Targeted covalent inhibitors, primarily targeting cysteine residues, have attracted great attention as potential drug candidates due to good potency and prolonged duration of action. However, their discovery is challenging. In this research, a database-assisted liquid chromatography-tandem mass spectrometry (LC-MS/MS) strategy was developed to quickly discover potential cysteine-targeting compounds. First, compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes. And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database. Second, substrate-independent product ions produced from N-acetyl-cysteine moiety were selected. Third, multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds. This strategy showed broad applicability, and covalent compounds with diverse structures were screened out, offering structural resources for covalent inhibitors development. Moreover, the screened compounds, norketamine and hydroxynorketamine, could modify synaptic transmission-related proteins in vivo, indicating their potential as covalent inhibitors. This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.

Objective To observe the influence of dapagliflozin tablets on myocardial enzymes,mitral valve blood flow and major adverse cardiovascular events(MACE)in patients with acute myocardial infarction(AMI)complicated with type 2 diabetes mellitus(T2DM)after interventional therapy.Methods AMI patients with T2DM were divided into control group and treatment group by cohort method.The control group was given aspirin tablets 300 mg and ticagrelor 180 mg orally,qd,until the day of interventional treatment.After interventional therapy,aspirin tablets 100 mg,qd,oral ticagrelor tablets 90 mg each time,once in the morning and once in the evening.On the basis of the treatment in the control group,the patients in the treatment group were given dapagliflozin tablets 5-10 mg,qd,every morning after admission.After 3 months of continuous treatment,the clinical efficacy,blood glucose control effect[fasting plasma glucose(FPG),2 hour postprandial blood glucose(2 h PG)],myocardial enzymes indicators[creatine kinase(CK),creatine kinase isoenzyme-MB(CK-MB)],ventricular remodeling indicators[left ventricular ejection fraction(LVEF),left ventricular end systolic diameter(LVESD)],adverse drug reactions and MACE were compared between the two groups.Results There were 55 cases in the control group and 59 cases in the treatment group.After treatment,the total effective rates of the treatment group and the control group were 88.14％(52 cases/59 cases)and 72.73％(40 cases/55 cases),respectively,the difference was statistically significant(P＜0.05).After treatment,the FPG of the treatment group and the control group were(7.29±0.71)and(7.81±0.75)mmol·L-1,respectively;the 2 h PG were(8.66±1.33)and(9.59±1.38)mmol·L-1,respectively;the CK were(145.68±29.82)and(163.68±42.16)U·L-1,respectively;the CK-MB were(8.21±2.37)and(10.33±3.08)U·L-1,respectively;the LVEF were(57.63±8.74)％and(51.41±6.49)％,respectively;LVESD were(33.26±5.33)and(39.51±5.38)mm,respectively.The above indexes in the treatment group were significantly different from those in the control group(all P＜0.05).During the treatment,the adverse drug reactions in the treatment group mainly included nausea and vomiting,diarrhea,constipation.The adverse drug reactions in the control group mainly included hypoglycemia,diarrhea,headache.The total incidence of adverse drug reactions in the treatment group and the control group was 6.68％(4 cases/59 cases)and 9.09％(5 cases/55 cases),respectively,and the difference was not statistically significant(P＞0.05).After 3 months of follow-up,the total incidence of MACE in the treatment group and the control group was 5.08％and 18.18％,respectively,the difference was statistically significant(P＜0.05).Conclusion Dapagliflozin has a significant efficacy in the treatment of AMI patients with T2DM,and it can enhance the effect of blood glucose control,reduce the myocardial injury,inhibit the ventricular remodeling,and reduce the risk of MACE,with high safety.

Objective:To investigate the efficacy and side effects of concurrent chemoradiotherapy with or without nimotuzumab in the treatment of locally advanced nasopharyngeal carcinoma after neoadjuvant chemotherapy.Methods:In the prospective study, 100 patients with stage Ⅲ-Ⅳa locally advanced nasopharyngeal carcinoma (except T 3N 0M 0 stage) who met the inclusion criteria were randomly divided into the experimental and control groups using the random number table method. Patients in both groups were treated with neoadjuvant chemotherapy using TPF (paclitaxel liposome, cisplatin, and 5-fluorouracil) regimen for 2 cycles. At 2 weeks after chemotherapy, concurrent chemoradiotherapy plus nimotuzumab targeted therapy was given in the experimental group, and concurrent chemoradiotherapy was delivered in the control group. The main observation index was the distant metastasis-free survival (DMFS) rate. Log-rank test and multivariate Cox regression analysis were used. Results:The objective remission rate and complete remission rate in the experimental and control groups were 100% vs. 98% ( P=1.000) and 92.0% vs. 80% ( P=0.084). The 3-year DMFS in the experimental and control groups were 91.4 % vs. 76.1 % ( P=0.043). The 3-year progression-free survival (PFS), locoregional recurrence-free survival (LRFS) and overall survival (OS) in two groups were 87.3 % vs. 74.1 % ( P=0.097), 94.5 % vs. 85.6 % ( P=0.227) and 90.5% vs. 85.2% ( P=0.444). Subgroup analysis showed that patients with age<60 years ( HR=0.34, 95% CI=0.12-0.94, P=0.037), neutrophil-to-lymphocyte ratio (NLR)≤4 ( HR=0.34, 95% CI=0.13-0.89, P=0.028) received concurrent chemoradiotherapy plus nimotuzumab obtained better PFS. Multivariate analysis showed that NLR was an independent risk factor for disease progression ( HR=5.94, 95% CI=1.18-29.81, P=0.030) and distant metastasis ( HR=13.76, 95% CI=1.52-124.36, P=0.020). Conclusions:Compared with concurrent chemoradiotherapy alone, concurrent chemoradiotherapy combined with nimotuzumab after neoadjuvant chemotherapy can significantly increase DMFS rate for patients with locally advanced nasopharyngeal carcinoma. The incidence of side effects is similar in two groups. Concurrent chemoradiotherapy plus nimotuzumab after neoadjuvant chemotherapy may be a preferred treatment strategy for locally advanced nasopharyngeal carcinoma.

About 1%of the patients with acute hepatitis B can progress to acute liver failure,and 75%of the patients with hepatitis B virus(HBV)-related acute liver failure need to undergo liver transplantation or face death.This article reports a patient with HBV infection-related acute liver failure who achieved clinical cure and HBsAg seroconversion after antiviral therapy and symptomatic/supportive treatment,and dynamic monitoring was performed for immunological markers in peripheral blood.

Objective: To assess the role of dynamic contrast-enhanced (DCE)-MRI of the extraocular muscles (EOMs) for determining the activity of thyroid-associated ophthalmopathy (TAO) and treatment response to glucocorticoids (GCs). Materials and Methods: We prospectively enrolled 65 patients with TAO (41 active, 82 eyes; 24 inactive, 48 eyes). Twenty-two active patients completed the GC treatment and follow-up assessment, including 15 patients (30 eyes) and 7 patients (14 eyes), defined as responsive and unresponsive, respectively. Model-free (time to peak [TTP], area under the curve [AUC], and Slope max) and model-based (Ktrans , Kep, and Ve) parameters of EOMs in embedded simplified histogram analyses were calculated and compared between groups. Multivariable logistic regression analysis was used to identify the independent predictors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance. Results: Active patients exhibited significantly higher TTP at the 10th percentile (-10th), TTP-mean, and TTP at the 90th percentile (-90th); AUC-10th, AUC-mean, AUC-90th, and AUC-max; Ktrans -10th and Ktrans -mean; and Ve-10th, Ve-mean, Ve-90th, and Ve-max than inactive patients (P < 0.05). Responsive patients exhibited significantly lower TTP-min; higher Ktrans -mean and Ktrans -max; and higher Kep-10th, Kep-mean, and Kep-max than unresponsive patients (P < 0.05). TTP-mean and Ve-mean were independent variables for determining disease activity (P = 0.017 and 0.022, respectively). A combination of the two parameters could determine active TAO with moderate performance (AUROC = 0.687). TTP-min and Ktrans -mean were independent predictors of the response to GCs (P = 0.023 and 0.004, respectively), uniting which could determine the response to GCs with decent performance (AUROC = 0.821). Conclusion DCE-MRI-derived model-free and model-based parameters of EOMs can assist in the evaluation of TAO. In particular, TTP-mean and Ve-mean could be useful for determining the activity of TAO, whereas TTP-min and K trans -mean could be promising biomarkers for determining the response to GCs.

Objective: To assess the role of dynamic contrast-enhanced (DCE)-MRI of the extraocular muscles (EOMs) for determining the activity of thyroid-associated ophthalmopathy (TAO) and treatment response to glucocorticoids (GCs). Materials and Methods: We prospectively enrolled 65 patients with TAO (41 active, 82 eyes; 24 inactive, 48 eyes). Twenty-two active patients completed the GC treatment and follow-up assessment, including 15 patients (30 eyes) and 7 patients (14 eyes), defined as responsive and unresponsive, respectively. Model-free (time to peak [TTP], area under the curve [AUC], and Slope max) and model-based (Ktrans , Kep, and Ve) parameters of EOMs in embedded simplified histogram analyses were calculated and compared between groups. Multivariable logistic regression analysis was used to identify the independent predictors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance. Results: Active patients exhibited significantly higher TTP at the 10th percentile (-10th), TTP-mean, and TTP at the 90th percentile (-90th); AUC-10th, AUC-mean, AUC-90th, and AUC-max; Ktrans -10th and Ktrans -mean; and Ve-10th, Ve-mean, Ve-90th, and Ve-max than inactive patients (P < 0.05). Responsive patients exhibited significantly lower TTP-min; higher Ktrans -mean and Ktrans -max; and higher Kep-10th, Kep-mean, and Kep-max than unresponsive patients (P < 0.05). TTP-mean and Ve-mean were independent variables for determining disease activity (P = 0.017 and 0.022, respectively). A combination of the two parameters could determine active TAO with moderate performance (AUROC = 0.687). TTP-min and Ktrans -mean were independent predictors of the response to GCs (P = 0.023 and 0.004, respectively), uniting which could determine the response to GCs with decent performance (AUROC = 0.821). Conclusion DCE-MRI-derived model-free and model-based parameters of EOMs can assist in the evaluation of TAO. In particular, TTP-mean and Ve-mean could be useful for determining the activity of TAO, whereas TTP-min and K trans -mean could be promising biomarkers for determining the response to GCs.