strategies targeting cell death pathways that have been investigated to enhance the radiosensitivity of HNSCC cells in response to RT, including those that may present with clinical opportunities for eventual patient benefit.
头颈部鳞状细胞癌(HNSCC)是一种常见的恶性肿瘤,发生在喉咙、喉部、鼻子、鼻窦和口腔内或周围,主要采用化疗和放疗(RT)联合治疗。放疗的主要目标是杀死足够多的癌细胞群,同时保留周围正常和健康的组织。几十年来,人们对传统光子RT实现这一目标的机制进行了广泛的研究,但对增加线性能量转移(LET)的RT(包括质子束治疗和重离子)激活的细胞死亡途径知之甚少。在这里,我们提供了最新的回顾,观察到低与高let RT在HNSCC细胞模型中的放射生物学效应,特别是在特定细胞死亡机制的背景下,包括凋亡,坏死,自噬,衰老和有丝分裂死亡。我们还详细介绍了目前针对细胞死亡途径的一些治疗策略,这些策略已被研究以增强HNSCC细胞对放疗的放射敏感性,包括那些可能为最终患者带来临床机会的策略。
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引用次数: 5
Decellularised extracellular matrix-based biomaterials for repair and regeneration of central nervous system. 用于中枢神经系统修复和再生的脱细胞细胞外基质生物材料。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-01-07 DOI: 10.1017/erm.2021.22
Burcu Yaldiz, Pelin Saglam-Metiner, Ozlem Yesil-Celiktas
Abstract The central nervous system (CNS), consisting of the brain and spinal cord, regulates the mind and functions of the organs. CNS diseases, leading to changes in neurological functions in corresponding sites and causing long-term disability, represent one of the major public health issues with significant clinical and economic burdens worldwide. In particular, the abnormal changes in the extracellular matrix under various disease conditions have been demonstrated as one of the main factors that can alter normal cell function and reduce the neuroregeneration potential in damaged tissue. Decellularised extracellular matrix (dECM)-based biomaterials have been recently utilised for CNS applications, closely mimicking the native tissue. dECM retains tissue-specific components, including proteoglycan as well as structural and functional proteins. Due to their unique composition, these biomaterials can stimulate sensitive repair mechanisms associated with CNS damages. Herein, we discuss the decellularisation of the brain and spinal cord as well as recellularisation of acellular matrix and the recent progress in the utilisation of brain and spinal cord dECM.
中枢神经系统(CNS),由大脑和脊髓组成,调节思想和器官的功能。中枢神经系统疾病导致相应部位的神经功能改变并导致长期残疾,是世界范围内具有重大临床和经济负担的主要公共卫生问题之一。特别是,在各种疾病条件下,细胞外基质的异常变化已被证明是改变正常细胞功能和降低受损组织神经再生潜力的主要因素之一。基于脱细胞细胞外基质(dECM)的生物材料最近被用于中枢神经系统应用,密切模仿天然组织。dECM保留了组织特异性成分,包括蛋白聚糖以及结构和功能蛋白。由于其独特的成分,这些生物材料可以刺激与中枢神经系统损伤相关的敏感修复机制。在此,我们讨论了脑和脊髓的脱细胞化以及脱细胞基质的再细胞化,以及脑和脊髓dECM利用的最新进展。
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引用次数: 10
Association between genetic polymorphisms in cytochrome P450 enzymes and survivals in women with breast cancer receiving adjuvant endocrine therapy: a systematic review and meta-analysis. 细胞色素P450酶基因多态性与接受辅助内分泌治疗的乳腺癌患者存活率之间的关系:一项系统综述和荟萃分析
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-01-07 DOI: 10.1017/erm.2021.28
Carmen Wing Han Chan, Caixia Li, Eleven Jinnan Xiao, Minjie Li, Patrick Gladson McLeywick Phiri, Tingting Yan, Judy Yuet Wa Chan

Tamoxifen is commonly prescribed for preventing recurrence in patients with breast cancer. However, the responses of the patients on tamoxifen treatment are variable. Cytochrome P450 genetic variants have been reported to have a significant impact on the clinical outcomes of tamoxifen treatment but no tangible conclusion can be made up till now. The present review attempts to provide a comprehensive review on the associative relationship between genetic polymorphisms in cytochrome P450 enzymes and survival in breast cancer patients on adjuvant tamoxifen therapy. The literature search was conducted using five databases, resulting in the inclusion of 58 studies in the review. An appraisal of the reporting quality of the included studies was conducted using the assessment tool from the Effective Public Health Practice Project (EPHPP). Meta-analyses were performed on CYP2D6 studies using Review Manager 5.3 software. For other studies, descriptive analyses were performed. The results of meta-analyses demonstrated that shorter overall survival, disease-free survival and relapse-free survival were found in the patients with decreased metabolisers when compared to normal metabolisers. The findings also showed that varying and conflicting results were reported by the included studies. The possible explanations for the variable results are discussed in this review.

他莫昔芬通常用于预防乳腺癌患者复发。然而,患者对他莫昔芬治疗的反应是可变的。细胞色素P450基因变异已被报道对他莫昔芬治疗的临床结果有显著影响,但目前还没有明确的结论。本文旨在全面回顾细胞色素P450酶基因多态性与辅助他莫昔芬治疗的乳腺癌患者生存之间的关系。文献检索使用了5个数据库,结果纳入了58项研究。使用有效公共卫生实践项目(EPHPP)的评估工具对纳入研究的报告质量进行了评估。使用Review Manager 5.3软件对CYP2D6研究进行meta分析。对于其他研究,进行描述性分析。荟萃分析的结果表明,与正常代谢者相比,代谢降低的患者的总生存期、无病生存期和无复发生存期较短。研究结果还表明,纳入的研究报告了不同和相互矛盾的结果。本文讨论了不同结果的可能解释。
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引用次数: 2
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