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.

ObjectiveTo explore the clinical efficacy and safety of Qifu Yixin prescription in treating chronic heart failure in the patients with the syndrome of heart Qi deficiency， so as to provide clinical evidence for the treatment of chronic heart failure with this prescription and promote the clinical application and transformation of this prescription. MethodA total of 106 chronic heart failure patients with the syndrome of heart Qi deficiency who met the criteria in Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine （TCM） from September 2022 to May 2023 were selected and randomized into an observation group （53 cases） and a control group （53 cases）. Both groups received routine Western medicine treatment. In addition， the observation group received Qifu Yixin prescription， while the control group received placebo. The treatment course for both groups was 12 weeks. The New York heart association （NYHA） cardiac function grading， N-terminal pro-B-type natriuretic peptide （NT-proBNP）， soluble growth-stimulating expression gene 2 （sST2）， left ventricular ejection fraction （LVEF）， the ratio of early diastolic maximum mitral flow velocity （E） to early diastolic mitral annular motion velocity （e'） （E/e'）， left ventricular end diastolic diameter （LVEDD）， TCM syndrome scores， 6-minute walking test （6MWT）， Minnesota Living with Heart Failure Questionnaire （MLHFQ）， and Kansas City Cardiomyopathy Questionnaire （KCCQ） were determined before and after treatment. ResultFinally， 102 patients were included for analysis， including 51 patients in the observation group and 51 patients in the control group. After treatment， 42 patients in the observation group showed improved cardiac function grading， with a total response rate of 82.35%， and 32 patients in the control group showed improved cardiac function grading， with a total response rate of 62.75%. The total response rate regarding the cardiac function in the observation group was higher than that in the control group （χ²=4.923， P<0.05）. The observation group outperformed the control group in lowering the NT-proBNP level， elevating LVEF， decreasing the E/e' ratio （P<0.05）， reducing LVEDD and sST2 levels， and recovering TCM syndrome score， 6MWT score， MLHFQ score， and KCCQ score （P<0.05）. None of the safety indexes in the two groups showed abnormal values before and after treatment， and no serious adverse reaction was observed. ConclusionQifu Yixin prescription can improve the heart function， exercise tolerance， and quality of life and alleviate the TCM syndrome of the chronic heart failure patients with the syndrome of heart Qi deficiency by inhibiting myocardial fibrosis.

Objective:To investigate the level of death anxiety and its related factors in patients with newly diagnosed cancer at different stages.Methods:A total of 266 cancer patients in a tertiary oncology hospital were se-lected and investigated at admission(Tl),discharge(T2),and 1 month after discharge(T3).They were assessed with the self-compiled general information questionnaire,Templer's Death Anxiety Scale(T-DAS),Acceptance and Action Questionnaire Second Edition(AAQ-Ⅱ.),and the Chinese version of the Meaning in Life Questionnaire(C-MLQ).The Kruskal-Wallis H test and generalized estimating equation were used to analyze the level of death anxi-ety and its influencing factors in cancer patients at different time points.Results:The Kruskal-Wallis H test showed that the total T-DAS scores and the difference in the scores of the four dimensions were statistically significant at three time points(Ps＜0.01),with the highest T1 score and the lowest T3 score.The results of generalized estima-ting equation showed that male gender(β=1.25),junior high school education(β=2.59),worker(β=1.46),farmer(β=1.67),respiratory(β=1.74),digestive system tumor(β=2.51),and AAQ-Ⅱ score(β=0.23)posi-tively predicted death anxiety in patients with cancer.Head and neck(β=-1.73),breast tumors(β=-1.84),stage Ⅰ(β=-2.58)and stage Ⅱ tumors(β=-2.11),and C-MLQ score(β=-0.15)negatively predicted death anxiety in patients with cancer.Conclusion:Death anxiety in patients with newly diagnosed cancer is highest on ad-mission and gradually relieves after discharge.

OBJECTIVE To study the pharmacokinetic characters of Baihe -zhimu decoction （BZD） and its single herbs . METHODS A liquid chromatography -tandem mass spectrometry method was developed to simultaneously determine the blood concentrations of 7 effective components （neomangiferin，mangiferin，regaloside A ，regaloside Ⅰ，timosaponin B Ⅱ，timosaponin E and timosaponin A Ⅲ）in rats after oral administration of BZD extract ，single herb extract of Lilium brownii and Anemarrhena asphodeloides. The pharmacokinetic parameters were calculated . RESULTS The linear range of 7 effective components as neomangiferin were 1-1 000，1-1 000，0.1-100，0.4-400，1-1 000，0.1-100 and 0.5-500 ng/mL（all r＞0.998），respectively. The accuracy of the method ranged from 87.50% to 115.00%，and the RSDs of intra -day and inter -day precision were 0.62%-14.35%. RSDs of matrix factor were 2.68%-14.03%，and deviation of stability were within ±15%. Compared with L. brownii and A. asphodeloides，AUC0－24h，AUC0－∞ and cmax of 7 effective components in BZD were increased significantly （P＜0.05），while CL z/Fof 6 effective components （except timosaponin B Ⅱ）decreased significantly （P＜0.05）. CONCLUSIONS BZD can increase the absorption of effective ingredients in rats ，slow down their elimination and prolong their retention time ，indicating pharmacokinetic behaviors of effective components in BZD possess more advantages over those of single herbs .

OBJECTIVE：To systematically evaluate the effectiveness and safety of Shenfu qiangxin pills combined with chemical medicine conventional therapy in the treatment of chronic heart failure ，and to provide evidence-based reference for clinical drug use. METHODS ：Retrieved from CNKI ，Wanfang database ，VIP，Google Scholar ，PubMed，the Cochrane Library and Embase database ，RCTs about Shengfu qiangxin pills combined with chemical medicine conventional therapy （trial group ） versus chemical medicine conventional treatment （control group ）were collected during the inception to May 12th，2020. After literature screening and data extraction ，the quality of the literatures was evaluated with risk bias assessment tool recommended by Cochrane 5.1.0 system evaluator manual. Meta-analysis and sensitivity analysis were performed by using Stata 14.0 software. RESULTS：A total of 7 RCTs were included ，involving 596 patients. Meta-analysis results showed that the total response rate of trial group was significantly higher than that of control group [OR ＝4.14，95％CI（2.15，7.97），P＜0.000 01]；the results of sub-group analysis according to the different criteria for determining the efficacy showed that the total response rates of trial group determined by Lee integral method and cardiac function grading method were sig nificantly higher than that of the control group （P＜0.05）. After treatment ，N-terminal pro-B-type natriuretic peptide （NT-proBNP） level of trial group was significantly lower than that of control group [OR ＝－1.33，95％CI（－1.55， qq.com －1.11），P＜0.000 01]. Results of sub-group analysis accor- ding to cardiac failure type showed that NT-proBNP level of patients with chronic heart failure in trial group was lower than control group （P＜0.001）. The level of left ventricular ejection fraction （LVEF）in trial group after treatment [WMD ＝5.76，95％CI （5.05，6.47），P＜0.000 01] was significantly higher than control group ；after treatment ，the level of B-type natriuretic peptide [SMD＝－1.61，95％CI（－2.58，－0.54），P＜0.000 01]，left ventricular end-diastolic diameter （LVEDD）level [WMD ＝ －6.06，95％CI（－6.84，－5.27），P＜0.000 01]，left ventricular end-systolic diameter level [WMD ＝－0.52，95％CI（－5.70，－4.33）， P＜0.000 01] were significantly lower than control group. There was no statistically significant difference in the incidence of ADR between 2 groups（P＞0.05）. Results of sensitivity analysis showed that when NT-proBNP ，LVEF level ，LVEDD level after treatment were used as indicators ，there was no significant difference in the analysis results after eliminating heterogeneity source ， compared with before elimination. CONCLUSIONS ：Shenfu qiangxin pills combined with chemical medicine conventional treatment has good efficacy and safety.

OBJECTIVE：To explo re the clinical characteristics of voriconazole-induced neurological ADR and the occurrence of hypokalemia and hyponatremia before ADR. METHODS ：The medical records of 411 patients receiving voriconazole therapy ， who admitted to our hospital from January 2018 to November 2020，were retrospectively analyzed. The general information of all patients，including sex ，age，body weight ，type of infection ，underlying disease ，type of pathogenic fungal infection and administration route of voriconazole ，maintenance dose ，blood drug concentration ，were collected. The basic information of patients with neurological ADR ，including sex ，age，types of infection ，underlying disease ，drug combination ，occurrence time and clinical manifestations ，were collected . The levels of blood potassium ，blood sodium and liver function indexes （ALT，AST， γ-GT，ALP，total bilirubin ，direct bilirubin ）within 3 days before the neurological ADR were also collected. The relationship of neurological ADR with voriconazole trough concentration ，blood potassium and blood sodium levels was analyzed. RESULTS ： Among 411 patients，31（7.54％）patients suffered from neurological ADR ，which were higher in male （64.52％）than in female （35.48％），mainly in patients aged 50 and over （74.20％）. The major infection type was lung infection （96.77％）. Among 31 patients with neurological ADR ，26 patients suffered from neurological ADR after 1-7 days after voriconazole administration ， accounting for 83.87％. Thirty patients received intravenous drip ，accounting for 96.77％. The incidence of neurological ADR in patients with voriconazole trough concentration ＞5.0 μ g/mL （8.99％）was significantly higher than that in patients with trough concentration ≤5.0 μg/mL（3.42％，χ2＝4.91，P＝0.027）. The clinical manifestations of the patients were mainly 023-68766797。E-mail：cheng7zhu@163.com hallucinations（32.35％），irritability（32.35％）and poor sleep （17.65％），etc. Within 3 days before 30 patients，receiving related indexes test ，suffered from neurological ADR ，16 patients（53.33％）had hypokalemia and 12 patients（40.00％） had hyponatremia ，which w ere significantly higher than the incidence of hypokalemia （24.74％，P＝0.001）and hyponatremia （12.89％，P＜0.001）in those without neurological ADR . There were 8，10，7，13，7 and 10 patients with ALT ，AST，ALP， γ-GT，total bilirubin and direct bilirubin increased. In 31 patients with neurological ADR ，the neurological ADR were relieved or disappeared after reducing the dosage or discontinuing voriconazole. CONCLUSIONS ：The neurological ADR of voriconazole mostly occurs 1-7 days after voriconazole administration ，mainly by intravenous drip ，mostly in male and people aged 50 and over. The occurrence of neurological ADR may be related to trough concentration of voriconazole ，and most patients suffer from hypokalemia or hyponatremia before the occurrence of ADR .

OBJECTIVE： To establish the method for simultaneous determination of clopidogrel （CLP）， its intermediate metabolite （2-O-CLP）， inactive metabolite （CLPCA） and active metabolite （CLPTM） in human plasma. METHODS： Totally 90 patients diagnosed as stroke were selected from the First Affiliated Hospital of Army Medical University. They were given one CLP tablet （75 mg/tablet） orally on an empty stomach in the morning. Blood samples were collected 2 h after taking the tablet. CLPTM- D was formed by derivation of CLPTM with 2-bromo-3’-methoxyacetophenone and extracted by precipitation of acetonitrile protein together with the other three substances to be measured. LC-MS/MS method was adopted. The determination was performed on Agilent poroshell 120 EC-C18 column with mobile phase consisted of acetonitrile （0.1％ formic acid） and water （0.1％ formic acid） （90 ∶ 10， V/V）. The quantitation analysis was performed using multiple reaction monitoring at the specific ion transitions of m/z 308.1→198.1 （CLPCA）， 322.3→212.0 （CLP）， 338.3→155.0 （2-O-CLP）， 504.4→354.1 （CLPTM-D） and 264.0→154.1 （ticlopidine， internal standard）， respectively. RESULTS： The retention time of CLPCA， CLP， 2-O-CLP， CLPTM-D and internal standard were 2.01， 3.32， 2.83， 2.68， 1.87 min， respectively. The linear range of CLPCA， CLP， 2-O-CLP and CLPTM-D were 100-10 000， 0.2-20， 0.3-30， 0.5-50 ng/mL （all r≥0.999 5）. The intra-day and inter-day RSD were all less than 9.5％ （n＝5）. Accuracy ranged from 93.5％-98.9％ （n＝5）， and extraction recovery was from 85.4％ to 95.9％ （n＝5）. The matrix effect ranged from 2.7％-6.2％ （n＝5）. In stability tests （storing at －80 ℃ for 3 months， 3 freeze-thaw cycles， storing at 4 ℃ for 8 h）， RE of CLP， CLPCA and CLPTM-D were all lower than 10.0％ （n＝5）. CONCLUSIONS： Established LC-MS/MS method has the advantages of high specificity， accuracy and reliability， and can be used to detect the concentration of CLP and its three metabolites in human plasma.

Object: To explore the electrocardiographic characteristics of ventricular arrhythmias (VAs) originating from tricuspid annulus region. Methods: Present study included 169 consecutive patients undergoing catheter ablation of VAs from tricuspid annulus origin in our department from August 2007 to September 2016. Based on the origin sites, the patients were divided into two subgroups, the free wall group (81 cases) and septal wall group (88 cases). Based on the location, patients in the free wall group were classified into anterolateral (22 cases), lateral (26 cases) and posterolateral (33 cases) subgroups. Patients in the septal group were classified into anteroseptal (10 cases), midseptal (71 cases) and posteroseptal (7 cases) subgroups. We analyzed the electrocardiographic features of these patients and in 87 patients with PVCs/VT originating from right ventricular outflow tract. Results: (1) A positive R wave inⅠ, aVL, V₅-V₆ leads were found among most of patients, only few cases originating from tricuspid annulus anteroseptum group and tricuspid annulus anterolateral group demonstrated qr or qs pattern in aVL lead. 97.53% (79/81) patients demonstrated rS pattern in V₁-V₃ leads with VAs originating from tricuspid annulus free wall, and 9/10 patients demonstrated rS pattern in V₁ lead with VAs originating from anteroseptum, and 97.44% (76/78) patients demonstrated QS pattern in V₁ lead with VAs originating from midseptum and posteroseptum. Precordial lead transition zone was on or behind V₃ for tricuspid annulus free wall group (96.3%, 78/81), but in front of V₃ for tricuspid annulus septum wall group (47.73%, 42/88) (P<0.01). The S wave's amplitude smaller than-1.81 mV in lead V₂ can be used as a cutoff value to identify if PVC/VT is originating from free wall or septum of TA. R wave in inferior wall leads was found among 98.85% (86/87) patients with PVCs/VT originating from right ventricular outflow tract. Conclusion A positive R wave in Ⅰ, aVL, V₅-V₆ leads was found among most of patients with idiopathic ventricular arrhythmias originating from the tricuspid annulus regions, but VAs originating from different portions of tricuspid annulus area have distinct electrocardiographic characteristics.

Although oxymatrine (OMT) has been shown to directly inhibit the replication of hepatitis B virus (HBV), limited research has been done with this drug. In the present study, the antiviral effect of OMT was investigated in an immunocompetent mouse model of chronic HBV infection. The infection was achieved by tail vein injection of a large volume of DNA solution. OMT (2.2, 6.7 and 20 mg/kg) was administered by daily intraperitoneal injection for 6 weeks. The efficacy of OMT was evaluated by the levels of HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B core antigen (HBcAg). The immunoregulatory activity of OMT was evaluated by serum ELISA and flow cytometry. Results shows that OMT at 20 mg/kg inhibited HBV replication, and it was more efficient than entecavir (ETV) in the elimination of serum HBsAg and intrahepatic HBcAg. In addition, OMT accelerated the production of interferon-(IFN-) in a dose-dependent manner in CD4T cells. Our findings demonstrate the beneficial effects of OMT on the enhancement of immunological function and in the control of HBV antigens. The findings suggest this drug to be a good antiviral therapeutic candidate for the treatment of HBV infection.

Objective To investigate the effect of MMP-8 on cornea. Methods Fifteen C57BL/6J healthy mice were selected. The right eyes corneal stroma was injected by 10μL MMP-8 as the experimental group and the left eyes were injected by same amount of normal saline as the control group. At 0,4,8 h, the two-photon microscope second harmonic generation imaging technology was used to scan mice corneal stroma layer by layer in vivo. The obtained images were performed the 3D reconstruction by Imaris software and the signal intensity of the images were calculated. At 4,8 h, the corneal opacity degree was evaluated under slit lamp. At 8 h,mice were killed and corneas were collected to determine the hydroxyproline concentration. Results The cornea stromal fiber signal strengthes at 0 h in the experimental group and control group were (89.7±11.2) and (85.3±7.0),which at 4 h were (14.5±3.4) and (46.6±14. 0) respectively,which at 8 h were (11.0±4.6) and (34.6±12.5) respectively. The cornea stromal signal strength at 4,8 h in the experiemental group was significantly decreased compared with that in the control group (P<0.05) ;the cornea at 4 ,8 h in the experimental group was significantly turbid than that in the control group (P<0.05);the cornea hydroxyproline concentrations detected at 8h in the experiemental group and control group were (0.433±0. 090) μg/mg and (0. 590±0. 133) μg/mg respectively,the experimental group was significantly lower than the control group (F=7. 193,P=0. 014). Conclusion MMP-8 has obvious degradation and destroy effect on mice corneal stroma collagen,which leads to the decrease of corneal opacity.