Iron accumulation and deposition have been reported in patients with amyotrophic lateral sclerosis (ALS). Previous work in mutant SOD1 mice mouse models of ALS have indicated that iron chelation with a chemical agent extends lifespan. Therefore, we propose the use of apo-ferritin, the iron-storage protein ferritin that is iron-poor, as a natural ionophore to sequester excess iron and redistribute it. The overall hypothesis is that infusion of apo- ferritin protein into the brain will provide neuroprotection by limiting the availability of excess iron to catalyze free-radical production. The most significant findings from this project are: (1) Infusion of artificial cerebrospinal fluid (aCSF) containing nutrients, including H-ferritin, increases lifespan and delays onset of disease in SOD1G93A mice; (2) This effect is not achieved by infusion of saline, suggesting that there is more than just a mechanical benefit to increasing flow of CSF (3) In an accelerated disease model of ALS where mice carry both the HFEH67D allelic variant, present in 30% of ALS patients, and the SOD1G93A mutation, infusion of aCSF with or without H-ferritin is not beneficial. The high rate of oxidative stress in these animals may be too great for an infusion strategy; (4) Infusion of H- ferritin protein encapsulated in liposomes is even more effective at delaying onset and extending lifespan than H-ferritin protein directly infused. The potential clinical significance of this work is that increasing turn-over of cerebrospinal fluid, and providing H-ferritin in a manner that may be more likely to be taken up by cells, appear to be viable therapeutic options for ALS patients.

关键词：蛋白质；脑脊液；铁；脂质体；运动神经元

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Antimicrobial resistance is one of our most serious health threats. Infections from resistant bacteria are now too common, and some pathogens have even become resistant to multiple types or classes of antibiotics (antimicrobials used to treat bacterial infections). The loss of effective antibiotics will undermine our ability to fight infectious diseases and manage the infectious complications common in vulnerable patients undergoing chemotherapy for cancer, dialysis for renal failure, and surgery, especially organ transplantation, for which the ability to treat secondary infections is crucial.

关键词：抗生素耐药性；传染病；卫生威胁

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Work done during the first year of the award resulted in the identification and characterization of a set of 29 A. baumannii strains isolated from wounded military personnel with regard to their capacity to grow under iron-limiting conditions, produce iron chelators siderophores and form biofilms on abiotic surfaces found in medical settings. This analysis indicates that all isolates form biofilms on abiotic surfaces and different strains produce and/or use different siderophores when cultured under iron chelation. However, all tested strains produce dihydroxybenzoic acid derivatives, the synthesis of which could be used as a therapeutic target. Accordingly, salicylic acid derivatives seem to inhibit bacterial growth under iron chelation. Equally encouraging is the observation that gallium-containing derivatives, particularly Gaprotoporphyrin IX, inhibit bacterial growth independently of the iron and nutrient content of the medium. These are encouraging observations that will be tested in animal models proposed in this project and promote future basic studies since the mechanisms by which Ga-PPIX inhibit A. baumannii growth are unknown. Work done during this first year together with preliminary data collected by collaborators also resulted in the selection of the AB5075 isolate as a model strain for more extensive studies. This clinical isolate proved to be virulent when tested using ex vivo and in vivo experimental infection models and amenable to genetic manipulations, including high throughput insertion mutagenesis and genetic complementation with shuttle cloning vectors under construction.

关键词：细菌性疾病；革兰阴性菌；传染病

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Prostatic adenocarcinoma (PC) is the most common form of non- cutaneous cancer and second most lethal cancer in American men but demonstrates tremendous disparity in both incidence and severity between African American men (AAM) and Caucasian men (CM). We have identified prostatic intratumoral steroidogenesis as a biological factor that may explain some or much of the disparity in lethal PC rates between AAM and CM. We proposed testing this hypothesis by examining intratumoral steroidogenesis in the prostates of men following radical prostatectomy and in vivo model systems. In this project period we have finished our initial round of in vivo modeling and have demonstrated that hypercholesterolemia contributes to prostate tumor growth in our model mimicking the human patient situation in which androgen deprivation therapy (castration) is applied after tumor initiation. End point testing is currently underway and we anticipate finding excess androgen and nuclear AR in tumors undergoing relapse in hypercholesterolemic mice. Blinded analysis is ongoing and will be unblinded as soon as all end point data has been collected. The final data are anticipated to reveal that, as hypothesized, hypercholesterolemia contributes to faster relapse after castration and increases intratumoral steroidogenesis.

关键词：前列腺癌；类固醇；雄激素

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With funds from this grant, Youngstown State University has purchased a Quantachrome iQ Chemisorption Analyzer and built a Chemical Reactor with Gas Chromatographer for catalyst characterization. PI has been involved in the purchase and installation of the instruments. The two new instruments were fully operational in the spring of 2013 and have so far been used for student research. For the research projects, we found that the nucleation and oxidation of Ce(OH)3 are critical steps which needs careful control in order to synthesize different morphological CeO2 nanocrystals. The combination of stirring and oxidation of suspension could destroy the nucleation and growth of Ce(OH)3, resulting in the formation of irregular CeO2 nanocrystals during the hydrothermal reactions. We demonstrated a general route for shape-controlled synthesis of CeO2 nanocrystals via mediation of the Ce(OH)3 seed before hydrothermal reactions. It was revealed that the shape of CeO2 support plays a critical role in metal-CeO2 catalytic activity for low-temperature CO oxidation. Out of this project, six refereed and four proceeding papers were published, along with several oral presentations made by PI and students.

关键词：催化转换器；化学反应；化学吸附

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Sampling and analysis of beryllium in the workplace can be more challenging than for many other metals. For starters, the occupational exposure limits for beryllium tend to be in the microgram or sub-microgram per cubic meter range, rather than in the milligram range. Some forms of beryllium, especially beryllium oxide, are not fully dissolved in many commonly used sample preparation methods. And, in many cases, interpreting results for beryllium samples is difficult as well, particularly if most results come back below the laboratory's reporting limit and you dont have the luxury of collecting enough samples for a nonparametric statistical treatment. At the time this article was written, new rulemakings were under consideration at OSHA and the U.S. Department of Energy (DOE) that would propose changes to occupational exposure limits for beryllium. Given these developments, its a good time to review the tools and methods available to IHs for assessing beryllium air and surface contamination in the workplace--what's new and different, and what's tried and true.

关键词：铍；职业暴露；采样；航空

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Endogenous opiate peptides (enkephalins and endorphins) are more potent and specific than morphine and congeners. Specificity is determined by the 'address segment' while binding is determined by the 'message segment.' Incorporation of carbohydrates into the address segment results in improved biodistribution and enhanced penetration of the blood-brain barrier (BBB). Thus, glycosylation of mu- or delta-selective peptides allows the resulting glycopeptides to be used as potent and safer alternatives to classical opiates such as morphine. Morphine and other muselective agonists are immunosuppressants, while the glycopeptide enkephalins are selective delta- agonists, which are known to be immunostimulants. Hypothesis: Enkephalin transport and penetration of the blood-brain barrier can be determined by reversible binding to membranes, which may be manipulated by altering the amphipathicity of the address segment directly by introduction of hydrophilic sugar moieties, and lipophilic side chains. Conclusion: Glycopeptide analogues of enkephalins are viable drug candidates. Obstacles regarding the synthesis and design of analgesics have been overcome. Further studies are required in order to meet FDA requirements. See attached .pdf file (14 pg and 22 pg reviews) for details.

关键词：镇痛药；伤亡；内啡肽；医疗服务

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Patients with prostate cancer frequently receive radiation therapy. Although radiation therapy is effective for the treatment of primary tumors, bystander bone absorbs approximately half of the radiation dose and thus may cause adverse radiation-induced effects at skeletal sites. Indeed, within five years of radiation treatment at the pelvic region (cervical, rectal or anal cancer), the risk of hip fracture increases by up to 20% in cancer patients relative to the general population. During the reported project period, a dose- response and time-course study using in situ bone calvarial assays demonstrated that radiation exposure (6-10Gy) causes osteocyte apoptosis one week following exposure. Osteoblast apoptosis was not observed during the time course (1-10 days) at any dose (2-10Gy). Next, using a single-limb therapeutic radiation model, I examined the direct and indirect effects of radiation on bone in vivo. Our data demonstrate that a relatively low dose of site-directed radiation (2Gy) caused direct and systemic bone loss in C57Bl/6 mice relative to previously untested sham-irradiated controls and that osteoclastogenesis and marrow adiposity were drastically increased one week following radiation exposure at site of direct irradiation. Assayed sera from irradiated mice revealed no change in classic inflammatory pro-resorptive cytokines (IL-1 , IL- 6, IL-17, TNF- ); however, we did observe a significant decline in anti- inflammatory cytokines (IL-3, IL-4, IL-10 and RANTES/CCL2) relative to sham- irradiated controls. Using dynamic histomorphometry, mineralized surface area of bone at sites of irradiation was reduced, with no change in the number of osteoblasts, indicating that osteoblast function may be impaired by irradiation. We therefore conclude that bone loss resulting from radiation exposure in vivo can be attributed to an increase in osteoclastic bone resorption and reduced mineralization of bone surfaces.

关键词：转移；前列腺癌；辐射剂量；细胞凋亡

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Immune-based therapy for solid tumors is a promising area of research, providing the potential for cell-mediated immunotherapies to provide long-lived protection against various stage cancer. Unfortunately, even the most successful clinical trials using T cells or dendritic cells (DC) only show objective response rates in <50% of patients. This is due, in part, to a variety of tumor-derived immunosuppressive mechanisms that arise in cancer patients, rerendering antitumor immune responses ineffective. In addition, epidemiological studies have demonstrated that obese individuals face an increased risk of developing cancers, including breast cancer. The reasons for this are likely complex and multi-factorial, , but a state of generalized immune suppression may contribute to these findings. Regardless of the body-mass index of the patient, successful long-term treatment of breast cancer must not only reduce the localized tumor burden, but must also target undetected or known metastases that may exist at the time the primary tumor is identified and treated.

关键词：乳腺癌；免疫；;肥胖；细胞凋亡

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The TSC1/TSC2 complex integrates multiple cues to regulate protein translation and cell growth via mammalian target of rapamycin complex I (mTORC1). Loss of TSC functions leads to constitutive activation of mTORC1 and uncontrolled mRNA translation. The goal of this res earch project to elucidate cis -regulatory elements and trans -acting factors in TSC-mTORC1- mediated translational regulation. We have discovered that the stress -induced preferential translation of Hsp70 mRNA is deficient in cells lacking TSC2. This finding provides a plausible mechanism about how persistent mTOR signaling favors the development of various pathologies of TSC by attenuating stress resistance. We recently discovered that TSC -mTORC1 increased the yield of protein synthesis at the expense of protein quality. By harnessing the power of ribosome profiling, we also discovered post-initiation ribosomal pausing that is subject to TSC-mTORC1 regulation. In addition, we have established a novel approach called Global Translation Initiation sequencing (GTI-seq) to investigate alternative translation. These studies are significant because TSC- mTORC1-controlled alternative translation initiation has never been defined.

关键词：基因组；应力（生理）；衰减；电池（生物学）

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