CHI3L1 Research Articles

Association of CG Genotype at rs4950928 Promoter in CHI3L1 Gene with YKL-40 Levels and Asthma Susceptibility in North Indian Asthma Patients

YKL-40 is a chitinase like protein associated with inflammation in asthma. The role of single nucleotide polymorphisms in CHI3L1 gene on asthma susceptibility and YKL-40 levels has been widely investigated on different ethnic groups, and contradictory results were obtained on susceptibility allele. In the present study, surface plasmon resonance technology and polymerase chain reaction based methods were utilized for serum YKL-40 evaluation and genotyping in 100 asthma patients and 50 healthy controls. Data analysis was done by STATA 11.1 software. Our preliminary observations in patients and controls revealed a total of 22 SNP’s in CHI3L1 gene. A non-synonymous SNP in exon 3 (64 D>N) (p = 0.05) and a synonymous SNP in exon 10 (364 C>C) (p = 0.004) were found to be significantly present in patients as compared to that in controls. We also observed two novel variations at genomic positions g.203153630 (p < 0.001) and g.203148418 (p < 0.001). We observed the −131C→G (rs4950928) promoter region variation and predominant expression of G allele in both groups. A statistically significant elevation of serum YKL-40 was observed in patients with CG genotype in comparison with GG (p < 0.001). Our findings concluded that the increased level of YKL-40 and hence asthma susceptibility may be due to the presence of CG genotype at rs4950928 promoter region.

Exacerbating Factors Induce Different Gene Expression Profiles in Peripheral Blood Mononuclear Cells from Asthmatics, Patients with Chronic Obstructive Pulmonary Disease and Healthy Subjects

Background: Despite several common phenotypic features, chronic obstructive pulmonary disease (COPD) and severe asthma differ with regard to their causative factors and pathophysiology. Both diseases may be exacerbated by environmental factors, however, the molecular profiles of disease episodes have not been comprehensively studied. We identified differences in gene and protein expression profiles expressed by peripheral blood mononuclear cells (PBMC) of COPD patients, patients with atopic asthma and healthy subjects when challenged with exacerbating factors in vitro: lipopolysaccharide (LPS), house dust mite (HDM) and cat allergen. Methods: PBMC isolated from patients with severe atopic asthma and COPD, as well as healthy subjects were stimulated with rDer p 1 DG, rFel d 1 DG and LPS. The changes in the expression of 47 genes belonging to five groups (phospholipase A₂, eicosanoids, transcription factors, cytokines and airway remodeling) were studied using TaqMan low density array cards. Immunoblotting was used to study relative protein expression. Results: rDer p 1 significantly up-regulated the expression of PLA2G4A, PLA2G6, PLA2G15, CYSLTR1, LB4R2, PTGS1, PTGS2, FOXP1, GATA3, HDAC2, IREB2, PPARG, STAT4, TSLP and CHI3L1 genes in asthmatics in comparison to healthy subjects. LPS induced significant expression of ANXA1 and LTA4H in asthmatics when compared to COPD patients and healthy subjects. SOX6,STAT4 and IL1RL1 were induced in COPD after LPS stimulation. Analysis of protein expression revealed a pattern similar to mRNA expression. Conclusions: LPS-induced exacerbation of asthma and COPD is characterized by differential expression of selected genes in PBMC. HDM allergen changed the expression profile of inflammatory genes between patients with asthma of atopic origin and healthy controls.

Assessment of human cartilage glycoprotein 39 (YKL-40), preptin, and nitric oxide in adolescent patients with type 1 diabetes and its relation to cardiorenal affection.

To evaluate new biomarkers such as YKL-40, preptin, and nitric oxide (NO) in patients with diabetes and to assess its relation to cardiorenal injury. The study included 62 patients with type 1 diabetes and 30 healthy volunteers. Blood sample was taken for assessment of glycosylated hemoglobin, lipid profile, YKL-40, preptin, and NO. Also, urine sample was taken for analysis of albumin/creatinine ratio. Echocardiography was also done. NO was lower, whereas YKL-40, preptin, and albumin/creatinine ratio were significantly higher in patients with diabetes. NO had a significant negative correlation with LVEDD, LVESD, PWT, LV mass, YKL-40, preptin, and albumin/creatinine ratio. YKL-40 had a significant positive correlation with waist/height ratio, preptin and negative correlation with E/A ratio. Stepwise multiple regression revealed that E/A ratio is the only parameter related to YKL-40. On the contrary, NO and systolic blood pressure are related to preptin. A significant reduction of NO and elevation of YKL-40 and preptin was found in patients with diabetes. A decrease in NO is associated with diastolic dysfunction, LV hypertrophy, and renal impairment, whereas YKL-40 is associated with diastolic dysfunction. An increase in preptin level was associated with hypertension.

YKL-40 and genetic status of CHI3L1 in a large group of asthmatics

BackgroundStudies have shown a relationship between asthma, serum YKL-40, and the single nucleotide polymorphism (SNP) (−131 C/G, rs4950928) in the CHI3L1 gene that codes for YKL-40. However, the findings differ. We studied the relationship between clinical asthma phenotypes, serum YKL-40, and SNP (−131 C/G, rs4950928).MethodsIn this study, 1,137 patients with asthma, 415 with rhinitis only, and 275 non-asthmatic controls were included. Assessment included a clinical interview concerning the diagnosis of asthma, severity of asthma, and asthma treatment as well as clinical tests to assess asthma and rhinitis. Serum YKL-40 was measured, and genotyping for the SNP (−131 C/G) was conducted.ResultsNo significant difference in the serum concentration of YKL-40 was found between patients with asthma, patients with rhinitis, and non-asthmatic controls; however, YKL-40 was increased in patients with severe asthma. No association was found between the SNP (−131 C/G rs4950982) and the risk of having asthma (odds ratio = 0.90, p=0.4). Higher levels of serum YKL-40 were found in all subjects when comparing CC genotype to CG and GG genotypes (45 µg/L vs. 32 µg/L and 19 µg/L, p<0.0001).ConclusionThere was no association between polymorphisms of SNP (−131 C/G) and asthma. The highest serum YKL-40 concentrations were seen in severe asthmatics. Individuals with less severe asthma showed a smaller difference against controls, limiting its clinical usefulness. More research is needed to clarify the relationship between different asthma phenotypes, YKL-40, and CHI3L1.

Effects of combined aerobic and resistance training on the glycolipid metabolism and inflammation levels in type 2 diabetes mellitus.

[Purpose] To investigate the effects of combined aerobic and resistance training on glycolipid metabolism and inflammation levels in type 2 diabetes mellitus patients. [Subjects and Methods] Forty-two diabetes patients were randomized to the conventional therapy group (n = 20) or intensive therapy group (n = 22). The control group contained 20 healthy people. The conventional therapy group received routine drug therapy and diet control, while the intensive therapy group additionally underwent combined aerobic and resistance training for 12 weeks. The oral glucose tolerance test and cardiopulmonary exercise testing were performed. Toll-like receptor 4 and NF-κBp65 protein and mRNA expressions were determined by qPCR and western blotting. ELISA was used to determine the expression levels of interleukin-18, interleukin-33, pentraxin-related protein 3, and human cartilage glycoprotein 39. [Results] After exercise training, the intensive therapy group had significantly lower postprandial blood glucose, postprandial insulin, and glycated hemoglobin level and insulin resistance index than the conventional therapy group. The intensive therapy group had significantly lower toll-like receptor 4 and NF-κBp65 protein and mRNA expressions, and serum interleukin-18 levels but significantly higher serum interleukin-33 levels. [Conclusion] Combined aerobic and resistance training can improve glycolipid metabolism and reduce low-grade inflammation in patients with diabetes mellitus patients.

Serum YKL-40 levels are associated with type 2 diabetes mellitus in patients with obstructive sleep apnea syndrome.

Patients with obstructive sleep apnea syndrome (OSAS) have an increased risk for type 2 diabetes mellitus (T2DM). It has been recently demonstrated that serum YKL-40 levels, also named as human cartilage glycoprotein 39, are elevated in T2DM patients. The aim of this study was to determine whether serum YKL-40 levels are associated with T2DM in patients with OSAS. This study consisted of 432 patients with OSAS (234 and 198 patients with and without T2DM, respectively). Serum YKL-40 levels were examined using the enzyme-linked immunosorbent assay method. OSAS patients with T2DM had significantly elevated serum YKL-40 levels compared to those without T2DM [205.02 (146.16-272.70) vs 135.72 (114.06-163.38)]. According to the multivariable logistic regression analysis, serum YKL-40 levels were an independent determinant of T2DM in patients with OSAS. Furthermore, based on the linear regression analysis, serum YKL-40 levels were positively associated with the body mass index, systolic blood pressure, serum triglyceride levels, homeostasis model assessment of insulin resistance, and levels of C-reactive protein, fasting plasma glucose, 2-h postprandial plasma glucose, and HbA1c in patients with OSAS. Elevated serum YKL-40 levels may serve as a new biomarker to predict T2DM in patients with OSAS.

Disease indicators for sepsis and analysis of sepsis treatment in children using the continuous blood purification technique.

We analyzed disease severity, inflammation markers, and dynamic changes in cartilage glycoprotein 39 (YKL-40) and C-reactive protein (CRP) levels in children with sepsis before and after treatment with continuous blood purification (CBP). Study participants were 30 children with severe sepsis who were cured from the disease (experimental group) in the Children's Serious Disease Center of In-ner Mongolia People's Hospital between June 2012 and October 2013. Symptomatic CBP treatment was performed after disease severity scoring. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), YKL-40, and CRP levels were tested 0, 12, 24, and 48 h after CBP treatment. YKL-40 mRNA expression in whole blood was determined biochemically, and its expression in peripheral blood was determined with an immunochemical method. We found a significant difference in disease severity scores before and 48 h after CBP treatment (P < 0.05). IL-6, TNF-α, YKL-40, and CRP levels in children with sepsis at 12, 24, and 48 h after CBP treatment significantly differed from those before treatment (P < 0.05). The relative expression of YKL-40 mRNA in the experimental group before CBP treatment significantly increased from that of the control group (P < 0.05). We found a positive correlation between IL-6, TNF-α, YKL-40, and CRP levels 48 h after CBP treatment. In conclusion, CBP is an effective treatment strategy for pediatric sepsis. YKL-40 and CRP can be used to evaluate the effects of sepsis treatment.

Step-wise and punctuated genome evolution drive phenotype changes of tumor cells

The pattern of genome evolution can be divided into two phases: the step-wise continuous phase (step-wise clonal evolution, stable dominant clonal chromosome aberrations (CCAs), and low frequency of non-CCAs, NCCAs) and punctuated phase (marked by elevated NCCAs and transitional CCAs). Depending on the phase, system stresses (the diverse CIN promoting factors) may lead to the very different phenotype responses. To address the contribution of chromosome instability (CIN) to phenotype changes of tumor cells, we characterized CCAs/NCCAs of HeLa and HEK293 cells, and their derivatives after genotoxic stresses (a stable plasmid transfection, ectopic expression of cancer-associated CHI3L1 gene or treatment with temozolomide) by conventional cytogenetics, copy number alterations (CNAs) by array comparative genome hybridization, and phenotype changes by cell viability and soft agar assays. Transfection of either the empty vector pcDNA3.1 or pcDNA3.1_CHI3L1 into 293 cells initiated the punctuated genome changes. In contrast, HeLa_CHI3L1 cells demonstrated the step-wise genome changes. Increased CIN correlated with lower viability of 293_pcDNA3.1 cells but higher colony formation efficiency (CFE). Artificial CHI3L1 production in 293_CHI3L1 cells increased viability and further contributed to CFE. The opposite growth characteristics of 293_CHI3L1 and HeLa_CHI3L1 cells were revealed. The effect and function of a (trans)gene can be opposite and versatile in cells with different genetic network, which is defined by genome context. Temozolomide treatment of 293_pcDNA3.1 cells intensified the stochastic punctuated genome changes and CNAs, and significantly reduced viability and CFE. In contrast, temozolomide treatment of HeLa_CHI3L1 cells promoted the step-wise genome changes, CNAs, and increased viability and CFE, which did not correlate with the ectopic CHI3L1 production. Thus, consistent coevolution of karyotypes and phenotypes was observed. CIN as a driving force of genome evolution significantly influences growth characteristics of tumor cells and should be always taken into consideration during the different experimental manipulations.

Circulating YKL-40 level, but not CHI3L1 gene variants, is associated with atherosclerosis-related quantitative traits and the risk of peripheral artery disease.

YKL-40, a pleotropic cytokine, is emerging as a risk factor and a prognostic predictor of atherosclerotic cardiovascular disease. We attempted to elucidate the genetic, clinical and biochemical correlates of circulating YKL-40 level and, by combining it with CHI3L1 gene variants, with the risk and long-term mortality of peripheral artery disease (PAD). Plasma YKL-40 concentrations were measured in 612 Taiwanese individuals who had no clinically overt systemic disease. Clinical parameters, CHI3L1 gene promoter variants and 18 biomarker levels were analyzed. Eighty-six PAD patients were further enrolled for analysis. Significant associations were found between CHI3L1 genotypes/haplotypes and YKL-40 levels for the health examination subjects (smallest p = 8.36 × 10−7 for rs4950928 and smallest p = 1.72 × 10−10 for haplotype TGG) and also for PAD patients. For the health examination subjects, circulating YKL-40 level, but not CHI3L1 gene variants, were positively associated with age, smoking, and circulating levels of triglyceride, lipocalin 2 and multiple inflammatory biomarkers and negatively associated with low-density-lipoprotein cholesterol levels. Circulating YKL-40 level is also significantly associated with the risk of PAD (p = 3.3 × 10−23). Circulating YKL40 level, but not CHI3L1 gene promoter variants, is associated with the risk of PAD in Taiwanese. The association of YKL-40 levels with multiple quantitative traits relating to the risk of PAD may provide a molecular basis linking YKL-40 to atherosclerotic cardiovascular disease.

Expression of CHI3L1 and CHIT1 in osteoarthritic rat cartilage model. A morphological study.

Osteoarthritis is a degenerative joint disease, which affects millions of people around the world. It occurs when the protective cartilage at the end of bones wears over time, leading to loss of flexibility of the joint, pain and stiffness. The cause of osteoarthritis is unknown, but its development is associated with different factors, such as metabolic, genetic, mechanical and inflammatory ones. In recent years the biological role of chitinases has been studied in relation to different inflammatory diseases and more in particular the elevated levels of human cartilage glycoprotein 39 (CHI3L1) and chitotriosidase (CHIT1) have been reported in a variety of diseases including chronic inflammation and degenerative disorders. The aim of this study was to investigate, by immunohistochemistry, the distribution of CHI3L1 and CHIT1 in osteoarthritic and normal rat articular cartilage, to discover their potential role in the development of this disease. The hypothesis was that the expression of chitinases could increase in OA disease. Immunohistochemical analysis showed that CHI3L1 and CHIT1 staining was very strong in osteoarthritic cartilage, especially in the superficial areas of the cartilage most exposed to mechanical load, while it was weak or absent in normal cartilage. These findings suggest that these two chitinases could be functionally associated with the development of osteoarthritis and could be used as markers, so in the future they could have a role in the daily clinical practice to stage the severity of the disease. However, the longer-term in vivoand in vitro studies are needed to understand the exact mechanism of these molecules, their receptors and activities on cartilage tissue.

Effects of an energy-restricted diet rich in plant-derived α-linolenic acid on systemic inflammation and endothelial function in overweight-to-obese patients with metabolic syndrome traits.

Plant-derived α-linolenic acid (ALA) may reduce the risk of CVD, possibly by decreasing systemic inflammation and improving endothelial function. In the present study, the effects of a hypoenergetic diet rich in ALA (3·4g/d) on the biomarkers of systemic inflammation and vascular function were investigated in eighty-one overweight-to-obese patients with metabolic syndrome traits in comparison with a hypoenergetic diet low in ALA (0·9g/d, control). After a 6-month dietary intervention, there were significant decreases in the serum concentrations of C-reactive protein (CRP), TNF-α, IL-6, soluble intercellular adhesion molecule-1 (sICAM-1), soluble endothelial selectin (sE-selectin) and asymmetric dimethylarginine in both dietary groups. However, no inter-group differences were observed for all these changes. The serum concentration of YKL-40 (human cartilage glycoprotein 39 or chitinase-3-like protein 1) decreased after the ALA diet when compared with the control diet (P<0·05 for time×treatment interaction). Plasma concentrations of fibrinogen did not significantly change in the two dietary groups. The decreases in the serum concentrations of sICAM-1, sE-selectin, CRP and YKL-40 were significantly correlated with the decreases in body fat mass. In conclusion, the present study indicates that in overweight-to-obese patients with metabolic syndrome traits, both vascular function and inflammation are improved during body-weight loss. The high ALA intake led to a more pronounced reduction in the serum concentration of YKL-40 compared with the intake of the low-ALA control diet, indicating the existence of independent favourable physiological effects of ALA during weight loss.

Antigen-specific over-expression of human cartilage glycoprotein 39 on CD4+ CD25+ forkhead box protein 3+ regulatory T cells in the generation of glucose-6-phosphate isomerase-induced arthritis.

Human cartilage gp-39 (HC gp-39) is a well-known autoantigen in rheumatoid arthritis (RA). However, the exact localization, fluctuation and function of HC gp-39 in RA are unknown. Therefore, using a glucose-6-phosphate isomerase (GPI)-induced model of arthritis, we investigated these aspects of HC gp-39 in arthritis. The rise in serum HC gp-39 levels was detected on the early phase of GPI-induced arthritis (day 7) and the HC gp-39 mRNA was increased significantly on splenic CD4(+) T cells on day7, but not on CD11b(+) cells. Moreover, to identify the characterization of HC gp-39(+) CD4(+) T cells, we assessed the analysis of T helper (Th) subsets. As a result, HC gp-39 was expressed dominantly in CD4(+) CD25(+) forkhead box protein 3 (FoxP3)(+) refulatory T cells (T(reg)), but not in Th1, Th2 or Th17 cells. Furthermore, to investigate the effect of HC gp-39 to CD4(+) T cells, T cell proliferation assay and cytokine production from CD4(+) T cells using recombinant HC gp-39 was assessed. We found that GPI-specific T cell proliferation and interferon (IFN)-γ or interleukin (IL)-17 production were clearly suppressed by addition of recombinant HC gp-39. Antigen-specific over-expression of HC gp-39 in splenic CD4(+) CD25(+) FoxP3(+) T(reg) cells occurs in the induction phase of GPI-induced arthritis, and addition of recombinant HC gp-39 suppresses antigen-specific T-cell proliferation and cytokine production, suggesting that HC gp-39 in CD4(+) T cells might play a regulatory role in arthritis.

Simulating tumor microenvironment: changes in protein expression in an in vitro co-culture system.

BackgroundThe role of the microenvironment during the initiation and progression of carcinogenesis is thought to be of critical importance, both for the enhanced understanding of fundamental cancer biology as well as for improving molecular diagnostics and therapeutics. The aim of this study was to establish an in vitro model based on a co-culture of healthy human fibroblasts (HFs) and human osteosarcoma cells (MG-63s) to simulate the microenvironment including tumor and healthy cells.MethodsThe HFs and MG-63s were in vitro co-cultured for a period of time ranging from 24 h to 7 days. Cell morphology and organization were studied using phase contrast microscopy while the expression of Human Cartilage Glycoprotein 39 (YKL-40), Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloprotease 1 (MMP1) was investigated by Real Time PCR and Western Blotting.ResultsThe results showed a characteristic disposition of tumor and healthy co-cultured cells in columns which are not visible in tumor and healthy cells grown singularly. The expression of YKL-40, VEGF and MMP1 significantly changed in co-cultured cells compared to HFs and MG-63s separately cultured.ConclusionsWe concluded that the tumor microenvironment has an influence on the protein expression of the healthy surrounding tissues and the process of tumorigenicity.

The clinical significance of plasma human cartilage glycoprotein 39 and C-reactive protein for evaluating intrauterine infection

目的 探讨血浆人类软骨糖蛋白39(YKL-40)和CRP检测对宫内感染的评价意义.方法 选择孕30～36周胎膜早破分娩的200例孕妇作为观察组(按病理结果提示是否有绒毛膜炎将孕妇分为感染组109例和非感染组91例),并以同期健康的孕30～36周99例孕妇为对照组.测定两组孕妇血浆YKL-40、CRP水平,以及WBC计数和中性粒计数分析,同时行产后胎膜病检.结果 感染组YKL-40、CRP均明显高于非感染组(均P<0.01).应用YKL-40、CRP的临界点分别为23.58 μg/L,和10.48 mg/L,均为单一因素最适预测有无绒毛膜炎的预测值;YKL-40和CRP的灵敏度、特异性、阳性预测值和阴性预测值分别为80.63%和81.25%,89.71%和90.00%;87.64%和88.14%;85.65%和84.00%.血中YKL-40水平与孕产妇预后有相关性(r=0.694,P＜0.01).结论 临床上结合血浆YKL-40和CRP能够更迅速、更准确地诊断胎膜早破并发感染,并能更好地评价预后。

Acceleration of Bone Repair in NOD/SCID Mice by Human Monoosteophils, Novel LL-37-Activated Monocytes

BackgroundAn incomplete understanding of bone forming cells during wound healing and ectopic calcification has led to a search for circulating cells that may fulfill this function. Previously, we showed that monoosteophils, a novel lineage of calcifying/bone-forming cells generated by treatment of monocytes with the natural peptide LL-37, are candidates. In this study, we have analyzed their gene expression profile and bone repair function.Methods and FindingsHuman monoosteophils can be distinguished from monocytes, macrophages and osteoclasts by their unique up-regulation of integrin α3 and down-regulation of CD14 and CD16. Monoosteophils express high mRNA and protein levels of SPP1 (osteopontin), GPNMB (osteoactivin), CHI3L1 (cartilage glycoprotein-39), CHIT1 (Chitinase 1), MMP-7, CCL22 and MAPK13 (p38MAPKδ). Monocytes from wild type, but not MAPK13 KO mice are also capable of monoosteophil differentiation, suggesting that MAPK13 regulates this process. When human monoosteophils were implanted in a freshly drilled hole in mid-diaphyseal femurs of NOD/SCID mice, significant bone repair required only 14 days compared to at least 24 days in control treated injuries.ConclusionHuman derived monoosteophils, characterized as CD45+α3+α3β+CD34−CD14−BAP (bone alkaline phosphatase)− cells, can function in an animal model of bone injury.

Serum Biomarkers and Transient Elastography as Predictors of Advanced Liver Fibrosis in a United States Cohort: The Boston Children's Hospital Experience

To evaluate and compare the ability of serum hyaluronic acid (HA) and human cartilage glycoprotein-39 (YKL-40) values, as well as transient elastography (TE) findings, to predict advanced hepatic fibrosis in a cohort from a single pediatric center. Subjects who underwent liver biopsy analysis within 12 months before enrollment were eligible for this prospective study. HA and YKL-40 measurements were obtained within 1 month of TE. A METAVIR score of F3 or F4 was considered to indicate advanced fibrosis. A total of 128 patients (51% males) aged 1.4 months to 27.6 years (22% aged <2 years) were enrolled. Thirty-one subjects had data on only HA and YKL-40 measurements, and 97 subjects had data on both blood tests and TE. For the prediction of advanced fibrosis, the area under the receiver operating characteristic curve (AUC) values were 0.83 for TE, 0.72 for HA, and 0.52 for YKL-40. The AUC of 0.83 for TE was statistically significantly greater than the AUCs for HA (P = .03) and YKL-40 (P < .0001). Optimal cutpoints for predicting F3-F4 fibrosis were 8.6 kPa for TE (P < .0001), 43 ng/mL for HA (P < .0001), and 26.2 ng/mL for YKL-40 (P = .85). The combination of TE and HA was not better than TE alone for predicting advanced fibrosis (P = .15). In this study, which evaluated TE, HA, and YKL-40 to predict liver fibrosis in children in the US, YKL-40 had no predictive value and TE was superior to HA, but the addition of HA did not improve the performance of TE. Our data suggest that TE and HA may be useful noninvasive tools for assessing liver fibrosis in children.

SAT0003 Microarray studies of synovial tissue of early human (CHECK) and experimental OA identify pathways and processes associated with cartilage damage

BackgroundMany osteoarthritis (OA) patients show synovial inflammation, even relatively early during the disease. Mechanisms through which synovial activation contributes to the joint pathology that characterizes OA, are not known.ObjectivesTo identify...

Plasma YKL-40 and CHI3L1 in systemic inflammation and sepsis—Experience from two prospective cohorts

YKL-40, derived from the CHI3L1 gene, has been associated with outcome of infectious and inflammatory diseases. We hypothesized that plasma YKL-40 concentrations and CHI3L1 genotype could be used as prognostic biomarkers in the assessment of systemic inflammatory response syndrome (SIRS) and sepsis. The objective of the study was to assess the prognostic value of plasma YKL-40 and CHI3L1 genotype in patients with SIRS and sepsis.Plasma YKL-40 and CHI3L1 genotype (rs4950928) were analyzed at time of admission to intensive care units (ICU), in two prospective cohorts of consecutive SIRS patients (cohort 1, n=272; cohort 2, n=502). The plasma YKL-40 cut-off for predicting survival was determined in cohort 1 by receiver operator characteristic analyses and validated in cohort 2.In cohort 1 patients with plasma YKL-40 ≤505ng/ml (area under the curve 0.64 (95% confidence interval (CI) 0.57–0.70), p<0.001, sensitivity 53%, specificity 76%) had superior day 90 survival (81% vs. 55%, p<0.001, hazard ratio (HR) 2.29 (95% CI 1.29–4.07)). In the second cohort plasma YKL-40 ≤505ng/ml was also associated with superior survival (61% vs. 38%, p<0.001, HR 1.43 (1.03–1.99)). CHI3L1 minor allele homozygosity was associated with low plasma YKL-40 at time of admission (p=0.002) and no variation (p=0.462) in concentrations throughout the first 14 days in the ICU, but this was not associated with better survival.In conclusion patients with SIRS and sepsis, plasma YKL-40 ≤505ng/ml at time of ICU admission was associated with better survival. However, this association was not observed for patients homozygous for the low expressing YKL-40 CHI3L1 allele.

Physiology and pathophysiology of musculoskeletal aging: current research trends and future priorities

EDITORIAL article Front. Physiol., 09 April 2013Sec. Striated Muscle Physiology Volume 4 - 2013 | https://doi.org/10.3389/fphys.2013.00073

Leukocyte Recruitment Alters Pathological Angiogenesis Gene Expression During DSS Colitis

Experimental models of colitis in mice have been extensively used to study molecular events that occur during inflammatory bowel disease (IBD) development. However, direct and comprehensive comparison of mouse and human inflamed colon tissue at the genome level remains largely unknown and to what extent such differences reflect changes associated with human IBD. Here we report comparative functional genomic analysis between experimental colitis models and pediatric IBD. Two sets of pediatric IBD microarray data (GEO accession number GSE9686 and GSE10616) and experimental colitis microarray data (DSS colitis model GEO number GSE22307 and T-cell transfer colitis model GEO number 27302) were used for comparative functional genome expression pattern analysis. All microarray data were obtained using Affymetrix GeneChip arrays providing the most comprehensive coverage of transcribed genomes of human or mouse. Microarray data were input into Genesifter software and normalized for comparison using the Robust Multichip Averaging (RMA) method. Threshold value for significant differences in gene expression was set at 2 fold and the Benjamini-Hochberg test used to diminish false discovery rates. Identified genes were uploaded into Ingenuity software for network analysis, and cREMaG (cis-Regulatory Elements in the Mammalian Genome) software for transcription factor/promoter analysis. Microarray analysis revealed that chitinase 3-like 1(cartilage glycoprotein-39, CHI3L1), Cysteine-rich, angiogenic inducer 61 (CYR61, or CCN1), and Chemokine (C-C motif) ligand 2 (CCL2) were up regulated in both pediatric CD and UC. Ingenuity network analysis of differentially expressed genes from pediatric CD was clustered into 8 networks and pediatric UC into 25 networks. By comparison of pediatric IBD and experimental colitis microarray data, we found the following common features: 1) CXCL9 and S100A8 were abundantly up regulated; 2) cytokine-cytokine receptor networks were dysregulated; and 3) IRF-1 transcription binding sites were over represented in the promoter region of up regulated genes, while HNF1A and Lhx3 binding sites were over represented in the promoter region of the down regulated genes. Together, our study provides a comprehensive comparative view of genome expression and transcription factor profile changes between pediatric IBD and experimental colitis models revealing common pathways that may be useful for future therapeutics.