The value of a nursing course revision for the purpose of improved student learning and outcomes is discussed in this descriptive, quasi-experimental study. An instructor of a nursing pathophysiology course devised and implemented the study to determine if outcomes would differ between two groups of first semester baccalaureate nursing students taking the required pathophysiology course. The revisions, which were applied and then evaluated, demonstrated improvement in student learning.

The aim of this thesis is to develop a better understanding of the mechanisms and modalities exploited by breast cancer cells during invasion, paying particular attention to those mechanisms employed during cell migration in 3D spheroid culture, a context that more accurately recapitulates the complexities seen in vivo. Using a hydrogel-based model system, we investigated the roles of cellular blebs in cancer migration, developed a novel protocol that enhances optical microscopy images and facilitates high content imaging techniques including mass spectrometry imaging, and then used this new technology to investigate gain of function activity of mutant p53 in breast cancer cell migration in terms of both actomyosin contractility and in lipid abundances and distributions. Chapter 1 begins with an overview of breast cancer, an introduction to cancerous behavior and migration, a discussion of the importance of 3D cell culture and interactions of breast cancer cell and the extracellular matrix, and an overview of the various imaging techniques used in this work. In Chapter 2 we describe a novel mode of breast cancer migration that we term bleb – driven migration. This migratory mode is characterized by invasive cells that are both round and bleb bearing. This migratory mode is highly dependent on actomyosin contractility, a mechanism that is imperative to bleb formation. We show that blebs can actively attach to and rearrange the extracellular matrix via accumulations of β1 integrins at the bleb necks. We show both polarization of blebs as well as collagen alignment in regions of the cell enriched in blebs, both of which are dependent on the expression of β1 integrins by the cell. The discovery of this new migratory mode is important, as many cancers are able to overcome cancer therapies by using escape mechanisms, such as alternate migratory mechanisms. As such, developing a fuller understanding of the migratory modes used by cancer cells is vital in our fight to prevent cancer deaths. Chapter 3 tackles a significant problem associated with working in 3D spheroid culture: obtaining high quality, high resolution images. 3D samples tend to be highly refractive and poorly diffusive, and image acquisition can be severely hindered due to these factors. Further, the depth at which 3D samples can be imaged is limited by the low working distances of high numerical aperture objectives. As such, we developed a protocol that enables the sectioning of invasive spheroids, which we term DISC-3D (dual hydrogel invasive cryosectioning of spheroids in 3D). This protocol enables us to capture images that are higher in resolution and signal to background noise, removes imaging depth related constraints, and enables images to be acquired using dyes and techniques that have not previously been demonstrated in invasive 3D in vitro samples. Using this technology, Chapter 4 then examines the gain of function activity mutant p53 imparts on invasive breast cancer cells. We show that mutant p53 plays a role in increasing actomyosin contractility by promoting targeting of RhoA to the cell membrane. We also show an alteration in lipid expression in mutant p53 bearing cells, a feat that is made possible through use of the DISC-3D technology. Collectively, this work provides insights in to the invasive mechanisms exploited by breast cancer cells. We repeatedly demonstrate the importance of in vitro, 3D cell culture in the study of breast cancer migration. Using such cell culture techniques, we outline previously unknown aspects of breast cancer cellular migration both in regards to the importance of blebs and to the gain of function activity of mutant p53, the latter of which was made possible through use of the DISC-3D protocol. We argue that continued study in this area will provide insights into how breast cancer cells migrate, providing paths and new treatment strategies for preventing such migration.

<p>  </p> <p>The disruption of homeostasis in tendon extracellular matrix and altered biomechanical properties lead to poor tendon healing, creating a significant clinical challenge for millions of diabetics. Furthermore, improving blood glucose levels doesn't normalize tendon properties in diabetics. Diabetes-related tendon complications are often associated with advanced glycation end products (AGEs) crosslinking with collagen. However, recent studies have found no evidence of higher collagen crosslinking in diabetics and no correlation between tendon AGE content and tensile strength. The interaction between serum AGEs and AGE receptors (RAGE) is a less explored mechanism of AGE-mediated effects. People with diabetes are more likely to accumulate AGEs in their serum as a result of hyperglycemia, the consumption of AGE-rich foods, and diminished kidney clearance of AGEs. In previous studies, advanced glycation end-products (AGEs) have been shown to inhibit cell proliferation and migration, both of which are critical to tendon healing. We hypothesized that serum AGEs and activation of RAGE represent a mechanism underlying impaired tendon properties with diabetes. The increasing serum AGE levels would impair tendon biomechanical properties and tendon healing, while inhibition of RAGE [Azeliragon (AZ)] would improve tendon mechanics.</p> <p>Db/db mice with naturally elevated serum AGEs and impaired tendon function were treated daily with a RAGE inhibitor [Azeliragon (AZ), n=9] or vehicle (n=10) for three weeks. Patellar tendon stiffness and modulus were greater (p<0.05) in mice receiving AZ (stiffness: 9.6±1.2 N/mm, modulus: 78.2±8.2 MPa) compared to vehicle (5.8±0.9 N/mm, modulus: 49.0±8.3 MPa). Maximum strain (vehicle: 0.9±0.1, AZ: 0.8±0.05) and toughness (vehicle: 6.1±1.4, AZ: 6.5±1.2 J·m−3) were not different between groups (p>0.05). Maximum stress tended to be greater in the AZ group (vehicle: 14.6±2.4, AZ: 23.3±2.9 N/mm2, p=0.156).</p> <p>Ten-week-old non-diabetic mice were assigned to receive daily injections of bovine serum albumin (BSA-only, n=6), BSA and AZ (BSA-AZ, n=5), 200 mg/ml glycated BSA (AGE-BSA, n=4), and AGE with AZ (AGE-AZ, n=6). A full-thickness, partial-width defect was created in both patellar tendons. Treatments were started one week before surgery and continued for three weeks after surgery. Three Tendon stiffness was lower in mice treated with AGEs (p<0.05, 10.8±1.4 N/mm) compared to BSA-only (17.6±1.3 N/mm). Further, tendon stiffness in AGE-treated mice given AZ was not different from AGE-BSA (p<0.05, 12.7±1.8 N/mm). Tendon modulus was lower in mice treated with AGEs (p<0.05, 28.0±7.0 MPa) compared to BSA-only (63.5±9.0 MPa). Additionally, modulus in AGE-treated mice given AZ was not different from AGE-BSA (p>0.05, 47.6±10.4 N/mm). </p> <p>We demonstrate that administering a RAGE inhibitor improves tendon properties in an established mouse model for type 2 diabetes. In healthy mice, serum AGE levels inhibit the recovery of tendon biomechanical properties after injury; RAGE inhibitors did not have an effect on mice given AGEs. Based on these data, we suggest elevated serum AGEs, as seen with diabetes, are associated with poor mechanical properties and delayed tendon healing.</p>

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No / Knowledge of clinically and cost-effective wound management is an obvious requirement for surgeons, yet wound care education rarely features within the medical curriculum. As a result surgical trainees are often poorly placed to join in multidisciplinary wound management and may feel threatened when asked to manage wound complications. A vast range of dressing products exists yet robust evidence of the function and effectiveness of individual products is often lacking. An understanding of wound pathophysiology, a defined treatment goal and regular wound assessment combined with knowledge of basic wound dressing categories will provide guidance on product selection for different clinical situations and wound types.

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No / Knowledge of clinically and cost-effective wound management is an obvious requirement for surgeons, yet wound care education rarely features within the medical curriculum. As a result surgical trainees are often poorly placed to join in multidisciplinary wound management and may feel threatened when asked to manage wound complications. A vast range of dressing products exists yet robust evidence of the function and effectiveness of individual products is often lacking. An understanding of wound pathophysiology, a defined treatment goal and regular wound assessment combined with knowledge of basic wound dressing categories will provide guidance on product selection for different clinical situations and wound types.

Adult neurogenesis is affected in neurodegenerative diseases and also represents an important therapeutic target. The goal of this dissertation research was to test the hypothesis that regeneration of neurons and glia in the adult brain can be manipulated by neurotrophic drugs in the context of two mouse models of neurodegenerative disease : Parkinson's disease and Huntington's disease.... These findings have implications for the pathophysiology of Huntington's disease and neurodegeneration in general. Specific alterations to the SVZ neurogenic niche parallel some of the pre-motor symptoms of Parkinson's disease and Huntington's disease. This dissertation research contributes to the growing body of literature concerning the pharmacological modulation of SVZ-derived neurogenesis designed to attenuate the progressive loss of neurons in neurodegenerative diseases and perhaps delay the onset of symptoms. / by Mark Harvey McCollum. / Vita. / Thesis (Ph.D.)--Florida Atlantic University, 2012. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

In the studies about ovarian cancer cells, basal iNOS expression in the chemosensitive OV2008 cells was significantly higher than in the chemoresistant C13* cells. Cisplatin further increased iNOS expression in OV2008 cells, but had no effect in C13* cells. Furthermore, cisplatin dramatically reduced the expression levels of eNOS and nNOS, but again only in OV2008 cells. The data suggest that failure of cisplatin to upregulate iNOS and downregulate eNOS and nNOS in C13* cells could be an etiological factor in chemoresistance. Addition of exogenous NO at high levels, using SNAP, significantly increased p53 protein levels and caused apoptosis in both cell types. Specific iNOS inhibitor (1400W) partially blocked the pro-apoptotic effects of cisplatin in OV2008 cells, suggesting involvement of iNOS in cisplatin-induced apoptosis. However, blocking of all three isoforms of NOS with NG-amino-L-arginine in C13* cells dramatically changed these cells from chemoresistant to chemosensitive, greatly potentiating the pro-apoptotic effects of cisplatin. / Inhibition of Src-kinase activity reduces DNA synthesis in ovarian cancer cells. In an in vitro experiment, Src phosphorylated PKG on a tyrosine residue and PKG, presumable via serine-phosphorylation of Src, enhanced Src auto(tyrosine)phosphorylation. In ovarian cancer cells, inhibition of basal PKG activity with DT-2 decreased both basal and EGF-stimulated Src kinase activation and DNA synthesis. The data suggest that PKG at basal activity, is necessary for both basal and growth factor-stimulated Src kinase activation and enhanced DNA synthesis in human ovarian cancer cells. / The novel role of sGC/cGMP/PKG pathway on stimulating cell proliferation, potentially via interaction with the Src kinase pathway in human ovarian cancer cells, was demonstrated. ODQ dramatically reduced DNA synthesis rates, suggesting that basal sGC activity and basal cGMP levels are needed for ovarian cancer cell proliferation. DT-2 also reduced cell proliferation, suggesting the direct involvement of PKG. ANP and BNP had no effect on cell proliferation, suggesting that further activation of cGMP/PKG pathway above basal levels does not further enhance cell proliferation. / The present study also demonstrated that elevating cGMP slightly above the basal levels further protects pancreatic islet cells against spontaneous onset of apoptosis. The results showed that natriuretic peptides (both ANP and BNP) and low-level NO (i.e. physiological levels) as supply by NO donor, S-nitroso-N-acetylpenicilamine (SNAP) further prevented spontaneous apoptosis in pancreatic islets after isolation, whereas NO at high concentrations (i.e. pathological levels) promoted apoptosis in pancreatic islet cells. The commonly-used PKG inhibitor KT5823 and the newly-developed specific PKG inhibitor DT-2 completely prevented anti-apoptosic effect of ANP, suggesting the direct involvement of PKG in protection against spontaneous apoptosis. / The present study demonstrated that basal activity of sGC/cGMP/PKG signaling pathway is essential for partially limiting spontaneous apoptosis in pancreatic islet cells. The sGC inhibitor ODQ caused induction of apoptosis, which was completely blocked by co-treatment with ANP or BNP, agents that elevate cGMP via pGC, bypassing the ODQ block. Co-treatment with 8-Br-cGMP, a direct activator of PKG also completely prevented ODQ-induced apoptosis in islets. / Leung Lai-han. / "July 2006." / Adviser: Ronald Ray Fiscus. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1483. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 175-191). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.