A Validated Preclinical Animal Model for Primary Bone Tumor Research

Funding for this study was provided by the German Research Foundation (Grant DFG WA 3606/1-1 to F. Wagner and Grant HO 5056/1-1 to B.M. Holzapfel), the Australian Research Council (Future Fellowship Program) and the Technical University Munich Hans Fischer Senior Fellowship (D.W. Hutmacher), and a Research Fellowship from the National Health and Medical Research Council (#1044091 to J.-P. Lévesque

Co-nanoencapsulated doxorubicin and Dz13 control osteosarcoma progression in a murine model

Objectives: Chitosan is a green (natural, abundant, biodegradable, biocompatible) biopolymer that can be formulated to encapsulate a variety of therapeutic compounds. This study aimed to investigate chitosan nanoparticles (NPs) as a means of improving delivery of the clinically used anti-cancer agent doxorubicin (Dox) and the preclinical lead compound Dz13 oligonucleotide together. Methods: A novel chitosan NP system encapsulating Dox and Dz13 was designed, biophysically characterised and tested in a clinically relevant model of the metastasising bone tumour, osteosarcoma (OS). Key findings: By careful alteration of the concentration of the individual components, a final formulation of Dz13-Dox NPs (DDNPs) was achieved, with high (>91%) loading of both compounds, which consisted of individual 50-nm particles forming aggregates as large as 500 nm, with a large positive ζ-potential. The DDNPs could be stored at various temperatures for a week without loss in activity but were prone to degradation in serum. DDNPs successfully inhibited OS tumour growth more effectively than treatment with NPs of Dz13 and Dox-chitosan, as well as Dox administered intraperitoneally. Apart from inhibiting tumour growth, DDNPs protected the affected bone from substantial destruction by aggressive tumour growth and reduced the incidence of metastasis to the lungs without causing adverse effects in mice. Conclusion: This NP is a promising formulation that could be useful for clinical management of OS

RECK in osteosarcoma: A novel role in tumour vasculature and inhibition of tumorigenesis in an orthotopic model

BackgroundTargeted therapy in osteosarcoma (OS) is needed to improve patient outcomes. Human RECK may have a role because it inhibits cancer invasion and regulates angiogenesis. This study aimed to characterize RECK expression in human OS, to examine in vitro effects of RECK on vascular endothelium and OS cell behavior, and to analyze the effect of RECK on OS grown orthotopically in nude mice.MethodsRECK was examined in human OS samples. Interactions between RECK and VEGF were studied in tissue and cells. RECK transfection was used to study its effects on vascular endothelial (HMEC-1) and OS (SaOS-2) cell behavior in vitro and in vivo. SaOS-2 co-culture with RAW 246.7-derived osteoclasts on osteoslides was used to assess effects on osteoclast activity.ResultsRECK was absent from OS cells but was expressed in tumor vessel endothelium. Via microarray analysis, RECK mRNA was elevated in samples with low proliferative activity, a trend most evident in poorly differentiated samples. VEGF induced RECK expression in HMEC-1. RECK transfection inhibited HMEC-1 invasion and induced thicker, although more numerous, tube formation. RECK inhibited SaOS-2 invasion, proliferation, colony formation, and osteoclast activity but supported SaOS-2 adhesion to collagen I. In vivo, RECK inhibited SaOS-2 tumor growth, bone destruction, and consequent metastasis.ConclusionsRECK expression is downregulated in highly proliferative OS but is present in tumor vessels and upregulated in endothelium by VEGF. RECK inhibits invasion and tumorigenic properties in SaOS-2, as confirmed in vivo. Further testing of RECK delivery in OS is warranted.Jonathan C. M. Clark, Toru Akiyama, David M. Thomas, Agatha Labrinidis, Andreas Evdokiou, Stuart J. Galloway, Han-Soo Kim, Crispin R. Dass and Peter F. M. Choon

Black Box Parenting Program for Substance-Abusing Fathers: A Feasibility Study

Substance-abusing fathers have reported parenting difficulties and there is a need for interventions that address these concerns and support these men. The present study conducted a feasibility trial of the Black Box Parenting Program for fathers in residential substance abuse treatment settings. The study had a mixed methods design that assessed for demand, implementation, preliminary efficacy, and acceptability. Measures included pre- and post-questionnaires on parenting self-efficacy and satisfaction, perceived closeness in the parent-child relationship, feelings of guilt and engagement, and satisfaction with treatment. In addition, semi-structured interviews were conducted with participants post-treatment. Across four groups, the 19 fathers successfully completed the program. Following the intervention, there was a significant decrease in feelings of guilt and a strong motivation to continue to seek help with parenting. Parental self-efficacy and perceived closeness in the parent-child relationship did not significantly improve from pre to post-treatment. Qualitative data indicate that fathers were very satisfied with the program. Satisfaction with treatment was strongly related to parental self-efficacy. Systemic barriers prevented delivery of the program at some treatment sites and parts of the program could not be implemented at multiple sites. Overall, the program shows promise in being able to reduce the barriers to help-seeking such as guilt and poor retention. However, it requires the right service structure to achieve successful implementation