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Bosch, Canals Begoña María. "A bioengineering approach for corneal endothelial regeneration." Doctoral thesis, Universitat Internacional de Catalunya, 2019. http://hdl.handle.net/10803/667398.
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Nowadays, there are approximately 10 million people worldwide with visual impairment due to corneal diseases. Currently, the main therapeutic solution is the transplant of a donor's cornea. The great majority of transplants is due to some failure in the inner layer of the cornea, which is called the corneal endothelium and this is mainly related with the inability of this layer to regenerate in vivo. However, transplants present several limitations such as the low number of healthy donors or immunological rejection by the patient.
In order to overcome these problems, several researchers have focused in culturing corneal endothelial cells (CEC) to subsequently replace non-functional CEC. However, cell therapy is still very recent and still presents a series of drawbacks. For instance, using animal CEC or cells from other patients has shown to lead into immunological rejection. In order to avoid this, it is possible to use stem cells from the same patient, which have the ability to differentiate into many cell types, including the corneal endothelium. Currently, the stem cells used to regenerate CEC are mainly pluripotent stem cells, either embryonic stem cells (ESC) or induced pluripotent stem cells (iPSC), which are derived from adult cells. Despite their great potential for treating diseases, these types of stem cells present major limitations such as the risk of teratoma formation. In addition, they present other disadvantages such as ethical problems associated with the use of ESCs, safety problems related to iPSC since they requires the use of virus for their production hence limiting its clinical application.
For this reason, and in order to solve the current problems in the regeneration of corneal endothelium, this thesis project uses dental pulp stem cells (DPSC) for the formation of CEC. DPSC are an accessible source derived from the same patient, avoiding possible future problems of rejection. In addition, the use of DPSC avoids the ethical and security problems associated with ESC and iPSC. Furthermore, DPSC and CEC have the same embryological origin, as they both arise from neural crest stem cells. In fact, DPSC express neural crest stem cells markers, which facilitates their differentiation into neural crest stem cells (NCSC), which is an intermediate step for the formation of CEC. Therefore, this thesis project uses a two-step protocol, where DPSC are differentiated into NCSC and, subsequently, NCSC are derived into CEC.
Because the use of cell therapies alone may present limited cell viability once it is injected, the field of tissue engineering is a new discipline that has appeared to overcome this limitation. Tissue engineering combines the use of cells, biomaterials and biological molecules. It has been demonstrated that the use of different topographies in cell culture modulates cell behavior, and may have an effect on their functionality, cell distribution or cell size. Therefore, this thesis project applies tissue engineering as another strategy for the generation of functional CEC with its characteristic phenotype and morphology. For doing this, we have mimicked the natural CEC environment by cultivating the cells on substrates with different curvatures, composition or topographies that are able to mimic those of the human eye.
In conclusion, this thesis project proposes the use of bioengineering, by differentiating CEC from stem cells derived from the patient and the use of biomaterials with different topographies and curvatures, for the regeneration of corneal endothelium.
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Sooriyajeevan, M. J. S. J. "Image filtering in nuclear medicine." Thesis, University of Aberdeen, 1996. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU090122.
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Nuclear medicine images are degraded by blurring caused by the gamma camera system response function and the inherent Poisson noise of radioactivity. Well known digital filters proposed for the restoration of these images have been investigated in this thesis. Particularly, Metz filter and a two-step filter have been extensively studied by the FROC methodology. The effectiveness and practical limitations of the FROC methodology in the assessment of nuclear medicine images have also been investigated. It was observed from the results that the closeness of test patterns to the real clinical cases was a crucial factor for a successful assessment. Therefore, a method to simulate clinical bone scans with focal abnormalities at a given depth has been developed in this thesis. A binormal model is used for the analysis of the FROC and AFROC results. A method has been developed in this thesis to determine the parameters that completely specify the binormal model. Using this method it has been shown in this work that the two-step filter may be useful in detecting focal abnormalities from complicated structures such as bone scans at strict criteria. It also has been observed in this work, that the Metz filter is useful for the detection of focal abnormalities in flat noise fields, but not in complicated structures such as bone scans.
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Campbell, Niall Gordon Simon. "An investigation of initial retention of stem/progenitor cells following intracoronary injection : implications to cell therapy for the treatment of heart failure." Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8659.
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Intracoronary injection is a frequently used clinical protocol for stem/progenitor cell therapy to the heart. Initial donor cell retention in the heart is the key to the success of this approach; however, this process has been poorly investigated. I established an original model to quantitatively assess initial donor cell retention after intracoronary cell injection in rats using an ex-vivo heart perfusion system and investigated factors that could affect retention. The initial retention efficiency of bone marrow mononuclear cells (BMMNC) was 20% after injection into normal hearts. The majority (>90%) of BMMNC loss into the coronary effluent occurred within the first minute of injection. Increased BMMNC dose increased absolute retention with a linear dose-effect relationship, while retention efficiency was unaltered. Retention efficiency increased to 30% in hearts with ischaemia-reperfusion, while flow cytometric studies showed that surface marker expression was unchanged between the pre-injection donor cell population and the population in the coronary effluent in both normal and ischemia-reperfused hearts. This suggests that active interactions between donor cells and coronary endothelium were not critical for donor cell retention using these experimental conditions. Instead, cell size assessment revealed that larger subpopulations of BMMNC were preferentially retained compared to smaller BMMNC in both normal and ischemia-reperfused hearts. Furthermore, a larger cell type, bone-marrow derived mesenchymal stem cells (MSC; median cell size=10.1 μm), had a markedly increased retention efficiency (80%) compared to BMMNC (median cell size=7.0 μm). A greater proportion of MSC with a larger diameter were retained compared to smaller diameter MSC; this enhanced retention plateaued with MSC ≥ 9 μm. Immunohistochemical analysis using fluorescently labeled donor cells demonstrated that all BMMNC retained in normal and ischaemia-reperfusion hearts were located within the coronary vasculature, without extravasation, up to 60 minutes after injection. Heart perfusion parameters and histological features exhibited evidence of coronary embolism after intracoronary injection of MSC, but not BMMNC (up to 40x106). These data collectively suggest that passive mechanical entrapment, and not active endothelial cell-donor cell interactions, is responsible for initial donor cell retention after intracoronary injection. This has important implications for future clinical protocols of intracoronary injection of stem / progenitor cells to the heart.
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Harrison, Robert Neil. "A bioengineering analysis of muscle and joint forces acting in the human lower limbs during running." Thesis, Liverpool John Moores University, 1989. http://researchonline.ljmu.ac.uk/5126/.
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Leonard, Alex. "Elastin Like Polypeptides as Drug Delivery Vehicles in Regenerative Medicine Applications." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/5981.
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Elastin like polypeptides (ELPs) are a class of naturally derived biomaterials that are non-immunogenic, genetically encodable, and biocompatible making them ideal for a variety of biomedical applications, ranging from drug delivery to tissue engineering. Also, ELPs undergo temperature-mediated inverse phase transitioning, which allows them to be purified in a relatively simple manner from bacterial expression hosts. Being able to genetically encode ELPs allows for the incorporation of bioactive peptides and functionalization of ELPs. This work utilizes ELPs for regenerative medicine and drug delivery.
The goal of the first study was to synthesize a biologically active epidermal growth factor-ELP (EGF-ELP) fusion protein that could aid in the treatment of chronic wounds. EGF plays a crucial role in wound healing by inducing epithelial cell proliferation and migration, and fibroblast proliferation. The use of exogenous EGF has seen success in the treatment of acute wounds, but has seen relatively minimal success in chronic wounds because the method of delivery does not protect exogenous EGF from degradation, or prevent it from diffusing away from the application site.
We created an EGF-ELP fusion protein to combat these issues. As demonstrated through the proliferation of human skin fibroblasts in vitro, the EGF-ELP may be able to aid in the treatment of chronic wounds. Furthermore, the ability of the EGF-ELP to self-assemble near physiological temperatures could allow for the formation of drug depots at the wound site and minimize diffusion, increasing the bioavailability of EGF and enhancing tissue regeneration.
The objective of the second study was to create an injectable hydrogel platform that does not require conjugation of functional moieties for crosslinking or biological activity. Hydrogels are three-dimensional polymer networks that are able to absorb water and biological fluids without dissolving. Their high water content gives them physical properties similar to soft tissues, making them useful as scaffolds for cell migration and drug delivery vehicles. Injectable hydrogels that crosslink in situ are particularly useful because they can form to the shape of the defect, providing a near perfect fit. However, many hydrogel platforms cannot be crosslinked in situ because cytotoxic crosslinking reagents are required. Additionally, hydrogels typically require the chemical conjugation of crosslinking domains and bioactive peptides to the polymer backbone, adding more steps and time required for hydrogel production.
We devised an injectable hydrogel platform that can be synthesized in a single step using photoreactive ELPs as the polymer backbone. Leucine auxotrophic Eshcherichia coli expressed ELPs containing photoleucine, a leucine analog and photoreactive diazirine crosslinker, which is substituted for leucine periodically throughout the ELP sequence. Upon exposure to ultraviolet radiation (~370 nm), photoleucine is able to form covalent crosslinks with amino acid side chains, forming a polymer network for hydrogel formation. Additionally, recombinant growth factors and morphogens can be encoded into the ELP sequence providing a simple method of hydrogel functionalization for regenerative medicine applications.
The potential for this platform was demonstrated through in vivo crosslinking of photoreactive ELPs in the expression hosts. Though the production of the photoreactive ELP was not as forthright as originally assumed. The substitution of noncanonical amino acids typically requires the auxotrophic expression hosts to be starved of the amino acid that they are auxotrophic for. A noncanonical analog of said amino acid can then be supplemented into expression media, maximizing incorporation. In this investigation, it was found the addition of photoleucine alone inhibited photoreactive ELP expression. ELP expression only occurred in the presence of photoleucine if valine or leucine was also present in the media. Furthermore, valine was found to aid the production of ELPs as much as leucine. It was postulated the bacterial translational machinery might need to be altered for optimal ELP expression.
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Srinivasan, Supriya. "Multifunctional Nanoparticles for Theranostic Applications." FIU Digital Commons, 2015. http://digitalcommons.fiu.edu/etd/2171.
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Multifunctional agents for the management of highly heterogeneous diseases, like cancer, are gaining increased interest with the intent of improving the diagnostics and therapy of cancer patients. These agents are also important because more than one treatment modality is typically used for cancer therapy in the clinic. Further, nanotechnology offers a platform where more than one agent can be combined to help provide improved cancer diagnosis and therapy. Near-infrared light-activatable phototherapeutic agents have great potential in vivo. Body tissues have minimum absorption in the near- infrared range. They also have been shown to enhance the cytotoxic effect of chemotherapeutic drugs when used in combination with them. We have, hence, investigated the potential of two multifunctional targeted nanoparticles for combined chemo-phototherapy (employing near- infrared light activable agent) and for understanding their underlying cellular responses. The first is employing polymeric Poly-lactic acid-co-glycolic acid (PLGA) nanoparticles with simultaneous incorporation of Indocyanine Green (ICG) (a near-infrared light-activatable photothermal agent) and Doxorubicin (DOX) and surface conjugated with anti-Human Epithelial Receptor-2 (HER-2). The PLGA nanoparticles were subjected to two modes of hyperthermia, incubator and laser hyperthermia, to mimic whole-body and localized hyperthermia used clinically. These nanoparticles upon laser exposure showed a rapid heat shock protein 70 (HSP70) response in comparison to the cellular HSP70 response upon incubator hyperthermia exposure. However, 12h post-treatment, downregulation of HSP70, was observed, thus, causing cellular apoptosis or necrosis based on the degree of thermal insult. These targeted nanoparticles, simultaneously incorporating agents, suffer from the limitation of release of both the agents from the nanoparticles and the need to control their release for bringing in effective therapy. Therefore, the second multifunctional nanoparticle employing silver nanoparticles (AgNPs) conjugated with Doxorubicin was formulated. AgNP serve as a near-infrared activatable agent itself, other than serving as a drug delivery vehicle. Thus, these nanoparticles only require the need to control the release of DOX alone. We further studied their mechanism of action, which included enhanced reactive oxygen species (ROS) production and reduction of intracellular thiol levels.
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Schlicher, Robyn Kathryn. "Mechanistic Features of Ultrasound-Mediated Bioeffects." Diss., Georgia Institute of Technology, 2005. http://hdl.handle.net/1853/14149.
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The inability to transport molecules efficiently and easily into cells and across tissues is one of the major limitations of developing drug delivery systems. A novel approach to overcoming this problem could be the use of low-frequency ultrasound to make cell membranes and tissues more permeable. Previous studies show that normally impermeant molecules can be transported into cells exposed to ultrasound; however, the mechanism by which this occurs is not well understood.
Our hypothesis is that low frequency ultrasound can reversibly disrupt membrane structure, thus allowing diffusion-driven intracellular delivery of molecules through a breach in the cell membrane. The effects of ultrasound are not limited to uptake of molecules; there can also be significant loss of cell viability after sonication. Therefore, the focus of this work is to determine the mechanisms by which molecular uptake and cell death occur from ultrasound exposure. The long-term goal of this work is to increase the number of viable cells that experience uptake by controlling the effects that cause cell death.
Our data have show that large molecules (r ≤ 28 nm) can be taken into cells after exposure to 24 kHz (10% duty cycle for 2 s of exposure time at 0.1 pulse length over a range of pressures) ultrasound and that uptake of these molecules can occur even after sonication ended. In experiments developed to isolate the mechanism(s) of uptake, DU145 prostate cancer cells depleted of ATP energy and intracellular calcium showed no uptake of calcein, a small fluorescent molecule (MW = 623 Da), nor did sonicated lipid bilayers (red blood cell ghosts), suggesting that uptake is calcium mediated and requires active mechanisms in viable cells.
Multiple types of microscopy, including electron and laser scanning confocal, showed evidence of large plasma membrane disruptions which support the hypothesis that transport of molecules into cells occurs through repairing wounds. Microscopy studies also indicated that much if the sonication-mediated death can occur by instantaneous cellular lysing and rapid cell death (within minutes post-exposure) due to wound-instigated necrosis; in addition, characteristics of rapidly induced controlled death modes were seen and found to be non-caspase-mediated within an hour after sonication ended.
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Archibong, Edikan. "Optofluidic Spectroscopy Platform for Detection of Hemolysis." Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/5902.
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In the United States alone, hundreds of millions of blood tests are performed annually, and a significant number of those tests are compromised due to hemolysis: e.g., 31% compromised in emergency rooms (inpatient) and 10% at blood banks, clinics, and other outpatient venues. Currently there is no way to reliably detect hemolysis without plasma separation. As a result, significant delays ensue, potentially negatively affecting patient diagnosis and treatment. In addition to in vitro hemolysis, which compromises the quality of blood tests, hemolysis can also occur in vivo. The in vivo occurrence of hemolysis is an indication of life-threatening complications. Being able to detect early signs of in vivo hemolysis would significantly improve outcomes for many patients, including pregnant women affected by HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelet counts) syndrome. Therefore, there is a critical need to be able to detect hemolysis near the patient, immediately following the collecting of blood sample.
The goal of this research is to provide an alternative to the traditional testing of blood samples, which requires large volumes of blood, centrifugation, and bulky instrumentation. The proposed alternative hemolysis detection system is a simple miniature setup that produces test results in minutes. This miniature, near-patient sensor would improve patients’ diagnosis, treatments, general satisfaction, and overall experience. The potential reduction of healthcare costs associated with hemolysis would be another significant benefit.
The technology demonstrated in this dissertation is based on a novel combination of microfluidics, spectroscopy, and optical-fiber sensing. The microfluidics provide the capability to handle small volumes of liquid and to filter particles from solution. Novel membrane fabrication and modular integration provides the means to characterize and culture the captured particles. Spectroscopy and optical fibers provide the means to characterize the filtrate. These capabilities can be used for not only the detection of hemolysis but also other biomedical applications. .
The first step in detecting hemolysis is to separate blood cells and other unwanted particulates from the plasma needed for optical analysis of concentration of hemoglobin. To that end, we focused initially on the problem of particle separation—specifically, within a microfabricated chamber with a custom-designed transparent membrane. To create a miniature microfluidic system capable of processing microliter blood samples, microelectromechanical systems (MEMS) fabrication techniques were required. The fabrication process included steps such as low-stress vapor deposition, photolithography, plasma, and wet etching. The resulting microdevice proved capable of filtering a variety of biological test fluids, including human lung fibroblast cancer cells from medium. The transparent membrane also allows for spectroscopic studies in broader applications, such as spectroscopic analysis or culturing of the cells retained on the filter. These capabilities were demonstrated using microbeads and cancer cells in solution.
Optical techniques are used to analyze the separated blood plasma for concentration of hemoglobin. To integrate spectroscopic capabilities with the above microfluidics system, an optical fiber–based miniature probe was attached to the microfabricated chamber. As proof of concept, this system was tested in an application that required the measurement of physiologically relevant concentrations of cobalamin (vitamin B12). This application was used to address human error in drug administration showing measurements of cobalamin concentration as an example drug that can be monitored. The clinical means range of concentrations is from 1 µg/ml to 1000 µg/ml. The achieved results showed measurements of concentrations between 1 µg /mL to 5 mg/mL to monitor the physiological range and potential overdose in microliter of volume.
This device has potential for numerous applications, ranging from single cell spectroscopy to measurements of glucose concentrations.
This integrated system was then applied to the detection of hemolysis. The complete system conducts optofluidic spectroscopy with the optical fiber probe connected to the microfabricated chamber, which locally filters out blood cells, and reliably determine amount of free hemoglobin with the need for centrifuging. The utility of the device was demonstrated by its accurate measurement of hemoglobin concentrations in blood plasma.
Finally, to apply the concept of the detection system to clinical condition with a reliable, and low-cost system, especially useful for developing countries, a smartphone-based technology, is proposed. This technology delivers ultra-fast results for the detection of early signs of HELLP syndrome and preeclampsia with the goal to decrease mortality and morbidity. The smartphone-based diagnostics is low cost, high speed of operation together with high accuracy. Detection of 1 mg/dL of free hemoglobin was achieved which is comparable to gold standard assay which are time consuming, difficult to operate and expensive.
This technology, in summary, integrates microfluidics with microfiltration and spectroscopic technology to conveniently separate and characterize blood plasma. The device can also provide important information about other complex biological samples. These measurements require only very small sample volumes.
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Vazquez, Natalie. "Android-based smartphone application simulation and systematic design to reduce medication administration error in prehospital emergency care." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3491.
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Since 1999 when the report To Err is Human: Building a Safer Health System was released, medical errors have come into focus (Kohn, 2000). In an effort to reduce medication administration errors in prehospital emergency care, an android-based smartphone application simulation was created. The app has components including QR barcode scanning, text to speech for medication cross-checking, weight-based medication dose calculations, and time stamped medication data wirelessly transferring to a database in real-time. Color standard identification was implemented, aiding to a designed systematic process for patient treatment to reduce medication errors. Direct observation was performed of emergency patient calls with Richmond Ambulance Authority’s providers for a preliminary assessment. Device testing was assessed with emergency medical interns and functionally tested in different light environments. Results showed how similar different pharmaceutical vendors created medication labeling and that 58.3% of medical experts would say this device served to reduce medication administration errors.
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Antonio, Ana Maria. "A bioengenharia no Brasil, século XX: estado da arte." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/82/82131/tde-28062005-101940/.
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Apresenta-se uma retrospectiva histórica do conhecimento e aplicação da engenharia biomédica/bioengenharia no Brasil; no período do século XX, enfocando a história da arte brasileira com relação à engenharia biomédica/bioengenharia, evidenciando perspectivas de desenvolvimento deste interessante campo de conhecimento. Por razões metodológicas e didáticas dividirão a engenharia biomédica/bioengenharia em áreas de aplicação: cardiologia, ortopedia, odontologia, oftalmologia, medicina regenerativa coadunando as áreas de ciências exatas e da terra onde, por exemplo, os conhecimentos das propriedades dos materiais utilizados, são evidenciados como composição química, estrutura, propriedades e aplicações, contextualmente definida como aplicação da engenharia biomédica/bioengenharia na medicina, de forma transitória ou permanente pelos diversos tecidos dos organismos dos seres vivos. Eles são utilizados como um todo ou parte de um biológico que trata, restaura ou substitui algum tecido, órgão ou função do corpo humano ou ainda como um material não viável utilizado em um dispositivo médico, com a intenção de interagir com o sistema biológico. A definição de bioengenharia foi encarada nessa dissertação de forma a direcionar a pesquisa de campo em empresas e núcleos que desenvolvem biomateriais, entrevistas com pessoas que vivenciaram o desenvolvimento da bioengenharia no Brasil, preparando um compêndio da história da bioengenharia no Brasil, no século XX<br>Show up a historical retrospective of knowledge and appliance of biomedic engineering in Brazil, on period of XX century, focus the history of brazilian art with relation of biomedic engineering, connecting perspective of development of this interesting knowledge filld. For methodological and didactic reasons biomedic engineering was divide in areas of appliance cardiologic, orthopedic, odontology, ophthalmology, regenerate medicine connecting areas of exact science and earth where, for example, the knowledge of property of material used, are evidence like chemistry composition, structure, properties and appliances contextualmente defined like appliance of biomedic engineering in medicine, on transitory or permanent form by several tissues of creature organisms. They are used as a whole or a part of a biological than treat, repair or replace some tissue, organ or function of human body or even like a material not possible to use in a medical gadget, with purpose of interragir with a biological system. The definition of bioengineering was look at in that dissertation so that direction to research field in enterprises and centers that development biomaterials, interview with peoples that live the development of bioengineering in Brazil, make compêndio of brazilian bioengineering history, on XX century
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Baker, Mark Ralph. "Late radiation effects in radiotherapy : changes in the biomechanical properties of normal skin, and surgically produced lesions after X irradiation measured in vivo and in vitro." Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335860.
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Jacobson, Timothy. "A Trans-Dimensional View of Drug Resistance Evolution in Multiple Myeloma Patients." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6099.
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Multiple Myeloma (MM) is a treatable, yet incurable, malignancy of bone marrowplasma cells. This cancer affects many patients and many succumb to relapse of tumor burden despite a large number of available chemotherapeutic agents developed for therapy. This is because MM tumors are heterogeneous and receive protection from therapeutic agents by the microenvironment and other mechanisms including homologous MM-MM aggregation. Therefore, therapy failure and frequent patient relapse is due to the evolution of drug resistance, not a lack of available drugs. To analyze and understand this problem, the evolution of drug resistance has been explored and presented herein. We seek to describe the methods through which MM cells become resistant to therapy, and how this resistance evolves throughout a patient’s treatment history. We achieve this in five steps.
First we review the patient’s clinical history, including treatments and changes in tumor burden. Second, we trace the evolutionary tree of sub-clones within the tumor burden using standard of care fluorescence in situ hybridization (FISH). Thirdly, immunohistochemistry slides are stained and aligned to quantify the level of environmental protection received by surrounding cells and plasma in the bone marrow microenvironment (coined environment mediated drug resistance score [EMDR]). The fourth analysis type is produced through a novel 384-well plate ex vivo chemosensitivity assay to quantify sensitivity of primary MM cells to chemotherapeutic agents and extrapolate these findings to 90-day clinical response predictions. In addition to direct clinical application in the choice of best treatment, this tool was also used to study changes in sensitivity of patient tumors to other drugs, and it was observed that, upon relapse, in addition to developing resistance to the current line of therapy, tumors become cross-resistant to agents that they were never exposed to. Finally, MM-MM homologous aggregation is quantified to assess the level of drug resistance contributed by clustering of patient tumor cells, which causes upregulation of Bcl-2 expression and other resistance mechanisms1.
The findings of such experimentation improve comprehension of the driving factors that contribute to drug resistance evolution on a personalized treatment basis. The aforementioned factors all contribute in varying degrees for unique patient cases, seven of which are presented in depth for this project. In summary: Environmental protection plays a critical initial role in drug resistance, which is followed by increase in tumor genetic heterogeneity as a result of mutations and drug-induced Darwinian selection. Eventually, environment-independent drug resistant subpopulations emerge, allowing the tumor to spread to unexplored areas of the bone marrow while maintaining inherited drug resistant phenotype2. It is our hope that these findings will help in shifting perspective regarding optimal management of MM by finding new therapeutic procedures that address all aspects of drug resistance to minimize chance of relapse and improve quality of life for patients.
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Brecht, Ellliott James. "Neuropeptide Modulation of the Large Conductance Potassium (BK) Channel in the Auditory System: Therapeutic Implications for Age-Related Hearing Loss." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6641.
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The auditory temporal processing deficits associated with age-dependent hearing decline have been increasingly attributed to issues beyond peripheral hearing loss. Age-related hearing loss (ARHL), also known as presbycusis, is linked with changes in the expression of both excitatory and inhibitory neurotransmitters in the central auditory system. There are also age-related changes in the expression and function of the ion channels which mediate action potential firing. The slow, Ca2+ activated, K+ channels of the BK-type are essential in controlling both neurotransmitter release and neural communication via alteration of action potential durations, firing frequency, and neural adaptation. There are many subsets of this type of ion channel located throughout the body, and though it is evident that these channels are involved in cellular activation within the peripheral auditory system, little is known about their contribution to auditory processing in the brain. There is a need for further understanding of the functional involvement and mechanisms of neurotransmitter loss and how this relates to the BK channel and auditory disorders such as presbycusis and tinnitus (the perception of a phantom sound). My research focused on investigating how the downregulation of neurotransmitter production and the reductions in BK channel expression affect ARHL. I also evaluated a custom BK-channel modulating peptide as a path towards a possible therapeutic intervention for age-related hearing loss. This custom peptide is especially useful because it reduces the potential for serious side effects, due to mechanisms which best mimic natural occurring peptide systems.
The initial investigation described in this dissertation measured auditory system changes in aged mice that occurred following a drug-induced increase in the availability of the inhibitory neurotransmitter GABA. This increase in GABA decreased minimum response thresholds in the auditory midbrain of aged mice, bringing them to levels seen in young adult animals. The other changes that occurred following increased GABA availability were increased acoustically driven neuronal firing rates, frequency-dependent decreases in spontaneous rates, and increases in the symmetry of the receptive fields. The return of clear and fine-tuned acoustically-evoked responses in aged mice was a major finding of this experiment.
The second phase of the dissertation built on this demonstration that modulation of the aged auditory system was possible by changing neurotransmitter levels. This second portion of the study focused on how a novel potent neuropeptide (LS3), which increases the probability of the BK channel remaining in the closed conformational state, might invoke alterations in auditory-evoked responses. First, the LS3 neuropeptide was used to modify addictive behavior in the C. Elegans; followed by evaluation of in vitro changes to a human cell line. This study then confirmed that LS3 is a potent BK channel modulator with a greater affinity than those known toxins classified as high-affinity toxins. In vivo testing demonstrated that LS3 could rapidly cross the blood-brain barrier (BBB) following systemic injections, where it altered auditory evoked activity in a manner similar to that of the direct application to the dura over the midbrain. This work demonstrates that the BK channel is highly responsible for the control of auditory-evoked neurological processes, and that a potent BK channel modulator may be useful for the treatment of certain neurological disorders.
The third study was designed to confirm that the BK channel plays an important role in sound-evoked activity generated in the auditory midbrain, by testing the effects of a general BK channel pore blocker, PAX. The results established that the BK channel is vital for sound processing in the midbrain of young adult mice, and is responsible for the maintenance of receptive field properties. I also evaluated the role it plays in temporal processing, which is an underlying mechanism for the processing of neurologically-relevant complex acoustic signals such as speech. Here, blocking of the channel increased (worsened) the threshold for the detection of a silent gap-in-noise and the neural recovery functions that occurred following the stimuli.
The fourth study significantly expanded the in vivo testing of the custom peptide channel blocker, LS3, and added a behavioral measure of changes to auditory perception in addition to the electrophysiology recordings. The auditory-evoked receptive fields from midbrain neurons were modulated in a dose-dependent manner following the application of LS3. The neural recordings took place in the inferior colliculus, where the dorsal region responds to low-frequency sounds and ventral areas to high frequencies. The LS3-induced suppression or enhancement of evoked responses was different for the various tonotopic regions of the auditory midbrain. The improvements shown in receptive fields and improvement in auditory perception indicates a plausible route for direct translational treatment of auditory disorders through small custom peptide therapeutics. These studies provide supportive information about how auditory evoked responses in the midbrain, including the coding of different sound features, are affected by the down-regulation of a key inhibitory neurotransmitter (GABA), and how GABA-dependent neural evoked responses are altered in older mice through the modulation of BK channel activity.
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Qin, Yiru. "Graphene Quantum Dots-Based Drug Delivery for Ovarian Cancer Therapy." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6358.
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Ovarian cancer, one of the most dreadful malignancies of the female reproductive system, poses a lethal threat to women worldwide. In this dissertation, the objective was to introduce a novel type of graphene quantum dots (GQDs) based nano-sized drug delivery systems (DDS) for ovarian cancer treatment. As a starting point, the facile synthesis method of the GQDs was established. Subsequently, the targeting ligand,folic acid (FA), was conjugated to GQDs. Next, a FDA approved chemotherapeutic drug, Doxorubicin (DOX), was loaded to form the GQDs-FA-DOX nano-conjugation as the DDS. Moreover, the uptake profile and anti-cancer effect of the GQDs-FA-DOX were validated in ovarian cancer cells. Finally, the immunotoxicity of GQDs and its mechanism were investigated and elucidated. Taken together, the findings described in this dissertation provide a novel and powerful strategy of targeted treatment for ovarian cancer.
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Conners, Christopher. "Bisphosphonate Functionalized Gold Nanoparticles for the Study and Treatment of Osteoporotic Disease." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6818.
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The use of nanoparticles for disease treatment is an increasingly popular area of research. The potential for multi-functionality allows nanoparticles to be used as transport and delivery vehicles for drugs and as diagnostic aides, among other applications, to address the unmet needs of many disease treatments. One such class of disease is osteoporosis including severe disorders, like Paget’s disease, Osteogenesis Imperfecta and Legg Calve Perthes disease. In this dissertation, we discuss a nanoparticle system consisting of gold nanoparticles surface functionalized with primary amine bisphosphonates, which is a classification of pharmaceuticals that is common in the treatment of osteoporosis. Functionalized nanoparticles allow for greater intracellular concentrations of pharmaceutical, while the properties of the gold nanoparticles provide the ability to track the pharmaceutical and enhance imaging.
We have synthesized and characterized bisphosphonate functionalized gold nanoparticles of controlled size of approximately 15 nm, which are suitable for cellular uptake, and functionalized the surface using self-assembly with pamidronate and alendronate. In one major finding of this study, inductively coupled plasma mass spectrometry was used to estimate approximate surface density of the bisphosphonates on the gold nanoparticles. This resulted in concentrations of approximately 0.65 molecules per nm2 (approximately 154 Å2/molecule) for pamidronate functionalized on gold, and approximately 2.6 molecules per nm2 (approximately 39 Å2/molecule) for alendronate functionalized on gold. This allows for more accurate estimates of pharmaceutical concentrations, during in vitro and in vivo studies.
Additionally, we investigated the effects of bisphosphonate functionalized gold nanoparticles on the viability and morphology of osteoclast and osteoblast cells in vitro. We found that attaching the bisphosphonates to the surface of the nanoparticles leads to increased apoptotic effects of the bisphosphonates on the osteoclast cells compared to free bisphosphonates. Further, we showed bisphosphonate functionalized gold nanoparticles may have an effect on nuclei morphology that may provide an additional means of modulating bone resorption rather than just through influencing viability. Further we showed that it may be possible to target concentrations that are safe for osteoblasts, which is critical in determining potential treatment concentrations. These viability results bring to light a number of potential considerations into the optimization of potential treatments, such as dosing concentrations.
Finally, detailed results are given on effects of bisphosphonate functionalized gold nanoparticles on important behavior and activity of osteoclast and osteoblast cells in vitro. We showed that while using concentrations below the toxicity threshold, some of the normal activity of the cells could be maintained. RANKL and ALP expression in osteoblasts were maintained when removing viability as a variable. Additionally, bone nodule formation was also maintained for osteoblasts and co-cultured in vitro systems. Finally, we showed that the introduction of bone in the in vitro studies adds a new degree of consideration as to the interaction of the bisphosphonates with the hydroxyapatite surface. This strong interaction with bone is an important consideration in further developing potential treatments for osteoporotic disease.
This dissertation provides insights into the use of bisphosphonate functionalized gold nanoparticles as a potential treatment and means of study for bone remodeling disorders.
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Mortensen, Trent W. "The Hypericum Perforatum Herb as an Antimycobacterial Agent and Its Implications as an Additional Tuberculosis Medication." DigitalCommons@USU, 2010. https://digitalcommons.usu.edu/etd/714.
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An immediate demand exists for new tuberculosis (TB) antibiotics due to the ever-increasing spread of drug-resistant strains. The drug-development process goes through four phases, the first (Phase 0) of which is to demonstrate and investigate drug effectiveness and toxicity. This research investigated the effectiveness of the Hypericum perforatum herb (commonly St. John's wort (SJW)) in its growth inhibition of mycobacteria and its viability effect on human lung cells. Organic-solvent SJW extracts were effective at inhibiting every nonpathogenic genetically sequenced Mycobacterium isolate currently available (six isolates) in preliminary studies. Quantitative studies of five Mycobacterium isolates showed an order of concentration sensitivity to the SJW methanol (MeOH) extract as (high to low) M. JLS, M. KMS, M. phlei (not sequenced), M. MCS, B. subtilis, M. smegmatis, and E. coli, with minimal bactericidal concentrations (MBCs) ranging from 0.33-2.66 mg extract/ml. The SJW compounds hyperforin (Hfn), hypericin (Hpn), and pseudohypericin (Phn) were quantified using a novel HPLC method that utilized common HPLC equipment. A crude MeOH extract solution of 133 mg extract/ml contained 2.26 mg Hfn/ml, 0.77 mg Hpn/ml, and 2.67 mg Phn/ml. Purified Hfn had a MBC of between 6-13 μg/ml for M. JLS in the absence of Tween 80. Tween 80 repressed Hfn (46 μg/ml) inhibition of M. JLS at ≥ 0.025% (v/v). Purified Hpn and Phn showed no inhibition of M. JLS at all assayed concentrations, which were ≤ 27 μg/ml and ≤ 25 μg/ml, respectively. Inhibitory results from the five quantitatively assayed Mycobacterium samples could be extrapolated to M. tuberculosis, as these isolates have as high as 72% genetic homology to the pathogen. The crude MeOH extract and Hfn were lethal to the human carcinomic alveolar epithelial lung cell line A549 at 1.3 mg extract/ml (crude extract) and ≥ 11 μg/ml (Hfn), with a Hfn LD50 of 3-6 μg/ml (5.6-11.2 μmol/L). Because Hfn is antiproliferative to a list of other carcinomic cell lines in the same concentration range, the A549 cell line may be added to that list. The addition of M. JLS cells (5x106 cells/cm2) to penicillin-streptomycin-containing A549 culture (which killed the bacteria) did not affect A549 viability.
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Arvaneh, Tia. "Morphometric Analysis of the Talus on the Cohort of Healthy and Arthritic Patient Population:." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6797.
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Prevalence of osteoarthritis (OA) is less common in the ankle compared to other joints; however, deformation brought on by degeneration causes pain, loss of function, and overall decreased quality of life. Current surgical interventions for end-stage ankle OA are not as reliable as surgical treatments for other joints. Ankle arthroplasty currently has high failure rates, and there are lack of substantial data from long-term outcome studies. By understanding the morphometric changes that occur during the different stages of OA, we are able to identify early signs of the disease with the intention to apply treatment earlier in order to preclude the need for end-stage surgical intervention. The goals of this study are to assess morphometric parameters of the talus as it relates to the progression of OA and to evaluate the effect of gender and anatomical side. A retrospective study was performed where data from sixty-eight CT scans were obtained from two study groups, one with OA and one without. The subjects were segmented, standardized, and normalized in order to study several 3D parameters of the talus, including height, radius of curvature, and volume. Results showed that talar morphometry is influenced by gender and that geometric changes are a function of OA progression. The lateral radii of subjects with OA was significantly larger than those of normal ankles (p<0.0001), and there is evidence of inherent changes between KL grades (p=0.0003). Identifying morphometric changes of the talus at each stage of OA can inherently contribute to better understanding the degenerative process. Assessing specific characteristics at earlier stages of the diseases may help clinicians to diagnose more accurately and to better provide treatment.
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Holton, Angela. "Microfluidic Biopsy Trapping Device for the Real-time Monitoring of the Tumor Microenvironment." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/7036.
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The tumor microenvironment is composed of cellular and stromal components such as tumor cells, mesenchymal cells, immune cells, cancer associated fibroblasts and the supporting extracellular matrix. The tumor microenvironment provides crucial support for growth and progression of tumor cells and affects tumor response to therapeutic interventions. To better understand tumor biology and to develop effective cancer therapeutic agents it is important to develop preclinical platforms that can faithfully recapitulate the tumor microenvironment and the complex interaction between the tumor and its surrounding stromal elements. Drug studies performed in vitro with conventional two-dimensional cancer cell line models do not optimally represent clinical drug response as they lack true tumor heterogeneity and are often performed in static culture conditions lacking stromal tumor components that significantly influence the metabolic activity and proliferation of cells. Recent microfluidic approaches aim to overcome such obstacles with the use of cell lines derived in artificial three-dimensional supportive gels or micro-chambers. However, absence of a true tumor microenvironment and full interstitial flow, leads to less than optimal evaluation of tumor response to drug treatment. Here we report a continuous perfusion microfluidic device coupled with microscopy and image analysis for the assessment of drug effects on intact fresh tumor tissue. We have demonstrated that fine needle aspirate biopsies obtained from patient-derived xenograft models of adenocarcinoma of the lung can successfully be analyzed for their response to ex vivo drug treatment within this biopsy trapping microfluidic device, wherein a protein kinase C inhibitor, staurosporine, was used to assess tumor cell death as a proof of principle. Lastly, we tested the model for its ability to demonstrate similar results found in clinic when using a Wee1 inhibitor on osteosarcoma and an epidermal growth factor receptor inhibitor, Erlotinib, and inhibitors of programmed death 1 receptor and programmed death ligand 1 on lung adenocarcinoma fine needle aspirate biopsies. This approach has the potential to study tumor tissue within its intact microenvironment to better understand tumor response to drug treatments and eventually to choose the most effective drug and drug combination for individual patients in a cost effective and timely manner.
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Strauss, Graham L. "Hybrid Fusion Protein for Inhibition of Multiple Proteases for Chronic Wound Healing." Scholar Commons, 2019. https://scholarcommons.usf.edu/etd/7957.
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Many diseases display a multitude of relevant factors that contribute to the persistence of the disease and difficulty treating it. The multifactorial characteristics of some diseases lead to the requirement of combination of treatments in order to restore health. The latter may necessitate the mixing of treatments, medications, and therapeutics to first halt the disease, then assist the human body in returning itself to a state of normality. For example, chronic wounds exhibit this multifactor characteristic in which there exist many factors that lead to the body’s inability to properly heal in a timely manner. This presents a further threat to the body, such as exposure to infection and long-term pain. In this example, it is important to look at the ultimate cause of a chronic wound, which may be due to presence of other diseases impairing the body’s ability to properly heal. This may include diabetes, initial antibiotic-resistant infection, autoimmune disorders, and poor vasculature. Furthermore, the mentioned causes for chronic wounds may have associations with one another in a single case of a chronic wound. Treating each interrelated cause with drug combinations may run the risk of adverse side effects or further complications due to mixing drugs in a systemic method.
The goal of this study is to develop a point-specific, protein-based therapy that incorporates a single-protein molecule with multifunctional characteristics based on what we know about chronic wounds and infections, as a proof of concept of multifunctional proteins. Multifunctionality of a single therapeutic molecule is desirable because it may eliminate the unknowns of how differing individual chemical or protein therapies may interact when simply mixed. In addition, examples of peptides, such as antimicrobial peptides, are known to have synergy, and creating a single protein platform that consists of two synergistic peptides could be of value in the making of a protein with greater activity by guaranteeing that the synergistic peptides are local to one another. Furthermore, broad spectrum activity can be obtained by combining two differing peptides.
This proof of concept was accomplished by targeting two proteinases that are upregulated in chronic wounds: Matrix Metalloproteinase-2 (MMP-2) and Neutrophil Elastase. Recombinant DNA techniques were used to create a fusion protein that incorporates an inhibitor of MMP-2, which is a β-Amyloid Precursor Protein-derived Inhibitory Peptide (APP-IP), and PMP-D2, an inhibitor of Neutrophil Elastase. PMP-D2 was joined to the N-terminus of an Elastin-like peptide, while the APP-IP was joined to the C-terminus of the same Elastin-like peptide. Elastin-like peptides (ELPs) are commonly used as a backbone for recombinant protein production as their distinct thermoresponsive characteristics provide adequate protein purification using an inverse transition cycling [3]. In addition, ELPs can serve as point-specific drug delivery platforms with a transition temperature (Tt) near that of normal body temperature causing low diffusivity [3]. Therefore, when ELPs are applied to a site at their Tt, they will aggregate, which provides diffusional limitations of the protein in the application site, and may decrease the reapplication rate needed for a therapeutic, as well as eliminate adverse side effects by retaining the protein to the specific application site.
From this dual fusion, the final resulting protein is PMP-D2٠ELP٠APP-IP. This protein was tested for its inhibitory activity of both MMP-2 and Neutrophil Elastase. It was hypothesized that the fusion protein, PMP-D2٠ELP٠APP-IP, would inhibit MMP-2 just as effectively as APP-IP·ELP unaccompanied by PMP-D2, as well as effectively inhibit Neutrophil Elastase to the same degree as PMP-D2·ELP unaccompanied by APP-IP.
Furthermore, an additional dually fused ELP fusion protein was currently made with two synergistic antimicrobial peptides fused to each end of the ELP. The two antimicrobial peptides used were human-derived LL37 and insect-derived Cecropin A. This novel fusion peptide contains synergistic increase in antibacterial activity in which preliminary data suggests.
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Shazeeb, Mohammed S. "MRI Contrast Agent Studies of Compartmental Differentiation, Dose-Dependence, and Tumor Characterization in the Brain: A Dissertation." eScholarship@UMMS, 2011. http://escholarship.umassmed.edu/gsbs_diss/504.
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Magnetic resonance imaging (MRI) has increasingly become the preferred imaging modality in modern day research to study disease. MRI presents an imaging technique that is practically non-invasive and without any ionizing radiation. This dissertation presents the use of contrast agents in MRI studies to differentiate compartments, to study dose dependence of relaxation times, and to characterize tumors using signal amplifying enzymes in the brain.
Differentiating compartments in the brain can be useful in diffusion studies to detect stroke at an early stage. Diffusion-weighted NMR techniques have established that the apparent diffusion coefficient (ADC) of cerebral tissue water decreases during ischemia. However, it is unclear whether the ADC change occurs due to changes in the intracellular (IC) space, extracellular (EC) space, or both. To better understand the mechanism of water ADC changes in response to ischemic injury, making IC and EC compartment specific measurements of water diffusion is essential. The first study was done where manganese (Mn2+) was used as an IC contrast agent. Mn2+ uptake by cells causes shortening of the T1 relaxation time of IC water. The relative difference in T1 relaxation times between the IC and EC compartments can be used to discriminate between the MR signals arising from water in the respective compartments.
Mn2+ is also widely used in manganese-enhanced MRI (MEMRI) studies to visualize functional neural tracts and anatomy in the brain in vivo. In animal studies, the goal is to use a dose of Mn2+ that will maximize the contrast while minimizing its toxic effects. The goal of dose study was to investigate the MRI dose response of Mn2+ in rat brain following SC administration of Mn2+. The dose dependence and temporal dynamics of Mn2+ after SC injection can prove useful for longitudinal in vivo studies that require brain enhancement to persist for a long period of time to visualize neuroarchitecture like in neurodegenerative disease studies.
Contrast agents, in addition to their use in compartmental differentiation and dose studies, can be used for imaging tumors. The last study in this dissertation focuses on imaging EGF receptors in brain tumors. We tested a novel pretargeting imaging approach that includes the administration of humanized monoclonal antibody (anti-EGFR mAb, EMD72000) linked to enzymes with complementing activities that use a low-molecular weight paramagnetic molecule (diTyr-GdDTPA) as a reducing substrate administered following the mAb conjugates. We analyzed the differential MR tumor signal decay in vivo using orthotopic models of human glioma. The patterns of MR signal change following substrate administration revealed differences in elimination patterns that allowed distinguishing between non-specific and specific modes of MR signal decay.
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Chada, Kinnera. "COMPUTATIONAL ANALYSES OF THE UPTAKE AND DISTRIBUTION OF CARBON MONOXIDE (CO) IN HUMAN SUBJECTS." UKnowledge, 2011. http://uknowledge.uky.edu/gradschool_diss/224.
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Carbon monoxide (CO) is an odorless, colorless, tasteless gas that binds to hemoglobin with high affinity. This property underlies the use of low doses of CO to determine hemoglobin mass (MHb) in the fields of clinical and sports medicine. However, hemoglobin bound to CO is unable to transport oxygen and exposure to high CO concentrations is a significant environmental and occupational health concern. These contrasting aspects of CO—clinically useful in low doses but potentially lethal in higher doses—mandates a need for a quantitative understanding of the temporal profiles of the uptake and distribution of CO in the human body. In this dissertation I have (i) used a mathematical model to analyze CO-rebreathing techniques used to estimate total hemoglobin mass and proposed a CO-rebreathing procedure to estimate hemoglobin mass with low errors, (ii) enhanced and validated a multicompartment model to estimate O2, CO and CO2 tensions, bicarbonate levels, pH levels, blood carboxyhemoglobin (HbCO) levels, and carboxymyoglobin (MbCO) levels in all the vascular (arterial, mixed venous and vascular subcompartments of the tissues) and tissue (brain, heart and skeletal muscle) compartments of the model in normoxia, hypoxia, CO hypoxia, hyperoxia, isocapnic hyperoxia and hyperbaric oxygen, and (iii) used this developed mathematical model to propose a treatment to improve O2 delivery and CO removal by comparing O2 and CO levels during different treatment protocols administered for otherwise-healthy CO-poisoned subjects.
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Piao, Zhenhui. "INTERACTIVE CLINICAL EVENT PATTERN MINING AND VISUALIZATION USING INSURANCE CLAIMS DATA." UKnowledge, 2018. https://uknowledge.uky.edu/cs_etds/70.
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With exponential growth on a daily basis, there is potentially valuable information hidden in complex electronic medical records (EMR) systems. In this thesis, several efficient data mining algorithms were explored to discover hidden knowledge in insurance claims data. The first aim was to cluster three levels of information overload(IO) groups among chronic rheumatic disease (CRD) patient groups based on their clinical events extracted from insurance claims data. The second aim was to discover hidden patterns using three renowned pattern mining algorithms: Apriori, frequent pattern growth(FP-Growth), and sequential pattern discovery using equivalence classes(SPADE). The SPADE algorithm was found to be the most efficient method for the dataset used. Finally, a prototype system named myDietPHIL was developed to manage clinical events for CRD patients’ and visualize the relationships of frequent clinical events. The system has been tested and visualization of relationships could facilitate patient education.
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Moore, Ryan James. "An Investigation of Humeral Stress Fractures in Racing Thoroughbreds using a 3D Finite Element Model in Conjunction with a Bone Remodeling Algorithm." DigitalCommons@CalPoly, 2010. https://digitalcommons.calpoly.edu/theses/239.
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The humerus of a racing horse Thoroughbred is highly susceptible to stress fractures at a characteristic location as a result of cyclic loading. The propensity of a Thoroughbred to exhibit humeral fracture has made equines useful models in the epidemiology of stress fractures. In this study, a racing Thoroughbred humerus was simulated during training using a 3D finite element model in conjunction with a bone remodeling algorithm. Nine muscle forces and two contact forces were applied to the 3-dimensional finite element model, which contains four separate load cases representing fore-stance, mid-stance, aft-stance, and standing. Four different training programs were incorporated into the model, which represent Baseline Layup and Long Layup training programs along with two newly implemented programs for racing, which have an absence of a layup period, last a period of 24 weeks, and a race once every four weeks. Muscle and contact forces were rescaled for all load cases to simulate dirt, turf, and synthetic track surfaces. Bone porosity, damage, and BMU activation frequency were examined at the stress fracture site and compared with a control location called the caudal diaphysis. It was found that race programs exhibited similar remodeling patterns between each other. Damage at the stress fracture site and caudal diaphysis was reduced during all training programs for the turf and synthetic track surfaces with respect to the dirt track surface. Key findings also included changes in bone remodeling at the stress fracture site and caudal diaphysis as a result of turf and synthetic track surfaces. This model can serve as a framework for further studies in human or equine athletes who are susceptible to stress fractures.
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Chabo, Ablahad. "Treatment of a mantle cell lymphoma cell line with cannabinoids and cytostatics : - effects on DNA synthesis and ceramide metabolism." Thesis, Mälardalen University, Mälardalen University, School of Sustainable Development of Society and Technology, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-7584.
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<p>Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with bad prognosis, which predominates in males with advanced age. However, studies of the endocannabinoid system and how it affects tumour behaviour provides the basis for designing innovative therapeutic strategies that could open new opportunities for treatment of patient with MCL. It has earlier been shown that the cannabinoid receptor ligand (R)-(+)-methanandamide (R-MA) induce cell death in MCL by accumulation of ceramide. Ceramide has a pro-apoptotic effect on the cell but could be metabolized by the enzymes glucosylceramide synthase (GCS) and sphingosine kinase 1 (SphK1) to molecules with pro-proliferative effect. Therefore, treatments with R-MA on Jeko-1 MCL cell line were performed in this study to determine interference in the proliferative behaviour as well as in the gene expression of the enzymes GCS and SphK1. In addition, treatments with chemotherapeutic substances, such as doxorubicin or cytarabine (Ara-C), and combinations of R-MA and chemotherapeutic substance, were performed for the same reason. Results showed that the proliferation behaviour of Jeko cells remained unaffected when treated with R-MA, in contrast to the decreased proliferative effects shown when treated with cytostatics or combinations of R-MA and cytostatics. Furthermore, a tendency for up-regulation of GCS and SphK1 expression was recognized when cells were treated with cytostatics or combination of cytostatics and R-MA, in contrast to cells treated with R-MA alone. Although, R-MA alone had a tendency for a small down-regulation of GCS expression, it contributed to a potential elevation of GCS expression when combined with Ara-C or doxorubicin. It is believed that the effect from upregulated levels of the metabolizing enzymes GCS and SphK1 is balanced by, earlier observed, up-regulations of the ceramide synthesis enzymes.</p>
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Olivero, Lara Humberto Jose. "Quantifying the Ergonomic Impact on Healthcare Workers Using a Needle-free Injector Device." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4739.
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Background: Jet injectors are advantageous over needle injectors by eliminating sharps hazards. The Government Accountability Office estimates 29% preventable sharp injuries with an estimated direct cost of more than $500 million out of the CDC's reported incidence of 385,000 needle stick injuries per year among US hospital healthcare workers. Yet the forces required to set and trigger devices using spring mechanisms for medication delivery have not been explored. This laboratory experiment measured forces exerted by healthcare workers (HCWs) using a particular jet injector approved by FDA in 2011.
Objectives: In order to quantify the ergonomic impact on HCWs using a needle-free injector, the first objective was to evaluate the dynamic forces required to activate the trigger injector button and the reset station for the injector, with their respective means, for each of the parameters studied. The second objective was to compare these forces to those required to use four previously analyzed retractable intramuscular syringes with needles. Finally, the third objective was to assess potential psychophysics ergonomic impact on HCWs with use of these devices to formulate future design changes and recommendations for manufacturers and HCWs, respectively.
Methods: This laboratory experiment was conducted through a multi-disciplinary team approach. It included a total of 136 trials (10 validation trials, 116 experimental trials and 10 padded trials for soft tissue simulation), which were conducted using the PharmaJetTM Injector. A force gauge and a load cell were integrated into the triggering setup and reset station, correspondingly, enabling force measurements to be obtained directly from the human-machine interfaces. These force data allowed for observations of force profiles in time by the healthcare worker as researcher while preparing for and administering injections. Data collection used three software applications for force conversions and data manipulation. Data were analyzed using descriptive statistics and analytical results by using ANOVA for the trigger injector & reset station with multiple comparison tests for parametric and non-parametric distributions, respectively.
Results: The descriptive results indicated an average force for triggering the injector in the 116 trials was 15.92 lbs. (70.8 N) with a range of 9.77-26.46 lbs. (43.46-117.69 N). The measured forces for the reset station ranged from 5.35-82.78 lbs. (5.35-368.22 N) with an average of 25.32 lbs. (112.62 N) (SD 12.36). Spurious findings presented with tensile forces to fill the syringes resulting in hand strain in the first metacarpal joint after repetitive pinprick motion. The analytical results showed an ANOVA for trigger injector with a parametric-normal distribution with an F (2,133) Ratio 10.0472, p- value (F) 0.0001<0.05, showing statistical significance and with a Tukey's comparison test showing a significant difference in between the means of the padded trials vs. the validation & experimental trial groups. The ANOVA for the reset station showed a Kruskal Wallis H-statistic of 0.2568, p-value (H) 0.8795>0.05 presenting NO statistical significance with a Dunn's comparison test confirming NO difference in between the medians or mean ranks of all three groups.
Conclusions: Triggering the injector and resetting the station required considerable effort in comparison to activating 4 retractable intramuscular syringes with needles from our previous studies, the range of mean forces were 3.63-17 lbs (16.19-77.53 N) for those syringes with the trigger injector maximum voluntary force of 71 N being above the recommend 56.6 N.The jet injector required more force per effort than 2 (4.4x) syringes & similar to other 2 syringes (0.9x) previously tested when considering the compression forces related with the trigger injector. Additional vector forces (displacement & gripping of reset station) could increase the cumulative effort affecting different musculoskeletal components when the whole components of the procedure are taken into account.
Suggestions for the manufacturer regarding design changes to facilitate HCWs' use of this device are warranted, since some of the summation forces during the 12 mini-steps could be avoided to achieve a higher efficiency. This information may be useful for health care facilities when choosing devices to protect their workers from ergonomic injuries.
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Mann, Karen Michelle. "Evaluation of Transfer Technologies to Preserve Shoulder Function in SCI." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4143.
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This study investigated a series of independent unassisted and device-assisted transfers from a wheelchair to vehicle mock-up and vice versa while simultaneously capturing kinematic, kinetic and electromyographic (EMG) data of impaired volunteers. The study provides a venue for observation and evaluation of upper extremity (UE) joint stresses, muscular force and functional demands associated with transfers in persons with spinal cord injury (SCI) to ultimately prevent UE injury, minimize excessive stress, preserve functionality and limit pain. If people with SCI lose function of their UEs, due to pain and/or degeneration, they must then rely on others for everyday tasks.
Five paraplegic males from the Tampa Bay area were recruited to take part in the study. Participants were asked to perform a series of transfers using 4 commercially available devices or mock-ups of that device as well as an unassisted transfer, which permitted the use of no assistive device. Three data types were captured: kinematic data using motion capture, kinetic data using force transducers which were integrated into the vehicle mock-up and EMG of 5 bilateral muscle groups. Data collection took approximately 4 hours per subject.
Forces occurring during the unassisted transfers were found to be the highest. This is also supported by the EMG data. Performing level transfers lessened stresses at the UE versus non-level transfers. The highest moments of the UEs were found at the shoulders with high variability between subjects. It was also found that body mass index (BMI) had an affect on a subjects ability to perform transfers.
Ultimately this study found that using an assistive device is better than not using an assistive device. This is proven by EMG and force data, which were both found to be less with the use of an assistive device as opposed to transferring independently with no assistance. Performing level transfers, maintaining ones body mass and staying active are all factors that will limit stresses at the UEs during wheelchair transfers to and from a vehicle.
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Czarnecki, Jarema S. "Engineered carbon-based scaffolds for hard and soft tissue repair, reconstruction or regeneration." University of Dayton / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1386953861.
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Brown, Dustin Paul. "TARGET-DIRECTED BIOSYNTHETIC EVOLUTION: REDIRECTING PLANT EVOLUTION TO GENOMICALLY OPTIMIZE A PLANT’S PHARMACOLOGICAL PROFILE." UKnowledge, 2015. http://uknowledge.uky.edu/neurobio_etds/13.
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The dissertation describes a novel method for plant drug discovery based on mutation and selection of plant cells. Despite the industry focus on chemical synthesis, plants remain a source of potent and complex bioactive metabolites. Many of these have evolved as defensive compounds targeted on key proteins in the CNS of herbivorous insects, for example the insect dopamine transporter (DAT). Because of homology with the human DAT protein some of these metabolites have high abuse potential, but others may be valuable in treating drug dependence. This dissertation redirects the evolution of a native Lobelia species toward metabolites with greater activity at this therapeutic target, i.e. the human DAT. This was achieved by expressing the human DAT protein in transgenic plant cells and selecting gain-of-function mutants for survival on medium containing a neurotoxin that is accumulated by the human DAT. This created a sub-population of mutants with increased DAT inhibitory activity. Some of the active metabolites in these mutants are novel (i.e. not detectable in wild-type cells). Others are cytoprotective, and also protect DAergic neurons against the neurotoxin. This provides proof-of-concept for a novel plant drug discovery platform, which is applicable to many different therapeutic target proteins and plant species.
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Frischkorn, Kate E. "Preparation of Supramolecular Amphiphilic Cyclodextrin Bilayer Vesicles for Pharmaceutical Applications." DigitalCommons@CalPoly, 2018. https://digitalcommons.calpoly.edu/theses/1894.
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Recent pharmaceutical developments have investigated using supramolecular nanoparticles in order to increase the bioavailability and solubility of drugs delivered in various methods. Modification of the carbohydrate cyclodextrin increases the ability to encapsulate hydrophobic pharmaceutical molecules by forming a carrier with a hydrophobic core and hydrophilic exterior. Guest molecules are commonly added to these inclusion complexes in order to add stability and further increase targeting abilities of the carriers. One such guest molecule is adamantine combined with a poly(ethylene glycol) chain. Vesicles are formed by hydrating a thin film of amphiphilic cyclodextrin and guest molecules in buffer solution that mimics physiological conditions. The solution is subject to freeze-thaw cycles and extrusion, and the complexes are separated out via size exclusion chromatography. Dynamic Light Scattering instrumentation is used to observe the particle size distribution. Cargo release can be observed in fluorescent dye-loaded vesicles by addition of a membrane-cleaving agent under a fluorimeter instrument. Future work involving this drug delivery technology includes synthesizing a chemically sensitive guest that will cleave in the presence of an intra-cellular anti-oxidant, and finally observing the uptake of these vesicles into live cells and testing the delivery of cargo in vitro under physiological conditions.
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Napan, Kandy L. "Investigation of the Tailoring Steps in Pradimicin Biosynthesis." DigitalCommons@USU, 2016. https://digitalcommons.usu.edu/etd/4730.
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The actinobacteria Actinomadura hibisca synthesizes the natural products pradimicin A-C through a type II polyketide biosynthetic pathway. Eight tailoring enzymes in pradimicin biosynthesis have been investigated in this work, including PdmJ, PdmW, PdmN, PdmT, PdmO, PdmS, PdmQ and PdmF. PdmJ and PdmW were characterized as cytochrome P450 hydroxylases that catalyze the incorporation of two hydroxyl groups at C-5 and C-6, respectively. These enzymes worked synergistically and their co-expression significantly improved the efficiency of the hydroxylation steps. PdmN is an amino acid ligase that accepts a variety of substrates and ligates a D-alanine moiety to C-16 to form the corresponding derivatives. PdmS and PdmQ were functionally identified as Oglycosyltransferases. Disruption of pdmS in the genome of A. hibisca generated a biosynthetic precursor without sugar moieties, which validated that PdmS is the first glycosyltransferase that attaches the first sugar to the 5-OH of pradimicins. In contrast, disruption of pdmQ led to the synthesis of pradimicin B, confirming that PdmQ was responsible for attaching the D-xylose moiety to the 3'-OH of the first sugar portion in pradimicins. Naturally, the first sugar moiety 4',6'-dideoxy-4'-amino-D-galactose of pradimicin A and B is methylated at 2'-NH. When the expression of PdmO was compromised, the mutant strain produced mainly pradimicin C, which contains the 4',6'- dideoxy-4'-amino-D-galactose in its structure. This suggested that PdmO was responsible for the N-methylation of the amino sugar. PdmF was identified as the C-11 Omethyltransferase. Moreover, PdmT was confirmed to be an O-methyltransferase through gene disruption and in vitro biochemical reactions. PdmT methylates the 7-OH to form a methoxy group that in a later step is removed to generate the pradimicin aglycon. In summary, this research has identified eight important pradimicin biosynthetic enzymes that are involved in various tailoring steps in pradimicin biosynthesis. Several new pradimicin analogues has been generated by manipulating these enzymes. Their enzymatic properties and collaborative actions were investigated. These results not only provide new insights into type II polyketide biosynthetic pathways, but also enable rational engineering of the pradimicin biosynthetic pathway to create new analogues for drug development.
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Altgärde, Noomi. "Local release of lithium from sol-gel coated orthopaedic screws : an in vitro and in vivo study." Thesis, Linköpings universitet, Institutionen för fysik, kemi och biologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-19440.
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In orthopaedic practice, fractures are usually stabilised with metal screws or rods. This is done in order to keep the fracture parts in place during the rather slow healing process. The healing time can potentially be reduced by local- or systemic treatment with different bone promoting drugs. In later years, lithium, otherwise used to treat bipolar disease, has shown promise to be such a drug. The aim of this master thesis was to find a way to coat metal bone screws with lithium and to characterise the coating. The coating was to be designed in such a way that it could release lithium to the surrounding bone tissue. Lithium chloride was incorporated into a titanate sol-gel and attached to silicon wafers and stainless steel screws by dip coating. Wafers were used for initial in vitro studies of how lithium changed coating characteristics. This was studied using ellipsometry, AFM and SEM. Lithium is most probably physisorbed and not incorporated into the network building up the sol-gel. Coating structure is changed as more lithium is incorporated. For large amounts of lithium, the nanoparticles normally formed when curing the sol-gel are inhibited. One effect of this is reduced bioactivity, seen as a reduced ability for calcium phosphate crystals to nucleate on the coating when immersed in simulated body fluid. Lithium release was investigated using AAS. Lithium is released from the coating, showing a burst effect. By changing the number of coating layers used, the release profile can be partly altered. The coating was also applied to screws, showing good attachment, and the lithium release profile was similar to the one seen from wafers. Finally, a screw model was used in rats to assess the effect of local lithium treatment from screws and systemic lithium treatment on fracture healing. In the model, a screw was inserted in tibia, mimicking a fracture. When the bone around the screw was healed, a pullout test was performed, giving information about the strength of the bone surrounding the screw. No significant difference could be found for either local- or systemic lithium treatment compared to control. However, when evaluating the strength of intact bone in a similar way, a positive effect of systemic lithium treatment could be seen. Therefore, it is still likely that lithium has a positive effect on bone and further studies are needed to fully evaluate its role in fracture healing.<br>Vid behandling av benbrott stabiliseras vanligtvis frakturen internt med metallskruvar och metallstavar. Detta görs för att hålla brottbitarna på plats under den relativt långsamma läkprocessen. Det är möjligt att minska tiden för frakturläkning genom att lokalt eller systemiskt behandla med olika läkemedel som främjar bentillväxt. På senare år har det presenterats bevis för att litium, som annars används som psykofarmaka, fungerar som ett sådant läkemedel. Syftet med detta examensarbete var att hitta en metod för att fästa litium på benimplantat. Litium skulle fästas på ett sådant sätt att frisläppning till omgivande vävnad blev möjlig. Litiumklorid inkorporerades i en titanat-solgel och lager av detta lades på kiselytor och rostfria skruvar genom s.k. ”dip-coating”. Kiselytorna användes för initiala in vitro-studier av hur litium ändrade beläggningens egenskaper. Litium sitter antagligen fast på ytan av det tredimensionella nätverk som utgör solgelen, istället för att sitta inbundet i nätverket. Lagerstrukturen ändras ju mer litium som inkorporeras och vid stora mängder skapas inte de nanopartiklar som vanligtvis finns i en solgel-baserad beläggning. En följd av detta är reducerad bioaktivitet för beläggningen, dvs. en minskad förmåga för kalciumfosfatkristaller att bildas på ytan. Litium frisläpps från beläggningen, dock sker denna frisläppning snabbt. Genom att belägga ytan med flera lager av solgel kan frisläppningskinetiken delvis ändras. Solgelen kunde också med god vidhäftning appliceras på skruvar och frisläppningskinetiken från en skruv är liknande den från en kiselyta. Slutligen användes en skruvmodell i råtta för att undersöka vilken effekt lokal respektive systemisk litiumbehandling har på frakturläkning. I modellen efterliknas ett benbrott genom att en skruv sätts in i skenbenet. När benvävnaden runt skruven har läkt görs ett utdragstest på skruven vilket ger information om benets styrka. Ingen signifikant skillnad i skruvens utdragskraft kunde ses mellan de båda försöksgrupperna och kontrollgruppen. Däremot hade gruppen som fick systemisk litiumbehandling fått starkare ben totalt, vilket indikerar att litium har effekt på intakt ben. På grund av dessa resultat finns det fortfarande skäl att tro att litium har en positiv påverkan på ben, varför dess effekt på frakturläkning bör undersökas ytterligare.
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Johansson, Fredrik. "Microscale measurement of kinetic binding properties of monoclonal antibodies in solution using Gyrolab." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-155575.
Full textAbstract:
The number of monoclonal antibodies approved for therapeutic use has increased rapidlyover the last decade. As a consequence, precise and robust kinetic characterization techniquesare crucial in order to select the best suitable candidates. A kinetic characterization methodwas developed in Gyrolab with automated sample transfers. The characterization wasperformed in solution in a mixing CD, containing an integrated nanoliter mixing chamberwith affinity binding columns. Association rate constants were determined for four anti-TSHantibodies with values ranging from 3x105 M-1s-1 to 10x105 M-1s-1. The antibodies wereranked according to kass. Reproducibility
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Juliani, Didier. "Etude de la fragmentation lors de la réaction 12C+12C à 95 MeV/n et 400MeV/n dans le cadre de la hadronthérapie." Phd thesis, Université de Strasbourg, 2013. http://tel.archives-ouvertes.fr/tel-01062704.
Full textAbstract:
La hadronthérapie est une méthode de radiothérapie utilisant des ions (ici le carbone) comme faisceau plutôt que des rayons X plus conventionnels pour le traitement des cancers. Étant donné le parcours spécifique des ions dans la matière, ils permettent de traiter des tumeurs profondes dans des zones délicates telles que le cerveau par exemple. Ceci est complémentaire à tout ce qui existe depuis des dizaines d'années (intervention chirurgicale, rayons X, chimiothérapie). Deux futurs centres de traitement et de recherche (ARCHADE à Caen et ETOILE à Lyon) seront opérationnels en France à partir de 2018 en ce qui concerne ARCHADE afin de profiter des avancées récentes et de poursuivre les recherches sur cette méthode. La perte d'énergie des ions carbone dans la matière suit la loi de Bethe-Bloch, le maximum de dépôt d'énergie se situant dans une zone restreinte appelée " pic de Bragg ". En modulant la position et l'énergie du faisceau, il est possible d'irradier l'ensemble du volume de la tumeur. Cependant, les réactions nucléaires de l'ion carbone dans les tissus entrainent la production de fragments plus légers (H, He, Li etc.) qui déposent leur énergie au-delà du pic de Bragg. Les modèles implémentés dans les codes de simulation couramment utilisés en hadronthérapie (FLUKA, GEANT4 etc.) sont incapables de reproduire en même temps les distributions angulaires des fragments générés ainsi que les distributions en énergie. Le fait de ne pas reproduire fidèlement ce phénomène de fragmentation nuit à la précision des systèmes de planification de traitement utilisés cliniquement. En effet, une mauvaise estimation du processus de fragmentation entraine un biais dans le calcul de la dose déposée dans les cellules saines en arrière du pic de Bragg. Ainsi, afin de mieux contraindre les modèles, deux expériences de mesure de sections efficaces de fragmentation du carbone ont été menées. La première en mai 2011 avec un faisceau à 95MeV/n au GANIL à CAEN avec les collaborateurs du LPC Caen et la seconde en août 2011 avec un faisceau à 400 MeV/n au GSI à Darmstadt, avec la collaboration FIRST. L'expérience E600 étudie la fragmentation des ions du faisceau de carbone à 95 MeV/n dans différentes cibles minces (Au, C, , Ti etc.) correspondant aux différents constituants élémentaires du corps humain. Les différents fragments sont détectés à l'aide de cinq télescopes. Chacun d'eux est constitué de 3 étages (2 détecteurs silicium et un scintillateur CsI) afin de faire des mesures de perte d'énergie et d'énergie totale permettant une identification par la méthode du ΔE-E. Ces télescopes étaient disposés sur des raquettes pilotées à distance afin de pouvoir modifier leur position angulaire par rapport à la position de la cible. Ainsi, les taux de production des différents fragments permettent de remonter aux sections efficaces de fragmentation doublement différentielles (en énergie et en angle). [...]
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Jalal, Ahmed Hasnain. "Multivariate Analysis for the Quantification of Transdermal Volatile Organic Compounds in Humans by Proton Exchange Membrane Fuel Cell System." FIU Digital Commons, 2018. https://digitalcommons.fiu.edu/etd/3886.
Full textAbstract:
In this research, a proton exchange membrane fuel cell (PEMFC) sensor was investigated for specific detection of volatile organic compounds (VOCs) for point-of-care (POC) diagnosis of the physiological conditions of humans. A PEMFC is an electrochemical transducer that converts chemical energy into electrical energy. A Redox reaction takes place at its electrodes whereas the volatile biomolecules (e.g. ethanol) are oxidized at the anode and ambient oxygen is reduced at the cathode. The compounds which were the focus of this investigation were ethanol (C2H5OH) and isoflurane (C3H2ClF5O), but theoretically, the sensor is not limited to only those VOCs given proper calibration.
Detection in biosensing, which needs to be carried out in a controlled system, becomes complex in a multivariate environment. Major limitations of all types of biosensors would include poor selectivity, drifting, overlapping, and degradation of signals. Specific detection of VOCs in multi-dimensional environments is also a challenge in fuel cell sensing. Humidity, temperature, and the presence of other analytes interfere with the functionality of the fuel cell and provide false readings. Hence, accurate and precise quantification of VOC(s) and calibration are the major challenges when using PEMFC biosensor.
To resolve this problem, a statistical model was derived for the calibration of PEMFC employing multivariate analysis, such as the “Principal Component Regression (PCR)” method for the sensing of VOC(s). PCR can correlate larger data sets and provides an accurate fitting between a known and an unknown data set. PCR improves calibration for multivariate conditions as compared to the overlapping signals obtained when using linear (univariate) regression models.
Results show that this biosensor investigated has a 75% accuracy improvement over the commercial alcohol breathalyzer used in this study when detecting ethanol. When detecting isoflurane, this sensor has an average deviation in the steady-state response of ~14.29% from the gold-standard infrared spectroscopy system used in hospital operating theaters.
The significance of this research lies in its versatility in dealing with the existing challenge of the accuracy and precision of the calibration of the PEMFC sensor. Also, this research may improve the diagnosis of several diseases through the detection of concerned biomarkers.
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Nordesjö, Olle, Victor Pontén, Stephanie Herman, Joel Ås, Sabri Jamal, and Alona Nyberg. "Ett sannolikhetsbaserat kvalitetsmått förbättrar klassificeringen av oförväntade sekvenser i in situ sekvensering." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-225999.
Full textAbstract:
In situ sekvensering är en metod som kan användas för att lokalisera differentiellt uttryck av mRNA direkt i vävnadssnitt, vilket kan ge viktiga ledtrådar om många sjukdomstillstånd. Idag förloras många av sekvenserna från in situ sekvensering på grund av det kvalitetsmått man använder för att säkerställa att sekvenser är korrekta. Det finns troligtvis möjlighet att förbättra prestandan av den nuvarande base calling-metoden eftersom att metoden är i ett tidigt utvecklingsskede. Vi har genomfört explorativ dataanalys för att undersöka förekomst av systematiska fel och korrigerat för dessa med hjälp av statistiska metoder. Vi har framförallt undersökt tre metoder för att korrigera för systematiska fel: I) Korrektion av överblödning som sker på grund avöverlappande emissionsspektra mellan fluorescenta prober. II) En sannolikhetsbaserad tolkningav intensitetsdata som resulterar i ett nytt kvalitetsmått och en alternativ klassificerare baseradpå övervakad inlärning. III) En utredning om förekomst av cykelberoende effekter, exempelvisofullständig dehybridisering av fluorescenta prober. Vi föreslår att man gör följande saker: Implementerar och utvärderar det sannolikhetsbaserade kvalitetsmåttet Utvecklar och implementerar den föreslagna klassificeraren Genomför ytterligare experiment för att påvisa eller bestrida förekomst av ofullständigdehybridisering<br>In situ sequencing is a method that can be used to localize differential expression of mRNA directly in tissue sections, something that can give valuable insights to many statest of disease. Today, many of the registered sequences from in situ sequencing are lost due to a conservative quality measure used to filter out incorrect sequencing reads. There is room for improvement in the performance of the current method for base calling since the technology is in an early stage of development. We have performed exploratory data analysis to investigate occurrence of systematic errors, and corrected for these by using various statistical methods. The primary methods that have been investigated are the following: I) Correction of emission spectra overlap resulting in spillover between channels. II) A probability-based interpretation of intensity data, resulting in a novel quality measure and an alternative classifier based on supervised learning. III) Analysis of occurrence of cycle dependent effects, e.g. incomplete dehybridization of fluorescent probes. We suggest the following: Implementation and evaluation of the probability-based quality measure Development and implementation of the proposed classifier Additional experiments to investigate the possible occurrence of incomplete dehybridization
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Sá, João Alberto Pacheco Marques de Vasconcelos. "Metabolic Systems Biology for Stem Cell Bioprocesses." Doctoral thesis, 2020. http://hdl.handle.net/10362/96830.
Full textAbstract:
"The application of stem cell-derived products for human health is in its infancy. Different applications of stem cell bioprocesses – cell therapy, discovery of new targets for regenerative medicine, disease modeling, drug and toxicity testing – have common hurdles. The most relevant hurdle is the lack of quality of cell products due to inefficient and ineffective stem cell differentiation procedures. Differentiated cells in vitro do not behave similarly to mature cells in vivo despite presenting similar surface and intracellular protein biomarkers. Our current weak understanding of cell “behavior” contributes to lack of cell functionality of produced cells and make these inadequate for cell therapy, disease modeling, drug screening and toxicity. Cells communicate with the environment and with neighboring cells, usually through secreted factors and through metabolites. This communication is guaranteed by an adjustable and controlled internal system in which metabolism is very important. (...)"