BackgroundThe Wnt inhibitor Dickkopf-1 (DKK-1) has been linked to the progression of malignant bone disease by impairing osteoblast activity. In addition, there is increasing data to suggest direct tumor promoting effects of DKK-1. The prognostic role of DKK-1 expression in prostate cancer remains unclear.MethodsA prostate cancer tissue microarray (n = 400) was stained for DKK-1 and DKK-1 serum levels were measured in 80 patients with prostate cancer. The independent prognostic value of DKK-1 expression was assessed using multivariate analyses.ResultsDKK-1 tissue expression was significantly increased in prostate cancer compared to benign disease, but was not correlated with survival. However, high DKK-1 serum levels at the time of the diagnosis were associated with a significantly shorter overall and disease-specific survival. Multivariate analyses defined high serum levels of DKK-1 as an independent prognostic marker in prostate cancer (HR 3.73; 95%CI 1.44-9.66, p = 0.007).ConclusionHigh DKK-1 serum levels are associated with a poor survival in patients with prostate cancer. In light of current clinical trials evaluating the efficacy of anti-DKK-1 antibody therapies in multiple myeloma and solid malignancies, the measurement of DKK-1 in prostate cancer may gain clinical relevance.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-649) contains supplementary material, which is available to authorized users.

The Wnt inhibitor Dickkopf-1 (DKK-1) has been associated with the occurrence of bone metastases in osteotropic prostate cancer by inhibiting osteoblastogenesis. P38 mitogen-activated protein kinase (MAPK) activity is also dysregulated in advanced prostate cancer. However, the impact of p38 MAPK signaling on DKK-1 remains unknown. Inhibition of p38 MAPK signaling in osteolytic PC3 cells by small molecule inhibitors (doramapimod, LY2228820 and SB202190) suppressed DKK-1 expression, whereas activation of p38 MAPK by anisomycin increased DKK-1. Further dissection by targeting individual p38 MAPK isoforms with siRNA revealed a stronger role for MAPK11 than MAPK14 and MAPK12 in the regulation of DKK-1. Moreover, prostate cancer cells with a predominantly osteolytic phenotype produced sufficient amounts of DKK-1 to inhibit Wnt3a-induced osteoblastic differentiation in C2C12 cells. This inhibition was blocked directly by neutralizing DKK-1 using a specific antibody and also indirectly by blocking p38 MAPK. Furthermore, tissue expression in human prostate cancer revealed a correlation between p38 MAPK and DKK-1 expression with higher expression in tumor compared with normal tissues. These results reveal that p38 MAPK regulates DKK-1 in prostate cancer and may present a potential target in osteolytic prostate cancers.

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Purpose: We assessed serum concentrations of the receptor activator of NFkB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG), two proteins implicated in the development and progression of breast cancer, in 509 patients with primary, nonmetastatic breast cancer. Then the results were evaluated with regards to the occurrence of bone metastases, the presence of disseminated tumor cells (DTC) in the bone marrow, survival, and risk of developing metastatic disease.Experimental Design: Before surgery, two bone marrow aspirates were analyzed for DTC using density centrifugation followed by immunocytochemistry (pan-cytokeratin antibody A45-B/B3). RANKL and OPG levels in the serum were measured by ELISA.Results: RANKL levels were significantly lower in women >60 years (P < 0.0001) and RANKL/OPG ratios higher in lymph node-positive patients (P < 0.05). High OPG serum levels were associated with a higher risk of death from breast cancer [HR 1.94; 95% confidence interval (CI) 1.23-3.07; P ¼ 0.005] and OPG was an independent prognostic marker for breast cancer-specific survival (BCSS; multivariate analyses, P ¼ 0.035). RANKL levels were 33% higher (P < 0.0001) in DTC pos patients (41%), whereas high levels were associated with a significantly better BCSS in DTC neg patients as compared with low levels (HR 0.524; 95% CI 0.30-0.95; P ¼ 0.04). RANKL serum levels were significantly increased in patients who developed bone metastases (P ¼ 0.01) and patients within the highest quartile of RANKL had a significantly increased risk of developing bone metastases compared with those in the lowest (HR 4.62; 95% CI 1.49-14.34; P ¼ 0.03).Conclusions: These findings warrant further investigation as they provide a rationale for novel diagnostic or therapeutic approaches.NOTE: Values of RANKL and OPG are given in pmol/L. RANKL/OPG is displayed as a ratio of the two values. Significant values (P < 0.05) are shown in bold.Rachner et al.

Background/Objectives: Blood donors attending a donation session may be deferred from donating blood due to a failure to meet low hemoglobin (Hb) thresholds. This costs the blood donor service, and donors, valuable time and resources. In addition, donors who are deferred may have more symptoms and as a direct and/or indirect effect of their experience return rates of donors deferred for low Hb are reduced, even in repeat donors. It is therefore vital that low Hb deferral (LHD) is minimized. The aim of this updated systematic review is to expand the evidence base for factors which affect a donor's risk of deferral due to low Hb. Materials/Methods: Studies were identified by searching MEDLINE, Embase, The Cochrane Library and the WHO International Clinical Trials Registry to March 2019. Demographic data, donor history, hematological/biological factors and the primary outcome of deferral due to low Hb were extracted. Our primary outcome was deferral due to low Hb. Analyses were descriptive and quantitative; pooled odds ratios (ORs) and 95% confidence intervals (CIs) were obtained by meta-analysis using random effects models. Results: A total of 116 studies met the inclusion criteria. Meta-analysis showed a significantly greater risk of LHD in females compared with males in studies applying universal Hb thresholds for males and females (OR 14.62 95%CI 12.43-17.19) and in those which used sex-specific thresholds (OR 5.73, 95%CI 4.36-7.53). Higher rates of LHD were also associated with increasing age in men, low body weight, shorter inter-donation interval, donors of Hispanic or African descent, higher ambient temperature, donors with low ferritin levels and donation in a fixed donor center. There was conflicting evidence on the effect of new and repeat donor status, and blood group. Conclusion: This work has strengthened the evidence of the previous review in identifying factors that should be considered in studies of donor deferral and highlighting areas in need of further study, including ABO and Rh blood groups, previous platelet donation, diet, smoking, time of day, and genetic data. These factors may lead to individually tailored donation criteria for safe and efficient donation in the future.