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.

Objective:To examine the relationship between subcortical volumes and ketamine’s antidepressant effects.Methods:Forty-five depressive patients with treatment resistance or suicide ideation were involved and received six infusions of ketamine for two weeks（0.5 mg/kg，thrice-weekly）. Depressive symptoms were assessed by Montgomery-?sberg Depression Rating Scale (MADRS) and suicide ideation was assessed by Beck Scale for Suicide Ideation-part one (SSI-Ⅰ). Subcortical volumes underwent 3.0T-weighted MRI. The Freesurfer software was used to process the T 1 images, which used a set of automated sequences to analyze subcortical volumes. Forty-five healthy controls were collected and their subcortical volumes were compared with the patients’ volumes. Linear regression analysis was used to determine the association between pre-treatment subcortical volumes and change in MADRS score as well as SSI scores after ketamine treatment (change=pre-treatment scores minus post-treatment scores). Results:In comparison to the healthy controls, depressive patients had decreased bilateral hippocampal volumes (Left:(2 993±276) mm 3vs. (2 785±263) mm 3， F=12.928， P=0.001； Right: (3 117±254) mm 3vs. (2 949±270) mm 3, F=8.217， P=0.005). Pre-treatment volumes of right thalamus were positively correlated with change in MADRS scores after six infusions in patients with treatment resistance （ B=0.009， t=3.434, P=0.002）. Conclusion:Six ketamine infusions exerted enhanced antidepressant effects in treatment-resistant depression patients with relatively larger thalamus. Volume of thalamus could be used as a biomarker of six ketamine’s antidepressants treatment outcome.

Objective:To examine the relationship between subcortical volumes and ketamine’s antidepressant effects.Methods:Forty-five depressive patients with treatment resistance or suicide ideation were involved and received six infusions of ketamine for two weeks（0.5 mg/kg，thrice-weekly）. Depressive symptoms were assessed by Montgomery-?sberg Depression Rating Scale (MADRS) and suicide ideation was assessed by Beck Scale for Suicide Ideation-part one (SSI-Ⅰ). Subcortical volumes underwent 3.0T-weighted MRI. The Freesurfer software was used to process the T 1 images, which used a set of automated sequences to analyze subcortical volumes. Forty-five healthy controls were collected and their subcortical volumes were compared with the patients’ volumes. Linear regression analysis was used to determine the association between pre-treatment subcortical volumes and change in MADRS score as well as SSI scores after ketamine treatment (change=pre-treatment scores minus post-treatment scores). Results:In comparison to the healthy controls, depressive patients had decreased bilateral hippocampal volumes (Left:(2 993±276) mm 3vs. (2 785±263) mm 3， F=12.928， P=0.001； Right: (3 117±254) mm 3vs. (2 949±270) mm 3, F=8.217， P=0.005). Pre-treatment volumes of right thalamus were positively correlated with change in MADRS scores after six infusions in patients with treatment resistance （ B=0.009， t=3.434, P=0.002）. Conclusion:Six ketamine infusions exerted enhanced antidepressant effects in treatment-resistant depression patients with relatively larger thalamus. Volume of thalamus could be used as a biomarker of six ketamine’s antidepressants treatment outcome.

OBJECTIVETo investigate both genetic and environmental influences on the exercise participation and sedentary behavior in Qingdao, Shandong province and 326 in Lishui, Zhejiang province.

METHODS568 twin pairs, including 242 in Qingdao and 326 in Lishui, were studied. Exercise participation was measured by two questions on the frequency and intensity and then divided into two groups. Sedentary behavior was measured by one question as 'how long do you spend on sitting every day'. Variance component models based on twins was used to estimate the genetic and environmental factors on these traits.

RESULTSThe average age in monozygotic twins was (41.14 ± 10.11)while in dizygotic twins it was (41.23 ± 9.89). Genetic factors accounted 78% (35%-96%) and 59% (0-94%) for exercise participation variance in Qingdao and Lishui in people aged between 20 and 40. However, there were no heritability noticed on physical activity in people older than 40 years of age. Rates of heritability on sedentary behavior in Qingdao and Lishui were 68% (59%-75%) and 32% (7%-62%), respectively.

CONCLUSIONResults from the study suggested that sedentary behavior in Chinese people was influenced by genetic factors, which could also explain much of the exercise participation variance in people aged between 20 and 40.

Adult ; China ; Cross-Sectional Studies ; Exercise ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Sedentary Lifestyle ; Surveys and Questionnaires ; Twins ; genetics ; Young Adult

Objective To investigate both genetic and environmental influences on the exercise participation and sedentary behavior in Qingdao,Shandong province and 326 in Lishui, Zhejiang province. Methods 568 twin pairs,including 242 in Qingdao and 326 in Lishui,were studied. Exercise participation was measured by two questions on the frequency and intensity and then divided into two groups. Sedentary behavior was measured by one question as‘how long do you spend on sitting every day’. Variance component models based on twins was used to estimate the genetic and environmental factors on these traits. Results The average age in monozygotic twins was(41.14 ± 10.11)while in dizygotic twins it was(41.23 ± 9.89). Genetic factors accounted 78%(35%-96%)and 59%(0-94%)for exercise participation variance in Qingdao and Lishui in people aged between 20 and 40. However,there were no heritability noticed on physical activity in people older than 40 years of age. Rates of heritability on sedentary behavior in Qingdao and Lishui were 68%(59%-75%)and 32%(7%-62%),respectively. Conclusion Results from the study suggested that sedentary behavior in Chinese people was influenced by genetic factors,which could also explain much of the exercise participation variance in people aged between 20 and 40.

Objective To observe the clinical effect of using single epidural injection of S-Ropivacaine Mesylate to ease the pain after gynaecology and obstetrics operations.Methods 180 patients who need gynaecological operations were randomly divided into two groups.The group of therapy was injected the analgesic(ropivacaine + morphia)at once when suturing the skin.And the comparing group only injected 5～6ml of analgesic at the stage of skin suture,then selfoperated analgesia pump will be used.The changes of hemodynamics and SpO_2 pf the two groups,the analgesic activities after 48 hours,occurrence of adverse reaction,etc were analyzed.Results The differences of MAP,SpO_2,and HR had statistical significance(P＞0.05);After the surgery,the effept of analgesic of 24h and 48h grade 0(pain-free rate)in therapy group is much more obvious than comparing group(χ~2=3.974,4.031,P＜0.05);Neither group has severe adverse reaction.Conclusion The effect of using sihgle epidural injection of S-Ropivacaine Mesylate to ease the pain after gynaecology and obstetrics surgeries is gopd,and has little adverse reaction.