ObjectiveTo construct a risk prediction model for frequent acute exacerbations of chronic obstructive pulmonary disease （COPD） under disease-syndrome combination， thus providing decision support for precise clinical intervention. MethodsA total of 2 029 patients with acute exacerbations of COPD admitted to the First Affiliated Hospital of Anhui University of Chinese Medicine from January 2020 to August 2024 were retrospectively included. These patients were classified into groups of frequent acute exacerbations （≥2 times/year） and infrequent acute exacerbations （<2 times/year） according to the hospitalization times per year. Risk factors were screened by LASSO regression combined with logistic regression， and a nomogram model was constructed. The model performance was assessed based on the area under the curve （AUC）， calibration curves， and decision curve analysis （DCA）. ResultsThe differences in baseline characteristics between the frequent acute exacerbations group （1 196 cases） and infrequent acute exacerbations group （833 cases） were not statistically significant. LASSO regression combined with multivariate logistic regression screened the following independent risk factors： body mass index （BMI）， hospitalization days， number of smoking years， place of residence， use of noninvasive ventilators， oxygen-demanding therapy， liver cirrhosis， use of systemic glucocorticosteroids， and traditional Chinese medicine syndrome （phlegm and stasis obstructing the lung）. The nomogram model showed good discrimination and calibration in both the training set （AUC=0.748） and validation set （AUC=0.774）. ConclusionThe risk prediction model for frequent acute exacerbations of COPD， integrating traditional Chinese medicine syndrome， constructed in this study has high accuracy. It can provide a scientific basis for early clinical identification of high-risk patients and individualized intervention.

ObjectiveTo explore the mechanism of action of Wendantang on ApoE^-/- hyperlipidemic mice using non-targeted metabolomics technology. MethodsMale C57BL/6J mice served as the normal control group （n=6）， and they were fed with regular chow， while male ApoE^-/- mice constituted the high-fat group （n=30）， and they were fed with a 60% high-fat diet. After 11 weeks of model establishment， the mice in the high-fat group were randomly divided into the model group， simvastatin group （3.3 mg·kg^-1）， and high-dose， medium-dose， and low-dose groups of Wendantang （26， 13， 6.5 g·kg^-1， respectively， in terms of crude drug amount）， with six mice in each group. The normal control group and the model group were gavaged with an equivalent volume of normal saline， and all groups continued to be fed their respective diets， receiving daily medication for 10 weeks with weekly body weight measurements. Serum levels of total cholesterol （TC）， triglycerides （TG）， high-density lipoprotein cholesterol （HDL-C）， low-density lipoprotein cholesterol （LDL-C）， free fatty acids （NEFA）， blood glucose （GLU）， alanine aminotransferase （ALT）， and aspartate aminotransferase （AST） were detected in the mice. Pathological changes in liver tissue were observed using hematoxylin-eosin （HE） staining， and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF-MS/MS） was employed for metabolomic analysis of mouse liver tissue. ResultsCompared to the normal control group， the model group exhibited significantly increased body weight， blood lipid levels， and liver function （P<0.05， P<0.01）， with disordered liver tissue structure， swollen hepatocytes， and accompanying vacuolar fatty degeneration and inflammatory cell infiltration. Compared to the model group， the simvastatin group and Wendantang groups showed significantly reduced body weight， TG， NEFA， GLU， ALT， and AST levels （P<0.05， P<0.01）， with a significant increase in HDL-C levels （P<0.05， P<0.01）， demonstrating a dose-dependent effect. The lesion of the liver tissue section was obviously improved after administration， tending towards a normal liver tissue morphology. Analysis of liver metabolites revealed 86 differential metabolites between the normal control group and the model group， with the high-dose group of Wendantang able to regulate 56 of these metabolites. Twenty-two differential metabolites associated with hyperlipidemia were identified， mainly including chenodeoxycholic acid， hyocholic acid， taurine， glycocholic acid， dihydroceramide， hydroxy sphingomyelin C14∶1， arachidonic acid， and linoleic acid， enriching 22 metabolic pathways， with 4 being the most significant （P<0.05）， namely primary bile acid biosynthesis， sphingolipid metabolism， unsaturated fatty acid biosynthesis， and linoleic acid metabolism pathways. ConclusionWendantang can improve blood lipid levels and liver function in ApoE^-/- hyperlipidemic mice， which may be related to the regulation of primary bile acid biosynthesis， sphingolipid metabolism， unsaturated fatty acid biosynthesis， and linoleic acid metabolism pathways.

BACKGROUND:Type 2 diabetes mellitus impairs renal function,and studies have shown that exercise interventions can protect the kidneys.Irisin can protect renal function in diabetic nephropathy patients by restoring autophagy through inhibition of the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)signaling pathway. OBJECTIVE:To explore whether exercise can restore autophagy and ameliorate renal injury by inhibiting over-activation of the renal PI3K/Akt/mTOR signaling pathway,as well as to analyze the differences in the effects of different modalities of exercise. METHODS:Six-week-old Sprague-Dawley rats were randomly divided into a blank control group(normal rats)and a diabetic group,and then the diabetic group was randomly divided into a diabetic model group,a moderate-intensity continuous exercise group,and a high-intensity intermittent exercise group after successful modeling using high-fat,high-sugar feeding plus intraperitoneal administration of low-dose 1%streptozotocin(30 mg/kg).The two exercise groups were subjected to 8 weeks of exercise intervention with different exercise intensities.The fasting blood glucose concentration was detected by glucose oxidase method,glycated hemoglobin levels was measured using a kit,serum insulin concentration was detected by Elisa method,and insulin resistance index was calculated.Gene expression of PI3K,AKT,mTOR,Beclin-1,podocin,and nephrin was detected by RT-PCR.Protein expression of mTOR and autophagy marker proteins LC3-1,LC3-2,and Beclin-1 was detected by western blot RESULTS AND CONCLUSION:Fasting blood glucose and glycosylated hemoglobin levels were highly significantly increased,insulin resistance levels were significantly increased,and insulin levels were significantly decreased in type 2 diabetic rats.Both exercises resulted in highly significant decreases in fasting blood glucose and glycosylated hemoglobin levels,significant decreases in insulin resistance levels and significant increases in insulin levels in type 2 diabetic rats.Insulin levels were significantly higher in the high-intensity intermittent exercise group compared with the moderate-intensity continuous exercise group.The expression of podocin and nephrind genes was significantly reduced in type 2 diabetic rats and two different forms of exercise significantly the gene expression.There was a further trend toward an increase in gene expression of podocyte-associated proteins in the moderate-intensity continuous exercise group compared with the high-intensity intermittent exercise group,but there was no significant difference.The mRNA and protein expression of PI3K,AKT and mTORC1 in kidney tissues of type 2 diabetic rats were significantly increased,and the expression of autophagy marker proteins Beclin-1 and LC3-2 and LC3-2/LC3-1 were significantly decreased.Both different forms of exercise significantly decreased the mRNA and protein expression of PI3K,AKT,and mTORC1,and significantly increased the autophagy marker proteins Beclin-1,LC3-2,and LC3-2/LC3-1 in renal tissues.Compared with the moderate-intensity continuous exercise group,there was a trend toward further decreases in mRNA expression of PI3K,AKT,and mTORC1 and protein expression of mTOR,and a trend toward further elevation of Beclin-1,LC3-2,and LC3-2/LC3-1 in the high-intensity intermittent exercise group,but only Beclin-1 showed a significant difference between groups.In summary,renal podocyte injury in type 2 diabetes mellitus with suppressed autophagy is closely related to aberrant activation of the PI3K/AKT/mTORC1 signaling pathway.Both moderate-intensity continuous exercise and high-intensity intermittent exercise can protect the diabetic kidney,reduce podocyte damage,and restore renal podocyte autophagy,which may be achieved by inhibiting the excessive activation of the PI3K/AKT/mTOR signaling pathway.High-intensity intermittent exercise shows a trend toward more favorable restoration of autophagy compared with moderate-intensity continuous exercise,but with a slight decrease in podocyte protein expression.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent type of cancer with a high mortality rate in its late stages. One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor (EGFR) inhibitors. Therefore, it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy. METHODS: To evaluate the efficacy of the combination of the Ca 2+ /calmodulin-dependent protein kinase II (CAMK2) inhibitor KN93 and EGFR inhibitors, we performed in vitro and in vivo experiments using two FAT atypical cadherin 1 ( FAT1 )-deficient (SCC9 and SCC25) and two FAT1 wild-type (SCC47 and HN12) OSCC cell lines. We assessed the effects of EGFR inhibitors (afatinib or cetuximab), KN93, or their combination on the malignant phenotype of OSCC in vivo and in vitro . The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2 (SOX2) were analyzed. Changes in the yes-associated protein 1 (YAP1) protein were characterized. Moreover, we analyzed mitochondrial dysfunction. Besides, the effects of combination therapy on mitochondrial dynamics were also evaluated. RESULTS: OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment. The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation, survival, and migration of FAT1 -mutated OSCC cells and suppressed tumor growth in vivo . Mechanistically, combination therapy enhanced the therapeutic sensitivity of FAT1 -mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins. Furthermore, combination therapy induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics, ultimately resulting in tumor suppression. CONCLUSION Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.
Humans ; ErbB Receptors/metabolism* ; Mouth Neoplasms/metabolism* ; Cell Line, Tumor ; Animals ; Drug Resistance, Neoplasm/genetics* ; Cadherins/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Mice ; Mutation/genetics* ; Mice, Nude ; Protein Kinase Inhibitors/therapeutic use* ; Cetuximab/pharmacology* ; Afatinib/therapeutic use* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects*

BACKGROUND: Inflammation plays a critical role in severe cerebral venous thrombosis (CVT) pathogenesis, but the benefits of anti-inflammatory therapies remain unclear. This study aimed to investigate the association between steroid therapy combined with anticoagulation and the prognosis of acute/subacute severe CVT patients. METHODS: A prospective cohort study enrolled patients with acute/subacute severe CVT at Xuanwu Hospital (July 2020-January 2024). Patients were allocated into steroid and non-steroid groups based on the treatment they received. Functional outcomes (modified Rankin scale [mRS]) were evaluated at admission, discharge, and 6 months after discharge. Serum high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), cerebrospinal fluid (CSF) IL-6, and intracranial pressure were measured at admission and discharge in the steroid group. Fundoscopic Frisén grades were assessed at admission and 6 months after discharge. Univariate and multivariate logistic regression were used to evaluat associations between steroid use and favorable outcomes (mRS ≤2) at the 6-month follow-up. Paired tests assessed changes in hs-CRP and other variables before and after treatment, and Spearman's correlations were used to analyze relationships between these changes and functional improvements. RESULTS: A total of 107 and 58 patients in the steroid and non-steroid groups, respectively, were included in the analysis. Compared with the non-steroid group, the steroid group had a higher likelihood of achieving an mRS score of 0-2 (93.5% vs . 82.5%, odds ratio [OR] = 2.98, P  = 0.037) at the 6-month follow-up. After adjusting for confounding factors, the result remained consistent. Pulsed steroid therapy did not increase mortality during hospitalization or follow-up, nor did it lead to severe steroid-related complications (all P  >0.05). Patients in the steroid group showed a significant reduction in serum hs-CRP, IL-6, CSF IL-6, and intracranial pressure at discharge compared to at admission, as well as a significant reduction in the fundoscopic Frisén grade at the 6-month follow-up compare to at admission (all P  <0.001). A reduction in serum inflammatory marker levels during hospitalization positively correlated with improvements in functional outcomes ( P  <0.05). CONCLUSION: Short-term steroid use may be an effective and safe adjuvant therapy for acute/subacute severe CVT when used alongside standard anticoagulant treatments, which are likely due to suppression of the inflammatory response. However, these findings require further validation in randomized controlled trials. TRAIL REGISTRATION ClinicalTrials.gov , NCT05990894.
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Anticoagulants/therapeutic use* ; C-Reactive Protein/metabolism* ; Interleukin-6/metabolism* ; Intracranial Thrombosis/drug therapy* ; Prospective Studies ; Steroids/therapeutic use* ; Venous Thrombosis/drug therapy*

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

ObjectiveTo explore the construction of a machine learning model for the diagnosis of traditional Chinese medicine （TCM） syndromes in chronic cough and the optimization of this model using the Voting ensemble algorithm. MethodsA retrospective analysis was conducted using clinical data from 921 patients with chronic cough treated at the Respiratory Department of Dongfang Hospital， Beijing University of Chinese Medicine. After standardized processing， 84 clinical features were extracted to determine TCM syndrome types. A specialized dataset for TCM syndrome diagnosis in chronic cough was formed by selecting syndrome types with more than 50 cases. The synthetic minority over-sampling technique （SMOTE） was employed to balance the dataset. Four base models， logistic regression （LR）， decision tree （dt）， multilayer perceptron （MLP）， and Bagging， were constructed and integrated using a hard voting strategy to form a Voting ensemble model. Model performance was evaluated using accuracy， recall， precision， F1-score， receiver operating characteristic （ROC） curve， area under the curve （AUC）， and confusion matrix. ResultsAmong the 921 cases， six syndrome types had over 50 cases each， phlegm-heat obstructing the lung （294 cases）， wind pathogen latent in the lung （103 cases）， cold-phlegm obstructing the lung （102 cases）， damp-heat stagnating in the lung （64 cases）， lung yang deficiency （54 cases）， and phlegm-damp obstructing the lung （53 cases）， yielding a total of 670 cases in the specialized dataset. High-frequency symptoms among these patients included cough， expectoration， odor-induced cough， throat itchiness， itch-induced cough， and cough triggered by cold wind. Among the four base models， the MLP model showed the best diagnostic performance （test accuracy： 0.9104； AUC： 0.9828）. Compared with the base models， the Voting ensemble model achieved superior performance with an accuracy of 0.9289 on the training set and 0.9253 on the test set， showing a minimal overfitting gap of 0.0036. It also achieved the highest AUC （0.9836） in the test set， outperforming all base models. The model exhi-bited especially strong diagnostic performance for damp-heat stagnating in the lung （AUC： 0.9984） and wind pathogen latent in the lung （AUC： 0.9970）. ConclusionThe Voting ensemble algorithm effectively integrates the strengths of multiple machine learning models， resulting in an optimized diagnostic model for TCM syndromes in chronic cough with high accuracy and enhanced generalization ability.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.