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.

Strengthening the cultivation of innovation ability is the new requirement put forward by the state for higher educa-tion.High-quality curriculum design is the primary means of achieving high-quality talent cultivation.By constructing the"disease case library"and"problem graph"of immune system and related diseases,and adopting the teaching method of"combining large and small cases and integrating online and offline",this study not only consolidates students'basic knowledge,but also builds a bridge for students from theory to practice,from knowledge accumulation to creation and application.It further exercises students'ability to dis-cover,analyze and solve problems,and enhances students'innovation awareness and ability.

Strengthening the cultivation of innovation ability is the new requirement put forward by the state for higher educa-tion.High-quality curriculum design is the primary means of achieving high-quality talent cultivation.By constructing the"disease case library"and"problem graph"of immune system and related diseases,and adopting the teaching method of"combining large and small cases and integrating online and offline",this study not only consolidates students'basic knowledge,but also builds a bridge for students from theory to practice,from knowledge accumulation to creation and application.It further exercises students'ability to dis-cover,analyze and solve problems,and enhances students'innovation awareness and ability.

OBJECTIVE: To investigate the effectiveness of tibial transverse transport (TTT) in treating Wagner grade 3-4 type 2 diabetic foot ulcers and analyze dynamic changes in immunoglobulin levels. METHODS: The clinical data of 68 patients with Wagner grade 3-4 type 2 diabetic foot ulcers treated with TTT between May 2022 and September 2023 was retrospectively analyzed. The cohort included 49 males and 19 females, aged 44-91 years (mean, 67.3 years), with 40 Wagner grade 3 and 28 grade 4 ulcers. The duration of type 2 diabetes ranged from 5 to 23 years, with an average of 10 years. The number of wound healing cases, healing time, amputation cases, death cases, and complications were observed and recorded. Serum samples were collected at 6 key time points [1 day before TTT and 3 days, 7 days (the first day of upward transverse transfer), 14 days (the first day of downward transverse transfer), 21 days (the first day after the end of transfer), 36 days (the first day after the removal of the transfer device)], and the serum immunoglobulin levels were detected by flow cytometry including immunoglobulin G (IgG), IgA, IgM, IgE, complement C3 (C3), C4, immunoglobulin light chain κ (KAP), immunoglobulin light chain λ (LAM). RESULTS: All the 68 patients were followed up 6 months. Postoperative pin tract infection occurred in 3 cases and incision infection in 2 cases. Amputation occurred in 5 patients (7.4%) at 59-103 days after operation, and 8 patients (11.8%) died at 49-77 days after operation; the wounds of the remaining 55 patients (80.9%) healed in 48-135 days, with an average of 80 days. There was no recurrence of ulcer, peri-osteotomy fracture, or local skin necrosis during follow-up. The serum immunoglobulin levels of 55 patients with wound healing showed that the levels of IgG and IgM decreased significantly on the 3rd and 7th day after operation compared with those before operation ( P<0.05), and gradually returned to the levels before operation after 14 days, and reached the peak on the 36th day. IgA levels continued to decrease with time, and there were significant differences at all time points when compared with those before operation ( P<0.05). The level of IgE significantly decreased at 21 days after operation compared with that before operation ( P<0.05), while it was higher at other time points than that before operation, but the difference was not significant ( P>0.05). The level of C3 showed a clear treatment-related increase, which was significantly higher on the 7th, 14th, and 21st days after operation than that before operation ( P<0.05), and the peak appeared on the 14th day. The change trend of C4 level was basically synchronous with that of C3, but the amplitude was smaller, and the difference was significant at 7 and 14 days after operation compared with that before operation ( P<0.05). There was no significant difference in KAP/LAM between different time points before and after operation ( P>0.05). CONCLUSION TTT can accelerate wound healing, effectively treat diabetic foot ulcer, and reduce amputation rate, and has definite effectiveness. The potential mechanisms of TTT in the treatment of diabetic foot ulcers include the dynamic regulation of IgG, IgA, IgM, and IgE levels to balance the process of inflammation and repair, and the periodic increase of C3 and C4 levels may promote tissue cleaning, angiogenesis, and anti-infection defense.
Humans ; Male ; Female ; Middle Aged ; Aged ; Diabetic Foot/immunology* ; Wound Healing ; Adult ; Retrospective Studies ; Aged, 80 and over ; Treatment Outcome ; Tibia/transplantation* ; Diabetes Mellitus, Type 2/complications* ; Amputation, Surgical ; Immunoglobulins/blood* ; Immunoglobulin G/blood*

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.

Objective To evaluate the application value of superb microvascular imaging(SMI)in pre-dicting ovarian cancer staging.Methods One hundred and thirty-six patients with ovarian cancer who under-went surgical treatment in our hospital from March 2019 to May 2024 were enrolled.Transvaginal,transab-dominal low-frequency,and transabdominal high-frequency two-dimensional grayscale imaging,Color Doppler Flow Imaging(CDFI),and SMI were performed before surgery for staging prediction.Taking surgical-patho-logical staging as the gold standard,the sensitivity,specificity,and accuracy of the combined application of transvaginal SMI,transabdominal low-frequency SMI,and transabdominal high-frequency SMI for predicting ovarian cancer staging were calculated.The receiver operating characteristic(ROC)curve was established,the area under the ROC curve(AUC)was calculated,and the diagnostic efficacy of SMI for predicting ovarian cancer staging was determined.Results The combined application of transvaginal SMI,transabdominal low-frequency SMI,and transabdominal high-frequency SMI for predicting ovarian cancer staging showed that sen-sitivity was 89.35%,92.36%,81.65%,and 83.21%for stages Ⅰ,Ⅱ,Ⅲ,Ⅳ,respectively;specificity was 86.93%,84.29%,83.39%,and 82.88%;accuracy was 92.50%,94.38%,80.15%,and 84.96%;and AUC was 0.799,0.760,0.695,and 0.727.Conclusion SMI has a high application value in predicting the stage of ovarian cancer,especially for stage Ⅰ and stage Ⅱ ovarian cancer.

Objective:To develop a risk assessment scale for infusion port occlusion in patients with malignant tumors and to test its reliability and validity.Methods:An initial item pool was constructed based on literature review. Through purposive sampling, two rounds of Delphi consultations with 20 experts were conducted from March to May 2023. Weights were assigned to the indicators using the analytic hierarchy process (AHP), and the risk assessment scale was finalized. From June to September 2023, a convenience sample of 278 malignant tumor patients with infusion ports from four Class Ⅲ Grade A hospitals in Shanxi Province was selected for item analysis and reliability and validity testing.Results:The risk assessment scale for infusion port occlusion in malignant tumor patients includes five dimensions, 16 primary indicators, and 35 secondary indicators. The content validity index at the scale level was 0.925, and at the item level ranged from 0.818 to 1.000. A total of five factors were extracted by exploratory factor analysis, with a cumulative contribution rate of 57.081% to the variance. The area under the receiver operating characteristic curve was 0.815, with a cutoff score of 24.50. The overall Cronbach's α coefficient was 0.910, and the split-half reliability coefficient was 0.762.Conclusions:The risk assessment scale for infusion port occlusion in malignant tumor patients demonstrates good reliability and validity, and has high predictive power, which provides a scientific basis for identifying high-risk populations in clinical settings.

Diabetic Retinopathy (DR) is a chronic, progressive and potentially harmful retinal microvascular disease that is associated with persistent hyperglycemia.Without timely and effective treatment, it will seriously damage the vision of patients and bring great inconvenience to their lives.The development of DR involves various mechanisms such as blood-retinal barrier damage, inflammation and neurodegeneration.Intraocular fluids, including aqueous humor and vitreous fluid, can directly reflect the changes in the intraocular environment and have a good indication of the progress of intraocular lesions.In recent years, the changes of various cytokines in intraocular fluid during the occurrence of DR and their influence on the disease course and their changes after treatment have been widely studied.This article focuses on the changes in angiogenesis-related cytokines such as vascular endothelial growth factor, placental growth factor, galectin-1, angiotensin 1 (Ang1), Ang2 and inflammation-related cytokines such as tumor necrosis factor-α, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, transforming growth factor-β, interleukin (IL)-1β, IL-6, IL-8, IL-10 in the intraocular fluid of DR patients, and the changes of these cytokines and the significance after treatment in patients with diabetic macular edema and proliferative DR to provide potential targets for exploring new and personalized clinical treatment and theoretical basis to improve the prognosis of patients with DR.

Objective:To analyze the clinical efficacy of the Yuying powder combined with the Huanglian Shangqing pill for the treatment of subacute thyroiditis (SAT) with cervical anterior pain as the main complaint, as well as its impact on serum pain factors and oxidative stress levels in patients.Methods:A prospective selection of 100 SAT patients with anterior cervical pain as the main complaint admitted to the Hebei Provincial Hospital of Traditional Chinese Medicine from January 2020 to May 2022 was conducted. They were randomly divided into two groups, with 50 patients in each group. The control group was treated with sustained-release diclofenac sodium tablets, while the observation group was treated with external application of the Yuying powder and internal administration of the Huanglian Shangqing pill. After 2 weeks of continuous treatment, the analgesic efficacy and adverse drug reactions of both groups were observed. The analgesic onset time of two groups of anterior cervical pain was compared. Two simplified McGill pain questionnaires before and after treatment [the SF-MPQ scores, including Pain Rating Index (PRI), Visual Analog Scale (VAS), and Current Pain Intensity (PPI) ], were compared; the traditional Chinese Medicine Syndrome Score, Serum Pain Factors levels [ tumor necrosis factor (TNF)- α, interleukin-1 β(IL-1β), prostaglandin E 2 (PGE 2), and nitric oxide (NO) ] and oxidative stress indicators [the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) ] were also compared. Results:The total effective rate of analgesia in the observation group [98.00%(49/50)] was significantly higher than that in the control group [82.00%(41/50)] ( P<0.05). The analgesic onset time in the observation group was significantly shorter than that in the control group ( P<0.05). After treatment, the scores of various components (PRI, VAS, PPI) and traditional Chinese medicine syndrome scores in the two groups of SF-MPQ were significantly reduced compared to before treatment (all P<0.05); and the decrease was more significant in the observation group (all P<0.05). After treatment, the serum levels of TNF -α, IL-1β, PGE 2, and NO in both groups significantly decreased compared to before treatment (all P<0.05), and the levels of serum pain inducing factors in the observation group were significantly lower than those in the control group (all P<0.05). After treatment, both groups showed a significant decrease in serum MDA content (all P<0.05), and a significant increase in serum SOD and GSH-Px levels (all P<0.05); And the improvement was more significant in the observation group (all P<0.05). The incidence of adverse reactions in the observation group [4.00%(2/50)] was lower than that in the control group [16.00%(8/50)] ( P<0.05). Conclusions:The overall efficacy of external application of Yuying powder combined with oral administration of Huanglian Shangqing pill in the treatment of SAT with cervical anterior pain as the main complaint is definite, and its effect may be related to significantly downregulating the expression level of serum related pain inducing factors in patients and reducing the level of oxidative stress in the body.

Objective To explore the predictive efficacy of three machine learning algorithms for carotid plaque stability in patients with cerebral infarction.Methods The clinical data of 500 pa-tients with cerebral infarction were retrospectively analyzed.Univariate analysis and multivariate anal-ysis were used to determine the predictive factors entering the model.The prediction model of carotid plaque stability in patients with cerebral infarction was constructed based on nomogram,decision tree and random forest respectively.The enrolled patients were randomly divided into training set and test set according to the ratio of 7∶3.Sensitivity,specificity,accuracy,recall,accuracy and area under the curve(AUC)were used to compare the application efficiency of the model.Results The AUC of the nomogram model for evaluating the stability of carotid plaque in patients with cerebral infarction in the training set was 0.910(95％CI,0.950 to 0.983),the sensitivity was 0.910,the specificity was 0.917,the accuracy was 0.886,the recall rate was 0.910,and the accuracy rate was 0.914.The AUC of the decision tree model for evaluating the stability of carotid plaque in patients with cerebral infarction in the training set was 0.932(95％CI,0.903 to 0.961),the sensitivity was 0.903,the specificity was 0.922,the accuracy was 0.891,the recall rate was 0.903,and the accuracy rate was 0.914.The AUC of the random forest model for evaluating the stability of carotid plaque in patients with cerebral infarction in the training set was 0.984(95％CI,0.970 to 0.998),the sensitivity was 0.972,the specificity was 0.995,the accuracy was 0.993,the recall rate was 0.972,and the ac-curacy was 0.986.Conclusion The model based on the random forest algorithm has a better pre-diction effect and stability in evaluating the stability of carotid plaque in patients with cerebral infarc-tion,and its prediction efficiency is better than that of the Nomogram and decision tree.