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Objective:To construct a random forest classification model of DNA double strand breaks (DSB) induced by ionizing radiation and investigate the genome-wide distribution of DSB.Methods:The GRCh38 reference genome was divided into 50 kilobase fragments. Then these genomic fragments were separated into low-level or high-level regions of ionizing radiation-induced DSB according to the sequencing data of MCF-7 cells. The data of eight epigenetic features were used as input. Two thirds of the data were randomly assigned to the training set, and the rest of the data was assigned to the test set. A random forest classification model with 100 decision trees was constructed. The importance of epigenetic features in the classification model was analyzed and displayed.Results:The accuracy score of the random forest classification model on the test set was 99.4%, the precision score was 98.9% and the recall score was 99.9%. The area under the receiver operating characteristic curve was 0.994. Among the eight epigenetic features, H3K36me3 and DNase markers were the most important variables. The enrichments of the two markers in DSB high-level regions were much higher than those in DSB low-level regions.Conclusions:The random forest classification model could precisely predict the genome-wide levels of DSB induced by ionizing radiation in the 50 kilobase window based on epigenetic features. Analysis revealed that these DSB might primarily distribute in the actively transcribed sites in the genome.
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Objective To investigate the effects of titanium dioxide ( TiO2 ) nanoparticles coupled with nuclear localization sequence ( NLS ) on the radiosensitivity of U251 glioma cells. Methods Synthesis and characterization of the TiO2-NLS nanoparticles with nuclear targeting property. U251 cells were treated with nanoparticles and/or ionizing radiation. Flow cytometry analysis was performed to measure the ROS content and the cell apoptotic percentage. The DNA damage was detected by using γ-H2AX foci staining. Clonogenic survival assay was used to evaluate the radiosensitivity of U251 cells. Results NLS modification promoted nuclear translocation of TiO2 nanoparticles. Compared with the control nanoparticles, TiO2-NLS treatment increased radiation-induced cell apoptosis (t=8. 96, P<0. 05). Clonogenic survival assay showed the radiosensitization ratios of TiO2 nanoparticle-treated group and TiO2-NLSnanoparticle-treated group were 1. 18 and was 1. 29, respectively. These two ratios had statistically difference ( t =14. 72, P< 0. 05). Conclusions Nuclear targeting TiO2 nanoparticles enhances the radiosensitivity of U251 glioma cells.
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Objective To evaluate the internal irradiation biological effects of 125I-UdR chitosan nanoparticles in hepatoma cells.Methods The accumulation and distribution of 125I-UdR-CS-DLN in hepatoma cells HepG2 and human liver tissue cells HL-7702 were observed with a confocal microscopy.The internal irradiation biological effects were evaluated by MTT assay,flow cytometry and single cell gel electrophoresis.The apoptosis of in situ rabbit liver tumor treated with 125I-UdR-CS-DLN was assayed by TUNEL staining technique.Results After 30 min of nano-particle treatment,its accumulation in the cytoplasm of HepG2 cells was significantly greater than that in HL-7702 cells.When the concentrations of 125I-UdR-CS-DLN was higher than 37 kBq/ml,the cell viability of HepG2 was significantly lower than that of lL-7702 at 24 and 48 h post-treatment(t =-4.46-6.31,P＜0.05),and the HepG2 cells were arrested at G1 phase and significantly impaired at G2/M phase.In addition,the degrees of DNA doublestrand break of both cell lines irradiated by 125I-UdR-CS-DLN were significantly higher than those treated with 125I-UdR,and the DNA repair capacity of HepG2 cells was significantly lower than that of HL-7702 cells(OTM:t =2.94,P ＜0.05;TDNA％:t =10.64,P ＜0.01).TUNEL staining showed that cell apoptosis could be induced in the rabbit liver carcinoma by 125I-UdR-CS-DLN but not by 125I-UdR.Conclusions The amount of 125I-UdR-CS-DLN absorbed by hepatoma cells is significantly higher than that of 125I-UdR,which suggests that 125 I-UdR-CS-DLN induces more stronger internal radiation biological effects of apoptosis and DNA damage on hepatoma cells.
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Objective To investigate the biological effect of 125I seeds continuous low dose rate (CLDR) irradiation and 60Co γ-ray high dose rate (HDR) irradiation on H1299 cell line of non-small cell lung cancer (NSCLC). Methods H1299 cells in exponential growth were separately irradiated with 125I seeds CLDR irradiation and 60Co γ-ray HDR irradiation. The cell survival fraction was inspected with clone formation experiment, the cell cycle and apoptosis rate was determined with flow cytometry, and the expressions of Bax and Bcl-2 proteins were measured by Western blot method. Results With the irradiation dose increasing, the anti-proliferation effect of 125I seeds CLDR irradiation on H1299 cells became more remarkable than that of 60Coγ-ray HDR irradiation. When the irradiation dose reached 4 Gy, the G2/M phase percentage and the apoptotic ratio of H1299 cells in 125I seeds CLDR irradiation group were 21.77±0.31%and 13.79±0.50% respectively, which were only 18.85±0.99% and 8.79±0.22% respectively in 60Co γ-ray HDR irradiation group, the difference was statistically significant (P<0.05). In 125I seeds CLDR irradiation group the expression of Bax protein was remarkably up-regulated, while the expression of Bcl-2 protein was down-regulated. Conclusion The inhibition effect of 125I seeds CLDR internal irradiation on the proliferation of H1299 cells is more obvious than that of 60Co γ-ray HDR irradiation. In 125I seeds CLDR irradiation group, the imbalance of Bcl-2/Bax ratio may play an important role in achieving the antitumor effect.
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Objective To investigate the biological effects of 125I seeds and 60Co γ-rays on the non-small cell lung cancer cells A549 and the normal bronchial epithelium cells BEAS-2B.Methods A549 and BEAS-2B cells were irradiated with 125I seeds and 60Co γ-rays.The survival fraction was detected by colony formation assay.The cell cycle and cell apoptotic ratio were detected by flow cytometry.The expression of cell apoptotic related proteins was examined by western blot.Results After irradiation with different doses,the survival of A549 cells irradiated with 125I seeds was lower than that irradiated with γ-rays (t =6.06,9.42,4.90,P ＜0.05).After irradiation with 4 Gy of 125I seeds and 60Co γ-rays,the G1 phase percentages of A549 cells were 70.67％ ± 1.49％ and 59.59％ ± 0.71％ (t =10.77,P ＜ 0.05),and the apoptotic ratios of A549 cells were 18.09％ ±0.73％ and 9.81％ ±0.16％ (t =19.40,P＜ 0.05),respectively.125I seeds irradiation remarkably up-regulated the expressions of Bax and cleaved Caspase-3 proteins,down-regulated the expression of Bcl-2 proteins compared with 60Co γ-rays irradiation on A549 cells.However,the apoptotic ratio and the expressions of apoptosis-related proteins in BEAS-2B cells had little difference between two types of radiation.Conclusions The anti-proliferative effect of 125I seeds irradiation on A549 cell is more remarkably than that of 60Co γ-rays.The imbalance of Bcl-2/Bax ratio and the eventually activation of Caspase-3 proteins may play an important role in the anti-proliferative effect induced by the continuous low dose radiation of 125I-seeds.
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OBJECTIVE: This study was designed to compare the clinical effectiveness of intraluminal radioactive stent loaded with iodine-125 seeds implantation versus covered stent alone insertion in patients with malignant esophageal stricture. METHODS: We studied two groups of patients with malignant esophageal stricture. Group A comprised 28 patients (19 men and 9 women) who underwent intraluminal radioactive stent loaded with iodine-125 seeds implantation and were followed prospectively. Group B comprised 30 patients (18 men and 12 women) who had previously received covered stent alone insertion; these patients were evaluated retrospectively. There was no crossover between the two groups during follow-up. Informed consent was obtained from each patient, and our institutional review board approved the study. The dysphagia score, overall survival rates, complication rates, and reintervention rates were compared in the two groups. RESULTS: There were no significant differences between the two groups in terms of baseline characteristics. Stent placement was technically successful and well tolerated in all patients. The dysphagia score was improved in both groups after stent placement. The median survival was significantly longer in group A than in group B: 11 versus 4.9 months, respectively (P < 0.001). The complications of chest pain, esophageal reflux, and stent migration was more frequent in group B, but this difference did not reach statistical significance. There was no statistical difference in reintervention between two groups. CONCLUSIONS: Intraluminal radioactive stent loaded with iodine-125 seeds implantation was a feasible and practical management in treating malignant esophageal stricture and was superior to covered stent alone insertion, as measured by survival.
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Brachytherapy/methods , Esophageal Neoplasms/complications , Esophageal Stenosis/therapy , Iodine Radioisotopes/therapeutic use , Stents , Aged , Aged, 80 and over , Catheterization/methods , Deglutition Disorders/classification , Deglutition Disorders/etiology , Deglutition Disorders/prevention & control , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophageal Stenosis/diagnostic imaging , Esophageal Stenosis/etiology , Esophageal Stenosis/mortality , Female , Follow-Up Studies , Gastroesophageal Reflux/etiology , Humans , Male , Middle Aged , Neoplasm Staging , Pain/etiology , Radiography, Interventional , Recurrence , Retrospective Studies , Stents/adverse effects , Survival Rate , Treatment OutcomeABSTRACT
Objective To separate NK cells of mice from NK cell separation medium and study inhibitory effect of proliferated NK cell induced by low dose radiation on the leukemia model of K562 cells.Methods Flow cytometry and 3H-TdR methods were respectively used to measure proliferation index and activity of NK cells treated with low-dose radiation( which means exposure dose in 20 cGy low LET beam or 5 cGy high LET beam).CD13 + cells were measured by flow cytometry and TNF-α content in blood-serum was detected by ELISA.In vivo,peripheral blood leucocyte count,index of liver,indexes of spleen and kidney were observed in control group and experimental group.Results The purity of NK cell separation was (82.54 ± 0.18)%.The proliferation index of NK cells at 24 hours after 80 mGy irradiated was 36.31 ± 1.32% ,(t =24.69,P ＜0.05).Killing activity of NK cell induced by low dose radiation to K562 cell was (12.59±0.63)%(t=6.63,P＜0.05)and the inhibition ratio was 29.52%.Conclusion The injection of proliferated NK cell induced by low dose radiation demonstrated significant inhibitory effect on the growth of leukemia nude mouse.
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Objective To investigate the application value of early evaluation and monitoring of 125Ⅰ interstitial implantation in a pancreatic cancer xeuograft.Methods Xenograft models were created by subcutaneous injection of Sw 1990 human pancreatic cancer cell suspensions into the right hind limbs of the immunodeficient BABL/c nude mice.The tumors size were about 8-10 mm after two weeks.The mice were randomly divided into 3 groups,including control group (n = 4) ,empty seed implantation group (n = 4)and 125Ⅰ implantation group (n = 4).Before treatment and one week after treatment,18F-FDG Micro-PET/CT scan was performed and then maximum standardized uptake values (SUVmax),mean standardized uptake values (SUVmean),tumor size and necrosis rate were measured.HE staining and TK1 immunohistochemistry examination were carried out in the paraffin-embedded sample.Results Before treatment the SUVmax and SUVmean values of three groups did not reach statistical significance.One week after treatment the SUVmax and SUV values of three groups were 3.53 + 1.20 and 0.57±0.26 vs.3.83±2.13 and0.59 ±0.24vs.0.29±0.23 and0.016±0.001,respectively,with a significant difference (F =7.62,P =0.01 ; F = 10.34,P =0.005).The SUVmax and SUVmean values of 125Ⅰ implant group were significantly lower than empty seed implant group and control group and were significantly lower than before treatment.Before treatment,tumor necrosis rate of three groups were not significantly different.Immunohistochemical staining found the TK1 positive staining index of three groups were respectively (64.25±1.71) % ,(62.25±2.22) % and (38.25±1.71) % with statistically significant difference (F =233.67,P < 0.001).The TK1 positive staining index of 125Ⅰ implant group was significantly lower than empty seed implant group and control group.The SUVmax values had some positive correlation with TK1 positive staining index (r = 0.85,P = 0.001).Conclusions 18F-FDG Micro-PET/CT may be useful as a noninvasive imaging modality to assess early response to 125Ⅰ seed brachytherapy in a pancreatic cancer xenograft.
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OBJECTIVE: To examine the clinical efficacy of CT-guided radioactive iodine-125 (125I) seeds implantation treatment in patients with unresectable pancreatic cancer. METHODS: Thirty-one patients with inoperable pancreatic cancer were enrolled in this study. The 125I seeds were implanted into pancreatic tumor under CT guidance. In addition, 10 patients received routine gemcitabine and 5-fluorouracil chemotherapy 1 week after brachytherapy. Median diameter of the tumor was 5.8 cm. RESULTS: Follow-up period was 2 to 25 months. Symptoms of refractory pain were significantly resolved post-interventionally (P < 0.05), and Karnofsky physical score increased dramatically (P < 0.05). Tumor response which was demonstrated on repeated CT film 2 months post-treatment revealed complete response (CR) in 3 cases, partial response (PR) in 16 cases, stable disease (SD) in 9 cases, and progressive disease (PD) in 3 cases. Overall responding rate (CR+PR) was 61.3%. Median survival time for all patients was 10.31 months. Two seeds of radioactive 125I migrated to the liver in 2 patients. There were no serious complications detected during the follow-up period. CONCLUSIONS: This study suggests that CT-guided brachytherapy using 125I seeds implantation appears to be safe, effective, uncomplicated, and could produce adequate pain relief for treating unresectable pancreatic cancer.
Subject(s)
Iodine Radioisotopes/therapeutic use , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/radiotherapy , Tomography, X-Ray Computed , Adult , Aged , Aged, 80 and over , Brachytherapy , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Pain , Radionuclide Imaging , Survival Analysis , Tumor BurdenABSTRACT
Objective To prepare the chitosan nanoparticles loading 5-[125Ⅰ] Iodo-2'-deoxyuridine (125Ⅰ-UdR-CS-DLN) at 100-200 nm in diameter, and analyze the characteristic of drug sustained-releasing and tumor targeting. Methods Orthogonal experimental design and One-way analysis were applied to optimize the preparation of 125Ⅰ-UdR-CS-DLN using tripolyphosphate cross-linking. Dynamic dialysis was utilized to investigate the in vitro releasing characteristics of the nanoparticles. The tumor targeting effect of the nanoparticles was observed with laser confocal microscopy. Results The optimal conditions for preparing the nanoparticles at particle diameters (70. 39 ± 5.12 ) nm (PDI 0. 16 ± 0. 012 ) were 1 g/L of CS, 2 g/L of TPP, stirring rate 600 r/min, relative molecular mass of CS 3 × 103. The TEM results showed that the exterior of the nanoparticles was spheroid, with a uniform and fine dispersivity. The optimized condition with the initial 125Ⅰ-UdR concentration of 2. 96 MBq/ml at pH5 provided the highest loading capacity (1253. 55 MBq/g) and the highest entrapment rate (42. 35% ). The in vitro releasing curves of 125Ⅰ-UdR-CS-DLN followed Higuchi equation, shown a characteristic of long-acting preparation.Laser confocal microscopy observations approved that the tumor cells uptake of FITC-CS-nanoparticles were significantly more than that of normal cells. Conclusions Chitosan nanoparticles loading 125Ⅰ-UdR at diameters range 127. 81 ± 15. 25 nm (PDI 0. 240 ± 0. 035 ) were successfully prepared with the optimized conditions, and showed a characteristic of sustained-releasing and tumor targeting. The chitosan-based nanotechnology provided a new and efficient approach for the application of 125Ⅰ-UdR in intracellular radiotherapy for tumor.
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Objective To explore the radiosensitization effect of thalidomide combined with X-ray on esophageal carcinoma TE1 cells.Methods Cell scratch assay Was used to detect the inhibition ability of different concentration of Thalidomide on cell invasion and metastasis.H3-TdR incorporation assay Was used to investigate the inhibition of DNA synthesis in TE1 cells by treated with Thalidomide singly or combination with X-rays.The colony formation assay Was used to analyze the radiosensitization of Thalidomide effect on TE1 cells.Results Thalidomide had obvious inhibition effect on TE1 cell metastasis.DNA synthesis and colony formation,which were correlated with drug concentration.The values D0,Dq and SF2 in TE1 cells were gradually decreased with thalidomide concentration increased.When the concentration of thalidomide was 100μg/ml,the SERD0 and SERDq were(1.4±0.2)and(1.5±0.1),respectively,While the concentration of thalidomide Was 1 50μg/ml,the SERD0 and SERDq were metastasis,DNA synthesis,and significantly enhance the radiosensitizing effect on esophageal carcinoma TE1 cells.
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Clinical trials with rituximab in combination with chemotherapeutic regimens have shown promising results. Data on the effects of rituximab treatment in combination with irradiation are, however, limited and inconsistent. This study aims to investigate the effects of rituximab (R) on cell death induced by X-irradiation in Raji lymphoma cells and to evaluate its mechanisms. We found the cell growth inhibition by irradiation was enhanced by additional rituximab exposure both in cells precultured with rituximab followed by irradiation (R + irradiation) or in cells treated in the reverse sequence (irradiation + R). R + irradiation combination treatment induced more apoptotic cells than irradiation and irradiation + R treatment as early as 12 h after treatment. At 24 h, both combination treatments, R + irradiation and irradiation + R, showed apoptotic cells, which were significantly different from irradiation alone. G2/M cell cycle arrest was observed after irradiation alone and the combination treatment. The combination treatment revealed an elevation in reactive oxygen species (ROS) generation in a radiation dose-dependent manner. In addition, rituximab enhanced the cell growth inhibition and apoptotic cell death induced by the oxidative agent, H(2)O(2). We propose that rituximab mediates a significant in vitro radiosensitizing effect and induces cell cycle changes and apoptosis in Raji cells. ROS probably play an important role in these events.
