RESUMEN
Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.
RESUMEN
Objective To explore the effect of diammonium glycyrrhizinate(DG) and astragalus membranaceus (AM) injection on the clinical comprehensive score in patients with acute lung injury (ALI). Methods According to the random number table method,a prospective random controlled study was conducted in which 60 cases of patients with ALI were divided into a study group and a control group(each,30 cases). Both groups received a comprehensive treatment based on the new guidelines,and the study group was additionally given DG and AM injection(DG 150 mg+AM 20 ml)one time per day for 7 days. The scores of lung injury,acute physiology and chronic health evaluationⅡ(APACHEⅡ)and systemic inflammatory response syndrome(SIRS)were measured at baseline,3rd and 7th day after treatment,and ventilation support time and final disease mortality rate were also calculated in all the patients. Results There were no statistically significant differences between the two groups in the scores of lung injury,APACHEⅡand SIRS before treatment and after treatment for 3 days(all P>0.05),with prolonged treatment,the above indexes were significantly reduced compared with those before treatment in the two groups,and the decreases in scores of indexes in study group was more significant than those in control group after treatment(lung injury score:1.31±0.99 vs. 2.29±1.08,APACHEⅡscore:18.43±8.17 vs. 24.23±6.98,SIRS score:1.69±0.89 vs. 2.60±1.04,all P0.05). Conclusion The results suggest that DG and AM injection improve the scores of lung injury,APACHEⅡand SIRS,and alleviate the lung injury,so that the injection is beneficial to the early weaning from the ventilator to support treatment in patients with acute lung injury,and has certain therapeutic effect on ALI.