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Sparing and enhancing dose protraction effects for radiation damage to the aorta of wild-type mice. 野生型小鼠主动脉辐射损伤的减量和增量效应
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2024-01-01 Epub Date: 2023-08-07 DOI: 10.1080/09553002.2023.2242939
Nobuyuki Hamada, Ki-Ichiro Kawano, Seiko Hirota, Yusuke Saito, Farina Mohamad Yusoff, Tatsuya Maruhashi, Makoto Maeda, Takaharu Nomura, Ayumu Nakashima, Shinji Yoshinaga, Yukihito Higashi

Purpose: Our previous work indicated the greater magnitude of damage to the thoracic aorta at 6 months after starting 5 Gy irradiation in descending order of exposure to X-rays in 25 fractions > acute X-rays > acute γ-rays > X-rays in 100 fractions ≫ chronic γ-rays, in which the limitations of the study included a lack of data for fractionated γ-ray exposure. To better understand effects of dose protraction and radiation quality, the present study examined changes after exposure to γ-rays in 25 fractions, and compared its biological effectiveness with five other irradiation regimens.

Materials and methods: Male C57BL/6J mice received 5 Gy of 137Cs γ-rays delivered in 25 fractions spread over six weeks. At 6 months after starting irradiation, mice were subjected to echocardiography, followed by tissue sampling. The descending thoracic aorta underwent scanning electron microscopy, immunofluorescence staining and histochemical staining. The integrative analysis of multiple aortic endpoints was conducted for inter-regimen comparisons.

Results: Exposure to γ-rays in 25 fractions induced vascular damage (evidenced by increases in endothelial detachment and vascular endothelial cell death, decreases in endothelial waviness, CD31, endothelial nitric oxide synthase and vascular endothelial cadherin), inflammation (evidenced by increases in tumor necrosis factor α, CD68 and F4/80) and fibrosis (evidenced by increases in transforming growth factor β1, alanine blue stain and intima-media thickness). The integrative analysis revealed biological effectiveness in descending order of exposure to X-rays in 25 fractions > acute X-rays > γ-rays in 25 fractions > acute γ-rays > X-rays in 100 fractions ≫ chronic γ-rays.

Conclusions: The results suggest that dose protraction effects on aortic damage depend on radiation quality, and are not a simple function of dose rate and the number of fractions.

目的:我们之前的研究表明,在开始接受 5 Gy 照射 6 个月后,胸主动脉受到的损伤程度依次为 25 分段 X 射线照射 > 急性 X 射线照射 > 急性 γ 射线照射 > 100 分段 X 射线照射 ≫ 慢性 γ 射线照射,其中研究的局限性包括缺乏分段γ 射线照射的数据。为了更好地了解剂量缩短和辐射质量的影响,本研究考察了25次分段γ射线照射后的变化,并将其生物有效性与其他五种照射方案进行了比较:雄性 C57BL/6J 小鼠在六周内接受 5 Gy 的 137Cs γ 射线照射,共分 25 次照射。开始照射 6 个月后,对小鼠进行超声心动图检查,然后进行组织取样。对降胸主动脉进行扫描电子显微镜检查、免疫荧光染色和组织化学染色。对主动脉的多个终点进行了综合分析,以便在不同研究组之间进行比较:结果:暴露于 25 分量的 γ 射线会诱发血管损伤(表现为内皮脱落和血管内皮细胞死亡的增加,内皮波浪度、CD31、内皮一氧化氮合酶和血管内皮粘连蛋白的减少)、炎症(表现为肿瘤坏死因子α、CD68 和 F4/80 的增加)和纤维化(表现为转化生长因子 β1、丙氨酸蓝染色和血管内膜厚度的增加)。综合分析表明,生物效应从大到小的顺序为:暴露于 25 分段 X 射线 > 急性 X 射线 > 25 分段 γ 射线 > 急性 γ 射线 > 100 分段 X 射线 ≫ 慢性 γ 射线:结果表明,剂量缩短对主动脉损伤的影响取决于辐射质量,而不是剂量率和分段数的简单函数。
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引用次数: 1
A pooled analysis of nine studies in one institution to assess effects of whole heart irradiation in rat models. 对一家机构的九项研究进行汇总分析,以评估大鼠模型全心辐照的影响。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2024-01-01 Epub Date: 2023-08-21 DOI: 10.1080/09553002.2023.2242937
Reid D Landes, Chenghui Li, Vijayalakshmi Sridharan, Carmen Bergom, Marjan Boerma

Purpose: Over the years, animal models of local heart irradiation have provided insight into mechanisms of and treatments for radiation-induced heart disease in human populations. However, it is not completely clear which manifestations of radiation injury are most commonly seen after whole heart irradiation, and whether certain biological factors impact experimental results. Combining 9 homogeneous studies in rat models of whole heart irradiation from one laboratory, we sought to identify experimental and/or biological factors that impact heart outcomes. We evaluated the usefulness of including (1) heart rate and (2) bodyweight as covariates when analyzing biological parameters, and (3) we determined which echocardiography, histological, and immunohistochemistry parameters are most susceptible to radiation effects. Finally, (4) as an educational example, we illustrate a hypothetical sample size calculation for a study design commonly used in evaluating radiation modifiers, using the pooled estimates from the 9 rat studies only for context. The results may assist investigators in the design and analyses of pre-clinical studies of whole heart irradiation.

Materials and methods: We made use of data from 9 rat studies from our labs, 8 published elsewhere in 2008-2017, and one unpublished study. Echocardiography, histological, and immunohistochemical parameters were collected from these studies. Using mixed effects analysis of covariance models, we estimated slopes for heart rate and bodyweight and estimated the radiation effect on each of the parameters.

Results: Bodyweight was related to most echocardiography parameters, and heart rate had an effect on echocardiography parameters related to the diameter of the left ventricle. For some parameters, there was evidence that heart rate and bodyweight relationships with the parameter depended on whether the rats were irradiated. Radiation effects were found in systolic measures of echocardiography parameters related to the diameter of the left ventricle, with ejection fraction and fractional shortening, with atrial wall thickness, and with histological measures of capillary density, collagen deposition, and mast cells infiltration in the heart.

Conclusion: Accounting for bodyweight, as well as heart rate, in analyses of echocardiography parameters should reduce variability in estimated radiation effects. Several echocardiography and histological parameters were particularly susceptible to whole heart irradiation, showing robust effects compared to sham-irradiation. Lastly, we provide an example approach for a sample size calculation that will contribute to a rigorous study design and reproducibility in experiments studying radiation modifiers.

目的:多年来,局部心脏辐照动物模型为人类了解辐射诱发心脏病的机制和治疗方法提供了启示。然而,目前还不完全清楚全心辐照后最常见的辐射损伤表现是什么,以及某些生物因素是否会影响实验结果。结合一个实验室对全心照射大鼠模型进行的 9 项同类研究,我们试图找出影响心脏结果的实验和/或生物学因素。我们评估了在分析生物参数时将(1)心率和(2)体重作为协变量的有用性,(3)我们确定了哪些超声心动图、组织学和免疫组化参数最易受辐射影响。最后,(4) 作为一个教育实例,我们仅使用 9 项大鼠研究的汇总估计值作为背景,说明了评估辐射改良剂时常用的研究设计的假设样本量计算方法。这些结果可能有助于研究人员设计和分析全心辐照的临床前研究:我们使用了来自我们实验室的 9 项大鼠研究数据、2008-2017 年在其他地方发表的 8 项研究数据和一项未发表的研究数据。这些研究收集了超声心动图、组织学和免疫组化参数。利用混合效应协方差分析模型,我们估算了心率和体重的斜率,并估算了辐射对每个参数的影响:结果:体重与大多数超声心动图参数有关,心率对与左心室直径有关的超声心动图参数有影响。有证据表明,心率和体重与某些参数的关系取决于大鼠是否受到辐射。在与左心室直径相关的收缩期超声心动图参数、射血分数和分数缩短、心房壁厚度以及心脏毛细血管密度、胶原沉积和肥大细胞浸润的组织学测量中,都发现了辐射影响:结论:在分析超声心动图参数时考虑体重和心率,可减少辐射效应估计值的变化。一些超声心动图和组织学参数特别容易受到全心辐照的影响,与假辐照相比,这些参数显示出强大的效应。最后,我们提供了一个样本大小计算的示例方法,这将有助于在研究辐射改变因子的实验中进行严格的研究设计和可重复性。
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引用次数: 0
Epidemiological and experimental evidence for radiation-induced health effects in the progeny after exposure in utero 宫内辐照对后代健康影响的流行病学和实验证据
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-12-11 DOI: 10.1080/09553002.2023.2283088
Mohammed Abderrafi Benotmane, Klaus Ruediger Trott
It has been known for many decades that radiation exposure of the developing embryo or fetus may cause two fundamentally different types of severe health effects: on the one hand, radiation may int...
几十年前,人们就已经知道,发育中的胚胎或胎儿受到辐照可能会对健康造成两种截然不同的严重影响:一方面,辐照可能会对胚胎或胎儿造成...
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引用次数: 0
Ionizing radiation exposure effects across multiple generations: evidence and lessons from non-human biota 电离辐照对多代人的影响:非人类生物群的证据和教训
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-12-11 DOI: 10.1080/09553002.2023.2281512
Shayenthiran Sreetharan, Sandrine Frelon, Nele Horemans, Patrick Laloi, Sisko Salomaa, Christelle Adam-Guillermin
A Task Group (TG121) of the International Commission on Radiological Protection (ICRP) Committee 1 was launched in 2021 to study the effects of ionizing radiation in offspring and next generations....
国际辐射防护委员会(ICRP)第 1 委员会的一个工作组(TG121)于 2021 年启动,研究电离辐射对后代和下一代的影响....。
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引用次数: 0
In memoriam: Naomi Harley. 悼念纳奥米-哈雷
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-08-14 DOI: 10.1080/09553002.2023.2247298
Vincent Holahan, Jing Chen
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引用次数: 0
Insights into radiation carcinogenesis based on dose-rate effects in tissue stem cells. 基于组织干细胞剂量率效应的辐射致癌研究。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 Epub Date: 2023-03-31 DOI: 10.1080/09553002.2023.2194398
Kensuke Otsuka, Toshiyasu Iwasaki

Purpose: Increasing epidemiological and biological evidence suggests that radiation exposure enhances cancer risk in a dose-dependent manner. This can be attributed to the 'dose-rate effect,' where the biological effect of low dose-rate radiation is lower than that of the same dose at a high dose-rate. This effect has been reported in epidemiological studies and experimental biology, although the underlying biological mechanisms are not completely understood. In this review, we aim to propose a suitable model for radiation carcinogenesis based on the dose-rate effect in tissue stem cells.

Methods: We surveyed and summarized the latest studies on the mechanisms of carcinogenesis. Next, we summarized the radiosensitivity of intestinal stem cells and the role of dose-rate in the modulation of stem-cell dynamics after irradiation.

Results: Consistently, driver mutations can be detected in most cancers from past to present, supporting the hypothesis that cancer progression is initiated by the accumulation of driver mutations. Recent reports demonstrated that driver mutations can be observed even in normal tissues, which suggests that the accumulation of mutations is a necessary condition for cancer progression. In addition, driver mutations in tissue stem cells can cause tumors, whereas they are not sufficient when they occur in non-stem cells. For non-stem cells, tissue remodeling induced by marked inflammation after the loss of tissue cells is important in addition to the accumulation of mutations. Therefore, the mechanism of carcinogenesis differs according to the cell type and magnitude of stress. In addition, our results indicated that non-irradiated stem cells tend to be eliminated from three-dimensional cultures of intestinal stem cells (organoids) composed of irradiated and non-irradiated stem cells, supporting the stem-cell competition.

Conclusions: We propose a unique scheme in which the dose-rate dependent response of intestinal stem cells incorporates the concept of the threshold of stem-cell competition and context-dependent target shift from stem cells to whole tissue. The concept highlights four key issues that should be considered in radiation carcinogenesis: i.e. accumulation of mutations; tissue reconstitution; stem-cell competition; and environmental factors like epigenetic modifications.

目的:越来越多的流行病学和生物学证据表明,辐射暴露以剂量依赖的方式增加癌症风险。这可归因于“剂量率效应”,即低剂量率辐射的生物学效应低于高剂量率下相同剂量的生物学效应。流行病学研究和实验生物学中已经报道了这种影响,尽管其潜在的生物学机制尚不完全清楚。在这篇综述中,我们的目的是基于组织干细胞的剂量率效应,提出一个合适的辐射致癌模型。方法:对肿瘤发生机制的最新研究进行综述。接下来,我们总结了肠道干细胞的放射敏感性以及剂量率在辐射后干细胞动力学调节中的作用。结果:从过去到现在,在大多数癌症中都可以检测到驱动突变,这支持了癌症进展是由驱动突变积累引发的假设。最近的报告表明,即使在正常组织中也可以观察到驱动突变,这表明突变的积累是癌症进展的必要条件。此外,组织干细胞中的驱动突变会导致肿瘤,而当它们发生在非干细胞中时还不够。对于非干细胞来说,除了突变的积累外,组织细胞损失后由显著炎症诱导的组织重塑也很重要。因此,致癌机制因细胞类型和应激程度而异。此外,我们的研究结果表明,未经辐照的干细胞往往会从由经辐照和未经辐照干细胞组成的肠道干细胞(类器官)的三维培养物中被消除,从而支持干细胞的竞争。结论:我们提出了一种独特的方案,其中肠道干细胞的剂量率依赖性反应结合了干细胞竞争阈值和从干细胞到整个组织的上下文依赖性靶点转移的概念。该概念强调了辐射致癌过程中应考虑的四个关键问题:即突变的积累;组织重建;干细胞竞争;以及环境因素,如表观遗传修饰。
{"title":"Insights into radiation carcinogenesis based on dose-rate effects in tissue stem cells.","authors":"Kensuke Otsuka,&nbsp;Toshiyasu Iwasaki","doi":"10.1080/09553002.2023.2194398","DOIUrl":"10.1080/09553002.2023.2194398","url":null,"abstract":"<p><strong>Purpose: </strong>Increasing epidemiological and biological evidence suggests that radiation exposure enhances cancer risk in a dose-dependent manner. This can be attributed to the 'dose-rate effect,' where the biological effect of low dose-rate radiation is lower than that of the same dose at a high dose-rate. This effect has been reported in epidemiological studies and experimental biology, although the underlying biological mechanisms are not completely understood. In this review, we aim to propose a suitable model for radiation carcinogenesis based on the dose-rate effect in tissue stem cells.</p><p><strong>Methods: </strong>We surveyed and summarized the latest studies on the mechanisms of carcinogenesis. Next, we summarized the radiosensitivity of intestinal stem cells and the role of dose-rate in the modulation of stem-cell dynamics after irradiation.</p><p><strong>Results: </strong>Consistently, driver mutations can be detected in most cancers from past to present, supporting the hypothesis that cancer progression is initiated by the accumulation of driver mutations. Recent reports demonstrated that driver mutations can be observed even in normal tissues, which suggests that the accumulation of mutations is a necessary condition for cancer progression. In addition, driver mutations in tissue stem cells can cause tumors, whereas they are not sufficient when they occur in non-stem cells. For non-stem cells, tissue remodeling induced by marked inflammation after the loss of tissue cells is important in addition to the accumulation of mutations. Therefore, the mechanism of carcinogenesis differs according to the cell type and magnitude of stress. In addition, our results indicated that non-irradiated stem cells tend to be eliminated from three-dimensional cultures of intestinal stem cells (organoids) composed of irradiated and non-irradiated stem cells, supporting the stem-cell competition.</p><p><strong>Conclusions: </strong>We propose a unique scheme in which the dose-rate dependent response of intestinal stem cells incorporates the concept of the threshold of stem-cell competition and context-dependent target shift from stem cells to whole tissue. The concept highlights four key issues that should be considered in radiation carcinogenesis: i.e. accumulation of mutations; tissue reconstitution; stem-cell competition; and environmental factors like epigenetic modifications.</p>","PeriodicalId":14261,"journal":{"name":"International Journal of Radiation Biology","volume":" ","pages":"1503-1521"},"PeriodicalIF":2.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9229469","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: 0
The injuries of spleen and intestinal immune system induced by 2-Gy 60Co γ-ray whole-body irradiation. 2-Gy 60Co γ射线全身照射对脾脏和肠道免疫系统的损伤。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 DOI: 10.1080/09553002.2022.2094017
An Wang, Zhongyu Shi, Lei Wang, Yan Wang, Xiaoying Chen, Changhao He, Xiaomeng Zhang, Wenhui Xu, Qian Fu, Tieshan Wang, Shujing Zhang, Yushan Gao, Sumin Hu

Purpose: The aim of the present study was to investigate the injuries of spleen and intestinal immune system induced by 2 Gy 60Co γ ray in mice.

Materials and methods: A total of 120 Balb/c mice were randomly divided into two groups: blank control (Ctrl) and model (IR). The IR mice were exposed to a single dose of total body irradiation (2 Gy, dose rate: 1 Gy/min) and sacrificed on 1st, 3rd, 7th, 14th and 21st day after irradiation. The indicators including general observations and body weight, the changes in peripheral hemogram, spleen index, histopathology examination and lymphocyte subsets of spleen. As well as the count and subsets of lymphocyte in gut-associated lymphoid tissue.

Results: Compared with the Ctrl group, the body weight, spleen index, peripheral blood cell and splenocyte amounts, intraepithelial lymphocytes number decreased significantly after exposure, accompanied by a notable decreased count of lymphocytes in Peyer's patch and mesenteric lymph nodes. Moreover, ionizing radiation also broke the balance of CD4+/CD8+ and increased the Treg proportion in spleen, which then triggered immune imbalance and immunosuppression. In general, the spleen injuries occurred on 1st day after exposure, worse on 3rd day, and were relieved on 7th day. The intestinal immune injuries were observed on 1st day, and attenuated on 3rd day. On 21st day after exposure, the spleen volume and index have returned to normal, except for the distribution of lymphocyte subpopulations. Furthermore, all indicators of gut-associated lymphoid tissue, except for mesenteric lymph nodes lymphocyte count, had returned to normal levels on 21st day.

Conclusion: In conclusion, our data showed the injuries of spleen and intestinal immune system induced by 2 Gy 60Co γ ray whole-body irradiation. These findings may provide the bases for further radiation protection in the immunity.

目的:研究2gy - 60Co γ射线对小鼠脾脏和肠道免疫系统的损伤。材料与方法:将120只Balb/c小鼠随机分为空白对照组(Ctrl)和模型组(IR)。分别于照射后第1、3、7、14、21天进行单剂量(2 Gy,剂量率1 Gy/min)全身照射,处死IR小鼠。指标包括一般观察及体重、外周血血象变化、脾脏指数、组织病理学检查及脾脏淋巴细胞亚群。以及肠道相关淋巴组织中淋巴细胞的计数和亚群。结果:与对照组相比,暴露后大鼠体重、脾脏指数、外周血细胞和脾细胞数量、上皮内淋巴细胞数量均显著减少,Peyer’s patch和肠系膜淋巴结淋巴细胞计数明显减少。此外,电离辐射还破坏了脾脏CD4+/CD8+的平衡,使脾脏Treg比例升高,从而引发免疫失衡和免疫抑制。脾脏损伤一般在暴露后第1天出现,第3天加重,第7天减轻。第1天观察到肠道免疫损伤,第3天肠道免疫损伤减弱。暴露后第21天,除淋巴细胞亚群分布外,脾脏体积和指数均恢复正常。此外,除肠系膜淋巴结淋巴细胞计数外,所有肠道相关淋巴组织指标在第21天恢复到正常水平。结论:2 Gy 60Co γ射线全身照射可引起脾脏和肠道免疫系统损伤。研究结果可为进一步开展辐射防护提供依据。
{"title":"The injuries of spleen and intestinal immune system induced by 2-Gy <sup>60</sup>Co <b>γ</b>-ray whole-body irradiation.","authors":"An Wang,&nbsp;Zhongyu Shi,&nbsp;Lei Wang,&nbsp;Yan Wang,&nbsp;Xiaoying Chen,&nbsp;Changhao He,&nbsp;Xiaomeng Zhang,&nbsp;Wenhui Xu,&nbsp;Qian Fu,&nbsp;Tieshan Wang,&nbsp;Shujing Zhang,&nbsp;Yushan Gao,&nbsp;Sumin Hu","doi":"10.1080/09553002.2022.2094017","DOIUrl":"https://doi.org/10.1080/09553002.2022.2094017","url":null,"abstract":"<p><strong>Purpose: </strong>The aim of the present study was to investigate the injuries of spleen and intestinal immune system induced by 2 Gy <sup>60</sup>Co γ ray in mice.</p><p><strong>Materials and methods: </strong>A total of 120 Balb/c mice were randomly divided into two groups: blank control (Ctrl) and model (IR). The IR mice were exposed to a single dose of total body irradiation (2 Gy, dose rate: 1 Gy/min) and sacrificed on 1st, 3rd, 7th, 14th and 21st day after irradiation. The indicators including general observations and body weight, the changes in peripheral hemogram, spleen index, histopathology examination and lymphocyte subsets of spleen. As well as the count and subsets of lymphocyte in gut-associated lymphoid tissue.</p><p><strong>Results: </strong>Compared with the Ctrl group, the body weight, spleen index, peripheral blood cell and splenocyte amounts, intraepithelial lymphocytes number decreased significantly after exposure, accompanied by a notable decreased count of lymphocytes in Peyer's patch and mesenteric lymph nodes. Moreover, ionizing radiation also broke the balance of CD4+/CD8+ and increased the Treg proportion in spleen, which then triggered immune imbalance and immunosuppression. In general, the spleen injuries occurred on 1st day after exposure, worse on 3rd day, and were relieved on 7th day. The intestinal immune injuries were observed on 1st day, and attenuated on 3rd day. On 21st day after exposure, the spleen volume and index have returned to normal, except for the distribution of lymphocyte subpopulations. Furthermore, all indicators of gut-associated lymphoid tissue, except for mesenteric lymph nodes lymphocyte count, had returned to normal levels on 21st day.</p><p><strong>Conclusion: </strong>In conclusion, our data showed the injuries of spleen and intestinal immune system induced by 2 Gy <sup>60</sup>Co γ ray whole-body irradiation. These findings may provide the bases for further radiation protection in the immunity.</p>","PeriodicalId":14261,"journal":{"name":"International Journal of Radiation Biology","volume":"99 3","pages":"406-418"},"PeriodicalIF":2.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9498849","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: 1
Molecular response of keloids to ionizing radiation: targeting FOXO1 radiosensitizes keloids. 瘢痕疙瘩对电离辐射的分子反应:靶向FOXO1放射致敏瘢痕疙瘩。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 DOI: 10.1080/09553002.2022.2121871
Min Hong, Xiaoqian Li, Yulan Liu, Wei Mo, Bin Shi, Shigao Chen, Tao Yan, Yuhong Shi, Daojiang Yu, Shuyu Zhang

Purpose: Keloids are benign dermal tumors that arise from abnormal wound healing processes following skin lesions. Surgical excision followed by radiotherapy plays an important role in the treatment of keloids. Nevertheless, radioresistance remains a serious impediment to treatment efficacy. Investigation of the molecular response of keloids to radiation may contribute to radiosensitizing strategies.

Materials and methods: Primary keloid fibroblasts from human keloids were isolated and irradiated with X-ray. The expression profiles of messenger RNA (mRNA) in nonradiated and irradiated primary keloid fibroblasts were measured by mRNA sequencing analysis. Then, we identified common motifs and corresponding transcription factors of dysregulated mRNAs by using bioinformatic analysis of the proximal promoters. Whereafter, GO and KEGG were used to analyze the functional enrichment of the differentially expressed genes.

Results: We found that radiation not only suppressed proliferation but also increased cell senescence of primary keloid fibroblasts. There were 184 mRNAs and 204 mRNAs that showed significant changes in 4 and 8 Gy irradiated primary keloid fibroblasts, respectively. Among them, 8 upregulated and 30 downregulated mRNAs showed consistent alterations in 4 and 8 Gy irradiated primary keloid fibroblasts. More importantly, the xForkhead box O1 (FOXO1) signaling pathway was involved in the irradiation response. Pretreatment with the FOXO1 signaling inhibitor AS1842856 significantly promoted LDH release, apoptosis and senescence of primary keloid fibroblasts following irradiation.

Conclusion: Our findings illustrated the molecular changes in human keloid fibroblasts in response to radiation, and FOXO1 pathway inhibition is expected to provide a novel strategy for the radiosensitization of keloids.

目的:瘢痕疙瘩是由皮肤病变后伤口愈合过程异常引起的良性真皮肿瘤。手术切除加放疗在瘢痕疙瘩的治疗中起着重要作用。然而,放射耐药仍然是影响治疗效果的一个严重障碍。研究瘢痕疙瘩对辐射的分子反应可能有助于制定放射增敏策略。材料和方法:分离人瘢痕疙瘩原代成纤维细胞,x线照射。采用mRNA测序法测定未辐照和辐照原代瘢痕疙瘩成纤维细胞mRNA的表达谱。然后,我们通过对近端启动子的生物信息学分析,确定了失调mrna的共同基序和相应的转录因子。然后用GO和KEGG分析差异表达基因的功能富集情况。结果:辐射不仅抑制瘢痕疙瘩成纤维细胞的增殖,而且增加细胞衰老。在4 Gy和8 Gy辐照的原代瘢痕疙瘩成纤维细胞中,分别有184个mrna和204个mrna表现出显著变化。其中,8个上调mrna和30个下调mrna在4 Gy和8 Gy辐照的原代瘢痕疙瘩成纤维细胞中表现出一致的改变。更重要的是,xForkhead box O1 (FOXO1)信号通路参与了辐照响应。FOXO1信号抑制剂AS1842856预处理可显著促进辐照后原代瘢痕疙瘩成纤维细胞LDH释放、细胞凋亡和衰老。结论:我们的研究结果说明了人类瘢痕疙瘩成纤维细胞在辐射反应中的分子变化,FOXO1通路抑制有望为瘢痕疙瘩的放射增敏提供一种新的策略。
{"title":"Molecular response of keloids to ionizing radiation: targeting FOXO1 radiosensitizes keloids.","authors":"Min Hong,&nbsp;Xiaoqian Li,&nbsp;Yulan Liu,&nbsp;Wei Mo,&nbsp;Bin Shi,&nbsp;Shigao Chen,&nbsp;Tao Yan,&nbsp;Yuhong Shi,&nbsp;Daojiang Yu,&nbsp;Shuyu Zhang","doi":"10.1080/09553002.2022.2121871","DOIUrl":"https://doi.org/10.1080/09553002.2022.2121871","url":null,"abstract":"<p><strong>Purpose: </strong>Keloids are benign dermal tumors that arise from abnormal wound healing processes following skin lesions. Surgical excision followed by radiotherapy plays an important role in the treatment of keloids. Nevertheless, radioresistance remains a serious impediment to treatment efficacy. Investigation of the molecular response of keloids to radiation may contribute to radiosensitizing strategies.</p><p><strong>Materials and methods: </strong>Primary keloid fibroblasts from human keloids were isolated and irradiated with X-ray. The expression profiles of messenger RNA (mRNA) in nonradiated and irradiated primary keloid fibroblasts were measured by mRNA sequencing analysis. Then, we identified common motifs and corresponding transcription factors of dysregulated mRNAs by using bioinformatic analysis of the proximal promoters. Whereafter, GO and KEGG were used to analyze the functional enrichment of the differentially expressed genes.</p><p><strong>Results: </strong>We found that radiation not only suppressed proliferation but also increased cell senescence of primary keloid fibroblasts. There were 184 mRNAs and 204 mRNAs that showed significant changes in 4 and 8 Gy irradiated primary keloid fibroblasts, respectively. Among them, 8 upregulated and 30 downregulated mRNAs showed consistent alterations in 4 and 8 Gy irradiated primary keloid fibroblasts. More importantly, the xForkhead box O1 (FOXO1) signaling pathway was involved in the irradiation response. Pretreatment with the FOXO1 signaling inhibitor AS1842856 significantly promoted LDH release, apoptosis and senescence of primary keloid fibroblasts following irradiation.</p><p><strong>Conclusion: </strong>Our findings illustrated the molecular changes in human keloid fibroblasts in response to radiation, and FOXO1 pathway inhibition is expected to provide a novel strategy for the radiosensitization of keloids.</p>","PeriodicalId":14261,"journal":{"name":"International Journal of Radiation Biology","volume":"99 5","pages":"835-844"},"PeriodicalIF":2.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9498863","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: 1
Improved radiosynthesis of 123I-MAPi, an auger theranostic agent. 改进螺旋放射治疗剂 123I-MAPi 的放射合成。
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 Epub Date: 2020-07-02 DOI: 10.1080/09553002.2020.1781283
Thomas C Wilson, Stephen A Jannetti, Navjot Guru, Nagavarakishore Pillarsetty, Thomas Reiner, Giacomo Pirovano

Purpose: 123I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently, 123I-MAPi is synthesized using multistep synthesis that results in modest yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize 123I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials.

Materials and methods: 123I-MAPi was prepared in a single step via 123I-iododetannylation of the corresponding tributylstannane precursor. In vitro internalization assay, subcellular fractionation and confocal microscopy where used to evaluate the performance of 123I-MAPi in a small cell lung cancer model.

Results: 123I-MAPi was synthesized in a single step from the corresponding stannane precursor in AY of 45 ± 2% and MA of 11.8 ± 4.8 GBq µmol-1. In vitro in LX22 cells showed rapid internalization (5 min) with accumulation found predominantly in the membrane, nucleus and chromatin of the cell as determined by subcellular fractionation.

Conclusions: Here, we have developed an improved radiosynthesis of 123I-MAPi, an Auger theranostic agent. This process was achieved using a single step, 123I-iododestannylation reaction from the corresponding stannane precursor in good AY and MA. 123I-MAPi was evaluated in vitro in a small cell lung cancer model with high PARP expression, rapid internalization and high nuclear uptake shown.

目的:123I-MAPi 是一种新型 PARP1 靶向奥杰放射治疗药物,在临床前胶质瘤模型中显示出良好的效果。目前,123I-MAPi 采用多步合成法合成,产量不高,摩尔活性(MA)较低,限制了将这项技术转化为大剂量人体研究的能力。材料与方法:123I-MAPi 是通过 123I-iododetannylation 对相应的三丁基锡前体进行单步合成制备的。体外内化试验、亚细胞分馏和共聚焦显微镜用于评估 123I-MAPi 在小细胞肺癌模型中的性能:123I-MAPi 由相应的锡烷前体一步合成,AY 为 45 ± 2%,MA 为 11.8 ± 4.8 GBq µmol-1。体外 LX22 细胞显示出快速内化(5 分钟),经亚细胞分馏确定主要在细胞膜、细胞核和染色质中积累:在此,我们开发了一种改进的奥杰治疗剂 123I-MAPi 的放射合成方法。该工艺采用单步123I-碘代二烷酰化反应,从相应的锡烷前体中获得良好的AY和MA。在小细胞肺癌模型中对 123I-MAPi 进行了体外评估,结果表明它具有 PARP 高表达、快速内化和高核摄取等特点。
{"title":"Improved radiosynthesis of <sup>123</sup>I-MAPi, an auger theranostic agent.","authors":"Thomas C Wilson, Stephen A Jannetti, Navjot Guru, Nagavarakishore Pillarsetty, Thomas Reiner, Giacomo Pirovano","doi":"10.1080/09553002.2020.1781283","DOIUrl":"10.1080/09553002.2020.1781283","url":null,"abstract":"<p><strong>Purpose: </strong><sup>123</sup>I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently, <sup>123</sup>I-MAPi is synthesized using multistep synthesis that results in modest yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize <sup>123</sup>I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials.</p><p><strong>Materials and methods: </strong><sup>123</sup>I-MAPi was prepared in a single step via <sup>123</sup>I-iododetannylation of the corresponding tributylstannane precursor. In vitro internalization assay, subcellular fractionation and confocal microscopy where used to evaluate the performance of <sup>123</sup>I-MAPi in a small cell lung cancer model.</p><p><strong>Results: </strong><sup>123</sup>I-MAPi was synthesized in a single step from the corresponding stannane precursor in AY of 45 ± 2% and MA of 11.8 ± 4.8 GBq <i>µ</i>mol<sup>-1</sup>. In vitro in LX22 cells showed rapid internalization (5 min) with accumulation found predominantly in the membrane, nucleus and chromatin of the cell as determined by subcellular fractionation.</p><p><strong>Conclusions: </strong>Here, we have developed an improved radiosynthesis of <sup>123</sup>I-MAPi, an Auger theranostic agent. This process was achieved using a single step, <sup>123</sup>I-iododestannylation reaction from the corresponding stannane precursor in good AY and MA. <sup>123</sup>I-MAPi was evaluated in vitro in a small cell lung cancer model with high PARP expression, rapid internalization and high nuclear uptake shown.</p>","PeriodicalId":14261,"journal":{"name":"International Journal of Radiation Biology","volume":"99 1","pages":"70-76"},"PeriodicalIF":2.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/09553002.2020.1781283","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10715777","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: 9
How to explain the sensitivity of DNA double-strand breaks yield to 125I position? 如何解释DNA双链断裂率对125I位置的敏感性?
IF 2.6 4区 医学 Q2 BIOLOGY Pub Date : 2023-01-01 DOI: 10.1080/09553002.2022.2047822
Mario Enrique Alcocer Ávila, Elif Hindié, Christophe Champion

Purpose: Auger emitters exhibit interesting features due to their emission of a cascade of short-range Auger electrons. Maximum DNA breakage efficacy is achieved when decays occur near DNA. Studies of double-strand breaks (DSBs) yields in plasmids revealed cutoff distances from DNA axis of 10.5 Å-12 Å, beyond which the mechanism of DSBs moves from direct to indirect effects, and the yield decreases rapidly. Some authors suggested that the average energy deposited in a DNA cylinder could explain such cutoffs. We aimed to study this hypothesis in further detail.

Materials and methods: Using the Monte Carlo code CELLDOSE, we investigated the influence of the 125I atom position on energy deposits and absorbed doses per decay not only in a DNA cylinder, but also in individual strands, each modeled as 10 spheres encompassing the fragility sites for phosphodiester bond cleavage.

Results: The dose per decay decreased much more rapidly for a sphere in the proximal strand than for the DNA cylinder. For example, when moving the 125I source from 10.5 Å to 11.5 Å, the average dose to the sphere dropped by 43%, compared to only 13% in the case of the cylinder.

Conclusions: Explaining variations in DSBs yields with 125I position should consider the probability of inducing damage in the proximal strand (nearest to the 125I atom). The energy received by fragility sites in this strand is highly influenced by the isotropic (4π) emission of 125I low-energy Auger electrons. The positioning of Auger emitters for targeted radionuclide therapy can be envisioned accordingly.

目的:俄歇发射体表现出有趣的特征,因为它们发射的是一串短程俄歇电子。当DNA附近发生衰变时,达到最大的DNA断裂效果。对质粒中双链断裂(DSBs)产率的研究表明,与DNA轴的切断距离为10.5 Å-12 Å,超过这个距离,DSBs的作用机制从直接作用转向间接作用,产率迅速下降。一些作者认为,储存在DNA圆柱体中的平均能量可以解释这种切断。我们的目的是进一步详细研究这一假设。材料和方法:使用蒙特卡罗代码CELLDOSE,我们研究了125I原子位置对能量沉积和每次衰变的吸收剂量的影响,不仅在DNA圆柱体中,而且在单个链中,每个链被建模为包含磷酸二酯键断裂的脆弱位点的10个球体。结果:在近端链中,每次衰减的剂量比在DNA圆柱体中下降得快得多。例如,当125I源从10.5 Å移动到11.5 Å时,球体的平均剂量下降了43%,而在圆柱体的情况下仅下降了13%。结论:解释dsb产率随125I位置的变化应考虑近端链(最靠近125I原子)诱导损伤的可能性。该链中脆弱位点所接收的能量受到125I低能俄歇电子的各向同性(4π)发射的高度影响。可以相应地设想用于靶向放射性核素治疗的俄歇发射器的定位。
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引用次数: 2
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International Journal of Radiation Biology
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