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Targeting the organelle for radiosensitization in cancer radiotherapy

Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 52-71页

作者： Xiaoyan Sun Linjie Wu Lina Du Wenhong Xu Min Han Institute of Pharmaceutics College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China department of Pharmaceutical Sciences Beijing Institute of Radiation MedicineBeijing 100850China department of radiation oncology Key Laboratory of Cancer Prevention and InterventionThe Second Afliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310058China Hangzhou Institute of Innovative Medicine Zhejiang UniversityHangzhou 310058China Jinhua Institute of Zhejiang University Jinhua 321299China National Key Laboratory of Advanced Drug Delivery and Release Systems Zhejiang UniversityHangzhou 310058China

Radiotherapy is a well-established cytotoxic therapy for local solid cancers, utilizing high-energy ionizing radiation to destroy cancer cells. However, this method has several limitations, including low radiation energy deposition, severe damage to surrounding normal cells, and high tumor resistance to radiation. Among various radiotherapy methods, boron neutron capture therapy (BNCT) has emerged as a principal approach to improve the therapeutic ratio of malignancies and reduce lethality to surrounding normal tissue, but it remains deficient in terms of insufficient boron accumulation as well as short retention time, which limits the curative effect. Recently, a series of radiosensitizers that can selectively accumulate in specific organelles of cancer cells have been developed to precisely target radiotherapy, thereby reducing side effects of normal tissue damage, overcoming radioresistance, and improving radiosensitivity. In this review, we mainly focus on the field of nanomedicine-based cancer radiotherapy and discuss the organelle-targeted radiosensitizers, specifically including nucleus, mitochondria, endoplasmic reticulum and lysosomes. Furthermore, the organelle-targeted boron carriers used in BNCT are particularly presented. Through demonstrating recent developments in organelle-targeted radiosensitization, we hope to provide insight into the design of organelle-targeted radiosensitizers for clinical cancer treatment.

关键词： Cancer radiotherapy Organelle-target Radiosensitization Boron neutron capture therapy Nanomedicines

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molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

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World Journal of Gastroenterology 2024年第13期30卷 1815-1835页

作者： Samantha Sharma Naresh Singh Anita Ahmed Turk Isabella Wan Akshay Guttikonda Julia Lily Dong Xinna Zhang Mateusz Opyrchal department of Medical and molecular Genetics Indiana University School of MedicineIndianapolisIN 46202United States Division of Hematology/oncology Department of MedicineIndiana University School of MedicineIndianapolisIN 46202United States Melvin and Bren Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202United States

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

关键词： Colorectal cancer Immune checkpoint inhibitors Clinical trials Immunotherapy Microsatellite instability Microsatellite stability DNA mismatch repair

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Dual-Fields Rotational Total Skin Electron Therapy: Investigation and Implementation

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International Journal of Medical Physics, Clinical Engineering and radiation oncology 2024年第1期13卷 1-15页

作者： M. Ming Xu Iris Rusu Richard P. Garza Northwestern Medicine Cancer Center Warrenville and Geneva Illinois USA department of radiation oncology Loyola University Medical Center Maywood Illinois USA The Austin Center for radiation oncology Austin Texas USA

Purpose: To present a protocol of a dual-field rotational (DFR) total skin electron therapy (TSET) and to provide an assessment of clinical implementation, dosimetry properties, and skin dose evaluation. Methods and Materials: The DFR-TSET combined the Stanford 6-field and McGill rotational methods. Dual 6 MeV electron beams in high dose total skin electron mode were used for DFR-TSET on a commercial linac. Beam profiles and dosimetric properties were measured using solid phantoms. The dose rate at expanded source-to-surface distance (SSD) was a combination of static rate and rotational rate. In vivo dosimetry of patient skin was performed on patients’ skin using film, metal oxide semiconductor field-effect transistors (MOSFET), and optically stimulated luminescent dosimeters (OSLD). Results: Dual field rotational total skin electron therapy exhibited good (≤±10%) uniformity in the beam profiles in the vertical direction at an extended SSD of 332 cm with a gantry angulation of ±20˚ deviated from the horizontal direction. In-vivo measurements confirmed acceptable uniformity of the patients’ total body surfaces and revealed anatomically self-blocked or shielded areas where underdosing occurred. Conclusions: The clinical implementation of DFR-TSET effectively utilizes the special mode on a linac. This technique provides short beam-on times, uniform dose distribution, large treatment field, and reduced dose of x-ray contamination to the patients. In-vivo measurements indicate satisfactory delivery and dose uniformity of the prescribed dose. Electron boost fields are recommended at normal SSDs to address underdosed areas.

关键词： Total Skin Electron Therapy Stanford 6 Field McGill Rotation Therapy In-Vivo Dosimetry

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Targeting LTA4H facilitates the reshaping of the immune microenvironment mediated by CCL5 and sensitizes ovarian cancer to Cisplatin

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Science China(Life Sciences) 2024年第6期67卷 1226-1241页

作者： Zhengyang Guo Jiaqi Huang Xiao Huo Chen Huang Xiaotong Yu Yan Sun Yanfang Li Tianhui He Hongyan Guo Jianling Yang Lixiang Xue Cancer Center of Peking University Third Hospital Beijing 100191China Center of Basic Medical Research Institute of Medical Innovation and ResearchPeking University Third HospitalBeijing 100191China Peking University Third Hospital Cancer Center Department of Radiation OncologyPeking University Third HospitalBeijing 100191China department of Obstetrics and Gynecology Peking University Third HospitalBeijing 100191China

Ovarian cancer is the most lethal and aggressive gynecological cancer with a high recurrence rate and is often diagnosed late.In ovarian cancer,multiple metabolic enzymes of lipid metabolism are abnormally expressed,resulting in metabolism disorder.As a characteristic pathway in polyunsaturated fatty acid(PUFA)metabolism,arachidonic acid(AA)metabolism is disturbed in ovarian cancer.Therefore,we established a 10-gene signature model to evaluate the prognostic risk of PUFA-related genes.This 10-gene signature has strong robustness and can play a stable predictive role in datasets of various platforms(TCGA,ICGC,and GSE17260).The high association between the risk subgroups and clinical characteristics indicated a good performance of the model.Our data further indicated that the high expression of LTA4H was positively correlated with poor prognosis in ovarian cancer.Deficiency of LTA4H enhanced sensitivity to Cisplatin and modified the characteristics of immune cell infiltration in ovarian cancer.Additionally,our results indicate that CCL5 was involved in the aberrant metabolism of the AA/LTA4H axis,which contributes to the reduction of tumor-infiltrating CD8+T cells and immune escape in ovarian cancer.These findings provide new insights into the prognosis and potential target of LTA4H/CCL5 in treating ovarian cancer.

关键词： ovarian cancer polyunsaturated fatty acids prognostic risk model LTA4H tumor immunity CCL5

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The Chinese Society of Clinical oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023

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Cancer Communications 2024年第1期44卷 127-172页

作者： Feng-Hua Wang Xiao-Tian Zhang Lei Tang Qi Wu Mu-Yan Cai Yuan-Fang Li Xiu-Juan Qu Hong Qiu Yu-Jing Zhang Jie-Er Ying Jun Zhang Ling-Yu Sun Rong-Bo Lin Chang Wang Hao Liu Miao-Zhen Qiu Wen-Long Guan Sheng-Xiang Rao Jia-Fu Ji Yan Xin Wei-Qi Sheng Hui-Mian Xu Zhi-Wei Zhou Ai-Ping Zhou Jing Jin Xiang-Lin Yuan Feng Bi Tian-Shu Liu Han Liang Yan-Qiao Zhang Guo-Xin Li Jun Liang Bao-Rui Liu Lin Shen Jin Li Rui-Hua Xu department of Medical oncology Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP.R.China department of Gastrointestinal oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer HospitalBeijingP.R.China department of Radiology Peking University Cancer HospitalBeijingP.R.China department of Endoscopy Center Peking University Cancer HospitalBeijingP.R.China department of Pathology Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineGuangzhouGuangdongP.R.China department of Gastric Surgery Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP.R.China department of Medical oncology The First Hospital of China Medical UniversityShenyangLiaoningP.R.China department of Medical oncology Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and TechnologyWuhanHubeiP.R.China department of Radiotherapy Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP.R.China department of Medical oncology Zhejiang Cancer HospitalHangzhouZhejiangP.R.China department of Medical oncology Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R.China department of Surgical oncology The Fourth Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangP.R.China department of Medical oncology Fujian Cancer HospitalFuzhouFujianP.R.China Tumor Center The First Hospital of Jilin UniversityChangchunJilinP.R.China department of General Surgery Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP.R.China department of Radiology Zhongshan HospitalFudan UniversityShanghaiP.R.China department of

The 2023 update of the Chinese Society of Clinical oncology(CSCO)Clini-cal Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China,reflecting the latest advancements in evidence-based medicine,healthcare resource availability,and precision medicine.These updates address the differences in epidemiological characteristics,clinicopatho-logical features,tumor biology,treatment patterns,and drug selections between Eastern and Western gastric cancer patients.Key revisions include a structured template for imaging diagnosis reports,updated standards for molecular marker testing in pathological diagnosis,and an elevated recommendation for neoadju-vant chemotherapy in stage III gastric cancer.For advanced metastatic gastric cancer,the guidelines introduce new recommendations for immunotherapy,anti-angiogenic therapy and targeted drugs,along with updated management strategies for human epidermal growth factor receptor 2(HER2)-positive and deficient DNA mismatch repair(dMMR)/microsatellite instability-high(MSI-H)patients.Additionally,the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer.The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice,particularly in the heterogeneous healthcare landscape of China,while maintaining a commitment to scientific rigor,impartiality,and timely revisions.

关键词： Chinese Society of Clinical oncology(CSCO) gastric cancer diagnosis surgery neoadjuvant adjuvant radiotherapy chemotherapy targeted therapy immunotherapy

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The activity and immune dynamics of PD-1 inhibition on high-risk pulmonary ground glass opacity lesions:insights from a single-arm,phase II trial

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2202-2214页

作者： Bo Cheng Caichen Li Jianfu Li Longlong Gong Peng Liang Ying Chen Shuting Zhan Shan Xiong Ran Zhong Hengrui Liang Yi Feng Runchen Wang Haixuan Wang Hongbo Zheng Jun Liu Chengzhi Zhou Wenlong Shao Yuan Qiu Jiancong Sun Zhanhong Xie Zhu Liang Chenglin Yang Xiuyu Cai Chunxia Su Wei Wang Jianxing He Wenhua Liang department of Thoracic Surgery and oncology the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory HealthState Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhouChina Medical department Genecast Biotechnology Co.LtdWuxiChina department of radiation oncology the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina department of Respiratory Medicine the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory HealthState Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhouChina department of Cardiothoracic Surgery Affiliated Hospital of Guangdong Medical UniversityZhanjiangChina department of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital&Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina department of VIP Inpatient Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaSun Yat-sen UniversityGuangzhouChina department of Medical oncology Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghaiChina

Immune checkpoint inhibitors targeting the programmed cell death-1(PD-1)protein significantly improve survival in patients with advanced non-small-cell lung cancer(NSCLC),but its impact on early-stage ground-glass opacity(GGO)lesions remains unclear.This is a single-arm,phase II trial(NCT04026841)using Simon’s optimal two-stage design,of which 4 doses of sintilimab(200 mg per 3 weeks)were administrated in 36 enrolled multiple primary lung cancer(MPLC)patients with persistent high-risk(Lung-RADS category 4 or had progressed within 6 months)GGOs.The primary endpoint was objective response rate(ORR).T/B/NK-cell subpopulations,TCR-seq,cytokines,exosomal RNA,and multiplexed immunohistochemistry(mIHC)were monitored and compared between responders and non-responders.Finally,two intent-to-treat(ITT)lesions(pure-GGO or GGO-predominant)showed responses(ORR:5.6%,2/36),and no patients had progressive disease(PD).No grade 3-5 TRAEs occurred.The total response rate considering two ITT lesions and three non-intent-to-treat(NITT)lesions(pure-solid or solid-predominant)was 13.9%(5/36).The proportion of CD8^(+)T cells,the ratio of CD8^(+)/CD4^(+),and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over time.Correspondingly,the mIHC analysis showed more CD8^(+)T cells infiltrated in responders.Besides,responders’cytokine concentrations of EGF and CTLA-4 increased during treatment.The exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among responders.Collectively,PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety concerns.Such effects were associated with specific T-cell re-distribution,EGF/CTLA-4 cytokine compensation,and regulation of metabolism pathways.

关键词： lesions metabolism doses

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Schistosoma infection,KRAS mutation status,and prognosis of colorectal cancer

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Chinese Medical Journal 2024年第2期137卷 235-237页

作者： Xinyi Li Hongli Liu Bo Huang Ming Yang Jun Fan Jiwei Zhang Mixia Weng Zhecheng Yan Li Liu Kailin Cai Xiu Nie Xiaona Chang department of Pathology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China Cancer Center Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China Hubei Key Laboratory of Precision radiation oncology WuhanHubei 430022China Institute of radiation oncology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China department of Epidemiology and Biostatistics The Ministry of Education Key Lab of Environment and HealthSchool of Public HealthHuazhong University of Science and TechnologyWuhanHubei 430022China department of Gastrointestinal Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China

To the Editor:Colorectal cancer(CRC)is a major cause of cancer-related death worldwide,and several pathogens with carcinogenic potential,such as Schistosoma,have been associated with an increased risk of CRC.As a frequently mutated gene in CRC patients,kirsten rat sarcoma viral oncogene homolog(KRAS)helps to determine the selection of CRC therapies.Therefore,we aimed to elucidate the association among Schistosoma infection,KRAS mutation status,and the prognosis of CRC in this study.

关键词： Schistosoma KRAS prognosis

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PLAU plays a functional role in driving lung squamous cell carcinoma metastasis

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Genes & Diseases 2024年第2期11卷 554-557页

作者： Pengbo Ning Fuyu Du Xiaocheng Gong Jingtong Yuan Caixia Ding Xilian Zhao Wei Li School of Life Science and Technology Xidian UniversityXi'anShaanxi 710071China Engineering Research Center of molecular & Neuroimaging Ministry of EducationXi'anShaanxi 710071China department of Medical oncology Zhongshan HospitalFudan UniversityShanghai 200032China department of Pathology Shaanxi Provincial Tumor HospitalXi'an Jiaotong UniversityXi'anShaanxi 710061China

The high mortality of patients with lung squamous cell carcinoma(LUSC)results from metastasis rather than primary tumors,1 whereas the molecular pathogenesis of cancer metastasis remains poorly understood.PLAU encodes urokinase-type plasminogen activator(uPA)which is closely related to tumor diagnosis,treatment target,and prognosis of patients.2.3 We previously predicted that PLAU is a key gene negatively associated with overall survival by integrated multidimensional analyses of The Cancer Genome Atlas(TCGA)datasets from 504 samples of LUSC tumor tissues and 46 samples of adjacent non-tumorous lung tissues.4 However,whether the role of PLAU contributes to the metastasis of LUC remains unclear.Here,we analyzed the association between uPA levels and LUSC and found that uPA levels were associated with pathological variations in LUSC patients.

关键词： metastasis lung squamous

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Changes in acute and late toxicity and patient-reported health-related quality of life following radiotherapy in women with breast cancer:A 1-year longitudinal study

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Journal of Integrative Nursing 2024年第1期6卷 15-21页

作者： Gonca Hanedan USLU Aydanur AYDIN Ayla GÜRSOY department of radiation oncology Faculty of MedicineRecep Tayyip Erdogan UniversityRizeTurkey department of Nursing Antalya Bilim UniversityFaculty of Health SciencesGumushane UniversityGumushaneTurkey department of Nursing Faculty of Health SciencesAntalya Bilim UniversityAntalyaTurkey

Objective:The objective of this study was to investigate the frequency of acute and late toxicities,as well as changes in the quality of life(QOL)for breast cancer patients following radiotherapy(RT).Materials and Methods:A total of 108 breast cancer women were recruited for this prospective study.Data were collected at various intervals;prior to,and 1,3,6 months,and 1 year after radiation therapy.The primary outcomes were toxicity radiation therapy oncology group/European Organization for Research and Treatment of Cancer(EORTC)criteria.Our secondary outcome was QOL,measured using EORTC QLQ-C30 and Edmonton Symptom Assessment Scale.We employed Friedman’s two-way analysis to evaluate the changes in QOL over the course of 1 year.Results:The early toxicities that are most commonly experienced include pharyngeal,skin,and mucous membrane toxicity.Late toxicities frequently involve skin and submucosal toxicity.To measure patient functionality,all functional subscale scores except for the patient’s emotional state increased over time compared to pre-RT.Symptoms of the patients,which were included in the QOL symptom scale,decreased during the follow-up period,except for fatigue;however,changes in pain,insomnia,and loss of appetite did not significantly change.We identified the analogous symptom profiles in Edmonton.Although patients’overall health scores declined in the 1st and 3rd months after radiotherapy(RT),they rebounded at 6 and 12 months.Conclusion:For breast cancer patients,RT did not adversely affect functional capacity or exacerbate symptoms,but persistent fatigue did increase during the observation period.Health-care professionals ought to devise strategies to assist patients with skin toxicity and fatigue.

关键词： Breast cancer health‑related quality of life radiotherapy toxicity

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The generation and use of animal models of osteosarcoma in cancer research

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Genes & Diseases 2024年第2期11卷 664-674页

作者： Feifei Pu Haoyu Guo Deyao Shi Fengxia Chen Yizhong Peng Xin Huang Jianxiang Liu Zhicai Zhang Zengwu Shao department of Orthopedics Wuhan Hospital of Traditional Chinese and Western Medicine (Wuhan No.1 Hospital)Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China department of radiation and Medical oncology Zhongnan HospitalWuhan UniversityWuhanHubei 430071China Hubei Cancer Clinical Study Center Zhongnan HospitalWuhan UniversityWuhanHubei 430071China

Osteosarcoma is the most common malignant bone tumor affecting children and adolescents.Currently,the most common treatment is surgery combined with neoadjuvant chemotherapy.Although the survival rate of patients with osteosarcoma has improved in recent years,it remains poor when the tumor(s)progress and distant metastases develop.Therefore,better animal models that more accurately replicate the natural progression of the disease are needed to develop improved prognostic and diagnostic markers,as well as targeted therapies for both primary and metastatic osteosarcoma.The present review described animal models currently being used in research investigating osteosarcoma,and their characteristics,advantages,and disadvantages.These models may help elucidate the pathogenic mechanism(s)of osteosarcoma and provide evidence to support and develop clinical treatment strategies.

关键词： Animal model Cancer Osteosarcoma Pathogenic mechanism Translational research

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