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.

Objective To analyze the genomic characteristics of Legionella pneumophila (L. pneumophila) isolated from industrial circulating cooling water in workplace. Methods A total of 20 L. pneumophila strains isolated from industrial circulating cooling water collected from eight chemical enterprises were selected as the research subjects. Whole-genome sequencing was performed on the strains, followed by multilocus sequence typing (MLST), whole-genome single nucleotide polymorphism analysis, virulence factor profiling, and antibiotic resistance gene detection. Results The dominant MLST typing among the 20 L. pneumophila strains was ST2. Serogroup 1 (Lp1) strains exhibited high genetic diversity. Strains from different enterprises showed substantial genomic diversity, suggesting possible inter-enterprise dissemination. Each isolate harbored 175-295 virulence genes; among them, virulence genes were identified, and 139 genes were detected in all the 20 strains. These genes primarily included those related to the Dot/Icm type Ⅳ bacterial secretion system, flagellar synthesis and motility, and type Ⅳ pili. The number of virulence genes carried by L. pneumophila strains of different ST types differed (P<0.01), with unidentified sequence types harboring more virulence genes than other STs (P<0.01). A total of four resistance genes were predicted, including aminoglycoside phosphotransferase-encoding gene APH(9)-Ia, carbapenemase-encoding gene OXA-29, and efflux pump genes-encoding genes LpeA and LpeB, with detection rates of 100.00%, 100.00%, 10.00%, and 10.00%, respectively. These genes may confer resistance to cephalosporins, penicillins, and aminoglycosides, and all strains were multidrug resistance. Conclusion L. pneumophila isolated from industrial recirculating cooling water exhibits high genetic diversity, strong pathogenicity, and significant multidrug resistance potential.

As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.

ObjectiveTo investigate the mechanism by which Wendantang regulates the silent information regulator 3 （SIRT3）/peroxisome proliferator-activated receptor-gamma coactivator-1α （PGC-1α） pathway to influence energy metabolism and thereby prevent and treat myocardial ischemia （MI） in a rat model of hyperlipidemia （HL）. MethodsThirty SD rats were randomly assigned into five groups： control， model， low-dose （3.702 g·kg^-1·d^-1） Wendantang， high-dose （7.404 g·kg^-1·d^-1） Wendantang， and positive control （trimetazidine， 0.006 g·kg^-1·d^-1）， with six rats in each group. The control group was fed normally， while the other groups were fed with a high-fat diet for six weeks for the modeling of HL. Subsequently， the drug intervention groups were administrated with corresponding drugs by gavage， and the control and model groups received an equivalent volume of normal saline for 14 days. One hour after the last gavage， the other groups except the control group were injected intraperitoneally with posterior pituitary hormone （30 U·kg^-1） to induce MI. Electrocardiography （ECG） was employed to detect changes in the electrocardiogram. Hematoxylin-eosin staining was performed to observe cardiac pathological changes. Enzyme-linked immunosorbent assay was employed to measure the serum levels of cardiac troponin I（cTnI）， myoglobin （MYO）， and creatine kinase-MB （CK-MB）. Colorimetry was used to determine the levels of total cholesterol （TC） and triglycerides （TG） in the serum and ATP， malondialdehyde （MDA）， and superoxide dismutase （SOD） in the myocardial tissue. Western blot was employed to determine the protein levels of SIRT3， PGC-1α， adenosine monophosphate-activated protein kinase （AMPK）， and phosphorylated AMPK （p-AMPK） in the myocardial tissue. Real-time PCR was employed to measure the mRNA levels of SIRT3， PGC-1α， and AMPKα in the myocardial tissue. ResultsCompared with the control group， the model group showed significant J-point deviation and elevation in the ECG image， increased heart rate， disarrangement of myocardial fibers with unclear boundaries， elevated levels of CK-MB， cTnI， MYO， TC， and TG （P<0.05， P<0.01）， declined levels of SOD and ATP （P<0.01）， down-regulated mRNA levels of SIRT3， PGC-1α， and AMPK （P<0.05）， and down-regulated protein levels of SIRT3， PGC-1α， and p-AMPK （P<0.05）. Compared with the model group， the low-dose and high-dose Wendantang groups and the trimetazidine group showed inhibited J-point deviation and elevation in the ECG image， slowed heart rate， reduced inflammatory cell infiltration， alleviated disarrangement of myocardial fibers， declined levels of CK-MB， cTnI， MYO， TC， and TG （P<0.05， P<0.01）， elevated level of SOD （P<0.01）， up-regulated mRNA levels of SIRT3， PGC-1α， and AMPK （P<0.05， P<0.01） and up-regulated protein levels of SIRT3， PGC-1α， and p-AMPK （P<0.05， P<0.01）. ConclusionWendantang can effectively intervene in HL-associated MI in rats by reducing oxidative stress in myocardial cells， alleviating lipid metabolism disorders， and improving myocardial energy metabolism via the SIRT3/PGC-1α signaling pathway.

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.

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

As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.

Objective:To investigate the inpact of thyroid cancer-derived cancer-associated fibroblasts(CAF) autophagy on papillary thyroid cancer(PTC).Methods:CAF and normal fibroblasts were isolated from cancerous and adjacent normal thyroid tissues from four PTC patients. Expressions of fibroblast activation protein(FAP) and α-smooth muscle actin in cells were assessed. Conditioned medium of CAF and normal fibroblasts were prepared and used to culture PTC cells. The effects of CAF and normal fibroblasts on survival, proliferation, migration, invasion and iodine uptake of PTC cells were evaluated through cell proliferation assay, cell scratch assay, cell invasion assay, and cell iodine uptake assay. The autophagy level of CAF was also evaluated. Autophagy inhibition and activation were used to regulate the autophagy of CAF, and then their effects on PTC cell proliferation, migration and invasion were further evaluated. The in vivo effect of CAF autophagy on PTC xenograft tumor growth was evaluated.Results:CAF exhibited higher FAP expression and basal autophagy levels. PTC cells co-cultured with CAF-conditioned media showed enhanced proliferation, migration, invasion, and reduced iodine uptake. Autophagy inhibition reduced these effects, while autophagy activation further promoted them. In vivo, inhibiting CAF autophagy suppressed tumor growth.Conclusions:CAF promotes PTC cell malignancy through autophagy activation, enhancing proliferation, migration, and invasion while reducing iodine uptake.

Objective:To investigate the value of biparametric-MRI (bpMRI) based peritumoral radiomics for preoperative prediction of extraprostatic extension (EPE) in prostate cancer (PCa).Methods:In this cross-sectional study, consecutive bpMRI of patients undergoing prostatectomy for PCa were retrospectively collected from the First Medical Center (center 1) and the Third Medical Center (center 2) of Chinese PLA General Hospital. A total of 274 patients were finally enrolled. Patients at center 1 from January 2020 to December 2022 were randomly divided into a training set (149 cases) and an internal validation set (63 cases) by stratified random sampling. Patients at center 2 from January 2023 to March 2024 were assigned to the external test set (62 cases). Patients were categorized into EPE-positive group and EPE-negative group according to pathological assessment postoperatively. In the training set, there were 49 cases in EPE-positive group and 100 cases in EPE-negative group. In the internal validation set, there were 26 cases in EPE-positive group and 37 cases in EPE-negative group. In the external test set, there were 22 cases in EPE-positive group and 40 cases in EPE-negative group. Axial T 2WI and apparent diffusion coefficient (ADC) images were manually annotated to obtain index lesion regions of interest (ROIs), with the peritumoral ROIs subsequently delineated by semi-automatic segmentation technique. Radiomics features were extracted from intra-tumoral, peri-tumoral, and intra-tumoral plus peri-tumoral ROIs. The training set data was employed to select and optimize features to build the radiomics models. The logistic regression analysis was used to develop radiomics, clinical, and integrated models. The predictive performance was assessed by the area under the receiver operating characteristic curve (AUC) in the external test set, and compared by the DeLong test. The sensitivity and specificity were compared by the exact McNemar test. Results:In the external test set, the peri-tumoral radiomics model based on bpMRI showed the highest performance in evaluating EPE, with an AUC of 0.739 (95% CI 0.611-0.842), which was identified as the optimal radiomics model. EPE grade ( OR=6.151, 95% CI 3.371-11.226, P<0.001) was incorporated into the clinical model, with an AUC of 0.780 (95% CI 0.657-0.875) in the external test set. The integrated model had an AUC of 0.817 (95% CI 0.698-0.904) in the external test set. There was no statistically significant difference in comparisons of AUCs among the three models (all P>0.05). The sensitivity of the integrated model (68.2%) showed no significant difference from those of the clinical model and the optimal radiomics model (77.3% and 86.4%, respectively; P=0.500 and P=0.289). However, the specificity of the integrated model (85.0%) was significantly higher than those of the clinical model (67.5%, P=0.016) and the optimal radiomics model (50.0%, P<0.001). Conclusion:A bpMRI-based peritumoral radiomics integrating clinical model demonstrates high performance for preoperative prediction of EPE in PCa.