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5. BamABCDE bound to substrate EspP

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Doyle, M.T., primary, Jimah, J.R., additional, Dowdy, T., additional, Ohlemacher, S.I., additional, Larion, M., additional, Hinshaw, J.E., additional, and Bernstein, H.D., additional

Published
2022
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12. Elective cancer surgery in COVID-19–Free surgical pathways during the SARS-cov-2 pandemic: An international, multicenter, comparative cohort study

Author

James C Glasbey, Dmitri Nepogodiev, Joana Ff Simoes, Omar Omar, Elizabeth Li, Mary L Venn, Mohammad Abou Chaar, Vita Capizzi, Daoud Chaudhry, Anant Desai, Jonathan G Edwards, Jonathan P Evans, Marco Fiore, Jose Flavio Videria, Samuel J Ford, Ian Ganyli, Ewen A Griffiths, Rohan R Gujjuri, Angelos G Kolias, Haytham Ma Kaafarani, Ana Minaya-Bravo, Siobhan C McKay, Helen M Mohan, Keith Roberts, Carlos San Miguel-Méndez, Peter Pockney, Richard Shaw, Neil J Smart, Grant D Stewart, Sudha Sundar, Raghavan Vidya, Aneel A Bhangu, James C Glasbey, Omar Omar, Aneel A Bhangu, Kwabena Siaw-Acheampong, Ruth A Benson, Edward Bywater, Daoud Chaudhry, Brett E Dawson, Jonathan P Evans, James C Glasbey, Rohan R Gujjuri, Emily Heritage, Conor S Jones, Sivesh K Kamarajah, Chetan Khatri, Rachel A Khaw, James M Keatley, Andrew Knight, Samuel Lawday, Elizabeth Li, Harvinder S Mann, Ella J Marson, Kenneth A McLean, Siobhan C McKay, Emily C Mills, Dmitri Nepogodiev, Gianluca Pellino, Maria Picciochi, Elliott H Taylor, Abhinav Tiwari, Joana Ff Simoes, Isobel M Trout, Mary L Venn, Richard Jw Wilkin, Aneel A Bhangu, James C Glasbey, Neil J Smart, Ana Minaya-Bravo, Jonathan P Evans, Gaetano Gallo, Susan Moug, Francesco Pata, Peter Pockney, Salomone Di Saverio, Abigail Vallance, Dale Vimalchandran, Ewen A Griffiths, Sivesh K Kamarajah, Richard Pt Evans, Philip Townend, Keith Roberts, Siobhan McKay, John Isaac, Sohei Satoi, John Edwards, Aman S Coonar, Adrian Marchbank, Edward J Caruana, Georgia R Layton, Akshay Patel, Alessandro Brunelli, Samuel Ford, Anant Desai, Alessandro Gronchi, Marco Fiore, Max Almond, Fabio Tirotta, Sinziana Dumitra, Angelos Kolias, Stephen J Price, Daniel M Fountain, Michael D Jenkinson, Peter Hutchinson, Hani J Marcus, Rory J Piper, Laura Lippa, Franco Servadei, Ignatius Esene, Christian Freyschlag, Iuri Neville, Gail Rosseau, Karl Schaller, Andreas K Demetriades, Faith Robertson, Alex Alamri, Richard Shaw, Andrew G Schache, Stuart C Winter, Michael Ho, Paul Nankivell, Juan Rey Biel, Martin Batstone, Ian Ganly, Raghavan Vidya, Alex Wilkins, Jagdeep K Singh, Dinesh Thekinkattil, Sudha Sundar, Christina Fotopoulou, Elaine Leung, Tabassum Khan, Luis Chiva, Jalid Sehouli, Anna Fagotti, Paul Cohen, Murat Gutelkin, Rahel Ghebre, Thomas Konney, Rene Pareja, Rob Bristow, Sean Dowdy, T S Shylasree, R Kottayasamy Seenivasagam, Joe Ng, Keiiji Fujiwara, Grant D Stewart, Benjamin Lamb, Krishna Narahari, Alan McNeill, Alexandra Colquhoun, John McGrath, Steve Bromage, Ravi Barod, Veeru Kasivisvanathan, Tobias Klatte, Joana Ff Simoes, Tom Ef Abbott, Sadi Abukhalaf, Michel Adamina, Adesoji O Ademuyiwa, Arnav Agarwal, Murat Akkulak, Ehab Alameer, Derek Alderson, Felix Alakaloko, Markus Albertsmeiers, Osaid Alser, Muhammad Alshaar, Sattar Alshryda, Alexis P Arnaud, Knut Magne Augestad, Faris Ayasra, José Azevedo, Brittany K Bankhead-Kendall, Emma Barlow, David Beard, Ruth A Benson, Ruth Blanco-Colino, Amanpreet Brar, Ana Minaya-Bravo, Kerry A Breen, Chris Bretherton, Igor Lima Buarque, Joshua Burke, Edward J Caruana, Mohammad Chaar, Sohini Chakrabortee, Peter Christensen, Daniel Cox, Moises Cukier, Miguel F Cunha, Giana H Davidson, Anant Desai, Salomone Di Saverio, Thomas M Drake, John G Edwards, Muhammed Elhadi, Sameh Emile, Shebani Farik, Marco Fiore, J Edward Fitzgerald, Samuel Ford, Tatiana Garmanova, Gaetano Gallo, Dhruv Ghosh, Gustavo Mendonça Ataíde Gomes, Gustavo Grecinos, Ewen A Griffiths, Madalegna GrÜndl, Constantine Halkias, Ewen M Harrison, Intisar Hisham, Peter J Hutchinson, Shelley Hwang, Arda Isik, Michael D Jenkinson, Pascal Jonker, Haytham Ma Kaafarani, Debby Keller, Angelos Kolias, Schelto Kruijff, Ismail Lawani, Hans Lederhuber, Sezai Leventoglu, Andrey Litvin, Andrew Loehrer, Markus W Löffler, Maria Aguilera Lorena, Maria Marta Modolo, Piotr Major, Janet Martin, Hassan N Mashbari, Dennis Mazingi, Symeon Metallidis, Ana Minaya-Bravo, Helen M Mohan, Rachel Moore, David Moszkowicz, Susan Moug, Joshua S Ng-Kamstra, Mayaba Maimbo, Ionut Negoi, Milagros Niquen, Faustin Ntirenganya, Maricarmen Olivos, Kacimi Oussama, Oumaima Outani, Marie Dione Parreno-Sacdalanm, Francesco Pata, Carlos Jose Perez Rivera, Thomas D Pinkney, Willemijn van der Plas, Peter Pockney, Ahmad Qureshi, Dejan Radenkovic, Antonio Ramos-De la Medina, Keith Roberts, April C Roslani, Martin Rutegård, Juan José Segura-Sampedro, Irène Santos, Sohei Satoi, Raza Sayyed, Andrew Schache, Andreas A Schnitzbauer, Justina O Seyi-Olajide, Neil Sharma, Richard Shaw, Sebastian Shu, Kjetil Soreide, Antonino Spinelli, Grant D Stewart, Malin Sund, Sudha Sundar, Stephen Tabiri, Philip Townend, Georgios Tsoulfas, Gabrielle H van Ramshorst, Raghavan Vidya, Dale Vimalachandran, Oliver J Warren, Duane Wedderburn, Naomi Wright, C Allemand, L Boccalatte, M Figari, M Lamm, J Larrañaga, C Marchitelli, F Noll, D Odetto, M Perrotta, J Saadi, L Zamora, C Alurralde, E L Caram, D Eskinazi, J P Mendoza, M Usandivaras, R Badra, A Esteban, J S García, P M García, J I Gerchunoff, S M Lucchini, M A NIgra, L Vargas, T Hovhannisyan, A Stepanyan, T Gould, R Gourlay, B Griffiths, S Gananadha, M McLaren, J Cecire, N Joshi, S Salindera, A Sutherland, J H Ahn, G Charlton, S Chen, N Gauri, R Hayhurst, S Jang, F Jia, C Mulligan, W Yang, G Ye, H Zhang, M Ballal, D Gibson, D Hayne, J Moss, T Richards, P Viswambaram, U G Vo, J Bennetts, T Bright, M Brooke-Smith, R Fong, B Gricks, Y H Lam, B S Ong, M Szpytma, D Watson, K Bagraith, S Caird, E Chan, C Dawson, D Ho, E Jeyarajan, S Jordan, A Lim, G J Nolan, A Oar, D Parker, H Puhalla, A Quennell, L Rutherford, P Townend, M Von Papen, M Wullschleger, A Blatt, D Cope, N Egoroff, M Fenton, J Gani, N Lott, P Pockney, N Shugg, M Elliott, D Phung, D Phan, D Townend, C Bong, J Gundara, A Frankel, S Bowman, G R Guerra, J Bolt, K Buddingh, N N Dudi-Venkata, S Jog, H M Kroon, T Sammour, R Smith, C Stranz, M Batstone, K Lah, W McGahan, D Mitchell, A Morton, A Pearce, M Roberts, G Sheahan, B Swinson, N Alam, S Banting, L Chong, P Choong, S Clatworthy, D Foley, A Fox, M W Hii, B Knowles, J Mack, M Read, A Rowcroft, S Ward, G Wright, M Lanner, I Königsrainer, M Bauer, C Freyschlag, M Kafka, F Messner, D Öfner, I Tsibulak, K Emmanuel, M Grechenig, R Gruber, M Harald, L Öhlberger, J Presl, A Wimmer, I Namazov, E Samadov, D Barker, R Boyce, S Corbin, A Doyle, A Eastmond, R Gill, A Haynes, S Millar, M O'Shea, G Padmore, N Paquette, E Phillips, S St John, K Walkes, N Flamey, P Pattyn, W Oosterlinck, J Van den Eynde, R Van den Eynde, A Gatti, C Nardi, R Oliva, R De Cicco, I Cecconello, P Gregorio, L Pontual Lima, U Ribeiro Junior, F Takeda, R M Terra, M Sokolov, B Kidane, S Srinathan, M Boutros, N Caminsky, G Ghitulescu, G Jamjoum, J Moon, J Pelletier, T Vanounou, S Wong, M Boutros, S Dumitra, A Kouyoumdjian, B Johnston, C Russell, M Boutros, S Demyttenaere, R Garfinkle, J Abou-Khalil, C Nessim, J Stevenson, F Heredia, A Almeciga, A Fletcher, A Merchan, L O Puentes, J Mendoza Quevedo, G Bacic, D Karlovic, D Krsul, M Zelic, I Luksic, M Mamic, B Bakmaz, I Coza, E Dijan, Z Katusic, J Mihanovic, I Rakvin, K Frantzeskou, N Gouvas, G Kokkinos, P Papatheodorou, I Pozotou, O Stavrinidou, A Yiallourou, L Martinek, M Skrovina, I Szubota, J Žatecký, V Javurkova, J Klat, T Avlund, P Christensen, J L Harbjerg, L H Iversen, D W Kjaer, Hø Kristensen, M Mekhael, A L Ebbehøj, P Krarup, N Schlesinger, H Smith, A Abdelsamed, A Y Azzam, H Salem, A Seleim, A Abdelmajeed, M Abdou, N E Abosamak, M Al Sayed, F Ashoush, R Atta, E Elazzazy, M Elhoseiny, M Elnemr, M S Elqasabi, M E Elsayed Hewalla, I Elsherbini, E Essam, M Eweda, I Ghallab, E Hassan, M Ibrahim, M Metwalli, M Mourad, M S Qatora, M Ragab, A Sabry, H Saifeldin, M Saleh Mesbah Mohamed Elkaffas, A Samih, A Samir Abdelaal, S Shehata, K Shenit, D Attia, N Kamal, N Osman, A M Abbas, Has Abd Elazeem, M M Abdelkarem, S Alaa, A K Ali, A Ayman, M G Azizeldine, H Elkhayat, S M Elghazaly, F A Monib, M A Nageh, M M Saad, M Salah, M Shahine, E A Yousof, A Youssef, A Eldaly, M ElFiky, A Nabil, G Amira, I Sallam, M Sherief, A Sherif, A Abdelrahman, H Aboulkassem, G Ghaly, R Hamdy, A Morsi, H Salem, G Sherif, H Abdeldayem, I Abdelkader Salama, M Balabel, Y Fayed, A E Sherif, D Bekele, J Kauppila, E Sarjanoja, O Helminen, H Huhta, J H Kauppila, C Beyrne, L Jouffret, L Lugans, L Marie-Macron, E Chouillard, B De Simone, J Bettoni, S Dakpé, B Devauchelle, N Lavagen, S Testelin, S Boucher, R Breheret, A Gueutier, A Kahn, J KÜn-Darbois, A Barrabe, Z Lakkis, A Louvrier, S Manfredelli, P Mathieu, A Chebaro, V Drubay, M El Amrani, C Eveno, K Lecolle, G Legault, L Martin, G Piessen, F R Pruvot, S Truant, P Zerbib, Q Ballouhey, B Barrat, J Laloze, H Salle, A Taibi, J Usseglio, D Bergeat, A Merdrignac, Roy B Le, L O Perotto, A Scalabre, A Aimé, A Ezanno, B Malgras, P Bouche, S Tzedakis, E Cotte, O Glehen, V Kepenekian, J Lifante, G Passot, A D'Urso, E Felli, D Mutter, P Pessaux, B Seeliger, J Bardet, R Berry, G Boddaert, S Bonnet, E Brian, C Denet, D Fuks, D Gossot, M Grigoroiu, A Laforest, Y Levy-Zauberman, C Louis-Sylvestre, A Moumen, G Pourcher, A Seguin-Givelet, E Tribillon, E Duchalais, F Espitalier, C Ferron, O Malard, U Bork, M Distler, J Fritzmann, J Kirchberg, C Praetorius, C Riediger, J Weitz, T Welsch, P Wimberger, K Beyer, C Kamphues, J Lauscher, F N Loch, C Schineis, M Albertsmeier, M Angele, A Kappenberger, H Niess, T Schiergens, J Werner, R Becker, J Jonescheit, I Pergolini, D Reim, C Boeker, I Hakami, J Mall, P Liokatis, W Smolka, K Nowak, T Reinhard, F Hölzle, A Modabber, P Winnand, M Knitschke, P Kauffmann, S Wolfer, J Kleeff, K Lorenz, C Michalski, U Ronellenfitsch, R Schneider, E Bertolani, A Königsrainer, M W Löffler, M Quante, C Steidle, L ÜberrÜck, C Yurttas, C S Betz, J Bewarder, A Böttcher, S Burg, C Busch, M Gosau, A Heuer, J Izbicki, T O Klatte, D Koenig, N Moeckelmann, C Nitschke, M Priemel, R Smeets, U Speth, S Thole, F G Uzunoglu, T Vollkommer, N Zeller, M J Battista, K Gillen, A Hasenburg, S Krajnak, V Linz, R Schwab, K Angelou, D Haidopoulos, A Rodolakis, P Antonakis, K Bramis, L Chardalias, I Contis, N Dafnios, D Dellaportas, G Fragulidis, A Gklavas, M Konstadoulakis, N Memos, I Papaconstantinou, A Polydorou, T Theodosopoulos, A Vezakis, M I Antonopoulou, D K Manatakis, N Tasis, N Arkadopoulos, N Danias, P Economopoulou, P Kokoropoulos, A Larentzakis, N Michalopoulos, J Selmani, T Sidiropoulos, V Tsaousis, P Vassiliu, K Bouchagier, S Klimopoulos, D Paspaliari, G Stylianidis, K Baxevanidou, K Bouliaris, P Chatzikomnitsa, M Efthimiou, A Giaglaras, C Kalfountzos, G Koukoulis, A M Ntziovara, K Petropoulos, K Soulikia, I Tsiamalou, K Zervas, S Zourntou, I Baloyiannis, A Diamantis, E Gkrinia, J Hajiioannou, C Korais, O Koukoura, K Perivoliotis, A Saratziotis, C Skoulakis, D Symeonidis, K Tepetes, G Tzovaras, D Zacharoulis, V Alexoudi, K Antoniades, I Astreidis, P Christidis, D Deligiannidis, T Grivas, O Ioannidis, I Kalaitsidou, L Loutzidou, A Mantevas, D Michailidou, K Paraskevopoulos, S Politis, A Stavroglou, D Tatsis, I Tilaveridis, K Vahtsevanos, G Venetis, I Karaitianos, T Tsirlis, A Charalabopoulos, T Liakakos, E Mpaili, D Schizas, E Spartalis, A Syllaios, C Zografos, C Anthoulakis, C Christou, V Papadopoulos, A Tooulias, D Tsolakidis, G Tsoulfas, D Zouzoulas, E Athanasakis, E Chrysos, J Tsiaoussis, S Xenaki, E Xynos, K Futaba, M F Ho, S F Hon, Twc Mak, Ssm Ng, C C Foo, B Banky, N Suszták, M Aremu, A Canas-Martinez, O Cullivan, C Murphy, P Owens, L Pickett, L Akmenkalne, J Byrne, M Corrigan, C Cullinane, A Daly, C Fleming, P Jordan, S Killeen, N Lynch, A McCarthy, H Mustafa, S O'Brien, P O'Leary, Was Syed, L Vernon, D Callanan, L Huang, A Ionescu, P Sheahan, I Balasubramanian, M Boland, K Conlon, D Evoy, N Fearon, T Gallagher, J Geraghty, H Heneghan, N Kennedy, D Maguire, D McCartan, E W McDermott, R S Prichard, D Winter, D Alazawi, C Barry, T Boyle, W Butt, E M Connolly, N Donlon, C Donohue, B A Fahey, R Farrell, C Fitzgerald, J Kinsella, J O Larkin, P Lennon, P J Maguire, P Mccormick, B J Mehigan, H Mohan, T Nugent, H O'Sullivan, N Ravi, J V Reynolds, A Rogers, P Shokuhi, J Smith, L A Smith, C Timon, Y Bashir, G Bass, T Connelly, B Creavin, H Earley, J A Elliott, A Gillis, D Kavanagh, P Neary, J O'riordan, I S Reynolds, D Rice, P Ridgway, M Umair, M Whelan, P Carroll, C Collins, K Corless, L Finnegan, A Fowler, A Hogan, M Kerin, A Lowery, P McAnena, K McKevitt, K Nizami, É Ryan, A Samy, J C Coffey, R Cunningham, M Devine, D Nally, C Peirce, S Tormey, N Hardy, P Neary, S O'Malley, M Ryan, S Macina, N M Mariani, E Opocher, A Pisani Ceretti, F Ferrari, F Odicino, E Sartori, C Cotsoglou, S Granieri, F Bianco, A Camillo, M Colledan, S Tornese, M F Zambelli, G Bissolotti, S Fusetti, F Lemma, M V Marino, A Mirabella, G Vaccarella, C Agostini, G Alemanno, I Bartolini, C Bergamini, A Bruscino, C Checcucci, R De Vincenti, A Di Bella, M Fambrini, L Fortuna, G Maltinti, P Muiesan, F Petraglia, P Prosperi, M N Ringressi, M Risaliti, F Sorbi, A Taddei, R Tucci, C Bassi, L Bortolasi, T Campagnaro, L Casetti, M De Pastena, A Esposito, M Fontana, A Guglielmi, L Landoni, G Malleo, G Marchegiani, S Nobile, S Paiella, C Pedrazzani, S Rattizzato, A Ruzzenente, R Salvia, G Turri, M Tuveri, P Bellora, G D'Aloisio, M Ferrari, E Francone, S Gentilli, H Nikaj, M Bianchini, M Chiarugi, F Coccolini, G Di Franco, N Furbetta, D Gianardi, S Guadagni, L Morelli, M Palmeri, D Tartaglia, G Anania, P Carcoforo, M Chiozza, A De Troia, M Koleva Radica, M Portinari, M G Sibilla, A Urbani, N Fabbri, C V Feo, S Gennari, S Parini, E Righini, L Ampollini, L Bellanti, M Bergonzani, G Bertoli, G Bocchialini, G D'Angelo, D Lanfranco, L Musini, T Poli, G P Santoro, A Varazzani, L Aguzzoli, G Borgonovo, C Castro Ruiz, S Coiro, G Falco, V D Mandato, V Mastrofilippo, M T Montella, V Annessi, M Zizzo, U Grossi, S Novello, M Romano, S Rossi, G Zanus, G Esposito, F Frongia, A Pisanu, M Podda, C Belluco, A Lauretta, G Montori, L Moras, M Olivieri, F Bussu, A G Carta, M L Cossu, P Cottu, A Fancellu, C F Feo, G C Ginesu, G Giuliani, M Madonia, T Perra, A Piras, A Porcu, D Rizzo, A M Scanu, A Tedde, M Tedde, P Delrio, D Rega, G Badalamenti, G Campisi, A Cordova, M Franza, G Maniaci, G Rinaldi, F Toia, M Calabrò, F Farnesi, E G Lunghi, A Muratore, N S Pipitone Federico, F Bàmbina, G D'Andrea, P Familiari, V Picotti, G De Palma, G Luglio, G Pagano, F P Tropeano, L Baldari, G A Beltramini, L Boni, E Cassinotti, A Gianni, L Pignataro, S Torretta, C Abatini, M Baia, D Biasoni, G Bogani, P Cadenelli, V Capizzi, Spb Cioffi, D Citterio, L V Comini, M Cosimelli, M Fiore, S Folli, M Gennaro, L Giannini, A Gronchi, M Guaglio, A Macchi, F Martinelli, V Mazzaferro, A Mosca, S Pasquali, C Piazza, F Raspagliesi, L Rolli, R Salvioni, G Sarpietro, C Sarre, L Sorrentino, A Agnes, S Alfieri, F Belia, A Biondi, V Cozza, A D'Amore, D D'Ugo, V De Simone, A Fagotti, G Gasparini, L Gordini, F Litta, C P Lombardi, L Lorenzon, A A Marra, F Marzi, A Moro, A Parello, E Perrone, R Persiani, C Ratto, F Rosa, G Saponaro, G Scambia, O Scrima, G Sganga, R Tudisco, A Belli, V Granata, F Izzo, R Palaia, R Patrone, F M Carrano, M M Carvello, A De Virgilio, F Di Candido, F Ferreli, F Gaino, G Mercante, V Rossi, A Spinelli, G Spriano, D M Donati, T Frisoni, E Palmerini, A Aprile, F Barra, P Batistotti, S Ferrero, P Fregatti, S Scabini, M Sparavigna, E Asti, D Bernardi, L Bonavina, A Lovece, L Adamoli, M Ansarin, S Cenciarelli, F Chu, R De Berardinis, U Fumagalli Romario, F Mastrilli, G Pietrobon, M Tagliabue, E Badellino, A Ferrero, R Massobrio, A De Manzoni Garberini, P Federico, P Maida, E Marra, G Marte, A Petrillo, T Tammaro, A Tufo, M Berselli, G Borroni, E Cocozza, L Conti, M Desio, L Livraghi, V Quintodei, A Rizzi, A Zullo, C Baldi, C Corbellini, G M Sampietro, P Cellerino, E Baldini, P Capelli, L Conti, S M Isolani, M Ribolla, A Bondurri, F Colombo, L Ferrario, C Guerci, A Maffioli, T Armao, M Ballabio, P Bisagni, A Gagliano, M Longhi, M Madonini, P PizziCni, A M Baietti, M Biasini, P Maremonti, F Neri, G M Prucher, S Ricci, F Ruggiero, A G Zarabini, R Barmasse, S Mochet, L Morelli, A Usai, F Bianco, P Incollingo, S Mancini, L Marino Cosentino, A Sagnotta, R Fruscio, T Grassi, L C Nespoli, N Tamini, A Anastasi, B Bartalucci, A Bellacci, G Canonico, L Capezzuoli, C Di Martino, P Ipponi, C Linari, M Montelatici, T Nelli, G Spagni, L Tirloni, A Vitali, E Abate, M Casati, T Casiraghi, L Laface, M Schiavo, A Arminio, A Cotoia, V Lizzi, F Vovola, R Vergari, S D'Ugo, N Depalma, M G Spampinato, P Bartolucci, G Brachini, P Bruzzaniti, A Chiappini, V Chiarella, F Ciccarone, P M Cicerchia, B Cirillo, G De Toma, A Di Bartolomeo, E Fiori, G B Fonsi, G Franco, A Frati, M Giugliano, I Iannone, F La Torre, P Lapolla, C Leonardo, G Marruzzo, S Meneghini, A Mingoli, D Ribuffo, M Salvati, A Santoro, P Sapienza, A K Scafa, L Simonelli, M Zambon, G T Capolupo, F Carannante, M Caricato, G Mascianà, E Mazzotta, A Gattolin, M Migliore, R Rimonda, D Sasia, E Travaglio, M Cervellera, A Gori, L Sartarelli, V Tonini, M Giacometti, S Zonta, A Chessa, A Fiorini, C Norcini, G Colletti, M Confalonieri, A Costanzi, C Frattaruolo, G Mari, M Monteleone, A Bandiera, L Bocciolone, G Bonavina, M Candiani, G Candotti, P De Nardi, F Gagliardi, M Medone, P Mortini, G Negri, P Parise, M Piloni, P Sileri, A Vignali, A Belvedere, P Bernante, P Bertoglio, S Boussedra, E Brunocilla, R Cipriani, G Cisternino, E De Crescenzo, P De Iaco, G Dondi, F Frio, E Jovine, F Mineo Bianchi, J Neri, D Parlanti, A M Perrone, A P Pezzuto, M Pignatti, V Pinto, G Poggioli, M Ravaioli, M Rottoli, R Schiavina, M Serenari, M Serra, P Solli, M Taffurelli, M Tanzanu, M Tesei, T Violante, S Zanotti, F Borghi, D Cianflocca, S Di Maria Grimaldi, D Donati, E Gelarda, P Geretto, G Giraudo, M C Giuffrida, A Marano, S Palagi, L Pellegrino, C Peluso, V Testa, F Agresta, D Prando, M Zese, F Aquila, C Gambacciani, L Lippa, F Pieri, O S Santonocito, G Armatura, G Bertelli, A Frena, P Marinello, F Notte, S Patauner, G Scotton, S F Fulginiti, G Gallo, G Sammarco, G Vescio, P Balercia, L Catarzi, G Consorti, F Di Marzo, T Fontana, H Daiko, M Ishikawa, K Ishiyama, S Iwata, K Kanematsu, Y Kanemitsu, T Kato, A Kawai, E Kobayashi, M Kobayashi Kato, K Moritani, F Nakatani, J Oguma, Y Tanase, M Uno, M Al Abdallah, F Ayasra, Y Ayasra, A Qasem, F J Abu Za'nouneh, T Fahmawee, A Hmedat, A Ibrahim, K Obeidat, S Abdel Al, R Abdel Jalil, M K Abou Chaar, M Al-Masri, H Al-Najjar, F Alawneh, O Alsaraireh, M Elayyan, R Ghanem, I Lataifeh, G Z Alkadeeki, F S Al Maadany, N Aldokali, O Senossi, M T Subhi, D Burgan, E Kamoka, A I Kilani, A Salamah, M Salem, A Shuwayyah, E Abdulwahed, E Alshareea, N Aribi, S Aribi, M Biala, R Ghamgh, M Morgom, Z Aldayri, I Ellojli, A Kredan, S Bradulskis, E Dainius, E Kubiliute, J Kutkevicius, A Parseliunas, A Subocius, D Venskutonis, F Rasoaherinomenjanahary, J B Razafindrahita, L H Samison, E C Ong, K H Hamdan, M R Ibrahim, J A Tan, M R Thanapal, N Amin Sahid, F Hayati, J Jayasilan, R K Sriram, S Subramaniam, A Che Jusoh, A H Hussain, A S Mohamed Sidek, M F Mohd Yunus, J Y Soh, Mpk Wong, A D Zakaria, Z Zakaria, A Fadzli, N Q Fathi, P S Koh, Y T Liew, A C Roslani, C Y Tang, L Y Teoh, W J Wong, A S Yahaya, M R Alvarez, R Arrangoiz, F Cordera, M A De la Rosa Abaroa, A Gómez-Pedraza, R Hernandez, A Maffuz-Aziz, J A Posada, F C Becerra García, A Alfaro-Goldaracena, G A Buerba, R A Castillejos-Molina, C Chan, I Dominguez-Rosado, H Medina-Franco, Má Mercado, M Oropeza-Aguilar, E Peña Gómez Portugal, O E Posadas-Trujillo, F Rodriguez-Covarrubias, N Salgado-Nesme, C Sarre, M Vilatoba, Y Arkha, H Bechri, A El Ouahabi, M Y Oudrhiri, F Derkaoui Hassani, N El Abbadi, L Amrani, Z H Belkhadir, A Benkabbou, O Chakib, B El Ahmadi, Y El Bouazizi, H Essangri, A Ghannam, A M Majbar, R Mohsine, A Souadka, R Hompes, E M Meima-van Praag, Ajm Pronk, S Sharabiany, B Grotenhuis, L Hartveld, S Reijers, W Van Houdt, J Baaij, M Bolster-van Eenennaam, M De Graaff, D Sloothaak, P Van Duijvendijk, L Posma-Bouman, T Derksen, J Franken, S Oosterling, R De Bree, J Konsten, M Van Heinsbergen, L Fidelis, T T Sholadoye, M A Tolani, J Olaogun, I K Egbuchulem, T A Lawal, O Ogundoyin, D I Olulana, L Abdur-Rahman, A Adeyeye, I Aremu, J Bello, O Olasehinde, A Popoola, J Massoud, R Massoud, T M Sorour, A Jamal, A A Kerawala, A S Memon, R Nafees Ahmed, L Rai, B Ayub, N Hassan, R S Martins, P Ramesh, R Sayyed, U Butt, M Kashif, M Kashif, W H Khan, A Qureshi, M Umar, M Waris Farooka, T Wasim, A Ayubi, I Rashid, S H Waqar, G M Falcon, R Robles, R Jocson, C Teh, P Major, M Bobinski, J Kotarski, K Rasoul-Pelinska, C Azevedo, D Machado, F Mendes, X De Sousa, U Fernandes, C Ferreira, G Guidi, C Leal, A Marçal, R Marques, D Martins, A Melo, N Tenreiro, R Vaz Pereira, B Vieira, J I Almeida, T Correia de Sá, Mjma Costa, V Fernandes, I Ferraz, C G Gil, C Lima da Silva, L Lopes, N Machado, J Marialva, M Nunes Coelho, J Pedro, C Pereira, R Reis, A Ribeiro, R Santos, P Saraiva, R Silva, F Tavares, M Teixeira, A C Almeida, M J Amaral, R Andrade, R Athayde Nemésio, D Breda, C Camacho, C Canhoto, M Colino, S Correia, M Costa, J De Barros, A L De Oliveira López, M Duque, S Garrido, P Guerreiro, A Guimarães, A Lázaro, C Lopes, R Martins, O Nogueira, A Oliveira, J M Oliveira, M Rodrigues, A Ruivo, E Santos, M Silva, J Simões, A Valente da Costa, A Almeida, S Cavaleiro, V Devezas, C S Faria, F Jácome, M Magalhães Maia, J Nogueiro, A Pereira, A Pereira-Neves, T Pina-Vaz, H Santos-Sousa, H Silveira, S Vaz, P Vieira, A Gomes da Costa, I Lobo Antunes, J Pinto, A Tojal, N Cardoso, P Cardoso, J C Domingues, P Henriques, M I Manso, G Martins Dos Santos, R Martins, H Morais, R Pereira, T Revez, R Ribeiro, V I Ribeiro, A Soares, S Sousa, J Teixeira, E Amorim, V H Baptista, B Cunha MFDias, A Fazenda, J P Melo Neves, F Policarpo, I I Sampaio da Nóvoa Gomes Miguel, D Veiga, A K Andrade, J P Bandovas, N Borges, A Branquinho, B Chumbinho, J Correia, H Fidalgo, I Figueiredo de Barros, S Frade, J Gomes, J Maciel, S Pina, A Rodrigues, N Silva, I Silveira Nunes, R Sousa, J Ascensão, P Azevedo, B Costeira, C Cunha, R Garrido, H Gomes, I Lourenço, G Mendinhos, P Miranda, A Nobre Pinto, M Peralta Ferreira, J Ribeiro, L Rio Rodrigues, M Sousa Fernandes, J Azevedo, D Galvão, A C Soares, A Vieira, B Vieira, B Patrício, Pmdd Santos, A C Vieira Paiva Lopes, R Cunha, A Faustino, A Freitas, J R Martins ABMendes, R Parreira, J Rosa, M Teves, A Abreu da Silva, M Claro, D Costa Santos, A C Deus, J V Grilo, F Borges, J Corte Real, S Henriques, M J Lima, P Matos Costa, F Brito da Silva, A Caiado, F Fonseca, M Ângelo, J M Baiao, D Martins Jordão, T Vieira Caroço, J Messias, A Millan, I Salgado, P Santos, C Baía, R Canotilho, A M Correia, A P Ferreira Pinto, M Peyroteo, J F Videira, P Escobar, M Maldonado Santiago, R Kassir, F Sauvat, C Bezede, A Chitul, E Ciofic, D Cristian, F Grama, L Pirtea, C Secosan, E Bonci, V Gata, S Titu, O Ginghina, N Iordache, R V Iosifescu, T Garmanova, E Kazachenko, D Markaryan, S Rodimov, P Tsarkov, I Tulina, Y Litvina, A Provozina, M Agapov, E Galliamov, V Kakotkin, V Kubyshkin, А Kamalov, M Alshahrani, F Alsharif, M Eskander, R Al Raddadi, S Majrashi, A Mashat, N Akeel, M Alharthi, M Aljiffry, M Basendowah, A Farsi, M Ghunaim, A Khoja, A Maghrabi, N Malibary, M Nassif, A Nawawi, A Saleem, A Samkari, N Trabulsi, S Al Awwad, M Alghamdi, T Alnumani, M Nasser, A Said Bayazeed, A Alhefdhi, O Almalik, A Alomair, N Alotaibi, F Alresaini, R Alsalamah, S Alsobhi, Z Mahasin, E Othman, S Velagapudi, S Ghedan, R Alharthi, S Awad, M I Sharara, S Abdelrahman, W Althobaiti, H Al Habes, A Alamri, S Alkarak, M Alqannas, M Alyami, M Alzamanan, D Cortés Guiral, A Elawad, O AlAamer, L Alriyees, N Alselaim, A Abdulkareem, A Ajlan, K Akkour, A Al-Habib, K Al-Khayal, A Alatar, A Alburakan, H Alhalal, B Alhassan, N Alhassan, O Alobeed, A Alsaif, F Alsaif, S Alshammari, I Alshaygy, M Barry, A Bin Nasser, T Bin Traiki, A Bokhari, S Elwatidy, H Helmi, A Madkhali, T Nouh, P D Rabah, A Zubaidi, I Paunovic, N Slijepcevic, L Aleksic, A Antic, G Barisic, M Ceranic, D Galun, Ž Grubac, J Jelenkovic, D Kecmanovic, S Kmezic, D Knezevic, Z Krivokapic, S Latincic, V Markovic, S Matic, M Miladinov, M Pavlov, I Pejovic, D Radenkovic, B Tadic, J Vasljevic, D Velickovic, M Zivanovic, M Perovic, L Srbinovic, S Andrijasevic, T Bozanovic, R Cerovic Popovic, M Dokic, T Janjic, K Jeremic, S Kadija, I Ladjevic Likic, L Mirkovic, S Pantovic, I Pilic, M Radojevic, A Stefanovic, S Vidakovic, Z Vilendecic, S Antic, D Dunderovic, D Jelovac, Z Jezdic, V Konstantinovic, B Kotlar, C Kuzmanovic, M Lazic, M Petrovic, F Popovic, A Pucar, M Romic, S Sumrak, V Vujanac, V Bascarevic, I Bogdanovic, D Grujicic, R Ilic, M Milicevic, F Milisavljevic, A Miljkovic, A Paunovic, V Scepanovic, A Stanimirovic, M Todorovic, A Jotic, J Milovanovic, A Trivic, U Bumbasirevic, Z Dzamic, B Kajmakovic, N Prijovic, M Zivkovic, M Buta, A Cvetkovic, I Djurisic, S Gacic, M Goran, Z Inic, N Jeftic, M Jevric, V Jokic, I Markovic, M Milanovic, S Nikolic, L Pejnovic, N Savkovic, I Spurnic, D Stevic, D Stojiljkovic, N Vucic, M Zegarac, A Karamarkovic, M Kenic, B Kovacevic, I Krdzic, V Milutinovic, C W Chan, B Lieske, B Gális, K Šimko, N Almgla, M Bernon, A Boutall, L Cairncross, A Herman, T Hilton, E Jonas, C Kloppers, F Malherbe, W Mugla, D Nel, S Rayamajhi, T Van Wyngaard, J Vogel, A M Castaño-Leon, J Delgado Fernandez, C Eiriz Fernandez, M Espino Segura-Illa, O Esteban Sinovas, D Garcia Perez, P Gomez, L Jimenez-Roldan, A Lagares, L Moreno-Gomez, I Paredes, A Pérez Núñez, G Sánchez Aniceto, M Santas, P Fernández Rodríguez, M Paniagua García Señorans, R Sanchez-Santos, V Vigorita, E Acrich, E Baena Sanfeliu, O Barrios, T Golda, C Santanach, M Serrano-Navidad, M Sorribas Grifell, R V Vives, D Escolà, A Jiménez, L Cayetano Paniagua, L Gómez Fernández, E Artigues, J C Bernal-Sprekelsen, J C Catalá Bauset, P Collera, L Diaz De, R Gobbo, R Farre Font, R Flores Clotet, C J Gómez Díaz, N Guàrdia, C A Guariglia, A Osorio, R Sanchez Jimenez, L Sanchon, C Soto Montesinos, B Albi Martin, J E García Villayzán, L Alonso-Lamberti, M Assaf, N Baeza Pintado, A Carabias, J García-Quijada, M A Huertas Fernandez, J Jimenez Miramón, V Jimenez, J M Jover, S A Landeo AgÜero, R Leon, M B Martín Salamanca, V Pérez Simón, S Ponce, J L Rodriguez, A Salazar, A Valle Rubio, H Aguado, I Aldecoa Ansorregui, R Bravo Infante, F B De Lacy, A Di Somma, B Díaz-Feijoo, J Enseñat Nora, N Fabregas, A Ferrés, B Gil Ibañez, J J Gonzalez Sanchez, I Gracia, J A Hoyos Castro, A M Lacy, C Langdon, D Momblán, X Morales, L Oleaga, A Otero, L Pedrosa, J Poblete Carrizo, L A Reyes Figueroa, P Roldan Ramos, J Rumia-Arboix, A I Tercero-Uribe, T E Topczewski, J Torales, A Torne, R Torné, V Turrado-Rodriguez, R Valero, S Valverde, R Anula, O Cano-Valderrama, M Del Campo Martín, L Díez-Valladares, I Domínguez, J Dziakova, M García Alonso, E García Romero, L Gómez Latorre, J M Muguerza, M J Pizarro, P Saez Carlin, C Sánchez Del Pueblo, A Sánchez-Pernaute, G Sanz Ortega, R Sanz-Lopez, A Torres, M Garcés-Albir, F Lopez, J Martín-Arévalo, D Moro-Valdezate, V Pla-Marti, J Beltrán de Heredia, B De Andrés Asenjo, T Gómez Sanz, C Jezieniecki, H Nuñez Del Barrio, F J Ortiz de Solórzano Aurusa, A Romero de Diego, M Ruiz Soriano, J Trujillo Díaz, A Vazquez Fernandez, P Lora-Cumplido, M V Sosa, E Gonzalez-Gonzalez, A M Minaya Bravo, N Alonso de la Fuente, M Cazador Labat, L Cecchini, C A Espinosa, M Jimenez Toscano, A López Campillo, G Mancebo, P Martorell, M Munarriz, E J Grau-Talens, B Martin-Perez, J A Benavides Buleje, M Carrasco Prats, P V Fernández, A Fernández-López, D García Escudero, V J García Porcel, V Garcia Soria, C Giménez Francés, F M González Valverde, E Gurrea, P López-Morales, A Marco Garrido, J A Martínez Alonso, E Medina, J M Muñoz Camarena, P A Parra Baños, E Peña Ros, M Ramirez Faraco, M Ruiz-Marín, C Sanchez Rodriguez, M Valero Soriano, M Estaire Gómez, Á Fernández Camuñas, E P Garcia Santos, E Jimenez Higuera, C Martínez-Pinedo, V Muñoz-Atienza, D Padilla-Valverde, R Picón Rodríguez, F J Redondo Calvo, S Sánchez-García, D Sanchez-Pelaez, R C Colombari, E Del Valle, M Fernández, P Lozano Lominchar, L Martín, C Rey Valcarcel, M A Steiner, M Tudela, J Zorrilla Ortúzar, F Alcaide Matas, J M García Pérez, P Troncoso Pereira, I Mora-Guzmán, M Abellán, M Achalandabaso Boira, R Jorba, R Memba Ikuga, C Olona, R Sales Mallafré, P Cavallé Busquets, Mgp Gavalda Pellice, J Salinas Peña, E J Aragon Achig, L Barbier, P Caja Vivancos, A Gainza, J J García Gutierrez, G Mallabiabarrena Ormaechea, H Marín, P Martin Playa, I Melchor Corcóstegui, M Prieto Calvo, A Rodriguez Fraga, I Villalabeitia Ateca, U De Andres Olabarria, M Durán Ballesteros, F J Fernández Pablos, F J Ibáãez-Aguirre, A Sanz Larrainzar, B Ugarte-Sierra, Á De la Hoz Rodríguez, M Di Martino, J García Septiem, E Martin-Perez, J L Muñoz de Nova, P Calvo Espino, P Guillamot Ruano, L Colao García, D Díaz Pérez, E Esteban Agustí, P Galindo Jara, M Gutierrez Samaniego, M A Hernandez Bartolome, J Serrano González, A Alonso Poza, B Diéguez, M García-Conde, M Hernández-García, M Losada, C M Chiesa-Estomba, Já González García, E Larruscain, J A Sistiaga-Suárez, E Alvarez, N Chavarrias, L Frías, V García Pineda, A Gegúndez Simón, S Gortázar, M Gracia, J Guevara, A Hernández Gutierrez, A Loayza, D T María Dolores, C Martí, M Melendez, E Moreno-Palacios, Y Perez, M I Prieto Nieto, P Ramos-Martín, I Rubio-Perez, J Saavedra, J I Sanchez-Mendez, J Siegrist Ridruejo, A Urbieta, I Zapardiel, M Cantalejo Diaz, Mdc De Miguel Ardevines, V Duque-Mallén, I Gascon Ferrer, M T González-Nicolás Trébol, C Gracia-Roche, M Herrero Lopez, U M Jariod Ferrer, A Lanzon, A Martinez German, M Matute, C Redondo, N Sánchez Fuentes, M Sánchez-Rubio, M S Santero-Ramirez, S Saudí, M V Simón Sanz, T Uson-Bouthelier, A Blazquez Martin, M Diez Alonso, E García Rico, E Garcia-Loarte Gomez, F Garcia-Moreno Nisa, A Gutierrez Calvo, P Hernandez, I Lasa, F Mendoza-Moreno, N Morales Palacios, E Ovejero Merino, C Vera Mansilla, F Acebes García, M Bailón, A D Bueno Cañones, E Choolani Bhojwani, P Marcos-Santos, T Miguel, D Pacheco Sánchez, B Pérez-Saborido, J Sanchez Gonzalez, F J Tejero-Pintor, F Alconchel, A Conesa, J Gil Martínez, A I Gutiérrez Fernández, A Lopez Abad, T Nicolás-López, P Ramirez Romero, M J Roca Calvo, K Rodrigues, J J Ruiz Manzanera, A I Soriano, A Cano, L Capitan-Morales, J Cintas Catena, J Gomez-Rosado, F Oliva Mompean, M A Pérez Sánchez, F D Río Lafuente, C Torres Arcos, J Valdes-Hernandez, H Cholewa, S Domingo, M Frasson, V Lago, T Marina Martin, C Martínez Chicote, J Sancho-Muriel, A Landaluce-Olavarria, D Lecumberri, A Abad Gurumeta, A Abad-Motos, E Martínez-Hurtado, J Ripollés-Melchor, A Ruiz Escobar, A Cuadrado-García, L Garcia-Sancho Tellez, J Heras Aznar, P Maté, I Ortega Vázquez, A L Picardo, J A Rojo López, F Sanchez Cabezudo Noguera, D Serralta de Colsa, J Anchuelo Latorre, C Cagigas Fernandez, R Caiña Ruiz, M Gomez Ruiz, F Hernanz, J Jimeno Fraile, P Martínez-Pérez, C Poch, S Santarrufina Martinez, V Valbuena Jabares, C Moliner-Sánchez, L Pingarron-Martin, J Rey-Biel, I Ruiz Martin, J L Blas Laina, B Cros, J Escartin, J Garcia Egea, A Nogués, I Talal El-Abur, C Yánez, E P Cagigal Ortega, I Cervera, P Díaz Peña, Gdcr Elena, D Enjuto, P Fernández Bernabé, R Garcés García, J Gonzalez, I Hernández, N Herrera-Merino, M Marqueta De Salas, P Martinez Pascual, M Perez Gonzalez, A Ramos Bonilla, L Rodríguez Gómez, C Bescós, R Blanco-Colino, I Brana, B Caimari, A De Pablo García-Cuenca, F Duran-Valles, E Espin-Basany, J Giralt Lóez de Sagredo, J Pamias, G Pellino, N Prat, R Pujol Pina, M Saez Barba, A Arulanantham, Gbk Bandara, U Jayarajah, S Ravindrakumar, V S Rodrigo, S Srishankar, A A Ali Karar, P Elbe, E K Lindqvist, H Taflin, A Älgå, G Heinius, M Nordberg, E Pieniowski, I Gkekas, N Löfgren, M Rutegård, M Sund, M Arigoni, M Bernasconi, D Christoforidis, M Di Giuseppe, D La Regina, F Mongelli, M Chevallay, O Dwidar, E Gialamas, M Sauvain, F Klenke, A Kollàr, C Kurze, M Adamina, T Bächler, A S Crugnale, M Giardini, L Guglielmetti, G Peros, F Solimene, A Aghayeva, I Hamzaoglu, I Sahin, E Akaydin, Z Aliyeva, E Aytac, B Baca, O DÜlgeroğlu, V Ozben, B B Ozmen, C Uras, A E Arikan, I A Bilgin, B Bozkirli, G O Ceyhan, H Kara, T Karahasanoglu, C Uras, H Celik, M M Meydanli, H Akilli, A Ayhan, E Kuscu, M A Onan, U Akgor, H A Dincer, T Erol, M Gultekin, N Orhan, N Ozgul, M C Salman, B Soyak, A Alhamed, S ErgÜn, M F OZcelik, A N Sanli, S S Uludag, M Velidedeoglu, A K Zengin, M A Bozkurt, Y Kara, A Kocatas, B Cimenoglu, R Demirhan, K Saracoglu, I F Azamat, E Balik, D Bugra, B Giray, C B Kulle, C Taskiran, D Vatansever, K Gözal, S A GÜler, H Köken, O C Tatar, N Z Utkan, A Yildirim, E YÜksel, E Akin, F Altintoprak, Z Bayhan, G Cakmak, R Çapoglu, F Çelebi, H Demir, E Dikicier, N Firat, E GönÜllÜ, M B Kamburoglu, B Kocer, I F KÜçÜk, B Mantoglu, E Çolak, G O Kucuk, M S Uyanik, B Göksoy, E Bozkurt, B Citgez, M Mihmanli, M Tanal, G Yetkin, M Akalin, C Arican, E K Avci, C Aydin, S Demirli Atici, M Emiroglu, T Kaya, E Kebabçi, G Kilinc, Y Kirmizi, H Ogucu, S Salimoglu, I Sert, C Tugmen, K Tuncer, G Uslu, D Yesilyurt, E Karaman, A Kolusari, A Yildiz, O Benson, H Lule, J Agilinko, A Ahmeidat, M Barabasz, M Bekheit, L K Cheung, T Colloc, W Cymes, M Elhusseini, G Gradinariu, A Hannah, B S Kamera, G Mignot, S Shaikh, P Sharma, I Abu-Nayla, A Agrawal, A Al-Mohammad, S Ali, J Ashcroft, A Azizi, O Baker, A Balakrishnan, M Byrne, A Colquhoun, A Cotter, P Coughlin, R J Davies, A Durrani, M Elshaer, S Fordington, P Forouhi, F Georgiades, H Grimes, A Habeeb, V Hudson, P Hutchinson, E Irune, A Jah, D Z Khan, A Kolias, H Kyriacou, B Lamb, S Liau, L Luke, R Mahmoud, R Mannion, L Masterson, C G Mitrofan, M Mohan, A Morris, S Murphy, R O'Neill, S Price, J Pushpa-Rajah, W Raby-Smith, J Ramzi, S Rooney, T Santarius, A Singh, G D Stewart, X S Tan, A Townson, E Tweedle, C Walker, S Waseem, S Yordanov, T Jones, A Kattakayam, C Loh, R Lunevicius, S Pringle, A Schache, R Shaw, A Sheel, C Rossborough, D Angelou, M Choynowski, B McAree, A McCanny, D Neely, G Tutoveanu, S Ahad, Mfi De La Cruz Monroy, F Mosley, V Oktseloglou, A Alanbuki, M Patel, A Shabana, E Perera, D Raveendran, K Ravi-Shankar, J Thiruchelvam, L Arrowsmith, W Campbell, T Grove, C Kontovounisios, O Warren, P Rolland, A Aggarwal, S Brown, C Jelley, N Neal, R Clifford, N Eardley, E Krishnan, N Manu, E Martin, S Roy Mahapatra, O L Serevina, C Smith, D Vimalachandran, M Bordenave, R Houston, G Putnam, A Robson, H Tustin, K Emslie, P L Labib, A Marchbank, D Miller, G Minto, J Natale, H Nwinee, P Panahi, L Rogers, A Abubakar, M M Akhter Rahman, E Chan, Kyk Ko, H O'Brien, K Sasapu, H Woodun, R Inglis, H J Ng, A De Gea Rico, N Ghazali, J Lambert, G Markose, S Math, I Sarantitis, D Shrestha, A Sultana, M Taggarsi, S Timbrell, O P Vaz, L Vitone, A Day, H Dent, M Fahim, S Waheed, A Hunt, N Laskar, A Gupta, J Steinke, S Thrumurthy, E Massie, K McGivern, D Rutherford, M Wilson, J Hardie, S Kazzaz, S Handa, M Kaushal, A Kler, P Patel, J Redfern, S Tezas, Y Aawsaj, S Amonkar, C Barry, L Blackwell, D Blake, J Carter, H Emerson, A Fisher, M Katory, P Korompelis, W McCormick, A Mustafa, L Pearce, N Ratnavelu, R Reehal, L Kretzmer, L Lalou, B Manku, I Parwaiz, J Stafford, M Abdelkarim, A Asqalan, T Gala, S Ibrahim, A Maw, R Mithany, R Morgan, G Sundaram Venkatesan, K Ang, E J Caruana, M F Chowdhry, A Mohammad, A Nakas, S Rathinam, M Boal, O Brown, S Dwerryhouse, S Higgs, A Vallance, E Boyd, V Irvine, A Kirk, G Bakolas, A Boulton, A Chandock, T Khan, M Kumar, P Agoston, A Bille, B Challacombe, S Fraser, K Harrison-Phipps, J King, G Mehra, L Mills, M Najdy, R Nath, L Okiror, J Pilling, V Rizzo, T Routledge, A Sayasneh, L Stroman, A Wali, M Fehervari, C Fotopoulou, N Habib, S Hamrang-Yousefi, Z Jawad, L Jiao, M Pai, J Ploski, P Rajagopal, S Saso, M Sodergren, D Spalding, S Laws, C Hardie, C McNaught, R Alam, A Budacan, J Cahill, M Kalkat, S Karandikar, L Kenyon, D Naumann, A Patel, J Ayorinde, T Chase, T Cuming, A Ghanbari, L Humphreys, S Tayeh, A Aboelkassem Ibrahim, R Bichoo, H Cao, Akw Chai, J Choudhury, C Evans, H Fitzjohn, H Ikram, M Langstroth, M Loubani, A McMillan, S Nazir, Ssa Qadri, A Robinson, E Ross, T Sehgal, A Wilkins, J Dixon, J Dunning, K Freystaetter, M Jha, S Lester, A Madhavan, S V Thulasiraman, Y Viswanath, T Curl-Roper, C Delimpalta, Ccl Liao, V Velchuru, E Westwood, E Belcher, G Bond-Smith, S Chidambaram, F Di Chiara, K Fasanmade, L Fraser, H Fu, M Ganau, S Gore, J Graystone, D Jeyaretna, H Khatkar, M Lami, M Maher, S Mastoridis, R Mihai, R Piper, S Prabhu, Obf Risk, U Selbong, K Shah, R Smillie, H Soleymani Majd, S Sravanam, D Stavroulias, G D Tebala, M Vatish, C Verberne, K Wallwork, S Winter, M I Bhatti, H Boyd-Carson, E Elsey, E Gemmill, P Herrod, M Jibreel, E Lenzi, T Saafan, D Sapre, T Sian, N Watson, A Athanasiou, G Bourke, L Bradshaw, A Brunelli, J Burke, P Coe, F Costigan, H Elkadi, M Ho, J Johnstone, A Kanatas, V Kantola, A Kaufmann, A Laios, S Lam, E MacInnes, S Munot, C Nahm, M Otify, C Pompili, I Smith, G Theophilou, G Toogood, R Wade, D Ward, C West, S Annamalai, C Ashmore, A Boddy, T Hossain, A Kourdouli, A Gvaramadze, A Jibril, L Prusty, D Thekkinkattil, A Harky, M Shackcloth, A Askari, C Chan, N Cirocchi, S Kudchadkar, K Patel, J Sagar, S Shaw, R Talwar, M Abdalla, R Edmondson, O Ismail, D Jones, K Newton, N Stylianides, A Aderombi, U Andaleeb, O Bajomo, K Beatson, W Garrett, M Mehmood, V Ng, R Al-Habsi, G S Divya, B Keeler, B Al-Sarireh, R Egan, R Harries, A Henry, M Kittur, Z Li, K Parkins, F Soliman, N Spencer, D Thompson, C Burgess, C Gemmell, C Grieco, M Hollyman, L Hunt, J Morrison, S Ojha, N Ryan, F Abbadessa, S Barnard, C Chan, N Dawe, J Hammond, Ali F Mahmoud, I McPherson, C Mellor, J Moir, S Pandanaboyana, J Powell, B Rai, A Rogers, C Roy, A Sachdeva, C Saleh, S Tingle, T Williams, J Manickavasagam, C McDonald, N McGrath, N McSorley, K Ragupathy, L Ramsay, A Solth, O Kakisi, K Seebah, I Shaikh, L Sreedharan, M Youssef, J Shah, P Ameerally, N McLarty, S Mills, A Shenfine, K Sahnan, J Abu, E Addae-Boateng, D Bratt, L Brock, N Burnside, S Cadwell-Sneath, K Gajjar, C Gan, C Grundy, K Hallam, K Hassell, M Hawari, A Joshi, H Khout, K Konstantinidi, Rxn Lee, D Nunns, R Schiemer, T Walton, H Weaver, L Whisker, K Williamson, J McVeigh, R Myatt, M A Williams, R Kaur, E Leung, S Sundar, M Michel, S Patil, S Ravindran, J Sarveswaran, L Scott, M Edmond, E King, M Almond, A Bhangu, O Breik, L D Cato, A Desai, S Ford, E Griffiths, M Idle, M Kamal, A Kisiel, R Kulkarni, Jkc Mak, T Martin, P Nankivell, A Parente, S Parmar, A M Pathanki, L Phelan, P Praveen, S Saeed, N Sharma, J Singh, F Tirotta, D Vijayan, A Geddes, J McCaul, J McMahon, A H Khan, F Khan, A Mansuri, S Mukherjee, M Patel, M Sarigul, S Singh, K L Tan, A Woodham, A Adiamah, H Brewer, A Chowdhury, J Evans, D Humes, J Jackman, A Koh, C Lewis-Lloyd, O Oyende, J Reilly, D Worku, P Cool, G Cribb, K Shepherd, C Bisset, S Moug, N Elson, G Faulkner, P Saleh, C Underwood, G Brixton, L Findlay, T Klatte, A Majkowska, J Manson, R Potter, A Bhalla, Z Chia, P Daliya, A Goyal, E Grimley, A Hamad, A Kumar, F L Malcolm, E Theophilidou, J Bowden, N Campain, I Daniels, C Evans, G Fowler, J John, L Massey, F McDermott, J McGrath, A McLennan, M Ng, J Pascoe, N Rajaretnam, S Bulathsinhala, B Davidson, G Fusai, C Hidalgo Salinas, N Machairas, T Pissanou, J M Pollok, D A Raptis, F Soggiu, H Tzerbinis, S E Xyda, A Beamish, E Davies, R Foulkes, D Magowan, H Nassa, R Ooi, C Price, L Smith, F Solari, A Tang, G Williams, Y Al-Tamimi, A Bacon, N Beasley, D Chew, M Crank, N Ilenkovan, M Macdonald, B Narice, O Rominiyi, A Thompson, I Varley, T Drake, E Harrison, G Linder, J Mayes, R McGregor, R Skipworth, V Zamvar, E Davies, P Hawkin, T Raymond, O Ryska, R Baron, D Dunne, S Gahunia, C Halloran, N Howes, R McKinney, F McNicol, J Russ, P Szatmary, J R Tan, A Thomas, P Whelan, A Anzak, A Banerjee, O Fuwa, F Hughes, J D Jayasinghe, C Knowles, H Kocher, I Leal Silva, F S Ledesma, A Minicozzi, L Navaratne, R Rahman, R Ramamoorthy, C Sohrabi, M Thaha, B Thakur, M Venn, V Yip, R Baumber, J Parry, S Evans, L Jeys, G Morris, M Parry, J Stevenson, N Ahmadi, G Aresu, Z M Barrett-Brown, A S Coonar, H Durio Yates, D Gearon, J Hogan, M King, A Peryt, I S Pradeep, C Smith, M Adishesh, R Atherton, K Baxter, M Brocklehurst, M Chaudhury, N Krishnamohan, J McAleer, G Owens, E Parkin, P Patkar, I Phang, A Aladeojebi, M Ali, B Barmayehvar, A Gaunt, M Gowda, E Halliday, M Kitchen, F Mansour, M Thomas, D Zakai, N Abbassi-Ghadi, H Assalaarachchi, A Currie, M Flavin, A Frampton, M Hague, C Hammer, J Hopper, J Horsnell, S Humphries, A Kamocka, T K Madhuri, S Preston, P Singh, J Stebbing, A Tailor, D Walker, F Aljanadi, M Jones, P Mhandu, C O'Donnell, R Turkington, Z Al-Ishaq, S Bhasin, A S Bodla, A Burahee, A Crichton, R Fossett, N Pigadas, S Pickford, E Rahman, D Snee, R Vidya, N Yassin, F Colombo, D Fountain, M T Hasan, K Karabatsou, R Laurente, O Pathmanaban, A Al-Mukhtar, S Brown, J Edwards, A Giblin, C Kelty, M Lee, G Lye, T Newman, A Sharkey, C Steele, N Sureshkumar Shah, E Whitehall, R Athwal, A Baker, L Jones, C Konstantinou, S Ramcharan, S Singh, J Vatish, R Wilkin, M Ethunandan, G K Sekhon, H Shields, R Singh, F Wensley, S Lawday, A Lyons, T Abbott, S Anwar, K Ghufoor, C Sohrabi, E Chung, R Hagger, A Hainsworth, A Karim, H Owen, A Ramwell, K Williams, C Baker, A Davies, J Gossage, M Kelly, W Knight, J Hall, G Harris, G James, C Kang, D J Lin, A D Rajgor, T Royle, R Scurrah, B Steel, L J Watson, D Choi, R Hutchison, A Jain, V Luoma, H Marcus, R May, A Menon, B Pramodana, L Webber, I A Aneke, P Asaad, B Brown, J Collis, S Duff, A Khan, F Moura, B Wadham, H Warburton, T Elmoslemany, M Jenkinson, C Millward, R Zakaria, S Mccluney, C Parmar, S Shah, J Allison, M S Babar, B Collard, S Goodrum, K Lau, A Patel, R Scott, E Thomas, H Whitmore, D Balasubramaniam, B Jayasankar, S Kapoor, A Ramachandran, A Elhamshary, Smb Imam, K Kapriniotis, V Kasivisvanathan, J Lindsay, S Rakhshani-Moghadam, N Beech, M Chand, L Green, N Kalavrezos, H Kiconco, R McEwen, C Schilling, D Sinha, J Pereca, J Singh, S Chopra, D Egbeare, R Thomas, T Combellack, Sef Jones, M Kornaszewska, M Mohammed, A Sharma, G Tahhan, V Valtzoglou, J Williams, P Eskander, K Gash, L Gourbault, M Hanna, T Maccabe, C Newton, J Olivier, S Rozwadowski, E Teh, D West, H Al-Omishy, M Baig, H Bates, G Di Taranto, K Dickson, N Dunne, C Gill, D Howe, D Jeevan, A Khajuria, K Martin-Ucar AMcEvoy, P Naredla, V Ng, S Robertson, M Sait, D R Sarma, S Shanbhag, T Shortland, S Simmonds, J Skillman, N Tewari, G Walton, M A Akhtar, A Brunt, J McIntyre, K Milne, M M Rashid, A Sgro, K E Stewart, A Turnbull, M Aguilar Gonzalez, S Talukder, C Boyle, D Fernando, K Gallagher, A Laird, D Tham, M Bath, P Patki, C Sohrabi, C Tanabalan, T Arif, C Magee, T Nambirajan, S Powell, R Vinayagam, I Flindall, A Hanson, V Mahendran, S Green, M Lim, L MacDonald, V Miu, L Onos, K Sheridan, R Young, F Alam, O Griffiths, C Houlden, R Jones, V S Kolli, A K Lala, S Leeson, R Peevor, Z Seymour, L Chen, E Henderson, A Loehrer, K Brown, D Fleming, A Haynes, C Heron, C Hill, H Kay, E Leede, K McElhinney, K Olson, E C Osterberg, C Riley, P Srikanth, M Thornhill, D Blazer, G DiLalla, E S Hwang, W Lee, M Lidsky, J Plichta, L Rosenberger, R Scheri, K Shah, K Turnage, J Visgauss, S Zani, J Farma, J Clark, D Kwon, E Etchill, H E Gabre-Kidan AJenny, A Kent, M Ladd, C Long, H Malapati, A Margalit, S Rapaport, J Rose, K Stevens, L Tsai, D Vervoort, P Yesantharao, A Dehal, D Klaristenfeld, K Huynh, L Brown, I Ganly, J Mullinax, N Gusani, J Hazelton, J Maines, J S Oh, A Ssentongo, P Ssentongo, M Azam, A Choudhry, W Marx, J Fleming, A Fuson, J Gigliotti, A Ovaitt, Y Ying, M K Abel, V Andaya, K Bigay, M A Boeck, L Chen, H Chern, C Corvera, I El-Sayed, A Glencer, P Ha, Bcs Hamilton, C Heaton, K Hirose, D M Jablons, K Kirkwood, L Z Kornblith, J R Kratz, R Lee, P N Miller, E Nakakura, B Nunez-Garcia, R O'Donnell, D Ozgediz, P Park, B Robinson, A Sarin, B Sheu, M Varma, K Wai, R Wustrack, M J Xu, D Beswick, J Goddard, J Manor, J Song, T Fullmer, C Gaskill, N Gross, K Kiong, C L Roland, S N Zafar, M Abdallah, A Abouassi, M Almasri, G Kulkarni, H Marwan, M Mehdi, S Aoun, V S Ban, H H Batjer, J Caruso, D Abbott, A Acher, T Aiken, J Barrett, E Foley, P Schwartz, S N Zafar, A Hawkins, A Maiga, J Laufer, S Scasso

Subjects
Aged, 80 and over, Male, Critical Care, SARS-CoV-2, International Cooperation, COVID-19, Middle Aged, Cohort Studies, Logistic Models, Postoperative Complications, Elective Surgical Procedures, Neoplasms, Outcome Assessment, Health Care, Humans, Female, Epidemics, Aged
Abstract

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks.

Published
2021

13. Fuel Cell Power Plant Initiative. Volume I: Solid Oxide Fuel Cell/Logistics Fuel Processor 27 kWe Power System Demonstration for ARPA

Author

WESTINGHOUSE SCIENCE AND TECHNOLOGY CENTER PITTSBURGH PA, Veyo, S. E., Dowdy, T. E., WESTINGHOUSE SCIENCE AND TECHNOLOGY CENTER PITTSBURGH PA, Veyo, S. E., and Dowdy, T. E.

Abstract

This report describes the successful testing of a 27 kWe Solid Oxide Fuel Cell (SOFC) generator fueled by natural gas and/or a fuel gas produced by a brassboard logistics fuel preprocessor (LFP). The test period began on May 24, 1995 and ended on February 26, 1996 with the successful completion of all program requirements and objectives. During this time period, this power system produced 118.2 MWh of electric power. No degradation of the generator's performance was measured after 5,582 accumulated hours of operation on these fuels: The report presents the measured electrical performance of the generator on all three fuel types and notes the small differences due to fuel type. Operational difficulties due to component failures are well documented even though they did not affect the overall excellent performance of this SOFC power generator., See Also ADA399473 .

Published
1997

14. Fuel Cell Power Plant Initiative. Volume II: Preliminary Design of a Fixed-Base LFP/SOFC Power System

Author

WESTINGHOUSE SCIENCE AND TECHNOLOGY CENTER PITTSBURGH PA, Veyo, S. E., Dowdy, T. E., WESTINGHOUSE SCIENCE AND TECHNOLOGY CENTER PITTSBURGH PA, Veyo, S. E., and Dowdy, T. E.

Abstract

This report documents the preliminary design for a military fixed-base power system of 3 MWe nominal capacity using Westinghouse's tubular Solid Oxide Fuel Cell SOFC and Haldor Topsoe's logistic fuels processor LFP. The LFP provides to the fuel cell a methane rich sulfur free fuel stream derived from either DF-2 diesel fuel, or JP-8 turbine fuel. Fuel cells are electrochemical devices that directly convert the chemical energy contained in fuels such as hydrogen, natural gas, or coal gas into electricity at high efficiency with no intermediate heat engine or dynamo., See Also ADA399472 .

Published
1997

24. Raman-based machine-learning platform reveals unique metabolic differences between IDHmut and IDHwt glioma.

Author

Lita A, Sjöberg J, Păcioianu D, Siminea N, Celiku O, Dowdy T, Păun A, Gilbert MR, Noushmehr H, Petre I, and Larion M

Subjects
Humans, Mutation, DNA Methylation, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Isocitrate Dehydrogenase genetics, Glioma genetics, Glioma metabolism, Glioma pathology, Spectrum Analysis, Raman methods, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms pathology, Machine Learning
Abstract

Background: Formalin-fixed, paraffin-embedded (FFPE) tissue slides are routinely used in cancer diagnosis, clinical decision-making, and stored in biobanks, but their utilization in Raman spectroscopy-based studies has been limited due to the background coming from embedding media., Methods: Spontaneous Raman spectroscopy was used for molecular fingerprinting of FFPE tissue from 46 patient samples with known methylation subtypes. Spectra were used to construct tumor/non-tumor, IDH1WT/IDH1mut, and methylation-subtype classifiers. Support vector machine and random forest were used to identify the most discriminatory Raman frequencies. Stimulated Raman spectroscopy was used to validate the frequencies identified. Mass spectrometry of glioma cell lines and TCGA were used to validate the biological findings., Results: Here, we develop APOLLO (rAman-based PathOLogy of maLignant gliOma)-a computational workflow that predicts different subtypes of glioma from spontaneous Raman spectra of FFPE tissue slides. Our novel APOLLO platform distinguishes tumors from nontumor tissue and identifies novel Raman peaks corresponding to DNA and proteins that are more intense in the tumor. APOLLO differentiates isocitrate dehydrogenase 1 mutant (IDH1mut) from wild-type (IDH1WT) tumors and identifies cholesterol ester levels to be highly abundant in IDHmut glioma. Moreover, APOLLO achieves high discriminative power between finer, clinically relevant glioma methylation subtypes, distinguishing between the CpG island hypermethylated phenotype (G-CIMP)-high and G-CIMP-low molecular phenotypes within the IDH1mut types., Conclusions: Our results demonstrate the potential of label-free Raman spectroscopy to classify glioma subtypes from FFPE slides and to extract meaningful biological information thus opening the door for future applications on these archived tissues in other cancers., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Published
2024
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25. A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.

Author

Banu MA, Dovas A, Argenziano MG, Zhao W, Sperring CP, Cuervo Grajal H, Liu Z, Higgins DM, Amini M, Pereira B, Ye LF, Mahajan A, Humala N, Furnari JL, Upadhyayula PS, Zandkarimi F, Nguyen TT, Teasley D, Wu PB, Hai L, Karan C, Dowdy T, Razavilar A, Siegelin MD, Kitajewski J, Larion M, Bruce JN, Stockwell BR, Sims PA, and Canoll P

Subjects
Animals, Mice, Humans, Mitochondria metabolism, Astrocytes metabolism, Brain Neoplasms metabolism, Brain Neoplasms pathology, Brain Neoplasms genetics, Cell Line, Tumor, Lipid Peroxidation, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Reactive Oxygen Species metabolism, Signal Transduction, Ferroptosis, Phospholipid Hydroperoxide Glutathione Peroxidase metabolism, Phospholipid Hydroperoxide Glutathione Peroxidase genetics, Glioblastoma metabolism, Glioblastoma pathology, Glioblastoma genetics
Abstract

Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment., (© 2024. The Author(s).)

Published
2024
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26. The patatin-like protein PlpD forms structurally dynamic homodimers in the Pseudomonas aeruginosa outer membrane.

Author

Hanson SE, Dowdy T, Larion M, Doyle MT, and Bernstein HD

Subjects
Periplasm metabolism, Protein Domains, Bacterial Outer Membrane metabolism, Models, Molecular, Bacterial Proteins metabolism, Bacterial Proteins chemistry, Bacterial Proteins genetics, Pseudomonas aeruginosa metabolism, Pseudomonas aeruginosa genetics, Bacterial Outer Membrane Proteins metabolism, Bacterial Outer Membrane Proteins chemistry, Bacterial Outer Membrane Proteins genetics, Protein Multimerization
Abstract

Members of the Omp85 superfamily of outer membrane proteins (OMPs) found in Gram-negative bacteria, mitochondria and chloroplasts are characterized by a distinctive 16-stranded β-barrel transmembrane domain and at least one periplasmic POTRA domain. All previously studied Omp85 proteins promote critical OMP assembly and/or protein translocation reactions. Pseudomonas aeruginosa PlpD is the prototype of an Omp85 protein family that contains an N-terminal patatin-like (PL) domain that is thought to be translocated across the OM by a C-terminal β-barrel domain. Challenging the current dogma, we find that the PlpD PL-domain resides exclusively in the periplasm and, unlike previously studied Omp85 proteins, PlpD forms a homodimer. Remarkably, the PL-domain contains a segment that exhibits unprecedented dynamicity by undergoing transient strand-swapping with the neighboring β-barrel domain. Our results show that the Omp85 superfamily is more structurally diverse than currently believed and suggest that the Omp85 scaffold was utilized during evolution to generate novel functions., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Published
2024
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27. DMT1 contributes to MF- 438 - mediated inhibition of glioma cells.

Author

Zhang L, Yamasaki T, Dowdy T, and Larion M

Abstract

Elevated SCD1 expression has been associated with enhanced cancer cell survival, proliferation, and resistance to therapy in many cancer types including gliomas. Hereby, we investigate the impact of MF-438 on SCD1-mediated lipid metabolism and its consequences on glioma growth and survival. Our data reveals an IDH mut -specific inhibitory effect of MF438 on gliomas. Also, we delineate a dual mechanism of action: while SCD1-mediated lipid metabolism is hindered by MF-438 treatment, MF-438 also exerts an SCD1-independent inhibition on DMT1 expression. Supporting data from the DMT1 blocker underscores its significance in MF-438's anti-glioma efficacy.

Published
2024
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28. Targeting IDH1-Mutated Oligodendroglioma with Acid Ceramidase Inhibitors.

Author

Muley H, Dowdy T, Zaibaq F, Karadimov G, Li A, Song H, Zhang M, Zhang W, Wong Z, Zhang L, Lita A, and Larion M

Abstract

Oligodendroglioma is genetically defined as a tumor harboring isocitrate dehydrogenase 1 or 2 mutations (IDH1 mut /IDH2 mut ) and 1p/19q co-deletions. Previously, we reported that in IDH1 mut gliomas, D-2HG, the product of IDH1 mutant enzyme produces an increase in monounsaturated fatty acid levels that are incorporated into ceramides, tilting the S1P-to-ceramide rheostat toward apoptosis. Herein, we exploited this imbalance to further induce and IDH mut -specific glioma cell death. We report for the first time that the inhibition of acid ceramidase (AC) induces apoptosis and provides a benefit in mice survival in IDH1 mut oligodendroglioma. We demonstrated an IDH1 mut -specific cytotoxicity of SABRAC, an irreversible inhibitor of AC, in patient-derived oligodendroglioma cells. Exploring the mechanism of action of this drug, we found that SABRAC activates both extrinsic and intrinsic apoptosis in an ER stress-independent manner, pointing to a direct action of AC-related ceramides in mitochondria permeability. The activation of apoptosis detected under SABRAC treatment was associated with up to 30-fold increase in some ceramide levels and its derivatives from the salvage pathway. We propose that this novel enzyme, AC, has the potential to increase survival in oligodendroglioma with IDH1 mut and should be considered in the future.

Published
2024
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29. Targeting the sphingolipid rheostat in IDH1 mut glioma alters cholesterol homeostasis and triggers apoptosis via membrane degradation.

Author

Dowdy T, Vilamu HM, Lita A, Li A, Yamasaki T, Zhang L, Chari R, Song H, Zhang M, Zhang W, Briceno N, Davis D, Gilbert MR, and Larion M

Abstract

The cross-regulation of metabolism and trafficking is not well understood for the vital sphingolipids and cholesterol constituents of cellular compartments. While reports are starting to surface on how sphingolipids like sphingomyelin (SM) dysregulate cholesterol levels in different cellular compartments (Jiang et al., 2022), limited research is available on the mechanisms driving the relationship between sphingolipids and cholesterol homeostasis, or its biological implications. Previously, we have identified sphingolipid metabolism as a unique vulnerability for IDH1 mut gliomas via a rational drug design. Herein, we show how modulating sphingolipid levels affects cholesterol homeostasis in brain tumors. However, we unexpectedly discovered for the first time that C17 sphingosine and NDMS addition to cancer cells alters cholesterol homeostasis by impacting its cellular synthesis, uptake, and efflux leading to a net decrease in cholesterol levels and inducing apoptosis. Our results reflect a reverse correlation between the levels of sphingosines, NDMS, and unesterified, free cholesterol in the cells. We show that increasing sphingosine and NDMS (a sphingosine analog) levels alter not only the trafficking of cholesterol between membranes but also the efflux and synthesis of cholesterol. We also demonstrate that despite the effort to remove free cholesterol by ABCA1-mediated efflux or by suppressing machinery for the influx (LDLR) and biosynthetic pathway (HMGCR), apoptosis is inevitable for IDH1 mut glioma cells. This is the first study that shows how altering sphingosine levels directly affects cholesterol homeostasis in cancer cells and can be used to manipulate this relationship to induce apoptosis in IDH1 mut gliomas.

Published
2024
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30. Resolving Challenges in Detection and Quantification of D-2-hydroxyglutarate and L-2-hydroxyglutarate via LC/MS.

Author

Dowdy T and Larion M

Abstract

D-2-Hydroxyglutarate and L-2-Hydroxyglutarate (D-2HG/L-2HG) are typically metabolites of non-specific enzymatic reactions that are kept in check by the housekeeping enzymes, D-2HG /L-2HG dehydrogenase (D-2HGDH/L-2HGDH). In certain disease states, such as D-2HG or L-2HG aciduria and cancers, accumulation of these biomarkers interferes with oxoglutarate-dependent enzymes that regulate bioenergetic metabolism, histone methylation, post-translational modification, protein expression and others. D-2HG has a complex role in tumorigenesis that drives metabolomics investigations. Meanwhile, L-2HG is produced by non-specific action of malate dehydrogenase and lactate dehydrogenase under acidic or hypoxic environments. Characterization of divergent effects of D-2HG/L-2HG on the activity of specific enzymes in diseased metabolism depends on their accurate quantification via mass spectrometry. Despite advancements in high-resolution quadrupole time-of-flight mass spectrometry (HR-QTOF-MS), challenges are typically encountered when attempting to resolve of isobaric and isomeric metabolites such as D-2HG/L-2HG for quantitative analysis. Herein, available D-2HG/L-2HG derivatization and liquid chromatography (LC) MS quantification methods were examined. The outcome led to the development of a robust, high-throughput HR-QTOF-LC/MS approach that permits concomitant quantification of the D-2HG and L-2HG enantiomers with the benefit to quantify the dysregulation of other intermediates within interconnecting pathways. Calibration curve was obtained over the linear range of 0.8-104 nmol/mL with r 2 ≥ 0.995 for each enantiomer. The LC/MS-based assay had an overall precision with intra-day CV % ≤ 8.0 and inter-day CV % ≤ 6.3 across the quality control level for commercial standard and pooled biological samples; relative error % ≤ 2.7 for accuracy; and resolution, R s = 1.6 between 2HG enantiomers (m/z 147.030), D-2HG and L-2HG (at retention time of 5.82 min and 4.75 min, respectively) following chiral derivatization with diacetyl-L-tartaric anhydride (DATAN). Our methodology was applied to disease relevant samples to illustrate the implications of proper enantioselective quantification of both D-2HG and L-2HG. The stability of the method allows scaling to large cohorts of clinical samples in the future.

Published
2024
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31. TGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis.

Author

Gauthier T, Yao C, Dowdy T, Jin W, Lim YJ, Patiño LC, Liu N, Ohlemacher SI, Bynum A, Kazmi R, Bewley CA, Mitrovic M, Martin D, Morell RJ, Eckhaus M, Larion M, Tussiwand R, O'Shea JJ, and Chen W

Subjects
Mice, Animals, Transforming Growth Factor beta metabolism, Lipopolysaccharides toxicity, Macrophages metabolism, Inflammation metabolism, Cytokines metabolism, Glycolysis, COVID-19 metabolism, Sepsis metabolism
Abstract

Changes in metabolism of macrophages are required to sustain macrophage activation in response to different stimuli. We showed that the cytokine TGF-β (transforming growth factor-β) regulates glycolysis in macrophages independently of inflammatory cytokine production and affects survival in mouse models of sepsis. During macrophage activation, TGF-β increased the expression and activity of the glycolytic enzyme PFKL (phosphofructokinase-1 liver type) and promoted glycolysis but suppressed the production of proinflammatory cytokines. The increase in glycolysis was mediated by an mTOR-c-MYC-dependent pathway, whereas the inhibition of cytokine production was due to activation of the transcriptional coactivator SMAD3 and suppression of the activity of the proinflammatory transcription factors AP-1, NF-κB, and STAT1. In mice with LPS-induced endotoxemia and experimentally induced sepsis, the TGF-β-induced enhancement in macrophage glycolysis led to decreased survival, which was associated with increased blood coagulation. Analysis of septic patient cohorts revealed that the expression of PFKL , TGFBRI (which encodes a TGF-β receptor), and F13A1 (which encodes a coagulation factor) in myeloid cells positively correlated with COVID-19 disease. Thus, these results suggest that TGF-β is a critical regulator of macrophage metabolism and could be a therapeutic target in patients with sepsis.

Published
2023
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32. Metabolic biomarkers of radiotherapy response in plasma and tissue of an IDH1 mutant astrocytoma mouse model.

Author

Ruiz-Rodado V, Dowdy T, Lita A, Kramp T, Zhang M, Shuboni-Mulligan D, Herold-Mende C, Armstrong TS, Gilbert MR, Camphausen K, and Larion M

Abstract

Astrocytomas are the most common subtype of brain tumors and no curative treatment exist. Longitudinal assessment of patients, usually via Magnetic Resonance Imaging (MRI), is crucial since tumor progression may occur earlier than clinical progression. MRI usually provides a means for monitoring the disease, but it only informs about the structural changes of the tumor, while molecular changes can occur as a treatment response without any MRI-visible change. Radiotherapy (RT) is routinely performed following surgery as part of the standard of care in astrocytomas, that can also include chemotherapy involving temozolomide. Monitoring the response to RT is a key factor for the management of patients. Herein, we provide plasma and tissue metabolic biomarkers of treatment response in a mouse model of astrocytoma that was subjected to radiotherapy. Plasma metabolic profiles acquired over time by Liquid Chromatography Mass Spectrometry (LC/MS) were subjected to multivariate empirical Bayes time-series analysis (MEBA) and Receiver Operating Characteristic (ROC) assessment including Random Forest as the classification strategy. These analyses revealed a variation of the plasma metabolome in those mice that underwent radiotherapy compared to controls; specifically, fumarate was the best discriminatory feature. Additionally, Nuclear Magnetic Resonance (NMR)-based 13 C-tracing experiments were performed at end-point utilizing [U- 13 C]-Glutamine to investigate its fate in the tumor and contralateral tissues. Irradiated mice displayed lower levels of glycolytic metabolites (e.g. phosphoenolpyruvate) in tumor tissue, and a higher flux of glutamine towards succinate was observed in the radiation cohort. The plasma biomarkers provided herein could be validated in the clinic, thereby improving the assessment of brain tumor patients throughout radiotherapy. Moreover, the metabolic rewiring associated to radiotherapy in tumor tissue could lead to potential metabolic imaging approaches for monitoring treatment using blood draws., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ruiz-Rodado, Dowdy, Lita, Kramp, Zhang, Shuboni-Mulligan, Herold-Mende, Armstrong, Gilbert, Camphausen and Larion.)

Published
2022
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33. IDH-mutated gliomas promote epileptogenesis through d-2-hydroxyglutarate-dependent mTOR hyperactivation.

Author

Mortazavi A, Fayed I, Bachani M, Dowdy T, Jahanipour J, Khan A, Owotade J, Walbridge S, Inati SK, Steiner J, Wu J, Gilbert M, Yang CZ, Larion M, Maric D, Ksendzovsky A, and Zaghloul KA

Subjects
Glutarates, Humans, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Mutation, Quality of Life, Seizures, TOR Serine-Threonine Kinases, Brain Neoplasms pathology, Glioma pathology
Abstract

Background: Uncontrolled seizures in patients with gliomas have a significant impact on quality of life and morbidity, yet the mechanisms through which these tumors cause seizures remain unknown. Here, we hypothesize that the active metabolite d-2-hydroxyglutarate (d-2-HG) produced by the IDH-mutant enzyme leads to metabolic disruptions in surrounding cortical neurons that consequently promote seizures., Methods: We use a complementary study of in vitro neuron-glial cultures and electrographically sorted human cortical tissue from patients with IDH-mutant gliomas to test this hypothesis. We utilize micro-electrode arrays for in vitro electrophysiological studies in combination with pharmacological manipulations and biochemical studies to better elucidate the impact of d-2-HG on cortical metabolism and neuronal spiking activity., Results: We demonstrate that d-2-HG leads to increased neuronal spiking activity and promotes a distinct metabolic profile in surrounding neurons, evidenced by distinct metabolomic shifts and increased LDHA expression, as well as upregulation of mTOR signaling. The increases in neuronal activity are induced by mTOR activation and reversed with mTOR inhibition., Conclusion: Together, our data suggest that metabolic disruptions in the surrounding cortex due to d-2-HG may be a driving event for epileptogenesis in patients with IDH-mutant gliomas., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2022.)

Published
2022
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34. Targeting the Sphingolipid Rheostat in Gliomas.

Author

Zaibaq F, Dowdy T, and Larion M

Subjects
Apoptosis physiology, Cell Death, Ceramides metabolism, Humans, Lysophospholipids metabolism, Sphingosine metabolism, Glioma drug therapy, Glioma genetics, Sphingolipids metabolism
Abstract

Gliomas are highly aggressive cancer types that are in urgent need of novel drugs and targeted therapies. Treatment protocols have not improved in over a decade, and glioma patient survival remains among the worst of all cancer types. As a result, cancer metabolism research has served as an innovative approach to identifying novel glioma targets and improving our understanding of brain tumors. Recent research has uncovered a unique metabolic vulnerability in the sphingolipid pathways of gliomas that possess the IDH1 mutation. Sphingolipids are a family of lipid signaling molecules that play a variety of second messenger functions in cellular regulation. The two primary metabolites, sphingosine-1-phosphate (S1P) and ceramide, maintain a rheostat balance and play opposing roles in cell survival and proliferation. Altering the rheostat such that the pro-apoptotic signaling of the ceramides outweighs the pro-survival S1P signaling in glioma cells diminishes the hallmarks of cancer and enhances tumor cell death. Throughout this review, we discuss the sphingolipid pathway and identify the enzymes that can be most effectively targeted to alter the sphingolipid rheostat and enhance apoptosis in gliomas. We discuss each pathway's steps based on their site of occurrence in the organelles and postulate novel targets that can effectively exploit this vulnerability.

Published
2022
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35. Cysteine is a limiting factor for glioma proliferation and survival.

Author

Ruiz-Rodado V, Dowdy T, Lita A, Kramp T, Zhang M, Jung J, Dios-Esponera A, Zhang L, Herold-Mende CC, Camphausen K, Gilbert MR, and Larion M

Subjects
Animals, Cell Proliferation, Cystine metabolism, Glutathione metabolism, Humans, Mice, Tumor Microenvironment, Cysteine metabolism, Glioma
Abstract

Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. However, little is known about the mechanisms that make cancer cells require certain nutrients from the microenvironment. Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13 C-tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to support glutathione synthesis through the transsulfuration pathway, which allows methionine to be converted to cysteine in cysteine/cystine-deprived conditions. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine-free diet survived longer, although this increase did not attain statistical significance, with concomitant reductions in plasma glutathione and cysteine levels. At the end point, however, tumors displayed the ability to synthesize glutathione, even though higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine-related metabolite levels in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Published
2022
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36. Cryo-EM structures reveal multiple stages of bacterial outer membrane protein folding.

Author

Doyle MT, Jimah JR, Dowdy T, Ohlemacher SI, Larion M, Hinshaw JE, and Bernstein HD

Subjects
Bacterial Outer Membrane Proteins metabolism, Cryoelectron Microscopy, Escherichia coli metabolism, Escherichia coli Proteins metabolism, Bacterial Outer Membrane Proteins ultrastructure, Protein Folding
Abstract

Transmembrane β barrel proteins are folded into the outer membrane (OM) of Gram-negative bacteria by the β barrel assembly machinery (BAM) via a poorly understood process that occurs without known external energy sources. Here, we used single-particle cryo-EM to visualize the folding dynamics of a model β barrel protein (EspP) by BAM. We found that BAM binds the highly conserved "β signal" motif of EspP to correctly orient β strands in the OM during folding. We also found that the folding of EspP proceeds via "hybrid-barrel" intermediates in which membrane integrated β sheets are attached to the essential BAM subunit, BamA. The structures show an unprecedented deflection of the membrane surrounding the EspP intermediates and suggest that β sheets progressively fold toward BamA to form a β barrel. Along with in vivo experiments that tracked β barrel folding while the OM tension was modified, our results support a model in which BAM harnesses OM elasticity to accelerate β barrel folding., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Published
2022
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37. Reversing Epigenetic Gene Silencing to Overcome Immune Evasion in CNS Malignancies.

Author

Ratnam NM, Sonnemann HM, Frederico SC, Chen H, Hutchinson MND, Dowdy T, Reid CM, Jung J, Zhang W, Song H, Zhang M, Davis D, Larion M, Giles AJ, and Gilbert MR

Abstract

Glioblastoma (GBM) is an aggressive brain malignancy with a dismal prognosis. With emerging evidence to disprove brain-immune privilege, there has been much interest in examining immunotherapy strategies to treat central nervous system (CNS) cancers. Unfortunately, the limited success of clinical studies investigating immunotherapy regimens, has led to questions about the suitability of immunotherapy for these cancers. Inadequate inherent populations of tumor infiltrating lymphocytes (TILs) and limited trafficking of systemic, circulating T cells into the CNS likely contribute to the poor response to immunotherapy. This paucity of TILs is in concert with the finding of epigenetic silencing of genes that promote immune cell movement (chemotaxis) to the tumor. In this study we evaluated the ability of GSK126, a blood-brain barrier (BBB) permeable small molecule inhibitor of EZH2, to reverse GBM immune evasion by epigenetic suppression of T cell chemotaxis. We also evaluated the in vivo efficacy of this drug in combination with anti-PD-1 treatment on tumor growth, survival and T cell infiltration in syngeneic mouse models. GSK126 reversed H3K27me 3 in murine and human GBM cell lines. When combined with anti-PD-1 treatment, a significant increase in activated T cell infiltration into the tumor was observed. This resulted in decreased tumor growth and enhanced survival both in sub-cutaneous and intracranial tumors of immunocompetent, syngeneic murine models of GBM. Additionally, a significant increase in CXCR3 + T cells was also seen in the draining lymph nodes, suggesting their readiness to migrate to the tumor. Closer examination of the mechanism of action of GSK126 revealed its ability to promote the expression of IFN-γ driven chemokines CXCL9 and CXCL10 from the tumor cells, that work to traffic T cells without directly affecting T maturation and/or proliferation. The loss of survival benefit either with single agent or combination in immunocompromised SCID mice, suggest that the therapeutic efficacy of GSK126 in GBM is primarily driven by lymphocytes. Taken together, our data suggests that in glioblastoma, epigenetic modulation using GSK126 could improve current immunotherapy strategies by reversing the epigenetic changes that enable immune cell evasion leading to enhanced immune cell trafficking to the tumor., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ratnam, Sonnemann, Frederico, Chen, Hutchinson, Dowdy, Reid, Jung, Zhang, Song, Zhang, Davis, Larion, Giles and Gilbert.)

Published
2021
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38. IDH1 mutations induce organelle defects via dysregulated phospholipids.

Author

Lita A, Pliss A, Kuzmin A, Yamasaki T, Zhang L, Dowdy T, Burks C, de Val N, Celiku O, Ruiz-Rodado V, Nicoli ER, Kruhlak M, Andresson T, Das S, Yang C, Schmitt R, Herold-Mende C, Gilbert MR, Prasad PN, and Larion M

Subjects
Cell Line, Tumor, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum ultrastructure, Glioblastoma pathology, Golgi Apparatus metabolism, Golgi Apparatus ultrastructure, Humans, Models, Biological, Oligodendroglioma pathology, Stearoyl-CoA Desaturase metabolism, Isocitrate Dehydrogenase genetics, Mutation genetics, Organelles metabolism, Phospholipids metabolism
Abstract

Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring a mutation in isocitrate dehydrogenase 1 mutation (IDH1 mut ) acquire a different tumor biology and clinical manifestation from those that are IDH1 WT . Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we uncover increased monounsaturated fatty acids (MUFA) and their phospholipids in endoplasmic reticulum (ER), generated by IDH1 mutation, that are responsible for Golgi and ER dilation. We demonstrate a direct link between the IDH1 mutation and this organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate-limiting enzyme in MUFA biosynthesis. Inhibition of IDH1 mutation or SCD silencing restores ER and Golgi morphology, while D-2HG and oleic acid induces morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produces IDH1 mut -specific cellular apoptosis. Collectively, these results suggest that IDH1 mut -induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing new insight into the link between lipid metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.

Published
2021
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39. Metabolic plasticity of IDH1 -mutant glioma cell lines is responsible for low sensitivity to glutaminase inhibition.

Author

Ruiz-Rodado V, Lita A, Dowdy T, Celiku O, Saldana AC, Wang H, Yang CZ, Chari R, Li A, Zhang W, Song H, Zhang M, Ahn S, Davis D, Chen X, Zhuang Z, Herold-Mende C, Walters KJ, Gilbert MR, and Larion M

Abstract

Background: Targeting glutamine metabolism in cancer has become an increasingly vibrant area of research. Mutant IDH1 (IDH1 mut ) gliomas are considered good candidates for targeting this pathway because of the contribution of glutamine to their newly acquired function: synthesis of 2-hydroxyglutarate (2HG)., Methods: We have employed a combination of 13 C tracers including glutamine and glucose for investigating the metabolism of patient-derived IDH1 mut glioma cell lines through NMR and LC/MS. Additionally, genetic loss-of-function (in vitro and in vivo) approaches were performed to unravel the adaptability of these cell lines to the inhibition of glutaminase activity., Results: We report the adaptability of IDH1 mut cells' metabolism to the inhibition of glutamine/glutamate pathway. The glutaminase inhibitor CB839 generated a decrease in the production of the downstream metabolites of glutamate, including those involved in the TCA cycle and 2HG. However, this effect on metabolism was not extended to viability; rather, our patient-derived IDH1 mut cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition., Conclusions: Major metabolic adaptations involved pathways that can generate glutamate by using alternative substrates from glutamine, such as alanine or aspartate. Indeed, asparagine synthetase was upregulated both in vivo and in vitro revealing a new potential therapeutic target for a combinatory approach with CB839 against IDH1 mut gliomas., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Published
2020
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40. Sphingolipid Pathway as a Source of Vulnerability in IDH1 mut Glioma.

Author

Dowdy T, Zhang L, Celiku O, Movva S, Lita A, Ruiz-Rodado V, Gilbert MR, and Larion M

Abstract

In addition to providing integrity to cellular structure, the various classes of lipids participate in a multitude of functions including secondary messengers, receptor stimulation, lymphocyte trafficking, inflammation, angiogenesis, cell migration, proliferation, necrosis and apoptosis, thus highlighting the importance of understanding their role in the tumor phenotype. In the context of IDH1 mut glioma, investigations focused on metabolic alterations involving lipidomics' present potential to uncover novel vulnerabilities. Herein, a detailed lipidomic analysis of the sphingolipid metabolism was conducted in patient-derived IDH1 mut glioma cell lines, as well as model systems, with the of identifying points of metabolic vulnerability. We probed the effect of decreasing D-2HG levels on the sphingolipid pathway, by treating these cell lines with an IDH1 mut inhibitor, AGI5198. The results revealed that N,N-dimethylsphingosine (NDMS), sphingosine C17 and sphinganine C18 were significantly downregulated, while sphingosine-1-phosphate (S1P) was significantly upregulated in glioma cultures following suppression of IDH1 mut activity. We exploited the pathway using a small-scale, rational drug screen and identified a combination that was lethal to IDH mut cells. Our work revealed that further addition of N,N-dimethylsphingosine in combination with sphingosine C17 triggered a dose-dependent biostatic and apoptotic response in a panel of IDH1 mut glioma cell lines specifically, while it had little effect on the IDH WT cells probed here. To our knowledge, this is the first study that shows how altering the sphingolipid pathway in IDH1 mut gliomas elucidates susceptibility that can arrest proliferation and initiate subsequent cellular death.

Published
2020
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41. Metabolic Landscape of a Genetically Engineered Mouse Model of IDH1 Mutant Glioma.

Author

Ruiz-Rodado V, Seki T, Dowdy T, Lita A, Zhang M, Han S, Yang C, Cherukuri MK, Gilbert MR, and Larion M

Abstract

Understanding the metabolic reprogramming of aggressive brain tumors has potential applications for therapeutics as well as imaging biomarkers. However, little is known about the nutrient requirements of isocitrate dehydrogenase 1 (IDH1) mutant gliomas. The IDH1 mutation involves the acquisition of a neomorphic enzymatic activity which generates D-2-hydroxyglutarate from α-ketoglutarate. In order to gain insight into the metabolism of these malignant brain tumors, we conducted metabolic profiling of the orthotopic tumor and the contralateral regions for the mouse model of IDH1 mutant glioma; as well as to examine the utilization of glucose and glutamine in supplying major metabolic pathways such as glycolysis and tricarboxylic acid (TCA). We also revealed that the main substrate of 2-hydroxyglutarate is glutamine in this model, and how this re-routing impairs its utilization in the TCA. Our 13 C tracing analysis, along with hyperpolarized magnetic resonance experiments, revealed an active glycolytic pathway similar in both regions (tumor and contralateral) of the brain. Therefore, we describe the reprogramming of the central carbon metabolism associated with the IDH1 mutation in a genetically engineered mouse model which reflects the tumor biology encountered in glioma patients.

Published
2020
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42. Metabolic reprogramming associated with aggressiveness occurs in the G-CIMP-high molecular subtypes of IDH1mut lower grade gliomas.

Author

Ruiz-Rodado V, Malta TM, Seki T, Lita A, Dowdy T, Celiku O, Cavazos-Saldana A, Li A, Liu Y, Han S, Zhang W, Song H, Davis D, Lee S, Trepel JB, Sabedot TS, Munasinghe J, Yang C, Herold-Mende C, Gilbert MR, Cherukuri MK, Noushmehr H, and Larion M

Subjects
DNA Methylation, Guanine, Humans, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Mutation, Phenotype, Brain Neoplasms genetics, Glioma genetics
Abstract

Background: Early detection of increased aggressiveness of brain tumors is a major challenge in the field of neuro-oncology because of the inability of traditional imaging to uncover it. Isocitrate dehydrogenase (IDH)-mutant gliomas represent an ideal model system to study the molecular mechanisms associated with tumorigenicity because they appear indolent and non-glycolytic initially, but eventually a subset progresses toward secondary glioblastoma with a Warburg-like phenotype. The mechanisms and molecular features associated with this transformation are poorly understood., Methods: We employed model systems for IDH1 mutant (IDH1mut) gliomas with different growth and proliferation rates in vivo and in vitro. We described the metabolome, transcriptome, and epigenome of these models in order to understand the link between their metabolism and the tumor biology. To verify whether this metabolic reprogramming occurs in the clinic, we analyzed data from The Cancer Genome Atlas., Results: We reveal that the aggressive glioma models have lost DNA methylation in the promoters of glycolytic enzymes, especially lactate dehydrogenase A (LDHA), and have increased mRNA and metabolite levels compared with the indolent model. We find that the acquisition of the high glycolytic phenotype occurs at the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP)-high molecular subtype in patients and is associated with the worst outcome., Conclusion: We propose very early monitoring of lactate levels as a biomarker of metabolic reprogramming and tumor aggressiveness., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2020
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43. Targeting Glycolysis through Inhibition of Lactate Dehydrogenase Impairs Tumor Growth in Preclinical Models of Ewing Sarcoma.

Author

Yeung C, Gibson AE, Issaq SH, Oshima N, Baumgart JT, Edessa LD, Rai G, Urban DJ, Johnson MS, Benavides GA, Squadrito GL, Yohe ME, Lei H, Eldridge S, Hamre J 3rd, Dowdy T, Ruiz-Rodado V, Lita A, Mendoza A, Shern JF, Larion M, Helman LJ, Stott GM, Krishna MC, Hall MD, Darley-Usmar V, Neckers LM, and Heske CM

Subjects
Animals, Cell Line, Tumor, Cell Proliferation drug effects, Humans, Mice, Mice, SCID, Sarcoma, Ewing metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Enzyme Inhibitors pharmacology, Glycolysis drug effects, L-Lactate Dehydrogenase antagonists & inhibitors, Sarcoma, Ewing pathology
Abstract

Altered cellular metabolism, including an increased dependence on aerobic glycolysis, is a hallmark of cancer. Despite the fact that this observation was first made nearly a century ago, effective therapeutic targeting of glycolysis in cancer has remained elusive. One potentially promising approach involves targeting the glycolytic enzyme lactate dehydrogenase (LDH), which is overexpressed and plays a critical role in several cancers. Here, we used a novel class of LDH inhibitors to demonstrate, for the first time, that Ewing sarcoma cells are exquisitely sensitive to inhibition of LDH. EWS-FLI1, the oncogenic driver of Ewing sarcoma, regulated LDH A (LDHA) expression. Genetic depletion of LDHA inhibited proliferation of Ewing sarcoma cells and induced apoptosis, phenocopying pharmacologic inhibition of LDH. LDH inhibitors affected Ewing sarcoma cell viability both in vitro and in vivo by reducing glycolysis. Intravenous administration of LDH inhibitors resulted in the greatest intratumoral drug accumulation, inducing tumor cell death and reducing tumor growth. The major dose-limiting toxicity observed was hemolysis, indicating that a narrow therapeutic window exists for these compounds. Taken together, these data suggest that targeting glycolysis through inhibition of LDH should be further investigated as a potential therapeutic approach for cancers such as Ewing sarcoma that exhibit oncogene-dependent expression of LDH and increased glycolysis. SIGNIFICANCE: LDHA is a pharmacologically tractable EWS-FLI1 transcriptional target that regulates the glycolytic dependence of Ewing sarcoma., (©2019 American Association for Cancer Research.)

Published
2019
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44. Detection of Metabolic Changes Induced via Drug Treatments in Live Cancer Cells and Tissue Using Raman Imaging Microscopy.

Author

Larion M, Dowdy T, Ruiz-Rodado V, Meyer MW, Song H, Zhang W, Davis D, Gilbert MR, and Lita A

Subjects
Animals, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Humans, Mice, Mice, SCID, Neoplasms, Experimental drug therapy, Tumor Cells, Cultured, Acrylamides pharmacology, Antineoplastic Agents pharmacology, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Piperidines pharmacology, Spectrum Analysis, Raman
Abstract

Isocitrate dehydrogenase 1 (IDH1) mutations in gliomas, fibrosarcoma, and other cancers leads to a novel metabolite, D-2-hydroxyglutarate, which is proposed to cause tumorigenesis. The production of this metabolite also causes vulnerabilities in cellular metabolism, such as lowering NADPH levels. To exploit this vulnerability, we treated glioma and fibrosarcoma cells that harbor an IDH1 mutation with an inhibitor of nicotinamide adenine dinucleotide (NAD⁺) salvage pathway, FK866, and observed decreased viability in these cells. To understand the mechanism of action by which the inhibitor FK866 works, we used Raman imaging microscopy and identified that proteins and lipids are decreased upon treatment with the drug. Raman imaging showed a different distribution of lipids throughout the cell in the presence of the drug compared with the untreated cells. We employed nuclear magnetic resonance NMR spectroscopy and mass spectrometry to identify the classes of lipids altered. Our combined analyses point to a decrease in cell division due to loss of lipid content that contributes to membrane formation in the in vitro setting. However, the FK866 drug did not have the same potency in vivo. The use of Raman imaging microscopy indicated an opposite trend of lipid distribution in the tissue collected from treated versus untreated mice when compared with the cells. These results demonstrate the role of Raman imaging microscopy to identify and quantify metabolic changes in cancer cells and tissue.

Published
2018
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45. A high-throughput screening campaign to identify inhibitors of DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD).

Author

Haymond A, Dowdy T, Johny C, Johnson C, Ball H, Dailey A, Schweibenz B, Villarroel K, Young R, Mantooth CJ, Patel T, Bases J, Dowd CS, and Couch RD

Subjects
Aldose-Ketose Isomerases metabolism, Anti-Bacterial Agents pharmacology, Enzyme Inhibitors pharmacology, Molecular Structure, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis enzymology, Nucleotidyltransferases metabolism, Recombinant Proteins metabolism, Yersinia pestis drug effects, Yersinia pestis enzymology, Aldose-Ketose Isomerases antagonists & inhibitors, Anti-Bacterial Agents analysis, Enzyme Inhibitors analysis, High-Throughput Screening Assays, Nucleotidyltransferases antagonists & inhibitors
Abstract

The rise of antibacterial resistance among human pathogens represents a problem that could change the landscape of healthcare unless new antibiotics are developed. The methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for novel antibiotic design, considering each enzyme of the pathway is both essential and has no human homologs. Here we describe a pilot scale high-throughput screening (HTS) campaign against the first and second committed steps in the pathway, catalyzed by DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD), using compounds present in the commercially available LOPAC 1280 library as well as in an in-house natural product extract library. Hit compounds were characterized to deduce their mechanism of inhibition; most function through aggregation. The HTS workflow outlined here is useful for quickly screening a chemical library, while effectively identifying false positive compounds associated with assay constraints and aggregation., (Copyright © 2017. Published by Elsevier Inc.)

Published
2018
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46. Chemopreventive Metabolites Are Correlated with a Change in Intestinal Microbiota Measured in A-T Mice and Decreased Carcinogenesis.

Author

Cheema AK, Maier I, Dowdy T, Wang Y, Singh R, Ruegger PM, Borneman J, Fornace AJ Jr, and Schiestl RH

Subjects
4-Butyrolactone metabolism, Adenine metabolism, Animals, Mice, Mice, Knockout, 4-Butyrolactone analogs & derivatives, Adenine analogs & derivatives, Cell Transformation, Neoplastic, Gastrointestinal Microbiome, Intestinal Neoplasms
Abstract

Intestinal microbiota play a significant role in nutrient metabolism, modulation of the immune system, obesity, and possibly in carcinogenesis, although the underlying mechanisms resulting in disease or impacts on longevity caused by different intestinal microbiota are mostly unknown. Herein we use isogenic Atm-deficient and wild type mice as models to interrogate changes in the metabolic profiles of urine and feces of these mice, which are differing in their intestinal microbiota. Using high resolution mass spectrometry approach we show that the composition of intestinal microbiota modulates specific metabolic perturbations resulting in a possible alleviation of a glycolytic phenotype. Metabolites including 3-methylbutyrolactone, kyneurenic acid and 3-methyladenine known to be onco-protective are elevated in Atm-deficient and wild type mice with restricted intestinal microbiota. Thus our approach has broad applicability to study the direct influence of gut microbiome on host metabolism and resultant phenotype. These results for the first time suggest a possible correlation of metabolic alterations and carcinogenesis, modulated by intestinal microbiota in A-T mice.

Published
2016
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47. Kinetic characterization and allosteric inhibition of the Yersinia pestis 1-deoxy-D-xylulose 5-phosphate reductoisomerase (MEP synthase).

Author

Haymond A, Johny C, Dowdy T, Schweibenz B, Villarroel K, Young R, Mantooth CJ, Patel T, Bases J, San Jose G, Jackson ER, Dowd CS, and Couch RD

Subjects
Aldose-Ketose Isomerases genetics, Allosteric Regulation, Bacterial Proteins genetics, Catalysis, Erythritol analogs & derivatives, Erythritol biosynthesis, Erythritol chemistry, Fosfomycin analogs & derivatives, Fosfomycin chemistry, Kinetics, Yersinia pestis genetics, Aldose-Ketose Isomerases chemistry, Bacterial Proteins chemistry, Yersinia pestis enzymology
Abstract

The methylerythritol phosphate (MEP) pathway found in many bacteria governs the synthesis of isoprenoids, which are crucial lipid precursors for vital cell components such as ubiquinone. Because mammals synthesize isoprenoids via an alternate pathway, the bacterial MEP pathway is an attractive target for novel antibiotic development, necessitated by emerging antibiotic resistance as well as biodefense concerns. The first committed step in the MEP pathway is the reduction and isomerization of 1-deoxy-D-xylulose-5-phosphate (DXP) to methylerythritol phosphate (MEP), catalyzed by MEP synthase. To facilitate drug development, we cloned, expressed, purified, and characterized MEP synthase from Yersinia pestis. Enzyme assays indicate apparent kinetic constants of KMDXP = 252 µM and KMNADPH = 13 µM, IC50 values for fosmidomycin and FR900098 of 710 nM and 231 nM respectively, and Ki values for fosmidomycin and FR900098 of 251 nM and 101 nM respectively. To ascertain if the Y. pestis MEP synthase was amenable to a high-throughput screening campaign, the Z-factor was determined (0.9) then the purified enzyme was screened against a pilot scale library containing rationally designed fosmidomycin analogs and natural product extracts. Several hit molecules were obtained, most notably a natural product allosteric affector of MEP synthase and a rationally designed bisubstrate derivative of FR900098 (able to associate with both the NADPH and DXP binding sites in MEP synthase). It is particularly noteworthy that allosteric regulation of MEP synthase has not been described previously. Thus, our discovery implicates an alternative site (and new chemical space) for rational drug development.

Published
2014
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48. Are you delivering and communicating value?

Author

Dowdy T

Subjects
Animals, Costs and Cost Analysis, Humans, Practice Management economics, Communication, Income statistics & numerical data, Income trends, Practice Management standards, Veterinary Medicine economics, Veterinary Medicine methods, Veterinary Medicine standards
Published
2010

49. Identification of breast cancer in patients with pathologic nipple discharge: does ductoscopy predict malignancy?

Author

Louie LD, Crowe JP, Dawson AE, Lee KB, Baynes DL, Dowdy T, and Kim JA

Subjects
Female, Humans, Predictive Value of Tests, Retrospective Studies, Therapeutic Irrigation, Adenocarcinoma pathology, Breast Neoplasms pathology, Endoscopy, Exudates and Transudates metabolism, Mammary Glands, Human pathology, Nipples metabolism
Abstract

Objective: The purpose of the current study was to review characteristics of patients with nipple discharge who underwent ductoscopy-assisted excisional biopsy who had a final diagnosis of carcinoma., Methods: A retrospective review was performed of patients presenting with pathologic nipple discharge (PND) who underwent ductoscopy-assisted excisional biopsy and had a final diagnosis of carcinoma., Results: A total of 14 (7%) of 188 patients who underwent ductoscopy-assisted excision had a final pathology of ductal carcinoma-in-situ (DCIS) (12/14, 86%) or invasive breast cancer with DCIS (2/14, 14%). Duct wall irregularities or intraluminal growths were visualized during ductoscopy in 8 of the 14 (57%) breast cancer patients. There were no visual abnormalities noted during ductoscopy that accurately predicted a final diagnosis of malignancy., Conclusions: Although occult malignancies can be identified in patients undergoing ductoscopy-assisted biopsy for PND, no clear morphologic changes visualized during ductoscopy definitively indicated the presence of malignancy.

Published
2006
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