Background/Aims: Regorafenib is recommended by guidelines and trials as a sequential second-line therapy following progression on first-line sorafenib or lenvatinib in hepatocellular carcinoma (HCC). However, efficacy is limited, highlighting the urgent need to screen suitable patients and develop sensitization strategies. Methods: Acquired sorafenib- or lenvatinib-resistant (SR or LR) HCC cell lines and organoids were established. Genome-wide CRISPR library screen was performed in SR or LR cell strains to identify synthetic lethal targets of regorafenib. RNA-seq and FITC-regorafenib efflux assay were used to elucidate ERBB3-driven downstream signaling. Preclinical mouse models of cell line- and patient-derived xenografts and clinical cohorts of HCC patients were employed to validate the efficacy of ERBB3-guided patient stratification. Results: Screening with CRISPR library, we showed that inhibition of ERBB3 was synthetic lethal with regorafenib in SR or LR cell strains and organoids. Mechanistically, SR or LR triggered feedback activation of ERBB3 signaling and mediated regorafenib efflux via ERBB3-HIF1A-ABCB1 cascade pathway, limiting sensitivity to regorafenib. Moreover, ERBB3-low tumors following SR or LR exhibited significant sensitivity to regorafenib, suggesting its potential as a predictive biomarker to screen optimal candidates for sequential therapy. Seribantumab, an ERBB3-targeting monoclonal antibody, inhibited ERBB3-HIF1A-ABCB1 cascade, and its combination with regorafenib exerted marked synergistic anti-tumor effects on ERBB3-high tumors resistant to sorafenib or lenvatinib both in vitro and in vivo. Conclusions This study revealed that ERBB3 was a key resistance factor driving limited efficacy to sequential regorafenib, but also an effective therapeutic target whose inhibition enhanced regorafenib sensitivity after SR or LR.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

This study innovatively incorporates on-site teaching with the International Museum of Stomatology into the curriculum to establish an immersive and intuitive teaching mode,promoting education from both theoretical and practical dimensions.The teaching effect is comprehensively evaluated to explore the pathway to optimization.Multi-dimensional questionnaires are designed to collect feedback data from students on teaching satisfaction,knowledge mastery,professional identity,and humanistic literacy perception,fol-lowed by in-depth quantitative and qualitative analyses.The results demonstrate that this teaching mode significantly enhances literacy,playing a critical role in helping stomatological students fully understand professional knowledge and humanistic connotations while sub-stantially improving their professional identity.This teaching mode gives a direction for innovative stomatological education,holds sig-nificant importance for cultivating stomatological professionals with both clinical skills and humanistic literacy,possessing substantial potential for promotion,application,and further refinement.

Objective:To explore the application effect of intelligent precision feeding guidance mode in postoperative feeding of children with congenital heart disease, in order to provide a scientific, dynamic and effective feeding management method for postoperative children with congenital heart disease.Methods:A prospective, controlled study design was adopted to select 144 pairs of congenital heart disease patients and their primary caregivers who visited the Pediatric Heart Center of Beijing Anzhen Hospital affiliated to Capital Medical University from March to December 2023 using convenience sampling method. They were randomly divided into a control group and an experimental group, with 72 pairs in each group, using a random number table method. The control group received routine feeding guidance, while the experimental group received intelligent precision feeding guidance mode intervention on the basis of the control group. Compared the infant and child feeding index (ICFI), malnutrition and physical development status, and primary caregiver′s Positive Aspects of Caregiving (PAC) scores between two groups of children with congenital heart disease.Results:Finally, 130 pairs of children and their primary caregivers completed this study, with 64 pairs in the control group and 66 pairs in the experimental group. There were 30 males and 34 females in the control group, with an aged of (11.64 ± 5.03) months; there were 35 males and 31 females in the experimental group, with an aged of (11.03 ± 5.07) months. Among the primary caregivers of the control group, there were 53 mothers and 11 fathers/grandparents/other caregivers; among the main caregivers of the experimental group, there were 62 mothers and 4 fathers/grandparents/other caregivers. The ICFI of the experimental group at 3 and 6 months after surgery were 13.0(10.0, 14.0) and 15.0(13.0, 15.0) points, respectively, which were higher than those of the control group at 11.0(9.0, 13.0) and 12.0(9.0, 14.0) points, and the differences were statistically significant ( Z=8.23, 22.32, both P<0.05). The ICFI qualification rates of the experimental group at 3 and 6 months after surgery were 37.1% (23/62) and 59.3% (35/59), respectively, which were higher than the control group′s 19.7% (12/61) and 31.6% (18/57), and the differences were statistically significant ( χ2=4.59, 8.99, both P<0.05). At 6 months after surgery, the body weight of the experimental group increased was (1.78 ± 0.46) kg, which was higher than that of the control group (1.50 ± 0.52) kg, and the difference was statistically significant ( t=-3.23, P<0.05). In addition, at 6 months after surgery, the incidence of acute malnutrition in the experimental group was 12.1% (8/66), which was lower than that of the control group 25.0% (16/64), and the difference was statistically significant ( χ2=4.36, P<0.05). At 6 months after surgery, the scores of self affirmation, life outlook dimension and the total PAC score of the primary caregiver in the experimental group were (23.45 ± 3.57), (11.97 ± 1.91), and (35.96 ± 4.92) points, respectively, which were higher than those in the control group (22.11 ± 3.40), (11.02 ± 1.90) and (33.13 ± 4.86) points, and the differences were statistically significant ( t=-2.20, -2.86, -2.68, all P<0.05). Conclusions:The use of intelligent precision feeding guidance mode for feeding management of postoperative children with congenital heart disease can effectively improve the positive feelings of caregivers, achieve scientific feeding, increase the ICFI and its qualification rate of children, thereby improving their nutritional status and promoting growth and development.

Sepsis constitutes a predominant cause of mortality in critically ill patients,and early determination of the type of infection is crucial for influencing patient management and forecasting outcomes.Currently,blood culture serves as the gold standard for diagnosing sepsis.Yet,its limitations,such as a lengthy culture period and low positivity rate,hinder its ability to provide a microbiological basis for early initiation of antimicrobial therapy in clinical practice.Serological markers have engendered significant interest due to their convenience and rapid detection in vitro,emerging as indispensable laboratory indices for early inference of infection.In recent years,with extensive research on sepsis across diverse academic domains,numerous novel serological markers exhibit promise in diagnosing sepsis.Therefore,this review explores the characteristics and applicatron value of new serological markers for early diagnosis of sepsis,and reviews them in combination with relevant predictive models,bringing new ideas for early clinical diagnosis of sepsis.

Objective To analyze the clinical characteristics and prognosis of Pseudomonas aeruginosa peritoneal dialysis-associated peritonitis(PaeP).Methods Peritoneal dialysis-associated peritonitis(PDAP)patients who were followed up in the nephrology outpatient department of a hospital from January 2019 to December 2020 were analyzed retrospectively.According to bacterial culture results,patients were divided into the PaeP group and non-PaeP group.Clinical characteristics of PaeP patients and antimicrobial susceptibility testing results of Pseudomonas aeruginosa were analyzed,clinical manifestations,laboratory test results,and prognosis of two groups of patients were compared.Results A total of 124 peritoneal dialysis patients were included in analysis,164 cases of peritoni-tis occurred,16 cases were in the PaeP group and 148 in the non-PaeP group.11 patients developed 16 episodes of Pseudomonas aeruginosa infection,accounting for 8.9％of PDAP patients.Among them,4 patients had peritoneal dialysis catheter exit-site infection,with 5 recurrence cases,1 case cured,1 case died,and 9 cases were extubated.Among the extubated patients,1 withdrew dialysis,3 were recovered to peritoneal dialysis after hemodialysis,5 changed to permanently hemodialysis,with a technical failure rate of 54.5％.Compared with the non-PaeP group,patients in the PaeP group had a shorter dialysis time(13.83±4.92 vs 38.53±35.77 months).During the infection period,C-reactive protein levels were higher(96.61±6.17 vs 45.87±44.65 mg/L),while albumin levels were lower(25.62±4.42 vs 29.46±8.25 g/L).At the onset of infection,the proportion of polymorphonuclear cells in perito-neal dialysis fluid was relatively higher.On the 5th day of treatment,the negative conversion rate of white blood cell count in peritoneal dialysis fluid was relatively low.Differences were all statistically significant(all P＜0.05).The cure rate of patients in the PaeP group was lower than that in the non-PaeP group,the technical failure rate was higher than that in the non-PaeP group,both with statistically significant differences(both P＜0.05).There was no statistically significant difference in the mortality between two groups of patients(P＞0.05).Conclusion PaeP patients have severe clinical manifestations,poor clinical treatment prognosis,high recurrence and extubation rates.For patients with repeated episodes,resetting and replacing the tunnel after extubation is an effective means to re-duce technical failures.

Objective To explore the association between walking exercise guided by 6 minute walking test(6MWT)and the incidences of 3-year major adverse cardiovascular event(MACE)in elderly patients with acute coronary syndrome(ACS)after percutaneous coronary intervention(PCI).Methods A total of 628 elderly ACS patients who undergoing PCI and obtaining success-ful coronary revascularization in our department from November 2018 to April 2019 were enrolled,and divided into 6MWT group(n=147)and control group(n=481)based on participa-ting in walking exercise guided by 6MWT or not.All of them were followed up for 3 years.The incidences of MACE[including coronary target vascular restenosis,acute myocardial infarction,heart failure,ischemic or hemorrhagic stroke]and all-cause death were observed.Univariate and multivariate Cox proportional analyses and Kaplan-Meier survival curve analysis were employed for data statistical analyses.Results At the end of follow-up,the incidences of target vascular restenosis(6.9％vs 2.0％,P=0.028),heart failure(3.7％vs 0％,P=0.036),stroke(3.7％vs 0％,P=0.036),and total MACE incidence(15.0％vs 4.1％,P=0.000)were statistically higher in the control group than the 6MWT group.Kaplan-Meier survival curve analysis showed that the cumulative incidence of MACE was significantly lower in the 6MWT group than the control group(Plog rank=0.001).Multivariate Cox regression analysis showed that not participating in walking exercise guided by 6MWT was an independent risk factor for occurrence of 3-year MACE(HR=3.102,95％CI:1.327-7.250,P=0.009).Conclusion Walking exercise guided by 6MWT reduces the incidence of 3-year MACE and improves the long-term prognosis of elderly ACS patients after PCI.

Objective:To investigate the therapeutic effect of combined extracranial-intracranial revascularization on elderly patients with symptomatic chronic internal carotid artery occlusion, and to evaluate its safety and efficacy in the elderly population.Methods:A retrospective analysis was conducted on 35 elderly patients(aged ≥60 years)who underwent combined extracranial-intracranial revascularization for symptomatic chronic internal carotid artery occlusion in the Department of Neurosurgery, Renmin Hospital of Wuhan University from January 2017 to June 2022.The clinical data during hospitalization, as well as the follow-up data within 2 years after operation, were collected and analyzed.Results:A total of 35 cases of combined extracranial-intracranial revascularization were performed on 35 patients.The age at surgery ranged from 60 to 74 years(mean age 65.5 ± 4.2 years). The incidence of reversible neurological deficits within 2 weeks postoperation was 34.3%, and the incidence of focal cerebral infarction within 30 days postoperation was 5.7%.The patency rate of the bridging vessel was 97.1% at 3 months postoperation., and the incidence of focal cerebral infarction during the follow-up period of 30 days to 2 years postoperation was 2.9%.At 3 months after surgery, computed tomography perfusion imaging showed that regional cerebral blood flow(rCBF), regional cerebral blood volume(rCBV), regional mean transit time(rMTT), and regional time to peak(rTTP)were improved compared with those before surgery.The modified Rankin scale score decreased compared to preoperative values, while the Montreal Cognitive Assessment showed improvement in cognitive function compared to preoperative levels(all P<0.05). From 6 months to 1-year postoperation, cerebral angiography showed that 38.7% of the patients had neovascularization of Matsushima grade A or grade B. No cases of cerebral hemorrhage or death was observed during the treatment and follow-up. Conclusions:Combined extracranial-intracranial revascularization is safe and effective for elderly patients with symptomatic chronic internal carotid artery occlusion, which can improve the patient′s hemodynamic disorders, prevent infarction events, and improve the patients′ neurological function and cognitive ability.

Objective To characterize the features of patent foramen ovale(PFO)-related cryptogenic stroke using diffusion-weighted imaging(DWI)and to investigate the correlation between infarct size and cardiac CT characteristics of PFO.Methods A retrospective,consecutive cohort study was conducted on acute ischemic stroke patients admitted to Neurology Department of Xuanwu Hospital,Capital Medical University from January 2022 to September 2024.Patients were categorized into PFO group,arterio-arterial embolism(AAE)group,and atrial fibrillation(AF)group based on etiological diagnosis.Baseline clinical data,including age,height,body mass index,admission National Institutes of Health stroke scale(NIHSS)score,history of old cerebral infarction,hypertension,diabetes mellitus,coronary heart disease,dyslipidemia,and smoking history were collected and compared.All patients underwent head MR within 24 h of admission.DWI was used to analyze and compare infarct characteristics across the three groups,including lesion number(single or multiple),location(cortical+subcortical,deep white matter,cortical+subcortical+deep white matter,cerebellum+thalamus+brainstem),size(≥15 mm or＜15 mm,based on maximum transverse diameter;for multiple lesions,if any lesion had a maximum diameter≥15 mm,it was categorized as≥15 mm),infarcted vascular territory(anterior,posterior,or both circulations),and specific arterial supply(anterior cerebral artery,middle cerebral artery,posterior cerebral artery,basilar artery,posterior inferior cerebellar artery,superior cerebellar artery,anterior choroidal artery,or multiple arteries).Patients in the PFO group additionally underwent cardiac CT to measure PFO-related parameters:tunnel length,width,height,septum secundum thickness,and fossa ovalis length.Spearman correlation analysis was performed to evaluate the relationship between infarct size and PFO cardiac CT features.Results A total of 232 acute ischemic stroke patients were included(mean age[57±17]years,ranged 19-86 years;141 males,91 females),comprising 116 in the PFO group,36 in the AAE group,and 80 in the AF group.(1)The proportion of males in the PFO group was higher than that in the AF group,it was lower than that in the AAE group.The age,body mass index and proportions of patients with hypertension,diabetes,hyperlipidemia,coronary heart disease were all lower than those in the other two groups(both P＜0.016 7),while other baseline characteristics showed no significant differences(all P＞0.05).(2)The PFO group exhibited a higher proportion of multiple infarcts compared to the AAE group(83.62％[97/116]vs.61.11％[22/36],P＜0.016 7),but a lower proportion than the AF group(83.62％[97/116]vs.98.75％[79/80],P＜0.016 7).The PFO group also showed a significantly higher proportion of cortical+subcortical infarcts(47.41％[55/116]vs.11.11％[4/36]and 6.25％[5/80],respectively,both P＜0.016 7)and infarcts with a maximum diameter＜15 mm compared to both AAE and AF groups(66.38％[77/116]vs.36.11％[13/36]and 11.25％[9/80],respectively,both P＜0.016 7).Furthermore,the PFO group had a lower proportion of anterior circulation infarcts(27.59％[32/116]vs.69.44％[25/36]in AAE group and 67.50％[54/80]in AF group,both P＜0.016 7),but a higher proportion of posterior circulation infarcts(62.07％[72/116]vs.16.67％[6/36]in AAE group and 8.75％[7/80]in AF group,both P＜0.016 7).Specifically,middle cerebral artery infarcts were less common in the PFO group(18.97％[22/116]vs.66.67％[24/36]in AAE group and 52.50％[42/80]in AF group,both P＜0.016 7),while posterior cerebral artery infarcts were more common(48.28％[56/116]vs.8.33％[3/36]in AAE group and 8.75％[7/80]in AF group,both P＜0.016 7).(3)Spearman correlation analysis revealed that infarct size was negatively correlated with PFO tunnel length(rs=-0.429,P=0.029),fossa ovalis length(rs=-0.408,P=0.038),and septum secundum thickness(rs=-0.525,P=0.006),but not correlated with PFO width or height(both P＞0.05).Conclusions PFO-related cryptogenic stroke is predominantly characterized by multiple small infarcts,primarily located in the cortical+subcortical regions and posterior circulation.Infarct size was found to be negatively correlated with PFO tunnel length,fossa ovalis length,and septum secundum thickness.Comprehensive assessment integrating DWI and cardiac CT features may facilitate the identification of PFO-related stroke.These findings warrant further validation through larger,prospective studies.

Objective To compare the effect of moderate-intensity continuous training(MICT)and high-intensity interval training(HIIT)on gait and balance for stroke patients.Methods From December,2023 to December,2024,96 patients with post-stroke gait and balance dysfunction were se-lected from the First Affiliated Hospital of Bengbu Medical University,and randomly divided into control group(n=32),MICT group(n=32)and HIIT group(n=32).The control group received routine comprehensive reha-bilitation therapy,while MICT and HIIT groups received additional respective training,for four weeks.They were measured with symmetry indexes(SI)of mean pressure and footprint area during eyes-open and eyes-closed condition,as well as anterior-posterior and medial-lateral displacement of the center of mass,before and after treatment;while they were assessed with Berg Balance Scale(BBS),distance of 6-minute walk test(6MWT),time of Timed Up&Go test(TUGT)and 10-meter walk test(10MWT),and Fugl-Meyer Assessment-Lower Extremities(FMA-LE).Results The main effects of time(F>351.683,P<0.001)and groups(F>4.945,P<0.05),and the interaction effects(F>16.919,P<0.001)were significant for BBS scores,distance of 6MWT,time of TUGT and 10MWT,and FMA-LE scores;and all the indicators were better in MICT group and HIIT group than in the control group(P<0.05)after treatment,and they were better in HIIT group than in MICT group(P<0.05)except BBS score.Un-der eyes-open condition,the main effects of time(F>64.684,P<0.001)and groups(F>9.472,P<0.001),and the interaction effects(F>10.562,P<0.001)were significant for SI of mean pressure and footprint area,and an-terior-posterior and medial-lateral displacement of the center of mass;and all the indicators were better in MICT group and HIIT group than in the control group(P<0.001)after treatment,and they were better in HIIT group than in MICT group(P<0.05).Under eyes-closed condition,the main effects of time(F>107.730,P<0.001)and groups(F>4.275,P<0.05),and the interaction effects(F>7.985,P<0.05)were significant for SI of mean pressure and footprint area,and anterior-posterior and medial-lateral displacement of the center of mass;and SI of mean pressure was better in HIIT group than in MICT group(P<0.05),the other indicators were better in MICT group and HIIT group than in the control group(P<0.001)after treatment.Conclusion Both HIIT and MICT can improve gait and balance for stroke patients,and HIIT is more effective on gait and static balance with eyes open,but similar on static balance with eyes closed.