Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Objective To investigate the expression characteristics and clinical significance of endothelial cell-derived extracellular vesicles(EC-EVs)in the peripheral blood of patients with sep-sis-induced cardiomyopathy(SIC).Methods A total of 143 sepsis patients were enrolled and divid-ed into cardiomyopathy group(n=72)and non-cardiomyopathy group(n=71)based on occurrence of SIC.Peripheral blood samples were collected from patients in both groups upon admission for isola-tion and identification of EC-EVs.The number of EC-EVs,apoptosis,and the activity and expression levels of caspase-1 in EC-EVs were compared between the two groups.Spearman correlation analysis was used to assess the correlations of the number of EC-EVs,caspase-1 activity,and N-terminal pro-brain natriuretic peptide(NT-proBNP)with cardiac troponin Ⅰ(cTnⅠ).Multivariable Logistic regres-sion analysis was conducted to explore the factors influencing the occurrence of SIC in sepsis patients.Receiver operating characteristic(ROC)curves were plotted to analyze the predictive value of the number of EC-EVs and caspase-1 activity for SIC.Results EC-EVs with a diameter of approximately 100 nm,intact membrane structure,and expression of extracellular vesicles(EVs)marker molecules(CD9,CD63,CD81)were successfully isolated from samples in both groups.The cardiomyopathy group had significantly higher numbers of EC-EVs in peripheral blood,EC-EV apoptosis levels,caspase-1 activity,and protein expression levels compared to the non-cardiomyopathy group(P＜0.05).Spearman correlation analysis revealed positive correlations between the number of EC-EVs and NT-proBNP(r=0.603,0.685,P＜0.001),and between caspase-1 activity and cTnⅠ(r=0.474,0.711,P＜0.001).Multivariable Logistic regression analysis showed that the number of EC-EVs,caspase-1 activity,NT-proBNP levels,and cTnⅠ levels were all independent influencing factors for the occurrence of SIC in sepsis patients(P＜0.05).The ROC curves indicated that the areas under the curve for predicting SIC based on the number of EC-EVs and caspase-1 activity in peripheral blood were 0.721 and 0.858,respectively.Conclusion The number of EC-EVs and caspase-1 activity in EC-EVs in the peripheral blood of SIC patients are significantly increased,and are closely related to cardiac function and myocardial injury in sepsis patients.Thus,they have the potential to become biomarkers for predicting SIC.

Objective To summarize and analyze the clinical and imaging features in patients with initial onset of anti-myelin oli-godendrocyte glycoprotein-IgG(MOG-IgG)associated disease(MOGAD).Methods The clinical and MRI data of 39 patients with serum MOG-IgG positive were analyzed retrospectively.Clinical features(including history of prior infection,initial symptoms and clinical phenotypes,cerebrospinal fluid examination,and serum antibody levels)and location,distribution,and enhancement patterns of lesions were all compared between adult and pediatric groups.Results Blurred vision was the most common initial symptom,with no statistically significant difference between the two groups.Compared to the adult group,the pediatric group more frequently presented with acute disseminated encephalomyelitis(ADEM)as the clinical phenotype.There were no statistically significant differ-ences between the two groups in cerebrospinal fluid examination results,including leukocyte count,protein content,and oligoclonal bands(OCB)positive.The pediatric group showed a higher prevalence of lesions in the cortical and subcortical white matter,deep white matter,and basal ganglia regions compared with the adult group.There was no statistically significant difference in the inci-dence of optic neuritis between the two groups.Spinal cord inflammation predominantly affected the cervical and thoracic segments,with central gray matter involvement presenting as the"H-sign".Conclusion The clinical and imaging features of MOGAD exhibit certain variations across different patient populations.Accurate recognition and early diagnosis of MOGAD and prompt examination and treatment are instrumental in improving patients'prognosis.

Objectives:To investigate the predictive value of the hemoglobin to serum creatinine ratio(Hb/SCr)for all-cause mortality within 3 years after percutaneous coronary intervention(PCI)in patients with ST-segment elevation myocardial infarction(STEMI).Methods:A total of 687 STEMI patients who successfully underwent the first PCI at the Department of Cardiology,Gansu Provincial People's Hospital,from June 2016 to June 2020 were retrospectively enrolled.Patients were divided into survival and non-survival groups according to their vital status at 3 years post-PCI.Cox regression analysis was performed to identify predictive factors of all-cause mortality.Receiver operating characteristic(ROC)curves were constructed to evaluate the predictive value of Hb/SCr for all-cause mortality,and Kaplan-Meier survival curves were used to compare cumulative survival rates between subgroups stratified by Hb/SCr levels.Results:The median follow-up duration was 37(25,50)months.Among the 663 patients(96.51%)with complete follow-up data,41 cases(6.18%)experiencing all-cause death.Multivariable Cox regression analysis revealed that age(HR=1.086,95%CI:1.037-1.137,P=0.000),body mass index(HR=1.195,95%CI:1.128-1.266,P=0.000),fasting blood glucose(HR=1.069,95%CI:1.007-1.135,P=0.030),fibrinogen(HR=1.418,95%CI:1.120-1.795,P=0.004),TIMI flow grade 1(HR=4.968,95%CI:1.194-20.667,P=0.028),TIMI flow grade 2(HR=3.861,95%CI:1.336-11.156,P=0.013),and Hb/SCr(HR=0.858,95%CI:0.766-0.961,P=0.008)were the independent predictors of all-cause mortality.ROC curve analysis demonstrated that the area under the curve(AUC)of Hb/SCr was 0.721(95%CI:0.645-0.798)for predicting all-cause mortality,with a sensitivity of 65.9%and specificity of 71.2%,at the optimal cut-offvalue of 16.627.Kaplan-Meier analysis showed that patients with Hb/SCr<16.627 had significantly lower survival rates than those with Hb/SCr≥16.627(log-rank P=0.000).Conclusions:Hb/SCr is an independent predictor of 3-year all-cause mortality in STEMI patients after PCI and this indicator could be used as risk stratification parameter and patients with lower Hb/SCr might benefit comprehensive post-PCI management to improve their outcome.

Objective To summarize and analyze the clinical and imaging features in patients with initial onset of anti-myelin oli-godendrocyte glycoprotein-IgG(MOG-IgG)associated disease(MOGAD).Methods The clinical and MRI data of 39 patients with serum MOG-IgG positive were analyzed retrospectively.Clinical features(including history of prior infection,initial symptoms and clinical phenotypes,cerebrospinal fluid examination,and serum antibody levels)and location,distribution,and enhancement patterns of lesions were all compared between adult and pediatric groups.Results Blurred vision was the most common initial symptom,with no statistically significant difference between the two groups.Compared to the adult group,the pediatric group more frequently presented with acute disseminated encephalomyelitis(ADEM)as the clinical phenotype.There were no statistically significant differ-ences between the two groups in cerebrospinal fluid examination results,including leukocyte count,protein content,and oligoclonal bands(OCB)positive.The pediatric group showed a higher prevalence of lesions in the cortical and subcortical white matter,deep white matter,and basal ganglia regions compared with the adult group.There was no statistically significant difference in the inci-dence of optic neuritis between the two groups.Spinal cord inflammation predominantly affected the cervical and thoracic segments,with central gray matter involvement presenting as the"H-sign".Conclusion The clinical and imaging features of MOGAD exhibit certain variations across different patient populations.Accurate recognition and early diagnosis of MOGAD and prompt examination and treatment are instrumental in improving patients'prognosis.

Objective:To screen risk factors for ICU-acquired weakness in patients with mechanical ventilation and construct a predictive model, so as to provide a basis for the health management of patients with mechanical ventilation.Methods:Convenience sampling was used to select 312 ICU patients with mechanical ventilation admitted to the Tenth People's Hospital of Tongji University from October 2019 to August 2020 for the study. Patients were divided into training set ( n=220) and test set ( n=92) in a 7∶3 ratio. Based on machine learning algorithms, decision random forest (DRF), extremely-randomized trees (XRT) and generalized linear model (GLM) were used to construct three ICU-acquired weakness risk prediction models for patients with mechanical ventilation, respectively. The performance of the prediction model was evaluated using the area under the receiver operating characteristic curve ( AUC), the area under the precision-recall curve ( AUPRC), and the root mean square error ( RMSE) . Results:There were 7 predictors of risk of ICU-acquired weakness in patients with mechanical ventilation, including age, gender, braking, duration of mechanical ventilation, blood glucose, lactic acid, and parenteral nutrition. Test set and training set validation showed that AUC and AUPRC of GLM prediction model were greater than those of DRF, XRT prediction model. Test set validation indicated that the RMSE, logarithmic loss of GLM prediction model was less than those of DRF, XRT prediction model. Conclusions:Machine learning algorithm based GLM prediction model has good prediction performance. Healthcare professionals can construct evidence-based decisions for interventions in areas such as braking, duration of mechanical ventilation, and blood glucose management.

Objectives:To investigate the predictive value of the hemoglobin to serum creatinine ratio(Hb/SCr)for all-cause mortality within 3 years after percutaneous coronary intervention(PCI)in patients with ST-segment elevation myocardial infarction(STEMI).Methods:A total of 687 STEMI patients who successfully underwent the first PCI at the Department of Cardiology,Gansu Provincial People's Hospital,from June 2016 to June 2020 were retrospectively enrolled.Patients were divided into survival and non-survival groups according to their vital status at 3 years post-PCI.Cox regression analysis was performed to identify predictive factors of all-cause mortality.Receiver operating characteristic(ROC)curves were constructed to evaluate the predictive value of Hb/SCr for all-cause mortality,and Kaplan-Meier survival curves were used to compare cumulative survival rates between subgroups stratified by Hb/SCr levels.Results:The median follow-up duration was 37(25,50)months.Among the 663 patients(96.51%)with complete follow-up data,41 cases(6.18%)experiencing all-cause death.Multivariable Cox regression analysis revealed that age(HR=1.086,95%CI:1.037-1.137,P=0.000),body mass index(HR=1.195,95%CI:1.128-1.266,P=0.000),fasting blood glucose(HR=1.069,95%CI:1.007-1.135,P=0.030),fibrinogen(HR=1.418,95%CI:1.120-1.795,P=0.004),TIMI flow grade 1(HR=4.968,95%CI:1.194-20.667,P=0.028),TIMI flow grade 2(HR=3.861,95%CI:1.336-11.156,P=0.013),and Hb/SCr(HR=0.858,95%CI:0.766-0.961,P=0.008)were the independent predictors of all-cause mortality.ROC curve analysis demonstrated that the area under the curve(AUC)of Hb/SCr was 0.721(95%CI:0.645-0.798)for predicting all-cause mortality,with a sensitivity of 65.9%and specificity of 71.2%,at the optimal cut-offvalue of 16.627.Kaplan-Meier analysis showed that patients with Hb/SCr<16.627 had significantly lower survival rates than those with Hb/SCr≥16.627(log-rank P=0.000).Conclusions:Hb/SCr is an independent predictor of 3-year all-cause mortality in STEMI patients after PCI and this indicator could be used as risk stratification parameter and patients with lower Hb/SCr might benefit comprehensive post-PCI management to improve their outcome.

Objective:To screen risk factors for ICU-acquired weakness in patients with mechanical ventilation and construct a predictive model, so as to provide a basis for the health management of patients with mechanical ventilation.Methods:Convenience sampling was used to select 312 ICU patients with mechanical ventilation admitted to the Tenth People's Hospital of Tongji University from October 2019 to August 2020 for the study. Patients were divided into training set ( n=220) and test set ( n=92) in a 7∶3 ratio. Based on machine learning algorithms, decision random forest (DRF), extremely-randomized trees (XRT) and generalized linear model (GLM) were used to construct three ICU-acquired weakness risk prediction models for patients with mechanical ventilation, respectively. The performance of the prediction model was evaluated using the area under the receiver operating characteristic curve ( AUC), the area under the precision-recall curve ( AUPRC), and the root mean square error ( RMSE) . Results:There were 7 predictors of risk of ICU-acquired weakness in patients with mechanical ventilation, including age, gender, braking, duration of mechanical ventilation, blood glucose, lactic acid, and parenteral nutrition. Test set and training set validation showed that AUC and AUPRC of GLM prediction model were greater than those of DRF, XRT prediction model. Test set validation indicated that the RMSE, logarithmic loss of GLM prediction model was less than those of DRF, XRT prediction model. Conclusions:Machine learning algorithm based GLM prediction model has good prediction performance. Healthcare professionals can construct evidence-based decisions for interventions in areas such as braking, duration of mechanical ventilation, and blood glucose management.

Objective To investigate the effect of CXXC finger protein 4 (CXXC4) on the proliferation and apoptosis of pancreatic cancer PANC-1 cells.Methods The expression level of CXXC4 in pancreatic canc-er tissues and its relationship with prognosis and clinicopathological stage of the patients were analyzed in on-line databases.The qRT-PCR technique was used to detect the mRNA expression level of CXXC4 in human normal pancreatic ductal epithelial cell line (HPNE) and pancreatic cancer cell PANC-1,AsPC-1 and BxPC-3. si-NC,si-CXXC4,pcDNA3.1 and pCDNA3.1-CXXC4 were respectively transfected into PANC-1 cells.West-ern blot was conducted to detect the effectiveness of CXXC4 knockdown and overexpression.CCK-8,colony formation,EdU and immunofluorescence assays were conducted to analyze the effect of CXXC4 knockdown or overexpression on the proliferation and apoptosis of PANC-1 cells.The bioinformatic websites was used to predict the upstream microRNA (miRNA) of CXXC4.The Starbase database was adopted to analyze the cor-relation between miR-450b-5p and CXXC4 expression in pancreatic cancer tissues.Results The TCGA data-base results showed that the expression of CXXC4 in pancreatic cancer tissues was lowly expressed compared with in paracancerous pancreatic tissues (P<0.001),moreover which was associated with the overall survival and poor prognosis in the patients with pancreatic cancer (P<0.05).The GEPIA database analysis results showed that compared with stage Ⅰ pancreatic cancer,the CXXC4 expression in stage Ⅱ pancreatic cancer was decreased (P<0.05).Compared with HPNE cells,the CXXC4 expression in 3 kinds of pancreatic cancer cells was decreased (P<0.05).Compared with the si-NC group,the proliferation and colony formation ability of PANC-1 cells in the si-CXXC4 group were enhanced,the expressions of proliferation markers Ki67 and PC-NA were increased,and the expressions of apoptosis markers Bax,caspase-3 and caspase-9 were decreased;compared with the pcDNA3.1 group,the PANC-1 cells in the pcDNA3.1-CXXC4 group obtained the opposite results (all P<0.05).The bioinformatic websites predicted that miR-450b-5p was the upstream miRNA of CXXC4,CXXC4 in pancreatic cancer tissues was negatively correlated with the miR-450b-5p expression (r=-0.227) and miR-450b-5p in various mammalian species was highly conserved.Conclusion CXXC4 inhibits the proliferation of PANC-1 cells in pancreatic cancer and promotes theirs apoptosis.

Objective:To investigate the dynamic changes of oral saliva flow, pH value, and bacterial flora before and after radiotherapy in patients with nasopharyngeal carcinoma (NPC) treated with intensity modulated radiotherapy, and to analyze the influencing factors of severe radioactive oral mucositis.Methods:One hundred NPC patients who received radiotherapy for the first time in the Head and Neck Radiotherapy Ward of Shandong Cancer Hospital and Institute from June 2, 2021 to December 30, 2022 were selected. Oral saliva flow, pH value and bacterial flora were measured at 5 time points, namely before radiotherapy, 15 times of radiotherapy, 35 times of radiotherapy, 1 month and 3 months after radiotherapy in patients with NPC, and the dynamic changes of 3 indicators were analyzed at each time. The factors of the occurrence of severe radioactive oral mucositis in patients with NPC were analyzed by univariate and multivariate logistic regression 15 times of radiotherapy.Results:The saliva flow of patients with NPC before radiotherapy, 15 times of radiotherapy, 35 times of radiotherapy, 1 month after and 3 months after radiotherapy were (16.51±1.29), (8.64±1.31), (5.15±1.14), (4.78±1.36) and (5.67±1.27) ml, respectively, with a statistically significant difference ( F=2 171.94, P<0.001). Oral saliva flow decreased to the lowest level 1 month after radiotherapy and then increased (all P<0.05). The pH values of patients with NPC before radiotherapy, 15 times of radiotherapy, 35 times of radiotherapy, 1 month after and 3 months after radiotherapy were 8.28±0.67, 5.87±0.53, 5.32±0.55, 6.04±0.83, 6.74±0.63, respectively, with a statistically significant difference ( F=370.43, P<0.001). The pH value decreased successively after 15 and 35 times of radiotherapy, and gradually increased 1 month and 3 months after radiotherapy (all P<0.05). There was a statistically significant difference ( χ2=18.24, P<0.001) in the detection rate of pathogenic bacteria in patients with NPC before radiotherapy (6%, 6/100), 15 times of radiotherapy (62%, 62/100), 35 times of radiotherapy (60%, 60/100), 1 month after radiotherapy (40%, 40/100) and 3 months after radiotherapy (29%, 29/100). Compared with before radiotherapy, there were statistically significant differences in the detection rates of pathogenic bacteria between 15 times of radiotherapy and 35 times of radiotherapy ( χ2=1.90, P=0.001; χ2=1.63, P=0.005). There was no statistically significant difference in the detection rate of pathogenic bacteria between 15 times of radiotherapy and 35 times of radiotherapy ( χ2=0.27, P=0.644). Compared with before radiotherapy, there was no statistically significant difference in the detection rate of pathogenic bacteria 1 month after radiotherapy and 3 months after radiotherapy ( χ2=1.30, P=0.024; χ2=0.83, P=0.149). Of 100 cases of NPC radiotherapy, 70 patients developed severe radiation oral mucositis (≥ grade 3). There were statistically significant differences in severe radioactive oral mucositis among patients with different smoking history ( χ2=8.84, P=0.003), alcohol drinking ( χ2=23.94, P<0.001), chemotherapy ( χ2=40.41, P<0.001), oral hygiene ( χ2=8.16, P=0.004), oral pH ( χ2=16.83, P<0.001) and oral pathogens ( χ2=8.80, P=0.003). Multivariate analysis showed that, alcohol drinking ( OR=2.23, 95% CI: 1.98-6.04, P=0.006), chemotherapy ( OR=3.13, 95% CI: 2.62-6.87, P<0.001) and oral pathogens ( OR=3.11, 95% CI: 1.04-9.31, P=0.043) were independent influencing factors for the occurrence of severe radioactive oral mucositis in NPC patients with radiotherapy. Conclusion:The oral saliva flow of patients with NPC decreases gradually from the beginning of radiotherapy to the lowest 1 month after radiotherapy and then increases. The pH value gradually decreases from the beginning of radiotherapy to 35 times of radiotherapy, and gradually increases from 1 month to 3 months after radiotherapy. The detection rate of pathogenic bacteria increases rapidly from the beginning of radiotherapy to 15 times of radiotherapy, and the growth rate is stable from 15 times of radiotherapy to 35 times of radiotherapy, and tended to be normal 1 month after radiotherapy. Drinking history, chemotherapy history and oral pathogens are independent risk factors influencing the occurrence of severe radioactive oral mucositis.