13 results for Patel, R

  • Appropriate use of pagers in a New Zealand tertiary hospital.

    Reilly, KM; Patel, R; Old, A; Naden, G; Child, S (2006)

    Journal article
    The University of Auckland Library

    Aims To identify the appropriateness of calls to on-call house officers in a major tertiary teaching hospital. Methods A prospective observational study was conducted at Auckland City Hospital over the months of June, July, and August 2004. Fourteen house officers from a range of medical and surgical services categorised calls received while on-call after-hours into one of three groups: ‘appropriate and urgent’; ‘appropriate but not urgent’; and ‘inappropriate’. Results 844 calls were recorded and categorised, with approximately even distribution between medical services (431 calls) and surgical services (413 calls); 30% of calls were deemed clinically appropriate and required a response within 1 hour; 53% of calls were deemed clinically appropriate but did not require a response within an hour; while 17% of calls were deemed inappropriate. Conclusions The most important function an on-call house officer performs is responding to urgent medical situations. Frequent interruptions mean that house officers may become less efficient and more prone to making mistakes. The majority of calls received by on-call house officers did not need immediate responses and would have been better communicated via a less intrusive system such as text-messaging or the keeping of a non-urgent jobs list. If house officers were paged more appropriately then they would be interrupted less frequently and would be able to provide safer, more efficient, and timelier patient care.

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  • Homologous recombination repair-dependent cytotoxicity of the benzotriazine di-N-oxide CEN-209: Comparison with other hypoxia-activated prodrugs

    Hunter, FW; Wang, J; Patel, R; Hsu, H; Hickey, AJ; Hay, MP; Wilson, WR (2012)

    Journal article
    The University of Auckland Library

    CEN-209 (SN30000) is a second-generation benzotriazine di-N-oxide currently in advanced preclinical development as a hypoxia-activated prodrug (HAP). Herein we describe the DNA repair-, hypoxia- and one-electron reductase-dependence of CEN-209 cytotoxicity. We deployed mutant CHO cell lines to generate DNA repair profiles for CEN-209, and compared the profiles with those for other HAPs. Hypoxic selectivity of CEN-209 was significantly greater than PR-104A and the nitro-chloromethylbenzindoline (nCBI/SN29428) and comparable to tirapazamine and TH-302. CEN-209 was selective for homologous recombination (HR) repair-deficient cells (Rad51d−/−), but less so than nitrogen mustard prodrugs TH-302 and PR-104A. Further, DNA repair profiles for CEN-209 differed under oxic and hypoxic conditions, with oxic cytotoxicity more dependent on HR. This feature was conserved across all three members of the benzotriazine di-N-oxide class examined (tirapazamine, CEN-209 and CEN-309/SN29751). Enhancing one-electron reduction of CEN-209 by forced expression of a soluble form of NADPH:cytochrome P450 oxidoreductase (sPOR) increased CEN-209 cytotoxicity more markedly under oxic than hypoxic conditions. Comparison of oxygen consumption, H2O2 production and metabolism of CEN-209 to the corresponding 1-oxide and nor-oxide reduced metabolites suggested that enhanced oxic cytotoxicity in cells with high one-electron reductase activity is due to futile redox cycling. This study supports the hypothesis that both oxic and hypoxic cell killing by CEN-209 is mechanistically analogous to tirapazamine and is dependent on oxidative DNA damage repaired via multiple pathways. However, HAPs that generate DNA interstrand cross-links, such as TH-302 and PR-104, may be more suitable than benzotriazine di-N-oxides for exploiting reported HR repair defects in hypoxic tumour cells.

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  • An opening of Tanwir

    Patel, R (2011-11-10)

    Journal article
    Auckland University of Technology

    Experiments with political liberation and democratisation took place during the 1980s in the Middle East. However, the movement towards significant democratic change was not completed and authoritarian rule continued throughout the region. Now we are witnessing overt dissatisfaction with several authoritarian regimes across the Middle East. Prompted by Tunisia’s successful revolution in January 2011, Cairo's citizens began an occupation of Tahrir Square on Tuesday 25 January 2011, the Day of Revolt, to protest against President Mubarak's rule. Protestors placed themselves at a frontier where democratic rights and space were to be fought for. Prior to the protests, Tahrir Square had been closed off by the government for many years, arguably to prevent precisely such public assemblies and to hold the public at the edge of democracy. I will present an argument that the 2011 Revolt in Egypt created a moment of enlightenment, tanwir , despite the Egyptian Government’s assertion in the 1990s that it was an enlightened government. The enlightenment of the 2011 revolt was not one based on Western cultural meta-narratives of universal and rational knowledge, but as Michel Foucault would suggest, enlightenment based on transforming critique into a form of transgression - a rupture. This rupture, a force formed by the will and actions of protestors to redistribute power, reconfigured boundaries according to new rules of knowledge and truth and presented a "kind of moral energy, wholly remarkable". This paper will also discuss how the rupturing allowed the public to reclaim Tahrir Square and opened it up as an agora - a democratic public outdoor room where bodies gather, debate, and collectively share opinions, how the boundary of exclusion was removed, and the occupation of Tahrir Square saw a new internal borderland established.

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  • Search for resonances in the dijet mass spectrum from 7 TeV pp collisions at CMS

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    Journal article
    The University of Auckland Library

    A search for narrow resonances with a mass of at least 1 TeV in the dijet mass spectrum is performed using pp collisions at Sqrt(s) = 7 TeV. View the MathML source corresponding to an integrated luminosity of 1 fb???1, collected by the CMS experiment at the LHC. No resonances are observed. Upper limits at the 95% confidence level are presented on the product of the resonance cross section, branching fraction into dijets, and acceptance, separately for decays into quark???quark, quark???gluon, and gluon???gluon pairs. The data exclude new particles predicted in the following models at the 95% confidence level: string resonances with mass less than 4.00 TeV, E6 diquarks with mass less than 3.52 TeV, excited quarks with mass less than 2.49 TeV, axigluons and colorons with mass less than 2.47 TeV, and W??? bosons with mass less than 1.51 TeV. These results extend previous exclusions from the dijet mass search technique.

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  • Indications of Suppression of Excited Upsilon States in Pb-Pb Collisions at root(NN)-N-s=2.76 TeV

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Lecomte, P; Lustermann, W; Marchica, C; del Arbol, PMR; Milenovic, P; Moortgat, F; Naegeli, C; Nef, P; Nessi-Tedaldi, F; Pape, L; Pauss, F; Punz, T; Rizzi, A; Ronga, FJ; Rossini, M; Sala, L; Sanchez, AK; Sawley, MC; Stieger, B; Tauscher, L; Thea, A; Theofilatos, K; Treille, D; Urscheler, C; Wallny, R; Wehrli, L; Weng, J; Aguilo, E; Amsler, C; Chiochia, V; De Visscher, S; Favaro, C; Rikova, MI; Mejias, BM; Otiougova, P; Robmann, P; Schmidt, A; Snoek, H; Chang, YH; Chen, KH; Kuo, CM; Li, SW; Lin, W; Liu, ZK; Lu, YJ; Mekterovic, D; Volpe, R; Wu, JH; Yu, SS; Bartalini, P; Chang, P; Chang, YW; Chao, Y; Chen, KF; Hou, WS; Hsiung, Y; Kao, KY; Lei, YJ; Lu, RS; Shiu, JG; Tzeng, YM; Wang, M; Adiguzel, A; Bakirci, MN; Cerci, S; Dozen, C; Dumanoglu, I; Eskut, E; Girgis, S; Gokbulut, G; Hos, I; Kangal, EE; Topaksu, AK; Onengut, G; Ozdemir, K; Ozturk, S; Polatoz, A; Sogut, K; Cerci, DS; Tali, B; Topakli, H; Uzun, D; Vergili, LN; Vergili, M; Akin, IV; Aliev, T; Bilin, B; Bilmis, S; Deniz, M; Gamsizkan, H; 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Papageorgiou, A; Pesaresi, M; Petridis, K; Pioppi, M; Raymond, DM; Rogerson, S; Rompotis, N; Rose, A; Ryan, MJ; Seez, C; Sharp, P; Sparrow, A; Tapper, A; Tourneur, S; Acosta, MV; Virdee, T; Wakefield, S; Wardle, N; Wardrope, D; Whyntie, T; Barrett, M; Chadwick, M; Cole, JE; Hobson, PR; Khan, A; Kyberd, P; Leslie, D; Martin, W; Reid, ID; Teodorescu, L; Hatakeyama, K; Liu, H; Henderson, C; Bose, T; Jarrin, EC; Fantasia, C; Heister, A; St John, J; Lawson, P; Lazic, D; Rohlf, J; Sperka, D; Sulak, L; Avetisyan, A; Chou, JP; Cutts, D; Ferapontov, A; Heintz, U; Jabeen, S; Kukartsev, G; Landsberg, G; Luk, M; Narain, M; Nguyen, D; Segala, M; Sinthuprasith, T; Speer, T; Tsang, KV; Breedon, R; Breto, G; Sanchez, MCDLB; Chauhan, S; Chertok, M; Conway, J; Cox, PT; Dolen, J; Erbacher, R; Friis, E; Ko, W; Kopecky, A; Lander, R; Maruyama, S; Miceli, T; Nikolic, M; Pellett, D; Robles, J; Salur, S; Schwarz, T; Searle, M; Smith, J; Squires, M; Tripathi, M; Sierra, RV; Veelken, C; Arisaka, K; Cline, D; Cousins, R; Deisher, A; Duris, J; Erhan, S; Farrell, C; Hauser, J; Ignatenko, M; Jarvis, C; Plager, C; Rakness, G; Schlein, P; Tucker, J; Valuev, V; Babb, J; Chandra, A; Clare, R; Ellison, J; Gary, JW; Giordano, F; Hanson, G; Jeng, GY; Kao, SC; Liu, F; Long, OR; Luthra, A; Nguyen, H; Shen, BC; Stringer, R; Sturdy, J; Sumowidagdo, S; Wilken, R; Wimpenny, S; Andrews, W; Branson, JG; Cerati, GB; Evans, D; Golf, F; Holzner, A; Kelley, R; Lebourgeois, M; Letts, J; Mangano, B; Padhi, S; Palmer, C; Petrucciani, G; Pi, H; Pieri, M; Ranieri, R; Sani, M; Sharma, V; Simon, S; Sudano, E; Tadel, M; Tu, Y; Vartak, A; Wasserbaech, S; Wuerthwein, F; Yagil, A; Yoo, J; Barge, D; Bellan, R; Campagnari, C; D'Alfonso, M; Danielson, T; Flowers, K; Geffert, P; Incandela, J; Justus, C; Kalavase, P; Koay, SA; Kovalskyi, D; Krutelyov, V; Lowette, S; Mccoll, N; Pavlunin, V; Rebassoo, F; Ribnik, J; Richman, J; Rossin, R; Stuart, D; To, W; Vlimant, JR; Apresyan, A; Bornheim, A; Bunn, J; Chen, Y; Gataullin, M; Ma, Y; Mott, A; Newman, HB; Rogan, C; Shin, K; Timciuc, V; Traczyk, P; Veverka, J; Wilkinson, R; Yang, Y; Zhu, RY; Akgun, B; Carroll, R; Ferguson, T; Iiyama, Y; Jang, DW; Jun, SY; Liu, YF; Paulini, M; Russ, J; Vogel, H; Vorobiev, I; Cumalat, JP; Dinardo, ME; Drell, BR; Edelmaier, CJ; Ford, WT; Gaz, A; Heyburn, B; Lopez, EL; Nauenberg, U; Smith, JG; Stenson, K; Ulmer, KA; Wagner, SR; Zang, SL; Agostino, L; Alexander, J; Cassel, D; Chatterjee, A; Eggert, N; Gibbons, LK; Heltsley, B; Henriksson, K; Hopkins, W; Khukhunaishvili, A; Kreis, B; Kaufman, GN; Patterson, JR; Puigh, D; Ryd, A; Saelim, M; Salvati, E; Shi, X; Sun, W; Teo, WD; Thom, J; Thompson, J; Vaughan, J; Weng, Y; Winstrom, L; Wittich, P; Biselli, A; Cirino, G; Winn, D; Abdullin, S; Albrow, M; Anderson, J; Apollinari, G; Atac, M; Bakken, JA; Bauerdick, LAT; Beretvas, A; Berryhill, J; Bhat, PC; Bloch, I; Borcherding, F; Burkett, K; Butler, JN; Chetluru, V; Cheung, HWK; Chlebana, F; Cihangir, S; Cooper, W; Eartly, DP; Elvira, VD; Esen, S; Fisk, I; Freeman, J; Gao, Y; Gottschalk, E; Green, D; Gunthoti, K; Gutsche, O; Hanlon, J; Harris, RM; Hirschauer, J; Hooberman, B; Jensen, H; Johnson, M; Joshi, U; Khatiwada, R; Klima, B; Kousouris, K; Kunori, S; Kwan, S; Leonidopoulos, C; Limon, P; Lincoln, D; Lipton, R; Lykken, J; Maeshima, K; Marraffino, JM; Mason, D; McBride, P; Miao, T; Mishra, K; Mrenna, S; Musienko, Y; Newman-Holmes, C; O'Dell, V; Pordes, R; Prokofyev, O; Saoulidou, N; Sexton-Kennedy, E; Sharma, S; Spalding, WJ; Spiegel, L; Tan, P; Taylor, L; Tkaczyk, S; Uplegger, L; Vaandering, EW; Vidal, R; Whitmore, J; Wu, W; Yang, F; Yumiceva, F; Yun, JC; Acosta, D; Avery, P; Bourilkov, D; Chen, M; Das, S; De Gruttola, M; Di Giovanni, GP; Dobur, D; Drozdetskiy, A; Field, RD; Fisher, M; Fu, Y; Furic, IK; Gartner, J; Hugon, J; Kim, B; Konigsberg, J; Korytov, A; Kropivnitskaya, A; Kypreos, T; Low, JF; Matchev, K; Mitselmakher, G; Muniz, L; Prescott, C; Remington, R; Rinkevicius, A; Schmitt, M; Scurlock, B; Sellers, P; Skhirtladze, N; Snowball, M; Wang, D; Yelton, J; Zakaria, M; Gaultney, V; Lebolo, LM; Linn, S; Markowitz, P; Martinez, G; Rodriguez, JL; Adams, T; Askew, A; Bochenek, J; Chen, J; Diamond, B; Gleyzer, SV; Haas, J; Hagopian, S; Hagopian, V; Jenkins, M; Johnson, KF; Prosper, H; Quertenmont, L; Sekmen, S; Veeraraghavan, V; Baarmand, MM; Dorney, B; Guragain, S; Hohlmann, M; Kalakhety, H; Ralich, R; Vodopiyanov, I; Adams, MR; Anghel, IM; Apanasevich, L; Bai, Y; Bazterra, VE; Betts, RR; Callner, J; Cavanaugh, R; Dragoiu, C; Gauthier, L; Gerber, CE; Hofman, DJ; Khalatyan, S; Kunde, GJ; Lacroix, F; Malek, M; O'Brien, C; Silkworth, C; Silvestre, C; Smoron, A; Strom, D; Varelas, N; Akgun, U; Albayrak, EA; Bilki, B; Clarida, W; Duru, F; Lae, CK; McCliment, E; Merlo, JP; Mermerkaya, H; Mestvirishvili, A; Moeller, A; Nachtman, J; Newsom, CR; Norbeck, E; Olson, J; Onel, Y; Ozok, F; Sen, S; Wetzel, J; Yetkin, T; Yi, K; Barnett, BA; Blumenfeld, B; Bonato, A; Eskew, C; Fehling, D; Giurgiu, G; Gritsan, AV; Guo, ZJ; Hu, G; Maksimovic, P; Rappoccio, S; Swartz, M; Tran, NV; Whitbeck, A; Baringer, P; Bean, A; Benelli, G; Grachov, O; Kenny, RP; Murray, M; Noonan, D; Sanders, S; Wood, JS; Zhukova, V; Barfuss, AF; Bolton, T; Chakaberia, I; Ivanov, A; Makouski, M; Maravin, Y; Shrestha, S; Svintradze, I; Wan, Z; Gronberg, J; Lange, D; Wright, D; Baden, A; Boutemeur, M; Eno, SC; Ferencek, D; Gomez, JA; Hadley, NJ; Kellogg, RG; Kirn, M; Lu, Y; Mignerey, AC; Rossato, K; Rumerio, P; Santanastasio, F; Skuja, A; Temple, J; Tonjes, MB; Tonwar, SC; Twedt, E; Alver, B; Bauer, G; Bendavid, J; Busza, W; Butz, E; Cali, IA; Chan, M; Dutta, V; Everaerts, P; Ceballos, GG; Goncharov, M; Hahn, KA; Harris, P; Kim, Y; Klute, M; Lee, YJ; Loizides, C; Luckey, PD; Ma, T; Nahn, S; Paus, C; Ralph, D; Roland, C; Roland, G; Rudolph, M; Stephans, GSF; Stoeckli, F; Sumorok, K; Sung, K; Velicanu, D; Wenger, EA; Xie, S; Yang, M; Yilmaz, Y; Yoon, AS; Zanetti, M; Cooper, SI; Cushman, P; Dahmes, B; De Benedetti, A; Dudero, PR; Franzoni, G; Gude, A; Haupt, J; Klapoetke, K; Kubota, Y; Mans, J; Pastika, N; Rekovic, V; Rusack, R; Sasseville, M; Singovsky, A; Tambe, N; Cremaldi, LM; Godang, R; Kroeger, R; Perera, L; Rahmat, R; Sanders, DA; Summers, D; Bloom, K; Bose, S; Butt, J; Claes, DR; Dominguez, A; Eads, M; Keller, J; Kelly, T; Kravchenko, I; Lazo-Flores, J; Malbouisson, H; Malik, S; Snow, GR; Baur, U; Godshalk, A; Iashvili, I; Kharchilava, A; Shipkowski, SP; Smith, K; Zennamo, J; Alverson, G; Barberis, E; Baumgartel, D; Boeriu, O; Chasco, M; Reucroft, S; Swain, J; Trocino, D; Wood, D; Zhang, J; Anastassov, A; Kubik, A; Odell, N; Ofierzynski, RA; Pollack, B; Pozdnyakov, A; Stoynev, S; Velasco, M; Won, S; Antonelli, L; Berry, D; Brinkerhoff, A; Hildreth, M; Jessop, C; Karmgard, DJ; Kolb, J; Kolberg, T; Lannon, K; Luo, W; Lynch, S; Marinelli, N; Morse, DM; Pearson, T; Ruchti, R; Slaunwhite, J; Valls, N; Wayne, M; Ziegler, J; Bylsma, B; Durkin, LS; Gu, J; Hill, C; Killewald, P; Kotov, K; Ling, TY; Rodenburg, M; Williams, G; Adam, N; Berry, E; Elmer, P; Gerbaudo, D; Halyo, V; Hebda, P; Hunt, A; Jones, J; Laird, E; Pegna, DL; Marlow, D; Medvedeva, T; Mooney, M; Olsen, J; Piroue, P; Quan, X; Safdi, B; Saka, H; Stickland, D; Tully, C; Werner, JS; Zuranski, A; Acosta, JG; Huang, XT; Lopez, A; Mendez, H; Oliveros, S; Vargas, JER; Zatserklyaniy, A; Alagoz, E; Barnes, VE; Bolla, G; Borrello, L; Bortoletto, D; De Mattia, M; Everett, A; Garfinkel, AF; Gutay, L; Hu, Z; Jones, M; Koybasi, O; Kress, M; Laasanen, AT; Leonardo, N; Liu, C; Maroussov, V; Merkel, P; Miller, DH; Neumeister, N; Shipsey, I; Silvers, D; Svyatkovskiy, A; Yoo, HD; Zablocki, J; Zheng, Y; Jindal, P; Parashar, N; Boulahouache, C; Ecklund, KM; Geurts, FJM; Padley, BP; Redjimi, R; Roberts, J; Zabel, J; Betchart, B; Bodek, A; Chung, YS; Covarelli, R; de Barbaro, P; Demina, R; Eshaq, Y; Flacher, H; Garcia-Bellido, A; Goldenzweig, P; Gotra, Y; Han, J; Harel, A; Miner, DC; Orbaker, D; Petrillo, G; Sakumoto, W; Vishnevskiy, D; Zielinski, M; Bhatti, A; Ciesielski, R; Demortier, L; Goulianos, K; Lungu, G; Mesropian, C; Atramentov, O; Barker, A; Duggan, D; Gershtein, Y; Gray, R; Halkiadakis, E; Hidas, D; Hits, D; Lath, A; Panwalkar, S; Patel, R; Rose, K; Schnetzer, S; Somalwar, S; Stone, R; Thomas, S; Cerizza, G; Hollingsworth, M; Spanier, S; Yang, ZC; York, A; Eusebi, R; Flanagan, W; Gilmore, J; Gurrola, A; Kamon, T; Khotilovich, V; Montalvo, R; Osipenkov, I; Pakhotin, Y; Pivarski, J; Safonov, A; Sengupta, S; Tatarinov, A; Toback, D; Weinberger, M; Akchurin, N; Bardak, C; Damgov, J; Jeong, C; Kovitanggoon, K; Lee, SW; Libeiro, T; Mane, P; Roh, Y; Sill, A; Volobouev, I; Wigmans, R; Yazgan, E; Appelt, E; Brownson, E; Engh, D; Florez, C; Gabella, W; Issah, M; Johns, W; Kurt, P; Maguire, C; Melo, A; Sheldon, P; Snook, B; Tuo, S; Velkovska, J; Arenton, MW; Balazs, M; Boutle, S; Cox, B; Francis, B; Goodell, J; Hirosky, R; Ledovskoy, A; Lin, C; Neu, C; Yohay, R; Gollapinni, S; Harr, R; Karchin, PE; Lamichhane, P; Mattson, M; Ne, CM; Sakharov, A; Anderson, M; Bachtis, M; Bellinger, JN; Carlsmith, D; Dasu, S; Efron, J; Gray, L; Grogg, KS; Grothe, M; Hall-Wilton, R; Herndon, M; Herve, A; Klabbers, P; Klukas, J; Lanaro, A; Lazaridis, C; Leonard, J; Loveless, R; Mohapatra, A; Palmonari, F; Reeder, D; Ross, I; Savin, A; Smith, WH; Swanson, J; Weinberg, M (2011-07-28)

    Journal article
    The University of Auckland Library

    A comparison of the relative yields of Upsilon resonances in the mu(+)mu(-) decay channel in Pb-Pb and pp collisions at a center-of-mass energy per nucleon pair of 2.76 TeV is performed with data collected with the CMS detector at the LHC. Using muons of transverse momentum above 4 GeV/c and pseudorapidity below 2.4, the double ratio of the Upsilon(2S) and Upsilon(3S) excited states to the Upsilon(1S) ground state in Pb-Pb and pp collisions, [Upsilon(2S + 3S)/Upsilon(1S)](Pb-Pb) /[Upsilon 2S + 3S)/Upsilon(1S)](pp), is found to be 0.31(-0.15)(+0.19) (stat_ +/- 0.03(syst). The probability to obtain the measured value, or lower, if the true double ratio is unity, is calculated to be less than 1%.

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  • Digital Technologies for Splints Manufacturing

    Meisel, EM; Daw, PA; Xu, Xun; Patel, R (2015-03-28)

    Conference item
    The University of Auckland Library

    This paper will detail a proposed methodology for utilising digital technology for orthotic production, specifically for Ankle Foot Orthotics (AFOs) used to treat children with prolonged plantar flexion. Splints created by traditional methods from thermoplastic materials involve long, labour-intensive and messy production which is highly dependent on the skill of the clinician. An orthotic produced by digital means can be made lighter, with more ventilation and greater aesthetic appeal than existing splints. The stages of production to which digital technology can be applied include surface capture, data processing, design and production. A novel production methodology has been established and a functioning prototype has been created as a proof of concept. The methodology proposed is unique when compared to existing studies for the digital production of orthotics as it focuses on practical implementation and ease of use so that it may be applied to the Mass Customisation of orthotics.

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  • The 2-nitroimidazole EF5 is a biomarker for oxidoreductases that activate the bioreductive prodrug CEN-209 under hypoxia.

    Wang, Jingli; Foehrenbacher, A; Su, J; Patel, R; Hay, Michael; Hicks, Kevin; Wilson, William (2012)

    Journal article
    The University of Auckland Library

    Purpose. Benzotriazine-N-oxide bioreductive prodrugs such as tirapazamine and its improved analogue CEN-209 (SN30000) have potential for exploiting hypoxia in tumors. Here, we test the hypothesis that the 2-nitroimidazole EF5, in clinical development for both immunohistochemical and PET imaging of hypoxia, can detect not only hypoxia but also the one-electron reductases required for activation of these hypoxia-targeted prodrugs. Experimental design. Aerobic and hypoxic covalent binding of [14C]-EF5 was determined in human tumor cell lines, including lines with overexpression of NADPH:cytochrome P450 oxidoreductase (CYPOR), and reductive metabolism of tirapazamine and CEN-209 by mass spectrometry. DNA damage response was measured by gammaH2AX formation. Bioreductive metabolism was modulated in HCT116 tumor xenografts by over-expression of CYPOR and breathing of hyperbaric oxygen or 10% oxygen. Results. Overexpression of CYPOR induced similar 2- to 4-fold increases in EF5 binding and metabolic reduction of tirapazamine and CEN-209 in SiHa and HCT116 cell lines, and similar enhancement of gammaH2AX formation. EF5 binding and metabolic reduction of the prodrugs were highly correlated in a panel of 14 hypoxic tumor cell lines. In HCT116 xenografts, CYPOR overexpression also significantly increased EF5 binding and CEN-209 reduction, and modification of tumor hypoxia caused similar changes to the bioreductive activation of both agents resulting in a strong correlation between EF5 binding and CEN209-induced DNA damage (r2 0.68, p < 0.0001) at the individual tumor level. Conclusions. EF5 binding is a promising stratification biomarker for benzotriazine-N-oxide bioreductive prodrugs because of its potential for interrogating reductase activity as well as hypoxia in individual tumors.

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  • Homologous recombination repair-dependent cytotoxicity of the benzotriazine di-N-oxide CEN-209: Comparison with other hypoxia-activated prodrugs

    Hunter, Francis; Wang, Jingli; Patel, R; Hsu, H-L; Hickey, Anthony; Hay, Michael; Wilson, William (2012)

    Journal article
    The University of Auckland Library

    CEN-209 (SN30000) is a second-generation benzotriazine di-N-oxide currently in advanced preclinical development as a hypoxia-activated prodrug (HAP). Herein we describe the DNA repair-, hypoxia- and one-electron reductase-dependence of CEN-209 cytotoxicity. We deployed mutant CHO cell lines to generate DNA repair profiles for CEN-209, and compared the profiles with those for other HAPs. Hypoxic selectivity of CEN-209 was significantly greater than PR-104A and the nitro-chloromethylbenzindoline (nCBI/SN29428) and comparable to tirapazamine and TH-302. CEN-209 was selective for homologous recombination (HR) repair-deficient cells (Rad51d???/???), but less so than nitrogen mustard prodrugs TH-302 and PR-104A. Further, DNA repair profiles for CEN-209 differed under oxic and hypoxic conditions, with oxic cytotoxicity more dependent on HR. This feature was conserved across all three members of the benzotriazine di-N-oxide class examined (tirapazamine, CEN-209 and CEN-309/SN29751). Enhancing one-electron reduction of CEN-209 by forced expression of a soluble form of NADPH:cytochrome P450 oxidoreductase (sPOR) increased CEN-209 cytotoxicity more markedly under oxic than hypoxic conditions. Comparison of oxygen consumption, H2O2 production and metabolism of CEN-209 to the corresponding 1-oxide and nor-oxide reduced metabolites suggested that enhanced oxic cytotoxicity in cells with high one-electron reductase activity is due to futile redox cycling. This study supports the hypothesis that both oxic and hypoxic cell killing by CEN-209 is mechanistically analogous to tirapazamine and is dependent on oxidative DNA damage repaired via multiple pathways. However, HAPs that generate DNA interstrand cross-links, such as TH-302 and PR-104, may be more suitable than benzotriazine di-N-oxides for exploiting reported HR repair defects in hypoxic tumour cells.

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  • A rapid and sensitive method to detect siRNA-mediated mRNA cleavage in vivo using 5' RACE and a molecular beacon probe

    Lasham, Annette; Herbert, M; 't Wallant, NC; Patel, R; Feng, S; Eszes, M; Cao, H; Reid, G (2010)

    Journal article
    The University of Auckland Library

    Specific detection of mRNA cleavage by 5'RACE is the only method to confirm the knockdown of mRNA by RNA interference, but is rarely reported for in vivo studies. We have combined 5'-RNA-linker-mediated RACE (5'-RLM-RACE) with real-time PCR using a molecular beacon to develop a rapid and specific method termed MBRACE, which we have used to detect small-interfering RNA (siRNA)-induced cleavage of ApoB, RRM1 and YBX1 transcripts in vitro, and ApoB in vivo. When RNA from siRNA-transfected cells was used for 5'-RLM-RACE and a cleavage site-specific molecular beacon probe was included in subsequent real-time PCR analysis, the specific mRNA cleavage product was detected. Detection of siRNA-mediated cleavage was also observed when RNA from mouse liver following administration of ApoB-specific siRNA was analysed, even in cases where ApoB knockdown measured by real-time PCR was < 10%. With its sensitivity and specificity, this variation on the 5'RACE method should prove a useful tool to detect mRNA cleavage and corroborate knockdown studies following siRNA use in vivo.

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  • YB-1, the E2F pathway, and regulation of tumor cell growth

    Lasham, Annette; Samuel, W; Cao, H; Patel, R; Mehta, R; Stern, JL; Reid, G; Woolley, AG; Miller, LD; Black, MA; Shelling, Andrew; Print, Cristin; Braithwaite, AW (2012-01-18)

    Journal article
    The University of Auckland Library

    Background: Y-box binding factor 1 (YB-1) has been associated with prognosis in many tumor types. Reduced YB-1 expression inhibits tumor cell growth, but the mechanism is unclear. Methods: YB-1 mRNA levels were compared with tumor grade and histology using microarray data from 771 breast cancer patients and with disease-free survival and distant metastasis???free survival using data from 375 of those patients who did not receive adjuvant therapy. Microarrays were further searched for genes that had correlated expression with YB-1 mRNA. Small interfering RNA (siRNA) was used to study the effects of reduced YB-1 expression on growth of three tumor cell lines (MCF-7 breast, HCT116 colon, and A549 lung cancer cells), on tumorigenesis by A549 cells in nude mice, and on global transcription in the three cancer cell lines. Reporter gene assays were used to determine whether YB-1 siRNAs affected the expression of E2F1, and chromatin immunoprecipitation was used to determine whether YB-1 bound to various E2F promoters as well as E2F1-regulated promoters. All P values were from two-sided tests. Results: YB-1 levels were elevated in more aggressive tumors and were strongly associated with poor disease-free survival and distant metastasis???free survival. YB-1 expression was often associated with the expression of genes with E2F sites in their promoters. Cells expressing YB-1 siRNA grew substantially more slowly than control cells and formed tumors less readily in nude mice. Transcripts that were altered in cancer cell lines with YB-1 siRNA included 32 genes that are components of prognostic gene expression signatures. YB-1 regulated expression of an E2F1 promoter???reporter construct in A549 cells (eg, relative E2F1 promoter activity with control siRNA = 4.04; with YB-1 siRNA = 1.40, difference= ???2.64, 95% confidence interval = ???3.57 to ???1.71, P < .001) and bound to the promoters of several well-defined E2F1 target genes. Conclusion: YB-1 expression is associated with the activity of E2F transcription factors and may control tumor cell growth by this mechanism.

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  • Maternal plasma miRNAs as biomarkers during mid-pregnancy to predict later spontaneous preterm birth: A pilot study

    Gray, C; McCowan, Lesley; Patel, R; Taylor, Rennae; Vickers, Mark (2017-04-11)

    Journal article
    The University of Auckland Library

    More than 10% of babies are born too early resulting in over 15 million preterm births and more than one million new-born deaths globally. Although women with a previous spontaneous preterm birth (SPTB) are considered at high risk for recurrence, the majority occur in women without prior history. Prediction of SPTB risk allows for improved care and potential for targeting novel and existing therapeutics to prevent SPTB, which may result in improved outcomes for infant and mother. In this pilot study, a miRNA array was used to analyse plasma from healthy women in their first pregnancy at 20 weeks of gestation who then went on to deliver either at term or experience SPTB at 28-32 weeks. We identified specific miRNA expression profiles that differentiated between those mothers who delivered at term or delivered following SPTB. miR302b, miR1253 and a clustering of miR548 miRNAs were underexpressed in SPTB cases compared to term controls. Conversely, miR223 was elevated in mothers that later experienced a SPTB. The circulating miRNAs identified in the present study may therefore be attractive candidates as non-invasive biomarkers for the early prediction of SPTB. Further larger studies are now warranted to investigate the potential clinical utility of these markers.

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  • Search for a low-mass pseudoscalar Higgs boson produced in association with a bb[U+203E] pair in pp collisions at ???s=8 TeV

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Kunori, S; Lamichhane, K; Lee, SW; Libeiro, T; Undleeb, S; Volobouev, I; Appelt, E; Delannoy, AG; Greene, S; Gurrola, A; Janjam, R; Johns, W; Maguire, C; Melo, A; Ni, H; Sheldon, P; Snook, B; Tuo, S; Velkovska, J; Xu, Q; Arenton, MW; Boutle, S; Cox, B; Francis, B; Goodell, J; Hirosky, R; Ledovskoy, A; Li, H; Lin, C; Neu, C; Sun, X; Wang, Y; Wolfe, E; Wood, J; Xia, F; Clarke, C; Harr, R; Karchin, PE; Don, CKK; Lamichhane, P; Sturdy, J; Belknap, DA; Carlsmith, D; Cepeda, M; Christian, A; Dasu, S; Dodd, L; Duric, S; Friis, E; Gomber, B; Grothe, M; Hall-Wilton, R; Herndon, M; Herve, A; Klabbers, P; Lanaro, A; Levine, A; Long, K; Loveless, R; Mohapatra, A; Ojalvo, I; Perry, T; Pierro, GA; Polese, G; Ruggles, T; Sarangi, T; Savin, A; Smith, N; Smith, WH; Taylor, D; Woods, N (2016-07-10)

    Journal article
    The University of Auckland Library

    A search is reported for a light pseudoscalar Higgs boson decaying to a pair of ?? leptons, produced in association with a bb pair, in the context of two-Higgs-doublet models. The results are based on pp collision data at a centre-of-mass energy of 8 TeV collected by the CMS experiment at the LHC and corresponding to an integrated luminosity of 19.7 fb-1. Pseudoscalar boson masses between 25 and 80 GeV are probed. No evidence for a pseudoscalar boson is found and upper limits are set on the product of cross section and branching fraction to ?? pairs between 7 and 39 pb at the 95% confidence level. This excludes pseudoscalar A bosons with masses between 25 and 80 GeV, with SM-like Higgs boson negative couplings to down-type fermions, produced in association with bb pairs, in Type II, two-Higgs-doublet models.

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  • Pharmacokinetic/pharmacodynamic modeling identifies SN30000 and SN29751 as tirapazamine analogues with improved tissue penetration and hypoxic cell killing in tumors.

    Hicks, Kevin; Siim, BG; Jaiswal, Jagdish; Pruijn, Frederik; Fraser, AM; Patel, R; Hogg, A; Liyanage, HD; Dorie, MJ; Brown, JM; Denny, William; Hay, Michael; Wilson, William (2010-10)

    Journal article
    The University of Auckland Library

    Tirapazamine (TPZ) has attractive features for targeting hypoxic cells in tumors but has limited clinical activity, in part because of poor extravascular penetration. Here, we identify improved TPZ analogues by using a spatially resolved pharmacokinetic/pharmacodynamic (SR-PKPD) model that considers tissue penetration explicitly during lead optimization.

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