RESUMEN
Background: Quantitative flow ratio (QFR) is a novel diagnostic modality for the functional testing of coronary artery stenosis, but evidence concerning the postoperative prognostic implication of QFR in noncardiac surgery (NCS) of patients with coronary artery disease (CAD) is limited. The purpose of this study was to examine the role of QFR in perioperative risk prediction in patients with coronary heart disease. Methods: This retrospective cohort study was conducted in The First Affiliated Hospital of Wenzhou Medical University between 2013 and 2022, and consecutively included patients with CAD who had undergone NCS <1 year after coronary angiography. The primary endpoint was major adverse cardiovascular events (MACEs), which were defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, cardiopulmonary arrest, malignant ventricular arrhythmia (MVA), congestive heart failure, and revascularization. Univariate and multifactorial Cox regression was used to identify the independent risk factors for perioperative cardiovascular events and to construct new models. The area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to compare the newly constructed model with existing traditional models. Results: Among the 929 participants enrolled (median age 68 years; 72.0% male), the primary endpoint was met in 67 (7.2%) patients within 30 days of follow-up. There was no significant difference in the incidence of the primary endpoint between patients with QFR <0.75 and those with "gray zone" lesions (0.75≤ QFR ≤0.8) (log-rank P=0.325). Patients with QFR <0.75 and those with "gray zone" lesions (0.75≤ QFR ≤0.8) had a higher incidence of primary endpoint events compared to patients with QFR >0.8. [QFR <0.75 vs. QFR >0.8: adjusted hazard ratio (HR) =20.70, P<0.001; 0.75≤ QFR ≤0.8 vs. QFR >0.8: HR =15.99, P<0.001]. The independent predictors of MACEs events within 30 days after NCS were albumin level [HR =0.92, 95% confidence interval (CI): 0.87-0.98; P=0.008], emergency surgery (HR =4.12, 95% CI: 1.66-10.23; P=0.002), and QFR ≤0.8 (HR =15.92, 95% CI: 5.96-42.51; P<0.001). In addition, adjusting the original Revised Cardiac Risk Index (RCRI) with QFR ≤0.8 as a risk factor significantly improved the risk stratification of postoperative adverse events, with the adjusted AUC rising from 0.574 to 0.740 (P<0.001). Conclusions: QFR ≤0.8 could independently predict perioperative cardiovascular adverse events in patients with CAD undergoing NCS and improve the predictive value of original predictive index. Gray-zone lesions (0.75≤ QFR ≤0.8) should be actively treated.
RESUMEN
Dyslipidemia and hepatic steatosis are the characteristics of the initial stage of nonalcohol fatty liver disease (NAFLD), which can be reversed by lifestyle intervention, including dietary supplementation. However, such commercial dietary supplements with solid scientific evidence and in particular clear mechanistic elucidation are scarce. Here, the health benefits of MHP, a commercial mulberry and Hippophae-based solid beverage, were evaluated in NAFLD rat model and the underlying molecular mechanisms were investigated. Histopathologic examination of liver and white adipose tissue found that MHP supplementation reduced hepatic lipid accumulation and adipocyte hypertrophy. Serum biochemical results confirmed that MHP effectively ameliorated dyslipidemia and decreased circulation-free fatty acid level. RNA-Seq-based transcriptomic analysis showed that MHP-regulated genes are involved in the inhibition of lipolysis of adipose tissue and thus may contribute to the reduction of hepatic ectopic lipid deposition. Furthermore, MHP upregulated ACSL1-CPT1a-CPT2 pathway, a canonical pathway that regulated mitochondrial fatty acid metabolism, and promoted liver and adipose tissue fatty acid ß-oxidation. These results suggest that adipose tissue-liver crosstalk may play a key role in maintaining glucose and lipid metabolic hemostasis. In addition, MHP can also ameliorate chronic inflammation through regulating the secretion of adipokines. Our study demonstrates that MHP is able to improve dyslipidemia and hepatic steatosis through crosstalk between adipose tissue and liver and also presents transcriptomic evidence to support the underlying mechanisms of action, providing solid evidence for its health claims.
RESUMEN
BACKGROUND: Abdominal aortic aneurysm (AAA) is a severe aortic disease without effective pharmacological approaches. The nuclear hormone receptor LXRα (liver X receptor α), encoded by the NR1H3 gene, serves as a critical transcriptional mediator linked to several vascular pathologies, but its role in AAA remains elusive. METHODS: Through integrated analyses of human and murine AAA gene expression microarray data sets, we identified NR1H3 as a candidate gene regulating AAA formation. To investigate the role of LXRα in AAA formation, we used global Nr1h3-knockout and vascular smooth muscle cell-specific Nr1h3-knockout mice in 2 AAA mouse models induced with angiotensin II (1000 ng·kg·min; 28 days) or calcium chloride (CaCl2; 0.5 mol/L; 42 days). RESULTS: Upregulated LXRα was observed in the aortas of patients with AAA and in angiotensin II- or CaCl2-treated mice. Global or vascular smooth muscle cell-specific Nr1h3 knockout inhibited AAA formation in 2 mouse models. Loss of LXRα function prevented extracellular matrix degeneration, inflammation, and vascular smooth muscle cell phenotypic switching. Uhrf1, an epigenetic master regulator, was identified as a direct target gene of LXRα by integrated analysis of transcriptome sequencing and chromatin immunoprecipitation sequencing. Susceptibility to AAA development was consistently enhanced by UHRF1 (ubiquitin-like containing PHD and RING finger domains 1) in both angiotensin II- and CaCl2-induced mouse models. We then determined the CpG methylation status and promoter accessibility of UHRF1-mediated genes using CUT&Tag (cleavage under targets and tagmentation), RRBS (reduced representation bisulfite sequencing), and ATAC-seq (assay for transposase-accessible chromatin with sequencing) in vascular smooth muscle cells, which revealed that the recruitment of UHRF1 to the promoter of miR-26b led to DNA hypermethylation accompanied by relatively closed chromatin states, and caused downregulation of miR-26b expression in AAA. Regarding clinical significance, we found that underexpression of miR-26b-3p correlated with high risk in patients with AAA. Maintaining miR-26b-3p expression prevented AAA progression and alleviated the overall pathological process. CONCLUSIONS: Our study reveals a pivotal role of the LXRα/UHRF1/miR-26b-3p axis in AAA and provides potential biomarkers and therapeutic targets for AAA.
Asunto(s)
Aneurisma de la Aorta Abdominal , Proteínas Potenciadoras de Unión a CCAAT , Epigénesis Genética , Receptores X del Hígado , Ratones Noqueados , MicroARNs , Ubiquitina-Proteína Ligasas , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Animales , Receptores X del Hígado/metabolismo , Receptores X del Hígado/genética , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Ratones , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Masculino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Metilación de ADN , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Angiotensina II/farmacologíaRESUMEN
Obesity, a multifactorial disease with many complications, has become a global epidemic. Weight management, including dietary supplementation, has been confirmed to provide relevant health benefits. However, experimental evidence and mechanistic elucidation of dietary supplements in this regard are limited. Here, the weight loss efficacy of MHP, a commercial solid beverage consisting of mulberry leaf aqueous extract and Hippophae protein peptides, was evaluated in a high-fat high-fructose (HFF) diet-induced rat model of obesity. Body component analysis and histopathologic examination confirmed that MHP was effective to facilitate weight loss and adiposity decrease. Pathway enrichment analysis with differential metabolites generated by serum metabolomic profiling suggests that PPAR signal pathway was significantly altered when the rats were challenged by HFF diet but it was rectified after MHP intervention. RNA-Seq based transcriptome data also indicates that MHP intervention rectified the alterations of white adipose tissue mRNA expressions in HFF-induced obese rats. Integrated omics reveals that the efficacy of MHP against obesogenic adipogenesis was potentially associated with its regulation of PPARγ and FGFR1 signaling pathway. Collectively, our findings suggest that MHP could improve obesity, providing an insight into the use of MHP in body weight management.
Asunto(s)
Hippophae , Morus , Ratas , Animales , PPAR gamma/genética , PPAR gamma/metabolismo , Hippophae/metabolismo , Morus/metabolismo , Dieta Alta en Grasa/efectos adversos , Obesidad/metabolismo , Tejido Adiposo Blanco/metabolismo , Transducción de Señal , Pérdida de PesoRESUMEN
Purpose: The objective of this work was to investigate whether including additional dosiomic features can improve biochemical failure-free survival prediction compared with models with clinical features only or with clinical features as well as equivalent uniform dose and tumor control probability. Methods and Materials: This retrospective study included 1852 patients who received diagnoses of localized prostate cancer between 2010 and 2016 and were treated with curative external beam radiation therapy in Albert, Canada. A total of 1562 patients from 2 centers were used for developing 3 random survival forest models: Model A included only 5 clinical features; Model B included 5 clinical features, equivalent uniform dose, and tumor control probability; and Model C considered 5 clinical features and 2074 dosiomic features derived from the planned dose distribution of the clinical target volume and planning target volume with further feature selection to determine prognostic features. No feature selection was performed for models A and B. Two hundred ninety patients from another 2 centers were used for independent validation. Individual model-based risk stratification was examined, and the log-rank tests were performed to test statistically significant differences between the risk groups. The 3 models' performances were evaluated using Harrell's concordance index (C-index) and compared using one-way repeated-measures analysis of variance with post hoc paired t test. Results: Model C selected 6 dosiomic features and 4 clinical features to be prognostic. There were statistically significant differences between the 4 risk groups for both training and validation data sets. The C-index for the out-of-bag samples of the training data set was 0.650, 0.648, and 0.669 for models A, B, and C, respectively. The C-index for the validation data set for models A, B, and C was 0.653, 0.648, and 0.662, respectively. Although gains were modest, Model C was statistically significantly better than models A and B. Conclusions: Dosiomics contain information beyond common dose-volume histogram metrics from planned dose distributions. Incorporation of prognostic dosiomic features in biochemical failure-free survival outcome models can lead to statistically significant although modest improvement in performance.
RESUMEN
Over 3 billion doses of inactivated vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been administered globally. However, our understanding of the immune cell functional transcription and T cell receptor (TCR)/B cell receptor (BCR) repertoire dynamics following inactivated SARS-CoV-2 vaccination remains poorly understood. Here, we performed single-cell RNA and TCR/BCR sequencing on peripheral blood mononuclear cells at four time points after immunization with the inactivated SARS-CoV-2 vaccine BBIBP-CorV. Our analysis revealed an enrichment of monocytes, central memory CD4+ T cells, type 2 helper T cells and memory B cells following vaccination. Single-cell TCR-seq and RNA-seq comminating analysis identified a clonal expansion of CD4+ T cells (but not CD8+ T cells) following a booster vaccination that corresponded to a decrease in the TCR diversity of central memory CD4+ T cells and type 2 helper T cells. Importantly, these TCR repertoire changes and CD4+ T cell differentiation were correlated with the biased VJ gene usage of BCR and the antibody-producing function of B cells post-vaccination. Finally, we compared the functional transcription and repertoire dynamics in immune cells elicited by vaccination and SARS-CoV-2 infection to explore the immune responses under different stimuli. Our data provide novel molecular and cellular evidence for the CD4+ T cell-dependent antibody response induced by inactivated vaccine BBIBP-CorV. This information is urgently needed to develop new prevention and control strategies for SARS-CoV-2 infection. (ClinicalTrials.gov Identifier: NCT04871932).
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Humanos , COVID-19/prevención & control , Leucocitos Mononucleares , SARS-CoV-2 , Receptores de Antígenos de Linfocitos B , Inmunización Secundaria , Análisis de Secuencia de ARN , Anticuerpos AntiviralesRESUMEN
INTRODUCTION: Interest in using higher order features of the planned 3D dose distributions (i.e., dosiomics) to predict radiotherapy outcomes is growing. This is driving many retrospective studies where historical data are mined to train machine learning models; however, recent decades have seen considerable advances in dose calculation that could have a direct impact on the dosiomic features such studies seek to extract. Is it necessary to recalculate planned dose distributions using a common algorithm if retrospective datasets from different institutions are included? Does a change in dose calculation grid size part way through a retrospective cohort, introduce bias in the extracted dosiomic features? The purpose of this study is to assess the stability of dosiomic features against variations in three factors: the dose calculation algorithm type, version, and dose grid size. METHODS: Dose distributions for 27 prostate patients who received EBRT were recalculated in the Eclipse Treatment Planning System (Varian Medical Systems, Palo Alto, California, USA) using two algorithms (AAA and Acuros XB), two versions (version 13.6 and 15.6), and three dose grids (2, 2.5 s, and 3 mm) - 12 dose distributions for each patient. Ninety-three dosiomic features were extracted from each dose distribution and each of the following regions-of-interest: high dose PTV (PTV_High), 1 cm rind around PTV_High (PTV_Ring), low dose PTV (PTV_Low), rectum, and bladder using PyRadiomics. The coefficient of variation (CV) was calculated for each dosiomic feature. Hierarchical clustering was used to group features with high and low variability. Three-way repeated measures ANOVA was performed to investigate the effect of the three different factors on dosiomic features that were classified with high variation. Additionally, CVs were calculated for cumulative dose volume histograms (DVHs) to test their ability to detect the variations in dose distributions. RESULTS: For PTV_Ring, PTV_Low, and rectum, all the dosiomic features had low CV (average CV ≤ 0.26) across the varying dose calculation conditions. For PTV_High, six dosiomic features showed CV > 0.26, and dose calculation algorithm type and grid size were the major sources of within-patient variation. For bladder, one dosiomic feature had average CV > 0.26, but none of the three dose calculation-related factors led to a statistically significant variation. The CVs for all the DVHs were very small (CV < 0.05). CONCLUSION: For all the regions-of-interest examined in this study, the majority of the dosiomic features were stable against variations in dose calculation; however, some of the dosiomic features for PTV_High and bladder had significant variations due to differences in dose calculation details. DVHs were detecting less variation than dosiomic features.
Asunto(s)
Próstata , Radioterapia de Intensidad Modulada , Masculino , Humanos , Estudios Retrospectivos , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , AlgoritmosRESUMEN
BACKGROUND: Metabolic disorder increases the risk of abdominal aortic aneurysm (AAA). NRs (nuclear receptors) have been increasingly recognized as important regulators of cell metabolism. However, the role of NRs in AAA development remains largely unknown. METHODS: We analyzed the expression profile of the NR superfamily in AAA tissues and identified NR1D1 (NR subfamily 1 group D member 1) as the most highly upregulated NR in AAA tissues. To examine the role of NR1D1 in AAA formation, we used vascular smooth muscle cell (VSMC)-specific, endothelial cell-specific, and myeloid cell-specific conditional Nr1d1 knockout mice in both AngII (angiotensin II)- and CaPO4-induced AAA models. RESULTS: Nr1d1 gene expression exhibited the highest fold change among all 49 NRs in AAA tissues, and NR1D1 protein was upregulated in both human and murine VSMCs from AAA tissues. The knockout of Nr1d1 in VSMCs but not endothelial cells and myeloid cells inhibited AAA formation in both AngII- and CaPO4-induced AAA models. Mechanistic studies identified ACO2 (aconitase-2), a key enzyme of the mitochondrial tricarboxylic acid cycle, as a direct target trans-repressed by NR1D1 that mediated the regulatory effects of NR1D1 on mitochondrial metabolism. NR1D1 deficiency restored the ACO2 dysregulation and mitochondrial dysfunction at the early stage of AngII infusion before AAA formation. Supplementation with αKG (α-ketoglutarate, a downstream metabolite of ACO2) was beneficial in preventing and treating AAA in mice in a manner that required NR1D1 in VSMCs. CONCLUSIONS: Our data define a previously unrecognized role of nuclear receptor NR1D1 in AAA pathogenesis and an undescribed NR1D1-ACO2 axis involved in regulating mitochondrial metabolism in VSMCs. It is important that our findings suggest αKG supplementation as an effective therapeutic approach for AAA treatment.
Asunto(s)
Aneurisma de la Aorta Abdominal , Humanos , Ratones , Animales , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/prevención & control , Aorta Abdominal/patología , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismo , Músculo Liso Vascular/metabolismo , Ciclo del Ácido Cítrico , Miocitos del Músculo Liso/metabolismo , Angiotensina II/efectos adversos , Ratones Noqueados , Aconitato Hidratasa/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Angiotensin II (AngII) induces disruption of mitochondrial homeostasis and oxidative stress. Nuclear receptor NR4A1 (Nur77) plays an important role in vascular smooth muscle cells (VSMCs) function. However, the role of Nur77 in AngII-induced mitochondrial dynamics and oxidative stress in VSMCs remains unknown. In an in vitro model of AngII-treated cells, we discovered that Nur77 knockout aggravated AngII-induced oxidative stress in VSMCs, whereas activation of Nur77 by celastrol diminished them. Concomitantly, disturbance of mitochondrial dynamics induced by AngII was further exacerbated in Nur77 deficient VSMCs compared to wild-type (WT) VSMCs. Interestingly, Nur77 deletion increased mitochondrial fission but not fusion as evidenced by upregulated fission related genes (Fis1 and Drp1) but not fusion (Opa1 and Mfn2) under AngII stimulation in VSMCs. Mechanically, Nur77 could directly bind to the promoter regions of Fis1 and Drp1 and repress their transcription. Furthermore, we observed that Nur77 additionally promoted mitochondrial homeostasis by increasing mitophagic flux in a transcription-independent manner upon AngII challenge. By using an in vivo model of AngII-induced abdominal aortic aneurysm (AAA), we finally validated the protective role of Nur77 involved in the mitochondrial fission process and mitophagic flux in aortas, which was correlated with the occurrence and development of AAA in AngII-infused mice. Our data defines an essential role of Nur77 in regulating oxidative stress by maintaining mitochondrial homeostasis in VSMCs via both transcription-dependent and transcription-independent manner, supporting the therapeutic potential of Nur77 targeting in vascular diseases.
Asunto(s)
Aneurisma de la Aorta Abdominal , Dinámicas Mitocondriales , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Estrés Oxidativo , Angiotensina II/metabolismo , Animales , Aneurisma de la Aorta Abdominal/metabolismo , Homeostasis , Ratones , Mitofagia , Miocitos del Músculo Liso/metabolismo , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismoRESUMEN
BACKGROUND AND PURPOSE: The goal of this work is to identify specific treatment planning and delivery features that are prognostic of biochemical failure-free survival (BFFS) for prostate cancer patients treated with external beam radiotherapy (EBRT). MATERIALS AND METHODS: This study reviewed patients diagnosed with localized prostate adenocarcinoma between 2005 and 2016, and treated with EBRT on a Varian linear accelerator at one of the four cancer centers in Alberta, Canada. BFFS was calculated using the Kaplan-Meier estimator. Patient demographics, tumor characteristics, and EBRT treatment planning and delivery factors, were collected for each patient. The patient cohort was split into a training dataset with patients from two centers and a validation dataset with patients from another two centers. A random survival forest was used to identify features associated with BFFS. RESULTS: This study included 2827 patients with a median follow-up of 6.4 years. The BFFS for this cohort collectively was 84.9% at 5 years and 69.3% at 10 years. 2519 patients from two centers were used for model training and 308 patients from two different centers were used for model validation. The prognostic features were Gleason score, prostate-specific antigen (PSA) at diagnosis, clinical T stage, CTV D99, pelvic irradiation, IGRT frequency, and PTV V98. Variables including bladder volume, dose calculation algorithm, PTV D99, age at diagnosis, hip prosthesis, number of malignancies, fiducial marker usage, PTV volume, RT modality, PTV HI, rectal volume, hormone treatment, PTV D1cc, equivalent PTV margin, IGRT type, and EQD2_1.5 were unlikely to be prognostic. A random survival forest using only the seven prognostic variables was built. The Harrell's concordance index for the model was 0.65 for the whole training dataset, 0.62 for out-of-bag samples of the training dataset, and 0.62 for the validation dataset. CONCLUSION: EBRT features prognostic of BFFS were identified and a random survival forest was developed for predicting prostate cancer patients' BFFS after EBRT.
Asunto(s)
Adenocarcinoma , Neoplasias de la Próstata , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/radioterapia , Alberta/epidemiología , Humanos , Masculino , Pronóstico , Antígeno Prostático Específico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/radioterapia , Estudios RetrospectivosRESUMEN
Objectives: Pressure-strain loop (PSL) is a novel method to quantify myocardial work in many cardiovascular diseases. To investigate the value of myocardial work parameters derived from PSL for evaluating cardiac function and clinical prognosis in patients with pulmonary hypertension (PH). Methods: A total of 52 patients with PH and 27 healthy controls were enrolled in this prospective study. PSLs determined by echocardiography were used to calculate global work index (GWI) of left ventricle (LV) and right ventricle (RV). Global constructive work (GCW) comprised the sum of myocardial work performed during shortening in systole and during lengthening in isovolumic relaxation. Global wasted work (GWW) comprised the sum of myocardial work performed during lengthening in systole and during shortening in isovolumic relaxation. Global work efficiency (GWE) was defined as GCW/(GCW + GWW). Results: LVGWW, RVGWI, RVGCW and RVGWW were significantly higher in patients than controls (all P < 0.001). LVGWE, LVGWI, LVGCW, and RVGWE were lower in patients than controls (all P < 0.01). Myocardial work parameters correlated well with clinical and other conventional echocardiographic assessments (all P < 0.05). In binary logistic regression analysis, the combination of RVGWE and estimation of pulmonary arterial systolic pressure (ePASP) was the best model to predict clinical outcomes (OR = 0.803, P = 0.002 and OR = 1.052, P = 0.015, respectively). Receiver operating characteristic curv demonstrated the combination of RVGWE and ePASP was the best predictor of adverse events with 100% sensitivity and 76.3% specificity (AUC = 0.910, P < 0.001). Conclusion: Myocardial work parameters derived from PSL are emerging markers of cardiac function. And the combination of RVGWE and ePASP is a useful predictor of clinical outcome in PH patients.
RESUMEN
Objectives: To evaluate the effect of thrombus aspiration (TA) strategy on the outcomes and its interaction with D-dimer levels in patients with ST-segment elevation myocardial infarction (STEMI) during primary percutaneous coronary intervention (PCI) in "real-world" settings. Materials and Methods: This study included 1,295 patients with STEMI who had undergone primary PCI with or without TA between January 2013 and June 2017. Patients were first divided into a TA+PCI group and a PCI-only group, and the baseline characteristics and long-term mortality between the two groups were analyzed. Furthermore, we studied the effect of TA on the clinical outcomes of patients grouped according to quartiles of respective D-dimer levels. The primary outcome was all-cause mortality, and the secondary outcomes were new-onset heart failure (HF), rehospitalization, re-PCI, and stroke. Results: In the original cohort, there were no significant differences in all-cause mortality between the TA+PCI and PCI-only groups (hazard ratio, 0.789; 95% confidence interval, 0.556-1.120; p = 0.185). After a mean follow-up of 2.5 years, the all-cause mortality rates of patients in the TA + PCI and PCI-only groups were 8.5 and 16.2%, respectively. Additionally, differences between the two groups in terms of the risk of HF, re-PCI, rehospitalization, and stroke were non-significant. However, after dividing into quartiles, as the D-dimer levels increased, the all-cause mortality rate in the PCI group gradually increased (4.3 vs. 6.0 vs. 7.0 vs. 14.7%, p < 0.001), while the death rate in the TA+PCI group did not significantly differ (4.6 vs. 5.0 vs. 4.0 vs. 3.75%, p = 0.85). Besides, in the quartile 3 (Q3) and quartile 4 (Q4) groups, the PCI-only group was associated with a higher risk of all-cause mortality than that of the TA+PCI group (Q3: 4.0 vs. 7.0%, p = 0.029; Q4: 3.75 vs. 14.7%, p < 0.001). Moreover, the multivariate logistic regression analysis demonstrated that TA is inversely associated with the primary outcome in the Q4 group [odds ratio (OR), 0.395; 95% CI, 0.164-0.949; p = 0.038]. Conclusions: The findings of our real-world study express that routine manual TA during PCI in STEMI did not improve clinical outcomes overall. However, patients with STEMI with a higher concentration of D-dimer might benefit from the use of TA during primary PCI. Large-scale studies are recommended to confirm the efficacy of TA.
RESUMEN
Background Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder characterized by chronic inflammation of the aortic wall, which lacks effective pharmacotherapeutic remedies and has an extremely high mortality. Nuclear receptor NR4A1 (Nur77) functions in various chronic inflammatory diseases. However, the influence of Nur77 on AAA has remained unclear. Herein, we sought to determine the effects of Nur77 on the development of AAA. Methods and Results We observed that Nur77 expression decreased significantly in human and mice AAA lesions. Deletion of Nur77 accelerated the development of AAA in mice, as evidenced by increased AAA incidence, abdominal aortic diameters, elastin fragmentation, and collagen content. Consistent with genetic manipulation, pharmacological activation of Nur77 by celastrol showed beneficial effects against AAA. Microscopic and molecular analyses indicated that the detrimental effects of Nur77 deficiency were associated with aggravated macrophage infiltration in AAA lesions and increased pro-inflammatory cytokines secretion and matrix metalloproteinase (MMP-9) expression. Bioinformatics analyses further revealed that LOX-1 was upregulated by Nur77 deficiency and consequently increased the expression of cytokines and MMP-9. Moreover, rescue experiments verified that LOX-1 notably aggravated inflammatory response, an effect that was blunted by Nur77. Conclusions This study firstly demonstrated a crucial role of Nur77 in the formation of AAA by targeting LOX-1, which implicated Nur77 might be a potential therapeutic target for AAA.
Asunto(s)
Aorta , Inflamación/metabolismo , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Receptores Depuradores de Clase E/metabolismo , Animales , Aorta/inmunología , Aorta/patología , Aneurisma de la Aorta Abdominal/metabolismo , Citocinas/metabolismo , Descubrimiento de Drogas , Elastina/metabolismo , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Noqueados , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/deficiencia , Tamaño de los Órganos , Transducción de Señal , Remodelación Vascular/inmunologíaRESUMEN
Background: Mineralocorticoid receptor antagonists (MRA) improve outcomes in chronic kidney disease (CKD) and acute myocardial infarction (AMI) patients. However, the lack of evidence regarding long-term clinical outcomes in the use of MRA, including spironolactone, in patients with AMI combined with CKD. Objectives: This study aimed to investigate whether spironolactone could significantly reduce the risk of all-cause mortality and re-admission in patients with AMI and CKD. Methods: In this single center, observational, retrospective, registry based clinical study, a total of 2,465 AMI patients were initially screened; after excluding patients with estimated glomerular filtration rate more than 60 ml/min/1.73 m2, 360 patients in the standard treatment group and 200 patients in the spironolactone group met the criteria. All enrolled patients follow-up for 30 months. The primary outcomes were all-cause mortality and re-admission. The key safety outcome was hyperkalemia rates during the 30 months follow-up period. Results: 160 (44.4%) and 41 (20.5%) patients in the standard treatment and spironolactone groups died, respectively [hazard ratio (HR): 0.389; 95% confidence interval (CI): 0.276-0.548; p < 0.001]. Re-admission occurred in 217 (60.3%) and 95 (47.5%) patients in the standard treatment and spironolactone groups, respectively (HR: 0.664; 95% CI: 0.522-0.846; p = 0.004). The spironolactone group was divided into two based on the daily dose, low dose group (no more than 40 mg) and high dose group (more than 40 mg); the differences in the mortality rate between low dose group (16.7%) and the standard treatment group (44.4%) (HR: 0.309; 95% CI: 0.228-0.418; p < 0.001) and high dose group (34.1%) (HR: 0.429; 95% CI: 0.199-0.925; p = 0.007) were significant. The differences in re-hospitalization rate between low dose group (43.6%) and the standard treatment group (60.3%) (HR: 0.583; 95% CI: 0.457-0.744; p < 0.001) and high dose group (61.4%) (HR: 0.551; 95% CI: 0.326-0.930; p = 0.007) was significant. Hyperkalemia occurred in 18 (9.0%) and 18 (5.0%) patients in the spironolactone group and standard treatment group, respectively (HR: 1.879; 95% CI: 0.954-3.700; p = 0.068). Whereas, Hyperkalemia occurred in high dose group (20.5%) significantly more often than in the standard treatment group (p < 0.001) and low dose group (5.8%) (p = 0.003). Conclusion: Using MRA, such as spironolactone, may substantially reduce the risk of both all-cause mortality and re-admission in patients with AMI and CKD; the use of low-dose spironolactone has the best efficacy and safety. However, this was a relatively small sample size, single center, observational, retrospective, registry based clinical study and further prospective evaluation in adequately powered randomized trials were needed before further use of spironolactone in AMI with CKD population.
RESUMEN
Mucor irregularis is a frequently found fungus in Asia, especially China, and it causes primary cutaneous mucormycosis with a high rate of disfigurement. Caspase recruitment domain-containing protein 9 (Card9) is an essential adaptor molecule downstream of C-type lectin receptors. It mediates the activation of nuclear factor kappa B (NF-κB), regulates T helper 1 (Th1) and Th17 differentiation, and plays an important role in fungal immune surveillance. CARD9 deficiency correlates with the increased susceptibility to many fungal infections, including cutaneous mucormycosis caused by M. irregularis However, the underlying immunological mechanisms were not elucidated. Our study established a murine model of subcutaneous M. irregularis infection, and we isolated immune cells, including bone marrow-derived macrophages, bone marrow-derived dendritic cells, naive T cells, and neutrophils, from wild-type (WT) and Card9 knockout (Card9-/- ) mice to examine the antifungal effect of Card9 on M. irregularis in vivo and in vitroCard9-/- mice exhibited increased susceptibility to M. irregularis infection. Impaired local cytokine and chemokine production, NF-κB (p65) activation, and Th1/17 cell differentiation and partially impaired neutrophil-dependent antifungal immunity were observed in Card9-/- mice. This work enriches our knowledge of the relationship between CARD9 deficiency and mucormycosis.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/deficiencia , Mucor/inmunología , Mucormicosis/inmunología , Mucormicosis/microbiología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Animales , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Predisposición Genética a la Enfermedad , Ratones , Mucormicosis/genética , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
PURPOSE: This study quantified plan quality differences across the 4 cancer centers in Alberta, Canada for plans that followed the PROstate Fractionated Irradiation Trial protocol. METHODS AND MATERIALS: Prostate plans of 235 patients were retrospectively reviewed. Interinstitutional plan quality comparisons were made based on distributions of protocol-specified parameters using 1-way analysis of variance with Games-Howell post hoc analysis. Dosimetrically representative cases were selected from each center using k-medoid clustering, enabling side-by-side comparison of dose-volume histograms and dose distributions. Fourteen anatomic features were investigated to explore interinstitutional patient population differences. Anatomically representative cases were selected from each center to explore differences in planning practices. Tumor control probability (TCP), as well as rectal wall and bladder wall normal tissue complication probabilities (NTCPs), were calculated to quantify the clinical effect of the differences in plan quality. RESULTS: Comparing the mean value of each center to the other 3, statistically significant differences were observed for bladder wall D30% and D50%, left and right femoral heads D5%, planning target volume D99% and D1cc, and clinical target volume D99%. Dosimetrically representative cases demonstrated consistent results. Although anatomic differences were observed between the center-specific populations, an analysis using anatomically similar cases demonstrated consistent trends in the dosimetric differences, suggesting the dosimetric variation is not exclusively due to anatomic differences. Minimal differences (<1%) among the 4 centers were noted for TCP and NTCPs, suggesting the reported differences in plan quality may not have any clinical significance. CONCLUSIONS: Despite common guidelines, statistically significant differences in plan quality metrics occurred among the 4 investigated centers. The differences are due at least in part to variation in local planning practices. TCP and NTCP calculations suggest that the clinical significance of the differences is minimal. These results can serve as a reference for the degree of variation among centers that can be accepted when a common protocol is adopted.
Asunto(s)
Neoplasias de la Próstata/radioterapia , Hipofraccionamiento de la Dosis de Radiación , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia Conformacional , Humanos , Masculino , Órganos en Riesgo/efectos de la radiación , Control de Calidad , Radiometría , Radioterapia Conformacional/efectos adversosRESUMEN
Purpose. To assess in vitro activities of nine antifungal agents (amphotericin B, fluconazole, voriconazole, itraconazole, posaconazole, caspofungin, micafungin, terbinafine and 5-flucytosine) against 93 strains of rare pathogenic fungi and the combined effects of drug combinations against several multidrug-resistant fungi.Methodology. The broth microdilution method M38-A3 and M27-A4 from the Clinical and Laboratory Standards Institute and the checkerboard method were performed in this study.Results. Low MICs for fluconazole were observed in moulds including Tritirachium oryzae, Exophiala attenuata and yeasts. MICs for amphotericin B>2 µg ml-1 were found among Aspergillus nidulans, Fusarium napiforme, Trichoderma longibrachiatum, Tritirachium oryzae, Cunninghamella bertholletiae, Cunninghamella phaeospora, Conidiobolus coronatus, Exophiala attenuata, Ochroconis mirabilis and Rhinocladiella basitona. Multidrug resistance was observed in Microascus spp., Lomentospora prolificans and Pythium insidiosum.Conclusion. Our study illustrated in vitro drug susceptibilities of some rare pathogenic fungi, which provide data to guide clinical treatment of fungal infections.
Asunto(s)
Antifúngicos/farmacología , Hongos/efectos de los fármacos , Micosis/microbiología , Anfotericina B/farmacología , Farmacorresistencia Fúngica , Fluconazol/farmacología , Hongos/clasificación , Hongos/genética , Hongos/aislamiento & purificación , Humanos , Itraconazol/farmacología , Pruebas de Sensibilidad Microbiana , Triazoles/farmacología , Voriconazol/farmacologíaRESUMEN
Card9 is a signalling adaptor protein in the downstream of many innate pattern recognition receptors (PRRs) and exerts a significant role in antifungal immunity. To date, Card9 deficiency has been reported to be related to increased susceptibility to many fungal infections. In this study, we established mucormycosis murine model of Rhizopus arrhizus (R. arrhizus) using wild-type (WT) mice and Card9 knockout (Card9-/- ) mice to investigate the antifungal effect of Card9 against R. arrhizus infection. Card9-/- mice were more susceptible to R. arrhizus infection than WT mice, which could be related to the impaired NF-κB pathway activation, local cytokine production and Th cell responses in Card9-/- mice.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/fisiología , Interacciones Huésped-Patógeno/inmunología , Mucormicosis/inmunología , Rhizopus/fisiología , Linfocitos T Colaboradores-Inductores/fisiología , Animales , Citocinas/sangre , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mucormicosis/microbiología , Factor de Transcripción ReIA/metabolismoRESUMEN
PURPOSE: To assess in vitro activities of six antifungal agents (amphotericin B, itraconazole, voriconazole, posaconazole, caspofungin and terbinafine) and the combined effects of eight pairs of them (caspofungin or terbinafine with amphotericin B, itraconazole, voriconazole or posaconazole) against 22 isolates of Chaetomium spp. METHODOLOGY: The broth microdilution method drafted by the Clinical and Laboratory Standards Institute and the checkerboard method were used in this study to evaluate in vitro activities of antifungal drugs both alone and in combination against Chaetomium spp. RESULTS: Amphotericin B and triazoles exhibited lower geometric mean, MIC50 and MIC90 than caspofungin and terbinafine. Besides, all the paired drugs displayed varying degrees of synergism, with the interactions between caspofungin and itraconazole ranking first (86.36 %). CONCLUSION: Our study illustrated varying degrees of synergism between caspofungin or terbinafine and itraconazole, voriconazole, posaconazole or amphotericin B towards Chaetomium spp., which could be a reference for the clinical treatment of Chaetomium spp. infections.