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 investigate mechanism of phosphodiesterase 5(PDE5)inhibitor Sildenafil in treatment of pain and inflammation in chronic pelvic pain mediated by macrophage polarization.Methods:A total of 32 adult Wistar rats were divided into 4 groups:Sham group,Experimental autoimmune prostatitis(EAP)group,Sildenafil+EAP group,MET+Sildenafil+EAP group,with 8 rats in each group.EAP model was induced by subcutaneous injection of prostate antigen(PAg)and complete Fredrin adjuvant,Sham group was injected with equivalent normal saline.EAP rats were treated with Sildenafil.Metformin was injected on basis of Silde-nafil+EAP.HE staining was used to analyze pathological changes of prostate.Response rate of pelvic pain in rats was measured by von Frey fiber method.Serum cytokines IL-10 and TNF-α levels were determined by ELISA.Numbers of iNOS+and CD16/32+macrophages and CD206+and CD10+macrophages in serum were detected by flow cytometry.Results:Compared with Sham group,EAP group showed obvious focal or multifocal inflammation in ventral prostate gland tissues,pelvic pain response rate,serum inflammatory factor TNF-α level,and number of M1-type polarization characteristic iNOS+and CD16/32+cells in EAP group were significantly increased(all P<0.05),while M2-type polarization characteristics of macrophages,IL-10 level and number of CD206+and CD10+macrophages were significantly decreased(all P<0.05).Compared with EAP group,pelvic pain response rate,TNF-α level,iNOS+and CD16/32+cell number in Sildenafil+EAP group were significantly decreased(all P<0.05),while IL-10 level and CD206+and CD10+macrophage number were significantly increased(all P<0.05).Compared with Sildenafil+EAP group,pelvic pain response rate,TNF-α level,iNOS+and CD16/32+cells in MET+Sildenafil+EAP group were significantly increased(all P<0.05),while IL-10 level and number of CD206+and CD10+macrophages were significantly decreased(all P<0.05).Conclusion:Sildenafil,a PDE5 inhibitor,blocks chronic pelvic pain and inflammation by promoting polarization of M2 macrophages.

Objective:To observe the clinical efficacy of manual therapy based on the Discovery of Posture Secret (DPS) in treating adolescent idiopathic scoliosis (AIS).Methods:Thirty-six AIS patients were randomly divided into an observation group of 17 and a control group of 16. In addition to 10 minutes of side-shift training each week, the control group was given 20 minutes of sling exercise training (SET), while the observation group underwent weekly 20-minute manual therapy sessions based on DPS on the days without SET. Before and after the 4 weeks of treatment spine curvature (Cobb angle), clavicular angle (CA), angle of trunk rotation (ATR) and vertebral rotation (VR) were measured, and the Scoliosis Research Society′s patient questionnaire 22 (SRS-22) was administered.Results:After the treatment the average Cobb angle, CA, ATR and SRS-22 score of the observation group had improved significantly compared with before the treatment. The average Cobb angle, ATR and SRS-22 score of the control group were also significantly higher, but the improvements were not as great as in the observation group. There was no significant difference in VR improvement between the two groups.Conclusion:Manual therapy based on the DPS can effectively ameliorate the scoliosis and shoulder imbalance of AIS patients.

Background Non-occupational carbon monoxide (CO) poisoning is a public health problem that seriously affect people’s health and lives. Objective To describe the prevalence of non-occupational CO poisoning during 2007—2018 in Shanghai, analyze its epidemiological characteristics and potential influencing factors, and explore effective prevention and control measures. Methods Daily reported non-occupational CO poisoning cases and meteorological factors from 2007 to 2018 were collected in Shanghai, epidemiological characteristics were analyzed by descriptive epidemiology methods, and a distributed lag nonlinear model was used to assess the association between temperature and non-occupational CO poisoning. Results A total of 2264 non-occupational CO poisoning events and 3866 cases from 2007 to 2018 were reported in Shanghai, including 59 death cases. More than half of the poisoning cases were female (56.3%), and young adults accounted for more cases than any other age group (54.8%). The poisoning events mainly occurred in winter (from December to next February); however, cases reported in summer increased in recent years. The peak period of the events was from 20:00 to 24:00. Households (85.2%) and restaurants (8.0%) were the common places of non-occupational CO poisoning events, and the main cause was improper use of gas water heater (36.9%). A nonlinear curve was found between daily average temperature of current day and the occurrence of non-occupational CO poisoning. Temperature was negatively associated with the risk of non-occupational CO poisoning when the temperature was lower than 9.6 ℃, while a positive association was found during 9.7-26.0 ℃. Conclusion Winter is a high season for non-occupational CO poisoning in Shanghai, rising cases reported in summer is also worthy of attention. Supervision should be strengthened to ban sales of unqualified gas water heaters, and health education on CO poisoning prevention and control should be conducted through multiple channels, in order to reduce the incidence of CO poisoning.

Macular edema is formed by the accumulation of extracellular fluid or intracellular fluid in the macular area of the retina. In a physiological state, the retina is kept relatively dehydrated and transparent, thereby ensuring the transmission of optical signals. This process requires multiple active or passive liquid transport systems to be performed together, and any of these process anomalies can disrupt the retinal water ion homeostasis, causing an imbalance between fluid entry and exit processes, leading to fluid formation. Macular edema is not an independent disease, it can occur in the process of many retinal diseases. It is the main cause of serious damage to the central vision, the main causes of diabetes, retinal vein occlusion, choroidal angiogenesis, uveitis, postoperative inflammation and tumor. This review mainly discusses the complex mechanism of macular edema caused by retinal barrier dysfunction when retinal water ion homeostasis is abnormal at the cellular and molecular levels. The purpose of this review is to provide a deeper overview of macular edema and its mechanisms of development, opening up new prospects for new prevention and treatment strategies for macular edema, a serious threat to vision.

To evaluate effects of reinfusion of the remaining blood filtered by leukocyte depletion filter on postoperative cellular immune function after cardiopulmonary bypass (CPB). Methods Forty patients who underwent selective cardiac valve replacement surgery with CPB in department of anesthesiology of Haikou Municipal Hospital from January to June in 2018 were enrolled. All the patients were divided into the control group and experimental group according to the random number table method, with 20 patients in each group. In the experimental group, patients received residual pump blood transfusion which had been filtered by leukocyte depletion filter and stored in sterile blood collection bags. In the control group, patients received residual pump blood transfusion which was stored in sterile blood collection bags without being filtered. The remaining blood was reinfused after CPB in two groups. Blood samples were taken before CPB (T1), 2 hours following CPB (T2), and 1, 3, 5 days after reinfusion of the remaining blood (T3, T4, T5), the levels of T lymphocyte subsets CD3+, CD4+, CD8+ and natural killer cells (NK cells) were detected by flow cytometer, and CD4+/CD8+ ratio was calculated. The levels of plasma tumor necrosis factor-α (TNF-α), interleukins (IL-2, IL-6, IL-8) were measured by enzyme linked immunosorbent essay (ELISA). The duration of mechanical ventilation, the length of intensive care unit (ICU) stay, the length of hospital stay, and incidence of wound and pulmonary infection after surgery were compared between two groups. Results Among 40 patients, there were 22 males and 18 females; with an age of (47.88±12.29) years old; and with 25 cases of American Society of Anesthesiologists (ASA) physical status Ⅱ, and 15 cases of ASAⅢ. There was no statistical difference in the volume of the remaining blood between the two groups (mL: 959.00±116.84 vs. 971.50±115.68, P > 0.05). Compared with T1, the levels of T lymphocyte subsets CD3+, CD4+, CD8+, NK cells and plasma levels of IL-2 were significantly decreased from T2, the CD4+/CD8+ ratio was significantly decreased from T3 in two groups, but there was no statistical difference in CD3+, CD4+, CD8+, NK cells, CD4+/CD8+ ratio or plasma level of IL-2 at each time between the two groups. Compared with T1, the plasma levels of TNF-α, IL-6 and IL-8 were significantly increased at T2 in two groups and then decreased gradually. The plasma levels of TNF-α, IL-6 and IL-8 from T3 in experimental group were lower than those in control group [TNF-α (ng/L): 28.49±4.66 vs. 33.82±4.30, IL-6 (ng/L): 25.98±4.51 vs. 31.38±5.42, IL-8 (ng/L):38.98±4.67 vs. 45.76±5.33, all P < 0.05], they restored to the level of T1 at T5. In addition, compared with control group, the duration of mechanical ventilation, the length of ICU stay in experimental group were significantly decreased (hours: 8.07±1.30 vs. 9.16±1.52, 28.22±2.78 vs. 31.25±3.18, both P < 0.05), and there was no statistical difference in the length of hospital stay (days: 20.65±2.76 vs. 22.45±3.22), incidence of wound and pulmonary infection (25.0% vs. 15.0%, 5.0% vs. 15.0%) between the two groups (all P > 0.05). Conclusion Reinfusion of the remaining blood filtered by leukocyte depletion filtercan inhibit inflammatory responses and don't affect the function of cellular immunity, and don't increase the incidence of infection.

Objective To evaluate the lung protection of residual pump blood processed by microaggregate blood filter-reinfusion in patients undergoing cardiac surgery under cardiopulmonary bypass (CPB).Methods A total of 40 patients,aged 28-55 yr,weighing 46-66 kg,of American Society of Anesthesiologists physical status Ⅱ or Ⅲ,with New York Heart Association of Ⅱ or Ⅲ,with left ventricular ejection fraction＞50％,scheduled for elective cardiac valve replacement under general anesthesia,were divided into 2 groups (n =20 each) using a random number table method:residual pump blood reinfusion group (group C) and residual pump blood processed by microaggregate blood filter-reinfusion group (group M).Residual pump blood was collected immediately after the end of CPB.The residual pump blood was stored in sterile blood collection bags without being filtered in group C.The residual pump blood was stored in sterile blood collection bags after being processed by microaggregte blood filter in group M.Residual pump blood was intravenously reinfused after the CPB pipe was removed.At 10 min before CPB (T1),immediately after the end ofCPB (T2),immediately after processing (T3) and at 12 and 24 h after residual pump blood reinfusion (T4,5),blood samples were collected to measure blood components and serum tumor necrosis factor-alpha and intedeukin-6 concentrations (by enzyme-linked immunosorbent assay).Airway plateau pressure was recorded,arterial blood samples were collected for blood gas analysis,and static lung compliance,oxygenation index and respiratory index were calculated at T1.5.The postoperative mechanical ventilation time,duration of intensive care unit stay,length of hospital stay,and incidence of hypoxemia and pulmonary infection were recorded.Results Compared with group C,white blood cell count was significantly decreased at T3-5,and static lung compliance and oxygenation index were increased,respiratory index was decreased,serum tumor necrosis factor-alpha and interleukin-6 concentrations were decreased,postoperative mechanical ventilation time and duration of intensive care unit stay were shortened,and the incidence of hypoxemia was decreased at T4.5 in group M (P＜0.05).Conclusion Residual pump blood proccessed by microaggregate blood filter-reinfusion can reduce systemic inflammatory responses and exerts lung protection to some extent in the patients undergoing cardiac surgery under CPB.

Objective To observe the changes of subfoveal choroidal thickness (SFCT) in diabetic patients with non-proliferative diabetic retinopathy (NPDR) and clinically significant macular edema(CSME),and then investigate diabetic SFCT and the relationship of diabetic CT with diabetic retinopathy (DR).Methods The patients were divided into 2 groups according to clinical guidelines of DR in China in 2014,including NPDR CSME + group(21 eyes) and NPDR CSME-group(36 eyes).All patients were underwent best corrected visual acuity (BCVA),intraocular pressure,axial length,slit lamp microscope,indirect ophthalmoscope,EDI-OCT examination,and mean arterial blood pressure measurement.The differences of BCVA,central retinal thickness (CRT) and SFCT between NPDR CSME + group and NPDR CSME-group were studied as well by means of using SPSS 18.0 for data statistics.Results There was no significant difference in gender,age,eye axis and intraocular pressure between NPDR CSME + group and NPDR CSME-group (all P ＞ 0.05).There was significant difference in BCVA between the two groups (P =0.001).The mean SFCT were (328.24 ± 101.92) μm in the NPDR CSME + group and (235.31 ± 66.98) μm in the NPDR CSME-group,and the difference was statistically significant (t =4.156,P=0.000).And plotting changes in CRT against changes in SFCT in patients with CSME revealed a positive correlation(r =0.473,P =0.000).Conclusion SFCT in NPDR CSME + patient is thicker than that in NPDR CSME-patient.And plotting changes in CRT against changes in SFCT in patients with CSME reveals a positive correlation.

Objective To observe the effect of preoperative intravitreal ranibizumab injection (IVR) on the operation duration of vitrectomy and postoperative vision for the treatment of proliferative diabetic retinopathy (PDR).Methods A prospective study was carried out with the 90 PDR patients (90 eyes) who underwent vitrectomy.The 90 patients(90 eyes)were assigned to the vitrectomy only group(43 eyes) and the IVR combined with vitrectomy group (47 eyes).The IVR was performed 5-13 days prior to vitrectomy in the IVR combined with vitrectomy group.There were 15 eyes with fibrous proliferation PDR (FPDR),16 eyes with advanced PDR (APDR) without involving the macular and 16 eyes with APDR involving the macular in the vitrectomy only group.There were 14 eyes with FPDR,15 eyes with APDR without involving the macular and 14 eyes with APDR involving the macular patients in the IVR combined with vitrectomy group.All the eyes in the two groups were regularly operated by the same doctor to complete the vitrectomy.The start and end time of vitrectomy were recorded.The average follow-up time was 10 months.The changes of best corrected visual acuity (BCVA) before and 1,3 and 6 months after surgery were compared between the two groups.Results The duration of operation of the FPDR type (t=-8.300) and the APDR involving the macular type (t=-2.418) in the IVR combined with vitrectomy group was shorter than vitrectomy only group (P＜0.05).The comparison of duration of operation of the APDR without involving the macular type in the two groups has no statistically significant difference (t=-1.685,P＞0.05).At 1 month after surgery,the comparison of BCVA of the IVR combined vitrectomy group and the vitrectomy only group in APDR involving the macular type has no statistically significant difference (t=0.126,P＞0.05).At 3,6 months after surgery,the BCVA of the IVR combined vitrectomy group in APDR involving the macular type was significantly better than the BCVA of the vitrectomy only group (t=8.014,7.808;P＜0.05).At 1,3,and 6 months after surgery,the BCVA of the IVR combined vitrectomy group in FPDR type (t=3.809,1.831,0.600) and APDR without involving the macular type (t=0.003,1.092,3.931) compared with pre-treatment,the difference were not statistically significant (P＞0.05);the BCVA in APDR without involving the macular type compared with pre-treatment,the difference was distinctly statistically significant (t=2.940,4.162,6.446;P＜0.05);the BCVA in APDR involving the macular type (t =0.953,1.682,1.835) compared with pre-treatment,the difference were not statistically significant (P＞0.05).Conclusion Preoperative IVR of PDR can shorten the operation duration and improve the BCVA of APDR involving the macular type.

Objective To evaluate the detection performance of the cobas8000 c702 fully automatic biochemical analyzer for de‐tecting the second generation Roche urine trace albumin (ALBU2) .Methods (1) The precise evaluation :with the allowable error stipulated by CLIA 88 as the basis ,the requirements were the repeat precision <1/4TEa ,and intermediate precision <1/3TEa;(2) the linear range and the evaluation of the reportable range :the EP6‐A scheme was adopted ,and extend to calculate the average re‐covery rate of dilution ,the clinical reportable range was evaluated by the average dilution recovery of 90% -110% ;(3) the carry o‐ver pollution assessment :the carry over pollution of serum albumin on urine trace albumin detection was evaluated by the judgment standard of carry over pollution rate of 0 .5% ;(4)the methodological comparative analysis :with SIEMENS BN Ⅱas the reference system ,the Roche Cobas 8000 C702 and the BN2 results were performed the correlation contrastive analysis .Results The repeat precision :low concentration CV=1 .98% .high concentration CV=1 .64% ;intermediate precision :low concentration CV=4 .35% , high concentration CV=1 .20% ;the linear range verification :the measurement range 5 .6-413 .55 mg/L ;clinical reportable range :in the maximum diluted multiples of 30 times ,the clinical reportable range was 5 .6-12 406 .5 mg/L ;the carry over pollution rate :serum albumin (42 .6 g/L) on urine trace albumin(6 .9 mg/L) ,the carry over pollution rate was 0 .28% ;the indoor comparison :in the concentration within 200 mg/L ,the regression line was Y=0 .896 X+5 .049 ,the correlation coefficient r2 =0 .994 4 ,the system shift was passed at the medical decision level .When the specimen concentration within 201-413 .55 mg/L ,the regression line was Y=0 .848X-10 .44 ,the correlation coefficient r2 =0 .917 ,the system shift was not passed at the medical decision level .Conclusion The detection of the Roche ALBU2 in the Cobas 8000 C702 platform can meet the clinical needs ,the comparison among different instruments has difference in different concentration ranges ,therefore the independent reference ranges should be established ac‐cording to the each instrument system .