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.

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.

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*

In order to comprehensively deepen the reform of medical insurance payment methods and explore the establishment of a medical insurance payment system with Chinese features,five representative cities have been selected for analysis:Jinhua City in Zhejiang Province,Xiamen City in Fujian Province,Suixi City in Anhui Province,TianjinCity,and Zhenjiang City in Jiangsu Province.These regions have been chosen due to their typical ambulatory care payment reform.It summarises the features of ambulatory care payment reforms in different regions regarding implementing agencies,covered crowds and types of illnesses,and payment methods.It is recommended that a reasonable scope of implementation be selected and the reform purpose and basic conditions should be taken into account to explore an appropriate ambulatory care payment reform.It is proposed that an innovative payment method reform be implemented to promote healthcare and prevention integration,and to incorporate a value-oriented paradigm,thereby realizing the benefits of the doctor and patient insurance.

As global greenhouse gases continue rising, the urgency of more ambitious action is clearer than ever before. China is the world's biggest emitter of greenhouse gases and one of the countries affected most by climate change. The evidence about the impacts of climate change on the environment and human health may encourage China to take more decisive action to mitigate greenhouse gas emissions and adapt to climate impacts. This article aimed to review the evidence of environmental damages and health risks posed by climate change and to provide a new science-based perspective for the delivery of sustainable development goals. Over recent decades, China has experienced a strong warming pattern with a growing frequency of extreme weather events, and the impacts of climate change on China's environment and human health have been consistently observed, with increasing O ₃ air pollution, decreases in water resources and availability, land degradation, and increased risks for both communicable and non-communicable diseases. Therefore, China's climate policy should target the key factors driving climate change and scale up strategic measures to curb carbon emissions and adapt to inevitable increasing climate impacts. It provides new insights for not only China but also other countries, particularly developing and emerging economies, to ensure climate and environmental sustainability whilst pursuing economic growth.
Climate Change ; China ; Humans ; Greenhouse Gases ; Air Pollution ; Sustainable Development ; Environment

OBJECTIVE: The study aim was to investigate the effects of exposure to multiple environmental organic pollutants on cardiopulmonary health with a focus on the potential mediating role of oxidative stress. METHODS: A repeated-measures randomized crossover study involving healthy college students in Beijing was conducted. Biological samples, including morning urine and venous blood, were collected to measure concentrations of 29 typical organic pollutants, including hydroxy polycyclic aromatic hydrocarbons (OH-PAHs), bisphenol A and its substitutes, phthalates and their metabolites, parabens, and five biomarkers of oxidative stress. Health assessments included blood pressure measurements and lung function indicators. RESULTS: Urinary concentrations of 2-hydroxyphenanthrene (2-OH-PHE) ( β = 4.35% [95% confidence interval ( CI): 0.85%, 7.97%]), 3-hydroxyphenanthrene ( β = 3.44% [95% CI: 0.19%, 6.79%]), and 4-hydroxyphenanthrene (4-OH-PHE) ( β = 5.78% [95% CI: 1.27%, 10.5%]) were significantly and positively associated with systolic blood pressure. Exposures to 1-hydroxypyrene (1-OH-PYR) ( β = 3.05% [95% CI: -4.66%, -1.41%]), 2-OH-PHE ( β = 2.68% [95% CI: -4%, -1.34%]), and 4-OH-PHE ( β = 3% [95% CI: -4.68%, -1.29%]) were negatively associated with the ratio of forced expiratory volume in the first second to forced vital capacity. These findings highlight the adverse effects of exposure to multiple pollutants on cardiopulmonary health. Biomarkers of oxidative stress, including 8-hydroxy-2'-deoxyguanosine and extracellular superoxide dismutase, mediated the effects of multiple OH-PAHs on blood pressure and lung function. CONCLUSION Exposure to multiple organic pollutants can adversely affect cardiopulmonary health. Oxidative stress is a key mediator of the effects of OH-PAHs on blood pressure and lung function.
Humans ; Oxidative Stress/drug effects* ; Male ; Cross-Over Studies ; Female ; Young Adult ; Environmental Pollutants/toxicity* ; Environmental Exposure/adverse effects* ; Biomarkers/blood* ; Adult ; Blood Pressure/drug effects* ; Polycyclic Aromatic Hydrocarbons/urine* ; Beijing

Insulin is an important protein hormone that participates in multiple metabolic pathways.Biosynthetic insulin has been widely used in the treatment of type 1 and type 2 diabetes.Currently,the number of reported cases of insulin overdose both at home and abroad is gradually increasing,and insulin homicide is no longer a means of"committing murder without leaving a trace".At present,there are no systematic protocols for the identification of insulin overdose in the field of forensic medi-cine in China.This article introduces the causes,toxicological characteristics,forensic examination,labo-ratory testing methods and indicator reference of insulin overdose.Based on the identification practice and research results and referring to relevant studies on insulin overdose at home and abroad,this pa-per aims to provide recommendations and references for the formulation of forensic identification guide-lines for insulin overdose cases.

BACKGROUND:Dexamethasone and hindlimb suspension are commonly used methods for modeling sarcopenia in animal experiments due to their short modeling time,ease of operation,and low cost.OBJECTIVE:To compare the differences in muscle mass,strength and functional phenotypes and molecular mechanisms between two mouse sarcopenia models induced by dexamethasone and hindlimb suspension.METHODS:Thirty male C57BL/6 mice were randomly divided into three groups(n=10 per group).The normal control group received no intervention.The dexamethasone group received daily intraperitoneal injections of 1 mg/kg/d dexamethasone sodium phosphate solution for 6 continuous days to establish sarcopenia models in mice,while mice in the hindlimb suspension group were suspended by tail harness for 16 hours,once per day,to establish sarcopenia models.Within 6 weeks after modeling,changes in body mass were monitored.After 6 weeks of modeling,mice were tested for limb grip strength,mobility(swimming test),skeletal muscle wet mass,and skeletal muscle pathological morphology.Expressions of skeletal muscle protein synthesis and catabolism indexes as well as the AMPK/FoXO3α signaling pathway were detected by RT-PCR and western blot.RESULTS AND CONCLUSION:(1)Two weeks after modeling,both dexamethasone and hindlimb suspension groups showed a significant decrease in body mass compared with the normal control group(P<0.001).After 6 weeks of modeling,grip strength of mice in both dexamethasone and hindlimb suspension groups was lower than that in the normal control group(P<0.001).The wet mass of gastrocnemius and extensor digitorum longus muscles and the cross-sectional area of gastrocnemius and soleus muscles in the dexamethasone group were lower than those in the normal control group(P<0.05).Compared with the hindlimb suspension group,the cross-sectional area of gastrocnemius muscle was significantly smaller in the dexamethasone group(P<0.05),while the cross-sectional area of soleus muscle was larger in the dexamethasone group(P<0.05).Mice in the dexamethasone group had reduced mobility when compared with those in the normal control group and the hindlimb suspension group(P<0.05).(3)Compared with the normal control group,PI3K,mTOR,AMPK,and PGC-1α mRNA expression and P-AMPK/AMPK protein were decreased in the two modeling groups(P<0.05),and FoXO3α mRNA expression and PGC-1α and FoXO3 protein expression were elevated(P<0.05);in the dexamethasone group,Akt1 mRNA expression was decreased(P<0.05),while Atrogin-1 and MuRF-1 mRNA expression was elevated(P<0.05);in the hindlimb suspension group,Akt1 mRNA expression was elevated(P<0.05).(4)Compared with the dexamethasone group,mTOR,Akt1,and FoXO3α mRNA expression was elevated in the hindlimb suspension group(P<0.05),while Atrogin-1 and MuRF-1 mRNA expression was decreased(P<0.05).To conclude,both modeling methods could decrease the levels of mitochondrial energy metabolism in skeletal muscle,with the dexamethasone group mediating atrophy of skeletal muscle through the dual action of ubiquitin proteasome and energy metabolism pathways,and the hindlimb suspension group inducing atrophy of skeletal muscle by mediating the energy metabolism pathway through the AMPK/FoXO3α signaling pathway,subsequently causing a reduction in mass,strength,and function of skeletal muscle.

BACKGROUND:Dexamethasone and hindlimb suspension are commonly used methods for modeling sarcopenia in animal experiments due to their short modeling time,ease of operation,and low cost.OBJECTIVE:To compare the differences in muscle mass,strength and functional phenotypes and molecular mechanisms between two mouse sarcopenia models induced by dexamethasone and hindlimb suspension.METHODS:Thirty male C57BL/6 mice were randomly divided into three groups(n=10 per group).The normal control group received no intervention.The dexamethasone group received daily intraperitoneal injections of 1 mg/kg/d dexamethasone sodium phosphate solution for 6 continuous days to establish sarcopenia models in mice,while mice in the hindlimb suspension group were suspended by tail harness for 16 hours,once per day,to establish sarcopenia models.Within 6 weeks after modeling,changes in body mass were monitored.After 6 weeks of modeling,mice were tested for limb grip strength,mobility(swimming test),skeletal muscle wet mass,and skeletal muscle pathological morphology.Expressions of skeletal muscle protein synthesis and catabolism indexes as well as the AMPK/FoXO3α signaling pathway were detected by RT-PCR and western blot.RESULTS AND CONCLUSION:(1)Two weeks after modeling,both dexamethasone and hindlimb suspension groups showed a significant decrease in body mass compared with the normal control group(P<0.001).After 6 weeks of modeling,grip strength of mice in both dexamethasone and hindlimb suspension groups was lower than that in the normal control group(P<0.001).The wet mass of gastrocnemius and extensor digitorum longus muscles and the cross-sectional area of gastrocnemius and soleus muscles in the dexamethasone group were lower than those in the normal control group(P<0.05).Compared with the hindlimb suspension group,the cross-sectional area of gastrocnemius muscle was significantly smaller in the dexamethasone group(P<0.05),while the cross-sectional area of soleus muscle was larger in the dexamethasone group(P<0.05).Mice in the dexamethasone group had reduced mobility when compared with those in the normal control group and the hindlimb suspension group(P<0.05).(3)Compared with the normal control group,PI3K,mTOR,AMPK,and PGC-1α mRNA expression and P-AMPK/AMPK protein were decreased in the two modeling groups(P<0.05),and FoXO3α mRNA expression and PGC-1α and FoXO3 protein expression were elevated(P<0.05);in the dexamethasone group,Akt1 mRNA expression was decreased(P<0.05),while Atrogin-1 and MuRF-1 mRNA expression was elevated(P<0.05);in the hindlimb suspension group,Akt1 mRNA expression was elevated(P<0.05).(4)Compared with the dexamethasone group,mTOR,Akt1,and FoXO3α mRNA expression was elevated in the hindlimb suspension group(P<0.05),while Atrogin-1 and MuRF-1 mRNA expression was decreased(P<0.05).To conclude,both modeling methods could decrease the levels of mitochondrial energy metabolism in skeletal muscle,with the dexamethasone group mediating atrophy of skeletal muscle through the dual action of ubiquitin proteasome and energy metabolism pathways,and the hindlimb suspension group inducing atrophy of skeletal muscle by mediating the energy metabolism pathway through the AMPK/FoXO3α signaling pathway,subsequently causing a reduction in mass,strength,and function of skeletal muscle.

Objective:To investigate the effectiveness and safety of secondary cytoreductive surgery (SCS) in patients with platinum-sensitive recurrent epithelial ovarian cancer who progressed after first-line maintenance therapy with poly adenosine diphosphate ribose polymerase inhibitor (PARPi).Methods:Clinical pathological data and prognostic information were retrospectively collected from 30 ovarian cancer patients who underwent SCS between January 2018 and June 2024. The Kaplan-Meier method was used to analyze the second progression-free survival (PFS2) time and 3-year overall survival (OS) rate.Results:(1) Primary treatment: the median age at diagnosis was 51.3 years. A total of 40% (12/30) patients underwent primary debulking surgery with an expectation of achieving no gross residual disease (R0), while 60% (18/30) received neoadjuvant chemotherapy and interval debulking surgery. Optimal cytoreduction was achieved in 93% (28/30) of patients. BRCA1/2 gene testing was performed in 29 patients (testing rate 97%, 29/30), identifying 11 BRCA-mutated (37%, 11/30) and 18 BRCA wild-type (60%, 18/30) patients. The median duration of PARPi maintenance therapy among the 30 patients was 11.9 months; patients with BRCA gene mutations had a median duration of 19.2 months, while those with BRCA wild-type had a median duration of 10.1 months. (2) Secondary surgery: pathologically confirmed recurrence patterns, single lesion in 9 patients (30%, 9/30), oligo-lesion (2 lesions) in 3 patients (10%, 3/30), and multi-lesion (≥3 lesions) in 18 patients (60%, 18/30). Among the 30 patients, optimal cytoreduction was achieved in 97% (29/30) of SCS patients, with suboptimal cytoreduction in 1 patient (3%, 1/30). Adjuvant chemotherapy included platinum+paclitaxel in 24 (80%, 24/30) patients and platinum+liposomal doxorubicin in 6 (20%, 6/30) patients. PARPi re-treatment was administered to 17 patients (57%, 17/30) after chemotherapy. (3) Efficacy and safety: as of the follow-up cutoff in June 2024, the median follow-up time was 28.0 months. A total of 19 (63%, 19/30) patients experienced the next recurrence. The median PFS2 time after SCS was 18.5 months. Recurrence occurred in 7 BRCA-mutated and 12 BRCA gene wild-type patients. Median PFS2 time was significantly longer in BRCA-mutated patients compared to BRCA wild-type patients (25.7 vs 14.1 months; P=0.028). Three deaths occurred during follow-up, resulting in a 3-year OS rate of 90%. Among the 30 patients, postoperative complications occurred in 4 patients (13%, 4/30). One patient developed a ureteral fistula on 7 days post-SCS requiring ureteral stenting, and one patient was transferred to the intensive care unit on 1 day post-SCS due to hypovolemic shock. No deaths occurred within 30 days after SCS. Conclusion:For platinum-sensitive recurrent ovarian cancer patients progressed after first-line PARPi maintenance therapy who are anticipated to achieve R0 resection, SCS represents a safe and effective second-line treatment option.