BACKGROUND:Rev-erbα is involved in the regulation of inflammation,but pharmacological activation of Rev-erbα increases the risk for cardiovascular diseases.To reduce the relevant risk,an exploration on SR9009,a Rev-erbα agonist,combined with other drugs to relieve inflammation in skeletal myoblasts was conducted,laying the theoretical foundation for the treatment of inflammation-associated skeletal muscle atrophy. OBJECTIVE:To investigate the relationship of SR9009,indolepropionic acid and nuclear factor-κB signaling pathways in lipopolysaccharide-induced C2C12 myoblasts. METHODS:(1)C2C12 myoblasts were induced to differentiate in the presence of lipopolysaccharide(1 μg/mL).RNA-seq and KEGG pathway analysis were used to study signaling pathways.(2)C2C12 myoblast viability was assessed using the cell counting kit-8 assay to determine optimal concentrations of indolepropionic acid.Subsequently,cells were categorized into control group,lipopolysaccharide(1 μg/mL)group,SR9009(10 μmol/L)+lipopolysaccharide group,indolepropionic acid(80μmol/L)+lipopolysaccharide group,and SR9009+indolepropionic acid+lipopolysaccharide group.ELISA was employed to measure protein expression levels of interleukin-6 in the cultured supernatant.Real-time quantitative PCR were employed to measure mRNA expression levels of interleukin-6,tumor necrosis factor α,TLR4 and CD14.Western blot assay were employed to measure protein expression levels of NF-κB p65 and p-NF-κB p65.(3)After Rev-erbα was knocked down by siRNA,knockdown efficiency was assessed by RT-qPCR.And mRNA levels of interleukin-6 and tumor necrosis factor α were also measured. RESULTS AND CONCLUSION:Compared with the blank control group,lipopolysaccharide time-dependently inhibited myofibroblast fusion to form myotubes,the mRNA expression levels of interleukin-6 and tumor necrosis factor α were elevated,and the level of interleukin-6 in the cell supernatant was significantly increased.The results of KEGG pathway showed that the nuclear factor-κB signaling pathway was activated by lipopolysaccharide.Indolepropionic acid exhibited significant suppression of C2C12 myoblasts viability when its concentration exceeded 80 μmol/L.Indolepropionic acid and SR9009 inhibited the activation of NF-κB signaling pathway,thereby played an anti-inflammatory role,and suppressed the mRNA expression levels of interleukin-6,tumor necrosis factor α,TLR4 and CD14.Compared with the lipopolysaccharide group,the ratio of p-NF-κB p65/NF-κB p65 protein expression were downregulated.SR9009 combined with indolepropionic acid notably reduced lipopolysaccharide-induced inflammation,further downregulated the mRNA expression levels of interleukin-6,tumor necrosis factor α,TLR4 and CD14.The ratio of p-NF-κB p65/NF-κB p65 protein expression was significantly lower than that in the SR9009+lipopolysaccharide group or indolepropionic acid+lipopolysaccharide group.Rev-erbα increases time-dependently with lipopolysaccharide induction.The knockdown efficiency of Rev-erbα by siRNA reached over 58%,and lipopolysaccharide was added after Rev-erbα was successfully knocked down.Compared with the lipopolysaccharide group,the mRNA expression levels of interleukin-6 and tumor necrosis factor α were significantly up-regulated.These results conclude that Rev-erbα may act as a promising pharmacological target to reduce inflammation.SR9009 targeted activation of Rev-erbα combined with indolepropionic acid significantly inhibits the nuclear factor-κB signaling pathway and attenuates the inflammatory response of C2C12 myofibroblasts.Moreover,the combined anti-inflammatory effect is superior to that of the intervention alone.

BACKGROUND: The available evidence regarding the benefits of percutaneous coronary intervention (PCI) on patients receiving dialysis with coronary artery disease (CAD) is limited and inconsistent. This study aimed to evaluate the association between PCI and clinical outcomes as compared with medical therapy alone in patients undergoing dialysis with CAD in China. METHODS: This multicenter, retrospective study was conducted in 30 tertiary medical centers across 12 provinces in China from January 2015 to June 2021 to include patients on dialysis with CAD. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Secondary outcomes included all-cause death, the individual components of MACE, and Bleeding Academic Research Consortium criteria types 2, 3, or 5 bleeding. Multivariable Cox proportional hazard models were used to assess the association between PCI and outcomes. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were performed to account for potential between-group differences. RESULTS: Of the 1146 patients on dialysis with significant CAD, 821 (71.6%) underwent PCI. After a median follow-up of 23.0 months, PCI was associated with a 43.0% significantly lower risk for MACE (33.9% [ n  = 278] vs . 43.7% [ n  = 142]; adjusted hazards ratio 0.57, 95% confidence interval 0.45-0.71), along with a slightly increased risk for bleeding outcomes that did not reach statistical significance (11.1% vs . 8.3%; adjusted hazards ratio 1.31, 95% confidence interval, 0.82-2.11). Furthermore, PCI was associated with a significant reduction in all-cause and cardiovascular mortalities. Subgroup analysis did not modify the association of PCI with patient outcomes. These primary findings were consistent across IPTW, PSM, and competing risk analyses. CONCLUSION This study indicated that PCI in patients on dialysis with CAD was significantly associated with lower MACE and mortality when comparing with those with medical therapy alone, albeit with a slightly increased risk for bleeding events that did not reach statistical significance.
Humans ; Percutaneous Coronary Intervention/methods* ; Male ; Female ; Coronary Artery Disease/drug therapy* ; Retrospective Studies ; Renal Dialysis/methods* ; Middle Aged ; Aged ; China ; Proportional Hazards Models ; Treatment Outcome

Triple-negative breast cancer is therapeutically challenging due to the low expression of tumor markers and 'cold' tumor immunosuppressive microenvironment. Here, we present a dual-targeting peptide-drug conjugate (PDC) for tumor inhibition. Our PDC efficiently and selectively delivers cytotoxic Monomethyl Auristatin E (MMAE) into tumor cells via C-X-C chemokine receptor type 4 (CXCR4) and folate receptor 1 (FOLR1) for synergistic inhibition of growth and metastasis. Our results show that the dual-targeting PDC has potent antitumor activity in cultured human cells and several murine transplanted tumor models without apparent toxicity. The combination of dual-targeting PDC and radiotherapy modulates the tumor immunosuppressive microenvironment by increasing CD8⁺ T cell infiltration and attenuating the proportion of myeloid-derived suppressor and regulatory T cells. Therefore, our dual-targeting PDC represents a promising new strategy for cancer therapy that rebalances the immune system and promotes tumor regression.

Early correction of childhood malocclusion is timely managing morphological, structural, and functional abnormalities at different dentomaxillofacial developmental stages. The selection of appropriate imaging examination and comprehensive radiological diagnosis and analysis play an important role in early correction of childhood malocclusion. This expert consensus is a collaborative effort by multidisciplinary experts in dentistry across the nation based on the current clinical evidence, aiming to provide general guidance on appropriate imaging examination selection, comprehensive and accurate imaging assessment for early orthodontic treatment patients.
Humans ; Malocclusion/diagnostic imaging* ; Child ; Consensus

Objective:To investigate the relationship between three-dimensional choroidal vascularity index (3D CVI) and the severity of diabetic retinopathy (DR) using swept-source optical coherence tomography angiography (SS-OCTA).Methods:A cross-sectional study was conducted.A total of 139 eyes of 139 subjects, including 115 eyes with diabetes mellitus and 24 control eyes without diabetes, were enrolled in the Second People's Hospital of Hefei from March to December 2022.DR was graded according to the standard seven-field ETDRS color fundus photographs.Eyes with diabetes mellitus were divided into non-DR (NDR) group (34 eyes), non-proliferative DR (NPDR) group (42 eyes), NPDR with diabetic macular edema (DME) group (21 eyes) and PDR group (18 eyes).3D CVI in central fovea 1 mm (C1) and parafoveal 3 mm (C3), choroidal vascular volume (CVV), and choroidal thickness were measured by SS-OCTA in the area of 3 mm×3 mm centered on the fovea using the built-in automated quantification software.Parafoveal region was divided into superior, inferior, temporal and nasal quadrants, and 3D CVI of the different quadrants was detected.3D CVI was defined as the ratio of CVV to total choroidal volume.The monocular data were analyzed to compare 3D CVI among the five groups, and multiple linear regression analysis was used to evaluate the influencing factors.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of the Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University (No.2022064).All subjects were aware of the study purpose and agreed to participate the study.Results:There were significant differences in 3D CVI-C1 and 3D CVI-C3 among all groups ( F=3.103, 3.036, both at P<0.05).In PDR group, 3D CVI-C1 was lower than in non-DR group, and 3D CVI-C3 was lower than in control group and non-DR group, with statistically significant differences (all at P<0.05).There were significant differences in 3D CVI in the inferior and nasal quadrants among all groups ( F=2.714, 4.020, both at P<0.05).In PDR group, 3D CVI in the inferior quadrant was lower than that in non-DR group, and 3D CVI in nasal quadrant in PDR group was lower than that in control group, non-DR group, NPDR group and NPDR with DME group, with statistically significant differences (all at P<0.05).Multiple linear regression showed that after controlling for age, course of disease and glycosylated hemoglobin, the severity of DR was the influencing factor of 3D CVI in fovea and parafovea.PDR eyes had the greatest impact on 3D CVI in fovea and parafovea.Compared with non-DR eyes, there was a -0.019(95% CI: -0.031--0.007, P=0.003) decrease in central foveal 3D CVI and a -0.019(95% CI: -0.030--0.008, P=0.001) decrease in parafoveal 3D CVI in PDR eyes, followed by a 0.014(95% CI: -0.027-0.000, P=0.044) decrease in central foveal 3D CVI in NPDR with DME eyes. Conclusions:Macular foveal 3D CVI correlates with DR severity, and a decrease in 3D CVI of large vessels in the macular choroid may be a sensitive indicator of DR exacerbation.

ObjectiveTo determine the mechanism of Yitangkang in correcting excessive apoptosis of skeletal muscle cells to improve insulin resistance （IR） by inhibiting the advanced glycation end product （AGE）/receptor for the advanced glycation end product （RAGE） signaling pathway. Method① In vitro experiments. Yitangkang-medicated serum was prepared. C2C12 cells were divided into a blank group， a model group， high-， medium-， and low-dose Yitangkang-medicated serum groups （40， 20， and 10 g·kg^-1）， and a RAGE inhibitor group. The IR model was induced by palmitic acid in C2C12 cells except for those in the blank group. After the corresponding intervention methods were conducted，the cell viability and glucose consumption level of each group were determined. In addition，the apoptosis rate was determined using flow cytometry. The mRNA and protein expression levels of the important apoptotic proteins ［B-cell lymphoma 2 （Bcl-2）， Bcl-2-associated X protein （Bax）， p53， cysteinyl aspartate-specific protease-3 （Caspase-3）， and cysteinyl aspartate-specific protease-9 （Caspase-9）］ were determined using Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot. ② In vivo experiments. Ninety-six eligible Wistar rats were divided into a blank group， a model group， high-，medium-，and low-dose Yitangkang groups （40， 20， and 10 g·kg^-1）， and a western medicine group （pioglitazone hydrochloride，1.35 mg·kg^-1）. The IR model was induced using high-glucose and high-fat feed for diabetes combined with intraperitoneal injection of low-dose streptozotocin （STZ） in animals and verified by the hyperinsulinemic-euglycemic clamp （HEC） test. After the model was determined successfully， the rats in each group were given intragastric administration of drugs as required. Terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） assay was performed to determine the number of positive apoptotic cells in the skeletal muscle tissues of rats in each group，while Real-time polymerase chain reaction（Real-time PCR） and Western blot were performed to determine the mRNA and protein expression levels of the important apoptotic proteins Bcl-2， Bax， p53， Caspase-3， and Caspase-9. Result① In vitro experiments. compared with the blank group， the model groups showed increased apoptosis rate of C2C12 cells and decreased cell viability and glucose consumption （P<0.01）. Compared with the model group， the Yitangkang-medicated serum groups and the RAGE inhibitor group showed decreased apoptosis rate of C2C12 cells and increased cell viability and glucose consumption （P<0.01）. Compared with the blank group， the model group showed decreased expression levels of Bcl-2 mRNA and protein in C2C12 cells and increased mRNA and protein expression levels of Bax， p53， Caspase-3， and Caspase-9 （P<0.01）. Compared with the model group， the Yitangkang-medicated serum groups and the RAGE inhibitor group showed increased expression levels of Bcl-2 mRNA and protein in C2C12 cells （P<0.01） and decreased mRNA and protein expression levels of Bax， p53， Caspase-3， and Caspase-9 （P<0.05， P<0.01）. ② In vivo experiments. The number of positive apoptotic cells in the skeletal muscle tissues of rats in the model group significantly increased as compared with that in the blank group （P<0.01）. The number of positive apoptotic cells in the skeletal muscle tissues of rats in the Yitangkang groups and the western medicine group decreased as compared with that in the model group （P<0.01）. Compared with the blank group， the model group showed decreased expression levels of Bcl-2 mRNA and protein in skeletal muscle tissues of rats and increased mRNA and protein expression levels of Bax， p53， Caspase-3， and Caspase-9 （P<0.01）. Compared with the model group， the Yitangkang groups and the western medicine group showed increased expression levels of Bcl-2 mRNA and protein in skeletal muscle tissues of rats （P<0.01） and decreased mRNA and protein expression levels of Bax， p53， Caspase-3， and Caspase-9 （P<0.05， P<0.01）. The medium-dose Yitangkang showed a similar effect as RAGE inhibitor， and the effect was equivalent to that of pioglitazone hydrochloride. ConclusionYitangkang can inhibit skeletal muscle cell apoptosis by inhibiting the AGE/RAGE signaling pathway.

Objective : To investigate the effects of hypoxia , high glucose single factor and hypoxia high glucose compound factors on the pyroptosis of rat glomerular podocytes . Methods : Rat glomerular podocytes were cultured in vitro and randomly divided into control group , high glucose group , hypoxia group and hypoxia high glucose group , EdU method was used to detect the cell proliferation , transmission electron microscope was used to observe the morphology and size changes of nucleus and mitochondria , and Western blot was used to detect pyroptosis related proteins nucleotide⁃binding oligomerization domain⁃like receptor protein 3(NLRP3) , Cysteinyl aspartate specific proteinase⁃1(Caspase⁃1) , gasdermin( GSDMD) and inflammatory factor pro⁃interleukin⁃1β( Pro⁃IL⁃1β) , interleukin(IL) Ⅳ1β , IL⁃18 . The effect of hypoxia and high glucose on the pyroptosis of rat glomerular podocytes was analyzed . Results : EdU results showed that hypoxia and high glucose inhibited the proliferation ability of rat glomerlar podocytes (P < 0. 05) . The results of transmission electron microscopy suggested that hypoxia and high glucose promoted the occurrence of pyroptosis of rat glomerular podocytes . Western blot showed that hypoxia and high glucose promoted pyroptosis of rat glomerular podocytes , and increased the expression of pyroptosis related proteins NLRP3 , Caspase⁃1 and GSDMD , among which the expression of pyroptosis protein increased most significantly in hypoxia and high glucose group (P < 0. 05) . At the same time , it also increased the expression of pro⁃inflammatory factor Pro⁃IL⁃1β , IL⁃1β and IL⁃18 (P < 0. 05) . Conclusion hypoxia and high glucose can induce pyroptosis of rat glomerular podocytes , one of the mechanisms may be through affecting NLRP3 ⁃Caspase⁃1 ⁃GSDMD and its down⁃ stream inflammatory factors .

Objective:To investigate the effect of the mechanism of lnc-SLC2A12-10:1 derived from tumor-associated macrophages (TAMs) exosomes on the proliferation and invasion of breast cancer (BC) cells.Methods:GEO microarray analysis was used to screen out the differentially expressed lnc-SLC2A12-10:1 in BC. qRT-PCR was performed to determine the expression level of lnc-SLC2A12-10:1 and miR-296-5p in tissue and cells. Then TAMs and exosomes were isolated. After, interfering the expression level of lnc-SLC2A12-10:1 in exosomes and miR-296-5p expression in cells, then cell proliferation and invasion were detected with the help of MTT and Transwell assays.Results:Compared with adjacent tissues, lnc-SLC2A12-10:1 was significantly up-regulated in BC tissues ( t=7.09, P<0.001) . Compared with normal breast cells, the expression of lnc-SLC2A12-10:1 in T47D and MDA-MB-468 cells was significantly up-regulated ( t=9.90, P<0.001) ( t=12.18, P<0.001) . lnc-SLC2A12-10:1 could act as a ceRNA of miR-296-5p. Knockdown of lnc-SLC2A12-10:1 inhibited BC cell proliferation and invasion, miR-296-5p inhibitor promoted BC cell proliferation and invasion, but this effect could be partially rescued by si--lnc-SLC2A12-10:1-Exo (all P<0.05) . Conclusion:lnc-SLC2A12-10:1 derived from TAMs exosomes promotes BC cell proliferation, invasion and thus advance BC progression.

Objective:To evaluate the possible mediation effect of smoking and healthy diet score on the association between educational level and the risk of lung cancer incidence.Methods:After excluding individuals with missing educational levels and cancer information at baseline, 446?772 participants in the UK Biobank (UKB) prospective cohort study were included. Cox regression models were used to investigate the associations of educational level and smoking and healthy diet score with the incidence of lung cancer. Mediating effect analysis was conducted to analyze the mediating effect of smoking and healthy diet score on the correlation between educational level and lung cancer.Results:During a median follow-up of 7.13 years, 1?994 new- onset lung cancer cases were observed. Per 1 standard deviation (5 years) increase in educational level was associated with a 12% lower risk of lung cancer ( HR=0.88, 95% CI: 0.84-0.92). The corresponding level 1-5 in the International Standard Classification for Education (ISCED) were mapped to UKB self‐report highest qualification to estimate the educational level. A higher rank means a higher educational level. Compared with level ISCED-1, the HR(95% CI) of level ISCED-2, ISCED-3, ISCED-4 and ISCED-5 were respectively 0.83 (0.72-0.94), 0.67 (0.53-0.85), 0.76 (0.65-0.89) and 0.72 (0.64-0.80) for lung cancer. Education years were negatively correlated with smoking, with β coefficients (95% CI) being -0.079 (-0.081- -0.077), but positively correlated with healthy diet score ( β=0.042, 95% CI: 0.039-0.045). Analysis of mediating effect indicated that the association of educational level with lung cancer risk was mediated by smoking and healthy diet score, the proportions of mediating effect were 38.952% (95% CI: 31.802%-51.659%) and 1.784% (95% CI: 0.405%-3.713%), respectively. Conclusion:Smoking and healthy diet score might mediate the effect of educational level on the incidence of lung cancer, indicating that improving the level of education can reduce the risk of lung cancer by changing lifestyles such as smoking and diet.

Objective:To construct a core competency evaluation index system for ophthalmic specialist nurses so as to provide theoretical reference for cultivation and evaluation of ophthalmic specialized nurses in China.Methods:A research group was set up in October 2020, and the core competency evaluation index system for ophthalmic specialist nurses was initially formed by means of literature review, semi-structured interview and group discussion. From December 2020 to January 2021, an online questionnaire was used to conduct Delphi letter consultation among 23 experts in related fields nationwide, and the items were screened and modified. The weight of indicators was determined by the proportional distribution method.Results:Two rounds of consultation were conducted. The positive coefficients of experts were respectively 91.30% and 100.00%, Kendall's concordance coefficients were respectively 0.172 and 0. 192 ( P<0.05) , and the expert authority coefficient was 0.90. Finally, an index system consisting of 5 first-level indicators, 12 second-level indicators and 58 third-level indicators was formed. Conclusions:The core competence evaluation index system of ophthalmic specialist nurses constructed in this study has a high degree of enthusiasm and authority of experts, which reflects the characteristics of the ophthalmic nursing specialty and provides theoretical reference for cultivation and ability evaluation of ophthalmic specialist nurses in China.