BACKGROUND: Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens. METHODS: Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ. RESULTS: This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 ( COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival. CONCLUSION P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM.
Temozolomide ; Humans ; Glioblastoma/drug therapy* ; Animals ; Mice ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; YAP-Signaling Proteins ; Hydroxylation ; Dacarbazine/pharmacology* ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Collagen/biosynthesis* ; Collagen Type I/metabolism* ; Prolyl Hydroxylases/metabolism* ; Antineoplastic Agents, Alkylating/therapeutic use*

OBJECTIVE: To investigate the associations between eight serum per- and polyfluoroalkyl substances (PFASs) and regional fat depots, we analyzed the data from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 cycles. METHODS: Multiple linear regression models were developed to explore the associations between serum PFAS concentrations and six fat compositions along with a fat distribution score created by summing the concentrations of the six fat compositions. The associations between structurally grouped PFASs and fat distribution were assessed, and a prediction model was developed to estimate the ability of PFAS exposure to predict obesity risk. RESULTS: Among females aged 39-59 years, trunk fat mass was positively associated with perfluorooctane sulfonate (PFOS). Higher concentrations of PFOS, perfluorohexane sulfonate (PFHxS), perfluorodecanoate (PFDeA), perfluorononanoate (PFNA), and n-perfluorooctanoate (n-PFOA) were linked to greater visceral adipose tissue in this group. In men, exposure to total perfluoroalkane sulfonates (PFSAs) and long-chain PFSAs was associated with reductions in abdominal fat, while higher abdominal fat in women aged 39-59 years was associated with short-chain PFSAs. The prediction model demonstrated high accuracy, with an area under the curve (AUC) of 0.9925 for predicting obesity risk. CONCLUSION PFAS exposure is associated with regional fat distribution, with varying effects based on age, sex, and PFAS structure. The findings highlight the potential role of PFAS exposure in influencing fat depots and obesity risk, with significant implications for public health. The prediction model provides a highly accurate tool for assessing obesity risk related to PFAS exposure.
Humans ; Fluorocarbons/blood* ; Female ; Adult ; Middle Aged ; Male ; Environmental Pollutants/blood* ; Abdominal Fat ; Nutrition Surveys ; Alkanesulfonic Acids/blood* ; Obesity ; Environmental Exposure

Objective To explore the accumulated effects of physical activity,sedentary behavior,and sleep on cardiorespiratory fitness(CRF)among college students and provide effective measures for enhancing their CRF. Methods From May to June in 2023,223 college students aged 18 to 24 years old were recruited from Tianjin University of Science and Technology for a 24 hours activity behavior survey and CRF testing.Compositional analysis was employed to investigate the relationships of physical activity,sedentary behavior,and sleep with CRF.Isotemporal substitution models were established to predict the effects of substituting various activity behaviors on CRF.Results The proportion of time spent on moderate-to-vigorous physical activity(MVPA)was positively correlated with CRF of college students(β=6.40,P=0.002),while the proportion of time spent on sedentary behavior was negatively correlated with CRF(β=-3.02,P=0.004).Light physical activity(LPA)and sleep were not correlated with CRF(β=-1.06,P=0.504).Isotemporal substitution results for 15-min increments showed that replacing other activity behaviors with MVPA significantly increased the CRF of college students[SB:1.72 mL/(kg·min),95% CI=0.94-2.51;LPA:1.82 mL/(kg·min),95% CI=0.95-2.68;sleep:1.64 mL/(kg·min),95% CI=0.84-2.45].In the dose-response relationship from -30 min to 30 min,reallocating time from other behaviors to MVPA had greater adverse effect on CRF than reallocating time from MVPA to other behaviors.Among all the substitutions,replacing LPA with MVPA had the most beneficial effect on improving CRF.Additionally,a 5-min increment was considered the optimal tipping point for MVPA replacing other activities.Conclusions This study underscores the importance of participating in MVPA for improving the CRF of college students.The isotemporal substitution model provides clear goals for the allocation of time for these behaviors,aiding in future intervention measure development and policy-making.
Humans ; Sedentary Behavior ; Sleep ; Students ; Cardiorespiratory Fitness ; Exercise ; Young Adult ; Adolescent ; Universities ; Male ; Female

Objective To explore the effects of time reallocation among moderate-to-vigorous physical activity(MVPA),light physical activity(LPA),sedentary behavior(SB),and sleep on a body shape index(ABSI),body roundness index(BRI),conicity index(CI),and relative fat mass(RFM)of college students by the compositional isotemporal substitution method,thus providing measures for alleviating the obesity problem of college students. Methods Two hundred and ten college students(111 males and 99 females)aged 18-22 years old were recruited from Tianjin University of Science and Technology from April to June in 2023.Three-dimensional acceleration sensors were used to collect data of MVPA,LPA,SB,and sleep of college students.The body height,body weight,and waist circumference were measured,and four novel obesity indicators(ABSI,BRI,CI,and RFM)were calculated.The effects of substituting each activity behavior for 15 min on the obesity indicators were predicted,and the dose-effect relationship was explored at intervals of 5 min from -30 to 30 min.Results MVPA was negatively correlated with ABSI(β=-0.03,P=0.001),BRI(β=-0.27,P=0.049),CI(β=-0.10,P=0.001),and RFM(β=-9.95,P=0.004).LPA was negatively correlated with CI(β=-0.05,P=0.011)and RFM(β=-8.74,P=0.007).Neither SB nor sleep had correlations with ABSI,BRI,CI,and RFM.The results of 15 min isotemporal substitutions showed that increasing the MVPA time decreased the ABSI,BRI,CI,and RFM by 0.006-0.008,0.306-0.393,0.162-0.205,and 2.468-2.897,respectively.Decreasing the MVPA time increased the ABSI,BRI,CI,and RFM by 0.012-0.014,0.548-0.632,0.286-0.328,and 4.358-4.748,respectively.In the dose-effect relationship from -30 min to 30 min,MVPA was irreplaceable,and the negative benefits from substituting MVPA for other activity behaviors were much greater than the positive benefits from substituting MVPA for other activity behaviors.Conclusions Future research should take 24 hours activity behaviors as a whole.Increasing the time spent on MVPA and LPA and decreasing the time spent on SB is one of the effective ways to alleviate the obesity problem among college students.
Humans ; Male ; Students ; Female ; Young Adult ; Obesity ; Sleep ; Adolescent ; Exercise ; Universities ; Sedentary Behavior ; Body Mass Index ; Body Weight

Compounds isolated from Epimedium include the total flavonoids of Epimedium , icariin, and its metabolites (icaritin, icariside I, and icariside II), which have similar molecular structures. Modern pharmacological research and clinical practice have proved that Epimedium and its active components have a wide range of pharmacological effects, especially in improving sexual function, hormone regulation, anti-osteoporosis, immune function regulation, anti-oxidation, and anti-tumor activity. To date, we still need a comprehensive source of knowledge about the pharmacological effects of Epimedium and its bioactive compounds on the male reproductive system. However, their actions in other tissues have been reviewed in recent years. This review critically focuses on the Epimedium , its bioactive compounds, and the biochemical and molecular mechanisms that modulate vital pathways associated with the male reproductive system. Such intrinsic knowledge will significantly further studies on the Epimedium and its bioactive compounds that protect the male reproductive system and provide some guidances for clinical treatment of related male reproductive disorders.
Male ; Epimedium/chemistry* ; Humans ; Genitalia, Male/drug effects* ; Flavonoids/therapeutic use* ; Animals

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by impaired motility of cilia and flagella. Mutations in cilia- and flagella-associated protein 300 ( CFAP300 ) are associated with human PCD and male infertility; however, the underlying pathogenic mechanisms remain poorly understood. In a consanguineous Chinese family, we identified a homozygous CFAP300 loss-of-function variant (c.304delC) in a proband presenting with classical PCD symptoms and severe sperm abnormalities, including dynein arm deficiency and acrosomal malformation, as confirmed by transmission electron microscopy (TEM). Histological analysis revealed multiple morphological abnormalities of the sperm flagella in CFAP300 -mutant individual, whereas immunofluorescence demonstrated markedly reduced CFAP300 expression in the spermatozoa of the proband. Furthermore, tandem mass tag (TMT)-based quantitative proteomics showed that the CFAP300 mutation reduced key spermatogenesis proteins (e.g., sperm flagellar 2 [SPEF2], solute carrier family 25 member 31 [SLC25A31], and A-kinase anchoring protein 3 [AKAP3]) and mitochondrial ATP synthesis factors (e.g., SLC25A31, cation channel sperm-associated 3 [CATSPER3]). It also triggered abnormal increases in autophagy-related proteins and signaling mediator phosphorylation. These molecular alterations are likely to contribute to progressive deterioration of sperm ultrastructure and function. Notably, successful pregnancy was achieved via intracytoplasmic sperm injection (ICSI) using the proband's sperm. Overall, this study expands the known CFAP300 mutational spectrum and offers novel mechanistic insights into its role in spermatogenesis.
Humans ; Male ; Infertility, Male/pathology* ; Acrosome/pathology* ; Sperm Tail/pathology* ; Pedigree ; Spermatozoa ; Adult ; Loss of Function Mutation ; Ciliary Motility Disorders/genetics* ; Spermatogenesis/genetics* ; Female

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

Protrusive facial deformities, characterized by the forward displacement of the teeth and/or jaws beyond the normal range, affect a considerable portion of the population. The manifestations and morphological mechanisms of protrusive facial deformities are complex and diverse, requiring orthodontists to possess a high level of theoretical knowledge and practical experience in the relevant orthodontic field. To further optimize the correction of protrusive facial deformities, this consensus proposes that the morphological mechanisms and diagnosis of protrusive facial deformities should be analyzed and judged from multiple dimensions and factors to accurately formulate treatment plans. It emphasizes the use of orthodontic strategies, including jaw growth modification, tooth extraction or non-extraction for anterior teeth retraction, and maxillofacial vertical control. These strategies aim to reduce anterior teeth and lip protrusion, increase chin prominence, harmonize nasolabial and chin-lip relationships, and improve the facial profile of patients with protrusive facial deformities. For severe skeletal protrusive facial deformities, orthodontic-orthognathic combined treatment may be suggested. This consensus summarizes the theoretical knowledge and clinical experience of numerous renowned oral experts nationwide, offering reference strategies for the correction of protrusive facial deformities.
Humans ; Orthodontics, Corrective/methods* ; Consensus ; Malocclusion/therapy* ; Patient Care Planning ; Cephalometry

South Korea’s current vaccination policies leave a surveillance gap for non-National Immunization Program (NIP) vaccines. In this study, we proposed a sentinel surveillance approach for monitoring the safety of non-NIP vaccines. Vaccination data were collected retrospectively among patients hospitalized with pre-defined adverse events of special interest (AESI) by reviewing electronic medical records in five university hospitals. This approach incorporates expert assessment to determine the causal relationship. We confirmed that 16 patients had received non-NIP vaccines among 860 patients diagnosed with AESI.We concluded one case of preeclampsia was possibly related to tetanus-diphtheria-pertussis vaccination. We propose a multi-hospital-based, retrospective assessment system for predefined AESIs as an alternative to active vaccine safety monitoring method. These efforts are expected to enhance both the accuracy and timeliness of safety monitoring in South Korea.