1.Mechanical analysis of fiber post combined with different crown restorations for endodontically treated non-carious cervical lesions
Yilong CHEN ; Xu ZHANG ; Hong LI
Chinese Journal of Tissue Engineering Research 2025;29(4):866-871
BACKGROUND:The use of fiber post to repair the endodontically treated non-carious cervical lesions teeth can change the stress distribution of the tooth and significantly reduce the risk of fracture of the affected tooth.However,the mechanical mechanism of fiber posts improving tooth fracture resistance and the optimal crown restoration for endodontically treated non-carious cervical lesions teeth are still debated. OBJECTIVE:To review the stress distribution pattern after restoration of endodontically treated non-carious cervical lesions teeth with fiber posts,the fracture resistance and fracture pattern under various stress states,and the latest research progress on fiber posts combined with different crown restorations. METHODS:The computerized search was applied in PubMed and CNKI to retrieve articles published from September 2008 to September 2023 with Chinese and English search terms"non-carious cervical lesions,endodontically treated teeth restoration,endodontically treated teeth stress distribution."Finally,56 articles were included for analysis. RESULTS AND CONCLUSION:The application of fiber post restoration for endodontically treated non-carious cervical lesion teeth can partially improve the cervical stress of the tooth without increasing the risk of vertical root fracture,can lead to a more consistent distribution of stress and enhance the tooth's ability to withstand fractures.Non-carious cervical lesion teeth with fiber posts that fracture would show favorable,restorable,or repairable fracture patterns.Fiber posts in combination with porcelain veneers or veneer-type inlays may become a more desirable minimally invasive restoration for repairing endodontically treated non-carious cervical lesion teeth.
2.Role and mechanism of platelet-derived growth factor BB in repair of growth plate injury
Hongcheng PENG ; Guoxuan PENG ; Anyi LEI ; Yuan LIN ; Hong SUN ; Xu NING ; Xianwen SHANG ; Jin DENG ; Mingzhi HUANG
Chinese Journal of Tissue Engineering Research 2025;29(7):1497-1503
BACKGROUND:In the initial stage of growth plate injury inflammation,platelet-derived growth factor BB promotes the repair of growth plate injury by promoting mesenchymal progenitor cell infiltration,chondrogenesis,osteogenic response,and regulating bone remodeling. OBJECTIVE:To elucidate the action mechanism of platelet-derived growth factor BB after growth plate injury. METHODS:PubMed,VIP,WanFang,and CNKI databases were used as the literature sources.The search terms were"growth plate injury,bone bridge,platelet-derived growth factor BB,repair"in English and Chinese.Finally,66 articles were screened for this review. RESULTS AND CONCLUSION:Growth plate injury experienced early inflammation,vascular reconstruction,fibroossification,structural remodeling and other pathological processes,accompanied by the crosstalk of chondrocytes,vascular endothelial cells,stem cells,osteoblasts,osteoclasts and other cells.Platelet-derived growth factor BB,as an important factor in the early inflammatory response of injury,regulates the injury repair process by mediating a variety of cellular inflammatory responses.Targeting the inflammatory stimulation mediated by platelet-derived growth factor BB may delay the bone bridge formation process by improving the functional activities of osteoclasts,osteoblasts,and chondrocytes,so as to achieve the injury repair of growth plate.Platelet-derived growth factor BB plays an important role in angiogenesis and bone repair tissue formation at the injured site of growth plate and intrachondral bone lengthening function of uninjured growth plate.Inhibition of the coupling effect between angiogenesis initiated by platelet-derived growth factor BB and intrachondral bone formation may achieve the repair of growth plate injury.
3.Disease burden of chronic kidney disease attributable to high BMI in China and trend prediction in 1992-2021
Hong LIU ; Guimao YANG ; Yan SUI ; Xia ZHANG ; Xuebing CHENG ; Yaxing WU ; Xu GUO ; Yanfeng REN
Journal of Public Health and Preventive Medicine 2025;36(1):27-31
Objective To analyze the disease burden of chronic kidney diseases (CKD) attributed to high body mass index (BMI) in China from 1992 to 2021 and predict the disease burden for the next decade, and to provide evidence for the prevention and treatment of CKD. Methods Using the Global Burden of Disease (GBD) database and the Joinpoint model, the average annual percentage rate change (AAPC) of the mortality rate and disability-adjusted life year (DALY) rate was calculated to describe and analyze the CKD disease burden attributed to high BMI in China from 1992 to 2021. The ARIMA model was employed to predict and analyze the change trend of the CKD disease burden. Results From 1992 to 2021, the mortality rate and DALY rate attributed to high BMI-induced chronic kidney disease showed an upward trend. Compared to 1992, the attributed number of deaths increased by 324.38%, and DALYs increased by 268.56%; the mortality rate increased by 64.00%, and the DALY rate grew by 51.62%. From 1992 to 2021, the mortality rate and DALY rate for males were lower than those for females, but the growth rate for males exceeded that of females. From 1992 to 2021, the mortality rate and DALY rate of chronic kidney disease attributed to high BMI in China increased with age. The average annual change rate of chronic kidney disease attributed to high BMI in China from 1992 to 2021 (mortality rate: 1.40 per 100,000 (95% CI: 1.04–1.76), DALY rate: 1.43 per 100 000 (95% CI: 1.17–1.70)) was higher than thHuaiyin Normal University, Huai'anher social demographic index (SDI) regions. The ARIMA model predicted that the age-standardized mortality rate increased from 2.91 per 100 000 in 2022 to 3.05 per 100 000 in 2026, and the age-standardized DALY rate increased from 69.65 per 100 000 in 2022 to 73.58 per 100 000 in 2026. Conclusion Chronic kidney disease attributed to high BMI in China is on the rise, and it will continue to grow in the future. The focus of CKD prevention and control should be on males and the elderly, while active measures should be taken to reduce the occurrence and progression of chronic kidney disease.
4.Cytotoxicity Studies of Light-oxygen-voltage (LOV) Domain Photosensitizers
Shuang XU ; Ben WAN ; Na SHA ; Kai-Hong ZHAO
Progress in Biochemistry and Biophysics 2025;52(2):487-500
ObjectiveAt present, the most commonly used photosensitizers in photodynamic therapy are still chemical photosensitizers, such as porphyrin and methylene blue, in order to specifically target cellular tissues, and thus poison cells, chemical photosensitizers need to use antibody conjugation or a transgenically encoded tag with affinity for the modified photosensitizing ligand, e.g. FlAsH, ReAsh or Halo Tag. Gene-encoded photosensitizers can directly poison cells by targeting specific cell compartments or organelles. However, currently developed gene-encoded photosensitizers have low reactive oxygen species production and low cytotoxicity, so it is necessary to continue to develop and obtain photosensitizers with higher reactive oxygen species production for the treatment of microbial infections and tumors. MethodsIn this study, we developed a photosensitizer LovPSO2 based on the light-oxygen-voltage (LOV) structural domain of phototropin-1B-like from Oryza sativa japonica. LovPSO2 was expressed in E. coli BL21(DE3) and purified to obtain protein samples, the purified protein samples were added 3 µmol/L singlet oxygen probe of SOSG and 5 µmol/L superoxide anion probe of DHE after fixed to A445=0.063±0.003, respectively, then measured every 2 min of singlet oxygen production for 10 min and every 1 min of superoxide anion production for 5 min under blue light irradiation at 445 nm, 70 µmol·m-2·s-1. ResultsThe results showed that LovPSO2 could produce a large amount of singlet oxygen under blue light irradiation at 445 nm, 70 µmol·m-2·s-1, and its singlet oxygen quantum yield was 0.61, but its superoxide anion yield was low, so in order to improve the superoxide anion yield of LovPSO2, a mutant with a relatively high superoxide anion yield was obtained by further development and design on its basis LovPRO2. The stability of proteins is crucial for research in drug development and drug delivery, among others. Temperature and light are the key factors affecting the production of reactive oxygen species (ROS) by photosensitive proteins and their stability, while the temperature in cell culture and mammals in vivo is about 37°C, and the temperature inside tumor cells is about 42-45°C. Therefore, we further analyzed the photostability of miniSOG, SOPP3, LovPSO2, and LovPRO2 and their thermostability at 37℃ and 45℃. The analysis of proteins thermostability showed that LovPSO2 and LovPRO2 had better thermostability at 37℃ and 45℃, respectively. Analysis of the photostability of the proteins showed that LovPRO2 had better photostability. In addition, to further determine the phototoxic effects of photosensitizers, LovPSO2 and LovPRO2 were expressed in E. coli BL21(DE3) and HeLa cells, respectively. The results showed that LovPSO2 and LovPRO2 had better phototoxicity to E. coli BL21(DE3) under blue light irradiation, and the cellular phototoxicity lethality was as high as 90% after 30 min of continuous light irradiation, but the phototoxicity was weaker in HeLa cells. The reason for this result may be that the intracellular environment exacerbated the photobleaching of FMN encapsulated by LovPSO2 and LovPRO2, respectively, which attenuated the damage of reactive oxygen species to animal cellular tissues, limiting its use as a mechanistic tool to study oxidative stress. ConclusionLovPSO2 and LovPRO2 can be used as antibacterial photosensitizers, which have broader application prospects in the food and medical fields.
5.Study on the antibacterial property of EGCG/PLL phenolamine coating integrated chlorhexidine on porous titanium surface
Huilei Hong ; Jianguang Xu ; Hua Qiu
Acta Universitatis Medicinalis Anhui 2025;60(1):109-116
Objective:
To construct a phenolamine cross-linked coating composed of epigallocatechin gallate(EGCG) and poly-L-lysine(PLL) on the surface of the porous pure Ti integrated with the antibacterial substance chlorhexidine(CHX), and to study the antibacterial property and biosafety.
Methods:
A porous structure(pTi group) was formed on the surface of titanium samples by alkaline heat treatment. Then the pTi group was immersed in the mixed solution of EGCG and PLL in an alkaline aerobic environment for 24 h to obtain the phenolamine group samples(EP group). Finally, the titanium tablets were further immersed in the aqueous solution of chlorhexidine(CHX) for 24 h to obtain the antibacterial groups(EPC group). Microstructure and properties of the surface were characterized by scanning electron microscopy(SEM), X-ray photoelectron spectrometer(XPS) and water contact angle measuring instrument. The antibacterial properties of coating were observed and evaluated by nephelometry, inhibition zone method and live/dead bacterial staining. The cytocompatibility of the coating was evaluated by MTT method and cell fluorescence staining, and the cell adhesion and proliferation ability in bacterial environment were evaluated by the co-culture of bacteria and cells.
Results:
SEM results showed that the pore size of samples after alkali heat treatment decreased with the deposition of the phenolamine coating. The measurement of water contact angle showed that the contact angle increased significantly with the grafting of coating. The intensity of N1s and C1s peaks increased and Ti2p and O1s peaks decreased detected by XPS tests. The Cl2p peak appeared in EPC group referred to the control group. The antibacterial experimentsin vitroshowed that the antibacterial samples could perform effective antibacterial effects on Staphylococcus aureus and Aggregatibacter actinomycetem-comitans for at least 7 days. In the biocompatibility experiments, MTT and cell fluorescence staining results showed that the adherent cells had good morphology and proliferative activity. The bacteria-cell co-culture results showed that the EPC groups could provide a good environment for cell proliferation and growth with excellent antibacterial properties.
Conclusion
Chlorhexidine-grafted phenolamine deposited on porous titanium surface displays an effective antibacterial effect with good biosafety performance, which can play an antibacterial role in the bacterial environment while ensuring cell adhesion and proliferation.
6.Effects of Ningxin Shugan Decoction Combined with Antagonist Fixation Regimen on IVF-ET Outcomes and Serum Kisspeptin Expression in Infertility Patients with Polycystic Ovary Syndrome
Hua FENG ; Dan XU ; Xuelan HONG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(5):177-184
ObjectiveTo investigate the effects of Ningxin Shugan decoction combined with an antagonist fixation regimen on in vitro fertilization and embryo transfer (IVF-ET) outcomes and serum kisspeptin expression in infertility patients with polycystic ovary syndrome. MethodsA total of 96 infertile patients with polycystic ovary syndrome treated in Yancheng No.1 People's Hospital and Yancheng Affiliated Hospital of Nanjing University of Chinese Medicine were enrolled in this study and randomized into control and observation groups (n=48). The control group was treated with an antagonist fixation regimen, and the observation group was treated with Ningxin Shugan decoction on the basis of the treatment in the control group. The clinical efficacy was compared between the two groups. The total score and single scores of TCM symptoms, ovulation promotion status, and serum levels of reproductive hormones, miR-335-5p, miR-141-3p, and kisspeptin were determined before and after treatment. The IVF-ET outcome indicators and treatment safety were evaluated. Pearson test was conducted to analyze the correlations of serum levels of follicle-stimulating hormone (FSH), kisspeptin, miR-335-5p, and miR-141-3p with IVF-ET outcomes. ResultsThe total response rate in the observation group was 90.91%, which was higher than that (70.45%) in the control group (P<0.05). The total score and single scores of TCM symptoms and the testosterone, luteinizing hormone (LH), and LH/FSH levels declined after treatment (P<0.05), and they were lower in the observation group than in the control group (P<0.05). After treatment, the serum levels of FSH, kisspeptin, miR-335-5p, and miR-141-3p rose in both groups, being higher in the observation group than in the control group (P<0.05). The observation group showed higher ovulation number, number of MⅡ oocytes, embryo implantation rate, clinical pregnancy rate, and live birth rate than the control group (P<0.05, P<0.01). Serum levels of FSH, kisspeptin, miR-335-5p, and miR-141-3p were positively correlated with embryo implantation rate, clinical pregnancy rate, and live birth rate (P<0.01). ConclusionNingxin Shugan decoction combined with the antagonist fixation regimen can improve the IVF-ET outcome, promote the serum kisspeptin expression, and increase the ovulation rate and pregnancy rate in infertility patients with polycystic ovary syndrome.
7.Factors influencing repeat blood donor lapsing in Guangzhou: based on the zero-inflated poisson regression model
Rongrong KE ; Guiyun XIE ; Xiaoxiao ZHENG ; Yingying XU ; Xiaochun HONG ; Shijie LI ; Yongshi DENG ; Jinyu SHEN ; Jinyan CHEN ; Jian OUYANG
Chinese Journal of Blood Transfusion 2025;38(1):73-78
[Objective] To analyze the influencing factors of repeat blood donor lapsing using a zero-inflated poisson regression model (ZIP). [Methods] The blood donation behavior of 12 498 whole blood donors from 2020 was tracked until December 31, 2023. The factors influencing the frequency of blood donations in a given year was analyzed using ZIP, and donors with 0 blood donation in that year were considered to have lapsed. The changes in relevant influencing factors associated with each blood donation were measured and modeled for analysis. [Results] The zero-inflated part of ZIP showed that the risk of lapsing of male blood donors was 2.24 times that of female blood donors (OR 95% CI:1.864-2.696, P<0.001); the risk of lapsing of the 35-44 age group and over 45 age group was respectively 40% (OR 95% CI:0.455-0.790, P<0.001) and 61%(OR 95% CI:0.268-0.578, P<0.001) lower than that of the under 25 age group; the risk of lapsing for those who have donated blood twice and ≥3 times was respectively 50% (OR 95% CI:0.405-0.609, P<0.001) and 81% (OR 95% CI:0.154-0.225, P<0.001) lower than that of first-time donors; the risk of lapsing of those with junior high or high school education was 1.2 times that of those with a college degree or higher (OR 95% CI:1.033-1.384, P<0.05); the risk of lapsing for the divorced group was 2.02 times that of the married group (OR 95% CI:1.445-2.820, P<0.001); the risk of lapsing for those with an income (Yuan) of 10 000 to 50 000, 50 000 to 100 000 and more than 100 000 was respectively 0.67 (OR 95% CI:0.552-0.818, P<0.001), 0.72 (OR 95% CI:0.591-0.884, P=0.002) and 0.67 (OR 95% CI:0.535-0.834, P<0.001) times that of those with an income (Yuan) of less than 10 000. The results of the Poisson part are consistent with the results of the zero-inflated part in terms of age and education level. [Conclusion] Blood donor lapsing is overall related to factors such as gender, age, donation frequency, education, marital status and family income. It's essential to care for those blood donors prone to lapse to retain more regular blood donors.
8.Mitochondria: The Target of Ionizing Radiation Damage
Lian-Chen TIAN ; Ya-Yi YUAN ; Xu-Hong DANG
Progress in Biochemistry and Biophysics 2025;52(4):836-844
In recent years, due to the development of radiotherapy technology and nuclear energy, people have paid more and more attention to the various effects of ionizing radiation on organisms. Ionizing radiation can induce protein, DNA and other biological macromolecules to damage, resulting in apoptosis, senescence, cancer and a series of changes. For a long time, it has been believed that the main target of ionizing radiation damage is DNA in the nucleus. However, it has been reported in recent years that ionizing radiation has both direct and indirect effects, and the theory of ROS damage in the indirect effects believes that ionizing radiation has target uncertainty, so it is not comprehensive enough to evaluate only the DNA damage in the nucleus. It has been reported that ionizing radiation can cause damage to organelles as well as damage to cells. Mitochondria are important damaged organelles because mitochondria occupy as much as 30% of the entire cell volume in the cytoplasm, which contains DNA and related enzymes that are closely related to cellular ATP synthesis, aerobic respiration and other life activities. What is more noteworthy is that mitochondria are the only organelles in which DNA exists in the human body, which makes researchers pay attention to various damage to mitochondrial DNA caused by ionizing radiation (such as double-strand breaks, base mismatching, and fragment loss). Although these damages also occur in the nucleus, mitochondrial DNA is more severely damaged than nuclear DNA due to its lack of histone protection, so mitochondria are important targets of ionizing radiation damage in addition to the nucleus. Mitochondrial DNA is not protected by histones and has little repair ability. When exposed to ionizing radiation, common deletions occur at an increased frequency and are passed on to offspring. For large-scale mitochondrial DNA damage, mitochondria indirectly compensate for the amount of damaged DNA by increasing the number of DNA copies and maintaining the normal function of mitochondrial DNA. Mitochondria are in a state of oxidative stress after exposure to ionizing radiation, and this oxidative stress will promote the change in mitochondrial function. When mitochondria are damaged, the activity of proteins related to aerobic respiration decreases, and oxidative respiration is inhibited to a certain extent. At the same time, a large amount of active superoxide anions are continuously produced to stimulate mitochondrial oxidative stress, and the signal of such damage is transmitted to the surrounding mitochondria, resulting in a cascade of damage reaction, which further activates the signalling pathway between mitochondria and nucleus. The cell nucleus is also in a state of oxidative stress, and finally, the level of free radicals is high, causing secondary damage to the genetic material DNA of mitochondria and nucleus. In this paper, the damage effects of ionizing radiation on mitochondria are reviewed, to provide a new idea for radiation protection.
9.Inhibition of HDAC3 Promotes Psoriasis Development in Mice Through Regulating Th17
Fan XU ; Xin-Rui ZHANG ; Yang-Chen XIA ; Wen-Ting LI ; Hao CHEN ; An-Qi QIN ; Ai-Hong ZHANG ; Yi-Ran ZHU ; Feng TIAN ; Quan-Hui ZHENG
Progress in Biochemistry and Biophysics 2025;52(4):1008-1017
ObjectiveTo investigate the influence of histone deacetylase 3 (HDAC3) on the occurrence, development of psoriasis-like inflammation in mice, and the relative immune mechanisms. MethodsHealthy C57BL/6 mice aged 6-8 weeks were selected and randomly divided into 3 groups: control group (Control), psoriasis model group (IMQ), and HDAC3 inhibitor RGFP966-treated psoriasis model group (IMQ+RGFP966). One day prior to the experiment, the back hair of the mice was shaved. After a one-day stabilization period, the mice in Control group was treated with an equal amount of vaseline, while the mice in IMQ group was treated with imiquimod (62.5 mg/d) applied topically on the back to establish a psoriasis-like inflammation model. The mice in IMQ+RGFP966 group received intervention with a high dose of the HDAC3-selective inhibitor RGFP966 (30 mg/kg) based on the psoriasis-like model. All groups were treated continuously for 5 d, during which psoriasis-like inflammation symptoms (scaling, erythema, skin thickness), body weight, and mental status were observed and recorded, with photographs taken for documentation. After euthanasia, hematoxylin-eosin (HE) staining was used to assess the effect of RGFP966 on the skin tissue structure of the mice, and skin thickness was measured. The mRNA and protein expression levels of HDAC3 in skin tissues were detected using reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB), respectively. Flow cytometry was employed to analyze neutrophils in peripheral blood and lymph nodes, CD4+ T lymphocytes, CD8+ T lymphocytes in peripheral blood, and IL-17A secretion by peripheral blood CD4+ T lymphocytes. Additionally, spleen CD4+ T lymphocyte expression of HDAC3, CCR6, CCR8, and IL-17A secretion levels were analyzed. Immunohistochemistry was used to detect the localization and expression levels of HDAC3, IL-17A, and IL-10 in skin tissues. ResultsCompared with the Control group, the IMQ group exhibited significant psoriasis-like inflammation, characterized by erythema, scaling, and skin wrinkling. Compared with the IMQ group, RGFP966 exacerbated psoriasis-like inflammatory symptoms, leading to increased hyperkeratosis. The psoriasis area and severity index (PASI) skin symptom scores were higher in the IMQ group than those in the Control group, and the scores were further elevated in the IMQ+RGFP966 group compared to the IMQ group. Skin thickness measurements showed a trend of IMQ+RGFP966>IMQ>Control. The numbers of neutrophils in the blood and lymph nodes increased sequentially in the Control, IMQ, and IMQ+RGFP966 groups, with a similar trend observed for CD4+ and CD8+ T lymphocytes in the blood. In skin tissues, compared with the Control group, the mRNA and protein levels of HDAC3 decreased in the IMQ group, but RGFP966 did not further reduce these expressions. HDAC3 was primarily located in the nucleus. Compared with the Control group, the nuclear HDAC3 content decreased in the skin tissues of the IMQ group, and RGFP966 further reduced nuclear HDAC3. Compared with the Control and IMQ groups, RGFP966 treatment decreased HDAC3 expression in splenic CD4+ and CD8+ T cells. RGFP966 treatment increased the expression of CCR6 and CCR8 in splenic CD4+ T cells and enhanced IL-17A secretion by peripheral blood and splenic CD4+ T lymphocytes. Additionally, compared with the IMQ group, RGFP966 reduced IL-10 protein levels and upregulated IL-17A expression in skin tissues. ConclusionRGFP966 exacerbates psoriatic-like inflammatory responses by inhibiting HDAC3, increasing the secretion of the cytokine IL-17A, and upregulating the expression of chemokines CCR8 and CCR6.
10.Pharmacoeconomic evaluation of iruplinalkib therapy for advanced ALK-positive non-small cell lung cancer
Hong WANG ; Haonan LI ; Hui ZHANG ; Yuhang LIU ; Yeyou XU ; Kaiyuan WENG
China Pharmacy 2025;36(8):945-950
OBJECTIVE To evaluate the cost-effectiveness of iruplinalkib for ALK-positive non-small cell lung cancer (NSCLC) patients who had not previously received ALK-tyrosine kinase inhibitors (TKIs) from the perspective of the Chinese healthcare system. METHODS Based on the INSPIRE clinical trial, a three-health state partitioned survival model was developed to simulate the progression of disease, with model cycle of 3 weeks and a life-year time range of 15 years; the discount rate was 5%. For the treatment of ALK-positive advanced NSCLC, total cost, quality-adjusted life year (QALY), and incremental cost- effectiveness ratio (ICER) were compared between iruplinalkib and crizotinib; using 1-3 times China’s per capita gross domestic product (GDP) (89 358-268 074 yuan) in 2023 as the willingness-to-pay (WTP) threshold, the cost-effectiveness of two regimens were compared. The sensitivity analysis and scenario analysis (altering the distribution of survival curves, utility values) were conducted to assess model robustness. RESULTS Compared with the crizotinib regimen, the ICER for the iruplinalkib regimen was 194 412.74 yuan/QALY, which was below the WTP threshold of three times China’s per capita GDP in 2023 yuan). The results under the scenario of altering the survival curve distribution were consistent with the base case analysis. However, after increasing the utility value of the disease progression state, the ICER exceeded the WTP threshold, and iruplinalkib no longer had a cost-effective advantage. The results of the one-way sensitivity analysis indicated that the cost of iruplinalkib and the utility values of disease progression states had a significant impact on the ICER. The probabilistic sensitivity analysis confirmed the robustness of the base case analysis results. CONCLUSIONS From the perspective of China’s healthcare system, compared with crizotinib regimen, the therapy with iruplinalkib is cost-effective for ALK-positive NSCLC patients who have not previously received ALK-TKIs.


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