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      • SCIESCOPUS

        The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects.

        Schwartz, David L,Powis, Garth,Thitai-Kumar, Arun,He, Yi,Bankson, James,Williams, Ryan,Lemos, Robert,Oh, Junghwan,Volgin, Andrei,Soghomonyan, Suren,Nishii, Ryuichi,Alauddin, Mian,Mukhopadhay, Uday,Pen American Association for Cancer Research, Inc 2009 Molecular Cancer Therapeutics Vol.8 No.4

        <P>Hypoxia inducible factor-1 (HIF-1) promotes tumor cell adaptation to microenvironmental stress. HIF-1 is up-regulated in irradiated tumors and serves as a promising target for radiosensitization. We initially confirmed that the orally bioavailable HIF-1 inhibitor PX-478 reduces HIF-1 protein levels and signaling in vitro in a dose-dependent manner and provides direct radiosensitization of hypoxic cancer cells in clonogenic survival assays using C6 glioma, HN5 and UMSCCa10 squamous cells, and Panc-1 pancreatic adenocarcinoma cell lines. However, PX-478 yields striking in vivo tumor sensitization to single-dose irradiation, which cannot be explained by incremental improvement in direct tumor cell killing. We show that PX-478 prevents postradiation HIF-1 signaling and abrogates downstream stromal adaptation in C6 and HN5 reporter xenografts as measured by serial ultrasound, vascular magnetic resonance imaging, and hypoxia response element-specific micro-positron emission tomography imaging. The primacy of indirect PX-478 in vivo effects was corroborated by our findings that (a) either concurrent or early postradiation sequencing of PX-478 provides roughly equivalent sensitization and (b) constitutive vascular endothelial growth factor expression maintains refractory tumor vessel function and progression following combined radiation and PX-478. These results confirm that disruption of postradiation adaptive HIF-1 signaling by PX-478 imparts increased therapeutic efficacy through blockade of HIF-1-dependent reconstitution of tumor stromal function. Successful translation of targeted HIF-1 radiosensitization to the clinical setting will require specific consideration of tumor microenvironmental effects and mechanisms.</P>

      • Ligand-field symmetry effects in Fe(<small>II</small>) polypyridyl compounds probed by transient X-ray absorption spectroscopy

        Cho, Hana,Strader, Matthew L.,Hong, Kiryong,Jamula, Lindsey,Gullikson, Eric M.,Kim, Tae Kyu,de Groot, Frank M. F.,McCusker, James K.,Schoenlein, Robert W.,Huse, Nils The Royal Society of Chemistry 2012 Faraday discussions Vol.157 No.-

        <P>Ultrafast excited-state evolution in polypyridyl Fe(<SMALL>II</SMALL>) complexes is of fundamental interest for understanding the origins of the sub-ps spin-state changes that occur upon photoexcitation of this class of compounds as well as for the potential impact such ultrafast dynamics have on incorporation of these compounds in solar energy conversion schemes or switchable optical storage technologies. We have demonstrated that ground-state and, more importantly, ultrafast time-resolved X-ray absorption methods can offer unique insights into the interplay between electronic and geometric structure that underpins the photo-induced dynamics of this class of compounds. The present contribution examines in greater detail how the symmetry of the ligand field surrounding the metal ion can be probed using these X-ray techniques. In particular, we show that steady-state K-edge spectroscopy of the nearest-neighbour nitrogen atoms reveals the characteristic chemical environment of the respective ligands and suggests an interesting target for future charge-transfer femtosecond and attosecond spectroscopy in the X-ray water window.</P>

      • A bodipy based hydroxylamine sensor

        Sedgwick, Adam C.,Chapman, Robert S. L.,Gardiner, Jordan E.,Peacock, Lucy R.,Kim, Gyoungmi,Yoon, Juyoung,Bull, Steven D.,James, Tony D. The Royal Society of Chemistry 2017 Chemical communications Vol.53 No.75

        <P>With this research, we have developed a bodipy based system as the first “turn-on” fluorescence system for the detection hydroxylamine.</P>

      • Dynamics of Precise Ethylene Ionomers Containing Ionic Liquid Functionality

        Choi, U Hyeok,Middleton, L. Robert,Soccio, Michelina,Buitrago, C. Francisco,Aitken, Brian S.,Masser, Hanqing,Wagener, Kenneth B.,Winey, Karen I.,Runt, James American Chemical Society 2015 Macromolecules Vol.48 No.2

        <P>This paper presents the first findings on the molecular dynamics of the remarkable new class of linear and precisely functionalized ethylene copolymers. Specifically, we utilize broadband dielectric relaxation spectroscopy to investigate the molecular dynamics of linear polyethylene (PE)-based ionomers containing 1-methylimidazolium bromide (<B>ImBr</B>) pendants on exactly every 9th, 15th, or 21st carbon atom, along with one pseudorandom analogue. We also employed FTIR spectroscopy to provide insight into local ionic interactions and the nature of the ordering of the ethylene spacers between pendants. Prior X-ray scattering experiments revealed that the polar ionic groups in these ionomers self-assemble into microphase-separated aggregates dispersed throughout the nonpolar PE matrix. We focus primarily on the dynamics of the segmental relaxations, which are significantly slowed down compared to linear PE due to ion aggregation. Relaxation times depend on composition, the presence of crystallinity, and microphase-separated morphologies. Segmental relaxation strengths are much lower than predicted by the Onsager theory for mobile isolated dipoles but much higher than linear PE, demonstrating that at least some <B>ImBr</B> pendants participate in the segmental process. Analysis of the relaxation strengths using the Kirkwood <I>g</I> correlation factor demonstrates that ca. 10–40% of the <B>ImBr</B> ion dipoles (depending on copolymer composition and temperature) participate in the segmental motions of the precise ionomers under study, with the remainder immobilized or having net antiparallel arrangements in ion aggregates.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/mamobx/2015/mamobx.2015.48.issue-2/ma502168e/production/images/medium/ma-2014-02168e_0011.gif'></P>

      • KCI등재

        Fusarium oxysporum Protects Douglas-fir (Pseudotsuga menziesii) Seedlings from Root Disease Caused by Fusarium commune

        R. Kasten Dumroese,김미숙,Robert L. James 한국식물병리학회 2012 Plant Pathology Journal Vol.28 No.3

        Fusarium root disease can be a serious problem in forest and conservation nurseries in the western United States. Fusarium inoculum is commonly found in most container and bareroot nurseries on healthy and diseased seedlings, in nursery soils, and on conifer seeds. Fusarium spp. within the F. oxysporum species complex have been recognized as pathogens for more than a century, but attempts to distinguish virulence by correlating morphological characteristics with results of pathogenicity tests were unsuccessful. Recent molecular characterization and pathogenicity tests, however, revealed that selected isolates of F. oxysporum are benign on Douglas-fir (Pseudotsuga menziesii) seedlings. Other morphologically indistinguishable isolates, which can be virulent, were identified as F. commune, a recently described species. In a replicated greenhouse study,inoculating Douglas-fir seedlings with one isolate of F. oxysporum prevented expression of disease caused by a virulent isolate of F. commune. Moreover, seedling survival and growth was unaffected by the presence of the F. oxysporum isolate, and this isolate yielded better biological control than a commercial formulation of Bacillus subtilis. These results demonstrate that an isolate of nonpathogenic F. oxysporum can effectively reduce Fusarium root disease of Douglas-fir caused by F. commune under nursery settings, and this biological control approach has potential for further development.

      • SCISCIESCOPUS

        Gold Nanoparticles Disrupt Zebrafish Eye Development and Pigmentation

        Kim, Ki-Tae,Zaikova, Tatiana,Hutchison, James E.,Tanguay, Robert L. Oxford University Press 2013 TOXICOLOGICAL SCIENCES Vol.133 No.2

        <P>Systematic toxicological study is still required to fully understand the hazard potentials of gold nanoparticles (AuNPs). Because their biomedical applications are rapidly evolving, we investigated developmental toxicity of AuNPs in an <I>in vivo</I> embryonic zebrafish model at exposure concentration ranges from 0.08 to 50mg/l. Exposure of zebrafish embryos to 1.3nm AuNPs functionalized with a cationic ligand, N,N,N-trimethylammoniumethanethiol (TMAT-AuNPs), resulted in smaller malpigmented eyes. We determined that TMAT-AuNPs caused a significant increase of cell death in the eye, which was correlated with an increase in gene expression of <I>p53</I> and <I>bax</I>. Expression patterns of key transcription factors regulating eye development (<I>pax6a</I>, <I>pax6b</I>, <I>otx2</I>, and <I>rx1</I>) and pigmentation (<I>sox10</I>) were both repressed in a concentration-dependent manner in embryos exposed to TMAT-AuNPs. Reduced spatial localization of <I>pax6a</I>, <I>rx1</I>, <I>sox10</I>, and <I>mitfa</I> was observed in embryos by whole-mount <I>in situ</I> hybridization. The swimming behavior of embryos exposed to sublethal concentrations of TMAT-AuNPs showed hypoactivity, and embryos exhibited axonal growth inhibition. Overall, these results demonstrated that TMAT-AuNPs disrupt the progression of eye development and pigmentation that continues to behavioral and neuronal damage in the developing zebrafish.</P>

      • SCOPUSKCI등재

        Development and Evaluation of an Oral Controlled Release Delivery System for Melatonin

        Lee,Beom Jin,Keith A Parrott,Robert L Sack,James W Ayres 한국약제학회 1993 Journal of Pharmaceutical Investigation Vol.23 No.3

        Sugar spheres loaded with melatonin (MT) were coated with Aquacoat^ⓡ to control the release rate of MT over 8 hours. A zero-order release pattern over 8 hours was obtained with 20% coating on 8-10 mesh beads in USP basket dissolution studies. MT in 20% coated beads was quite stable at room temperature with less than 5% MT degraded during 6 months' storage. Dissolution profiles were also unchanged after 6 months. An oral preparation containing MT-loaded uncoated beads for immediate release and 20% coated beads with Aquacoat^ⓡ for controlled release over 8 hours was evaluated in six human subjects. When total 0.5 ㎎ MT as low dose (immediate release portion of MT, 0.1 ㎎) was administered to four subjects, average peak plasma MT concentration was reached at about 600 pg/㎖ and maintained at about 10 pg/㎖ over 8 hours. Plasma MT concentration-time profiles were similar in shape to computer-simulated profiles. However, maximal plasma MT concentrations were three times greater compared to computer simulated curve. These results suggest that MT dose, ratio of immediate and controlled release MT, and pharmacokinetic parameters selected are adjusted to mimic endogenous MT concentration-time curve. In another study, 0.2 ㎎ MT having 10% of immediate release portion and 80% controlled release portion produced plasma MT concentration-time curve which is more similar to endogenous profiles. A low bioavailability (<20%) may result from extensive first pass metabolism and remaining amounts of MT from controlled beads. A good correlation between plasma MT concentration and urinary excretion rate of 6-sulphatoxymelatonin (6-STMT), a major metabolite of MT was observed. As plasma MT concentration increased, urinary excretion rate of 6-STMT increased concomitantly. The linear relation between plasma MT and urinary excretion rate of 6-STMT was statistically significant. This result suggests that urinary 6-STMT may be used as an index of circadian rhythms of MT in humans.

      • SCIEKCI등재

        Fusarium oxysporum Protects Douglas-fir (Pseudotsuga menziesii) Seedlings from Root Disease Caused by Fusarium commune

        Dumroese, R. Kasten,Kim, Mee-Sook,James, Robert L. The Korean Society of Plant Pathology 2012 Plant Pathology Journal Vol.28 No.3

        Fusarium root disease can be a serious problem in forest and conservation nurseries in the western United States. Fusarium inoculum is commonly found in most container and bareroot nurseries on healthy and diseased seedlings, in nursery soils, and on conifer seeds. Fusarium spp. within the F. oxysporum species complex have been recognized as pathogens for more than a century, but attempts to distinguish virulence by correlating morphological characteristics with results of pathogenicity tests were unsuccessful. Recent molecular characterization and pathogenicity tests, however, revealed that selected isolates of F. oxysporum are benign on Douglas-fir (Pseudotsuga menziesii) seedlings. Other morphologically indistinguishable isolates, which can be virulent, were identified as F. commune, a recently described species. In a replicated greenhouse study, inoculating Douglas-fir seedlings with one isolate of F. oxysporum prevented expression of disease caused by a virulent isolate of F. commune. Moreover, seedling survival and growth was unaffected by the presence of the F. oxysporum isolate, and this isolate yielded better biological control than a commercial formulation of Bacillus subtilis. These results demonstrate that an isolate of nonpathogenic F. oxysporum can effectively reduce Fusarium root disease of Douglas-fir caused by F. commune under nursery settings, and this biological control approach has potential for further development.

      • SCIESCOPUS

        Field testing and numerical modeling of a low-fill box culvert under a flexible pavement subjected to traffic loading

        Acharya, Raju,Han, Jie,Parsons, Robert L.,Brennan, James J. Techno-Press 2016 Geomechanics & engineering Vol.11 No.5

        This paper presents field study and numerical modeling results for a single-cell low-fill concrete box culvert under a flexible pavement subjected to traffic loading. The culvert in the field test was instrumented with displacement transducers to capture the deformations resulting from different combinations of static and traffic loads. A low-boy truck with a known axle configuration and loads was used to apply seven static load combinations and traffic loads at different speeds. Deflections under the culvert roof were measured during loading. Soil and pavement samples were obtained by drilling operation on the test site. The properties of the soil and pavement layers were determined in the laboratory. A 3-D numerical model of the culvert was developed using a finite difference program FLAC3D. Linear elastic models were used for the pavement layers and soil. The numerical results with the material properties determined in the laboratory were compared with the field test results. The observed deflections in the field test were generally smaller under moving loads than static loads. The maximum deflections measured during the static and traffic loads were 0.6 mm and 0.41 mm respectively. The deflections computed by the numerical method were in good agreement with those observed in the field test. The deflection profiles obtained from the field test and the numerical simulation suggest that the traffic load acted more like a concentrated load distributed over a limited area on the culvert. Elastic models for culverts, pavement layers, and surrounding soil are appropriate for numerical modeling of box culverts under loading for load rating purposes.

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