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Unraveling the multifaceted insights into amyotrophic lateral sclerosis: Genetic underpinnings, pathogenesis, and therapeutic horizons. 解开肌萎缩侧索硬化症的多面之谜:遗传基础、发病机制和治疗前景。
IF 6.4 2区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-11-02 DOI: 10.1016/j.mrrev.2024.108518
Ramaish Sharma, Zuber Khan, Sidharth Mehan, Ghanshyam Das Gupta, Acharan S Narula

Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease, primarily impairs upper and lower motor neurons, leading to debilitating motor dysfunction and eventually respiratory failure, widely known as Lou Gehrig's disease. ALS presents with diverse symptomatology, including dysarthria, dysphagia, muscle atrophy, and hyperreflexia. The prevalence of ALS varies globally, with incidence rates ranging from 1.5 to 3.8 per 100,000 individuals, significantly affecting populations aged 45-80. A complex interplay of genetic and environmental factors underpins ALS pathogenesis. Key genetic contributors include mutations in chromosome 9 open reading frame 72 (C9ORF72), superoxide dismutase type 1 (SOD1), Fusedin sarcoma (FUS), and TAR DNA-binding protein (TARDBP) genes, accounting for a considerable fraction of both familial (fALS) and sporadic (sALS) cases. The disease mechanism encompasses aberrant protein folding, mitochondrial dysfunction, oxidative stress, excitotoxicity, and neuroinflammation, contributing to neuronal death. This review consolidates current insights into ALS's multifaceted etiology, highlighting the roles of environmental exposures (e.g., toxins, heavy metals) and their interaction with genetic predispositions. We emphasize the polygenic nature of ALS, where multiple genetic variations cumulatively influence disease susceptibility and progression. This aspect underscores the challenges in ALS diagnosis, which currently lacks specific biomarkers and relies on symptomatology and familial history. Therapeutic strategies for ALS, still in nascent stages, involve symptomatic management and experimental approaches targeting molecular pathways implicated in ALS pathology. Gene therapy, focusing on specific ALS mutations, and stem cell therapy emerge as promising avenues. However, effective treatments remain elusive, necessitating a deeper understanding of ALS's genetic architecture and the development of targeted therapies based on personalized medicine principles. This review aims to provide a comprehensive understanding of ALS, encouraging further research into its complex genetic underpinnings and the development of innovative, effective treatment modalities.

肌萎缩侧索硬化症(ALS)是一种进行性神经退行性疾病,主要损害上下运动神经元,导致衰弱的运动功能障碍,最终导致呼吸衰竭,被广泛称为卢伽雷氏病。渐冻人症的症状多种多样,包括构音障碍、吞咽困难、肌肉萎缩和反射亢进。肌萎缩性脊髓侧索硬化症在全球的发病率各不相同,发病率为每 10 万人 1.5 至 3.8 例,主要影响 45-80 岁的人群。肌萎缩侧索硬化症的发病机理是遗传和环境因素的复杂相互作用。主要的遗传因素包括第 9 号染色体开放阅读框 72(C9ORF72)、1 型超氧化物歧化酶(SOD1)、Fusedin 肉瘤(FUS)和 TAR DNA 结合蛋白(TARDBP)基因的突变,在家族性(fALS)和散发性(sALS)病例中均占相当大的比例。该病的发病机制包括蛋白质折叠异常、线粒体功能障碍、氧化应激、兴奋毒性和神经炎症,从而导致神经元死亡。本综述整合了目前对 ALS 多方面病因的见解,强调了环境暴露(如毒素、重金属)的作用及其与遗传倾向的相互作用。我们强调了 ALS 的多基因性质,即多种基因变异累积影响疾病的易感性和进展。这一方面凸显了 ALS 诊断所面临的挑战,目前 ALS 诊断缺乏特定的生物标志物,只能依赖症状学和家族病史。ALS 的治疗策略仍处于初级阶段,包括对症治疗和针对与 ALS 病理有关的分子通路的实验方法。针对特定 ALS 基因突变的基因疗法和干细胞疗法是很有希望的途径。然而,有效的治疗方法仍然难以捉摸,这就需要对 ALS 的基因结构有更深入的了解,并根据个性化医疗原则开发针对性疗法。本综述旨在提供对 ALS 的全面了解,鼓励进一步研究其复杂的遗传基础,并开发创新、有效的治疗方法。
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引用次数: 0
Genome-scale mutational signature analysis in fixed archived tissues 固定存档组织的基因组规模突变特征分析
IF 6.4 2区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.mrrev.2024.108512

Mutation spectra and mutational signatures in cancerous and non-cancerous tissues can be identified by various established techniques of massively parallel sequencing (or next-generation sequencing) including whole-exome or whole-genome sequencing, and more recently by error-corrected/duplex sequencing. One rather underexplored area has been the genome-scale analysis of mutational signatures as markers of mutagenic exposures, and their impact on cancer driver events applied to formalin-fixed or alcohol-fixed paraffin embedded archived biospecimens. This review showcases successful applications of the next-generation sequencing methodologies in archived fixed tissues, including the delineation of the specific tissue fixation-related DNA damage manifesting as artifactual signatures, distinguishable from the true signatures that arise from biological mutagenic processes. Overall, we discuss and demonstrate how next-generation sequencing techniques applied to archived fixed biospecimens can enhance our understanding of cancer causes including mutagenic effects of extrinsic cancer risk agents, and the implications for prevention efforts aimed at reducing avoidable cancer-causing exposures.

癌症和非癌症组织中的突变谱和突变特征可通过各种成熟的大规模并行测序(或下一代测序)技术(包括全外显子组或全基因组测序)以及最近的纠错/双工测序技术来确定。在福尔马林固定或酒精固定石蜡包埋的存档生物样本中,对作为诱变暴露标记的突变特征及其对癌症驱动事件的影响进行基因组规模的分析是一个尚未充分开发的领域。本综述展示了新一代测序方法在存档固定组织中的成功应用,包括对特定组织固定相关DNA损伤的界定,这些损伤表现为伪特征,可与生物诱变过程产生的真实特征区分开来。总之,我们讨论并展示了下一代测序技术如何应用于存档固定生物样本,从而提高我们对癌症成因(包括外在癌症风险因子的诱变效应)的认识,以及对旨在减少可避免的致癌接触的预防工作的影响。
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引用次数: 0
Clonal expansion of cancer driver gene mutants investigated using advanced sequencing technologies 利用先进的测序技术研究癌症驱动基因突变的克隆扩增。
IF 6.4 2区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.mrrev.2024.108514
Advanced sequencing technologies (ASTs) have revolutionized the quantitation of cancer driver mutations (CDMs) as rare events, which has utility in clinical oncology, cancer research, and cancer risk assessment. This review focuses on studies that have used ASTs to characterize clonal expansion (CE) of cells carrying CDMs and to explicate the selective pressures that shape CE. Importantly, high-sensitivity ASTs have made possible the characterization of mutant clones and CE in histologically normal tissue samples, providing the means to investigate nascent tumor development. Some ASTs can identify mutant clones in a spatially defined context; others enable integration of mutant data with analyses of gene expression, thereby elaborating immune, inflammatory, metabolic, and/or stromal microenvironmental impacts on CE. As a whole, these studies make it clear that a startlingly large fraction of cells in histologically normal tissues carry CDMs, CDMs may confer a context-specific selective advantage leading to CE, and only a small fraction of cells carrying CDMs eventually result in neoplasia. These observations were integrated with available literature regarding the mechanisms underlying clonal selection to interpret how measurements of CDMs and CE can be interpreted as biomarkers of cancer risk. Given the stochastic nature of carcinogenesis, the potential functional latency of driver mutations, the complexity of potential mutational and microenvironmental interactions, and involvement of other types of genetic and epigenetic changes, it is concluded that CDM-based measurements should be viewed as probabilistic rather than deterministic biomarkers. Increasing inter-sample variability in CDM levels (as a consequence of CE) may be interpretable as a shift away from normal tissue homeostasis and an indication of increased future cancer risk, a process that may reflect normal aging or carcinogen exposure. Consequently, analyses of variability in levels of CDMs have the potential to bolster existing approaches for carcinogenicity testing.
先进的测序技术(AST)彻底改变了癌症驱动突变(CDMs)作为罕见事件的定量研究,这在临床肿瘤学、癌症研究和癌症风险评估中都很有用。本综述将重点介绍利用 AST 来描述携带 CDMs 的细胞的克隆扩增(CE)特征并解释形成 CE 的选择性压力的研究。重要的是,高灵敏度的 AST 使突变克隆和组织学正常组织样本中的 CE 的特征描述成为可能,为研究新生肿瘤的发展提供了手段。有些 AST 能在空间定义的环境中识别突变克隆;有些 AST 则能将突变数据与基因表达分析相结合,从而阐明免疫、炎症、代谢和/或基质微环境对 CE 的影响。总体而言,这些研究清楚地表明,组织学上正常的组织中有很大一部分细胞携带 CDMs,CDMs 可能赋予特定环境的选择性优势,从而导致 CE,而只有一小部分携带 CDMs 的细胞最终导致肿瘤。这些观察结果与有关克隆选择机制的现有文献相结合,解释了如何将CDMs和CE的测量结果解释为癌症风险的生物标志物。鉴于癌变的随机性、驱动突变的潜在功能潜伏性、潜在突变与微环境相互作用的复杂性以及其他类型遗传和表观遗传变化的参与,得出的结论是,基于 CDM 的测量结果应被视为概率生物标志物,而非确定性生物标志物。CDM 水平样本间变异性的增加(CE 的结果)可能被解释为偏离正常组织稳态的转变和未来癌症风险增加的迹象,这一过程可能反映正常衰老或致癌物暴露。因此,对 CDM 水平变异性的分析有可能加强现有的致癌性测试方法。
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引用次数: 0
A critical review of the impact of candidate copy number variants on autism spectrum disorder 候选拷贝数变异对自闭症谱系障碍影响的批判性回顾。
IF 6.4 2区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.mrrev.2024.108509

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder (NDD) influenced by genetic, epigenetic, and environmental factors. Recent advancements in genomic analysis have shed light on numerous genes associated with ASD, highlighting the significant role of both common and rare genetic mutations, as well as copy number variations (CNVs), single nucleotide polymorphisms (SNPs) and unique de novo variants. These genetic variations disrupt neurodevelopmental pathways, contributing to the disorder's complexity. Notably, CNVs are present in 10 %-20 % of individuals with autism, with 3 %-7 % detectable through cytogenetic methods. While the role of submicroscopic CNVs in ASD has been recently studied, their association with genomic loci and genes has not been thoroughly explored. In this review, we focus on 47 CNV regions linked to ASD, encompassing 1632 genes, including protein-coding genes and long non-coding RNAs (lncRNAs), of which 659 show significant brain expression. Using a list of ASD-associated genes from SFARI, we detect 17 regions harboring at least one known ASD-related protein-coding gene. Of the remaining 30 regions, we identify 24 regions containing at least one protein-coding gene with brain-enriched expression and a nervous system phenotype in mouse mutants, and one lncRNA with both brain-enriched expression and upregulation in iPSC to neuron differentiation. This review not only expands our understanding of the genetic diversity associated with ASD but also underscores the potential of lncRNAs in contributing to its etiology. Additionally, the discovered CNVs will be a valuable resource for future diagnostic, therapeutic, and research endeavors aimed at prioritizing genetic variations in ASD.

自闭症谱系障碍(ASD)是一种复杂的神经发育障碍(NDD),受遗传、表观遗传和环境因素的影响。基因组分析的最新进展揭示了与 ASD 相关的众多基因,凸显了常见和罕见基因突变以及拷贝数变异 (CNV)、单核苷酸多态性 (SNP) 和独特的从头变异的重要作用。这些基因变异扰乱了神经发育的通路,导致了该疾病的复杂性。值得注意的是,10%-20% 的自闭症患者存在 CNVs,其中 3%-7% 可通过细胞遗传学方法检测到。虽然近来对亚显微CNVs在自闭症中的作用进行了研究,但它们与基因组位点和基因的关联尚未得到深入探讨。在这篇综述中,我们重点研究了与ASD相关的47个CNV区域,涵盖1,632个基因,包括蛋白编码基因和长非编码RNA(lncRNA),其中659个基因在大脑中有显著表达。利用 SFARI 中的 ASD 相关基因列表,我们检测到 17 个区域至少含有一个已知的 ASD 相关蛋白编码基因。在剩余的 30 个区域中,我们发现 24 个区域至少含有一个蛋白编码基因,这些基因在小鼠突变体中具有脑丰富表达和神经系统表型,还有一个 lncRNA 同时具有脑丰富表达和在 iPSC 到神经元分化过程中的上调。这篇综述不仅拓展了我们对与 ASD 相关的遗传多样性的认识,而且强调了 lncRNA 在促进其病因学方面的潜力。此外,所发现的 CNVs 将成为未来诊断、治疗和研究工作的宝贵资源,旨在优先考虑 ASD 的遗传变异。
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引用次数: 0
Advances in base editing: A focus on base transversions 碱基编辑的进展:聚焦碱基转换。
IF 6.4 2区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.mrrev.2024.108515
Single nucleotide variants (SNVs) constitute the most frequent variants that cause human genetic diseases. Base editors (BEs) comprise a new generation of CRISPR-based technologies, which are considered to have a promising future for curing genetic diseases caused by SNVs as they enable the direct and irreversible correction of base mutations. Two of the early types of BEs, cytosine base editor (CBE) and adenine base editor (ABE), mediate C-to-T, T-to-C, A-to-G, and G-to-A base transition mutations. Together, these represent half of all the known disease-associated SNVs. However, the remaining transversion (i.e., purine–pyrimidine) mutations cannot be restored by direct deamination and so these require the replacement of the entire base. Recently, a variety of base transversion editors were developed and so these add to the currently available BEs enabling the correction of all types of point mutation. However, compared to the base transition editors (including CBEs and ABEs), base transversion editors are still in the early development stage. In this review, we describe the basics and advances of the various base transversion editors, highlight their limitations, and discuss their potential for treating human diseases.
单核苷酸变异(SNV)是导致人类遗传疾病的最常见变异。碱基编辑器(BE)是新一代基于CRISPR的技术,可直接且不可逆地校正碱基突变,因此被认为在治疗由SNV引起的遗传疾病方面前景广阔。早期的两种 BE,即胞嘧啶碱基编辑器(CBE)和腺嘌呤碱基编辑器(ABE),介导 C-to-T、T-to-C、A-to-G 和 G-to-A 碱基转换突变。这些突变占所有已知疾病相关 SNV 的一半。然而,其余的碱基转换(即嘌呤-嘧啶)突变无法通过直接脱氨来恢复,因此需要替换整个碱基。最近,人们开发出了多种碱基转换编辑器,这些编辑器是对现有 BE 的补充,可以纠正所有类型的点突变。然而,与碱基转换编辑器(包括 CBE 和 ABE)相比,碱基转换编辑器仍处于早期开发阶段。在这篇综述中,我们将介绍各种碱基转换编辑器的基本原理和进展,强调它们的局限性,并讨论它们在治疗人类疾病方面的潜力。
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引用次数: 0
State of art of micronuclei assay in exfoliative cytology as a clinical biomarker of genetic damage in oral carcinogenesis: A systematic review and meta-analysis 将脱落细胞学中的微核检测作为口腔癌发生过程中遗传损伤的临床生物标志物的最新进展:系统回顾与元分析》。
IF 6.4 2区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.mrrev.2024.108508
Vito Carlo Alberto Caponio , Fábio França-Vieira e Silva , Francesco Popolo , Sara Giugliano , Francesca Spizzirri , Alejandro I. Lorenzo-Pouso , María Elena Padín-Iruegas , Khrystyna Zhurakivska , Lorenzo Lo Muzio , Rosa María López-Pintor

Oral squamous cell carcinoma (OSCC) is the most common oral malignancy, often preceded by oral potentially malignant disorders (OPMDs). Currently, no clinical biomarker exists to predict malignancy, necessitating OPMD follow-up. Habits and environmental factors, such as smoking, and alcohol consumption, influence OSCC onset. Increased micronuclei (MNs) formation has been observed in the development of OSCC. Non-invasive diagnostic tests like exfoliative cytology offer painless and regular monitoring options. This study evaluates the impact of tobacco, alcohol, and pesticide exposure on MNs occurrence in exfoliative cytology-collected oral mucosal cells, assessing their potential as non-invasive biomarker for OSCC development prediction and monitoring in high-risk patients. Despite results from this meta-analysis supporting the existence of a stepwise increase from controls to patients with OPMD to OSCC, the translation of these findings into clinical practice is limited due to intra- and inter-individual heterogeneity, as well as methodological variability in MNs quantification. Various factors contribute to this heterogeneity, including demographic variables, methodological variability of different laboratories, staining techniques, sample collection location, and patient characteristics. All these points were discussed to provide further insights and improve standardization for future studies.

口腔鳞状细胞癌(OSCC)是最常见的口腔恶性肿瘤,发病前往往先出现口腔潜在恶性疾病(OPMD)。目前,尚无临床生物标志物可预测恶性程度,因此有必要对口腔潜在恶性疾病进行随访。吸烟和饮酒等习惯和环境因素会影响 OSCC 的发病。微核(MNs)的形成与正常粘膜和 OSCC 的进展有关。脱落细胞学等非侵入性诊断测试提供了无痛和定期监测的选择。本研究评估了烟草、酒精和杀虫剂暴露对脱落细胞学收集的口腔黏膜细胞中MNs发生的影响,评估了它们作为非侵入性生物标记物预测和监测高危患者OSCC发展的潜力。尽管这项荟萃分析的结果表明,从对照组到口腔黏膜病变患者再到 OSCC,存在一个逐步上升的过程,但由于个体内和个体间的异质性,以及 MNs 定量方法的差异性,这些发现在临床实践中的应用受到了限制。造成这种异质性的因素有很多,包括人口统计学变量、不同实验室的方法学变量、染色技术、样本采集地点和患者特征。讨论了所有这些问题,以便为今后的研究提供进一步的见解并提高标准化程度。
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引用次数: 0
Use of micronucleus cytome assays with buccal cells for the detection of genotoxic effects: A systematic review and meta-analysis of occupational exposures to metals 利用口腔细胞微核试验检测基因毒性效应:对职业接触金属的系统回顾和荟萃分析。
IF 6.4 2区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.mrrev.2024.108510

Micronucleus (MN) assays with buccal cells are at present widely used to investigate occupational exposures to genotoxic carcinogens. This article describes their use for the monitoring of metal exposed workers. We found in total 73 relevant articles, in the majority (97 %) increased MN and/or other nuclear anomalies were reported. Most studies were realized in South East Asia and South America. A variety of different occupations was studied including welders, electroplaters, painters, workers in battery recycling and production, tannery workers, dental technicians, miners, workers in foundries and smelters, and also subjects working in waste recycling, glass, aluminum and steel production. In many investigations the effects increased with the duration of the working period. The quality of individual studies was evaluated with a quality score tool. The number of cells was in most studies sufficient and DNA-specific stains were used. However, many studies have shortcomings, e.g. they focused solely on MN formation and did not evaluate anomalies, which provide additional information about the stability of the genetic material and acute cytotoxic effects. Only 35 % of the investigations contain quantitative information about exposures to metals and other toxicants. In 6 of these studies, correlations were observed between the concentrations of specific metals (As, Pb, Cr, Cd) in body fluids and MN frequencies. Taken together, the available data indicate that the MN assay can be used to detect chromosomal damage in metal exposed groups; furthermore, it enables also comparisons between subgroups differing in regard to their exposure and allows an estimation of the efficiency of protective measures. The exposure of workers to metals is currently controlled with chemical analytical measurements only, MN assays with buccal cells could contribute to further improve the safety at workplaces as they reflect the biological consequences including synergistic and antagonistic interactions between toxicants.

目前,口腔细胞微核试验(MN)被广泛用于调查职业性接触遗传毒性致癌物质的情况。本文介绍了这种方法在监测接触金属的工人方面的应用。我们共找到 73 篇相关文章,其中大多数(97%)都报告了 MN 和/或其他核异常的增加。大多数研究是在东南亚和南美洲进行的。研究涉及多种不同职业,包括焊工、电镀工、油漆工、电池回收和生产工人、制革工人、牙科技师、矿工、铸造厂和冶炼厂工人,以及废物回收、玻璃、铝和钢铁生产工人。在许多调查中,影响随着工作时间的延长而增加。我们使用质量评分工具对各项研究的质量进行了评估。在大多数研究中,细胞的数量是足够的,并且使用了 DNA 特异性染色剂。然而,许多研究存在不足之处,例如,它们只关注 MN 的形成,而没有评估异常现象,而异常现象可提供有关遗传物质稳定性和急性细胞毒性效应的更多信息。只有 35% 的调查包含有关接触金属和其他有毒物质的定量信息。在其中 6 项研究中,体液中特定金属(砷、铅、铬、镉)的浓度与 MN 频率之间存在相关性。总之,现有数据表明,MN 检测法可用于检测暴露于金属的群体中的染色体损伤情况;此外,它还能对暴露程度不同的亚群体进行比较,并对保护措施的效率进行评估。目前,只能通过化学分析测量来控制工人接触金属的情况,而利用口腔细胞进行的 MN 检测能反映生物后果,包括毒物之间的协同作用和拮抗作用,因此有助于进一步提高工作场所的安全性。
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引用次数: 0
Mechanistic insights into cisplatin response in breast tumors: Molecular determinants and drug/nanotechnology-based therapeutic opportunities 乳腺肿瘤中顺铂反应的机理透视:分子决定因素和基于药物/纳米技术的治疗机会。
IF 6.4 2区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.mrrev.2024.108513

Breast cancer continues to be a major global health challenge, driving the need for effective therapeutic strategies. Cisplatin, a powerful chemotherapeutic agent, is widely used in breast cancer treatment. However, its effectiveness is often limited by systemic toxicity and the development of drug resistance. This review examines the molecular factors that influence cisplatin response and resistance, offering crucial insights for the scientific community. It highlights the significance of understanding cisplatin resistance's genetic and epigenetic contributors, which could lead to more personalized treatment approaches. Additionally, the review explores innovative strategies to counteract cisplatin resistance, including combination therapies, nanoparticle-based drug delivery systems, and targeted therapies. These approaches are under intensive investigation and promise to enhance breast cancer treatment outcomes. This comprehensive discussion is a valuable resource to advance breast cancer therapeutics and address the challenge of cisplatin resistance.

乳腺癌仍然是全球健康面临的一大挑战,因此需要有效的治疗策略。顺铂是一种强效化疗药物,被广泛用于乳腺癌治疗。然而,其有效性往往受到全身毒性和耐药性发展的限制。这篇综述探讨了影响顺铂反应和耐药性的分子因素,为科学界提供了重要的见解。它强调了了解顺铂耐药性的遗传和表观遗传因素的重要性,这可能会带来更个性化的治疗方法。此外,该综述还探讨了应对顺铂耐药性的创新策略,包括联合疗法、纳米颗粒给药系统和靶向疗法。这些方法正在深入研究中,有望提高乳腺癌的治疗效果。本综述是推进乳腺癌治疗和应对顺铂耐药性挑战的宝贵资源。
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引用次数: 0
Methodologies for the detection and sequencing of the epigenetic-like oxidative DNA modification, 8-oxo-7,8-dihydroguanine 检测和测序类似表观遗传的 DNA 氧化修饰--8-氧代-7,8-二氢鸟嘌呤的方法。
IF 6.4 2区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.mrrev.2024.108516
The human genome is constantly threatened by endogenous and environmental DNA damaging agents that can induce a variety of chemically modified DNA lesions including 8-oxo-7,8-dihydroguanine (OG). Increasing evidence has indicated that OG is not only a biomarker for oxidative DNA damage but also a novel epigenetic-like modification involved in regulation of gene expression in mammalian cells. Here we summarize the recent progress in OG research focusing on the following points: (i) the mechanism of OG production in organisms and its biological consequences in cells, (ii) the accurate identification of OG in low-abundance genomes and complex biological backgrounds, (iii) the development of OG sequencing methods. These studies will be helpful for further understanding of the molecular mechanisms of OG-induced mutagenesis and its potential roles in human development and diseases such as cancer.
人类基因组不断受到内源性和环境 DNA 损伤因子的威胁,这些损伤因子可诱发各种化学修饰的 DNA 病变,包括 8-氧代-7,8-二氢鸟嘌呤(OG)。越来越多的证据表明,OG 不仅是氧化 DNA 损伤的生物标志物,还是一种新型的表观遗传修饰,参与哺乳动物细胞中基因表达的调控。在此,我们总结了 OG 研究的最新进展,重点关注以下几点:(i) OG 在生物体内的产生机制及其在细胞中的生物学后果;(ii) 在低丰度基因组和复杂生物背景中准确鉴定 OG;(iii) OG 测序方法的发展。这些研究将有助于进一步了解 OG 诱导诱变的分子机制及其在人类发育和癌症等疾病中的潜在作用。
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引用次数: 0
Objectives and achievements of the HUMN project on its 26th anniversary HUMN 项目 26 周年的目标和成就。
IF 6.4 2区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.mrrev.2024.108511

Micronuclei (MN) are a nuclear abnormality that occurs when chromosome fragments or whole chromosomes are not properly segregated during mitosis and consequently are excluded from the main nuclei and wrapped within nuclear membrane to form small nuclei. This maldistribution of genetic material leads to abnormal cellular genomes which may increase risk of developmental defects, cancers, and accelerated aging. Despite the potential importance of MN as biomarkers of genotoxicity, very little was known about the optimal way to measure MN in humans, the normal ranges of values of MN in healthy humans and the prospective association of MN with developmental and degenerative diseases prior to the 1980’s. In the early 1980’s two important methods to measure MN in humans were developed namely, the cytokinesis-block MN (CBMN) assay using peripheral blood lymphocytes and the Buccal MN assay that measures MN in epithelial cells from the oral mucosa. These discoveries greatly increased interest to use MN assays in human studies. In 1997 the Human Micronucleus (HUMN) project was founded to initiate an international collaboration to (i) harmonise and standardise the techniques used to perform the lymphocyte CBMN assay and the Buccal MN assay; (ii) establish and collate databases of MN frequency in human populations world-wide which also captured demographic, lifestyle and environmental genotoxin exposure data and (iii) use these data to identify the most important variables affecting MN frequency and to also determine whether MN predict disease risk. In this paper we briefly describe the achievements of the HUMN project during the period from the date of its foundation on 9th September 1997 until its 26th Anniversary in 2023, which included more than 200 publications and 23 workshops world-wide.

小核(MN)是一种核异常现象,当染色体片段或整条染色体在有丝分裂过程中不能正确分离,从而被排除在主核之外,并被核膜包裹形成小核。这种遗传物质的分布不当会导致细胞基因组异常,从而增加发育缺陷、癌症和加速衰老的风险。尽管 MN 作为遗传毒性的生物标志物具有潜在的重要性,但在 20 世纪 80 年代之前,人们对测量人体 MN 的最佳方法、健康人体内 MN 的正常值范围以及 MN 与发育和退行性疾病的前瞻性关联知之甚少。20 世纪 80 年代初,人们开发出了两种测量人体 MN 的重要方法,即使用外周血淋巴细胞的细胞因子阻滞 MN(CBMN)检测法和测量口腔粘膜上皮细胞 MN 的口腔 MN 检测法。这些发现大大提高了在人体研究中使用 MN 检测的兴趣。1997 年,人类微核(HUMN)项目成立,启动了一项国际合作项目,旨在:(i) 统一淋巴细胞 CBMN 检测和颊黏膜 MN 检测技术并使之标准化;(ii) 建立和整理全球人类 MN 频率数据库,其中还包括人口统计学、生活方式和环境遗传毒素暴露数据;(iii) 利用这些数据确定影响 MN 频率的最重要变量,并确定 MN 是否可预测疾病风险。本文简要介绍了 HUMN 项目自 1997 年 9 月 9 日成立至 2023 年 26 周年期间所取得的成就,其中包括在全球范围内发表了 200 多篇论文和举办了 23 次研讨会。
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Mutation Research-Reviews in Mutation Research
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