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 application of plasma 7 microRNA (miR7) testing in the differential diagnosis of very early-stage hepatocellular carcinoma (HCC). Methods This study is a multicenter real-world study. Patients with single hepatic lesion (maximum diameter≤2 cm) who underwent plasma miR7 testing at Zhongshan Hospital, Fudan University, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Anhui Provincial Hospital, and Peking University People’s Hospital between January 2019 and December 2024 were retrospectively enrolled. Patients were divided into very early-stage HCC group and non-HCC group, and the clinical pathological characteristics of the two groups were compared. The value of plasma miR7 levels, alpha-fetoprotein (AFP), and des-gamma-carboxy prothrombin (DCP) in the differential diagnosis of very early-stage HCC was evaluated using receiver operating characteristic (ROC) curves and area under the curve (AUC). In patients with both negative AFP and DCP (AFP＜20 ng/mL, DCP＜40 mAU/mL), the diagnostic value of plasma miR7 for very early-stage HCC was analyzed. Results A total of 64 528 patients from 4 hospitals underwent miR7 testing, and 1 682 were finally included, of which 1 073 were diagnosed with very early-stage HCC and 609 were diagnosed with non-HCC. The positive rate of miR7 in HCC patients was significantly higher than that in non-HCC patients (67.9% vs 24.3%, P＜0.001). ROC curves showed that the AUCs for miR7, AFP, and DCP in distinguishing HCC patients from the non-HCC individuals were 0.718, 0.682, and 0.642, respectively. The sensitivities were 67.85%, 43.71%, and 44.45%, and the specificities were 75.70%, 92.78%, and 83.91%, respectively. The pairwise comparison of AUCs showed that the diagnostic efficacy of plasma miR7 detection was significantly better than that of AFP or DCP (P＜0.05). Although its specificity was slightly lower than AFP and DCP, the sensitivity was significantly higher. Among patients negative for both AFP and DCP, miR7 maintained an AUC of 0.728 for diagnosing very early-stage HCC, with 67.82% sensitivity and 77.73% specificity. Conclusions Plasma miR7 testing is a potential molecular marker with high sensitivity and specificity for the differential diagnosis of small hepatic nodules. In patients with very early-stage HCC lacking effective molecular markers (negative for both AFP and DCP), miR7 can serve as a novel and effective molecular marker to assist diagnosis.

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 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.

In this study,a method for detecting heavy metal ions using potentiometric sensor and voltammetric sensor was proposed.By exploiting the complementary advantages of potentiometric and voltammetric electrochemical sensor,the traditional electrochemical electrode without special material preparation and modification could be used for the wide range and accurate detection of heavy metal ions in actual water samples.During detection,the concentration of target ion was measured by a potentiometric electrochemical sensor to determine the concentration range.The amperometric electrochemical sensor was then used for calibration and accurate measurement in the appropriate concentration range.Taking copper ion(Cu2+)as an example,the prepared Cu2+water sample and the actual water sample were tested.First,the copper ion selective electrode was used to determine the concentration range of Cu2+in the sample.Then,based on the gold electrode in different concentration range(0.86-100 μg/L and 100-300 μg/L)using two different optimization parameter settings to calibrate the electrochemical sensor and measure,the test results had a good correlation with those by professional water quality testing institutions.The recoveries ranged from 86.7%to 103.0%.The experimental results showed that the combination of potential sensor and current sensor could improve the accuracy of detection of heavy metal ions in water samples by electrochemical sensor.

The purpose of this research is to study the effect of small molecule compound piceatannol (PIC) on host inflammation in adenine induced chronic kidney disease (CKD) mice, and then to explore its mechanism based on the regulation of gut microbiota. All procedures were approved by the Institutional Animal Care and Use Committee of the Nanjing University of Chinese Medicine. The level of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was detected by enzyme linked immunosorbent assay (ELISA); UPLC-TQ/MS technology was used to monitor the level of proinflammatory uremic toxin indoxyl sulfate (IS) and p-cresol sulfate (PCS); the expression of occludin was tested by Western blot; in vitro anaerobic culture of gut bacteria was used to produce indole; the abundance of gut microbiota was evaluated by 16S rDNA sequencing. The results showed that PIC had no effect on inflammatory infiltration in kidney tissue of CKD mice, but could decrease IL-6 level in blood and IL-6/TNF-α level in colon tissue. PIC did not improve intestinal occludin protein expression in CKD mice; while it could significantly reduce the levels of IS and PCS in blood and liver of CKD mice. Further mechanism studies showed that PIC could inhibit the synthesis of IS precursor indole in gut bacteria. Moreover, PIC could decrease the abundance of gut bacteria which producing uremic toxin, such as reducing the abundance of indole and p-cresol producing gut bacteria. In conclusion, PIC could regulate gut microbiota and inhibit the synthesis of uremic toxin precursor, thereafter reducing the accumulation of IS and PCS in vivo, ultimately relieving the inflammation of CKD mice.

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

In this study, 280 batches of Zingiberis Rhizoma samples from nine producing areas were analyzed to obtain infrared spectral information based on near-infrared spectroscopy(NIRS). Pluralistic chemometrics such as principal component analysis(PCA), partial least squares-discriminant analysis(PLS-DA), orthogonal partial least squares-discriminant analysis(OPLS-DA), K-nearest neighbors(KNN), support vector machine(SVM), random forest(RF), artificial neural network(ANN), and gradient boosting(GB) were applied for tracing of origins. The results showed that the discriminative accuracy of the spectral preprocessing by standard normal variate transformation coupled with the first derivative was 93.9%, which could be used for the construction of the discrimination model. PCA and PLS-DA score plots showed that samples from Shandong, Sichuan, Yunnan, and Guizhou could be effectively distinguished, but the remaining samples were partially overlapped. As revealed by the analysis results by machine learning algorithms, the AUC values of KNN, SVM, RF, ANN, and GB algorithms were 0.96, 0.99, 0.99, 0.99, and 0.98, respectively, with overall prediction accuracies of 83.3%, 89.3%, 90.5%, 91.7%, and 89.3%. It indicated that the developed model was reliable and the machine learning algorithm combined with NIRS for origin identification was sufficiently feasible. OPLS-DA showed that Zingiberis Rhizoma from Sichuan(genuine producing areas) could be significantly distinguished from other regions, with good discriminative accuracy, suggesting that the NIRS established in this study combined with chemometrics can be used for the identification of Zingiberis Rhizoma from Sichuan. This study established a rapid and nondestructive identification and reliable data analysis method for origin identification of Zingiberis Rhizoma, which is expected to provide a new idea for the origin tracing of Chinese medicinal materials.
Algorithms ; Chemometrics ; China ; Ginger ; Least-Squares Analysis ; Plant Extracts ; Principal Component Analysis ; Support Vector Machine

Objective: To investigate the predicting value of different risk prediction models for short-term death in patients with ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock and treated with extracorporeal membrane oxygenation (ECMO). Methods: This study was a retrospective case-control study. Forty patients with STEMI complicated by cardiogenic shock who hospitalized in the First Affiliated Hospital of Zhengzhou University from April 2017 to August 2021 and treated with percutaneous coronary intervention (PCI) and ECMO, were enrolled in this study. Patients were divided into survival group and death group according to their clinical outcomes at 30 days after ECMO implantation, and clinical data of the two groups were collected and analyzed. Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to compare the predictive value of ACEF, AMI-ECMO, Encourage and SAVE risk scores for mortality at 30 days after ECMO implantation. According to the evaluation results of DCA, the optimal risk score was selected. Kaplan-Meier curve estimating the 30-day survival after ECMO implantation was plotted by grouping risk scores with reference to previous literatures. Results: A total of 40 patients with STEMI combined with cardiogenic shock were included, age was (57.4±16.7) years, 31 (77.5%) patients were male, there were 21 (52.5%) patients in the death group and 19 (47.5%) in the survival group. Compared with the survival group, patients in the death group had higher lactic acid values, higher proportion of anterior descending artery or left main artery lesions, and a higher proportion of acute renal failure and continuous renal replacement therapy during hospitalization (all P<0.05). Compared with survival group, ACEF, AMI-ECMO and Encourage scores were higher in death group, SAVE score was lower in death group (all P<0.05). The ROC curve analysis showed that the area under the curve (AUC) of ACEF, AMI-ECMO, Encourage and SAVE scores in predicting mortality were 0.707, 0.816, 0.757, and 0.677 respectively (P>0.05). ACEF score demonstrated the highest sensitivity (90.5%) and Encourage score exhibited the highest specificity (89.5%). DCA indicated that the AMI-ECMO and Encourage scores had the best performance in predicting the 30-day mortality after ECMO therapy. Kaplan-Meier survival curve analysis showed that the 30-day mortality after ECMO implantation increased with the increase of AMI-ECMO and Encourage scores (log-rank P≤0.001). Conclusions: The 4 scoring systems are all suitable for predicting 30-day mortality after VA-ECMO therapy in patients with ST-segment elevation myocardial infarction complicated by cardiogenic shock. Among them, AMI-ECMO and Encourage scores have better predicting performance.
Adult ; Aged ; Case-Control Studies ; Extracorporeal Membrane Oxygenation/methods* ; Female ; Humans ; Male ; Middle Aged ; Percutaneous Coronary Intervention/methods* ; Retrospective Studies ; ST Elevation Myocardial Infarction/therapy* ; Shock, Cardiogenic/therapy*

Child ; Humans ; Nephrotic Syndrome/diagnosis* ; Biomarkers ; Steroids/therapeutic use*