Kirsten rat sarcoma viral oncogene homolog(KRAS)protein inhibitors are a promising class of thera-peutics,but research on molecules that effectively penetrate the blood-brain barrier(BBB)remains limited,which is crucial for treating central nervous system(CNS)malignancies.Although molecular generation models have recently advanced drug discovery,they often overlook the complexity of bio-logical and chemical factors,leaving room for improvement.In this study,we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug effi-cacy and drug absorption properties.Our approach utilizes a variational autoencoder(VAE)generative model integrated with reinforcement learning for multi-objective optimization.This method specifically aims to enhance BBB permeability(BBBp)while maintaining high-affinity substructures of KRAS in-hibitors.To support this,we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models.Additionally,we introduce two novel metrics,the knowledge-integrated reproduction score(KIRS)and the composite diversity score(CDS),to assess structural performance and biological relevance.Retrospective validation with KRAS inhibitors,AMG510 and MRTX849,demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications.This study provides a robust framework for accelerating the structural enhancement of lead compounds,advancing the drug development process across diverse targets.

Objective To investigate and compare the effects of electroacupuncture and dexamethasone on lung function and histomorphology and behavior in the offspring of perinatal nicotine exposure(PNE)rats.Methods Twenty-four pregnant Sprague-Dawley rats were randomly divided into control,model,electroacupuncture shallow needling,and dexamethasone groups using the random number table method(n=6 rats per group).A pulmonary dysplasia model in offspring rats with PNE was prepared by cervicodorsal subcutaneous injection with nicotine,and successful establishment of the model was confirmed by demonstrating statistically significant differences in growth parameters,lung function,and lung morphology compared to the control group.From the sixth day of maternal conception,the control group received cervicodorsal subcutaneous injection with 0.9%sodium chloride solution(1 mg/kg once per day),and the remaining groups were similarly injected with nicotine(1 mg/kg once per day).Concurrent with the nicotine injections,the electroacupuncture shallow needling group received electroacupuncture interventions at the"Zusanli"(ST 36)acupoint on both sides once a day for 20 min.In contrast,the offspring rats in the dexamethasone group received intraperitoneal dexamethasone injections from postnatal day 8(1.5 mg/kg once per day for 3 days),with a later dose of 0.75 mg/kg once per day for 4 days.Following successful model establishment,four offspring per rat were retained in each group using the random number table method.Until the 21st day after the birth of the offspring,using the random number table method,one offspring randomly selected from the four retained offspring per rat in each group was assigned to growth parameter assessment including body weight,lung weight,and lung index;simultaneously,one offspring was randomly selected for pulmonary function which was detected by a small animal pulmonary function machine,with the parameters of forced vital capacity(FVC),functional residual capacity(FRC),dynamic lung compliance(Cdyn),peak expiratory flow(PEF),peak inspiratory flow(PIF),and airway resistance(RL);concurrently,one offspring was randomly selected for hematoxylin and eosin staining to observe the histomorphology of the lung tissue,alveolar numbers,and mean alveolar septal thickness;additionally,one offspring was randomly selected for Morris water maze testing to evaluate the effects of the two intervention methods on learning and memory capabilities in offspring rats with PNE.Results Compared with the control group,the body weight,lung weight,lung index,FVC,PEF,FRC,Cdyn,alveolar number,platform crossing times,target quadrant time percentage,and target quadrant path percentage in the Morris water maze experiment were significantly decreased in the offspring rats of the model group(P<0.01).In contrast,PIF,RL,average thickness of alveolar septa,and latency of the Morris water maze experiment were significantly increased in the offspring rats of the model group(P<0.01).Compared with the model group,both electroacupuncture shallow needling group and dexamethasone group exhibited significant increases in body weight,lung weight,lung index,FVC,PEF,FRC,Cdyn,and alveolar numbers(P<0.05,P<0.01),along with significant decreases in PIF,RL values,and mean alveolar septal thickness(P<0.01).However,in the Morris water maze experiment,compared with the model group,the electroacupuncture shallow needling group demonstrated significantly more platform crossing times and a higher target quadrant time percentage and target quadrant path percentage(P<0.01),coupled with reduced latency period(P<0.01),whereas the dexamethasone group showed no significant differences compared to the model group.Compared to the electroacupuncture shallow needling group,the dexamethasone group showed significantly less platform crossing times and a lower target quadrant time percentage and target quadrant path percentage,coupled with increased latency period(P<0.01).Conclusion Both electroacupuncture and dexamethasone demonstrated protective effects on lung development in PNE offspring rats by ameliorating lung histomorphology and pulmonary function.However,offspring receiving late,small-dose,short-course dexamethasone exhibited inferior learning and memory capabilities,whereas the electroacupuncture group showed significantly superior cognitive performance compared to the dexamethasone group.

Objective:To retrospectively analyze the pathogenic factors of retrograde peri-implantitis (RPI) and assess the effectiveness of treatment, and to provide clinicians evidence for the prevention and treatment of RPI.Methods:A total of 2 731 patients with missing teeth (4 016 implants) who underwent implant restoration in the Department of Stomatology, The First Affiliated Hospital of Wenzhou Medical University between January 2004 and December 2022 were included in the study. According to the diagnostic criteria of RPI, a total of 20 cases (23 implants) of RPI were collected, including 4 female (5 implants) and 16 male (18 implants), and the treatment medical records, intraoral photos and cone beam CT or oral panoramic radiographs records of each patient were collected. Each patient with RPI was treated accordingly and followed up regularly to evaluate its efficacy.Results:After treatment, the follow-up time for 20 patients with clinical symptoms of RPI was 13 (6, 40) months (1 month to 13 years), and the survival rate of the treated implants was 91% (21/23). There were 7 patients (8 implants) with inactive RPI, no clinical symptoms, no loosening of the implant, with normal occlusal load, and the disease was at the inactive stage and was not treated. The pulp vitality of the natural tooth adjacent to the implant was normal, and the implant could function normally. There were 13 patients (15 implants) with infected RPI, 1 patient (1 implant) had no loosening of the implant, and the periapical radiolucency of the implant disappeared after endodontic treatment of the natural tooth adjacent to the implant; 12 patients (14 implants) had clinical symptoms such as implant loosening, pus discharge, etc. Among them, 10 patients (12 implants) were successfully implanted in situ or in adjacent sites after removing the implants, and were successfully implanted after 3 to 20 months. Two patients(2 implants) were removed and no further implants were placed. Among them, 2 implants with infected RPI had cystic lesions, which was similar to natural root apex cysts.Conclusions:The etiology of RPI is related to inflammation of adjacent tooth root tips or bacterial residues from inflammatory lesions in the alveolar bone and bone augmentation. RPI can be treated by perfect root canal treatment of adjacent teeth, removal of inflammatory tissue, or simultaneous guided bone regeneration techniques.

Objective:To adapt the English version of exteroceptive body awareness questionnaire (EBA-q) into Chinese, and evaluate its reliability and validity in college students.Methods:English version EBA-q was translated and culturally adapted into Chinese, and the tests were administered from October to December 2024, with valid data collected from 1 071 college students. Item analysis, exploratory factor analysis, confirmatory factor analysis, criterion-related validity analysis, and reliability analysis were conducted by SPSS 23.0 and Mplus 8.3 softwares.Results:(1) The Chinese version of EBA-q contained seventeen items across five factors: visual awareness, tactile awareness, body coordination, awareness of body changes and awareness of clothing fit. The five-factor measurement model fitted the data well ( χ2/ df=2.24, CFI=0.95, TLI=0.94, RMSEA=0.05, SRMR=0.06). (2) The EBA-q scores were positively correlated with the scores of noticing, body listening, public self-consciousness, and private self-consciousness ( r=0.46, 0.36, 0.09, 0.25, all P<0.01). (3)The Cronbach's α coefficient, split-half reliability and test-retest reliability of the Chinese version of EBA-q were 0.79, 0.85 and 0.77, respectively(all P<0.01). Conclusion:The Chinese version of the EBA-q has demonstrated good reliability in assessing external body awareness among college students, but its validity requires further verification.

Objective·To construct truncations of CYLD,and to preliminarily analyze their effects on the proliferation of gastric cancer cells.Methods·TCGA,GTEx,and Kaplan-Meier Plotter databases were used to analyze the differences in the expression levels of CYLD between gastric cancer tissues and normal tissues,and their relationship with the prognosis of gastric cancer patients.Immunohistochemistry and Western blotting were used to detect the expression of CYLD in cancer tissues and adjacent noncancerous tissues.Western blotting and qRT-PCR were used to analyze the protein and mRNA expression levels of CYLD in gastric mucosal epithelial cells and gastric cancer cells.According to the sequence and structural characteristics of CYLD gene,primers were designed to construct its truncations.Their expression was detected and identified by agarose gel electrophoresis and Western blotting,and localization was observed by immunofluorescence.In the human gastric adenocarcinoma cells(AGS)with CYLD knockdown,blank NC was added to the control group,and the full-length CYLD,enzyme-inactivated mutant,and three truncated plasmids were added to the experimental group.The proliferation changes of cells in each group were detected by CCK-8 and plate cloning assays.Co-immunoprecipitation,deubiquitination,and Western blotting assays were performed to examine the binding ability of full-length CYLD,the enzyme-inactivated mutant,and the truncated variants to CAMK2A,the level of CAMK2A deubiquitination,and the expression of STAT3 and p-STAT3 proteins.Results·CYLD expression in normal gastric tissues and cells was significantly higher than in gastric cancer tissues and cells,and the prognosis of patients with high expression of CYLD was better.The truncations of human CYLD were successfully constructed,and full length CYLD,enzyme-inactivated mutant,and truncations were mainly localized in the cytoplasm.Knockdown of CYLD in gastric cancer cells significantly enhanced the proliferative ability of gastric cancer cells.Reconstitution of CYLD-knockdown cells with CYLD-WT,or truncated variants containing the CAP3 or USP domains significantly inhibited the proliferation of gastric cancer cells.In addition,CYLD bound to CAMK2A mediated K63 deubiquitination modification,and inhibited CAMK2A-induced phosphorylation of STAT3.Conclusion·The human CYLD truncation plasmids are successfully constructed,and the full length CYLD and its CAP3 and USP segments significantly inhibit the proliferation of gastric cancer cells.

Kirsten rat sarcoma viral oncogene homolog (KRAS) protein inhibitors are a promising class of therapeutics, but research on molecules that effectively penetrate the blood-brain barrier (BBB) remains limited, which is crucial for treating central nervous system (CNS) malignancies. Although molecular generation models have recently advanced drug discovery, they often overlook the complexity of biological and chemical factors, leaving room for improvement. In this study, we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties. Our approach utilizes a variational autoencoder (VAE) generative model integrated with reinforcement learning for multi-objective optimization. This method specifically aims to enhance BBB permeability (BBBp) while maintaining high-affinity substructures of KRAS inhibitors. To support this, we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models. Additionally, we introduce two novel metrics, the knowledge-integrated reproduction score (KIRS) and the composite diversity score (CDS), to assess structural performance and biological relevance. Retrospective validation with KRAS inhibitors, AMG510 and MRTX849, demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications. This study provides a robust framework for accelerating the structural enhancement of lead compounds, advancing the drug development process across diverse targets.

Purpose To compare the clinical and cardiovascular magnetic resonance(CMR)characteristics of hypertrophic cardiomyopathy(HCM)with and without diabetes mellitus,and to investigate the effect of diabetes mellitus on left ventricular remodeling in HCM patients.Materials and Methods A total of 96 HCM patients diagnosed with CMR in Chengdu Fifth People's Hospital from January 2021 to March 2023,retrospectively.They were divided into HCM with diabetes mellitus group(n=22)and HCM without diabetes mellitus group(n=74)according to whether they had diabetes mellitus.The clinical baseline and CMR data of HCM patients were analyzed,and left ventricular function and strain were compared between the two groups.Results The HCM group with diabetes mellitus was observed to have a significantly higher left ventricular mass index compared to HCM without diabetes mellitus group[(1.33±0.50)g/ml vs.(1.10±0.23)g/ml;t=3.002,P=0.003],along with a significantly lower left ventricular global circumferential strain[-19.69(-21.82,-17.06)%vs.-16.33(-20.84,-13.86)%;Z=543.000,P<0.05]and global longitudinal strain[(-8.69±3.94)%vs.(-10.74±3.62)%;t=2.227,P<0.05)].Furthermore,diabetes mellitus was identified as an independent factor associated with an increased left ventricular mass index(β=0.330,P<0.05)by multivariate linear regression analysis.Conclusion In patients with HCM,diabetes mellitus is independently associated with left ventricular remodeling.The global circumferential strain and longitudinal strain of HCM patients with diabetes mellitus decreases significantly,suggesting that diabetes mellitus has a significant impact on left ventricular strain in HCM patients.

Purpose: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has the potential to emerge as a distinct subtype. Several studies have compared the differences between HER2-low and HER2-0 breast cancers, but no consensus has been reached.Additionally, a biomarker to predict pathological complete response (pCR) rates in patients with HER2-low breast cancer remains to be identified. Methods: We collected data from 777 patients across three centers, stratifying them into HER2-low and HER2-0 groups. We compared differences in survival and pCR rates between the two groups and investigated potential biomarkers that could reliably predict pCR. Results: The study found that patients with HER2-0 breast cancer had higher pCR rates compared to patients with HER2-low tumors (289 patients [30.1%] vs. 475 patients [18.1%], p < 0.0001). Survival analysis showed no significant advantage for HER2-low tumors over HER2-0 breast cancers. Binary logistic analysis revealed that androgen receptor (AR) expression predicts poorer pCR rates in both the overall patient group and the HER2-0 breast cancer group (overall patients: odds ratio [OR], 0.479; 95% confidence interval [CI], 0.250–0.917; p = 0.026 and HER2-0 patients: OR, 0.267; 95% CI, 0.080–0.892; p = 0.032). In contrast, programmed death ligand 1 (PD-L1) expression was associated with more favorable pCR rates in the overall patient group (OR, 3.199; 95% CI, 1.020–10.037; p = 0.046). Conclusion There is currently insufficient evidence to classify HER2-low breast cancer as a distinct subtype. Our study revealed that AR expression, along with negative PD-L1 expression, contributes to lower pCR rates.

Purpose: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has the potential to emerge as a distinct subtype. Several studies have compared the differences between HER2-low and HER2-0 breast cancers, but no consensus has been reached.Additionally, a biomarker to predict pathological complete response (pCR) rates in patients with HER2-low breast cancer remains to be identified. Methods: We collected data from 777 patients across three centers, stratifying them into HER2-low and HER2-0 groups. We compared differences in survival and pCR rates between the two groups and investigated potential biomarkers that could reliably predict pCR. Results: The study found that patients with HER2-0 breast cancer had higher pCR rates compared to patients with HER2-low tumors (289 patients [30.1%] vs. 475 patients [18.1%], p < 0.0001). Survival analysis showed no significant advantage for HER2-low tumors over HER2-0 breast cancers. Binary logistic analysis revealed that androgen receptor (AR) expression predicts poorer pCR rates in both the overall patient group and the HER2-0 breast cancer group (overall patients: odds ratio [OR], 0.479; 95% confidence interval [CI], 0.250–0.917; p = 0.026 and HER2-0 patients: OR, 0.267; 95% CI, 0.080–0.892; p = 0.032). In contrast, programmed death ligand 1 (PD-L1) expression was associated with more favorable pCR rates in the overall patient group (OR, 3.199; 95% CI, 1.020–10.037; p = 0.046). Conclusion There is currently insufficient evidence to classify HER2-low breast cancer as a distinct subtype. Our study revealed that AR expression, along with negative PD-L1 expression, contributes to lower pCR rates.

Purpose: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has the potential to emerge as a distinct subtype. Several studies have compared the differences between HER2-low and HER2-0 breast cancers, but no consensus has been reached.Additionally, a biomarker to predict pathological complete response (pCR) rates in patients with HER2-low breast cancer remains to be identified. Methods: We collected data from 777 patients across three centers, stratifying them into HER2-low and HER2-0 groups. We compared differences in survival and pCR rates between the two groups and investigated potential biomarkers that could reliably predict pCR. Results: The study found that patients with HER2-0 breast cancer had higher pCR rates compared to patients with HER2-low tumors (289 patients [30.1%] vs. 475 patients [18.1%], p < 0.0001). Survival analysis showed no significant advantage for HER2-low tumors over HER2-0 breast cancers. Binary logistic analysis revealed that androgen receptor (AR) expression predicts poorer pCR rates in both the overall patient group and the HER2-0 breast cancer group (overall patients: odds ratio [OR], 0.479; 95% confidence interval [CI], 0.250–0.917; p = 0.026 and HER2-0 patients: OR, 0.267; 95% CI, 0.080–0.892; p = 0.032). In contrast, programmed death ligand 1 (PD-L1) expression was associated with more favorable pCR rates in the overall patient group (OR, 3.199; 95% CI, 1.020–10.037; p = 0.046). Conclusion There is currently insufficient evidence to classify HER2-low breast cancer as a distinct subtype. Our study revealed that AR expression, along with negative PD-L1 expression, contributes to lower pCR rates.