Background and aims As a ferroptosis inducer, sorafenib, a first-line treatment for hepatocellular carcinoma (HCC), has a significant antitumor effect. Nonetheless, HCC patients frequently develop sorafenib resistance. Here, we investigated the impacts of progestagen-associated endometrial protein (PAEP), which controls sorafenib resistance and tumorigenesis in HCC. Furthermore, we investigated the function of PAEP and the underlying molecular mechanisms that cause HCC ferroptosis when sorafenib is applied. Methods Western blot analysis, cell proliferation, colony formation and animal experiments were performed to investigate the function of PAEP in sorafenib resistance and tumorigenesis in HCC. We detected the levels of reactive oxygen species, iron, and malondialdehyde and preformed transmission electron microscopy to investigate the relationship between PAEP and ferroptosis. Co-immunoprecipitation (co-IP) assay was performed to investigate the underlying molecular mechanisms of PAEP that cause HCC ferroptosis. Results PAEP was significantly overexpressed in HCC tissues, and this was associated with a poor clinical prognosis. PAEP silencing dramatically reduced HCC cells’ malignant phenotype. We found that sorafenib-induced ferroptosis was more sensitive to HCC cells with PAEP knockdown. Furthermore, the orthotopic cell line-derived xenograft mouse model results showed that sorafenib sensitivity can be effectively increased in vivo by PAEP knockdown. We determined that transferrin (TF) was a PAEP target using the String database, and we further supported this finding with Co-IP analysis. Additionally, on sorafenib-induced ferroptosis in HCC cells, TF partially reversed the effects of PAEP knockdown. Conclusions Our research indicates that PAEP may be a potential biomarker for predicting sorafenib resistance in HCC and disruption of PAEP expression may be a potential cancer-directed therapeutic option for HCC.

Abstract Children s emotional and behavioral problems are characterized by a relatively high incidence, concealed manifestations, and a potential correlation with an increased risk of subsequent mental disorders. These problems have a sustained impact on children s social-emotional development, learning adaptation, and peer relationships. The study reviews the main influencing factors and their mechanisms of action regarding children s emotional and behavioral problems from three levels:individual, family, and social. Under a multi-level integrated perspective, it deepens the understanding of these mechanisms and proposes that future efforts should focus on factors such as improving physical fitness, enhancing sleep, and reducing sedentary behavior. Furthermore, it suggests strengthening collaborative interventions among schools, families, and communities to promote the early prevention of childrens emotional and behavioral problems and support their healthy development.

Objective:To investigate the interactive effects of loss of the only child and childhood trauma on brain structure, function, and structure-function coupling, and to analyze their association with clinical symptom.Methods:A total of 112 parents who lost their only child and participated in the psychological aid project organized by Local Civil Affairs Department in Sunan aear of Jiangsu Province in China from April 2021 to July 2021 and 36 healthy controls recruited from the community during the same period were selected. Based on childhood trauma questionnaire scores, parents who had lost their only child were divided into those with childhood trauma (group A, n=55) and those without childhood trauma (group B, n=57); similarly, the healthy controls were divided into a group with childhood trauma (group C, n=12) and a group without childhood trauma (group D, n=24). All participants were evaluated by clinical scales such as Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Mini-Mental State Examination (MMSE). MRI 3D-T1 structural images and resting-state functional magnetic resonance imaging data were collected; gray matter volume (GMV) and degree centrality (DC) were calculated by standardized image preprocessing procedure, and ratio of DC to GMV within each voxel was computed to obtain the structure-function coupling map. A two-factor analysis of variance was used to analyze the independent effect and interactive effect of loss of the only child and childhood trauma on GMV, DC, and DC/GMV coupling value. Spearman rank correlation analysis was used to evaluate the associations of above indicators in brain regions with significant difference in independent effect and interactive effect with clinical scale scores. Results:(1) Compared with the participants without childhood trauma (group B+group D), the participants with childhood trauma (group A+group C) showed significantly reduced GMV in the left middle temporal gyrus and right dorsolateral superior frontal gyrus (voxel-level P<0.01, cluster-level P<0.05, Gaussian random field [GRF] corrected). A significant interactive effect of loss of the only child and childhood trauma on GMV in the right precuneus was observed (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). (2) Compared with the healthy controls, parents who had lost their only child exhibited significantly increased DC in the left middle frontal gyrus (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). Compared with participants without childhood trauma, participants with childhood trauma showed significantly increased DC in the right thalamus (voxel-level P<0.01, cluster-level P< 0.05, GRF corrected). A significant interactive effect of loss of the only child and childhood trauma on DC in the left dorsolateral superior frontal gyrus was observed (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). (3) Compared with the healthy controls, parents who had lost their only child showed significantly decreased DC/GMV coupling value in the left middle frontal gyrus (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). Compared with participants without childhood trauma, participants with childhood trauma showed significantly increased DC/GMV coupling value in the right thalamus (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). A significant interactive effect of loss of the only child and childhood trauma on DC/GMV coupling value in the left dorsolateral superior frontal gyrus was observed (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). (4) Correlation analysis revealed that GMV in the right precuneus with significant interactive effect of loss of the only child and childhood trauma was positively correlated with MMSE score ( r s=0.317, P=0.010, Bonferroni corrected). GMV in the left middle temporal gyrus with significant independent effect of childhood trauma was positively correlated with both HAMD score and HAMA score ( r s=0.362, P=0.006; r s= 0.349, P=0.008, Bonferroni corrected). Conclusion:Loss of the only child and childhood trauma can interact to jointly affect the brain structure, function, and structure-function coupling; and some of these brain structure alterations are closely associated with clinical symptoms.

Objective Based on the assumption of spatial heterogeneity,the distribution pattern and risk characteristics of health poverty in middle-aged and elderly people with chronic diseases are described from the perspective of spatial differentiation.In order to providing a theoretical basis for the optimization of subsequent poverty reduction policies and a model policy for other countries.Methods It used factor detector and interaction detector to capture the role of single-factor and multi-factor interactions on the spatial differentiation of health poverty,and risk detectors were utilized to explore the high-risk factors in risky areas Results The single factor explanation of medical assistance and health education activities is prominent,and the factors such as PM2.5,old-age dependency ratio and urban unemployment rate have strong interaction.Furthermore,it identified high-risk factor characteristics in areas at high risk of health poverty.Conclusion The spatial differentiation pattern of health poverty among the middle-aged and elderly chronic disease population in China is the result of the synergistic driving effect of multidimensional factors,and there is variability in the risk characteristics among regions.The government should establish a contextual optimization strategy and pay attention to the joint effect of multiple factors to establish a synergistic management system.

Objective:To evaluate the efficacy and safety of obinutuzumab combined with glucocorticoid-based therapy in patients with relapsed immune thrombotic thrombocytopenic purpura (iTTP).Methods:This study analyzed the efficacy and adverse reactions of four patients with relapsed iTTP who were treated with a combination of obinutuzumab and glucocorticoids to assess the effectiveness and safety of the treatment.Results:All four patients had a history of multiple relapses and had previously undergone treatment with rituximab and bortezomib. Three patients exhibited additional autoantibodies. Following the combined therapy, all patients achieved clinical remission, with ADAMTS13 activity returning to normal levels and inhibitors testing negative. During a median follow-up period of 11 months (range: 3–17 months), all patients maintained sustained remission. No severe adverse events were reported during treatment or follow-up.Conclusion:The combination of obinutuzumab and glucocorticoid-based therapy is effective and safe for treating relapsed iTTP.

Objective Based on the assumption of spatial heterogeneity,the distribution pattern and risk characteristics of health poverty in middle-aged and elderly people with chronic diseases are described from the perspective of spatial differentiation.In order to providing a theoretical basis for the optimization of subsequent poverty reduction policies and a model policy for other countries.Methods It used factor detector and interaction detector to capture the role of single-factor and multi-factor interactions on the spatial differentiation of health poverty,and risk detectors were utilized to explore the high-risk factors in risky areas Results The single factor explanation of medical assistance and health education activities is prominent,and the factors such as PM2.5,old-age dependency ratio and urban unemployment rate have strong interaction.Furthermore,it identified high-risk factor characteristics in areas at high risk of health poverty.Conclusion The spatial differentiation pattern of health poverty among the middle-aged and elderly chronic disease population in China is the result of the synergistic driving effect of multidimensional factors,and there is variability in the risk characteristics among regions.The government should establish a contextual optimization strategy and pay attention to the joint effect of multiple factors to establish a synergistic management system.

Objective:To evaluate the efficacy and safety of obinutuzumab combined with glucocorticoid-based therapy in patients with relapsed immune thrombotic thrombocytopenic purpura (iTTP).Methods:This study analyzed the efficacy and adverse reactions of four patients with relapsed iTTP who were treated with a combination of obinutuzumab and glucocorticoids to assess the effectiveness and safety of the treatment.Results:All four patients had a history of multiple relapses and had previously undergone treatment with rituximab and bortezomib. Three patients exhibited additional autoantibodies. Following the combined therapy, all patients achieved clinical remission, with ADAMTS13 activity returning to normal levels and inhibitors testing negative. During a median follow-up period of 11 months (range: 3–17 months), all patients maintained sustained remission. No severe adverse events were reported during treatment or follow-up.Conclusion:The combination of obinutuzumab and glucocorticoid-based therapy is effective and safe for treating relapsed iTTP.

Objective:To investigate the interactive effects of loss of the only child and childhood trauma on brain structure, function, and structure-function coupling, and to analyze their association with clinical symptom.Methods:A total of 112 parents who lost their only child and participated in the psychological aid project organized by Local Civil Affairs Department in Sunan aear of Jiangsu Province in China from April 2021 to July 2021 and 36 healthy controls recruited from the community during the same period were selected. Based on childhood trauma questionnaire scores, parents who had lost their only child were divided into those with childhood trauma (group A, n=55) and those without childhood trauma (group B, n=57); similarly, the healthy controls were divided into a group with childhood trauma (group C, n=12) and a group without childhood trauma (group D, n=24). All participants were evaluated by clinical scales such as Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Mini-Mental State Examination (MMSE). MRI 3D-T1 structural images and resting-state functional magnetic resonance imaging data were collected; gray matter volume (GMV) and degree centrality (DC) were calculated by standardized image preprocessing procedure, and ratio of DC to GMV within each voxel was computed to obtain the structure-function coupling map. A two-factor analysis of variance was used to analyze the independent effect and interactive effect of loss of the only child and childhood trauma on GMV, DC, and DC/GMV coupling value. Spearman rank correlation analysis was used to evaluate the associations of above indicators in brain regions with significant difference in independent effect and interactive effect with clinical scale scores. Results:(1) Compared with the participants without childhood trauma (group B+group D), the participants with childhood trauma (group A+group C) showed significantly reduced GMV in the left middle temporal gyrus and right dorsolateral superior frontal gyrus (voxel-level P<0.01, cluster-level P<0.05, Gaussian random field [GRF] corrected). A significant interactive effect of loss of the only child and childhood trauma on GMV in the right precuneus was observed (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). (2) Compared with the healthy controls, parents who had lost their only child exhibited significantly increased DC in the left middle frontal gyrus (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). Compared with participants without childhood trauma, participants with childhood trauma showed significantly increased DC in the right thalamus (voxel-level P<0.01, cluster-level P< 0.05, GRF corrected). A significant interactive effect of loss of the only child and childhood trauma on DC in the left dorsolateral superior frontal gyrus was observed (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). (3) Compared with the healthy controls, parents who had lost their only child showed significantly decreased DC/GMV coupling value in the left middle frontal gyrus (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). Compared with participants without childhood trauma, participants with childhood trauma showed significantly increased DC/GMV coupling value in the right thalamus (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). A significant interactive effect of loss of the only child and childhood trauma on DC/GMV coupling value in the left dorsolateral superior frontal gyrus was observed (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). (4) Correlation analysis revealed that GMV in the right precuneus with significant interactive effect of loss of the only child and childhood trauma was positively correlated with MMSE score ( r s=0.317, P=0.010, Bonferroni corrected). GMV in the left middle temporal gyrus with significant independent effect of childhood trauma was positively correlated with both HAMD score and HAMA score ( r s=0.362, P=0.006; r s= 0.349, P=0.008, Bonferroni corrected). Conclusion:Loss of the only child and childhood trauma can interact to jointly affect the brain structure, function, and structure-function coupling; and some of these brain structure alterations are closely associated with clinical symptoms.

Background::Hypothermia therapy has been suggested to attenuate myocardial necrosis; however, the clinical implementation as a valid therapeutic strategy has failed, and new approaches are needed to translate into clinical applications. This study aimed to assess the feasibility, safety, and efficacy of a novel selective intracoronary hypothermia (SICH) device in mitigating myocardial reperfusion injury.Methods::This study comprised two phases. The first phase of the SICH was performed in a normal porcine model for 30 minutes ( n = 5) to evaluate its feasibility. The second phase was conducted in a porcine myocardial infarction (MI) model of myocardial ischemia/reperfusion which was performed by balloon occlusion of the left anterior descending coronary artery for 60 minutes and maintained for 42 days. Pigs in the hypothermia group ( n = 8) received hypothermia intervention onset reperfusion for 30 minutes and controls ( n = 8) received no intervention. All animals were followed for 42 days. Cardiac magnetic resonance analysis (five and 42 days post-MI) and a series of biomarkers/histological studies were performed. Results::The average time to lower temperatures to a steady state was 4.8 ± 0.8 s. SICH had no impact on blood pressure or heart rate and was safely performed without complications by using a 3.9 F catheter. Interleukin-6 (IL-6), tumor necrosis factor-α, C-reactive protein (CRP), and brain natriuretic peptide (BNP) were lower at 60 min post perfusion in pigs that underwent SICH as compared with the control group. On day 5 post MI/R, edema, intramyocardial hemorrhage, and microvascular obstruction were reduced in the hypothermia group. On day 42 post MI/R, the infarct size, IL-6, CRP, BNP, and matrix metalloproteinase-9 were reduced, and the ejection fraction was improved in pigs that underwent SICH.Conclusions::The SICH device safely and effectively reduced the infarct size and improved heart function in a pig model of MI/R. These beneficial effects indicate the clinical potential of SICH for treatment of myocardial reperfusion injury.

Objective:This study aims to develop a country prioritization index system for China's international vaccine cooperation,providing a screening tool and referenceindicators.Method:Based on the PESTEL analysis model,the indicator system was preliminarily determined through literature review and expert interviews.Additional expert consultations were conducted to refine and finalize this system.The weight of the indicators was determined using the Analytic Hierarchy Process(AHP).Result:A comprehensive screening index system for identifying preferred countries in China's international vaccine cooperation has been established.This indicator system covers 5 factors including economy,politics,society,technology,law,and regulations,with 15 secondary indicators and 34 tertiary indicators subdivided.Legal and regulatory factors received the highest weight(0.48),followed by economic(0.23),political(0.15),social(0.095),and technological(0.045).The authority of the experts and the coordination of their opinions were both deemed satisfactory.All judgment matrices in the AHP passed the consistency tests,affirming the reliability of the indicator weight results.Conclusion:The study has established an evidence-based and reliable index system for prioritizing countries in China'sinternational vaccine cooperation,providing references for the selection process.