Increase In YKL-40 Research Articles

Prognostic utility of serum YKL-40 in patients with cervical cancer

Inflammation is one of the hallmarks of cancer and plays a crucial role in the development and progression. The objective of the present study was to investigate if high serum YKL-40 is related to poor prognosis in cervical cancer (CC) patients. A prospective biomarker study of 116 patients with CC (FIGO stage Ia: n = 4; Ib: n = 55; II: n = 26; III: n = 26; IV: n = 5) and 152 patients with cervical intraepithelial neoplasia (CIN). The patients received primary surgery, radiotherapy and chemotherapy according to standard guidelines during the period 2001–2004. Seventy patients died during the follow-up period (median 117 months, range 104–131). Serum concentrations of YKL-40 were measured by ELISA. Serum concentrations of YKL-40 were increased (p < .001) in CC patients (median 76 µg/L, IQR 45–148) compared to CIN patients (44 µg/L, IQR 30–61) and healthy women (41 µg/L, IQR 29–58). YKL-40 was elevated (>age-corrected 95th percentile of YKL-40 in healthy women) in 30 (26%) of the CC patients. Univariate Cox analysis demonstrated that YKL-40 (included as a log-transformed continuous variable (base 2)) was associated with recurrence-free survival (RFS) (HR = 1.48, 95% CI: 1.11–1.98, p = .008) and overall survival (OS) (HR = 1.74, 1.44–2.10, p < .0001). Multivariate Cox analysis showed that stage (II + III vs. I: HR = 2.92, 1.37–6.20, p = .005), YKL-40 (HR = 1.35, 1.06–1.73, p = .018) and age (HR = 1.56, 1.21–1.99, p = .0005) were independent prognostic variables of OS. During treatment, a 2-fold increase in YKL-40 compared to baseline level was associated with short RFS (HR = 1.87, 1.27–2.77, p = .0016) and OS (HR = 1.78, 1.26–2.50, p = .0010). Serum YKL-40 is an independent biomarker of OS in patients with cervical cancer.

Elevated plasma YKL-40 and risk of infectious disease: a prospective study of 94665 individuals from the general population

ObjectivesYKL-40 is an acute phase protein elevated in patients with infectious and inflammatory diseases. We tested the hypothesis that baseline elevated YKL-40 is associated with increased risk of future infectious disease in healthy individuals in the general population. MethodsWe prospectively followed 94 665 individuals from the Danish general population for up to 23 years and analysed for plasma YKL-40 levels (n = 21 584) and CHI3L1 rs4950928 genotype (n = 94 184). Endpoints were any infection, bacterial pneumonia, urinary tract infection, skin infection, sepsis, diarrhoeal disease, and other infections. ResultsFor YKL-40 percentile category 91–100% versus 0–33%, the multifactorially and C-reactive protein (CRP) adjusted hazard ratios were 1.71 (95% confidence interval 1.50–1.96; p 4 × 10−14) for any infection, 1.97 (1.64–2.37; p 4 × 10−13) for bacterial pneumonia, 1.62 (1.24–2.11; p 0.002) for urinary tract infection, 1.74 (1.31–2.32; p 2 × 10−4) for skin infection, 1.76 (1.25–2.46; p 0.004) for sepsis, 1.90 (1.29–2.78; p 0.002) for diarrhoeal disease and 2.71 (1.38–5.35; p 0.01) for other infections. In multifactorially and CRP-adjusted models, a twofold increase in YKL-40 was associated with increased risk of all infectious disease endpoints. Mendelian randomization did not support causality, as CHI3L1 rs4950928 was associated with 94% and 190% higher YKL-40 levels (for CG and CC versus GG genotype), but not with increased risk of any infectious disease endpoint. DiscussionBaseline elevated plasma YKL-40 was not a cause but a strong marker of increased risk of future infectious diseases in individuals in the general population.

Determination of high sensitivity troponin I in diagnosis of myocardial infarction

YKL-40 is an acute phase protein elevated in patients with infectious and inflammatory diseases. We tested the hypothesis that baseline elevated YKL-40 is associated with increased risk of future infectious disease in healthy individuals in the general population.We prospectively followed 94 665 individuals from the Danish general population for up to 23 years and analysed for plasma YKL-40 levels (n = 21 584) and CHI3L1 rs4950928 genotype (n = 94 184). Endpoints were any infection, bacterial pneumonia, urinary tract infection, skin infection, sepsis, diarrhoeal disease, and other infections.For YKL-40 percentile category 91–100% versus 0–33%, the multifactorially and C-reactive protein (CRP) adjusted hazard ratios were 1.71 (95% confidence interval 1.50–1.96; p 4 × 10−14) for any infection, 1.97 (1.64–2.37; p 4 × 10−13) for bacterial pneumonia, 1.62 (1.24–2.11; p 0.002) for urinary tract infection, 1.74 (1.31–2.32; p 2 × 10−4) for skin infection, 1.76 (1.25–2.46; p 0.004) for sepsis, 1.90 (1.29–2.78; p 0.002) for diarrhoeal disease and 2.71 (1.38–5.35; p 0.01) for other infections. In multifactorially and CRP-adjusted models, a twofold increase in YKL-40 was associated with increased risk of all infectious disease endpoints. Mendelian randomization did not support causality, as CHI3L1 rs4950928 was associated with 94% and 190% higher YKL-40 levels (for CG and CC versus GG genotype), but not with increased risk of any infectious disease endpoint.Baseline elevated plasma YKL-40 was not a cause but a strong marker of increased risk of future infectious diseases in individuals in the general population.

Hippocampal YKL-40 expression in rats after status epilepticus

ObjectiveThis study aims to investigate rat hippocampal cartilage glycoprotein-39 (YKL-40) expression levels following status epilepticus (SE), and the potential mechanism of YKL-40 in SE-induced neuronal injury. MethodsSeventy-two healthy adult male Sprague-Dawley rats were randomly assigned into two groups: control and SE groups. A lithium chloride-pilocarpine SE model was established, and the control group was injected with sodium chloride. The hippocampus was assessed at three, six, 12, 24 and 72h after SE. YKL-40 protein was detected via immunohistochemistry (n=6). Cellular YKL-40/neuronal nuclei antigen (NeuN) expression levels were determined with double immunofluorescence. YKL-40 mRNA was detected via quantitative real-time polymerase chain reaction (qRT-PCR, n=6). ResultsYKL-40 immunoreactivity was poor and was mainly localized to the cytoplasm within hippocampal CA3/CA4 neurons with limited immunoreactivity in the nucleus in the control group. Following SE, YKL-40 immunoreactivity exhibited a diffused distribution throughout the cytoplasm in neurons and increased distribution in the nucleus. CA3 and CA4 YKL-40 protein expression significantly increased at six hours post-SE (P<0.05), peaked at 12h (P<0.01), and decreased at 24h (P<0.05) and 72h (P<0.05) in the SE group, compared with the control group. Double-label immunofluorescence of YKL-40/NeuN exhibited a hippocampal CA3/CA4 neuron location. Furthermore, SE induced a significant increase inYKL-40 mRNA at six, 24, or 72h (P<0.05); which peaked at 12h (P<0.01). ConclusionsYKL-40 was expressed in neurons, and elevated rat hippocampal YKL-40 expression levels may be involved in the pathogenesis of injury following SE.

The Inflammatory Marker YKL-40 Is Elevated in Cerebrospinal Fluid from Patients with Alzheimer's but Not Parkinson's Disease or Dementia with Lewy Bodies.

A major difference in the revised diagnostic criteria for Alzheimer’s disease (AD) is the incorporation of biomarkers to support a clinical diagnosis and allow the identification of preclinical AD due to AD neuropathological processes. However, AD-specific fluid biomarkers which specifically distinguish clinical AD dementia from other dementia disorders are still missing. Here we aimed to evaluate the disease-specificity of increased YKL-40 levels in cerebrospinal fluid (CSF) from AD patients with mild to moderate dementia (n = 49) versus Parkinson’s disease (PD) (n = 61) and dementia with Lewy bodies (DLB) patients (n = 36), and non-demented controls (n = 44). Second we aimed to investigate whether altered YKL-40 levels are associated with CSF levels of other inflammation-associated molecules. When correcting for age, AD patients exhibited 21.3%, 27.7% and 38.8% higher YKL-40 levels compared to non-demented controls (p = 0.0283), DLB (p = 0.0027) and PD patients (p<0.0001). The AD-associated increase in YKL-40 was not associated with CSF P-tau, T-tau or Aβ42. No relationship between increased YKL-40 and levels of the astrocytic marker glial-fibrillary acidic protein (GFAP), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein 10 (IP-10) could be identified. Our results confirm previous reports of an age-associated increased in CSF YKL-40 levels and further demonstrate increased CSF YKL-40 in AD patients versus non-demented controls and patients with DLB or PD. The increase in YKL-40 levels in the AD patients was unrelated to the established CSF AD biomarkers and the inflammatory markers GFAP, MCP-1, IP-10 and IL-8, proposing YKL-40 as a marker of yet to be identified AD-related pathological processes.

Association between serum YKL-40 level and dysglycemia in cystic fibrosis

BackgroundYKL-40, a chitinase-like protein, is a biomarker for type 1 and type 2 diabetes prognosis. We hypothesized that YKL-40 protein levels are elevated in CF patients with dysglycemia. MethodsSeventeen healthy control subjects and 66 CF patients were prospectively recruited and subjected to an oral glucose tolerance test. In all participants, fasting serum YKL-40 was compared between control and CF patients and between normal glucose-tolerant patients (NG-CF) and CF patients with dysglycemia (DG-CF). A Botnia clamp procedure was performed on a subset of patients for each group to determine the impact of acute increases of either glucose or insulin on YKL-40 concentration. ResultsCF patients had higher serum YKL-40 values than the controls (113 [49;288] vs. 38 [30;50] ng/ml, p<0.001). YKL-40 concentrations in CF patients were mainly increased in the DG-CF group, who had significantly higher values: 213 [93;383] vs. 67 [27;97] ng/ml in the NG-CF group, p<0.001). No significant modulation of YKL-40 concentration was observed in serum of CF (NG or DG-CF) or non-CF patients, after acute exposure to glucose or insulin. ConclusionsHigher serum YKL-40 levels in CF patients are significantly associated with dysglycemia. The increase in YKL-40 is potentially associated with an inflammatory response resulting from chronic glucose intolerance or CF disease evolution.

Plasma YKL-40 levels in healthy subjects from the general population

Background Plasma YKL-40 is a new biomarker in patients with cancer and inflammatory diseases. High plasma YKL-40 is associated with poor prognosis. Our aim was to determine reference levels in healthy subjects. Methods Plasma YKL-40 was determined in 3130 participants aged 20–80 years from the Danish general population, the Copenhagen City Heart Study. They had no known disease at time of blood sampling in 1991–1994 and remained healthy and alive during a 16-year follow-up period. In 644 participants, YKL-40 was measured again in samples taken 10 years after the first. Results The median plasma YKL-40 was 40 μg/L (2.5–97.5% reference levels: 14–155) with no difference between sexes. YKL-40 increased exponentially with age. For age-adjusted reference levels, the YKL-40 percentile as a function of age in years and plasma YKL-40 in μg/L was derived: percentile = 100 / (1 + (YKL-40 ^ −3) * (1.062 ^ age) * 5000). In subjects with two YKL-40 measurements 10 years apart, the mean increase in YKL-40 was 1.5 μg/L/year (SE: 0.2), while the mean change in the calculated age percentile was minimal (−0.3; SE: 0.1). Conclusions Plasma YKL-40 increases with age within and across healthy individuals from the general population. Age-stratified or age-adjusted reference levels are important when YKL-40 test results are evaluated.

Plasma YKL-40 and recovery of left ventricular function after acute myocardial infarction

Background: Plasma YKL-40 is increased early in patients with ST-elevation myocardial infarction (STEMI). It is not known whether plasma YKL-40 is related to infarct size and recovery of ventricular function after primary percutaneous coronary intervention (PCI) of STEMI and whether granulocyte colony-stimulating factor (G-CSF) therapy influence plasma YKL-40 concentration. Materials and methods: A total of 72 patients (age: 56 ± 9 years (mean ± SD), 56 men and 16 women) with STEMI treated with PCI were included in a double-blind, randomized, placebo-controlled trial with subcutaneous G-CSF or placebo injections from day 1 to 7 after the STEMI. Plasma YKL-40, high-sensitivity C-reactive protein (hs-CRP) and CK-MB concentrations were measured at baseline and during the first month. Infarct size and left ventricular ejection fraction (LVEF) were measured by magnetic resonance imaging at baseline and after 6 months. Results: Baseline plasma YKL-40 was increased (median 92 μg/L) compared to healthy subjects (median 34 μg/L, p <0.001). In the placebo group hs-CRP and YKL-40 correlated at baseline (p = 0.04) and day 3 (p = 0.01), but not at day 7 and 30. Moreover, YKL-40 correlated negatively to LVEF recovery (p = 0.04) but not infarct size. G-CSF injections increased YKL-40 compared to placebo (p <0.001), but were not associated with infarct size or LVEF recovery. Conclusion: Plasma YKL-40 was significantly increased in STEMI patients at admission and G-CSF treatment caused a further increase in YKL-40. Plasma YKL-40 may be an indirect marker of LVEF recovery, independent of hs-CRP, and higher plasma YKL-40 indicates a lower recovery.

YKL-40, a Marker of Simian Immunodeficiency Virus Encephalitis, Modulates the Biological Activity of Basic Fibroblast Growth Factor

Human immunodeficiency virus encephalitis causes dementia in acquired immune deficiency syndrome patients. Using proteomic analysis of postmortem cerebrospinal fluid (CSF) and brain tissue from the simian immunodeficiency virus primate model, we demonstrate here a specific increase in YKL-40 that was tightly associated with lentiviral encephalitis. Longitudinal analysis of CSF from simian immunodeficiency virus-infected pigtailed macaques showed an increase in YKL-40 concentration 2 to 8 weeks before death from encephalitis. This increase in YKL-40 correlated with an increase in CSF viral load; it may therefore represent a biomarker for the development of encephalitis. Analysis of banked human CSF from human immunodeficiency virus-infected patients also demonstrated a correlation between YKL-40 concentration and CSF viral load. In vitro studies demonstrated increased YKL-40 expression and secretion by macrophages and microglia but not by neurons or astrocytes. We found that YKL40 displaced extracellular matrix-bound basic fibroblast growth factor (bFGF) as well as inhibited the mitogenic activity of both fibroblast growth factor receptor 1-expressing BaF3 cells and bFGF-induced axonal branching in hippocampal cultures. Taken together, these findings demonstrate that during lentiviral encephalitis, YKL-40 may interfere with the biological activity of bFGF and potentially of other heparin-binding growth factors and chemokines that can affect neuronal function or survival.

Regulation of YKL‐40 expression during genotoxic or microenvironmental stress in human glioblastoma cells

YKL-40 is a 40 kDa secreted glycoprotein belonging to the family of 'mammalian chitinase-like proteins', but without chitinase activity. YKL-40 has a proliferative effect on fibroblasts, chondrocytes and synoviocytes, and chemotactic effect on endothelium and vascular smooth muscle cells. Elevated YKL-40 levels are found in serum of patients with diseases characterized by inflammation, fibrosis and tissue remodeling. Several studies have reported that high serum YKL-40 levels in patients with cancer are associated with poor prognosis. YKL-40 expression is strongly elevated in serum and biopsy material from glioblastomas patients. We investigated the expression of YKL-40 in three human malignant glioma cell lines exposed to different types of stress. Whereas a polymerase chain reaction transcript was detectable in all three cell lines, only U87 produced measurable amounts of YKL-40 protein. In U87, hypoxia and ionizing radiation induced a significant increase in YKL-40 after 24-48 h. The hypoxic induction of YKL-40 was independent of HIF1. Etoposide, ceramide, serum depletion and confluence all led to elevated YKL-40. Inhibition of p53 augmented the YKL-40 expression indicating that YKL-40 is attenuated by p53. In contrast, both basic fibroblast growth factor and tumor necrosing factor-alpha repressed YKL-40. These are the first data on regulation of YKL-40 in cancer cells. Diverse types of stress resulted in YKL-40 elevation, which strongly supports an involvement of YKL-40 in the malignant phenotype as a cellular survival factor in an adverse microenvironment.