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195 results on '"Hein, N"'

1. Patient History Is Often Reliable in Cases of Venom-Induced Anaphylaxis: A Retrospective Observational Study

Author

Hein N, Callaway C, Ford D, and Carlson JC

Subjects
venom, venom hypersensitivity, anaphylaxis, allergy testing, venom immunotherapy, hymenoptera, time-to-treatment, Immunologic diseases. Allergy, RC581-607
Abstract

Nina Hein,1 Conner Callaway,2 Devin Ford,2 John C Carlson1 1Ochsner Health System, Department of Allergy and Clinical Immunology, New Orleans, LA, USA; 2Tulane University, School of Medicine, New Orleans, LA, USACorrespondence: John C Carlson, Department of Pediatrics, Ochsner Health System, 1315 Jefferson Hwy, New Orleans, LA, 20121, USA, Tel +1-504-842-3900, Fax +1-504-842-5848, Email john.carlson@ochsner.org

Published
2024

2. Profiling age and body fluid DNA methylation markers using nanopore adaptive sampling.

Author

Yuen, ZW-S, Shanmuganandam, S, Stanley, M, Jiang, S, Hein, N, Daniel, R, McNevin, D, Jack, C, Eyras, E, Yuen, ZW-S, Shanmuganandam, S, Stanley, M, Jiang, S, Hein, N, Daniel, R, McNevin, D, Jack, C, and Eyras, E

Abstract

DNA methylation plays essential roles in regulating physiological processes, from tissue and organ development to gene expression and aging processes and has emerged as a widely used biomarker for the identification of body fluids and age prediction. Currently, methylation markers are targeted independently at specific CpG sites as part of a multiplexed assay rather than through a unified assay. Methylation detection is also dependent on divergent methodologies, ranging from enzyme digestion and affinity enrichment to bisulfite treatment, alongside various technologies for high-throughput profiling, including microarray and sequencing. In this pilot study, we test the simultaneous identification of age-associated and body fluid-specific methylation markers using a single technology, nanopore adaptive sampling. This innovative approach enables the profiling of multiple CpG marker sites across entire gene regions from a single sample without the need for specialized DNA preparation or additional biochemical treatments. Our study demonstrates that adaptive sampling achieves sufficient coverage in regions of interest to accurately determine the methylation status, shows a robust consistency with whole-genome bisulfite sequencing data, and corroborates known CpG markers of age and body fluids. Our work also resulted in the identification of new sites strongly correlated with age, suggesting new possible age methylation markers. This study lays the groundwork for the systematic development of nanopore-based methodologies in both age prediction and body fluid identification, highlighting the feasibility and potential of nanopore adaptive sampling while acknowledging the need for further validation and expansion in future research.

Published
2024

3. Targeting RNA Polymerase I Transcription Activity in Osteosarcoma: Pre-Clinical Molecular and Animal Treatment Studies

Author

Kang, C-W, Blackburn, AC, Loh, AHP, Hong, KC, Goh, JY, Hein, N, Drygin, D, Parish, CR, Hannan, RD, Hannan, KM, Coupland, LA, Kang, C-W, Blackburn, AC, Loh, AHP, Hong, KC, Goh, JY, Hein, N, Drygin, D, Parish, CR, Hannan, RD, Hannan, KM, and Coupland, LA

Abstract

The survival rate of patients with osteosarcoma (OS) has not improved over the last 30 years. Mutations in the genes TP53, RB1 and c-Myc frequently occur in OS and enhance RNA Polymerase I (Pol I) activity, thus supporting uncontrolled cancer cell proliferation. We therefore hypothesised that Pol I inhibition may be an effective therapeutic strategy for this aggressive cancer. The Pol I inhibitor CX-5461 has demonstrated therapeutic efficacy in different cancers in pre-clinical and phase I clinical trials; thus, the effects were determined on ten human OS cell lines. Following characterisation using genome profiling and Western blotting, RNA Pol I activity, cell proliferation and cell cycle progression were evaluated in vitro, and the growth of TP53 wild-type and mutant tumours was measured in a murine allograft model and in two human xenograft OS models. CX-5461 treatment resulted in reduced ribosomal DNA (rDNA) transcription and Growth 2 (G2)-phase cell cycle arrest in all OS cell lines. Additionally, tumour growth in all allograft and xenograft OS models was effectively suppressed without apparent toxicity. Our study demonstrates the efficacy of Pol I inhibition against OS with varying genetic alterations. This study provides pre-clinical evidence to support this novel therapeutic approach in OS.

Published
2023

5. Transcutaneous vagus nerve stimulation affects subjective stress perception, but not heart rate variability indices for cardiac vagal modulation

Author

Schiweck, C., primary, Brandt, E., additional, Moritz, S., additional, Hamzehloiya, T., additional, Amaral, K., additional, Parise, A., additional, Meyer, K., additional, Hein, N., additional, Uckermark, C., additional, Qubad, M., additional, Aichholzer, M., additional, Reif, A., additional, and Thanarajah, S. Edwin, additional

Published
2023
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10. The therapeutic potential of RNA Polymerase I transcription inhibitor, CX-5461, in uterine leiomyosarcoma

Author

Kang, C-W, Hannan, KM, Blackburn, AC, Loh, AHP, Hong, KC, Yuan, GJ, Hein, N, Drygin, D, Hannan, RD, Coupland, LA, Kang, C-W, Hannan, KM, Blackburn, AC, Loh, AHP, Hong, KC, Yuan, GJ, Hein, N, Drygin, D, Hannan, RD, and Coupland, LA

Abstract

BACKGROUND: Uterine leiomyosarcoma is a rare aggressive smooth muscle cancer with poor survival rates. RNA Polymerase I (Pol I) activity is elevated in many cancers supporting tumour growth and prior studies in uterine leiomyosarcoma revealed enlarged nucleoli and upregulated Pol I activity-related genes. This study aimed to investigate the anti-tumour potential of CX-5461, a Pol I transcription inhibitor currently being evaluated in clinical trials for several cancers, against the human uterine leiomyosarcoma cell line, SK-UT-1. METHODS: SK-UT-1 was characterised using genome profiling and western blotting. The anti-tumour effects of CX-5461 were investigated using cell proliferation assays, expression analysis using qRT-PCR, and BrdU/PI based cell cycle analysis. RESULTS: Genetic analysis of SK-UT-1 revealed mutations in TP53, RB1, PTEN, APC and TSC1 & 2, all potentially associated with increased Pol I activity. Protein expression analysis showed dysregulated p53, RB1 and c-Myc. CX-5461 treatment resulted in an anti-proliferation response, G2 phase cell-cycle arrest and on-target activity demonstrated by reduced ribosomal DNA transcription. CONCLUSIONS: SK-UT-1 was confirmed as a representative model of uterine leiomyosarcoma and CX-5461 has significant potential as a novel adjuvant for this rare cancer.

Published
2022

11. Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway

Author

Hannan, KM, Soo, P, Wong, MS, Lee, JK, Hein, N, Poh, P, Wysoke, KD, Williams, TD, Montellese, C, Smith, LK, Al-Obaidi, SJ, Nunez-Villacis, L, Pavy, M, He, J-S, Parsons, KM, Loring, KE, Morrison, T, Diesch, J, Burgio, G, Ferreira, R, Feng, Z-P, Gould, CM, Madhamshettiwar, PB, Flygare, J, Gonda, TJ, Simpson, KJ, Kutay, U, Pearson, RB, Engel, C, Watkins, NJ, Hannan, RD, George, AJ, Hannan, KM, Soo, P, Wong, MS, Lee, JK, Hein, N, Poh, P, Wysoke, KD, Williams, TD, Montellese, C, Smith, LK, Al-Obaidi, SJ, Nunez-Villacis, L, Pavy, M, He, J-S, Parsons, KM, Loring, KE, Morrison, T, Diesch, J, Burgio, G, Ferreira, R, Feng, Z-P, Gould, CM, Madhamshettiwar, PB, Flygare, J, Gonda, TJ, Simpson, KJ, Kutay, U, Pearson, RB, Engel, C, Watkins, NJ, Hannan, RD, and George, AJ

Abstract

The nucleolar surveillance pathway monitors nucleolar integrity and responds to nucleolar stress by mediating binding of ribosomal proteins to MDM2, resulting in p53 accumulation. Inappropriate pathway activation is implicated in the pathogenesis of ribosomopathies, while drugs selectively activating the pathway are in trials for cancer. Despite this, the molecular mechanism(s) regulating this process are poorly understood. Using genome-wide loss-of-function screens, we demonstrate the ribosome biogenesis axis as the most potent class of genes whose disruption stabilizes p53. Mechanistically, we identify genes critical for regulation of this pathway, including HEATR3. By selectively disabling the nucleolar surveillance pathway, we demonstrate that it is essential for the ability of all nuclear-acting stresses, including DNA damage, to induce p53 accumulation. Our data support a paradigm whereby the nucleolar surveillance pathway is the central integrator of stresses that regulate nuclear p53 abundance, ensuring that ribosome biogenesis is hardwired to cellular proliferative capacity.

Published
2022

13. Lawson Criterion for Ignition Exceeded in an Inertial Fusion Experiment

Author

Abu-Shawareb, H, Acree, R, Adams, P, Adams, J, Addis, B, Aden, R, Adrian, P, Afeyan, BB, Aggleton, M, Aghaian, L, Aguirre, A, Aikens, D, Akre, J, Albert, F, Albrecht, M, Albright, BJ, Albritton, J, Alcala, J, Alday, C, Alessi, DA, Alexander, N, Alfonso, J, Alfonso, N, Alger, E, Ali, SJ, Ali, ZA, Alley, WE, Amala, P, Amendt, PA, Amick, P, Ammula, S, Amorin, C, Ampleford, DJ, Anderson, RW, Anklam, T, Antipa, N, Appelbe, B, Aracne-Ruddle, C, Araya, E, Arend, M, Arnold, P, Arnold, T, Asay, J, Atherton, LJ, Atkinson, D, Atkinson, R, Auerbach, JM, Austin, B, Auyang, L, Awwal, AS, Ayers, J, Ayers, S, Ayers, T, Azevedo, S, Bachmann, B, Back, CA, Bae, J, Bailey, DS, Bailey, J, Baisden, T, Baker, KL, Baldis, H, Barber, D, Barberis, M, Barker, D, Barnes, A, Barnes, CW, Barrios, MA, Barty, C, Bass, I, Batha, SH, Baxamusa, SH, Bazan, G, Beagle, JK, Beale, R, Beck, BR, Beck, JB, Bedzyk, M, Beeler, RG, Behrendt, W, Belk, L, Bell, P, Belyaev, M, Benage, JF, Bennett, G, Benedetti, LR, Benedict, LX, Berger, R, Bernat, T, Bernstein, LA, Berry, B, Bertolini, L, Besenbruch, G, Betcher, J, Bettenhausen, R, Betti, R, Bezzerides, B, Bhandarkar, SD, Bickel, R, Biener, J, Biesiada, T, Bigelow, K, Bigelow-Granillo, J, Bigman, V, Bionta, RM, Birge, NW, Bitter, M, Black, AC, Bleile, R, Bleuel, DL, Bliss, E, Blue, B, Boehly, T, Boehm, K, Boley, CD, Bonanno, R, Bond, EJ, Bond, T, Bonino, MJ, Borden, M, Bourgade, J-L, Bousquet, J, Bowers, J, Bowers, M, Boyd, R, Bozek, A, Bradley, DK, Bradley, KS, Bradley, PA, Bradley, L, Brannon, L, Brantley, PS, Braun, D, Braun, T, Brienza-Larsen, K, Briggs, TM, Britten, J, Brooks, ED, Browning, D, Bruhn, MW, Brunner, TA, Bruns, H, Brunton, G, Bryant, B, Buczek, T, Bude, J, Buitano, L, Burkhart, S, Burmark, J, Burnham, A, Burr, R, Busby, LE, Butlin, B, Cabeltis, R, Cable, M, Cabot, WH, Cagadas, B, Caggiano, J, Cahayag, R, Caldwell, SE, Calkins, S, Callahan, DA, Calleja-Aguirre, J, Camara, L, Camp, D, Campbell, EM, Campbell, JH, Carey, B, Carey, R, Carlisle, K, Carlson, L, Carman, L, Carmichael, J, Carpenter, A, Carr, C, Carrera, JA, Casavant, D, Casey, A, Casey, DT, Castillo, A, Castillo, E, Castor, JI, Castro, C, Caughey, W, Cavitt, R, Celeste, J, Celliers, PM, Cerjan, C, Chandler, G, Chang, B, Chang, C, Chang, J, Chang, L, Chapman, R, Chapman, T, Chase, L, Chen, H, Chen, K, Chen, L-Y, Cheng, B, Chittenden, J, Choate, C, Chou, J, Chrien, RE, Chrisp, M, Christensen, K, Christensen, M, Christopherson, AR, Chung, M, Church, JA, Clark, A, Clark, DS, Clark, K, Clark, R, Claus, L, Cline, B, Cline, JA, Cobble, JA, Cochrane, K, Cohen, B, Cohen, S, Collette, MR, Collins, G, Collins, LA, Collins, TJB, Conder, A, Conrad, B, Conyers, M, Cook, AW, Cook, D, Cook, R, Cooley, JC, Cooper, G, Cope, T, Copeland, SR, Coppari, F, Cortez, J, Cox, J, Crandall, DH, Crane, J, Craxton, RS, Cray, M, Crilly, A, Crippen, JW, Cross, D, Cuneo, M, Cuotts, G, Czajka, CE, Czechowicz, D, Daly, T, Danforth, P, Darbee, R, Darlington, B, Datte, P, Dauffy, L, Davalos, G, Davidovits, S, Davis, P, Davis, J, Dawson, S, Day, RD, Day, TH, Dayton, M, Deck, C, Decker, C, Deeney, C, DeFriend, KA, Deis, G, Delamater, ND, Delettrez, JA, Demaret, R, Demos, S, Dempsey, SM, Desjardin, R, Desjardins, T, Desjarlais, MP, Dewald, EL, DeYoreo, J, Diaz, S, Dimonte, G, Dittrich, TR, Divol, L, Dixit, SN, Dixon, J, Dodd, ES, Dolan, D, Donovan, A, Donovan, M, Döppner, T, Dorrer, C, Dorsano, N, Douglas, MR, Dow, D, Downie, J, Downing, E, Dozieres, M, Draggoo, V, Drake, D, Drake, RP, Drake, T, Dreifuerst, G, DuBois, DF, DuBois, PF, Dunham, G, Dylla-Spears, R, Dymoke-Bradshaw, AKL, Dzenitis, B, Ebbers, C, Eckart, M, Eddinger, S, Eder, D, Edgell, D, Edwards, MJ, Efthimion, P, Eggert, JH, Ehrlich, B, Ehrmann, P, Elhadj, S, Ellerbee, C, Elliott, NS, Ellison, CL, Elsner, F, Emerich, M, Engelhorn, K, England, T, English, E, Epperson, P, Epstein, R, Erbert, G, Erickson, MA, Erskine, DJ, Erlandson, A, Espinosa, RJ, Estes, C, Estabrook, KG, Evans, S, Fabyan, A, Fair, J, Fallejo, R, Farmer, N, Farmer, WA, Farrell, M, Fatherley, VE, Fedorov, M, Feigenbaum, E, Feit, M, Ferguson, W, Fernandez, JC, Fernandez-Panella, A, Fess, S, Field, JE, Filip, CV, Fincke, JR, Finn, T, Finnegan, SM, Finucane, RG, Fischer, M, Fisher, A, Fisher, J, Fishler, B, Fittinghoff, D, Fitzsimmons, P, Flegel, M, Flippo, KA, Florio, J, Folta, J, Folta, P, Foreman, LR, Forrest, C, Forsman, A, Fooks, J, Foord, M, Fortner, R, Fournier, K, Fratanduono, DE, Frazier, N, Frazier, T, Frederick, C, Freeman, MS, Frenje, J, Frey, D, Frieders, G, Friedrich, S, Froula, DH, Fry, J, Fuller, T, Gaffney, J, Gales, S, Le Galloudec, B, Le Galloudec, KK, Gambhir, A, Gao, L, Garbett, WJ, Garcia, A, Gates, C, Gaut, E, Gauthier, P, Gavin, Z, Gaylord, J, Geissel, M, Génin, F, Georgeson, J, Geppert-Kleinrath, H, Geppert-Kleinrath, V, Gharibyan, N, Gibson, J, Gibson, C, Giraldez, E, Glebov, V, Glendinning, SG, Glenn, S, Glenzer, SH, Goade, S, Gobby, PL, Goldman, SR, Golick, B, Gomez, M, Goncharov, V, Goodin, D, Grabowski, P, Grafil, E, Graham, P, Grandy, J, Grasz, E, Graziani, F, Greenman, G, Greenough, JA, Greenwood, A, Gregori, G, Green, T, Griego, JR, Grim, GP, Grondalski, J, Gross, S, Guckian, J, Guler, N, Gunney, B, Guss, G, Haan, S, Hackbarth, J, Hackel, L, Hackel, R, Haefner, C, Hagmann, C, Hahn, KD, Hahn, S, Haid, BJ, Haines, BM, Hall, BM, Hall, C, Hall, GN, Hamamoto, M, Hamel, S, Hamilton, CE, Hammel, BA, Hammer, JH, Hampton, G, Hamza, A, Handler, A, Hansen, S, Hanson, D, Haque, R, Harding, D, Harding, E, Hares, JD, Harris, DB, Harte, JA, Hartouni, EP, Hatarik, R, Hatchett, S, Hauer, AA, Havre, M, Hawley, R, Hayes, J, Hayes, S, Hayes-Sterbenz, A, Haynam, CA, Haynes, DA, Headley, D, Heal, A, Heebner, JE, Heerey, S, Heestand, GM, Heeter, R, Hein, N, Heinbockel, C, Hendricks, C, Henesian, M, Heninger, J, Henrikson, J, Henry, EA, Herbold, EB, Hermann, MR, Hermes, G, Hernandez, JE, Hernandez, VJ, Herrmann, MC, Herrmann, HW, Herrera, OD, Hewett, D, Hibbard, R, Hicks, DG, Hill, D, Hill, K, Hilsabeck, T, Hinkel, DE, Ho, DD, Ho, VK, Hoffer, JK, Hoffman, NM, Hohenberger, M, Hohensee, M, Hoke, W, Holdener, D, Holdener, F, Holder, JP, Holko, B, Holunga, D, Holzrichter, JF, Honig, J, Hoover, D, Hopkins, D, Berzak Hopkins, L, Hoppe, M, Hoppe, ML, Horner, J, Hornung, R, Horsfield, CJ, Horvath, J, Hotaling, D, House, R, Howell, L, Hsing, WW, Hu, SX, Huang, H, Huckins, J, Hui, H, Humbird, KD, Hund, J, Hunt, J, Hurricane, OA, Hutton, M, Huynh, KH-K, Inandan, L, Iglesias, C, Igumenshchev, IV, Izumi, N, Jackson, M, Jackson, J, Jacobs, SD, James, G, Jancaitis, K, Jarboe, J, Jarrott, LC, Jasion, D, Jaquez, J, Jeet, J, Jenei, AE, Jensen, J, Jimenez, J, Jimenez, R, Jobe, D, Johal, Z, Johns, HM, Johnson, D, Johnson, MA, Gatu Johnson, M, Johnson, RJ, Johnson, S, Johnson, SA, Johnson, T, Jones, K, Jones, O, Jones, M, Jorge, R, Jorgenson, HJ, Julian, M, Jun, BI, Jungquist, R, Kaae, J, Kabadi, N, Kaczala, D, Kalantar, D, Kangas, K, Karasiev, VV, Karasik, M, Karpenko, V, Kasarky, A, Kasper, K, Kauffman, R, Kaufman, MI, Keane, C, Keaty, L, Kegelmeyer, L, Keiter, PA, Kellett, PA, Kellogg, J, Kelly, JH, Kemic, S, Kemp, AJ, Kemp, GE, Kerbel, GD, Kershaw, D, Kerr, SM, Kessler, TJ, Key, MH, Khan, SF, Khater, H, Kiikka, C, Kilkenny, J, Kim, Y, Kim, Y-J, Kimko, J, Kimmel, M, Kindel, JM, King, J, Kirkwood, RK, Klaus, L, Klem, D, Kline, JL, Klingmann, J, Kluth, G, Knapp, P, Knauer, J, Knipping, J, Knudson, M, Kobs, D, Koch, J, Kohut, T, Kong, C, Koning, JM, Koning, P, Konior, S, Kornblum, H, Kot, LB, Kozioziemski, B, Kozlowski, M, Kozlowski, PM, Krammen, J, Krasheninnikova, NS, Kraus, B, Krauser, W, Kress, JD, Kritcher, AL, Krieger, E, Kroll, JJ, Kruer, WL, Kruse, MKG, Kucheyev, S, Kumbera, M, Kumpan, S, Kunimune, J, Kustowski, B, Kwan, TJT, Kyrala, GA, Laffite, S, Lafon, M, LaFortune, K, Lahmann, B, Lairson, B, Landen, OL, Langenbrunner, J, Lagin, L, Land, T, Lane, M, Laney, D, Langdon, AB, Langer, SH, Langro, A, Lanier, NE, Lanier, TE, Larson, D, Lasinski, BF, Lassle, D, LaTray, D, Lau, G, Lau, N, Laumann, C, Laurence, A, Laurence, TA, Lawson, J, Le, HP, Leach, RR, Leal, L, Leatherland, A, LeChien, K, Lechleiter, B, Lee, A, Lee, M, Lee, T, Leeper, RJ, Lefebvre, E, Leidinger, J-P, LeMire, B, Lemke, RW, Lemos, NC, Le Pape, S, Lerche, R, Lerner, S, Letts, S, Levedahl, K, Lewis, T, Li, CK, Li, H, Li, J, Liao, W, Liao, ZM, Liedahl, D, Liebman, J, Lindford, G, Lindman, EL, Lindl, JD, Loey, H, London, RA, Long, F, Loomis, EN, Lopez, FE, Lopez, H, Losbanos, E, Loucks, S, Lowe-Webb, R, Lundgren, E, Ludwigsen, AP, Luo, R, Lusk, J, Lyons, R, Ma, T, Macallop, Y, MacDonald, MJ, MacGowan, BJ, Mack, JM, Mackinnon, AJ, MacLaren, SA, MacPhee, AG, Magelssen, GR, Magoon, J, Malone, RM, Malsbury, T, Managan, R, Mancini, R, Manes, K, Maney, D, Manha, D, Mannion, OM, Manuel, AM, Mapoles, E, Mara, G, Marcotte, T, Marin, E, Marinak, MM, Mariscal, C, Mariscal, DA, Mariscal, EF, Marley, EV, Marozas, JA, Marquez, R, Marshall, CD, Marshall, FJ, Marshall, M, Marshall, S, Marticorena, J, Martinez, D, Maslennikov, I, Mason, D, Mason, RJ, Masse, L, Massey, W, Masson-Laborde, P-E, Masters, ND, Mathisen, D, Mathison, E, Matone, J, Matthews, MJ, Mattoon, C, Mattsson, TR, Matzen, K, Mauche, CW, Mauldin, M, McAbee, T, McBurney, M, Mccarville, T, McCrory, RL, McEvoy, AM, McGuffey, C, Mcinnis, M, McKenty, P, McKinley, MS, McLeod, JB, McPherson, A, Mcquillan, B, Meamber, M, Meaney, KD, Meezan, NB, Meissner, R, Mehlhorn, TA, Mehta, NC, Menapace, J, Merrill, FE, Merritt, BT, Merritt, EC, Meyerhofer, DD, Mezyk, S, Mich, RJ, Michel, PA, Milam, D, Miller, C, Miller, D, Miller, DS, Miller, E, Miller, EK, Miller, J, Miller, M, Miller, PE, Miller, T, Miller, W, Miller-Kamm, V, Millot, M, Milovich, JL, Minner, P, Miquel, J-L, Mitchell, S, Molvig, K, Montesanti, RC, Montgomery, DS, Monticelli, M, Montoya, A, Moody, JD, Moore, AS, Moore, E, Moran, M, Moreno, JC, Moreno, K, Morgan, BE, Morrow, T, Morton, JW, Moses, E, Moy, K, Muir, R, Murillo, MS, Murray, JE, Murray, JR, Munro, DH, Murphy, TJ, Munteanu, FM, Nafziger, J, Nagayama, T, Nagel, SR, Nast, R, Negres, RA, Nelson, A, Nelson, D, Nelson, J, Nelson, S, Nemethy, S, Neumayer, P, Newman, K, Newton, M, Nguyen, H, Di Nicola, J-MG, Di Nicola, P, Niemann, C, Nikroo, A, Nilson, PM, Nobile, A, Noorai, V, Nora, R, Norton, M, Nostrand, M, Note, V, Novell, S, Nowak, PF, Nunez, A, Nyholm, RA, O'Brien, M, Oceguera, A, Oertel, JA, Okui, J, Olejniczak, B, Oliveira, J, Olsen, P, Olson, B, Olson, K, Olson, RE, Opachich, YP, Orsi, N, Orth, CD, Owen, M, Padalino, S, Padilla, E, Paguio, R, Paguio, S, Paisner, J, Pajoom, S, Pak, A, Palaniyappan, S, Palma, K, Pannell, T, Papp, F, Paras, D, Parham, T, Park, H-S, Pasternak, A, Patankar, S, Patel, MV, Patel, PK, Patterson, R, Patterson, S, Paul, B, Paul, M, Pauli, E, Pearce, OT, Pearcy, J, Pedrotti, B, Peer, A, Pelz, LJ, Penetrante, B, Penner, J, Perez, A, Perkins, LJ, Pernice, E, Perry, TS, Person, S, Petersen, D, Petersen, T, Peterson, DL, Peterson, EB, Peterson, JE, Peterson, JL, Peterson, K, Peterson, RR, Petrasso, RD, Philippe, F, Phipps, TJ, Piceno, E, Ping, Y, Pickworth, L, Pino, J, Plummer, R, Pollack, GD, Pollaine, SM, Pollock, BB, Ponce, D, Ponce, J, Pontelandolfo, J, Porter, JL, Post, J, Poujade, O, Powell, C, Powell, H, Power, G, Pozulp, M, Prantil, M, Prasad, M, Pratuch, S, Price, S, Primdahl, K, Prisbrey, S, Procassini, R, Pruyne, A, Pudliner, B, Qiu, SR, Quan, K, Quinn, M, Quintenz, J, Radha, PB, Rainer, F, Ralph, JE, Raman, KS, Raman, R, Rambo, P, Rana, S, Randewich, A, Rardin, D, Ratledge, M, Ravelo, N, Ravizza, F, Rayce, M, Raymond, A, Raymond, B, Reed, B, Reed, C, Regan, S, Reichelt, B, Reis, V, Reisdorf, S, Rekow, V, Remington, BA, Rendon, A, Requieron, W, Rever, M, Reynolds, H, Reynolds, J, Rhodes, J, Rhodes, M, Richardson, MC, Rice, B, Rice, NG, Rieben, R, Rigatti, A, Riggs, S, Rinderknecht, HG, Ring, K, Riordan, B, Riquier, R, Rivers, C, Roberts, D, Roberts, V, Robertson, G, Robey, HF, Robles, J, Rocha, P, Rochau, G, Rodriguez, J, Rodriguez, S, Rosen, M, Rosenberg, M, Ross, G, Ross, JS, Ross, P, Rouse, J, Rovang, D, Rubenchik, AM, Rubery, MS, Ruiz, CL, Rushford, M, Russ, B, Rygg, JR, Ryujin, BS, Sacks, RA, Sacks, RF, Saito, K, Salmon, T, Salmonson, JD, Sanchez, J, Samuelson, S, Sanchez, M, Sangster, C, Saroyan, A, Sater, J, Satsangi, A, Sauers, S, Saunders, R, Sauppe, JP, Sawicki, R, Sayre, D, Scanlan, M, Schaffers, K, Schappert, GT, Schiaffino, S, Schlossberg, DJ, Schmidt, DW, Schmitt, MJ, Schneider, DHG, Schneider, MB, Schneider, R, Schoff, M, Schollmeier, M, Schölmerich, M, Schroeder, CR, Schrauth, SE, Scott, HA, Scott, I, Scott, JM, Scott, RHH, Scullard, CR, Sedillo, T, Seguin, FH, Seka, W, Senecal, J, Sepke, SM, Seppala, L, Sequoia, K, Severyn, J, Sevier, JM, Sewell, N, Seznec, S, Shah, RC, Shamlian, J, Shaughnessy, D, Shaw, M, Shaw, R, Shearer, C, Shelton, R, Shen, N, Sherlock, MW, Shestakov, AI, Shi, EL, Shin, SJ, Shingleton, N, Shmayda, W, Shor, M, Shoup, M, Shuldberg, C, Siegel, L, Silva, FJ, Simakov, AN, Sims, BT, Sinars, D, Singh, P, Sio, H, Skulina, K, Skupsky, S, Slutz, S, Sluyter, M, Smalyuk, VA, Smauley, D, Smeltser, RM, Smith, C, Smith, I, Smith, J, Smith, L, Smith, R, Sohn, R, Sommer, S, Sorce, C, Sorem, M, Soures, JM, Spaeth, ML, Spears, BK, Speas, S, Speck, D, Speck, R, Spears, J, Spinka, T, Springer, PT, Stadermann, M, Stahl, B, Stahoviak, J, Stanton, LG, Steele, R, Steele, W, Steinman, D, Stemke, R, Stephens, R, Sterbenz, S, Sterne, P, Stevens, D, Stevers, J, Still, CB, Stoeckl, C, Stoeffl, W, Stolken, JS, Stolz, C, Storm, E, Stone, G, Stoupin, S, Stout, E, Stowers, I, Strauser, R, Streckart, H, Streit, J, Strozzi, DJ, Suratwala, T, Sutcliffe, G, Suter, LJ, Sutton, SB, Svidzinski, V, Swadling, G, Sweet, W, Szoke, A, Tabak, M, Takagi, M, Tambazidis, A, Tang, V, Taranowski, M, Taylor, LA, Telford, S, Theobald, W, Thi, M, Thomas, A, Thomas, CA, Thomas, I, Thomas, R, Thompson, IJ, Thongstisubskul, A, Thorsness, CB, Tietbohl, G, Tipton, RE, Tobin, M, Tomlin, N, Tommasini, R, Toreja, AJ, Torres, J, Town, RPJ, Townsend, S, Trenholme, J, Trivelpiece, A, Trosseille, C, Truax, H, Trummer, D, Trummer, S, Truong, T, Tubbs, D, Tubman, ER, Tunnell, T, Turnbull, D, Turner, RE, Ulitsky, M, Upadhye, R, Vaher, JL, VanArsdall, P, VanBlarcom, D, Vandenboomgaerde, M, VanQuinlan, R, Van Wonterghem, BM, Varnum, WS, Velikovich, AL, Vella, A, Verdon, CP, Vermillion, B, Vernon, S, Vesey, R, Vickers, J, Vignes, RM, Visosky, M, Vocke, J, Volegov, PL, Vonhof, S, Von Rotz, R, Vu, HX, Vu, M, Wall, D, Wall, J, Wallace, R, Wallin, B, Walmer, D, Walsh, CA, Walters, CF, Waltz, C, Wan, A, Wang, A, Wang, Y, Wark, JS, Warner, BE, Watson, J, Watt, RG, Watts, P, Weaver, J, Weaver, RP, Weaver, S, Weber, CR, Weber, P, Weber, SV, Wegner, P, Welday, B, Welser-Sherrill, L, Weiss, K, Widmann, K, Wheeler, GF, Whistler, W, White, RK, Whitley, HD, Whitman, P, Wickett, ME, Widmayer, C, Wiedwald, J, Wilcox, R, Wilcox, S, Wild, C, Wilde, BH, Wilde, CH, Wilhelmsen, K, Wilke, MD, Wilkens, H, Wilkins, P, Wilks, SC, Williams, EA, Williams, GJ, Williams, W, Williams, WH, Wilson, DC, Wilson, B, Wilson, E, Wilson, R, Winters, S, Wisoff, J, Wittman, M, Wolfe, J, Wong, A, Wong, KW, Wong, L, Wong, N, Wood, R, Woodhouse, D, Woodruff, J, Woods, DT, Woods, S, Woodworth, BN, Wooten, E, Wootton, A, Work, K, Workman, JB, Wright, J, Wu, M, Wuest, C, Wysocki, FJ, Xu, H, Yamaguchi, M, Yang, B, Yang, ST, Yatabe, J, Yeamans, CB, Yee, BC, Yi, SA, Yin, L, Young, B, Young, CS, Young, CV, Young, P, Youngblood, K, Zacharias, R, Zagaris, G, Zaitseva, N, Zaka, F, Ze, F, Zeiger, B, Zika, M, Zimmerman, GB, Zobrist, T, Zuegel, JD, Zylstra, AB, Indirect Drive ICF Collaboration, Collaboration, Indirect Drive ICF, AWE Plc, Lawrence Livermore National Laboratory, and U.S Department of Energy

Subjects
General Physics, 02 Physical Sciences, General Physics and Astronomy, Indirect Drive ICF Collaboration, 01 Mathematical Sciences, 09 Engineering
Abstract

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion.

Published
2022

17. The Ribosomal Gene Loci-The Power behind the Throne

Author

Panov, KI, Hannan, K, Hannan, RD, Hein, N, Panov, KI, Hannan, K, Hannan, RD, and Hein, N

Abstract

Nucleoli form around actively transcribed ribosomal RNA (rRNA) genes (rDNA), and the morphology and location of nucleolus-associated genomic domains (NADs) are linked to the RNA Polymerase I (Pol I) transcription status. The number of rDNA repeats (and the proportion of actively transcribed rRNA genes) is variable between cell types, individuals and disease state. Substantial changes in nucleolar morphology and size accompanied by concomitant changes in the Pol I transcription rate have long been documented during normal cell cycle progression, development and malignant transformation. This demonstrates how dynamic the nucleolar structure can be. Here, we will discuss how the structure of the rDNA loci, the nucleolus and the rate of Pol I transcription are important for dynamic regulation of global gene expression and genome stability, e.g., through the modulation of long-range genomic interactions with the suppressive NAD environment. These observations support an emerging paradigm whereby the rDNA repeats and the nucleolus play a key regulatory role in cellular homeostasis during normal development as well as disease, independent of their role in determining ribosome capacity and cellular growth rates.

Published
2021

18. rDNA Chromatin Activity Status as a Biomarker of Sensitivity to the RNA Polymerase I Transcription Inhibitor CX-5461

Author

Son, J, Hannan, KM, Poortinga, G, Hein, N, Cameron, DP, Ganley, ARD, Sheppard, KE, Pearson, RB, Hannan, RD, Sanij, E, Son, J, Hannan, KM, Poortinga, G, Hein, N, Cameron, DP, Ganley, ARD, Sheppard, KE, Pearson, RB, Hannan, RD, and Sanij, E

Abstract

Hyperactivation of RNA polymerase I (Pol I) transcription of ribosomal RNA (rRNA) genes (rDNA) is a key determinant of growth and proliferation and a consistent feature of cancer cells. We have demonstrated that inhibition of rDNA transcription by the Pol I transcription inhibitor CX-5461 selectively kills tumor cells in vivo. Moreover, the first-in human trial of CX-5461 has demonstrated CX-5461 is well-tolerated in patients and has single-agent anti-tumor activity in hematologic malignancies. However, the mechanisms underlying tumor cell sensitivity to CX-5461 remain unclear. Understanding these mechanisms is crucial for the development of predictive biomarkers of response that can be utilized for stratifying patients who may benefit from CX-5461. The rDNA repeats exist in four different and dynamic chromatin states: inactive rDNA can be either methylated silent or unmethylated pseudo-silent; while active rDNA repeats are described as either transcriptionally competent but non-transcribed or actively transcribed, depending on the level of rDNA promoter methylation, loading of the essential rDNA chromatin remodeler UBF and histone marks status. In addition, the number of rDNA repeats per human cell can reach hundreds of copies. Here, we tested the hypothesis that the number and/or chromatin status of the rDNA repeats, is a critical determinant of tumor cell sensitivity to Pol I therapy. We systematically examined a panel of ovarian cancer (OVCA) cell lines to identify rDNA chromatin associated biomarkers that might predict sensitivity to CX-5461. We demonstrated that an increased proportion of active to inactive rDNA repeats, independent of rDNA copy number, determines OVCA cell line sensitivity to CX-5461. Further, using zinc finger nuclease genome editing we identified that reducing rDNA copy number leads to an increase in the proportion of active rDNA repeats and confers sensitivity to CX-5461 but also induces genome-wide instability and sensitivity to DNA damag

Published
2020

25. Changes in long-range rDNA-genomic interactions associate with altered RNA polymerase II gene programs during malignant transformation

Author

Diesch, J, Bywater, MJ, Sanij, E, Cameron, DP, Schierding, W, Brajanovski, N, Son, J, Sornkom, J, Hein, N, Evers, M, Pearson, RB, McArthur, GA, Ganley, ARD, O'Sullivan, JM, Hannan, RD, Poortinga, G, Diesch, J, Bywater, MJ, Sanij, E, Cameron, DP, Schierding, W, Brajanovski, N, Son, J, Sornkom, J, Hein, N, Evers, M, Pearson, RB, McArthur, GA, Ganley, ARD, O'Sullivan, JM, Hannan, RD, and Poortinga, G

Abstract

The three-dimensional organization of the genome contributes to its maintenance and regulation. While chromosomal regions associate with nucleolar ribosomal RNA genes (rDNA), the biological significance of rDNA-genome interactions and whether they are dynamically regulated during disease remain unclear. rDNA chromatin exists in multiple inactive and active states and their transition is regulated by the RNA polymerase I transcription factor UBTF. Here, using a MYC-driven lymphoma model, we demonstrate that during malignant progression the rDNA chromatin converts to the open state, which is required for tumor cell survival. Moreover, this rDNA transition co-occurs with a reorganization of rDNA-genome contacts which correlate with gene expression changes at associated loci, impacting gene ontologies including B-cell differentiation, cell growth and metabolism. We propose that UBTF-mediated conversion to open rDNA chromatin during malignant transformation contributes to the regulation of specific gene pathways that regulate growth and differentiation through reformed long-range physical interactions with the rDNA.

Published
2019

29. New Roles for the Nucleolus in Health and Disease

Author

Villacis, LN, Wong, MS, Ferguson, LL, Hein, N, George, AJ, Hannan, KM, Villacis, LN, Wong, MS, Ferguson, LL, Hein, N, George, AJ, and Hannan, KM

Abstract

Over the last decade, our appreciation of the importance of the nucleolus for cellular function has progressed from the ordinary to the extraordinary. We no longer think of the nucleolus as simply the site of ribosome production, or a dynamic subnuclear body noted by pathologists for its changes in size and shape with malignancy. Instead, the nucleolus has emerged as a key controller of many cellular processes that are fundamental to normal cell homeostasis and the target for dysregulation in many human diseases; in some cases, independent of its functions in ribosome biogenesis. These extra-nucleolar or new functions, which we term "non-canonical" to distinguish them from the more traditional role of the nucleolus in ribosome synthesis, are the focus of this review. In particular, we explore how these non-canonical functions may provide novel insights into human disease and in some cases new targets for therapeutic development.

Published
2018

31. Two-year clinical evaluation of cerec 3D ceramic inlays inserted by undergraduate dental students.

Author

Wrbas K, Hein N, Schirrmeister J, Altenburger MJ, and Hellwig E

Abstract

OBJECTIVE: To evaluate the clinical results of final-year dental students' clinical performance after a practical computer-based course and training in the new Cerec 3 method. METHOD AND MATERIALS: Cerec 3D restorations (Sirona) were made and inserted in patients by 50 dental students. The students were in their final semester in the Department of Operative Dentistry. Before treatment of the patients began, the students had undergone computer-based Cerec 3D training. The training included lessons comprising the whole Cerec procedure from planning to insertion of the restoration. Vital permanent premolars or molars requiring a 2- or 3-surface restoration were selected for the study. The evaluation started 1 week after luting. The inlays were examined in accordance with the US Public Health Service (USPHS) criteria at baseline and after 6, 12, and 24 months. RESULTS: The 2-year survival rate of the restorations was estimated to be 93.3% according to Kaplan-Meier. No statistically significant changes were observed in color match, surface texture, and anatomic form. The decrease of pulpal hypersensitivity during the observation period was statistically significant (P <.05). CONCLUSION: Dental students are capable of delivering demanding clinical tasks after appropriate training. The introduction of CAD/CAM restorations to the dental curriculum resulted in high short-term success rates. Further investigations are required to evaluate the long-term success of those restorations. To achieve a clinically adequate performance, it is necessary to consider the basic rules and technology associated with ceramic restorations. [ABSTRACT FROM AUTHOR]

Published
2007

32. Advanced pancreatic ductal adenocarcinoma - Complexities of treatment and emerging therapeutic options.

Author

Diwakarla, C, Hannan, K, Hein, N, Yip, D, Diwakarla, C, Hannan, K, Hein, N, and Yip, D

Abstract

Pancreatic ductal adenocarcinoma is a devastating disease with a poor prognosis regardless of stage. To date the mainstay of therapy for advanced disease has been chemotherapy with little incremental improvements in outcome. Despite extensive research investigating new treatment options the current practices continue to utilise fluorouracil or gemcitabine containing combinations. The need for novel therapeutic approaches is mandated by the ongoing poor survival rates associated with this disease. One such approach may include manipulation of ribosome biogenesis and the nucleolar stress response, which has recently been applied to haematological malignancies such as lymphoma and prostate cancer with promising results. This review will focus on the current therapeutic options for pancreatic ductal adenocarcinoma and the complexities associated with developing novel treatments, with a particular emphasis on the role of the nucleolus as a treatment strategy.

Published
2017

34. Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling

Author

Quin, J, Chan, KT, Devlin, JR, Cameron, DP, Diesch, J, Cullinane, C, Ahern, J, Khot, A, Hein, N, George, AJ, Hannan, KM, Poortinga, G, Sheppard, KE, Khanna, KK, Johnstone, RW, Drygin, D, McArthur, GA, Pearson, RB, Sanij, E, Hannan, RD, Quin, J, Chan, KT, Devlin, JR, Cameron, DP, Diesch, J, Cullinane, C, Ahern, J, Khot, A, Hein, N, George, AJ, Hannan, KM, Poortinga, G, Sheppard, KE, Khanna, KK, Johnstone, RW, Drygin, D, McArthur, GA, Pearson, RB, Sanij, E, and Hannan, RD

Abstract

RNA polymerase I (Pol I)-mediated transcription of the ribosomal RNA genes (rDNA) is confined to the nucleolus and is a rate-limiting step for cell growth and proliferation. Inhibition of Pol I by CX-5461 can selectively induce p53-mediated apoptosis of tumour cells in vivo. Currently, CX-5461 is in clinical trial for patients with advanced haematological malignancies (Peter Mac, Melbourne). Here we demonstrate that CX-5461 also induces p53-independent cell cycle checkpoints mediated by ATM/ATR signaling in the absence of DNA damage. Further, our data demonstrate that the combination of drugs targeting ATM/ATR signaling and CX-5461 leads to enhanced therapeutic benefit in treating p53-null tumours in vivo, which are normally refractory to each drug alone. Mechanistically, we show that CX-5461 induces an unusual chromatin structure in which transcriptionally competent relaxed rDNA repeats are devoid of transcribing Pol I leading to activation of ATM signaling within the nucleoli. Thus, we propose that acute inhibition of Pol transcription initiation by CX-5461 induces a novel nucleolar stress response that can be targeted to improve therapeutic efficacy.

Published
2016

37. Target Development for the National Ignition Campaign

Author

Hamza, A. V., primary, Nikroo, A., additional, Alger, E., additional, Antipa, N., additional, Atherton, L. J., additional, Barker, D., additional, Baxamusa, S., additional, Bhandarkar, S., additional, Biesiada, T., additional, Buice, E., additional, Carr, E., additional, Castro, C., additional, Choate, C., additional, Conder, A., additional, Crippen, J., additional, Dylla-Spears, R., additional, Dzenitis, E., additional, Eddinger, S., additional, Emerich, M., additional, Fair, J., additional, Farrell, M., additional, Felker, S., additional, Florio, J., additional, Forsman, A., additional, Giraldez, E., additional, Hein, N., additional, Hoover, D., additional, Horner, J., additional, Huang, H., additional, Kozioziemski, B., additional, Kroll, J., additional, Lawson, B., additional, Letts, S. A., additional, Lord, D., additional, Mapoles, E., additional, Mauldin, M., additional, Miller, P., additional, Montesanti, R., additional, Moreno, K., additional, Parham, T., additional, Nathan, B., additional, Reynolds, J., additional, Sater, J., additional, Segraves, K., additional, Seugling, R., additional, Stadermann, M., additional, Strauser, R., additional, Stephens, R., additional, Suratwala, T. I., additional, Swisher, M., additional, Taylor, J. S., additional, Wallace, R., additional, Wegner, P., additional, Wilkens, H., additional, and Yoxalla, B., additional

Published
2016
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38. A novel role for the pol I transcription factor ubtf in maintaining genome stability through the regulation of highly transcribed pol II genes

Author

Sanij, E, Diesch, J, Lesmana, A, Poortinga, G, Hein, N, Lidgerwood, G, Cameron, DP, Ellul, J, Goodall, GJ, Wong, LH, Dhillon, Amardeep, Hamdane, N, Rothblum, LI, Pearson, RB, Haviv, I, Hannan, RD, Sanij, E, Diesch, J, Lesmana, A, Poortinga, G, Hein, N, Lidgerwood, G, Cameron, DP, Ellul, J, Goodall, GJ, Wong, LH, Dhillon, Amardeep, Hamdane, N, Rothblum, LI, Pearson, RB, Haviv, I, and Hannan, RD

Published
2015

39. Cost effectiveness analysis of improved blood pressure control in hypertensive patients with type 2 diabetes: UKPDS 40

Author

Stearne, MR, Palmer, SL, Hammersley, MS, Franklin, SL, Spivey, RS, Levy, JC, Tidy, CR, Bell, NJ, Steemson, J, Barrow, BA, Coster, R, Waring, K, Nolan, L, Truscott, E, Walravens, N, Cook, L, Lampard, H, Merle, C, Parker, P, McVittie, J, Draisey, I, Murchison, LE, Brunt, AHE, Williams, MJ, Pearson, DW, Petrie, XMP, Lean, MEJ, Walmsley, D, Lyall, F, Christie, E, Church, J, Thomson, E, Farrow, A, Stowers, JM, Stowers, M, McHardy, K, Patterson, N, Wright, AD, Levi, NA, Shearer, ACI, Thompson, RJW, Taylor, G, Rayton, S, Bradbury, M, Glover, A, Smyth-Osbourne, A, Parkes, C, Graham, J, England, P, Gyde, S, Eagle, C, Chakrabarti, B, Smith, J, Sherwell, J, Kohner, EM, Dornhorst, A, Doddridge, MC, Dumskyj, M, Walji, S, Sharp, P, Sleightholm, M, Vanterpool, G, Rose, C, Frost, G, Roseblade, M, Elliott, S, Forrester, S, Foster, M, Myers, K, Chapman, R, Hayes, JR, Henry, RW, Featherston, MS, Archbold, GPR, Copeland, M, Harper, R, Richardson, I, Martin, S, Davison, HA, Hadden, DR, Kennedy, L, Atkinson, AB, Culbert, AM, Hegan, C, Tennet, H, Webb, N, Robinson, I, Holmes, J, Bell, PM, McCance, DR, Rutherford, J, Nesbitt, S, Spathis, AS, Hyer, S, Nanson, ME, James, LM, Tyrell, JM, Davis, C, Strugnell, P, Booth, M, Petrie, H, Clark, D, Rice, B, Hulland, S, Barron, JL, Yudkin, JS, Gould, BJ, Singer, J, Badenock, A, Eckert, M, Alibhai, K, Marriot, E, Cox, C, Price, R, Fernandez, M, Ryle, A, Clarke, S, Wallace, G, Mehmed, E, MacFarlane, S, Greenwood, RH, Wilson, J, Denholm, MJ, Temple, RC, Whitfield, K, Johnson, F, Munroe, C, Gorick, S, Duckworth, E, Flatman, M, Rainbow, S, Borthwick, LJ, Wheatcroft, DJ, Seaman, RJ, Christie, RA, Wheatcroft, W, Musk, P, White, J, McDougal, S, Bond, M, Raniga, P, Newton, RW, Jung, RT, Roxburgh, C, Kilgallon, B, Dick, L, Waugh, N, Kilby, S, Ellington, A, Burns, J, Fox, CV, Holloway, MC, Coghill, HM, Hein, N, Fox, A, Cowan, W, Richard, M, Quested, K, Evans, SJ, Paisey, RB, Brown, NPR, Tucker, AJ, Paisey, R, Garrett, F, Hogg, J, Park, P, Williams, K, Harvey, P, Wilcocks, R, Mason, S, Frost, J, Warren, C, Rocket, P, Bower, L, Roland, JM, Brown, DJ, Youens, J, Stanton-King, K, Mungall, H, Ball, V, Maddison, W, Donnelly, D, King, S, Griffin, P, Smith, S, Church, S, Dunn, G, Wilson, A, Palmer, K, Brown, PM, Humphriss, D, Davidson, AJM, Rose, R, Armistead, L, Townsend, S, Poon, P, Peacock, IDA, Culverwell, NJC, Charlton, MH, Connolly, BPS, Peacock, J, Barrett, J, Wain, J, Beeston, W, King, G, Hill, PG, Boulton, AJM, Robertson, AM, Katoulis, V, Olukoga, A, McDonald, H, Kumar, S, Abouaesha, F, Abuaisha, B, Knowles, EA, Higgins, S, Booker, J, Sunter, J, Breislin, K, Parker, R, Raval, P, Curwell, J, Davenport, J, Shawcross, G, Prest, A, Grey, J, Cole, H, Sereviratne, C, Young, RJ, Dornan, TL, Clyne, JR, Gibson, M, O'Connell, I, Wong, LM, Wilson, SJ, Wright, KL, Wallace, C, McDowell, D, Burden, AC, Sellen, EM, Gregory, R, Roshan, M, Vaghela, N, Burden, M, Sherriff, C, Clarke, J, Grenfell, J, Tooke, JE, MacLeod, K, Searnark, C, Rammell, M, Pym, C, Stockman, J, Yeo, C, Piper, J, Leighton, L, Green, E, Hoyle, M, Jones, K, Hudson, A, James, AJ, Shore, A, Higham, A, Martin, B, and Grp, UKPDS

Subjects
General Engineering, HC Economic History and Conditions, General Earth and Planetary Sciences, General Medicine, R Medicine (General), General Environmental Science
Abstract

Objectives: To estimate the economic efficiency of tight blood pressure control, with angiotensin converting enzyme inhibitors or beta blockers, compared with less tight control in hypertensive patients with type 2 diabetes. Design: Cost effectiveness analysis incorporating within trial analysis and estimation of impact on life expectancy through use of the within trial hazards of reaching a defined clinical end point. Use of resources driven by trial protocol and use of resources in standard clinical practice were both considered. Setting: 20 hospital based clinics in England, Scotland, and Northern Ireland. Subjects: 1148 hypertensive patients with type 2 diabetes from UK prospective diabetes study randomised to tight control of blood pressure (n=758) or less tight control (n=390). Main outcome measure: Cost effectiveness ratios based on (a) use of healthcare resources associated with tight control and less tight control and treatment of complications and (b) within trial time free from diabetes related end points, and life years gained. Results: Based on use of resources driven by trial protocol, the incremental cost effectiveness of tight control compared with less tight control was cost saving. Based on use of resources in standard clinical practice, incremental cost per extra year free from end points amounted to £1049 (costs and effects discounted at 6% per year) and £434 (costs discounted at 6% per year and effects not discounted). The incremental cost per life year gained was £720 (costs and effects discounted at 6% per year) and £291 (costs discounted at 6% per year and effects not discounted). Conclusions: Tight control of blood pressure in hypertensive patients with type 2 diabetes substantially reduced the cost of complications, increased the interval without complications and survival, and had a cost effectiveness ratio that compares favourably with many accepted healthcare programmes.

Published
1998
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40. A Phase 1, Open-Label, Dose Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of a first in class Pol1 inhibitor (CX-5461) in Patients with Advanced Haematologic Malignancies (HM)

Author

Khot, A., primary, Brajanovski, N., additional, Cameron, D., additional, Hein, N., additional, McArthur, G.A., additional, Lim, J.K.C., additional, O'Brien, S.E., additional, Ryckman, D., additional, Yu, G.I., additional, Link, E., additional, Donohoe, C., additional, Snowden, A., additional, Hannan, R., additional, and Harrison, S.J., additional

Published
2015
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49. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Author

Turner, RC, Holman, RR, Cull, CA, Stratton, IM, Matthews, DR, Frighi, V, Manley, SE, Neil, A, McElroy, K, Wright, D, Kohner, E, Fox, C, Hadden, D, Mehta, Z, Smith, A, Nugent, Z, Peto, R, Adlel, AI, Mann, JI, Bassett, PA, Oakes, SF, Dornan, TL, Aldington, S, Lipinski, H, Collum, R, Harrison, K, MacIntyre, C, Skinner, S, Mortemore, A, Nelson, D, Cockley, S, Levien, S, Bodsworth, L, Willox, R, Biggs, T, Dove, S, Beattie, E, Gradwell, M, Staples, S, Lam, R, Taylor, F, Leung, L, Carter, RD, Brownlee, SM, Fisher, KE, Islam, K, Jelfs, R, Williams, PA, Williams, FA, Sutton, PJ, Ayres, A, Logie, LJ, Lovatt, C, Evans, MA, Stowell, LA, Ross, I, Kennedy, IA, Croft, D, Keen, AH, Rose, C, Raikou, M, Fletcher, AE, Bulpitt, C, Battersby, C, Yudkin, JS, Stevens, R, Stearn, MR, Palmer, SL, Hammersley, MS, Franklin, SL, Spivey, RS, Levy, JC, Tidy, CR, Bell, NJ, Steemson, J, Barrow, BA, Coster, R, Waring, K, Nolan, L, Truscott, E, Walravens, N, Cook, L, Lampard, H, Merle, C, Parker, P, McVittie, J, Draisey, I, Murchison, LE, Brunt, AHE, Williams, MJ, Pearson, DW, Petrie, XMP, Lean, MEJ, Walmsley, D, Lyall, F, Christie, E, Church, J, Thomson, E, Farrow, A, Stowers, JM, Stowers, M, McHardy, K, Patterson, N, Wright, AD, Levi, NA, Shearer, ACI, Thompson, RJW, Taylor, G, Rayton, S, Bradbury, M, Glover, A, Smyth-Osbourne, A, Parkes, C, Graham, J, England, P, Gyde, S, Eagle, C, Chakrabarti, B, Smith, J, Sherwell, J, Oakley, NW, Whitehead, MA, Hollier, GP, Pilkington, T, Simpson, J, Anderson, M, Martin, S, Kean, J, Rice, B, Rolland, A, Nisbet, J, Kohner, EM, Dornhorst, A, Doddridge, MC, Dumskyij, M, Walji, S, Sharp, P, Sleightholm, M, Vanterpool, G, Frost, G, Roseblade, M, Elliott, S, Forrester, S, Foster, M, Myers, K, Chapman, R, Hayes, JR, Henry, RW, Featherston, MS, Archbold, GPR, Copeland, M, Harper, R, Richardson, I, Davison, HA, Alexander, L, Scarpello, JHB, Shiers, DE, Tucker, RJ, Worthington, JRH, Angris, S, Bates, A, Walton, J, Teasdale, M, Browne, J, Stanley, S, Davis, BA, Strange, RC, Hadden, DR, Kennedy, L, Atkinson, AB, Bell, PM, McCance, DR, Rutherford, J, Culbert, AM, Hegan, C, Tennet, H, Webb, N, Robinson, I, Holmes, J, Nesbitt, S, Spathis, AS, Hyer, S, Nanson, ME, James, LM, Tyrell, JM, Davis, C, Strugnell, P, Booth, M, Petrie, H, Clark, D, Hulland, S, Barron, JL, Gould, BC, Singer, J, Badenoch, A, McGregor, M, Isenberg, L, Eckert, M, Alibhai, K, Marriot, E, Cox, C, Price, R, Fernandez, M, Ryle, A, Clarke, S, Wallace, G, Mehmed, E, Lankester, JA, Howard, E, Waite, A, MacFarlane, S, Greenwood, RH, Wilson, J, Denholm, MJ, Temple, RC, Whitfield, K, Johnson, F, Munroe, C, Gorick, S, Duckworth, E, Fatman, M, Rainbow, S, Borthwick, L, Wheatcroft, DJ, Seaman, RJ, Christie, RA, Wheatcroft, W, Musk, P, White, J, McDougal, S, Bond, M, Raniga, P, Day, JL, Doshi, MJ, Wilson, JG, Howard-Williams, JR, Humphreys, H, Graham, A, Hicks, K, Hexman, S, Bayliss, P, Pledger, D, Newton, RW, Jung, RT, Roxburgh, C, Kilgallon, B, Dick, L, Waugh, N, Kilby, S, Ellingford, A, Burns, J, Fox, CV, Holloway, MC, Coghill, HM, Hein, N, Fox, A, Cowan, W, Richard, M, Quested, K, Evans, SJ, Paisey, RB, Brown, NPR, Tucker, AJ, Paisey, R, Garrett, F, Hogg, J, Park, P, Williams, K, Harvey, P, Wilcocks, R, Mason, S, Frost, J, Warren, C, Rocket, P, Bower, L, Roland, JM, Brown, DJ, Youens, J, Stanton-King, K, Mungall, H, Ball, V, Maddison, W, Donnelly, D, King, S, Griffin, P, Smith, S, Church, S, Dunn, G, Wilson, A, Palmer, K, Brown, PM, Humphriss, D, Davidson, AJM, Rose, R, Armistead, L, Townsend, S, Poon, P, Peacock, IDA, Culverwell, NJC, Charlton, MH, Connolly, BPS, Peacock, J, Barrett, J, Wain, J, Beeston, W, King, G, Hill, PG, Boulton, AJM, Robertson, AM, Katoulis, V, Olukoga, A, McDonald, H, Kumar, S, Abouaesha, F, Abuaisha, B, Knowles, EA, Higgins, S, Booker, J, Sunter, J, Breislin, K, Parker, R, Raval, P, Curwell, J, Davenport, H, Shawcross, G, Prest, A, Grey, J, Cole, H, Sereviratne, C, Young, RJ, Clyne, JR, Gibson, M, O'Connell, I, Wong, LM, Wilson, SJ, Wright, KL, Wallace, C, McDowell, D, Burden, AC, Sellen, EM, Gregory, R, Roshan, M, Vaghela, N, Burden, M, Sherriff, C, Mansingh, S, Clarke, J, Grenfell, J, Tooke, JE, MacLeod, K, Seamark, C, Rammell, M, Pym, C, Stockman, J, Yeo, C, Piper, J, Leighton, L, Green, E, Hoyle, M, Jones, K, Hudson, A, James, AJ, Shore, A, Higham, A, Martin, B, Neil, HAW, Butterfield, WJH, Doll, WRS, Eastman, R, Ferris, FR, Kurinij, N, McPherson, K, Mahler, RF, Meade, TW, Shafer, G, Watkins, PJ, Keen, H, Siegel, D, Betteridge, DJ, Cohen, RD, Currie, D, Darbyshire, J, Forrester, JV, Guppy, T, Johnston, DG, McGuire, A, Murphy, M, el-Nahas, AM, Pentecost, B, Spiegelhalter, D, Alberti, KGMM, Denton, R, Home, PD, Howell, S, Jarrett, JR, Marks, V, Marmot, M, Ward, JD, and Grp, UKPDS

Subjects
General Medicine
Published
1998

50. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group

Author

Stearne, MR, Palmer, SL, Hammersley, MS, Franklin, SL, Spivey, RS, Levy, JC, Tidy, CR, Bell, NJ, Steemson, J, Barrow, BA, Coster, R, Waring, K, Nolan, J, Truscott, E, Walravens, N, Cook, L, Lampard, H, Merle, C, Parker, P, McVittie, J, Draisey, I, Murchison, LE, Brunt, AHE, Williams, MJ, Pearson, DW, Petrie, XMP, Lean, MEJ, Walmsley, D, Lyall, MJ, Christie, E, Church, J, Thomson, E, Farrow, A, Stowers, JM, Stowers, M, McHardy, K, Patterson, N, Wright, AD, Levi, NA, Shearer, ACI, Thompson, RJW, Taylor, G, Rayton, S, Bradbury, M, Glover, A, Smyth-Osbourne, A, Parkes, C, Graham, J, England, P, Gyde, S, Eagle, C, Chakrabarti, B, Smith, J, Sherwell, J, Kohner, EM, Dornhurst, A, Doddridge, MC, Dumskyj, M, Walji, S, Sharp, P, Sleightholm, M, Vanterpool, G, Rose, C, Frost, G, Roseblade, M, Elliott, S, Forrester, S, Foster, M, Myers, K, Chapman, R, Hayes, JR, Henry, RW, Featherston, MS, Archbold, GPR, Copeland, M, Harper, R, Richardson, I, Martin, S, Davison, HA, Hadden, DR, Kennedy, L, Atkinson, AB, Culbert, AM, Hegan, C, Tennet, H, Webb, N, Robinson, I, Holmes, J, Bell, PM, McCance, DR, Rutherford, J, Nesbitt, S, Spathis, AS, Hyer, S, Nanson, ME, James, LM, Tyrell, JM, Davis, C, Strugnell, P, Booth, M, Petrie, H, Clark, D, Rice, B, Hulland, S, Barron, JL, Yudkin, JS, Gould, BJ, Singer, J, Badenock, A, Eckert, M, Alibhai, K, Marriot, E, Cox, C, Price, R, Fernandez, M, Ryle, A, Clarke, S, Wallace, G, Mehmed, E, MacFarlane, S, Greenwood, RH, Wilson, J, Denholm, MJ, Temple, RC, Whitfield, K, Johnson, F, Munroe, C, Gorick, S, Duckworth, E, Flatman, M, Rainbow, S, Borthwick, LJ, Wheatcroft, DJ, Seaman, RJ, Christie, RA, Wheatcroft, W, Musk, P, White, J, McDougal, S, Bond, M, Raniga, P, Newton, RW, Jung, RT, Roxburgh, C, Kilgallon, B, Dick, L, Waugh, N, Kilby, S, Ellingford, A, Burns, J, Fox, CV, Holloway, MC, Coghill, HM, Hein, N, Fox, A, Cowan, W, Richard, M, Quested, K, Evans, SJ, Paisey, RB, Brown, NPR, Tucker, AJ, Paisey, R, Garrett, F, Hogg, J, Park, P, Williams, K, Harvey, P, Wilcocks, R, Mason, S, Frost, J, Warren, C, Rocket, P, Bower, L, Roland, JM, Brown, DJ, Youens, J, Stanton-King, K, Mungall, H, Ball, V, Maddison, W, Donnelly, D, King, S, Griffin, P, Smith, S, Church, S, Dunn, G, Wilson, A, Palmer, K, Brown, PM, Humphriss, D, Davidson, AJM, Rose, R, Armistead, L, Townsend, S, Poon, P, Peacock, IDA, Culverwell, NJC, Charlton, MH, Connolly, BPS, Peacock, J, Barrett, J, Wain, J, Beeston, W, King, G, Hill, PG, Boulton, AJM, Robertson, AM, Katoulis, V, Olukoga, A, McDonald, H, Kumar, S, Abouaesha, F, Abuaisha, B, Knowles, EA, Higgins, S, Booker, J, Sunter, J, Breislin, K, Parker, R, Raval, P, Curwell, J, Davenport, H, Shawcross, G, Prest, A, Grey, J, Cole, H, Sereviratne, C, Young, RJ, Dornan, TL, Clyne, JR, Gibson, M, O'Connell, I, Wong, LM, Wilson, SJ, Wright, KL, Wallace, C, McDowell, D, Burden, AC, Sellen, EM, Gregory, R, Roshan, M, Vaghela, N, Burden, M, Sherriff, C, Clarke, J, Grenfell, J, Tooke, JE, MacLeod, K, Searnark, C, Rammell, M, Pym, C, Stockman, J, Yeo, C, Piper, J, Leighton, L, Green, E, Hoyle, M, Jones, K, Hudson, A, James, AJ, Shore, A, Higham, A, Martin, B, and Grp, USPDS

Abstract

OBJECTIVE: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes. DESIGN: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of

Published
1998

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