Mre11 inhibition by oncolytic adenovirus associates with autophagy and underlies synergy with ionizing radiation

New treatment approaches are needed for hormone refractory prostate cancer. Oncolytic adenoviruses are promising anti‐cancer agents, and their efficacy can be improved by combining with conventional therapies such as ionizing radiation. The aim of this study was to determine the timing of oncolytic adenovirus treatment with regard to radiation and study the mechanisms of synergy in combination treatment. Prostate cancer cells were infected with oncolytic adenoviruses, irradiated and synergy mechanisms were assessed. In vivo models of combination treatment were tested. Radiation and oncolytic viruses were synergistic when viral infection was scheduled 24 hr after irradiation. Combination of oncolytic adenovirus with radiotherapy significantly increased antitumor efficacy in vivo compared to either agent alone. Microarray analysis showed dysregulated pathways including cell cycle, mTOR and antigen processing pathways. Functional analysis showed that adenoviral infection was accompanied with degradation of proteins involved in DNA break repair. Mre11 was degraded for subsequent inactivation of Chk2‐Thr68 in combination treated cells, while γH2AX‐Ser139 was elevated implicating the persistence of DNA double strand breaks. Increased autophagocytosis was seen in combination treated cells. Combination treatment did not increase apoptosis or virus replication. The results provide evidence of the antitumor efficacy of combining oncolytic adenoviruses with irradiation as a therapeutic strategy for the treatment of prostate cancer. Further, these findings propose a molecular mechanism that may be important in radiation induced cell death, autophagy and viral cytopathic effect. © 2009 UICC     

不同胰岛素促泌剂单药治疗对2型糖尿病患者死亡率和心血管风险的影响

研究纳入丹麦1997～2006年间107806例起始胰岛素促泌剂或二甲双胍单药治疗的2型糖尿病患者(年龄>20岁,没有使用过胰岛素单药和联合治疗)其中9607例患者既往存在心肌梗死史.随访时间3.3年,每3个月为一个区间,收集不同胰岛素促泌剂或二甲双胍的处方,如果某区间无处方量则以之前最多3个处方量的区间 作为参考.