Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

Kidney-Yang deficiency syndrome is a common geriatric disease that underlies chronic conditions such as diabetic nephropathy, chronic kidney disease, and osteoporosis. As age progresses, the kidney-Yang deficiency syndrome showcases increasingly pronounced manifestations, emerging as a key factor in the comorbidities experienced by elderly patients and affecting their quality of life and overall health status. Traditional Chinese medicine(TCM) has been extensively utilized in the treatment of kidney-Yang deficiency syndrome, with Epimedii Folium, Cinnamomi Cortex, and Lycii Fructus widely used in clinical settings. Despite the complexity of the molecular mechanisms involved in treating kidney-Yang deficiency syndrome, the potential therapeutic value of TCM remains compelling. Delving into the mechanisms of TCM treatment of kidney-Yang deficiency syndrome by regulating the neuro-endocrine-immune system can provide a scientific basis for targeted treatments of this syndrome and lay a foundation for the modernization of TCM. The pathophysiology of kidney-Yang deficiency syndrome involves multiple systems, including the interaction of the neuro-endocrine-immune system, the decline in renal function, the intensification of oxidative stress responses, and energy metabolism disorders. Understanding these mechanisms and their interrelationships can help untangle the etiology of kidney-Yang deficiency syndrome, aiding clinicians in making more precise diagnoses and treatments. Furthermore, the research on the specific applications of TCM in research on these pathological mechanisms can enhance the international recognition and status of TCM, enabling it to exert a greater global influence.
Humans ; Yang Deficiency/physiopathology* ; Drugs, Chinese Herbal/therapeutic use* ; Medicine, Chinese Traditional ; Kidney Diseases/physiopathology* ; Neurosecretory Systems/physiopathology* ; Animals ; Kidney/physiopathology* ; Endocrine System/physiopathology* ; Immune System/physiopathology*

BACKGROUND: Based on the China-VHD database, this study sought to develop and validate a Valvular Heart Disease- specific Age-adjusted Comorbidity Index (VHD-ACI) for predicting mortality risk in patients with VHD. METHODS & RESULTS: The China-VHD study was a nationwide, multi-centre multi-centre cohort study enrolling 13,917 patients with moderate or severe VHD across 46 medical centres in China between April-June 2018. After excluding cases with missing key variables, 11,459 patients were retained for final analysis. The primary endpoint was 2-year all-cause mortality, with 941 deaths (10.0%) observed during follow-up. The VHD-ACI was derived after identifying 13 independent mortality predictors: cardiomyopathy, myocardial infarction, chronic obstructive pulmonary disease, pulmonary artery hypertension, low body weight, anaemia, hypoalbuminaemia, renal insufficiency, moderate/severe hepatic dysfunction, heart failure, cancer, NYHA functional class and age. The index exhibited good discrimination (AUC, 0.79) and calibration (Brier score, 0.062) in the total cohort, outperforming both EuroSCORE II and ACCI (P < 0.001 for comparison). Internal validation through 100 bootstrap iterations yielded a C statistic of 0.694 (95% CI: 0.665-0.723) for 2-year mortality prediction. VHD-ACI scores, as a continuous variable (VHD-ACI score: adjusted HR (95% CI): 1.263 (1.245-1.282), P < 0.001) or categorized using thresholds determined by the Yoden index (VHD-ACI ≥ 9 vs. < 9, adjusted HR (95% CI): 6.216 (5.378-7.184), P < 0.001), were independently associated with mortality. The prognostic performance remained consistent across all VHD subtypes (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid valve disease, mixed aortic/mitral valve disease and multiple VHD), and clinical subgroups stratified by therapeutic strategy, LVEF status (preserved vs. reduced), disease severity and etiology. CONCLUSION The VHD-ACI is a simple 13-comorbidity algorithm for the prediction of mortality in VHD patients and providing a simple and rapid tool for risk stratification.

Objective To investigate the predictive value of serum circular RNA(circRNA)CDYL and circRNA ACAP2 expression levels for major adverse cardiovascular events(MACE)in pa-tients with acute myocardial infarction(AMI).Methods A total of 98 AMI patients were enrolled into the observation group,and divided into MACE group(n=45)and no-MACE group(n=53)based on whether they experienced MACE.Another 98 healthy individuals who underwent physical ex-amination during the same period were selected as the control group.The expression levels of serum cir-cRNA CDYL and circRNA ACAP2 were compared among groups.Multivariate logistic regression analysis was used to identify factors influencing the occurrence of MACE in AMI patients.Receiver operating characteristic(ROC)curve analysis was conducted to evaluate the predictive value of serum circRNA CDYL and circRNA ACAP2 levels for MACE in AMI patients.Results The serum circRNA CDYL level in the observation group was significantly lower than that in the control group,while the circRNA ACAP2 level was significantly higher(P＜0.05).The circRNA CDYL level in the MACE group was significantly lower,and the circRNA ACAP2 level was significantly higher than that in the no-MACE group(P＜0.05).Heart rate and circRNA ACAP2 were identified as independent risk factors for MACE in AMI patients,whereas circRNA CDYL served as independent protective factor(P＜0.05).The area under the ROC curve(AUC)for predicting MACE in AMI patients using se-rum circRNA CDYL,circRNA ACAP2 and their combination were 0.814,0.821 and 0.921,re-spectively.The sensitivity and specificity of combined prediction using serum circRNA CDYL and circRNA ACAP2 were 91.11％and 79.25％,respectively.The combined prediction efficacy of serum circRNA CDYL and circRNA ACAP2 was superior to their individual prediction(Zcombined-circRNA CDYL=1.975,Zcombined-circRNAACAP2=2.064,P=0.048,0.039).Conclusion Serum circRNA CDYL lev-el is down-regulated and circRNA ACAP2 level is up-regulated in AMI patients,and circRNA ACAP2 is an independent risk factor for MACE,while circRNA CDYL is a independent protective factor.The combined value of circRNA CDYL and circRNA ACAP2 in predicting the occurrence of MACE is higher.

Objective:To investigate long-term auditory changes and characteristics of Alport syndrome（AS） patients with different degrees of renal injury. Methods:Retrospectively analyzing clinical data of patients diagnosed AS from January 2007 to September 2022, including renal pathology, genetic detection and hearing examination. A long-term follow-up focusing on hearing and renal function was conducted. Results:This study included 70 AS patients, of which 33（25 males, 8 females, aged 3.4-27.8 years） were followed up, resulting in a loss rate of 52.9%.The follow-up period ranged from 1.1to 15.8 years, with 16 patients followed-up for over 10 years. During the follow-up, 10 patients presenting with hearing abnormalities at the time of diagnosis of AS had progressive hearing loss, and 3 patients with new hearing abnormalities were followed up, which appeared at 5-6 years of disease course. All of which were sensorineural deafness. While only 3 patients with hearing abnormalities among 13 patients received hearing aid intervention. Of these patients,7 developed end-stage renal disease（ESRD）, predominantly males （6/7）. The rate of long-term hearing loss was significantly different between ESRD group and non-ESRD group（P=0.013）. There was no correlation between the progression of renal disease and long-term hearing level（P>0.05）. kidney biopsies from 28 patients revealed varying degrees of podocyte lesion and uneven thickness of basement membrane. The severity of podocyte lesion was correlated with the rate of long-term hearing loss（P=0.048）, and there was no correlation with the severity of hearing loss（P>0.05）. Among 11 cases, theCOL4A5mutationwas most common （8 out of 11）, but there was no significant correlation between the mutation type and hearing phenotype（P>0.05）. Conclusion:AS patients exhibit progressive hearing loss with significant heterogeneity over the long-term.. THearing loss is more likely to occur 5-6 years into the disease course. Hearing abnormalities are closely related to renal disease status, kidney tissue pathology, and gene mutations, emphasizing the need for vigilant long-term hearing follow-up and early intervention.
Male ; Child ; Female ; Humans ; Nephritis, Hereditary/pathology* ; Retrospective Studies ; Kidney ; Deafness ; Hearing Loss/genetics* ; Kidney Failure, Chronic/pathology* ; Mutation

Heart failure with preserved ejection fraction (HFpEF) accounts for about half of the number of patients with heart failure. In addition to the typical features of heart failure such as myocardial stiffness and diastolic function impairment, the key characteristic of HFpEF is the normal left ventricular ejection fraction, which increases the difficulty of clinical diagnosis. QiShenYiQi Dripping Pills (QSYQ) is a standardized traditional Chinese medicine approved by the China Food and Drug Administration (CFDA), and many clinical studies have demonstrated the efficacy and safety of QSYQ in the treatment of heart failure with reduced ejection fraction, but the role of QSYQ in HFpEF has not been clarified. In this paper, high fat diet (HFD) and drinking water containing N-nitro-L-arginine methyl ester (L-NAME, 0.5 g·L^-1, pH=7.4) were used in C57BL/6N male mice to construct the classical HFpEF model (the experiment was approved by the Animal Ethics Committee of Hefei University of Technology, the approval number is HFUT20220921002), and at the 8^th week, the mice were dosed with ① empagliflozin, ② low-dose QSYQ (LQ), ③ high-dose QSYQ (HQ), ④ empagliflozin plus low-dose QSYQ (ELQ) for 4 weeks, the body weight of the mice was recorded during the experiment, echocardiography, blood pressure and glucose tolerance were detected and the exercise capacity of mice was evaluated, and pathological and biochemical experiments were used to detect cardiac fibrosis, liver fibrosis and serum biochemical indexes in mice, RNAseq assay was performed with mice heart tissues. The results showed that QSYQ as well as QSYQ+empagliflozin could significantly reduce the body weight, improve diastolic function and hypertension, improve glucose tolerance and enhance exercise ability of HFpEF mice. At the biochemical and molecular levels, QSYQ and QSYQ+empagliflozin can reduce the cross-sectional area of cardiomyocytes and reduce cardiac collagen contents, thereby alleviating myocardial hypertrophy and fibrotic phenotypes, and improve metabolic disorders. The RNAseq results suggest that the function of QSYQ in improving HFpEF may be related to calsequestrin 1. In conclusion, this study shows that QSYQ and QSYQ+empagliflozin can significantly improve HFpEF-related cardiac dysfunction and metabolic disorders, which provides a theoretical basis for the clinical treatment of HFpEF.

Anabolic androgenic steroids(AASs)are a class of synthetic steroid hormones that mimic androgens,and they rank as the most widely abused doping agents worldwide.High resolution mass spectrometry(HRMS)has unique advantages in the detection of AASs due to its high resolution,high sensitivity,high selectivity and data traceability.HRMS can not only be used for the qualitative and quantitative analysis of AASs and their metabolites in different biological samples,effectively improving the ability to analyze complex samples and increasing the reliability of analytical results,but can also infer AASs metabolites and reveal metabolic pathways by combining in vitro and in vivo metabolic models.This paper reviews the research progress of HRMS in AASs analysis methods,in vitro and in vivo metabolism of AASs,and also explores its application prospects in the field of forensic science.

OBJECTIVE: To develop and validate a user-friendly risk score for older mitral regurgitation (MR) patients, referred to as the Elder-MR score. METHODS: The China Senile Valvular Heart Disease (China-DVD) Cohort Study functioned as the development cohort, while the China Valvular Heart Disease (China-VHD) Study was employed for external validation. We included patients aged 60 years and above receiving medical treatment for moderate or severe MR (2274 patients in the development cohort and 1929 patients in the validation cohort). Candidate predictors were chosen using Cox's proportional hazards model and stepwise selection with Akaike's information criterion. RESULTS: Eight predictors were identified: age ≥ 75 years, body mass index < 20 kg/m², NYHA class III/IV, secondary MR, anemia, estimated glomerular filtration rate < 60 mL/min per 1.73 m², albumin < 35 g/L, and left ventricular ejection fraction < 60%. The model displayed satisfactory performance in predicting one-year mortality in both the development cohort (C-statistic = 0.73, 95% CI: 0.69-0.77, Brier score = 0.06) and the validation cohort (C-statistic = 0.73, 95% CI: 0.68-0.78, Brier score = 0.06). The Elder-MR score ranges from 0 to 15 points. At a one-year follow-up, each point increase in the Elder-MR score represents a 1.27-fold risk of death (HR = 1.27, 95% CI: 1.21-1.34, P < 0.001) in the development cohort and a 1.24-fold risk of death (HR = 1.24, 95% CI: 1.17-1.30, P < 0.001) in the validation cohort. Compared to EuroSCORE II, the Elder-MR score demonstrated superior predictive accuracy for one-year mortality in the validation cohort (C-statistic = 0.71 vs. 0.70, net reclassification improvement = 0.320, P < 0.01; integrated discrimination improvement = 0.029, P < 0.01). CONCLUSIONS The Elder-MR score may serve as an effective risk stratification tool to assist clinical decision-making in older MR patients.

Objective:To establish the common carotid artery aneurysm models of Wallstent double stent overlapping implantation in miniature pigs, and evaluate the safety and effectiveness of this procedure by observing the imaging and pathological changes.Methods:Sidewall aneurysm and fusiform aneurysm models in Bama miniature pigs were established surgically and 2 Wallstent stents were overlapped and implanted in situ. Aneurysm healing immediately after surgery and during 8 weeks of follow-up were evaluated according to 2D-DSA by O'Kelly-Marotta (OKM) grading scale and Kamran scale; degrees of stent adhesion immediately after surgery and status of stent endothelialization and aneurysm healing at 2, 4, and 8 weeks after surgery were observed by high resolution C-arm CT(HR-CBCT) and optical coherence tomography (OCT); and the changes of stent endothelialization were evaluated by comparing the HR-CBCT and OCT results with histopathology at 8 weeks after surgery. Perioperative adverse events were recorded.Results:After successful establishment of common carotid artery aneurysm models (including 4 sidewall aneurysms and 4 fusiform aneurysms with average diameter of [11.0±2.8] mm) in 8 miniature pigs, a total of 16 Wallstent stents (2 in each aneurysm) were implanted across the aneurysmal neck, with a technical success rate of 100%. No serious complications such as acute stent thrombosis, or aneurysm rupture and bleeding were observed in the perioperative period. The 2D-DSA immediately after surgery showed obvious intracranial contrast agent retention in 6 patients (1 patient in grading 1, 3 in grading 2, and 2 in grading 3) and aneurysm occlusion in 2 patients (grading 4). Eight weeks after follow-up, all 8 aneurysms had complete occlusions (grading 4); and 2 experimental pigs had in-stent restenosis, with stenosis rates of 52% and 67%, respectively. HR-CBCT and OCT immediately after surgery and during follow-up indicated that the stent metal braid was gradually covered by proliferating intima, with disappeared aneurysm. The cause of in-stent restenosis in 2 experimental pigs was local intima hyperplasia resulted from poor stent adhesion, and pathological findings indicated that the intima hyperplasia was mainly composed of smooth muscle cells and fibrous connective tissues.Conclusion:In animal models, Wallstent stent overlapping implantation is safe and effective in common carotid aneurysms, but intraoperative adverse adhesion of overlapping stent should be avoided.

As a unique medical resource in China, Chinese herbal medicine plays a key role in the prevention and treatment of human diseases. With the gradual expansion of applications, the quality of Chinese herbal medicine has become the focus of attention. The quality of Chinese herbal medicines depends largely on their source authenticity. Tracing the origin of Chinese herbal medicines plays an important role in ensuring their quality and efficacy and reducing the mixing and adulteration of Chinese herbal medicines from different regions. Stable isotope technology, as a key technology for origin tracing of agricultural products and food, has been used in the research of Chinese herbal medicines from multiple sources and origins in recent years. This new technological means contributes to standardizing the origin of Chinese herbal medicines and controlling their quality from the source. Apart from introducing the basic principles of stable isotope technology and the characteristics of common stable isotopes, this study reviewed the application status of light and heavy stable isotopes in the origin tracing of Chinese herbal medicines and their correlation with ecological factors, and forecasted the application prospect of this technology in the authentication of Chinese herbal medicines, aiming to provide reference for the geographical origin tracing of Chinese herbal medicines and promote the sustainable development of traditional Chinese medicine.
Drug Contamination ; Drugs, Chinese Herbal/analysis* ; Humans ; Isotopes ; Medicine, Chinese Traditional ; Quality Control