Skin pigmentation is an important issue in most cultures. Until recently we have not understood the most important elements of pigmentation regarding detailed chemical structure. The synthesis of melanin is very complex, and although core enzymes, other important proteins, and parts of the melanin structure have been identified much information in this context awaits disclosure. The function of the melanocyte and the deposition of melanin pigments into the keratinocytes are very important in the protection against UV light. Melanin pigments consist of high-molecular structures often described as brown to black eumelanin and yellow to red pheomelanin. Eumelanin is photoprotective, whereas pheomelanin is believed to be carcinogenic after UV radiation. There is strong evidence that people of fair complexion with freckles who tan poorly are at higher risk of developing melanoma. These people have a higher pheomelanin to eumelanin ratio in their skin. Melanoma, one of the most widely spread cancers, is derived from melanocytes. There is accumulating evidence that pigment constitution is highly involved in the development of melanoma. We found that patients with advanced melanoma secrete substantial amounts of pigment structures into the urine, in particular those with diffuse melanosis. In subsequently performed experiments we purified these pigments and subjected the product to chemical degradation by either hydrogen peroxide oxidation or hydriodic hydrolysis. Several new chromatographic methods were developed for the structural analysis of these products. Structural analysis of new chromatographic peaks was performed. In conclusion, complex pheomelanin structures as well as low molecular weight pigments and free benzothiazoles have been identified in the urine of patients with melanoma and diffuse melanosis. The present thesis provides new insight into melanogenesis and melanoma progression. This opens the doorway to further approaches to the investigation of melanins and can help to understand fundamental problems about the structure and biosynthesis of natural melanins.

Prior research suggests aggressive cancer treatments contribute to cognitive impairments in children diagnosed with pediatric brain tumors. The literature also suggests that younger age at diagnosis (AAD) and treatment may result in disrupted cognitive trajectories due to limited brain plasticity. In line with this research, we hypothesized an interaction between radiation therapy (RT) and young AAD of brain tumors, where young AAD and RT results in lower standard scores on the WRAT-R Reading Comprehension Subtest. Analyses included archival data; the sample consists of 134 children diagnosed with pediatric brain tumors with multiple assessments resulting in 487 cases for analysis. Participants were diagnosed with mixed tumor types and locations. A two level multilevel model was used to analyze reading trajectories while taking into account AAD, time since diagnosis, socioeconomic status (SES), and RT. Results detected a positive interaction between AAD and RT (γ =2.08, p=.02). For participants with RT, younger AAD was associated with lower reading scores, whereas AAD had no effect for participants without RT. Results also detected a negative interaction between radiation and time (γ =-2.29, p=.00) indicating that children treated with RT have reading scores that decrease over time. These data suggested that children diagnosed with pediatric brain tumors treated with RT are at higher risk of reading impairment as reflected in their reading scores.

Two immersed boundary methods (IBM) for the simulation of conjugate heat transfer problems with complex geometries are introduced: a finite element (IFEM) and a finite volume (IFVM) immersed boundary methods are discussed. In the IFEM a projection approach is presented for the coupled system of time-dependent incompressible Navier-Stokes equations (NSEs) and energy equation in conjunction with the immersed boundary method for solving fluid flow and heat transfer problems in the presence of rigid objects not represented by the underlying mesh. The IBM allows solving the flow for geometries with complex objects without the need of generating a body-fitted mesh. Dirichlet boundary constraints are satisfied applying a boundary force at the immersed body surface. Using projection and interpolation operators from the fluid volume mesh to the solid surface mesh (i.e., the “immersed” boundary) and vice versa, it is possible to impose the extra constraint to the NSEs as a Lagrange multiplier in a fashion very similar to the effect pressure has on the momentum equations to satisfy the divergence-free constraint. The IFEM approach presented shows third order accuracy in space and second order accuracy in time when the simulation results for the Taylor-Green decaying vortex are compared to the analytical solution. For the IFVM a ghost-cell approach with sharp interface scheme is used to enforce the boundary condition at the fluid/solid interface. The interpolation procedure at the immersed boundary preserves the overall second order accuracy of the base solver. The developed ghost-cell method is applied on a staggered configuration with the Semi-Implicit Method for Pressure-Linked Equations Revised algorithm. Second order accuracy in space and first order accuracy in time are obtained when the Taylor-Green decaying vortex test case is compared to the IFVM analytical solution. Computations were performed using the IFEM and IFVM approaches for the two-dimensional flow over a backward-facing step, two-dimensional flow past a stationary circular cylinder, three-dimensional flow past a sphere and two and three-dimensional natural convection in an enclosure with/without immersed body. The numerical results obtained with the discussed IFEM and IFVM were compared against other IBMs available in literature and simulations performed with the commercial computational fluid dynamics code STAR-CCM+/V7.04.006. The benchmark test cases showed that the numerical results obtained with the implemented immersed boundary methods are in good agreement with the predictions from STAR-CCM+ and the numerical data from the other IBMs. The immersed boundary method based of finite element approach is numerically more accurate than the IBM based on finite volume discretization. In contrast, the latter is computationally more efficient than the former.

<p>Breast conserving surgery (BCS) is a common treatment option for breast cancer patients. The goal of BCS is to remove the entire tumor from the breast while preserving as much normal tissue as possible for a better cosmetic outcome after surgery. Specifically, the excised specimen must have at least 2 mm of normal tissue surrounding the diseased mass. Unfortunately, a staggering 20-70% of patients undergoing BCS require repeated surgeries due to the incomplete removal of the tumor diagnosed post-operatively. Due to these high re-excision rates as well as limited post-operative histopathological sampling of the tumor specimen, there is an unmet clinical need for margin assessment. Quantitative diffuse reflectance spectral imaging has previously been explored as a promising, method for providing real-time visual maps of tissue composition to help surgeons determine breast tumor margins to ensure the complete removal of the disease during breast conserving surgery. We have leveraged the underlying sources of contrast in breast tissue, specifically total hemoglobin content, beta-carotene content, and tissue scattering, and developed various fiber optics based spectral imaging systems for this clinical application. Combined with a fast inverse Monte Carlo model of reflectance, previous studies have shown that this technology may be able to decrease re-excision rates for BCS. However, these systems, which all consist of a broadband source, fiber optics probes, an imaging spectrograph and a CCD, have severe limitations in system footprint, tumor area coverage, and speed for acquisition and analysis. The fiber based spectral imaging systems are not scalable to smaller designs that cover a large surveillance area at a very fast speed, which ultimately makes them impractical for use in the clinical environment. The objective of this dissertation was to design, develop, test, and show clinical feasibility of a novel wide field spectral imaging system that utilizes the same scientific principles of previously developed fiber optics based imaging systems, but improves upon the technical issues, such as size, complexity, and speed,to meet the demands of the intra-operative setting. </p><p>First, our simple re-design of the system completely eliminated the need for an imaging spectrograph and CCD by replacing them with an array of custom annular photodiodes. The geometry of the photodiodes were designed with the goal of minimizing optical crosstalk, maximizing SNR, and achieving the appropriate tissue sensing depth of up to 2 mm for tumor margin assessment. Without the imaging spectrograph and CCD, the system requires discrete wavelengths of light to launch into the tissue sample. A wavelength selection method that combines an inverse Monte Carlo model and a genetic algorithm was developed in order to optimize the wavelength choices specifically for the underlying breast tissue optical contrast. The final system design consisted of a broadband source with an 8-slot filter wheel containing the optimized set of wavelength choices, an optical light guide and quartz light delivery tube to send the 8 wavelengths of light in free space through the back apertures of each annular photodiode in the imaging array, an 8-channel integrating transimpedance amplifier circuit with a switch box and data acquisition card to collect the reflectance signal, and a laptop computer that controls all the components and analyzes the data.</p><p>This newly designed wide field spectral imaging system was tested in tissue-mimicking liquid phantoms and achieved comparable performance to previous clinically-validated fiber optics based systems in its ability to extract optical properties with high accuracy. The system was also tested in various biological samples, including a murine tumor model, porcine tissue, and human breast tissue, for the direct comparison with its fiber optics based counterparts. The photodiode based imaging system achieved comparable or better SNR, comparable extractions of optical properties extractions for all tissue types, and feasible improvements in speed and coverage for future iterations. We show proof of concept in performing fast, wide field spectral imaging with a simple, inexpensive design. With a reduction in size, cost, number of wavelengths used, and overall complexity, the system described by this dissertation allows for a more seamless scaling to higher pixel number and density in future iterations of the technology, which will help make this a clinically translatable tool for breast tumor margin assessment.</p> / Dissertation

<p>Among women worldwide, cervical cancer is the third most common cancer with an incidence rate of 15.3 per 100,000 and a mortality rate of 7.8 per 100,000 women. This is largely attributed to the lack of infrastructure and resources in the developing countries to support the organized screening and diagnostic programs that are available to women in developed nations. Hence, there is a critical global need for a screening and diagnostic paradigm that is effective in low-resource settings. Various strategies are described to design an optical spectroscopic sensor capable of collecting reliable diffuse reflectance data to extract quantitative optical contrasts for cervical cancer screening and diagnosis. </p><p> A scalable Monte Carlo based optical toolbox can be used to extract absorption and scattering contrasts from diffuse reflectance acquired in the cervix in vivo. [Total Hb] was shown to increase significantly in high-grade cervical intraepithelial neoplasia (CIN 2+), clinically the most important tissue grade to identify, compared to normal and low-grade intraepithelial neoplasia (CIN 1). Scattering was not significantly decreased in CIN 2+ versus normal and CIN 1, but was significantly decreased in CIN relative to normal cervical tissues. </p><p> Immunohistochemistry via anti-CD34, which stains the endothelial cells that line blood vessels, was used to validate the observed absorption contrast. The concomitant increase in microvessel density and [total Hb] suggests that both are reactive to angiogenic forces from up-regulated expression of VEGF in CIN 2+. Masson's trichrome stain was used to assess collagen density changes associated with dysplastic transformation of the cervix, hypothesized as the dominant source of decreased scattering observed. Due to mismatch in optical and histological sampling, as well as the small sample size, collagen density and scattering did not change in a similar fashion with tissue grade. Dysplasia may also induce changes in cross-linking of collagen without altering the amount of collagen present. Further work would be required to elucidate the exact sources of scattering contrast observed. </p><p> Common confounding variables that limit the accuracy and clinical acceptability of optical spectroscopic systems are calibration requirements and variable probe-tissue contact pressures. Our results suggest that using a real-time self-calibration channel, as opposed to conventional post-experiment diffuse reflectance standard calibration measurements, significantly improved data integrity for the extraction of scattering contrast. Extracted [total Hb] and scattering were also significantly associated with applied contact probe pressure in colposcopically normal sites. Hence, future contact probe spectroscopy or imaging systems should incorporate a self-calibration channel and ensure spectral acquisition at a consistent contact pressure to collect reliable data with enhanced absorption and scattering contrasts. </p><p> Another method to enhance optical contrast is to selectively interrogate different depths in the dysplastic cervix. For instance, scattering has been shown to increase in the epithelium (increase in nuclear-to-cytoplasmic ratio) while decrease in the stroma (re-organization of the extra-cellular matrix and changes in of collagen fiber cross-links). A fiber-optic probe with 45° illumination and collection fibers with a separation distance of 330 &#956;m was designed and constructed to selectively interrogate the cervical epithelium. Mean extraction errors from liquid phantoms with optical properties mimicking the cervical epithelium for &#956;a and &#956;s' were 11.3 % and 12.7 %, respectively. Diffuse reflectance spectra from 9 sites in four loop electrosurgical excision procedure (LEEP) patients were analyzed. Preliminary data demonstrate the utility of the oblique fiber geometry in extracting scattering contrast in the cervical epithelium. Further work is needed to study the systematic error in optical property extraction and to incorporate simultaneous extraction of epithelial and stromal contrasts using both flat and oblique illumination and collection fibers. </p><p> Various strategies, namely self-calibration, consistent contact pressure, and the incorporation of depth-selective sensing, have been proposed to improve the data integrity of an optical spectroscopic system for maximal contrast. In addition to addressing field operation requirements (such as power and operator training requirement), these improvements should enable the collection of reliable spectral data to aid in the adoption of optical smart sensors in the screening and diagnosis of cervical precancer, especially in a global health setting.</p> / Dissertation

Heterogeneities in concrete caused by the random distribution of aggregate in the cement-paste matrix lead to strong scattering of ultrasound waves at wavelengths on the order of the aggregate. Use of these high frequencies is necessary to detect damage at an early stage, something that is not possible with conventional ultrasonic methods. The ultrasound energy density in this regime can be described by the diffusion equation. The objective of this research is to develop a quantitative understanding of the effects of additional scattering sources, such as small cracks in the cement-paste matrix, on the parameters of the diffusion equation; these parameters are the diffusion and the dissipation coefficients. Experimentally measured ultrasonic waves are processed using the diffusion theory to determine the diffusivity and the dissipation coefficients as a function of frequency. The samples employed are made of a Portland cement-paste matrix and regular aggregate such as gravel and sand. The results provide a basic understanding of the repeatability and consistency of diffusion measurements, with an emphasis on the nondestructive evaluation of damage in concrete. In addition, a method to describe concrete in the coherent regime is examined. Existing wave propagation models for inhomogeneous materials deal with two-phase mixtures, mostly the matrix-inclusion system such as fiber-reinforced composites. There are, however, numerous examples of multi-phase materials in which more than one phase is suspended in a matrix-phase. This research considers concrete, in which cement paste and aggregates with different sizes and mechanical properties are mixed together. Most of the models for two-phase composites cannot be extended to a multi-phase composite. Among others, the effective medium theory is considered here for two reasons: first, the formalism in this theory can easily be extended to multi-phase cases; second, the theory does not strictly define a specific microstructure between phases, which allows for a simulation of the microstructure in which different inclusions are in contact. The mathematical formulation is presented that yields the formulae for the effective density and the effective bulk and shear moduli. Finally, the calculated wave speeds and attenuations for different materials are compared with experimental results.

The eastern California shear zone (ECSZ) and Walker Lane belt represent an important inland component of the Pacific-North America plate boundary. Current geodetic data indicate accumulation of transtensional shear at a rate of ~9.2 ± 0.3 mm/yr across the region, more than double the total geologic rate (<3.5 mm/yr) for faults in the northern ECSZ over the late Pleistocene [Bennett et al., 2003, Kirby et al., 2006, Lee et al., 2009, Frankel et al., 2007]. Unraveling the strain puzzle of the Walker Lane is therefore essential to understanding both how deformation is distributed through the lithosphere along this transtensional part of the Pacific-North America plate boundary and how the plate boundary is evolving through time. The observed mismatch between geodetic and geologic slip rates in the central Walker Lane is characteristic of other active tectonic settings, including the nearby Mojave segment of the ECSZ [Oskin et al., 2008] and the Altyn Tagh fault in China [Cowgill, 2007]. In each case, lack of fault slip data spanning multiple temporal and spatial scales hinders interpretation of fault interactions and their implications for lithospheric dynamics. The discrepancy between geodetic and geologic slip rates in the central Walker Lane indicates that if strain rates have remained constant since the late Pleistocene [e.g. Frankel et al., in press], then the "missing" strain is distributed on structures other than the two major dextral faults at this latitude (Death Valley-Fish Lake Valley fault and White Mountains fault). Otherwise the region could presently be experiencing a strain transient similar to that of the nearby Mojave section of the ECSZ [e.g., Oskin et al., 2008], or the rate of strain accumulation could actually increasing over the late Pleistocene [e.g. Reheis and Sawyer, 1997; Hoeft and Frankel, 2010]. The Silver Peak-Lone Mountain extensional complex (SPLM), to which the Clayton Valley faults belong, is the prime candidate to account for the "missing" strain. The down-to-the-northwest orientation of the SPLM faults makes them the most kinematically suitable structures to accommodate the regional pattern of NW-SE dextral shear. We use differential GPS to measure fault offset and terrestrial cosmogenic nuclide (TCN) geochronology to date offset landforms. Using these tools, we measure extension rates that are time-invariant, ranging from 0.1 ± 0.1 to 0.3 ± 0.1 mm/yr for fault dips of 30° and 60°. These rates are not high enough to account for the discrepancy between geologic and geodetic data in the ECSZ-Walker Lane transition zone. Based on geologic mapping and previously published geophysical data [Davis, 1981; Zampirro, 2005], deformation through Clayton Valley appears to be very widely-distributed. The diffuse nature of deformation leads to geologic slip rates that are underestimated due to the effects of off-fault deformation and unrecognized fault strands. Our results from Clayton Valley suggest that the discrepancy between geodetic and geologic strain rates at the latitude of the northern ECSZ is a result of long-term geologic rates that are underestimated. If the true geologic rates could be calculated, they would likely be significantly higher and therefore in closer agreement with geodetic data, as is the case everywhere else in the ECSZ north of the Garlock fault [Frankel et al., 2007a, in press; Kirby et al., 2008; Lee et al., 2009a].

Surface-breaking cracks pose a serious threat to the service life of concrete structures and health monitoring is presently conducted by a visual inspection method, yielding a potential risk to safety. Diffuse ultrasonic techniques have shown their potential as an ultrasonic technique for measuring crack depth in concrete and are currently under development. In this research, the finite element method (FEM) is employed to model the ultrasound diffusion in a concrete specimen. The objectives are to use the commercial finite element (FE) tool Ansys to develop the finite element model of a concrete specimen and verify the applicability of the model by comparing with an analytic solution and experiment data. Further, various crack types are analyzed with the FE model in order to gain physical insight into the interpretation of experimental measurements. The results of this research suggest that a preliminary knowledge of the cracking process is required to correctly interpret the measured impulse responses for an unknown crack geometry, as the impulse response expresses the response of the shortest path through a system of cracks between source and receiver. Moreover, the impulse response can carry some ambiguity, as certain crack types are not uniquely determined.

Die vorliegende Arbeit beschäftigt sich mit dem schnellen Lösen von Randintegralgleichungen auf polygonalen oder polygonal approximierten Oberflächen basierend auf Wavelet-Galerkinverfahren. Ein besonderes Augenmerk gilt dabei der speziellen Problematik der diffusen Beleuchtungsgleichung. Während traditionelle Ansätze für Randintegralgleichungen zu vollbesetzten Systemmatrizen und damit zu einem quadratischen Aufwand führen, nutzen Waveletverfahren spezielle Multiskalenbasen, die eine Kompression der Systemmatrix zu einer dünnbesetzten Matrix und damit einen linear-logarithmischen Aufwand ermöglichen. In der Arbeit wird das H^2-Waveletverfahren als effiziente Umsetzung der Waveletverfahren auf polygonal approximierten Oberflächen basierend auf den Tausch-White-Wavelets entwickelt. Es stellt eine Kombination aus H^2-Techniken, bekannt von dem Gebiet der hierarchischen Matrizen, und rekusiven Wavelettechniken dar. Zum besseren Verständnis werden dazu innerhalb der Arbeit in eigenen Kapiteln das Wichtigste zu den Tausch-White-Wavelets, zu dem allgemeinen Waveletverfahren und der Waveletkompression sowie zu den H^2-Matrizen präsentiert, bevor das H^2-Waveletverfahren detailiert hergeleitet und der entsprechende linear-logarithmische Aufwand bewiesen wird. Der zweite Schwerpunkt der Arbeit liegt auf der diffusen Beleuchtungsgleichung. Die in ihr enthaltene Sichbarkeitsproblematik verhindertete bis jetzt die Anwendung moderner schneller Verfahren und die Reduktion der Kosten auf linear-logarithmischen Aufwand. Mit Hilfe der in dieser Arbeit neu entwickelten speziell auf die diffuse Beleuchtungsgleichung angepassten Waveletkompression ist es jedoch möglich ein dünnbesetzte Systemmatrix aufzustellen und im Bereich des Speichers den gewünschten linear-logarithmischen Aufwand zu erreichen. Alle in der Arbeit entwickelten Algorithmen sind detailiert dargestellt und mit numerische Ergebnissen unterlegt.

Considerable effort worldwide has gone into monitoring heat and mass transfer at active volcanoes, as this information may provide clues about changes in volcanic activity and impending eruptions. One method used is the self-potential (SP) method, which has been employed on volcanoes to map hydrothermal systems and structural features and to monitor changes in the hydrothermal system due to volcanic activity. Continuous monitoring of SP has been employed on a few volcanoes and has produced encouraging results. This study presents new time series data collected from continuous monitoring stations at Masaya and Telica, and spatial series data from Masaya, Telica, and Cerro Negro, three active volcanoes in Nicaragua. The primary goals of this study were to determine whether correlations between SP anomalies and CO2 flux exist and to investigate temporal variations in temperature, SP, rainfall, and barometric pressure. To achieve these goals, SP and CO2 flux surveys were conducted on Masaya, Telica, and Cerro Negro, and continuous monitoring stations were installed on Masaya and Telica. The continuous monitoring station on Masaya recorded temperature, SP, rainfall, and barometric pressure. The station on Telica recorded temperature and SP. Profiles collected on Masaya and Cerro Negro show broad correlation between SP and CO2 flux. However, profiles on Telica revealed virtually no SP anomaly or CO2 flux for the majority of the profile, at the time of data collection. Data collected from the continuous monitoring station at Masaya showed a persistent positive SP anomaly that fluctuated between 60 and 240 mV. Rainfall was seen to supress the anomaly for time scales of several hours to several days. Correlations between temperature, SP, and barometric pressure were also seen at Masaya. Curiously, no increases in SP were seen during two temperature transients that occurred during volcanic activity in June and October. Continuous monitoring data from Telica showed only decreases in temperature and SP, which coincided with rainfall. The continuous monitoring data collected in this study and others have begun to provide a better understanding of the nature of SP anomalies, which may aid in the development of the SP method as a volcano monitoring tool.