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Browsing Duke Student Scholarship by Affiliation "Clinical Science Departments"

Now showing 1 - 18 of 18
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    ItemOpen Access
    A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.
    (2011) Curtis, Valerie Forbes
    In many cancer types, infiltration of bone marrow-derived myeloid cells in the tumor microenvironment is often associated with enhanced angiogenesis and tumor progression, resulting in poor prognosis. The polypeptide chemokine PK2 (Bv8) regulates myeloid cell mobilization from the bone marrow, leading to activation of angiogenesis as well as accumulation of macrophages and neutrophils in the tumor site. Neutralizing antibodies against PK2 display potent anti-tumor efficacy, illustrating the potential of PK2-antagonists as therapeutic agents for the treatment of cancer. However, antibody-based therapies can be too large to treat certain diseases and too expensive to manufacture while small molecule therapeutics are not prohibitive in these ways. In this study, we demonstrate the anti-tumor activity of a small molecule PK2 antagonist, PKRA7, in the contexts of glioblastoma and pancreatic cancer xenograft tumor models. In the highly vascularized glioblastoma, PKRA7 decreased blood vessel density while increasing necrotic areas in the tumor mass. Consistent with the anti-angiogenic activity of PKRA7 in vivo, this compound effectively reduced PK2-induced microvascular endothelial cell branching in vitro. For the poorly vascularized pancreatic cancer, the primary anti-tumor effect of PKRA7 is mediated by the blockage of myeloid cell migration and infiltration. At the molecular level, PKRA7 inhibits PK2-induced expression of several pro-migratory chemokines and chemokine receptors in macrophages. Combining PKRA7 treatment with standard chemotherapeutic agents resulted in enhanced effects in xenograft models for both glioblastoma and pancreatic tumors. Taken together, our results indicate that the anti-tumor activity of PKRA7 can be mediated by distinct mechanisms that are relevant to the pathological features of the specific type of cancer. This small molecule PK2 antagonist holds the promise to be further developed as an effective agent for combinational cancer therapy.
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    An entirely cell-based system to generate single-chain antibodies against cell surface receptors.
    (2008) Chen, Yu-Hsun Jason
    The generation of recombinant antibodies (Abs) using phage display is a proven method to obtain a large variety of Abs that bind with high affinity to a given antigen (Ag). Traditionally, the generation of single chain Abs depends on the use of recombinant proteins in several stages of the procedure. This can be a problem, especially in the case of cell surface receptors, because Abs generated and selected against recombinant proteins may not bind the same protein expressed on a cell surface in its native form and because the expression of some receptors as recombinant proteins is problematic. To overcome these difficulties, we developed a strategy to generate single chain Abs that does not require the use of purified protein at any stage of the procedure. In this strategy, stably transfected cells are used for the immunization of mice, measuring Ab responses to immunization, panning the phage library, high throughputs creening of arrayed phage clones, and characterization of recombinant single chain variable regions(scFvs). This strategy was used to generate a panel of single chain Abs specific for the innate immunity receptor Toll‐like receptor2 (TLR2). Once generated, individual scFvs were subcloned into an expression vector allowing the production of recombinant antibodies in insect cells, thus avoiding the contamination of recombinant Abs with microbial products. This cell‐based system efficiently generates Abs that bind native molecules displayed on cell surfaces, bypasses the requirement of recombinant protein production, and avoids risks of microbial component contamination. However, an inconvenience of this strategy is that it requires construction of a new library for each target TLR. This problem might be solved by using non‐immune antibody libraries to obtain antibodies against multiple TLRs. Non‐immune libraries contain a wide variety of antibodies but these are often low affinity, while immune libraries, derived from immunized animals, containa high frequency of high affinity antibodies, but are typically limited to a single antigen. In addition, it can be difficult to produce non‐immune libraries with sufficient complexity to select Abs against multiple Ags. Because the re‐assortment of VH and VL regions that occurs during antibody library construction greatly increases library complexity, we hypothesized that an immune antibody library produced against one member of a protein family would contain antibodies specific for other members of the same protein family. Here, we tested this hypothesis by mining an existing anti‐hTLR2 antibody library for antibodies specific for other members of the TLR family. This procedure, which we refer to as homolog mining, proved to be effective. Using a cell‐based system to pan and screen our anti‐hTLR2 library, we identified single chain antibodies specific for three of the four hTLR2 homologs we targeted. The antibodies identified, anti‐murine TLR2, anti‐hTLR5, and anti‐hTLR6, bind specifically to their target, with no cross‐reactivity to hTLR2 or other TLRs tested. These results demonstrate that combinatorial re‐assortment of VH and VL fragments during Ab library construction increases Ab repertoire complexity, allowing antibody libraries produced by immunization with one antigen to be used to obtain antibodies specific to related antigens. The principle of homolog mining may be extended to other protein families and will facilitate and accelerate antibody production processes. In conclusion, we developed an entirely cell‐based method to generate antibodies that bind to native molecules on the cell surface, while eliminating the requirement of recombinant proteins and the risk of microbial component contamination. With homolog mining, this system is capable of generating antibodies not only against the original immunized Ag, but also against homologous Ags. In combination, this system proved to be an effective and efficient means for generating multiple antibodies that bind to multiple related Ags as they are displayed on cell surfaces.
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    ItemOpen Access
    Attenuation of inflammatory events in human intervertebral disc cells with a tumor necrosis factor antagonist.
    (2010) Sinclair, Steven Michael
    STUDY DESIGN: The inflammatory responses of primary human intervertebral disc (IVD) cells to tumor necrosis factor α (TNF-α) and an antagonist were evaluated in vitro. OBJECTIVE: To investigate an ability for soluble TNF receptor type II (sTNFRII) to antagonize TNF-α-induced inflammatory events in primary human IVD cells in vitro. SUMMARY OF BACKGROUND DATA: TNF-α is a known mediator of inflammation and pain associated with radiculopathy and IVD degeneration. sTNFRs and their analogues are of interest for the clinical treatment of these IVD pathologies, although information on the effects of sTNFR on human IVD cells remains unknown. METHODS: IVD cells were isolated from surgical tissues procured from 15 patients and cultured with or without 1.4 nmol/L TNF-α (25 ng/mL). Treatment groups were coincubated with varying doses of sTNFRII (12.5-100 nmol/L). Nitric oxide (NO), prostaglandin E₂ (PGE₂), and interleukin-6 (IL6) levels in media were quantified to characterize the inflammatory phenotype of the IVD cells. RESULTS: Across all patients, TNF-α induced large, statistically significant increases in NO, PGE₂, and IL6 secretion from IVD cells compared with controls (60-, 112-, and 4-fold increases, respectively; P < 0.0001). Coincubation of TNF-α with nanomolar doses of sTNFRII significantly attenuated the secretion of NO and PGE₂ in a dose-dependent manner, whereas IL6 levels were unchanged. Mean IC₅₀ values for NO and PGE₂ were found to be 35.1 and 20.5 nmol/L, respectively. CONCLUSION: Nanomolar concentrations of sTNFRII were able to significantly attenuate the effects of TNF-α on primary human IVD cells in vitro. These results suggest this sTNFR to be a potent TNF antagonist with potential to attenuate inflammation in IVD pathology.
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    ItemOpen Access
    B-lymphocyte effector functions in health and disease.
    (2010) DiLillo, David John
    B cells and humoral immunity make up an important component of the immune system and play a vital role in preventing and fighting off infection by various pathogens. B cells also have been implicated in the pathogenesis of autoimmune disease. However, the various functions that B cells perform during the development and maintenance of autoimmune conditions remain unclear. Therefore, the overall goal of this dissertation was to determine what roles B cells play during autoimmune disease. In the Chapter 3 of this dissertation, the function of B cells was assessed during tumor immunity, a model of immune system activation and cellular immunity. To quantify B cell contributions to T cell-mediated anti-tumor immune responses, mature B cells were depleted from wild type adult mice using CD20 monoclonal antibody (mAb) prior to syngeneic B16 melanoma tumor transfers. Remarkably, subcutaneous (s.c.) tumor volume and lung metastasis were increased two-fold in B cell-depleted mice. Effector-memory and interferon (IFN)γ or tumor necrosis factor (TNF)α-secreting CD4+ and CD8+ T cell induction was significantly impaired in B cell-depleted mice with tumors. Tumor antigen (Ag)-specific CD8+ T cell proliferation was also impaired in tumor-bearing mice that lacked B cells. Thus, B cells were required for optimal T cell activation and cellular immunity in this in vivo non-lymphoid tumor model. In Chapter 4 of this dissertation, the roles that B cells play during immune responses elicited by different allografts were assessed, since allograft rejection is thought to be T cell-mediated. The effects of B cell-depletion on acute cardiac rejection, chronic renal rejection, and skin graft rejection were compared using CD20 or CD19 mAbs. Both CD20 and CD19 mAbs effectively depleted mature B cells, while CD19 mAb treatment depleted plasmablasts and some plasma cells. B cell depletion did not affect acute cardiac allograft rejection, although CD19 mAb treatment prevented allograft-specific IgG production. Nonetheless, CD19 mAb treatment significantly reduced renal allograft rejection and abrogated allograft-specific IgG development, while CD20 mAb treatment did not. By contrast, B cell depletion exacerbated skin allograft rejection and augmented the proliferation of adoptively transferred alloAg-specific CD4+ T cells, demonstrating that B cells can also negatively regulate allograft rejection. Thereby, B cells can either positively or negatively regulate allograft rejection depending on the nature of the allograft and the intensity of the rejection response. Serum antibody (Ab) is, at least in part, responsible for protection against pathogens and tissue destruction during autoimmunity. In Chapter 5 of this dissertation, the mechanisms responsible for the maintenance of long-lived serum Ab levels were examined, since the relationship between memory B cells, long-lived plasma cells, and long-lived humoral immunity remains controversial. To address the roles of B cell subsets in the longevity of humoral responses, mature B cells were depleted in mice using CD20 mAb. CD20+ B cell depletion prevented humoral immune responses and class switching, and depleted existing and adoptively-transferred B cell memory. Nonetheless, B cell depletion did not affect serum Ig levels, Ag-specific Ab titers, or bone marrow (BM) Ab-secreting plasma cell numbers. Co-blockade of LFA-1 and VLA-4 adhesion molecules temporarily depleted long-lived plasma cells from the BM. CD20+ B cell depletion plus LFA-1/VLA-4 mAb treatment significantly prolonged Ag-specific plasma cell depletion from the BM, with a significant decrease in Ag-specific serum IgG. Collectively, these results indicate that BM plasma cells are intrinsically long-lived. Further, these studies now demonstrate that mature and memory B cells are not required for maintaining BM plasma cell numbers, but are required for repopulation of plasma cell-deficient BM. Thereby, depleting mature and memory B cells does not have a dramatic negative effect on pre-existing Ab levels. Collectively, the studies described in this dissertation demonstrate that B cells function through multiple effector mechanisms to influence the course and intensity of normal and autoreactive immune responses: the promotion of cellular immune responses and CD4+ T cell activation, the negative regulation of cellular immune responses, and the production and maintenance of long-lived Ag-specific serum Ab titers. Therefore, each of these three B cell effector mechanisms can contribute independently or in concert with the other mechanisms to clear pathogens or cause tissue damage during autoimmunity.
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    Characterization of Image Quality for 3D Scatter Corrected Breast CT Images.
    (2012) Pachon, Jan Harwin
    The goal of this study was to characterize the image quality of our dedicated, quasi-monochromatic spectrum, cone beam breast imaging system under scatter corrected and non-scatter corrected conditions for a variety of breast compositions. CT projections were acquired of a breast phantom containing two concentric sets of acrylic spheres that varied in size (1-8mm) based on their polar position. The breast phantom was filled with 3 different concentrations of methanol and water, simulating a range of breast densities (0.79-1.0g/cc); acrylic yarn was sometimes included to simulate connective tissue of a breast. For each phantom condition, 2D scatter was measured for all projection angles. Scatter-corrected and uncorrected projections were then reconstructed with an iterative ordered subsets convex algorithm. Reconstructed image quality was characterized using SNR and contrast analysis, and followed by a human observer detection task for the spheres in the different concentric rings. Results show that scatter correction effectively reduces the cupping artifact and improves image contrast and SNR. Results from the observer study indicate that there was no statistical difference in the number or sizes of lesions observed in the scatter versus non-scatter corrected images for all densities. Nonetheless, applying scatter correction for differing breast conditions improves overall image quality.
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    Comparative performance of multiview stereoscopic and mammographic display modalities for breast lesion detection.
    (2010) Webb, Lincoln Jon
    PURPOSE: Mammography is known to be one of the most difficult radiographic exams to interpret. Mammography has important limitations, including the superposition of normal tissue that can obscure a mass, chance alignment of normal tissue to mimic a true lesion and the inability to derive volumetric information. It has been shown that stereomammography can overcome these deficiencies by showing that layers of normal tissue lay at different depths. If standard stereomammography (i.e., a single stereoscopic pair consisting of two projection images) can significantly improve lesion detection, how will multiview stereoscopy (MVS), where many projection images are used, compare to mammography? The aim of this study was to assess the relative performance of MVS compared to mammography for breast mass detection. METHODS: The MVS image sets consisted of the 25 raw projection images acquired over an arc of approximately 45 degrees using a Siemens prototype breast tomosynthesis system. The mammograms were acquired using a commercial Siemens FFDM system. The raw data were taken from both of these systems for 27 cases and realistic simulated mass lesions were added to duplicates of the 27 images at the same local contrast. The images with lesions (27 mammography and 27 MVS) and the images without lesions (27 mammography and 27 MVS) were then postprocessed to provide comparable and representative image appearance across the two modalities. All 108 image sets were shown to five full-time breast imaging radiologists in random order on a state-of-the-art stereoscopic display. The observers were asked to give a confidence rating for each image (0 for lesion definitely not present, 100 for lesion definitely present). The ratings were then compiled and processed using ROC and variance analysis. RESULTS: The mean AUC for the five observers was 0.614 +/- 0.055 for mammography and 0.778 +/- 0.052 for multiview stereoscopy. The difference of 0.164 +/- 0.065 was statistically significant with a p-value of 0.0148. CONCLUSIONS: The differences in the AUCs and the p-value suggest that multiview stereoscopy has a statistically significant advantage over mammography in the detection of simulated breast masses. This highlights the dominance of anatomical noise compared to quantum noise for breast mass detection. It also shows that significant lesion detection can be achieved with MVS without any of the artifacts associated with tomosynthesis.
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    Distinct functions of POT1 at telomeres.
    (2008) Kendellen, Megan Fuller
    Telomeres are nucleoprotein complexes that constitute the ends of eukaryotic chromosomes. Telomeres differentiate the end of the chromosome from sites of DNA damage and control cellular replicative potential. The loss of function of telomeres results in several biological consequences. First, dysfunctional telomeres elicit DNA damage responses and repair activities, which frequently induce cytogenetic abnormalities and genomic instability that are characteristic of human cancer. Second, cellular immortalization resulting from inappropriate elongation of telomeres is a critical component of tumorigenesis. Alternatively, as telomere shortening limits replicative potential, abnormally short telomeres can result in premature cellular senescence that is associated with human pathology ranging from anemia to atherosclerosis. Telomeric DNA is composed of tandem repeats of G‐rich double‐stranded (ds)DNA that terminates in a G‐rich 3’ single‐stranded (ss)DNA overhang. Telomeres are thought to assume a lariat structure termed the t‐loop, which is decorated by an assortment of telomere‐associated proteins. The most unique and least well characterized of these proteins is POT1. POT1 binds telomeric ssDNA via a pair of Nterminal OB‐folds. Through its C‐terminal protein‐interaction domain, POT1 directly binds the telomeric dsDNA‐binding protein TRF2 and participates in heterodimeric complex with the protein TPP1. Inhibition of POT1 induces a robust DNA damage response at telomeres and deregulation of telomere length homeostasis, indicating that POT1 is important in maintaining telomere stability and in regulating telomere length. The goal of my thesis work was to determine which of the three major functions of POT1– telomeric ssDNA‐, TPP1‐, or TRF2‐binding – were required to properly localize POT1 to telomeres and to prevent the telomere instability and length deregulation that occur in the absence of POT1. Using separation‐of‐function mutants of POT1 deficient in at least one of these activities, I found that POT1 depends on its heterodimeric partner TPP1 in cis with telomeric ssDNA‐binding to preserve telomere stability, while POT1 depends on its protein interaction with TRF2 to localize to telomeres and its TRF2‐ and telomeric ssDNA‐binding activities in cis to regulate telomere length.
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    Epigenetic regulation of the nitrosative stress response and intracellular macrophage survival by extraintestinal pathogenic Escherichia coli.
    (2011) Bateman, Stacey Lynn
    Escherichia coli is a typical constituent of the enteric tract in many animals, including humans. However, specialized extraintestinal pathogenic E. colistrains (ExPEC) may transition from benign occupation of the enteric and vaginal tracts to sterile sites such as the urinary tract, bloodstream, and central nervous system. ExPEC isolates of urinary tract origin express type 1 pili as a critical virulence determinant mediating adherence to and invasion into urinary tract tissues. Type 1 pili expression is under epigenetic regulation by a family of site-specific recombinases, including FimX, which is encoded from a genomic islet called PAI-X for Pathogenicity Islet of FimX. A goal of this study was to determine the prevalence of the type 1 pili epigenetic regulator genes (fimB, fimE, fimX, ipuA, ipuB) and associated PAI-X genes (hyxR, hyxA, hyxB) present among an extended, diverse collection of pathogenic and commensal E. coli isolates. Using a new multiplex PCR, fimX and the additional PAI-X genes were found to be highly associated with ExPEC (83.2%) and more prevalent in ExPEC of lower urinary tract origin (87.5%) than upper urinary tract origin (73.6%) or human commensal isolates (20.6%; p < 0.05, all comparisons). Fim-like recombinase genes ipuA and ipuB also had a significant association with ExPEC compared to commensal isolates, but had a low overall prevalence (23.8% vs. 11.1%; p < 0.05). PAI-X also showed a strong positive correlation with the presence of virulence genes in the genomes of pathogenic isolates. Combined, our molecular epidemiology studies indicate PAI-X is highly associated with ExPEC isolates, and its high prevalence suggests a potential role in the ExPEC lifestyle. Further investigation into the regulation of PAI-X factors showed that FimX is also an epigenetic regulator of a LuxR-like response regulator HyxR, encoded on PAI-X. In multiple clinical ExPEC isolates, FimX regulated hyxR expression through bidirectional phase inversion of its promoter region at sites different from the inversion sites of the type 1 pili promoter and independent of integration host factor IHF. Additional studies into the role of HyxR during ExPEC pathogenesis uncovered that HyxR is involved in regulation of the nitrosative stress response. In vitro, transition from high to low HyxR expression produced enhanced tolerance of reactive nitrogen intermediates (RNI), primarily through derepression of hmpA, encoding a nitric oxide detoxifying flavohemoglobin. However, in the macrophage, HyxR expression produced large effects on intracellular survival in the presence and absence of RNI, and independent of Hmp. Collectively, we have shown that the ability of ExPEC to survive in macrophages is contingent upon the proper transition from high to low HyxR expression through epigenetic regulatory control by FimX. ExPEC reside in the enteric tract as commensal reservoirs, but can transition to a pathogenic state by invading normally sterile niches, establishing infection, and disseminating to invasive sites like the bloodstream. Macrophages are required for ExPEC dissemination, suggesting the pathogen has developed mechanisms to persist within professional phagocytes. This study demonstrates the functional versatility of the FimX recombinase and identifies novel epigenetic and transcriptional regulatory controls for ExPEC tolerance to RNI challenge and survival during intracellular macrophage infection. Further investigation of these pathways may shed light on the regulatory cues and programming that provoke the commensal to pathogen transition.
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    Functional neuroimaging of autobiographical memory.
    (2010) St. Jacques, Peggy L.
    Autobiographical memory (AM) refers to memory for events from our own personal past. Functional neuroimaging studies of AM are important because they can investigate the neural correlates of processes that are difficult to study using laboratory stimuli, including: complex constructive processes, subjective qualities of memory retrieval, and remote memory. Three functional magnetic resonance imaging (fMRI) studies are presented to examine these important contributions of AM. The first study investigates the neural correlates of temporal-order memory for autobiographical events using a novel photo paradigm. Participants took photographs at many campus locations over a period of several hours, and the following day they were scanned while making temporal-order judgments to pairs of photographs from different locations. It was found that temporal-order decisions associated with recollection recruited left prefrontal (PFC) and left posterior parahippocampal cortex, whereas temporal-order decisions relying on familiarity recruited greater activity in the right PFC. The second study examines self-projection, the capacity to re-experience the personal past and to mentally infer another person’s perspective. A novel camera technology was used to examine self-projection by prospectively generating dynamic visuospatial images taken from a first-person perspective. Participants were literally asked to self-project into the personal past or into the life of another person. Self-projection of one’s own past self recruited greater ventral medial PFC (mPFC), and self-projection of another individual recruited dorsal mPFC. Activity in ventral vs. dorsal mPFC was also sensitive to the ability to relive or understand the perspective taken on each trial. Further, task-related functional connectivity analysis revealed that ventral mPFC contributed to the medial temporal lobe network linked to memory processes, whereas dorsal mPFC contributed to the frontoparietal network linked to controlled processes. The third study focuses on the neural correlates underlying age-related differences in the recall of episodically rich AMs. Age-related attenuation in the episodic richness of AM was linked to reductions in activity elicited during elaboration. Age effects on AM were more pronounced during elaboration than search, with older adults showing less sustained recruitment of the hippocampus and ventrolateral PFC for less episodically rich AMs. Further, there was an age-related reduction in the top-down modulation of the PFC on the hippocampus by episodic richness, possibly reflecting fewer controlled processes operating on the recovery of information in the hippocampus. Ultimately, the goal of all memory research is to understand how memory operates in the real-world; the present research highlights the important contribution of functional neuroimaging studies of AM in attaining this goal.
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    Harmonic source wavefront aberration correction for ultrasound imaging.
    (2010) Dianis, Scott W.
    Aberration is a correctable phenomenon that degrades diagnostic quality in a significant number of ultrasound images. Previous aberration correction studies have focused on development of aberration estimation algorithms or on aberration reduction by using harmonic imaging. In the past, a major drawback of aberration estimation algorithms has been the assumptions required about the imaging target, assumptions that can limit clinical application where correction for multiple locations within a scan may be required. Harmonic imaging attempts to reduce the effect of aberration, without making assumptions about the imaging target, by using a lower-frequency transmit beam that is less prone to aberration. However, harmonic imaging does not correct for any aberration that may remain. It is hypothesized that a harmonic source wavefront correction technique is capable of creating a point-like acoustical source that allows for estimation and correction of two-dimensional aberration in a clinical setting. Harmonic source wavefront correction utilizes the reduced aberration of harmonic imaging to create a known acoustical source to satisfy the assumptions of the aberration estimation algorithms, thus improving their clinical application. Generation of a point-like acoustical source in the presence of aberration is demonstrated using both spatially correlated and spatially uncorrelated electronic aberrators varying in strength from 0.25π radians to 1.16π radians RMS focusing error. Beam properties of the 2.08 MHz fundamental, 4.16 MHz generated harmonic, and 4.17 MHz imaging beams were compared; in the presence of aberration, relative peak beam amplitude of the 4.16 MHz generated harmonic beam was up to 81% higher than the 4.17 MHz imaging beam, while -6 dB beam width indicated the 4.16 MHz generated harmonic beam was 88% narrower and more point-like than the 2.08 MHz fundamental beam. The feasibility of harmonic source wavefront correction was demonstrated by correcting for spatially uncorrelated electronic aberrators in a water tank using a point target, specular reflector, and speckle region as correction targets. Harmonic source wavefront correction was paired with a cross-correlation algorithm to estimate corrective delays and was most effective in correcting peak amplitude of the 4.17 MHz imaging beam using a point target (up to 94% improvement), followed by use of a specular reflector (up to 83% improvement), followed by use of a speckle region (up to 47% improvement). Aberration correction is sensitive to signal-to-noise ratio (SNR),and correction utilizing the 2.08 MHz fundamental, which provided higher SNR, was more effective than correction utilizing the more point-like 4.16 MHz harmonic for the experimental setup used. A harmonic SNR of 14 dB was estimated as necessary for harmonic-based correction performance to equal or surpass fundamental-based correction, regardless of fundamental SNR. Finally, performance of harmonic source wavefront correction was quantified in a clinical setting. Correction of spatially correlated electronic aberrators was performed using both ex vivo porcine kidneys and the left kidneys of 11 human volunteers as correction targets. Correction utilizing porcine kidney resulted in 10 dB greater improvement in peak beam amplitude than correction utilizing the left kidney of human volunteers. Body wall aberration present in the human volunteers was not accounted for during correction and likely caused the disparity in correction performance. An average upper limit for body wall aberration for the human subjects was estimated at 65 ns (±9 ns) RMS
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    Indication of electron neutrino appearance from an accelerator-produced off-axis muon neutrino beam.
    (2012) Albert, Joshua Benjamin
    T2K (Tokai to Kamioka) is a long baseline neutrino experiment with the primary goal of measuring the neutrino mixing angle 13. It uses a muon neutrino beam, produced at the J-PARC accelerator facility in Tokai, sent through a near detector complex on its way to the far detector, Super-Kamiokande. Appearance of electron neutrinos at the far detector due to oscillation is used to measure the value of 13. This dissertation describes the experimental setup, analysis methods, and results from the analysis of T2K data taken from January 2010 through March 2011. Six signal candidate events were observed on an expected background of 1:5 0:3. The probability to see six or more such events is 0.7% under the 13 = 0 hypothesis. This is the first experiment to exclude 13 = 0 at the 90% confidence level. The 90% confidence level allowed region is 0:03p0:04q   sin2 2 13   0:28p0:34q with a best fit point of sin2 2 13 = 0:11p0:14q for CP = 0 and | m2 32| = 2:4 x 10-3 eV2 in the normal (inverted) hierarchy.
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    Knowledge-based IMRT treatment planning for prostate cancer.
    (2011) Chanyavanich, Vorakarn
    The goal of intensity-modulated radiation therapy (IMRT) treatment plan optimization is to produce a cumulative dose distribution that satisfies both the dose prescription and the normal tissue dose constraints. The typical manual treatment planning process is iterative, time consuming, and highly dependent on the skill and experience of the planner. We have addressed this problem by developing a knowledge based approach that utilizes a database of prior plans to leverage the planning expertise of physicians and physicists at our institution. We developed a case-similarity algorithm that uses mutual information to identify a similar matched case for a given query case, and various treatment parameters from the matched case are then adapted to derive new treatment plans that are patient specific. We used 10 randomly selected cases matched against a knowledge base of 100 cases to demonstrate that new, clinically acceptable IMRT treatment plans can be developed. This approach substantially reduced planning time by skipping all but the last few iterations of the optimization process. Additionally, we established a simple metric based on the areas under the curve (AUC) of the dose volume histogram (DVH), specifically for the planning target volume (PTV), rectum, and bladder. This plan quality metric was used to successfully rank order the plan quality of a collection of knowledgebased plans. Further, we used 100 pre-optimized plans (20 query x 5 matches) to show that the average normalized MI score can be used as a surrogate of overall plan quality. Plans of lower pre-optimized plan quality tended to improve substantially after optimization, though its final plan quality did not improve to the same level as a plan that has a higher pre-optimized plan quality to begin with. Optimization usually improved PTV coverage slightly while providing substantial dose sparing for both bladder and rectum of 12.4% and 9.1% respectively. Lastly, we developed new treatment plans for cases selected from an outside institution matched against our sitespecific database. The knowledge-based plans are very comparable to the original manual plan, providing adequate PTV coverage as well as substantial improvement in dose sparing to the rectum and bladder. In conclusion, we found that a site-specific database of prior plans can be effectively used to design new treatment plans for our own institution as well as outside cases. Specifically, knowledge-based plans can provide clinically acceptable planning target volume coverage and clinically acceptable dose sparing to the rectum and bladder. This approach has been demonstrated to improve the efficiency of the treatment planning process, and may potentially improve the quality of patient care by enabling more consistent treatment planning across institutions.
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    Musculoskeletal symptoms among female garment factory workers in Sri Lanka.
    (2011) Lombardo, Sarah R.
    OBJECTIVES: To assess the prevalence of musculoskeletal symptoms and their association with sociodemographic risk factors among female garment factory workers in Sri Lanka. METHODS: 1058 randomly selected female garment factory workers employed in the free trade zone of Kogalla, Sri Lanka were recruited to complete two interviewer-administered questionnaires assessing musculoskeletal symptoms and health behaviors. DISCUSSION: Musculoskeletal complaints among female garment workers in the FTZ of Kogalla are less common than expected. Sociocultural factors may have resulted in underreporting and similarly contribute to the low rates of healthcare utilization by these women. RESULTS: 164 (15.5%) of workers reported musculoskeletal symptoms occurring more than 3 times or lasting a week or more during the previous 12-month period. Back (57.3%) and knee (31.7%) were the most common sites of pain. Although most symptomatic women reported that their problems interfered with work and leisure activities, very few missed work as a result of their pain. Prevalence correlated positively with increased age and industry tenure of less than 12 months. Job type, body mass index, and education were not significant predictors of musculoskeletal symptoms.
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    Optimized approach to decision fusion of heterogeneous data for breast cancer diagnosis.
    (Med Phys, 2006-08) Jesneck, Jonathan Lee
    As more diagnostic testing options become available to physicians, it becomes more difficult to combine various types of medical information together in order to optimize the overall diagnosis. To improve diagnostic performance, here we introduce an approach to optimize a decision-fusion technique to combine heterogeneous information, such as from different modalities, feature categories, or institutions. For classifier comparison we used two performance metrics: The receiving operator characteristic (ROC) area under the curve [area under the ROC curve (AUC)] and the normalized partial area under the curve (pAUC). This study used four classifiers: Linear discriminant analysis (LDA), artificial neural network (ANN), and two variants of our decision-fusion technique, AUC-optimized (DF-A) and pAUC-optimized (DF-P) decision fusion. We applied each of these classifiers with 100-fold cross-validation to two heterogeneous breast cancer data sets: One of mass lesion features and a much more challenging one of microcalcification lesion features. For the calcification data set, DF-A outperformed the other classifiers in terms of AUC (p < 0.02) and achieved AUC=0.85 +/- 0.01. The DF-P surpassed the other classifiers in terms of pAUC (p < 0.01) and reached pAUC=0.38 +/- 0.02. For the mass data set, DF-A outperformed both the ANN and the LDA (p < 0.04) and achieved AUC=0.94 +/- 0.01. Although for this data set there were no statistically significant differences among the classifiers' pAUC values (pAUC=0.57 +/- 0.07 to 0.67 +/- 0.05, p > 0.10), the DF-P did significantly improve specificity versus the LDA at both 98% and 100% sensitivity (p < 0.04). In conclusion, decision fusion directly optimized clinically significant performance measures, such as AUC and pAUC, and sometimes outperformed two well-known machine-learning techniques when applied to two different breast cancer data sets.
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    Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation.
    (2010) Jin, Cong
    In recent years, the incidence of allergic asthma as well as the severity of disease has rapidly increased worldwide. Numerous epidemiological studies have related the exacerbation of allergic asthma with exposure to increased ambient particles from air pollutants. However, the mechanism by which particulate allergens (pAg) exacerbate allergic asthma remains undefined. To evaluate this, we modeled environmental pAg induced allergic asthma by exposing mice to polystyrene beads coated with natural allergen extracts. Compared to equal amounts of soluble allergen extracts (sAg), pAg triggered markedly enhanced airway hyper-responsiveness and pulmonary eosinophilia in allergen sensitized mice. The cellular basis for this effect was determined to be mast cells (MCs), as both airway allergic responses were attenuated in MC deficient KitWsh/KitW-sh mice compared to MC reconstituted KitW-sh/KitW-sh mice. The divergent responses of MCs to pAg versus sAg were due to differences in the termination rate of IgE/FcεRI initiated signaling. Following ligation of sAg, IgE/FcεRI rapidly shuttled into a degradative endosome/lysosome pathway. However, following ligation by pAg, IgE/FcεRI migrated into lipid raft enriched compartments and subsequently failed to follow a degradative pathway, which resulted in a prolonged signaling and heightened synthesis of proinflammatory mediators. These observations highlight the overlooked contributions of the particulate nature of allergens and mast cell endocytic circuitry to the aggravation of allergic asthma.
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    Plate-specific gain map correction for the improvement of detective quantum efficiency in computed radiography.
    (2010) Schnell, Erich A.
    The purpose of this work is to improve the NPS, and thus DQE, of CR images by correcting for pixel-to-pixel gain variations specific to each plate. Ten high-exposure open field images were taken with an RQA5 spectrum, with a sixth generation CR plate suspended in air without a cassette. Image values were converted to exposure, the plates registered using fiducial dots on the plate, the ten images averaged, and then high-pass filtered to remove low frequency contributions from field inhomogeneity. A gain-map was then produced by converting all pixel values in the average into fractions with mean of one. The resultant gain-map of the plate was used to normalize subsequent single images to correct for pixel-to-pixel gain fluctuation. The normalized NPS (NNPS) for all images was calculated both with and without the gain-map correction. The NNPS with correction showed improvement over the non-corrected case over the range of frequencies from 0.15 –2.5 mm-1. At high exposure (40 mR), NNPS was 50-90% better with gain-map correction than without. A small further improvement in NNPS was seen from careful registering of the gain-map with subsequent images using small fiducial dots, because of slight misregistration during scanning. CR devices have not traditionally employed gain-map corrections common with DR detectors because of the multiplicity of plates used with each reader. This study demonstrates that a simple gain-map can be used to correct for the fixed-pattern noise and thus improve the DQE of CR imaging. Such a method could easily be implemented by manufacturers because each plate has a unique bar code and the gain-map could be stored for retrieval after plate reading. These experiments indicated that an improvement in NPS (and hence, DQE) is possible, depending on exposure level,over all frequencies with this technique.
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    Prostate Bed Motion During Post-Prostatectomy Radiotherapy
    (MEDICAL PHYSICS, 2012-06) Xu, Z; Li, T; Lee, W; Hood, R; Godfrey, D; Wu, Q
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