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BACKGROUND: Preoperative urinary dickkopf-3 (DKK3) is proposed as an early biomarker for the prediction of acute kidney injury (AKI) in patients undergoing cardiac surgery. We explored the clinical utility of urinary DKK3 for the early predictive value for AKI, sepsis-associated AKI (SA-AKI), and pediatric intensive care unit (PICU) mortality in critically ill children. METHODS: Urine samples were collected during the first 24 h after admission for measurement of DKK3. AKI diagnosis was based on serum creatinine and urine output using the KDIGO criteria. SA-AKI was defined as AKI that occurred in children who met the sepsis criteria in accordance with the surviving sepsis campaign international guidelines for children. RESULTS: Of the 420 children, 73 developed AKI, including 24 with SA-AKI, and 30 died during the PICU stay. The urinary DKK3 level was significantly associated with AKI, SA-AKI, and PICU mortality, even after adjustment for confounders. The area under the receiver operating characteristic curve of urinary DKK3 for the discrimination of AKI, SA-AKI, and PICU mortality was 0.70, 0.80, and 0.78, respectively. CONCLUSION: Urinary DKK3 was independently associated with an increased risk for AKI, SA-AKI, and PICU mortality and may be predictive of the aforementioned issues in critically ill children. IMPACT: Urinary dickkopf-3 (DKK3) has been identified as a preoperative biomarker for the prediction of acute kidney injury (AKI) following cardiac surgery or coronary angiography in adult patients. However, little is known about the clinical utility of urinary DKK3 in pediatric cohorts. This study demonstrated that urinary DKK3 is capable of early predicting AKI and pediatric intensive care unit (PICU) mortality and discriminating sepsis-associated AKI (SA-AKI) from other types of AKI. Urinary DKK3 may be an early biomarker for predicting AKI, SA-AKI, and PICU mortality in critically ill children.
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Injúria Renal Aguda , Sepse , Criança , Humanos , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Biomarcadores/urina , Estado Terminal , Unidades de Terapia Intensiva Pediátrica , Estudos Prospectivos , Sepse/complicaçõesRESUMO
BACKGROUND: Bronchopulmonary dysplasia (BPD) has long been considered the most challenging chronic lung disease for neonatologists and researchers due to its complex pathological mechanisms and difficulty in prediction. Growing evidence indicates that BPD is associated with the dysregulation of circular RNAs (circRNAs). Therefore, we aimed to explore the expression profiles of circRNAs and investigate the underlying molecular network associated with BPD. METHODS: Peripheral blood was collected from very-low-birth-weight (VLBW) infants at 5-8 days of life to extract PBMCs. Microarray analysis and qRT-PCR tests were performed to determine the differentially expressed circRNAs (DEcircRNAs) between BPD and non-BPD VLBW infants. Simultaneous analysis of GSE32472 was conducted to obtain differentially expressed mRNAs (DEmRNA) from BPD infants. The miRNAs were predicted by DEcircRNAs and DEmRNAs of upregulated, respectively, and then screened for overlapping ones. GO and KEGG analysis was performed following construction of the competing endogenous RNA regulatory network (ceRNA) for further investigation. RESULTS: A total of 65 circRNAs (52 upregulated and 13 downregulated) were identified as DEcircRNAs between the two groups (FC >2.0 and p.adj <0.05). As a result, the ceRNA network was constructed based on three upregulated DEcircRNAs validated by qRT-PCR (hsa_circ_0007054, hsa_circ_0057950, and hsa_circ_0120151). Bioinformatics analysis indicated these DEcircRNAs participated in response to stimulus, IL-1 receptor activation, neutrophil activation, and metabolic pathways. CONCLUSIONS: In VLBW infants with a high risk for developing BPD, the circRNA expression profiles in PBMCs were significantly altered in the early post-birth period, suggesting immune dysregulation caused by infection and inflammatory response already existed.
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Displasia Broncopulmonar , MicroRNAs , RNA Circular , Humanos , Recém-Nascido , Displasia Broncopulmonar/genética , Biologia Computacional , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , RNA Mensageiro/genética , Perfilação da Expressão GênicaRESUMO
BACKGROUND: Stromal vascular fraction (SVF) has been proved in promoting the vascularization of fascial flap through cell differentiation and paracrine effect and can be autologous transplanted without culture after isolation in vitro. We intend to establish a novel co-grafted flap model of rats to investigate the efficacy and mechanism of SVF on flaps and skinsin facilitating angiogenesis and immune regulation. METHOD: 60 female Sprague Dawley rats were divided into the SVF group and the control group. A pedicled fascial flap combined with a free skin model was established, and 4×106 CM-DIl labeled SVF cells were transplanted into the fascia flap; the rats were executed on days 1, 2, 3, 7, 10 postoperatively (n = 6). Flow cytometry was carried out to determine the cell proportion and surface marker of SVFs. The therapeutic effects of SVF were evaluated via Doppler blood perfusion imager, flap survival rates, histology, immunohistochemistry and immunofluorescence. The bioinformatic mechanism analysis was achieved by high-throughput RNAseq of mRNA and LncRNA. RESULT: Flow cytometry confirmed SVF contains heterogeneous cellular composition, especially hematopoietic cells. Doppler blood perfusion imager showed SVF significantly improved flap survival with higher blood perfusion and survival rates. Immunohistochemistry of CD31 displayed higher level of angiogenesis in SVF-treated group, and CM-DIL-labeled SVF cells could survive and participate in revascularization, and RNA sequencing results revealed SVF promoted wound healing by facilitating intercellular adhesion, cell migration and positive immune response. CONCLUSION: SVF could reduce skin flap necrosis and activated neovascularization in rats by facilitating intercellular adhesion, cell migration and regulate positive immune response. LEVEL OF EVIDENCE N/A: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.
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RNA Longo não Codificante , Animais , Carbocianinas , Feminino , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Fração Vascular EstromalRESUMO
ABSTRACT: Cyanotic congenital heart disease (CCHD) is the main cause of death in infants worldwide. Long noncoding RNAs (lncRNAs) have been pointed to exert crucial roles in development of CHD. The current research is designed to illuminate the impact and potential mechanism of lncRNA SNHG14 in CCHD in vitro. The embryonic rat ventricular myocardial cells (H9c2 cells) were exposed to hypoxia to establish the model of CCHD in vitro. Quantitative real-time polymerase chain reaction was conducted to examine relative expressions of SNHG14, miR-25-3p, and KLF4. Cell viability was determined by the MTT assay. Lactate dehydrogenase (LDH) was measured by an LDH assay kit. Apoptosis-related proteins (Bax and Bcl-2) and KLF4 were detected by Western Blot. The targets of SNHG14 and miR-25-3p were verified by the dual-luciferase reporter assay. SNHG14 and KLF4 were upregulated, whereas miR-25-3p was downregulated in hypoxia-induced H9c2 cells and cardiac tissues of patients with CCHD compared with their controls. Knockdown of SNHG14 or overexpression of miR-25-3p facilitated cell viability, while depressing cell apoptosis and release of LDH in hypoxia-induced H9c2 cells. MiR-25-3p was a target of SNHG14 and inversely modulated by SNHG14. MiR-25-3p could directly target KLF4 and negatively regulate expression of KLF4. Repression of miR-25-3p or overexpression of KLF4 reversed the suppression impacts of sh-SNHG14 on cell apoptosis and release of LDH as well as the promotion impact of sh-SNHG14 on cell viability in hypoxia-induced H9c2 cells. Sh-SNHG14 protected H9c2 cells against hypoxia-induced injury by modulating miR-25-3p/KLF4 axis in vitro.
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Apoptose , Cianose/prevenção & controle , Cardiopatias Congênitas/complicações , Fator 4 Semelhante a Kruppel/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Hipóxia Celular , Linhagem Celular , Cianose/etiologia , Cianose/metabolismo , Cianose/patologia , Feminino , Regulação da Expressão Gênica , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Humanos , Lactente , Fator 4 Semelhante a Kruppel/genética , Masculino , MicroRNAs/genética , Miócitos Cardíacos/patologia , RNA Longo não Codificante/genética , Ratos , Transdução de SinaisRESUMO
The exosome of MSCs derived from human umbilical cord blood (HUCB-MSC) has been reported to have cardioprotective effects on mouse models of acute myocardial infarction (AMI) and cardiomyocyte hypoxia injury, but the exact mechanisms involved require further investigation. This paper aimed to study the role of HUCB-MSC-exosomes in inhibiting ferroptosis to attenuate myocardial injury. Compared with sham or normoxia groups, RT-PCR and western blotting showed that divalent metal transporter 1 (DMT1) expression was significantly increased, and Prussian blue staining, ferrous iron (Fe2+), MDA, and GSH level detection demonstrated that ferroptosis occurred in the infraction myocardium and in cardiomyocyte following hypoxia-induced injury. Overexpression of DMT1 promoted H/R-induced myocardial cell ferroptosis, while knockdown of DMT1 significantly inhibited the ferroptosis. HUCB-MSCs-derived exosomes inhibited ferroptosis and reduced myocardial injury, which was abolished in exosome with miR-23a-3p knockout. Moreover, dual luciferase reporter assay confirmed that DMT1 was a target gene of miR-23a-3p. In conclusion, HUCB-MSCs-exosomes may suppress DMT1 expression by miR-23a-3p to inhibit ferroptosis and attenuate myocardial injury.
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Exossomos/metabolismo , Ferroptose , Sangue Fetal/metabolismo , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/patologia , Animais , Exossomos/ultraestrutura , Ferroptose/genética , Humanos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Traumatismo por Reperfusão/patologia , Fatores de Transcrição/metabolismo , Regulação para CimaRESUMO
BACKGROUND: During the process of deep decay, when decay approaches the pulp, an immune response is triggered inside the pulp, which activates the complement cascade. The effect of complement component 5a (C5a) on the differentiation of dental pulp mesenchymal stem cells (DPSCs) is related to dentin reparation. The aim of the present study was to stimulate DPSCs with different concentrations of C5a and evaluate the differentiation of odontoblasts using dentin sialoprotein (DSP). METHODS: DPSCs were divided into the following six groups: (i) Control; (ii) DPSCs treated with 50 ng/ml C5a; (iii) DPSCs treated with 100 ng/ml C5a; (iv) DPSCs treated with 200 ng/ml C5a; (v) DPSCs treated with 300 ng/ml C5a; and (vi) DPSCs treated with 400 ng/ml C5a. Flow cytometry and multilineage differentiation potential were used to identify DPSCs. Mineralization induction, Real-time PCR and Western blot were conducted to evaluate the differentiation of odontoblast in the 6 groups. RESULT: DPSCs can express mesenchymal stem cell markers, including CD105, CD90, CD73 and, a less common marker, mesenchymal stromal cell antigen-1. In addition, DPSCs can differentiate into adipocytes, neurocytes, chondrocytes and odontoblasts. All six groups formed mineralized nodules after 28 days of culture. Reverse transcription-quantitative PCR and western blotting indicated that the high concentration C5a groups expressed higher DSP levels and promoted DPSC differentiation, whereas the low concentration C5a groups displayed an inhibitory effect. CONCLUSION: In this study, the increasing concentration of C5a, which accompanies the immune process in the dental pulp, has demonstrated an enhancing effect on odontoblast differentiation at higher C5a concentrations in vitro.
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Células-Tronco Mesenquimais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Polpa Dentária , Humanos , Células-TroncoRESUMO
Long noncoding RNAs (lncRNAs) serve as competitive endogenous RNAs (ceRNAs) that play significant regulatory roles in the pathogenesis of tumors. However, the role of lncRNAs, especially the lncRNA-related ceRNA regulatory network, in glioblastoma (GBM) has not been fully elucidated. The goal of the current study was to construct lncRNA-microRNA-mRNA-related ceRNA networks for further investigation of their mechanism of action in GBM. We downloaded data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases and identified differential lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) associated with GBM. A ceRNA network was constructed and analyzed to examine the relationship between lncRNAs and patients' overall survival. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGGs) were used to analyze the related mRNAs to indirectly explain the mechanism of action of lncRNAs. The potential effective drugs for the treatment of GBM were identified using the connectivity map (CMap). After integrated analysis, we obtained a total of 210 differentially expressed lncRNAs, 90 differentially expressed miRNAs, and 2508 differentially expressed mRNAs (DEmRNAs) from the TCGA and GEO databases. Using these differential genes, we constructed a lncRNA-associated ceRNA network. Six lncRNAs in the ceRNA network were associated with the overall survival of patients with GBM. Through KEGG analysis, it was found that the DEmRNAs involved in the network are related to cancer-associated pathways, for instance, mitogen-activated protein kinase and Ras signaling pathways. CMap analysis revealed four small-molecule compounds that could be used as drugs for the treatment of GBM. In this study, a multi-database joint analysis was used to construct a lncRNA-related ceRNA network to help identify the regulatory functions of lncRNAs in the pathogenesis of GBM.
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Neoplasias Encefálicas/genética , Glioblastoma/genética , RNA Longo não Codificante/genética , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Linhagem Celular Tumoral , Sobrevivência Celular , Análise por Conglomerados , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Glioblastoma/diagnóstico , Humanos , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Mapeamento de Interação de ProteínasRESUMO
Cardiac rupture and ventricular remodeling are recognized as the severe complications and major risk factors of acute myocardial infarction (AMI). This study aims to evaluate the regulatory roles of interleukin-1 receptor-associated kinase 3 (IRAK3) and nuclear factor-κB (NF-κB) signaling pathway in cardiac rupture and ventricular remodeling. Microarray analysis was performed to screen AMI-related differentially expressed genes and IRAK3 was identified. The models of AMI were established in male C57BL/6 mice to investigate the functional role of IRAK3. Afterwards, lentivirus recombinant plasmid si-IRAK3 was constructed for IRAK3 silencing. Next, cardiac function parameters were measured in response to IRAK3 silencing. The regulatory effects that IRAK3 had on myocardial infarct size and the content of myocardial interstitial collagen were analyzed. The regulation of IRAK3 silencing on the NF-κB signaling pathway was further assayed. The obtained results indicated that highly expressed IRAK3 and activated NF-κB signaling pathway were observed in myocardial tissues of mouse models of AMI, accompanied by increased expression of matrix metalloproteinase (MMP)-2/9 and tissue inhibitor of metalloproteinase 2 (TIMP-2). Notably, IRAK3 gene silencing inhibited the activation of NF-κB signaling pathway. Furthermore, IRAK3 gene silencing led to the decreased thickness of infarct area and collagen content of myocardial interstitium, alleviated diastolic, and systolic dysfunctions, as well as, facilitated cardiac functions in mice with AMI, corresponding to decreased expression of MMP-2/9 expression and increased expression of TIMP-2. Taken together, silencing of IRAK3 inactivates the NF-κB signaling pathway, and thereby impeding the cardiac rupture and ventricular remodeling, which eventually prevents AMI progression.
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Inativação Gênica , Ruptura Cardíaca/prevenção & controle , Ruptura Cardíaca/fisiopatologia , Quinases Associadas a Receptores de Interleucina-1/genética , Infarto do Miocárdio/fisiopatologia , NF-kappa B/metabolismo , Transdução de Sinais , Remodelação Ventricular , Animais , Colágeno/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Ruptura Cardíaca/genética , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/complicações , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Remodelação Ventricular/genéticaRESUMO
OIP5-AS1, a highly abundant imprinted long non-coding RNA (lncRNA), has been implicated in calcific aortic valve disease (CAVD). However, the function and underlying mechanism of OIP5-AS1 in CAVD progression remains unknown. In this study, osteoblastic differentiation of valve interstitial cells (VICs) isolated from human calcific aortic valves was induced by osteogenic medium. The protein levels of osteogenic markers were determined by immunofluorescence and western blotting. OIP5-AS1, miR-137 and TWIST-related protein 1 (TWIST1) expressions were detected by quantitative real-time PCR (qRT-PCR). ALP activity was evaluated by spectrophotometry. Mineralized bone matrix formation was assessed by Alizarin Red S staining. The interaction between OIP5-AS1 and miR-137 was studied using luciferase reporter assay, RNA pull-down assay and RNA-binding protein immunoprecipitation (RIP) assay. Luciferase reporter assay was also used to identify the possible interaction between miR-137 and TWIST11. The results showed that downregulated expression of OIP5-AS1 was observed in human aortic VICs after osteogenic induction. In vitro experiments revealed that OIP5-AS1 acted as a negative regulator of osteogenic differentiation. Mechanistically, we further showed that OIP5-AS1 could relieve osteogenic differentiation of VICs via upregulating miR-137 target gene TWIST1. Our study provides novel mechanistic insights into the cross-talk between OIP5-AS1, miR-137, and TWIST11, shedding light on the therapy for CAVD.
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Valva Aórtica/citologia , MicroRNAs/genética , Proteínas Nucleares/genética , Osteoblastos/citologia , RNA Longo não Codificante/genética , Proteína 1 Relacionada a Twist/genética , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Estenose da Valva Aórtica/genética , Calcinose/genética , Diferenciação Celular , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Osteoblastos/metabolismo , OsteogêneseRESUMO
The incidence of Mycobacterium tuberculosis (Mtb) infection in patients with mechanical circulatory support devices is extremely rare. We present a case involving a 38-year-old male who experienced a delayed sternal Mtb infection following left ventricular assist device (LVAD) implantation. More than 5 months post-surgery, the patient was readmitted to the hospital presenting a subxiphoid abscess. The incision site displayed an unsatisfactory healing process after the incision and drainage of the abscess. Despite engaging in a rigorous treatment protocol, which included anti-infective therapy, vacuum-assisted closure, and surgical debridement, the patient's wound remained unhealed. Ultimately, after pus gene sequencing confirmed the diagnosis, the patient was administered a regimen combining anti-tuberculosis and anti-infective therapy, which culminated in the successful healing of the wound. This singular case study not only reveals the clinical progression of an unexpected Mtb infection post-implantation but also emphasizes the challenges encountered in diagnosis and management.
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Insuficiência Cardíaca , Coração Auxiliar , Tuberculose , Masculino , Humanos , Adulto , Abscesso , Esterno/cirurgia , Cicatrização , Resultado do Tratamento , Insuficiência Cardíaca/cirurgiaRESUMO
Pakchoi (Brassica rapa ssp. chinensis) is cultivated for its high nutritional value; however, the nutritional diversity of different pakchoi cultivars is rarely investigated. Herein, we performed widely targeted metabolic profiling analyses of five popular pakchois. A total of 670 metabolites were detected, which could be divided into 13 categories. The accumulation patterns of main nutritional metabolites among the five pakchois were significantly different and complementary. Moreover, the pakchoi cultivar 'QYC' showed quite different metabolomic profiles compared with other pakchois. The Venn diagram showed that the 75 differential metabolites were shared among the comparison groups ('QYC' vs. 'MET'/ 'NBC'/ 'PPQ'/ 'XQC'), of which 52 metabolites were upregulated in 'QYC'. The phenolic acids had the largest variations between 'QYC' and the other pakchoi cultivars. These findings expand metabolomic information on different pakchoi cultivars and further provide new insights into the selection and breeding of excellent pakchoi cultivars.
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Background: Acute kidney injury (AKI) is a common and serious organ dysfunction in critically ill children. Early identification and prediction of AKI are of great significance. However, current AKI criteria are insufficiently sensitive and specific, and AKI heterogeneity limits the clinical value of AKI biomarkers. This study aimed to establish and validate an explainable prediction model based on the machine learning (ML) approach for AKI, and assess its prognostic implications in children admitted to the pediatric intensive care unit (PICU). Methods: This multicenter prospective study in China was conducted on critically ill children for the derivation and validation of the prediction model. The derivation cohort, consisting of 957 children admitted to four independent PICUs from September 2020 to January 2021, was separated for training and internal validation, and an external data set of 866 children admitted from February 2021 to February 2022 was employed for external validation. AKI was defined based on serum creatinine and urine output using the Kidney Disease: Improving Global Outcome (KDIGO) criteria. With 33 medical characteristics easily obtained or evaluated during the first 24 h after PICU admission, 11 ML algorithms were used to construct prediction models. Several evaluation indexes, including the area under the receiver-operating-characteristic curve (AUC), were used to compare the predictive performance. The SHapley Additive exPlanation method was used to rank the feature importance and explain the final model. A probability threshold for the final model was identified for AKI prediction and subgrouping. Clinical outcomes were evaluated in various subgroups determined by a combination of the final model and KDIGO criteria. Findings: The random forest (RF) model performed best in discriminative ability among the 11 ML models. After reducing features according to feature importance rank, an explainable final RF model was established with 8 features. The final model could accurately predict AKI in both internal (AUC = 0.929) and external (AUC = 0.910) validations, and has been translated into a convenient tool to facilitate its utility in clinical settings. Critically ill children with a probability exceeding or equal to the threshold in the final model had a higher risk of death and multiple organ dysfunctions, regardless of whether they met the KDIGO criteria for AKI. Interpretation: Our explainable ML model was not only successfully developed to accurately predict AKI but was also highly relevant to adverse outcomes in individual children at an early stage of PICU admission, and it mitigated the concern of the "black-box" issue with an undirect interpretation of the ML technique. Funding: The National Natural Science Foundation of China, Jiangsu Province Science and Technology Support Program, Key talent of women's and children's health of Jiangsu Province, and Postgraduate Research & Practice Innovation Program of Jiangsu Province.
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OBJECTIVE: To assess the effect of different antiplatelet strategies on clinical outcomes after coronary artery bypass grafting. DESIGN: Five year follow-up of randomised Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Grafting (DACAB) trial. SETTING: Six tertiary hospitals in China; enrolment between July 2014 and November 2015; completion of five year follow-up from August 2019 to June 2021. PARTICIPANTS: 500 patients aged 18-80 years (including 91 (18.2%) women) who had elective coronary artery bypass grafting surgery and completed the DACAB trial. INTERVENTIONS: Patients were randomised 1:1:1 to ticagrelor 90 mg twice daily plus aspirin 100 mg once daily (dual antiplatelet therapy; n=168), ticagrelor monotherapy 90 mg twice daily (n=166), or aspirin monotherapy 100 mg once daily (n=166) for one year after surgery. After the first year, antiplatelet therapy was prescribed according to standard of care by treating physicians. MAIN OUTCOME MEASURES: The primary outcome was major adverse cardiovascular events (a composite of all cause death, myocardial infarction, stroke, and coronary revascularisation), analysed using the intention-to-treat principle. Time-to-event analysis was used to compare the risk between treatment groups. Multiple post hoc sensitivity analyses examined the robustness of the findings. RESULTS: Follow-up at five years for major adverse cardiovascular events was completed for 477 (95.4%) of 500 patients; 148 patients had major adverse cardiovascular events, including 39 in the dual antiplatelet therapy group, 54 in the ticagrelor monotherapy group, and 55 in the aspirin monotherapy group. Risk of major adverse cardiovascular events at five years was significantly lower with dual antiplatelet therapy versus aspirin monotherapy (22.6% v 29.9%; hazard ratio 0.65, 95% confidence interval 0.43 to 0.99; P=0.04) and versus ticagrelor monotherapy (22.6% v 32.9%; 0.66, 0.44 to 1.00; P=0.05). Results were consistent in all sensitivity analyses. CONCLUSIONS: Treatment with ticagrelor dual antiplatelet therapy for one year after surgery reduced the risk of major adverse cardiovascular events at five years after coronary artery bypass grafting compared with aspirin monotherapy or ticagrelor monotherapy. TRIAL REGISTRATION: NCT03987373ClinicalTrials.gov NCT03987373.
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Aspirina , Ponte de Artéria Coronária , Inibidores da Agregação Plaquetária , Ticagrelor , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , Ticagrelor/uso terapêutico , Aspirina/uso terapêutico , Aspirina/administração & dosagem , Idoso , Seguimentos , Adulto , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Adolescente , Complicações Pós-Operatórias/prevenção & controle , Resultado do Tratamento , Adulto Jovem , China , Terapia Antiplaquetária Dupla/métodosRESUMO
Deep tooth decay approaching the pulp may develop into pulpitis; to prevent this, pulp cells need to balance the rapid immune response to avoid rapid swelling of the pulp. Current treatment of deep decay that approaches the pulp involves the application of drugs that induce low-level inflammation in the dental pulp to promote its repair, but this treatment is sometimes insufficient. However, the unsuccessful treatment often resulted in pulpitis. The C5a-C5aR is the initial stage of the immune cascade response. Blocking the binding of C5a-C5aR can slow the immune response in the narrow pulp cavity, so that dental pulp cells have enough time to proliferate, migrate, and differentiate. In this study, we compared lipoteichoic acid (LTA) and lipopolysaccharides (LPS) at different concentrations and time points and used the C5aR antagonist W54011 to block the C5a-C5aR axis. The blocking effect was detected by analyzing the expression of C5a, C5aR, interleukin (IL)-6, and Toll-like receptors 2 and 4 (TLR-2, 4). Next, we determined the optimal concentration and duration of LTA and LPS treatment in combination with W54011. Based on our results, we selected 1.0 µg·mL-1 LPS treatment for 48 h to generate an inflammatory model of human dental pulp cells. We then regrouped the cells and conducted expression analyses to monitor the expression of C5a, C5aR, IL-6, and TLR-4 at the protein and mRNA levels. LPS stimulation for 48 h and treatment with W54011 for 48 h effectively inhibited inflammation and did not affect C5a expression. This study provides a basis for follow-up studies of W54011 in dental pulp cells.
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Lipopolissacarídeos , Pulpite , Humanos , Lipopolissacarídeos/farmacologia , Complemento C5a/metabolismo , Polpa Dentária/metabolismo , Interleucina-6 , Inflamação/tratamento farmacológicoRESUMO
Purpose: The objective was to evaluate the influence of low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] on clinical outcomes in patients undergoing coronary artery bypass grafting (CABG). Methods: This is a secondary analysis of a 5-year follow-up of the DACAB trial (NCT02201771), in which 500 patients who underwent primary isolated CABG were randomized to three-antiplatelet therapy for 1 year after surgery. Of them, 459 patients were recruited in this secondary analysis. Baseline LDL-C and Lp(a) levels were collected, and repeated measurement of LDL-C levels during the follow-up were recorded. Cut-off values for LDL-C were set at 1.8 and 2.6â mmol/L; thus, the patients were stratified into LDL-C <1.8, 1.8-<2.6, and ≥2.6â mmol/L subgroups. Cut-off value for Lp(a) was 30â mg/dL; thus, the patients were divided into Lp(a) <30 and ≥30â mg/dL subgroups. The primary outcome was 4-point major adverse cardiovascular events (MACE-4), a composite of all-cause death, myocardial infarction, stroke, and repeated revascularization. Median follow-up time was 5.2 (interquartile range, 4.2-6.1)â years. Results: During the follow-up, 129 (28.1%) patients achieved the attainment of LDL-C <1.8â mmol/L, 186 (40.5%) achieved LDL-C 1.8-<2.6â mmol/L, and 144 (31.4%) remained LDL-C ≥2.6â mmol/L. Compared with the postoperative LDL-C <1.8â mmol/L group, the risk of MACE-4 was significantly higher in the LDL-C 1.8-<2.6â mmol/L group [adjusted hazard ratio (aHR) = 1.92, 95% CI, 1.12-3.29; P = 0.019] and LDL-C ≥2.6â mmol/L group (aHR = 3.90, 95% CI, 2.29-6.64; P < 0.001). Baseline Lp(a) ≥30â mg/dL was identified in 131 (28.5%) patients and was associated with an increased risk of MACE-4 (aHR = 1.52, 95% CI, 1.06-2.18; P = 0.022). Conclusions: For CABG patients, exposure to increased levels of postoperative LDL-C or baseline Lp(a) was associated with worse mid-term clinical outcomes. Our findings suggested the necessity of achieving LDL-C target and potential benefit of adding Lp(a) targeted lipid-lowering therapy in CABG population.
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Cardiac arrest is the fourth stage of sudden cardiac death, which is characterized by the cessation of electrical activity in the heart, rapid circulatory and respiratory failure, and the prognosis is often poor. How to effectively predict cardiac arrest is the key and difficult point in the diagnosis and treatment process. In recent years, the research on the application of early warning scoring system in cardiac arrest has made continuous breakthroughs, from initially formulating a traditional scoring system containing only basic vital signs indicators according to a certain number of samples to continuously increasing and changing indicators, increasing the sample size, and formulating an improved scoring system with better sensitivity and specificity. Nowadays, with the continuous development of electronic information technology, machine learning technology is introduced into the formulation of scoring system, which breaks through the limitations of previous scoring system and has achieved good results in clinic. This article analyzes and compares the relevant research and cutting-edge progress of different early warning scoring systems at home and abroad, and summarizes the research results, gaps and shortcomings. Finally, combined with the relevant policies of graded diagnosis and treatment in China, this paper discusses the development and application direction of cardiac arrest early warning scoring system in the future.
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Parada Cardíaca , Parada Cardíaca/diagnóstico , Humanos , Aprendizado de Máquina , Prognóstico , Sensibilidade e Especificidade , Sinais VitaisRESUMO
Background: The influence of baseline HbA1c levels on vein graft outcomes post coronary artery bypass grafting (CABG) remains unclear. Objective: The purpose of this study was to assess the association between baseline HbA1c and 1-year vein graft patency, and the effects of antiplatelet therapy on the 1-year vein graft patency after CABG in patients with baseline HbA1c <6.5% vs ≥6.5%. Methods: We examined the subgroups with baseline HbA1c <6.5% vs ≥6.5% from the DACAB trial (NCT02201771), in which 500 patients were randomly allocated to receive ticagrelor plus aspirin (T+A), ticagrelor alone (T), or aspirin alone (A) for 1 year after CABG. The primary outcome was the vein graft patency (FitzGibbon grade A) at 1 year. Results: A total of 405 patients with available baseline HbA1c data were included in this subgroup analysis. Of them, there were 233 patients (678 vein grafts) with baseline HbA1c <6.5% and 172 patients (512 vein grafts) with baseline HbA1c ≥6.5%. Compared with the HbA1c <6.5% subgroup, the HbA1c ≥6.5% subgroup showed worse 1-year vein graft patency (adjusted odds ratio [OR] for nonpatency: 1.69, 95% confidence interval [CI]: 1.08-2.64). T+A showed higher vein graft patency than A in both HbA1c <6.5% (adjusted OR for nonpatency: 0.34, 95% CI: 0.15-0.75) and HbA1c ≥6.5% subgroups (adjusted OR for nonpatency: 0.45, 95% CI: 0.19-1.09), without an interaction effect (P for interaction = 0.335), whereas T did not show more significant improvement than A in both subgroups. Conclusions: In the DACAB trial, lower baseline HbA1c was associated with higher vein graft patency 1 year after CABG. T+A improved 1-year vein graft patency vs A, irrespective of baseline HbA1c.
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OBJECTIVE: It remains unclear whether aggressive low-density lipoprotein cholesterol (LDL-C) management (<1.8 mmol/L) can slow the process of vein graft stenosis. This study aimed to explore the impact of baseline LDL-C levels on vein graft patency in patients on ticagrelor with or without aspirin 1 year after coronary artery bypass grafting (CABG). METHODS: This was a post hoc analysis of the DACAB (Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery) trial (NCT02201771), a randomized controlled trial (ticagrelor + aspirin or ticagrelor vs aspirin) of patients undergoing CABG in China. The study subjects were stratified as LDL-low (baseline LDL-C <1.8 mmol/L, 148 patients with 430 vein grafts) versus LDL-high (baseline LDL-C ≥1.8 mmol/L, 352 patients with 1030 vein grafts). The primary outcome was the 1-year vein graft patency (Fitzgibbon grade A) assessed by coronary computed tomographic angiography or coronary angiography. RESULTS: Baseline/1-year LDL-C were 1.4/1.6 and 2.6/2.4 mmol/L in the LDL-low and LDL-high subgroups, respectively. Regardless of antiplatelet regimen, no significant inter-subgroup difference was observed for 1-year graft patency (LDL-low: 83.8% [359/430 grafts]; LDL-high: 82.3% [848/1030 grafts]; adjusted OR for non-patency [ORadj], 0.96; 95% confidence interval [CI], 0.62-1.50, P = .857). For both subgroups, the 1-year graft patency rates were greater with ticagrelor + aspirin versus aspirin (LDL-low: ORadj, 0.41; 95% CI, 0.17-0.97; LDL-high: ORadj, 0.38; 95% CI, 0.20-0.71; inter P = .679). CONCLUSIONS: In general, baseline LDL-C is not associated with 1-year vein graft patency after CABG. Regardless of the baseline LDL-C levels, ticagrelor + aspirin was superior to aspirin alone in maintaining vein graft patency. The primary factor causing early vein graft disease might not be atherosclerosis but thrombosis.
Assuntos
Aspirina/uso terapêutico , LDL-Colesterol/sangue , Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Oclusão de Enxerto Vascular/prevenção & controle , Inibidores da Agregação Plaquetária/uso terapêutico , Ticagrelor/uso terapêutico , Grau de Desobstrução Vascular/efeitos dos fármacos , Idoso , Aspirina/efeitos adversos , Biomarcadores/sangue , China , Ponte de Artéria Coronária/efeitos adversos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/fisiopatologia , Terapia Antiplaquetária Dupla , Feminino , Oclusão de Enxerto Vascular/diagnóstico por imagem , Oclusão de Enxerto Vascular/etiologia , Oclusão de Enxerto Vascular/fisiopatologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Medição de Risco , Fatores de Risco , Trombose/etiologia , Trombose/fisiopatologia , Trombose/prevenção & controle , Ticagrelor/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: In the present post hoc analysis of the DACAB trial, we evaluated the effects of ticagrelor with or without aspirin on 1-year vein graft outcomes after coronary artery bypass grafting (CABG) with and without cardiopulmonary bypass (CPB) (on-pump and off-pump). METHODS: The DACAB trial was a multicenter, randomized, open-label, parallel control study enrolling 500 patients with 1,460 vein grafts undergoing CABG. For current post-hoc study, all patients in the DACAB study were included in the analysis to compare the effects of different antiplatelet regimens under on/off pump. Patients were randomly assigned to 1 of 3 antiplatelet treatment regimens (ticagrelor plus aspirin, T + A; ticagrelor alone, T; or aspirin alone, A) within 24 hours after CABG, and were stratified into on-pump and off-pump subgroups. The primary outcome was 1-year vein graft patency rate. RESULTS: Totally 121 patients underwent on-pump CABG (39 with 121 vein grafts in T + A, 36 with 101 vein grafts in T, and 46 with 137 vein grafts in A) and 379 patients underwent off-pump CABG (129 with 336 vein grafts in T + A, 130 with 387 vein grafts in T, and 120 with 348 vein grafts in A). Compared with A, T + A showed a higher 1-year vein graft patency rate in both on-pump (adjusted OR for non-patency =0.62, 95% CI: 0.16-2.45) and off-pump (adjusted OR for non-patency =0.35, 95% CI: 0.20-0.62) subgroups, P interaction =0.647; whereas T did not in either on-pump (adjusted OR for non-patency = 0.92, 95% CI: 0.31-2.76) or off-pump (adjusted OR for non-patency =0.58, 95% CI: 0.34-1.00) subgroups, P interaction =0.430. CONCLUSIONS: In the DACAB trial, for patients underwent either on-pump or off-pump CABG, ticagrelor plus aspirin showed consistent benefit for achieving 1-year vein graft patency, with particular benefit being seen in the off-pump.
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PURPOSE: Myocardial ischemia/reperfusion injury (IRI) induces cardiomyocytes death and leads to loss of cardiac function. Circular RNAs (circRNA) have gain increasing interests in modulating myocardial IRI. In this study, we aim to investigate the role and exact mechanism of circTLK1 in the pathogenesis of myocardial IRI. METHODS: Myocardial IRI was developed in mice with measuring hemodynamic parameters and the activity of serum myocardial enzymes to evaluate cardiac function. HE and TTC staining were performed to assess infarct area. Expression patterns of circTLK1 and miR-214 were investigated using qRT-PCR assay. Gene expression of circTLK1, miR-214 or RIPK was altered by transfecting with their overexpression or knockdown vectors. The apoptosis of cardimyocytes was assessed by TUNEL staining and Caspase-3 activity analysis. Apoptosis-related markers Bcl-2, Bax, and caspase3, as well as TNF-α signals were determined by western blotting. The interactions of circTLK1/miR-214 and miR-214/RIPK1 were verified using luciferase reporter assay. RNA immunoprecipitation (RIP) was subjected to further definite the direct binding of circTLK1/miR-214. The regulatory network of circTLK1/miR-214/RIPK1 was further validated in vivo. RESULTS: circTLK1 was an up-regulated circRNA found in a myocardial IRI mouse model. Mice with silencing circTLK1 significantly alleviated the impaired cardiac function indexes and decreased infarct area, thus attenuating the pathogenesis of myocardial IRI. Knockdown of circTLK1 dramatically decreased cardiomyocytes apoptosis, which was determined by apoptosis-related proteins. miR-214 was identified as a downstream effector to reverse circTLK1-mediated damage effects in myocardial IRI. miR-214 could directly target RIPK1 via binding to its' 3'-UTR. Overexpression of RIPK1 led to impaired cardiac function indexes, increased infarct area, and cell apoptosis, which abolished the protective effects of miR-214. The TNF signaling pathway was demonstrated to be involved in the circTLK1/miR-214/RIPK1 regulatory network in myocardial IRI. CONCLUSION: Taken together, our study revealed an up-regulated circRNA, circTLK1, could exacerbate myocardial IRI via targeting miR-214/RIPK1-mediated TNF signaling pathway, which may provide therapeutic targets for treatment.