Systemic levels of neuropeptide Y and dipeptidyl peptidase activity in patients with Ewing sarcoma--associations with tumor phenotype and survival.

BACKGROUND: Ewing sarcoma (ES) is driven by fusion of the Ewing sarcoma breakpoint region 1 gene (EWSR1) with an E26 transformation-specific (ETS) transcription factor (EWS-ETS), most often the Friend leukemia integration 1 transcription factor (FLI1). Neuropeptide Y (NPY) is an EWS-FLI1 transcriptional target; it is highly expressed in ES and exerts opposing effects, ranging from ES cell death to angiogenesis and cancer stem cell propagation. The functions of NPY are regulated by dipeptidyl peptidase IV (DPPIV), a hypoxia-inducible enzyme that cleaves the peptide and activates its growth-promoting actions. The objective of this study was to determine the clinically relevant functions of NPY by identifying the associations between patients' ES phenotype and their NPY concentrations and DPP activity. METHODS: NPY concentrations and DPP activity were measured in serum samples from 223 patients with localized ES and 9 patients with metastatic ES provided by the Children's Oncology Group. RESULTS: Serum NPY levels were elevated in ES patients compared with the levels in a healthy control group and an osteosarcoma patient population, and the elevated levels were independent of EWS-ETS translocation type. Significantly higher NPY concentrations were detected in patients with ES who had tumors of pelvic and bone origin. A similar trend was observed in patients with metastatic ES. There was no effect of NPY on survival in patients with localized ES. DPP activity in sera from patients with ES did not differ significantly from that in healthy controls and patients with osteosarcoma. However, high DPP levels were associated with improved survival. CONCLUSIONS: Systemic NPY levels are elevated in patients with ES, and these high levels are associated with unfavorable disease features. DPPIV in serum samples from patients with ES is derived from nontumor sources, and its high activity is correlated with improved survival.

Dipeptidyl peptidases as survival factors in Ewing sarcoma family of tumors: implications for tumor biology and therapy.

Ewing sarcoma family of tumors (ESFT) is a group of aggressive pediatric malignancies driven by the EWS-FLI1 fusion protein, an aberrant transcription factor up-regulating specific target genes, such as neuropeptide Y (NPY) and its Y1 and Y5 receptors (Y5Rs). Previously, we have shown that both exogenous NPY and endogenous NPY stimulate ESFT cell death via its Y1 and Y5Rs. Here, we demonstrate that this effect is prevented by dipeptidyl peptidases (DPPs), which cleave NPY to its shorter form, NPY(3-36), not active at Y1Rs. We have shown that NPY-induced cell death can be abolished by overexpression of DPPs and enhanced by their down-regulation. Both NPY treatment and DPP blockade activated the same cell death pathway mediated by poly(ADP-ribose) polymerase (PARP-1) and apoptosis-inducing factor (AIF). Moreover, the decrease in cell survival induced by DPP inhibition was blocked by Y1 and Y5R antagonists, confirming its dependence on endogenous NPY. Interestingly, similar levels of NPY-driven cell death were achieved by blocking membrane DPPIV and cytosolic DPP8 and DPP9. Thus, this is the first evidence of these intracellular DPPs cleaving releasable peptides, such as NPY, in live cells. In contrast, another membrane DPP, fibroblast activation protein (FAP), did not affect NPY actions. In conclusion, DPPs act as survival factors for ESFT cells and protect them from cell death induced by endogenous NPY. This is the first demonstration that intracellular DPPs are involved in regulation of ESFT growth and may become potential therapeutic targets for these tumors.

To ignore or not to ignore placental calcifications on prenatal ultrasound: a systematic review and meta-analysis.

OBJECTIVE: The human placenta is known to calcify with advancing gestational age, and, in fact, the presence of significant calcifications is one of the components of grade III placenta, typical of late gestation. As such, the presence of significant placental calcifications often prompts obstetric providers to expedite delivery. This practice has been attributed, in part, to the presumed association between grade III placenta and adverse pregnancy outcomes. Such approach, however, can be the source of major anxiety and may lead to unnecessary induction of labor, with its associated predisposition to cesarean delivery as well as a myriad of maternal and neonatal morbidities. The objective of this study was to examine the association between grade III placental calcifications and pregnancy outcomes. MATERIALS AND METHODS: A systematic review of the literature was performed for studies evaluating the association between grade III placenta and a number of pregnancy outcomes, including labor induction, fetal distress (abnormal fetal heart tracing), low Apgar score (less than 7 at 5 min), need for neonatal resuscitation, admission to the Neonatal Intensive Care Unit, perinatal death, meconium liquor, and low birth weight. RESULTS: There was a five-fold increase in risk of labor induction with the presence of grade III placenta (OR 5.41; 95% CI 2.98-9.82). There was no association between grade III placenta and the incidence of abnormal fetal heart tracing (OR 1.62; 95% CI 0.94-2.78), low Apgar score of less than 7 at 5 min (OR 1.68; 95% CI 0.84-3.36), need for neonatal resuscitation (OR 1.08; 95% CI 0.67-1.75), and admission to the Neonatal Intensive Care Unit (OR 0.90; 95% CI 0.21-3.74). In turn, the incidence of meconium liquor was higher in the setting of grade III placentae (OR 1.68; 95% CI 1.17-2.39). Similarly, a positive association between grade III placental calcifications and low birth weight (OR 1.63; 95% CI 1.19-2.22) and perinatal death (OR 7.41; 95% CI 4.94-11.09) was identified. CONCLUSION: The study alerts us to a significant association between grade 3 placental calcifications and labor induction, although it demonstrates that these sonographic findings do not appear to predispose to fetal distress, low Apgar score, need for neonatal resuscitation, or admission to the NICU.