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 analyze the association between short term PM 2.5 exposure and high blood pressure in adolescents and its modification effect of overweight and obesity, and to provide a reference for the refined management of students physical health and the scientific prevention and controlling of air pollution. Methods: A total of 148 956 junior high school students and senior high school students who passed the annual physical examination data of middle school students in Beijing from 2017 to 2018 were selected; The inverse distance weighted interpolation method was used to get the meteorological elements and air quality of the research area; Linear mixed effect model was used to estimate the cumulative lag effect of short term PM 2.5 exposure on systolic and diastolic blood pressure within 7 days, and analyze the modification effect of overweight and obesity on the association between short term PM 2.5 exposure and high blood pressure in adolescents. Results: From September 1, 2017 to June 30, 2018, the average concentration of PM 2.5 was (56.53±45.85)μg/m 3; The detection rate of overweight and obesity was 34.22%, and the detection rate of high blood pressure was 8.03%. The cumulative lag effect of PM 2.5 on systolic blood pressure in overweight and obesity group was the largest at lag07, that is, the daily average concentration of PM 2.5 increased by 10 μg/m 3 was significantly correlated with higher systolic blood pressure ( OR =1.05,95% CI =1.03-1.07); the cumulative lag effect of PM 2.5 on systolic blood pressure in non overweight and obese group was the largest at lag05, that is, the daily average concentration of PM 2.5 increased by 10 μg/m 3 was significantly correlated with higher systolic blood pressure ( OR =1.04,95% CI =1.02-1.06). Short term exposure to PM 2.5 did not affect the high diastolic blood pressure in adolescents. Overweight and obese adolescents were more susceptible to high blood pressure caused by short term PM 2.5 exposure within 3 days of cumulative lag (lag01-lag03). Conclusion The short term exposure of PM 2.5 has a significant positive correlation with adolescent blood pressure, and shows a lag effect. Overweight and obese adolescents have higher blood pressure after PM 2.5 short term exposure.

Objective:To explore the feasibility of the application of optical coherence tomography (OCT) in the diagnosis of congenital pseudarthrosis of tibia (CPT) in children.Methods:Ten children with neurofibromatosis type Ⅰ (NF1) and CPT were treated in the Third Affiliated Hospital of Zhengzhou University from January 2016 to December 2019, and enrolled as the experimental group.The bone tissue samples were collected and subjected to OCT scanning after intraoperative observation and evaluation, and were contrasted with conventional histological examination.During the same period, the bone tissues of 5 non-NF1 and non-CPT induced-labor fetuses were collected as the control group for the above examination, and the bone tissue examination results of the experimental group and the control group were compared as well.Results:Compared with the bone tissues of the control group, that of the experimental group displayed thickening trabecular bone, part of trabecular bone fusion, disordered arrangement, proliferation and fatification of interstitial fibrous tissue.OCT scan can directly show the nerves and blood vessels in the bone tissue, scattered in adipose tissue.OCT scan showed that the bone tissues of the control group were neatly arranged, with dense and regular shadows.The bone tissues of the experimental group could be observed with strong refraction, loose arrangement, and disordered bone fractures, fibrous ossification, scattered nerves, blood vessels, and increased vacuolar fat cells.Conclusions:OCT can quickly and clearly scan the freshly isolated tissues and directly display the internal structure of the tissues.It is highly compatible with routine pathological examinations and can be an effective supplement to the pathological diagnosis of children with CPT and retain samples for subsequent genetic studies.

Objective: To analyze the relationship between short term exposure of PM 2.5 and the vital capacity of children and adolescents and the modification effect of overweight and obesity, and to provide a scientific reference for appropriate outdoor activities and strengthening prevention of air pollution. Methods: A total of 1 036 273 students who qualified in the annual health examination data of primary and secondary school students in a city from 2017 to 2018 were selected; the meteorological factors and air quality of the study area were obtained by inverse distance weighted interpolation method; the generalized linear mixed model was used to estimate the individual lag effect and average lag effect of PM 2.5 short term exposure on lung capacity with in 7 days, and to analyze the modification effect of overweight and obesity on the relationship between short term PM 2.5 exposure and vital capacity in children and adolescents. Results: From September 1, 2017 to June 30, 2018, the average PM 2.5 concentration in this city was 66.36 μg/m 3, the detection rate of overweight and obesity was 33.38%, and the average lung capacity was (2 286.72±956.77)mL. The single lag effect of PM 2.5 on vital capacity was the biggest when lag6, the average daily PM 2.5 concentration increased by 10 μg/m 3 and the decrease of vital capacity of children and adolescents by 2.81(95% CI =2.60-3.03)mL. The average lag effect of PM 2.5 on lung capacity was the largest when lag07, the average concentration of PM 2.5 sliding was significantly correlated with the decrease of lung capacity of children and adolescents by 5.82(95% CI =5.37-6.27)mL every 10 μg/m 3 increase. The prevalence of PM 2.5 short term exposure to pulmonary capacity decreased in overweight and obese children and adolescents was higher ( P ＜0.01). Conclusion The short term exposure of PM 2.5 has a significant negative correlation with the lung capacity of children and adolescents, and there is a lag effect. The decrease of the vital capacity of overweight and obese children and adolescents after PM 2.5 short term exposure is more significant.

Objective To evaluate the role of group Ⅱ metabotropic glutamate receptors (mGluRs) in cognitive decline caused by multiple administrations of ketamine in mice and the relationship with hippocampal glycogen synthase kinase-3 beta (GSK-3β) expression.Methods Forty-five SPF healthy female C57BL/6 mice,aged 6-8 weeks,weighing 20-30 g,were randomized into 3 groups (n=15 each) using a random number table method:control group (group C),ketamine group (group K) and mGluR agonist LY354740 group (group L+K).In K and L+K groups,ketamine 30 mg/kg was intraperitoneally injected three times a day at an 30-min interval for 14 consecutive days.LY354740 was intraperitoneally injected at 30 min before the first injection of ketamine in group L+K.The equal volume of normal saline was given instead in group C.Morris water maze test was performed the day after the last administration.The mice were then sacrificed,and hippocampi were harvested to determine the expression of GSK3β,NR2A and postsynaptic density protein 95 (PSD95) by Western blot.Results Compared with group C,the escape latency was significantly prolonged,the time of staying at the original platform quadrant was shortened,the frequency of crossing the original platform was decreased,the expression of GSK3β3 and NR2A was up-regulated,and the expression of PSD95 was down-regulated in group K (P＜0.05),and no significant change was found in the parameters mentioned above in group L+K (P＞0.05).Compared with group K,the escape latency was significantly shortened,the time of staying at the original platform quadrant was prolonged,the frequency of crossing the original platform was increased,the expression of GSK3β and NR2A was down-regulated,and the expression of PSD95 was up-regulated in group L+K (P＜0.05).Conclusion Group Ⅱ mGluRs are involved in the process of cognitive decline caused by multiple administrations of ketamine in mice,which is associated with up-regulated expression of hippocampal GSK-3β.

Objective To evaluate the role of nuclear factor kappa B (NF-κB) in cognitive decline in aged mice with sepsis.Methods Forty-five SPF healthy aged female C57BL/6 mice,aged 10-12 months,weighing 20-30 g,were assigned into 3 groups (n=15 each) using a random number table:control group (group C),sepsis group (group Sep) and NF-κB selective inhibitor pyrrolidine dithiocarbamate (PDTC) group (group PDTC).Lipopolysaccharide 250 μg/kg was injected intraperitoneally once a day for 7 consecutive days in Sep and PDTC groups,and in addition PDTC 50 mg/kg was injected intraperitoneally at 30 min before lipopolysaccharide injection once a day for 7 consecutive days in group PDTC.The equal volume of normal saline was given in group C.Five mice in each group were sacrificed at 2 h after the last administration,cardiac puncture was performed and blood samples were collected,and then the mice were sacrificed and hippocampi were harvested for determination of the levels of tumor necrosis factor-α (TNF-α),interleukin-1β (IL-1β) and IL-6 in plasma and hippocampal tissues using enzyme-linked immunosorbent assay.Cognitive function was assessed using open field,elevated plus maze and Morris water maze tests at 24 h after the last administration in the other mice left in each group.Results Compared with group C,the levels of TNF-α,IL-1β and IL-6 in plasma and hippocampal tissues were significantly increased,the time of movement at the central region was shortened,the percentage of time spent in the open arms and number of entries into the open and closed arms were decreased,the escape latency was prolonged,the time of staying at the original platform quadrant was shortened,and the frequency of crossing the platform was decreased in group Sep (P＜0.05).Compared with group Sep,the levels of TNF-α,IL-1β5 and IL-6 in plasma and hippocampal tissues were significantly decreased,the time of movement at the central region was prolonged,the percentage of time spent in the open arms and number of entries into the open and closed arms were increased,the escape latency was shortened,and the time of staying at the original platform quadrant was prolonged in group PDTC (P＜0.05).Conclusion NF-κB is involved in cognitive decline in aged mice with sepsis.

Objective To analyze the clinicopathological characteristics of renal lesions in type 2 diabetic patients and to differentiate diabetic nephropathy (DN) from non-diabetic renal diseases (NDRD).Methods Type 2 diabetic patients who received renal biopsy in Ruijin Hospital from January 2011 to December 2015 were recruited in this study. Clinical history, laboratory results and pathological data were retrospectively collected. According to the pathological findings, the patients were divided into 3 groups: DN, NDRD, DN+NDRD. Logistic model was applied to explore the independent clinical predictive factors in differentiating DN from NDRD. Results A total of 207 type 2 diabetic patients received renal biopsy, accounting for 6.82% of all biopsy population. Fifty-one patients were diagnosed with DN, 142 with NDRD and 14 with both DN and NDRD. In NDRD, membranous nephropathy(MN) (34.5%) was the most common finding, followed by IgA nephropathy(19.7%).By contrast, NDRD patients manifested a shorter diabetic course, a higher baseline hemoglobin level, a lower baseline serum creatinine, a higher prevalence of hematuria, a lower prevalence of hypertension and diabetic retinopathy, a better control of blood glucose, better compliance of monitoring blood glucose and less family history of diabetes. In multivariate logistic model, diabetic family history(OR=4.68, P=0.04) and long history of diabetes(OR=1.01, P=0.02) were risk factors of DN. Conclusion There is a high prevalence of NDRD in diabetic patients with renal lesions. Family history of diabetes and duration of diabetes are independent predictors of DN.

Objective: To study the clinicopathologic, immunohistochemical features, differential diagnoses and prognosis of mammary microglandular adenosis with carcinoma (MGACA) with micropapillary pattern. Methods: Five cases of MGACA were collected from 2010 to 2016 and reviewed for their clinical, histologic features and outcome.EnVision method were done for S-100 protein, cytokeratin (CK), p63, Calponin, smooth muscle myosin heavy chain (SMMHC), PR, ER and HER2. Results: Histologically, microglandular adenosis(MGA), atypical MGA (AMGA) and invasive carcinoma were seen in all five cases of MGACA. The invasive component was metaplastic carcinoma in one case and ductal in four cases. All epithelial cells were S-100 and CK positive in MGA, AMGA and invasive carcinoma. p63, Calponin and SMMHC negativity confirmed the lack of a myoepithelial cell layer in MGA, AMGA and MGACA. PR was weakly focally positive in one case, but ER and HER2 were negative in all cases (four cases were triple negative). Ki-67 index was 20% to 40%. Laminin and collagen Ⅳ staining showed the presence of basement membrane in MGA and AMGA, except MGACA. The follow-up time ranged from 3 months to 6 years, and all patients were alive without recurrence or distant metastasis. Conclusions MGACA is a rare tumor with distinct morphological and IHC features. Compared to most triple-negative breast cancers, MGACA seems to have a relatively favorable outcome.

Objective Comprehensive standards of active implantable medical devices with high risks are required by China's current industrial development, and standard problems and ideas are discussed in this paper.Methods Analysis of the status of China's active implantable medical device standards and international standards. For the booming field for active implantable medical devices with high risks, international standard’s problems, ideas and trends are analyzed. Results Bottleneck of the development of China's active implantable medical device standards is the lack of Chinese medical devices industry actual independent research and development capability. China's independent standard research on the basis of independent core technology of active implantable medical devices is the opportunity to promote the internationalization of China standard.Conclusion Improving the standards of active implantable medical devices based on independent core technology, combined with problems of existing international standards, to further improve and develop international standards and lead high level international technical standards.

Objective To investigate the effects of ultrasound-targeted microbubble destructionmediated MicroRNA-21 on cardiomyocyte apoptosis after coronary microembolization (CME) in swine.Methods Twenty Bama miniature swine were randomLy (random number) divided into sham-operated,CME,CME plus gene transfection and CME plus ultrasound mediated gene transfection groups (n =5 per group).The CME model was established by microcatheter-mediated injection of microspheres into the left anterior descending artery.The sham-operated group were made by injection of saline instead.The CME plus ultrasound mediated gene transfection group was made by injection of plasmid-microbubble mixture through the marginal ear vein 4 days before CME established.Meanwhile,ultrasound treatment was given to the myocardium through chest wall.The CME plus gene transfection group was made by injection of plasmidmicrobubble mixture through the marginal ear vein 4 days before CME established without exposure to ultrasound.Left ventricular ejection fraction (LVEF) was examined by cardiac ultrasound.Tissue biopsy was stained with hematoxylin-eosin (HE) and hematoxylin basic fuchsin picric acid (HBFP) to measure the size of infarction area.Green fluorescent protein (GFP)-labeled gene expression was evaluated by fluorescent microscopy in frozen sections.Cardiomyocyte apoptosis was detected with terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL staining).The expression of PTEN mRNA was measured by fluorescent quantitative PCR.The levels of PTEN protein and Caspase-3 protein was measured by western blot.Results ①Compared to CME plus gene transfection group,the CME plus ultrasound mediated gene group had over eightfold expression of exogenous genes in myocardium (P ＜ 0.05) measured by using optical density of green fluorescence protein;② Compared with shamoperated group [(67.87 ±2.36)％],the LVEF of CME group [(50.94 ±3.52)％] and CME plus gene transfection group [(52.47 ±3.71)％] were markedly decreased (P ＜ 0.05).Compared with CME group,the CME plus ultrasound mediated gene transfection group [(64.79 ± 2.95)％] improved CME-induced cardiac dysfunction as evidenced by increased LVEF (P ＜ 0.05);③Compared with sham-operated group,the expression of PTEN mRNA and levels of PTEN protein and Caspase-3 protein in the CME group increased significantly (P ＜ 0.05).Compared with CME group,the levels of PTEN protein and Caspase-3 protein and the expression of PTEN mRNA in CME plus ultrasound mediated gene transfection group was dramatically decreased (P ＜ 0.05).Conclusions Ultrasound microbubble-mediated MicroRNA-21 transfection effectively improved CME-induced cardiac dysfunction by down-regulating the expression of targeted gene PTEN in myocardial cells,mainly reducing the post-CME myocardial cell apoptosis.