Lumbar disc (LD) herniation and aging are prevalent conditions that can result in substantial morbidity. This study aimed to clarify the mechanisms connecting the LD aging and herniation, particularly focusing on cellular senescence and molecular alterations in the nucleus pulposus (NP). We performed a detailed analysis of NP samples from a diverse cohort, including individuals of varying ages and those with diagnosed LD herniation. Our methodology combined histological assessments with single-nucleus RNA sequencing to identify phenotypic and molecular changes related to NP aging and herniation. We discovered that cellular senescence and a decrease in nucleus pulposus progenitor cells (NPPCs) are central to both processes. Additionally, we found an age-related increase in NFAT1 expression that promotes NPPC senescence and contributes to both aging and herniation of LD. This research offers fresh insights into LD aging and its associated pathologies, potentially guiding the development of new therapeutic strategies to target the root causes of LD herniation and aging.
Intervertebral Disc Displacement/metabolism* ; Humans ; Aging/pathology* ; Nucleus Pulposus/pathology* ; Male ; Female ; Transcriptome ; Middle Aged ; Lumbar Vertebrae/pathology* ; Adult ; Cellular Senescence ; Stem Cells/pathology* ; Aged ; Intervertebral Disc Degeneration/metabolism*

At present,the quality and safety management of multiple districts of hospital still has problems such as low informatization level,inconsistent quality and safety management mode,and insufficient quality and safety management concept.It takes an orthopedic hospital of Traditional Chinese Medicine as an example to explore the quality and safety management practice of multiple districts of hospital under the homogenization strategy.A three-level quality control management system composed of leadership,executive level and guidance level was constructed,and the general framework of the integrated quality management system and the specific work contents of quality management in each hospital were proposed,in order to provide a standardized and operable management mode for medical institutions to carry out medical quality management.

At present,the quality and safety management of multiple districts of hospital still has problems such as low informatization level,inconsistent quality and safety management mode,and insufficient quality and safety management concept.It takes an orthopedic hospital of Traditional Chinese Medicine as an example to explore the quality and safety management practice of multiple districts of hospital under the homogenization strategy.A three-level quality control management system composed of leadership,executive level and guidance level was constructed,and the general framework of the integrated quality management system and the specific work contents of quality management in each hospital were proposed,in order to provide a standardized and operable management mode for medical institutions to carry out medical quality management.

Background::Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for β-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 ( CTNNB1), the most frequently altered proto-oncogene in hepatic neoplasms. Methods::Constitutive β-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 ( β-cateninΔ(ex3)/+ ), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited β-cateninΔ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on β-catenin-activated human liver cancer cells were determined in vitro. Immuno-deficient nude mice subcutaneously inoculated with β-catenin wild-type or mutant liver cancer cells and hepatitis B virus ( HBV); β-cateninlox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of β-catenin mutant liver cancer. Results::MTX was identified and validated as a preferential agent against the proliferation and tumor formation of β-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in β-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV; β-cateninlox(ex3)/+ mice, which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer. Conclusion::MTX is a promising chemotherapeutic agent for β-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of β-catenin mutant liver cancer.

Background::Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism.Methods::We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments.Results::The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 ( ERAP1) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1. The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes. Conclusion::The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1. Trial Registration::No. NCT00454519 (https://clinicaltrials.gov/)

At present,the quality and safety management of multiple districts of hospital still has problems such as low informatization level,inconsistent quality and safety management mode,and insufficient quality and safety management concept.It takes an orthopedic hospital of Traditional Chinese Medicine as an example to explore the quality and safety management practice of multiple districts of hospital under the homogenization strategy.A three-level quality control management system composed of leadership,executive level and guidance level was constructed,and the general framework of the integrated quality management system and the specific work contents of quality management in each hospital were proposed,in order to provide a standardized and operable management mode for medical institutions to carry out medical quality management.

At present,the quality and safety management of multiple districts of hospital still has problems such as low informatization level,inconsistent quality and safety management mode,and insufficient quality and safety management concept.It takes an orthopedic hospital of Traditional Chinese Medicine as an example to explore the quality and safety management practice of multiple districts of hospital under the homogenization strategy.A three-level quality control management system composed of leadership,executive level and guidance level was constructed,and the general framework of the integrated quality management system and the specific work contents of quality management in each hospital were proposed,in order to provide a standardized and operable management mode for medical institutions to carry out medical quality management.