Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Liraglutide (Lira), a glucagon-like peptide-1 (GLP-1) receptor agonist approved for diabetes and obesity, has shown significant potential in treating metabolic dysfunction-associated steatotic liver disease (MASLD). However, its systematic molecular regulation and mechanisms remain underexplored. In this study, a mouse model of MASLD was developed using a high-fat diet (HFD), followed by Lira administration. Proteomics and glycoproteomics were analyzed using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS), while potential molecular target analysis was conducted via quantitative real-time polymerase chain reaction (qPCR) and Western blotting. Our results revealed that Lira treatment significantly reduced liver weight and serum markers, including alanine aminotransferase (ALT) and others, with glycosylation changes playing a more significant role than overall protein expression. The glycoproteome identified 255 independent glycosylation sites, emphasizing the impact of Lira on amino acid, carbohydrate metabolism, and ferroptosis. Simultaneously, proteomic analysis highlighted its effects on lipid metabolism and fibrosis pathways. 21 signature molecules, including 7 proteins and 14 N-glycosylation sites (N-glycosites), were identified as potential targets. A Lira hydrogel formulation (Lira@fibrin (Fib) Gel) was developed to extend drug dosing intervals, offering enhanced therapeutic efficacy in managing chronic metabolic diseases. Our study demonstrated the importance of glycosylation regulation in the therapeutic effects of Lira on MASLD, identifying potential molecular targets and advancing its clinical application for MASLD treatment.

Objective:To investigate the value of coronary CTA (CCTA)-based traditional features and radiomics of plaque in the identification of culprit lesions that caused acute myocardial infarction (AMI).Methods:This was a retrospective multicenter study. From July 2016 to November 2023, a total of 344 patients from the Affiliated Hospital of Qingdao University (training cohort, n=184), Shandong Provincial Hospital Affiliated to Shandong First Medical University (validation cohort, n=88) and Qilu Hospital of Shandong University (test cohort, n=72) who received percutaneous coronary intervention (PCI) due to AMI and underwent CCTA within 48 hours of AMI were enrolled. The culprit plaques and non-culprit plaques were identified using a combination of electrocardiogram, CCTA, and angiographic findings. The vessel, plaque location, plaque type, Coronary Artery Disease-Reporting and Data System (CAD-RADS) score, high-risk plaque characteristics, plaque length, plaque volume, and burden were analyzed, and 1 904 radiomics features were extracted for each plaque. The traditional imaging model, the radiomics model, and the combined model were established by using multivariate Logistic regression analysis. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of each model in identifying culprit lesions. The DeLong test was used for the comparison of AUC between every two models. The net reclassification index (NRI) was used to evaluate the incremental value of the combined model to the traditional imaging model and the radiomics model. The decision curve analysis (DCA) was used to assess the clinical net benefit of these models. A correlation heatmap was used to evaluate the correlation between the radiomics score and traditional CCTA factors. The interpretable analysis of the decision process of the combined model was performed by the Shapley Additive exPlanations (SHAP). Results:In the validation cohort and the test cohort, the AUC of the traditional imaging model developed by the vessel, plaque type, positive remodeling and CAD-RADS score was 0.898 (95% CI 0.869-0.922) and 0.881 (95% CI 0.848-0.910), respectively. The radiomics model developed by six radiomics features was 0.863 (95% CI 0.831-0.891) and 0.863 (95% CI 0.827-0.864), respectively. The AUC of the combined model was 0.930 (95% CI 0.905-0.950)and 0.919 (95% CI 0.889-0.942), respectively. In the validation cohort and the test cohort, the AUC of the combined model was higher than that of the traditional imaging model ( Z=4.013, 4.272, P<0.001) and that of the radiomics model ( Z=4.819, 3.784, P<0.001), respectively. In the validation cohort, the combined model yielded an NRI of 20.43% (95% CI 10.43%-30.44%, P<0.001) and 20.21% (95% CI 9.62%-30.80%, P<0.001) for identifying culprit lesions compared with the traditional imaging model and the radiomics model, respectively. In the test cohort, the combined model yielded an NRI of 28.05% (95% CI 16.72%-39.38%, P<0.001) and 23.57% (95% CI 13.58%-33.56%, P<0.001) for identifying culprit lesions compared with the traditional imaging model and the radiomics model, respectively. DCA showed the combined model had the highest clinical net benefit. The correlation heatmap showed the radiomics score was not correlated or only weakly correlated with traditional CCTA factors. SHAP indicated the radiomics and CAD-RADS score contributed significantly to the model. Conclusion:The CCTA-based traditional features and radiomics of plaque have favorable performance for the identification of culprit plaques in patients with AMI.

Cholangiocarcinoma has an extremely poor prognosis, and the efficacy of existing treatment methods is limited. In the highly desmoplastic tumor microenvironment of cholangiocarcinoma, cancer-associated fibroblasts (CAFs) are the core regulators. Their significant heterogeneity and complex intercellular crosstalk network are not only key factors driving cholangiocarcinoma progression and drug resistance, but also highly promising therapeutic targets. This review focuses on the characteristics of CAFs in cholangiocarcinoma and the key crosstalk mechanisms between CAFs and tumor cells as well as immune cells, and summarizes the research progress and limitations of current therapeutic strategies targeting CAFs.

Objective To investigate the effec of oscillating field stimulation on the proliferation of endogenous neural stem cell(ENSC)and recovery of motor function after spinal cord injury(SCI)in rats.Methods The SCI model was established by using the improved Allen's strike method and was randomly divided into experimental group and control group,with 60 rats in each group.The experimental group received an oscillating field implant as the intervention,while the control group was equipped with the same device but without activation.After successful modeling,the spinal cord of rats was removed on the 3rd,7th and 14th day,respectively.The proliferation of ENSC was detected by neuroepithelial stem cell protein(Nestin)/5-bromodeoxyuridine(BrdU)immunofluorescence,and the expression of Wnt-3a protein in spinal cord was detected by immunohistochemistry.At the 4th,6th and 8th week,the spinal cord was stained with osmic acid to observe the formation of myelin sheath in rats,and Basso-Beattle-Bresnahan(BBB)functional score of each group of rats was performed before sampling.Results The immunofluorescence results showed that Nestin/BrdU double positive cells in the injured area could be seen in both groups on the 3rd day after SCI,reaching a peak on the 7th day,and gradually decreased on the 14th day,and still maintained at a high level.At the same time,number of Nestin/BrdU double positive cells in experimental group rats at each time point was more than that in control group.The immunohistochemical results showed that the expression level of Wnt-3a protein in experimental group rats at each time point was higher than that in control group(P＜0.05).At the 6th and 8th weeks,the number of myelin sheaths in experimental group rats was significantly higher than that in control group(P＜0.05).At the 4 th,6th and 8th weeks,the BBB scores of rats in experimental group were significantly higher than those in control group(P＜0.05).Conclusion The oscillating field stimulation can induce the proliferation of ENSC after SCI by activating Wnt/β-catenin signaling pathway,promote myelin regeneration,and improve motor function of rats.

Objective:To explore the impact of body constitutional metabolic phenotype on the outcomes of hypertensive intracerebral hemorrhage (HICH) patients one year after onset.Methods:This study retrospectively studied the clinical data of 467 HICH patients admitted to the First People's Hospital of Lianyungang City from May 2021 to May 2023. Based on telephone follow-up after one year, the patients were categorized into two groups: a good outcome group (287 cases) and a poor outcome group (180 cases). According to the patients' body mass index (BMI) and metabolic status, the population was divided into six phenotypes: metabolically healthy with normal weight (MH-NW), metabolically healthy with overweight (MH-OW), metabolically healthy obesity (MHO), metabolically unhealthy normal weight (MU-NW), metabolically unhealthy with overweight (MU-OW), and metabolically unhealthy with obesity (MUO). The baseline data of the two groups were compared between two groups. The influencing factors of adverse outcomes in patients with HICH one year after onset were analyzed. Quantitative data that conforms to normal distribution were represented by xˉ±s, and independent sample t-test was used for comparison between two groups; The measurement data of skewed distribution was represented by M ( Q1, Q3), and Mann Whitney U test was used for comparison between the two groups; Count data was presented as an example (%), and comparison between groups was conducted using the χ2 test. Multivariate logistic regression analysis was used to analyze the influencing factors of poor prognosis in HICH patients one year after onset. Results:BMI, high density lipoprotein cholesterol(HDL-C) levels and baseline Glasgow coma score(GCS) score in the poor outcome group were lower than those in the good outcome group [23.8 (22.4, 26.1) kg/m 2 vs. 25.0 (22.5, 27.4) kg/m 2, Z=-2.31, P=0.021; 1.1 (1.0,1.4) mmol/L vs. 1.3 (1.0,1.6) mmol/L, Z=-4.18, P<0.001; 14 (13,15) score vs. 10 (7,13) score, Z=-10.20, P<0.001]. The incidence of hemorrhage into the ventricle, cerebral hernia, pulmonary infection and hydrocephalus [43.3%(78/180) vs. 23.7% (68/287). 5.6%(10/180) vs. 0.7% (2/287), 48.9%(88/180) vs. 6.6% (19/287), 5.0%(9/180) vs. 1.4% (4/287), χ2=19.86, P<0.001, χ2=10.43, P<0.001, χ2=111.90, P<0.001, χ2=5.32, P=0.021], proportion of surgical removal of hematoma [41.1%(74/180) vs. 19.5% (56/287), χ2=25.69, P<0.001], systolic blood pressure [158 (141,173) mmHg vs. 152 (138,169) mmHg, Z=-2.18, P=0.029] and fasting blood glucose [6.9 (5.7,8.2) mmol/L vs. 6.3 (5.4,7.8) mmol/L, Z=-2.08, P=0.038] were higher than those in good outcome group. The metabolic phenotypes in the poor conversion group were as follows: 41 cases (22.8%) of MH-NW, 23 cases (12.8%) of MH-OW, 9 cases (5.0%) of MHO, 54 cases (30.0%) of MU-NW, 33 cases (18.3%) of MU-OW, and 20 cases (11.1%) of MUO. Conversely, the metabolic phenotypes in the good conversion group were as follows: 67 cases (23.3%) of MH-NW, 77 cases (26.8%) of MH-OW, 31 cases (10.8%) of MHO, 40 cases (13.9%) of MU-NW, 46 cases (16.0%) of MU-OW, and 26 cases (9.1%) of MUO. Regarding metabolic types, the poor conversion group comprised 73 healthy cases (40.6%) and 107 unhealthy cases (59.4%), whereas the good conversion group had 177 healthy cases (61.7%) and 110 unhealthy cases (38.3%). In terms of body mass, the poor conversion group included 94 cases (52.2%) of normal weight, 57 cases (31.7%) of overweight, and 29 cases (16.1%) of obesity. Conversely, the good conversion group had 108 cases (37.6%) of normal weight, 122 cases (42.5%) of overweight, and 57 cases (19.9%) of obesity.There were statistically significant differences in the composition ratios of physical metabolic phenotype, metabolic type, and xBMI type between the two groups of patients ( χ2=29.56, P<0.001, χ2=19.83, P<0.001, χ2=9.68, P=0.008). Multivariate Logistic regression analysis showed that after adjusting for other risk factors related to the prognosis of HICH, HDL-C ( OR=0.30, 95% CI: 0.12-0.75, P=0.010), admission GCS score ( OR=0.71, 95% CI:0.64-0.79, P<0.001), MH-OW ( OR=0.38, 95% CI: 0.17-0.82, P=0.013) and MHO ( OR=0.30, 95% CI:0.09-0.99, P=0.048) were all protective factors for adverse outcomes in patients with HICH 1 year after the onset of the disease, and hemorrhage into the ventricle ( OR=2.46, 95% CI:1.41-4.32, P=0.002) and pulmonary infection ( OR=9.13, 95% CI: 4.78- 17.44, P<0.001) were risk factors for adverse outcomes. Conclusions:MH-OW and MHO are beneficial to the prognosis of HICH patients 1 year after the onset of HICH. The secondary prevention of HICH patients should pay attention to the BMI level and comprehensive metabolic status of the patients.

Objective:This study analyzed the clinical characteristics and early mortality risk factors in patients with hyperleukocytic acute leukemia (HAL) to provide a basis for predicting early prognosis.Methods:Data were retrospectively collected from 211 patients with primary HAL who visited the Emergency Center of the Hematology Hospital, Chinese Academy of Medical Sciences, between July 1, 2019 and November 30, 2021. The value of each indicator in early risk stratification and prognosis was analyzed.Results:The early-death group exhibited higher WBC, peripheral blood immature cell proportions, prothrombin times (PT), fibrinogen degradation products (FDP), and D-dimer levels than the non-early death group ( P<0.05). Mortality in hyperleukocytic AML (20.5% ) was significantly higher than that in hyperleukocytic ALL (9.3% ) ( P<0.05). There were significant differences in age, creatinine, PT, fibrinogen (FIB) levels, WBC, lactic dehydrogenase (LDH), uric acid, blood potassium, blood calcium, and blood phosphorus levels between the two groups of patients ( P<0.05). A WBC threshold of 255.96×10?/L predicted early mortality with 65.6% sensitivity and 69.0% specificity, with higher WBC levels associated with a 5.164-fold increased mortality risk ( P<0.05). The age, WBC, LDH, urea, PT, FDP and D-dimer of patients at the time of consultation are risk factors affecting the survival of HAL ( P<0.05) . Conclusion:HAL is a life-threatening condition with a high early mortality. Age, WBC, LDH, urea, PT, FDP and D-dimer are risk factors for early death in HAL.

Objective:Utilizing the principles of mechanical vibrations dissections and low-temperature coagulation of harmonic scalpel, and combining the magnifying effect of 3D thoracoscopy and the advantage of low trauma, we used harmonic scalpel to harvest the left internal mammary artery (LIMA) under thoracoscopy, and explored the feasibility and early effect of harmonic scalpel in minimally invasive coronary artery bypass grafting (MICABG).Methods:A total of 488 patients who underwent MICABG from July 2021 to December 2023 in Dong E Hospital were collected. Among them, 347 patients was harvested using harmonic scalpel under thoracoscopy. Following anastomosis, the blood flow and pulsatility index (PI) from the graft to the target vessel were determined using a transit time flow meter (MiraQ, Medistim, Norway), and patency was checked. Data from 347 patients were analyzed.Results:All 347 patients were performed under non-extracorporeal circulation and successful graft patency was achieved in all patients. Analysis of 79 patients revealed a median time to LIMA acquisition of 32 min and a median length of acquisition of 15 cm. No graft-related events or complications occurred in any of the patients, and 2 patients died postoperatively. During a median follow-up of 12.1 months, only one patient experienced graft occlusion necessitating intervention.Conclusion:The utilization of harmonic scalpel for LIMA harvesting in MICABG is feasible and yields stable early results.

Objective:To analyze the clinical characteristics and identify predictive factors for spontaneous passage of common bile duct (CBD) stones.Methods:A retrospective analysis was conducted on patients diagnosed as having choledocholithiasis via abdominal imaging at outpatient and emergency departments of Jiangsu Province Hospital of Chinese Medicine and other medical institutions from January 2021 to November 2023. Participants were stratified into spontaneous passage versus non-passage groups. Multivariate logistic regression analysis was used to identify predictors for the spontaneous passage of common bile duct stones.Results:Spontaneous stone passage were confirmed in 70 cases (15.5%). Multivariate logistic regression analysis identified that an admission diagnosis of acute biliary pancreatitis ( OR=3.317, 95% CI: 1.427-7.713, P=0.005), larger common bile duct diameter ( OR=1.117, 95% CI: 1.000-1.248, P=0.049), and solitary stones ( OR=11.135, 95% CI: 3.602-34.418, P<0.001) significantly increased the probability of spontaneous stones. In contrast, larger stone long diameter ( OR=0.539, 95% CI: 0.441-0.659, P<0.001) markedly decreased passage likelihood. Receiver operator characteristic (ROC) curve analysis demonstrated that the common bile duct diameter predicted spontaneous stone passage with an area under the curve (AUC) of 0.662, yielding sensitivity of 52.9% (37/70) and specificity of 73.6% (51/70) at a cutoff value of 9.5 mm. The common bile duct stone diameter achieved an AUC of 0.852 for predicting spontaneous stone passage, with sensitivity of 75.7% (53/70) and specificity of 89.0% (62/70) at a cutoff value of 4.5 mm. Conclusion:Solitary small stones, ductal dilation, and an admission diagnosis of acute biliary pancreatitis are key predictive factors for spontaneous common bile duct stone passage. A common bile duct diameter ≥9.5 mm and stone long diameter ≤4.5 mm are more likely to result in spontaneous stone passage.

Oral squamous cell carcinoma(OSCC)is a malignant lesion originating from the oral mucosal squamous epithelium,account-ing for over 80％of oral and maxillofacial malignancies.Key etiological factors include tobacco,alcohol abuse,and betel quid chewing.In China,its incidence has shown an overall upward trend,posing a significant threat to public health.OSCC exhibits high local invasive-ness,making early diagnosis critical for improving prognosis.Its clinical management requires close multidisciplinary collaboration among oral and maxillofacial surgery,head and neck surgery,radiation oncology,medical oncology,reconstructive surgery,radiology,patholo-gy,and nutritional support teams.Given the increasing disease burden of OSCC and rapid development of multidisciplinary collaborative models,an expert panel has formulated this integrated management consensus based on evidence-based medicine and extensive deliber-ation.Centered on the'Prevention-Screening-Diagnosis-Treatment-Rehabilitation'framework,the consensus provides comprehensive guidance for the entire disease course of OSCC patients,aiming to standardize clinical practice.