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Metastatic cancer is difficult to treat and is responsible for the majority of cancer-related deaths. After cancer cells initiate metastasis and successfully seed a distant site, resident cells in the tissue play a key role in determining how metastatic progression develops. The lung is the second most frequent site of metastatic spread, and the primary site of metastasis within the lung is alveoli. The most abundant cell type in the alveolar niche is the epithelium. This review will examine the potential contributions of the alveolar epithelium to metastatic progression. It will also provide insight into other ways in which alveolar epithelial cells, acting as immune sentinels within the lung, may influence metastatic progression through their various interactions with cells in the surrounding microenvironment.
The increasing availability of "real-world" data in the form of written text holds promise for deepening our understanding of societal and health-related challenges. Textual data constitute a rich source of information, allowing the capture of lived experiences through a broad range of different sources of information (eg, content and emotional tone). Interviews are the "gold standard" for gaining qualitative insights into individual experiences and perspectives. However, conducting interviews on a large scale is not always feasible, and standardized quantitative assessment suitable for large-scale application may miss important information. Surveys that include open-text assessments can combine the advantages of both methods and are well suited for the application of natural language processing (NLP) methods. While innovations in NLP have made large-scale text analysis more accessible, the analysis of real-world textual data is still complex and requires several consecutive steps.
We developed and subseqs a precedent for applied researchers. Our study thereby contributes to both the dissemination of NLP techniques in applied health sciences and the identification of previously unknown experiences and burdens of persons with MS during the pandemic, which may be relevant for future treatment.Over the past 15 years, there have been significant advances in the treatment of acute and chronic medical consequences of stroke in childhood. Given high rates of survival in pediatric stroke, practitioners are tasked with treating the ongoing motor and neuropsychological sequelae in patients over the course of their development. This article provides a review of the current literature on neuropsychological outcomes in pediatric stroke, including intelligence, academics, language, visual-spatial skills, attention, executive functions, memory, and psychosocial function. Recent developments in functional neuroimaging are discussed, with a particular focus on language outcomes. We further review the current research on cognitive and behavioral rehabilitation and introduce intervention models in pediatric stroke. In the final section, we discuss future directions for clinical practice and research in pediatric stroke.
ABCA1 (ATP-binding cassette transporter A1) mediates cholesterol efflux to apo AI to maintain cellular cholesterol homeostasis. The current study aims to investigate whether T-cell-specific deletion of ABCA1 modulates the phenotype/function of T cells and the development of atherosclerosis.
Mice with T-cell-specific deletion of ABCA1 on low-density lipoprotein receptor knockout (
) background (
) were generated by multiple steps of (cross)-breedings among
, CD4-
, and
mice.
Deletions of ABCA1 greatly suppressed cholesterol efflux to apo AI but slightly reduced membrane lipid rafts on T cells probably due to the upregulation of ABCG1. Moreover, ABCA1 deficiency impaired TCR (T-cell receptor) signaling and inhibited the survival and proliferation of T cells as well as the formation of effector memory T cells. Despite the comparable levels of plasma total cholesterol after Western-type diet feeding,
mice showed significantly attenuated arterial accumulations of T cells and smaller atherosclerotic lesions than
controls, which were associated with reduced surface CCR5 (CC motif chemokine receptor 5) and CXCR3 (CXC motif chemokine receptor 3), decreased antiapoptotic Bcl-2 (B-cell lymphoma 2) and Bcl-xL (B-cell lymphoma extra-large), and hampered abilities to produce IL (interleukin)-2 and IFN (interferon)-γ by ABCA1-deficient T cells.
ABCA1 is essential for T-cell cholesterol homeostasis. Deletion of ABCA1 in T cells impairs TCR signaling, suppresses the survival, proliferation, differentiation, and function of T cells, thereby providing atheroprotection in vivo.
ABCA1 is essential for T-cell cholesterol homeostasis. Deletion of ABCA1 in T cells impairs TCR signaling, suppresses the survival, proliferation, differentiation, and function of T cells, thereby providing atheroprotection in vivo.
Dysregulated BMP (bone morphogenetic protein) or TGF-β (transforming growth factor beta) signaling pathways are imperative in idiopathic and familial pulmonary arterial hypertension (PAH) as well as experimental pulmonary hypertension (PH) in rodent models. MED1 (mediator complex subunit 1) is a key transcriptional co-activator and KLF4 (Krüppel-like factor 4) is a master transcription factor in endothelium. However, MED1 and KLF4 epigenetic and transcriptional regulations of the BMP/TGF-β axes in pulmonary endothelium and their dysregulations leading to PAH remain elusive. We investigate the MED1/KLF4 co-regulation of the BMP/TGF-β axes in endothelium by studying the epigenetic regulation of BMPR2 (BMP receptor type II), ETS-related gene (
), and TGFBR2 (TGF-β receptor 2) and their involvement in the PH.
High-throughput screening involving data from RNA-seq, MED1 ChIP-seq, H3K27ac ChIP-seq, ATAC-seq, and high-throughput chromosome conformation capture together with in silico computations were used to ex resulting impairment of the BMP/TGF-β signaling is implicated in the disease progression of PAH in humans and PH in rodent models.
A homeostatic regulation of BMPR2, ERG, and TGFBR2 in ECs by MED1 synergistic with KLF4 is essential for the normal function of the pulmonary endothelium. Dysregulation of MED1 and the resulting impairment of the BMP/TGF-β signaling is implicated in the disease progression of PAH in humans and PH in rodent models.
Enthusiasm for using polygenic risk scores (PRSs) in clinical practice is tempered by concerns about their portability to diverse ancestry groups, thus motivating genome-wide association studies in non-European ancestry cohorts.
We conducted a genome-wide association study for coronary heart disease in a Middle Eastern cohort using whole genome sequencing and assessed the performance of 6 PRSs developed with methods including LDpred (PGS000296), metaGRS (PGS000018), Pruning and Thresholding (PGS000337), and an EnsemblePRS we developed. Additionally, we evaluated the burden of rare variants in lipid genes in cases and controls. 6-Benzylaminopurine cost Whole genome sequencing at 30× coverage was performed in 1067 coronary heart disease cases (mean age=59 years; 70.3% males) and 6170 controls (mean age=40 years; 43.5% males).
The majority of PRSs performed well; odds ratio (OR) per 1 SD increase (OR
) was highest for PGS000337 (OR
=1.81, 95% CI [1.66-1.98],
=3.07×10
). EnsemblePRS performed better than individual PRSs (OR
=1.8, 95% CI [1.66-1.96],
=5.89×10
). The OR for the 10th decile versus the remaining deciles was >3.2 for PGS000337, PGS000296, PGS000018, and reached 4.58 for EnsemblePRS. Of 400 known genome-wide significant loci, 33 replicated at
<10
. However, the 9p21 locus did not replicate. Six suggestive (
<10
) new loci/genes with plausible biological function were identified (eg,
,
,
). The burden of rare functional variants in
,
,
, and
was greater in cases than controls.
Overall, we demonstrate that PRSs derived from European ancestry genome-wide association studies performed well in a Middle Eastern cohort, suggesting these could be used in the clinical setting while ancestry-specific PRSs are developed.
Overall, we demonstrate that PRSs derived from European ancestry genome-wide association studies performed well in a Middle Eastern cohort, suggesting these could be used in the clinical setting while ancestry-specific PRSs are developed.
The causes of cardiomyopathy in children are less well described than in adults. We evaluated the clinical diagnoses and genetic causes of childhood cardiomyopathy and outcomes of cascade genetic testing in family members.
We recruited children from a pediatric cardiology service or genetic heart diseases clinic. We performed Sanger, gene panel, exome or genome sequencing and classified variants for pathogenicity using American College of Molecular Genetics and Genomics guidelines.
Cardiomyopathy was diagnosed in 221 unrelated children aged ≤18 years. Children mostly had hypertrophic cardiomyopathy (n=98, 44%) or dilated cardiomyopathy (n=89, 40%). The highest genetic testing diagnostic yields were in restrictive cardiomyopathy (n=16, 80%) and hypertrophic cardiomyopathy (n=65, 66%), and lowest in dilated cardiomyopathy (n=26, 29%) and left ventricular noncompaction (n=3, 25%). Pathogenic variants were primarily found in genes encoding sarcomere proteins, with
and
variants associated with more severe clinical outcomes. Ten children (4.5%) had multiple pathogenic variants. Genetic test results prompted review of clinical diagnosis in 14 families with syndromic, mitochondrial or metabolic gene variants. Cascade genetic testing in 127 families confirmed 24 de novo variants, recessive inheritance in 8 families, and supported reclassification of 12 variants.
Genetic testing of children with cardiomyopathy supports a precise clinical diagnosis, which may inform prognosis.
Genetic testing of children with cardiomyopathy supports a precise clinical diagnosis, which may inform prognosis.
Hypertrophic cardiomyopathy often causes major adverse cardiovascular events (MACE), for example, arrhythmias, stroke, heart failure, and sudden cardiac death. Currently, there are no models available to predict MACE. Furthermore, it remains unclear which signaling pathways mediate MACE. Therefore, we aimed to prospectively determine protein biomarkers that predict MACE in hypertrophic cardiomyopathy and to identify signaling pathways differentially regulated in patients who subsequently develop MACE.
In this multi-centre prospective cohort study of patients with hypertrophic cardiomyopathy, we conducted plasma proteomics profiling of 4979 proteins upon enrollment. We developed a proteomics-based model to predict MACE using data from one institution (training set). We tested the predictive ability in independent samples from the other institution (test set) and performed time-to-event analysis. Additionally, we executed pathway analysis of predictive proteins using a false discovery rate threshold of < study serves as the first to demonstrate the ability of proteomics profiling to predict MACE in hypertrophic cardiomyopathy, exhibiting both novel (eg, Ras-MAPK) and known (eg, TGF-β) pathways differentially regulated in patients who subsequently experience MACE.
