ObjectiveTo observe the clinical efficacy of Anzi Tiaochong decoction combined with aspirin and the effects of this therapy on the peripheral blood phospholipid antibody titers， coagulation function， and CD19⁺CD24^hiCD27⁺regulatory B （Breg） cells in patients with obstetric antiphospholipid syndrome （OAPS） （pattern of kidney deficiency and blood stasis）. MethodsPatients who meet the inclusion criteria were randomly allocated into an observation group （50 patients， with 4 patients dropped out and 46 patients completed） and a control group （50 patients， with 2 patients dropped out， 1 patient excluded， and 47 patients completed） through a random number table method. The control group was treated with aspirin enteric-coated tablets， 75 mg/time， once a day， and the observation group with Anzi Tiaochong decoction， 1 bag/day on the basis of the therapy in the control group. The treatment course for both groups was 8 weeks， and the patients were followed up for 4 weeks. The traditional Chinese medicine （TCM） symptom scores， titers of peripheral blood phospholipid antibodies ［anti-cardiolipin antibody IgM （ACA IgM）， anti-cardiolipin antibody IgG （ACA IgG）， anti-β₂-glycoprotein 1 antibody IgM （β₂GP1-IgM）， and anti-β₂-glycoprotein 1 antibody IgG （β₂GP1-IgG）］， D-dimer （D-D）， thromboelastography parameters ［clotting factor activity （R）， platelet function maximum amplitude （MA）， coagulation composite index （CI）， and clot strength （G）］， CD19⁺CD24^hiCD27⁺ Breg expression rate， and adverse drug reactions were recorded for the two groups before and after treatment. ResultsAfter treatment， both groups showed decreased ACA IgM， ACA IgG， β₂GP1-IgM， β₂GP1-IgG， D-D， MA， and G （P<0.05） and increased R （P<0.05）. There was no statistically significant difference in CI. Compared with the control group， the observation group showed more significant decreases in TCM symptom scores and phospholipid antibody titers （P<0.05）. After treatment， the expression rate of Breg in the observation group was higher than that before treatment （P<0.05）.There was no significant difference in Breg expression rate before and after treatment in the control group. Neither group experienced significant adverse reactions. ConclusionAnzi Tiaochong decoction combined with aspirin can alleviate the symptoms， reduce the phospholipid antibody titers， and restore the coagulation status of patients with obstetric antiphospholipid syndrome （pattern kidney deficiency and blood stasis）. It may exert the therapeutic effects by regulating Breg to maintain the patient's immune balance.

ObjectiveTo investigate the functional role and underlying molecular mechanisms of fumarylacetoacetate hydrolase （FAH） in the progression of glioblastoma （GBM）. MethodsDifferential expression analysis was performed on the TCGA-GBM， GSE4290， and GSE116520 datasets. Weighted gene co-expression network analysis （WGCNA） was used to identify key modules， and Cox regression and risk modeling were used to screen prognostic genes. Immune infiltration analysis of prognostic genes was carried out by using single-cell RNA sequencing panels. The clinical expression signature of FAH in GBM was analyzed in the TCGA and HPA databases. The functional role of FAH was validated by in vitro and in vivo experiments， and pathway analysis was performed to explore the underlying mechanisms. ResultsA total of 152 overlapping genes were identified across the three GBM datasets （P<0.05）. WGCNA revealed that the turquoise module was most strongly associated with tumor purity， stromal score， immune score， and ESTIMATE score （P<0.001）. Compared with normal tissues， three prognostic genes （CTSD， FAH， and THBD） were upregulated in GBM and correlated with immune infiltration （P<0.05）. FAH mRNA and protein levels were elevated in GBM tissues relative to normal tissues， and its expression was significantly associated with age stratification and TP53 mutation （P<0.05）. CCK-8 assay results showed that， compared with the shNC group， the proliferative activity of GBM cells in the shFAH group was reduced （P<0.001）. Transwell migration and invasion assays demonstrated that， relative to the shNC group， the numbers of migrated and invaded cells in the shFAH group decreased （P<0.05）. Western blot analysis revealed that the protein expression levels of PI3K， p-AKT， and p-mTOR in the shFAH group decreased compared with those in the shNC group （P<0.05）. In vivo subcutaneous xenograft experiments further confirmed that tumor volume and weight significantly decreased in the shFAH group compared with the shNC group （P<0.001）. ConclusionFAH promotes GBM progression by activating the PI3K/AKT/mTOR signaling pathway and may serve as a potential therapeutic target for GBM.

Diabetes is a very complex endocrine disease whose common feature is the increase in blood glucose concentration. Persistent hyperglycemia can lead to blindness, kidney and heart disease, neurodegeneration, and many other serious complications that have a significant impact on human health and quality of life. The number of people with diabetes is increasing yearly. The global diabetes prevalence in 20-79 year olds in 2021 was estimated to be 10.5% (536.6 million), and it will rise to 12.2% (783.2 million) in 2045. The main modes of intervention for diabetes include medication, dietary management, and exercise conditioning. Medication is the mainstay of treatment. Marketed diabetes drugs such as metformin and insulin, as well as GLP-1 receptor agonists, are effective in controlling blood sugar levels to some extent, but the preventive and therapeutic effects are still unsatisfactory. Peptide drugs have many advantages such as low toxicity, high target specificity, and good biocompatibility, which opens up new avenues for the treatment of diabetes and other diseases. Currently, insulin and its analogs are by far the main life-saving drugs in clinical diabetes treatment, enabling effective control of blood glucose levels, but the risk of hypoglycemia is relatively high and treatment is limited by the route of delivery. New and oral anti-diabetic drugs have always been a market demand and research hotspot. Inhibitor cystine knot (ICK) peptides are a class of multifunctional cyclic peptides. In structure, they contain three conserved disulfide bonds (C3-C20, C7-C22, and C15-C32) form a compact “knot” structure, which can resist degradation of digestive protease. Recent studies have shown that ICK peptides derived from legume, such as PA1b, Aglycin, Vglycin, Iglycin, Dglycin, and aM₁, exhibit excellent regulatory activities on glucose and lipid metabolism at the cellular and animal levels. Mechanistically, ICK peptides promote glucose utilization by muscle and liver through activation of IR/AKT signaling pathway, which also improves insulin resistance. They can repair the damaged pancrease through activation of PI3K/AKT/Erk signaling pathway, thus lowering blood glucose. The biostability and hypoglycemic efficacy of the ICK peptides meet the requirements for commercialization of oral drugs, and in theory, they can be developed into natural oral anti-diabetes peptide drugs. In this review, the structural properties, activity and mechanism of ICK pattern peptides in regulating glucose and lipid metabolism were summaried, which provided a reference for the development of new oral peptides for diabetes.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Objective To investigate the prevalence and risk factors of work-related musculoskeletal disorders (WMSDs) among construction workers. Methods A total of 5 783 workers were selected as participants from 12 construction companies in Guangdong Province, Guangxi Zhuang Autonomous Region and Zhejiang Province using a convenient sampling method. The revised Musculoskeletal Disorders Questionnaire was used to investigate the prevalence and influencing factors of WMSDs. Results The prevalence of WMSDs was 27.4% among the construction workers. The prevalence of WMSDs in shoulder, neck, waist/lower back and hand/wrist was 10.6%, 9.5%, 9.5% and 9.4% respectively, which was higher than that in other body parts. Bianry logistic regression analysis showed that the risk of WMSDs in construction workers with junior high school education and below was higher than that of high school/ college and above (P<0.05). The risk of WMSDs was higher in drinkers than that in non-drinkers (P<0.01). The worse the health status of construction workers, the higher the risk of WMSDs (P<0.01). The risk of WMSDs in those who exercised once or twice a month was lower than that in those who did not exercise (P<0.05). The risk of WMSDs was higher in construction workers with longer working hours in uncomfortable postures and greater back bending amplitude at work (all P<0.01). The risk of WMSDs in construction workers with hands holding above the shoulder was higher than that with hands below the shoulder (P<0.05). Construction workers who repeated the same work daily, involved in high-temperature work, often worked overtime, had insufficient rest time, and had a shortage of department personnel had a relatively high risk of WMSDs (all P<0.01). Conclusion The prevalence of WMSDs among the construction workers was relatively high, and the most common WMSDs occurred in shoulder, neck, waist/lower back and hand/wrist. Individual characteristic, work type, work posture and work organization are the influencing factors of WMSDs. Comprehensive measures, especially ergonomic measures based on personal and occupational characteristics should be taken to reduce the risk of WMSDs among construction workers.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

BACKGROUND: The association between uric acid-albumin ratio (UAR) with different diseases has been evaluated before. However, the association between UAR with spontaneous reperfusion (SR) in patients with ST-segment elevation myocardial infarction (STEMI) has not been explored. METHODS: STEMI patients admitted to our department and underwent primary coronary angiography between 1^st November 2018 and 31^st December 2020 were retrospectively enrolled. The patients were divided into the SR group and the non-SR group according to the index coronary angiography results. The association between UAR and SR was evaluated by uni-variable and multi-variable logistic analysis. Receiver operating characteristic curve analysis was used to determine the optimum cut-off level of UAR in predicting SR. RESULTS: Three hundred and fifty-seven patients were finally enrolled in our study, 55 patients were divided into the SR group and 302 patients were divided into the non-SR group. In uni-variable analysis, patients with SR were older (P = 0.032), with higher red blood cell distribution width (P < 0.001) and red blood cell distribution width-to-platelet ratio (P < 0.001), higher level of C-reactive protein (P = 0.046), higher level of uric acid (P < 0.001) compared with patients without SR. Patients with SR had a lower level of platelets (P = 0.008), lower level of on-admission B-type natriuretic peptide (P < 0.001). As for the level of UAR, STEMI patients with SR had significantly higher levels of UAR compared with STEMI patients without SR [11.1 (8.9-13.4) vs. 8.3 (6.6-10.0), P < 0.001]. Further multi-variable logistic analysis reveals that UAR was the independent risk factor of SR in different models after adjusting different variables. Receiver operating characteristic analysis showed that UAR had good predictive value in SR (AUC = 0.75, 95% CI: 0.702-0.794, P < 0.01). CONCLUSIONS Our study shows that UAR is an independent risk factor for predicting SR in STEMI patients.

Integrins are transmembrane receptors that can coordinate signal transduction between cells and extracellular matrix or between cells.The abnormal function of integrins is one of the recognized mechanisms of tumor development.As an important regulatory mode,post-translational modification can change the conformation and physicochemical properties of proteins,thus affecting their activities,stability and functions.After the modification of the integrin,such as glycosylation and methylation,the corresponding signal transduction pathway changes,and then affects cell adhesion,migration,differentiation and other life activities,involving in diverse physiology and pathological processes.Post-translational modifications of integrins are abundant in tumor progression and play a key role in regulating the growth,metastasis and drug resistance of different tumor cells.In this review,the structure and function,post-translational modification of integrins,and their relationship with occurrence and development of tumors will be discussed,in order to provide more explorable targets for the treatment of cancer.

The tumor microenvironment is a crucial factor in tumor occurrence and progression. The hypoxic microenvironment is widely present in tumor tissue and is a key endogenous factor accelerating tumor deterioration. The "blood stasis toxin" theory, as an emerging perspective in tumor research, is regarded as the unique "soil" in tumor progression from the perspective of traditional Chinese medicine(TCM) due to its dynamic evolution mechanism, which closely resembles the formation of the hypoxic microenvironment. Scientifically integrating TCM theories with the biological characteristics of tumors and exploring precise syndrome differentiation and treatment strategies are key to achieving comprehensive tumor prevention and control. This article focused on the hypoxic microenvironment of the tumor, elucidating its formation mechanisms and evolutionary processes and carefully analyzing the internal relationship between the "blood stasis toxin" theory and the hypoxic microenvironment. Additionally, it explored the interaction among blood stasis, toxic pathogens, and hypoxic environment and proposed micro-level prevention and treatment strategies targeting the hypoxic microenvironment based on the "blood stasis toxin" theory, aiming to provide TCM-based theoretical support and therapeutic approaches for precise regulation of the hypoxic microenvironment.
Humans ; Tumor Microenvironment/drug effects* ; Neoplasms/therapy* ; Animals ; Medicine, Chinese Traditional ; Disease Progression ; Drugs, Chinese Herbal