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.

This study was aimed at understanding the pollution distribution pattern of avian influenza virus in the environ-ment in poultry related places in Shandong Province,to provide a scientific basis for the prevention,control,prediction,and early warning regarding human infection with avian influenza.From 2020 to 2023,6 523 environmental samples were collected in 16 cities in Shandong Province from four types of poultry-related places.Fluorescence quantitative PCR was used for nucleic acid testing of influenza A virus.Positive samples were further identified for the H5,H7,and H9 subtypes of avian influenza virus.The epidemiological characteristics of avian influenza viruses in the poultry related environment of Shandong Province were described,and inter-rate comparisons were performed with the x2 test.During 2020-2023,6 523 environmental samples were collected,and 1 007 cases positive for avian influenza virus were detected,with a positivity rate of 15.44％.H5,H7,and H9 subtypesand mixed infections were detected.H9 was the main subtype(88.48％)in positive specimens.A significant difference in positivity rates was observed among regions(x2=431.956,P＜0.001),and the highest positivity rate was 28.93％.Significant differences in positivity rates were observed among monitoring sites(x2=304.604,P＜0.001),sample types(x2=109.678,P＜0.001),and quarters(x2=64.963,P＜0.001).The positive detection rate was highest at monitoring sites in urban and rural live poultry markets(20.12％),and the positive detection rate of samples collected by wiping meat cut-ting board surfaces was higher than that of other samples(22.56％).The peak positive detection rate occurred in spring(20.31％).Widespread contamination with avian influenza virus was observed in poultry environments in Shandong Prov-ince.The H9 subtype,the main pathogen,coexisted with H5 and H7 subtypes,thus posing a risk of human infection with avian influenza.Therefore,prevention and control of avian influenza must be strengthened in key seasons,areas,places,and links.

Humans ; Pulmonary Embolism/etiology* ; Humeral Fractures/surgery*

Toll-like receptor 2 (TLR2) mediated macrophages regulate the protective immune response to infectious microorganisms, but the aberrant activation of macrophages often leads to pathological inflammation, including tissue damage. In this study, we identified antagonists of TLR2 by screening 2100 natural products and subsequently identified Taspine, an aporphine alkaloid, as an excellent candidate. Furthermore, analysis of the 10 steps chemical synthesis route and structural optimization yielded the Taspine derivative SMU-Y6, which has higher activity, better solubility, and improved drug-feasible property. Mechanistic studies and seq-RNA analysis revealed that SMU-Y6 inhibited TLR2 over other TLRs, hindered the formation of TLR2/MyD88 complex, and blocked the downstream NF-κB and MAPK signaling pathway, thus suppressing the release of inflammatory cytokines. SMU-Y6 could stabilize TLR2 and bind to TLR2 protein with a K_d of 0.18 μmol/L. Additionally, SMU-Y6 could efficiently reverse the M1 phenotype macrophage polarization, reduce the production of cytokines as well as infiltration of neutrophiles and alleviate the local inflammation in mice with acute paw edema and colitis. Collectively, we reported the first aporphine alkaloid derivative that selectively inhibits TLR2 with high binding affinity and superior drug-feasible property, thus providing an urgently-needed molecular probe and potential drug candidate for inflammatory and autoimmune disease therapy.

Objective:To explore the current status of surgery for portal hypertension to grasp current status and future development of surgery in China.Methods:This study is jointly sponsored by China Hepatobiliary & Pancreatic Specialist Alliance & Portal Hypertension Alliance in China (CHESS).Comprehensive surveying is conducted for basic domestic situations of surgery for portal hypertension, including case load, surgical approaches, management of postoperative complications, primary effects, existing confusion and obstacles, liver transplantation(LT), laparoscopic procedures and transjugular intrahepatic portosystemic shunt(TIPS), etc.Results:A total of 8 512 cases of portal hypertension surgery are performed at 378 hospitals nationwide in 2021.Splenectomy plus devascularization predominated(53.0%)and laparoscopy accounted for 76.1%.Primary goal is preventing rebleeding(67.0%) and 72.8% of hospitals used preventive anticoagulants after conventional surgery.And 80.7% of teams believe that the formation of postoperative portal vein thrombosis is a surgical dilemma and 65.3% of hospitals practiced both laparoscopy and TIPS.The major reasons for patients with portal hypertension not receiving LT are due to a lack of qualifications for LT(69.3%)and economic factors(69.0%).Conclusions:Surgery is an integral part of management of portal hypertension in China.However, it is imperative to further standardize the grasp of surgical indications, the handling of surgical operation and the management of postoperative complications.Moreover, prospective, multi-center randomized controlled clinical studies should be performed.

Epilepsy is a common disease in nervous system, of which patients often present with spontaneous unpredictable spontaneous seizures. Sudden unexpected death in epilepsy (SUDEP) is one of the most serious complications of epilepsy, and it is also the main cause of premature death of epileptic patients. Generalized tonic-clonic seizures, age and genetic factors are common risk factors of SUDEP. This article summarizes the classification of SUDEP and epidemiology, mechanism, risk factors, risk assessment and preventive methods of SUDEP to help physicians to understand the difference between SUDEP and sudden cardiac death.

OBJECTIVE: To establish a prognostic nomogram based on response to bortezomib and BTK expression for treatment-experienced multiple myeloma patients. METHODS: The Oncomine database was utilized to determine BTK expression, sex, age, albumin, Mayo index, response to bortezomib treatment, follow-up time and survival status in multiple myeloma(MM) patients. Cut-off point for BTK expression was calculated using R software. Univariate and multivariate analyses by Cox proportional hazards regression were then performed. Significant prognostic factors were combined to build a nomogram. The discrimination ability and predictive accuracy of the nomogram were evaluated using the index of concordance (C-index) and calibration curves. RESULTS: Multivariate analysis showed that response to bortezomib, BTK expression and sex were independent risk factors for prognosis. The C-index value of the nomogram made according to the independent risk factors was 0.729 (95%CI, 0.642-0.8164). The calibration curves showed good consistency between predicted and actual survivals for 1-year and 2-year overall survival. CONCLUSION The proposed nomogram is accurate in predicting the prognosis of patients with MM.
Bortezomib/therapeutic use* ; Humans ; Multiple Myeloma/drug therapy* ; Nomograms ; Prognosis ; Proportional Hazards Models

Objective: To analyze the epidemiological characteristics, etiology and hemagglutinin (HA) gene characteristics of prevalent strains in Shandong Province from 2021 to 2022. Methods: The sentinel surveillance data of influenza-like illness (ILI) were collected in Shandong Province from 2021 to 2022. ILI specimens were detected with Real-Time PCR and virus isolation to explore the distribution of influenza viruses in different months. Three virus strains of each city were selected for gene sequencing, and the HA phylogenetic analysis was carried out. Results: In the surveillance-year from 2021 to 2022, 528 263 ILI cases were totally reported in 54 sentinel hospitals for influenza surveillance in Shandong Province. ILI visiting ratio (ILI%) was 4.07%, with the largest number in 0-4 age group (45.86%). The highly frequent season for ILI was in winter and spring, with a peak in the 52nd week, 2021 (6.62%). Totally, nucleic acid was detected in 26 754 specimens, with a positive rate of 27.10%, all of which were type B Victoria influenza. The positive rate reached a peak in the 49th week, 2021 (63.78%). A total of 295 outbreaks of ILI had been reported, in which 269 were positive for influenza virus. Most of outbreaks occurred in the primary school, with a peak in December. Gene evolution analysis showed that the HA gene in Shandong possessed high homology, 98.6% to 99.5%, with the recommended vaccine strains in 2020-2023, which was divided into two branches, V1A.3a.1 and V1A.3a.2. Conclusion: In the surveillance-year of 2021-2022, influenza is prevalent in December in Shandong Province, with a single circulating strain type. The positive rate of influenza virus and outbreak are higher than those in the previous surveillance-year. The circulating strain possesses high HA gene homology with those of the WHO vaccine recommended strains. However, the overall immune barrier of influenza virus is weak.
Humans ; Influenza, Human/prevention & control* ; Phylogeny ; Influenza Vaccines ; Orthomyxoviridae ; Seasons ; China/epidemiology* ; Virus Diseases

Based on the investigation of wild medicinal plant resources in Dexing city, Jiangxi province, and the collected plant specimens, which were identified by taxonomy, two new record species of geographical distribution were found, which are Meehania zheminensis A. Takano, Pan Li & G.-H. Xia and Corydalis huangshanensis L.Q.Huang & H.S.Peng. The voucher specimens are kept in Dexing museum of traditional Chinese medicine. In this paper, the new distribution species were reported, which provides valuable information for further enriching and supplementing the species diversity of medicinal plant resources in Jiangxi province.
China ; Corydalis ; Humans ; Lamiaceae ; Medicine, Chinese Traditional ; Museums ; Plants, Medicinal

Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer. Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment. A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate, conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a (Ppa) with a branched glycopolymer. The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B, and PTX was simultaneously released to exert its therapeutic effect. The theranostic nanomedicine, branched glycopolymer-PTX-DOTA-Gd, had an extended circulation time, enhanced accumulation in tumors, and excellent biocompatibility with significantly reduced gadolinium ion (Gd