| BACKGROUNDRadiotherapy is one of the important strategies for treatment of cancer. More than 1.6 million new patients were diagnosed with cancer each year, and nearly two-thirds of patients receiving radiotherapy in the United States. The benefits of radiotherapy for the treatment of cancer have been reported in many literatures. However, radiotherapy kills the tumor cells may also cause damage to the surrounding normal tissues at the same time. It also brings damages to the normal tissues though the so-called "bystander effect" way.The pathological processes of radiation-induced injury begin immediately after receiving radiation, but the clinical and histological characteristics may not become obviously for weeks, months, or even several years after treatment. For example, in the lung, changes detected 6 weeks after ionizing irradiation are mild even after a high dose but by 6 months there is widespread fibrosis. Radiation injury is generally classified as acute, consequential late, or late effects, in accordance to the time before occurring of symptoms. Acute effects are those that are observed during the course of treatment or within a few weeks after treatment. Consequential late effects emerge later, and are caused by continuous acute damage. Late effects occur months to years after radiation exposure. Radiotherapy may cause systemic damage to the normal tissues, including skin damage, damage of the oral mucosa, gastrointestinal injury, lung injury, auditory hair cells injury, brain injury, etc. How to attenuate the radiation-induced normal tissue injuries is one of the highlight concerns in the radiotherapy research.Radiation-induced brain and neuron injury is one of the serious complications for the treatment of the intracranial tumors in head and neck after radiotherapy. Radiation-induced cognitive injury occurs in up to 90% of adult brain tumor patients who survive >6 months after whole brain irradiation. The symptoms of radiation-induced cognitive dysfunction appear decrements in verbal memory, spatial memory, attention, and novel problem-solving ability. These consequences are seriously affecting the quality of life in patients with cancer. The exact pathogenic mechanisms of radiation-induced brain injury are not clearly defined, the exact mechanism may be related to the following factors:X-Ray directly damage to the brain normal tissue; vascular injury; autoimmune reactions; oxidative stress damages produced by free radical. More studies are required to investigate the underlying mechanisms of radiation-induced injury.Zebrafish as a kind of highly homologous to human model, is now widely applied in many human diseases research. A variety of human diseases can be replicated in zebrafish model. Comparison with rodents, zebrafish has the following advantages:spawning quantity, development quickly, easy to obtain enough sample sizes; raising economic, small in size, occupying less space, and having the ability of high-through screening; transparent, easy to observe in water and having less stress, more objective results, etc. Using zebrafish in radiation injury research has been widely reported. It is reported that radiation resulted to whole body injury in zebrafish embryos, and depletion or acute inhibition of checkpoint kinase 1 (Chkl) is sufficient to restore gamma-radiation-induced apoptosis and protect radiation-induced injury. Another study reported that Ccdc94 protected cells from ionizing radiation by inhibiting the expression of p53 in zebrafish embryos receiving a whole body irradiation. Another study also reported that X-ray caused damage to the eyes of zebrafish through production of excessive of reactive oxygen species.However, using adult zebrafish to investigate radiation-induced brain injury has not reported so far.The methods of prevention radiation-induced brain and neuron injury are including anti-inflammatory, antioxidant, embryonic stem cell transplantation therapy treatment, rennin-angiotensin inhibitor drugs therapy, hyperbaric oxygen therapy, etc. Increasing research is focus on prevention of radiation-induced normal tissue injury after radiation exposure. However, there are still lacks of the very effective drugs that can be widely applied in clinic. There is an urgent need to find some effective drugs in future.Valproic acid (VPA) is widely used in the treatment of epilepsy in clinical medicine, and can be used in the treatment of many human diseases. Plenty of reports have been reported that VPA has antioxidative activity and anti-inflammatory effect. It is reported that a single injection of VPA(300mg/kg) may have anti-inflammatory as well as antioxidative effects, leading to reduced cell death in ischemia-reperfusion injury in rats. Some literatures reported that VPA has a role in neruoprotective and a role in improvement of cognitive function. VPA treatment showed neruoprotective role, lessened cortical contusion volume, and improved motor function and spatial memory in rats with traumatic brain injury. However, whether VPA plays a radioprotective role in radiation-induced normal tissue injury is not clearly defined.Gastric cancer is one of the fouth most common cancers worldwide and is deeply threaten the health of patients. It is reported that an estimated 140,000 new cases of gastric cancer are diagnosed, with the disease accounting for about 107,000 deaths in Europe in 2012.Gastric cancer is one of the most common tumors in China, the incidence of gastric cancer is the second most occurred tumors and the mortality rate of gastric cancer is the third from the data reported in the cancer registration in China. For resectable gastric cancer, surgery is the main treatment. But its prognosis after gastrectomy is still poor, it is required multi-disciplinary comprehensive treatment including chemotherapy, radiotherapy and chemoradiotherapy. We used the evidence-based medicine method to explore the advantages of multi-disciplinary comprehensive treatment for treating gastric cancer, mainly focus on the intraoperative radiation therapy and robotic laparoscopy for treatment of gastric cancer.This study is divided into four parts. The first part:to investigate the feasibility of using zebrafish to establish the radiation-induced brain injury model. In the second part:to investigate the radiaoprotective role of VPA in prevention of radiation-induced normal tissue injury, mainly using radiation-induced brain injury zebrafish model and in the cochlear nerve cells. The third and fourth part:using evidence-based medicine view to explore the application of the comprehensive treatment for gastric cancer, mainly focus on the pros and cons of intraoperative radiotherapy and robotic-assisted laparoscopic surgery for the treatment of gastric cancer.Radiation-induced brain injury in zebrafishObjective:To investigate the feasibility of using zebrafish to establish radiation-induced brain injury model and to explore the related changes of radiation-induced brain injury in zebrafish.Methods:A total of 160 adult zebrafish,3-6month old, were randomly divided into normal control group and radiotherapy group. The zebrafish of radiotherapy group were exposure to a single dose of 20 Gy cranial radiation, the apoptosis cells in the brain tissue were measured by Tunel staining at 6h,24h and 72h after radiotherapy, the expression of P53, P21 and BBC3 genes in the zebrafish brain were analyzed by using real-time fluorescent quantitative PCR at at 6h,24h and 72h after radiotherapy. Moreover,the proinflammatory factor (tumor necrosis factor-alpha(TNF-α), interleukin-1beta (IL-1β)) and inflammatory cytokine (Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase -2(INOS2)) were detected using real-time fluorescent quantitative PCR at 6h,12h,24h and 72h after radiotherapy, the protein level of P53 was measured using westernblot method at 72h post-irradiation, the oxidative stress related parameters including reactive oxygen species (ROS), lipid peroxidation products malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) were detected in commercial detective kits.The behavior changes of zebrafish were detected after 1 month post-irradiation. The data are analysis using SPSS 19.0, and the data are expression as the means ± standard deviation. Student’s t test or analysis of variance (ANOVA) is applied for the samples analyzing. A P value less than 0.05 was considered significantly.Results:The apoptosis cells in the zebrafish brain were significantly increased after irradiation comparison with the control group with statistical significance,the apoptosis cells were peak at 6h post-irradiation(F=263.793,P<0.001). The expressions of apoptosis related genes P53 increased significantly after irradiation (F=113.815, P<0.001), the expression of P21 aslo increseased (F=128.551,p<0.001),the expression of BBC3 increased significantly(F=65.483, p<0.001), the p53 protein levels also increased significantly. The expression of TNF-a(F=25.575,P<0.001), IL-1β(F=12.012, p=0.002), COX-2 F=19.238,p=0.001), iNOS2(F=15.026,p=0.001) were also increased, indicating an inflammation reaction, comparison with normal control group with statistical significance. Radiation caused to the generation of ROS increased(F=11.067,P<0.001), and MDA levels were increased(F=104.578,P<0.001), and reduced the levels of GSH (F=651.864, P<0.001)and SOD activity(F=67.704,P<0.001). Radiation also caused to reduce the swimming distance and velocity in zebrafish in the open tank test(P<0.01). Moreover, radiation resulted to decrease of zebrafish exploration ability at 1 month after irradiation, comparison with normal control group with statistical significance (P< 0.05).Conclusion:Using of adult zebrafish can successfully replicate radiation-induced brain injury model, and this model is with similar pathogenesis as other animal models with radiation-induced injury.The radiaoprotective role of Valproate acid in radiation-induced brain and neuron injuryObjective:Radiation-induced production of reactive oxygen species (ROS) play a critical role in normal tissues response. In this study we have examined some aspects of these effects in zebrafish brain and HEI-OC1 cells after Valproate acid(VPA) treatment.Methods:VPA, a drug that was most applied in treatment of seizure disorder, recently has been reported with antioxidative activity, was investigated to protect the radiation-induced injury in zebrafish and in HEI-OC1 cells. The radioprotective role of VPA was investigated in zebrafish after an acute lethal total body irradiation after administration of VPA.The generation of ROS, MDA levels, GSH levels and the activity of SOD were detected after receiving a single dose of 20Gy irradiation in zebrafish and in cochlear hair cells. The antioxidant pathway nuclear factor erythroid-derived 2 like 2/heme oxygenase 1(Nrf2/HO-1) protein and gene levels are measured by using westernblot and real-time quantitative PCR. The cell aviablity was analysed in HEI-OC1 cells. The behavioral changes were also tested in zebrafsih at 1 month after irradiation. RNA interference method was used for interference of Nrf2 in cochlear hair cells. The underlying mechanism of radioprotective role of VPA was investigated in hair cells lack of Nrf2. The data are expression as the means ± standard deviation. Student’s t test or analysis of variance (ANOVA) is applied for the samples analyzing. Survival analysis was using the log Rank test. P< 0.05 was considered as statistical significance.Results:VPA treatment improved the survival rate(at 300mg/VPA 76.67% and 100mg/kg VPA 56.7%) of zebrafish at 1 month after a whole-body lethal dose irradiation(log rank test χ2=70.371, P<0.001). VPA treatment reduced the generation ROS(F=421.159,p<0.001), decreased MDA levels(F=1797.790, P<0.001), increased the levels of GSH(F=18667.751,P<0.001) and SOD activity(F=2514.697, P<0.001). VPA treatment activated of Nrf2/HO-1, increased the Nrf2 nuclear translocation and increased the HO-1 gene(F=2187.762, P<0.001) and protein level to prevent the radiation induced brain and neuron injury. In the absence of Nrf2 gene,VPA cannot attenuate radiation injury in the cochlear hair cells(with or without VPA (40.09±1.76)% versus (41.14±1.09)%,r=-0.877, P=0.430)). VPA also improved the the cognitive ability of the zebrafish after radiation brain injury (5.74±1.42) min versus (16.39±4.03)min versus (7.18±1.79)min,F=16.453, P<0.001).Conclusions:VPA has radioprotective role in radiation-induced normal tissue injury, mainly through activation of Nrf2/HO-1 pathway.The benefits of introperative radiotherapy for gastric cancerObjective:Gastric cancer is a refractory cancer and its prognosis is poor and is required comprehensive treatment. The benefits of adjuvant intraoperative radiotherapy (IORT) for resectable gastric cancer have been studied in plenty of works, but data on the survival benefits remains inconclusive.The aim of this study was to investigate the efficacy of IORT for treatment of resectable gastric cancer compared with that without IORT for treating gastric cancer.Funnel plot was used for assessing publication bias.Methods:We searched PUBMED, EMBASE, and the Cochrane Library for testing adjuvant IORT for resectable gastric cancer. Hazard ratios describing the impact of IORT on overall survival (OS) and locoregional control rate were extracted directly from the original studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method.Results:Our search yield 8 studies that included in our analysis. The results revealed that IORT did not significantly increased the overall survival (OS) in gastric cancer with different stage(Hazard ratio(HR)=0.84,95% confidence interval (CI)=0.67-1.05, P=0.12). However, IORT significantly increased the OS in patients with gastric cancer at stage III or more (HR=0.60,95% CI=0.40-0.89, P=0.01). Moreover, IORT significantly increased the locoregional control rate (HR=0.40,95% CI=0.26-0.61, P<0.001).Conclusion:Our study indicated that IORT can increase OS in patients with gastric cancer at stage III or more. The study also revealed that IORT significantly increased the locoregional control rate. However, the advantages of IORT are still required large randomized clinical controlled trials to investigate its benefits, in order to improve the efficacy of comprehensive treatment for gastric cancer.Robotic versus Open Gastrectomy for Gastric CancerObjects:To evaluate the safety and efficacy of robotic gastrectomy versus open gastrectomy for gastric cancer.Methods:A comprehensive search of PubMed, EMBASE, Cochrane Library, and Web of Knowledge was performed.Analysis was carried out to identify studies comparing robotic gastrectomy and open gastrectomy in gastric cancer. Intraoperative and postoperative outcomes were also analyzed to evaluate the safety and efficacy of the surgery. A fixed effects model or a random effects model was utilized according to the heterogeneity.Results:Four studies involving 5780 patients with 520 (9.00%) cases of robotic gastrectomy and 5260 (91.00%) cases of open gastrectomy were included in this meta-analysis. Compared to open gastrectomy, robotic gastrectomy has a significantly longer operation time (weighted mean differences (WMD)=92.37,95% confidence interval (CI):55.63 to 129.12, P<0.00001), lower blood loss (WMD:-126.08,95% CI:-189.02 to-63.13, P<0.0001), and shorter hospital stay (WMD=-2.87; 95% CI:-4.17 to-1.56; P<0.0001). No statistical difference was noted based on the rate of overall postoperative complication, wound infection, bleeding, number of harvested lymph nodes, anastomotic leakage and postoperative mortality rate.Conclusions:The results of this study suggest that robotic gastrectomy is a better alternative technique to open gastrectomy for gastric cancer. However, more prospective, well-designed, multicenter, randomized controlled trials are necessary to further evaluate the safety and efficacy as well as the long-term outcome. |
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