Biomarkers Associated with Radiation-Induced Lung Injury in Cancer Patients

Radiotherapy (RT) is a common and effective non-surgical treatment for thoracic solid tumors, and radiation-induced lung injury (RILI) is the most common side effect of radiotherapy. Even if RT is effective in the treatment of cancer patients, severe radiation pneumonitis (RP) or pulmonary fibrosis (PF) can reduce the quality of life of patients and may even lead to serious consequences of death. Therefore, how to overcome the problem of accurate prediction and early diagnosis of RT for pulmonary toxicity is very important. This review summarizes the related factors of RILI and the related biomarkers for early prediction of RILI.

Rabbit model of radiation-induced lung injury

Objective:To explore the feasibility of establishing an animal model of chronic radiationinduced lung injury.Methods:Twenty-eight New Zealand white rabbits were randomly divided into 3 groups(the right lung irradiation group,the whole lung irradiation group and the control group).Animal model of radiation-induced lung injury was established b) highdoes radiotherapy in the irradiation groups,then all rabbits underwent CT and pathological examinations at 1.2.4.8.12.16 weeks,respectively after radiation.Results:Within 4 weeks of irradiation,some rabbits in the right lung irradiation group and whole lung irradiation group died. CT and pathological examinations all showed acute radiation pneumonitis.At 8-12 weeks after irradiation,CT scanning showed ground glass samples signs,patchy shadows and fibrotic stripes. Pathological examination showed the fibrosis pulmonary alveolar wall thickened obviously. Conclusions:The clinical animal model of chronic radiation-induced lung injury which corresponds to practical conditions in clinic can be successfully established.

Correlation between miR-564, TGF-β1, and radiation-induced lung injury

Objective Our study aimed to analyze the expression of miR-564 and TGF-β1 in cancer tissues and the serum of patients with radiation-induced lung injury,and to investigate the relationship between them and radiation-induced lung injury.Methods In situ hybridization and real-time fluorescence quantitative method were used to detect the expression of miR-564.Additionally,immunohistochemistry and enzyme-linked immunosorbent assay(ELISA)were performed to detect the expression of TGF-β1.Results The overall incidence of acute radiation pneumonia was 55.9%(100/179).The incidence of≥grade 2 radioactive pneumonia was 24.0%(43/179)and that of grade 1 was 31.8%(57/179).The expression of miR-564 in grade≥2 was slightly higher than that in patients without or with grade 1,but there was no statistical difference(P=0.86).The serum level and ratio of miR-564 in patients with grade≥2 were significantly higher than those without or with grade 1(P=0.005,P=0.025,respectively).The expression of TGF-β1 in grade≥2 was significantly higher than that of patients without or with grade 1(P=0.017).The serum levels of TGF-β1 in grade≥2 were significantly higher than those in patients without or with grade 1(P=0.038).Although the ratio of TGF-β1 in radiation pneumonia of grade≥2 was significantly higher than that of without or with grade 1,there was no significant difference(P=0.24).Moreover,patients with higher expression of miR-564 and lower expression of TGF-β1 had better prognosis.Conclusion MiR-564 and TGF-β1 are predictors of radiation-induced lung injury.Monitoring its changing trend can improve the accuracy of predicting radiation-induced lung injury.The levels and ratio of serum miR-564 and TGF-β1 in patients with radiation-induced lung injury are related to the severity of radiationinduced lung injury.

Differential Proteomics Reveals the Potential Injury Mechanism Induced by Heavy Ion Radiation in Mice Ovaries

In the present study, we used a proteomics approach based on a two-dimensional electrophoresis （2-DE） reference map to investigate protein expression in the ovarian tissues of pubertal Swiss-Webster mice subjected to carbon ion radiation （CIR）. Among the identified proteins, ubiquitin carboxy-terminal hydrolase L1 （UCH-L1） is associated with the cell cycle[1] and that it influences proliferation in ovarian tissues. We analyzed the expression of UCH-L1 and the proliferation marker proliferation cell nuclear antigen （PCNA） following CIR using immunoblotting and immunofluorescence. The proteomics and biochemical results provide insight into the underlying mechanisms of CIR toxicity in ovarian tissues.

Radiation-induced brain injury after a conventional dose of intensity-modulated radiotherapy for nasopharyngeal carcinoma:a case report and literature review

A 61-year-old female nasopharyngeal carcinoma patient was admitted to the hospital with sudden cognitive dysfunction one month after Volumetric Intensity Modulated Arc Therapy(VMAT)conventional dose radiotherapy,and the initial diagnosis was radiation-induced brain injury(RBI).After comprehensive treatment with steroid hormones,the patient’s condition rapidly improved.Typically,in nasopharyngeal carcinoma patients treated with VMAT,the incidence of RBI is extremely low when the temporal lobe dose is less than 65 Gy or 1%of the volume is less than 65 Gy.When this limit is exceeded,RBI may occur in varying degrees.However,in this case,even though the temporal lobe dose was under the prescribed limit,the patient still experienced RBI.The rare observations in this case can be used as a reference,and clinicians should seriously consider the possibility of RBI in similar cases.

Neuron-specific enolase expression in a rat model of radiation-induced brain injury following vascular endothelial growth factor-modified neural stem cell transplantation

BACKGROUND： Previous studies have shown that transplantation of vascular endothelial growth factor （VEGF）-modified neural stem cells （NSC） provides better outcomes, compared with neural stem cells, in the treatment of brain damage. OBJECTIVE： To compare the effects of VEGF-modified NSC transplantation and NSC transplantation on radiation-induced brain injury, and to determine neuron-specific enolase （NSE） expression in the brain. DESIGN, TIME, AND SETTING： The randomized, controlled study was performed at the Linbaixin Experimental Center, Second Affiliated Hospital, Sun Yat-sen University, China from November 2007 to October 2008. MATERIALS： VEGF-modified C17.2 NSCs were supplied by Harvard Medical School, USA. Streptavidin-biotin-peroxidase-complex kit （Boster, China） and 5, 6-carboxyfluorescein diacetate succinimidyl ester （Fluka, USA） were used in this study. METHODS： A total of 84 Sprague Dawley rats were randomly assigned to a blank control group （n = 20）, model group （n = 20）, NSC group （n = 20）, and a VEGF-modified NSC group （n = 24）. Rat models of radiation-induced brain injury were established in the model, NSC, and VEGF-modified NSC groups. At 1 week following model induction, 10 pL （5 ×10^4 cells/μL） VEGF-modified NSCs or NSCs were respectively infused into the striatum and cerebral cortex of rats from the VEGF-modified NSC and NSC groups. A total of 10μL saline was injected into rats from the blank control and model groups. MAIN OUTCOME MEASURES： NSE expression in the brain was detected by immunohistochemistry following VEGF-modified NSC transplantation. RESULTS： NSE expression was significantly decreased in the brains of radiation-induced brain injury rats （P 〈 0.05）. The number of NSE-positive neurons significantly increased in the NSC and VEGF-modified NSC groups, compared with the model group （P 〈 0.05）. NSE expression significantly increased in the VEGF-modified NSC group, compared with the NSC group, at 6 weeks following transplantation （P 〈 0.05）. CONCLUSION： VEGF-modified NSC transplantation increased NSE expression in rats with radiation-induced brain injury, and the outcomes were superior to NSC transplantation.

Prevention and treatment of radiation-induced lung injury by hydroxypiperquin phosphate: a clinical and experimental study

Objective: To evaluate the hydroxypiperquin phosphate (HPQP) as a modifier of radiation-induced injury in human and rat lungs. Methods: Sixty-five patients with lung cancer treated with conventional radiotherapy were divided into 2 groups randomly: Thirty cases were treated with HPQP and the others were in a control group. The changes of X - ray manifestation before, after and during taking drug were compared. An animal model of radiation-induced fibrosis of lungs was also established. Hydroxyproling (HP) content in lung tissue and the pathological changes in rat lungs were checked with microscope and electron microscope after 4 months and 6 months respectively. Results: The changes of lung X-ray manifestation in treatment group were much lighter than that in control group. The HP content and the change of pathology in the lungs of those rats with HPQP treatment were obviously less than that in control group. Conclusion: HPQP plays an important role in prevention and treatment of radiation-induced injury in lungs.

Time-dependent Changes in CT of Radiation-induced Liver Injury:A Preliminary Study in Gastric Cancer Patients

In this study, the time-dependent changes on dynamic computed tomograph (CT) of radiation-induced liver injury in gastric cancer patients was examined.The CT images of 52 gastric cancer patients who had received chemoradiotherapies were reviewed on the PACS system.Dynamic CT scan was performed in all the subjects.Our results showed that 18 patients were found to have radiation-induced liver injury.The CT findings of radiation-induced liver injury in gastric cancer patients tend to show up one month after radiation treatment.The damaged area was of low density on all three phases, and then it was enhanced on portal vein phase or delay phase.The focal radiation reaction of liver without basic disease vanished 9-11 months later after treatment.We are led to conclude that dynamic CT is of help in the diagnosis of CRT-induced liver injury, and it may be the method of choice for following up the whole course of the CRT-induced liver injury, i.e., form hepatic damage to healing.The classification of CT findings we recommend can avoid the influence of technological factors, and thereby serve as a better guide for treatment of CRT-induced liver injury.

Radiation dermatitis wet healing:a concept analysis

Objective:To explore the concept of radiation dermatitis wet healing through a literature review and provide references for future treatment of patients with radiation skin injury.Methods:Related ar ticles selected from China National Knowledge Infrastructure(CNKI),Wanfang Database,Pub Med,Web of Science,Medline,and EBSCO were analyzed with Rodger’s concept analysis.Results:We identified the application status of wet healing in domestic and foreign literature,defined explicit attributes of the procedure,and clarified concepts related to wet healing of radiation skin injury to provide a reference for the management of radiation dermatitis with wet healing.Conclusions:Treatment of radiation dermatitis with wet healing is a unique procedure.Analyzing this concept can contribute to its development in the future and can offer a theoretical basis for treatment of patients with radiation skin injury.

Prevention and treatment for radiation-induced skin injury during radiotherapy

The skin tissue has the largest area in the human body and functions as both a barrier and a defender.As such,it tends to be the first tissue to be damaged.Advances in medical technology provide prospects as well as side effects,for example,radiation therapy for cancer.With increasing cancer morbidity and radiation widely applied for cancer therapy,radiation-induced skin injury(RSI)has become a serious concern.In recent decades,research efforts have focused on the mechanisms underlying RSI.This review summarizes the mainstream opinions on these mechanisms,including the pathological,molecular biological,and cytobiological alterations.Radiationinduced reactive oxygen species(ROS),cytokines and involved signaling pathways are evaluated.Other relevant aspects include radiation-induced skin fibrosis(RSF)and radiation-related skin cell senescence.Moreover,we review strategies for the prevention and treatment in clinical and pre-clinical studies to support the treatment of RSI during radiotherapy.The prevention strategies include dose control,pre-irradiation instructions,and RSI assessments,while the main treatments include physical therapy,external-use dressings or creams,biological therapy and surgical reconstruction.

RXRα agonist bexarotene attenuates radiation-induced skin injury by relieving oxidative stress

Objective: To investigate the protective effect of bexarotene in radiation-induced skin injury and elucidate underlying mechanism.Methods: Irradiated cellular and animal models were established using an X-ray linear accelerator. Cell viabilityand apoptosis were evaluated by CCK8 and flow cytometry. In vivo protective effect of bexarotene was measuredin irradiated SD rats. The antioxidant capacity of bexarotene was validated by DCF-DA method. The signalingpathways involved in bexarotene-mediated skin repair were enriched by RNA sequencing.Results: Bexarotene could significantly restore the proliferation and inhibit the apoptosis of WS1 cells with radiation damage (P < 0.05). Moreover, bexarotene could effectively shorten the process of skin damage andpromote skin repair in a rat model of radiation-induced skin injury (P < 0.05). Mechanistically, bexaroteneeffectively reduced the expression of RXRα (P < 0.05), thus leading to an early decrease in reactive oxygen species(ROS) after radiation exposure. Furthermore, a transcriptome analysis indicated that bexarotene-mediated recovery of radiation damage involves redox signaling, immune regulation, lipid metabolism and autophagy.Conclusion: Bexarotene is a promising therapeutic agent in the treatment of radiation-induced skin injury.

Potential for a pluripotent adult stem cell treatment for acute radiation sickness

Accidental radiation exposure and the threat of deliberate radiation exposure have been in the news and are a public health concern. Experience with acute radiation sickness has been gathered from atomic blast survivors of Hiroshima and Nagasaki and from civilian nuclear accidents as well as experience gained during the development of radiation therapy for cancer. This paper reviews the medical treatment reports relevant to acute radiation sickness among the survivors of atomic weapons at Hiroshima and Nagasaki, among the victims of Chernobyl, and the two cases described so far from the Fukushima Dai-Ichi disaster. The data supporting the use of hematopoietic stem cell transplantation and the new efforts to expand stem cell populations ex vivo for infusion to treat bone marrow failure are reviewed. Hematopoietic stem cells derived from bone marrow or blood have a broad ability to repair and replace radiation induced damaged blood and immune cell production and may promote blood vessel formation and tissue repair. Additionally, a constituent of bone marrow-derived, adult pluripotent stem cells, very small embryonic like stem cells, are highly resistant to ioniz-ing radiation and appear capable of regenerating radiation damaged tissue including skin, gut and lung.

Computer-assisted formulas predicting cancer mortality risk after exposure to acute low dose ionizing radiation in humans

A clear relationship between dose of radiation and mortality in humans is still not known because of lack of human data that would enable to determine human tolerance in total body irradiation. Human data for analysis have been primarily from radiation accidents, radiotherapy and the atomic bomb victims. A general formula that predicts mortality probability as a function of dose rate and duration of exposure to acute high dose ionizing radiation in humans was published by the author, applying the “probacent” model to the reported data on animal-model-predicted dose versus mortality. In this study, the “probacent” model is applied to the data on dose versus cancer mortality risk, published by the United Nations (UNSCEAR, 2010) and other investigators to construct general formulas expressing a relationship between dose and solid cancer or leukemia mortality probability after exposure to acute low dose ionizing radiation in humans. There is a remarkable agreement between formula-derived and published values of dose and solid cancer or leukemia mortality probability (p > 0.99). The general formula might be helpful in preventing radiation hazard and injury in acute low dose ionizing radiation, and for safety in radiotherapy.

Effect of Depth-Dependent Nociceptor Density on the Heat-Induced Withdrawal Reflex

Previously we introduced a concise dose-response model for the heat-induced withdrawal reflex caused by millimeter wave radiation. The model predicts the occurrence of withdrawal reflex from the given spatial temperature profile. It was formulated on the assumption that the density of nociceptors in skin is uniform, independent of the depth. The model has only two parameters: the activation temperature of heat-sensitive nociceptors and the critical threshold on the activated volume for triggering withdrawal reflex. In this study, we consider the case of depth-dependent nociceptor density in skin. We use a general parametric form with a scaling parameter in the depth direction to represent the nociceptor density. We analyze system behaviors for four density types of this form. Based on the theoretical results, we develop a methodology for 1) identifying from test data the density form of nociceptors distribution, 2) finding from test data the scaling parameter in the density form, and 3) determining from test data the activation temperature of nociceptors.

放射性脑损伤的治疗进展

放射治疗在控制头颈部肿瘤提高患者生存率的同时,对周围正常脑组织也造成不同程度的损伤,引起放射性脑坏死和认知功能下降,其发生率最高可达90%,严重影响患者的生活质量。研究人员近年来在多个层面上对放射性脑损伤的潜在病因进行了探索,通过筛查和鉴定不同干预靶点,为预防和治疗放射性损伤提供了新的策略。本文对放射性脑损伤的发生发展机制进行了综述,并回顾了现有的药物及非药物干预手段,提出了目前该领域面临的挑战及未来的研究方向。

不同时相服用清燥救肺汤加减方对防治放射性肺损伤的影响

目的探讨不同时相服用清燥救肺汤加减方对防治放射性肺损伤(RILI)的影响。方法将111例放射性肺损伤患者按就诊顺序随机分为治疗1组、治疗2组、治疗3组,各37例,3组均进行常规药物治疗,并给予清燥救肺汤加减方,治疗1组给药时间为放疗前1 h,治疗2组给药时间为放疗结束后1 h,治疗3组给药时间为放疗开始与结束后1 h内,比较3组中医证候评分、卡氏功能评分(KPS)、放射性肺损伤程度、肺功能、相关生化指标水平。结果3组放疗后中医证候评分均高于放疗前(P<0.05),且与治疗2组、治疗3组比较,治疗1组升高幅度较小(P<0.05);3组KPS评分均低于放疗前,且与对治疗2组、治疗3组比较,治疗1组升降低幅度较小(P<0.05);3组放射性肺损伤程度比较,治疗1组与治疗3组的总发生率较低,与治疗2组比较,差异有统计学意义(P<0.05);3组放疗后用力肺活量(FVC)、第1秒用力呼吸容积(FEVl)、第1秒用力呼吸容积/用力肺活量(FEVl/VC)、肿瘤坏死因子-α(TNF-α)、C反应蛋白(CRP)、转化生长因子-β1(TGF-β1)水平均低于放疗前,且与对治疗2组、治疗3组比较,治疗1组降低幅度较小(P<0.05)。结论运用清燥救肺汤加减方防治放射性肺损伤疗效显著,但需在放疗前1 h给药。

专利中药处方治疗放射性肺损伤的用药规律及作用机制研究

目的:搜集国家专利中治疗放射性肺损伤的中药处方,探索其用药规律及作用机制。方法:检索国家知识产权局中国专利公布网站中治疗放射性肺损伤的中药处方,利用古今医案云平台进行统计分析、关联分析、聚类分析及网络构建分析等;通过网络药理学方法探讨治疗放射性肺损伤核心处方的作用靶点及相关通路。结果:纳入从专利数据库建立至2022年8月治疗放射性肺损伤的中药处方专利17项,共包含153味中药,药物出现频次较高的有甘草、生地黄;常用的药对为玄参-生地黄、苦杏仁-甘草、鱼腥草-甘草、生地黄-玄参;核心处方组成包括甘草、生地黄、苦杏仁、玄参和鱼腥草;核心处方治疗放射性肺损伤的主要靶点可能为JUN、IL-6、PTGS2、FOS、IL-8、IL-10等,相关的作用通路有脂质与动脉粥样硬化、化学致癌-受体激活、化学致癌-活性氧物种、PI3K-Akt信号通路、MAPK信号通路等。结论:专利中药处方主要可能通过抑制炎症反应从而发挥减轻放射性引起的肺损伤作用。

鼻咽癌放射治疗患者放射性脑损伤的危险因素分析及风险预测模型构建

目的探讨影响鼻咽癌放射治疗患者发生放射性脑损伤的危险因素,并构建风险预测模型。方法回顾性选取郑州大学第五附属医院2021年1月至2022年1月放射治疗后发生放射性脑损伤的40例鼻咽癌患者作为发生组,另选取同期接受放射治疗后未发生放射性脑损伤的61例鼻咽癌患者作为未发生组。收集两组患者的一般资料及临床指标,采用logistic回归性分析检验影响鼻咽癌放射治疗患者并发放射性脑损伤的危险因素,同时依据回归分析结果构建风险预测模型,绘制受试者工作特征(ROC)曲线检验风险预测模型对鼻咽癌放射治疗患者放射性脑损伤发生的预测价值。结果两组患者双侧颞叶最高照射剂量、血清胶质纤维酸性蛋白(GFAP)、血清环氧化酶-2(COX-2)及血浆纤维蛋白原(Fib)差异有统计学意义(P<0.05)。logistic回归性分析显示,高水平双侧颞叶最高照射剂量、血清GFAP、血清COX-2及血浆Fib是影响鼻咽癌放射治疗患者放射性脑损伤发生的危险因素(P<0.05)。构建风险预测模型,ROC内部验证显示曲线下面积(AUC)为0.911,AUC的95%CI为0.851~0.972,特异度0.967,敏感度0.775,约登指数0.742,(P<0.001)。结论双侧颞叶最高照射剂量、血清GFAP、血清COX-2及血浆Fib是影响鼻咽癌放射治疗患者放射性脑损伤发生的危险因素。

An Appreciation for the Rabbit Ladderlike Modeling of Radiation-induced Lung Injury with High-energy X-Ray

Background：To evaluate the utility of rabbit ladderlike model of radiation-induced lung injury （RILI） for the future investigation of computed tomography perfusion.Methods：A total of 72 New Zealand rabbits were randomly divided into two groups：36 rabbits in the test group were administered 25 Gy of single fractionated radiation to the whole lung of unilateral lung;36 rabbits in the control group were sham-radiated.All rabbits were subsequently sacrificed at 1,6,12,24,48,72 h,and 1,2,4,8,1 6,24 weeks after radiation,and then six specimens were extracted from the upper,middle and lower fields of the bilateral lungs.The pathological changes in these specimens were observed with light and electron microscopy;the expression of tumor necrosis factor-α （TNF-a） and transforming growth factor-βl （TGF-β1） in local lung tissue was detected by immunohistochemistry.Results：（1） Radiation-induced lung injury occurred in all rabbits in the test group.（2） Expression of TNF-a and TGF-β1 at 1 h and 48 h after radiation,demonstrated a statistically significant difference between the test and control groups （each P 〈 0.05）.（3） Evaluation by light microscopy demonstrated statistically significant differences between the two groups in the following parameters （each P 〈 0.05）：thickness of alveolar wall,density of pulmonary interstitium area （1 h after radiation）,number offibroblasts and fibrocytes in interstitium （24 h after radiation）.The test group metrics also correlated well with the time ofpostradiation.（4） Evaluation by electron microscopy demonstrated statistically significant differences in the relative amounts of collagen fibers at various time points postradiation in the test group （P 〈 0.005）,with no significant differences in the control group （P 〉 0.05）.At greater than 48 h postradiation the relative amount of collagen fibers in the test groups significantly differ from the control groups （each P 〈 0.05）,correlating well with the time postradiation （r =0.99318）.Conclusions：A consistent and reliable rabbit model of RILI can be generated in gradient using 25 Gy of high-energy X-ray,which can simulate the development and evolution of RILI.

基于免疫-炎症轴的化斑汤合参苓白术散预防放疗放射性肺损伤的临床效果

目的探讨化斑汤合参苓白术散对癌症放疗放射性肺损伤(RILI)的预防效果及对免疫-炎症轴的影响。方法将2021年1月—2023年1月收治的120例癌症放疗患者均分研究组和对照组。2组均持续放疗6周,放疗期间研究组予化斑汤合参苓白术散治疗,对照组予中药安慰剂治疗。比较2组放疗效果、RILI发生率,以及放疗前后血清炎性因子[白细胞介素-6(IL-6)、转化生长因子-β(TGF-β)、肿瘤坏死因子-α(TNF-α)],免疫指标(CD3+、CD4+、CD4+/CD8+)水平,肺功能指标[肺总量(TLC)、用力肺活量(FVC)],血浆外泌体miR-17-5p、miR-7-5p水平。结果研究组放疗总有效率[91.67%(55/60)]高于对照组[78.33%(47/60)],RILI发生率低于对照组(P<0.05);研究组放疗3周、6周后血清TNF-α、TGF-β、IL-6及血浆外泌体miR-17-5p、miR-7-5p水平低于对照组,CD3+、CD4+、CD4+/CD8+及TLC、FVC水平高于对照组(P<0.05)。结论化斑汤合参苓白术散对癌症放疗RILI有良好的预防效果,并可减轻炎症反应,改善免疫功能、肺功能,降低RILI发生率,其作用机制可能与抑制miR-17-5p、miR-7-5p表达有关。