With the proportion of elderly people increasing in many countries, osteoporosis has become a growing public health problem, with rising medical, social, and economic consequences. It is well recognized that a combination of low bone mass and the deterioration of the trabecular architecture underlies osteoporotic fractures. A comprehensive understanding of the relationships between bone mass, the three-dimensional (3D) architecture of bone and bone function is fundamental to the study of new and existing therapies for osteoporosis. Detailed analysis of 3D trabecular architecture, using high-resolution digital imaging techniques such as magnetic resonance microimaging (MRI), micro-computed tomography (CT), and direct image analysis, has become feasible only recently. Rapid prototyping technology is used to replicate the complex trabecular architecture on a macroscopic scale for visual or biomechanical analysis. Further, a complete set of 3D image data provides a basis for finite element modeling (FEM) to predict mechanical properties. The goal of this paper is to describe how we can integrate three-dimensional microimaging and image analysis techniques for quantitation of trabecular bone architecture, FEM for virtual biomechanics, and rapid prototyping for enhanced visualization. The integration of these techniques provide us with an unique ability to investigate the role of bone architecture in osteoporotic fractures and to support the development of new therapies. Anat Rec (New Anat) 265:101-110, 2001.

The study objective was to analyze the three-dimensional (3D) trabecular architecture and mechanical properties in vertebral specimens of young and mature Sinclair minipigs to assess the relative contribution of architecture to bone strength. We used 3D magnetic resonance microimaging (MRI) and direct image analysis to evaluate a set of standard structural measurements and new architectural descriptors of trabecular bone in biopsy specimens from L2, L3, and L4 vertebrae (n ‫؍‬ 16 in each group) from young (mean age, 1. .05). Overall, ConnD, star volume, % plate, and % bone LD provided a coherent picture of the architectural changes between the two age groups. Apparent modulus and maximum stress were determined experimentally on biopsy specimens from L2 vertebrae (n ‫؍‬ 16). When apparent modulus was predicted using 3D MRI data sets as input for finite element modeling (FEM), the results were similar to the experimentally determined apparent modulus (p ‫؍‬ 0.12). Both methods were then used to compare the young and the mature animals; the experimental and predicted apparent modulus were significantly higher for the mature group (p ‫؍‬ 0.003 and 0.012, respectively). The experimental maximum stress in the vertebra of the mature animals was twice as high as that for the young animals (p ‫؍‬ 0.006). Bone quantity (BV/TV or bone mineral content [BMC]) alone could explain approximately 74 -85% of the total variability in stress and modulus.

Gadolinium and microCT allow an improved 3D visualization of cartilage and quantification of its proteoglycan content.

Values are considered to be a major influence on sport behaviour. The values underlying sports participation among young (12-16 yrs) football and tennis players (n=93) were examined by discussion of sport-specific moral dilemmas. Eighteen sport-relevant values which showed good correspondence with recent formulations of value structures were identified. Moral dilemmas in sport are explained as a conflict between competing types of values. It is suggested that examination of the values of significant others may explain value development in young athletes.

The Hedgehog (Hh) pathway is a highly conserved signaling system that plays an important role in embryonic development and tissue homeostasis through regulation of cell differentiation and proliferation, and deregulated Hh signaling has been implicated in variety of cancers. Two distinct mechanisms are responsible for inappropriate and uncontrolled Hh pathway activation in human malignancies: ligand-dependent, due to over-expression of Hh ligand, and ligand-independent, resulting from genetic mutations in pathway components such as Patched (Ptch) and Smoothened (Smo). Smo, a member of the class F G-protein coupled receptor family, is a key regulator of Hh signaling pathway, and therefore is an attractive target for pathway modulation. We have identified a potent and selective small molecule antagonist of Smo. This novel molecule (LY2940680) binds to the Smo receptor and potently inhibits Hh signaling in Daoy, a human medulloblastoma tumor cell line, and C3H10T½, a mouse mesenchymal cell line. Importantly, LY2940680 binds to and inhibits the functional activity of resistant Smo mutant (D473H) produced by treatment with GDC-0449 (a Smo antagonist from Genentech). LY2940680 also has excellent pharmacokinetic properties in rodent and non-rodent species. Treatment of Ptch+/− p53−/− transgenic mice, which spontaneously develop medulloblastoma, with oral administration of LY2940680 produced remarkable efficacy and significantly improved their survival. Magnetic resonance imaging of these mice revealed rapid kinetics of anti-tumor activity. Immunohistochemistry analysis of medulloblastoma tumors showed that LY2940680 treatment induced Caspase-3 activity and reduced proliferation. LY2940680 inhibited Hh regulated gene expression in the subcutaneous xenograft tumor stroma and produced significant anti-tumor activity. In summary, we have characterized an orally bio-available small molecule Smo antagonist that may provide therapeutic benefit to cancer patients with deregulated Hh signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2819. doi:10.1158/1538-7445.AM2011-2819