Objective To analyze clinical characteristics affecting survival outcomes in gastric adenocarcinoma(GAC)patients with second primary malignancies(SPM)and construct a predictive model with a web-based calculator.Methods Patients diagnosed with GAC between January 2010 and December 2017 in the SEER database(n=24 085)were analyzed,comparing non-SPM(n=22 963)and SPM cohorts(n=1 122).SPM patients were randomized(3:1)into training(n=842)and internal validation cohorts(n=280).Univariate/multivariate Cox regression identified prognostic factors for model construction.Model performance was evaluated via ROC curves,calibration plots,and decision curve analysis(DCA).A web-based calculator was deployed using DynNom(https://kunma697.shinyapps.io/dynnomapp-1/).External validation used 192 SPM patients diagnosed at Yantai Yuhuangding Hospital(2010-2017).Results χ2 tests revealed SPM patients had higher age(56.3%),earlier T-stage(T1:29.2%;T2:10.5%),predominant gastric cardia involvement(43.7%),fewer distant metastases(12.3%),and higher rates of radiotherapy(32.5%)and surgery(77.2%)vs.non-SPM(P<0.05).Cox analyses identified GAC primary site,T-stage,SEER stage,radiotherapy/surgery history,plus SPM grade/stage/treatment history as significant predictors(P<0.05).AUCs in the training cohort were 0.771(95%CI:0.722～0.820),0.839(95%CI:0.796～0.882),and 0.836(95%CI:0.792～0.879)for 1-/3-/5-year survival;internal validation showed 0.751(95%CI:0.700～0.801),0.746(95%CI:0.695～0.797),and 0.772(95%CI:0.723～0.821);external validation yielded 0.713(95%CI:0.648～0.778),0.805(95%CI:0.749～0.861),and 0.851(95%CI:0.801～0.901).Calibration indicated high prediction-actuality concordance;DCA confirmed clinical utility.Conclusion The model and web calculator incorporating GAC/SPM characteristics effectively predict SPM patient prognosis.

Objective:To establish a quality control method for Aiye standard decoction.Methods:The ultra performance liquid chromatogrphy (UPLC) column Waters ACQUITY HSS T3 C18 (2.1 mm×150 mm,1.8 μm) was used to gradient elution by acetonitrile and 0.1% formic acid in water. 16 batches of Aiye standard decoction fingerprints were established by UPLC and the common peaks were determined in the fingerprints. The contents of 12 components were determined. The 16 batches of Aiye standard decoction were analyzed by similarity calculation, hierarchical cluster analysis (HCA), principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) for analysis of differential components of Artemisiae Argyi Folium from different origins.Results:A total of 13 common peaks were marked in the fingerprints of 16 batches of Aiye standard decoction, 12 of which were identified by comparison with reference substance, including chlorogenic acid, sochlorogenic acid A, neochlorogenic acid, cryptochlorogenic acid, caffeic acid,1,3-O-Dicaffeoylquinic acid, schaftoside, isochlorogenic acid B,1,5-O-Dicaffeoylquinic acid, isochlorogenic acid C, jaceosidin and eupatilin. Similarity evaluation, PCA and HCA all classified the 16 batches of Aiye standard decoction into 2 categories. Orthogonal partial least squares discriminant analysis screened 5 differential biomarkers from 13 common peaks. The content determination results showed that the phenolic compounds and flavonoids in samples from Hubei were significantly higher than that in samples from other areas.Conclusion:This method can effectively analyze the differences in the quality of Aiye standard decoction from different origins, and provide reference for the formulation of quality standards for Aiye standard decoction and related preparations.

Objective:To establish a method for the determination of triterpenes and nucleosides in Poria based on HPLC; To accurately determine the various bioactive components in Poria.Methods:Similarity evaluation, clustering analysis and principal component analysis were used to analyze the similarities and differences of different medicinal parts of Poria, and the key chromatographic peaks that could reflect the characteristics were found.Results:The Poricoic acid A and dehydroeburiconic acid could be used as the identification basis for Poriae Cutis and White Poria; at the same time, Polyporenic acid C, dehydropachymic acid and dehydrotrametenolic acid could be used to evaluate Rubra Poria and Poriae Cutis; uridine, guanosine and adenosine may be essential ingredients for evaluating the quality of White Poria, Poriae Cutis and Rubra Poria. In different medicinal parts of Poria, the triterpenes were showed significant differences; by contrary, there were little differences among the same medicinal parts.Conclusion:This study reveals the quality differences between different medicinal parts of Poria, which can provide a scientific basis for the rational application and pharmacodynamic standardization of Poria.

Background The decline of physical activity in the elderly due to aging may increase the risk of sarcopenia. Currently, there is a lack of evidence from large natural populations on the relationship between PA and sarcopenia. Objective To explore the relationship between PA and sarcopenia in the elderly aged 60 years and above in 10 provinces (autonomous regions) of China. Methods Data were retrieved from the 2022—2023 round of the China Development and Nutrition Health Impact Cohort. Personal basic information and PA data were collected by questionnaire survey. Skeletal muscle mass was measured by bio-electrical impedance analysis, muscle strength was measured using a grip dynamometer, and physical performance was reflected by 6-meter walk speed. The Asian Working Group for Sarcopenia (AWGS) 2019 criteria were used to diagnose sarcopenia. Light physical activity (LPA) duration, moderate-to-vigorous physical activity (MVPA) duration, and total physical activity volume were calculated. A total of 3326 residents aged ≥60 years with complete data were selected as the survey participants. Multiple logistic regression models and restricted cubic splines (RCS) were used to assess the association between PA duration/volume and sarcopenia. Results In 10 provinces (autonomous regions) of China, the prevalence of sarcopenia in the elderly aged 60 years and above was 5.5% (95%CI: 4.7%, 6.2%). The logistic regression analysis showed that compared with the elderly reporting 0-7.0 h·week⁻¹ in LPA duration, the risk of sarcopenia in the elderly with LPA duration of >14.0-21.0 h·week⁻¹ was reduced by 51% (OR=0.49, 95%CI: 0.26, 0.96). Compared with the elderly with total physical activity ≥15.0 metabolic equivalent of task (MET)-h·week⁻¹, those with <7.5 MET-h·week⁻¹ had a 2.24-fold increased risk of sarcopenia (OR=2.24, 95%CI: 1.17, 4.29). The RCS results found that LPA duration and total physical activity volume each showed a nonlinear dose-response relationship with the risk of sarcopenia (P_overall<0.05, P_non-linear<0.05). Compared with the elderly with an LPA duration of 0 h· week⁻¹, the risk of sarcopenia in the elderly with an LPA duration of 12.6 h· week⁻¹ was the lowest (OR=0.42, 95%CI: 0.21, 0.83). Compared with the elderly with a total physical activity volume of 15.0 MET-h· week⁻¹, the elderly with a total physical activity volume of 46.0 MET-h· week⁻¹ had the lowest risk of sarcopenia (OR=0.57, 95%CI: 0.38, 0.84). There was no statistically significant association between weekly MVPA duration and the risk of sarcopenia (P>0.05). Conclusion Increasing weekly LPA duration and total physical activity volume would help to reduce the risk of sarcopenia.

Objective: To analyze the association between each regional fat mass and total body bone mineral density (BMD) in children and adolescents aged 7-17 years in Beijing, so as to provide theoretical basis and practical guidance for implementing interventions. Methods: From September to December 2020, a stratified cluster random sampling method was used to select 1 423 children and adolescents aged 7-17 years in Tongzhou District, Beijing. Dual energy X-ray absorptiometry (DXA) was employed to measure regional body composition and total body BMD. Multiple linear regression was used to analyze the association between regional fat mass and total body BMD. Results: The median (interquartile range) fat mass values for total body, upper limbs, abdomen, hips, and thighs were 13.51(8.84, 19.21), 1.59(1.08, 2.23), 0.73(0.39, 1.29), 2.32(1.46, 3.26), 5.29(3.59, 7.21)kg, respectively. After adjusting for covariates, the results of multiple linear regression analysis showed that total body fat mass (β=0.010), abdominal fat mass (β=-0.100), and hip fat mass (β=0.104) were significant associations with total body BMD (all P<0.01). Sexstratified analysis revealed that in boys, total body fat mass (β=0.008) and hip fat mass (β=0.058) were positively associated with BMD, while thigh fat mass (β=-0.038) showed a negative association with total body BMD (all P<0.05). In girls, total body fat mass (β=0.013), hip fat mass (β=0.163), and thigh fat mass (β=0.023) were positively associated with total body BMD, whereas abdominal fat mass (β=-0.196) showed a negative association with total body BMD (all P<0.05). Among children and adolescents with body fat percentage below the standard range, within the standard range and above the standard range, total body fat masses were positively associated with total body BMD (β=0.021, 0.016, 0.015); among children and adolescents with body fat percentage within the standard range while upper limb (β=-0.042), abdominal (β=-0.067), and thigh fat mass (β=-0.018) showed negative associations with total body BMD, and hip fat mass demonstrated a positive association with total body BMD (β=0.082) (all P<0.05). Conclusion Regional fat distribution is associated with total body BMD in children and adolescents, with the nature of these associations varying by sex and body fat percentage.

Ferroptosis has been shown to mediate the development of fibrosis. Polyphyllin VII (PP7), a bioactive component of Paris polyphylla, exhibits potent anti-inflammatory activity and can significantly alleviate liver fibrosis. In this study, treatment with PP7 significantly inhibited the proliferation and activation of hepatic stellate cells (HSCs), which could be suppressed by a ferroptosis inhibitor. In addition, it promoted HSC ferroptosis by suppressing glutathione (GSH) peroxidase 4 (GPX4) and enhanced the expression of CX3C chemokine ligand 1 (CX3CL1). Depletion of CX3CL1 attenuated the effects of PP7 on the activation and ferroptosis of HSCs and the expression of GPX4. Notably, CX3CL1 directly interacted with GPX4, triggering HSC ferroptosis. The transcription factor hypermethylated in cancer 1 (Hic1), which binds to the Cx3cl1 promoter, increased the expression of CX3CL1. Its absence resulted in downregulation of CX3CL1, suppressing the GPX4-dependent ferroptosis of PP7-treated HSCs and promoting their activation. HIC1 was found to directly interact with PP7 at the GLY164 site. Co-culture experiments showed that PP7-induced HSC ferroptosis attenuated macrophage recruitment by regulating inflammation-related genes. HSC-specific inhibition of HIC1 counteracted PP7-induced collagen depletion and HSC ferroptosis in vivo. These findings suggest that PP7 induces HSC ferroptosis through the HIC1/CX3CL1/GPX4 axis.

Proteolysis-targeting chimeras (PROTACs) represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can, potentially revolutionizing drug discovery and treatment strategies. However, the links between in vitro and in vivo data are poorly understood, hindering a comprehensive understanding of the absorption, distribution, metabolism, and excretion (ADME) of PROTACs. In this work, ¹⁴C-labeled vepdegestrant (ARV-471), which is currently in phase III clinical trials for breast cancer, was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics (PK) by establishing a physiologically based pharmacokinetics (PBPK) model. For in vitro-in vivo extrapolation (IVIVE), hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did. PBPK models, which were initially developed and validated in rats, accurately simulate ARV-471's PK across fed and fasted states, with parameters within 1.75-fold of the observed values. Human models, informed by in vitro ADME data, closely mirrored postoral dose plasma profiles at 30 mg. Furthermore, no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans. This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.

Objective:To establish the HPLC fingerprint of Bolbostemmatis Rhizoma standard decoction; To determine the three effective components with similar structure by quantitative analysis of multi-components by single marker (QAMS); To evaluate the quality of Bolbostemmatis Rhizoma standard decoction.Methods:HPLC was adopted to establish the fingerprints of 15 batches of Bolbostemmatis Rhizoma standard decoction. The Chromatographic column was Waters XBridge Phenyl (4.6 mm×250 mm, 5 μm). The mobile phase was acetonitrile-0.1% phosphoric acid solution with gradient elution. Cluster analysis (HCA) and principal component analysis (PCA) were conducted based on the relative peak area of common peaks. The same method as the fingerprint was used to establish QAMS of tubeimoside A, B, C on Bolbostemmatis Rhizoma standard decoction.Results:There were 14 common peaks in the fingerprint of Bolbostemmatis Rhizoma standard decoction. It was confirmed that the peak 3 was L-tryptophan, the peak 11 was tubeimoside B, the peak 12 was tubeimoside C, and the peak 13 was tubeimoside A. 15 batches of Bolbostemmatis Rhizoma standard decoction from different origins were divided into 3 categories by HCA and PCA. There was no significant difference between QAMS and the external standard method (ESM) through the system suitability inspection. Conclusion:This method is accurate, reliable and has good specificity, which can effectively evaluate the quality of Bolbostemmatis Rhizoma standard decoction.

Objective:To investigate the incidence and prothrombotic risk factors of postoperative venous thromboembolism(VTE) in Cushing′s disease and to further develop an assessment model to identify those at high risk of postoperative VTE events.Methods:A retrospective study was performed in 82 patients who were admitted to Huashan Hospital, Fudan University during January 2019 and January 2020 and diagnosed with Cushing′s disease. These patients underwent the evaluation about their clinical, hormonal, and coagulation parameters, as well as ultrasonography and pulmonary angio-CT when necessary. The least absolute shrinkage and selection operator(LASSO) regression analysis was used to screen independent risk factors, and a nomogram model for postsurgical VTE risk assessment in Cushing′s disease was initially established, and Bootstrap method was used for internal verification. Finally, the predictive model was evaluated for calibration and clinical applicability in the study cohort.Results:Nineteen patients(23.17%) developed VTE events, with 14 cases occurring after endoscopic transsphenoidal surgery. Compared to patients without VTE, those in the VTE group were older( P<0.001), had longer postoperative bed rest, higher rates of current infection, higher HbA 1C levels, and more severe glucose tolerance impairment(all P<0.05). Through LASSO regression analysis, two independent risk factors for postoperative VTE were identified: Age and current infection. Then a VTE risk assessment nomogram model was established to predict the patients at high risk of VTE. In the nomogram model for VTE risk assessment, the area under the receiver operating characteristic curve was 0.868(95% CI 0.787-0.949), with the calibration curve closely aligning with the ideal diagonal line and the clinical decision curve exceeding the two extreme curves. Conclusions:Advanced perioperative assessment needs to be taken to screen those with high VTE risks in patients diagnosed with Cushing′s disease. Additionally, during the perioperative period, patients with Cushing′s disease should undergo mandatory physical activity or prophylactic anticoagulant therapy.