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 establish an early warning model to assess the mortality risk of patients with heat stroke disease.Methods:The case data of patients diagnosed with heat stroke disease admitted to the comprehensive ICU of Shanshan County from January 2016 to December 2020 were selected. According to the short-term outcome (28 days) of patients, they were divided into death group (20 cases) and survival group (53 cases) . The relevant indicators with statistically significant differences between groups within 24 hours after admission were selected. By drawing the subject work curve (ROC) and calculating the area under the curve, the relevant indicators with the area under the curve greater than 0.7 were selected, Fisher discriminant analysis was used to establish an assessment model for the death risk of heat stroke disease. The data of heat stroke patients from January 1, 2021 to December 2022 in the comprehensive ICU of Shanshan County were collected for external verification. Results There were significant differences in age, cystatin C, procalcitonin, platelet count, CKMB, CK, CREA, PT, TT, APTT, heart rate, respiratory rate and GLS score among the groups. Cystatin C, CKMB, CREA, PT, TT, heart rate AUC area at admission was greater than 0.7. Fisher analysis method is used to build a functional model.Results:The diagnostic sensitivity, specificity and AUC area of the functional model were 95%, 83% and 0.937 respectively. The external validation results showed that the accuracy of predicting survival group was 85.71%, the accuracy of predicting death group was 88.89%.Conclusion:The early warning model of heat stroke death constructed by ROC curve analysis and Fisher discriminant analysis can provide objective reference for early intervention of heat stroke.

Objective To investigate the clinical value of matrix-assisted laser desorption/ionization time of flight mass spectrometry(MALDI-TOF MS)in rapid detection of carbapenemase produced by Klebsiella pneumoniae and Pseudomonas aeruginosa.Methods A total of 60 strains of Klebsiella pneumoniae and 80 strains of Pseudomonas aeruginosa isolated from Pizhou People's Hospital affiliated to Xuzhou Medical University from January 2022 to October 2023 were collected,including 30 strains of carbapenem-resistant Klebsiella pneumoniae(CRKP),30 strains of carbapenem-sensitive Klebsiella pneumoniae(CSKP),50 strains of carbapenem-resistant Pseudo-monas aeruginosa(CRPA)and 30 strains of carbapenem-sensitive Pseudomonas aeruginosa(CSPA).Three detection methods were applied,i.e.,modified carbapenem inactivation method(mCIM),colloidal gold immunochromatography and Autof MS 1000 mass spectrometry identification system to evaluate the ability of Autof MS 1000 mass spectrometry identification system in detecting carbape-nase production of Klebsiella pneumoniae and Pseudomonas aeruginosa.Results The results of Autof MS 1000 mass spectrometry iden-tification system were consistent with those of both mCIM and colloidal gold immunochromatography.Carbapenemase was detected in 28 of the 30 CRKP strains,and it was negative in 2 CRKP strains.Carbapenamase was detected in 15 of the 50 CRPA strains and it was negative in 35 CRPA strains.Thirty strains of CSKP and 30 strains of CSPA were all Carbapenemase negative.The coincidence rate of the results of the three methods in the detection for carbapenase was 100％.Conclusion The result of Autof MS 1000 mass spectrome-try identification system has been consistent with those of mCIM and colloidal gold immunochromatography.It not only has the charac-teristics of cost-saving compare with of mCIM method,but also hold the advantages of fast speed and high accuracy of colloidal gold im-munochromatography method.Thus,Autof MS 1000 system can be used for the rapid identification of carbapenemase produced by Kleb-siella pneumoniae and Pseudomonas aeruginosa.

Objective To explore the mechanism of Angelica Sinensis polysaccharide(ASP)promoting donor bone marrow transplantation(BMT)to reconstruct hematopoietic function of receptor mice by regulating bone marrow stromalcells(BMSCs).Methods Bone marrow mononuclear cells(BMMNCs)of male C57BL/6J mice aged 8-10 weeks were separated,purified and transplanted into female receptor mice of the same age.On the ninth day,receptor mice BMMNCs were separated,purified and transplanted again into female receptor mice.The transplanted receptor mice were divided into control group:sham irradiation;Irradiation(IR)group:a whole-body irradiation with a total dose of 8.0 Gy X-ray;BMT group:the receptor mice treated in the same way as the IR group and transplanted BMMNCs(5×106 cells)from male donor via the tail vein;BMT+ASP group:the receptor mice treated in the same way as the BMT group,and injected ASP[100 mg/(kg·d)×9]by intraperitoneal route from the first day of transplantation.Changes in body weight and survival rate of mice were recorded during modeling,receptor mice BMMNCs were collected to detect sex-determining region of Y(SRY)gene after building model,peripheral blood indexes,the number of BMMNCs in femur and histopathology of bone marrow were detected;BMSCs in receptor mice was separated and purified,BMSCs adhesion ability was observed,proliferation ability was detected by 5-ethynyl-2-deoxyuridine(EdU);The level of reactive oxygen species(ROS),the activity of superoxide dismutase(SOD)and the content of malondialdehyde(MDA)in BMSCs were detected;The levels of granulocyte-macrophage colony-stimulating factor(GM-CSF),stem cell factor(SCF),insulin-like growth factor 1(IGF-1)in culture supernatant of BMSCs were determined,CFU-Mix was counted after BMMNCs co-cultured with receptor BMSCs in each group for 48 hours;The expression of Notch signaling pathway related genes(Notch1,Jagged1,Hes1)in BMMNCs were measured by Real-time PCR.Results All mice in IR group were died,the body weight loss in BMT+ASP group was not obvious.The SRY gene was detected in the receptor female mice BMMNCs.Peripheral blood indexes and the number of BMMNCs were not significantly decreased in BMT+ASP group receptor mice,and bone marrow histopathological injury was reduced.ASP promoted the proliferation of BMSCs,decreased the contents of ROS and MDA,and increased the activity of SOD in BMSCs.ASP promoted the secretion of SCF,GM-CSF and IGF-1 in BMSCs,and increased CFU-Mix yield of BMMNCs co-cultured with receptor BMSCs.ASP increased the expression of Notch1,Jagged1 and Hes1 mRNA in BMMNCs.Conclusion The mechanism of ASP promoting receptor hematopoietic function reconstruction is related to reducing the oxidative stress damage of hematopoietic microenvironment,improving the secretion of hematopoietic growth factors in BMSCs,and regulating Notch signaling pathway.

In automatic skin damage analysis,segmentation is a challenging and critical operation due to factors such as the shape and contrast of hair and skin lesions on the skin.Compared with traditional segmentation methods,deep learning seamlessly integrates feature extraction and task-specific decision-making,achieving segmentation tasks more accurately and efficiently,and effectively reducing the burden and cost of skin cancer screening.This article first introduces the background of dermoscopic segmentation and deep learning models,and introduces the application of deep learning in dermoscopic segmentation.Secondly,this article introduces the algorithm models of convolutional neural networks and attention mechanisms,reviews the application of fused attention convolutional neural networks in dermoscopic segmentation since Jan 2022,and summarizes the improvement strategies,the advantages and disadvantages of the model.The model is further analyzed based on commonly used datasets of dermoscopy and evaluation indicators of image segmentation.Finally,the application of fused attention convolutional neural network in dermoscopic segmentation is summarized and prospected.

Objective:To establish an early warning model to assess the mortality risk of patients with heat stroke disease.Methods:The case data of patients diagnosed with heat stroke disease admitted to the comprehensive ICU of Shanshan County from January 2016 to December 2020 were selected. According to the short-term outcome (28 days) of patients, they were divided into death group (20 cases) and survival group (53 cases) . The relevant indicators with statistically significant differences between groups within 24 hours after admission were selected. By drawing the subject work curve (ROC) and calculating the area under the curve, the relevant indicators with the area under the curve greater than 0.7 were selected, Fisher discriminant analysis was used to establish an assessment model for the death risk of heat stroke disease. The data of heat stroke patients from January 1, 2021 to December 2022 in the comprehensive ICU of Shanshan County were collected for external verification. Results There were significant differences in age, cystatin C, procalcitonin, platelet count, CKMB, CK, CREA, PT, TT, APTT, heart rate, respiratory rate and GLS score among the groups. Cystatin C, CKMB, CREA, PT, TT, heart rate AUC area at admission was greater than 0.7. Fisher analysis method is used to build a functional model.Results:The diagnostic sensitivity, specificity and AUC area of the functional model were 95%, 83% and 0.937 respectively. The external validation results showed that the accuracy of predicting survival group was 85.71%, the accuracy of predicting death group was 88.89%.Conclusion:The early warning model of heat stroke death constructed by ROC curve analysis and Fisher discriminant analysis can provide objective reference for early intervention of heat stroke.

Objectives: Insulin degludec (IDeg)/insulin aspart (IAsp; IDegAsp) is a co-formulation of 70% IDeg and 30% IAsp. According to several randomized controlled trials, IDegAsp is effective and safe for patients with type 2 diabetes mellitus (T2DM). A subgroup analysis of the ARISE study was conducted to explore the safety and efficacy of IDegAsp among Malaysian patients with T2DM in real-world settings. Methodology: ARISE, an open-label, multicenter, non-interventional, prospective study was conducted between August 2019 and December 2020. Adult Malaysian patients with T2DM who were enrolled from 14 sites received IDegAsp as per the local label for 26 weeks. The primary endpoint was change in glycated hemoglobin (HbA1c) levels from baseline to end of study (EOS). Results: Of the 182 patients included in the full analysis set, 159 (87.4%) completed the study. From baseline to EOS, HbA1c (estimated difference [ED]: –1.3% [95% CI: –1.61 to –0.90]) and fasting plasma glucose levels (ED: –1.8 mmol/L [95% CI: –2.49 to –1.13]) were significantly reduced (p<0.0001). The patient-reported reduced hypoglycemic episodes (overall and nocturnal) during treatment. Overall, 37 adverse events were observed in 23 (12.6%) patients. Conclusion Switching or initiating IDegAsp treatment resulted in significant improvements in glycemic control and a reduction in hypoglycemic episodes.

Objective: To evaluate the safety of simultaneous administration of quadrivalent influenza split virion vaccine and 23-valent pneumococcal polysaccharide vaccine in adults aged 60 years and older. Methods: From November 2021 to May 2022, eligible participants aged 60 years and older were recruited in Taizhou City, Jiangsu Province, China, and a total of 2 461 participants were ultimately enrolled in this study. Each participant simultaneously received one dose of quadrivalent influenza split virion vaccine and one dose of 23-valent pneumococcal polysaccharide vaccine. The safety was observed within 28 days after vaccination. Safety information was collected through voluntary reporting and regular follow-ups. Results: All 2 461 participants completed the simultaneous administration of both vaccines and the safety follow-ups for 28 days after vaccination. The mean age of the participants was (70.66±6.18) years, with 54.61% (1 344) being male, and all participants were Han Chinese residents. About 22.51% (554) of the participants had underlying medical conditions. The overall incidence of adverse reactions within 0-28 days after simultaneous vaccination was 2.07% (51/2 461), mainly consisting of Grade 1 adverse reactions [1.83% (45/2 461)], with no reports of Grade 4 or higher adverse reactions or vaccine-related serious adverse events. The incidence of local adverse reactions was 0.98% (24/2 461), primarily presenting as pain at the injection site [0.93% (23/2 461)]. The incidence of systemic adverse reactions was 1.42% (35/2 461), with fever [0.85% (21/2 461)] being the main symptom. In the group with underlying medical conditions and the healthy group, their overall incidence of adverse reactions was 2.53% (14/554) and 1.94% (37/1 907), respectively. The incidence of local adverse reactions in the two groups was 1.62% (9/554) and 0.79% (15/1 907), respectively, and the incidence of systemic adverse reactions was 1.44% (8/554) and 1.42% (27/1 907), respectively, with no statistically significant differences between them (all P>0.05). Conclusion: It is safe for adults aged 60 years and older to receive quadrivalent influenza split virion vaccine and 23-valent pneumococcal polysaccharide vaccine at the same time.

Objective:To conduct a meta-analysis to analyze the efficacy and adverse reactions of fractionated high dose rate brachytherapy (HDR-BT) as monotherapy for localized prostate cancer.Methods:Relevant databases were searched to collect the clinical trials on HDR-BT as monotherapy in patients with localized prostate cancer. Included studies were limited to full-text publications of fractionated HDR-BT as monotherapy with a median follow-up of at least 5 years, and adequate reporting of treatment outcomes and adverse reactions data. Stata 12.0 was used for data analysis.Results:According to the inclusion and exclusion criteria, a total of 11 clinical trials involving 2 683 patients with prostate cancer were included in this meta-analysis. The results of the meta-analysis showed that 5-year biochemical recurrence-free survival (bRFS) rate and overall survival (OS) rate were 94% (95% CI: 93% - 96%) and 96% (95% CI: 94% - 98%), respectively. Long-term (≥5 years) cancer-specific survival (CSS) rate and distant metastasis-free survival (DMFS) rate were 99% (95% CI: 98% - 100%) and 98% (95% CI: 98% - 99%), respectively. Long-term (≥5 years) late grade ≥3 grade gastrointestinal and genitourinary adverse reactions rates were 2% (95% CI: 1% - 3%) and 9% (95% CI: 6% - 13%), respectively. Conclusions:Fractionated HDR-BT as monotherapy is an effective treatment for patients with localized prostate cancer. Its long-term efficacy is encouraging, and the treatment is well tolerated and safe.

OBJECTIVES: To investigate the clinical phenotype and genotype characteristics of children withcardiomyopathy (CM) associated with MYH7 gene mutation. METHODS: A retrospective analysis was conducted on the medical data of five children with CM caused by MYH7 gene mutation who were diagnosed and treated in the Department of Cardiology, Hebei Children's Hospital. RESULTS: Among the five children with CM, there were three girls and two boys, all of whom carried MYH7 gene mutation. Seven mutation sites were identified, among which five were not reported before. Among the five children, there were three children with hypertrophic cardiomyopathy, one child with dilated cardiomyopathy, and one child with noncompaction cardiomyopathy. The age ranged from 6 to 156 months at the initial diagnosis. At the initial diagnosis, two children had the manifestations of heart failure such as cough, shortness of breath, poor feeding, and cyanosis of lips, as well as delayed development; one child had palpitation, blackness, and syncope; one child had fever, runny nose, and abnormal liver function; all five children had a reduction in activity endurance. All five children received pharmacotherapy for improving cardiac function and survived after follow-up for 7-24 months. CONCLUSIONS The age of onset varies in children with CM caused by MYH7 gene mutation, and most children lack specific clinical manifestations at the initial diagnosis and may have the phenotype of hypertrophic cardiomyopathy, dilated cardiomyopathy or noncompaction cardiomyopathy. The children receiving early genetic diagnosis and pharmacological intervention result in a favorable short-term prognosis.
Male ; Female ; Child ; Humans ; Retrospective Studies ; Cardiomyopathy, Dilated/genetics* ; Pedigree ; Phenotype ; Genotype ; Mutation ; Cardiomyopathy, Hypertrophic/diagnosis* ; Myosin Heavy Chains/genetics* ; Cardiac Myosins/genetics*