Background C/EBP homologous protein (Chop), a marker of endoplasmic reticulum (ER) stress, exhibits aberrant expression patterns during asthma development. However, its exact role in asthma ...pathogenesis is not fully understood. Objectives We aimed to determine the function and mechanism of Chop in the pathogenesis of allergic asthma in patients and animals. Methods Studies were conducted in asthmatic patients and Chop−/− mice to dissect the role of Chop and ER stress in asthma pathogenesis. An ovalbumin (OVA)–induced allergic airway inflammation model was used to address the effect of Chop deficiency on asthma development. Next, the effect of Chop deficiency on macrophage polarization and related signaling pathways was investigated to demonstrate the underlying mechanisms. Results Asthmatic patients and mice after OVA induction exhibited aberrant Chop expression along with ER stress. Specifically, Chop was noted to be specifically overexpressed in macrophages, and mice deficient in Chop were protected from OVA-induced allergic airway inflammation, as manifested by attenuated airway inflammation, remodeling, and hyperresponsiveness. Chop was found to exacerbate allergic airway inflammation by enhancing M2 programming in macrophages. Mechanistic studies characterized an IL-4/signal transducer and activator of transcription 6/transcription factor EC (Tfec)/IL-4 receptor α positive feedback regulatory loop, in which IL-4 induces Chop expression, which then promotes signal transducer and activator of transcription 6 signaling to transcribe Tfec expression. Finally, Tfec transcribes IL-4 receptor α expression to promote M2 programming in macrophages. Conclusions Chop and ER stress are implicated in asthma pathogenesis, which involves regulation of M2 programming in macrophages.
Objectives The aim of this study was to test the hypothesis that angiotensin (Ang)-converting enzyme-2 (ACE2) overexpression may inhibit myocardial collagen accumulation and improve left ventricular ...(LV) remodeling and function in diabetic cardiomyopathy. Background Hyperglycemia activates the renin-Ang system, which promotes the accumulation of extracellular matrix and progression of cardiac remodeling and dysfunction. Methods Ninety male Wistar rats were divided randomly into treatment (n = 80) and control (n = 10) groups. Diabetes was induced in the treatment group by a single intraperitoneal injection of streptozotocin. Twelve weeks after streptozotocin injection, rats in the treatment group were further divided into adenovirus-ACE2, adenovirus–enhanced green fluorescent protein, losartan, and mock groups (n = 20 each). LV volume; LV systolic and diastolic function; extent of myocardial fibrosis; protein expression levels of ACE2, Ang-converting enzyme, and Ang-(1-7); and matrix metalloproteinase–2 activity were evaluated. Cardiac myocyte and fibroblast culture was performed to assess Ang-II and collagen protein expression before and after ACE2 gene transfection. Results Four weeks after ACE2 gene transfer, the adenovirus-ACE2 group showed increased ACE2 expression, matrix metalloproteinase–2 activity, and LV ejection fractions and decreased LV volumes, myocardial fibrosis, and ACE, Ang-II, and collagen expression in comparison with the adenovirus–enhanced green fluorescent protein and control groups. ACE2 was superior to losartan in improving LV remodeling and function and reducing collagen expression. The putative mechanisms may involve a shift in balance toward an inhibited fibroblast-myocyte cross-talk for collagen and transforming growth factor–beta production and enhanced collagen degradation by matrix metalloproteinase–2. Conclusions ACE2 inhibits myocardial collagen accumulation and improves LV remodeling and function in a rat model of diabetic cardiomyopathy. Thus, ACE2 provides a promising approach to the treatment of patients with diabetic cardiomyopathy.
Despite marked clinical benefit, reduction in atheroma volume with statin therapy is minimal. Changes in plaque composition may explain this discrepancy. We aimed in the present study to assess the ...effect of statin therapy on coronary plaque composition and plaque volume using serial multimodality imaging. From an open-label, single-blinded study, patients with angiographically mild-to-moderate lesion were randomized to receive atorvastatin 60 (AT 60) mg or atorvastatin 20 (AT 20) mg for 12 months. Optical coherence tomography was used to assess fibrous cap thickness (FCT) and intravascular ultrasound to assess atheroma burden at 3 time points: baseline, at 6 months, and at 12 months. Thirty-six lipid-rich plaques in 27 patients with AT 60 mg and 30 lipid-rich plaques in 19 patients with AT 20 mg were enrolled in this study. Low-density lipoprotein cholesterol level was significantly decreased at 6 months without further reduction at 12 months. AT 60 mg induced greater reduction in low-density lipoprotein cholesterol compared with AT 20 mg. Optical coherence tomography revealed continuous increase in FCT from baseline to 6 months and to 12 months in both groups. AT 60 mg induced greater increase in FCT compared with AT 20 mg at both follow-up points. The prevalence of thin-cap fibroatheroma and the presence of macrophage at 6 months were significantly lower in AT 60 mg compared with AT 20 mg. Plaque burden did not change significantly in both groups. In conclusion, both intensive and moderate statin therapy stabilizes coronary plaques, with a greater benefit in the intensive statin group. However, no significant changes in plaque volume were observed over time regardless of the intensity of statin therapy.
Abstract Background In a previous review, we reported that ankle brachial index (ABI) ≤ 0.90 could reliably identify patients with peripheral artery disease (PAD). Since then, more studies have been ...published which may extend the power of a meta-analysis of studies of diagnostic accuracy of the ABI. MEDLINE and several other databases were searched for studies on sensitivity and specificity of using ABI ≤ 0.90 for PAD diagnosis compared with angiography. Methods Quality of each study was assessed by standards for reporting diagnostic accuracy initiative and quality assessment for studies of diagnostic accuracy tool. Heterogeneity was assessed using the Cochran Q statistic, χ2 , and inconsistency index. The area under the curve and Q* were estimated using summary receiver operator curve. The pooled diagnostic odds ratio (DOR), sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) of ABI ≤ 0.90 to diagnose PAD were estimated using Meta-DiSc software (Meta-DiSc, Madrid, Spain). Results Four studies comprising 569 patients (922 limbs) met inclusion criteria. Significant heterogeneity among these studies was not detected in DOR but was evident in pooled sensitivity, specificity, PLR, and NLR. The area under the curve under the summary receiver operator curve is 0.87 (standard error = 0.02) and diagnostic accuracy (Q*) is 0.80 (standard error = 0.02). Additionally, DOR was 15.33 with corresponding 95% confidence intervals of 9.39-25.02. The pooled sensitivity and specificity of ABI ≤ 0.90 for PAD diagnosis were 75% and 86% and the pooled PLR and NLR were 4.18 and 0.29, respectively. Conclusions We conclude that test of ABI ≤ 0.90 can be a useful tool to identify PAD with serious stenosis in clinical practice.
Recent studies have reported the development of neoatherosclerosis inside stents and subsequent acute coronary syndrome secondary to disruption of neointimal hyperplasia. The aim of the study was to ...compare the characteristics of neointimal hyperplasia and its time course between bare metal stents (BMSs) and drug-eluting stents (DESs) using optical coherence tomography. A total of 138 stents were divided into 3 groups according to the follow-up period: early phase, <9 months (25 BMSs and 27 DESs); intermediate phase, ≥9 and <48 months (18 BMSs and 43 DESs); and delayed phase, ≥48 months (13 BMSs and 12 DESs). Optical coherence tomographic analysis included the presence of lipid-laden intima, percentage of lipid-rich plaque, and signal attenuation. The optical coherence tomographic findings were compared between the BMSs and DESs in each period, and the difference between the periods was also determined. In the early phase, a greater incidence of lipid-laden plaque (37% vs 8%, p = 0.02) and a greater percentage of lipid-rich plaque (12.9 ± 25.1% vs 1.2 ± 4.3%, p = 0.01) were found in the DESs than in the BMSs. In the intermediate phase, the DES group continuously showed a significantly greater incidence of lipid-laden plaque (63% vs 28%, p = 0.03) and greater percentage of lipid-rich plaque (24.8 ± 28.1% vs 4.1 ± 7.3%, p <0.01). In addition, signal attenuation was greater in the DES group, suggesting early changes in neointimal hyperplasia properties. In the delayed phase, lipid-laden plaque was the predominant type in both groups. In conclusion, lipid-rich neoatherosclerosis develops inside stents earlier in DESs than in BMSs. After 48 months, most restenotic stents will have developed lipid-laden neointima in both groups.
Background: Head and neck squamous cell carcinoma (HNSCC) was the seventh most common cancer worldwide in 2018. Lymphatic metastasis (LM) is closely related to HNSCC prognosis and recurrence. ...However, the underlying mechanism of LM remains unclear. Therefore, this study aimed to identify the key genes in the LM of HNSCC. Methods: We used The Cancer Genome Atlas (TCGA) to identify differentially expressed genes (DEGs) between LM and non-LM cases. A random forest model, the Search Tool for the Retrieval of Interacting Genes, Cytoscape, and cytoHubba were used to identify hub genes among DEGs, including KRT20 (Cytokeratins 20). We analyzed the survival of KRT20 in TCGA, and we overexpressed KRT20 in HNSCC cell lines to investigate its effects on migration and invasion. We also correlated the expression of KRT20 in HNSCC tissue microarrays with survival and clinicopathological features. Results: We identified 243 DEGs—143 upregulated genes and 100 downregulated genes. Further analysis revealed that KRT20 is a potential key gene associated with LM and overall survival rates among patients with HNSCC. Overexpression of KRT20 increased the migration and invasion ability of HNSCC cell lines Tu686 and FD-LSC-1. Tissue microarray studies demonstrated an overexpression of KRT20 among N1+ patients (including N1-N3 patients). Survival analysis results and the clinicopathological features of HNSCC tissue microarrays were consistent with our analysis of TCGA. Thus, a high KRT20 expression level might suggest an adverse HNSCC prognosis. Our gene set enrichment analysis showed that KRT20 participates in many metabolic pathways, including those related to tumorigenesis and cancer development. Conclusions: We propose that KRT20 may be a key gene in HNSCC with LM.
Objectives
This retrospective cohort study investigated the association of socioeconomic status with survival outcomes among patients with nasopharyngeal carcinoma in an endemic area of China.
...Methods
The primary endpoint was overall survival. Survival outcomes were estimated by the Kaplan-Meier method and compared by the log-rank test, and the multivariate Cox proportional hazards model was used to estimate hazard ratios, 95% CIs, and independent prognostic factors.
Results
A total of 11 069 adult patients with NPC were enrolled and included in the analysis. Kaplan-Meier survival analysis revealed that overall survival was significantly different among socioeconomic status. Compared with high socioeconomic status patients, low socioeconomic status patients (HR, 1.190; 95% CI, 1.063-1.333) and medium socioeconomic status patients (HR, 1.111; 95% CI, 1.006-1.226) were associated with increased hazard ratio (HR) of overall survival.
Conclusion
This analysis highlights patients with nasopharyngeal carcinoma who had high socioeconomic status had better overall survival compared with those who had low and medium socioeconomic status.
Abstract Background Lipid-rich plaque (LRP) is thought to be a precursor to cardiac events. However, its clinical significance in coronary arteries has never been systematically investigated. ...Objectives This study investigated the prevalence and clinical significance of LRP in the nonculprit region of the target vessel in patients undergoing percutaneous coronary intervention (PCI). Methods The study included 1,474 patients from 20 sites across 6 countries undergoing PCI, who had optical coherence tomography (OCT) imaging of the target vessel. Major adverse cardiac events (MACE) were defined as a composite of cardiac death, acute myocardial infarction, and ischemia-driven revascularization. Patients were followed for up to 4 years (median of 2 years). Results Lipid-rich plaque was detected in nonculprit regions of the target vessel in 33.6% of patients. The cumulative rate of nonculprit lesion-related MACE (NC-MACE) over 48 months in patients with LRP was higher than in those without LRP (7.2% vs. 2.6%, respectively; p = 0.033). Acute coronary syndrome at index presentation (risk ratio: 2.538; 95% confidence interval CI: 1.246 to 5.173; p = 0.010), interruption of statin use ≥1 year (risk ratio: 4.517; 95% CI: 1.923 to 10.610; p = 0.001), and LRP in nonculprit regions (risk ratio: 2.061; 95% CI: 1.050 to 4.044; p = 0.036) were independently associated with increased NC-MACE. Optical coherence tomography findings revealed that LRP in patients with NC-MACE had longer lipid lengths (p < 0.001), wider maximal lipid arcs (p = 0.023), and smaller minimal lumen areas (p = 0.003) than LRPs in patients without MACE. Conclusions Presence of LRP in the nonculprit regions of the target vessel by OCT predicts increased risk for future NC-MACE, which is primarily driven by revascularization for recurrent ischemia. Lipid-rich plaque with longer lipid length, wider lipid arc, and higher degree of stenosis identified patients at higher risk of future cardiac events. (The Massachusetts General Hospital Optical Coherence Tomography Registry; NCT01110538 )
Objectives To identify an optimal growth trajectory for term small for gestational age (SGA) babies from birth to 7-years-old. Study design Data were from the Collaborative Perinatal Project, a US ...multicenter prospective cohort study from 1959-1976. Five weight growth trajectories of the 1957 term SGA babies were grouped by a latent class model. We selected the optimal growth pattern based on the lowest overall risks of childhood diseases. Results Compared with appropriate for gestational age children, SGA babies with no catch-up growth (439, 22.4%) had higher risks of infection in infancy (aOR 1.2, 95% CI 1.0-1.6), growth restriction (11.2, 8.6-14.6), and low IQ (2.1, 1.7-2.8) at age 7 years. Those with excessive catch-up growth (176, 8.9%) had higher risks of overweight/obesity (7.5, 5.4-10.5) and elevated blood pressure (1.7, 1.1-2.4) at age 7 years. Babies with slow catch-up growth (328, 16.8%) or regression after 4 months (285, 14.6%) were associated with higher risks of low IQ (1.6, 1.2-2.1) and growth restriction (2.2, 1.5-3.2), respectively. Only babies with appropriate catch-up growth (729, 37.3%) did not have increased risk of adverse outcomes. Further, we also tested linear growth trajectories with similar findings. Conclusions The optimal growth trajectory for term SGA infants may be fast catch-up growth to about the 30th percentile in the first several months, with modest catch-up growth thereafter, to be around the 50th percentile by 7-years-old.
Purpose To evaluate the risk factors and potential diagnostic criteria for pseudophakic cystoid macular edema (CME) in diabetic patients after phacoemulsification. Setting Department of ...Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai, China. Design Prospective nonrandomized study. Methods Diabetic patients were followed for up to 6 months after cataract surgery and examined to evaluate their foveal thickness, macular sensitivity, and corrected distance visual acuity. Multiple statistical analyses were performed to determine risk factors and diagnostic criteria for pseudophakic CME. Results The duration, type of diabetes, stage of diabetic retinopathy, nuclear opalescence grading, glycosylated hemoglobin A1c (HbA1c ), and ultrasound time were correlated with the change in foveal thickness and macular sensitivity after cataract surgery. Unsupervised data analysis showed 3 groups of patients as follows: nonpseudophakic CME, level 1 pseudophakic CME, and level 2 pseudophakic CME. Subclinical level 1 patients had a 30% to 40% increase in foveal thickness 1 month postoperatively, while level 2 patients had at least a 40% increase in foveal thickness and a 20% decrease in macular sensitivity. The incidence of clinical pseudophakic CME was 3.2% in diabetic patients as per the diagnostic criteria. The change in macular sensitivity was more consistent and correlated with foveal thickness. Conclusions The duration, severity, type of diabetes, hardness of the lens, and HbA1c were risks for pseudophakic CME in diabetic patients after cataract surgery. A 40% or more increase in foveal thickness and 20% or more decrease in macular sensitivity offer an objective and reliable diagnostic standard to report pseudophakic CME in diabetics.
PDF
