Dickkopf-1 Levels Research Articles

Study of Dickkopf-1 (DKK-1) in patients with chronic viral hepatitis C-related liver cirrhosis with and without hepatocellular carcinoma

Aim of the studyDickkopf-1 (DKK-1) is a secreted protein which acts as an inhibitor of Wnt/β-catenin signaling. DKK-1 was found to be a helpful biomarker for many cancers including hepatocellular carcinoma (HCC). HCC is multifactorial in origin and its main etiology in Egypt is attributed to chronic hepatitis C virus (HCV) infection. Objectives: To assess the serum level and diagnostic performance of DKK-1 and α-fetoprotein (AFP) in Egyptian patients with chronic HCV-related liver cirrhosis with and without HCC.Material and methods80 subjects were divided into: a control group (group I, 20 healthy volunteers) and two patient groups: group II (HCV with liver cirrhosis, 30 patients), and group III, (HCV-related liver cirrhosis with HCC, 30 patients). Thorough physical examination, triphasic computed tomography, calculation of Child-Pugh score, laboratory investigations (complete blood picture, liver profile, hepatitis B surface antigen, anti-HCV antibodies, AFP (chemiluminometry) and DKK-1 (ELISA) were performed.ResultsThere was a significant decrease in DKK-1 level in HCV patients with liver cirrhosis (group II) and HCV patients with HCC (group III) compared to the control group (group I) (p < 0.001). However, there was a significant increase in DKK-1 level in HCV patients with HCC (group III) compared to HCV patients with liver cirrhosis (group II) (p < 0.033). The ROC curve showed that DKK-1 has less sensitivity but higher specificity in HCV patients with HCC (group III) compared with HCV patients with liver cirrhosis (group II).ConclusionsThe combination of DKK-1 and AFP could further improve the diagnostic accuracy of HCV-related cirrhosis with or without HCC.

Joint remodeling outcome of serum levels of Dickkopf-1 (DKK1), cartilage oligomeric matrix protein (COMP), and C-telopeptide of type II collagen (CTXII) in rheumatoid arthritis.

IntroductionRheumatoid arthritis (RA) is the most widespread chronic inflammatory rheumatic disease over the world. It is characterized by chronic proliferation of synovium, cartilage destruction, and periarticular erosion/bone loss. We investigated the serum levels of the C-telopeptide of type II collagen (CTX-II), Dickkopf-1 (DKK1), and cartilage oligomeric matrix protein (COMP) in relationship to the disease activity.Material and methodsSerum COMP, CTX-II, and DKK1 levels were measured in 63 RA patients and 50 person age and gender matched as a healthy controls by ELISA test. Disease activity score (DAS) were calculated.ResultsThe mean level of and COMP and CTX-II were significantly higher in patients with RA than in healthy controls (5.71 ±7.04 vs. 2.70 ±1.31 ng/ml, and 0.45 ±0.27 vs. 0.23 ±0.16 ng/ml, respectively; p < 0.001). Also, DKK1 serum levels were significantly higher in patients with RA than in healthy controls (6970.68 ±7566.68 vs. 3276.96 ±1306.77 pg/m; p < 0.001). There was a positive significant correlation between DKK1 and swollen joint (r = 0.42, p < 0.001). There were no significant differences in the number of patients, gender, the duration of RA disease, DAS, and RF. Sensitivity was 58.7% and specificity was 85.7% at a cut-off point (> 3.6 ng/ml) for serum COMP in RA patients, while, sensitivity was 100% and specificity was 52.4% at a cut-off point (> 0.15 ng/ml) for serum CTX-II and sensitivity was 68.3% and specificity was 95.2 % at a cut-off point (> 4876 pg/ml) for serum DKK1.ConclusionsMeasurement of some serological biomarkers such as CTX-II, COMP, and DKK1 that reflect bone and cartilage destruction in RA patients could be used to indicate disease activity and early joint affection.

Association between Serum Dickkopf-1 (DKK-1) Glycoprotein and Calcific Deposits on Cardiac Valves and Carotid Intimal-Medial Thickness in Hemodialysis Patients

Background: Cardiac valve calcification (CVC) is common in hemodialysis (HD) patients, and associated with cardiovascular and all-cause mortality. Once believed to be a passive process, it is now understood that the Wnt signaling pathway has a major role. The aim of the current study was to assess the relationship between circulating DKK-1, a negative regulator of the Wnt signaling pathway, and CVC, as well as carotid intimal-medial thickness (CIMT) in HD patients. Methods: We enrolled 74 consecutive adults on maintenance HD. Echocardiographic calcification of the mitral valve (MV) and aortic valve (AV) were detected according to Wilkins score (range 0–4), and the study of Tenenbaum et al. [Int J Cardiol. 2004 Mar;94(1):7–13] (range 0–4), respectively. CVC severity was calculated by a supposed score (range 0–8) that represents the sum of calcification grade of MV and AV. CVC severity was classified into absent (CVC score = 0), mild (CVC score = 1–2), moderate (CVC score = 3–4), and severe (CVC score ≥5). Demographic and biochemical data were collected in addition to serum DKK-1 levels and CIMT. Results: CVC was present in 67 patients (91.0%). There was a highly significant negative correlation between serum DKK-1 level and CVC score (r = –0.492; p ≤ 0.001), as well as CIMT (r = –0.611; p ≤ 0.001). Age and CIMT were independent determinants of CVC. Conclusions: CVC is almost present in all HD patients. DKK-1 seems to have a direct relation with CVC and CIMT in HD patients. Age is the strongest independent determinant of CVC.

Effect of tumor necrosis factor inhibition on spinal inflammation and spinal ankylosis in SKG mice

To prevent spinal progression in ankylosing spondylitis, initiating TNF-inhibitor treatment as early as possible is suggested. However, the outcomes are inconsistent in previous clinical studies. Here, we investigated the effect of TNF inhibition alone on spinal progression when used during arthritis development in a murine model. We injected 8-week-old SKG mice with curdlan (curdlan group). We injected adalimumab at 3 and 9 weeks after the first curdlan injection (ADA group). The clinical scores of peripheral arthritis decreased in the ADA group at 3 weeks after first adalimumab injection. Using positron emission tomography–magnetic resonance imaging and histologic examination, spinal inflammation was observed in the curdlan group, and was significantly deceased in the ADA group. However, spinal osteoblast activities by imaging using OsteoSense 680 EX and bone metabolism-related cytokines such as receptor activator of nuclear factor-kappa B ligand, osteoprotegerin, Dickkopf-1, and sclerostin levels except IL-17A level were not different between the two groups. We conclude that treating TNF inhibitor alone reduced peripheral arthritis score and spinal inflammation in curdlan-injected SKG mice but did not decrease the spinal osteoblast activity, suggesting little effect on spinal ankylosis.

Dkk1 Controls Cell-Cell Interaction through Regulation of Non-nuclear β-Catenin Pools.

SummaryDickkopf-1 (Dkk1) is a secreted Wnt antagonist with a well-established role in head induction during development. Numerous studies have emerged implicating Dkk1 in various malignancies and neurodegenerative diseases through an unknown mechanism. Using zebrafish gastrulation as a model for collective cell migration, we unveil such a mechanism, identifying a role for Dkk1 in control of cell connectivity and polarity in vivo, independent of its known function. We find that Dkk1 localizes to adhesion complexes at the plasma membrane and regions of concentrated actomyosin, suggesting a direct involvement in regulation of local cell adhesion. Our results show that Dkk1 represses cell polarization and integrity of cell-cell adhesion, independently of its impact on β-catenin protein degradation. Concurrently, Dkk1 prevents nuclear localization of β-catenin by restricting its distribution to a discrete submembrane pool. We propose that redistribution of cytosolic β-catenin by Dkk1 concomitantly drives repression of cell adhesion and inhibits β-catenin-dependent transcriptional output.

Smoking and other determinants of bone turnover.

The balance between bone resorption and formation may be assessed by measurement of bone turnover markers (BTMs), like carboxyl-terminal cross-linked telopeptide of type 1 collagen (CTX-1) and procollagen type 1 amino-terminal propeptide (P1NP). Smoking has been shown to influence bone turnover and to reduce bone mass density (BMD), the exact mechanism for this is, however, not settled. In this post-hoc study including 406 subjects (mean age 51.9 years), we aimed to study the impact of smoking on bone turnover. Moreover, we wanted to assess the inter-correlation between substances regulating bone metabolism and BTMs, as well as tracking over time. BMD measurements and serum analyses of CTX-1, P1NP, osteoprotegerin (OPG), receptor activator of nuclear factor ĸB ligand (RANKL), Dickkopf-1 (DKK1), sclerostin, tumor necrosis factor-α (TNF-α), and leptin were performed. Repeated serum measurements were made in 195 subjects after four months. Adjustments were made for sex, age, body mass index (BMI), smoking status, insulin resistance, serum calcium, parathyroid hormone, 25-hydroxyvitamin D and creatinine. Smokers had higher levels of DKK1 and OPG, and lower levels of RANKL, as reflected in lower BTMs and BMD compared to non-smokers. There were strong and predominantly positive inter-correlations between BTMs and the other substances, and there was a high degree of tracking with Spearman’s rho from 0.72 to 0.92 (P < 0.001) between measurements four months apart. In conclusion, smokers exhibited higher levels of DKK1 and OPG and a lower bone turnover than did non-smokers. The strong inter-correlations between the serum parameters illustrate the coupling between bone resorption and formation and crosstalk between cells.

LncRNA-LET inhibits cell growth of clear cell renal cell carcinoma by regulating miR-373-3p

BackgroundClear cell renal cell carcinoma (ccRCC) is the most common renal cell carcinoma subtype with a poor prognosis. LncRNA-LET is a long non-coding RNA (lncRNA) that is down-regulated in ccRCC tissues. However, its role in ccRCC development and progress is unclear.MethodsLncRNA-LET expression was detected in ccRCC tissues and ccRCC cells using quantitative real-time PCR. The overexpression and knockdown experiments were performed in ccRCC cells and xenograft mouse model to evaluate role of lncRNA-LET. Cell cycle, apoptosis and JC-1 assays were conducted via flow cytometer. The protein levels were measured through western blot analysis and the interaction between lncRNA-LET and miR-373-3p was identified via luciferase reporter assay.ResultsLncRNA-LET expression was lower in ccRCC tissues than that in the matched adjacent non-tumor tissues (n = 16). In vitro, lncRNA-LET overexpression induced cell cycle arrest, promoted apoptosis and impaired mitochondrial membrane potential, whereas its knockdown exerted opposite effects. Moreover, we noted that lncRNA-LET may act as a target for oncomiR miR-373-3p. In contrast to lncRNA-LET, miR-373-3p expression was higher in ccRCC tissues. The binding between lncRNA-LET and miR-373-3p was validated. Two downstream targets of miR-373-3p, Dickkopf-1 (DKK1) and tissue inhibitor of metalloproteinase-2 (TIMP2), were positively regulated by lncRNA-LET in ccRCC cells. MiR-373-3p mimics reduced lncRNA-LET-induced up-regulation of DKK1 and TIMP2 levels, and attenuated lncRNA-LET-mediated anti-tumor effects in ccRCC cells. In vivo, lncRNA-LET suppressed the growth of ccRCC xenograft tumors.ConclusionThese findings indicate that lncRNA-LET plays a tumor suppressive role in ccRCC by regulating miR-373-3p.

Correlation of Dickkopf-1 with Inflammation in Crohn Disease

To explore the potential roles of Dickkopf-1 (DKK-1) and b-catenin in Crohn disease, and to evaluate the effects of a tumor necrosis factor (TNF)-a inhibitor on Wnt signaling in patients with the disease. We enrolled 21 patients who received infliximab treatment for one year and achieved clinical remission during the treatment period. Disease activity was graded according to the Pediatric Crohn's Disease Activity Index (PCDAI). Peripheral blood and colonic mucosal specimens were collected from all patients with Crohn disease and from 14 healthy controls. DKK-1 levels in serum were detected by enzyme-linked immunosorbent assay (ELISA). Total RNA for DKK-1 and b-catenin from the frozen colonic tissue were obtained via real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Serum C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR), and albumin were also measured in patients with Crohn disease before and after infliximab therapy. The serum levels of DKK-1 were significantly higher in patients with Crohn disease than in healthy controls (P=0.003) and were decreased in those treated with infliximab (P=0.026). Serum DKK-1 level was correlated with levels of ESR (r=0.527, P=0.025), CRP (r=0.502, P=0.034), albumin (r=0.363, P=0.021) and PCDAI (r =0.462, P=0.054) in Crohn disease. DKK-1 mRNA expression in the colonic mucosa was higher in patients than in controls and decreased after infliximab treatment. b-catenin expression in the colonic mucosa was lower in patients than in controls and increased after infliximab treatment. However, the differences were not significant (P<0.05). DKK-1 might be an important mediator of the pathogenesis of Crohn disease, and changes in DKK-1 levels may serve as biomarkers of inflammation in these patients.

Elevations in Serum Dickkopf-1 and Disease Progression in Community-Dwelling Older Adults With Mild Cognitive Impairment and Mild-to-Moderate Alzheimer's Disease.

Background: Disruption of Wnt signaling has been implicated in dysfunctional synaptic plasticity, the degree of which correlates with Alzheimer’s disease severity. We sought to examine whether serum levels of Dickkopf-1 (Dkk-1), a Wnt antagonist, are associated with global disease progression in older adults with mild cognitive impairment (MCI) and mild-to-moderate AD.Methods: We prospectively followed 88 older adults with MCI and mild-to-moderate AD attending a Memory Clinic. Cognitive performance, functional performance and neuropsychological symptoms were assessed at baseline and after 1 year. We reviewed neuroimaging for white matter changes and medial temporal atrophy, and performed ApoE genotyping at baseline. Serum Dkk-1 was assayed at baseline and 1 year, along with blood biomarkers of inflammation and endocrine dysfunction. We defined global disease progression (“progressors”) as an increase in Clinical Dementia Rating Sum-of-Boxes (CDR-SB) score by >2 points at 1 year.Results: Fifteen (17.0%) participants had global disease progression. At baseline, there was no difference in cognitive performance and neuropsychiatric symptoms between groups, although progressors were more impaired in instrumental activities of daily living (p = 0.008). Progressors had significantly greater deterioration in cognitive performance (p = 0.002), with significantly worse functional performance and more severe neuropsychiatric symptoms (p = 0.042) at follow-up. Serum inflammatory and endocrine biomarkers at baseline and 1 year were similar between progressors and non-progressors. Serum Dkk-1 had increased significantly from baseline amongst progressors, while non-progressors exhibited decremental Dkk-1 over time (Dkk-1change: 354.304 ± 670.467 vs. −173.582 ± 535.676 ng/ml, p = 0.001). Adjusting for age, gender and baseline cognitive performance, incremental Dkk-1 independently predicted global cognitive decline (p = 0.012).Conclusion: Our results suggest progressively dysfunctional Wnt signaling through Dkk-1 antagonism contributes to disease progression amongst older adults with MCI and mild-moderate AD.

DKK1 promotes hepatocellular carcinoma inflammation, migration and invasion: Implication of TGF-β1.

Dickkopf-1 (DKK1), an inhibitor of the most frequently impaired signaling pathway in hepatocellular carcinoma (HCC), the Wnt/beta-catenin pathway, seems to fulfill contradictory functions in the process of tumorigenesis, acting either as an oncogenic promoter of metastasis or as a tumor suppressor. Elevated serum levels of DKK1 have been reported in HCC; however, little is known about its functional significance. In the current study, we treated HepG2/C3A and PLC/PRF/5 with the recombinant protein DKK1. Cytotoxicity was first determined by the WST-8 assay. AFP expression was measured at both the mRNA and protein levels. Expression of the oncogenes MYC, CCND1, hTERT, and MDM2 and the tumor suppressor genes TP53, P21 and RB was assessed. Western blot analysis of non-phosphorylated ẞ-catenin and Sanger sequencing were performed to explain the functional differences between the two cell lines. Subsequently, inflammation, migration and invasion were evaluated by qPCR, ELISA, the Boyden chamber assay, zymography, and MMP-2 and MMP-9 western blot analysis. Knockdown of DKK1 and TGF-β1 were also performed. Our results suggest that DKK1 exerts an oncogenic effect on HepG2/C3A cell line by upregulating the expression of oncogenes and downregulating that of tumor suppressor genes, whereas the opposite effect was demonstrated in PLC/PRF/5 cells. This differential impact of DKK1 can be explained by the mutations that affect the canonical Wnt pathway that were detected in exon 3 of the CTNNB1 gene in the HepG2 cell line. We further confirmed that DKK1 promotes inflammation, tumor invasion and migration in both cell types. The canonical pathway was not responsible for the DKK1 proinvasive effect, as indicated by the active ẞ-catenin levels in the two cell lines upon DKK1 treatment. Interestingly, knockdown of TGF-β1 negatively affected the DKK1 proinvasive effect. Taken together, DKK1 appears to facilitate tumor invasion and migration through TGF- β1 by remodeling the tumor microenvironment and inducing inflammation. This finding endorses the relevance of TGF-β1 as a therapeutic target.

Serum levels of inhibitors of wingless / beta-catenin in patients with ankylosing spondylitis and the relationship with anti-tumour necrosis factor alpha treatments

Aim: The primary aim of the study was to compare the serum levels of Dickkopf-1 (DKK-1) and sclerostin in patients with ankylosing spondylitis (AS) and healthy controls. The secondary aim was to evaluate the effects of anti-tumor necrosis factor alpha (TNF-α) treatments on levels of DKK-1 and sclerostin. The last aim was to evaluate any relationship between DKK-1, sclerostin, and radiologic progression in AS. Material and Method: We included 70 patients with AS (35 anti-TNF-α treated, 35 anti-TNF-α naive) and 31 healthy controls in this study. Serum DKK-1, sclerostin, C reactive protein, and erythrocyte sedimentation rate (ESR) were assessed in patients and healthy controls. The Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Metrology Index (BASMI), and Bath Ankylosing Spondylitis Functional Index (BASFI) were calculated for the patients. Radiographs were scored according to the modified Stoke AS Spine Score (mSASSS) by an experienced radiologist who was blinded to the patients’ identity. Results: Patients with AS who were treated with anti-TNF-α agent had higher scores of BASMI and mSASSS compared with the anti-TNF-α naive patients. Serum levels of DKK-1 and sclerostin were significantly lower in patients with AS than in healthy controls. There was a negative correlation between DKK-1 levels with ASDAS and BASMI in patients with AS. There was no correlation between DKK-1 or sclerostin levels with mSASSS. There was a positive correlation between BASMI score with mSASSS in patients with AS. Conclusion: DKK-1 levels in patients with AS were negatively correlated with BASMI, on the other hand, BASMI had a strong positive correlation with mSASSS. Therefore, these findings suggest that lower DKK-1 levels in patients with AS may play a role in new bone formation.

Circulating CD40 ligand, Dickkopf-1 and P-selectin in HIV-infected patients.

The aim of this study was to evaluate the circulating levels of CD40 ligand (CD40 L), Dickkopf-1 (DKK-1) and P-selectin, their relationships and their contributions to cardiovascular risk in subjects with HIV infection. The study population included 80 HIV-infected patients, 14 (17.5%) of whom had diabetes mellitus (DM) and 32 (40.0%) of whom had arterial hypertension (AH). The HIV-infected patients were compared with a control group with similar demographic and clinical features. CD40L, DKK-1 and P-selectin levels were measured using an enzyme-linked immunosorbent assay. The HIV-infected patients showed higher levels of all the cardiovascular disease (CVD) markers. Both serum CD40L and DKK-1 were significantly higher in HIV-infected patients than in the HIV-negative controls (P<0.001), while soluble P-selectin showed no significant between-group difference (P=0.133), reflecting the role of HIV infection in CVD. In the HIV-infected group, patients with DM showed lower levels of CD40L and DKK-1 in comparison with the nondiabetic patients and patients with AH (P<0.05, with Bonferroni correction). In contrast, patients with AH showed higher levels of CD40L and DKK-1 in comparison to patients without DM or AH (P<0.05, with Bonferroni correction). Patients with AH showed higher levels of CD40L and DKK-1 than patients with DM (P<0.05, with Bonferroni correction). In this study, we found that HIV-infected patients displayed significantly higher circulating levels of both CD40L and DKK-1, which were linearly and directly correlated, when compared to HIV-negative patients. The presence of diabetes was associated with lower levels of both CD40L and DKK-1, whereas the presence of hypertension was associated with higher levels of CD40L.

Increased Levels of DKK1 in Vitreous Fluid of Patients with Pathological Myopia and the Correlation between DKK1 Levels and Axial Length

ABSTRACT Purpose Dickkopf 1 (DKK1) functions as a natural antagonist of the canonical Wnt/β-catenin pathway. The purpose of this study was to examine the expression of DKK1 in vitreous samples of patients with pathological myopia, in order to search for possible correlations between DKK1 and axial length. Materials and Methods The expression of DKK1 and other cytokines in vitreous samples of 44 non-myopic eyes, 42 eyes with low-to-moderate myopia, and 51 eyes with pathological myopia were examined using multiplex cytokine detection technology. Ophthalmologic characteristics, including axial length and subfoveal choroidal thickness, were clinically measured for further analysis. Results The intravitreous levels of DKK1 (P < .0001) were markedly higher in the pathological myopia group than in the control group. There were no differences of DKK1 levels in different vitreoretinal conditions. Additionally, we found that the DKK1 levels were positively correlated with HGF (β = 0.268, P = .032), and TIMP-3 (β = 0.209, P = .047) levels, as well as with axial length (β = 0.714, P < .0001) in the pathological myopia group. Conclusions Elevated levels of DKK1 were found in the eyes with elongated axial length.

CKAP4 Regulates Cell Migration via the Interaction with and Recycling of Integrin.

Cytoskeleton-associated protein 4 (CKAP4) is an endoplasmic reticulum protein that is also present in the cell surface membrane, where it acts as a receptor for Dickkopf1 (DKK1). In this study, we found that CKAP4 interacts with β1 integrin and controls the recycling of α5β1 integrin independently of DKK1. In S2-CP8 cells, knockdown of CKAP4 but not DKK1 enlarged the size of cell adhesion sites and enhanced cell adhesion to fibronectin, resulting in decreased cell migration. When CKAP4 was depleted, the levels of α5 but not β1 integrin were increased in the cell surface membrane. A similar phenotype was observed in other cells expressing low levels of DKK1. In S2-CP8 cells, α5 integrin was trafficked with β1 integrin and CKAP4 to the lysosome or recycled with β1 integrin. In CKAP4-depleted cells, the internalization of α5β1 integrin was unchanged, but its recycling was upregulated. Knockdown of sorting nexin 17 (SNX17), a mediator of integrin recycling, abrogated the increased α5 integrin levels caused by CKAP4 knockdown. CKAP4 bound to SNX17, and its knockdown enhanced the recruitment of α5β1 integrin to SNX17. These results suggest that CKAP4 suppresses the recycling of α5β1 integrin and coordinates cell adhesion sites and migration independently of DKK1.

Dickkopf-1 and Amphiregulin as Novel Biomarkers and Potential Therapeutic Targets in Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is a highly fatal tumor which represents a major health problem worldwide. Due to asymptomatic nature of HCC, most patients present with the progressive stage of disease, so, unfortunately, there are no effective therapies. Existing techniques for HCC surveillance and diagnosis lack the required accuracy. Therefore, searching for new diagnostic and/or therapeutic tools could improve patient survival. This study aimed to estimate the diagnostic role of Dickkopf-1 (DKK1) and amphiregulin (AREG) and to find out their correlation with different clinicopathological parameters in HCC patients. Materials and Methods: Serum levels of DKK1 and AREG in 55 HCC patients, 20 cirrhotic patients, and 15 healthy subjects as control group were measured using the ELISA technique. Results: Both of DKK1 and AREG showed a significant increase in the HCC group compared to cirrhotic and healthy groups. DKK1 at a cutoff point of 8.92 ng/ml showed that the area under the curve (AUC) was 0.826 with 87.3% sensitivity and 82.9% specificity. DKK1 showed a significant correlation with tumor size, liver dysfunction, and poor performance status in HCC patients. AREG at a cutoff point of 8.74 pg/ml showed a sensitivity of 74.5% but low specificity (47.1%). AREG showed a significant correlation with portal vein thrombosis and tumor metastasisin HCC patients. Conclusion: Serum DKK1 could be a diagnostic biomarker for HCC. Both of DKK1 and AREG may play significant roles in tumor progression and may offer promising therapeutic targets in HCC patients.

The predictive values of serum dickkopf-1 and circulating tumor cells in evaluating the efficacy of transcatheter arterial chemoembolization treatment on hepatocellular carcinoma.

In this study, we aim to explore the values of serum dickkopf-1 (DKK1) and circulating tumor cells (CTCs) in predicting the efficacy and prognosis of transcatheter arterial chemoembolization (TACE) treatment on patients with hepatocellular carcinoma (HCC). We did a retrospective analysis on 155 HCC patients who underwent TACE treatment. The patients were divided into response group (complete response and partial response) and nonresponse group (stable disease and progressive disease), and their changes in serum DKK1 and CTCs after TACE were recorded. Receiver operating characteristic curve and survival analysis were used to assess the predictive values of DKK1 and CTCs for TACE efficacy and long-term prognosis of HCC. We found that the levels of preoperative DKK1 and CTCs in patients with HCC had a moderate positive correlation (r = 0.54). After TACE treatment, the serum DKK1 and CTCs in the response group were significantly decreased compared to pretreatment levels (P < .05), whereas the nonresponse group showed significantly increased serum DKK1 and CTCs levels (P < .05). The largest area under the curve (AUC) was achieved when using >0.02 μg/L reduction in DKK1 level after 4 weeks of TACE to predict the efficacy of TACE treatment (AUC = 0.913, 95% confidence interval: 0.856–0.952, P < .001), with the sensitivity of 78.26% and the specificity of 88.07%. The overall survival, disease-free survival, and 5-year survival rates were all significantly lower in the patients with positive preoperative levels of serum DKK1 and CTCs. COX multivariate regression analysis showed that Eastern Cooperative Oncology Group score, and preoperative levels of serum DKK1 and CTCs are independent influencing factors for the prognosis of patients with HCC. Overall, our results demonstrated that serum DKK1 and CTCs levels were good biomarkers for predicting the efficacy and prognosis of TACE treatment in patients with HCC. Moreover, these parameters exhibited different characteristics, and might have different potential applications.

SAT-059 SERUM SCLEROSTIN IS A PREDICTOR FOR CENTRAL ARTERIAL STIFFNESS IN CHRONIC HEMODIALYSIS PATIENTS

Wnt/β-catenin signaling inhibitors such as sclerostin and Dickkopf-1 (DKK1) may avoid further vascular calcification. Vascular calcification is associated with arterial stiffness and osteoprogenitor cells play an important role in the bone–vascular axis which regulates calcium metabolism around the arterial wall. This study aims to investigate the relationship between serum sclerostin, DKK1 levels and carotid–femoral pulse wave velocity (cfPWV) among patients in hemodialysis (HD). Blood samples were obtained from 122 chronic HD patients that had received standard 4-hour dialysis 3 times per week. Patients with cfPWV values of >10 m/s were classified in the high central arterial stiffness group, whereas those with cfPWV values of ≤ 10 m/s were assigned to the control group. Serum sclerostin and Dickkopf-1 (DKK1) levels were quantified using commercially available enzyme-linked immunosorbent assays. Fifty-three HD patients (43.4%) who belonged to the high central arterial stiffness group were generally older (P = 0.004), higher incidence of diabetes mellitus (P < 0.001), hypertension (P = 0.020), average systolic blood pressures (SBP, P = 0.018), serum C-reactive protein (CRP, P = 0.003), and sclerostin levels (P = 0.002) than their counterparts in the control group. A multivariable logistic regression analysis identified sclerostin as an independent predictor of central arterial stiffness in hypertensive patients (odds ratio, 1.017; 95% confidence interval (CI), 1.007–1.027; P = 0.001). Multivariable forward stepwise linear regression analysis also showed that serum logarithmically transformed sclerostin level (log-sclerostin, β = 0.311, adjusted R2 change: 0.125, P < 0.0013) was positively associated with cfPWV values in patients with chronic HD. In this study, serum sclerostin level, but not DKK1, is found to be positively correlated with cfPWV values and is identified as an independent predictor of central arterial stiffness in chronic HD patients.

Bone Matrix Levels of Dickkopf and Sclerostin are Positively Correlated with Bone Mass and Strength in Postmenopausal Osteoporosis.

Wnt signaling plays a pivotal role in maintaining bone mass. Secreted pathway modulators such as sclerostin (SOST) and Dickkopfs (DKKs) may influence bone mass inhibiting the canonical Wnt pathway. We evaluated whether bone protein content of secreted Wnt antagonists is related to age, bone mass, and strength in postmenopausal osteoporosis. We measured cortical and trabecular bone contents of SOST and Dickkopf-1 (DKK1) in combined extracts obtained after ethylenediaminetetraacetic acid and guanidine hydrochloride extraction in 56 postmenopausal women aged 47–74 (mean, 63) yr with a previous distal forearm fracture and a hip or spine Z-score less than 0. Our findings were (i) SOST and DKK1 protein levels were higher in trabecular bone, (ii) cortical and trabecular DKK1 and trabecular SOST correlated positively with bone matrix levels of osteocalcin (r between 0.28 and 0.45, p < 0.05), (iii) cortical DKK1 correlated with lumbar spine bone mineral density (BMD) (r = 0.32, p < 0.05) and femoral neck BMD (r = 0.41, p < 0.01), and (iv) cortical DKK1 and SOST correlated with apparent bone volumetric density and compressive strength (r between 0.34 and 0.51, p < 0.01). In conclusion, cortical bone matrix levels of DKK1 and SOST were positively correlated with bone mass and bone strength in postmenopausal osteoporotic women.

Early alterations in stem-like/resident T cells, innate and myeloid cells in the bone marrow in preneoplastic gammopathy.

Preneoplastic lesions carry many of the antigenic targets found in cancer cells but often exhibit prolonged dormancy. Understanding how the host response to premalignancy is maintained and altered during malignant transformation is needed to prevent cancer. In order to understand the immune microenvironment in precursor monoclonal gammopathy of undetermined significance (MGUS) and myeloma, we analyzed bone marrow immune cells from 12 healthy donors and 26 MGUS/myeloma patients by mass cytometry and concurrently profiled transcriptomes of 42,606 single immune cells from these bone marrows. Compared to age-matched healthy donors, memory T cells from both MGUS and myeloma patients exhibit greater terminal-effector differentiation. However, memory T cells in MGUS show greater enrichment of stem-like TCF1/7hi cells. Clusters of T cells with stem-like and tissue-residence genes were also found to be enriched in MGUS by single-cell transcriptome analysis. Early changes in both NK and myeloid cells were also observed in MGUS. Enrichment of stem-like T cells correlated with a distinct genomic profile of myeloid cells and levels of Dickkopf-1 in bone-marrow plasma. These data describe the landscape of changes in both innate and adaptive immunity in premalignancy and suggest that attrition of the bone-marrow-resident T cell compartment due to loss of stem-like cells may underlie loss of immune surveillance in myeloma.

Effect of Gut Involvement in Patients with High Probability of Early Spondyloarthritis: Data from the DESIR Cohort.

Inflammatory bowel disease (IBD) is a well-known extraarticular feature of spondyloarthritis (SpA). The aims of this study were to evaluate factors associated with IBD and incidence over 5 years of followup in the DESIR cohort. DESIR is a prospective observational cohort of patients with recent-onset inflammatory back pain suggestive of axial SpA. All available variables in the database were compared between patients with and without IBD at baseline and 5 years, and occurrence over 5 years of followup, with uni- and then multivariable analysis. At baseline, of 708 patients, 35 had IBD (prevalence 4.94%, CI 95% 3.3-6.5). IBD was associated (multivariable) with history of uveitis, levels of Dickkopf-1, and tumor necrosis factor, but not with phenotypic presentation (peripheral arthritis, enthesitis, dactylitis, uveitis) or baseline serum levels of other cytokines. At 5 years, 480 patients were analyzed, 58 with IBD. IBD was associated (multivariable) with fulfillment of modified New York criteria, sick leave, Bath Ankylosing Spondylitis Disease Activity Index, and smoking. There was no association with magnetic resonance imaging scores, enthesitis, psoriasis, and bone mineral density. Twenty-three incident cases of IBD were recorded: estimated occurrence rate of 0.95/100 (95% CI 0.57-1.35) patient-years (PY). Incidence of IBD is associated (multivariable) with HLA-B27 (OR 0.36, 95% CI 0.22-0.59), fulfillment of modified New York criteria (OR 3.35, 95% CI 1.85-6.08), and familial history of IBD (OR 3.31, 95% CI 1.62-6.77). In early SpA, IBD occurs with an incidence of 1/100 PY, and is associated with poor outcome, familial history of IBD, absence of HLA-B27, and fulfillment of modified New York criteria.