Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn-deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.

Objective To investigate the effect of forsythigenin on the malignant progression of lung cancer cells by regulating the cyclic adenosine monophosphate/exchange protein directly activated by cAMP1/Ras-associated protein 1(cAMP/EPAC1/RAP1)signaling pathway.Methods Lung cancer cell line A549 was cultured in vitro and grouped into the control group,the low dose forsythigenin group(25 mg/L),the medium dose forsythigenin group(50 mg/L),the high dose forsythigenin group(100 mg/L),the high dose forsythigenin+specific increase in intracellular cAMP content(pertussis toxin PTX)group(100 mg/L forsythigenin+5 μmol/L PTX)and high dose forsythigenin+EPAC1 antagonist(ESI-09)group(100 mg/L forsythigenin+1.5 μmol/L ESI-09).CCK-8 experiment was applied to detect cell proliferation.Scratch test was applied to detect cell migration.Flow cytometry was applied to detect cell apoptosis.Transwell was applied to detect cell invasion.ELISA method was applied to detect cAMP level in cell supernatant.Western blot assay was applied to detect expression levels of cAMP/EPAC1/RAP1 signaling pathway proteins and apoptotic proteins[B lymphoblastoma-2(Bcl-2)and Bcl-2 associated X protein(Bax)].Results Compared with the control group,the OD450 value of A549 cells,number of cell invasions,scratch healing rate,level of cAMP,expression levels of Bcl-2,EPAC1 and RAP1 proteins were significantly reduced in the low dose,medium dose and high dose forsythigenin groups,and the expression of Bax protein and the rate of cell apoptosis were significantly increased in a dose-dependent manner(P＜0.05).Compared with the high-dose forsythigenin group,the OD450 value of A549 cells,scratch healing rate,number of cell invasions,level of cAMP,expression levels of Bcl-2,EPAC1 and RAP1 proteins were obviously increased in the high-dose forsythigenin+PTX group,the expression of Bax protein and the apoptosis rate were obviously reduced(P＜0.05).Levels of all indexes in the high dose forsythigenin+ESI-09 group were opposite.Conclusion Forsythigenin inhibits proliferation,migration,and invasion of A549 cells and promotes apoptosis by down-regulating the cAMP/EPAC1/RAP1 signaling pathway.

Objective To investigate the effect of forsythigenin on the malignant progression of lung cancer cells by regulating the cyclic adenosine monophosphate/exchange protein directly activated by cAMP1/Ras-associated protein 1(cAMP/EPAC1/RAP1)signaling pathway.Methods Lung cancer cell line A549 was cultured in vitro and grouped into the control group,the low dose forsythigenin group(25 mg/L),the medium dose forsythigenin group(50 mg/L),the high dose forsythigenin group(100 mg/L),the high dose forsythigenin+specific increase in intracellular cAMP content(pertussis toxin PTX)group(100 mg/L forsythigenin+5 μmol/L PTX)and high dose forsythigenin+EPAC1 antagonist(ESI-09)group(100 mg/L forsythigenin+1.5 μmol/L ESI-09).CCK-8 experiment was applied to detect cell proliferation.Scratch test was applied to detect cell migration.Flow cytometry was applied to detect cell apoptosis.Transwell was applied to detect cell invasion.ELISA method was applied to detect cAMP level in cell supernatant.Western blot assay was applied to detect expression levels of cAMP/EPAC1/RAP1 signaling pathway proteins and apoptotic proteins[B lymphoblastoma-2(Bcl-2)and Bcl-2 associated X protein(Bax)].Results Compared with the control group,the OD450 value of A549 cells,number of cell invasions,scratch healing rate,level of cAMP,expression levels of Bcl-2,EPAC1 and RAP1 proteins were significantly reduced in the low dose,medium dose and high dose forsythigenin groups,and the expression of Bax protein and the rate of cell apoptosis were significantly increased in a dose-dependent manner(P＜0.05).Compared with the high-dose forsythigenin group,the OD450 value of A549 cells,scratch healing rate,number of cell invasions,level of cAMP,expression levels of Bcl-2,EPAC1 and RAP1 proteins were obviously increased in the high-dose forsythigenin+PTX group,the expression of Bax protein and the apoptosis rate were obviously reduced(P＜0.05).Levels of all indexes in the high dose forsythigenin+ESI-09 group were opposite.Conclusion Forsythigenin inhibits proliferation,migration,and invasion of A549 cells and promotes apoptosis by down-regulating the cAMP/EPAC1/RAP1 signaling pathway.

Objectives:To observe the incidence of residual shunt post patent foramen ovale(PFO)closure and the effect of PFO closure in these migraine patients at one year after PFO. Methods:This retrospective study included patients who underwent PFO closure for migraine in the Second Affiliated Hospital Zhejiang University School of Medicine from January 2019 to June 2022,patients were divided into the grade 0 shunt group(n=67),the grade Ⅰ shunt group(n=10),the grade Ⅱ shunt group(n=13)and the grade Ⅲ shunt group(n=16)according to the results of contrast transthoracic echocardiography(cTTE)at 1 year after PFO closure.The incidence of postoperative migraine attacks among different groups of patients were compared.The risk factors of residual shunt after PFO closure were explored. Results:The mean age of enrolled 106 patients with migraine was(35.80±11.70)years,of which 83 patients(78.30%)were female.One year after PFO closure,the migraine attack and rating scale were significantly decreased compared to baseline in the grade 0 shunt group,in the grade Ⅰ shunt group and in the grade Ⅱ shunt group(all P<0.05),but not in the grade Ⅲ shunt group(P>0.05).The rate of significant and complete migraine was significantly higher in the grade 0 shunt group(58.21%),in the gradeⅠ shunt group(60.00%),in the grade Ⅱ shunt group(69.23%)as compared to the grade Ⅲ shunt group(18.75%,P=0.02)at one year after PFO.The rate of grade 0 shunt after PFO closure in patients with the microvesicles appearing in≥6 cardiac cycles in resting state before operation was significantly lower than in patients with the microvesicles appearing within 6 cardiac cycles and no microvesicles in resting state(24.00%vs.83.87%vs.70.00%,P=0.04).Logistic multivariate regression analysis showed that patients with microvesicles appearing beyond 6 cardiac cycles in resting state were more likely to have residual shunts in postoperative cTTE compared to the patients with negative cTTE and microvesicles appearing within 6 cardiac cycles in the cTTE in resting state before operation(OR=0.06,95%CI:0.02-0.23,P<0.01;OR=0.014,95%CI:0.05-0.41,P<0.01). Conclusions:Migraine patients who underwent PFO closure and with grade 0 to grade Ⅱ residual shunt at one year after PFO are most likely to have significant remission of migraine,while the incidence of migraine remission is low in patients with grade Ⅲresidual shunt.The incidence of residual shunt after PFO closure is higher in patients with the microvesicles appearing in 6 cardiac cycles in resting state in the cTTE before operation than in patients with the microvesicles appearing within 6 cardiac cycles and no microvesicles.

The guidelines advocate for preoperative neoadjuvant radiotherapy and chemotherapy in cases of middle and low locally advanced rectal cancer. While some patients achieved pathological complete response (pCR), which is favorable and allows for potential organ preservation, treatment sensitivity varies and not all patients reach pCR. Identifying the factors influencing pCR is important for enhancing the effectiveness of neoadjuvant therapy and improving patient outcomes. Previous research has identified various factors associated with response to neoadjuvant therapy, which can serve as predictors of pCR. This study reviews recent literature on imaging, pathological, genetic, and molecular characteristics, laboratory indices, and therapeutic factors related to tumor response, both domestically and internationally. The aim is to summarize the latest advancements in understanding the factors associated with pCR in patients with locally advanced middle and low rectal cancer undergoing neoadjuvant therapy, thereby providing a theoretical foundation for standardized clinical treatment approaches.

The guidelines advocate for preoperative neoadjuvant radiotherapy and chemotherapy in cases of middle and low locally advanced rectal cancer. While some patients achieved pathological complete response (pCR), which is favorable and allows for potential organ preservation, treatment sensitivity varies and not all patients reach pCR. Identifying the factors influencing pCR is important for enhancing the effectiveness of neoadjuvant therapy and improving patient outcomes. Previous research has identified various factors associated with response to neoadjuvant therapy, which can serve as predictors of pCR. This study reviews recent literature on imaging, pathological, genetic, and molecular characteristics, laboratory indices, and therapeutic factors related to tumor response, both domestically and internationally. The aim is to summarize the latest advancements in understanding the factors associated with pCR in patients with locally advanced middle and low rectal cancer undergoing neoadjuvant therapy, thereby providing a theoretical foundation for standardized clinical treatment approaches.

Objective:To investigate the impact of the clinicopathological characteristics of anorectal malignant melanoma (ARMM) on the prognosis.Methods:The clinicopathological data of 40 ARMM patients undergoing surgery at the Department of Colorectal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences from Apr 2012 to Apr 2022 were collected, and the impact of different clinicopathological factors and treatment modalities on the overall survival of ARMM patients was investigated using Kaplan-Meier survival analysis and multifactorial Cox proportional risk model analysis.Results:Among 40 ARMM patients , 16 were male and 24 were female. The median age of onset was 61 yr. The median follow-up period for all patients was 47 (25-69) months, with a median survival of 19 (15-23) months and 1-year and 3-year survival rates of 74.3% and 21.7%, respectively. There was no statistically significant difference in survival time between the two groups of patients receiving wide local excision and abdominoperineal resection( χ2=1.281, P=0.258). Univariate analysis showed that overall survival in patients with ARMM was related to tumour diameter, depth of infiltration, specimen margin and lymph node metastasis ( χ2=1.281, P=0.039; χ2=3.760, P=0.042; χ2=6.581, P=0.010; χ2=21.683, P<0.001), and multivariate analysis suggested that lymph node metastasis was an independent risk factor for overall survival in patients with ARMM. Conclusion:Tumour diameter, depth of infiltration, specimen margin and lymph node metastasis were important prognostic influences in ARMM, and lymph node metastasis was an independent risk factor for overall survival in ARMM patients.

The effect of vitamin D supplementation on individuals with autism spectrum disorder (ASD) is inconclusive. We aimed to conduct a meta-analysis of the available randomized controlled trials (RCTs) to explore whether vitamin D supplementation can improve core symptoms and coexisting conditions in children with ASD. Data were obtained by searching the PubMed, Embase, Web of Science, CINAHL and Cochrane Library databases up to February 2022 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using a random-effects model, mean differences with 95% confidence intervals (CIs) were calculated through a meta-analysis. There were eight RCTs with 266 children with ASD in the present review, among which six RCTs were included in the meta-analysis.Children who received vitamin D supplementation showed a significant improvement in stereotypical behavior scores (pooled mean difference (MD): −1.39; 95% CI: −2.7, −0.07; p = 0.04) with low heterogeneity (I2 = 34%), and there was a trend toward decreased total scores on the Social Responsiveness Scale (SRS) and Childhood Autism Rating Scale (CARS, p = 0.05); however, there were no other significant differences in the core symptoms of ASD and coexisting conditions between groups as measured by the Aberrant Behavior Checklist (ABC). Vitamin D supplementation appears to improve stereotypical behaviors but does not improve other core symptoms and coexisting conditions. Further randomized controlled trials with large sample sizes and individualized doses are needed.

Objective:To compare the left ventricular (LV) reverse remodeling after transcatheter aortic valve replacement (TAVR) between patients with bicuspid aortic valve (BAV) stenosis and tricuspid aortic valve (TAV) stenosis.Methods:The data of patients who underwent TAVR procedure from March 2013 to December 2018 in the Second Affiliated Hospital of Zhejiang University were retrospectively reviewed. The patients were divided into BAV group and TAV group according to cardiac computed tomography. Echocardiographic parameters, including aortic valve peak velocity (Vmax), mean gradient (PGmean), effective orifice area(EOA), interventricular septum diastolic thickness (IVSd), left ventricular posterior wall diastolic thickness (LVPWd), left ventricular end diastolic diameter( LVEDd), LV mass index (LVMI), ΔLVMI%, left ventricular ejection fraction( LVEF) of the two groups at baseline, 1 week, 1 month and 1 year post TAVR procedure were obtained and compared.Results:①Compared with preoperative measurements, both groups showed decreases in Vmax, PGmean and increase in EOA at 1 week, 1 month, 1 year follow-ups(all P<0.05). No significant differences were found in Vmax, PGmean, EOA, moderate/sever perivalvular leakage(PVL), moderate/sever prosthetic-patient mismatch(PPM) between BAV group and TAV group at 1 year. ②Both groups showed decreases in IVSd, LVPWd, LVEDd at 1 month, 1 year post TAVR compared with those before the procedure (all P<0.05), as well as increases in LVEF at 1 week, 1 month, 1 year (all P<0.05). Downward trends of LVMI were detected in both groups within 1 year follow-up( P<0.05). ③Compared to TAV group, BAV group showed smaller baseline LVMI( P<0.05), while there were no significant differences in ΔLVMI% post TAVR for all follow-up times of the two groups(all P>0.05). Repeated measures analysis of variance also showed no significant differences in downward trend of LVMI between the two groups after TAVR within 1 year( P>0.05). Conclusions:Left ventricular reverse remodeling can be detected in both BAV and TAV patients after TAVR, which starts from 1 week and can be lasted for 1 year post procedure. Patients with bicuspid morphology might experience similar reverse LV remodeling post TAVR versus patients with tricuspid morphology.

Objective:To explore the value of transesophageal echocardiography(TEE) guidance for transcatheter DragonFly? system edge-to-edge tricuspid regurgitation (TR) repair.Methods:Five cases who were chosen in the Second Affiliated Hospital, Zhejiang University School of Medicine from December 2020 to January 2021 with surgical high-risk and severe functional TR underwent transcatheter DragonFly edge-to-edge repair with the guidance of TEE. Preoperative TEE was used to evaluate the tricuspid valve anatomy and the origin and etiology of regurgitation in detail; intra-procedure guidance of TEE was performed during the DragonFly system for tricuspid valve edge-to-edge repair intervention and after release of the DragonFly clip, the effect of surgery was assessed immediately and compared with pre-procedure TEE.Results:A total of 10 DragonFly clips were implanted in 5 patients (3 in each of patients, 2 in 1 patient, and 1 in each of patients). One of the 3 clips in 1 patient fell off unilaterally from the septal valve after release, and the other 9 clips were well positioned and fixed. Immediately post-operation assessment by TEE depicted the TR in 3 patients declined to mild and 2 to moderate. The vena contracta area by using three-dimensional color blood flow quantitative assessment was reduced[(0.93±0.26)cm 2 vs (0.20±0.11)cm 2]. No complications such as serious tricuspid valve injury, pericardial tamponade, thromboembolism occurred in the 5 patients. Conclusions:TEE plays an important role in guiding and monitoring transcatheter DragonFly system edge-to-edge TR repair during the entire procedure.