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489 results on '"Bayliss, R. A."'

4. Using 18F-DCFPyL Prostate-Specific Membrane Antigen–Directed Positron Emission Tomography/Magnetic Resonance Imaging to Define Intraprostatic Boosts for Prostate Stereotactic Body Radiation Therapy

Author

Floberg, John M., primary, Wells, Shane A., additional, Ojala, Diane, additional, Bayliss, R. Adam, additional, Hill, Patrick M., additional, Morris, Brett A., additional, Morris, Zachary S., additional, Ritter, Mark, additional, and Cho, Steve Y., additional

Published
2023
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5. Numerical simulations of current generation and dynamo excitation in a mechanically-forced, turbulent flow

Author

Bayliss, R. A., Forest, C. B., Nornberg, M. D., Spence, E. J., and Terry, P. W.

Subjects
Physics - Plasma Physics, Physics - Fluid Dynamics
Abstract

The role of turbulence in current generation and self-excitation of magnetic fields has been studied in the geometry of a mechanically driven, spherical dynamo experiment, using a three dimensional numerical computation. A simple impeller model drives a flow which can generate a growing magnetic field, depending upon the magnetic Reynolds number, Rm, and the fluid Reynolds number. When the flow is laminar, the dynamo transition is governed by a simple threshold in Rm, above which a growing magnetic eigenmode is observed. The eigenmode is primarily a dipole field tranverse to axis of symmetry of the flow. In saturation the Lorentz force slows the flow such that the magnetic eigenmode becomes marginally stable. For turbulent flow, the dynamo eigenmode is suppressed. The mechanism of suppression is due to a combination of a time varying large-scale field and the presence of fluctuation driven currents which effectively enhance the magnetic diffusivity. For higher Rm a dynamo reappears, however the structure of the magnetic field is often different from the laminar dynamo; it is dominated by a dipolar magnetic field which is aligned with the axis of symmetry of the mean-flow, apparently generated by fluctuation-driven currents. The fluctuation-driven currents have been studied by applying a weak magnetic field to laminar and turbulent flows. The magnetic fields generated by the fluctuations are significant: a dipole moment aligned with the symmetry axis of the mean-flow is generated similar to those observed in the experiment, and both toroidal and poloidal flux expulsion are observed., Comment: 14 pages, 14 figures

Published
2006
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8. The role of FxFG-repeat nucleoporins in nuclear trafficking

Author

Bayliss, R. W. R.

Subjects
572
Abstract

Trafficking of macromolecules between the nucleus and cytoplasm through nuclear pore complexes (NPCs) is an essential process in eukaryotic cells. For example, proteins containing a nuclear localisation sequence (NLS) are imported into the nucleus, whereas proteins containing a nuclear export sequence (NES) are exported into the cytoplasm. Many nucleoporins, the proteins from which NPCs are constructed, contain FxFG-repeats, sequences based on a hydrophobic core (of sequence PhexPheGly, where x is usually a small residue) and a hydrophilic linker. Previous work has shown that carrier molecules, including importin-β and Nuclear Transport Factor 2 (NTF2), bind to FxFG-repeats, and addition of soluble FxFG-repeats inhibits nuclear trafficking processes. This Thesis characterises the interactions between FxFG nucleoporin repeats and both NTF2 and importin-β. Binding studies on a rationally-designed NTF2 mutant localise the FxFG binding site to near Trp7. Although I show that the interaction between FxFG repeats and NTF2 is weak, I also show that the interaction is essential for NTF2 to mediate the nuclear import of Ran in permeabilised cells. An X-ray crystal structure of importin-β (residues 1-442) in complex with FxFG repeats is presented which shows, for the first time, how FxFG-repeats interact with a carrier molecule. The crystal structure is used to produce mutants of full-length importin-β which are deficient in FxFG repeat binding, and yet retain binding to RanGTP and importin-α. These mutants are used to demonstrate that an interaction with FxFG repeats is essential for importin-β to mediate nuclear protein import of a substrate containing a classical NLS. A model for how RanGTP may release importin-β from FxFG repeats is proposed.

Published
2000

16. PP35 Presentation Time: 11:30 AM

Author

Morris, Brett Aaron, primary, Merfeld, Emily, additional, Bayliss, R. Adam, additional, Wallace, Charles, additional, Schuster, Jessica, additional, and Anderson, Bethany, additional

Published
2021
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17. A Polytherapy Strategy Using Vincristine and ALK Inhibitors to Sensitise EML4-ALK-Positive NSCLC

Author

Sampson, J, Ju, H-M, Song, J-Y, Fry, AM, Bayliss, R, and Choi, J

Subjects
microtubules, Cancer Research, EML4-ALK, ALK tyrosine kinase inhibitors, vincristine, acetylation, NSCLC, cancer, Oncology, hemic and lymphatic diseases, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

The oncogenic fusion of EML4-ALK is present in about 4–6% of non-small cell lung cancer (NSCLC). A targeted approach with ALK tyrosine kinase inhibitors (TKIs) has been proven highly effective in ALK-positive NSCLC patients. However, despite the initial responses, the outcome of the treatment is variable. Previous studies have shown that the differential response depends in part on the type of EML4-ALK variant. Here, we examined the combination of ALK inhibitors and microtubule poison, vincristine, in cells expressing EML4-ALK V1 and V3, the two most common variants in NSCLC. We showed that combination therapy of ALK-TKIs with vincristine had anti-proliferative effects and blocked RAS/MAPK, PI3K/AKT and JAK/STAT3 signalling pathways in EML4-ALK V1 but not V3 cells. Our results demonstrate that high levels of tubulin acetylation are associated with poor response to vincristine in EML4-ALK V3 cells. Additionally, we demonstrated differences in microtubule stability between the two EML4-ALK fusions. EML4-ALK V3 cells exhibited dynamic microtubules that confer poor response to vincristine compared to V1 cells. Hence, we suggested that the portion of EML4 in the fusion has an important role for the outcome of the combination treatment.

Published
2022

19. 2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase

Author

Matheson, CJ, Coxon, CR, Bayliss, R, Boxall, K, Carbain, B, Fry, AM, Hardcastle, IR, Harnor, SJ, Mas-Droux, C, Newell, DR, Richards, MW, Sivaprakasam, M, Turner, D, Griffin, RJ, Golding, BT, and Cano, C

Abstract

Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7H-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. 6-Ethynyl-N-phenyl-7H-purin-2-amine [IC50 0.15 μM (Nek2)] and 4-((6-ethynyl-7H-purin-2-yl)amino)benzenesulfonamide (IC50 0.14 μM) were selected for determination of the mode of inhibition of Nek2, which was shown to be time-dependent, not reversed by addition of ATP and negated by site directed mutagenesis of Cys22 to alanine. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the N-phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. A typical activity profile was that for 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide [IC50 0.06 μM (Nek2); GI50 (SKBR3) 2.2 μM] which exhibited >5–10-fold selectivity for Nek2 over other kinases; it also showed > 50% growth inhibition at 10 μM concentration against selected breast and leukaemia cell lines. X-ray crystallographic analysis confirmed that binding of the compound to the Nek2 ATP-binding site resulted in covalent modification of Cys22. Further studies confirmed that 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide has the attributes of a drug-like compound with good aqueous solubility, no inhibition of hERG at 25 μM and a good stability profile in human liver microsomes. It is concluded that 6-ethynylpurines are promising agents for cancer treatment by virtue of their selective inhibition of Nek2.

Published
2020

20. Identification of Host Trafficking Genes Required for HIV-1 Virological Synapse Formation in Dendritic Cells

Author

Carien M. Niessen, Bayliss R, Wheeldon J, Stephan M. Caucheteux, and Piguet

Subjects
CD4-Positive T-Lymphocytes, Immunological Synapses, Retromer, dendritic cell, Endosome, Primary Cell Culture, Immunology, Endocytic cycle, Cell, virological synapse, HIV Infections, Biology, Virus Replication, gag Gene Products, Human Immunodeficiency Virus, Microbiology, Monocytes, Virus, T-cell immunity, 03 medical and health sciences, 0302 clinical medicine, Virology, medicine, Humans, Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, Innate immune system, Tumor Suppressor Proteins, Virion, Nuclear Proteins, Dendritic Cells, Dendritic cell, Virus-Cell Interactions, High-Throughput Screening Assays, 3. Good health, Cell biology, Protein Transport, medicine.anatomical_structure, host-cell interactions, rab GTP-Binding Proteins, Insect Science, HIV-1, ADP-Ribosylation Factor 1, Rab, 030217 neurology & neurosurgery
Abstract

The lentivirus human immunodeficiency virus (HIV) targets and destroys CD4+ T cells, leaving the host vulnerable to life-threatening opportunistic infections associated with AIDS. Dendritic cells (DCs) form a virological synapse (VS) with CD4+ T cells, enabling the efficient transfer of virus between the two cells. We have identified cellular factors that are critical in the induction of the VS. We show that ADP-ribosylation factor 1 (ARF1), bridging integrator 1 (BIN1), and Rab GTPases RAB7L1 and RAB8A are important regulators of HIV-1 trafficking to the VS and therefore the infection of CD4+ T cells. We found these cellular factors were essential for endosomal protein trafficking and formation of the VS and that depletion of target proteins prevented virus trafficking to the plasma membrane by retaining virus in intracellular vesicles. Identification of key regulators in HIV-1 trans-infection between DC and CD4+ T cells has the potential for the development of targeted therapy to reduce trans-infection of HIV-1 in vivo., Dendritic cells (DCs) are one of the earliest targets of HIV-1 infection acting as a “Trojan horse,” concealing the virus from the innate immune system and delivering it to T cells via virological synapses (VS). To explicate how the virus is trafficked through the cell to the VS and evades degradation, a high-throughput small interfering RNA screen targeting membrane trafficking proteins was performed in monocyte-derived DCs. We identified several proteins including BIN-1 and RAB7L1 that share common roles in transport from endosomal compartments. Depletion of target proteins resulted in an accumulation of virus in intracellular compartments and significantly reduced viral trans-infection via the VS. By targeting endocytic trafficking and retromer recycling to the plasma membrane, we were able to reduce the virus’s ability to accumulate at budding microdomains and the VS. Thus, we identify key genes involved in a pathway within DCs that is exploited by HIV-1 to traffic to the VS. IMPORTANCE The lentivirus human immunodeficiency virus (HIV) targets and destroys CD4+ T cells, leaving the host vulnerable to life-threatening opportunistic infections associated with AIDS. Dendritic cells (DCs) form a virological synapse (VS) with CD4+ T cells, enabling the efficient transfer of virus between the two cells. We have identified cellular factors that are critical in the induction of the VS. We show that ADP-ribosylation factor 1 (ARF1), bridging integrator 1 (BIN1), and Rab GTPases RAB7L1 and RAB8A are important regulators of HIV-1 trafficking to the VS and therefore the infection of CD4+ T cells. We found these cellular factors were essential for endosomal protein trafficking and formation of the VS and that depletion of target proteins prevented virus trafficking to the plasma membrane by retaining virus in intracellular vesicles. Identification of key regulators in HIV-1 trans-infection between DC and CD4+ T cells has the potential for the development of targeted therapy to reduce trans-infection of HIV-1 in vivo.

Published
2020

36. Mitotic phosphorylation by NEK6 and NEK7 reduces microtubule affinity of\ud EML4 to promote chromosome congression

Author

Adib, R., Montgomery, J.M., Atherton, J., O’Regan, L., Richards, M.W., Straatman, K.R., Roth, D., Straube, A., Bayliss, R., Moores, Carolyn A., and Fry, A.M.

Subjects
bcs
Abstract

EML4 is a microtubule-associated protein that promotes microtubule stability. We investigated\ud its regulation across the cell cycle and found that EML4 was distributed as punctate foci along\ud the microtubule lattice in interphase but exhibited reduced association with spindle\ud microtubules in mitosis. Microtubule sedimentation and cryo-electron microscopy with 3D\ud reconstruction revealed that the basic N-terminal domain of EML4 mediated its binding to the\ud acidic C-terminal tails of α- and β-tubulin on the microtubule surface. The mitotic kinases\ud NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro,\ud and depletion of these kinases in cells led to increased EML4 binding to microtubules in\ud mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic\ud microtubules but also increased their stability and interfered with chromosome congression.\ud Meanwhile, constitutive activation of NEK6 or NEK7 reduced EML4 association with\ud interphase microtubules. Together, these data support a model in which NEK6- and NEK7-\ud dependent phosphorylation promotes dissociation of EML4 from microtubules in mitosis in a\ud manner that is required for efficient chromosome congression.

Published
2019

37. Binding to an unusual inactive kinase conformation by highly selective inhibitors of inositol-requiring enzyme 1a kinase-endoribonuclease

Author

Colombano, G, Caldwell, JJ, Matthews, TP, Bhatia, C, Joshi, A, McHardy, T, Mok, N, Newbatt, Y, Pickard, L, Strover, J, Hedayat, S, Walton, MI, Myers, SM, Jones, AM, Saville, H, McAndrew, C, Burke, R, Eccles, SA, Davies, FE, Bayliss, R, and Collins, I

Subjects
sub_chemistry, Protein Conformation, Protein Serine-Threonine Kinases, Crystallography, X-Ray, Endoplasmic Reticulum Stress, Article, Biopolymers, HEK293 Cells, Allosteric Regulation, Endoribonucleases, Humans, Phosphorylation, Dimerization, Protein Kinase Inhibitors
Abstract

A series of imidazo[1,2- b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1α oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1α kinase domain that would be incompatible with back-to-back dimerization of the IRE1α protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1α protein conformations and can guide the discovery of highly selective ligands for the IRE1α kinase site that allosterically inhibit the endoribonuclease.

Published
2019

38. Liraglutide and Renal Outcomes in Type 2 Diabetes

Author

Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, Tornøe K, Zinman B, Buse JB, LEADER Steering Committee and Investigators. Bergenstal R, Daniels G, Moses AC, Nauck M, Nissen S, Pocock S, Steinberg W, Stockner M, Kristensen P, Ravn LS, Zychma M, Flyvbjerg A, Ford I, Kloos RT, Schactman MJ, Sleight P, Swedberg K, Tenner SM, Akalın S, Arechavaleta R, Bain S, Babkowski MC, Benroubi M, Berard L, Comlekci A, Czupryniak L, Eliasson B, Eriksson M, Fonseca V, Franek E, Gross J, Hafidh K, Haluzik M, Hayes F, Huang YY, Jacob S, Kaddaha G, Khalil A, Kilhovd B, Laakso M, Leiter L, Lalic N, Ji L, Luedemann J, Mannucci E, Marre M, Masmiquel L, Mota M, Omar M, O’Shea D, Pan C, Petrie J, Pieber T, Pratley R, Raz I, Rea R, Rutten G, Satman I, Shestakova M, Simpson R, Smith D, Tack C, Tarnow L, Thomas N, Van Gaal L, Travert F, Vidal J, Warren M, Yoon KH, Tuttle RM, Sheerman SI, Hegedüs L, Baerwald H, Bergenstal M, Celik S, Dias C, Eder M, Fitzgibbons S, Irvhage L, Kloluckova J, Kriulianski R, McDuffie R, Moen S, Paster A, Saalfeld RM, Sankar K, Shehaj E, Swierzewska P, Tiktin M, Tovey S, Gibson CM, Chakrabarti AK, Dashe JF, Hinchey J, Leary MC, Pride Y, Wiviott S, Allen S, Mehr AP, Mutter WP, Parikh S, Ray S, Cheifetz A, Leffler D, Sheth S, Alexander E, Gaglia JL, Goessling W, Mitzner LD, Rosenberg C, Snow KJ, Wagner A, Piazza G, Abell S, Davis T, D'Emden M, Ding SA, Gilfillan C, Greenaway T, Gunawan F, Ho J, Jackson R, Kalra B, Lau SL, Lin J, MacIsaac R, Makepeace A, Malabu U, Marjason J, McCallum R, McLean M, Moin N, Petersons C, Price S, Roberts A, Roberts D, Sangla K, Stranks S, Tan Y, Thynne T, Walters J, Ward G, Wen W, Zhang J, Brix J, Feder A, Höbaus C, Höllerl F, Höller V, Kotter T, Kratz E, Krzizek EC, Leb-Stoeger U, Mader J, Mras N, Novak E, Obendorf F, Peric S, Pesau G, Prager R, Ribitsch A, Schnack C, Schernthaner G, Wascher T, Batens AH, Benhalima K, De Block C, Ernest P, Fouckova A, Jandrain B, Lapauw B, Letiexhe M, Mathieu C, Neven S, Peiffer F, Ruige J, Scheen A, Taes Y, Van Boxelaer I, Vandistel G, Van Durme Y, Verhaegen A, Alencar E, Alencar R, Almeida AC, Alves B, Alves E, Alves G, Alves J, Araujo L, Arruda V, Augusto GA, Baggentoss R, Balestrassi L, Barbosa M, Barcelos I, Belem L, de Bem A, Betti RT, Bona R, Bosco A, Branda J, Bronstein M, Bueno T, Bulcão T, Caiado F, Camazzola F, Cambréa MF, Campos S, Canani L, Carra MK, Caruso S, Carvalho N, Casillo A, Castro D, Cavalcanti T, Cavichioli V, Cercato C, Chacra A, Challela W, Charchar HS, Chaves C, Chrisman C, Correia-Deur J, da Costa A Jr, Costa M, Costi B, Coutinho P, Coutinho W, Cunha MR, Daher J Jr, Davini E, Democh D Jr, Eliaschewitz F, Esmanhoto Facin G, Farias F, Felício J, Fernandes V, Filho CS, Filho FF, Filho M, Fontan D, Fontenele AP, Forti A, Franco D, Freire K, Fusaro A, Genestreti P, Gerchman F, Godi A, Gomes KF, Gonçalves P, Gonçalves R, Griz L, Grossman M, Gurgel MH, Vasconcellos Haddad AW, Halpern A, Hissa M, Inuy A, Jaime J, Jonasson T, Jorge JC, Malucelli FJ, Kohara S, Kramer C, Lacerda C, Ladeira S, Lana J, Lastebasse F, Leitão A, Leite S, Lerário AC, Lima D, Lima M, Lippi V, Lunardi M, Machado E, Maia F, Maia J, Maia KP, Mañas N, Marchisotti F, Marinho C, Martins C, Figueiredo de Medeiros F, Melo A, Melo F, Mendonca E, Mendonça P, Filho RM, Miguel M, Miléo K, Miyahara M, Montenegro AP, Moraes A, Moreira A, Ítalo Mota J, Mothe FS, Murro A, Nakatani V, Napoli TF, Neto BG, Neto OQ, Niclewicz E, Ohe LN, Oliveira F, Oliveira M, Panarotto D, Parente E, Parolin S, Pechmann L, Costa da Penha P, Perlamagna L, Perotta B, Pimentel L, Pinto M, Poço C, Ponte C, Prazeres P, Quintao E, Raduan R, Rassi DT, Rassi N, Reck L, Montenegro R Jr, Ribeiro R, Rodovalho S, Silveira Rodrigues G, Rollin G, Rossi S, Sabino C, Sales AP, Salles J, Sampaio CR, Santana L, Sato V, da Silva Santos M, Santos NL, Santos R, Saraiva J, Sartori C, Sena R, Sevilha M, Sgarbi J, Silva D, D'albuquerque Silva L, Silva ME, Siqueira K, Soares S, Sobreira W, Sousa B, Souza AC, Souza B, Tambascia M, Tarantino R, Tenor F, Tomarchio M, Triches C, Tristão LJ, Valenti A, Vasques E, Vencio S, Vianna A, Munhoz Vidotto T, Vieira S, Villar H, Visconti G, Volaco A, Wajchenberg B, Zanatta L, Zimmerman L, Abbott EC, Abu-Bakare A, Advani A, Allison R, Bishara P, Bowering CK, Cheng A, Chouinard S, Clayton D, Conway J, D'Amours M, de Tugwell B, DeYoung P, D'Ignazio G, Dube F, Ekoe JM, Fagan S, Garceau C, Gottesman I, Hanna A, Harris S, Hramiak IM, Hurd C, Imran S, Josse R, Joyce C, Kaiser S, Khan F, Kirouac I, Kovacs C, Labonte I, Langlois WJ, Levac MF, Liutkus J, McDonald C, Milosevic V, Nyomba BL, Paul T, Raby K, Ransom T, Reichert SM, Retnakaran R, Rabasa-Lhoret R, Raff E, Shaikholeslami R, Sigalas J, Yip CE, Weisnagel SJ, Woo V, Bao Y, Cai X, Chen J, Chen K, Chen M, Chen X, Chen Y, Ji Y, Lei J, Li H, Liu P, Mu Y, Ren M, Ren Y, Shi Y, Wang D, Wang F, Wang J, Wang Y, Yan L, Yang G, Yang J, Yu X, Yuan G, Xu M, Zhao X, Zheng J, Zhou L, Anderlová K, Brožová J, Haluzík M, Hanušová V, Kosák M, Křížová J, Mráz M, Owen K, Rušavý Z, Tomešová J, Trachta P, Žourek M, Andersen PH, Boesgaard T, Christensen S, Gram J, Gregersen S, Henriksen JE, Hermansen K, Jakobsen PE, Jensen J, Krogsaa A, Larsen M, Lervang HH, Madsbad S, Mortensen L, Olesen T, Pietraszek A, Ridderstråle M, Safai N, Schioldan AG, Schmidt C, Snorgaard O, Stidsen J, Cederberg H, Haapamäki H, Hukkanen J, Jauhiainen R, Kujari ML, Lahtela J, Laine M, Mäkelä J, Miilunpohja M, Savolainen M, Taurio J, Vänttinen M, Creton C, Cosma NV, Dillinger J, Jacques JL, Guedj AM, Moulla M, Petit C, Ratsianoharana V, Richter D, Rodier M, Roussel R, Hinz A, Politz E, Esser M, Deuse U, Mittag D, Hagenow A, Jacob F, Jordan R, Gantke D, Venschott-Jordan U, Löhr C, Klausmann G, Eschenbrücher K, Karakas M, Jahrsdörfer B, Kunze MR, Wöhrle J, König W, Spielhagen H, Kilimnik A, Lüdemann HP, Lüdemann J, Mölle A, Mölle M, Müller J, Appelt S, Sauter A, Sauter J, Hartmann U, Löw A, Krötz F, Sohn HY, von Schacky C, Klauss V, Braun D, Segner A, Degtyareva E, Kreutzmann K, Paschmionka R, Hauck N, Sihal O, Busch AK, Maus O, Stübler P, Füllgraf-Horst S, Vietzke A, Müller C, Tosch-Sisting R, Lengsfeld B, Thaler J, Schaum T, Steindorf J, Steindorf S, König A, Reitschuster S, Schlott D, Clever HU, Witzel P, Kempe HP, Stemler L, Benis A, Diakoumopoulou E, Kazakos K, Kypraios N, Liatis S, Pagkalos E, Siami E, Tentolouris N, Alur VC, Agrawal M, Ali M, Asirvatham A, Asirvatham E, Bandgar TR, Balaji M, Bardoloi N, Baruah M, Bekur R, Bhansali A, Bhatia S, Bhonsley S, Bhuyan S, Borah B, Bright N, Ambrish C, Chaudhury T, Choudhury S, Chellan G, Das M, Dharmalingam M, Dutta P, Erugu A, Vinutha FP, Gunasekaran P, Das Gupta R, Iqbal A, Jagadish P, Jain S, Jebasingh H, John A, John M, Kalra S, Kasaragod P, Kesavadev J, Kumar H, Kumar P, Lakshmanan V, Lila AR, Mathew T, Miyen H, Mohan T, Motha A, Murthy C, Shivashankara N, Nanaiah A, Ommen T, Pani K, Pandey K, Paramesh S, Paramesh V, Pillai B, Prabhu M, Kalki RC, Ramachandran S, Ramu M, Rao Y, Reddy S, Saikia P, Saravu K, Selvam K, Sethi B, Shankar A, Sharma A, Shah N, Shankar P, Shetty R, Shivane V, Srivalli S, Thaseen S, Sarada S, Shirisha A, Subramani M, Balaji V, Mohan V, Padmanaban V, Verma M, Vidyasagar S, Walinjkar V, Walia R, Davenport C, Forde H, Gadintshware G, Gan KJ, Khattak A, O'Connell J, O'Shea D, Beilin V, Cahn A, Cohen O, Cukierman-Yaffe T, Daoud D, Darawsha M, Dicker D, Gavish A, Hochberg I, Ilany J, Inbal U, Itzhak B, Karasik A, Karnieli E, Khader N, Khamaisi M, Lender D, Lieberman GS, Mahamid R, Marcoviciu D, Michael L, Minuchin O, Mosenzon O, Narevichius F, Percik R, Potekhin M, Sabbah M, Sawaed S, Schurr D, Segal E, Slezak L, Vollach I, Zaina A, Zloczower M, Zolotov S, Antenore A, Arnone M, Arturi F, Barbaro V, Barone M, Di Biagio R, Buscemi C, Buscemi S, Buzzetti R, Di Carlo A, Carlone A, Caruso V, Casadidio I, Cerrelli F, Ciavarella A, Cipolloni L, Colella A, Colotto M, Consoli A, Crippa VG, Cuccuru I, Cufone S, Desideri C, Fallarino M, Febo F, Filetti S, Foffi C, Formoso G, Frosio L, Di Fulvio P, Gambineri A, Ginestra F, Grimaldi MS, Lamanna C, Leto G, Lucotti P, Lugarà M, Lumera G, Magistro A, Maranghi M, Martelli D, Mattina A, Monti LD, Parise M, Pedace E, Perticone F, Piatti P, Pompea Antonia Baldassarre M, Ragghianti B, Repaci A, Ribichini D, Da Ros S, Rossi M, Santilli M, Sesti G, Setola E, Succurro E, Sussolano E, Tarquini G, Verga S, Vitale V, Alanis RR, del Rosario Arechavaleta-Granell M, de Jesús Beltran Jaramillo T, de Jesús Rodríguez Berrones DA, Rodríguez Briones I, Rodríguez Briones R, Acevedo Castañeda ES, Chapa Grimaldo JB, Flores-Moreno CA, Garza Felix S, Nieto Flores J, Morales Franco G, Garza Morán RA, Hernández González SO, González-Gálvez G, González González JG, Hernández Salazar E, García Hernández PA, Campos Hurtado S, López-Velázco ML, Cardona Muñóz EG, Nuñez Márquez R, Campos Moreno OV, Cavazos Oliveros FJ, Haro Ortiz JA, Pelayo-Orozco ES, Sida Perez P, Vazquez Ramírez R, Uribe Rios MA, López Rodríguez JC, Rodríguez Rosales M, Robledo Durón I, Alvarado Ruíz R, González Saldivar G, Reyes Sánchez R, Sánchez-Michel BL, Contreras Sandoval AY, Velasco Gutiérrez A, Perez Verdín AE, Ramos Zavala MG, Abbink-Zandbergen E, Ahdi M, Bugter A, van Dijk M, Eisma G, Erdtsieck R, Gerards M, Gerdes V, Haak H, Harbers V, Hoogenberg K, Huvers F, Janssen W, Kars M, Kooy A, Lafeber M, Landewé-Cleuren S, Lieverse A, Meesters E, Moerman S, van Moorsel D, Nijhuis J, Smit CJ, Thevissen K, Timmerman Thijssen DM, Willemsen A, Birkeland K, Cooper J, Gulseth H, Hjelmesæth J, Jørgensen P, Kilhovd BK, Kulseng B, Nicolaisen B, Skadberg Ø, Wium C, Antkowiak-Piatyszek K, Arciszewska M, Bajkowska-Fiedziukiewicz A, Bogdanski P, Czubek U, Cypryk K, Dabrowski J, Dabrowska M, Dziedzic S, Dziewit T, Faligowska M, Fedor-Plenkowska G, Gajos G, Galicka-Latala D, Galuszka-Bilinska A, Gladysz I, Grycewicz J, Hachula G, Janas I, Jazwinska-Tarnawska E, Jedynasty K, Jozefowska M, Kaminska A, Katra B, Kitowska-Koterla J, Klupa T, Koblik T, Konduracka E, Konieczny J, Konieczny M, Kosinski M, Kulkowski G, Kunecki M, Kurmaniak M, Lesniewski R, Lominska T, Losa B, Majkowska D, Malecki M, Mirocka J, Misztal M, Mruk K, Musialik K, Olejniczak H, Opadczuk P, Peczynska J, Plinta M, Polaszewska-Muszynska M, Przech E, Pupek-Musialik D, Ruzga Z, Scibor Z, Sidorowicz-Bialynicka A, Siegel A, Stankiewicz A, Strzelecka-Sosik A, Swierszcz T, Szulinska M, Szymkowiak K, Trybul I, Witek P, Wozniak I, Zambrzycki J, Zarzycka-Lindner G, Zuradzka-Wajda D, Zurawska-Klis M, Ahn HY, Chin SO, Choi SH, Chon S, Han KA, Jang HC, Jeong KC, Kang SM, Kim JW, Kim HS, Kim SJ, Kim SW, Kim YS, Lee EY, Lim S, Min KW, Nam JY, Oh SJ, Park SY, Rhee SY, Shin JA, Son JI, Song YD, Woo JT, Yang HK, Yoo JS, Yoon JW, Avram R, Braicu MD, Carlan L, Catrinoiu D, Ciomos D, Ciorba A, Ghise G, Girgavu S, Guja C, Mihai D, Nicodim S, Nistor L, Pintilei DR, Pintilei E, Pletea N, Pop A, Rosu M, Savu O, Serban V, Sima A, Sitterli-Natea C, Suciu G, Szabo M, Szilagyi I, Timar B, Vlad A, Vladu IM, Alfaraj A, Dubova V, Dvoryashina I, Gaysina L, Gromova S, Gudkova K, Ivanova S, Ivashkina I, Kalashnikova M, Kazankova T, Khaykina E, Khaykina O, Kiseleva T, Komissarova E, Kononenko I, Koreneva V, Koshcheeva O, Koshel L, Kozachuk D, Kufelkina T, Kunitsyna M, Likhodey N, Lysenko T, Makarova O, Malceva A, Mikhailova S, Ogorodnikova E, Pavlikova I, Pekareva E, Postoeva A, Reshedko D, Reshedko G, Reshedko L, Rogaleva A, Rogova L, Rozanov D, Runov G, Samylina I, Semikina T, Sergeeva-Kondrachenko M, Shatskaya O, Shimokhina O, Smetanina S, Startseva M, Strelkova A, Suplotova L, Suvorova L, Sych Y, Valeeva A, Valeeva F, Venjkova T, Vinokurova V, Voychik E, Yanovskaya E, Yanovskaya M, Yarkova N, Yarygina E, Yuzhakova N, Zakharova T, Zanozina O, Zenovko A, Zhuk S, Zhukova E, Aleksic S, Bulatovic A, Buric B, Cvijovic G, Jelic MA, Jojic B, Jotic A, Kendereski A, Lalic K, Lukic L, Macesic M, Petkovic MM, Micic D, Milicic T, Popovic L, Prostran M, Rajkovic N, Seferovic J, Singh S, Stojanovic R, Stosic L, Vuksanovic M, Zamaklar M, Zivkovic TB, Zoric S, Aboo N, Albertse HW, Badat A, Basson M, Bawa E, Bester F, Blignaut S, Booysen S, Bosch FJ, Burgess L, Cassimjee S, Coetzee K, Du Bois J, Engelbrecht J, Finegan K, Gibson GJ, Hansa S, Hemus A, Immink IP, Jacovides A, Joshi P, Joshi S, Kapp C, KhoeleMachobane S, Uys Knox HJ, Kok J, Komati S, Lai E, Lakha D, Lehloenyane K, Mahomed AG, Meeding R, Moodley R, Moosa N, Nel J, Nell H, Van Niekerk FJ, Pillay N, Pretorius M, Prozesky H, Ramduth S, Roos J, Sarvan M, Seeber M, Siebert M, Somasundram P, Stavrides A, Venter N, Wadvalla S, Alcolea JO, Álvarez de Arcaya Vicente A, Pérez Arroyo MB, Romero Bobillo E, Buño MM, Carreira Arias JN, Cepero García D, Masmiquel Comas L, Coves Figueras MJ, de la Cuesta Mayor C, Feria-Carot MD, Frade Fernández AM, Ferreiro Gómez M, García García C, García Delgado E, Durán García S, Gómez Gómez LA, Soto González A, Hernán García C, Ángeles Tapia Herrero M, Jodar Gimeno E, Quevedo Juanals J, López Jiménez M, Masanes F, Marco Mur ÁL, Navarro López M, Ramis JN, Palmer AG, Calle Pascual A, Romero Pérez LG, Morales Portillo C, Prieto González S, Mezquita Raya P, Reyes García R, Vera TR, Rodríguez Castro C, Rodríguez Rodríguez I, Sacanella Meseguer E, Serrano Olmedo I, Lopez Soto A, Toba Alonso F, Aliaga Verdugo A, Vidal Cortada J, Vigil Medina L, Ackefelt-Frick E, Alfredsson H, Beling E, Benedek P, Crisby M, Dorkhan M, Drescik T, Eeg-Olofsson K, Eliasson K, Fardelin P, Fredholm A, Frid A, Gerok-Andersson K, Hjelmaeus L, Hufnagl A, Jasinska E, Kowalska E, Lafolie P, Lindquist O, Lundvall M, Melander E, Nicander C, Moris L, Tengmark BO, Saphir U, Skagerberg P, Steczkó-Nilsson C, Strandell B, Tomson Y, Chen JY, Chen YC, Chiang CY, Chou CW, Ho CW, Hsiao PJ, Hsieh MC, Hsu RS, Hsu SR, Huang CH, Hung WW, Lee MY, Lee YM, Lin CW, Lin CH, Lin KD, Lin SD, Lin SF, Liou MJ, Lu WT, Shin SJ, Sia HK, Su MH, Su SL, Sun JH, Tien KJ, Tsai DH, Tsai SS, Tu ST, Wang CC, Wang SY, Yang CY, Yen FC, Acikgoz A, Akalin S, Akin S, Akinci B, Akkurt A, Akturk M, Alkis N, Altun I, Altunbas HA, Altuntas Y, Araz M, Aribas S, Arslan E, Arslan G, Arslan M, Ataoglu EH, Ayan F, Aydin K, Aydogan BI, Ayvaz G, Bahadir MA, Balci MK, Basaran MN, Baskal N, Bugra MZ, Calan M, Cavdar U, Cetin F, Cinar N, Colbay M, Dagdelen S, Damci T, Davutoglu V, Demir M, Demir T, Deyneli O, Dincer I, Dogan B, Kanipek Doker KY, Engin I, Eraydin A, Erbas T, Erdogan MF, Ersoy C, Gedik A, Gokay F, Gul OO, Guler S, Gumus T, Gunes E, Gurler MY, Hatipoglu E, Ilkova H, Iyidir OT, Kabakci G, Karadag B, Karatemiz G, Karci AC, Kartal E, Kaya EB, Keskin C, Keskin EF, Kocabas G, Kocak F, Kol AK, Korkmaz H, Kucukler FK, Mesci BA, Oguz A, Orbay E, Oz H, Ozcan ND, Ozdem S, Ozisik S, Ozkan C, Ozsan M, Ozyazar M, Parlar H, Sargin H, Sargin M, Saygili F, Selek A, Simsek Y, Sisman P, Solmaz K, Soydas C, Tatliagac S, Tamer I, Temizkan S, Tulunay C, Tuncel E, Turker F, Unluhizarci K, Unluturk U, Uygur MM, Vatansever B, Yazici D, Yavuz DG, Yener S, Yenigun M, Yilmaz M, Abbas S, Alawadi F, Aziz AA, Bashier A, Rashid F, Abraham P, Adamson K, Atkin S, Aye M, Azam M, Barnett AH, Bellary S, Dhatariya K, Eaton M, English P, Ewing J, Furlong N, Gibson M, Green D, Herring R, Hordern V, Jaap A, Javed Z, Johnson A, Konya J, Kumar S, Lindsay R, Mackie A, McGlynn S, McKenzie J, Millward A, Murthy N, Paisey R, Pearson E, Piya M, Ramell M, Robertson D, Russell-Jones D, Saravanan P, Sathyapalan T, Shakher J, Shiels H, Sivaraman S, Smith J, Srinivas-Shankar U, Stokes J, Tracey I, Vaidya B, Yee M, Yemparala P, Walker J, Wiggins P, Williams J, Wright J, Mackinnon C, Inkster J, Zeeshan J, Bejnariu C, Malipatil N, Giritharan S, Lonnen K, Kyrou I, Aamir S, Ababa M, Abreu M, Adams D, Adams P, Aden J, Aguilar D, Aguillon A, Ahmed A, Ahmed B, Ahmed I, Akhtar A, Akright B, Akright L, Albarracin C, Albert S, Ali S, Aliuddin B, Almasmary A, Al-Maweri A, Alzohaili O, Amador W, Amine M, Amini S, Anderson M, Anderson L, Anderson R, Andrews M, Angel J, Anteer W, Anthony V, Antillon A, Anzures P, Arcon-Rios S, Arkin D, Arodak B, Aronne L, Aronoff S, Arreola G, Arroyo S, Asnani S, Astudillo-Tee G, Ault S, Austin B, Avila V, Avitabile N, Awasty V, Azar M, Aziz A, Bahrami P, Baig M, Bailey K, Bailey T, Baker M, Bala NS, Balbes-Reyes I, Baldwin D, Baldwin E, Balentine T, Ballard T, Baloch K, Banarer S, Baney C, Banka A, Barber L, Barber M, Barker T, Barnes K, Barnum O, Barra J, Bartkowiak A, Baula G, Bautista A, Bayliss R, Beaman M, Beatty K, Becker J, Bedolla L, Begum G, Belejchak P, Bell A, Beltran M, Belucher C, Bensfield E, Benton J, Bergamo K, Bergman B, Berry M, Bettino K, Beyea M, Bhargava A, Bhattacharya A, Bilas A, Bischoff L, Bixler L, Bizjack S, Blank R, Blankfield R, Block L, Bloodworth J, Bloomberg K, Bloomberg R, Blustin J, Boban I, Bolden A, Boncu O, Bookless P, Brassie C, Brautigam D, Bressler P, Brewster R, Brown C, Brown D, Brown F, Bruskewitz M, Bryant D, Buchanan C, Buchanan N, Buck G, Buckley S, Bueno J, Burke D, Burton K, Buske S, Byars W, Bye R, Caldwell R, Calvin K, Camacho R, Campbell E, Cannon D, Cantrell J, Caplan J, Cardenas C, Carlton J, Carpio G, Carrol A, Cartwright L, Casanova G, Castaneda L, Castle M, Castro L, Catangay J, Chaidarun S, Chambers J, Chambliss T, Chandra L, Chang A, Chang S, Chappel J, Chappel C, Chappell T, Charles C, Chavira A, Chaykin L, Check E, Chee L, Cherry A, Chestnut A, Chiarot J, Chiniwala N, Chionh K, Choe J, Christiansen M, Chrzanowski S, Chuang E, Chuck L, Clyatt J, Cohan B, Cohen R, Comi R, Comulada-Rivera A, Conner K, Connor G, Contreras R, Cook K, Cook R, Corder C, Cornejo B Sr, Cornette L, Cortes G, Cortez L, Cox C, Cox G, Craig W, Cramer B, Cromer C, Cromer M, Cuddihy R, Culmer D, Curran H, Curran M, Dadis C, Dagogo-Jack S, Dairywala I, D'Alessio D, Damberg G, Dang A, Daniel K, Davidson M, Dean J, DeBold R, Deitz P, Del M, Delaney D, Delgado E, DeMicco M, DeMuro MA, DeSalle D, Desouza C, Devireddy K, DeVries B, Dezube M, Diab I, Diesburg-Stanwood A, Dilliard J, Dilling J, Diner J, Dishongh K, Dodis R, Doing C, Doll W, Donoho A, Donovan D, Doremus N, Dorfman 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Sutton T, Tabbah I, Talsania M, Tang R, Tapia J, Taylor K, Taylor-Hancher R, Teator R, Tekateka M, Temple B, Temple K, Teodori M, Tharp P, Thethi T, Theuma P, Thomas S, Thottan A, Thrasher J, Thrasher L, Tiemeyer M, Tinney I, Tobin T, Toma S, Tovar M, Townsend J, Trantow C, Traylor H, Trevino M, Troy M, Trumper D, Tryggestad J, Tucker C, Turner J, Turney R, Tuten C, Tyzack J, Ullo L, Underkofler C, Unger J, Urdanetta R, Valdivia V, Valenti S, Vanderheiden A, Vanderlinde-Wood M, Varma C, Vasquez E, Vazquez M, Vickery D, Villafuerte B, Villegas C, Vivar J, Vivekananthan K, Vo G, Vukojicic K, Wachter A, Wahl D, Waitmann J, Walker D, Walsh J, Walsh K, Walton A, Wang A, Wardell K, Watkins S, Watkinson J, Watts M, Watwe V, Weaver N, Weber R, Wedick C, Weeks D, Weeks L, Weindorff K, Weinstein R, Weiss S, Wenger K, Wentworth M, Werner A, West M, Whelan S, White B, White J, Whitmire M, Whittington R, Wical J, Wigley C, Wilkins F, Will K, Williams A, Wilson LE, Wince M, Wine S, Winkle P, Winner C, Wise J, Witte M, Wittenmyer J, Wood C, Wood R, Woodruff C, Worthington B, Wynn D, Wysham C, Xavier P, Yela S, Yenoby L, Young L, Younus N, Yourell V, Zaid M, Zubair I., Mann, Jfe, Ørsted, Dd, Brown-Frandsen, K, Marso, Sp, Poulter, Nr, Rasmussen, S, Tornøe, K, Zinman, B, Buse, Jb, Bergenstal R, LEADER Steering Committee and Investigators., Daniels, G, Moses, Ac, Nauck, M, Nissen, S, Pocock, S, Steinberg, W, Stockner, M, Kristensen, P, Ravn, L, Zychma, M, Flyvbjerg, A, Ford, I, Kloos, Rt, Schactman, Mj, Sleight, P, Swedberg, K, Tenner, Sm, Akalın, S, Arechavaleta, R, Bain, S, Babkowski, Mc, Benroubi, M, Berard, L, Comlekci, A, Czupryniak, L, Eliasson, B, Eriksson, M, Fonseca, V, Franek, E, Gross, J, Hafidh, K, Haluzik, M, Hayes, F, Huang, Yy, Jacob, S, Kaddaha, G, Khalil, A, Kilhovd, B, Laakso, M, Leiter, L, Lalic, N, Ji, L, Luedemann, J, Mannucci, E, Marre, M, Masmiquel, L, Mota, M, Omar, M, O’Shea, D, Pan, C, Petrie, J, Pieber, T, Pratley, R, Raz, I, Rea, R, Rutten, G, Satman, I, Shestakova, M, Simpson, R, Smith, D, Tack, C, Tarnow, L, Thomas, N, Van Gaal, L, Travert, F, Vidal, J, Warren, M, Yoon, Kh, Tuttle, Rm, Sheerman, Si, Hegedüs, L, Baerwald, H, Bergenstal, M, Celik, S, Dias, C, Eder, M, Fitzgibbons, S, Irvhage, L, Kloluckova, J, Kriulianski, R, Mcduffie, R, Moen, S, Paster, A, Saalfeld, Rm, Sankar, K, Shehaj, E, Swierzewska, P, Tiktin, M, Tovey, S, Gibson, Cm, Chakrabarti, Ak, Dashe, Jf, Hinchey, J, Leary, Mc, Pride, Y, Wiviott, S, Allen, S, Mehr, Ap, Mutter, Wp, Parikh, S, Ray, S, Cheifetz, A, Leffler, D, Sheth, S, Alexander, E, Gaglia, Jl, Goessling, W, Mitzner, Ld, Rosenberg, C, Snow, Kj, Wagner, A, Piazza, G, Abell, S, Davis, T, D'Emden, M, Ding, Sa, Gilfillan, C, Greenaway, T, Gunawan, F, Ho, J, Jackson, R, Kalra, B, Lau, Sl, Lin, J, Macisaac, R, Makepeace, A, Malabu, U, Marjason, J, Mccallum, R, Mclean, M, Moin, N, Petersons, C, Price, S, Roberts, A, Roberts, D, Sangla, K, Stranks, S, Tan, Y, Thynne, T, Walters, J, Ward, G, Wen, W, Zhang, J, Brix, J, Feder, A, Höbaus, C, Höllerl, F, Höller, V, Kotter, T, Kratz, E, Krzizek, Ec, Leb-Stoeger, U, Mader, J, Mras, N, Novak, E, Obendorf, F, Peric, S, Pesau, G, Prager, R, Ribitsch, A, Schnack, C, Schernthaner, G, Wascher, T, Batens, Ah, Benhalima, K, De Block, C, Ernest, P, Fouckova, A, Jandrain, B, Lapauw, B, Letiexhe, M, Mathieu, C, Neven, S, Peiffer, F, Ruige, J, Scheen, A, Taes, Y, Van Boxelaer, I, Vandistel, G, Van Durme, Y, Verhaegen, A, Alencar, E, Alencar, R, Almeida, Ac, B, Alve, Alves, E, Alves, G, Alves, J, Araujo, L, Arruda, V, Augusto, Ga, Baggentoss, R, Balestrassi, L, Barbosa, M, Barcelos, I, Belem, L, de Bem, A, Betti, Rt, Bona, R, Bosco, A, Branda, J, Bronstein, M, Bueno, T, Bulcão, T, Caiado, F, Camazzola, F, Cambréa, Mf, Campos, S, Canani, L, Carra, Mk, Caruso, S, Carvalho, N, Casillo, A, Castro, D, Cavalcanti, T, Cavichioli, V, Cercato, C, Chacra, A, Challela, W, Charchar, H, C, Chave, Chrisman, C, Correia-Deur, J, da Costa, A Jr, Costa, M, Costi, B, Coutinho, P, 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S, Pechmann, L, Costa da Penha, P, Perlamagna, L, Perotta, B, Pimentel, L, Pinto, M, Poço, C, Ponte, C, Prazeres, P, Quintao, E, Raduan, R, Rassi, Dt, Rassi, N, Reck, L, Montenegro, R Jr, Ribeiro, R, Rodovalho, S, Silveira Rodrigues, G, Rollin, G, Rossi, S, Sabino, C, Sales, Ap, Salles, J, Sampaio, Cr, Santana, L, Sato, V, da Silva Santos, M, Santos, Nl, Santos, R, Saraiva, J, Sartori, C, Sena, R, Sevilha, M, Sgarbi, J, Silva, D, D'albuquerque Silva, L, Silva, Me, Siqueira, K, Soares, S, Sobreira, W, Sousa, B, Souza, Ac, Souza, B, Tambascia, M, Tarantino, R, Tenor, F, Tomarchio, M, Triches, C, Tristão, Lj, Valenti, A, Vasques, E, Vencio, S, Vianna, A, Munhoz Vidotto, T, Vieira, S, Villar, H, Visconti, G, Volaco, A, Wajchenberg, B, Zanatta, L, Zimmerman, L, Abbott, Ec, Abu-Bakare, A, Advani, A, Allison, R, Bishara, P, Bowering, Ck, Cheng, A, Chouinard, S, Clayton, D, Conway, J, D'Amours, M, de Tugwell, B, Deyoung, P, D'Ignazio, G, Dube, F, Ekoe, Jm, Fagan, S, Garceau, C, Gottesman, I, 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T, Hagan, A, Hager, S, Haggag, A, Haggar, M, Hamilton, M, Hamlet, P, Hammond, J, Hansen, A, Harrell, W, Harris, E, Harris, K, Harris, M, Harrison, L, Hartman, I, Hatch, A, Hayes, D, Hayes, M, Heath, J, Heineman, R, Heinzman, A, Hendrick, M, Herbst, R, Hermayer, K, Hibbard, J, Hill, Wd, Hilliard, B, Hix, M, Hoch, B, Hollander, P, Holmes, Z, Horobetz, C, Horowitz, R, Hsieh, P, Hsieh, S, Htun, W, Huang, J, Huber, C, Hudson, T, Huizar, S, Hull, B, Hull, J, Hummer, K, Hundal, R, Hunt, G, Hunt, V, Hutchinson, P, Hwang, J, Iannamorelli, A, Iannuzzi, L, Ingram, M, Iram, N, Ismail-Beigi, F, Jabbour, S, Jackson, T, Jaen, L, Jain, V, Jannesari, R, Januski, V, Japa, U, Jarvis, K, Jayson, L, Jensen, R, Jester, D, Jocko, C, Johnson, C, Johnson, M, Johnston, K, Jones, D, Jones, J, Jordan, T, Juarez, M, Kaapuraala, A, Kain, A, Kaiser, V, Kamradt, K, Karatoprakli, P, Karegar, M, Karounos, C, Karounos, D, Karunaratne, H, Katalenich, B, Katic, K, Katz, M, Kaur, G, Kawa, A, Keib, C, Keider, G, Kem, D, Kennedy, R, Kenney, B, Kereiakes, D, Ketana, M, Kettinger, L, Khaira, A, Khan, A, Khan, K, Khan, M, Khoo, T, Khrlobyan, N, Kilgore, J, Kim, G, Kimble, S, Kinsley, M, Kitchen, T, Klick, M, Kniffen, W, Knight, R, Kodzwa, D, Koenig, T, Komarovskiy, K, Kong, Y, Koontz, D, Krishnasamy, S, Krueger, E, Kuechenmeister, L, Kuehl, A, Kuettel, K, Kugler, D, Kulow, T, Kupriyanchik, I, Kuruvanka, T, Kushner, D, Kwon, E, Kwon, S, Kyle, M, Labryer, L, Labuda, J, Lafave, J, Laguerre, J, Laliberte, A, Lane, J, Langel, C, Lann, D, Largay, J, Latif, K, Latus, T, Lawrence, J, Ledger, G, Lee, Fg, Lee, E, Leffert, J, Leinung, M, Lenhard, Mj, Lentino, J, Leon, J, Leonard, M, Letassy, N, Leuck, K, Levin, P, Levinson, D, Lewis, M, Light, T, Lim, J, Lindamood, R, Lingvay, I, Lipps, J, Lisa, A, Livingston, Y, Llamas, L, Loesch, R, Long, T, Looby, R, Lopez, C, Lorenz, T, Lovre, D, Lu, P, Lucas, K, Luevano, G, Luidens, M, Luna, B, Luttrell, L, Lyons, T, Macadams, M, Mack, D, Mack, M, Madden, M, Madder, R, Madireddy, S, Mae, L, Mahakala, A, Maheshwari, H, Malbari, H, Maldonado, N, Mallitz, M, Mandviwala, M, Mann, K, Mardahay, M, Marino, J, Marney, A, Marshall, L, Martin, A, Martin, E, Martinez, G, Martinez-Miss, S, Marx, P, Massara, L, Mastoor, M, Matfin, G, Maturu, A, Maurides, P, May, M, Mayfield, R, Maynard, B, Mazza, A, Mccann, K, Mccoy, J, Mccoy, T, Mccullen, Mk, Mcdaniel, C, Mcdaniel, Am, Mcdermott, M, Mcdonald, A, Mcmasters, B, Mcmurray, C, Medlin, T, Meinel, M, Mendez, I, Menefee, J, Meredith, M, Merriweather, M, Mersey, J, Messino, C, Meyer, S, Meyers, L, Michael, D, Midyett, C, Miklius, A, Milford, E, Miller, B, Miller, H, Milligan, M, Minor, A, Miranda-Palma, B, Mirarchi, N, Mittadodla, S, Mittle, J, Moffat, A, Mohaupt, S, Mohiuddin, K, Mokshagundam, S, Monaco, S, Monsaert, R, Montano-Pereira, C, Montgomery, A, Moody, K, Moon, M, Moore, D, Moore, L, Morawski, E, Moreau, C, Morin, D, Moscoa, C, Motzkin, C, Mueller, R, Munoz, C, Munoz, M, Myneni, A, Naderi, B, Nagireddy, P, Naidu, J, Naidu, R, Naik, S, Naimark, R, Nardicchi, M, Ndukwu, I, Neller, C, Netten-Foster, L, Neumiller, J, New, T, Newman, S, Newton, T, Nguyen, B, Nicol, B, Nicol, P, Ninivaggi, L, Niswender, K, Norman, L, Noworatzky, G, Nyenwe, E, O'Brien, H, O'Connell, T, Oden, W, Odugbesan, A, Oliver, M, Oliver, T, Olmeda, C, O'Neil, C, Oremus, R, Ortega, T, Ortiz-Santos, S, Osborn, T, Padmanabhan, S, Papacostea, O, Park, I, Parker, A, Parker, K, Parker, R, Patel, C, Patel, M, Patel, R, Patino, M, Patterson, S, Paulson, K, Paz, A, Pemba, R, Pepe, C, Perez, J, Perez, T, Perry, D, Phillips, B, Phillips, J, Pickett, A, Pinson, M, Pitzer, R, Poduri, M, Poehls, J, Poteat, T, Powell, L, Prasad, S, Prevost, J, Price, E, Priest, D, Prieto, L, Purewal, T, Purighalla, R, Purighalla, U, Quadrel, M, Qureshi, A, Radhamma, R, Rafla, E, Rajab, H, Ramalingam, R, Ramirez, A, J, Ramirez, Ramirez, K, Ramirez, M, Randall, M, Rangaraj, U, Rao, V, Rasmussen, P, Rasouli, N, Ray, A, Reed, J, Rems, L, Renaud, K, Reno, M, Resnick, M, Reusch, J, Reynolds, L, Rhoton, K, Rhudy, J, Ricci, C, Rice, L, Richardson, A, Richardson, L, Rickard, H, Rickels, M, Riff, D, Rightenour, N, Risser, J, Rizvi, A, Robertson, J, Robinson, A, Robinson, R, Rockwell, M, Rodriguez, Jp, Rodriguez, M, Rojas, M, Rojas, W, Rooker-Morris, L, Root, C, Rose, M, Rosenberg, R, Rosenstock, J, Roth, M, Ruby, R, Sachson, R, Sack, P, Sadler, Rk, Sahai, S, J, Salazar, Salgam, M, Samal, A, Samson, A, Sanagorski, R, Sanchez, A, Sandberg, J, Sanderson, M, Sandoval, J, Santiago, E, Sapp, T, Saunders, J, Schill, J, Schott, C, Schreiman, R, Schu, D, Schuh, K, Schutta, M, Schwartz, J, Schweppe, L, Scofield, H, Scribner, A, Seal, J, Sealock, J, Seaton, B, Sedlak-Hanslik, T, Seekins, K, Segal, M, Seggelke, S, Semenza, S, Sentman, P, Serra, M, Seshadri, P, Sevilla, E, Shah, S, Shaheen, K, Shanik, M, Shaw, J, Sheets, M, Shellabarger, C, Sher, J, Shippey, J, Shivaswamy, V, Shomali, M, Shore, D, Shroff, P, Siddiqui, T, Siegwald, A, Silver, R, Simmons, D, 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E, Vazquez, M, Vickery, D, Villafuerte, B, Villegas, C, Vivar, J, Vivekananthan, K, Vo, G, Vukojicic, K, Wachter, A, Wahl, D, Waitmann, J, Walker, D, Walsh, J, Walsh, K, Walton, A, Wang, A, Wardell, K, Watkins, S, Watkinson, J, Watts, M, Watwe, V, Weaver, N, Weber, R, Wedick, C, Weeks, D, Weeks, L, Weindorff, K, Weinstein, R, Weiss, S, Wenger, K, Wentworth, M, Werner, A, West, M, Whelan, S, White, B, White, J, Whitmire, M, Whittington, R, Wical, J, Wigley, C, Wilkins, F, Will, K, Williams, A, Wilson, Le, Wince, M, Wine, S, Winkle, P, Winner, C, Wise, J, Witte, M, Wittenmyer, J, Wood, C, Wood, R, Woodruff, C, Worthington, B, Wynn, D, Wysham, C, Xavier, P, Yela, S, Yenoby, L, Young, L, Younus, N, Yourell, V, Zaid, M, Zubair, I., Mann J.F.E., Orsted D.D., Brown-Frandsen K., Marso S.P., Poulter N.R., Rasmussen S., Tornoe K., Zinman B., Buse J.B., and Buscemi S.

Subjects
Male, Settore MED/09 - Medicina Interna, Acute Kidney Injury, Aged, Albuminuria, Creatinine, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Double-Blind Method, Female, Follow-Up Studies, Glomerular Filtration Rate, Glucagon-Like Peptide 1, Humans, Hypoglycemic Agents, Intention to Treat Analysis, Kidney Failure, Chronic, Liraglutide, Middle Aged, Type 2 diabetes, 030204 cardiovascular system & hematology, urologic and male genital diseases, GLOMERULAR-FILTRATION-RATE, KIDNEY-FUNCTION, DISEASE, law.invention, Kidney Failure, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Medicine, Settore MED/49 - Scienze Tecniche Dietetiche Applicate, Chronic, RISK, Kidney, Acute kidney injury, 11 Medical And Health Sciences, General Medicine, medicine.anatomical_structure, TRIAL, liraglutide, randomized controlled trial, type 2 diabetes, renal outcomes, Life Sciences & Biomedicine, Type 2, medicine.drug, medicine.medical_specialty, Renal function, 030209 endocrinology & metabolism, CARDIOVASCULAR OUTCOMES, Follow-Up Studie, 03 medical and health sciences, Medicine, General & Internal, General & Internal Medicine, Diabetes mellitus, Internal medicine, Diabetes Mellitus, Intensive care medicine, Science & Technology, business.industry, MORTALITY, medicine.disease, INTENSIVE GLUCOSE CONTROL, INDIVIDUALS, chemistry, Diabetic Nephropathie, LEADER Steering Committee and Investigators, business
Abstract

BACKGROUND: In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown. METHODS: We report the prespecified secondary renal outcomes of that randomized, controlled trial in which patients were assigned to receive liraglutide or placebo. The secondary renal outcome was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The risk of renal outcomes was determined with the use of time-to-event analyses with an intention-to-treat approach. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. RESULTS: A total of 9340 patients underwent randomization, and the median follow-up of the patients was 3.84 years. The renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4668 patients vs. 337 of 4672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P=0.003). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P=0.004). The rates of renal adverse events were similar in the liraglutide group and the placebo group (15.1 events and 16.5 events per 1000 patient-years), including the rate of acute kidney injury (7.1 and 6.2 events per 1000 patient-years, respectively). CONCLUSIONS: This prespecified secondary analysis shows that, when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .).

Published
2017

39. Mitotic spindle association of TACC3 requires Aurora‐A‐dependent stabilization of a cryptic α‐helix

Author

Burgess, SG, Mukherjee, M, Sabir, S, Joseph, N, Gutiérrez-Caballero, C, Richards, MW, Huguenin-Dezot, N, Chin, JW, Kennedy, EJ, Pfuhl, M, Royle, SJ, Gergely, F, and Bayliss, R

Subjects
Protein Conformation, alpha-Helical, phosphorylation, Cell Cycle, protein kinase, Articles, Spindle Apparatus, disorder–order transition, intrinsically disordered protein, QP, Article, Cell Line, QH301, protein–protein interaction, Structural Biology, Humans, Cell Adhesion, Polarity & Cytoskeleton, Microtubule-Associated Proteins, Aurora Kinase A
Abstract

Aurora‐A regulates the recruitment of TACC3 to the mitotic spindle through a phospho‐dependent interaction with clathrin heavy chain (CHC). Here, we describe the structural basis of these interactions, mediated by three motifs in a disordered region of TACC3. A hydrophobic docking motif binds to a previously uncharacterized pocket on Aurora‐A that is blocked in most kinases. Abrogation of the docking motif causes a delay in late mitosis, consistent with the cellular distribution of Aurora‐A complexes. Phosphorylation of Ser558 engages a conformational switch in a second motif from a disordered state, needed to bind the kinase active site, into a helical conformation. The helix extends into a third, adjacent motif that is recognized by a helical‐repeat region of CHC, not a recognized phospho‐reader domain. This potentially widespread mechanism of phospho‐recognition provides greater flexibility to tune the molecular details of the interaction than canonical recognition motifs that are dominated by phosphate binding.

Published
2018

50. EML4-ALK variants: biological and molecular properties, and the implications for patients

Author

Sabir, SR, Yeoh, S, Jackson, G, and Bayliss, R

Subjects
tyrosine kinase inhibitor, hemic and lymphatic diseases, echinoderm microtubule-associated protein, Review, anaplastic lymphoma kinase, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, non-small cell lung cancer
Abstract

Since the discovery of the fusion between EML4 (echinoderm microtubule associated protein-like 4) and ALK (anaplastic lymphoma kinase), EML4-ALK, in lung adenocarcinomas in 2007, and the subsequent identification of at least 15 different variants in lung cancers, there has been a revolution in molecular-targeted therapy that has transformed the outlook for these patients. Our recent focus has been on understanding how and why the expression of particular variants can affect biological and molecular properties of cancer cells, as well as identifying the key signalling pathways triggered, as a result. In the clinical setting, this understanding led to the discovery that the type of variant influences the response of patients to ALK therapy. Here, we discuss what we know so far about the EML4-ALK variants in molecular signalling pathways and what questions remain to be answered. In the longer term, this analysis may uncover ways to specifically treat patients for a better outcome.

Published
2017

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