Preclinical Models for Neuroblastoma: Establishing a Baseline for Treatment

Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system.Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a "standard of care" chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents.The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal combination for testing new chemotherapies for this devastating childhood cancer

Neighbourhood built environment associations with body size in adults:mediating effects of activity and sedentariness in a cross-sectional study of New Zealand adults

Background: The aim of this study was to determine the associations between body size and built environment walkability variables, as well as the mediating role of physical activity and sedentary behaviours with body size. Methods: Objective environment, body size (body mass index (BMI), waist circumference (WC)), and sedentary time and physical activity data were collected from a random selection of 2033 adults aged 20-65 years living in 48 neighbourhoods across four New Zealand cities. Multilevel regression models were calculated for each comparison between body size outcome and built environment exposure. Results and Discussion: Street connectivity and neighborhood destination accessibility were significant predictors of body size (1 SDchange predicted a 1.27 to 1.41 % reduction in BMI and a 1.76 to 2.29 % reduction in WC). Significantrelationships were also observed for streetscape (1 SD change predicted a 1.33 % reduction in BMI) anddwelling density (1 SD change predicted a 1.97 % reduction in BMI). Mediation analyses revealed asignificant mediating effect of physical activity on the relationships between body size and street connectivity and neighbourhood destination accessibility (explaining between 10.4 and 14.6 % of the total effect). No significant mediating effect of sedentary behaviour was found. Findings from this cross-sectional study of a random selection of New Zealand adults are consistent with international research. Findings are limited to individual environment features only; conclusions cannot be drawn about the cumulative and combined effect of individual features on outcomes. Conclusions: Built environment features were associated with body size in the expected directions. Objectively-assessed physical activity mediated observed built environment-body size relationships

Increased Activation of L‐Type Voltage‐Dependent Calcium Channels Is Associated with Glycine Enhancement of N‐Methyl‐d‐Aspartate‐Stimulated Dopamine Release in Global Cerebral Ischemia/Reperfusion

Abstract: We investigated the relationships among N‐methyl‐d‐aspartate, glycine, L‐type voltage‐dependent calcium channels, and [3H]dopamine release in a canine model of global cerebral ischemia/reperfusion. The binding of [3H]PN200‐110 ([3H]isradipine) to L‐type voltage‐dependent calcium channels, that open as a consequence of N‐methyl‐d‐aspartate‐induced changes in membrane potential, was approximately doubled in striatal membranes prepared from ischemic animals relative to controls, and remained significantly elevated at 30 min and 2 h of reperfusion. These changes coincided temporally with changes in the ability of the voltage‐sensitive calcium channel blocker nitrendipine to inhibit glycine enhancement of N‐methyl‐d‐aspartate‐stimulated [3H]dopamine release in striatal slices prepared from the same animals. Compared with nonischemic controls, N‐methyl‐d‐aspartate‐stimulated [3H]dopamine release was increased in ischemic animals and remained increased throughout reperfusion up to at least 24 h. Glycine enhanced N‐methyl‐d‐aspartate‐stimulated release in all treatment groups. The enhancement of N‐methyl‐d‐aspartate‐stimulated dopamine release by glycine was reduced by the inclusion of nitrendipine in striatal slices from ischemic and 30‐min reperfused animals. These data suggest that glycine may facilitate opening of the voltage‐dependent calcium channels activated by N‐methyl‐d‐aspartate and that this facilitation is blocked by the antagonist nitrendipine. Copyright © 1994, Wiley Blackwell. All rights reserve