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DNA damage repair:historical perspectives,mechanistic pathways and clinical translation for targeted cancer therapy

Signal Transduction and Targeted Therapy 2021年第8期6卷 2391-2425页

作者： Ruixue Huang Ping-Kun Zhou department of Occupational and Environmental Health Xiangya School of Public HealthCentral South UniversityChangshaHunanChina department of Radiation Biology Beijing Key Laboratory for RadiobiologyBeijing Institute of Radiation MedicineAMMSBeijingChina

Genomic instability is the hallmark of various cancers with the increasing accumulation of DNA *** application of radiotherapy and chemotherapy in cancer treatment is typically based on this property of ***,the adverse effects including normal tissues injury are also accompanied by the radiotherapy and *** cancer therapy has the potential to suppress cancer cells'DNA damage response through tailoring therapy to cancer patients lacking specific DNA damage response ***,understanding the broader role of DNA damage repair in cancers has became a basic and attractive strategy for targeted cancer therapy,in particular,raising novel hypothesis or theory in this field on the basis of previous scientists'findings would be important for future promising druggable emerging *** this review,we first illustrate the timeline steps for the understanding the roles of DNA damage repair in the promotion of cancer and cancer therapy developed,then we summarize the mechanisms regarding DNA damage repair associated with targeted cancer therapy,highlighting the specific proteins behind targeting DNA damage repair that initiate functioning abnormally duo to extrinsic harm by environmental DNA damage factors,also,the DNA damage baseline drift leads to the harmful intrinsic targeted cancer *** addition,clinical therapeutic drugs for DNA damage and repair including therapeutic effects,as well as the strategy and scheme of relative clinical trials were intensive *** on this background,we suggest two hypotheses,namely"environmental gear selection”to describe DNA damage repair pathway evolution,and"DNA damage baseline drift”,which may play a magnified role in mediating repair during cancer *** two new hypothesis would shed new light on targeted cancer therapy,provide a much better or more comprehensive holistic view and also promote the development of new research direction and new overcoming strategies for

关键词： damage clinical targeted

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Developmental Toxicity in Mice Following Paternal Exposure to Di-N-Butyl-Phthalate (DBP)

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Biomedical and Environmental Sciences 2011年第5期24卷 569-578页

作者： Malgorzata M.DOBRZY SKA Ewa J.TYRKIEL Krzysztof A.PACHOCKI department of Radiation Protection and radiobiology National Institute of Public Health-National Institute of Hygiene00-791 WarsawPoland department of Environmental Toxicology National Institute of Public Health-National Institute of Hygiene00-791 WarsawPoland

Objective The aim of the present study was to investigate the effects of paternal Di‐N‐butyl‐phthalate （DBP） exposure pre‐ and postnatally on F1 generation offspring,and prenatally on F2 generation *** Male mice were exposed to either 500 mg/kg or 2 000 mg/kg of DBP for 8 weeks,and mated with non‐exposed ***‐quarters of the females were sacrificed a day prior to parturition,and examined for the number of living and dead implantations,and incidence of gross *** from the remaining females were assessed for developmental markers,growth parameters,as well as sperm quantity and *** There were no changes in the fertility of parents and in intrauterine development of the *** of DBP‐exposed males demonstrated growth‐*** paternal exposure to 500 mg/kg bw of DBP,there were almost twice the number of males than females born in the F1 generation.F1 generation females had a 2.5‐day delay in vaginal *** exposure to 2 000 mg/kg bw of DBP increased the incidence of sperm head malformations in F1 generation males;however,there were no changes in the fertility and viability of foetuses in the F2 *** Paternal DBP exposure may disturb the sex ratio of the offspring,delay female sexual maturation,and deteriorate the sperm quality of F1 generation males.

关键词： Di‐n‐butyl phthalate Paternal exposure Pre‐ and postnatal effects Male‐mediated developmental toxicity

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A phenomenological model for the dynamics of cell cycle in responding to X-rays

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中华放射医学与防护杂志 2015年第1期35卷 15-22页

作者： Zhang Sheng Ao Bin Ye Caiyong Yang Lei Zhou Guangming ZhangSheng AoBin YeCaiyong YangLei ZhouGuangming 730000 Lanzhou Department of Space RadiobiologyKey Laboratory of Heavy Ion Radiation Biology and Medicine Institute ofModern Physics Chinese Academy of Sciences China

ObjectiveTo establish a model to predict the cell-cycle process in response to ionizing radiation.MethodsHuman choroidal malignant melanoma 92-1 cells were used and the cell cycle distribution of cells was analyzed in 0-96 h after exposure to X-rays. A phenomenological model was constructed based on biological knowledge to describe the cell cycle dynamics in experiments.ResultsIn the present study, a phenomenological model was constructed to describe the cellcycle dynamics of synchronized 92-1 cells in responding to various doses of ionizing radiation. The simulation results obtained with the model were consistent with the experimental data, demonstrating that the model had a good expansibility and could be used to predict the dynamics of cell cycle in responding to ionizing radiation. Further theoretical modeling of the cellcycle dynamics was made and the results were consistent with the simulation.ConclusionsA phenomenological model was constructed which could be used to describe the dynamics of cell cycle of cells exposed to ionizing radiation and was supported by the experimental data. Because this model is easy to run by the written code, it has a good expansibility for studying the behaviors of cell populations under various conditions.

关键词：临床医学诊断放射医学

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Non-alcoholic fatty liver disease:a multidisciplinary clinical practice approach—the institutional adaptation to existing Clinical Practice Guidelines

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Emergency and Critical Care Medicine 2022年第1期2卷 12-22页

作者： Zoran Gluvic Ratko Tomasevic Ksenija Bojovic Milan Obradovic Esma R.Isenovic University Clinical-Hospital Centre Zemun-Belgrade Clinic of Internal MedicineSchool of MedicineUniversity of BelgradeBelgradeSerbia Clinical Centre of Serbia Clinic of Infectious and Tropical DiseasesSchool of MedicineUniversity of BelgradeBelgradeSerbia department of radiobiology and Molecular Genetics “VINČA”Institute of Nuclear Sciences-National Institute of thеRepublic of SerbiaUniversity of BelgradeBelgradeSerbia

Non-alcoholic fatty liver disease(NAFLD)is among the most frequently encountered chronic liver diseases in everyday clinical *** is considered the hepatic manifestation of metabolic ***,liver biopsy is still the gold standard for NAFLD confirmation and assessing NAFLD’s possible progression to non-alcoholic steatohepatitis,fibrosis,cirrhosis,and hepatocellular *** of the high prevalence of NAFLD and potential associated risks of invasive diagnostic procedures,it is of great interest to recruit the patients for liver ***,as the presence of liver fibrosis determines the further clinical course,liver biopsy is expectedly reserved for those with increased fibrosis *** quality of liver biopsy recruitment and patient monitoring could be significantly improved by using non-invasive tools to assess liver fibrosis presence and interactive collaboration between general practitioners,gastroenterologists,and *** a result,the quality of liver biopsy recruitment and patients monitoring could be significantly ***,we proposed clinical practice guidelines that could be implemented for everyday clinical practice in NAFLD patients.

关键词： Diagnostics of NAFLD Fatty liver index Fibrosis score-4 Management of NAFLD Non-alcoholic fatty liver disease

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Identification of differential gene expression profiles of radioresistant lung cancer cell line established by fractionated ionizing radiation in vitro

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Chinese Medical Journal 2008年第18期121卷 1830-1837页

作者： XU Qing-yong GAO Yuan LIU Yan YANG Wei-zhi XU Xiang-ying department of Radiation Oncology Cancer Hospital Harbin Medical University Harbin Heilongjiang 150081 China department of Biochemistry Harbin Medical University Harbin Heilongjiang 150086 China department of radiobiology Cancer Institute (Hospital) Chinese Academy of Medical Sciences Peking Union Medical College Beijing 100021 China

Background Radiotherapy plays a critical role in the management of non-small cell lung cancer （NSCLC）. This study was conducted to identify gene expression profiles of acquired radioresistant NSCLC cell line established by fractionated ionizing radiation （FIR） by cDNA microarray. Methods The human lung adenocarcinoma cell line Anip973 was treated with high energy X-ray to receive 60 Gy in 4 Gy fractions. The radiosensitivity of Anip973R and its parental line were measured by clonogenic assay. Gene expression profiles of Anip973R and its parental line were analyzed using cDNA microarray consisting of 21 522 human genes. Identified partly different expressive genes were validated by quantitative reverse transcription-polymerase chain reaction （Q-RT-PCR）. Results Fifty-nine upregulated and 43 downregulated genes were identified to radio-resistant Anip973R. Up-regulated genes were associated with DNA damage repair （DDB2）, extracellular matrix （LOX）, cell adhesion （CDH2）, and apoptosis （CRYAB）. Down-regulated genes were associated with angiogenesis （GBP-1）, immune response （CD83）, and calcium signaling pathway （TNNC1）. Subsequent validation of selected eleven genes （CD24, DDB2, IGFBP3, LOX, CDH2, CRYAB, PROCR, ANXA1 DCN, GBP-1 and CD83） by Q-RT-PCR was consistent with microarray analysis. Conclusions Fractionated ionizing radiation can lead to the development of radiation resistance. Altered gene profiles of radioresistant cell line may provide new insights into mechanisms underlying clinical radioresistance for NSCLC.

关键词： radioresistance cDNA microarray non-small cell lung cancer fractionated ionizing radiation

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PET/CT and Hypo-Fractionated Radiotherapy of Patients with Head and Neck Cancer

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International Journal of Clinical Medicine 2018年第10期9卷 751-759页

作者： Misleidy Nápoles Morales Aldo Martínez Ramirez Juan P. Oliva Glez Claudia González Espinosa Joaquín González González Carlos Fabián Calderón Marín Waldo Quesada Cepero Fanny López Reina Rubén Elzaurdín Mora department of Radiotherapy Institute of Oncology and Radiobiology Havana Cuba Nuclear Medicine department and Molecular Imaging Institute of Oncology and Radiobiology Havana Cuba Radiotherapy department Medical Researchers Center Havana Cuba

Positron emission tomography/Computer tomography (PET/CT) is a multimodality imaging diagnostic technique that analyzes the uptake and retention of different radiopharmaceuticals by cells providing metabolic information on biochemical processes. PET/CT has been used for radiotherapy planning, providing useful information to the Radio-oncologist about the localization, size and metabolic activity of tumor lesions. In this paper, we show advantages of the 18F-FDG PET/CT respect to simple CT imaging for target volume delineation in patients with diagnosis of Squamous Head and Neck Carcinoma that has been scheduled to undergo a hypofractionated radiotherapy treatment. On ten studied patients, the target volume defined from PET/CT images was less extensive than those defined from simple CT images. In six patients the target volume was significantly less extensive and in two of them a new lymph node disease was reported, re-staging and corresponding target volume was also delineated with less extensive margins from PET/CT images. A greater accuracy in delineating the volumes and improving the distribution of doses in the planning of the radiant treatment in these patients was possible, allowing a high precision in the delivery of the prescribed dose to the target volume diminishing the maximum dose to the adjacent healthy tissues. In conclusion we show that the use of 18F-FDG PET/CT was superior than the simple CT as the primary modality of imaging for hypofractioned radiotherapy treatment planning in patients with Squamous Head and Neck Carcinoma.

关键词： PET-CT Hypofractionated Radiotherapy Head and Neck Cancer

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LncRNA HOTAIR promotes DNA damage repair and radioresistance by targeting ATR in colorectal cancer

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Oncology Research 2024年第8期32卷 1335-1346页

作者： HAIQING HU HAO YANG SHUAISHUAI FAN XUE JIA YING ZHAO HONGRUI LI department of Endoscopic Center Peking University Cancer Hospital(Inner Mongolia Campus)&Affiliated Cancer Hospital of Inner Mongolia Medical UniversityHuhhot010020China department of Radiation Oncology Peking University Cancer Hospital(Inner Mongolia Campus)&Affiliated Cancer Hospital of Inner Mongolia Medical UniversityKey Laboratory of Radiation Physics and Biology of Inner Mongolia Medical UniversityPeking University Cancer Hospital(Inner Mongolia Campus)&Affiliated Cancer Hospital of Inner Mongolia Medical UniversityHuhhot010020China Graduate School Inner Mongolia Medical UniversityHuhhot010020China

Long non-coding RNAs(lncRNAs)have been implicated in cancer progression and drug resistance ***,there is evidence that lncRNA HOX transcript antisense intergenic RNA(HOTAIR)is involved in colorectal cancer(CRC)*** present study aimed to examine the functional role of lncRNA HOTAIR in conferring radiotherapy resistance in CRC cells,as well as the underlying *** relative expression levels of HOTAIR were examined in 70 pairs of CRC tumor and para-cancerous tissues,as well as in radiosensitive and radioresistant *** correlations between HOTAIR expression levels and clinical features of patients with CRC were assessed using the Chi-square *** assays such as cell proliferation,colony formation and apoptosis assays were conducted to determine the radiosensitivity in CRC cells with HOTAIR silencing after treatment with different doses of *** pull-down assay andﬂuorescence in situ hybridization(FISH)were used to determine the interaction between HOTAIR and DNA damage response mediator ataxia-telangiectasia mutated-and Rad3-related(ATR).HOTAIR was signiﬁcantly upregulated in CRC tumor tissues,especially in radioresistant tumor *** elevated expression of HOTAIR was correlated with more advanced histological grades,distance metastasis and the poor prognosis in patients with *** HOTAIR suppressed the proliferation and promoted apoptosis and radiosensitivity in CRC *** knockdown also inhibited the tumorigenesis of CRC cells and enhanced the sensitivity to radiotherapy in a mouse xenograft ***,the data showed that HOTAIR could interact with ATR to regulate the DNA damage repair signaling *** HOTAIR impaired the ATR-ATR interacting protein(ATRIP)complex and signaling in cell cycle ***,the present results indicate that lncRNA HOTAIR facilitates the DNA damage response pathway and promotes radioresistance in CRC cells by targeting ATR.

关键词： LncRNA HOTAIR CRC radioresistance DNA damage repair ATR

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Increased Levels of p53 and PARP-1 in EL-4 Cells Probably Related with the Immune Adaptive Response Induced by Low Dose Ionizing Radiation in vitro

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Biomedical and Environmental Sciences 2010年第6期23卷 487-495页

作者： GUANG-HUI CHENG NING WU DE-Fu JIANG HONG-GUANG ZHAO QIAN ZHANG JIAN-FENG WANG SHou-LIANG GONG department of Radiotherapy China-Japan Union Hospital Jilin University Changchun 130033 Jilin China Key Laboratory of radiobiology Ministry of Health (School of Public Health Jilin University) Changchun 130021 Jilin China department of Nuclear Medicine the First Hospital Jilin University Changchun 130021 Jilin China

Objective This paper is to explore the DNA repair mechanism of immune adaptive response （AR） induced by low dose radiation （LDR）, the changes of mRNA levels and protein expressions of p53, ATM, DNA-PK catalytic subunit （DNA-PKcs） and PARP-1 genes in the LDR-induced AR in EL-4 cells. Methods The apoptosis and cell cycle progression of EL-4 cells were detected by flow cytometry in 12 h after the cells received the pre-exposure of 0.075 Gy X-rays （inductive dose, D 1） and the succeeding high dose irradiation （challenge dose, D2; 1.0, 1.5, and 2.0 Gy X-rays, respectively） with or without wortmannin （inhibitor of ATM and DNA-PK） and 3-aminobenzamid （inhibitor of PARP-1）. And the protein expressions and mRNA levels related to these genes were detected with flow cytometry and reverse transcription-polymerase chain reaction in 12 h after irradiation with D2. Results The mRNA and protein expressions of p53 and PARP-1 in EL-4 cells in the D1 ＋ D2 groups were much lower than those in the D2 groups, and those of PARP-1 in the 3-AB ＋ D2 and the 3-AB ＋ D1 ＋ D2 groups were much lower than those in the D2 and the D1 ＋ D2 groups. The percentage of apoptotic EL-4 cells in the 3-AB ＋ D1 ＋ D2 groups was much higher than that in the D1 ＋ D2 groups, that in the G0/G1 and the G2 ＋ M phases was much higher, and that in the S phase were much lower. Although the ATM and DNA-PKcs mRNA and protein expressions in wortmannin ＋ D1 ＋ D2 groups were much lower than those in the D1 ＋ D2 groups, there were no significant changes in the apoptosis and cell cycle progression between the wortmannin ＋ D1 ＋ D2 and the D1 ＋ D2 groups. Conclusion PARP-1 and p53 might play important roles in AR induced by LDR.

关键词： Low dose radiation (LDR) Adaptive response (AR) DNA repair

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Space Life Science of China in 2013

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空间科学学报 2014年第5期34卷 747-756页

作者： LEI Runhong ZHOU Guangming MA Hong ZHUANG Fengyuan DENG Yulin School of Life Science Beijing Institute of Technology department of Space radiobiology Key Laboratory of Heavy Ion Radiation Biology and MedicineInstitute of Modern Physics Chinese Academy of Sciences

In the past two years, space life science research in China is characterized by a wide area of basic researches for providing foundation for the future China Space Station. The effect of microgravity and radiation was further studied from physiology phenomena to the level of bio-molecule mechanisms. Chinese space life science is maturing in a new era of comprehensive ***, we review and summarize researches on space life sciences which were contributed by Chinese scientists.

关键词： Space life sciences Simulated microgravity Ionizing radiation

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Effects of 3-aminobenzamide on poly(ADP-ribose)polymerase expression,apoptosis and cell cycle progression of HeLa cells after X-ray irradiation

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Frontiers of Medicine 2008年第2期2卷 204-206页

作者： Xiang DU Hongguang ZHAO Wen WANG Wei GUO Shouliang GONG Key Laboratory of radiobiology of Ministry of Health School of Public HealthJilin UniversityChangchun 130021China department of Toxicology School of Public HealthJilin UniversityChangchun 130021China

The aim of this paper is to study the changes of apoptosis and cell cycle progression in HeLa cells after the poly(ADP-ribose)polymerase(PARP)was inhibited by its inhibitor 3-aminobenzamide(3-AB)and the mechan-isms of PARP action on HeLa cells damaged by *** cytometry(FCM)was used to examine the PARP expression and the percentage of apoptotic cells and cell cycle *** percentage of HeLa cells with positive expression of PARP protein 2,4,8 and 12 h after administrated with 3-AB was significantly lower than that of the control(P<0.01).The percentages of apoptotic cells in the 3-AB plus irradiation group at the time points of 2,8,12 and 24 h after 2 Gy irradiation were higher than that in the irradiation group(P<0.01 or P<0.05)and the percentage of G2 cells decreased signifi-cantly(P<0.01 or P<0.05).It indicates that 3-AB can rapidly inhibit PARP expression of HeLa cells,promote cell apoptosis and block G2 arrest induced by irradiation.

关键词： poly(ADP-ribose)polymerase ADP ribose transferases 3-aminobenzamide ionizing irradiation

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