E3 ubiquitin ligase is a key enzyme that determines substrate specificity during ubiquitination and plays an important role in regulating the degradation of tumor suppressor or oncogenic proteins. E3 ubiquitin ligase is involved in regulating leukemia cell differentiation, cell cycle and immune response, and it is closely related to the occurrence and development of acute myeloid leukemia (AML). Targeting highly specific E3 ubiquitin ligase can be used as an effective treatment for AML. This article reviewed the latest progress of E3 ubiquitin ligase in the diagnosis and treatment of AML, aiming to provide insights for the precise targeted therapy of this disease.
Humans ; Ubiquitin-Protein Ligases/metabolism* ; Leukemia, Myeloid, Acute/therapy*

Objective:To study the effects and mechanisms of juglone on the proliferation and apoptosis of acute myeloid leukemia(AML)cells.Methods:Juglone and AML targets were collected from public databases,and the intersecting target clusters were taken for functional enrichment analysis to explore the potential mechanism of juglone in the treatment of AML.Then wet experiments were performed to verify.AML cell lines including KG-1a,MV-411,THP-1 and MOLM-13 were treated with different concentrations of juglone for 24 h.MTT assay was used to detect cell viability and determine the IC50,and the most sensitive cell line was screened for subsequent experiments.Flow cytometry was used to detect the apoptosis of cells treated with different concentrations of juglone.Western blot was performed to check the expression of relevant proteins.Results:Eleven targets were obtained as potential targets for juglone in the treatment of AML,and the top ten significantly enriched pathways were intrinsic pathway of apoptosis,programmed cell death,cytochrome c-mediated apoptotic response,apoptosis,apoptotic factor-mediated response,regulated necrosis,cytokine signaling in immune system,signaling by interleukins,oncogene induced senescence,and signal transduction.The cell viability of KG-1a,MV-411,THP-1 and MOLM-13 was decreased with increasing juglone concentration after 24 h of juglone treatment(r=-0.992,-0.886,-0.956,-0.910).Among them,MOLM-13 was the most sensitive to juglone.The results of flow cytometry showed that the apoptosis rate of MOLM-13 tended to significantly increase with the increasing concentration of juglone(r=0.99).At the same time point,p-RIPK1/RIPK1,p-RIPK3/RIPK3,and p-MLKL/MLK were decreased in each juglone concentration group compared with control group.Conclusion:Juglone inhibits the viability of KG-1a,MV-411,THP-1 and MOLM-13 cells,and induces apoptosis of MOLM-13 cells,the mechanism of which may be related to the inhibition of RIPK1/RIPK3/MLKL signaling pathway.

Objective To compare the performance of machine learning(ML)and individualized treatment effect(ITE)models based on deep learning in providing personalized treatment recommendations using real-world clinical datasets,and construct personalized drug treatment recommendation models for pegylated liposomal doxorubicin(PLD)and epirubicin(EPI)in postoperative breast cancer patients,and assist clinical decision-making by evaluating the treatment effects of these drugs.Methods Clinical data of 904 breast cancer patients admitted at Sir Run Run Shaw Hospital,Zhejiang University School of Medicine was collected retrospectively,including 387 cases treated with PLD and 517 cases treated with EPI.The two groups were compared using propensity score matching to assess the 5-year disease free survival(DFS)outcome.Six ITE models,including CFR_WASS,were used to predict the 5-year DFS probability of patients under two drug treatments.Six machine learning(ML)models,including Random Forest,were used as baselines for performance analysis and comparison.Model's Predictive performance was evaluated based on the AUROC.The effectiveness of treatment recommendations was assessed by calculating the difference of 5-year rates between the group where the actual treatment used was consistent with the treatment recommended by the model and the control group.Results Among the 153 matched cases,there was no statistically significant difference in 5-year DFS outcomes between the two groups.In 16 pairs of cases,the PLD group showed better clinical outcomes than the EPI group,and in 12 pairs of cases,the EPI group had better clinical outcomes than the PLD group,confirming individual differences in treatment benefit between the two drugs.The CFR_WASS model achieved the optimal predictive performance(AUROC value was 0.736 8),and there was no significant difference in 5-year DFS rates between most ML groups and the control group;The 5-year DFS rate in the ITE group was lower than that in the control group(P<0.01),showing significant differences.Among them,the 5-year DFS rate in the CFR_WASS group was 2.13%lower than that in the control group.Conclusion The ITE model is more accurate in estimating the individualized treatment effects of two drugs compared to the ordinary ML model,providing effective individualized treatment recommendations,and has certain clinical application value.

Objective:To evaluate the efficacy, adverse reactions and compliance of vonoprazan (VPZ) dual therapy and bismuth-containing quadruple therapy with low-resistance antibiotics in the initial treatment of primary Helicobacter pylori ( H. pylori) infection. Methods:From March 7, 2022 to August 25, 2023, a total of 200 patients with H. pylori infection who visited the Department of Gastroenterology and Hepatology of the University of Hong Kong-Shenzhen Hospital were selected. According to the random number table method, the patients were randomly divided into the VPZ combined with amoxicillin treatment group (hereinafter referred as VPZ dual therapy group) and the proton pump inhibitor (PPI), tetracycline, full-dose (1 600 mg/d) metronidazole and bismuth treatment group (hereinafter referred as PPI quadruple therapy group). The patients of VPZ dual therapy group were given VPZ 20 mg (twice a day) combined with amoxicillin 1 000 mg (3 times a day), and the patients of PPI quadruple therapy group were given esomeprazol 20 mg (2 times a day), bismuth 0.6 g (twice a day), metronidazole 400 mg (4 times a day), and tetracycline 500 mg (3 times a day). The patients of both groups were treated for 14 days. The H. pylori infection status was re-examined 4 weeks after drug withdrawal. The results were analyzed by intention-to-treat (ITT) analysis, modified ITT analysis and per-protocol analysis (PPA). One-sided μ test was used for non-inferiority evaluation, and two-sided 95% confidence interval (95% CI) was obtained. Chi-square test was used for statistical analysis. Results:In the ITT analysis, 92.0% (92/100) of patients in the VPZ dual therapy group and 77.0% (77/100) of patients in the PPI quadruple therapy group completed the 14-day treatment, and the difference was statistically significant ( χ2=8.59, P=0.003). In the ITT analysis, the H. pylori eradication rates in the VPZ dual therapy group and the PPI quadruple therapy group were 96.0% (96/100) and 92.0% (92/100), respectively, and the difference was statistically significant (difference=4.0%, 95% CI -2.9% to 11.5%, P<0.001). In the modified ITT analysis, the H. pylori eradication rates of the VPZ dual therapy group and the PPI quadruple therapy group were 97.0% (96/99) and 95.8% (92/96), respectively, and the difference was statistically significant (difference=1.1%, 95% CI -4.9% to 7.6%, P=0.002). In the PPA, the H. pylori eradication rates of the VPZ dual therapy group and the PPI quadruple therapy group were 96.7% (89/92) and 97.4% (75/77), respectively, and the difference was statistically significant (difference=-0.7%, 95% CI -6.9% to 6.1%, P=0.009). In the ITT analysis, the incidence of adverse reaction in the VPZ dual therapy group was lower than that in the PPI quadruple therapy group (39.0%, 39/100 vs. 71.0%, 71/100), and the difference was statistically significant ( χ2=20.69, P<0.001). Conclusion:In initial treatment of H. pylori infection, the eradication rate of VPZ dual therapy is non-inferior to that of PPI quadruple therapy, and VPZ dual therapy demonstrates higher safety.

Objective:To evaluate the efficacy, adverse reactions and compliance of vonoprazan (VPZ) dual therapy and bismuth-containing quadruple therapy with low-resistance antibiotics in the initial treatment of primary Helicobacter pylori ( H. pylori) infection. Methods:From March 7, 2022 to August 25, 2023, a total of 200 patients with H. pylori infection who visited the Department of Gastroenterology and Hepatology of the University of Hong Kong-Shenzhen Hospital were selected. According to the random number table method, the patients were randomly divided into the VPZ combined with amoxicillin treatment group (hereinafter referred as VPZ dual therapy group) and the proton pump inhibitor (PPI), tetracycline, full-dose (1 600 mg/d) metronidazole and bismuth treatment group (hereinafter referred as PPI quadruple therapy group). The patients of VPZ dual therapy group were given VPZ 20 mg (twice a day) combined with amoxicillin 1 000 mg (3 times a day), and the patients of PPI quadruple therapy group were given esomeprazol 20 mg (2 times a day), bismuth 0.6 g (twice a day), metronidazole 400 mg (4 times a day), and tetracycline 500 mg (3 times a day). The patients of both groups were treated for 14 days. The H. pylori infection status was re-examined 4 weeks after drug withdrawal. The results were analyzed by intention-to-treat (ITT) analysis, modified ITT analysis and per-protocol analysis (PPA). One-sided μ test was used for non-inferiority evaluation, and two-sided 95% confidence interval (95% CI) was obtained. Chi-square test was used for statistical analysis. Results:In the ITT analysis, 92.0% (92/100) of patients in the VPZ dual therapy group and 77.0% (77/100) of patients in the PPI quadruple therapy group completed the 14-day treatment, and the difference was statistically significant ( χ2=8.59, P=0.003). In the ITT analysis, the H. pylori eradication rates in the VPZ dual therapy group and the PPI quadruple therapy group were 96.0% (96/100) and 92.0% (92/100), respectively, and the difference was statistically significant (difference=4.0%, 95% CI -2.9% to 11.5%, P<0.001). In the modified ITT analysis, the H. pylori eradication rates of the VPZ dual therapy group and the PPI quadruple therapy group were 97.0% (96/99) and 95.8% (92/96), respectively, and the difference was statistically significant (difference=1.1%, 95% CI -4.9% to 7.6%, P=0.002). In the PPA, the H. pylori eradication rates of the VPZ dual therapy group and the PPI quadruple therapy group were 96.7% (89/92) and 97.4% (75/77), respectively, and the difference was statistically significant (difference=-0.7%, 95% CI -6.9% to 6.1%, P=0.009). In the ITT analysis, the incidence of adverse reaction in the VPZ dual therapy group was lower than that in the PPI quadruple therapy group (39.0%, 39/100 vs. 71.0%, 71/100), and the difference was statistically significant ( χ2=20.69, P<0.001). Conclusion:In initial treatment of H. pylori infection, the eradication rate of VPZ dual therapy is non-inferior to that of PPI quadruple therapy, and VPZ dual therapy demonstrates higher safety.

AIM: To preliminarily evaluate the efficacy and safety of XEN drainage tube implantation in the treatment of refractory glaucoma.METHODS: The clinical data of 10 patients(11 eyes)with refractory glaucoma who underwent XEN gel drainage tube implantation in Peking University Third Hospital from September 2021 to January 2022 were retrospectively analyzed. All patients were followed-up for 8-12mo after surgery, the intraocular pressure(IOP)and the use of IOP lowering medication were observed, and the effect of the surgery was evaluated.RESULTS: The highest IOP was 21-55(median 35)mmHg before surgery and 10-40(median 15)mmHg at the last follow-up. There were 2-4(median 4)kinds of IOP lowering drugs before operation and 0-4(median 0)kinds of IOP lowering drugs at the last follow-up. Up to the last follow-up, the surgery was successful in 8 eyes and unsuccessful in 3 eyes.CONCLUSION: Implantation of XEN gel drainage tube is a safe and effective method for the treatment of refractory glaucoma.

Objective: To identify the main metals involved in cognitive impairment in the Chinese oldest old, and explore the association between these metal exposures and cognitive impairment. Methods: A cross-sectional study was conducted on 1 568 participants aged 80 years and older from Healthy Aging and Biomarkers Cohort Study (2017 to 2018). Fasting venous blood was collected to measure the levels of nine metals (selenium, lead, cadmium, arsenic, antimony, chromium, manganese, mercury, and nickel). The cognitive function of these participants was evaluated by using the Chinese version of the Mini-Mental State Examination (CMMSE). The random forest (RF) was applied to independently identify the main metals that affected cognitive impairment. The multivariate logistic regression model and restricted cubic splines (RCS) model were used to further verify the association of the main metals with cognitive impairment. Results: The age of 1 568 study subjects was (91.8±7.6) years old, including 912 females (58.2%) and 465 individuals (29.7%) with cognitive function impairment. Based on the RF model (the out-of-bag error rate was 22.9%), the importance ranking of variables was conducted and the feature screening of five times ten-fold cross-validation was carried out. It was found that selenium was the metal that affected cognitive function impairment, and the other eight metals were not included in the model. After adjusting for covariates, the multivariate logistic regression model showed that with every increase of 10 μg/L of blood selenium levels, the risk of cognitive impairment decreased (OR=0.921, 95%CI: 0.889-0.954). Compared with the lowest quartile(Q₁) of blood selenium, the ORs (95%CI) of Q₃ and Q₄ blood selenium were 0.452 (0.304-0.669) and 0.419 (0.281-0.622) respectively. The RCS showed a linear dose-response relationship between blood selenium and cognitive impairment (P_nonlinear>0.05). Conclusion: Blood selenium is negatively associated with cognitive impairment in the Chinese oldest old.
Aged, 80 and over ; Female ; Humans ; Selenium ; Cohort Studies ; Cross-Sectional Studies ; Metals/analysis* ; Cognitive Dysfunction/epidemiology* ; China/epidemiology*

Objective:To observe the curative effects and complications of open reduction and fixation with cannulated screws and an augmented plate for Pauwels type Ⅲ femoral neck fractures.Methods:A retrospective study was conducted to analyze the data of 8 patients with fresh Pauwels Ⅲ femoral neck fracture who had been treated from January 2015 to October 2018 at Department of Trauma and Orthopaedics, Xinjiang Uygur Autonomous Region Hospital of Traditional Chinese Medicine. There were 7 males and 1 female with an age of (47.7±14.0) years. The Pauwels angle ranged from 50° to 70° in 6 cases and was >70° in 2 cases. As the original closed reduction was not ideal in all the patients, open reduction via the modified Smith-Petersen approach and fixation with cannulated screws and an augmented plate were performed. Fracture healing, Harris hip score, and complications were followed up at 1 month, 6 months, 1 year, and 3 years postoperatively.Results:At 1 month after operation: 8 patients were followed up, their Harris hip score was (38.4±3.6) points, and there were 7 cases of femoral neck shortening and 1 case of incision fat liquefaction. At 6 months after operation: 7 patients were followed up, their Harris hip score was (70.6±2.8) points, and 1 patient healed anatomically, 4 patients healed with shortening, and 2 patients healed with delay and shortening. Femoral neck shortening, withdrawal of cannulated screws, and screw loosening within the augmented plate were all increased compared with 1 month after operation. At 1 year after operation: 7 patients were followed up, their Harris hip score was (85.5±4.4) points, there were no significant changes in fracture healing or complications compared with 6 months after operation. At 3 years after operation: the patient lost to prior follow-up died of heart disease 34 months after operation, 1 patient had to undergo total hip arthroplasty due to fracture nonunion and cutout of cannulated screws at 16 months after operation, and the other 6 patients had a Harris hip score of (93.6±2.5) points. Of the 6 patients, femoral neck fracture healed in 5 (shortening healing in 4, including 1 case complicated with femoral head necrosis, and anatomical healing in 1) but did not in one.Conclusions:In the treatment of Pauwels type Ⅲ femoral neck fractures, open reduction and fixation with cannulated screws and an augmented plate does not lead to ideal curative effects. The main complication is shortening of the femoral neck. The auxiliary role of augmented plate fixation is not obvious.

Cardiovascular diseases， with high incidence and high mortality， belong to the category of "chest impediment and heart pain" in traditional Chinese medicine （TCM）. Chinese medicines have unique effect on the prevention and treatment of cardiovascular diseases with little side effects. Huoxin pills， one of the National Essential Drugs， is formulated based on the basic pathogenesis of weak pulse at Yang and wiry pulse at Yin and the pathological basis of myocardial ischemia and hypoxia and used for treating angina pectoris of coronary heart disease （Qi deficiency and blood stasis syndrome）. This medicine is derived from the classic famous prescription and is composed of ten precious Chinese medicinal herbs. It can replenish Qi， activate blood， and warm collaterals to diffuse impediment by enhancing myocardial contractility and cardiac output to improve micro-circulation and increase coronary blood flow， regulating immune functions， alleviating inflammation， detoxifying， and tranquilizing mind. Clinically， it is suitable for patients with angina pectoris caused by the lack of heart Yang， chest tightness， shortness of breath， palpitation， fear of cold for limbs and so on， especially for the elderly with Yang deficiency or the patients with a history of myocardial infarction. On the basis of the available research reports， this paper explains the formula meaning of Huoxin pills from the perspective of the basic pathogenesis of coronary heart disease and predicts its action targets， location and links. Furthermore， we expound the mechanism of action of Huoxin pills based on basic research and clinical evidence-based research， aiming to provide data support and evidence for the clinical application of this medicine.

Objective: To understand the current situation regarding pediatric off-label use of drugs recommendations in Chinese clinical practice guidelines and to make recommendations for standardized reporting format regarding off-label use of drugs for children. Methods: This cross-sectional study was carried out by systematically searching the databases for Chinese guideline consensus articles published in journals between 2018 and 2020 and extracting recommendations regarding off-label use of drugs from those articles. The essential characteristics of the included guidelines, the ranking of off-label drug types, the order of drug information, the type of off-label drug use, and the percentage of citation studies on which the recommendations were based were analyzed. Results: Among 108 studies that included Chinese off-label guidelines and consensus, 364 recommendations on pediatric off-label use of drugs were included. The Chinese Medical Association published the most, 48 out of the 108 studies (44.4%), and of those 14 studies (13.0%) were on infectious and parasitic diseases. Of the 364 recommendations on off-label use of drugs, the most commonly addressed drugs were 16 recommendations (4.4%) for cyclosporine A, 11 recommendations (3.0%) for methotrexate , and 11 recommendations (3.0%) for fentanyl. The most commonly addressed drug categories were as follows: 68 recommendations (18.6%) were immune system drugs, 66 recommendations (18.1%) were anti-infectives, and 56 recommendations (15.4%) were oncology drugs. The most commonly addressed drug information accounts were as follows: 364 recommendations (100.0%) were indications, 204 recommendations (56.0%) were dosages, and 198 recommendations (54.4%) were the route of administration. Based on the instructions approved by the Chinese Food and Drug Administration, the main forms of the off-label drug were as follows: 175 recommendations (48.1%) were unapproved indications, 127 recommendations (34.9%) were unapproved populations, and 72 recommendations (19.8%) were unapproved ages. Only 129 recommendations (35.4%) were cited, mainly including clinical guidelines (48 studies, 23.4%), reviews (22 studies, 10.7%), and pediatric randomized controlled trials (22 studies, 10.7%). Conclusions: Off-label use of drugs is commonly recommended in pediatric guidelines and consensus documents written by Chinese authors. However, the reporting of the recommendations varies widely, and the quality of the supporting evidence is poor.
Child ; China ; Consensus ; Cross-Sectional Studies ; Humans ; Off-Label Use ; Pharmaceutical Preparations