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Observer variabilities for the diagnosis of coronary artery disease using anatomical and functional testing: the impact of certification
No full textAIM: To compare the reproducibility in reporting of coronary computed tomography angiography (CCTA) or cardiovascular magnetic resonance imaging (CMR) by certified readers for CCTA and CMR by the German Society of Cardiology (DGK) versus that by non-certified readers. METHODS: The study included 40 randomly selected CCTA and vasodilator stress CMR patient datasets. For CCTA, the degree of lumen narrowing, plaque composition, and high-risk plaque features were assessed. For CMR, wall motion and perfusion abnormalities and late gadolinium enhancement (LGE) were rated. All measures were conducted by segments and for individual patients. Intraclass correlation coefficients (ICC) were calculated to assess agreement between non-certified (n = 4) vs. DGK-certified readers (n = 4). RESULTS: ICC for assessment of luminal narrowing, plaque composition, and high-risk features were, respectively, 0.65 (95% confidence intervals [CI] 0.59–0.69), 0.64 (95%CI 0.45–0.80), and 0.45 (95%CI 0.22–0.66) for non-certified versus 0.78 (95%CI 0.74–0.81), 0.88 (95%CI 0.79–0.93), and 0.89 (95%CI 0.81–0.95) for DGK-certified readers (p < 0.001 for all). ICC for the assessment of wall motion, perfusion, and LGE were, respectively, 0.41 (95%CI 0.35–0.48), 0.27 (95%CI 0.18–0.38), and 0.48 (95%CI 0.41–0.54) for non-certified versus 0.71 (95%CI 0.67–0.75), 0.71 (95%CI 0.67–0.75) and 0.67 (95%CI 0.62–0.71) for DGK-certified readers (p < 0.001 for all). The agreement was excellent among DGK-certified readers for obstructive CAD (≥ 70% lumen narrowing) assessed by CCTA and high for abnormal perfusion and for LGE by CMR in a per-patient analysis (0.88; 95%CI 0.79–0.94 and 0.84; 95%CI 0.71–0.92), respectively. CONCLUSION: Substantially better CCTA and CMR reporting was observed for DGK-certified cardiologists, who achieved high agreement for diagnosing the presence or absence of obstructive CAD by CCTA and abnormal perfusion by CMR. Since important clinical decisions may be based on these readings, our data support quality-controlled education programs for advanced cardiac imaging
Myocardial native T1 mapping in the German National Cohort (NAKO): associations with age, sex, and cardiometabolic risk factors
No full textBACKGROUND AND AIMS: In cardiovascular magnetic resonance (CMR), myocardial native T1 mapping enables quantitative, non-invasive tissue characterization and is sensitive to subclinical changes in myocardial structure and composition. We investigated how age, sex, and cardiometabolic risk factors are associated with myocardial T1 in a population-based analysis within the German National Cohort (NAKO). METHODS: This cross-sectional study included 29,573 prospectively enrolled participants who underwent CMR-based midventricular T1 mapping at 3.0 T, alongside clinical phenotyping. After artificial intelligence-assisted myocardial segmentation, a subset of 9,162 outliers was subjected to manual quality control according to clinical evaluation standards. Associations with cardiometabolic risk factors, identified through self-reported medical history, clinical chemistry, and blood pressure measurements, were evaluated using adjusted linear regression models. RESULTS: Women had higher T1 values than men, with sex differences progressively declining with age. T1 was significantly elevated in individuals with diabetes (β=3.91 ms; p<0.001), kidney disease (β=3.44 ms; p<0.001), and current smoking (β=6.67 ms; p<0.001). Conversely, hyperlipidaemia was significantly associated with lower T1 (β=−4.41 ms; p<0.001). Associations with hypertension showed a sex-specific pattern: T1 was lower in women but increased with hypertension severity in men. CONCLUSIONS: Myocardial native T1 varies by sex and age and shows associations with major cardiometabolic risk factors. Notably, lower T1 times in participants with hyperlipidaemia may indicate a direct effect of blood lipids on the heart. Our findings support the utility of T1 mapping as a sensitive marker of early myocardial changes and highlight the sex-specific interplay between cardiometabolic health and myocardial tissue composition
Effect of gestational age on lymphocyte phenotypes in hospitalized preterm infants
Get PDFBACKGROUND: Preterm infants exhibit an increased susceptibility to infections. To assess the contribution of adaptive immunity to this vulnerability, it is crucial to study its postnatal development. OBJECTIVES: We sought to define profiles of adaptive immune-cell subsets in large cohorts of preterm infants, investigating the influence of gestational age (GA) and perinatal factors on their development. METHODS: Two German tertiary care neonatal intensive care unit cohorts (cohort 1: n = 499; cohort 2: n = 78) of hospitalized preterm infants (GA, 22.9-36.4 weeks) underwent f low cytometric phenotyping of peripheral blood lymphocyte subsets within the first 49 days of life. MetadeconfoundR package was used to evaluate (confounding) effects of clinical conditions on lymphocyte profiles. RESULTS: GA at birth was a primary determinant of profiles of lymphocyte subsets. The most premature infants displayed persistently lower CD4(+) T(H)-cell frequencies, an early transient increase in B cells, and a later expansion of natural killer cells (T(H)-low B-high natural killer–high phenotype). Detailed analysis revealed a less naive but more effector and regulatory CD4(+) T-cell phenotype in preterm infants with lower GA at birth. Amniotic infection syndrome further accentuated this "premature" immune profile, which was also more prevalent in infants with typical complications of prematurity. In contrast, female sex was associated with higher CD4(+) T(H)-cell frequencies. CONCLUSIONS: This study provides a comprehensive characterization of adaptive immune development in hospitalized preterm infants during the first weeks of life, demonstrating a strong dependence on GA and modulation by perinatal factors. The identified distinct developmental profiles offer a valuable reference framework for interpreting immune phenotyping data and highlight potential associations between immunologic immaturity and clinical outcomes in this vulnerable population
C-COMPASS: a user-friendly neural network tool profiles cell compartments at protein and lipid levels
Get PDFSystematic proteomic organelle profiling methods including protein correlation profiling and LOPIT have advanced our understanding of cellular compartmentalization. To manage the complexity of organelle profiling data, we introduce C-COMPASS, a user-friendly open-source software that employs a neural network-based regression model to predict the spatial cellular distribution of proteins. C-COMPASS handles complex multilocalization patterns and integrates protein abundance to model organelle composition changes across conditions. We apply C-COMPASS to mice with humanized livers to elucidate organelle remodeling during metabolic perturbations. Additionally, by training neural networks with co-generated marker protein profiles, C-COMPASS extends spatial profiling to lipids, overcoming the lack of organelle-specific lipid markers, allowing for determination of localization and tracking of lipid species across different compartments. This provides integrated snapshots of organelle lipid and protein compositions. Overall, C-COMPASS offers an accessible tool for multiomic studies of organelle dynamics without needing advanced computational skills, empowering researchers to explore new questions in lipidomics, proteomics and organelle biology
Investigation of a global mouse methylome atlas reveals subtype-specific copy number alterations in pediatric cancer models
Get PDFCopy number alterations (CNAs) are hallmarks of cancer, yet investigation of their oncogenic role has been hindered by technical limitations and missing model systems. Here we generated a genome-wide DNA methylation and CNA atlas of 106 genetic mouse models across 31 pediatric tumor types, including 18 new models for pediatric glioma. We demonstrated their epigenetic resemblance to human disease counterparts and identified entity-specific patterns of immune infiltration. We discovered that mouse tumors harbor highly recurrent CNA signatures that occur distinctly based on the tumor subgroup and driving oncogene and showed that these CNAs share syntenic regions with the matching human tumor types, thereby revealing a conserved but previously underappreciated role in subgroup-specific tumorigenesis that can be analyzed using the presented models. Our study provides insights into globally available mouse models for pediatric solid cancers and enables access to functional CNA interrogation, with the potential to unlock new translational targets in pediatric cancers
Gut-derived metabolites as treatment targets in chronic kidney disease - an avenue toward personalized medicine
Get PDFAryl hydrocarbon receptor activation promotes effector CD4(+) T cell homeostasis and restrains salt-sensitive hypertension
Get PDFExcess dietary salt and salt-sensitivity contribute to cardiovascular disease. Distinct T cell phenotypic responses to high salt and hypertension as well as influences from environmental cues are not well understood. The aryl hydrocarbon receptor (AhR) is activated by dietary ligands, promoting T cell and systemic homeostasis. We hypothesized that activating AhR supports CD4(+) homeostatic functions, such as cytokine production and mobilization, in response to high salt intake while mitigating salt-sensitive hypertension. In the intestinal mucosa, we demonstrate that a high salt diet (HSD) is a key driving factor, independent of hypertension, in diminishing interleukin 17A (IL-17A) production by CD4(+) T (Th17) cells without disrupting circulating cytokines associated with Th17 function. Previous studies suggest that hypertensive patients and individuals on a high salt diet are deficient in AhR ligands or agonistic metabolites. We found that activating AhR augments Th17 cells during experimental saltsensitive hypertension. Further, we demonstrate that activating AhR in vitro contributes to sustaining Th17 cells in the setting of excess salt. Using photoconvertible Kikume GreenRed mice, we also revealed that HSD drives CD4(+) T cell mobilization. Next, we found that excess salt augments T cell mobilization markers, validating HSD-driven T cell migration. Also, we found that activating AhR mitigates HSD-induced T cell migration markers. Using telemetry in a model of experimental salt-sensitivity, we found that activating AhR prevents the development of salt-sensitive hypertension. Collectively, stimulating AhR through dietary ligands facilitates immunologic and systemic functions amid excess salt intake and restrains the development of salt-sensitive hypertension
Herpesviruses mimic zygotic genome activation to promote viral replication
Get PDFZygotic genome activation (ZGA) is crucial for maternal to zygotic transition at the 2-8-cell stage in order to overcome silencing of genes and enable transcription from the zygotic genome. In humans, ZGA is induced by DUX4, a pioneer factor that drives expression of downstream germline-specific genes and retroelements. Here we show that herpesviruses from all subfamilies, papillomaviruses and Merkel cell polyomavirus actively induce DUX4 expression to promote viral transcription and replication. Analysis of single-cell sequencing data sets from patients shows that viral DUX4 activation is of relevance in vivo. Herpes-simplex virus 1 (HSV-1) immediate early proteins directly induce expression of DUX4 and its target genes, which mimics zygotic genome activation. Upon HSV-1 infection, DUX4 directly binds to the viral genome and promotes viral transcription. DUX4 is functionally required for infection, since genetic depletion by CRISPR/Cas9 as well as degradation of DUX4 by nanobody constructs abrogates HSV-1 replication. Our results show that DNA viruses including herpesviruses mimic an embryonic-like transcriptional program that prevents epigenetic silencing of the viral genome and facilitates herpesviral gene expression
hnRNPA2B1 drives colorectal cancer progression via the circCDYL/EIF4A3/PHF8 axis
Get PDFThe RNA-binding protein hnRNPA2B1 acts as an m6A reader and plays a role in tumor development. This study investigates the potential mechanism of hnRNPA2B1 in colorectal cancer (CRC) progression. The expression profiles of hnRNPA2B1, circCDYL, and PHF8 in CRC cell lines were analyzed. Following si-hnRNPA2B1 transfection, CRC cell proliferation, invasion, and migration were evaluated by CCK-8 and Transwell. CDYL expression was detected after actinomycin D and RNase R treatment. RIP was conducted to assess the enrichment of hnRNPA2B1 and m6A on circCDYL. RIP and RNA pull-down assays established the interaction between circCDYL and EIF4A3/PHF8. EIF4A3 expression was evaluated using RT-qPCR and Western blot techniques. hnRNPA2B1 and PHF8 displayed high expression levels, whereas circCDYL showed low expression levels in colorectal cancer cells. Inhibition of hnRNPA2B1 reduced CRC cell proliferation, migration, and invasion. hnRNPA2B1 mechanistically elevated the m6A level of circCDYL while decreasing its expression, which in turn reduced the binding of circCDYL to EIF4A3 and enhanced PHF8 expression. In summary, hnRNPA2B1-mediated m6A modification decreases circCDYL expression, which inhibits the interaction of circCDYL with EIF4A3, enhances PHF8 expression, and ultimately facilitates CRC progression
Cardiac MRI strain as an early indicator of myocardial dysfunction in hypertrophic cardiomyopathy
Get PDFHypertrophic cardiomyopathy (HCM) is often characterized by augmented cardiac contractility, which frequently remains undetectable in its early stages. Emerging evidence suggests that hypercontractility is linked to mitochondrial defects that develop early in HCM progression. However, imaging markers for identifying these early alterations in myocardial function are lacking. We used cardiac magnetic resonance feature tracking (CMR-FT) to assess myocardial strain in a Mybpc3-knockin (KI) mouse model that mimicked human HCM. While homozygous (HOM) mice exhibited cardiac hypertrophy, heterozygous (HET) mice represented an early, asymptomatic stage of HCM. To explore mitochondrial contributions to hypercontractility, we evaluated mitochondrial integrity via scanning electron microscopy (SEM) and correlated these findings with strain abnormalities. Young HET female, but not male mice exhibited significant torsion abnormalities (p = 0.02), reduced left ventricular global longitudinal strain (LVGLS, p = 0.009), and impaired right ventricular global longitudinal strain (RVGLS, p = 0.035) compared to the controls. Strain abnormalities correlated strongly with mitochondrial morphological alterations, including changes in volume and area distribution (R > 0.7). Abnormal myocardial strain patterns, including torsion and GLS, serve as early markers of HCM and are closely associated with underlying mitochondrial dysfunction. The HET Mybpc3-KI HCM model provides important insights into the initial stages of HCM progression, highlighting strain abnormalities and sex-specific differences to enhance early diagnosis and therapeutic strategies