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Multiple levels of stochasticity accounted for in different radiation biophysical models: from physics to biology. 在不同的辐射生物物理模型中考虑了多重水平的随机性:从物理学到生物学。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 DOI: 10.1080/09553002.2023.2146230
Francesco G Cordoni, Marta Missiaggia, Chiara La Tessa, Emanuele Scifoni

Purpose: In the present paper we investigate how some stochastic effects are included in a class of radiobiological models with particular emphasis on how such randomnesses reflect into the predicted cell survival curve.

Materials and methods: We consider four different models, namely the Generalized Stochastic Microdosimetric Model GSM2, in its original full form, the Dirac GSM2 the Poisson GSM2 and the Repair-Misrepair Model (RMR). While GSM2 and the RMR models are known in literature, the Dirac and the Poisson GSM2  have been newly introduced in this work. We further numerically investigate via Monte Carlo simulation of four different particle beams, how the proposed stochastic approximations reflect into the predicted survival curves. To achieve these results, we consider different ion species at energies of interest for therapeutic applications, also including a mixed field scenario.

Results: We show how the Dirac GSM2, the Poisson GSM2 and the RMR can be obtained from the GSM2 under suitable approximations on the stochasticity considered. We analytically derive the cell survival curve predicted by the four models, characterizing rigorously the high and low dose limits. We further study how the theoretical findings emerge also using Monte Carlo numerical simulations.

Conclusions: We show how different models include different levels of stochasticity in the description of cellular response to radiation. This translates into different cell survival predictions depending on the radiation quality.

目的:在本文中,我们研究了一些随机效应是如何包含在一类放射生物学模型中的,特别强调了这种随机性是如何反映到预测的细胞存活曲线中的。材料和方法:我们考虑了四种不同的模型,即原始完整形式的广义随机微剂量模型GSM2、狄拉克模型GSM2、泊松模型GSM2和修复-误修复模型(RMR)。虽然GSM2和RMR模型在文献中是已知的,但Dirac和泊松GSM2在这项工作中是新引入的。我们通过蒙特卡罗模拟进一步研究了四种不同粒子束的随机近似如何反映到预测的生存曲线中。为了获得这些结果,我们考虑了不同的离子种类在治疗应用的兴趣能量,也包括混合场场景。结果:我们展示了在考虑随机性的适当近似下,如何从GSM2得到狄拉克GSM2、泊松GSM2和RMR。我们分析地推导出了四种模型预测的细胞存活曲线,严格地描述了高、低剂量极限。我们还使用蒙特卡罗数值模拟进一步研究了理论结果是如何出现的。结论:我们展示了不同的模型如何在描述细胞对辐射的反应时包含不同水平的随机性。根据辐射质量的不同,这转化为不同的细胞存活预测。
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引用次数: 5
Therapeutic efficacy of cyclin-dependent kinase inhibition in combination with ionizing radiation for lung cancer. 细胞周期依赖性激酶抑制联合电离辐射治疗癌症的疗效。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 Epub Date: 2023-01-04 DOI: 10.1080/09553002.2023.2161658
Jenny Ling-Yu Chen, Chun-Kai Pan, Li-Cheng Lin, Ching-Yi Tsai, Ching-Ying Kuo, Yu-Sen Huang, Yu-Li Lin

Purpose: To evaluate the therapeutic efficacy of cyclin-dependent kinase (CDK) inhibition in combination with ionizing radiation for lung cancer.

Materials and methods: Human lung adenocarcinoma (A549) and squamous cell carcinoma (H520) cells were used to evaluate the therapeutic efficacy of CDK inhibition in combination with ionizing radiation in vitro using colony formation assay, γH2AX immunofluorescence staining, western blotting, and cell cycle phase analysis. We also performed in vivo evaluations of ectopic tumor growth.

Results: In vitro pretreatment with the CDK inhibitor, seliciclib, before irradiation significantly decreased the survival of A549 and H520 cells in a dose-dependent manner. Although CDK inhibition alone did not increase the intensity of γH2AX foci, its combination with ionizing radiation increased DNA double-strand breaks, as shown by γH2AX immunofluorescence staining and western blotting. The combination of CDK inhibition and ionizing radiation-induced G2/M arrest and increased apoptosis, as evidenced by the increased proportion of cells in G2/M arrest, subG1 apoptotic population, and expression of apoptotic markers (cleaved PARP-1 and cleaved caspase-3). Mechanistic studies showed reduced expression of cyclin A with combined treatment, indicating cell cycle shifting effects. An in vivo xenograft model showed that the combination of CDK inhibition and ionizing radiation delayed xenograft tumor growth, and increased the proportion of cleaved PARP-1- and cleaved caspase-3-positive cells, compared to either treatment alone.

Conclusions: We provide preclinical tumoricidal evidence that the combination of CDK inhibition and ionizing radiation is an efficacious treatment for lung cancer.

目的:评价细胞周期依赖性激酶(CDK)抑制联合电离辐射治疗癌症的疗效。材料和方法:用人肺腺癌(A549)和鳞状细胞癌(H520)细胞,采用集落形成试验、γH2AX免疫荧光染色、蛋白质印迹和细胞周期相分析等方法,评价CDK抑制联合电离辐射的体外疗效。我们还对异位肿瘤生长进行了体内评估。结果:CDK抑制剂seliciclib在照射前的体外预处理显著降低了A549和H520细胞的存活率,且呈剂量依赖性。尽管单独抑制CDK并没有增加γH2AX病灶的强度,但其与电离辐射的结合增加了DNA双链断裂,如γH2AX免疫荧光染色和蛋白质印迹所示。CDK抑制和电离辐射的组合诱导G2/M停滞和细胞凋亡增加,如G2/M停顿中细胞比例增加、亚G1细胞凋亡群体和凋亡标记物(裂解的PARP-1和裂解的胱天蛋白酶-3)的表达所证明的。机制研究表明,联合治疗可降低细胞周期蛋白A的表达,表明细胞周期改变的作用。体内异种移植物模型显示,与单独治疗相比,CDK抑制和电离辐射的组合延迟了异种移植物肿瘤的生长,并增加了裂解的PARP-1和裂解的胱天蛋白酶-3阳性细胞的比例。结论:我们提供了临床前的抑瘤证据,表明CDK抑制和电离辐射相结合是治疗癌症的有效方法。
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引用次数: 0
Machine intelligence for radiation science: summary of the Radiation Research Society 67th annual meeting symposium. 辐射科学的机器智能:辐射研究学会第67届年会研讨会纪要。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 DOI: 10.1080/09553002.2023.2173823
Lydia J Wilson, Frederico C Kiffer, Daniel C Berrios, Abigail Bryce-Atkinson, Sylvain V Costes, Olivier Gevaert, Bruno F E Matarèse, Jack Miller, Pritam Mukherjee, Kristen Peach, Paul N Schofield, Luke T Slater, Britta Langen

The era of high-throughput techniques created big data in the medical field and research disciplines. Machine intelligence (MI) approaches can overcome critical limitations on how those large-scale data sets are processed, analyzed, and interpreted. The 67th Annual Meeting of the Radiation Research Society featured a symposium on MI approaches to highlight recent advancements in the radiation sciences and their clinical applications. This article summarizes three of those presentations regarding recent developments for metadata processing and ontological formalization, data mining for radiation outcomes in pediatric oncology, and imaging in lung cancer.

高通量技术时代催生了医学领域和研究学科的大数据。机器智能(MI)方法可以克服如何处理、分析和解释这些大规模数据集的关键限制。第67届放射研究学会年会举办了一场关于心肌梗死方法的研讨会,以突出放射科学及其临床应用的最新进展。本文总结了其中三个关于元数据处理和本体论形式化、儿科肿瘤学放射结果数据挖掘和肺癌成像的最新进展的演讲。
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引用次数: 0
Structural study of wild-type and phospho-mimic XRCC4 dimer and multimer proteins using circular dichroism spectroscopy. 使用圆二色光谱法对野生型和磷酸模拟XRCC4二聚体和多聚体蛋白的结构研究。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 Epub Date: 2023-06-01 DOI: 10.1080/09553002.2023.2214210
Kai Nishikubo, Maho Hasegawa, Yudai Izumi, Kentaro Fujii, Koichi Matsuo, Yoshihisa Matsumoto, Akinari Yokoya

Purpose: To investigate the structural features of wild-type and phospho-mimicking mutated XRCC4 protein, a protein involved in DNA double-strand break repair.

Materials and methods: XRCC4 with a HisTag were expressed by E. coli harboring plasmid DNA and purified. Phospho-mimicking mutants in which one phosphorylation site was replaced with aspartic acid were also prepared in order to reproduce the negative charge resulting from phosphorylation. The proteins were separated into dimers and multimers by gel filtration chromatography. Circular dichroism (CD) spectroscopy was performed in the region from ultraviolet to vacuum-ultraviolet. The CD spectra were analyzed with two analysis programs to evaluate the secondary structures of the wild-type and phospho-mimicked dimers and multimers.

Result and discussion: The proportion of β-strand in the wild-type dimers was very low, particularly in their C-terminal region, including the five phosphorylation sites. The secondary structure of the phospho-mimic hardly changed in the dimeric form. In contrast, the β-strand content increased and the α-helix content decreased upon multimerization of the wild-type protein. The structural change of multimers slightly depended on the phospho-mimic site. These results suggest that the β-strand structure stabilizes the multimerization of XRCC4 and it is regulated by phosphorylation at the C-terminal site in living cells.

Conclusion: An increase in the β-strand content in XRCC4 is essential for stabilization of the multimeric form through C-terminal phosphorylation, allowing the formation of the large double-strand break repair machinery.

目的:研究参与DNA双链断裂修复的野生型和磷酸化模拟突变XRCC4蛋白的结构特征。材料和方法:用携带质粒DNA的大肠杆菌表达带有HisTag的XRCC4并进行纯化。还制备了一个磷酸化位点被天冬氨酸取代的磷酸化模拟突变体,以重现磷酸化产生的负电荷。通过凝胶过滤色谱法将蛋白质分离为二聚体和多聚体。在从紫外到真空紫外的区域中进行了圆二色性(CD)光谱。用两个分析程序分析CD光谱,以评估野生型和磷模拟的二聚体和多聚体的二级结构。结果与讨论:野生型二聚体中β链的比例非常低,尤其是在其C末端区域,包括五个磷酸化位点。磷酸模拟物的二级结构在二聚体形式中几乎没有变化。相反,野生型蛋白质的多聚化使β链含量增加,α螺旋含量减少。多聚体的结构变化略微依赖于磷酸模拟位点。这些结果表明,β链结构稳定了XRCC4的多聚化,并受活细胞C末端磷酸化的调节。结论:XRCC4中β链含量的增加对于通过C端磷酸化稳定多聚体形式至关重要,从而形成大型双链断裂修复机制。
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引用次数: 0
Microarray analysis of hub genes, non-coding RNAs and pathways in lung after whole body irradiation in a mouse model. 小鼠模型全身照射后肺部中枢基因、非编码RNA和通路的微阵列分析。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 Epub Date: 2023-06-01 DOI: 10.1080/09553002.2023.2214205
Molykutty J Aryankalayil, Michelle A Bylicky, Shannon Martello, Sunita Chopra, Mary Sproull, Jared M May, Aman Shankardass, Laurel MacMillan, Claire Vanpouille-Box, Iris Eke, Kevin M K Scott, Juan Dalo, C Norman Coleman

Purpose: Previous research has highlighted the impact of radiation damage, with cancer patients developing acute disorders including radiation induced pneumonitis or chronic disorders including pulmonary fibrosis months after radiation therapy ends. We sought to discover biomarkers that predict these injuries and develop treatments that mitigate this damage and improve quality of life.

Materials and methods: Six- to eight-week-old female C57BL/6 mice received 1, 2, 4, 8, 12 Gy or sham whole body irradiation. Animals were euthanized 48 h post exposure and lungs removed, snap frozen and underwent RNA isolation. Microarray analysis was performed to determine dysregulation of messenger RNA (mRNA), microRNA (miRNA), and long non-coding RNA (lncRNA) after radiation injury.

Results: We observed sustained dysregulation of specific RNA markers including: mRNAs, lncRNAs, and miRNAs across all doses. We also identified significantly upregulated genes that can indicate high dose exposure, including Cpt1c, Pdk4, Gdf15, and Eda2r, which are markers of senescence and fibrosis. Only three miRNAs were significantly dysregulated across all radiation doses: miRNA-142-3p and miRNA-142-5p were downregulated and miRNA-34a-5p was upregulated. IPA analysis predicted inhibition of several molecular pathways with increasing doses of radiation, including: T cell development, Quantity of leukocytes, Quantity of lymphocytes, and Cell viability.

Conclusions: These RNA biomarkers might be highly relevant in the development of treatments and in predicting normal tissue injury in patients undergoing radiation treatment. We are conducting further experiments in our laboratory, which includes a human lung-on-a-chip model, to develop a decision tree model using RNA biomarkers.

目的:先前的研究强调了辐射损伤的影响,癌症患者在辐射治疗结束数月后出现急性疾病,包括辐射诱导的肺炎或慢性疾病,包括肺纤维化。我们试图发现预测这些损伤的生物标志物,并开发减轻这种损伤和提高生活质量的治疗方法。材料和方法:6至8周龄雌性C57BL/6小鼠接受1、2、4、8、12 Gy或假全身照射。动物被安乐死48 暴露后h取出肺,快速冷冻并进行RNA分离。进行微阵列分析以确定辐射损伤后信使RNA(mRNA)、微小RNA(miRNA)和长非编码RNA(lncRNA)的失调。结果:我们观察到在所有剂量下,特异性RNA标记物持续失调,包括:mRNA、lncRNA和miRNA。我们还发现了可以指示高剂量暴露的显著上调的基因,包括Cpt1c、Pdk4、Gdf15和Eda2r,它们是衰老和纤维化的标志物。在所有辐射剂量下,只有三种miRNA显著失调:miRNA-142-3p和miRNA-142-5p下调,miRNA-34a-5p上调。IPA分析预测,随着辐射剂量的增加,几种分子途径会受到抑制,包括:T细胞发育、白细胞数量、淋巴细胞数量和细胞活力。结论:这些RNA生物标志物可能与放射治疗患者的治疗发展和正常组织损伤预测高度相关。我们正在实验室进行进一步的实验,其中包括一个人类芯片上肺模型,以使用RNA生物标志物开发决策树模型。
{"title":"Microarray analysis of hub genes, non-coding RNAs and pathways in lung after whole body irradiation in a mouse model.","authors":"Molykutty J Aryankalayil, Michelle A Bylicky, Shannon Martello, Sunita Chopra, Mary Sproull, Jared M May, Aman Shankardass, Laurel MacMillan, Claire Vanpouille-Box, Iris Eke, Kevin M K Scott, Juan Dalo, C Norman Coleman","doi":"10.1080/09553002.2023.2214205","DOIUrl":"10.1080/09553002.2023.2214205","url":null,"abstract":"<p><strong>Purpose: </strong>Previous research has highlighted the impact of radiation damage, with cancer patients developing acute disorders including radiation induced pneumonitis or chronic disorders including pulmonary fibrosis months after radiation therapy ends. We sought to discover biomarkers that predict these injuries and develop treatments that mitigate this damage and improve quality of life.</p><p><strong>Materials and methods: </strong>Six- to eight-week-old female C57BL/6 mice received 1, 2, 4, 8, 12 Gy or sham whole body irradiation. Animals were euthanized 48 h post exposure and lungs removed, snap frozen and underwent RNA isolation. Microarray analysis was performed to determine dysregulation of messenger RNA (mRNA), microRNA (miRNA), and long non-coding RNA (lncRNA) after radiation injury.</p><p><strong>Results: </strong>We observed sustained dysregulation of specific RNA markers including: mRNAs, lncRNAs, and miRNAs across all doses. We also identified significantly upregulated genes that can indicate high dose exposure, including <i>Cpt1c, Pdk4, Gdf15</i>, and <i>Eda2r</i>, which are markers of senescence and fibrosis. Only three miRNAs were significantly dysregulated across all radiation doses: miRNA-142-3p and miRNA-142-5p were downregulated and miRNA-34a-5p was upregulated. IPA analysis predicted inhibition of several molecular pathways with increasing doses of radiation, including: T cell development, Quantity of leukocytes, Quantity of lymphocytes, and Cell viability.</p><p><strong>Conclusions: </strong>These RNA biomarkers might be highly relevant in the development of treatments and in predicting normal tissue injury in patients undergoing radiation treatment. We are conducting further experiments in our laboratory, which includes a human lung-on-a-chip model, to develop a decision tree model using RNA biomarkers.</p>","PeriodicalId":14261,"journal":{"name":"International Journal of Radiation Biology","volume":" ","pages":"1702-1715"},"PeriodicalIF":2.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10615684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9946137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The need for consensus guidelines to address the mixed legacy of genetic damage assessments for radiofrequency fields. 需要协商一致的指导方针,以解决射频场遗传损害评估的混合遗留问题。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 DOI: 10.1080/09553002.2023.2188936
Vijayalaxmi, Kenneth R Foster

Purpose: This review considers issues related to interpreting the mixed legacy of >300 papers published during the past three decades on possible genotoxic effects of exposure of human and animal tissues to radiofrequency electromagnetic fields (RF-EMF). The main paper reviews the evolution of consensus guidelines for genotoxicity testing and the increasing emphasis on systematic reviews for evaluation of scientific studies for use in health risk assessments. An Appendix considers some issues in assessing the bioeffects literature by examining a subset of genotoxicity publications that employed the comet assay. While most studies found no statistically significant effects of exposure, a significant minority of studies (chiefly, in vivo studies) reported statistically significant effects of exposure. The quality of the studies was highly variable; while several studies were meticulously done and documented, none of these studies were compliant with currently accepted guidelines such as those of the Organization for Economic Cooperation and Development (OECD). Evaluation of the studies using risk of bias (RoB) criteria showed that, in this sample of studies, higher quality studies were less likely to find statistically significant results than those of lower quality.

Conclusion: The authors conclude that statistical significance should be only one consideration in evaluation of bioeffects studies. Simply listing 'statistically' significant effects identified using null hypothesis testing and the criterion p < 0.05 for statistical significance is misleading and uninformative in assessing health risks of exposure. A careful synthesis of evidence is needed, including assessment of study validity, biological significance of reported effects, and coherence of study results with those of other related studies.The authors recommend that all future RF genotoxicity studies intended for use in human health risk assessments and evaluations of the literature should be done in compliance with accepted quality guidelines, i.e. OECD or equivalent guidelines for genotoxicity screening studies and PRISMA or other accepted guideline for reviews of the literature. The positive studies in this group should be redone with tighter quality control to establish the reliability of the findings.

目的:本综述考虑了与解释过去三十年中发表的关于人类和动物组织暴露于射频电磁场(RF-EMF)可能的遗传毒性效应的300多篇论文的混合遗产相关的问题。主要文件回顾了遗传毒性测试共识准则的演变,以及越来越强调对用于健康风险评估的科学研究进行系统评价。附录考虑了一些问题,在评估生物效应文献,通过检查遗传毒性出版物的子集,采用彗星试验。虽然大多数研究没有发现暴露的统计显著影响,但少数研究(主要是体内研究)报告了暴露的统计显著影响。研究的质量参差不齐;虽然有几项研究是精心完成和记录的,但这些研究没有一项符合目前公认的准则,例如经济合作与发展组织(经合发组织)的准则。使用偏倚风险(risk of bias, RoB)标准对研究进行评估后发现,在本研究样本中,高质量的研究比低质量的研究更不可能发现具有统计学意义的结果。结论:在评价生物效应研究时,统计显著性只是考虑因素之一。简单地列出使用零假设检验和标准p确定的“统计”显著效应
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引用次数: 0
Dose reconstruction for plutonium-239 intakes at the Rocky Flats Plant. Rocky Flats核电站钚-239入口的剂量重建。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 Epub Date: 2023-08-14 DOI: 10.1080/09553002.2023.2241896
Caleigh Samuels, Rich Leggett

Purpose: The Rocky Flats (RF) Plant was a weapons manufacturing facility that operated from the early 1950s to 1989. Its primary missions were the production of plutonium (Pu) pits for thermonuclear weapons and the processing of retired weapons for Pu recovery. The purpose of this study was to estimate radiation doses to a cohort of 4499 RF workers from an intake of 239Pu, the primary plutonium isotope handled at the site.

Materials and methods: The latest biokinetic models of the International Commission on Radiological Protection, or site-specific variations of those models, were used to estimate 239Pu intakes for each worker based on model fits to bioassay data often coupled with lung measurements.

Results: Urinary excretion and lung retention data for most 239Pu intakes could be fit reasonably well by a mixture of Pu dioxide and moderately soluble material. For some workers, better fits were obtained by application of other absorption types including Type S, 239Pu nitrate, or pure 239Pu dioxide, or by assuming intake via a wound. The lungs typically received the highest tissue doses, with fifty-year committed equivalent doses in the range of 0.5-1 Sv for 275 workers, 1-5 Sv for 115 workers, and greater than 5 Sv for 12 workers.

Conclusions: RF was a unique site regarding a large number of lung measurements available for determining the appropriate absorption types for inhaled material. This provided higher confidence in reconstructed 239Pu doses than is generally gained from urinary data alone.

目的:Rocky Flats (RF)工厂是一个武器制造设施,从20世纪50年代初到1989年运作。它的主要任务是生产用于热核武器的钚(Pu)坑和处理退役武器以回收Pu。这项研究的目的是估计4499名射频工作人员因摄入239Pu(在现场处理的主要钚同位素)而受到的辐射剂量。材料和方法:使用国际放射防护委员会最新的生物动力学模型,或这些模型的特定地点变体,根据模型拟合生物测定数据(通常与肺部测量相结合)来估计每个工人的239 - pu摄入量。结果:用二氧化钛和中等可溶性物质的混合物可以很好地拟合大多数239Pu摄入者的尿排泄和肺潴留数据。对于一些工人来说,通过使用其他吸收类型,包括S型、硝酸239Pu或纯二氧化239Pu,或假设通过伤口吸收,可以获得更好的效果。肺部通常受到最高的组织剂量,275名工人的50年承诺等效剂量范围为0.5-1西沃特,115名工人为1-5西沃特,12名工人超过5西沃特。结论:射频是一个独特的位置,有大量的肺部测量可用于确定吸入物质的适当吸收类型。这为重建的239Pu剂量提供了比一般仅从尿液数据获得的更高的可信度。
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引用次数: 0
Comet Assay analysis of DNA strand breaks after exposure to the DNA-incorporated Auger Electron Emitter Iodine-125. 暴露于含DNA的俄歇电子发射器碘-125后DNA链断裂的彗星分析。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 DOI: 10.1080/09553002.2020.1851059
Marcus Unverricht-Yeboah, Kathrin Holtmann, Ralf Kriehuber

Purpose: Ionizing radiation causes various types of DNA damage e.g. single strand breaks (SSB) and double strand breaks (DSB), whereby the SSB/DSB ratio is shifted toward the DSB with increasing LET. For the DNA-incorporated Auger electron emitter Iodine-125 a SSB/DSB ratio of 5.4:1 is calculated based on computer simulations. In the presented work the SSB/DSB ratio of DNA-incorporated Iodine-125 was experimentally determined and compared to external homogenous γ-irradiation.

Materials and methods: Iodine-125-iododeoxyuridine (I-125-UdR) was incorporated into the DNA of SCL-II cells and cells were subsequently frozen for decay accumulation. Accordingly, external γ-irradiation (Cs-137) experiments were performed in frozen cells. After exposure the neutral or alkaline Comet Assay was performed to quantify DSB or DSB and SSB, respectively. Automated quantification of the comets was performed using the Olive Tail Moment (Metafer CometScan; MetaSystems). Calculation of absorbed dose for Auger electrons on cellular level is extremely biased due to the exclusive DNA localization of I-125-UdR. To avoid dose calculation the γ-H2AX assay was used in order to allow the comparison of the Comet Assay data between both investigated radiation qualities.

Results: For low-LET γ-radiation, a SSB/DSB ratio of 10:1 was determined. In contrast, a lower SSB/DSB ratio of 6:1 was induced by DNA-incorporated Iodine-125 which compares very well to the calculated values of Pomplun and co-authors.

Conclusion: DNA-incorporated Iodine-125 induces a high-LET type DNA damage pattern in respect to SSB/DSB ratio.

目的:电离辐射引起多种类型的DNA损伤,如单链断裂(SSB)和双链断裂(DSB),其中SSB/DSB比值随着LET的增加而向DSB偏移。在计算机模拟的基础上,计算出含dna的俄歇电子发射器碘- 125a的SSB/DSB比为5.4:1。本文通过实验测定了dna结合碘-125的SSB/DSB比值,并与外均质γ辐照进行了比较。材料和方法:将碘-125-碘脱氧尿苷(I-125-UdR)掺入SCL-II细胞的DNA中,冷冻细胞进行衰变积累。因此,在冷冻细胞中进行体外γ-辐照(Cs-137)实验。暴露后进行中性或碱性彗星试验分别定量DSB或DSB和SSB。使用Olive Tail Moment (Metafer CometScan;MetaSystems)。由于I-125-UdR的DNA定位,在细胞水平上计算俄歇电子的吸收剂量存在极大的偏差。为了避免剂量计算,使用了γ-H2AX测定法,以便在两种研究的辐射质量之间进行彗星测定数据的比较。结果:对于低let γ辐射,SSB/DSB比值为10:1。相比之下,dna结合碘-125诱导的SSB/DSB比较低,为6:1,与Pomplun及其合作者的计算值相当。结论:DNA掺入的碘-125诱导高let型DNA损伤模式,与SSB/DSB比值有关。
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引用次数: 4
Combination of PAKs inhibitors IPA-3 and PF-3758309 effectively suppresses colon carcinoma cell growth by perturbing DNA damage response. PAKs抑制剂IPA-3和PF-3758309联合使用可通过干扰DNA损伤反应有效抑制结肠癌细胞生长。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 DOI: 10.1080/09553002.2022.2110326
Muzaffer Dukel, Kayahan Fiskin

Purpose: PAKs proteins are speculated as new promising targets for cancer therapy due to their central role in many oncogenic pathways. Because PAKs proteins are very significant during carcinogenesis, we aimed to investigate the hypothesis that inhibition of PAKs with IPA-3 and PF-3758309 treatment could synergistically reduce colon carcinoma cell growth.

Materials and methods: The cytotoxic effects of both drugs were determined by a cell viability assay. Cell cycle and apoptosis were analyzed by flow cytometry. The effects of inhibitor drugs on marker genes of apoptosis, autophagy, cell cycle, and DNA damage were tested via immunoblotting.

Results and conclusions: We found out the synergistic effect of these drugs in pair on five colon cancer cell lines. Combined treatment with IPA-3+PF-3758309 in SW620 and Colo 205 cells markedly suppressed colon formation and induced apoptosis, cell cycle arrest, and autophagy compared with treatment with each drug alone. Additionally, this combination sensitized colon cancer cells to ionizing radiation that resulted in inhibition of cell growth.

Significance: Collectively, our findings show for the first time that cotreatment of IPA-3 with PF-3758309 exhibits superior inhibitory effects on colon carcinoma cell growth via inducing DNA damage-related cell death and also enforces a cell cycle arrest.

目的:PAKs蛋白在许多致癌途径中发挥核心作用,被推测为癌症治疗的新靶点。由于PAKs蛋白在癌变过程中非常重要,我们的目的是研究IPA-3和PF-3758309抑制PAKs是否可以协同抑制结肠癌细胞的生长。材料和方法:采用细胞活力法测定两种药物的细胞毒作用。流式细胞术分析细胞周期和凋亡情况。免疫印迹法检测抑制剂药物对细胞凋亡、自噬、细胞周期和DNA损伤标记基因的影响。结果与结论:我们发现了这些药物对5种结肠癌细胞系的协同作用。与单独用药相比,IPA-3+PF-3758309联合治疗SW620和Colo 205细胞可显著抑制结肠形成,诱导细胞凋亡、细胞周期阻滞和自噬。此外,这种组合使结肠癌细胞对电离辐射敏感,从而抑制细胞生长。意义:总的来说,我们的研究结果首次表明IPA-3与PF-3758309共处理通过诱导DNA损伤相关的细胞死亡对结肠癌细胞生长表现出卓越的抑制作用,并强制细胞周期阻滞。
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引用次数: 2
Determination of toxicity and radioprotective properties of bacterial and fungal eumelanin pigments. 细菌和真菌真黑色素的毒性和辐射防护特性的测定。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 Epub Date: 2023-04-27 DOI: 10.1080/09553002.2023.2204957
Sinan Bayram, Bünyamin Aygün, Mehmet Karadayi, Burak Alaylar, Medine Güllüce, Abdulhalik Karabulut

Purpose: Determination of the protective property of melanin, an organic polymer class consisting of phenolic and/or indolic compounds isolated from bacteria and fungi, against fast neutron radiation. To show that these melanin samples, which also have antioxidant and metal chelating properties, can be used as an active ingredient for a drug to be developed against neutrons used in nuclear research and medicine.

Materials and methods: Bacterial and fungal media were prepared, and melanin pigments were produced and isolated. For molecular characterization of pigments, bacterial genomic DNA extraction, 16S rDNA gene amplification processes, and fungal genomic DNA extraction, ITS1, and ITS4 Gene Regions amplification were performed. The DEL assay was implemented to determine the genotoxicity properties of bacterial and fungal melanin pigments. Samples were prepared in a pad measuring 10 ml volume (60 × 15 mm) at a concentration of 0.2-1 microgram in 1% agarose gel for radiation-absorbed dose measurements. Absorption measurements were made using 241Am-Be fast neutron source and Canberra brand NP series BF3 gaseous detector to determine the neutron radiation absorption capacity of all samples. The results obtained to determine the absorption degrees of melanin samples were compared with paraffin and normal concrete, which are widely used in neutron radiation shielding studies.

Results: Melanin pigments were obtained using different bacteria and fungi strains. Afterwards, the fast neutron radiation absorption capacity of these purified pigments were determined. Compared to reference samples, these pigments were found to have slightly lower radiation absorbing ability. In addition to these experiments, cytotoxicity tests were carried out using the Yeast DEL assay technique to evaluate the potential for use of these organic pigments in fields such as medicine and pharmacology. According to the results obtained from the tests, it was determined that these melanin samples did not have any toxic effects.

Conclusion: It was determined that these melanin samples have the potential to be used as a radioprotective drug active substance to protect the tissues and cells of people exposed to neutron radiation after a nuclear accident or nuclear war.Giving a drug that will be developed by using these active ingredients before or after people are exposed to a radiation environment can provide great benefits.

目的:测定黑色素对快中子辐射的保护性能。黑色素是一种有机聚合物,由从细菌和真菌中分离出的酚类和/或吲哚类化合物组成。为了证明这些黑色素样品也具有抗氧化和金属螯合特性,可以用作一种药物的活性成分,该药物将被开发用于核研究和医学中的中子。材料和方法:制备细菌和真菌培养基,制备并分离黑色素。为了对色素进行分子表征,进行了细菌基因组DNA提取、16S rDNA基因扩增过程和真菌基因组DNA提取,ITS1和ITS4基因区域扩增。DEL测定法用于测定细菌和真菌黑色素的遗传毒性特性。样品在一个10 ml体积(60 × 15 mm)在1%琼脂糖凝胶中以0.2-1微克的浓度进行辐射吸收剂量测量。使用241Am-Be快中子源和Canberra牌NP系列BF3气体探测器进行吸收测量,以确定所有样品的中子辐射吸收能力。将测定黑色素样品吸收程度的结果与中子辐射屏蔽研究中广泛使用的石蜡和普通混凝土进行了比较。结果:利用不同的细菌和真菌菌株获得黑色素。然后,测定了这些纯化颜料的快中子辐射吸收能力。与参考样品相比,发现这些颜料具有略低的辐射吸收能力。除了这些实验之外,还使用酵母DEL测定技术进行了细胞毒性测试,以评估这些有机颜料在医学和药理学等领域的应用潜力。根据测试结果,确定这些黑色素样品没有任何毒性作用。结论:这些黑色素样品具有作为放射性保护药物活性物质的潜力,可以保护核事故或核战争后暴露于中子辐射的人的组织和细胞。在人们暴露于辐射环境之前或之后,服用一种将通过使用这些活性成分开发的药物可以带来巨大的好处。
{"title":"Determination of toxicity and radioprotective properties of bacterial and fungal eumelanin pigments.","authors":"Sinan Bayram,&nbsp;Bünyamin Aygün,&nbsp;Mehmet Karadayi,&nbsp;Burak Alaylar,&nbsp;Medine Güllüce,&nbsp;Abdulhalik Karabulut","doi":"10.1080/09553002.2023.2204957","DOIUrl":"10.1080/09553002.2023.2204957","url":null,"abstract":"<p><strong>Purpose: </strong>Determination of the protective property of melanin, an organic polymer class consisting of phenolic and/or indolic compounds isolated from bacteria and fungi, against fast neutron radiation. To show that these melanin samples, which also have antioxidant and metal chelating properties, can be used as an active ingredient for a drug to be developed against neutrons used in nuclear research and medicine.</p><p><strong>Materials and methods: </strong>Bacterial and fungal media were prepared, and melanin pigments were produced and isolated. For molecular characterization of pigments, bacterial genomic DNA extraction, 16S rDNA gene amplification processes, and fungal genomic DNA extraction, ITS1, and ITS4 Gene Regions amplification were performed. The DEL assay was implemented to determine the genotoxicity properties of bacterial and fungal melanin pigments. Samples were prepared in a pad measuring 10 ml volume (60 × 15 mm) at a concentration of 0.2-1 microgram in 1% agarose gel for radiation-absorbed dose measurements. Absorption measurements were made using <sup>241</sup>Am-Be fast neutron source and Canberra brand NP series BF<sub>3</sub> gaseous detector to determine the neutron radiation absorption capacity of all samples. The results obtained to determine the absorption degrees of melanin samples were compared with paraffin and normal concrete, which are widely used in neutron radiation shielding studies.</p><p><strong>Results: </strong>Melanin pigments were obtained using different bacteria and fungi strains. Afterwards, the fast neutron radiation absorption capacity of these purified pigments were determined. Compared to reference samples, these pigments were found to have slightly lower radiation absorbing ability. In addition to these experiments, cytotoxicity tests were carried out using the Yeast DEL assay technique to evaluate the potential for use of these organic pigments in fields such as medicine and pharmacology. According to the results obtained from the tests, it was determined that these melanin samples did not have any toxic effects.</p><p><strong>Conclusion: </strong>It was determined that these melanin samples have the potential to be used as a radioprotective drug active substance to protect the tissues and cells of people exposed to neutron radiation after a nuclear accident or nuclear war.Giving a drug that will be developed by using these active ingredients before or after people are exposed to a radiation environment can provide great benefits.</p>","PeriodicalId":14261,"journal":{"name":"International Journal of Radiation Biology","volume":" ","pages":"1785-1793"},"PeriodicalIF":2.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9413244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 3
期刊
International Journal of Radiation Biology
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