Objective To evaluate the value of a nomogram model based on ultrasonographic features and inflammatory indicators in the preoperative noninvasive prediction of pathological grading of urothelial carcinoma of bladder(UCB).Methods A retrospective analysis was conducted on 471 patients with pathologically confirmed UCB,and the patients were assigned to high-grade group(401 cases)or low-grade group(70 cases).Basic clinical data(gender,age,macroscopic hematuria),ultrasonographic features(lesion location,blood flow signal,etc.),and blood inflammatory indicators(e.g.neutrophil-to-lymphocyte ratio[NLR])were collected.Independent predictors were screened using univariate and multivariate logistic regression,and a nomogram model was constructed.Model performance was evaluated using the receiver operating characteristic(ROC)curve,calibration curve,and decision curve analysis(DCA).Results Multivariate logistic analysis identified gender(odds ratio[OR]=2.68),age(OR=1.08),macroscopic hematuria(OR=3.19),lesion located in the trigone(OR=4.59),positive blood flow signal(OR=2.87),and NLR(OR=1.03)were independent predictors of high-grade UCB(all P＜0.05).The combined model(clinical features+ultrasonographic characteristics+inflammatory indicators)achieved an area under curve(AUC)of 0.892,which was significantly higher than the clinical feature-only model(AUC=0.799)and the clinical+ultrasonographic model(AUC=0.856).The calibration curve demonstrated good consistency between predicted and actual outcomes,and DCA confirmed its optimal clinical net benefit.Conclusion The nomogram model integrating clinical features,ultrasonographic characteristics,and inflammatory indicators can effectively discriminate UCB pathological grading,providing a reliable preoperative noninvasive assessment tool for personalized treatment decisions.

OBJECTIVE: This study aimed to explore the interplay between the life-course body mass index (BMI) trajectories and insulin resistance (IR) on incident diabetes. METHODS: This longitudinal cohort included 2,336 participants who had BMI repeatedly measured 3-8 times between 1989 and 2009, as well as glucose and insulin measured in 2009. BMI trajectories were identified using a latent class growth mixed model. The interplay between BMI trajectories and IR on diabetes was explored using the four-way effect decomposition method. Logistic regression and mediation models were used to estimate the interaction and mediation effects, respectively. RESULTS: Three distinct BMI trajectory groups were identified: low-stable ( n = 1,625), medium-increasing ( n = 613), and high-increasing ( n = 98). Both interaction and mediation effects of BMI trajectories and IR on incident diabetes were significant ( P < 0.05). The proportion of incident diabetes was higher in the IR-obesity than in the insulin-sensitivity (IS) obesity group (18.9% vs. 5.8%, P < 0.001). After adjusting for covariates, the odds ratios (95% confidence intervals) of the IR, IS-obesity, and IR-obesity groups vs. the normal group were 3.22 (2.05, 5.16), 2.05 (1.00, 3.97), and 7.98 (5.19, 12.62), respectively. IR mediated 10.7% of the total effect of BMI trajectories on incident diabetes ( P < 0.001). CONCLUSION We found strong interactions and weak mediation effects of IR on the relationship between life-course BMI trajectories and incident diabetes. IS-obesity is associated with a lower risk of incident diabetes than IR-obesity.
Humans ; Insulin Resistance ; Body Mass Index ; Male ; Female ; Middle Aged ; China/epidemiology* ; Adult ; Longitudinal Studies ; Incidence ; Diabetes Mellitus/epidemiology* ; Aged ; Obesity/epidemiology* ; Diabetes Mellitus, Type 2/epidemiology* ; East Asian People

OBJECTIVES: To explore the underlying pharmacological mechanisms and its potential effects of Chinese medicine herbal formula Sini Powder (SNP) on hepatocellular carcinoma (HCC). METHODS: The active components of SNP and their in vivo distribution were identified using ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Construction of component-target-disease networks, protein-protein interaction network, Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and molecular docking were employed to analyze the active components and anti-HCC mechanisms of SNP. Cell viability assay and wound healing assay were utilized to confirm the effect of SNP-containing serum (2.5%, 5.0%, 10%, 20%, and 40%), isoprenaline or propranolol (both 10, 100, and 1,000 µ mol/L) on proliferation and migration of HepG 2 or Huh7 cells. Meanwhile, the effect of isoprenaline or propranolol on the β 2 adrenergic receptor (ADRB2) mRNA expression on HepG2 cells were measured by real-time quantitative reverse transcription (RT-qPCR). Mice with subcutaneous tumors were either subjected to chronic restraint stress (CRS) followed by SNP administration (364 mg/mL) or directly treated with SNP (364 mg/mL). These two parallel experiments were performed to validate the effects of SNP on stress responses. Stress-related proteins and hormones were quantified using RT-qPCR, enzyme-linked immunosorbent assay, and immunohistochemistry. Metagenomic sequencing was performed to confirm the influence of SNP on the gut microbiota in the tumor-bearing CRS mice. RESULTS: The distribution of the 12 active components of SNP was confirmed in various tissues and feces. Network pharmacology analysis confirmed the anti-HCC effects of the 5 active components. The potential anti-HCC mechanisms of SNP may involve the epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein kinase Src (SRC) and signal transducer and activator of transcription 3 (STAT3) pathways. SNP-containing serum inhibited the proliferation of HepG2 and Huh7 cells at concentrations of 2.5% and 5.0%, respectively, after 24 h of treatment. Furthermore, SNP suppressed tumor progression in tumor-bearing mice exposed to CRS. SNP treatment also downregulated the expressions of stress-related proteins and pro-inflammatory cytokines, primarily by modulating the gut microbiota. Specifically, the abundance of Alistipes and Prevotella, which belong to the phylum Bacteroidetes, increased in the SNP-treated group, whereas Lachnospira, in the phylum Firmicutes, decreased. CONCLUSION SNP can combat HCC by alleviating stress responses through the regulation of gut microbiota.
Animals ; Gastrointestinal Microbiome/drug effects* ; Liver Neoplasms/microbiology* ; Carcinoma, Hepatocellular/microbiology* ; Humans ; Drugs, Chinese Herbal/therapeutic use* ; Powders ; Cell Proliferation/drug effects* ; Mice ; Molecular Docking Simulation ; Cell Line, Tumor ; Hep G2 Cells ; Receptors, Adrenergic, beta-2/genetics* ; Stress, Physiological/drug effects* ; Cell Movement/drug effects* ; Male ; Protein Interaction Maps/drug effects* ; Cell Survival/drug effects* ; Proto-Oncogene Mas

Gastric cancer is a malignant tumor with high prevalence worldwide and limited therapeutic options.Chimeric antigen receptor T-cell(CAR-T)therapy has emerged as a promising approach for gastric cancer treatment;however,its application faces substantial challenges.This review provides comprehensive summary of the recent advances in CAR-T cell therapy for gastric cancer,systematic analysis of critical break throughs and core challenges from target discovery to clinical translation,and outlining of future perspectives.We describe the criter-ia for ideal target selection and highlight the current research landscape of major targets,including CLDN18.2 that demonstrated efficacy,and targets facing distinct challenges,including HER-2,CEA,EpCAM,and MUC1.This review also finely dissects three central barriers restrict-ing CAR-T cell efficacy,and discusses corresponding countermeasures:overcoming the immunosuppressive tumor microenvironment through strategies such as local delivery,armored CAR-T cells,and combination therapies;engineering approaches including affinity modula-tion and logic-gate designs to mitigate on-target/off-tumor toxicity;and optimization of manufacturing processes and reduction of costs via early leukapheresis,rapid production platforms,and universal CAR-T cell strategies.Future multidimensional,integrative,and innovative strategies are pivotal for achieving comprehensive break throughs in CAR-T cell therapy for solid tumors.

Objective To explore the application effect of dexmedetomidine combined with ropivacaine for quadratus lumborum block at the lateral supra-arcuate ligament(QLB-LSAL) in open hepatocellular carcinoma resection.Methods A prospective study was conducted in 60 patients who underwent elective open hepatocellular carcinoma resection at Jining First People's Hospital. The patients were randomly divided into the compound group and the control group,with 30 cases in each group. Patients in the compound group received QLB-LSAL combined general anesthesia,and patients in the control group received simple general anesthesia. All patients underwent patient controlled intravenous analgesia (PCIA)postoperatively. The mean arterial pressure (MAP),heart rate (HR) and visual analogue scale (VAS) scores during rest and coughing at different time points were observed and compared between the two groups. The number of postoperative PCIA compressions,the dosage of sufentanil,the first postoperative exhaust time,the first postoperative ambulation time,the hospital stay and the occurrence of adverse reactions of the two groups were recorded. Results In the compound group,the HR and MAP were significantly lower than those of the control group at the time of skin incision (T2) and at the end of surgery (T3);the VAS scores during rest and coughing were significantly lower than those of the control group at the time of exiting the anesthesia recovery room and 6 hours and 12 hours after surgery;and the PCIA compression times were significantly less than those of the control group;the dosage of sufentanil was significantly lower than that in the control group 0 to 24 hours after surgery,and the dosage of sufentanil was higher than that in the control group 25 to 48 hours after surgery;the first postoperative ambulation time and the first postoperative exhaust time were significantly earlier than those in the control group;and the above differences were statistically significant(P<0.05). There was no significant difference in the HR or MAP at 5 minutes into the operating room (T0) and 5 minutes before skin incision (T1),VAS scores during rest and coughing 24 hours and 48 hours after surgery,hospital stay and incidence of adverse reactions between the two groups (P>0.05).Conclusion For patients with open hepatocellular carcinoma resection,dexmedetomidine combined with ropivazine for QLB-LSAL can provide more ideal postoperative analgesia,reduce perioperative opioid consumption,and have less impact on circulatory system,which is conducive to rapid postoperative recovery.

Gastric cancer is a malignant tumor with high prevalence worldwide and limited therapeutic options.Chimeric antigen receptor T-cell(CAR-T)therapy has emerged as a promising approach for gastric cancer treatment;however,its application faces substantial challenges.This review provides comprehensive summary of the recent advances in CAR-T cell therapy for gastric cancer,systematic analysis of critical break throughs and core challenges from target discovery to clinical translation,and outlining of future perspectives.We describe the criter-ia for ideal target selection and highlight the current research landscape of major targets,including CLDN18.2 that demonstrated efficacy,and targets facing distinct challenges,including HER-2,CEA,EpCAM,and MUC1.This review also finely dissects three central barriers restrict-ing CAR-T cell efficacy,and discusses corresponding countermeasures:overcoming the immunosuppressive tumor microenvironment through strategies such as local delivery,armored CAR-T cells,and combination therapies;engineering approaches including affinity modula-tion and logic-gate designs to mitigate on-target/off-tumor toxicity;and optimization of manufacturing processes and reduction of costs via early leukapheresis,rapid production platforms,and universal CAR-T cell strategies.Future multidimensional,integrative,and innovative strategies are pivotal for achieving comprehensive break throughs in CAR-T cell therapy for solid tumors.

Objective To explore the application effect of dexmedetomidine combined with ropivacaine for quadratus lumborum block at the lateral supra-arcuate ligament(QLB-LSAL) in open hepatocellular carcinoma resection.Methods A prospective study was conducted in 60 patients who underwent elective open hepatocellular carcinoma resection at Jining First People's Hospital. The patients were randomly divided into the compound group and the control group,with 30 cases in each group. Patients in the compound group received QLB-LSAL combined general anesthesia,and patients in the control group received simple general anesthesia. All patients underwent patient controlled intravenous analgesia (PCIA)postoperatively. The mean arterial pressure (MAP),heart rate (HR) and visual analogue scale (VAS) scores during rest and coughing at different time points were observed and compared between the two groups. The number of postoperative PCIA compressions,the dosage of sufentanil,the first postoperative exhaust time,the first postoperative ambulation time,the hospital stay and the occurrence of adverse reactions of the two groups were recorded. Results In the compound group,the HR and MAP were significantly lower than those of the control group at the time of skin incision (T2) and at the end of surgery (T3);the VAS scores during rest and coughing were significantly lower than those of the control group at the time of exiting the anesthesia recovery room and 6 hours and 12 hours after surgery;and the PCIA compression times were significantly less than those of the control group;the dosage of sufentanil was significantly lower than that in the control group 0 to 24 hours after surgery,and the dosage of sufentanil was higher than that in the control group 25 to 48 hours after surgery;the first postoperative ambulation time and the first postoperative exhaust time were significantly earlier than those in the control group;and the above differences were statistically significant(P<0.05). There was no significant difference in the HR or MAP at 5 minutes into the operating room (T0) and 5 minutes before skin incision (T1),VAS scores during rest and coughing 24 hours and 48 hours after surgery,hospital stay and incidence of adverse reactions between the two groups (P>0.05).Conclusion For patients with open hepatocellular carcinoma resection,dexmedetomidine combined with ropivazine for QLB-LSAL can provide more ideal postoperative analgesia,reduce perioperative opioid consumption,and have less impact on circulatory system,which is conducive to rapid postoperative recovery.

Objective To study the inhibitory effect of Huidu Yinhua powder from the Orthodox Manual of External Medicine on methicillin-resistant Staphylococcus aureus(MRSA),virulence factor α-hemolysin(Hla)activity,and biofilm formation,and to explore the optimal ratios of Huidu Yinhua powder and provide experimental support for its use.Methods The inhibitory effects of Huidu Yinhua powder and the herbs in the formula on USA300 were analyzed by the minimum inhibitory concentration(MIC),minimum bactericidal concentration(MBC),and disk diffusion assay(K-B method).Hemolysis,neutralization,oligomerization,and Western blot assays were used to verify in which form the drug inhibits the activity of virulence factor α-hemolysin(Hla).A biofilm assay was performed to evaluate the inhibitory effect of Huidu Yinhua powder on biofilm.Orthogonal experiments were performed to explore the optimal ratio of Huidu Yinhua powder.Results Huidu Yinhua powder inhibited the MRSA strain with a MIC90 of 64 mg/mL and an MBC of 256 mg/mL with antibacterial circle diameter of(7.50±0.50)mm.Huidu Yinhua powder inhibited Hla activity by inhibiting Hla secretion.The minimum effective concentration(MEC)was 16 mg/mL,and the MEC of biofilm was 8 mg/mL.In Huidu Yinhua powder,honeysuckle and astragalus only affected the hemolytic activity of MRSA and biofilm formation without inhibiting bacterial growth.The hemolytic activity and biofilm of MEC were both 32 mg/mL.Glycyrrhiza had a strong bacterial inhibitory capacity with a MIC90 of 8 mg/mL and biofilm MEC of 1 mg/mL without showing inhibitory hemolytic activity at subinhibitory concentrations.The orthogonal experiment showed that,at a ratio of honeysuckle,astragalus,and glycyrrhiza in Huidu Yinhua powder of 1∶2∶4,the MIC90 was 16 mg/mL,MEC of hemolytic activity was 8 mg/mL and that of biofilm was 4 mg/mL,both of which were the lowest among the nine groups.Conclusions Huidu Yinhua powder affects the hemolytic activity and biofilm formation of MRSA at subinhibitory concentrations with the optimal ratio of honeysuckle,astragalus,and glycyrrhiza being 1∶2∶4.

BACKGROUND:Kidney deficiency is the main pathogenesis of osteoporosis.To study the relationship between the two major syndrome types of kidney deficiency,Kidney-Yang deficiency and Kidney-Yin deficiency,is beneficial for the development of clinical diagnosis and treatments based on the combination of disease and syndrome. OBJECTIVE:To evaluate the biomechanical differences of the rat femurs with Kidney-Yang deficiency and Kidney-Yin deficiency caused by Yougui pills,and to demonstrate the scientific efficacy of medication based on the combination of disease and syndrome in osteoporosis from a biomechanical perspective. METHODS:The bilateral ovaries of 60 female Sprague-Dawley rats were surgically removed to establish an ovariectomized osteoporosis model.At 10 weeks after modeling,all the rats were randomly divided into a Kidney-Yang deficiency group(n=30)and a Kidney-Yin deficiency group(n=30).Rats with Kidney-Yang deficiency were given gluteal intramuscular injection of hydrocortisone,while rats with Kidney-Yin deficiency were orally administered with thyroid tablet suspension,once a day,for 14 consecutive days.After successful modeling,20 rats in each group were given a suspension of Yougui pills by gavage once a day for 12 consecutive weeks and the remaining 10 rats were used as the control group without intervention.After gavage,the microstructural parameters of the bone were measured using Micro-CT scanning.Three-point bending,finite element simulation,femoral head compression,and surface indentation distribution experiments of the femurs were performed on a mechanical testing machine. RESULTS AND CONCLUSION:Micro-CT revealed that the femoral bone density,bone volume fraction,bone surface density,trabecular number,and trabecular separation were improved in the Kidney-Yin deficiency+Yougui pills group compared with the Kidney-Yin deficiency group(P＜0.05);the femoral bone volume fraction,bone surface density,trabecular number,and trabecular thickness were improved in the Kidney-Yang deficiency+Yougui pills group compared with the Kidney-Yang deficiency group(P＜0.05).The three-point bending experiment showed that the femur elastic modulus,maximum bending strength and bending fracture strength were decreased(P＜0.05)and toughness was increased(P＜0.05)in the Kidney-Yang deficiency+Yougui pills group compared with the Kidney-Yang deficiency group.Finite element simulation showed that Yougui pills could significantly improve the bending resistance of the femurs in the Kidney-Yang deficiency group,but had no significant effect on the Kidney-Yin deficiency group.The femoral head compression experiments showed that Yougui pills could enhance the ability of the femoral head to resist deformation in the Kidney-Yang deficiency group,but there was no significant difference in the effect of Yougui pills on the surface properties of the femoral head in the Kidney-Yin deficiency group and the Kidney-Yang deficiency group.To conclude,Yougui pills can significantly enhance the biomechanical properties of the osteoporotic bones with Kidney-Yang deficiency,but have no significant effect on the osteoporotic bone with Kidney-Yin deficiency.

Objective To investigate the mechanism of Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma drug pair in the treatment of hypertension based on the network pharmacology method and animal experiment verification.Methods(1)TCMSP,BATMAN and TCMIP databases were used to screen the active components and targets of Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma drug pair.The hypertension-related targets were obtained by searching the Drugbank,Genecard,TTD and Disgenet databases.The intersection(common target)of the active component target and the target related to hypertension disease was taken,and the obtained intersection target was the potential target of Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma drug pair for the treatment of hypertension.The active ingredients and their targets of Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma drug pair were imported into Cytoscape 3.9.1 software to construct a'Chinese medicines-active ingredients-targets'network and screen key active ingredients.The protein-protein interaction(PPI)network of potential targets was constructed to screen potential core targets.The Metascape platform was used to analyze the GO function and KEGG pathway enrichment of potential targets.The key active components and potential core targets were selected for molecular docking verification.(2)Thirty male spontaneously hypertensive rats(SHR)were randomly divided into model group,western medicine group(Candesartan Cilexetil,0.72 mg·kg-1)and low-,medium-and high-dose groups of Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma(2.25,4.50,9.00 g·kg-1).Another male WKY rats were selected as blank group,with 6 rats in each group,once a day for 8 weeks.The systolic blood pressure of rat tail artery was detected before administration and 2,4,6 and 8 weeks after drug intervention.The pathological changes of thoracic aorta were observed by HE staining.The protein expression levels of GRP78,CHOP and Caspase-12 in aorta abdominalis were detected by Western Blot.Results(1)A total of 83 active components of Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma were obtained,and 158 potential targets(intersection targets)for the treatment of hypertension were screened out.Five key active ingredients:p-hydroxybenzoic acid,4-hydroxybenzylamine,tanshinone I,tanshinone,γ-sitosterol;6 potential core targets:IL6,TNF,CASP3,JUN,PTGS2,IL1B;GO functional enrichment analysis obtained 1 826 biological process items,89 cell component items,and 199 molecular function items.KEGG pathway enrichment analysis obtained 186 pathways,mainly involving neuroactive ligand-receptor interaction,calcium signaling pathway,inflammatory response(such as TNF and MAPK signaling pathway),vascular protection(such as HIF-1 and cAMP signaling pathway),oxidative stress(such as PI3K-Akt signaling pathway)and other signaling pathways.Tanshinone I and tanshinone had strong binding force to 6 potential core targets,and γ-sitosterol had strong binding force to IL6,CASP3,JUN,PTGS2 and IL1B.(2)Compared with the blank group,the systolic blood pressure of the model group was significantly increased(P＜0.01).The thoracic aortic endothelial injury was obvious,the endothelial cell morphology was abnormal,swelling and exfoliated cells could be seen,the intima of the tissue was disordered,the intima structure was incomplete,and the intima was thickened.The protein expressions of GRP78,CHOP and Caspase-12 in abdominal aorta were significantly increased(P＜0.01).Compared with the model group,the systolic blood pressure of the rats in the administration group was significantly decreased(P＜0.01);the injury of thoracic aorta was alleviated,and the morphology,intima structure and thickness of endothelial cells were improved to varying degrees.The protein expressions of GRP78,CHOP and Caspase-12 in abdominal aorta were significantly decreased(P＜0.01).Conclusion Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma drug pair may act on core targets such as IL6,TNF,CASP3,JUN,PTGS2,and IL1B through key active components such as p-hydroxybenzoic acid,tanshinone,and γ-sitosterol,and regulate key signaling pathways such as TNF signaling pathway,MAPK signaling pathway,PI3K-Akt signaling pathway,and PERK signaling pathway to improve vascular endothelial dysfunction,inhibit endoplasmic reticulum stress,and lower blood pressure.