The p21-activated kinase 4 (PAK4), a key regulator of malignancy, is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy. Given the lack of high efficacy PAK4 inhibitors, we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC₅₀ values of 0.38 and 0.50 μmol/L, respectively. This compound directly binds to PAK4 in a non-ATP competitive manner. In the mouse Pan02 model, compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg, accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue. Overall, compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo, thus making it worthy of further exploration.

Objective To explore the effect of the teaching model based on"Academic-Industrial-Education Integration"in the clinical probation and practice teaching of rehabilitation.Methods 57 rehabilitation students were divided into control group(n=28)and experimental group(n=29)according to their volunteers.The control group took the traditional teaching method,and the experimental group took the teaching method of"Academic-Industrial-Education Integration".The two groups of students were compared in the assessment results of scientific research related courses,the participation rate of students in scien-tific research and innovation related projects,the satisfaction results of teaching effect,learning effect,self-theoretical ability and self-practical ability.The data of teachers' teaching results were collected.Results The scores of students in the experimental group were better than those in the control group in terms of scientific research-related courses and participation rate of scientific research,innovation and entrepreneurship projects(P＜0.05).There was no statistical difference in the satisfaction of teaching effect and theoretical ability improvement.Students' self-learning effect satisfaction and practical ability improvement satisfaction in the experimental group were higher than those in the control group(P＜0.05).The teaching achievements of teachers are in-creased,and the teaching level is promoted.Conclusion The application of"Academic-Industrial-Education Integration"teaching mode in clinical teaching of rehabilitation is helpful to improve students' participation rate in scientific research courses and innova-tive projects,improve the satisfaction of learning effect and practical ability,and promote the improvement of teaching level.

Objective To investigate the factors influencing the efficacy of intravesical Bacille Calmette-Guérin(BCG)instillation after transurethral resection of bladder tumor(TURBT)in patients with intermediate-and high-risk non-muscle invasive bladder cancer(NMIBC),and to construct a prediction model for recurrence after BCG treatment.Methods A retrospective cohort study was conducted on the subjected patients diagnosed with intermediate-and high-risk NMIBC undergoing TURBT followed by standard BCG instillation.The 110 patients treated in Department of Urology of Army Medical Center of PLA from January 2018 to December 2023 were assigned into a training set,while the 52 patients treated at Department of Urology of General Hospital of Central Theater Command from January 2015 to December 2020 were into an external validation set.A total of 17 variables were included and analyzed.Univariate and multivariate Cox regression analyses were performed to identify factors associated with recurrence after BCG instillation,and nomograms were plotted to predict 1-year,3-year,and 5-year recurrence-free survival(RFS).Calibration curve,decision curve analysis(DCA),and receiver operating characteristic(ROC)curve analysis were conducted for internal and external validation to evaluate the predictive performance and clinical utility of the model.Results In the training set,26 patients(23.64%)experienced recurrence during the follow-up period,with a median RFS of 32.00(18.00～50.50)months.Univariate Cox regression analysis suggested that platelet count,eosinophil to lymphocyte ratio(ELR),neutrophil to lymphocyte ratio(NLR),platelet to lymphocyte ratio(PLR),systemic immune inflammation(SII)index,and neutrophil-monocyte to lymphocyte ratio(NMLR),pathological T1 stage(pT1)tumor and hemoglobin,albumin,lymphocyte,and platelet(HALP)score were potential factors influencing recurrence after BCG instillation.Multivariate Cox regression analysis identified high HALP score(HR=0.185,95%CI:0.046～0.736,P=0.017)as an independent protective factor,while high ELR(HR=3.599,95%CI:1.505～8.608,P=0.004)and pT1 stage(HR=3.240,95%CI:1.191～8.818,P=0.021)were independent risk factors for recurrence.Based on this,a nomogram prediction model was constructed.The calibration curves demonstrated good agreement between predicted and actual 1-,3-,and 5-year recurrence risks.Decision curve analysis indicated clinical utility across a wide threshold probability range.In the training set,the model showed strong predictive performance for 1-(AUC=0.842),3-(AUC=0.847),and 5-year(AUC=0.887)recurrence risks,which was further validated in the external cohort.Conclusion Higher HALP score prior to BCG instillation therapy is a protective factor against tumor recurrence,while higher ELR and pT1 stage are risk factors.Our nomogram prediction model based on HALP score,ELR and pathological T stage,can identify individuals at high risk of recurrence after BCG instillation therapy.

Objective To investigate risk factors for residual lesions after initial transurethral resection of bladder tumors(TURBT)and risk factors for tumor recurrence after second TURBT in patients with non-muscle-invasive bladder cancer(NMIBC)in order to provide reference for clinical management.Methods A case-control study design was adopted to include 120 NMIBC patients who underwent initial TURBT and then second surgery within 2～8 weeks in our department from January 2017 to January 2025.Based on the presence of residual lesions after the initial TURBT or not,the patients were divided into a residual lesion group(n=34)and a non-residual lesion group(n=86).Chi-square test and multivariate logistic regression analysis were performed to identify potential risk factors for residual lesions following the initial TURBT.Univariate and multivariate Cox regression models were used to analyze potential risk factors for tumor recurrence after the second TURBT.Results The residual lesion rate after initial TURBT was 28.33％.Chi-square test analysis revealed that tumor stage T1(Chi-square=5.756,P=0.016)and broad tumor base(Chi-square=4.331,P=0.037)were factors influencing residual lesions after initial TURBT.Multivariate logistic regression analysis identified tumor stage T1(OR=3.047,95％CI:1.128～8.226,P=0.028)as an independent risk factor for residual lesions after initial TURBT.The tumor recurrence rate after second TURBT was 17.5％.Multivariate Cox regression analysis identified tumor stage T1(OR=4.258,95％CI:1.248～14.532,P=0.021),intravesical chemotherapy instillation after second TURBT(OR=3.539,95％CI:1.284～9.752,P=0.015),history of urinary system tumors(OR=3.002,95％CI:1.145～7.873,P=0.025)and high platelet-to-lymphocyte(PLR)ratio(OR=2.798,95％CI:1.115～7.023,P=0.028)as independent risk factors for tumor recurrence after second TURBT.Conclusion Tumor stage T1 and broad tumor base are risk factors for residual lesions after initial TURBT,while tumor stage T1,intravesical chemotherapy instillation after second TURBT,history of urinary system tumors and high PLR ratio are risk factors for tumor recurrence after second TURBT.Comprehensive analysis on above 4 indicators can effectively assess the risk of tumor recurrence in NMIBC patients following second TURBT,and timely early medical intervention is beneficial for improving patient outcomes.

Objective To explore the effect of the teaching model based on"Academic-Industrial-Education Integration"in the clinical probation and practice teaching of rehabilitation.Methods 57 rehabilitation students were divided into control group(n=28)and experimental group(n=29)according to their volunteers.The control group took the traditional teaching method,and the experimental group took the teaching method of"Academic-Industrial-Education Integration".The two groups of students were compared in the assessment results of scientific research related courses,the participation rate of students in scien-tific research and innovation related projects,the satisfaction results of teaching effect,learning effect,self-theoretical ability and self-practical ability.The data of teachers' teaching results were collected.Results The scores of students in the experimental group were better than those in the control group in terms of scientific research-related courses and participation rate of scientific research,innovation and entrepreneurship projects(P＜0.05).There was no statistical difference in the satisfaction of teaching effect and theoretical ability improvement.Students' self-learning effect satisfaction and practical ability improvement satisfaction in the experimental group were higher than those in the control group(P＜0.05).The teaching achievements of teachers are in-creased,and the teaching level is promoted.Conclusion The application of"Academic-Industrial-Education Integration"teaching mode in clinical teaching of rehabilitation is helpful to improve students' participation rate in scientific research courses and innova-tive projects,improve the satisfaction of learning effect and practical ability,and promote the improvement of teaching level.

Objective To explore the clinical efficacy of Chinese herbal medicine with the actions of invigorating spleen,activating blood and resolving phlegm in the treatment of senile insomnia based on the theory of"muscular atrophy,qi-passage blockage"recorded in Huang Di Nei Jing(The Yellow Emperor's Inner Classic,shortened as Nei Jing).Methods A total of 120 elderly patients with insomnia were randomly divided into observation group and control group,with 60 cases in each group.The control group was treated with oral use of Dexzopiclone Tablets,and the observation group was treated with oral use of decoction of Chinese herbal medicine for invigorating spleen,activating blood and resolving phlegm.The course of treatment covered 4 weeks.Before and after treatment,the two groups were observed in the changes of Pittsburgh Sleep Quality Index(PSQI)score,Insomnia Severity Index(ISI)score,polysomnography(PSG)related parameters of total sleep time(TST),number of awakenings(AN)and sleep latency(SL),mean blood flow velocity of anterior cerebral artery(ACA),middle cerebral artery(MCA),and posterior cerebral artery(PCA),and serum levels of 5-hydroxytryptamine(5-HT)and melatonin(MT).After treatment,the clinical efficacy and safety of the two groups were evaluated.Results(1)After 4 weeks of treatment,the total effective rate of the observation group was 93.33%(56/60),which was slightly higher than 90.00%(54/60)of the control group,but the difference was not statistically significant(P＞0.05).(2)After treatment,the item scores and total scores of PSQI in the two groups were lower than those before treatment(P＜0.05),and the decrease of the scores of sleep quality,sleep time,sleep efficiency,and daytime function as well as total scores in the observation group was significantly superior to that in the control group(P＜0.05).However,there was no significant difference of time for falling asleep and sleep disorder scores between the two groups(P＞0.05).After 4 weeks of drug withdrawal,the item scores of PSQI in the observation group continued to decrease compared with those after treatment(P＜0.05),but there was no significant difference in the control group(P＜0.05).(3)After treatment,the ISI scores in the two groups were decreased when compared with those before treatment(P＜0.05),and the decrease in the observation group was superior to that in the control group(P＜0.05).After 4 weeks of drug withdrawal,the ISI score of the observation group continued to decrease compared with that after treatment(P＜0.05),while the control group had no significant change,and the difference was not statistically significant(P＞0.05).(4)After treatment,the PSG related parameters such as TST,AN and SL in the two groups were improved when compared with those before treatment(P＞0.05),and the improvement of TST and AN in the observation group was superior to that in the control group(P＞0.05).(5)After treatment,the mean blood flow velocity of ACA,MCA and PCA in the observation group was improved compared with that before treatment(P＜0.05),while there was no significant change in the control group compared with that before treatment(P＞0.05).The improvement of the mean blood flow velocity of ACA,MCA and PCA in the observation group was significantly superior to that in the control group(P＜0.05).(6)After treatment,the levels of serum 5-HT and MT in the two groups were increased when compared with those before treatment(P＜0.05),and the increase in the observation group was superior to that in the control group(P＜0.05).(7)The incidence of adverse reactions in the observation group was 5.00%(3/60),which was slightly lower than 13.33%(8/60)in the control group,but the difference was not statistically significant(P＞0.05).Conclusion Based on the theory of"muscular atrophy,qi-passage blockage"recorded in Nei Jing,the Chinese herbal medicine for invigorating spleen,activating blood and resolving phlegm exerts certain effect in treating senile insomnia.It can effectively improve the sleep quality and daytime function of patients,enhance sleep efficiency,increase sleep time,reduce the number of awakenings,alleviate the severity of insomnia,improve brain function,and regulate the level of neurotransmitters,with remarkably long-term effect and reliable safety.

Based on the technology of platelet proteomics, the key regulatory proteins and pathogenesis of coronary heart disease with phlegm and blood stasis syndrome were explored and analyzed. Based on the previous laboratory research, the model of coronary heart disease in mini-swine with phlegm-stasis cementation syndrome was duplicated. The model was judged by the changes in blood lipid and myocardial tissue characteristics. Furthermore, the platelet proteins were studied by quantitative proteomics, and the differentially expressed proteins were screened. The critical regulatory proteins and biological pathways of coronary heart disease with phlegm-stasis cementation syndrome were analyzed by bioinformatics. After ten weeks of modeling, the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low density lipoprotein (VLDL-C), triglyceride (TG), creatine kinase (CK) and creatine kinase-MB (CK-MB) in the model group were significantly increased, reflecting the pathological changes such as increased blood lipid, abnormal coagulation function and myocardial ischemia in the model group. In addition, compared with the sham group, there were 26 up-regulated proteins and 8 down-regulated proteins in the platelets of the model group. Combined with bioinformatics analysis, it was found that differential proteins mainly involved in glycolysis/gluconeogenesis, pyruvate metabolism, lipid and atherosclerosis, Ras protein signal transduction. Among them, lactate dehydrogenase B (LDHB), alcohol dehydrogenase 5 (ADH5), neuroblastoma ratsarcoma viral oncogene homolog (NRAS) and Kirsten ratsarcoma viral oncogene homolog (KRAS) play a central role when interacting with other proteins and simultaneously participate in multiple action pathways. The results showed that LDHB, ADH5, NRAS, and KRAS may be the marker proteins in CHD with phlegm-stasis cementation syndrome by regulating glycolysis/gluconeogenesis, pyruvate metabolism, lipid and atherosclerosis, Ras protein signal transduction and other biological processes.

Humans ; Diabetes Mellitus, Type 2/epidemiology* ; Air Pollution/adverse effects* ; Air Pollutants/toxicity* ; Risk Assessment ; Particulate Matter ; Environmental Exposure

Objective: To determine the causal association between long-term Nitrogen dioxide (NO₂) exposure and the risk of cardiovascular hospitalization. Methods: Based on a sub-cohort of a community-based prospective cohort study, a total of 36 271 participants were recruited from 35 communities randomly selected in Guangzhou in 2015. The annual average exposure of NO₂, demographic characteristics, lifestyle factors, and information on the causes of hospitalization was collected. We applied marginal structural Cox models to investigate the effect of NO₂ on cardiovascular hospitalization. Demographic and behavioral factors also stratified results. Results: The mean age of participants in the present study was (50.9±17.8) years, and the cardiovascular admission rate was 8.7%, with 203 822 person-years of follow-up. The annual mean NO₂ concentration was 48.7 μg/m³ during 2015-2020. For each 10 μg/m³ increase in NO₂ concentrations, the HRs (95%CIs) of total cardiovascular hospitalization, cardiovascular hospitalization, and cerebrovascular hospitalization were 1.33 (1.16-1.52), 1.36 (1.16-1.60) and 1.25 (1.00-1.55), respectively. Participants who were never married/married, with secondary education, high exercise frequency, or non-smokers/current smokers may be more susceptible than their counterparts. Conclusion: Long-term exposure to NO₂ significantly increased hospitalization risk for cardiovascular disease.
Humans ; Adult ; Middle Aged ; Aged ; Nitrogen Dioxide ; Prospective Studies ; Cardiovascular Diseases/epidemiology* ; Causality ; Hospitalization