Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disease worldwide, affecting approximately 32%-38% of the adult population and posing a growing public health burden. MASLD represents a continuous disease spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), progressive hepatic fibrosis, cirrhosis, and ultimately hepatocellular carcinoma (HCC). The pathological core of MASLD lies in disruption of hepatic lipid metabolic homeostasis, characterized by an imbalance among de novo lipogenesis, fatty acid β-oxidation, and very-low-density lipoprotein (VLDL)-mediated lipid export. This metabolic disequilibrium subsequently drives inflammatory injury and fibrotic progression. Among the multiple regulatory pathways involved, thyroid hormone (TH) signaling has emerged as a central regulator of hepatic metabolic homeostasis. The liver is a major peripheral target organ of TH action, where TH predominantly exerts its metabolic effects through thyroid hormone receptor β (TRβ). Large-scale epidemiological studies and meta-analyses have demonstrated that hypothyroidism is significantly associated with increased MASLD prevalence, more severe histological injury, and advanced hepatic fibrosis, suggesting that dysregulation of TH signaling may participate throughout the entire MASLD disease spectrum. At the molecular level, TH regulates hepatic lipid metabolism by coordinating suppression of lipogenesis, enhancement of mitochondrial fatty acid oxidation, and promotion of VLDL assembly and secretion through integrated genomic actions of the T3-TRβ axis and non-genomic signaling pathways. Across different stages of MASLD, TH signaling exerts stage-dependent protective effects. In the steatosis stage, TH improves metabolic flexibility by modulating insulin sensitivity, glucose metabolism, and lipid droplet clearance, thereby alleviating early lipotoxic stress. During progression to MASH, TH attenuates inflammatory amplification by improving mitochondrial homeostasis, suppressing activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, and modulating the gut-liver axis microenvironment. In advanced stages, TH signaling influences hepatic stellate cell activation and extracellular matrix deposition, partly through interaction with the transforming growth factor-β (TGF-β)/SMAD pathway, while alterations in intrahepatic TH availability, mediated by dynamic changes in iodothyronine deiodinase 1 (DIO1), contribute to fibrosis progression and hepatocellular dedifferentiation. In hepatocellular carcinoma, coordinated downregulation of TRβ and DIO1 establishes a tumor-associated hypothyroid state that promotes metabolic reprogramming and tumor progression. The clinical relevance of TH signaling in MASLD has been underscored by the recent approval of Resmetirom, a liver-targeted TRβ‑selective agonist, for the treatment of non-cirrhotic MASH with moderate-to-severe fibrosis (F2-F3). This approval represents a landmark transition from mechanistic understanding to metabolism-centered precision therapy in MASLD. Clinical trials have demonstrated that Resmetirom not only improves key histological endpoints, including MASH resolution and fibrosis regression, but also favorably modulates atherogenic lipid profiles, highlighting the therapeutic potential of selectively targeting hepatic TH pathways. This review systematically summarizes the multidimensional regulatory roles of TH across the MASLD disease spectrum and discusses emerging diagnostic and therapeutic implications of TH-based interventions, aiming to inform future mechanistic research and optimize clinical management strategies.

Objective:To retrospectively evaluate the clinical efficacy and safety of total 3D laparo-scopic ileal ureters replacement for bilateral ureters combined with bladder augmentation in patients with post-radiotherapy long-segment bilateral ureteral strictures and contracted bladder.Methods:Clinical data of two patients(aged 72 and 54 years)with radiation-induced long-segment bilateral ureteral stric-tures and reduced bladder capacity,treated at the Sixth Affiliated Hospital of Jinan University from Octo-ber 2023 to June 2024,were analyzed.Both presented with bilateral flank pain,recurrent chills/fever,urinary frequency,and urgency.Preoperative ureteral stricture lengths were measured as follows:left 10.4 cm and right 8.7 cm in the first case;left 10.6 cm and right 11.7 cm in the second case.Bladder capacity assessed by nephrostomy-assisted antegrade urography was 90 mL and 130 mL respectively.Both underwent single-position,one-stage totally 3D laparoscopic bilateral ileal ureteral replacement and blad-der augmentation based on membrane anatomy principles,with regular postoperative follow-up.Results:Procedures were completed by the same experienced urologist.Operative times were 420 min and 355 min,with intraoperative blood loss of 50 mL(no transfusion required).Postoperative bowel function re-sumed at the end of 4.5 and 3 days.No major perioperative complications occurred.Ureteral stents were removed at 2 months postoperatively,with imaging showing improved hydronephrosis,unobstructed ure-teral drainage,symmetrical bladder morphology,and smooth walls.Postoperative bladder capacities were 230 mL and 250 mL.Follow-up durations were 10 and 8 months.Both patients experienced significant relief of flank pain and lower urinary tract symptoms.No complications(enteric fistula,urinary fistula,or metabolic acidosis)were observed.At the final follow-up,one patient had mildly elevated serum cre-atinine,while the other showed reduced levels compared with preoperative values;both remained stable.Conclusion:Membrane anatomy-based dissection facilitates safe mobilization of fibrotic ureters with mini-mal bleeding and collateral damage.Total intracorporeal 3D laparoscopic ileal ureters replacement for bi-lateral ureters combined with bladder augmentation effectively addresses long-segment ureteral obstruction and improves bladder capacity.This approach is technically safe and feasible,though further validation with larger clinical cohorts is warranted.

Objective:To investigate the relationship between sarcopenic obesity(SO), defined by various obesity indicators, and mortality risk in older adults based on a prospective cohort from multiple nursing homes.Methods:Sarcopenia was diagnosed according to the 2019 consensus of the Asian Working Group for Sarcopenia.Obesity was defined using six different indicators: waist circumference(WC), waist-hip ratio(WHR), waist-height ratio(WHTR), body mass index(BMI), visceral fat area(VFA), and percentage of body fat(PBF).A prospective cohort of adults aged 60 and above was established across 15 nursing homes in Zigong City, with annual follow-ups on survival status conducted over two consecutive years.Cox proportional hazards regression models were employed to analyze the association between SO, defined by different obesity indicators, and mortality risk, calculating hazard ratios( HR)and their 95% confidence intervals( CI). Results:A total of 695 older adults were included in the study, of whom 67.1% were male.During the 2-year follow-up period, 88 participants died.The prevalence of SO as defined by WC, WHR, WHTR, BMI, VFA, PBF was found to be 17.6%, 30.1%, 48.9%, 3.0%, 28.3%, and 58.7%, respectively.When SO was defined using WC, WHR, WHTR, BMI, and VFA, there was no statistically significant difference in mortality rates between the SO and non-SO groups.However, when defined by PBF, the SO group exhibited a significantly higher mortality rate compared to the non-SO group(16.9% vs.6.6%, P<0.01).Cox proportional hazards regression analysis revealed that, compared to the non-SO group, the SO group defined by PBF had a significantly increased mortality risk( HR=2.81, 95% CI: 1.67-4.73, P<0.001).After adjusting for potential confounding factors, the mortality risk for the SO group remained significantly higher than that of the non-SO group( HR=1.97, 95% CI: 1.14-3.38, P=0.015). Conclusions:The prevalence of SO varies significantly across different obesity indicators.SO defined by PBF is significantly associated with mortality risk in nursing home residents.This study provides new evidence for further optimizing the diagnostic criteria for SO in this population.

Objective:To develop an ultrasound multi-view fusion recognition model and evaluate its clinical value in diagnosing fetal conotruncal defects (CTD).Methods:This prospective study collected cardiac ultrasound images from fetuses at 20-32 weeks of gestation undergoing prenatal ultrasound at Dongguan Maternal and Child Health Hospital between September 2022 and May 2024. The case group comprised fetuses diagnosed with CTD, while controls with normal cardiac structures were collected at a 1∶2 ratio. Both groups were divided into modeling training and validation sets at a 3∶1 ratio. One optimal standard image each from the four-chamber view, left ventricular outflow tract view, right ventricular outflow tract view, and three vessels and trachea view was included per fetus. A deep learning-based multi-view fusion recognition model was developed to differentiate normal conotruncal anatomy from CTD. Model performance was validated against post-abortion pathology or postnatal echocardiography results. SAS software was used for statistical analysis to calculate the sensitivity and specificity of three fusion models (based on positivity in any two, three, or four views, and were designated as Fusion Model 1, Fusion Model 2, and Fusion Model 3, respectively), with the optimal model determined by the maximum Youden index. Senior, intermediate, and junior prenatal sonologists independently diagnosed cases in the validation set under blinding conditions. Their diagnostic results were compared with those of the optimal model. Paired Chi-square test (Cochran's Q test) was employed to compare the differences between the diagnostic accuracy rates of sonologists at different experience levels and the sensitivity of the optimal model, thereby analyzing the auxiliary diagnostic value of the multi-view fusion recognition model. Results:The study included 88 CTD cases, excluding six cases (non-CTD diagnosed by post-abortion pathology or postnatal echocardiography or poor image quality), divided into 60 training and 22 validation cases (12 tetralogy of Fallot, four double outlet right ventricle, three transposition of great arteries, three persistent truncus arteriosus). The control group included 176 cases, excluding 15 cases (other cardiac abnormalities confirmed postnatally or poor image quality after re-evaluation), divided into 120 training and 41 validation cases. The sensitivities of Fusion Model 1, Fusion Model 2, and Fusion Mudel 3 were 0.86, 0.64, and 0.27, while their specificities were 0.76, 0.95, and 1.00, respectively. Fusion Model 1 demonstrated the highest Youden index (0.62) and was selected as optimal. Its diagnostic sensitivity showed no significant difference from senior sonologists [86% vs. 91% (20/22), Bonferroni-corrected P>0.999], but was significantly higher than intermediate [55% (12/22), Bonferroni-corrected P=0.049] and junior sonologists [32% (7/22), Bonferroni-corrected P=0.003]. Conclusion:The deep learning multi-view fusion model achieved diagnostic performance comparable to senior sonologists, demonstrating potential value in assisting CTD diagnosis, training less experienced sonologists, and supporting research and education.

OBJECTIVE: To investigate the effect of acupuncture on advanced cancer patients by meta-analysis. METHODS: Nine databases (the Cochrane Central Register of Controlled Trials, MEDLINE, Web of Science, Embase, China National Knowledge Infrastructure, the Cumulative Index to Nursing and Allied Health Literature, Chinese Biomedical Literature Database, China Science and Technology Journal Database, and WanFang Data) were searched for randomized controlled trials (RCTs) on acupuncture in advanced cancer patients published from inception to February 13, 2023 and updated to June 1, 2023. Primary outcomes were quality of life (QOL), while secondary outcomes were pain, fatigue, and adverse events (side effects). Data synthesis was performed using RevMan V.5.3 to calculate pooled effect sizes. RoB-2 was used for the risk of bias, and the quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. RESULTS: Totally 17 RCTs involving 1,178 participants were included, 15 of which were pooled for meta-analysis. Most studies demonstrated some concern for the overall risk of bias. The pooled data indicated that acupuncture was associated with improved QOL [mean difference (MD)=6.67, 95% confidence interval (CI): 5.09 to 8.26], pain (MD=-1.18, 95% CI -2.28 to -0.08), and adverse events (risk ratio=0.30, 95% CI: 0.26 to 0.57) compared with control groups. Fatigue outcome was not included. Heterogeneity was substantial, and GRADE evidence was very low for both QOL and pain. CONCLUSIONS Acupuncture could benefit patients with advanced cancer and is considered safe compared with usual care. However, the evidence regarding QOL and pain outcomes requires further validation. It is crucial to encourage the development of high-quality studies to strengthen this evidence. (Registry No. CRD42023423539).
Humans ; Acupuncture Therapy ; Neoplasms/therapy* ; Quality of Life ; Randomized Controlled Trials as Topic ; Treatment Outcome

OBJECTIVES: Osteoarthritis (OA) and sarcopenia are significant health concerns in the elderly, substantially impacting their daily activities and quality of life. However, the relationship between them remains poorly understood. This study aims to uncover common biomarkers and pathways associated with both OA and sarcopenia. METHODS: Gene expression profiles related to OA and sarcopenia were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between disease and control groups were identified using R software. Common DEGs were extracted via Venn diagram analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to identify biological processes and pathways associated with shared DEGs. Protein-protein interaction (PPI) networks were constructed, and candidate hub genes were ranked using the maximal clique centrality (MCC) algorithm. Further validation of hub gene expression was performed using 2 independent datasets. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of key genes for OA and sarcopenia. Mouse models of OA and sarcopenia were established. Hematoxylin-eosin and Safranin O/Fast Green staining were used to validate the OA model. The sarcopenia model was validated via rotarod testing and quadriceps muscle mass measurement. Real-time reverse transcription PCR (real-time RT-PCR) was employed to assess the mRNA expression levels of candidate key genes in both models. Gene set enrichment analysis (GSEA) was conducted to identify pathways associated with the selected shared key genes in both diseases. RESULTS: A total of 89 common DEGs were identified in the gene expression profiles of OA and sarcopenia, including 76 upregulated and 13 downregulated genes. These 89 DEGs were significantly enriched in protein digestion and absorption, the PI3K-Akt signaling pathway, and extracellular matrix-receptor interaction. PPI network analysis and MCC algorithm analysis of the 89 common DEGs identified the top 17 candidate hub genes. Based on the differential expression analysis of these 17 candidate hub genes in the validation datasets, AEBP1 and COL8A2 were ultimately selected as the common key genes for both diseases, both of which showed a significant upregulation trend in the disease groups (all P<0.05). The value of area under the curve (AUC) for AEBP1 and COL8A2 in the OA and sarcopenia datasets were all greater than 0.7, indicating that both genes have potential value in predicting OA and sarcopenia. Real-time RT-PCR results showed that the mRNA expression levels of AEBP1 and COL8A2 were significantly upregulated in the disease groups (all P<0.05), consistent with the results observed in the bioinformatics analysis. GSEA revealed that AEBP1 and COL8A2 were closely related to extracellular matrix-receptor interaction, ribosome, and oxidative phosphorylation in OA and sarcopenia. CONCLUSIONS AEBP1 and COL8A2 have the potential to serve as common biomarkers for OA and sarcopenia. The extracellular matrix-receptor interaction pathway may represent a potential target for the prevention and treatment of both OA and sarcopenia.
Sarcopenia/genetics* ; Osteoarthritis/genetics* ; Computational Biology/methods* ; Humans ; Protein Interaction Maps/genetics* ; Animals ; Mice ; Gene Expression Profiling ; Gene Ontology ; Transcriptome ; Male ; Signal Transduction/genetics* ; Gene Regulatory Networks

OBJECTIVES: Osteoarthritis (OA) is one of the most common chronic degenerative diseases, with chondrocyte apoptosis and extracellular matrix (ECM) degradation as the major pathological changes. The mechanical stimulation can attenuate chondrocyte apoptosis and promote ECM synthesis, but the underlying molecular mechanisms remain unclear. This study aims to investigate the role of primary cilia (PC) in mediating the effects of mechanical stimulation on OA progression. METHODS: In vivo, conditional knockout mice lacking intraflagellar transport 88 (IFT88^flox/flox IFT88 knockout; i.e., primary cilia-deficient mice) were generated, with wild-type mice as controls. OA models were established via anterior cruciate ligament transection combined with destabilization of the medial meniscus, followed by treadmill exercise intervention. OA progression was evaluated by hematoxylin-eosin staining, safranin O-fast green staining, and immunohistochemistry; apoptosis was assessed by TUNEL staining; and limb function by rotarod testing. In vitro, primary articular chondrocytes were isolated from mice and transfected with lentiviral vectors to suppress IFT88 expression, thereby constructing a primary cilia-deficient cell model. Interleukin-1β (IL-1β) was used to induce an inflammatory environment, while cyclic tensile strain (CTS) was applied via a cell stretcher to mimic mechanical loading on chondrocytes. Immunofluorescence and Western blotting were used to detect the protein expression levels of type II collagen α1 chain (COL2A1), primary cilia, IFT88, and caspase-12; reverse transcription polymerase chain reaction was performed to assess COL2A1 mRNA levels; and flow cytometry was used to evaluate apoptosis. RESULTS: In vivo, treadmill exercise significantly reduced Osteoarthritis Research Society International (OARSI) scores and apoptotic cell rates, and improved balance ability in wild-type OA mice, whereas IFT88-deficient OA mice showed no significant improvement. In vitro, CTS inhibited IL-1β-induced ECM degradation and apoptosis in primary chondrocytes; however, this protective effect was abolished in cells with suppressed primary cilia expression. CONCLUSIONS Mechanical stimulation delays OA progression by mediating signal transduction through primary cilia, thereby inhibiting cartilage degeneration and chondrocyte apoptosis.
Animals ; Chondrocytes/cytology* ; Apoptosis/physiology* ; Mice ; Cilia/metabolism* ; Osteoarthritis/pathology* ; Extracellular Matrix/metabolism* ; Mice, Knockout ; Disease Progression ; Interleukin-1beta ; Male ; Cells, Cultured

Sensorineural hearing loss is one of the most common sensory disorders. In recent years, auditory neuropathy spectrum disorders caused by mutations in the OTOF gene have garnered significant attention worldwide, marking it as the first deafness gene with breakthroughs in gene therapy. Most patients with OTOF gene mutations present with stable, congenital, or prelingual onset of hearing loss, which can range from severe to profound and even complete hearing loss. However, a minority of patients may exhibit mild to moderate progressive hearing loss or temperature-sensitive hearing loss. This review further explores the genotype-phenotype relationship of the OTOF gene based on reported cases in China and abroad. Additionally, we analyze the characteristics of the natural history of OTOF gene mutations within the Chinese population. This study aims to provide a reference for the clinical diagnosis, evaluation, and treatment of hearing loss associated with OTOF gene mutations.
Humans ; Mutation ; Phenotype ; Genotype ; Hearing Loss, Sensorineural/genetics* ; Membrane Proteins/genetics*

On October 9th,2023,the Disease Control and Prevention Center of Donghu High Tech Zone in Wuhan City received a report of a case of imported malaria.The patient was admitted due to intermittent fever that had persisted for 3 days,accompanied by a 1 h consciousness disorder,and the family of the patient reported a recent history of travel to the Democratic Republic of Congo in Africa.Upon admission,the rapid diagnostic method(RDT)was used to test for malarial parasite antigens and peripheral blood smear microscopy was performed to detect the presence of malignant malaria parasites.On the basis of epidemiology,clinical symptoms,and laboratory testing,a diagnosis of severe malignant malaria was made,and immediate standardized anti-malarial treatment was accordingly administered.After 4 days of treatment,peripheral blood smear microscopy revealed no plasmodium parasites observed.After 37 days,the patient was recovered and discharged from the hospital.

Computational approaches,encompassing both physics-based and machine learning(ML)methodolo-gies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA)transporter(hDAT)is the primary therapeutic target of numerous psychi-atric medications.However,traditional hDAT-targeting drugs,which interact with the primary binding site,encounter significant limitations,including addictive potential and stimulant effects.In this study,we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape(WHALES)descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs.Initially,WHALES descriptors facilitated a similarity search,employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates.Consequently,from a compound library of 4,921 marketed and clinically tested drugs,we identified 27 candidate atypical inhibitors.Subsequently,ADMETlab was employed to predict the pharmacokinetic and toxi-cological properties of these candidates,while induced-fit docking(IFD)was performed to estimate their binding affinities.Six compounds were selected for in vitro assessments of neurotransmitter re-uptake inhibitory activities.Among these,three exhibited significant inhibitory potency,with half maximal inhibitory concentration(IC50)values of 0.753 μM,0.542 μM,and 1.210 μM,respectively.Finally,molecular dynamics(MD)simulations and end-point binding free energy analyses were con-ducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation.In conclusion,our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.