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.

ObjectiveTo explore the function of DANCR during the differentiation of human embryonic stem cells （hESC） toward definitive endoderm （DE）. MethodsThe in vitro DE differentiation system was established and its efficiency was verified. The correlation between the expression level of DANCR and DE differentiation process was detected. Using lentivirus system， we stably knocked down DANCR in hESC. The shDANCR hESC line was applied to DE differentiation， using qPCR and Western blot to detect the expression of DE marker genes SOX17 and FOXA2， and that of primitive streak marker genes Brachyury （T）， EOMES， MIXL1 and GSC. Dual luciferase reporter assay and qPCR were used to confirm the interaction between DANCR and the WNT pathway during DE differentiation. ResultsThe in vitro differentiation system mimicked DE differentiation efficiently. And the expression of DANCR was gradually downregulated during differentiation. DANCR was efficiently knocked down in the shDANCR hESC line （P < 0.001）. Compared with those in the control group， the expression levels of primitive markers Brachyury （T）， EOMES， MIXL1 and GSC， as well as DE markers SOX17 and FOXA2， were significantly decreased in shDANCR groups （P < 0.05）. Furthermore， the transcriptional activity of the WNT pathway in shDANCR groups was lower than that in the control group （P < 0.05）. And RNA levels of downstream genes of the WNT pathway， FZD5， FZD8， SFRP1， FRZB and ANKRD6， were significantly decreased in shDANCR groups （P < 0.05）. However， differences in protein levels of the TGFβ pathway effectors SMAD2/3 and p-SMAD2 were statistically insignificant in shDANCR and control groups （P > 0.05）. Forced activation of β-CATENIN rescued DANCR knock down-induced deficiency in DE differentiation. ConclusionsThe expression of DANCR decreases during DE differentiation. DANCR may promote DE differentiation through modulating the activity of the WNT pathway.

Objective To explore the correlation between the total burden of cerebral small vessel disease and poor prognosis of branch atheromatous disease(BAD)in elderly patients.Methods A total of 114 BAD patients admitted to Shanghai Eighth People's Hospital between January 2021 and March 2023 were enrolled,and according to mRS score at 90 d after onset,they were divided into a good prognosis group(mRS score ≤2,67 cases)and a poor prognosis group(mRS score＞2,47 cases).The clinical and imaging characteristics were analyzed,and the relationship between total cerebral small vessel disease burden and clinical prognosis of BAD was investigated using lo-gistic regression analysis.ROC curve analysis was used to determine the threshold of the total cere-bral small vessel disease burden for predicting adverse outcomes and to evaluate its sensitivity and specificity.Results The good prognosis group had younger age,smaller proportion of diabetes,lower SBP,NIHSS score at admission and white matter hyperintensities,and reduced ratio of cerebral microbleeds than the poor prognosis group(P＜0.05,P＜0.01).Statistical difference was observed in the total cerebral small vessel disease burden between the two groups(P＜0.01).Binary logistic regression analysis showed that the total cerebral small vessel disease burden score and NIHSS score at admission were independent predicators of poor prognosis in BAD patients(OR=3.350,95％CI:1.439-7.798,P=0.005;OR=2.814,95％CI:1.586-4.993,P=0.001).ROC curve analysis indicated that the total cerebral small vessel disease burden had a cut-off val-ue of 1.5,and the sensitivity and specificity for predicting poor prognosis was 63.8％and 86.6％,respectively,for BAD patients.Conclusion The total cerebral small vessel disease burden is an in-dependent predictor for poor prognosis of BAD patients.

Objective　To assess the willingness of students with latent tuberculosis infection (LTBI) in Jiangsu Province to undergo preventive treatment and identify factors influencing their decision, aiming to provide insights for tuberculosis prevention and control strategies in school. Methods The physical examination information of tuberculosis latent infection cases was collected from screenings of new school enrollment and contacts of tuberculosis patients in 6 cities of Jiangsu Province from December 2022 to December 2023. Data on past medical history and understanding of preventive treatment were gathered through an online questionnaire survey on the website of Juanxing, and the influencing factors related to the willingness to take preventive medication were analyzed by logistic regression analysis model. Results In December 2022 to December 2023, a total of 13 school tuberculosis outbreaks occurred in 6 cities, and 1 661 contacts were screened, among which 162 cases met the criteria for prophylactic medication, 96 cases were included in the study by filling in the questionnaire. A total of 22 600 new students from 56 schools participated in the TB screening upon enrollment, of which 358 tested positive for the tuberculin skin test alone, meeting the criteria for preventive medication, and 251 of them completed the willingness survey. Finally, 347 students who met the criteria for preventive treatment were included in the study, with 164 expressing to accept preventive treatment representing a treatment acceptance rate of 47.3%. The results of multivariate analysis showed that university (OR=17.950, 95%CI: 3.078-104.686, P=0.001) and contact with the source of school tuberculosis epidemic (OR=19.542, 95%CI: 6.289-60.726, P<0.001) were associated with increased willingness to receive preventive treatment, while unclear whether to pay for the drugs themselves (OR=0.349, 95%CI:0.133-0.916, P=0.032) was associated with decreased willingness to receive preventive treatment. Compared with Huai'an City, the willingness to receive preventive treatment was significantly lower among students from Nantong City (OR=0.005, 95%CI:0.000-0.063, P<0.001), Nanjing City (OR=0.022, 95%CI: 0.003-0.703, P<0.001) and Lianyungang City (OR=0.074, 95%CI:0.008-0.703, P=0.023). Conclusions The acceptance rate of preventive treatment among LTBI students in Jiangsu Province is not high and is affected by multiple factors. Health education and medication mobilization for preventive medication are essential.

Objective:To explore the direct economic burden and factors affecting out-of-pocket direct costs of multidrug-/rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB) patients in Jiangsu Province.Methods:MDR/RR-PTB patients diagnosed and treated at 13 municipal tuberculosis (TB)-designated hospitals in Jiangsu Province between January 1, 2021, and December 31, 2022, were included, and basic information and direct economic costs were obtained through questionnaires and hospital information systems. Stepwise multiple linear regression was used to analyze the factors influencing patients' out-of-pocket direct costs.Results:The age of the 233 MDR/RR-PTB patients was (44.04±15.64) years. The M( Q1, Q3) direct medical expense of the patients was 134 051.00 (98 934.01,163 205.73) Yuan, of which the M( Q1, Q3) reimbursement by health insurance or policy reduction was 100 462.10 (78 120.00,130 816.00) Yuan, and the M( Q1, Q3) out-of-pocket direct medical expense was 21 694.62 (14 734.83,37 813.00) Yuan. The M( Q1, Q3) direct non-medical expense was 4 971.00 (3 138.00,7 870.00) Yuan. Age, registered residence location, TB resulting in divorce or separation from spouse or partner, drug resistance test results, and treatment regimens were the influencing factors associated with out-of-pocket direct costs for MDR/RR-PTB patients. Conclusions:The direct economic burden caused by MDR/RR-PTB in Jiangsu Province is heavy. It is necessary to emphasize psychological guidance and care for MDR/RR-PTB patients, improve the diagnosis, treatment, and management of MDR/RR-PTB, and effectively reduce the economic burden of MDR/RR-PTB patients.

Objective:To explore the potential application of two-dimensional speckle tracking echocardiography (2D-STE) in terms of quantification and evaluating left and right atrial function in normal fetuses, and to investigate the relevant factors affecting left and right atrial function in normal fetuses as well as differences between both atrial function.Methods:A total of 100 single fetuses underwent fetal echocardiography in the Department of Diagnostic Ultrasound & Echocardiography, Sir Run Run Shaw Hospital, Zhejiang University College of Medicine from January 2019 to October 2022 were retrospectively enrolled. The standard basal or apical four-chamber view clips were obtained, and the left and right atrial function were quantitatively analyzed using TomTec-ARENA off-line cardiac analysis software for quantitative assessment of both atrial strain measurements including left atrial reservoir phase longitudinal strain (LASr), left atrial ductal phase longitudinal strain (LAScd), left atrial systolic phase longitudinal strain (LASct), right atrial reservoir phase longitudinal strain (RASr), right atrial ductal phase longitudinal strain (RAScd), right atrial systolic phase longitudinal strain (RASct), and the ratio of systolic longitudinal strain to conduit longitudinal strain in left and right atrial systolic display groups were calculated which was denoted as Sct/Scd.Routine fetal obstetric ultrasound measurements and fetal echocardiographic parameters in the two groups were obtained including fetal heart rate (FHR), left atrial end-systolic length (LAESL), left atrial end-systolic diameter (LAESD), left atrial end-systolic area (LAESA), left ventricular end-diastolic transverse diameter (LVEDD), right atrial end-systolic length (RAESL), right atrial end-systolic diameter (RAESD), right atrial end-systolic area (RAESA), right ventricular end-diastolic transverse diameter (RVEDD), peak blood flow velocity of mitral valve and tricuspid valve in early and late diastolic period (E, A), peak ratio of E and A: E/A (MV), E/A (TV), and the difference between the left and right atrial strain indices and the routine fetal obstetric ultrasound and fetal echocardiographic parameters, as well as the correlation between the above parameters and gestational age were analyzed. The repeatability tests were performed using the intra-class correlation coefficientt (ICC).Results:Significant differences were found in LASr and RASr, LAScd and RAScd, LASct and LAScd, Sct/Scd between the left atrium and right atrium, E/A (MV) and E/A (TV), LAESD and RAESD, LAESL and RAESL (all P<0.05), there was significant difference in FHR between the left atrial contraction display group and the no atrial contraction display group ( P=0.011), no significant difference in other parameters (all P>0.05). Correlation analysis showed that, LASr, LASct, RASr, and RASct showed moderate negative correlation with gestational age ( rs=-0.570, -0.601, -0.469, -0.568; all P<0.001). While LAScd, RAScd, E/A (MV), E/A (TV) were moderately positively related with gestational age ( rs=0.310, 0.350, 0.330, 0.343; all P<0.05). LAESL, LAESD, LAESA, RAESL, RAESD, RAESA, LVEDD and RVEDD were significantly positively related with gestational age ( rs=0.662, 0.768, 0.792, 0.728, 0.828, 0.822, 0.838, 0.802, all P<0.001). The inter-examiner ICC of fetal LASr and RASr were 0.89 and 0.84 (both P<0.05) and the intra-examiner ICC of fetal RASr and LASr both were 0.80 (both P<0.05), with good consistency. Conclusions:2D-STE is highly feasible and reproducible in assessing fetal atrial function. The corresponding variation values of fetal atria at different gestational weeks were obtained in this study, which provides a new reference index for us to further study normal fetal atria as well as comparative analysis of fetal cardiac function under prenatal pathological conditions.

Objective:To explore the potential application of two-dimensional speckle tracking echocardiography (2D-STE) in terms of quantification and evaluating left atrial function in normal fetuses and fetuses with left ventricular outflow tract obstruction (LVOTO).Methods:A total of 32 fetuses diagnosed with LVOTO, who underwent fetal echocardiography at Sir Run Run Shaw Hospital, Zhejiang University College of Medicine between May 2020 to June 2022, were selected as the case group, and 100 pregnant women with normal singleton fetuses between January 2019 to October 2022 were chosen as the control group. The standard basal or apical four-chamber view clips were obtained and were quantitatively analyzed using TomTec-Arena off-line cardiac analysis software to obtain the left atrial strain parameters of the two groups of fetuses including left atrial reservoir phase longitudinal strain(LASr), left atrial ductal phase longitudinal strain(LAScd), left atrial systolic phase longitudinal strain (LASct), as well as the routine obstetric ultrasound measurements and fetal echocardiographic parameters of the two groups: biparietal diameter (BPD), femur length (FL), aortic annulus end-systolic inner diameter (AO), pulmonary annulus end-systolic inner diameter (PA), left atrial end-systolic long length (LAESL), left atrial end-systolic transverse diameter (LAESD), right atrial end-systolic long length (RAESL), right atrial end-systolic transverse diameter (RAESD), left ventricular end-diastolic transverse diameter (LVEDD) and right ventricular diastole end-diastolic transverse diameter (RVEDD). The ratio of right ventricular end-diastolic transverse diameter to left ventricular end-diastolic transverse diameter (RVd/LVd) and the ratio of pulmonary annulus diameter to aortic annulus diameter (PA/AO) were calculated. The differences of strain parameters between the two groups were compared, and the correlation between strain parameters and gestational age, RVd/LVd and other conventional measurement parameters were analyzed. ROC curve was used to compare the specificity and sensitivity of LASr and RVd/LVd in evaluating fetal cardiac dysfunction with LVOTO.Results:There were significant differences in LASr, LAScd, LASct, MAPSE, AO, LAESL, LVEDD, RVd/LVd and PA/AO between the two groups (all P<0.05), there were no significant differences in other parameters (all P>0.05). Correlation analysis showed that LASr was negatively correlated with RVd/LVd in LVOTO group ( rs=-0.394, P=0.025), and LASct was negatively correlated with RVd/LVd ( rs=-0.626, P=0.004). In the control group, LASr was negatively correlated with gestational age, AO and PA ( r/ rs=-0.570, -0.440, -0.493; all P<0.001), and LASct was negatively correlated with gestational age, AO and PA ( r/ rs=-0.601, -0.532, -0.568; all P<0.001). LAScd was positively correlated with gestational age, AO and PA ( r/ rs=0.310, 0.370, 0.314; all P<0.05). There were no significant correlations between the other parameters (all P>0.05). ROC curve analysis showed that the area under the curve(AUC) in LASr evaluation of fetal cardiac dysfunction with LVOTO was 0.890 (0.826, 0.953) and the AUC in RVd/LVd evaluation of fetal cardiac dysfunction with LVOTO was 0.742 (0.637, 0.846), there were significant differences between them( P<0.05). Conclusions:2D-STE is highly feasible and reproducible in assessing fetal left atrial function. Evaluation of fetal left atrial function by 2D-STE provides a new reference index for quantitative analysis of fetal cardiac dysfunction.

Objective To understand the status and influencing factors of kinesiophobia in patients with diabetic peripheral neuropathic pain(DPNP).Methods From February to June 2023,192 patients with DPNP in a tertiary general hospital in Nanchang City,Jiangxi Province were selected by convenience sampling method.The patients were investigated by the demographic information questionnaire,Tampa Scale for Kinesiophobia,Numerical Rating Scale,Medical Coping Modes Questionnaire,Diabetes Distress Scale,and Summary of Diabetes Self-care Activities.Multiple linear regression were used to analyze the influencing factors of kinesiophobia in patients with DPNP.Results The score of kinesiophobia in patients with DPNP was(36.68±3.88),and the incidence of kinesiophobia was 38.5％.Multiple linear regression analysis showed that marital status,pain level,coping style,diabetic distress and self-management behavior were influential factors for kinesiophobia in patients with DPNP(all P＜0.05).Conclusion Patients with DPNP have a moderate level of kinesiophobia.Nursing staff should pay attention to the early assessment of patients'kinesiophobia,promptly identify and take effective measures to reduce the level of patients'kinesiophobia,increase their motivation to exercise,and improve their prognosis and quality of life.

Objective:To compare the efficacy and safety of red light and daylight photodynamic therapy in the treatment of facial common acne.Methods:From March 2019 to November 2019, 52 patients with facial common acne who received 5-aminolevulinic acid photodynamic therapy in the Department of Dermatology, Chongqing Hospital of Traditional Chinese Medicine were enrolled, including 34 males and 18 females, aged 18-35 years, with an average age of 23.2 years. A 5% concentration of 5-aminolevulinic acid was applied to the entire face, with the right side of the face being exposed to red light for 20 minutes and the left side to daylight for 2 hours. The treatment was administered once a week for a total of 4 sessions. After the treatment, the acne remission, adverse reactions, and patient satisfaction on both sides of the face were compared.Results:Compared with before treatment, the number of inflammatory and non-inflammatory lesions on both sides of the face in the enrolled patients decreased, and there was no significant difference in the clearance rate of skin lesions between the two sides [53.7% (28/52) vs 59.1% (31/52), χ 2=0.89, P>0.05]. The overall effective rate on the red light side was 88.5% (46/52), and 82.7% (43/52) on the daylight side, with no significant difference between the two (χ 2=0.38, P>0.05). In terms of adverse reactions, mild erythema was common, and it was less on the daylight side than on the red light side [34.6% (18/52) vs 19.2% (10/52), χ 2=5.98, P<0.05]. During the treatment period, the pain score on the daylight side decreased compared to the red light side [(7.6±2.3) vs (4.1±1.3), t=13.10, P<0.001]. Overall satisfaction with the daylight side was reported in 49 cases (94.2%), and with the red light side in 37 cases (71.2%), with the daylight side being higher than the red light side, and the difference was statistically significant (χ 2=9.60, P<0.05). Conclusion:Daylight photodynamic therapy is as effective as red light photodynamic therapy for common acne, but it produces fewer adverse reactions and higher patient satisfaction.

Objective:To explore the application value of two-dimensional speckle tracking echocardiography (2D-STE) in measuring the global longitudinal peak strain of the right atrium (PRAGLS) in normal fetuses and evaluating PRAGLS in assessing right atrial function in fetuses with moderate and severe tricuspid regurgitation (TR).Methods:A total of 25 fetuses diagnosed with moderate and severe TR, who underwent fetal echocardiography at Run Run Shaw Hospital, Zhejiang University College of Medicine between October 2020 and May 2022, were selected as the case group. Their gestational age ranged from 25.00(24.00, 30.00)weeks. Additionally, 100 normal singleton fetuses were chosen as the control group, with a gestational age of 25.83(23.00, 28.75)weeks. Standard basal or apical four-chamber clips were acquired and inputted into TOMTEC-ARENA offline cardiac analysis software for analysis. The fetal PRAGLS values of the two groups were obtained, as well as the routine obstetric ultrasound measurements and fetal echocardiographic parameters of both groups: fetal heart rate (FHR), biparietal diameter (BPD), femur length (FL), aortic annulus inner diameter (AO), pulmonary annulus inner diameter (PA), PA/AO ratio, right atrial end-systolic length (RAESL), right atrial end-systolic diameter (RAESD), right atrial end-systolic area (RAESA), right ventricular end-diastolic diameter (RVEDD), and tricuspid annular plane systolic excursion (TAPSE). The peak TR velocity and pressure gradient were simultaneously measured in the case group.The differences in fetal PRAGLS and other parameters between the two groups were compared and analyzed. The correlation between fetal PRAGLS and gestational age (GA) and routine measurements was assessed for both groups. Intra- and inter-observer repeatability tests were conducted using the intragroup correlation coefficient (ICC).Results:A significant difference in PRAGLS was observed between the two groups ( t=11.55, P<0.01). The TAPSE difference between the two groups was also statistically significant ( Z=3.45, P=0.01). Notable differences were found in AO, PA, PA/AO, RAESL, RAESD, and RAESA between the two groups (all P<0.05), but no significant differences were identified in age, GA, FHR, BPD, FL, and RVEDD between the two groups (all P>0.05). PRAGLS in the control group exhibited a moderate negative correlation with GA ( r=-0.47, P<0.01) and were correlated with BPD, FL, AO, PA, RAESL, RAESD, RAESA, and RVEDD ( r=-0.50, -0.46, -0.39, -0.43, -0.45, -0.36, -0.43, -0.32, all P<0.05). No significant correlation was observed with maternal age, FHR, PA/AO, and TAPSE (all P>0.05). No significant correlation between PRAGLS and GA or other conventional parameters was found in the case group (all P>0.05). The inter-measurer and intra-measurer ICC of PRAGLS in the control group were 0.87 and 0.79, respectively, while the inter-measurer and intra-measurer ICC of PRAGLS in the case group were 0.94 and 0.97, respectively, demonstrating good consistency. Conclusions:2D-STE exhibits strong feasibility and reproducibility in assessing fetal atrial function.Fetuses with moderate and severe TR display decreased PRAGLS, suggesting impaired right atrial reservoir function. Right atrial strain introduces a novel method for evaluating fetal cardiac function.