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.

Purpose To explore the predictive value of nomogram model for invasive breast cancer with axillary lymph node metastasis.Materials and Methods Retrospective analysis was made on 122 patients suspected to be breast cancer in the General Hospital of Ningxia Medical University from September 2020 to March 2022.According to whether there was axillary lymph node metastasis,all subjects were divided into 57 patients in the metastasis group and 65 patients in the non-metastasis group.All lesions were pathologically confirmed by surgery.The two groups received synthesis of magnetic resonance imaging(syMRI),dynamic contrast enhancement magnetic resonance imaging(DCE-MRI)and diffusion weighted imaging(DWI)scans.The syMRI parameters[including T1,T2,proton density(PD)],DCE-MRI time signal intensity curve,apparent diffusion coefficient(ADC)value of breast lesions were measured.Compared the difference of parameters between the two groups,and screened the independent risk factors of invasive breast cancer with axillary lymph node metastasis.Results Logistic regression results showed that Ki-67(OR=2.971,95%CI 1.306-6.762,P=0.009),lesion size(OR=1.652,95%CI 1.067-2.556,P=0.024),ADCratio(OR=1.685,95%CI 1.014-2.801,P=0.044),T2ratio(OR=3.015,95%CI 1.433-6.340,P=0.003),PDratio(OR=2.782,95%CI 1.471-5.262,P=0.002)were independent risk factors for invasive breast cancer with axillary lymph node metastasis.The comparison of the five models showed that the Logistic regression model had the best performance,with the area under curve of 0.729(95%CI 0.621-0.789),the accuracy,specificity and sensitivity were 70.65%,62.79%and 77.55%,respectively.The accuracy of the nomogram model was tested,and C-index=0.844,the accuracy of the nomogram model established was good,cut-off risk was 0.468,and the cut-off score was 143.50,which means that when the total score exceeds 143.50,the risk of axillary lymph node metastasis would be higher than 46.8%.Conclusion Nomogram model has a good predictive ability for invasive breast cancer patients with axillary lymph node metastasis.

Artemisinin is a sesquiterpene lactone containing a peroxide group isolated from the plant Artemisia annua. It has antimalarial activity and is effective for the treatment of malaria. With the deepening of research on artemisinin， the pharmacological effects of artemisinin and its derivatives in other systems have gradually become a research hotspot. This article reviews the research progress of artemisinin and its derivatives in the prevention and treatment of cardiovascular diseases. Artemisinin and its derivatives in the prevention and treatment of cardiovascular disease have shown anti-atherosclerosis， lipid- lowering， inhibition of vascular remodeling， reducing vascular pressure， improving ventricular remodeling， anti-arrhythmia， protection of vascular endothelium， prevention and treatment of diabetic cardiovascular complications and protection of myocardial cells and other pharmacological effects. It provides a new treatment strategy for common cardiovascular diseases such as hypertension， arrhythmia， coronary heart disease complications after stent implantation， hyperlipidemia， etc. However， there are few studies on the antiplatelet aggregation and antithrombotic effects of artemisinin and its derivatives， the molecular mechanisms behind many pharmacological effects have not yet been clarified， and there is little clinical application. A large number of basic studies and clinical trials are still needed to answer these questions.

Objective : To investigate the current status of hearing loss in a fastener manufacturing enterprise, and to analyze its influencing factors, so as to provide insights into occupational disease prevention and control. Methods: The occupational health examination data of noise exposed workers and the workplace occupational disease hazard factors detection data in a fastener manufacturing enterprise in Jiaxing City in 2022 were collected through the Occupational Disease and Occupational Health Hazard Factors Detection System of China Disease Prevention and Control Information System, and factors affecting the development of high-frequency noise-induced hearing loss (HFNIHL) and speech-frequency noise-induced hearing loss (SFNIHL) were analyzed. Results: Totally 625 workers were investigated, with a median age of 44.00 (interquartile range, 13.00) years and a median length of service of 8.00 (interquartile range, 9.00) years, and including 519 men (83.04%) and 106 women (16.96%). There were 309 workers with single noise exposure (49.44%) and 316 workers with joint noise exposure (50.56%), and 518 workers exposed to noise with the normalized continuous A-weighted sound pressure level equivalent to a 40 h working week (LEX,40 h) that exceeded the national standard (82.88%). The detection rates of HFNIHL and SFNIHL were 49.12% and 35.04%, respectively. Multivariable logistic regression analysis indicated that males (OR=10.528, 95%CI: 5.271-21.025), length of service of 10 years and longer (OR=2.451, 95%CI: 1.599-3.759), LEX,40 h of >85 dB (A) (OR=2.227, 95%CI: 1.318-3.764) and joint noise exposure (OR=3.002, 95%CI: 2.080-4.334) were associated with an increased risk of HFNIHL, and male (OR=9.400, 95%CI: 4.211-20.985), LEX,40 h of >85 dB (A) (OR=2.305, 95%CI: 1.345-3.951), and joint noise exposure (OR=3.880, 95%CI: 2.677-5.623) were associated with an increased risk of SFNIHL. Conclusion Gender, length of service, noise intensity and exposure mode are factors affecting the risk of HFNIHL, while gender, noise intensity and exposure mode are factors affecting the risk of SFNIHL.

BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disorder characterized by sicca syndrome and/or systemic manifestations. The treatment is still challenging. This study aimed to explore the therapeutic role and mechanism of exosomes obtained from the supernatant of stem cells derived from human exfoliated deciduous teeth (SHED-exos) in sialadenitis caused by SS. METHODS: SHED-exos were administered to the submandibular glands (SMGs) of 14-week-old non-obese diabetic (NOD) mice, an animal model of the clinical phase of SS, by local injection or intraductal infusion. The saliva flow rate was measured after pilocarpine intraperitoneal injection in 21-week-old NOD mice. Protein expression was examined by western blot analysis. Exosomal microRNA (miRNAs) were identified by microarray analysis. Paracellular permeability was evaluated by transepithelial electrical resistance measurement. RESULTS: SHED-exos were injected into the SMG of NOD mice and increased saliva secretion. The injected SHED-exos were taken up by glandular epithelial cells, and further increased paracellular permeability mediated by zonula occluden-1 (ZO-1). A total of 180 exosomal miRNAs were identified from SHED-exos, and Kyoto Encyclopedia of Genes and Genomes analysis suggested that the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway might play an important role. SHED-exos treatment down-regulated phospho-Akt (p-Akt)/Akt, phospho-glycogen synthase kinase 3β (p-GSK-3β)/GSK-3β, and Slug expressions and up-regulated ZO-1 expression in SMGs and SMG-C6 cells. Both the increased ZO-1 expression and paracellular permeability induced by SHED-exos were abolished by insulin-like growth factor 1, a PI3K agonist. Slug bound to the ZO-1 promoter and suppressed its expression. For safer and more effective clinical application, SHED-exos were intraductally infused into the SMGs of NOD mice, and saliva secretion was increased and accompanied by decreased levels of p-Akt/Akt, p-GSK-3β/GSK-3β, and Slug and increased ZO-1 expression. CONCLUSION Local application of SHED-exos in SMGs can ameliorate Sjögren syndrome-induced hyposalivation by increasing the paracellular permeability of glandular epithelial cells through Akt/GSK-3β/Slug pathway-mediated ZO-1 expression.
Mice ; Animals ; Humans ; Sjogren's Syndrome/therapy* ; Proto-Oncogene Proteins c-akt/metabolism* ; Tight Junctions/metabolism* ; Glycogen Synthase Kinase 3 beta ; Mice, Inbred NOD ; Phosphatidylinositol 3-Kinases/metabolism* ; Exosomes/metabolism* ; Xerostomia ; Phosphatidylinositol 3-Kinase ; MicroRNAs/genetics*

Objective:To explore the relationship between low serum albumin levels and its duration on first episode of peritonitis in peritoneal dialysis (PD) patients.Methods:PD patients who were regularly followed up in the Pearl River Delta region from September 1, 2000 to July 6, 2021 in Shunde Hospital of Southern Medical University, Nanfang Hospital of Southern Medical University, and Foshan First People′s Hospital were retrospectively selected. The patients were divided into low serum albumin group (LSA group, mean albumin<35 g/L), moderate serum albumin group (MSA group, 35 g/L≤mean albumin<40 g/L) and high serum albumin group (HSA group, mean albumin≥40 g/L) according to the mean albumin of the patients, and the differences among the three groups were compared. The Kaplan-Meier survival analysis method was used to compare the risk of peritonitis events in different mean albumin groups and different durations of hypoalbuminemia. The multivariate Cox regression model was used to analyze the relationship between serum albumin levels and duration of hypoalbuminemia and new-onset peritonitis.Results:A total of 1 853 PD patients were included in this study, aged (49.72±15.34) years, and 1 036(55.9%) males. There were 551 patients (29.7%) in the LSA group, 920 patients (49.7%) in the MSA group, and 382 patients (20.6%) in the HSA group. The median follow-up was 37 (15, 66) months and there were 508 patients (27.4%) with new-onset peritonitis during the follow-up. Compared with the LSA group, the incidence of new peritonitis in the MSA group and HSA group was lower ( χ2=14.053, P<0.001; χ2=21.857, P<0.001), but there was no significant difference in the incidence of new peritonitis between the HSA group and MSA group. The Kaplan-Meier survival analysis showed that the cumulative incidence of peritonitis in the LSA group was significantly higher than that in the MSA group and HSA group (Log-rank χ2=22.128, P<0.001). Compared with PD patients with normal serum albumin, the patients with longer duration of hypoalbuminemia tended to have a higher incidence of new peritonitis. Multivariate Cox regression analysis showed that the mean albumin<35 g/L (LSA group/MSA group, HR=1.495, 95% CI 1.198-1.866, P<0.001; LSA group/HSA group, HR=1.459, 95% CI 1.104-1.928, P=0.008) was an independent risk factor of new-onset peritonitis in PD patients and the prolongation of duration of hypoalbuminemia had a significantly higher risk of new-onset peritonitis ( HR=1.013, 95% CI 1.003-1.024, P=0.014). Conclusion:The mean albumin<35 g/L and prolong duration of hypoalbuminemia are independent risk factors of PD-related peritonitis in PD patients.

Objective:To investigate the effect of the transcriptional coactivator Mediator 1 (Med1) on mouse hair regeneration, and to explore potential mechanisms.Methods:Med1 flox/flox C57BL/6J mice were mated with K14-Cre mice, and the mice with epidermis-specific knockout of Med1 gene, namely K14-Cre-expressing Med1 flox/flox mice (knockout group) , were obtained by using the Cre-Loxp system, while Med1 flox/flox mice without K14-Cre expression served as control group. Mice in the two groups (3 mice in each group) were raised together for 8 weeks followed by dorsal hair removal. Hair regeneration was observed for 12 consecutive days after hair removal. After 12 days, all mice in the two groups were sacrificed, their depilated and non-depilated dorsal skin tissues were resected, and total RNA was extracted from the tissues. Real-time quantitative PCR was performed to determine the mRNA expression of hair keratin genes, vitamin D receptor/β-catenin pathway-related genes, and genes associated with maintenance of hair follicle stem cell proliferation and quiescence. Paraffin-embedded sections of depilated and non-depilated mouse skin tissues were prepared, and immunofluorescence staining was conducted to determine the number of stem cells in the hair follicle bulge. Two-independent-sample t test was used for comparisons between two groups. Results:From days 0 to 12 after depilation, hair regeneration was delayed in the depilated skin area in the knockout group compared with the control group. Real-time quantitative PCR showed significantly decreased mRNA relative expression levels of hair keratin genes Ha1 and Krt2-16, vitamin D receptor/β-catenin pathway-related genes S100a3, Dlx3 and Tubb3, and genes associated with maintenance of hair follicle stem cell proliferation and quiescence including Lhx2, Sox9 and Nfatc1 in the depilated skin tissues in the knockout group (22.09 ± 12.32, 2.07 ± 0.20, 0.02 ± 0.01, 12.36 ± 2.12, 1.75 ± 0.46, 0.39 ± 0.02, 4.42 ± 0.76, 0.44 ± 0.07, respectively) compared with the control group (70.53 ± 9.46, 7.76 ± 0.49, 0.05 ± 0.01, 26.16 ± 2.96, 2.60 ± 0.14, 0.71 ± 0.09, 11.93 ± 0.42, 0.75 ± 0.04, respectively; t = 5.40, 18.64, 3.89, 6.57, 3.04, 6.10, 15.03, 6.18, respectively, all P < 0.05) . Immunofluorescence staining showed that the number of CD34 +K15 + hair follicle stem cells in the hair follicle bulge in both depilated and non-depilated skin tissues was significantly lower in the knockout group than in the control group. Conclusion:Med1 gene knockout may down-regulate the expression of downstream genes of the vitamin D receptor/β-catenin pathway and genes associated with maintenance of hair follicle stem cell proliferation and quiescence (Sox9, Nfatc1 and Lhx2) , and reduce the number of hair follicle stem cells, leading to hair follicle differentiation disorder and hair regeneration delay.

Tissue engineering has already become an important research direction of trachea substitute; the construction of the scaffold is one of the key factors for a tissue engineering trachea .With the development and the maturity of the technology of 3D-printing, the design and manufacture of the tissue engineered scaffold is widely broadened, various types of 3D-printed scaffold are researched constantly.This review aims to summarize and evaluates the latest progress of the experiments about 3D-printed tissue engineering scaffold.

BACKGROUND:Silk fibroin/mesoporous glass ceramic composites have been reported to exert satisfactory repair outcomes in bone defects and hold good biocompatibility. However, the biosafety and preparation methods are rarely reported. OBJECTIVE:To investigate the preparation method and treatment outcomes of silk fibroin/mesoporous bioactive glass ceramic in skul repair. METHODS:Thirty-two Sprague-Dawley rats were enrol ed to establish the skul defect models and were thenrandomized into two groups:fibroin/mesoporous glass ceramic materials and silk fibroin were respectively implanted into the defect region in experimental and control groups. At 4 and 8 weeks after implantation, the CT examination and histological observation were performed. RESULTS AND CONCLUSION:CT examination showed that at 4 weeks after implantation, the defect area in the experimental group diminished in size, showing more dense new bones. The defect area of the control group was reduced, and a smal amount of new bones were observed. At 8 weeks after implantation, bone defect repair was completed in the experimental group, but not in the control group. The bone volume in the experimental group was significantly larger than that in the control group at different time points after implantation (P<0.05). Hematoxylin-eosin staining found that at 4 weeks after implantation, in the experimental group, there was new bone between the implant and the bone, which did not cause inflammation;there were few new bones and fibrous tissues in the control group. At 8 weeks after implantation, many new bones formed in the experimental group, with similar morphology to the host bone and the scaffold was degraded completely. Conversely, the implant material stil existed in the control group. In conclusion, the silk fibroin/mesoporous glass ceramic composite can promote bone repair.

Objective To evaluate the effects of acute normovolemic hemodilution (ANH) on hemodynamics and oxygen supply in adult patients undergoing correction of tetralogy of Fallot.Methods Ten consecutive patients,aged 20-59 yr,weighing 41-61 kg,of American Society of Anesthesiologists physical status Ⅲ-Ⅳ,scheduled for elective correction of tetralogy of Fallot,were enrolled in the study.After induction of anesthesia,ANH was performed when hemodynamics was stable and stroke volume variation (SVV) ≤ 10％.Blood was withdrawn from the femoral artery,the blood collected was expected to be 15％ of blood volume,and the shed blood was reinfused after the end of cardiopulmonary bypass.The blood loss was simultaneously replaced with the equal volume of 6％ hydroxyethyl starch.Heart rate,mean arterial pressure,central venous pressure,cardiac output,SVV and peripheral vascular resistance were recorded before ANH and at 5 min after the end of ANH.Blood samples were collected for determination of hemoglobin and blood gas analysis,arterial oxygen saturation,arterial oxygen partial pressure and lactate concentrations were recorded,and oxygen supply was calculated.Results Compared with the baseline before ANH,cardiac output was significantly increased,and peripheral vascular resistance and hemoglobin were decreased after ANH (P＜0.05),and no significant change was found in heart rate,mean arterial pressure,central venous pressure,SVV,arterial oxygen partial pressure,arterial oxygen saturation or oxygen supply after ANH (P＞0.05).Conclusion ANH can increase cardiac output and maintain oxygen supply and hemodynamics stable when used for adult patients undergoing correction of tetralogy of Fallot.