Meta-analysis of efficacy and safety of induction chemotherapy combined with radiotherapy±concurrent chemotherapy for nasopharyngeal carcinoma patients in the era of intensity-modulated radiation therapy / 中华放射肿瘤学杂志

Objective:To compare the efficacy and adverse events of induction chemotherapy combined with radiotherapy alone (IC+ RT) and induction chemotherapy combined with concurrent chemoradiotherapy (IC+ CCRT) for nasopharyngeal carcinoma in the era of intensity-modulated radiation therapy in this Meta-analysis.Methods:Retrospective or randomized controlled clinical studies published between 2010 and 2020 were searched from the Cochrane Library, PubMed, and Web of Science databases. The selected studies included nasopharyngeal carcinoma patients treated with IC+ CCRT or IC+ RT. STATA 12 software was used to combine the hazard ratio (HR), risk ratio (RR) and 95% confidence interval (CI), and random or fixed effect models were used for statistical analysis.Results:A total of 2483 patients from eight retrospective studies were included. The overall survival in the IC+ CCRT group was similar to that in the IC+ RT group ( HR=0.78, 95% CI: 0.58-1.04, P=0.091). However, the distant metastasis-free survival ( HR=0.56, 95% CI: 0.42-0.74, P<0.001) and progression-free survival ( HR=0.65, 95% CI: 0.54-0.77, P<0.001) were improved in the IC+ CCRT group compared with those in the IC+ RT group. In terms of adverse reactions, the acute adverse reactions in the IC+ CCRT group were increased significantly compared with those in the IC+ RT group. Conclusions:In the treatment of nasopharyngeal carcinoma, the overall survival of two treatment modes is similar, but the distant metastasis-free survival and progression-free survival in the IC+ CCRT group are better than those in the IC+ RT group, whereas the incidence of adverse reactions is also increased. IC+ CCRT may be a recommended treatment for nasopharyngeal carcinoma patients, but more research is needed.

Research progress in microRNAs associated with radioresistance of nasopharyngeal carcinoma / 中华放射肿瘤学杂志

Nasopharyngeal carcinoma ( NPC) is a squamous cell carcinoma originating from the nasopharyngeal epithelial tissues with a high incidence in Southeast Asia and South China. At present, radiotherapy has become the primary therapeutic modality to treat NPC. Resistance to radiotherapy poses a serious obstacle to successful therapy for NPC. It is of great importance to identify the biomarkers related to the NPC radioresistance and unravel the mechanism of radioresistance for the diagnosis and treatment of NPC patients. MicroRNAs induce translational repression or degradation of targeted mRNAs by binding to their 3’ UTRs and regulate the expression of protein. MicroRNAs are involved in the regulation of all important cellular processes associated with response to the radiotherapy, such as DNA damage response and repair, cellular apoptosis, proliferation and angiogenesis. In recent years, the study of miRNAs associated with radioresistance of NPC has captivated widespread attention from researchers. In this review, relevant microRNAs and their potential mechanisms were summarized.

GLP-1/GIP/Gcg receptor Triagonist improves the cognitive behaviors in triple-transgenic mice of Alzheimer's disease / 生理学报

Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health but is still irreversible up to now. Recent studies indicate that type 2 diabetes mellitus (T2DM) is an important risk factor for AD, and the drugs used for treatment of T2DM have shown some neuroprotective effects in the treatment of AD. Glucagon-like peptide-1 (GLP-1)/ glucose-dependent insulinotropic polypeptide (GIP)/glucagon (Gcg) receptor Triagonist is a new monomeric polypeptide equally activating the GLP-1/GIP/Gcg receptors, which is built on the basis of GLP-1/Gcg receptor coagonist core sequence, and incorporated with partial amino acids of GIP. Recently, the Triagonist has been reported to be effective in alleviating diabetic complications in rodent models of obesity. The present study observed for the first time the cognitive improvement effects of the Triagonist in the triple-transgenic AD mice (3xTg-AD) by using multiple behavioral techniques, and explored its probable molecular mechanisms using ELISA and Western blot. The results showed that the chronic treatment with the Triagonist (i.p.) significantly reversed the impairments in working memory of 3xTg-AD mice, with an obvious increase in the percentage of correct spontaneous alternation in the Y maze; the Triagonist treatment also improved long-term spatial memory and re-learning ability of 3xTg-AD mice in classical Morris water maze and reverse water maze tests, with decreased escape latency in under water platform tests and increased swimming time in probe tests. ELISA and Western blot experiments showed that the Triagonist up-regulated the levels of cAMP, PKA and p-CREB in the hippocampus of 3xTg-AD mice. These results indicate that GLP-1/GIP/Gcg receptor Triagonist can improve the cognitive behaviors in 3xTg-AD mice, and the up-regulation of hippocampal cAMP/PKA/CREB signal pathway may mediate the neuroprotection of the Triagonist, suggesting that the GLP-1/GIP/Gcg receptor Triagonist may be a novel therapeutic strategy for the treatment of AD.

Effect of independent breath-holding technology on target geometry in radiotherapy for liver cancer / 中华放射肿瘤学杂志

Objective To use the fusion image of the end-inhalation holding (EIH) phase and endexhalation holding (EEH) phase to define the target volume of individual patient with liver cancer,and to evaluate the target geometry,feasibility,and clinical significance of the technology.Methods Eighteen patients with liver caucer who were treated in our hospital from 2012 to 2013 were enrolled as subjects.With the same posture and scan range,all patients underwent contrast-enhanced three-dimensional computed tomography (3DCT) scans in the phases of free breathing (FB),EIH,and EEH.Gross tumor volume (GTV),clinical target volume (CTV),and organ of risk (OAR) were delineated on the above images.CTVFB was defined as GTV on the FB phase image (GTVFB) plus a margin of 10 mm,while planning target volume (PTVFB) was defined as CTVFB plus a margin of 10 mm in the right-left and anterior-posterior directions and a margin of 20 mm in the superior-inferior direction.GTVEI and GTVEE were defined as GTV on the EIH and EEH images,respectively.Based on the EEH images,the registered EEH and EIH images were fused to form GTVEI+EI.CTVEI+EE was defined as GTVEI+EI plus a margin of 10 mm,while PTVEI+EE was defined as CTVEI+EE plus a margin of 5 mm in the right-left and anterior-posterior directions and a margin of 10 mm in the superior-inferior direction.The Pinnacle3 v8.0m treatment planning system was used to design two 3D conformal radiotherapy plans for each patient.The volume,degree of inclusion (DI),matching index (MI),and central displacement of CTVFB and CTVEI+EE,as well as PTVFB and PTVEI+EE,were compared between the two plans.Results In the 18 patients,the mean CTVFB was significantly smaller than the mean CTVEI+EE(149.00±87.54 cm3 vs.188.17± 125.72 cm3,P=0.014);there was no significant difference between the mean PTVFB and PTVEI+EE (276.68± 146.41 cm3 vs.253.66± 117.35 cm3,P=0.080).DI of CTVFB to CTVEI+EF,PTVFB to PTVEI+EE,CTVEI+EE to CTVFB,and PTVEI+EE to PTVFB were (99.83±0.09)％,(84.55±8.45) ％,(80.83± 12.31) ％,and (99.78±0.08) ％,respectively.MI of CTVEI+EE to CTVFB and PTVEI+EE to PTVFB were 0.83± 0.07 and 0.87± 0.03,respectively.The central displacements of CTVEI+EE from CTVFB in x,y,and z axes were 0.55± 1.07 cm,0.76±3.02 cm,and-0.26± 1.98 cm,respectively (P =0.432,0.971,0.587).Conclusions In the treatment of liver cancer,the target volume delineation and image fusion using 3DCT images in EIH and EEH phases may avoid target omission due to respiratory movement,making it possible to increase radiation dose to target volume and improve the efficacy of radiotherapy.

Comparison of efficacy and safety between intensity-modulated radiotherapy combined with chemotherapy plus targeted therapy and intensity-modulated radiotherapy combined with chemotherapy for locally advanced nasopharyngeal carcinoma / 中华放射肿瘤学杂志

Objective To retrospectively compare the efficacy and toxicity between intensity?modulated radiotherapy ( IMRT ) combined with chemotherapy plus targeted therapy and IMRT combined with chemotherapy in the treatment of patients with locally advanced nasopharyngeal carcinoma ( NPC) , and to preliminarily evaluate the necessity of adding targeted drugs to standard chemoradiotherapy . Methods Forty?two patients with stage Ⅲ?Ⅳb NPC who received IMRT combined with concurrent ± adjuvant chemotherapy plus targeted molecular therapy from January 2007 to December 2012 were assigned to experiment group,while 168 patients who received IMRT combined with concurrent ±adjuvant chemotherapy within the same period were assigned to control group. The experiment group was paired with the control group at a ratio of 1vs.4.The survival rates were caculated using Kaplan?Meier method and analyzed using log?rank method,other comparison was perfomed by χ2?test. Results The follow?up rate was 100%.The sample size of experiment group and control group were 42 patients and 168 patients. There were no significant differences in the 3?year OS, LRFS, or DMFS rates between the experiment group and the control group (94?3% vs. 87?3%, P=0?647;100?0% vs. 94?6%,P=0?193;92?2% vs. 89?1%, P=0?744).There were also no significant differences in the incidence rates of grade Ⅲ?Ⅳ gastrointestinal reaction or marrow suppression between the two groups ( 7?1%( 3/42 ) vs. 3?6%( 6/168 ) , P=0?388;26?2%( 11/42 ) vs. 17?3%(29/168),P=0?272).However,the experiment group had significantly higher incidence of grade Ⅲ?Ⅳoral mucositis than the control group ( 40?5%( 17/42 ) vs . 14?9%( 25/168 ) , P=0?000 ) . Conclusions The preliminary results indicate that IMRT combined with chemotherapy plus targeted molecular therapy is not able to substantially improve the OS, LRFS, or DMFS rates in patients with locally advanced NPC. Moreover, it may aggravate radiochemotherapy?induced oral mucositis.

Regulatory mechanisms of the radiosensitive effect of PARP-1 inhibitor on breast cancer cells with BRCA mutation / 中华放射医学与防护杂志

Objective To investigate the radiosensitivity effects of poly ADP-ribose polymerase-1 (PARP-1) inhibitor 3-amion benzamide (3-AB) on the BRCA non-mutant and BRCA mutant breast cancer cells,and to explore the regulatory mechanism of PARP-1 and BRCA in radiation-induced DNA damage repair.Methods MDA-MB-436 cells and MDA-MB-231 cells were divided into four groups respectively as the control (CTRL),ionizing radiation alone (IR),3-AB alone (3-AB),and ionizing radiation combined with 3-AB(IR + 3-AB)group.γ-H2AX foci were detected by immunofluorescence assay.The radiosensitivity of breast cancer cells was evaluated by clonogenic survival assay.The percentage of apoptotic cells was assessed by flow cytometry.Results Compared with MDA-MB-231 cells,MDA-MB-436 cells had a higher radiosensitivity and produced more γ-H2AX foci(t =4.57,P ＜ 0.05),which was further increased by 3-AB.The DNA damage of MDA-MB-436 cells in the IR + 3-AB group was the most remarkable (t =3.26,P ＜ 0.05).Flow cytometry showed that the cells in the IR + 3-AB group had the highest rate of apoptosis (t=3.81,P ＜ 0.05),and the apoptosis rate of MDA-MB-436 cells was significantly higher than MDA-MB-231 cells (t =2.96,P ＜ 0.05).Conclusions The radiosensetivity of BRCA mutant cells MDA-MB-436 is significantly higher than that of non-BRCA mutant cells MDA-MB-231.Inhibition of PARP-1 can further increase the apoptosis and radiosensitivity of BRCA-mutant cells by further blocking the repair of DNA single-strand break induced by ionizing radiation.

Suppression of autophagy activity enhances the radiosensitivity of human nasopharyngeal carcinoma CNE-2 cells / 中华放射医学与防护杂志

Objective To investigate the effect of autophagy in radiosensitivity of nasopharyngeal carcinoma CNE-2 cells.Methods The expression of ATG5 in CNE-2 cells was inhibited by lentiviral mediated RNA interference.The cells were divided into three groups:control group,NC group and ATG5 group.Cell proliferation,apoptosis and radiosensitivity were detected by CCK-8 method,flow cytometry and colony-forming assay,respectively.Results Compared with the NC group and control group,the survival of ATG5-interfected cells was reduced (F =3.755,46.086,8.609,44.160,P ＜ 0.05).After 6 Gy X-ray irradiation,the apoptosis index of the ATG5 group significantly higher than that of NC group and control group (F =394.876,P ＜ 0.05).In addition,the radiosensitivity of ATG5 group was also higher than that of control cells.Conclusions Suppression of autophagy activity enhances the radiosensitivity of human nasopharyngeal carcinoma cells.

Comparison between the 7th edition of International Union Against Cancer staging system and the Chinese 2008 staging system for nasopharyngeal carcinoma and suggestions for the updating of the staging system / 中华放射肿瘤学杂志

Objective To compare the 7th edition of International Union Against Cancer ( UICC) staging system with the Chinese 2008 staging system for nasopharyngeal carcinoma ( NPC) , and to provide evidence for further updating of the staging system. Methods A retrospective analysis was performed among 767 patients who were pathologically and newly diagnosed with non?metastatic NPC and treated with intensity?modulated radiotherapy from 2006 to 2012. Based on the main prognostic indices, overall survival ( OS) , locoregional failure?free survival( LFFS) local relapse?free survival ( LRFS) , and distant metastasis?free survival ( DMFS) rates, the value of T stage, N stage, and clinical stage in prognostic prediction was compared between the two staging systems. The Kaplan?Meier method was used for calculating survival rates. The log?rank test was used for survival difference analysis. The Cox model was used for multivariate prognostic analysis. Results In terms of T stage, the Chinese 2008 staging system was a significantly better predictor of the OS and LRFS rates than the 7th edition of UICC staging system. In terms of N stage, they were comparable in the prediction of the OS and DMFS rates. In terms of clinical stage, the 7th edition of UICC staging system was a significantly better predictor of the OS rate than the Chinese 2008 staging system. For the new staging system proposed based on the statistical results, the T, N, and clinical staging gave significantly better prognostic prediction. Conclusions The 7th edition of UICC staging system and the Chinese 2008 staging system for NPC have their own advantages in prognostic prediction. The new staging system proposed in this study could contribute to the updating of the current staging system for NPC.

Suppression of Amp activated protein kinase activity enhance the radiosensitivity of human nasopharyngeal carcinoma cells / 重庆医学

Objective To investigate the effect of Amp activated protein kinase(AMPK)activity in radiosensitivity of human na-sopharyngeal carcinoma cells .Methods Human nasopharyngeal carcinoma cells ,CNE-2 ,were treated with AMPK inhibitor ,Com-pound C(CC) ,for 1 h .Then cells were explored in X-ray .The expression of total AMPK (t-AMPK) ,phosphorylation AMPK (p-AMPK) ,and MAPlLC3 were detected by Western blot .The number of autophagosomes were observed and calculated by transmis-sion electron microscope(TEM) .Cells processed with CC were explored in X-ray .MTT assay was used to detect the difference of two groups in cell proliferation .Cell apoptosis were assayed by flow cytometry .Results The expression of p-AMPK in CC group cells were significantly downregulated compared to the negative control group cells (P0 .05) .The expression of MAPlLC3 and the number of autophagosomes in CC group cells were significantly decreased compared to the control group cells (P<0 .05) .Correspondingly ,the cell proliferation rate in CC group was lower than in control group ,and the percent of apoptosis cells was higher in CC group than in control group (P<0 .05) .Conclusion Suppression of AM PK activity could inhibited autophagy induced by decreasing the degree of p-AM PK ,then enhanced the effect of proliferation inhibition and apoptosis promotion in CNE-2 cells .The AMPK inhibitor ,CC ,can serve as an effective assistant treatment of radiotherapy for nasopharyngeal carcinoma .

Comparative proteomic analysis on radioresistant nasopharyngeal carcinoma cell / 中华放射医学与防护杂志

Objective To discover radioresistance-associated proteins by performing comparative proteomic analysis on nasopharyngeal carcinoma cell lines.Methods The total proteins were extracted from radioresistant human nasopharyngeal carcinoma cell line CNE-2R and its parental cell line CNE-2,respectively.These proteins were separated by high quality two-dimensional polyacrylamide gel electrophoresis (2-DE) and then the 2-DE profiles were screened for differentially expressed protein spots by the Image Master 5.0 software.Those spots were identified by a matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry.Results 32 significantly differentially expressed protein spots were screened in two different radiosensitivity cell lines and 11 proteins were identified by tandem mass spectrometry,among which 3 proteins were up-regulated in radioresistant human nasopharyngcal carcinoma cell line CNE-2R and the other 8 proteins were down-regulated.Conclusions The differentially expressed proteins of nasopharyegeal carcinoma cells with different radiosensitivity were mainly involved in apoptosis regulation,DNA damage and repair,cell cycle regulation,RNA transcription,cell signaling,cytoskeleton formation and radiation stress responses.

Radioresistance related genes screened by protein-protein interaction network analysis in nasopharyngeal carcinoma / 中华放射医学与防护杂志

Objective To discover radioresistance associated molecular biomarkers and its mechanism in nasopharyngeal carcinoma by protein-protein interaction network analysis.Methods Whole genome expression microarray was applied to screen out differentially expressed genes in two cell lines CNE- 2R and CNE-2 with different radiosensitivity.Four differentially expressed genes were randomly selected for further verification by the semi-quantitative RT-PCR analysis with self-designed primers. The common differentially expressed genes from two experiments were analyzed with the SNOW online database in order to find out the central node related to the biomarkers of nasopharyngeal carcinoma radioresistance. The expression of STAT1 in CNE-2R and CNE-2 cells was measured by Western blot.Results Compared with CNE-2 cells,374 genes in CNE-2R cells were differentially expressed while 197 genes showed significant differences.Four randomly selected differentially expressed genes were verified by RT-PCR and had same change trend in consistent with the results of chip assay. Analysis with the SNOW database demonstrated that those 197 genes could form a complicated interaction network where STAT1 and JUN might be two key nodes.Indeed,the STAT1-α expression in CNE-2R was higher than that in CNE-2 (t =4.96,P ＜ 0.05).Conclusions The key nodes of STAT1 and JUN may be the molecular biomarkers leading to radioresistance in nasopharyngeal carcinoma,and STAT1-α might have close relationship with radioresistance.

Contribution' of autophagy inhibitor to radiation sensitization in nasopharyngeal carcinoma cells / 中华放射医学与防护杂志

Objective To investigate the role of autophagy in radiation-induced death response of human nasopharyngeal carcinoma cells.Methods MTT method was used to detect cell viability of CNE-2 cells in different time after irradiation.Clonogenic survival assay was used to evaluate the effect of autophagy inhibitor (chloroquine phosphate) and autophagy inductor (rapamycin) on radiosensitivity of nasopharyngeal carcinoma cells.Cell apoptosis was assessed by flow cytometry.The expressions of LC3 and P62 were measured with Western blot.Cell ultrastructural analysis was performed under an electron microscope.Results Irradiation with 10 Gy induced a massive accumulation of autophagosomes accompanied with up-regulation of LC3-Ⅱ expression in CNE-2 cells.Compared with radiation alone,chloroquine phosphate (CDP) enhanced radiosensitivity significantly by decreasing cell viability (F =25.88,P ＜ 0.05),autophagic ratio (F =105.15,P ＜ 0.05),and LC3-Ⅱ protein level(F =231.68,P ＜0.05),while up-regulating the expression of P62 (F =117.52,P ＜ 0.05).Inhibition of autophagy increased radiation-induced apoptosis (F =143.72,P ＜ 0.05).Rapamycin (RAPA) also significantly decreased cell viability,but increased autophagic ratio and LC3-Ⅱ protein level while down-regulated the expression of P62.Induction of autophagy increased radiation-induced apoptosis(F =167.32,P ＜ 0.05).Conclusions Blockage of autophagy with CDP could enhance radiosensitivity in human nasopharyngeal carcinoma cells,suggesting that inhibition of autophagy could be used as an adjuvant treatment to nasopharyngeal carcinoma.

Radioresistance-related signaling pathways in nasopharyngeal carcinoma cells / 中华放射医学与防护杂志

Objective To study the difference of gene expression profile between the radioresistant human nasopharyngeal carcinoma cell line CNE-2R and CNE-2,and to screen the signaling pathway associated with radioresistance of nasopharyngeal carcinoma.Methods The radioresistant nasopharyngeal carcinoma cell line CNE-2R was constructed from the original cell line CNE-2.CNE-2R and CNE-2 cells were cultured and administered with 60Co γ-ray irradiation at the dose of 400 cGy for 15 times.Human-6v 3.0 whole genome expression profile was used to screen the differentially expressed genes.Bioinformatic analysis was used to identify the pathways related to radioresistance.Results The number of the differentially expressed genes that were found in these 2 experiments was 374.The Kegg pathway and Biocarta pathway analysis of the differentially expressed genes showed the biological importance of Toll-like receptor signaling pathway and IL-1 R-mediated signal transduction pathway to the radioresistance of the CNE-2R cells and the significant differences of 13 genes in these 2 pathways,including JUN,MYD88,CCL5,CXCL10,STAT1,LY96,FOS,CCL3,IL-6,IL-8,IL-1α,IL-1B,and IRAK2(t=13.47-66.57,P<0.05).Conclusions Toll-like receptor signaling pathway and IL-1R-mediated signal transduction pathway might be related to the occurrence of radioresistance.

Variabilities of serum proteomic spectra in patients with nasopharyngeal carcinoma before and after radiotherapy / 中华放射医学与防护杂志

Objective To study the changes of serum proteomic spectra in patients with nasopharyngeal carcinoma(NPC) before and after treatment in order to detect the protein biomarkers.Methods Proteomic spectra from serum of 50 NPC patients before radiotherapy,25 NPC patients who achieved complete remission(CR) after radiotherapy, and 40 persons from normal control subjects were analyzed by CM-10 protein chip and surface-enhanced laser desorption ionization time of flight mass spectrometry. Results Expressed proteins in serum were screened by analysis of the proteomic spectra of pre-radiotherapy patients and normal individuals. 4 kinds of proteins with the relative molecular masses of 2931,4098,5343,13 766 made up markers pattern which was able to classify the patients and normal individuals. The sensitivity and specificity results were 90.0% and 90. 0% , respectively. The twenty differential expression protein peaks of patients before and after radiotherapy were obviously different. The relative molecular masses of 2931 , 4182, 4688 and 13 766 were up-regulated in untreated NPC, while were close to the normal levels in CR group. Two other protein peaks of 4098 and 5343 were down-regulated in untreated NPC group, which were close to normal levels in CR group. Conclusions The expressions of protein levels are different before and after radiotherapy in NPC patients. Protein signatures of NPC may be screened using SELDI-TOF-MS. Those signatures may be helpful in assessing the minimal residual disease and predicting the treatment efficacy.