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Aldosterone receptor blockade using spironolactone may substantially reduce the risk of both CCV morbidity and death among HD patients; however, larger-scale studies are recommended to further confirm its efficacy. (Effects of Spironolactone on Cardio- and Cerebrovascular Morbidity and Mortality in Hemodialysis Patients; NCT01687699).

Translocation t(11;22) is a karyotypic abnormality detected in over 90% of Ewing's family tumors. This translocation results in the EWS-Fli1 fusion gene, which has been shown to be a potent, single-step transforming gene. We reported previously that suppression of the EWS-Fli1 fusion protein altered the expression of G 1 regulatory cyclins and cyclin-dependent kinase inhibitors both at mRNA and protein levels, resulting in G 1 growth arrest in Ewing's family tumor cell lines. These data suggest that the G 1 regulatory molecules may be targets of the EWS-Fli1 fusion protein, which functions as an aberrant transcription factor. By using electrophoretic mobility shift assays, we show here the direct association of EWS-Fli1 fusion protein with ETS consensus sequences, which are in the promoter of the p21 WAF1/CIP1 gene. Reporter gene assays revealed that the activity of the p21 WAF1/CIP1 promoter is negatively regulated by EWS-Fli1 fusion protein through at least two ETS-binding sites in the promoter. EWS-Fli1 interacted with p300 cotransactivator and suppressed its histone acetyltransferase activity, which may explain the down-regulation of p21 WAF1/CIP1 by EWS-Fli1. In the presence of a histone deacetylase inhibitor, the histone acetyltransferase activity of the Ewing's family tumor cell was recovered resulting in the induction of p21, and the cell growth was dramatically inhibited. These results demonstrated that p21 WAF1/CIP1 might be one of the direct targets of EWS-Fli1, and that p21 WAF1/CIP1 could serve as a target for a molecularly based therapy for Ewing's family tumors.Aberrant functions of transcription factors by structural alterations are frequent and crucial mechanisms for the development of malignant phenotypes. Chromosomal rearrangement is a major cause of structural alterations of transcription factors leading to aberrant functions. Translocation t(11;22) is a common chromosomal abnormality detected in Ewing's family tumors (EFT), 1 including Ewing's sarcoma (ES) and primitive neuroectodermal tumor (1). This translocation results in the EWS-Fli1 fusion gene, made up of the 5Ј half of the EWS gene, containing a glutamine-rich repeat on chromosome 22, fused to the 3Ј half of the Fli1 gene on chromosome 11, which harbors an ETS-like DNA binding domain. Recent studies (2) demonstrated that EWS-Fli1 fusion protein, created by the chimeric gene, acts as an aberrant transcription factor. Murine fibroblasts stably transfected with the EWS-Fli1 gene formed colonies in soft agar and gained tumorigenicity (3). These observations suggest that the chimeric gene is a potent, singlestep transforming gene. However, little is known about the mechanisms involved in the transformation of the chimeric gene, and the biological significance of EWS-Fli1 is not fully understood. Targeting the EWS-Fli1 fusion gene by stable transfection with an antisense expression plasmid resulted in the loss of tumorigenicity of EFT cells (4). We reported that treatment with EWS-Fli1 antisense oligonucleotides inhibited proliferation of ...

Ewing sarcoma-primitive neuroectodermal tumor (EWS) is associated with the most unfavorable prognosis of all primary musculoskeletal tumors. The objective of the present study was to investigate whether tumor-associated macrophages (TAMs) affect the development of EWS. TAMs were isolated from mouse xenografts using CD11b magnetic beads and examined for their cytokine expression and osteoclastic differentiation. To evaluate the role of TAMs in xenograft formation, liposome-encapsulated clodronate was used to deplete TAMs in mice. Macrophage infiltration and tumor microvascular density were histologically evaluated in 41 patients with EWS, and association with prognosis was examined using Kaplan-Meier survival analysis. In mouse EWS xenografts, TAMs expressed higher concentrations of cytokines including interleukin-6, keratinocyte-derived chemokine, and monocyte chemotactic protein-1. TAMs were more capable than normal monocytes of differentiating into tartrate-resistant acid phosphatase-positive giant cells. Depleting macrophages using liposome-encapsulated clodronate significantly inhibited development of EWS xenografts. In human EWS samples, higher levels of CD68-positive macrophages were associated with poorer overall survival. In addition, enhanced vascularity, increase in the amount of C-reactive protein, and higher white blood cell counts were also associated with poor prognosis and macrophage infiltration. TAMs seem to enhance the progression of EWS by stimulating both angiogenesis and osteoclastogenesis. Further investigation of the behavior of TAMs may lead to development of biologically targeted therapies for EWS.