Serum YKL-40 in coronary heart disease: linkage with inflammatory cytokines, artery stenosis, and optimal cut-off value for estimating major adverse cardiovascular events
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SUBMITTER: Song M
PROVIDER: S-EPMC10644235 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:ObjectivesThe combination of high YKL-40 (a glial inflammatory marker) and low sAPPβ (a soluble β fragment of amyloid precursor protein) in cerebrospinal fluid (CSF) has been associated with frontotemporal lobar degeneration (FTLD) in clinical series. We investigate these biomarkers in a neuropathologically confirmed cohort of patients with FTLD.MethodsCSF samples were selected from the Penn FTD Center (University of Pennsylvania). Participants were followed to autopsy and had a neuropathological diagnosis of FTLD-Tau (n=24), transactive response DNA-binding protein with 43 kDa (FTLD-TDP) (n=25) or Alzheimer's disease (AD, n=97). We compared levels of YKL-40 and sAPPβ between groups and with cognitively normal controls (n=77), and assessed their diagnostic utility using receiver operating characteristic curves. We also investigated the effect of AD copathology and the correlation between these CSF markers and tau burden at autopsy.ResultsBoth FTLD groups had lower levels of sAPPβ, higher levels of YKL-40 and lower sAPPβ:YKL-40 ratio in CSF compared with controls. The group of pure FTLD-Tau (without AD copathology) showed higher levels of YKL-40 than AD and than pure FTLD-TDP. YKL-40 levels correlated with pathological tau burden. The sAPPβ:YKL-40 ratio had an area under the curve (AUC) of 0.91 (95% CI 0.86 to 0.96) to distinguish subjects with FTLD from controls, but lower values to distinguish FTLD from AD (AUC 0.70; 95% CI 0.61 to 0.79) and to discriminate FTLD-Tau from FTLD-TDP (AUC 0.67; 95% CI 0.51 to 0.82).ConclusionsOur study provides pathological confirmation that the combination of low sAPPβ and high YKL-40 in CSF is associated with FTLD. These biomarkers could be useful in particular clinical settings when FTLD is suspected.
| S-EPMC6351153 | biostudies-literature
Project description:Background: Complex local and systemic immune dysfunction in glioblastoma (GBM) may affect survival. Interleukin (IL)-6 and YKL-40 are pleiotropic biomarkers present in the tumor microenvironment and involved in immune regulation. We therefore analyzed plasma IL-6, YKL-40, and genetic variation in YKL-40 and explored their ability to distinguish between glioma subtypes and predict survival in GBM. Methods: One hundred fifty-eight patients with glioma WHO grade II-IV were included in the study. Plasma collected at surgery was analyzed for IL-6 and YKL-40 (CHI3L1) by ELISA. CHI3L1 rs4950928 genotyping was analyzed on whole-blood DNA. Results: Neither plasma IL-6 nor YKL-40 corrected for age or rs4950928 genotype could differentiate GBM from lower grade gliomas. GC and GG rs4950928 genotype were associated with lower plasma YKL-40 levels (CC vs. GC, p = 0.0019; CC vs. GG, p = 0.01). Only 10 and 14 out of 94 patients with newly diagnosed GBM had elevated IL-6 or YKL-40, respectively. Most patients received corticosteroid treatment at time of blood-sampling. Higher pretreatment plasma IL-6 was associated with short overall survival (OS) [HR = 1.19 (per 2-fold change), p = 0.042] in univariate analysis. The effect disappeared in multivariate analysis. rs4950928 genotype did not associate with OS [HR = 1.30, p = 0.30]. In recurrent GBM, higher YKL-40 [HR = 2.12 (per 2-fold change), p = 0.0005] but not IL-6 [HR = 0.99 (per 2-fold change), p = 0.92] were associated with short OS in univariate analysis. Conclusion: In recurrent GBM high plasma YKL-40 may hold promise as a prognostic marker. In newly diagnosed GBM perioperative plasma IL-6, YKL-40, and genetic variation in YKL-40 did not associate with survival. Corticosteroid use may complicate interpretation of results.
| S-EPMC7180208 | biostudies-literature
Project description:Tumor angiogenesis is of paramount importance in solid tumor development. Elevated serum levels of YKL-40, which is a secreted heparin-binding glycoprotein, have been associated with a worse prognosis from various advanced human cancers. Yet the role of YKL-40 activity in these cancers is still missing. In this study, we showed that ectopic expression of YKL-40 in MDA-MB-231 breast cancer cells and in HCT-116 colon cancer cells led to larger tumor formation with an extensive angiogenic phenotype than did control cancer cells in mice. Affinity-purified recombinant YKL-40 protein promoted vascular endothelial cell angiogenesis in vitro, the effects of which are similar to the activities observed using MDA-MB-231 and HCT-116 cell-conditioned medium after transfection with YKL-40. Furthermore, YKL-40 was found to induce coordination of membrane-bound receptor syndecan-1 and integrin alpha(v)beta(3) and to activate an intracellular signaling cascade, including focal adhesion kinase and mitogen-activated protein kinase extracellular signal-related kinase1/2 in endothelial cells. Moreover, blockade of YKL-40 using small-interfering RNA gene knockdown suppressed tumor angiogenesis in vitro and in vivo. Immunohistochemical analysis of human breast cancer showed a correlation between YKL-40 expression and blood vessel density. These findings provide novel insights into angiogenic activities and molecular mechanisms of YKL-40 in cancer development.
| S-EPMC2795793 | biostudies-literature
Project description:Asthma is a heterogeneous chronic disorder of the airways, with inflammation and bronchial hyperresponsiveness as its major underlying phenomena. Asthmatics vary in terms of inflammation pattern, concomitant pathologies, and factors aggravating the course of the disease. As a result, there is a need for sensitive and specific biomarkers that could facilitate diagnosing asthma as well as phenotyping in everyday practice. Chitinases and chitinase-like proteins (CLPs) seem promising in this field. Chitinases are evolutionarily conserved hydrolases that degrade chitin. In contrast, CLPs bind chitin but do not have degrading activity. Mammalian chitinases and CLPs are produced by neutrophils, monocytes, and macrophages in response to parasitic or fungal infections. Recently, several questions have been raised about their role in chronic airway inflammation. Several studies demonstrated that overexpression of CLP YKL-40 was associated with asthma. Moreover, it correlated with exacerbation rate, therapy resistance, poor control of symptoms, and, inversely, with FEV1. YKL-40 facilitated allergen sensitization and IgE production. Its concentration was elevated in bronchoalveolar lavage fluid after an allergen challenge. It was also found to promote the proliferation of bronchial smooth muscle cells and correlate with subepithelial membrane thickness. Thus, it may be involved in bronchial remodeling. Associations between YKL-40 and particular asthma phenotypes remain unclear. Some studies showed that YKL-40 correlates with blood eosinophilia and FeNO, suggesting a role in T2-high inflammation. Quite the opposite, cluster analyses revealed the highest upregulation in severe neutrophilic asthma and obesity-associated asthma. The main limitation in the practical application of YKL-40 as a biomarker is its low specificity. High serum levels of YKL-40 were also found in COPD and several malignancies, in addition to infectious and autoimmune diseases. To conclude, the level of YKL-40 correlates with asthma and some clinical features in the whole asthmatic population. The highest levels are found in neutrophilic and obesity-related phenotypes. However, due to its low specificity, the practical application of YKL-40 remains uncertain but could be useful in phenotyping, especially when combined with other biomarkers.
| S-EPMC9945318 | biostudies-literature
Project description:The secreted protein, YKL-40, has been proposed as a biomarker of a variety of human diseases characterized by ongoing inflammation, including chronic neurologic pathologies such as multiple sclerosis and Alzheimer's disease. However, inflammatory mediators and the molecular mechanism responsible for enhanced expression of YKL-40 remained elusive. Using several mouse models of inflammation, we now show that YKL-40 expression correlated with increased expression of both IL-1 and IL-6. Furthermore, IL-1 together with IL-6 or the IL-6 family cytokine, oncostatin M, synergistically upregulated YKL-40 expression in both primary human and mouse astrocytes in vitro. The robust cytokine-driven expression of YKL-40 in astrocytes required both STAT3 and NF-κB binding elements of the YKL-40 promoter. In addition, YKL-40 expression was enhanced by constitutively active STAT3 and inhibited by dominant-negative IκBα. Surprisingly, cytokine-driven expression of YKL-40 in astrocytes was independent of the p65 subunit of NF-κB and instead required subunits RelB and p50. Mechanistically, we show that IL-1-induced RelB/p50 complex formation was further promoted by oncostatin M and that these complexes directly bound to the YKL-40 promoter. Moreover, we found that expression of RelB was strongly upregulated during inflammation in vivo and by IL-1 in astrocytes in vitro. We propose that IL-1 and the IL-6 family of cytokines regulate YKL-40 expression during sterile inflammation via both STAT3 and RelB/p50 complexes. These results suggest that IL-1 may regulate the expression of specific anti-inflammatory genes in nonlymphoid tissues via the canonical activation of the RelB/p50 complexes.
| S-EPMC4355396 | biostudies-literature
Project description:Estimating admixture histories is crucial for understanding the genetic diversity we see in present-day populations. Allele frequency or phylogeny-based methods are excellent for inferring the existence of admixture or its proportions. However, to estimate admixture times, spatial information from admixed chromosomes of local ancestry or the decay of admixture linkage disequilibrium (ALD) is used. One popular method, implemented in the programs ALDER and ROLLOFF, uses two-locus ALD to infer the time of a single admixture event, but is only able to estimate the time of the most recent admixture event based on this summary statistic. To address this limitation, we derive analytical expressions for the expected ALD in a three-locus system and provide a new statistical method based on these results that is able to resolve more complicated admixture histories. Using simulations, we evaluate the performance of this method on a range of different admixture histories. As an example, we apply the method to the Colombian and Mexican samples from the 1000 Genomes project. The implementation of our method is available at https://github.com/Genomics-HSE/LaNeta.
| S-EPMC9342778 | biostudies-literature
Project description:The chitinase-like protein YKL-40 mediates airway inflammation and serum levels are associated with asthma severity. However, asthma phenotypes associated with YKL-40 levels have not been precisely defined.We conducted an unsupervised cluster analysis of asthma patients treated at the Yale Center for Asthma and Airways Disease (n=156) to identify subgroups according to YKL-40 level. The resulting YKL-40 clusters were cross-validated in cohorts from the Severe Asthma Research Programme (n=167) and the New York University/Bellevue Asthma Repository (n=341). A sputum transcriptome analysis revealed molecular pathways associated with YKL-40 subgroups.Four YKL-40 clusters (C1-C4) were identified. C3 and C4 had high serum YKL-40 levels compared with C1 and C2. C3 was associated with earlier onset and longer duration of disease, severe airflow obstruction, and near-fatal asthma exacerbations. C4 had the highest serum YKL-40 levels, adult onset and less airflow obstruction, but frequent exacerbations. An airway transcriptome analysis in C3 and C4 showed activation of non-type 2 inflammatory pathways.Elevated serum YKL-40 levels were associated with two distinct clinical asthma phenotypes: one with irreversible airway obstruction and another with severe exacerbations. The YKL-40 clusters are potentially useful for identification of individuals with severe or exacerbation-prone asthma.
| S-EPMC5967238 | biostudies-literature
Project description:Background and objectivesYKL-40 is considered to be associated with cardiovascular disease (CVD). In this study, the effect of serum 25(OH) vitamin D [25(OH)VitD] differences between groups on YKL-40 was evaluated on a hypercholesterolemia rat model.MethodsThirty-two male rats (wistar albino) were equally divided into 4 groups. The first group was the control group; the second group was high-cholesterol (H-CH) adequate vitamin D (VitD) group (H-AdeVD). The third group was the H-CH deficient VitD group (H-DefVD), and the last group was designed with the H-CH supplement VitD (H-SupVD). The feeding process consisted of 2 stages. At the first stage (5 months), the H-DefVD group was fed on VitD deficient chow, while the other groups (control, H-AdeVD, H-SupVD) were fed on standard chow. At the second stage (3 months), the H-AdeVD and the H-SupVD groups were fed on the H-CH chow, whereas the H-DefVD group was fed on the H-CH-VitD deficient chow. Moreover, the H-SupVD group was given 100 IU/kg/day VitD along with the H-CH chow.ResultsCompared with the control group, interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and YKL-40 values in the H-DefVD groups increased significantly (p<0.001, p<0.001, p=0.009, p=0.005; sequentially).ConclusionIt can be concluded that VitD can suppress the YKL-40, thus, it will prevent CVD development in rat. Therefore, further clinical studies related with human will reveal the effect of VitD and YKL-40 on CVD development.
| S-EPMC9932220 | biostudies-literature
Project description:ObjectiveDietary supplement use has increased over past decades, resulting in reports of potentially serious adverse events. The aim of this study was to develop optimised methods to evaluate the causal relationships between adverse events and dietary supplements, and to test these methods using case reports.DesignCausal relationship assessment using prospectively collected data.Setting and participants4 dietary supplement experts, 4 pharmacists and 11 registered dietitians (5 men and 14 women) examined 200 case reports of suspected adverse events using the modified Naranjo scale and the modified Food and Drug Administration (FDA) algorithm.Primary outcome measuresThe distribution of evaluation results was analysed and inter-rater reliability was evaluated for the two modified methods employed using intraclass correlation coefficients (ICC) and Fleiss' κ.ResultsUsing these two methods, most of the 200 case reports were categorised as 'lack of information' or 'possible' adverse events. Inter-rater reliability among entire assessors ratings for the two modified methods, based on ICC and Fleiss' κ, were classified as more than substantial (modified Naranjo scale: ICC (95% CI) 0.873 (0.850 to 0.895); Fleiss' κ (95% CI) 0.615 (0.615 to 0.615). Modified FDA algorithm: Fleiss' κ (95% CI) 0.622 (0.622 to 0.622).ConclusionsThese methods may help to assess the causal relationships between adverse events and dietary supplements. By conducting additional studies of these methods in different populations, researchers can expand the possibilities for the application of our methods.
| S-EPMC4663420 | biostudies-literature
Project description:ObjectivesTo compare the effectiveness, reliability, and acceptability of estimating rates of adverse events and rates of preventable adverse events using three methods: cross sectional (data gathered in one day), prospective (data gathered during hospital stay), and retrospective (review of medical records).DesignIndependent assessment of three methods applied to one sample.Setting37 wards in seven hospitals (three public, four private) in southwestern France.Participants778 patients: medical (n = 278), surgical (n = 263), and obstetric (n = 237).Main outcome measuresThe main outcome measures were the proportion of cases (patients with at least one adverse event) identified by each method compared with a reference list of cases confirmed by ward staff and the proportion of preventable cases (patients with at least one preventable adverse event). Secondary outcome measures were inter-rater reliability of screening and identification, perceived workload, and face validity of results.ResultsThe prospective and retrospective methods identified similar numbers of medical and surgical cases (70% and 66% of the total, respectively) but the prospective method identified more preventable cases (64% and 40%, respectively), had good reliability for identification (kappa = 0.83), represented an acceptable workload, and had higher face validity. The cross sectional method showed a large number of false positives and identified none of the most serious adverse events. None of the methods was appropriate for obstetrics.ConclusionThe prospective method of data collection may be more appropriate for epidemiological studies that aim to convince clinical teams that their errors contribute significantly to adverse events, to study organisational and human factors, and to assess the impact of risk reduction programmes.
| S-EPMC318484 | biostudies-literature