Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

OBJECTIVE To study the extraction technology of Sophora flavescens-Phellodendron chinense drug pair and provide a reference for the development of new drugs for the treatment of anorectal diseases. METHODS Using the contents of total alkaloids of S. flavescens （matrine+oxymatrine）， berberine hydrochloride and total flavonoid， and extract yield as evaluation indicators， analytic hierarchy process-entropy weight method was used to calculate the weight coefficient of each indicator， and was combined with Box-Behnken design-response surface method to study the extraction technology of S. flavescens-P. chinense drug pair and verify it. RESULTS The optimal extraction technology of S. flavescens-P. chinense drug pair was immersed in 12-fold amount of 58% ethanol for 30 minutes and extracted twice， each time for 120 minutes. The relative error between the verification experimental results and the predicted value was 1.88%. CONCLUSIONS The obtained extraction technology is stable and feasible and can provide reference for the application of S. flavescens-P. chinense drug pair and development of new drugs.

Background::A phase II trial on recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA) has previously shown its preliminary efficacy in ST elevation myocardial infarction (STEMI) patients. This study was designed as a pivotal postmarketing trial to compare its efficacy and safety with rrecombinant human tissue-type plasminogen activator alteplase (rt-PA) in Chinese patients with STEMI.Methods::In this multicenter, randomized, open-label, non-inferiority trial, patients with acute STEMI were randomly assigned (1:1) to receive an intravenous bolus of 16 mg rhTNK-tPA or an intravenous bolus of 8 mg rt-PA followed by an infusion of 42 mg in 90 min. The primary endpoint was recanalization defined by thrombolysis in myocardial infarction (TIMI) flow grade 2 or 3. The secondary endpoint was clinically justified recanalization. Other endpoints included 30-day major adverse cardiovascular and cerebrovascular events (MACCEs) and safety endpoints.Results::From July 2016 to September 2019, 767 eligible patients were randomly assigned to receive rhTNK-tPA ( n = 384) or rt-PA ( n = 383). Among them, 369 patients had coronary angiography data on TIMI flow, and 711 patients had data on clinically justified recanalization. Both used a –15% difference as the non-inferiority efficacy margin. In comparison to rt-PA, both the proportion of patients with TIMI grade 2 or 3 flow (78.3% [148/189] vs. 81.7% [147/180]; differences: –3.4%; 95% confidence interval [CI]: –11.5%, 4.8%) and clinically justified recanalization (85.4% [305/357] vs. 85.9% [304/354]; difference: –0.5%; 95% CI: –5.6%, 4.7%) in the rhTNK-tPA group were non-inferior. The occurrence of 30-day MACCEs (10.2% [39/384] vs. 11.0% [42/383]; hazard ratio: 0.96; 95% CI: 0.61, 1.50) did not differ significantly between groups. No safety outcomes significantly differed between groups. Conclusion::rhTNK-tPA was non-inferior to rt-PA in the effect of improving recanalization of the infarct-related artery, a validated surrogate of clinical outcomes, among Chinese patients with acute STEMI.Trial registration::www.ClinicalTrials.gov (No. NCT02835534).

Objective:To evaluate the influence of 25-hydroxyvitamin D[25(OH)D]on dyslipidemia in elderly female patients with type 2 diabetes(T2DM)mellitus aged 60 or over.Methods:We retrospectively reviewed the clinical records of 175 type 2 diabetic older women meeting the inclusion criteria, admitted to the Department of Endocrinology, Beijing Chuiyangliu Hospital, between January and December 2020, with an average age of 66(63, 70)years.According to the diagnostic criteria of dyslipidemia(cholesterol ≥6.2 mmol/L, high density lipoprotein cholesterol <1.0 mmol/L, low-density lipoprotein cholesterol ≥4.1 mmol/L or triglycerides ≥2.3 mmol/L), 110 participants(62.9%)were divided into a dyslipidemia group and 65 participants(37.1%)were assigned into a normal blood lipid group.Logistic regression was employed to investigate factors influencing dyslipidemia.Spearman correlation analysis was employed to analyze the correlation between serum 25(OH)D and blood lipid indexes.Results:The median serum 25(OH)D level of the 175 subjects was 10.92(8.1, 15.2)μg/L.For the dyslipidemia group, it was 9.1(5.8, 12.9)μg/L, lower than 11.9(8.4, 22.6)μg/L in the normal blood lipid group.The proportion of people with hypertension in the dyslipidemia group was higher than in the normal blood lipid group.The dyslipidemia group also had higher BMI, waist circumference and homocysteine levels( P<0.05). Results of multivariate logistic regression analysis demonstrated that hypertension, waist circumference, and homocysteine were significant risk factors for dyslipidemia in elderly women with T2DM, whereas serum 25(OH)D was a protective factor( P<0.05). Correlation analysis results identified that cholesterol and low density lipoprotein cholesterol were inversely correlated to 25(OH)D while high density lipoprotein cholesterol was positively correlated to it( P<0.05). Conclusions:There is a serious deficiency of serum 25(OH)D in older women with T2DM.25(OH)D is protective factor in elderly T2DM women against dyslipidemia.Clinicians should pay attention to vitamin D deficiency in patients during diagnosis and treatment and correct the deficiency.

Objective:To observe any therapeutic effect of repeated transcranial direct current stimulation (tDCS) on rats modeling neuropathic pain and explore possible mechanisms.Methods:Forty adult male Sprague-Dawley rats were randomly divided into a normal group ( n=10), a sham operation group ( n=10), a treatment group ( n=10) and a sham treatment group ( n=10). A model of chronic constriction injury of the sciatic nerve was established in the latter two groups. Fourteen days after the modeling, the treatment group was given tDCS for 8 consecutive days, while the sham treatment group received sham stimulation, and the other 2 groups did not receive any intervention. Von Frey and hotplate tests were used to test the rats′ pain thresholds 1 day before, as well as 14 and 22 days after the surgery (i.e., 8 days after the end of the treatment). Spinal cord tissue samples were taken to detect the protein expressions of N-methyl-D-aspartic acid receptor 2B, gamma-aminobutyric acid receptor types A (GABA a-R) and B (GABA b-R) using western blotting. Results:On the 14th day after the operation the average 50% MWT and WTL values of the sham treatment and treatment groups had decreased significantly compared with the sham operation group. By the 22nd day the average 50% MWT and WTL values of the treatment group were significantly higher than those of the sham treatment group, but there was no significant change in the treatment group′s average WTL between the 21st and 22nd days. On the 22nd day after the operation the average NR2B-NMDA-R level of the sham treatment group were significantly higher than that of the sham operation group, while the average GABA a-R and GABA b-R levels were significantly lower. At the same time point the treatment group′s average NR2B-NMDA-R level had decreased significantly compared to the sham treatment group, while the average GABA a-R level had increased significantly. There was no significant difference in average GABA b-R level between the treatment group and the sham treatment group at that point. On the 22nd day there was also no significant difference in the average NR2B-NMDA-R level between the treatment group and the sham operation group. Conclusions:Repeated tDCS can effectively relieve neuropathic pain. The relief of hyperalgesia is more significant than that of mechanical allodynia. A possible mechanism may be the down-regulation of spinal NR2B-NMDA-R to normal levels and modest up-regulation of GABA a-R.

Objective:To clarify the clinical characteristics and related fators of children with delayed antibody production of mycoplasma pneumoniae pneumonia(MPP).Methods:Two hundreds and eithty-five cases of children hospitalized at Children′s Hospital of Soochow University with MPP(positive for nucleic acid testing of respiratory secretion)were chosen from January 1st, 2019 to September 31st, 2019.Delayed antibody production group included 36 cases, who were tested for negative IgM antibody meanwhile the titer of IgG antibody changed less than 4 folds within 14 days.Positive group included 249 cases who were tested for positive IgM antibody or the titer of IgG antibody changed over 4 folds within 14 days.The characteristics of clinical manifestation, immunology and radiology were comparatively analyzed.Results:The medium age of delayed antibody production group was 0.75(0.30, 2.78)years old, which was obviously younger than that from positive group[5.50(3.73, 7.20)years old]( P<0.001). Low level of serum immunoglobulin IgG was the independent effect factor of delayed production for Mycoplasma pneumoniae antibody( P=0.037). When the serum immunoglobulin IgG level was lower than 7.155mmol/L, the sensitivity of predicting delayed production for mycoplasma pneumoniae antibody would be 0.819 and the specificity was 0.833.The underlying diseases associated with delayed antibody production were hospitalization history during neonatal period( P=0.007)and congenital heart disease( P=0.001). There were 11.11%(4/36)of children appearing spasmodic cough, 41.67%(15/36)of children showing wheezing and 33.33%(12/36)showing diarrhea in delayed antibody group, which were significantly higher than those in positive group[0.40%(1/249), 24.50%(61/249)and 9.64%(24/249), respectively, P<0.05]. The incidence of fever in delayed antibody group were 63.89%(23/36), which was lower than that in positive group[92.37%(230/249)]( P<0.001), meanwhile, the fever last time was 2.50(0, 4.75)days in delayed antibody group, which was shorter than that in positive group[ 7(5.00, 8.50)days]( P<0.001). In the delayed antibody group, there was 19.44%(7/36)of children sufferring from lobar pneumonia, and no extrapulmonary manifestations occurred, which were significantly lower than those in positive group[75.50%(188/249), 14.86%(37/249)]( P<0.05). Conclusion:Delayed antibody production in children with MPP is more common when serum immunoglobulin IgG level is lower than 7.155 mmol/L, especially in the presence of neonatal hospital history and congenital heart disease.The clinical manifestations of these children are mainly characterized by spasmodic cough and wheezing, with low probability of fever, lobular pneumonia and extrapulmonary manifestations.

Objective:To study the types of pathogenic gene mutations and their main clinical characteristics in children with glucose-6-phosphate dehydrogenase (G6PD) deficiency in Zunyi area.Methods:Children with clinical manifestations of "yellow staining" or "suspected yellow staining" who were admitted to Guizhou Children's Hospital, Affiliated Hospital of Zunyi Medical University, from September 13, 2018 to September 13, 2020 were selected for G6PD gene mutation detection by multicolor probe melting curve analysis, and the pathogenic gene mutation types and clinical characteristics of children with G6PD deficiency were analyzed.Results:The results of G6PD gene mutation detection showed that among the 1 740 children tested, 119 were positive for gene mutation, and the positive detection rate was 6.84%. The proportion of male infants was higher than that of female infants, and the difference was statistically significant (91 males and 28 females, χ 2 = 15.10, P < 0.001); infancy accounted for 63.87% (76/119), and early childhood accounted for 18.49% (22/119). A total of 11 known pathogenic gene mutation types and 1 unknown mutation were detected. Among the top 4 pathogenic gene mutations, the overall was c.1024 C>T, c.1376 G>T, c.1388 G>A and c.95 A>G, male was c.1376 G>T, c.1388 G>A, c.1024 C>T and c.95 A>G; female was c.1024 C>T, c.95 A>G, c.1388 G>A and c.519 C>T. Among the 119 children with G6PD gene mutation, 90 cases had varying degrees of jaundice, including 36 cases of severe and more severe jaundice (including 2 cases of extremely severe neonatal bilirubin encephalopathy), and 54 cases of mild to moderate jaundice; 37 cases had anemia of different degrees, including 6 cases of mild anemia, 12 cases of moderate anemia, and 19 cases of severe or more severe anemia (including 1 case of extremely severe anemia). Conclusions:There are 12 types of gene mutations in children with G6PD deficiency in Zunyi area, and the most common mutation types are c.1024 C>T, c.1376 G>T, c.1388 G>A and c.95 A>G. Children with G6PD deficiency are often accompanied by varying degrees of jaundice and anemia.

Objective:To explore the effect of mind mapping combined with continuous quality improvement in the teaching of interns in gastroenterology department.Methods:The 55 students who interned in the gastroenterology department of our hospital from September 2019 to January 2020 were set as the control group and adopted traditional teaching methods; the other 54 students who interned in the gastroenterology department of our hospital from February 2020 to June 2020 were set as the control group; 55 students who interned in the gastroenterology department of our hospital from July 2020 to November 2020 were set as a combined group, and received mind mapping combined with continuous quality improvement teaching. The gastroenterology knowledge and theory assessment results, practical skills operation assessment results and learning initiative, self-study ability, comprehensive thinking ability, teamwork ability, analysis and problem-solving ability, induction and summary ability and so on were compared between the two groups, and the teaching satisfaction rate at the time of leaving the department were also compared. SPSS 20.0 was used for t test and chi-square test. Results:Before the training, there was no statistically significant difference in the three groups of theoretical assessment scores, practical skills operation assessment scores and various ability scores. When leaving the department, the theoretical assessment scores of the combined group and the mind mapping group were (89.74±4.18) points and (86.52±3.72) points, and the performance evaluation scores of practical skills were (90.04±4.86) points and (87.46±4.52) points, respectively. The theoretical evaluation scores and practical skills evaluation scores of the two groups were higher than those of the control group, and the combined group was higher than the mind mapping group, with statistically significant differences ( P<0.05). The scores of various abilities of the combined group and the mind mapping group were higher than those of the control group, and the scores of all indicators in the combined group were higher than those of the mind mapping group, with statistical significance ( P<0.05). The total teaching satisfaction of combined group and mind mapping group was higher than that of the control group, and the total teaching satisfaction of the combined group was higher than that of the mind mapping group. Conclusion:Mind mapping combined with continuous quality improvement has a significant effect on the teaching of gastroenterology interns, which can improve students' abilities and the teaching satisfaction.

Objective:To investigate the hierarchical management scheme of cervical adenocarcinoma in situ (AIS) based on cervical conization margin state.Methods:All medical records of 249 patients diagnosed as AIS by loop electrosurgical excision procedure (LEEP) conization from Jan. 2010 to Dec. 2015 in Obstetrics and Gynecology Hospital of Fudan University were retrospectively reviewed, to explore the relationship between the status of the resection margin and the residual lesion after LEEP, and the multivariate logistic regression method was used to analyze the related factors that affect the residual lesion after LEEP in cervical AIS patients.Results:(1) The age of 249 cervical AIS patients was (40±8) years old (range: 23-71 years old). Of the 249 patients, 19 (7.6%, 19/249) had residual lesions; 69 cases were pathologically diagnosed as AIS after LEEP, and the residual lesion rate was 13.0% (9/69), which was significantly higher than that of AIS + high-grade squamous intraepithelial lesion [5.6% (10/180); χ2=3.968, P=0.046]; 33 cases were multifocal lesions, the residual rate of lesions was 21.2% (7/33), which was significantly higher than that of single focal lesions patients [5.6% (12/216); χ2=7.858, P=0.005]; 181 patients underwent endocervical curettage (ECC) before surgery, the residual rate of lesions in ECC-positive patients was 14.0% (14/100) , significantly higher than that of ECC-negative patients [4.9% (4/81); χ2=4.103, P=0.043]. (2) Among 249 cases of AIS patients, the positive rate of resection margins after LEEP was 35.3% (88/249); the residual rate of lesions in patients with positive resection margins (14.8%, 13/88) was significantly higher than those with negative margins [3.8%(6/156); χ2=9.355, P=0.002]. The age of patients underwent total hysterectomy after LEEP was (43±7) years old, which was significantly higher than that of patients who did not undergo total hysterectomy [(37±8) years old; t=6.518, P<0.01].Among the patients underwent total hysterectomy after LEEP, 3 cases (2.0%, 3/152) had fertility requirements, while 38 cases (39.2%, 38/97) did not underwent total hysterectomy, the difference between the two groups was statistically significant ( χ2=59.579, P<0.01). Among the 152 patients who underwent total hysterectomy after LEEP, the residual rate of lesions was 11.8% (18/152); the residual rate of lesions in patients with positive resection margins was significantly higher than that of patients with negative resection margins [18.8% (12/64) vs 7.0% (6/86); χ2=4.861, P=0.028]. The median follow-up time of 97 patients who did not undergo total hysterectomy after LEEP was 32 months (range: 4-70 months). During the follow-up period, 3 cases of cervical AIS recurrence (3.1%, 3/97) and were followed by hysterectomy,no invasive adenocarcinoma were seen. (3) Multivariate logistic regression analysis showed that the positive resection margin ( OR=4.098, 95% CI: 1.235-13.595, P=0.021), multifocal lesions ( OR=5.464, 95% CI: 1.494-19.981, P=0.010) were independent risk factors that affected the residual lesions in patients with cervical AIS after LEEP. Conclusions:The cervical AIS patients after LEEP conization suggested be stratified by cone margin state as the first-line stratified index, age and fertility needs as the second-line stratified management index. The individualized management plan should be developed based on comprehensive assessment of high-risk factors of residual lesions.

Objective To assess the imported risk of COVID-19 in Guangdong province and its cities, and conduct early warning. Methods Data of reported COVID-19 cases and Baidu Migration Index of 21 cities in Guangdong province and other provinces of China as of February 25, 2020 were collected. The imported risk index of each city in Guangdong province were calculated, and then correlation analysis was performed between reported cases and the imported risk index to identify lag time. Finally, we classified the early warming levels of epidemic by imported risk index. Results A total of 1 347 confirmed cases were reported in Guangdong province, and 90.0% of the cases were clustered in the Pearl River Delta region. The average daily imported risk index of Guangdong was 44.03. Among the imported risk sources of each city, the highest risk of almost all cities came from Hubei province, except for Zhanjiang from Hainan province. In addition, the neighboring provinces of Guangdong province also had a greater impact. The correlation between the imported risk index with a lag of 4 days and the daily reported cases was the strongest (correlation coefficient: 0.73). The early warning base on cumulative 4-day risk of each city showed that Dongguan, Shenzhen, Zhongshan, Guangzhou, Foshan and Huizhou have high imported risks in the next 4 days, with imported risk indexes of 38.85, 21.59, 11.67, 11.25, 6.19 and 5.92, and the highest risk still comes from Hubei province. Conclusions Cities with a large number of migrants in Guangdong province have a higher risk of import. Hubei province and neighboring provinces in Guangdong province are the main source of the imported risk. Each city must strengthen the health management of migrants in high-risk provinces and reduce the imported risk of Guangdong province.