Purpose: Adjuvant chemotherapy (AC) is recommended for muscle-invasive or lymph node-positive upper urinary tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). However, disease recurrences are frequently observed in pT1 disease, and AC may increase the risk of overtreatment in pT2 UTUC patients. This study aimed to validate a risk-adapted scoring model for selecting UTUC patients with ≤pT2 disease who would benefit from AC. Materials and Methods: We retrospectively analyzed 443 ≤pT2 UTUC patients who underwent RNU. A risk-adapted scoring model was applied, categorizing patients into low- or high-risk groups. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were analyzed according to risk group. Results: Overall, 355 patients (80.1%) and 88 patients (19.9%) were categorized into the low- and high-risk groups, respectively, with the latter having higher pathological stages, concurrent carcinoma in situ, and synchronous bladder tumors. Disease recurrence occurred in 45 patients (10.2%), among whom 19 (5.4%) and 26 (29.5%) belonged to the low- and high-risk groups, respectively (p<0.001). High-risk patients had significantly shorter RFS (64.3% vs. 93.6% at 60 months; hazard ratio [HR] 13.66; p<0.001) and worse CSS (80.7% vs. 91.5% at 60 months; HR 4.25; p=0.002). Multivariate analysis confirmed that pT2 stage and the high-risk group were independent predictors of recurrence and cancer-specific death (p<0.001). Decision curve analysis for RFS showed larger net benefits with our model than with the T stage model. Conclusions The risk-adapted scoring model effectively predicts recurrence and identifies optimal candidates for AC post RNU in non-metastatic UTUC.

Objective This study aimed to investigate the potential relationship between urinary metals copper (Cu), arsenic (As), strontium (Sr), barium (Ba), iron (Fe), lead (Pb) and manganese (Mn) and grip strength. Methods We used linear regression models, quantile g-computation and Bayesian kernel machine regression (BKMR) to assess the relationship between metals and grip strength.Results In the multimetal linear regression, Cu (β=-2.119), As (β=-1.318), Sr (β=-2.480), Ba (β=0.781), Fe (β= 1.130) and Mn (β=-0.404) were significantly correlated with grip strength (P < 0.05). The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was -1.007 (95％ confidence interval:-1.362, -0.652; P < 0.001) when each quartile of the mixture of the seven metals was increased. Bayesian kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength, with Cu, As and Sr being negatively associated with grip strength levels. In the total population, potential interactions were observed between As and Mn and between Cu and Mn (Pinteractions of 0.003 and 0.018, respectively).Conclusion In summary, this study suggests that combined exposure to metal mixtures is negatively associated with grip strength. Cu, Sr and As were negatively correlated with grip strength levels, and there were potential interactions between As and Mn and between Cu and Mn.

Atherosclerosis caused by disorders of lipid metabolism is the main pathological basis of atherosclerotic cardiovascular disease.Statins are the cornerstone of lipid-modulating therapy for this type of disease,but in practice there are still some patients with suboptimal lipid management.Proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors have been gradually applied as a new class of lipid-modulating drugs for the treatment in patients with this type of disease,and recent studies have shown that in addition to regulating lipid metabolism,PCSK9 inhibitors also have potential anti-inflammatory and anti-platelet activation effects.This article sorts out the multiple pharmacological mechanisms of action of PCSK9 inhibitors and the current status of clinical research of PCSK9 inhibitors.Besides,it discusses the factors that may affect the efficacy of PCSK9 inhibitors,in order to provide a reference for the safe and rational medication of PCSK9 inhibitors.

Clinical cure (herein referred to as functional cure) is currently recognized as the ideal therapeutic goal by the guidelines for the prevention and treatment of chronic hepatitis B (CHB) at home and abroad. China has achieved significant results in research and exploration based on pegylated interferon alpha therapeutic strategies to promote the effectiveness of CHB clinical cure rates in clinical practice. The summary and optimization of clinical cure strategies in different clinical type classifications, as well as the exploration of clinical cure continuity and long-term outcomes, are of great significance for solving the current bottleneck problem and our future efforts in the developmental directions of clinical cure in CHB populations.

Objective To observe the effects of melatonin on autophagy in cortical neurons of neonatal rats with hypoxic-ischemic brain damage(HIBD)and to explore its mechanisms via the PI3K/AKT signaling pathway,aiming to provide a basis for the clinical application of melatonin.Methods Seven-day-old Sprague-Dawley neonatal rats were randomly divided into a sham operation group,an HIBD group,and a melatonin group(n=9 each).The neonatal rat HIBD model was established using the classic Rice-Vannucci method.Neuronal morphology in the neonatal rat cerebral cortex was observed with hematoxylin-eosin staining and Nissl staining.Autophagy-related protein levels of microtubule-associated protein 1 light chain 3(LC3)and Beclin-1 were detected by immunofluorescence staining and Western blot analysis.Phosphorylated phosphoinositide 3-kinase(p-PI3K)and phosphorylated protein kinase B(p-AKT)protein expression levels were measured by immunohistochemistry and Western blot.The correlation between autophagy and the PI3K pathway in the melatonin group and the HIBD group was analyzed using Pearson correlation analysis.Results Twenty-four hours post-modeling,neurons in the sham operation group displayed normal size and orderly arrangement.In contrast,neurons in the HIBD group showed swelling and disorderly arrangement,while those in the melatonin group had relatively normal morphology and more orderly arrangement.Nissl bodies were normal in the sham operation group but distorted in the HIBD group;however,they remained relatively intact in the melatonin group.The average fluorescence intensity of LC3 and Beclin-1 was higher in the HIBD group compared to the sham operation group,but was reduced in the melatonin group compared to the HIBD group(P<0.05).The number of p-PI3K+and p-AKT+cells decreased in the HIBD group compared to the sham operation group but increased in the melatonin group compared to the HIBD group(P<0.05).LC3 and Beclin-1 protein expression levels were higher,and p-PI3K and p-AKT levels were lower in the HIBD group compared to the sham operation group(P<0.05);however,in the melatonin group,LC3 and Beclin-1 levels decreased,and p-PI3K and p-AKT increased compared to the HIBD group(P<0.05).The correlation analysis results showed that the difference of the mean fluorescence intensity of LC3 and Beclin-1 protein in the injured cerebral cortex between the melatonin and HIBD groups was negatively correlated with the difference of the number of p-PI3K+and p-AKT+cells between the two groups(P<0.05).Conclusions Melatonin can inhibit excessive autophagy in cortical neurons of neonatal rats with HIBD,thereby alleviating HIBD.This mechanism is associated with the PI3K/AKT pathway.

Aim To study the effect of maternal high-fat diet during pregnancy on endothelial to mesenchymal transition of aortic vessels in adult offspring.Methods The pregnant mice were randomly divided into normal diet group and high-fat diet group,and the offspring mice were fed normally for 16 weeks after the mother gave birth.Western blot and RT-qPCR were used to detect the expression and transcription of related proteins,and immunofluorescence and im-munohistochemical staining were used for pathological analysis.Results Compared with the offspring of maternal nor-mal diet during pregnancy,the expressions of vascular inflammatory factors,macrophage infiltration,monocyte-endothelium adhesion were significantly increased in the offspring of maternal high-fat diet(OHF)during pregnancy(P＜0.05).Vas-cular endothelial nitric oxide synthase(eNOS)activity,nitric oxide(NO)level were dramatically reduced(P＜0.05).Immunofluorescence results showed reduced endothelial cell marker CD31 and increased mesenchymal marker α-smooth muscle actin(α-SMA)in OHF.Western blot analysis further confirmed the results,which showed that maternal high fat diet reduced vascular endothelial-cadherin(VE-cadherin)and CD31 and increased α-SMA and Vimentin in the offspring(P＜0.05).The maternal high fat diet increased the extracellular matrix protein disposition and transforming growth factor beta(TGF-β)/Smad signaling in endothelium(P＜0.05).Moreover,the maternal high fat diet reduced Kruppel-like factor 2(KLF2)expression by 76％in mRNA level and 59％in protein level(P＜0.05).Conclusion Maternal high-fat diet during pregnancy lead to a transition of endothelial to mesenchyme in the offspring aorta.The results provide a clue for prevention of vascular disease in early stage.

Objective:To discuss the expression levels of Eps15 homology domain-containing protein 2(EHD2),microRNA let-7c(miR-let-7c),and long non-coding RNA(lncRNA)FOXD2-AS1 in laryngeal squamous cell carcinoma(LSCC)tissue,and to clarify the association between EHD2/miR-let-7c/FOXD2-AS1 signaling axis and occurrence of LSCC.Methods:Forty LSCC tissue samples were collected and classified into low grade group(moderately or high differentiated,32 cases)and high grade group(poorly differentiated,8 cases)according to the pathology results;according to the tumor node metastasis(TNM)clinical staging results,the samples were divided into TNM early stage group(stagesⅠ-Ⅱ,13 cases)and TNM late stage group(stages Ⅲ-Ⅳ,27 cases);based on the lymph node metastasis results,the samples were divided into metastasis group(21 cases)and non-metastasis group(19 cases).Additionally,40 corresponding normal adjacent tissue samples were collected as control group.Immunohistochemistry method was used to detect the expressions of EHD2 in various groups and its relationships with clinical pathoparameters of the LSCC patients were analyzed;bioinformatics method was used to confirm that the miR-let-7c was the candidate microRNA(miRNA)and FOXD2-AS1,which had binding sites in its promoter region,was a candidate lncRNA.Ten pairs of fresh LSCC tissue samples and adjacent normal tissue samples were collected.Real-time fluorescence quantitative PCR(RT-qPCR)method was used to detect the expression levels of EHD2 mRNA,miR-let-7c,and FOXD2-AS1 in the samples in two groups,and their associations were verified.Results:Compared with adjacent normal tissue,the expression level of EHD2 in LSCC tissue was significantly decreased(P＜0.01).The positive expression rate of EHD2 in LSCC tissue of the patients in TNM early stage group was significantly higher than that in TNM late stage group(P＜0.05).There was no significant association between EHD2 expression and pathological type or lymph node metastasis(P＞0.05).Compared with control group,the expression level of miR-let-7c in LSCC tissue was significantly decreased(P＜0.05),while the expression level of FOXD2-AS1 was significantly increased(P＜0.05).In LSCC tissue,the expression level of FOXD2-AS1 was negatively correlated with the expression level of miR-let-7c(r=-0.67,P＜0.05),and the expression level of miR-let-7c was negatively correlated with the expression level of EHD2 mRNA(r=-0.83,P＜0.01).Conclusion:EHD2 and miR-let-7c both express at low levels in LSCC tissue and may be new tumor suppressor genes;FOXD2-AS1 is highly expressed in LSCC tissue and may be a new oncogene.FOXD2-AS1/miR-let-7c/EHD2 signaling axis may be involved in the occurrence and development of LSCC.

Objective To investigate the effects and mechanism of TET2 inhibitor itaconate in prolifer-ation and migration of breast cancer cell line MDA-MB-231.Methods The MDA-MB-231 cells were treated for 24 h with dimethyl sulfoxide(DMSO)and 1,5 μmol/L itaconate respectively.The cellular apoptosis was determined by flow cytometry to determine the available itaconic acid concentration.The immunofluorescence was performed to determine the inhibiting effect of itaconate on hydroxymethylcytosine(5hmC)expression level.The cell counting and MTS were performed to determine the effect of itaconate on cell proliferation and activity.The Transwell experiment was performed to determine the effect of itaconate on cell transfer ability.The methylation-specific real-time fluorescence quantitative PCR(qPCR)was used to detect the effects of ita-conic acid treatment on the methylation of promoter regions of genes related to cell proliferation and migra-tion.qPCR was used to detect the effects of itaconate on the cellular proliferation,migration related genes ex-pression.Results 5 μmol/L itaconate treating the cells had no significant effect on the cellular apoptosis,mo-reover could inhibit 5hmC expression level.The cell count and MTS results showed that itaconate could pro-mote the cell proliferation(increase by about 58％,P＜0.05)and increase the cell activity(increase by 42％,P＜0.05).The Transwell experiment results showed that itaconate increased the cell migration(increase by 55％,P＜0.05).The methylation-specific qPCR showed that the itaconate treatment significantly promoted the methyaltion of the promoters p21 and PTEN.The qPCR results showed that itaconate significantly inhibi-ted the expression levels of p21 and PTEN(P＜0.05).Conclusion Itaconate promotes the proliferation and migration of MDA-MB-231 cells through inhibiting 5hmC level of p21 and PTEN and decrease its expression.

Purpose::Under-foot impact loadings can cause serious lower limb injuries in many activities, such as automobile collisions and underbody explosions to military vehicles. The present study aims to compare the biomechanical responses of the mainstream vehicle occupant dummies with the human body lower limb model and analyze their robustness and applicability for assessing lower limb injury risk in underfoot impact loading environments.Methods::The Hybrid III model, the test device for human occupant restraint (THOR) model, and a hybrid human body model with the human active lower limb model were adopted for under-foot impact analysis regarding different impact velocities and initial lower limb postures.Results::The results show that the 2 dummy models have larger peak tibial axial force and higher sensitivity to the impact velocities and initial postures than the human lower limb model. In particular, the Hybrid III dummy model presented extremely larger peak tibial axial forces than the human lower limb model. In the case of minimal difference in tibial axial force, Hybrid III's tibial axial force (7.5 KN) is still 312.5% that of human active lower limb's (2.4 KN). Even with closer peak tibial axial force values, the biomechanical response curve shapes of the THOR model show significant differences from the human lower limb model.Conclusion::Based on the present results, the Hybrid III dummy cannot be used to evaluate the lower limb injury risk in under-foot loading environments. In contrast, potential improvement in ankle biofidelity and related soft tissues of the THOR dummy can be implemented in the future for better applicability.

Objective:To investigate the difference of the attention bias of the resilience level of professional technicians in hospital to negative information.Methods:A total of 383 professional technicians of logistics admin-istrative posts in a third-level military hospital were selected and divided into high and low groups according to their scores on the resilience scale(the top 27％of the participants were in the high resilience group,and the bottom 27％were in the low resilience group).There were 22 participants in each of the high and low resilience groups that met the requirements.The attention bias test was conducted on the professional technicians in the high and low resil-ience groups using the Dot-probe Paradigm.A mixed experimental design of 2(group:low resilience group,high re-silience group)x 2(stimulus clues:negative stimulus,neutral stimulus)was adopted.The dependent variables were correct rate and reaction time.Results:The interaction between the response group and the stimulus cue was statisti-cally significant(P＜0.05),the response time of negative stimulus in low resilience group was lower than that of neutral stimulus.The main effect of the cue condition was statistically significant in both groups(P＜0.05),the correct rate of negative stimulus was lower than that of neutral stimulus.Conclusion:This study shows that the pro-fessional technicians in the high resilience group do not have obvious attention bias to negative information,while the professional technicians in the low resilience group have obvious attention bias to negative emotional informa-tion.