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Birmingham, AL, United States

West Nile virus has become an important epidemiological problem attracting significant attention of health authorities, mass media, and the public. Although there are promising advancements toward addressing the vaccine need, the perspectives of the commercial availability of the vaccine remain uncertain. To a large extent this is due to lack of a sustained interest for further commercial development of the vaccines already undergoing the preclinical and clinical development, and a predicted insignificant cost effectiveness of mass vaccination. There is a need for a safe, efficacious and cost effective vaccine, which can improve the feasibility of a targeted vaccination program. In the present report, we summarize the background, the rationale, and the choice of the development pathway that we selected for the design of a live attenuated human West Nile vaccine in a novel infectious DNA format. © 2015 Elsevier Inc. Source

Shapiro A.M.,University of Toronto | Miller-Pinsler L.,University of Toronto | Miller-Pinsler L.,Southern Research | Wells P.G.,University of Toronto
Redox Biology

The breast cancer 1 (brca1) gene is associated with breast and ovarian cancers, and heterozygous (+/-) brca1 knockout progeny develop normally, suggesting a negligible developmental impact. However, our results show BRCA1 plays a broader biological role in protecting the embryo from oxidative stress. Sox2-promoted Cre-expressing hemizygous males were mated with floxed brca1 females, and gestational day 8 +/- brca1 conditional knockout embryos with a 28% reduction in protein expression were exposed in culture to the reactive oxygen species (ROS)-initiating drug ethanol (EtOH). Untreated +/- brca1-deficient embryos developed normally, but when exposed to EtOH exhibited increased levels of oxidatively damaged DNA, measured as 8-oxo-2'-deoxyguanosine, γH2AX, which is a marker of DNA double strand breaks that can result from 8-oxo-2'-deoxyguanosine, formation, and embryopathies at EtOH concentrations that did not affect their brca1-normal littermates. These results reveal that even modest BRCA1 deficiencies render the embryo more susceptible to drug-enhanced ROS formation, and corroborate a role for DNA oxidation in the mechanism of EtOH teratogenesis. © 2015 The Authors. Source

Lu A.,University of Alabama at Birmingham | Pallero M.A.,University of Alabama at Birmingham | Lei W.,University of Alabama at Birmingham | Hong H.,University of Alabama at Birmingham | And 3 more authors.
American Journal of Pathology

Transforming growth factor (TGF)-β supports multiple myeloma progression and associated osteolytic bone disease. Conversion of latent TGF-β to its biologically active form is a major regulatory node controlling its activity. Thrombospondin1 (TSP1) binds and activates TGF-β. TSP1 is increased in myeloma, and TSP1-TGF-β activation inhibits osteoblast differentiation. We hypothesized that TSP1 regulates TGF-β activity in myeloma and that antagonism of the TSP1-TGF-β axis inhibits myeloma progression. Antagonists (LSKL peptide, SRI31277) derived from the LSKL sequence of latent TGF-β that block TSP1-TGF-β activation were used to determine the role of the TSP1-TGF-β pathway in mouse models of myeloma. TSP1 binds to human myeloma cells and activates TGF-β produced by cultured human and mouse myeloma cell lines. Antagonists delivered via osmotic pump in an intratibial severe combined immunodeficiency CAG myeloma model or in a systemic severe combined immunodeficiency CAG-heparanase model of aggressive myeloma reduced TGF-β signaling (phospho-Smad 2) in bone sections, tumor burden, mouse IL-6, and osteoclasts, increased osteoblast number, and inhibited bone destruction as measured by microcomputed tomography. SRI31277 reduced tumor burden in the immune competent 5TGM1 myeloma model. SRI31277 was as effective as dexamethasone or bortezomib, and SRI31277 combined with bortezomib showed greater tumor reduction than either agent alone. These studies validate TSP1-regulated TGF-β activation as a therapeutic strategy for targeted inhibition of TGF-β in myeloma. © Copyright 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. Source

Agency: Department of Defense | Branch: Air Force | Program: STTR | Phase: Phase I | Award Amount: 149.92K | Year: 2016

ABSTRACT: This Phase I effort will identify and evaluate candidate materials to replace existing beryllium-copper alloy components for use in aerospace ground test flow facilities. The candidate materials must offer similar or better performance metrics (dimensional stability, lifetime, etc.), be domestically and readily available, offer similar or cheaper costs, and the ability to withstand temperatures and pressures on the order of 1000?F and 2000 psi, respectfully. This will be achieved through the identification of the wind tunnel nozzle details; selecting candidate materials based on the desirable melting temperature, mechanical erosion resistance, elevated temperature stability, thermodynamic stability, and theoretical thermal-structural performance; detailed design and analysis trade studies via the finite element method to establish preliminary design options; billets/test specimens fabrication; and characterization of critical material properties. The fabrication approaches will consider Vacuum Plasma Spray (VPS), electrochemical deposition (EL-Form?), and Hot Isostatic Pressing (HIP). The characterization efforts will measure critical properties including thermal diffusivity (thermal conductivity, density, and specific heat), thermal expansion, Young?s modulus, and tensile strength/strain capability at select temperatures within the range of 75 - 3000?F for two candidate materials to replace beryllium-copper.; BENEFIT: The anticipated results of this Phase I project will include material property database development for two candidate materials to replace beryllium-copper and the establishment of preliminary design concepts for their use within the high pressure wind tunnel. The material property database development will initially be derived from experimental results developed from previous and ongoing programs coupled with literature data. These databases will then be supplemented with experimentally-derived material property measurements to be performed in this proposed effort. The characterization will measure critical properties including thermal diffusivity (thermal conductivity, density, and specific heat), thermal expansion, Young?s modulus, and tensile strength/strain capability at select temperatures within the range of 75 - 3000?F. The preliminary designs will define theoretically attractive design options for the entire wind tunnel nozzle assembly, including the identification of any necessary modifications to the existing materials and hardware. This proposed STTR fits into MR&D?s expanding role as designers of advanced materials for extreme environments for demanding commercial and aerospace/defense applications. Technical success in this proposed effort will further enhance our position of offering unique and desirable design and analysis technology. Since MR&D is a design service-based company, the designs that we develop become the property of our customers. Thus the MR&D business plan does not envision growth in terms of numbers of fabricated components or growth in sales of developed software products or database systems. Rather the proposed Phase I program will result in design expertise coupled with applicable fabrication and experimentation that ultimately can be used to assist the Air Force. Additionally the high pressure wind tunnel design knowledge gained by MR&D from the Phase I program will open new opportunities to provide design and analysis services for various potential customers.

Liu F.,University of Alabama at Birmingham | Kozlovskaya V.,University of Alabama at Birmingham | Medipelli S.,University of Alabama at Birmingham | Xue B.,University of Alabama at Birmingham | And 4 more authors.
Chemistry of Materials

We report on a novel type of triblock copolymer polymersomes with temperature-controlled permeability within the physiologically relevant temperature range of 37-42 °C for sustained delivery of anticancer drugs. These polymersomes combine characteristics of liposomes, such as biocompatibility, biodegradability, monodispersity, and stability at room temperature, with tunable size and thermal responsiveness provided by amphiphilic triblock copolymers. The temperature-sensitive poly(N-vinylcaprolactam)n-poly(dimethylsiloxane)65-poly(N-vinylcaprolactam)n (PVCLn-PDMS65-PVCLn) copolymers with n = 10, 15, 19, 29, and 50 and polydispersity indexes less than 1.17 are synthesized by controlled RAFT polymerization. The copolymers are assembled into stable vesicles at room temperature when the ratio of PVCL to the total polymer mass is 0.36 < f < 0.52 with the polymersome diameter decreasing from 530 to 40 nm as the length of PVCL is increased from 10 to 19 monomer units. Importantly, the permeability of polymersomes loaded with the anticancer drug doxorubicin can be precisely controlled by PVCL length in the temperature range of 37-42 °C. Increasing the temperature above the lower critical solution temperature of PVCL results in either gradual vesicle shrinkage (n = 10 and n = 15) or reversible formation of beadlike aggregates with no size change (n = 19), both leading to sustained drug release. All temperature-triggered morphological changes are reversible and do not compromise the structural stability of the vesicles. Finally, concentration- and time-dependent cytotoxicity of drug-loaded polymersomes to human alveolar adenocarcinoma cells is demonstrated. Considering the high loading capacity (∼40%) and temperature responsiveness in the physiological range, these polymer vesicles have considerable potential as novel types of stimuli-responsive drug nanocarriers. © 2015 American Chemical Society. Source

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