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Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and Calu-3 were used for in vitro and in vivo analysis.Bioinformatic molecular docking prediction and following validation by surface plasmon resonance(SPR)technology,cellular thermal shift assay(CETSA),and isothermal titration calorimetry(ITC)were conducted to explore the binding between ginsenoside Rg5 and 90 kD heat shock protein alpha(HSP90α).The effects of ginsenoside Rg5 on HSP90-cell division cycle 37(CDC37)interaction,the client protein stability,and the downstream regulations were further explored.Results showed that ginsenoside Rg5 could induce cell-cycle arrest at the G1 phase and enhance irradiation-induced cell apoptosis.It could bind to HSP90α with a high affinity,but the affinity was drastically decreased by HSP90α Y61A mutation.Co-immunoprecipitation(Co-IP)and ITC assays confirmed that ginsenoside Rg5 disrupts the HSP90-CDC37 interaction in a dose-dependent manner.It reduced irradiation-induced upre-gulation of the HSP90-CDC37 client proteins,including SRC,CDK4,RAF1,and ULK1 in A549 cell-derived xenograft(CDX)tumors.Ginsenoside Rg5 or MRT67307(an IKKe/TBK1 inhibitor)pretreatment suppressed irradiation-induced elevation of the LC3-Ⅱ/β ratio and restored irradiation-induced downregulation of p62 expression.In A549 CDX tumors,ginsenoside Rg5 treatment suppressed LC3 expression and enhanced irradiation-induced DNA damage.In conclusion,ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma.It interacts with HSP90α and reduces the binding between HSP90 and CDC37,thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins.
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Objective To evaluate the radiosensitization effect and micro CT imaging of multifunctional gold nanoparticles in lung adenocarcinoma A549 tumor-bearing mouse models.Methods The tumor-bearing mice were injected with gold nanoparticles and irradiated with different energy levels of 160 kV and 6 MV X-ray.The tumor volume changes were measured.Intra-tumoral injection of gold nanoparticles was administered and micro CT scan was performed at different time points to observe the imaging and retention time of gold nanoparticles in the tumor tissues.Results The tumor volume did not significantly differ between the control and gold nanoparticles groups (P=0.941).The tumor volume in the 6 MV X-ray combined with gold nanoparticles group was slightly reduced compared with that in the 6 MV X-ray group with no statistical significance (P=0.730).The tumor volume in the 160 kV X-ray combined with gold nanoparticles group was significantly smaller than that in the 160 kV X-ray group (P=0.026).Micro CT scan demonstrated that gold nanoparticles could be deposited in the tumors for 30 d and yielded excellent imaging effect.No gold nanoparticles-induced toxicity was observed.Conclusions Multifunctional gold nanoparticles exert significant radiosensitization effect in the lung adenocarcinoma A549 transplanted tumors irradiated with 160 kV X-ray.Stable CT imaging of the gold nanoparticles-injected tumors can be used as a potential method for mapping and delineating the target area in tumor-guided radiotherapy.
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Objective To study the radiosensitization effect of thio-glucose capped gold nanoparticles (Glu-GNPs) on human lung adenocarcinoma A549 cells in vitro.Methods Human lung adenocarcinoma cell line A549 in logarithmic phase was divided into four groups:control group,drug group (Glu-GNPs),irradiation group (irradiation of 6 MV group and irradiation of 160 kV group),Glu-GNPs combined irradiation group (6 MV + Glu-GNPs group,160 kV + Glu-GNPs group).Transmission electron microscopy (TEM) was used to observe the distribution of Glu-GNPs in cells.Toxicity of Glu-GNPs on A549 cells and the inhibitory effect of Glu-GNPs combined with irradiation on cell proliferation were determined using crystal violet assay.Clonogenic assay were performed to evaluate radiosensitization of Glu-GNPs on A549 cells.Immunofluorescence assay of γ-H2AX,a biomarker of DNA damage that underlies cellular response to irradiation was used to evaluate radiation-induced DNA double-strand break (DSB).Results TEM images showed that Glu-GNPs were mainly distributed in the cytoplasm of A549 cells,including endosomes and mitochondria.Glu-GNPs had little cytotoxicity toward A549 cells with a concentration lower than 100 nmol/L.Different concentrations (0-100 nmol/L)of Glu-GNPs combined with different energy of X-rays had significant inhibitory effects on A549 cells.Under 160 kV and 6 MV X-ray conditions,the Glu-GNPs treatment further decreased the survival fraction of irradiation group (P < 0.05),and the sensitizing enhancement ratio (SER) was 1.41 and 1.15,respectively.Moreover,Glu-GNPs significantly increased radiation-induced γ-H2AX foci in A549 cells,and the number of γ-H2AX foci with 160 kV X-ray radiation was higher than that with 6 MV X-ray radiation (t =12.392,14.893,18.947,P < 0.05).Conclusions Uptake of Glu-GNPs by A549 cells could enhance radiation effects,especially for kilovolt X-ray radiation.
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Objective This study was conducted to evaluate treatment-related toxicities,the patterns of failure,overall survival(OS)and progression-free survival(PFS)by comparing IFI with ENI in combination with chemotherapy. Methods Eligible patients were treated with concurrent chemoradiotherapy and randomized into either an IFI or ENI arm. The primary end points wereacute treatment-related toxicities. The secondary end points were patterns of failure,OS and PFS. Kaplan?Meier survival rate of the method for calculating the Logrank test difference method. Results Between April 2012 and October 2016,a total of 228 patients were enrolled from nine centers in china. Grade≥3,Grade≥2 radiation esophagitis and pneumonitis in the IFI arm were significantly lower than that of the ENI arm(P=0.018,0.027).No significant differences were observed in overall failure rates,loco-regional failure,distant failure rates,in-field and out-field lymph node failure between the two arms(P=0.401,0.561,0.510,0.561,0.681).The 1-,2-, 3-,4-yearand median OS in the ENI arm and IFI arm were 84.1%,57.3%,39.4%,31.6%,28 months and 83.6%,62.1%,44.5%,31.5%,32 months(P=0.654),respectively. The 1-,2-,3-yearand median PFS in the ENI arm and IFI arm were 71.9%,42.3%,32.7%,20 months and 70.1%,45.0%,35.9%,22 months (P=0.885),respectively. Conclusions Compared to ENI,IFI resulted in decreased radiation pneumonitis and esophagitis without sacrificing loco-regional lymph nodal control,PFS and OS in thoracic ESCC. Clinical Trial Registry Chinese Clinical trail registry,registration number:NCT01551589.
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Objective To investigate the clinical efficacy and safety of preoperative hypofractionated and conventionally-fractionated chemoradiotherapy for thoracic esophageal cancer. Methods A total of 86 patients with thoracic esophageal cancer receiving chemoradiotherpy in Sichuan Cancer Hospital between 2002 and 2011 were enrolled and randomized into the preoperative hypofractionated chemoradiotherapy group ( group A, n=41, 30 Gy in 10 fractions for 2 weeks ) and conventionally-fractionated chemoradiotherapy group ( group B, n=45, 40 Gy in 20 fractions for 4 weeks ) . Surgery was performed at 2-6 weeks after chemoradiotherapy. The probability of patients' survival was estimated by Kaplan-Meier method and analyzed by log-rank test. Results In groups A and B, the pathological downstaging rates were 68% and 56%( P=0. 270) , the R0 resection rates were 95% and 89%( P=0. 437) and the pCR rates of 32% and 24%( P=0. 480).The 1-,3-and 5-year overall survival (OS) rates were 78% and 69%,44% and 44%,29% and 33%(P=0. 114,0. 223,0. 289), and the progression-free survival (PFS) rates were 71% and 62%,39% and 38%,24% and 29%(P=0. 211,0. 689,0. 331), respectively. The incidence rate of chemoradiothery-and surgery-related adverse events did not differ between two groups (P=0. 089-0. 872).The average length of hospital stay, radiotherapy cost and preoperative treatment costs in group A were significantly less compared with those in group B (P=0. 000,0. 000,0. 000). Conclusions Both preoperative hypofractionated and conventionally-fractionated chemoradiotherapy can be used as the regimen of preoperative chemoradiotherapy in patients with resectable thoracic esophageal carcinoma. Compared with conventionally-fractionated chemoradiotherapy, preoperative hypofractionated chemoradiotherapy has shorter treatment cycle, shorter length of hospital stay and lower radiotherapy cost, which is more easily accepted by patients.
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Objective To investigate the influence of enteral nutrition on body weight,nutritional status,treatment toxicities,and short-term outcomes in esophageal carcinoma patients treated with concurrent chemoradiotherapy(CCRT). Methods Eligible esophageal carcinoma patients were randomly assigned(2:1) to receive either CCRT combined with enteral nutrition (study group) or CCRT alone (control group). The primary endpoint was changes in the body weight during and after radiotherapy. The secondary endpoints were nutrition-related hematological parameters,the toxicities of chemoradiotherapy,the completion rate of treatment,and short-term outcomes. The differences was using χ2 or t-test. Results Between September 2014 and June 2017,203 patients were included in the study,consisting of 139 patients in the study group and 64 patients in the control group. Compared with the control group,the study group had significantly less body weight loss during and after radiotherapy (P<0.05) and significantly less decreases in serum albumin and hemoglobin (P<0.05),but there was no significant difference in the reduction in total lymphocyte count between the two groups (P>0.05).The study group had significantly lower incidence rates of grade ≥3 myelosuppression and infection and a significantly higher completion rate of chemoradiotherapy compared with the control group (P<0.05).The incidence of radiation pneumonitis and esophagitis showed no significant difference between the two groups (P>0.05).The study group had an insignificantly higher objective response rate than the control group (P>0.05). Conclusions For esophageal carcinoma patients treated with CCRT,enteral nutrition can reduce body weight loss during and after radiotherapy,improve nutritional status and treatment tolerance,and reduce toxicities.
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The radiation techniques for lung cancer stereotactic body radiotherapy (SBRT) include intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT).Concerning the target conformity and dosimetric homogeneity index, HT and VMAT technologies are superior to IMRT.On the contrary, HT and VMAT technology can increase low dose area irradiated of lung.Comparing to other two technologies, VMAT can obviously shorten the treatment time.At present, there is no consensus how to choose individually optimized radiotherapy technology for different location and stages lung tumors.
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Objective To evaluate the efficacy and safety of consolidation chemotherapy after thoracic radical concurrent chemoradiotherapy for patients with oligometastatic non?small cell lung cancer ( NSCLC) . Methods Sixty?six NSCLC patients with more than five metastases from 2008 to 2013 were enrolled, and image?guided radiotherapy with conventionally fractionated or hypofractionated doses were performed for these patients. Platinum?based doublets chemotherapy was applied for both concurrent chemoradiotherapy and consolidation chemotherapy. Short?term outcome, adverse reactions, and survival rate were assessed for the patients after treatment. Results Sixty?four patients completed the treatment. The median biologically equivalent dose for planning target volume of thoracic primary tumor lesions was 72 Gy, with a median number of chemotherapy cycles of 4. The objective response rate for thoracic lesions was 70%. The follow?up rate was 97%. The 1?, 2?, and 3?year overall survival ( OS) rates were 72%, 53%, and 31%, respectively, with a median OS time of 25 months;the 1?, 2?, and 3?year progression?free survival ( PFS) rates were 56%, 26%, and 7%, respectively, with a median PFS time of 14 months. The incidence of grade 2?3 acute radiation pneumonitis and radiation esophagitis was 1% and 17%, respectively, and the incidence of grade 3?4 decreases in leukocytes, hemoglobin, and platelet count was 39%, 11%, and 16%, respectively. Conclusions Radical radiotherapy combined with concurrent and consolidation chemotherapy for oligometastatic NSCLC can achieve good short?term outcome and long?term survival, with tolerable adverse effects.