Higher YKL-40 Levels Research Articles

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.

Prognostic Value of Combined Detection of Serum IL6, YKL-40, and C-reactive Protein in Patients with Unresectable Pancreatic Cancer.

IL6 and YKL-40 (also known as chitinase 3-like 1 protein, CHI3L1) are produced by pancreatic cancer cells and macrophages and activate inflammation. C-reactive protein (CRP) is synthesized mainly in hepatic cells and primarily stimulated by IL6. The aim of this study was to determine the prognostic value of combined detection of serum IL6, YKL-40, and CRP in patients with pancreatic cancer receiving palliative chemotherapy. In all, 592 patients with unresectable pancreatic cancer from five hospitals in Denmark were included in the BIOPAC biomarker study between 2008 and 2017. Pretreatment and longitudinal serum values of IL6 and YKL-40 were determined. Baseline CRP and CA19-9 values were available for the whole cohort. Patients were dichotomized as low versus high using cutoffs for IL6 of >4.92 pg/mL, YKL-40 of >95% age-corrected percentile, and CRP of >10 mg/L. The main outcome was overall survival. Combined elevations of serum IL6, YKL-40, and CRP were associated with worse survival in contrast to an isolated high concentration of a single marker. Serum IL6, YKL-40, and CRP were higher in patients with advanced stage disease and in patients with poor performance status. Higher IL6 and YKL-40 levels at the time of tumor progression and serum IL6 measured over time were associated with shorter overall survival. Combined high baseline serum levels of IL6, YKL-40, and CRP are associated with poor survival. Assessment of systemic inflammation via measurements of IL6, YKL-40, and CRP may be important for pancreatic cancer prognostication.

YKL-40 as a new biomarker of disease activity in Takayasu arteritis

ObjectiveTo evaluate the role of YKL-40 as a biomarker of disease activity in patients with Takayasu arteritis (TA). MethodsThe study included 40 patients diagnosed with TA between January 2017 and January 2018. 40 age and sex matched healthy controls were included. Serum levels of YKL-40, as well as IL-6, IL-8, IL-17, sCD163, VEGF, MMP-2, MMP-9, OPN, PTX-3 and IFN-γ, were detected at the base line and end of the 6-month follow-up. Modified Kerr criteria, in which MRA was performed instead of traditional angiography, was used a standard measure of disease activity. The association of the measured biomarkers with disease activity was analysed. ResultsThe serum levels of YKL-40, IL-6, IL-8, IFN-γ, MMP-2, MMP-9, PTX-3 and OPN were significantly higher in active disease than in inactive disease. Significant differences in the serum levels of YKL-40, IL-6 and PTX-3 were also observed according to the disease activity degree. Logistic analysis demonstrated that high YKL-40 levels and high IL-6 levels were independent risk factors for active disease. When YKL-40 was combined with IL-6, the specificity and sensitivity for detecting active disease were increased (87.6% and 70.4% respectively); similar findings were obtained when YKL-40 was combined with CRP (72.3% and 84.6% respectively). A predictive model of active disease using ESR, CRP, IL-6, PTX-3 and MMP-9 showed significantly improved diagnostic efficiency when YKL-40 was added to the model (sensitivity: 85.1%; specificity: 94.3%; NRI value: 12.4%; IDI value: 4.6%, p < 0.05). ConclusionsSerum YKL-40 concentrations may be a useful biomarker of disease activity in TA.

Abstract 1057: PDX models of solid cancer express distinct cytokine profiles in humanized mice relating to their tumor infiltrating lymphocyte landscape

Abstract Model selection is one critical step in anti-cancer drug development. In the advent of immune modulatory compounds being part of most of the oncology drug development pipelines, the available preclinical models have to be characterized with respect to those assets. In the current study we analyzed 26 PDX models covering a broad range of solid cancer entities with regard to the phenotypic characteristics in a humanized environment. Well established PDX models from six different entities (breast, colon, renal, pancreatic, NSCL cancer and glioblastoma) were implanted subcutaneously into immune-compromised mice substituted with CD34+ hematopoietic stem cells (hu-mice). Tumor characterization included: tumor growth curves, take rates, human immune cell infiltrates of tumor (=TILs), peripheral blood, spleen and bone marrow (determined by flow cytometry, FC, and IHC) and secretion of human cytokines in murine serum (determined by cytokine array &amp; Luminex based technology). Those data were compared to equivalent data-sets in non-humanized mice. The analysis of TILs revealed a large bandwidth of immune cell infiltration in the respective model ranging from 94% huCD45+ cells (renal cancer RXF 2773) to 3.54% huCD45+ (NSCLC LXFA 1041). Based on the percentage and of huCD4+ cell engraftment and the ratio of their subtypes (memory vs naïve) in untreated tumors the models were grouped into high (=hot), medium and low (=cold) infiltrated tumor models. The infiltration rate was stable across different experiments and specific for one distinct model. IHC analyses confirmed infiltration rates in tumor tissue determined by FC for CD45+, CD4+ and CD8+ cells. Furthermore, the models previously defined as “hot” or “cold” expressed distinct cytokine profiles in serum of tumor bearing mice. Amongst other cytokines, hot tumors secreted high levels of IL-17A, IL-18 BPa, MMP-9, Osteopontin, CD31, TIM-3 and YKL-40. In contrast, levels of GDF-15 and Lipocalin-2 were down regulated in those models compared to their cold counterpart. Of note, neither the amount nor the composition of human immune cell populations in peripheral blood of those mice was suitable to conclude on the amount of TILs in the respective model. Further validation of the cytokine profiles using immune modulating compounds on hot as well as cold PDX models are currently underway. Taken together, the characterization of PDX models with respect to their TIL composition facilitates model selection for innovative drugs in the immune-oncology field. The possibility to discriminate hot vs cold tumors by a minimal-invasive method like serum analysis of cytokine expression profile as potential biomarker will help to characterize the complete PDX collection of more than 500 models but will as well serve as additional read-out in preclinical I-O studies. Citation Format: Eva Oswald, Dorothee Lenhard, Stefanie Schmitt, Anna Edinger, Anne Löhr, Volker Knauff, Anke Behnke, Anne-Lise Peille, Julia Schüler. PDX models of solid cancer express distinct cytokine profiles in humanized mice relating to their tumor infiltrating lymphocyte landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1057.

Different pattern of CSF glial markers between dementia with Lewy bodies and Alzheimer\u2019s disease

The role of innate immunity in dementia with Lewy bodies (DLB) has been little studied. We investigated the levels in cerebrospinal fluid (CSF) of glial proteins YKL-40, soluble TREM2 (sTREM2) and progranulin in DLB and their relationship with Alzheimer’s disease (AD) biomarkers. We included patients with DLB (n = 37), prodromal DLB (prodDLB, n = 23), AD dementia (n = 50), prodromal AD (prodAD, n = 53), and cognitively normal subjects (CN, n = 44). We measured levels of YKL-40, sTREM2, progranulin, Aβ1–42, total tau (t-tau) and phosphorylated tau (p-tau) in CSF. We stratified the group DLB according to the ratio t-tau/Aβ1–42 (≥0.52, indicative of AD pathology) and the A/T classification. YKL-40, sTREM2 and progranulin levels did not differ between DLB groups and CN. YKL-40 levels were higher in AD and prodAD compared to CN and to DLB and prodDLB. Patients with DLB with a CSF profile suggestive of AD copathology had higher levels of YKL-40, but not sTREM2 or PGRN, than those without. T+ DLB patients had also higher YKL-40 levels than T−. Of these glial markers, only YKL-40 correlated with t-tau and p-tau in DLB and in prodDLB. In contrast, in prodAD, sTREM2 and PGRN also correlated with t-tau and p-tau. In conclusion, sTREM2 and PGRN are not increased in the CSF of DLB patients. YKL-40 is only increased in DLB patients with an AD biomarker profile, suggesting that the increase is driven by AD-related neurodegeneration. These data suggest a differential glial activation between DLB and AD.

The new marker YKL-40, a molecule related to inflammation, is associated with cardiovascular events in stable haemodialysis patients.

BackgroundYKL-40 is a glycoprotein associated with inflammatory conditions, including atherosclerosis and endothelial dysfunction. The objective was to analyse serum YKL-40 levels in a haemodialysis population and explore their association with dialysis dosing measures, inflammation, body composition and development of cardiovascular (CV) events. MethodsWe performed a prospective study of 78 chronic haemodialysis patients enrolled in 2013 and followed up until 2018. At baseline, serum YKL-40, inflammatory and nutrition markers and body composition were assessed. During a median follow-up of 43 (interquartile range 24–66) months, CV events were recorded.ResultsThe mean age of patients was 62 ± 16 years and 66% were men. The mean YKL-40 was 207 ± 106 ng/dL. Higher YKL-40 levels were associated with lower Kt/Vurea, convective volume, serum albumin and prealbumin and with higher troponin T. During follow-up, 50% developed CV events. Cox analysis showed an association between CV events and YKL-40, diabetes, hypertension, C-reactive protein, lower prealbumin, β2-microglobulin, glycosylated haemoglobin and troponin T values. The multivariate Cox analysis confirmed an independent association between CV events and YKL-40 {hazard ratio [HR] 1.067 [95% confidence interval (CI) 1.009–1.211]; P: 0.042}, troponin T [HR 1.037 (95% CI 1.009–1.683); P: 0.007], lower prealbumin [HR 0.827 (95% CI 0.224–0.988); P: 0.009] and diabetes [HR 2.103 (95% CI 1.554–3.172); P: 0.008]. Kaplan–Meier confirmed the association between CV events and YKL-40 (log rank 7.28; P = 0.007). ConclusionsYKL-40 is associated with CV events in haemodialysis patients. Higher dialysis dose and convective volume are associated with lower serum YKL-40 levels.

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.

Elevation in Circulating YKL-40 Levels in Patients with Stroke: A Review and Meta-Analysis

Background: Stroke is the second most common cause of mortality and the third most common cause of disability. Modifiable risk factors for ischemic stroke include obesity, diabetes, hypertension, cigarette smoking, atrial fibrillation, dyslipidemia, carotid artery stenosis, sickle cell disease, postmenopausal hormone therapy, poor diet, and physical inactivity. There is data establishing the role of atherosclerosis in stroke. Evidence suggests a role for inflammation in the development of atherosclerosis and cerebrovascular disease. YKL-40, also called chitinase-3-like-1 (CHI3L1), is a novel inflammatory biomarker secreted by monocytes which has been elevated in stroke patients in multiple studies. Objective: The aim of this study was to assess if patients with elevated YKL-40 have increased odds of having a stroke. Methods: PubMed, Embase, CINAHL, Cochrane, Web of Science, and google scholar were searched using the keywords YKL-40, chitinase-3-like-1 (CHI3L1), human cartilage glycoprotein 39 (HC-gp39), stroke, ischemic stroke, cerebrovascular disease, atherosclerosis, and inflammation. English studies from 1960 to August 2017 addressing YKL-40 and stroke as well as YKL-40 levels in subjects with and without stroke were analyzed. YKL-40 levels were converted to ng/mL if provided in any other scale. Results: Ten studies met the inclusion criteria. Twelve datasets were analyzed, as 1 study included more than 1 dataset. Seven studies were case-control studies (n = 702 cases and n = 389 controls), while 3 studies were cross-sectional (n = 13,811). A random effects model was used. The standardized mean difference in YKL-40 levels between the stroke group and the control group was 2.21 (1.28–3.14, p < 0.001). Sensitivity analysis and cumulative analysis showed unchanged results. Funnel plots/precision plots indicated publication bias. Meta-regression analysis of case-control studies for the variables age and gender showed no significant impact of age (p = 0.33) and male gender (p = 0.11). Conclusion: High YKL-40 levels appear to be associated with stroke.

Can YKL-40 be an Inflammatory Biomarker in Vitamin D Deficiency?

Vitamin D deficiency is associated with several non-homeostatic conditions and/or diseases like inflammation, atherosclerosis, cardiovascular disease and mortality. YKL-40 is a glycoprotein, secreted by macrophages, neutrophils and different cell types and it is also associated with inflammation and pathological tissue remodeling. In this study, we aimed to evaluate relationship between the proinflammatory biomarkers YKL-40 and hs-CRP levels and vitamin D deficiency. Our study group includes 45 subjects with vitamin D deficiency (Group 1) (20 M, 25 F; mean age 37.72 ± 7.70 years) and 40 age and sex-matched healthy subjects with normal serum levels of vitamin D (Group 2) (19 M, 21 F; mean age 39.26 ± 7.41 years). Plasma 25 (OH) vitamin D levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Plasma YKL-40 analysis was performed by ELISA. Serum hs-CRP levels were measured by nephelometric method. Plasma vitamin D levels below 20 ng/mL were accepted as vitamin D deficiency. Although we could not find any significant differences by means of serum hs-CRP levels between Group 1 and Group 2 (2.21 (0.27-11.70); 1.79 (0.16-9.85) mg/L, p = 0.247), plasma YKL-40 levels were significantly higher in group 1 than group2 (70.47 (17.84-198.50); 47.14 (4.80-135.48) ng/mL, p = 0.047). In literature, vitamin D deficiency is associated with inflammation. In our study, we found similar hs-CRP levels between groups and higher YKL-40 levels in group 1. Vitamin D deficiency may be related to high YKL-40 levels in terms of causing chronic inflammation.

Abstract P1-19-06: The prognostic value of HER2, YKL-40 and IL-6 in cerebrospinal fluid in trastuzumab naïve breast cancer patients diagnosed with meningeal carcinomatosis

Abstract Background With the improvements in treatment of patients with metastatic HER2-positive breast cancer (BC) the development of CNS metastases has become a major limitation of life expectancy and quality of life for many patients. Meningeal carcinomatosis represents approximately 10-20% of CNS metastases. The prognosis of meningeal carcinomatosis remains extremely poor. In the present study, we analysed the prognostic value of HER2, YKL-40 and IL-6 in cerebrospinal fluid (CSF) of meningeal carcinomatosis. Methods Between June 1985 and August 1992 sixty-nine CSF samples were collected at Herlev Hospital from trastuzumab naïve BC patients suspected of meningeal carcinomatosis. The cohort was composed of BC patients from two previous studies. Meningeal carcinomatosis was confirmed by tumour cells in CSF (or autopsy/scans). The samples were centrifuged, frozen and kept at -80oC. The concentrations of YKL-40, IL-6 and HER2 in CSF were measured by commercial ELISA (Quidel and R&amp;D) or Luminez (HER2 in second study). Overall survival in meningeal carcinomatosis was analysed with Kaplan-Meier curves and log rank tests using the median CSF value of HER2, YKL40 and IL-6 as cut off. Results 20 patients (29%) had meningeal carcinomatosis (18 patients had tumour cells in CFS, one was diagnosed by autopsy and one by CT scan; 13 of these patients participated in the first study and 7 in the second).10 patients had concomitant brain metastasis. The median survival was 35 days (4-305 days). The median [IQR] CSF concentration of YKL-40 was 284 ng/ml (187-597), IL-6 was15.9 pg/ml (6.5-51.0) and HER2 was 1.5 (0.36-8.70) in the patients with meningeal carcinomatosis. The survival was significantly shorter in patients with high levels of YKL-40 (p=0.03) and IL-6 (p=&amp;lt;0.01). The CSF HER2 level (p=0.51) or presence of brain metastasis (p=0.77) were not associated with survival. Conclusion In this cohort high levels of YKL-40 and IL-6 in CSF were associated with short survival in patients with BC and meningeal carcinomatosis. This was not found for HER2 in CSF or concomitant brain metastasis. Citation Format: Ryberg M, Johansen JS, Grantzau TL, Dehlendorff C, Nielsen DL. The prognostic value of HER2, YKL-40 and IL-6 in cerebrospinal fluid in trastuzumab naïve breast cancer patients diagnosed with meningeal carcinomatosis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-19-06.

Evaluation of serum chitinase-3-like protein 1, pentraxin-3, and neutrophil gelatinase-associated lipocalin levels in diabetic foot cases

Introduction: Diabetic foot is a chronic metabolic disease requiring a long duration of treatment and hospitalization in advanced stages. It requires a multidisciplinary approach to the different clinical presentations of the disease that complicate the process. In this study, the effects of serum chitinase-3-like protein 1 (YKL-40), pentraxin-3 (PTX-3), and neutrophil gelatinase-associated lipocalin (NGAL) levels on the prognosis of diabetic foot in different stages were evaluated. Subjects and Methods: A total of 65 patients with diabetes, and 13 healthy controls were included in the study. Wagner stage 0–1 patients were classified as mild disease (n = 26), Wagner stage 2–3 patients were classified as moderate disease (n = 26), and Wagner Stage 4 patients were classified as severe disease (n = 13). Venous blood was taken from the patients, and serum C-reactive protein, erythrocyte sedimentation rate, hemoglobin A1c, YKL-40, PTX-3, and NGAL levels were evaluated. In addition, the relationship between lower extremity vascular status and the markers was investigated. Results: YKL-40 was significantly higher in the severe disease group, PTX-3 was significantly higher in the moderate disease group, and NGAL was significantly higher in the mild disease group. In addition, YKL-40 and PTX-3 levels were found to be high in patients with arterial and venous insufficiency, but this was not observed for NGAL. Conclusions: High levels of serum YKL-40 are associated with advanced stage disease with atherosclerotic process at the forefront, high PTX-3 levels are associated with moderate stage disease with a high level of infection findings, and high NGAL levels are associated with the mild stage of diabetic foot.

Clinical utility of pleural fluid YKL-40 as a marker of malignant pleural effusion

Pleural effusion is a common presenting feature of malignancy. Malignant pleural effusion is primarily diagnosed by pleural fluid cytology, pleural biopsy, and tumor markers. The glycoprotein YKL-40 is a new tumor marker that has shown to have a good diagnostic accuracy to detect malignant pleural effusion. However, there are only a few studies that have evaluated pleural fluid YKL-40 for detecting malignant pleural effusions. Hence, we conducted this study to evaluate the utility of pleural fluid YKL-40 to detect malignant pleural effusion. This is a cross-sectional study conducted between February 2016 and December 2017 in a tertiary care referral hospital. One hundred and forty-seven consecutive patients with pleural effusion were included in the study. These patients were divided into 3 groups, viz malignant, tuberculous, and parapneumonic pleural effusion, based on clinical features, radiological examination, and pleural fluid analysis. Pleural fluid YKL-40 levels were measured using enzyme-linked immunosorbent assay. Out of the 147 consecutive patients included in the study, 47 patients (31.97%) had malignant pleural effusion, 51 patients (34.69%) had tuberculous pleural effusion, and 49 patients (33.33%) had parapneumonic pleural effusion. The median pleural fluid YKL-40 level was higher in malignant pleural effusion (114.80 ng/mL) compared to tuberculous (93.17 ng/mL) and parapneumonic pleural effusion (89.87 ng/mL; P < 0.05). A diagnostic cut-off for pleural fluid YKL-40 value of 99.76 ng/mL detected malignant pleural effusion with 83% sensitivity, 87% specificity, positive predictive value (PPV) of 75%, negative predictive value (NPV) of 91.58%, and diagnostic accuracy of 85.71%. The level of pleural fluid YKL-40 is significantly elevated in malignant pleural effusion. In lymphocytic pleural effusions presenting with low adenosine deaminase levels and high YKL-40 levels, a thorough diagnostic search for malignancy is warranted.

Relationship between YKL-40 and pulmonary arterial hypertension in systemic sclerosis

Objectives: Systemic sclerosis (SSc) is an intractable connective tissue disease that causes skin and organ fibrosis. Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) affect its prognosis. YKL-40 protein impacts inflammation and tissue remodeling. Therefore, we evaluated the utility of YKL-40 blood levels in identifying patients with SSc complicated by PAH, as confirmed by immunohistochemistry (IHC) examination.Methods: We retrospectively analyzed 78 patients with SSc and performed IHC on 7 normal and 7 SSc skin samples in the Japanese population. Age-adjusted YKL-40 serum levels were analyzed.Results: YKL-40 age percentile was significantly elevated in SSc patients. There was no difference between patients with SSc with and without ILD and PAH. YKL-40 age percentile was greater in patients with PAH complication. YKL-40 immunostaining was negative in normal skin and prominent in the subcutaneous vascular wall of all SSc samples. Receiver operating characteristic (ROC) curve analysis indicated that YKL-40 age percentile correctly differentiated between patients with and without PAH with a sensitivity of 80% and a specificity of 94.1%.Conclusion: A higher YKL-40 level with PAH may be reflective of angiogenesis due to capillary injury in SSc. YKL-40 may offer a useful and easily applicable diagnostic biomarker of SSc complicated with PAH.

Abstract B086: Monocytes-produced Chitinase-3-like 1 is a driver of metastatic behavior in advanced prostate cancer patients

Abstract Purpose: The identification, functional status, distribution, and interactions of immune cells in PCa patients have yet to be fully characterized. Understanding these details could provide key insights as to how promising current and developing immunotherapies might be directed toward PCa. Recruited myeloid cells promote cancer initiation, malignant progression, metastasis, and resistance to therapy in the tumor niche. In the present study, we tested the hypothesis that circulating blood monocytes from advanced prostate cancer (PCa) patients exhibit a tumor-promoting phenotype and directly influence the tumor microenvironment in response to tumor-derived signals. Experimental Design: Monocytes from metastatic (PCa-M) and nonmetastatic (PCa-N) patient blood samples were isolated, cultured, and conditioned media (CM) was obtained. To evaluate the role of monocytes in metastatic behavior of PCa cells, in vitro invasion (via Matrigel) and motility assays (Incucyte Live Cell Analysis System) were performed using monocyte-CM. To identify the candidate PCa-M monocyte-secreted protein(s) that might be implicated in tumor progression, we analyzed the CM using Proteome Profiler Analysis (R&amp;D). Data were validated using ELISA and qPCR. Results: Herein, we report that CM from circulating monocytes in patients with PCa/mCRPC (metastatic castration-resistant PCa) increased motility and invasion of epithelial PCa cells. Proteome Profiler Analysis revealed that monocyte-derived CM from metastatic PCa/mCRPC patients presented high levels of YKL-40 (Chitinase-3-like 1; CHI3L1) when compared with PCa-N patients and healthy controls (HC), classified as individuals with no known history of cancer. The only described receptor for YKL-40, interleukin-13 receptor α2 (IL-13Rα2), was significantly upregulated in ARCaPm cells; accordingly, we observed that the activation of IL-13Rα2 from PCa-M CM increased the invasiveness of ARCaPm. In addition, siRNA directed against this receptor in ARCaPm cells caused a significant reduction in the invasiveness of these cells in the presence of CM from PCa-M patients. Conclusions: We show that circulating monocytes from metastatic PCa/mCRPC patients exert a tumor-promoting role via the secretion of YKL-40, and YKL-40 demands further exploration as a possible therapeutic target in advanced PCa. Citation Format: Karen A. Cavassani, Rebecca Meza, David Habiel, Jie-Fu Chen, Alexander Montes, Manisha Tripathi, Gislaine Martins, Timothy R. Crother, Cory M. Hogaboam, Sungyong You, Neil Bhowmick, Edwin Posadas. Monocytes-produced Chitinase-3-like 1 is a driver of metastatic behavior in advanced prostate cancer patients [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B086.

The Role of YKL-40 in Predicting Resistance to Docetaxel Chemotherapy in Prostate Cancer

Introduction: High baseline YKL-40 serum levels are associated with drug resistance in several solid tumours. However, their role in predicting docetaxel (DOC) resistance in prostate cancer (PCa) is unknown. Methods: Pre-treatment serum levels of YKL-40 and prostate-specific antigen (PSA) were analyzed in 109 castration-resistant prostate cancer patients who underwent DOC-therapy. Responsive patients were retreated by repeated series of DOC. Results were compared with the clinical parameters as well as overall (OS) and disease-specific survival (DSS). Results: YKL-40 but not PSA serum levels were significantly higher in patients with baseline resistance to DOC (p = 0.035). Higher YKL-40 and PSA levels were detected in patients with bone metastasis (p = 0.032; p = 0.010) and in those who were not pre-treated with radical prostatectomy (p = 0.011, p = 0.008). High YKL-40 levels were associated with shorter OS (p = 0.037) and DSS (p = 0.017) in patients who received DOC in the first-line setting. In multivariable analysis, ECOG performance status (p = 0.009), presence of any metastases (p = 0.016) and high PSA levels (p = 0.005) remained independent predictors for DSS. Conclusions: YKL-40 may help to identify patients with baseline resistance to DOC and therefore may help to optimize treatment decisions. In accordance, high pre-treatment YKL-40 serum levels were associated with shorter OS and DSS in patients who received DOC as first-line therapy.

THE EFFECT OF ABATACEPT ON BLOOD BIOMARKERS IN PATIENTS WITH RHEUMATOID ARTHRITIS

Objective:to estimate changes in the cytokine profile in patients receiving abatacept (ABC).Subjects and methods.The investigation enrolled 44 patients with rheumatoid arthritis (RA) who had been unsuccessfully treated with disease-modifying antirheumatic drugs and biological agents. A control group included 16 healthy donors. The majority of patients were women who were positive for rheumatoid factor (RF) (80%) and antibodies to cyclic citrullinated peptide (ACCP) (79.5%); the mean age was 49.6±13.9 years; the median disease duration was 2 [1.4; 3] years with high RA activity (mean DAS28, 5.2±0.8). The serum concentrations of interleukin (IL) 1β, IL-6, IL-17AF, tumor necrosis factor-α (TNF-α), VEGF-A, IP-10, and YKL-40 were measured by enzyme immunoassay before and 6 months after ABC therapy. Disease activity was assessed using DAS28 every 3 months. ABC was infused intravenously according to the standard regimen.Results and discussion. The patients with RA as compared with the control group had significantly elevated levels of IL-6 (2.4 [1.1; 6.4] and 0.7 [0.62; 1.0] pg/ml; p=0.0002), YKL-40 (97 [68.4; 97.9] and 64 [52.4; 107.5] pg/ml; p=0.03), IP-10 (21 [12.9; 49.8] and 14 [9.2; 15.2] pg/ml, respectively; p=0.005). ABC caused a significant decrease in RA activity after 3 months of therapy (p&lt;0.05). Following 6 months, 86% of the patients achieved good and moderate EULAR responses; low RA activity according to DAS28 was recorded in 52%. ABC induced significant decreases in the concentrations of IL-6 to 1.29 [0.9; 2.2] pg/ml (p=0.0006) and IP-10 to 14 [7.5; 28] pg/ml (p=0.007) after 6 months of therapy. A similar trend was observed when assessing changes in the concentration of matrix metalloproteinase 3 (MMP-3), which reduced from 30.1 [13; 82] to 10 [7.4; 55] pg/ml (p=0.0003), and in that of RF, which declined from 218 [9.6; 187] to 159 [9.7; 155] pg/ml (p=0.02). The lower levels of IL-6 (r=0.5) and IP-10 (r=0.32) significantly correlated with a decrease in DAS28 (p&lt;0.05). There was a trend towards a more pronounced reduction in disease activity in patients positive for ACCP and antibodies to modified citrullinated vimentine (AMCV). The percentage of non-responders to therapy in the ACCP- and AMCV-negative groups was nearly twice as high as in those who were positive for these antibodies (27.2 and 16%; 26.7 and 14.8%, respectively), but these differences failed to reach significance. However, after 6-month of follow-up, the percentage of non-respondents in the AMCV-negative group was significantly higher than in the AMCV-positive group (20% and 0%, respectively; p=0.03). The patients who did not respond to ABC therapy had higher baseline levels of IL-6 (p=0.03) and YKL-40 (p=0.02). Conclusion.ABC therapy results in a substantial reduction in the concentration of the proinflammatory cytokines IL-6 and IP-10, as well as MMP-3 and RF. The lower levels of IL-6 and IP-10 significantly correlated with a decrease in RA activity. There was a tendency towards a more pronounced reduction of disease activity in ACCP- and AMCV-positive patients. The high baseline levels of IL-6 and YKL-40 and the absence of AMCV may suggest that ABC therapy can be ineffective.

YKL-40 is a novel biomarker for predicting hypertension incidence among prehypertensive subjects: A population-based nested case-control study in China

Background and aimsThe previous study suggested that Human cartilage glycoprotein-39 (YKL-40) was positively associated with hypertension incidence in certain high-risk groups of hypertension. We aimed to investigate that whether YKL-40 is an effective biomarker for predicting hypertension incidence among prehypertensive subjects. MethodsIn a 1:1 matched case-control study of 700 pairs with available YKL-40 levels nested in a prospective cohort of initially healthy Chinese subjects, 294 pairs additionally have matched baseline BP status (prehypertensive or normotensive). Multivariable conditional logistic regression analyses were used to calculate the odds ratios (95% confidential intervals) of hypertension associated with higher levels of YKL-40 in both prehypertensive and normotensive subgroups, respectively. ResultsIn the prehypertensive subgroup, the subjects in the highest quartile of plasma YKL-40 levels had a significantly higher risk of hypertension incidence, compared with those in the lowest quartile. The odds ratio (95% confidential intervals) is 2.01 (1.05–3.85). A positive association between YKL-40 levels and hypertension incidence was found (P for trend<0.05). However, this significant association was not observed in the normotensive subgroup. ConclusionsHigher YKL-40 levels at baseline were positively associated with hypertension incidence among prehypertensive subjects. YKL-40 may represent a novel biomarker for predicting hypertension risk in prehypertension population.

Genetic and epigenetic regulation of YKL-40 in childhood

Circulating levels of the chitinase-like protein YKL-40 are influenced by genetic variation in its encoding gene (chitinase 3-like 1 [CHI3L1]) and are increased in patients with several diseases, including asthma. Epigenetic regulation of circulating YKL-40 early in life is unknown. We sought to determine (1) whether methylation levels at CHI3L1 CpG sites mediate the association of CHI3L1 single nucleotide polymorphisms (SNPs) with YKL-40 levels in the blood and (2) whether these biomarkers (CHI3L1 SNPs, methylation profiles, and YKL-40 levels) are associated with asthma in early childhood. We used data from up to 2405 participants from the Spanish Infancia y Medio Ambiente; the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey; and the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohorts. Associations between 68 CHI3L1 SNPs, methylation levels at 14 CHI3L1 CpG sites in whole-blood DNA, and circulating YKL-40 levels at 4years of age were tested by using correlation analysis, multivariable regression, and mediation analysis. Each of these biomarkers was also tested for association with asthma at 4years of age by using multivariable logistic regression. YKL-40 levels were significantly associated with 7 SNPs and with methylation at 5 CpG sites. Consistent associations between these 7 SNPs (particularly rs10399931 and rs4950928) and 5 CpG sites were observed. Alleles linked to lower YKL-40 levels were associated with higher methylation levels. Participants with high YKL-40 levels (defined as the highest YKL-40 tertile) had increased odds for asthma compared with subjects with low YKL-40 levels (meta-analyzed adjusted odds ratio, 1.90 [95% CI, 1.08-3.36]). In contrast, neither SNPs nor methylation levels at CpG sites in CHI3L1 were associated with asthma. The effects of CHI3L1 genetic variation on circulating YKL-40 levels are partly mediated by methylation profiles. In our study YKL-40 levels, but not CHI3L1 SNPs ormethylation levels, were associated with childhood asthma.

Circulating miRNA-24 and its target YKL-40 as potential biomarkers in patients with coronary heart disease and type 2 diabetes mellitus.

Type 2 diabetes mellitus (DM2) is associated with cardiovascular complications and is characterized by high levels of YKL-40, an inflammatory glycoprotein involved in endothelial dysfunction. We investigated the predictive potential of circulating miR-24 in coronary heart diseases (CHD) DM2 patients with CHD, and control subjects. Blood samples were taken from 94 subjects of both genders, and divided over three groups as follows; patients with CHD, patients with DM2 and CHD, and control subjects. Both miR-24 (using real time PCR) and routine parameters were measured. Using bioinformatic analysis and luciferase assays, we found that miR-24 has high complementarity and a high degree of species conservation with respect to the binding sites within the 3′ UTR of the YKL-40 mRNA. The expression levels of circulating miR-24, determined by quantitative real time PCR, were significantly decreased in peripheral blood of DM2-CHD and CHD patients compared with controls. Furthermore, miR-24 strongly associated with DM2-CHD, negatively correlated with YKL-40 in DM2-CHD and DM2 patients after conducting multiple regression analysis. These results provide a novel regulatory mechanism of circulating miR-24 in regulating YKL-40 levels in DM2-CHD, may serve as a biomarker for predicting patients with DM2 and CHD.

The prognostic value of serum IL-6 and YKL-40 in patients with metastatic colorectal cancer.

e15060 Background: The prognostic value of serum IL-6, YKL-40 and CEA before first (1) and third line therapy (3LT) in metastatic colorectal cancer (mCRC) is lacking and was evaluated in this study. Methods: From 2004 to 2015 serum samples were collected from 160 and 255 patients with mCRC before 1LT and 3LT, respectively. Median age was 64 years (range 33-87) and male/female ratio 243(59%)/172(41%). Serum IL-6 (R&amp;D, UK) and YKL-40 (Quidel, USA) were determined by ELISA. Progression-free (PFS) and overall survival (OS), crude and adjusted hazard ratios (HR) and corresponding 95% confidence intervals (CI) were estimated with Cox regression analysis. CEA, IL-6 and YKL-40 were included as log2-transformed continuous variables with mutual adjustment between CEA, IL-6 and YKL-40, primary tumor location, sex and age. Results: In 3LT IL-6, YKL-40 and CEA levels were higher (P &lt; 0.001) than in 1LT (IL-6: 9.5 pg/ml [IQR4.2-18.5] vs. 4.6 [2.5-10.5]; YKL-40: 140 ng/ml [77-272] vs. 101 [62-172]; and CEA: 59 ug/l [14-288] vs. 23[5.8-153]). In 3LT univariate analysis showed that increased levels of IL-6, YKL-40 and CEA were associated with shorter PFS (IL-6: HR = 1.19, 95% CI 1.07-1.31, P &lt; 0.01; YKL-40: HR = 1.13, 1.04-1.24, P = 0.01; CEA: HR = 1.05, 1.00-1.09, P = 0.04). In 1LT only high IL-6 was associated with shorter PFS (HR = 1.09, 1.01-1.17, P = 0.03). In a multivariate analysis only high IL-6 was significantly associated with shorter PFS in 3LT (HR = 1.15, 1.03-1.29, P &lt; 0.01) and none of the biomarkers in 1LT. In 3LT univariate analysis showed that increased levels of all 3 biomarkers were associated with a shorter OS (IL-6: HR = 1.36, 1.23-1.51, P &lt; 0.01; YKL-40: HR = 1.21, 1.10-1.33, P &lt; 0.01; CEA: HR = 1.11, 1.06-1.16, P &lt; 0.01). In 1LT high levels of IL-6 (HR = 1.17, 1.08-1.27, P &lt; 0.01) and YKL-40 (HR = 1.18, 1.00-1.38, P = 0.05), but not CEA, were associated with short OS. In 3LT the multivariate analysis showed that both higher IL-6 (HR = 1.34, 1.20-1.50, P &lt; 0.01) and CEA (HR = 1.09, 1.03-1.14, P &lt; 0.01), but not YKL-40 were significantly associated with a shorter OS. In 1LT only higher IL-6 was associated with a shorter OS (HR = 1.19, 1.08-1.31, P &lt; 0.01) Conclusions: Serum IL-6 and YKL-40 may be useful prognostic biomarkers in combination with CEA in patients with mCRC