Membrane protein degradation is a cutting-edge field in targeted protein degradation (TPD). Herein, we developed glypican-3 (GPC3)-mediated lysosome-targeting chimeras (GLTACs) as a novel strategy for the targeted degradation of tumor-specific membrane proteins. GLTACs utilize tumor-specific expression and endocytosis properties of GPC3 to degrade membrane proteins. By conjugating a GPC3-targeting peptide with the ligand of protein of interest (POI), GLTACs induce the formation of a ternary complex that is internalized into lysosomes, leading to the degradation of the POI. The effectiveness and specificity of GLTACs were validated by designing PD-L1, c-Met, and FGFR1 degraders. In particular, GLTAC WP0 potently degraded PD-L1 and induced T-cell-mediated tumor killing against HepG2 cells, highlighting the potential therapeutic applications. The development of GLTAC technology expands the scope of TPD strategies and opens new avenues for discovering novel therapeutic modalities against challenging protein targets.

Checkpoint blockade immunotherapy has emerged as a transformative approach in cancer treatment by activating tumor-infiltrating T cells. However, the efficacy of PD-L1 blockade is restricted in "cold" tumors, which are characterized by low immunogenicity, presenting a challenge to immunotherapy. This study introduces an innovative strategy, utilizing cathepsin-cleavable N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-assisted combined photodynamic therapy (PDT) and PD-L1 degradation for the first time, effectively treating T cell-deficient tumors. The degradable main-chain polymer, conjugated with photosensitizer porphyrin, facilitates the accumulation of reactive oxygen species (ROS), triggering immunogenic cell death (ICD) and promoting cytotoxic T lymphocytes (CTLs) infiltration into tumors. Multivalent peptide antagonists of PD-L1 promote PD-L1 degradation in lysosomes through receptor crosslinking, overcoming the adaptive cycling of PD-L1 to the tumor cell surface. These findings demonstrate that polymer-assisted PDT and PD-L1 crosslinking degradation represent a potential novel strategy for anti-tumor immunotherapy, providing valuable tools for expanding immunotherapy applications in immunosuppressive cancers.

Objective:To investigate the incidence characteristics and influencing factors of non-alcoholic fatty liver disease (NAFLD) in rural Uyghur ethnic group residents in Xinjiang Production and Construction Corps and to provide scientific evidence for early identification and prevention of NAFLD for residents.Methods:A total of 10 158 participants were included from the Xinjiang Uygur ethnic group population cohort. A prospective cohort study and Cox proportional hazards regression model analysis were used to explore the influencing factors and clustering of NAFLD, and the dose-response relationship between related biochemical indicators and the risk of NAFLD was studied using a restricted cubic spline.Results:The cumulative incidence rate of NAFLD was 6.9%, and the incidence density of NAFLD was 12.06/1 000 person-years. The incidence density of NAFLD in females was higher than in males (14.72/1 000 person-years vs. 9.17/1 000 person-years, P<0.001). The incidence density of NAFLD gradually increased with age in the total population, both men and women (all P<0.001). In the general population, an education level of junior high school or above was a protective factor for NAFLD, while older age, divorce, widowhood, overweight, obesity, hypertension, increased glomerular filtration rate, decreased HDL-C, increased LDL-C, and increased ALT were risk factors for NAFLD. Estimated glomerular filtration rate (eGFR), HDL-C, LDL-C, and ALT were non-linearly correlated with the incidence of NAFLD, and there was a significant dose-response relationship between them. Only 19.1% of residents had no NAFLD risk factors; over 80.9% had ≥1 NAFLD risk factors. The risk of NAFLD increased with the number of risk factors. Conclusions:The incidence of NAFLD in rural Uygur ethnic group residents in Xinjiang Production and Construction Corps was relatively low, but most residents had one or more risk factors for NAFLD. Prevention and control of NAFLD in this population cannot be ignored. In addition, people of older age, divorced or widowed, low education level, overweight or obese, hypertension, and abnormal eGFR, HDL-C, LDL-C, and ALT were the high-risk groups of NAFLD that need to be paid attention to in this population.

The eukaryotic genome is folded into higher-order conformation accompanied with constrained dynamics for coordinated genome functions. However, the molecular machinery underlying these hierarchically organized three-dimensional (3D) chromatin architecture and dynamics remains poorly understood. Here by combining imaging and sequencing, we studied the role of lamin B1 in chromatin architecture and dynamics. We found that lamin B1 depletion leads to detachment of lamina-associated domains (LADs) from the nuclear periphery accompanied with global chromatin redistribution and decompaction. Consequently, the inter-chromosomal as well as inter-compartment interactions are increased, but the structure of topologically associating domains (TADs) is not affected. Using live-cell genomic loci tracking, we further proved that depletion of lamin B1 leads to increased chromatin dynamics, owing to chromatin decompaction and redistribution toward nucleoplasm. Taken together, our data suggest that lamin B1 and chromatin interactions at the nuclear periphery promote LAD maintenance, chromatin compaction, genomic compartmentalization into chromosome territories and A/B compartments and confine chromatin dynamics, supporting their crucial roles in chromatin higher-order structure and chromatin dynamics.
Chromatin ; Chromosomes ; Genome ; Humans ; Lamin Type B/genetics*

The dose-related adverse effects of MDM2‒P53 inhibitors have caused significant concern in the development of clinical safe anticancer agents. Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2‒P53 interaction. The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53. The new homo-PROTACs are designed to induce self-degradation of MDM2. The results of the investigation have shown that PROTAC

Objective To explore the relationship between single nucleotide polymorphism (SNP) locus rs1058587,rs1059519 and rs1059369 polymorphisms of growth differentiation factor-15 (GDF-15)gene and susceptibility to chronic Keshan disease in Gansu Province.Methods Using the case-control study method,56 individuals with chronic Keshan disease were taken as case group,and 53 individuals without chronic Keshan disease from the same villages were selected as control group in Gansu Keshan disease areas,venous blood samples were collected,and ethylenediamine tetraacetic acid disodium salt (EDTA) was used for anticoagulation,and the samples were sent for gene sequencing.Univariate and multivariate logistic regression analyses were conducted to analyze the influence of genotypes of rs1058587,rs1059519 and rs1059369 on the prevalence of chronic Keshan disease,and the risk factors for disease were expressed as odds ratio (OR).Results The age of the 56 patients in the case group was (60.93 + 21.99) years old,15 males and 41 females;the age of the 53 residents in control group was (47.49-+ 33.61) years old,26 males and 27 females.There was no significant difference in age between the two groups (t =46.16,P ＞ 0.05);the difference in gender was statistically significant (x2=5.76,P ＜ 0.05).The differences of allele frequencies of case group and control group rs1058587 (C:36.6％,32.1％,G:63.4％,67.9％),rs1059369 (A:61.6％,72.6％,T:38.4％,27.4％) between the two groups were not significantly different (x2 =0.50,3.00,P ＞ 0.05);the differences of allele frequencies of GDF-15 rs1059319 (C:25.0％,40.6％,G:75.0％,59.4％) between the two groups were significantly different (x2 =6.01,P ＜ 0.05).The genotype frequency distribution of GDF-15 gene rs1058587,rs1059519 and rs1059369 in the case group and the control group was not significantly different between the groups (P ＞ 0.05).However,in the case group,the mutant GG frequency of rs1059519 locus was higher than wild type CC (x2 =5.33,P ＜ 0.05).In multivariate logistic regression analysis,women were 3.81 times more likely to suffer from chronic Keshan disease than men,and people aged 45 or older were 5.30 times more likely to suffer from chronic Keshan disease than those younger than 45.The heterozygous and mutant types of GDF-15 gene rs1058587 and rs1059369 were compared with wild type,and the difference was not statistically significant (ORrs1058587 =0.46,0.50,ORrs1059369 =1.30,2.59,P ＞ 0.05);there was no significant difference between the heterozygous type of GDF-15 gene rs1059519 and wild type (OR =3.34,P ＞ 0.05),and the difference between the mutant and wild type was statistically significant (OR =8.58,P ＜ 0.05).Conclusions In this study,we find women of the study population are more likely to have chronic Keshan disease than men,and aged≥45 is a risk factor for chronic Keshan disease.Genetic polymorphisms of GDF-15 gene rs1058587,rs1059369 are not associated with susceptibility to chronic Keshan disease,and a certain correlation between genetic polymorphism of rs1059519 locus and susceptibility to chronic Keshan disease.

Objeetive To analyze the clinical efficacy of liver transplantation (OLT) for patients with hepatopulmonary syndrome (HPS).Methods From 2008 to 2013,420 adult patients underwent liver transplantation in our hospital.There were 91 patients with,and 329 patients without,HPS.The 5-year survival and mortality rates after OLT for the two groups were retrospectively analyzed.Results There were no significant differences between patients without and with HPS in age,primary disease,Child-Pugh score,MELD score,cold ischemia time and warm ischemia time.However,the differences on serum albumin [(29.6 ± 1.2) g/L vs.(26.4 ± 1.6) g/L] and blood oxygen pressure [(61.0 ±9.0) mmHg (1 mmHg =0.133 kPa) vs.(87.0 ± 6.0) mmHg] were significantly different (P ＜ 0.05).The 1-year cure rate was 65.9％ (60/91) in 91 patients with HPS after liver transplantation.The 1,3,5-year cumulative survival rates for patients without HPS were 97.3％,90.9％ and 80.3％,respectively,and the main causes of death were primary graft dysfunction,recurrent cardiovascular events and primary disease recurrence or tumors.The 1,3,5-year cumulative survival rates for patients with HPS were 65.9％,59.3％ and 56.0％,and the main causes of death were multiple-organ failure,pulmonary infection and cerebrovascular events.Kaplan-Meier survival curve analysis showed that the survival of patients with HPS was significantly lower than that of patients without HPS (P ＜ 0.05).Conclusions Liver transplantation is the most effective treatment for patients with HPS,but the short-term mortality rate is relatively high.We still need to learn more about HPS to improve the survival rate of patients with HPS after liver transplantation.

AIM To analyze the effects of glycyrrhetic acid (GA) on c-fos expression and cell proliferation in rat vascular smooth muscle cell (VSMC), and to figure out the mechanisms of binding GA to angiotensin Ⅱ(AⅡ) receptor. METHODS Primary cell culture of rat VSMC, Northern blot, TdR incorporation DNA assay and MTT assay were used in this study. RESULTS ① GA at both low (1?10 -9 mol?L -1) and high concentration (1?10 -5 mol?L -1) quickly induced c-fos expression in VSMC. Sar-AⅡ(1?10 -5 mol?L -1)inhibited both GA induced and AⅡ (1?10 -5 mol?L -1) induced c-fos expression. GA enhanced AⅡ induced c-fos expression at both low and high concentration in VSMC. ② Low level of GA stimulated the proliferation of VSMC. This stimulatory effect decreased with increasing GA concentration, and changed to be inhibitory at high concentration of GA. Not only did Sar-AⅡ eliminate the stimulatory effect of low concentration of GA on cell proliferation, it also eliminated the inhibitory effect of high concentration of GA. Low concentration of GA enhanced the stimulation of AⅡon cell proliferation, while the inhibitory effect of high concentration of GA on cell proliferation was relieved by adding 1?10 -7 mol?L -1 AⅡ. CONCLUSION This study suggests that GA activates transcription factor c-fos and promotes the proliferation of VSMC. GA may exert its effects on cells through AT 1 receptor since it induces similar changes as AⅡ and its effects can be inhibited by AT 1 receptor antagonist.