Tumours contain heterogeneous cell populations. A population enriched in tumour-initiating potential has been identified in soft-tissue sarcoma (STS) by the isolation of "side population" (SP) cells. In this study, we compared the gene expression profiles of SP and non-SP cells in STS and identified Hedgehog (Hh) and Notch pathways as potential candidates for the targeting of SP cells. Upon verification of the activation of these pathways in SP cells, using primary tumor xenografts in NOD-SCID mice as our experimental model, we used the Hh blocker Triparanol and the Notch blocker DAPT to demonstrate that the suppression of these pathways effectively depleted the abundance of SP cells, reduced tumour growth, and inhibited the tumour-initiating potential of the treated sarcoma cells upon secondary transplantation. The data provide additional evidence that SP cells act as tumour initiating cells and points to Hh and Notch pathways as enticing targets for developing potential cancer therapies.

Tumours contain heterogeneous cell populations. A population enriched in tumour-initiating potential has been identified in soft-tissue sarcoma (STS) by the isolation of "side population" (SP) cells. In this study, we compared the gene expression profiles of SP and non-SP cells in STS and identified Hedgehog (Hh) and Notch pathways as potential candidates for the targeting of SP cells. Upon verification of the activation of these pathways in SP cells, using primary tumor xenografts in NOD-SCID mice as our experimental model, we used the Hh blocker Triparanol and the Notch blocker DAPT to demonstrate that the suppression of these pathways effectively depleted the abundance of SP cells, reduced tumour growth, and inhibited the tumour-initiating potential of the treated sarcoma cells upon secondary transplantation. The data provide additional evidence that SP cells act as tumour initiating cells and points to Hh and Notch pathways as enticing targets for developing potential cancer therapies.

The research described in this thesis began with a single long-term objective: modelling of the vertebral artery during chiropractic manipulation of the cervical spine. Although chiropractic treatment has become prevalent, the possible correlation between neck manipulation and subsequent stroke in patients has been the subject of debate without resolution. Past research has been qualitative or statistical, whereas resolution demands a fundamental understanding of the associated mechanics.<p> Analysis in the thesis begins with a study of the anatomy and properties pertinent to the chiropractic problem. This indicates that the complexity of the problem will necessitate a long-term multidisciplinary effort including a nonlinear finite element formulation effective in analysing image data for soft tissue modelled as nearly incompressible. This leads to an assessment of existing finite element methods and the conclusion that new equation solving techniques are needed to ensure numerical stability.<p> Three techniques for effectively eliminating the source of numerical instability are developed and demonstrated with the aid of original finite element codes. Two of the methods are derived as modifications of matrix decomposition algorithms, while the third method constitutes a new finite element formulation. In addition, the understanding gained in developing these methods is used to produce a theorem for assessing a different but related problem: deformation of a nearly incompressible material subjected to a single concentrated force. Throughout the thesis, an interdisciplinary path from chiropractic problem to numerical algorithms is outlined, and results are in the form of mathematical proofs and derivations of both existing and new methods.

This thesis presents a tunable 3D real-time interactive simulator of the geometrical displacement of the thoracic diaphragm during physiological and mechanical ventilation. Particular attention is placed on capturing the heterogeneous tissue composition while maintaining computational efficiency and accuracy. The long term goal is to establish an accurate theoretical model to complement the experimental and clinical studies of the side effects associated with mechanical ventilation and to overcome the ethical difficulties of performing time resolved studies on human patients. The deformations are modelled using a commercial 3D model and a mass-spring model together with distance constraints and Verlet integration. The simulator is easily adjusted in real-time to many different cases of ventilation and validated through inspection and comparison with existing models. More research is needed to validate the model using patient specific data, as well as extending the model to include additional physiological and pathophysiological components. Long term goals includes considering the microscopic aspects of cellular mechanics to capture the underlying causes of ventilator-induced diaphragmatic dysfunction.

The research described in this thesis began with a single long-term objective: modelling of the vertebral artery during chiropractic manipulation of the cervical spine. Although chiropractic treatment has become prevalent, the possible correlation between neck manipulation and subsequent stroke in patients has been the subject of debate without resolution. Past research has been qualitative or statistical, whereas resolution demands a fundamental understanding of the associated mechanics.<p> Analysis in the thesis begins with a study of the anatomy and properties pertinent to the chiropractic problem. This indicates that the complexity of the problem will necessitate a long-term multidisciplinary effort including a nonlinear finite element formulation effective in analysing image data for soft tissue modelled as nearly incompressible. This leads to an assessment of existing finite element methods and the conclusion that new equation solving techniques are needed to ensure numerical stability.<p> Three techniques for effectively eliminating the source of numerical instability are developed and demonstrated with the aid of original finite element codes. Two of the methods are derived as modifications of matrix decomposition algorithms, while the third method constitutes a new finite element formulation. In addition, the understanding gained in developing these methods is used to produce a theorem for assessing a different but related problem: deformation of a nearly incompressible material subjected to a single concentrated force. Throughout the thesis, an interdisciplinary path from chiropractic problem to numerical algorithms is outlined, and results are in the form of mathematical proofs and derivations of both existing and new methods.

The purpose of this thesis is to search for the best material model for soft biological tissues in general. Different sections of human body exhibit different responses like stress relaxation, creep, hysteresis and preconditioning to external loading conditions. These body sections can be assumed as viscoelastic, poroelastic or pseudoelastic. After making the choice of the material model from one of these for the current study, the finite element model and the material code to be used with this model have been created. The material code has also been tried on a simple finite element model before implementing to the real model to prove the fact that it is working properly. Then, the constants in the code which simulates the in vivo experimental data that was obtained by indenting the elliptic indenter tip into the forearm, medial part as close as possible, have been derived by inverse finite element method. Consequently, the characteristic behaviors of the soft tissue could be simulated. Despite the big size of the finite element model and very long submission times (up to one day for preconditioning simulation), relaxation and creep behaviors could be simulated with the maximum normalized sum of square errors of 0.74 % and 0.43 %, respectively. The number of square errors for the hysteresis and preconditioning behaviors appeared as 2.56 % and 3.89 % which are also acceptable values. These values prove that these material models are well suited for the simulation of the behavior of soft biological tissues. By using different experimental data obtained from other sections of human body, simulation of the behavior of different soft tissues can be achieved by using these material models.

Our investigation sought to identify the incidence of treatment failure and its associated costs in patients with methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections (SSTIs) treated in the primary care setting. Thirteen clinics participated in this multi-site, observational study. Clinicians consented patients and collected clinical information, pictures, and wound swabs; isolates were processed in the principal investigator's laboratory. Treatment failure was defined as the occurrence of one or more of the following within 90 days: (1) change in antibiotic therapy, (2) subsequent need for incision and drainage, (3) SSTI at new site, (4) SSTI at same site, (5) emergency department visit, or (6) hospitalization. Cost estimates were obtained from the Agency for Healthcare Research and Quality (AHRQ) and Centers for Medicare and Medicaid Service's National Average Drug Acquisition Costs (NADAC). Patients were considered to have “moderate or complicated” SSTIs if they had a lesion ≥ 5cm in diameter, diabetes mellitus, or both. Patients not exhibiting these characteristics were classified as having “mild or uncomplicated” infections. Ninety-eight patients were enrolled. Most patients were of Hispanic ethnicity and more than half of all patients had a body mass index (BMI) ≥ 30kg/m2. The most common treatment modality was incision and drainage (I&D) plus antibiotics (57%). Treatment failure occurred in 21% of all patients at a mean additional cost of $1,933.71. Patients with moderate or complicated SSTIs who received I&D experienced significantly more treatment failures compared mild or uncomplicated patients who received I&D (36% vs. 10%; p = 0.04). The additional cost of treatment failure in patients with moderate or complicated SSTIs was nearly twice that of patients with mild or uncomplicated SSTIs ($2,093.40 vs. $1,255.02; p = 1.0). Treatment failure occurred sooner, on average, in the moderate or complicated group compared to the mild or uncomplicated group (11.8 days vs. 38.8 days; p = 0.06). Among patients with MRSA SSTIs treated in the primary care setting, the rate of treatment failure is high (21%) and costs are considerable ($1,933.71). / text

This thesis presents a foundation for developing a business case for companies interested in the reconstructive and cosmetic procedure markets. The focus is on reviewing adipose tissue engineering research and proposing technology opportunities that could be applied to challenging soft tissue reconstruction cases and adjacently applied to cosmetic applications. To establish the foundation for this type of program, this thesis includes an evaluation of the reconstructive and cosmetic procedure markets, current practices in these markets and their constraints, as well as a literature review of research in adipose tissue engineering and its potential clinical applications. Additionally it captures the competitive landscape of major players in the reconstructive market as well as up-and-coming players in the adipose tissue engineering field. Technology development opportunities with associated customer and business value are discussed with a recommendation for the development of a detailed business case to evaluate specific product development opportunities in these markets. / text

Osteoporosis is a major public health concern with origins in childhood and is potentially linked to childhood obesity. This study used novel approaches in bone imaging to characterize skeletal development in girls and to assess the influence of whole body and regional soft tissue composition on bone material, structural and geometric properties, the primary determinants of bone strength, controlling for important covariates such as maturation, diet and physical activity. Prospective analyses were conducted to assess associations between measures of total body fat (TBFM) and android fat masses (AFM) and skeletal muscle fat (SMF) content on bone mineral content, density and strength. The results showed that higher TBFM and AFM were inversely associated with changes in cortical bone sites of the femur and tibia. These findings suggest that gains in abdominal adiposity during the pre- and early- pubertal years may contribute to suboptimal bone development and skeletal fragility later in life. The analyses also showed inverse associations between baseline muscle density of the thigh and calf with 2-year changes in bone strength and bone density of the metaphyseal and diaphyseal sites of the femur and tibia. This paradoxical relationship between SMF and bone outcomes was explained by subsequent analyses showing that girls exhibiting larger gains in muscle density experienced larger increases in bone density and strength compared to girls who did not significantly increase muscle density. These findings suggest that fatty infiltration of skeletal muscle contributes to suboptimal bone development in peri-pubertal girls. Further longitudinal analyses were conducted to examine the individual effects of the muscle-bone unit components on 2-year changes in bone strength. These results showed that muscle size contributed to gains in bone strength, independent of its mechanostat effect on BMC. These results underscore the importance of muscle size for promoting bone development and bone strength during growth. A final set of analyses were conducted to examine the effects of dietary fatty acids on bone development. The results of these analyses suggest that while decreasing intakes of AA n-6 FA may benefit bone health, higher intakes n-3 FAs may benefit tibia bone density development in young girls.

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