Pub Date : 2025-01-01DOI: 10.1016/j.mrrev.2025.108533
Michael D. Waters , Stafford G. Warren
The orally administered antiviral drug Lagevrio or molnupiravir (MOV) and the combination antiviral drug nirmatrelvir/ritonavir or Paxlovid (PAX) have been shown to reduce the likelihood of hospitalization and death for high-risk patients with COVID-19. Clinical studies, including those comparing PAX and MOV, were reviewed; both drugs are effective in reducing morbidity and mortality in COVID patients, although PAX generally appears to be more efficacious. Both drugs received Emergency Use Authorization in the United States for mild to moderate COVID-19 infection, while only PAX has subsequently been given full FDA approval. The principal disadvantage of PAX is that it interacts with many commonly used drugs, while MOV does not. The purpose of this review is to summarize current information and knowledge about these two drugs. The two drugs have completely different mechanisms of action. PAX inhibits viral replication while MOV induces viral replication errors that are expected to lead to viral inactivation. There is, however, the potential that MOV also could mutate host DNA and cause the virus to mutate into variants with new features. The package insert for MOV states that patients should be notified of relevant toxicity issues before administration. Sensitive mutation detection/analysis studies, such as error corrected Next Generation Sequencing (ecNGS) or HPRT mutation detection assays, in MOV-treated patients are needed to establish the safety of MOV.
{"title":"A tale of two drugs: Molnupiravir and Paxlovid","authors":"Michael D. Waters , Stafford G. Warren","doi":"10.1016/j.mrrev.2025.108533","DOIUrl":"10.1016/j.mrrev.2025.108533","url":null,"abstract":"<div><div>The orally administered antiviral drug Lagevrio or molnupiravir (MOV) and the combination antiviral drug nirmatrelvir/ritonavir or Paxlovid (PAX) have been shown to reduce the likelihood of hospitalization and death for high-risk patients with COVID-19. Clinical studies, including those comparing PAX and MOV, were reviewed; both drugs are effective in reducing morbidity and mortality in COVID patients, although PAX generally appears to be more efficacious. Both drugs received Emergency Use Authorization in the United States for mild to moderate COVID-19 infection, while only PAX has subsequently been given full FDA approval. The principal disadvantage of PAX is that it interacts with many commonly used drugs, while MOV does not. The purpose of this review is to summarize current information and knowledge about these two drugs. The two drugs have completely different mechanisms of action. PAX inhibits viral replication while MOV induces viral replication errors that are expected to lead to viral inactivation. There is, however, the potential that MOV also could mutate host DNA and cause the virus to mutate into variants with new features. The package insert for MOV states that patients should be notified of relevant toxicity issues before administration. Sensitive mutation detection/analysis studies, such as error corrected Next Generation Sequencing (ecNGS) or HPRT mutation detection assays, in MOV-treated patients are needed to establish the safety of MOV.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"795 ","pages":"Article 108533"},"PeriodicalIF":6.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143348055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.mrrev.2024.108529
Ran Xu , Mengmeng Zhang , Xiaoming Yang , Weiming Tian , Changyan Li
In recent years, next-generation high-throughput sequencing technology has been widely used in clinical practice for the identification and diagnosis of Mendelian diseases as an auxiliary detection method. Nevertheless, due to the limitations in read length and poor coverage of complex genomic regions, the etiology of many genetic diseases is unclear. Long-read sequencing (LRS) addresses these limitations of next-generation sequencing. LRS is an effective tool for the clinical study of the etiology of complex genetic diseases. In this review, we summarized the current research on the application of LRS in diseases across various systems. We also reported the improvements in the diagnostic rate and common variant types of LRS in different studies, providing a foundation for the discovery of new disease mechanisms, which is anticipated to play a crucial role in future research on genetic diseases.
{"title":"Decoding complexity: The role of long-read sequencing in unraveling genetic disease etiologies","authors":"Ran Xu , Mengmeng Zhang , Xiaoming Yang , Weiming Tian , Changyan Li","doi":"10.1016/j.mrrev.2024.108529","DOIUrl":"10.1016/j.mrrev.2024.108529","url":null,"abstract":"<div><div>In recent years, next-generation high-throughput sequencing technology has been widely used in clinical practice for the identification and diagnosis of Mendelian diseases as an auxiliary detection method. Nevertheless, due to the limitations in read length and poor coverage of complex genomic regions, the etiology of many genetic diseases is unclear. Long-read sequencing (LRS) addresses these limitations of next-generation sequencing. LRS is an effective tool for the clinical study of the etiology of complex genetic diseases. In this review, we summarized the current research on the application of LRS in diseases across various systems. We also reported the improvements in the diagnostic rate and common variant types of LRS in different studies, providing a foundation for the discovery of new disease mechanisms, which is anticipated to play a crucial role in future research on genetic diseases.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"795 ","pages":"Article 108529"},"PeriodicalIF":6.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.mrrev.2025.108530
Nobuyuki Hamada , Yusuke Matsuya , Lydia B. Zablotska , Mark P. Little
Biological effects of ionizing radiation vary with radiation quality, which is often expressed as the amount of energy deposited per unit length, i.e., linear energy transfer (LET). For acute irradiation, high-LET radiation generally produces greater biological effects than low-LET radiation, but little knowledge exists as to how dose protraction modifies effects. In this regard, inverse dose protraction effects (IDPEs) are phenomena in which dose protraction enhances effects, contrasting with sparing dose protraction effects in which dose protraction reduces effects. Here, we review the current knowledge on IDPEs of high-LET radiation. To the best of our knowledge, since 1967, 80 biology or epidemiology papers have reported IDPEs following external or internal high-LET irradiation with neutrons, deuterons, α-particles, light ions, or heavy ions. IDPEs of high-LET radiation have been described for biochemical changes in cell-free macromolecules, neoplastic transformation, cell death, DNA damage responses and gene expression changes in mammalian cell cultures of human or rodent origin, gene mutations, cytogenetic changes, cancer, non-cancer effects (e.g., testicular effects, cataracts, cardiovascular diseases) and life shortening in non-human mammals (rodents and dogs), and induction of lung cancer and bone tumors in humans. For external irradiation of mammalian cells in vitro and mammals in vivo, IDPEs of low- and high-LET radiation have been reported for radiation doses spanning in excess of three or four orders of magnitude in slightly different ranges, and for radiation dose rates both spanning over six orders of magnitude in different ranges. IDPEs of high-LET radiation in humans have been reported following internal exposure, but not external exposure. Manifestations and mechanisms of IDPEs of high-LET radiation are far less understood than those of low-LET radiation, warranting further studies that will be pivotal to assess the implications for radiation protection.
{"title":"Inverse dose protraction effects of high-LET radiation: Evidence and significance","authors":"Nobuyuki Hamada , Yusuke Matsuya , Lydia B. Zablotska , Mark P. Little","doi":"10.1016/j.mrrev.2025.108530","DOIUrl":"10.1016/j.mrrev.2025.108530","url":null,"abstract":"<div><div>Biological effects of ionizing radiation vary with radiation quality, which is often expressed as the amount of energy deposited per unit length, i.e., linear energy transfer (LET). For acute irradiation, high-LET radiation generally produces greater biological effects than low-LET radiation, but little knowledge exists as to how dose protraction modifies effects. In this regard, inverse dose protraction effects (IDPEs) are phenomena in which dose protraction enhances effects, contrasting with sparing dose protraction effects in which dose protraction reduces effects. Here, we review the current knowledge on IDPEs of high-LET radiation. To the best of our knowledge, since 1967, 80 biology or epidemiology papers have reported IDPEs following external or internal high-LET irradiation with neutrons, deuterons, α-particles, light ions, or heavy ions. IDPEs of high-LET radiation have been described for biochemical changes in cell-free macromolecules, neoplastic transformation, cell death, DNA damage responses and gene expression changes in mammalian cell cultures of human or rodent origin, gene mutations, cytogenetic changes, cancer, non-cancer effects (e.g., testicular effects, cataracts, cardiovascular diseases) and life shortening in non-human mammals (rodents and dogs), and induction of lung cancer and bone tumors in humans. For external irradiation of mammalian cells in vitro and mammals in vivo, IDPEs of low- and high-LET radiation have been reported for radiation doses spanning in excess of three or four orders of magnitude in slightly different ranges, and for radiation dose rates both spanning over six orders of magnitude in different ranges. IDPEs of high-LET radiation in humans have been reported following internal exposure, but not external exposure. Manifestations and mechanisms of IDPEs of high-LET radiation are far less understood than those of low-LET radiation, warranting further studies that will be pivotal to assess the implications for radiation protection.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"795 ","pages":"Article 108530"},"PeriodicalIF":6.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.mrrev.2025.108534
Wei Fan , Xuemei Sun , Ruoran Yuan , Xiaojie Hou , Juyi Wan , Bin Liao
In the human sinoatrial node (SAN), HCN4 is the primary subtype among the four HCN (hyperpolarization activated cyclic nucleotide-gated) family subtypes. A tetramer of HCN subunits forms the ion channel conducting the hyperpolarization-activated “funny” current (If), which plays an important regulatory role in maintaining the pacemaker activity of the SAN. With the advancement of detection technologies over the past 20 years, the relationship between base mutations in the HCN4 gene encoding the HCN4 protein and arrhythmias has been continuously elucidated. The expression and kinetic changes of mutated channels were investigated in COS-7, CHO, HEK-293T cells, and Xenopus oocytes, but their functional changes were not elucidated in human myocardial cells. New genome editing methods, such as Base editor and Prime editor, use components of the CRISPR system and other enzymes to directly install single-gene mutation into cellular DNA without causing double-stranded DNA breaks, which reproduce and correct base mutations. In this review, we summarize all base mutations of the HCN4 gene, discuss the clinical characteristics and function of some base mutations, and combine base editors to explore the establishment of disease models and the potential for future gene correction.
{"title":"HCN4 and arrhythmias: Insights into base mutations","authors":"Wei Fan , Xuemei Sun , Ruoran Yuan , Xiaojie Hou , Juyi Wan , Bin Liao","doi":"10.1016/j.mrrev.2025.108534","DOIUrl":"10.1016/j.mrrev.2025.108534","url":null,"abstract":"<div><div>In the human sinoatrial node (SAN), HCN4 is the primary subtype among the four HCN (hyperpolarization activated cyclic nucleotide-gated) family subtypes. A tetramer of HCN subunits forms the ion channel conducting the hyperpolarization-activated “funny” current (I<sub>f</sub>), which plays an important regulatory role in maintaining the pacemaker activity of the SAN. With the advancement of detection technologies over the past 20 years, the relationship between base mutations in the <em>HCN4</em> gene encoding the HCN4 protein and arrhythmias has been continuously elucidated. The expression and kinetic changes of mutated channels were investigated in COS-7, CHO, HEK-293T cells, and Xenopus oocytes, but their functional changes were not elucidated in human myocardial cells. New genome editing methods, such as Base editor and Prime editor, use components of the CRISPR system and other enzymes to directly install single-gene mutation into cellular DNA without causing double-stranded DNA breaks, which reproduce and correct base mutations. In this review, we summarize all base mutations of the <em>HCN4</em> gene, discuss the clinical characteristics and function of some base mutations, and combine base editors to explore the establishment of disease models and the potential for future gene correction.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"795 ","pages":"Article 108534"},"PeriodicalIF":6.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.mrrev.2025.108532
Jinyi Han , Kexin Xu , Ting Xu , Qin Song , Ting Duan , Jun Yang
The DNA damage response (DDR) is a crucial regulatory mechanism for the survival of organisms, and irregularity of DDR may contribute to the development of various diseases, including tumors, making it is a prominent topic in therapeutic research. Extracellular vesicles (EVs), as important mediators of intercellular communication, have been extensively studied in recent years. Notably, an increasing number of studies have revealed a strong connection between DDR and EVs. On one hand, DNA damage affects the release of EVs and their compositional content; on the other hand, EVs can dictate cell survival or death by modulating DDR in both the parental and the recipient cells. This review outlines current progress in the inter-regulatory relationship between EVs and DDR, with special emphasis on the effects of EVs derived from various sources on DDR in recipient cells. In addition, the potential applications of EVs in research and tumor therapy are discussed.
{"title":"The functional regulation between extracellular vesicles and the DNA damage responses","authors":"Jinyi Han , Kexin Xu , Ting Xu , Qin Song , Ting Duan , Jun Yang","doi":"10.1016/j.mrrev.2025.108532","DOIUrl":"10.1016/j.mrrev.2025.108532","url":null,"abstract":"<div><div>The DNA damage response (DDR) is a crucial regulatory mechanism for the survival of organisms, and irregularity of DDR may contribute to the development of various diseases, including tumors, making it is a prominent topic in therapeutic research. Extracellular vesicles (EVs), as important mediators of intercellular communication, have been extensively studied in recent years. Notably, an increasing number of studies have revealed a strong connection between DDR and EVs. On one hand, DNA damage affects the release of EVs and their compositional content; on the other hand, EVs can dictate cell survival or death by modulating DDR in both the parental and the recipient cells. This review outlines current progress in the inter-regulatory relationship between EVs and DDR, with special emphasis on the effects of EVs derived from various sources on DDR in recipient cells. In addition, the potential applications of EVs in research and tumor therapy are discussed.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"795 ","pages":"Article 108532"},"PeriodicalIF":6.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.mrrev.2025.108531
Nobuyuki Hamada , Yusuke Matsuya , Lydia B. Zablotska , Mark P. Little
Biological effects of ionizing radiation vary not merely with total dose but also with temporal dose distribution. Sparing dose protraction effects, in which dose protraction reduces effects of radiation have widely been accepted and generally assumed in radiation protection, particularly for stochastic effects (e.g., solid cancer). In contrast, inverse dose protraction effects (IDPEs) in which dose protraction enhances radiation effects have not been well recognized, nor comprehensively reviewed. Here, we review the current knowledge on IDPEs of low linear energy transfer (LET) radiation. To the best of our knowledge, since 1952, 157 biology, epidemiology or clinical papers have reported IDPEs following external or internal low-LET irradiation with photons (X-rays, γ-rays), β-rays, electrons, protons or helium ions. IDPEs of low-LET radiation have been described for biochemical changes in cell-free macromolecules (DNA, proteins or lipids), DNA damage responses in bacteria and yeasts, DNA damage, cytogenetic changes, neoplastic transformation and cell death in mammalian cell cultures of human, rodent or bovine origin, mutagenesis in silkworms, cytogenetic changes, induction of cancer (solid tumors and leukemia) and non-cancer effects (male sterility, cataracts and diseases of the circulatory system), tumor inactivation and survival in non-human mammals (rodents, rabbits, dogs and pigs), and induction of cancer and non-cancer effects (skin changes and diseases of the circulatory system) in humans. In contrast to a growing body of phenomenological evidence for manifestations of IDPEs, there is limited knowledge on mechanistic underpinnings, but proposed mechanisms involve cell cycle-dependent resensitization and low dose hyper-radiosensitivity. These necessitate continued studies for further mechanistic developments and assessment of implications of scientific evidence for radiation protection (e.g., in terms of a dose rate effectiveness factor).
{"title":"Inverse dose protraction effects of low-LET radiation: Evidence and significance","authors":"Nobuyuki Hamada , Yusuke Matsuya , Lydia B. Zablotska , Mark P. Little","doi":"10.1016/j.mrrev.2025.108531","DOIUrl":"10.1016/j.mrrev.2025.108531","url":null,"abstract":"<div><div>Biological effects of ionizing radiation vary not merely with total dose but also with temporal dose distribution. Sparing dose protraction effects, in which dose protraction reduces effects of radiation have widely been accepted and generally assumed in radiation protection, particularly for stochastic effects (e.g., solid cancer). In contrast, inverse dose protraction effects (IDPEs) in which dose protraction enhances radiation effects have not been well recognized, nor comprehensively reviewed. Here, we review the current knowledge on IDPEs of low linear energy transfer (LET) radiation. To the best of our knowledge, since 1952, 157 biology, epidemiology or clinical papers have reported IDPEs following external or internal low-LET irradiation with photons (X-rays, γ-rays), β-rays, electrons, protons or helium ions. IDPEs of low-LET radiation have been described for biochemical changes in cell-free macromolecules (DNA, proteins or lipids), DNA damage responses in bacteria and yeasts, DNA damage, cytogenetic changes, neoplastic transformation and cell death in mammalian cell cultures of human, rodent or bovine origin, mutagenesis in silkworms, cytogenetic changes, induction of cancer (solid tumors and leukemia) and non-cancer effects (male sterility, cataracts and diseases of the circulatory system), tumor inactivation and survival in non-human mammals (rodents, rabbits, dogs and pigs), and induction of cancer and non-cancer effects (skin changes and diseases of the circulatory system) in humans. In contrast to a growing body of phenomenological evidence for manifestations of IDPEs, there is limited knowledge on mechanistic underpinnings, but proposed mechanisms involve cell cycle-dependent resensitization and low dose hyper-radiosensitivity. These necessitate continued studies for further mechanistic developments and assessment of implications of scientific evidence for radiation protection (e.g., in terms of a dose rate effectiveness factor).</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"795 ","pages":"Article 108531"},"PeriodicalIF":6.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1016/j.mrrev.2024.108519
Juliana Picinini-Zambelli , Ana Letícia Hilário Garcia , Juliana Da Silva
Urbanization and industrial growth have negatively impacted water quality, raising concerns about emerging aquatic pollutants. Despite advancements in water treatment, these substances persist, endangering aquatic life and human health. Although research has focused on the physiological effects of these pollutants, their genetic damage potential remains poorly understood. This systematic review aimed to consolidate existing knowledge on the genotoxic potential of emerging aquatic pollutants. A comprehensive search was conducted across major databases, encompassing articles published from 2001 to 2022. The review primarily focused on research articles that evaluated genotoxicity in environmental samples containing emerging pollutants, as well as in vitro studies using various concentrations of these substances. Fourteen articles were included in the review, with pharmaceutical compounds, personal care products, disinfection byproducts, and industrial chemicals being the most extensively investigated classes. Other notable pollutants included metals, cyanotoxins, antiseptics, pesticides, and caffeine. All these pollutants classes were found to cause DNA damage, either in vitro at specific concentrations or in complex environmental mixtures. The comet assay was the most frequently used method, owing to its sensitivity and practicality in assessing DNA damage. For some pollutants, different responses were observed when comparing in vitro and in vivo studies, emphasizing the need for studies employing both approaches. However, the limited number of available articles underscores the necessity for further research on the genotoxic potential of emerging pollutants. More research is required to clarify mutagenicity, DNA repair kinetics, and cumulative effects of pollutants, which are critical for shaping policies and ensuring safe water quality. A greater knowledge about these pollutants will enable better understanding risk mitigation, ultimately protecting public health and ecosystems.
城市化和工业增长对水质产生了负面影响，引起了人们对新出现的水生污染物的关注。尽管水处理技术不断进步，但这些物质依然存在，危及水生生物和人类健康。尽管研究主要集中在这些污染物的生理效应上，但对其潜在的遗传损伤仍知之甚少。本系统综述旨在整合有关新兴水生污染物潜在遗传毒性的现有知识。我们在主要数据库中进行了全面检索，涵盖了 2001 年至 2022 年发表的文章。综述主要侧重于评估含有新出现污染物的环境样本的遗传毒性的研究文章，以及使用这些物质的不同浓度进行的体外研究。综述共收录了 14 篇文章，其中研究最为广泛的是药物化合物、个人护理产品、消毒副产品和工业化学品。其他值得注意的污染物包括金属、氰毒素、杀菌剂、杀虫剂和咖啡因。研究发现，所有这些类别的污染物在特定浓度的体外或复杂的环境混合物中都会造成 DNA 损伤。彗星试验是最常用的方法，因为它在评估 DNA 损伤方面既灵敏又实用。对于某些污染物，在比较体外研究和体内研究时观察到了不同的反应，这就强调了采用这两种方法进行研究的必要性。不过，现有文章数量有限，这突出表明有必要进一步研究新出现的污染物的潜在遗传毒性。需要开展更多的研究来阐明污染物的诱变性、DNA 修复动力学和累积效应，这对于制定政策和确保水质安全至关重要。加深对这些污染物的了解将有助于更好地理解风险缓解问题，最终保护公众健康和生态系统。
{"title":"Emerging pollutants in the aquatic environments: A review of genotoxic impacts","authors":"Juliana Picinini-Zambelli , Ana Letícia Hilário Garcia , Juliana Da Silva","doi":"10.1016/j.mrrev.2024.108519","DOIUrl":"10.1016/j.mrrev.2024.108519","url":null,"abstract":"<div><div>Urbanization and industrial growth have negatively impacted water quality, raising concerns about emerging aquatic pollutants. Despite advancements in water treatment, these substances persist, endangering aquatic life and human health. Although research has focused on the physiological effects of these pollutants, their genetic damage potential remains poorly understood. This systematic review aimed to consolidate existing knowledge on the genotoxic potential of emerging aquatic pollutants. A comprehensive search was conducted across major databases, encompassing articles published from 2001 to 2022. The review primarily focused on research articles that evaluated genotoxicity in environmental samples containing emerging pollutants, as well as in vitro studies using various concentrations of these substances. Fourteen articles were included in the review, with pharmaceutical compounds, personal care products, disinfection byproducts, and industrial chemicals being the most extensively investigated classes. Other notable pollutants included metals, cyanotoxins, antiseptics, pesticides, and caffeine. All these pollutants classes were found to cause DNA damage, either in vitro at specific concentrations or in complex environmental mixtures. The comet assay was the most frequently used method, owing to its sensitivity and practicality in assessing DNA damage. For some pollutants, different responses were observed when comparing in vitro and in vivo studies, emphasizing the need for studies employing both approaches. However, the limited number of available articles underscores the necessity for further research on the genotoxic potential of emerging pollutants. More research is required to clarify mutagenicity, DNA repair kinetics, and cumulative effects of pollutants, which are critical for shaping policies and ensuring safe water quality. A greater knowledge about these pollutants will enable better understanding risk mitigation, ultimately protecting public health and ecosystems.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"795 ","pages":"Article 108519"},"PeriodicalIF":6.4,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/j.mrrev.2024.108514
Barbara L. Parsons
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。
{"title":"Clonal expansion of cancer driver gene mutants investigated using advanced sequencing technologies","authors":"Barbara L. Parsons","doi":"10.1016/j.mrrev.2024.108514","DOIUrl":"10.1016/j.mrrev.2024.108514","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"794 ","pages":"Article 108514"},"PeriodicalIF":6.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/j.mrrev.2024.108512
Bérénice Chavanel , François Virard , Vincent Cahais , Claire Renard , Cécilia Sirand , Kim M. Smits , Leo J. Schouten , Béatrice Fervers , Barbara Charbotel , Behnoush Abedi-Ardekani , Michael Korenjak , Jiri Zavadil
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.
{"title":"Genome-scale mutational signature analysis in fixed archived tissues","authors":"Bérénice Chavanel , François Virard , Vincent Cahais , Claire Renard , Cécilia Sirand , Kim M. Smits , Leo J. Schouten , Béatrice Fervers , Barbara Charbotel , Behnoush Abedi-Ardekani , Michael Korenjak , Jiri Zavadil","doi":"10.1016/j.mrrev.2024.108512","DOIUrl":"10.1016/j.mrrev.2024.108512","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"794 ","pages":"Article 108512"},"PeriodicalIF":6.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142095159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 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。
{"title":"Unraveling the multifaceted insights into amyotrophic lateral sclerosis: Genetic underpinnings, pathogenesis, and therapeutic horizons","authors":"Ramaish Sharma , Zuber Khan , Sidharth Mehan , Ghanshyam Das Gupta , Acharan S. Narula","doi":"10.1016/j.mrrev.2024.108518","DOIUrl":"10.1016/j.mrrev.2024.108518","url":null,"abstract":"<div><div>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 (<em>C9ORF72</em>), superoxide dismutase type 1 (<em>SOD1</em>), <em>Fused</em>in sarcoma (<em>FUS</em>), and TAR DNA-binding protein (<em>TARDBP</em>) 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.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"794 ","pages":"Article 108518"},"PeriodicalIF":6.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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