Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer death among men in the United States. Considering that PCa development requires the coordination of many genes, it is expected that a simultaneous evaluation of multiple genetic variants can improve the statistical power to detect additional PCa risk variants. Recent improvements in analytical methods and computation make it feasible to search for gene-gene interaction of SNPs in the genome. We hypothesized that multiple sequence variants in the genome may interact to increase PCa risk. These variants may or may not have known main effect on PCa risk and can be better detected by systematically evaluating gene-gene interactions for SNPs in the genome. We utilized data from an existing GWAS of a large NCI Cancer Genetic Markers of Susceptibility (CGEMS) study to systematically discover genes that interacted with known PCa risk variants in the genome. We also evaluated the genes that interacted with known PCa risk variants in another two independent populations, including a population based PCa case-control study from Sweden (CAPS) and a PCa patient population from Johns Hopkins Hospital (JHH). In addition, we performed an exhaustive search for pair-wide SNP-SNP interactions without main effect in the JHH and CGEMS populations using a novel statistical approach of Boolean Operation-based Screening and Testing (BOOST). We identified thirty- five pairs of SNPs that significantly interacted with the thirty-two known risk variants on PCa risk at a P-value of 1E-05 in the combined analysis of three populations. The most significant interaction detected was between rs12418451 in MYEOV and rs784411 in CEP152, with a Pinteraction of 1.15E-07 in the meta- analysis.

关键词：基因；前列腺癌；风险；案例研究

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The goal of this project is to analyze the entire microbial population of the mucosa in the upper gastrointestinal tract of children with autism to determine if there is an overgrowth of specific populations of bacteria and analyze the relationship between the intestinal flora and behavior. Our current sub-contractor from the institute of Genome Sciences, University of Maryland School of Medicine was not able to amplify and sequence DNA from the duodenal biopsies of autistic children and controls. A new sub-contractor the Research and Testing Laboratory was found. A new set of duodenal biopsies from children with and without autism will be sent to the Research and Testing Laboratory for DNA extraction, PCR for 16S rRNA, sequencing. No additional funding will be requested to complete this project.

关键词：胃肠道系统；精神障碍；活组织检查

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Adaptive radiotherapy (RT) is an advanced technique for prostate cancer treatment which employs kilovoltage (KV) cone-beam CT (CBCT) for guiding treatment. High quality CBCT images are important in achieving improved treatment effect, but they also require a non-negligible amount of imaging radiation dose which raises patient safety concern. Therefore, the goal of this project is to investigate and develop innovative, prior-image-based CBCT imaging techniques that can yield high quality images with reduced dose. Throughout the three years of this project, I have conducted research tasks as planned. I have investigated and developed prior-image-based, narrowly collimated KV CBCT imaging configurations, have developed prior-image- based, few-view CBCT image-reconstruction algorithms, and have validated and evaluated the proposed configurations and algorithms. I have achieved the goals planned for this project. The techniques developed can potentially improve current CBCT image quality, and can enable novel, high-quality, low-dose CBCT imaging configurations.

关键词：电脑断层；前列腺癌；放射疗法

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Gulf War Illness (GWI) is a multi-symptom syndrome with features of an inflammatory response due to infection or injury, findings suggestive of a chronic neuroimmune/neuroinflammatory disorder. Our overarching hypothesis is that exposure to GWI-relevant compounds lead to enhanced and/or prolonged expression of proinflammatory mediators in the brain. Our overall objective is to establish a neuroinflammatory model of GWI-related exposures, to define the contribution of high physiological stress, and to assess the potential for pharmacotherapy to ameliorate these effects. The results are suggestive of a possible critical and as yet unrecognized interaction between the stressful environs of the GW theater and agent exposure(s) unique to this war, exposures in which the CNS is primed to amplify future exposures to pathogens, injury or toxicity. Recently it has been shown that stress-induced augmentation of neuroinflammation induced by a positive control compound persists for 30 days after stress presentation, and that repeated intermittent stress presentations have a cumulative effect on the neuroinflammation. Such occurrences could potentially result in prolonged episodes of sickness behavior that would simulate GWiwell.

关键词：炎症；响应（生物学）；应力（心理学）；创伤和损伤

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Botulinum neurotoxin has no cure once it has entered neurons. One approach to finding a treatment is to determine the molecules that regulate the half-life of the toxin in the cell. The serotype BoNT/A has a very long half- life (months) whereas the serotype BoNT/E has a short half-life (days). We have made a chimeric protein consisting of the light chains (LCs) of both toxins and found the half-life to be short, similar to light chain E (LcE). This finding suggests that the molecules controlling intracellular degradation of LcE are dominant over those that control LcA. We have also completed an assessment of neuronal proteins that bind each LC by Yeast 2 Hybrid (Y2H) analysis. In the coming year, we will assess the contributions of these molecules to LC half- life by knock-down experiments. Furthermore, we have produced a designer ligase which is comprised of a VHH antibody binding region specific for LcA that is coupled to a ubiquitin ligase molecule. When delivered intracellularly as a plasmid by transfection, this molecule has been shown to shorten the half-life of LcA by ubiquitination and targeting to the proteasome. We have inserted the designer ligase into a protein delivery system and plan to test the ability of this system to rescue BoNT/A intoxicated neurons in the coming year.

关键词：肉毒杆菌；神经毒素；细胞（生物学）

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A platform technology to prepare enzyme sensitive nanomedicine (ESNM), which integrates the imaging and treatment capability, has been developed to report and cure diseases. ESNM is prepared with multiple layers of polyelectrolytes, sequentially assembled on an inert gold nanoparticle, using alternating charged polymers. Potentially the release kinetics could be controlled by varying polyelectrolytes with different properties, such as length, ionic strength and bond stability. Upon incubation with cells, the assembled ESNMs are taken up efficiently. The tight packing and layered assembly of the quenched polyelectrolytes slow subsequent intracellular degradation, and then result in a prolonged intracellular fluorescence signal and therapeutic effect for up to 3 weeks with no noticeable toxicity.

关键词：医疗服务；肽水解酶；核糖核酸

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We have discovered that the Akt pathway modulates breast cancer cell survival in response to genotoxic agents, and discovered a new substrate of Akt, MERIT40, that is phosphorylated upon exposure of cells to chemotherapeutic drugs. We propose that this represents a major mechanism by which cells exposed to these drugs evade cell death by apoptosis and thus become resistant to the damaging effects of clinically-relevant chemotherapy agents. These findings have important ramifications for the use of chemotherapy drugs in breast cancer patients, and many also suggest that MERIT40 may be used as a clinically relevant biomarker for resistance to doxorubicin.

关键词：乳腺癌细胞（生物学）；化疗；死亡

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As software and methodology develop, key aspects of molecular interactions such as detailed energetics and flexibility are continuously better represented in docking simulations. In the latest iteration of the XPairIt API and Docking Protocol, we perform a blind dock of a peptide into the cleavage site of the Anthrax lethal factor (LF) metalloprotein. Molecular structures are prepared from RCSB:1JKY and we demonstrate a reasonably accurate docked peptide through analysis of protein motion and, using NCI Plot, visualize and characterize the forces leading to binding. We compare our docked structure to the 1JKY crystal structure and the more recent 1PWV structure, and discuss both captured and overlooked interactions. Our results offer a more detailed look at secondary contact and show that both van der Waals and electrostatic interactions from peptide residues further from the enzyme's catalytic site are significant.

关键词：炭疽；计算机程序；杀伤力；肽

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In this project, we proposed to develop the imaging method for early detection of amyloid plaque in Alzheimer's disease. As specified in SA1 and the project timeline, the major tasks of year 1 are the construction and optimization of a prototype x-ray phase contrast CT system to carry out the tasks specified in SA2 and 3. Thus far, the construction of the prototype x- ray phase contrast CT is progressing well and is in the optimization process as anticipated. The major challenge of building the prototype x-ray phase contrast CT is the fabrication of x-ray gratings at high precision and performance. Enabled by the cutting-edge opti-mechanical equipment and devices at the Nano- Technology Research Center of GaTech (see Fig. 1), we have gained a plenty of experience in fabricating the x-ray gratings through a trial and error optimization process. We have also built three modules that are ready for filling of ABeta-peptide and ABeta-peptide/fibril to make the ABeta-peptide phantoms to carry out the tasks specified in SA2. Thus far, under partial support of this award, two journal papers have been published in Medical Physics- one of the leading journals in medical imaging, and five papers published in leading international conferences. Overall, the project's progression has been in pace with the project timeline specified in statement of work (SOW).

关键词：阿尔茨海默病；脑；电脑断层扫描；X射线

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During the past grant period, we obtained further evidence that eukaryotic elongation factor-2 kinase (eEF-2K) plays an important role in the development and progression of cancer by regulating cellular metabolism. In the study of the molecular mechanisms and pathways by which eEF-2K promotes glycolysis, we demonstrated that c-Myc-PKM2 pathway mediated the effect of eEF- 2K on glycolysis. We further showed that suppression of eEF-2K impeded the induction of glycolysis in tumor cells subjected to hypoxia, enhanced apoptosis, and sensitized breast cancer cells to hypoxic insult. The results obtained during the last grant period have identified eEF-2K as a critical regulator of cell proliferation by promoting cancer cell metabolism, and provide new evidence that the effect of eEF- 2K on glycolysis is mediated through PKM2 and c-Myc. In addition, depletion of eEF-2K prevented the hypoxia-induced glycolysis and enhanced the sensitivity of tumor cells to hypoxic stress. These results underscore the potential of eEF-2K as a target for prevention and treatment of breast cancer.

关键词：乳腺癌细胞（生物学）；治疗；细胞凋亡

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