112 results on '"Abedalthagafi M"'
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2. Whole-genome sequencing reveals host factors underlying critical COVID-19
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Kousathanas, A, Pairo-Castineira, E, Rawlik, K, Stuckey, A, Odhams, C, Walker, S, Russell, C, Malinauskas, T, Wu, Y, Millar, J, Shen, X, Elliott, K, Griffiths, F, Oosthuyzen, W, Morrice, K, Keating, S, Wang, B, Rhodes, D, Klaric, L, Zechner, M, Parkinson, N, Siddiq, A, Goddard, P, Donovan, S, Maslove, D, Nichol, A, Semple, M, Zainy, T, Maleady-Crowe, F, Todd, L, Salehi, S, Knight, J, Elgar, G, Chan, G, Arumugam, P, Patch, C, Rendon, A, Bentley, D, Kingsley, C, Kosmicki, J, Horowitz, J, Baras, A, Abecasis, G, Ferreira, M, Justice, A, Mirshahi, T, Oetjens, M, Rader, D, Ritchie, M, Verma, A, Fowler, T, Shankar-Hari, M, Summers, C, Hinds, C, Horby, P, Ling, L, Mcauley, D, Montgomery, H, Openshaw, P, Elliott, P, Walsh, T, Tenesa, A, Shelton, J, Shastri, A, Ye, C, Weldon, C, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, Auton, A, Pathak, G, Karjalainen, J, Stevens, C, Andrews, S, Kanai, M, Cordioli, M, Polimanti, R, Pirinen, M, Harerimana, N, Veerapen, K, Wolford, B, Nguyen, H, Solomonson, M, Liao, R, Chwialkowska, K, Trankiem, A, Balaconis, M, Hayward, C, Richmond, A, Campbell, A, Morris, M, Fawns-Ritchie, C, Glessner, J, Shaw, D, Chang, X, Polikowski, H, Petty, L, Chen, H, Wanying, Z, Hakonarson, H, Porteous, D, Below, J, North, K, Mccormick, J, Timmers, P, Wilson, J, D'Mellow, K, Kerr, S, Niemi, M, Nkambul, L, von Hohenstaufen, K, Sobh, A, Eltoukhy, M, Yassen, A, Hegazy, M, Okasha, K, Eid, M, Moahmed, H, Shahin, D, El-Sherbiny, Y, Elhadidy, T, Abd Elghafar, M, El-Jawhari, J, Mohamed, A, Elnagdy, M, Samir, A, Abdel-Aziz, M, Khafaga, W, El-Lawaty, W, Torky, M, El-shanshory, M, Batini, C, Lee, P, Shrine, N, Williams, A, Tobin, M, Guyatt, A, John, C, Packer, R, Ali, A, Free, R, Wang, X, Wain, L, Hollox, E, Venn, L, Bee, C, Adams, E, Niavarani, A, Sharififard, B, Aliannejad, R, Amirsavadkouhi, A, Naderpour, Z, Tadi, H, Aleagha, A, Ahmadi, S, Moghaddam, S, Adamsara, A, Saeedi, M, Abdollahi, H, Hosseini, A, Chariyavilaskul, P, Chamnanphon, M, Suttichet, T, Shotelersuk, V, Pongpanich, M, Phokaew, C, Chetruengchai, W, Jantarabenjakul, W, Putchareon, O, Torvorapanit, P, Puthanakit, T, Suchartlikitwong, P, Hirankarn, N, Nilaratanakul, V, Sodsai, P, Brumpton, B, Hveem, K, Willer, C, Zhou, W, Rogne, T, Solligard, E, Asvold, B, Abedalthagafi, M, Alaamery, M, Alqahtani, S, Barakeh, D, Al Harthi, F, Alsolm, E, Safieh, L, Alowayn, A, Alqubaishi, F, Al Mutairi, A, Mangul, S, Alshareef, A, Sawaji, M, Almutairi, M, Aljawini, N, Albesher, N, Arabi, Y, Mahmoud, E, Khattab, A, Halawani, R, Alahmadey, Z, Albakri, J, Felemban, W, Suliman, B, Hasanato, R, Al-Awdah, L, Alghamdi, J, Alzahrani, D, Aljohani, S, Al-Afghani, H, Alrashed, M, Aldhawi, N, Albardis, H, Alkwai, S, Alswailm, M, Almalki, F, Albeladi, M, Almohammed, I, Barhoush, E, Albader, A, Massadeh, S, Almalik, A, Alotaibi, S, Alghamdi, B, Jung, J, Fawzy, M, Lee, Y, Magnus, P, Trogstad, L, Helgeland, O, Harris, J, Mangino, M, Spector, T, Duncan, E, Smieszek, S, Przychodzen, B, Polymeropoulos, C, Polymeropoulos, V, Polymeropoulos, M, Fernandez-Cadenas, I, Perez-Tur, J, Llucia-Carol, L, Cullell, N, Muino, E, Carcel-Marquez, J, Dediego, M, Iglesias, L, Planas, A, Soriano, A, Rico, V, Aguero, D, Bedini, J, Lozano, F, Domingo, C, Robles, V, Ruiz-Jaen, F, Marquez, L, Gomez, J, Coto, E, Albaiceta, G, Garcia-Clemente, M, Dalmau, D, Arranz, M, Dietl, B, Serra-Llovich, A, Soler, P, Colobran, R, Martin-Nalda, A, Martinez, A, Bernardo, D, Rojo, S, Fiz-Lopez, A, Arribas, E, de la Cal-Sabater, P, Segura, T, Gonzalez-Villa, E, Serrano-Heras, G, Marti-Fabregas, J, Jimenez-Xarrie, E, de Felipe Mimbrera, A, Masjuan, J, Garcia-Madrona, S, Dominguez-Mayoral, A, Villalonga, J, Menendez-Valladares, P, Chasman, D, Buring, J, Ridker, P, Franco, G, Sesso, H, Manson, J, Medina-Gomez, C, Uitterlinden, A, Ikram, M, Kristiansson, K, Koskelainen, S, Perola, M, Donner, K, Kivinen, K, Palotie, A, Ripatti, S, Ruotsalainen, S, Kaunisto, M, Nakanishi, T, Butler-Laporte, G, Forgetta, V, Morrison, D, Ghosh, B, Laurent, L, Belisle, A, Henry, D, Abdullah, T, Adeleye, O, Mamlouk, N, Kimchi, N, Afrasiabi, Z, Rezk, N, Vulesevic, B, Bouab, M, Guzman, C, Petitjean, L, Tselios, C, Xue, X, Schurr, E, Afilalo, J, Afilalo, M, Oliveira, M, Brenner, B, Lepage, P, Ragoussis, J, Auld, D, Brassard, N, Durand, M, Chasse, M, Kaufmann, D, Lathrop, G, Mooser, V, Richards, J, Li, R, Adra, D, Rahmouni, S, Georges, M, Moutschen, M, Misset, B, Darcis, G, Guiot, J, Guntz, J, Azarzar, S, Gofflot, S, Beguin, Y, Claassen, S, Malaise, O, Huynen, P, Meuris, C, Thys, M, Jacques, J, Leonard, P, Frippiat, F, Giot, J, Sauvage, A, von Frenckell, C, Belhaj, Y, Lambermont, B, Pigazzini, S, Nkambule, L, Daya, M, Shortt, J, Rafaels, N, Wicks, S, Crooks, K, Barnes, K, Gignoux, C, Chavan, S, Laisk, T, Lall, K, Lepamets, M, Magi, R, Esko, T, Reimann, E, Milani, L, Alavere, H, Metsalu, K, Puusepp, M, Metspalu, A, Naaber, P, Laane, E, Pesukova, J, Peterson, P, Kisand, K, Tabri, J, Allos, R, Hensen, K, Starkopf, J, Ringmets, I, Tamm, A, Kallaste, A, Bochud, P, Rivolta, C, Bibert, S, Quinodoz, M, Kamdar, D, Boillat, N, Nussle, S, Albrich, W, Suh, N, Neofytos, D, Erard, V, Voide, C, de Cid, R, Galvan-Femenia, I, Blay, N, Carreras, A, Cortes, B, Farre, X, Sumoy, L, Moreno, V, Mercader, J, Guindo-Martinez, M, Torrents, D, Kogevinas, M, Garcia-Aymerich, J, Castano-Vinyals, G, Dobano, C, Renieri, A, Mari, F, Fallerini, C, Daga, S, Benetti, E, Baldassarri, M, Fava, F, Frullanti, E, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Mencarelli, M, Rizzo, C, Pinto, A, Beligni, G, Tommasi, A, Di Sarno, L, Palmieri, M, Carriero, M, Alaverdian, D, Busani, S, Bruno, R, Vecchia, M, Belli, M, Picchiotti, N, Sanarico, M, Gori, M, Furini, S, Mantovani, S, Ludovisi, S, Mondelli, M, Castelli, F, Quiros-Roldan, E, Antoni, M, Zanella, I, Vaghi, M, Rusconi, S, Siano, M, Montagnani, F, Emiliozzi, A, Fabbiani, M, Rossetti, B, Bargagli, E, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Bandini, M, Caldarelli, G, Piacentini, P, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Pancrazzi, A, Lorubbio, M, D'Arminio Monforte, A, Miraglia, F, Girardis, M, Venturelli, S, Cossarizza, A, Antinori, A, Vergori, A, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Scotton, P, Andretta, F, Panese, S, Scaggiante, R, Gatti, F, Parisi, S, Baratti, S, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Squeo, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Martinelli, E, Mancarella, S, Tavecchia, L, Crotti, L, Gabbi, C, Rizzi, M, Maggiolo, F, Ripamonti, D, Bachetti, T, La Rovere, M, Sarzi-Braga, S, Bussotti, M, Ceri, S, Pinoli, P, Raimondi, F, Biscarini, F, Stella, A, Zguro, K, Capitani, K, Suardi, C, Dei, S, Parati, G, Ravaglia, S, Artuso, R, Botta, G, Di Domenico, P, Rancan, I, Perrella, A, Bianchi, F, Romani, D, Bergomi, P, Catena, E, Colombo, R, Tanfoni, M, Vincenti, A, Ferri, C, Grassi, D, Pessina, G, Tumbarello, M, Di Pietro, M, Sabrina, R, Luchi, S, Barbieri, C, Acquilini, D, Andreucci, E, Segala, F, Tiseo, G, Falcone, M, Lista, M, Poscente, M, De Vivo, O, Petrocelli, P, Guarnaccia, A, Baroni, S, Smith, A, Boughton, A, Li, K, Lefaive, J, Annis, A, Chittoor, G, Josyula, N, Leader, J, Carey, D, Gass, M, Cantor, M, Yadav, A, van Heel, D, Hunt, K, Mason, D, Huang, Q, Finer, S, Trivedi, B, Griffiths, C, Martin, H, Wright, J, Trembath, R, Soranzo, N, Zhao, J, Butterworth, A, Danesh, J, Di Angelantonio, E, Franke, L, Boezen, M, Deelen, P, Claringbould, A, Lopera, E, Warmerdam, R, Vonk, J, van Blokland, I, Lanting, P, Ori, A, Zollner, S, Wang, J, Beck, A, Peloso, G, Ho, Y, Sun, Y, Huffman, J, O'Donnell, C, Cho, K, Tsao, P, Gaziano, J, Nivard, M, de Geus, E, Bartels, M, Jan Hottenga, J, Weiss, S, Karlson, E, Smoller, J, Green, R, Feng, Y, Murphy, S, Meigs, J, Woolley, A, Perez, E, Li, B, Verma, S, Lucas, A, Bradford, Y, Zeberg, H, Frithiof, R, Hultstrom, M, Lipcsey, M, Tardif, N, Rooyackers, O, Grip, J, Maricic, T, Karczewski, K, Atkinson, E, Tsuo, K, Baya, N, Turley, P, Gupta, R, Callier, S, Walters, R, Palmer, D, Sarma, G, Cheng, N, Lu, W, Bryant, S, Churchhouse, C, Cusick, C, Goldstein, J, King, D, Seed, C, Finucane, H, Martin, A, Satterstrom, F, Wilson, D, Armstrong, J, Rudkin, J, Band, G, Earle, S, Lin, S, Arning, N, Crook, D, Wyllie, D, O'Connell, A, Spencer, C, Koelling, N, Caulfield, M, Scott, R, Moutsianas, L, Pasko, D, Ball, C, Hong, E, Rand, K, Girshick, A, Guturu, H, Baltzell, A, Roberts, G, Park, D, Coignet, M, Mccurdy, S, Knight, S, Partha, R, Rhead, B, Zhang, M, Berkowitz, N, Gaddis, M, Noto, K, Ruiz, L, Pavlovic, M, Sloofman, L, Charney, A, Beckmann, N, Schadt, E, Jordan, D, Thompson, R, Gettler, K, Abul-Husn, N, Ascolillo, S, Buxbaum, J, Chaudhary, K, Cho, J, Itan, Y, Kenny, E, Belbin, G, Sealfon, S, Sebra, R, Salib, I, Collins, B, Levy, T, Britvan, B, Keller, K, Tang, L, Peruggia, M, Hiester, L, Niblo, K, Aksentijevich, A, Labkowsky, A, Karp, A, Zlatopolsky, M, Preuss, M, Loos, R, Nadkarni, G, Do, R, Hoggart, C, Choi, S, Underwood, S, O'Reilly, P, Huckins, L, Zyndorf, M, Daly, M, Neale, B, Ganna, A, Fawkes, A, Murphy, L, Rowan, K, Ponting, C, Vitart, V, Yang, J, Bretherick, A, Hendry, S, Law, A, Baillie, J, Kousathanas A., Pairo-Castineira E., Rawlik K., Stuckey A., Odhams C. A., Walker S., Russell C. D., Malinauskas T., Wu Y., Millar J., Shen X., Elliott K. S., Griffiths F., Oosthuyzen W., Morrice K., Keating S., Wang B., Rhodes D., Klaric L., Zechner M., Parkinson N., Siddiq A., Goddard P., Donovan S., Maslove D., Nichol A., Semple M. G., Zainy T., Maleady-Crowe F., Todd L., Salehi S., Knight J., Elgar G., Chan G., Arumugam P., Patch C., Rendon A., Bentley D., Kingsley C., Kosmicki J. A., Horowitz J. E., Baras A., Abecasis G. R., Ferreira M. A. R., Justice A., Mirshahi T., Oetjens M., Rader D. J., Ritchie M. D., Verma A., Fowler T. A., Shankar-Hari M., Summers C., Hinds C., Horby P., Ling L., McAuley D., Montgomery H., Openshaw P. J. M., Elliott P., Walsh T., Tenesa A., Shelton J. F., Shastri A. J., Ye C., Weldon C. H., Filshtein-Sonmez T., Coker D., Symons A., Esparza-Gordillo J., Aslibekyan S., Auton A., Pathak G. A., Karjalainen J., Stevens C., Andrews S. J., Kanai M., Cordioli M., Polimanti R., Pirinen M., Harerimana N., Veerapen K., Wolford B., Nguyen H., Solomonson M., Liao R. G., Chwialkowska K., Trankiem A., Balaconis M. K., Hayward C., Richmond A., Campbell A., Morris M., Fawns-Ritchie C., Glessner J. T., Shaw D. M., Chang X., Polikowski H., Petty L. E., Chen H. -H., Wanying Z., Hakonarson H., Porteous D. J., Below J., North K., McCormick J. B., Timmers P. R. H. J., Wilson J. F., D'Mellow K., Kerr S. M., Niemi M. E. K., Nkambul L., von Hohenstaufen K. A., Sobh A., Eltoukhy M. M., Yassen A. M., Hegazy M. A. F., Okasha K., Eid M. A., Moahmed H. S., Shahin D., El-Sherbiny Y. M., Elhadidy T. A., Abd Elghafar M. S., El-Jawhari J. J., Mohamed A. A. S., Elnagdy M. H., Samir A., Abdel-Aziz M., Khafaga W. T., El-Lawaty W. M., Torky M. S., El-shanshory M. R., Batini C., Lee P. H., Shrine N., Williams A. T., Tobin M. D., Guyatt A. L., John C., Packer R. J., Ali A., Free R. C., Wang X., Wain L. V., Hollox E. J., Venn L. D., Bee C. E., Adams E. L., Niavarani A., Sharififard B., Aliannejad R., Amirsavadkouhi A., Naderpour Z., Tadi H. A., Aleagha A. E., Ahmadi S., Moghaddam S. B. M., Adamsara A., Saeedi M., Abdollahi H., Hosseini A., Chariyavilaskul P., Chamnanphon M., Suttichet T. B., Shotelersuk V., Pongpanich M., Phokaew C., Chetruengchai W., Jantarabenjakul W., Putchareon O., Torvorapanit P., Puthanakit T., Suchartlikitwong P., Hirankarn N., Nilaratanakul V., Sodsai P., Brumpton B. M., Hveem K., Willer C., Zhou W., Rogne T., Solligard E., Asvold B. O., Abedalthagafi M., Alaamery M., Alqahtani S., Barakeh D., Al Harthi F., Alsolm E., Safieh L. A., Alowayn A. M., Alqubaishi F., Al Mutairi A., Mangul S., Alshareef A., Sawaji M., Almutairi M., Aljawini N., Albesher N., Arabi Y. M., Mahmoud E. S., Khattab A. K., Halawani R. T., Alahmadey Z. Z., Albakri J. K., Felemban W. A., Suliman B. A., Hasanato R., Al-Awdah L., Alghamdi J., AlZahrani D., AlJohani S., Al-Afghani H., Alrashed M., AlDhawi N., AlBardis H., Alkwai S., Alswailm M., Almalki F., Albeladi M., Almohammed I., Barhoush E., Albader A., Massadeh S., AlMalik A., Alotaibi S., Alghamdi B., Jung J., Fawzy M. S., Lee Y., Magnus P., Trogstad L. -I. S., Helgeland O., Harris J. R., Mangino M., Spector T. D., Duncan E., Smieszek S. P., Przychodzen B. P., Polymeropoulos C., Polymeropoulos V., Polymeropoulos M. H., Fernandez-Cadenas I., Perez-Tur J., Llucia-Carol L., Cullell N., Muino E., Carcel-Marquez J., DeDiego M. L., Iglesias L. L., Planas A. M., Soriano A., Rico V., Aguero D., Bedini J. L., Lozano F., Domingo C., Robles V., Ruiz-Jaen F., Marquez L., Gomez J., Coto E., Albaiceta G. M., Garcia-Clemente M., Dalmau D., Arranz M. J., Dietl B., Serra-Llovich A., Soler P., Colobran R., Martin-Nalda A., Martinez A. P., Bernardo D., Rojo S., Fiz-Lopez A., Arribas E., de la Cal-Sabater P., Segura T., Gonzalez-Villa E., Serrano-Heras G., Marti-Fabregas J., Jimenez-Xarrie E., de Felipe Mimbrera A., Masjuan J., Garcia-Madrona S., Dominguez-Mayoral A., Villalonga J. M., Menendez-Valladares P., Chasman D. I., Buring J. E., Ridker P. M., Franco G., Sesso H. D., Manson J. A. E., Glessner J. R., Medina-Gomez C., Uitterlinden A. G., Ikram M. A., Kristiansson K., Koskelainen S., Perola M., Donner K., Kivinen K., Palotie A., Ripatti S., Ruotsalainen S., Kaunisto M., Nakanishi T., Butler-Laporte G., Forgetta V., Morrison D. R., Ghosh B., Laurent L., Belisle A., Henry D., Abdullah T., Adeleye O., Mamlouk N., Kimchi N., Afrasiabi Z., Rezk N., Vulesevic B., Bouab M., Guzman C., Petitjean L., Tselios C., Xue X., Schurr E., Afilalo J., Afilalo M., Oliveira M., Brenner B., Lepage P., Ragoussis J., Auld D., Brassard N., Durand M., Chasse M., Kaufmann D. E., Lathrop G. M., Mooser V., Richards J. B., Li R., Adra D., Rahmouni S., Georges M., Moutschen M., Misset B., Darcis G., Guiot J., Guntz J., Azarzar S., Gofflot S., Beguin Y., Claassen S., Malaise O., Huynen P., Meuris C., Thys M., Jacques J., Leonard P., Frippiat F., Giot J. -B., Sauvage A. -S., von Frenckell C., Belhaj Y., Lambermont B., Pigazzini S., Nkambule L., Daya M., Shortt J., Rafaels N., Wicks S. J., Crooks K., Barnes K. C., Gignoux C. R., Chavan S., Laisk T., Lall K., Lepamets M., Magi R., Esko T., Reimann E., Milani L., Alavere H., Metsalu K., Puusepp M., Metspalu A., Naaber P., Laane E., Pesukova J., Peterson P., Kisand K., Tabri J., Allos R., Hensen K., Starkopf J., Ringmets I., Tamm A., Kallaste A., Bochud P. -Y., Rivolta C., Bibert S., Quinodoz M., Kamdar D., Boillat N., Nussle S. G., Albrich W., Suh N., Neofytos D., Erard V., Voide C., de Cid R., Galvan-Femenia I., Blay N., Carreras A., Cortes B., Farre X., Sumoy L., Moreno V., Mercader J. M., Guindo-Martinez M., Torrents D., Kogevinas M., Garcia-Aymerich J., Castano-Vinyals G., Dobano C., Renieri A., Mari F., Fallerini C., Daga S., Benetti E., Baldassarri M., Fava F., Frullanti E., Valentino F., Doddato G., Giliberti A., Tita R., Amitrano S., Bruttini M., Croci S., Meloni I., Mencarelli M. A., Rizzo C. L., Pinto A. M., Beligni G., Tommasi A., Di Sarno L., Palmieri M., Carriero M. L., Alaverdian D., Busani S., Bruno R., Vecchia M., Belli M. A., Picchiotti N., Sanarico M., Gori M., Furini S., Mantovani S., Ludovisi S., Mondelli M. U., Castelli F., Quiros-Roldan E., Antoni M. D., Zanella I., Vaghi M., Rusconi S., Siano M., Montagnani F., Emiliozzi A., Fabbiani M., Rossetti B., Bargagli E., Bergantini L., D'Alessandro M., Cameli P., Bennett D., Anedda F., Marcantonio S., Scolletta S., Franchi F., Mazzei M. A., Guerrini S., Conticini E., Cantarini L., Frediani B., Tacconi D., Spertilli C., Feri M., Donati A., Scala R., Guidelli L., Spargi G., Corridi M., Nencioni C., Croci L., Bandini M., Caldarelli G. P., Piacentini P., Desanctis E., Cappelli S., Canaccini A., Verzuri A., Anemoli V., Ognibene A., Pancrazzi A., Lorubbio M., D'Arminio Monforte A., Miraglia F. G., Girardis M., Venturelli S., Cossarizza A., Antinori A., Vergori A., Gabrieli A., Riva A., Francisci D., Schiaroli E., Paciosi F., Scotton P. G., Andretta F., Panese S., Scaggiante R., Gatti F., Parisi S. G., Baratti S., Della Monica M., Piscopo C., Capasso M., Russo R., Andolfo I., Iolascon A., Fiorentino G., Carella M., Castori M., Merla G., Squeo G. M., Aucella F., Raggi P., Marciano C., Perna R., Bassetti M., Di Biagio A., Sanguinetti M., Masucci L., Valente S., Mandala M., Giorli A., Salerni L., Zucchi P., Parravicini P., Menatti E., Trotta T., Giannattasio F., Coiro G., Lena F., Coviello D. A., Mussini C., Martinelli E., Mancarella S., Tavecchia L., Crotti L., Gabbi C., Rizzi M., Maggiolo F., Ripamonti D., Bachetti T., La Rovere M. T., Sarzi-Braga S., Bussotti M., Ceri S., Pinoli P., Raimondi F., Biscarini F., Stella A., Zguro K., Capitani K., Suardi C., Dei S., Parati G., Ravaglia S., Artuso R., Botta G., Di Domenico P., Rancan I., Perrella A., Bianchi F., Romani D., Bergomi P., Catena E., Colombo R., Tanfoni M., Vincenti A., Ferri C., Grassi D., Pessina G., Tumbarello M., Di Pietro M., Sabrina R., Luchi S., Barbieri C., Acquilini D., Andreucci E., Segala F. V., Tiseo G., Falcone M., Lista M., Poscente M., De Vivo O., Petrocelli P., Guarnaccia A., Baroni S., Smith A. V., Boughton A. P., Li K. W., LeFaive J., Annis A., Justice A. E., Chittoor G., Josyula N. S., Leader J. B., Carey D. J., Gass M. C., Cantor M. N., Yadav A., van Heel D. A., Hunt K. A., Mason D., Huang Q. Q., Finer S., Trivedi B., Griffiths C. J., Martin H. C., Wright J., Trembath R. C., Soranzo N., Zhao J. 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- Abstract
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
- Published
- 2022
3. A first update on mapping the human genetic architecture of COVID-19
- Author
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COVID-19 Host Genetics Initiative, Pathak, GA, Karjalainen, J, Stevens, C, Neale, BM, Daly, M, Ganna, A, Andrews, SJ, Kanai, M, Cordioli, M, Polimanti, R, Harerimana, N, Pirinen, M, Liao, RG, Chwialkowska, K, Trankiem, A, Balaconis, MK, Nguyen, H, Solomonson, M, Veerapen, K, Wolford, B, Roberts, G, Park, D, Ball, CA, Coignet, M, McCurdy, S, Knight, S, Partha, R, Rhead, B, Zhang, M, Berkowitz, N, Gaddis, M, Noto, K, Ruiz, L, Pavlovic, M, Hong, EL, Rand, K, Girshick, A, Guturu, H, Baltzell, AH, Niemi, MEK, Rahmouni, S, Guntz, J, Beguin, Y, Pigazzini, S, Nkambule, L, Georges, M, Moutschen, M, Misset, B, Darcis, G, Guiot, J, Azarzar, S, Gofflot, S, Claassen, S, Malaise, O, Huynen, P, Meuris, C, Thys, M, Jacques, J, Leonard, P, Frippiat, F, Giot, J-B, Sauvage, A-S, Frenckell, CV, Belhaj, Y, Lambermont, B, Nakanishi, T, Morrison, DR, Mooser, V, Richards, JB, Butler-Laporte, G, Forgetta, V, Li, R, Ghosh, B, Laurent, L, Belisle, A, Henry, D, Abdullah, T, Adeleye, O, Mamlouk, N, Kimchi, N, Afrasiabi, Z, Rezk, N, Vulesevic, B, Bouab, M, Guzman, C, Petitjean, L, Tselios, C, Xue, X, Afilalo, J, Afilalo, M, Oliveira, M, Brenner, B, Brassard, N, Durand, M, Schurr, E, Lepage, P, Ragoussis, J, Auld, D, Chassé, M, Kaufmann, DE, Lathrop, GM, Adra, D, Hayward, C, Glessner, JT, Shaw, DM, Campbell, A, Morris, M, Hakonarson, H, Porteous, DJ, Below, J, Richmond, A, Chang, X, Polikowski, H, Lauren, PE, Chen, H-H, Wanying, Z, Fawns-Ritchie, C, North, K, McCormick, JB, Glessner, JR, Gignoux, CR, Wicks, SJ, Crooks, K, Barnes, KC, Daya, M, Shortt, J, Rafaels, N, Chavan, S, Timmers, PRHJ, Wilson, JF, Tenesa, A, Kerr, SM, D’Mellow, K, Shahin, D, El-Sherbiny, YM, von Hohenstaufen, KA, Sobh, A, Eltoukhy, MM, Nkambul, L, Elhadidy, TA, Abd Elghafar, MS, El-Jawhari, JJ, Mohamed, AAS, Elnagdy, MH, Samir, A, Abdel-Aziz, M, Khafaga, WT, El-Lawaty, WM, Torky, MS, El-shanshory, MR, Yassen, AM, Hegazy, MAF, Okasha, K, Eid, MA, Moahmed, HS, Medina-Gomez, C, Ikram, MA, Uitterlinden, AG, Mägi, R, Milani, 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Giuseppe, Castori, Marco, Aucella, Filippo, Biagio, Antonio Di, Masucci, Luca, Valente, Serafina, Mandalà, Marco, Zucchi, Patrizia, Giannattasio, Ferdinando, Coviello, Domenico A., Mussini, Cristina, Tavecchia, Luisa, Crotti, Lia, Rizzi, Marco, Rovere, Maria Teresa La, Sarzi-Braga, Simona, Bussotti, Maurizio, Ravaglia, Sabrina, Artuso, Rosangela, Perrella, Antonio, Romani, Davide, Bergomi, Paola, Catena, Emanuele, Vincenti, Antonella, Ferri, Claudio, Grassi, Davide, Pessina, Gloria, Tumbarello, Mario, Pietro, Massimo Di, Sabrina, Ravaglia, Luchi, Sauro, Furini, Simone, Dei, Simona, Benetti, Elisa, Picchiotti, Nicola, Sanarico, Maurizio, Ceri, Stefano, Pinoli, Pietro, Raimondi, Francesco, Biscarini, Filippo, Stella, Alessandra, Zguro, Kristina, Capitani, Katia, Tanfoni, Marco, Fallerini, Chiara, Daga, Sergio, Baldassarri, Margherita, Fava, Francesca, Frullanti, Elisa, Valentino, Floriana, Doddato, Gabriella, Giliberti, Annarita, Tita, Rossella, Amitrano, Sara, Bruttini, Mirella, Croci, 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Andretta, Francesca, Gatti, Francesca, Parisi, Saverio Giuseppe, Baratti, Stefano, Piscopo, Carmelo, Russo, Roberta, Andolfo, Immacolata, Iolascon, Achille, Carella, Massimo, Merla, Giuseppe, Squeo, Gabriella Maria, Raggi, Pamela, Marciano, Carmen, Perna, Rita, Bassetti, Matteo, Sanguinetti, Maurizio, Giorli, Alessia, Salerni, Lorenzo, Parravicini, Pierpaolo, Menatti, Elisabetta, Trotta, Tullio, Coiro, Gabriella, Lena, Fabio, Martinelli, Enrico, Mancarella, Sandro, Gabbi, Chiara, Maggiolo, Franco, Ripamonti, Diego, Bachetti, Tiziana, Suardi, Claudia, Parati, Gianfranco, Bottà, Giordano, Domenico, Paolo Di, Rancan, Ilaria, Bianchi, Francesco, Colombo, Riccardo, Barbieri, Chiara, Acquilini, Donatella, Andreucci, Elena, Segala, Francesco Vladimiro, Tiseo, Giusy, Falcone, Marco, Lista, Mirjam, Poscente, Monica, Vivo, Oreste De, Petrocelli, Paola, Guarnaccia, Alessandra, Baroni, Silvia, van Heel, David A., Hunt, Karen A., Trembath, Richard C., Huang, Qin Qin, Martin, Hilary C., Mason, Dan, Trivedi, Bhavi, Wright, John, Finer, Sarah, Akhtar, Shaheen, Anwar, Mohammad, Arciero, Elena, Ashraf, Samina, Breen, Gerome, Chung, Raymond, Curtis, Charles J., Chowdhury, Maharun, Colligan, Grainne, Deloukas, Pano, Durham, Ceri, Griffiths, Chri, Hurles, Matt, Hussain, Shapna, Islam, Kamrul, Khan, Ahsan, Khan, Amara, Lavery, Cath, Lee, Sang Hyuck, Lerner, Robin, MacArthur, Daniel, MacLaughlin, Bev, Martin, Hilary, Miah, Shefa, Newman, Bill, Safa, Nishat, Tahmasebi, Farah, Griffiths, Christopher J., Smith, Albert V., Boughton, Andrew P., Li, Kevin W., LeFaive, Jonathon, Annis, Aubrey, Niavarani, Ahmadreza, Aliannejad, Rasoul, Sharififard, Bahareh, Amirsavadkouhi, Ali, Naderpour, Zeinab, Tadi, Hengameh Ansari, Aleagha, Afshar Etemadi, Ahmadi, Saeideh, Moghaddam, Seyed Behrooz Mohseni, Adamsara, Alireza, Saeedi, Morteza, Abdollahi, Hamed, Hosseini, Abdolmajid, Chariyavilaskul, Pajaree, Jantarabenjakul, Watsamon, Hirankarn, Nattiya, Chamnanphon, Monpat, Suttichet, Thitima B., Shotelersuk, Vorasuk, Pongpanich, Monnat, Phokaew, Chureerat, Chetruengchai, Wanna, Putchareon, Opa, Torvorapanit, Pattama, Puthanakit, Thanyawee, Suchartlikitwong, Pintip, Nilaratanakul, Voraphoj, Sodsai, Pimpayao, Brumpton, Ben M., Hveem, Kristian, Willer, Cristen, Zhou, Wei, Rogne, Tormod, Solligard, Erik, Åsvold, Bjørn Olav, Franke, Lude, Boezen, Marike, Deelen, Patrick, Claringbould, Annique, Lopera, Esteban, Warmerdam, Robert, Vonk, Judith. M., van Blokland, Irene, Lanting, Pauline, Ori, Anil P. S., Feng, Yen-Chen Anne, Mercader, Josep, Weiss, Scott T., Karlson, Elizabeth W., Smoller, Jordan W., Murphy, Shawn N., Meigs, James B., Woolley, Ann E., Green, Robert C., Perez, Emma F., Zöllner, Sebastian, Wang, Jiongming, Beck, Andrew, Sloofman, Laura G., Ascolillo, Steven, Sebra, Robert P., Collins, Brett L., Levy, Te, Buxbaum, Joseph D., Sealfon, Stuart C., Jordan, Daniel M., Thompson, Ryan C., Gettler, Kyle, Chaudhary, Kumardeep, Belbin, Gillian M., Preuss, Michael, Hoggart, Clive, Choi, Sam, Underwood, Slayton J., Salib, Irene, Britvan, Bari, Keller, Katherine, Tang, Lara, Peruggia, Michael, Hiester, Liam L., Niblo, Kristi, Aksentijevich, Alexandra, Labkowsky, Alexander, Karp, Avromie, Zlatopolsky, Menachem, Zyndorf, Marissa, Charney, Alexander W., Beckmann, Noam D., Schadt, Eric E., Abul-Husn, Noura S., Cho, Judy H., Itan, Yuval, Kenny, Eimear E., Loos, Ruth J. F., Nadkarni, Girish N., Do, Ron, O’Reilly, Paul, Huckins, Laura M., Ferreira, Manuel A. R., Abecasis, Goncalo R., Leader, Joseph B., Cantor, Michael N., Justice, Anne E., Carey, Dave J., Chittoor, Geetha, Josyula, Navya Shilpa, Kosmicki, Jack A., Horowitz, Julie E., Baras, Ari, Gass, Matthew C., Yadav, Ashish, Mirshahi, Tooraj, Hottenga, Jouke Jan, Bartels, Meike, de geus, Eco E. J. C., Nivard, Michel M. G., Verma, Anurag, Ritchie, Marylyn D., Rader, Daniel, Li, Binglan, Verma, Shefali S., Lucas, Anastasia, Bradford, Yuki, Abedalthagafi, Malak, Alaamery, Manal, Alshareef, Abdulraheem, Sawaji, Mona, Massadeh, Salam, AlMalik, Abdulaziz, Alqahtani, Saleh, Baraka, Dona, Harthi, Fawz Al, Alsolm, Ebtehal, Safieh, Leen Abu, Alowayn, Albandary M., Alqubaishi, Fatimah, Mutairi, Amal Al, Mangul, Serghei, Almutairi, Mansour, Aljawini, Nora, Albesher, Nour, Arabi, Yaseen M., Mahmoud, Ebrahim S., Khattab, Amin K., Halawani, Roaa T., Alahmadey, Ziab Z., Albakri, Jehad K., Felemban, Walaa A., Suliman, Bandar A., Hasanato, Rana, Al-Awdah, Laila, Alghamdi, Jahad, AlZahrani, Deema, AlJohani, Sameera, Al-Afghani, Hani, AlDhawi, Nouf, AlBardis, Hadeel, Alkwai, Sarah, Alswailm, Moneera, Almalki, Faisal, Albeladi, Maha, Almohammed, Iman, Barhoush, Eman, Albader, Anoud, Alotaibi, Sara, Alghamdi, Bader, Jung, Junghyun, fawzy, Mohammad S., Alrashed, May, Zeberg, Hugo, Nkambul, Lindo, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklo, Tardif, Nicola, Rooyackers, Olav, Grip, Jonathan, Maricic, Tomislav, Helgeland, Øyvind, Magnus, Per, Trogstad, Lill-Iren S., Lee, Yunsung, Harris, Jennifer R., Mangino, Massimo, Spector, Tim D., Emma, Duncan, Moutsianas, Louka, Caulfield, Mark J., Scott, Richard H., Kousathanas, Athanasio, Pasko, Dorota, Walker, Susan, Stuckey, Alex, Odhams, Christopher A., Rhodes, Daniel, Fowler, Tom, Rendon, Augusto, Chan, Georgia, Arumugam, Prabhu, Karczewski, Konrad J., Martin, Alicia R., Wilson, Daniel J., Spencer, Chris C. A., Crook, Derrick W., Wyllie, David H., O’Connell, Anne Marie, Atkinson, Elizabeth G., Tsuo, Kristin, Baya, Nikola, Turley, Patrick, Gupta, Rahul, Walters, Raymond K., Palmer, Duncan S., Sarma, Gopal, Cheng, Nathan, Lu, Wenhan, Churchhouse, Claire, Goldstein, Jacqueline I., King, Daniel, Seed, Cotton, Daly, Mark J., Finucane, Hilary, Bryant, Sam, Satterstrom, F. Kyle, Band, Gavin, Earle, Sarah G., Lin, Shang-Kuan, Arning, Nicola, Koelling, Nil, Armstrong, Jacob, Rudkin, Justine K., Callier, Shawneequa, Cusick, Caroline, Soranzo, Nicole, Zhao, Jing Hua, Danesh, John, Angelantonio, Emanuele Di, Butterworth, Adam S., Sun, Yan V., Huffman, Jennifer E., Cho, Kelly, O’Donnell, Christopher J., Tsao, Phil, Gaziano, J. Michael, Peloso, Gina, Ho, Yuk-Lam, Smieszek, Sandra P., Polymeropoulos, Christo, Polymeropoulos, Vasilio, Polymeropoulos, Mihael H., Przychodzen, Bartlomiej P., Fernandez-Cadenas, Israel, Planas, Anna M., Perez-Tur, Jordi, Llucià-Carol, Laia, Cullell, Natalia, Muiño, Elena, Cárcel-Márquez, Jara, DeDiego, Marta L., Iglesias, Lara Lloret, Soriano, Alex, Rico, Veronica, Agüero, Daiana, Bedini, Josep L., Lozano, Francisco, Domingo, Carlo, Robles, Veronica, Ruiz-Jaén, Francisca, Márquez, Leonardo, Gomez, Juan, Coto, Eliecer, Albaiceta, Guillermo M., García-Clemente, Marta, Dalmau, David, Arranz, Maria J., Dietl, Beatriz, Serra-Llovich, Alex, Soler, Pere, Colobrán, Roger, Martín-Nalda, Andrea, Martínez, Alba Parra, Bernardo, David, Rojo, Silvia, Fiz-López, Aida, Arribas, Elisa, de la Cal-Sabater, Paloma, Segura, Tomá, González-Villa, Esther, Serrano-Heras, Gemma, Martí-Fàbregas, Joan, Jiménez-Xarrié, Elena, de Felipe Mimbrera, Alicia, Masjuan, Jaime, García-Madrona, Sebastian, Domínguez-Mayoral, Anna, Villalonga, Joan Montaner, Menéndez-Valladares, Paloma, Chasman, Daniel I., Sesso, Howard D., Manson, JoAnn E., Buring, Julie E., Ridker, Paul M., Franco, Giulianini, Davis, Lea, Lee, Sulggi, Priest, Jame, Sankaran, Vijay G., van Heel, David, Biesecker, Le, Kerchberger, V. Eric, Baillie, J. Kenneth, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Biological Psychology, APH - Mental Health, AMS - Sports, AMS - Ageing & Vitality, APH - Methodology, Mccurdy, Shannon, Mccormick, Joseph B., Macarthur, Daniel, Maclaughlin, Bev, Lefaive, Jonathon, Almalik, Abdulaziz, Alzahrani, Deema, Aljohani, Sameera, Aldhawi, Nouf, Albardis, Hadeel, Fawzy, Mohammad S., Dediego, Marta L., Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), University of Zurich, COVID-19 Host Genetics Initiative, Barcelona Supercomputing Center, COVID-19 Genetics Initiative, including authors, Institute for Molecular Medicine Finland, and Data Science Genetic Epidemiology Lab
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Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC] ,Quantitative Trait Loci ,MUC5B PROMOTER POLYMORPHISM ,Genome-wide association studies ,COVID-19 (Malaltia) ,UFSP13-7 Evolution in Action: From Genomes to Ecosystems ,COVID-19 (Disease) ,Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA ,SDG 3 - Good Health and Well-being ,Humans ,genetics ,Genetic variation ,Genomes ,Medicinsk genetik ,1000 Multidisciplinary ,Multidisciplinary ,Chromosome Mapping ,COVID-19 ,Human Genetics ,10124 Institute of Molecular Life Sciences ,covid-19 ,3121 General medicine, internal medicine and other clinical medicine ,570 Life sciences ,biology ,Medical Genetics - Abstract
Matters arising from: Mapping the human genetic architecture of COVID-19 Original Article published on 08 July 2021 https://www.nature.com/articles/s41586-021-03767-x The COVID-19 pandemic continues to pose a major public health threat, especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity, we formed the COVID-19 Host Genetics Initiative1. Here we present a genome-wide association study meta-analysis of up to 125,584 cases and over 2.5 million control individuals across 60 studies from 25 countries, adding 11 genome-wide significant loci compared with those previously identified2. Genes at new loci, including SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity. Here we present meta-analyses bringing together 60 studies from 25 countries (Fig. 1 and Supplementary Table 1) for three COVID-19-related phenotypes: (1) individuals critically ill with COVID-19 on the basis of requiring respiratory support in hospital or who died as a consequence of the disease (9,376 cases, of which 3,197 are new in this data release, and 1,776,645 control individuals); (2) individuals with moderate or severe COVID-19 defined as those hospitalized due to symptoms associated with the infection (25,027 cases, 11,386 new and 2,836,272 control individuals); and (3) all cases with reported SARS-CoV-2 infection regardless of symptoms (125,584 cases, 76,022 new and 2,575,347 control individuals). Most studies have reported results before the roll out of the COVID-19 vaccination campaign. An overview of the study design is provided in Supplementary Fig. 1. We found a total of 23 genome-wide significant loci (P
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- 2022
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4. Whole genome sequencing reveals host factors underlying critical Covid-19
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Kousathanas, A., Pairo-Castineira, E., Rawlik, K., Stuckey, A., Odhams, C. A., Walker, S., Russell, C. D., Malinauskas, T., Wu, Y., Millar, J., Shen, X., Elliott, K. S., Griffiths, F., Oosthuyzen, W., Morrice, K., Keating, S., Wang, B., Rhodes, D., Klaric, L., Zechner, M., Parkinson, N., Siddiq, A., Goddard, P., Donovan, S., Maslove, D., Nichol, A., Semple, M. G., Zainy, T., Maleady-Crowe, F., Todd, L., Salehi, S., Knight, J., Elgar, G., Chan, G., Arumugam, P., Patch, C., Rendon, A., Bentley, D., Kingsley, C., Kosmicki, J. A., Horowitz, J. E., Baras, A., Abecasis, G. R., Ferreira, M. A. R., Justice, A., Mirshahi, T., Oetjens, M., Rader, D. J., Ritchie, M. D., Verma, A., Fowler, T. A., Shankar-Hari, M., Summers, C., Hinds, C., Horby, P., Mcauley, D., Montgomery, H., Openshaw, P. J. M., Elliott, P., Walsh, T., Tenesa, A., Fawkes, A., Murphy, L., Rowan, K., Ponting, C. P., Vitart, V., Wilson, J. F., Yang, J., Bretherick, A. D., Scott, R. H., Hendry, S. C., Moutsianas, L., Law, A., Caulfield, M. J., Baillie, J. K., Begg, C., Ling, L., Pereira, A. C., Aravindan, L., Armstrong, R., Biggs, H., Boz, C., Brown, A., Clark, R., Coutts, A., Coyle, J., Cullum, L., Das, S., Day, N., Donnelly, L., Duncan, E., Finernan, P., Fourman, M. H., Furlong, A., Furniss, J., Gallagher, B., Gilchrist, T., Golightly, A., Hafezi, K., Hamilton, D., Hendry, R., Law, D., Law, R., Law, S., Lidstone-Scott, R., Macgillivray, L., Maclean, A., Mal, H., Mccafferty, S., Mcmaster, E., Meikle, J., Moore, S. C., Murphy, S., Hellen, M., Zheng, C., Chen, J., Paterson, T., Schon, K., Stenhouse, A., Das, M., Swets, M., Szoor-McElhinney, H., Taneski, F., Turtle, L., Wackett, T., Ward, M., Weaver, J., Wrobel, N., Arbane, G., Bociek, A., Campos, S., Grau, N., Jones, T. O., Lim, R., Marotti, M., Ostermann, M., Whitton, C., Alldis, Z., Astin-Chamberlain, R., Bibi, F., Biddle, J., Blow, S., Bolton, M., Borra, C., Bowles, R., Burton, M., Choudhury, Y., Collier, D., Cox, A., Easthope, A., Ebano, P., Fotiadis, S., Gurasashvili, J., Halls, R., Hartridge, P., Kallon, D., Kassam, J., Lancoma-Malcolm, I., Matharu, M., May, P., Mitchelmore, O., Newman, T., Patel, M., Pheby, J., Pinzuti, I., Prime, Z., Prysyazhna, O., Shiel, J., Taylor, M., Tierney, C., Wood, S., Zak, A., Zongo, O., Bonner, S., Hugill, K., Jones, J., Liggett, S., Headlam, E., Bandla, N., Gellamucho, M., Davies, M., Thompson, C., Abdelrazik, M., Bakthavatsalam, D., Elhassan, M., Ganesan, A., Haldeos, A., Moreno-Cuesta, J., Purohit, D., Vincent, R., Xavier, K., Kumar, R., Frater, Alessia, Saleem, M., Carter, D., Jenkins, S., Lamond, Z., Wall, A., Fernandez-Roman, J., Hamilton, D. O., Johnson, E., Johnston, B., Martinez Guzman, Maria Loreto, Mulla, S., Shaw, D., Waite, A. A. C., Waugh, V., Welters, I. D., Williams, K., Cavazza, A., Cockrell, M., Corcoran, E., Depante, M., Finney, C., Jerome, E., Mcphail, M., Nayak, M., Noble, H., O'Reilly, K., Pappa, E., Saha, R., Saha, S., Smith, Jenovia Amisti, Knighton, A., Antcliffe, D., Banach, D., Brett, S., Coghlan, P., Fernandez, Z., Gordon, A., Rojo, R., Arias, S. S., Templeton, M., Meredith, M., Morris, L., Ryan, L., Clark, A., Sampson, J., Peters, C., Dent, M., Langley, M., Ashraf, Sana, Wei, S., Andrew, A., Bashyal, A., Davidson, N., Hutton, P., Mckechnie, S., Wilson, J., Baptista, D., Crowe, R., Fernandes, R., Herdman-Grant, R., Joseph, A., O'Connor, D., Allen, M., Loveridge, A., Mckenley, I., Morino, E., Naranjo, A., Simms, R., Sollesta, K., Swain, A., Venkatesh, H., Khera, J., Fox, J., Andrew, G., Barclay, L., Callaghan, M., Campbell, R., Clark, S., Hope, D., Marshall, L., Mcculloch, C., Briton, K., Singleton, J., Birch, S., Brimfield, L., Daly, Z., Pogson, D., Rose, S., Nown, A., Battle, C., Brinkworth, E., Harford, R., Murphy, C., Newey, L., Rees, T., Williams, M., Arnold, S., Polgarova, P., Stroud, K., Meaney, E., Jones, M., Ng, A., Agrawal, S., Pathan, N., White, D., Daubney, E., Elston, K., Grauslyte, L., Hussain, M., Phull, M., Pogreban, T., Rosaroso, L., Salciute, E., Franke, G., Wong, J., George, A., de Gordoa, L. O. -R., Peasgood, E., Phillips, C., Bates, M., Dasgin, J., Gill, J., Nilsson, A., Scriven, J., Collins, A., Khaliq, W., Gude, E. T., Delgado, C. C., Dawson, D., Ding, L., Durrant, G., Ezeobu, O., Farnell-Ward, S., Harrison, A., Kanu, R., Leaver, S., Maccacari, E., Manna, S., Saluzzio, R. P., Queiroz, J., Samakomva, T., Sicat, C., Texeira, J., Da Gloria, E. F., Lisboa, A., Rawlins, J., Mathew, J., Kinch, A., Hurt, W. J., Shah, N., Clark, V., Thanasi, M., Yun, N., Patel, K., Bennett, S., Goodwin, E., Jackson, M., Kent, A., Tibke, C., Woodyatt, W., Zaki, A., Abraheem, A., Bamford, P., Cawley, K., Dunmore, C., Faulkner, M., Girach, R., Jeffrey, H., Jones, R., London, E., Nagra, I., Nasir, F., Sainsbury, H., Smedley, C., Patel, T., Smith, M., Chukkambotla, S., Kazi, A., Hartley, J., Dykes, J., Hijazi, M., Keith, S., Khan, M., Ryan-Smith, J., Springle, P., Thomas, J., Truman, N., Saad, S., Coleman, D., Fine, C., Matt, R., Gay, B., Dalziel, J., Ali, S., Goodchild, D., Harling, R., Bhatterjee, R., Goddard, W., Davison, C., Duberly, S., Hargreaves, J., Bolton, R., Davey, M., Golden, D., Seaman, R., Cherian, S., Cutler, S., Heron, A. E., Roynon-Reed, A., Szakmany, T., Williams, G., Richards, O., Cheema, Y., Brooke, H., Buckley, S., Suarez, J. C., Charlesworth, R., Hansson, K., Norris, J., Poole, A., Rose, A., Sandhu, R., Sloan, B., Smithson, E., Thirumaran, M., Wagstaff, V., Metcalfe, A., Brunton, M., Caterson, J., Coles, H., Frise, M., Rai, S. G., Jacques, N., Keating, L., Tilney, E., Bartley, S., Bhuie, P., Gibson, S., Lyle, A., Mcneela, F., Radhakrishnan, J., Hughes, A., Yates, B., Reynolds, J., Campbell, H., Thompsom, M., Dodds, S., Duffy, S., Greer, S., Shuker, K., Tridente, A., Khade, R., Sundar, A., Tsinaslanidis, G., Birkinshaw, I., Carter, J., Howard, K., Ingham, J., Joy, R., Pearson, H., Roche, S., Scott, Z., Bancroft, H., Bellamy, M., Carmody, M., Daglish, J., Moore, F., Rhodes, J., Sangombe, M., Kadiri, S., Croft, M., White, I., Frost, V., Aquino, M., Jha, R., Krishnamurthy, V., Lim, L., Combes, E., Joefield, T., Monnery, S., Beech, V., Trotman, S., Christine, Almaden-Boyle, Austin, P., Cabrelli, L., Cole, S., Casey, M., Chapman, S., Whyte, C., Baird, Y., Butler, A., Chadbourn, I., Folkes, L., Fox, H., Gardner, A., Gomez, R., Hobden, G., Hodgson, L., King, K., Margarson, M., Martindale, T., Meadows, E., Raynard, D., Thirlwall, Y., Helm, D., Margalef, J., Criste, K., Cusack, R., Golder, K., Golding, H., Jones, O., Leggett, S., Male, M., Marani, M., Prager, K., Williams, T., Roberts, B., Salmon, K., Anderson, P., Archer, K., Austin, K., Davis, C., Durie, A., Kelsall, O., Thrush, J., Vigurs, C., Wild, L., Wood, H. -L., Tranter, H., Cowley, N., Mcalindon, M., Burtenshaw, A., Digby, S., Low, E., Morgan, A., Cother, N., Rankin, T., Clayton, S., Mccurdy, A., Ahmed, C., Baines, B., Clamp, S., Colley, J., Haq, R., Hayes, A., Hulme, J., Hussain, S., Joseph, S., Maqsood, Z., Purewal, M., Benham, L., Bradshaw, Z., Brown, J., Caswell, M., Cupitt, J., Melling, S., Preston, S., Slawson, N., Stoddard, E., Warden, S., Deacon, B., Lynch, C., Pothecary, C., Roche, L., Howe, G. S., Singh, Jaywant, Turner, K., Ellis, H., Stroud, N., Hunt, J., Dearden, J., Dobson, E., Drummond, A., Mulcahy, M., Munt, S., O'Connor, G., Philbin, J., Rishton, C., Tully, R., Winnard, S., Cathcart, S., Duffy, K., Puxty, A., Puxty, K., Turner, L., Ireland, J., Semple, G., Long, K., Whiteley, S., Wilby, E., Ogg, B., Cowton, A., Kay, Abigail, Kent, M., Potts, K., Wilkinson, A., Campbell, S., Brown, E., Melville, J., Naisbitt, J., Joseph, R., Lazo, M., Walton, O., Neal, A., Alexander, P., Allen, S., Bradley-Potts, J., Brantwood, C., Egan, J., Felton, T., Padden, G., Ward, L., Moss, S., Glasgow, S., Abel, L., Brett, M., Digby, B., Gemmell, L., Hornsby, J., Macgoey, P., O'Neil, P., Price, R., Rodden, N., Rooney, K., Sundaram, R., Thomson, N., Hopkins, B., Thrasyvoulou, L., Willis, H., Clark, M., Coulding, M., Jude, E., Mccormick, J., Mercer, O., Potla, D., Rehman, H., Savill, H., Turner, V., Downes, C., Holding, K., Riches, K., Hilton, M., Hayman, M., Subramanian, D., Daniel, P., Adanini, O., Bhatia, N., Msiska, M., Collins, R., Clement, I., Patel, B., Gulati, A., Hays, C., Webster, K., Hudson, A., Webster, A., Stephenson, E., Mccormack, L., Slater, V., Nixon, R., Hanson, H., Fearby, M., Kelly, S., Bridgett, V., Robinson, P., Camsooksai, J., Humphrey, C., Reschreiter, H., Wadams, B., Death, Y., Bastion, V., Clarke, D., David, B., Kent, H., Lorusso, Riccardo, Lubimbi, G., Murdoch, S., Penacerrada, M., Thomas, A., Valentine, J., Vochin, A., Wulandari, R., Djeugam, B., Bell, G., English, K., Katary, A., Wilcox, L., Bruce, M., Connolly, K., Duncan, T., Michael, H. T., Lindergard, G., Hey, S., Fox, C., Alfonso, J., Durrans, L. J., Guerin, J., Blackledge, B., Harris, J., Hruska, M., Eltayeb, A., Lamb, T., Hodgkiss, T., Cooper, L., Rothwell, J., Allan, A., Anderson, F., Kaye, C., Liew, J., Medhora, J., Scott, T., Trumper, E., Botello, A., Lankester, L., Nikitas, N., Wells, C., Stowe, B., Spencer, K., Brandwood, C., Smith, L., Birchall, K., Kolakaluri, L., Baines, D., Sukumaran, A., Apetri, E., Basikolo, C., Catlow, L., Charles, B., Dark, P., Doonan, R., Harvey, A., Horner, D., Knowles, K., Lee, S., Lomas, D., Lyons, C., Marsden, T., Mclaughlan, D., Mcmorrow, L., Pendlebury, J., Perez, J., Poulaka, M., Proudfoot, N., Slaughter, M., Slevin, K., Thomas, V., Walker, D., Michael, A., Collis, M., Cosier, T., Millen, G., Richardson, N., Schumacher, N., Weston, H., Rand, J., Baxter, N., Henderson, S., Kennedy-Hay, S., Mcparland, C., Rooney, L., Sim, M., Mccreath, G., Akeroyd, L., Bano, S., Bromley, M., Gurr, L., Lawton, T., Morgan, J., Sellick, K., Warren, D., Wilkinson, B., Mcgowan, J., Ledgard, C., Stacey, A., Pye, K., Bellwood, R., Bentley, M., Bewley, J., Garland, Z., Grimmer, L., Gumbrill, B., Johnson, R., Sweet, K., Webster, D., Efford, G., Convery, K., Fottrell-Gould, D., Hudig, L., Keshet-Price, J., Randell, G., Stammers, K., Bokhari, M., Linnett, V., Lucas, R., Mccormick, W., Ritzema, J., Sanderson, A., Wild, H., Rostron, A., Roy, A., Woods, L., Cornell, S., Wakinshaw, F., Rogerson, K., Jarmain, J., Parker, R., Reddy, A., Turner-Bone, I., Harding, P., Abernathy, C., Foster, L., Gratrix, A., Martinson, V., Parkinson, P., Stones, E., Carbral-Ortega, L., Bercades, G., Brealey, D., Hass, I., Maccallum, N., Martir, G., Raith, E., Reyes, A., Smyth, D., Zitter, L., Benyon, S., Marriott, S., Park, L., Keenan, S., Gordon, E., Quinn, H., Baines, K., Cagova, L., Fofano, A., Garner, L., Holcombe, H., Mepham, S., Mitchell, A. M., Mwaura, L., Praman, K., Vuylsteke, A., Zamikula, J., Purewal, B., Rivers, V., Bell, S., Blakemore, H., Borislavova, B., Faulkner, B., Gendall, E., Goff, E., Hayes, K., Thomas, M., Worner, R., Smith, K., Stephens, D., Mew, L., Mwaura, E., Stewart, R., Williams, F., Wren, L., Sutherland, S. -B., Bevan, E., Martin, J., Trodd, D., Watson, G., Brown, C. W., Akinkugbe, O., Bamford, A., Beech, E., Belfield, H., Bell, M., Davies, C., Jones, G. A. L., Mchugh, T., Meghari, H., O'Neill, L., Peters, M. J., Ray, S., Tomas, A. L., Burn, I., Hambrook, G., Manso, K., Penn, R., Shanmugasundaram, P., Tebbutt, J., Thornton, D., Cole, J., Davies, R., Duffin, D., Hill, H., Player, B., Thomas, E., Williams, A., Griffin, D., Muchenje, N., Mupudzi, M., Partridge, R., Conyngham, J. -A., Thomas, R., Wright, M., Corral, M. A., Jacob, R., Jones, C., Denmade, C., Beavis, S., Dale, K., Gascoyne, R., Hawes, J., Pritchard, K., Stevenson, L., Whileman, A., Doble, P., Hutter, J., Pawley, C., Shovelton, C., Vaida, M., Butcher, D., O'Sullivan, S., Butterworth-Cowin, N., Ahmad, N., Barker, J., Bauchmuller, K., Bird, S., Cawthron, K., Harrington, K., Jackson, Y., Kibutu, F., Lenagh, B., Masuko, S., Mills, G. H., Raithatha, A., Wiles, M., Willson, J., Newell, H., Lye, A., Nwafor, L., Jarman, C., Rowland-Jones, S., Foote, D., Thompson, R., Watson, J., Hesseldon, L., Macharia, I., Chetam, L., Ford, A., Anderson, S., Housley, K., Milner, L., Hanratty, H., Trower, H., Phillips, P., Oxspring, S., Donne, B., Jardine, C., Williams, D., Hay, A., Flanagan, R., Hughes, G., Latham, S., Mckenna, E., Anderson, J., Hull, R., Rhead, K., Cruz, C., Pattison, N., Charnock, R., Mcfarland, D., Cosgrove, D., Ahmed, A., Morris, A., Jakkula, S., Nune, A., Ali, Amjad, Brady, M., Dale, S., Dance, A., Gledhill, L., Greig, J., Hanson, K., Holdroyd, K., Home, M., Kelly, D., Kitson, R., Matapure, L., Melia, D., Mellor, S., Nortcliffe, T., Pinnell, J., Robinson, M., Shaw, L., Shaw, R., Thomis, L., Wilson, A., Wood, T., Bayo, L. -A., Merwaha, E., Ishaq, T., Hanley, S., Hibbert, M., Tetla, D., Woodford, C., Durga, L., Kennard-Holden, G., Branney, D., Frankham, J., Pitts, S., White, N., Laha, S., Verlander, M., Altabaibeh, A., Alvaro, A., Gilbert, K., Ma, L., Mostoles, L., Parmar, C., Simpson, K., Jetha, C., Booker, L., Pratley, A., Adams, C., Agasou, A., Arden, T., Bowes, A., Boyle, P., Beekes, M., Button, H., Capps, N., Carnahan, M., Carter, A., Childs, D., Donaldson, D., Hard, K., Hurford, F., Hussain, Y., Javaid, A., Jose, S., Leigh, M., Martin, T., Millward, H., Motherwell, N., Rikunenko, R., Stickley, J., Summers, J., Ting, L., Tivenan, H., Tonks, L., Wilcox, R., Skinner, D., Gaylard, J., Mullan, D., Newman, J., Holland, M., Keenan, N., Lyons, M., Wassall, H., Marsh, C., Mahenthran, M., Carter, E., Kong, T., Blackman, H., Creagh-Brown, B., Donlon, S., Michalak-Glinska, N., Mtuwa, S., Pristopan, V., Salberg, A., Smith, E., Stone, S., Piercy, C., Verula, J., Burda, D., Montaser, R., Harden, L., Mayangao, I., Marriott, C., Bradley, P., Harris, C., Andrews, E., Birch, J., Collins, E., Hammerton, K., O'Leary, R., Purvis, S., Barber, R., Hewitt, C., Hilldrith, A., Jackson-Lawrence, K., Shepardson, S., Wills, M., Butler, S., Tavares, S., Cunningham, A., Hindale, J., Arif, S., Bean, S., Burt, K., Spivey, M., Demetriou, C., Eckbad, C., Hierons, S., Howie, L., Mitchard, S., Ramos, L., Serrano-Ruiz, A., White, K., Kelly, F., Cristiano, D., Dormand, N., Farzad, Z., Gummadi, M., Liyanage, K., Salmi, S., Sloane, G., Thwaites, V., Varghese, M., Zborowski, A. C., Allan, J., Geary, T., Houston, G., Meikle, A., O'Brien, P., Forsey, M., Kaliappan, A., Nicholson, A., Riches, J., Vertue, M., Allan, E., Darlington, K., Davies, F., Easton, J., Kumar, S., Lean, R., Menzies, D., Pugh, R., Qiu, X., Davies, L., Williams, John Harford, Scanlon, J., Davies, G., Mackay, C., Lewis, J., Rees, S., Oblak, M., Popescu, M., Thankachen, M., Higham, A., Craig, J., Baruah, R., Morris, S., Ferguson, S., Shepherd, A., Moore, L. S. P., Vizcaychipi, M. P., de Almeida Martins, L. G., Carungcong, J., Ali, I. A. M., Beaumont, K., Blunt, M., Coton, Z., Curgenven, H., Elsaadany, M., Fernandes, K., Ally, S. M., Rangarajan, H., Sarathy, V., Selvanayagam, S., Vedage, D., White, M., Gill, M., Paul, P., Ratnam, V., Shelton, S., Wynter, I., Carmody, S., Page, V. J., Beith, C. M., Black, K., Clements, S., Morrison, A., Strachan, D., Clarkson, M., D'Sylva, S., Norman, K., Auld, F., Donnachie, J., Edmond, I., Prentice, L., Runciman, N., Salutous, D., Symon, L., Todd, A., Turner, P., Short, A., Sweeney, L., Murdoch, E., Senaratne, D., Hill, M., Kannan, T., Crawley, R., Crew, A., Cunningham, M., Daniels, A., Harrison, L., Hope, S., Inweregbu, K., Jones, S., Lancaster, N., Matthews, J., Wray, G., Langton, H., Prout, R., Watters, M., Novis, C., Barron, A., Collins, C., Kaul, S., Passmore, H., Prendergast, C., Reed, A., Rogers, P., Shokkar, R., Woodruff, M., Middleton, H., Polgar, O., Nolan, C., Mahay, K., Hormis, A., Maynard, V., Graham, C., Walker, R., Knights, E., Price, A., Thorpe, C., Behan, T., Burnett, C., Hatton, J., Heeney, E., Mitra, A., Newton, M., Pollard, R., Stead, R., Amin, V., Anastasescu, E., Anumakonda, V., Karthik, K., Kausar, R., Reid, K., Imeson-Wood, J., Crickmore, V., Debreceni, G., Wilkins, J., Nicol, L., Reece-Anthony, R., Birt, M., Ghosh, A., Williams, E., Allen, L., Beranova, E., Crisp, N., Deery, J., Hazelton, T., Knight, A., Price, C., Tilbey, S., Turki, S., Turney, S., Cooper, J., Finch, C., Liderth, S., Quinn, A., Waddington, N., Coventry, T., Fowler, S., Macmahon, M., Mcgregor, A., Cowley, A., Highgate, J., Gregory, J., O'Connell, S., Smith, T., Barberis, Lorenzo, Gopal, S., Harris, N., Lake, V., Metherell, S., Radford, E., Daniel, A., Finn, J., Donnison, P., Trim, F., Eapen, B., Bough, L., Goodsell, J., Tutton, R., Williams, P., Williams, S., Winter-Goodwin, B., Brickell, K., Smyth, M., Coetzee, S., Gales, A., Raj, M., Sell, C., Hilltout, P., Evitts, J., Tyler, A., Waldron, J., Beesley, K., Board, S., Kubisz-Pudelko, A., Lewis, A., Perry, J., Pippard, L., Wood, Dawn, Buckley, C., Barry, P., Flint, N., Rekha, P., Hales, D., Bunni, L., Jennings, C., Latif, Marco, Marshall, R., Subramanian, G., Mcguigan, P. J., Wasson, C., Finn, Stephen Edward, Green, J., King, B., Campbell, A., Smuts, S., Duffield, J., Smith, O., Mallon, L., Watkins, C., Botfield, L., Butler, J., Dexter, C., Fletcher, J., Garg, A., Kuravi, A., Ranga, P., Virgilio, E., Belagodu, Z., Fuller, B., Gherman, A., Olufuwa, O., Paramsothy, R., Stuart, C., Oakley, N., Kamundi, C., Tyl, D., Collins, K., Silva, P., Taylor, J., King, L., Coates, C., Crowley, M., Wakefield, P., Beadle, J., Johnson, L., Sargeant, J., Anderson, M., Brady, A., Chan, R., Little, J., Mcivor, S., Prady, H., Whittle, H., Mathew, B., Attwood, B., Parsons, P., Ward, G., Bremmer, P., Joe, W., Tracy, B., Jim, R., Davies, E., Sathe, S., Dennis, C., Parris, V., Srikaran, S., Sukha, A., Clarke, N., Whiteside, J., Mascarenhas, M., Donaldson, A., Matheson, J., Barrett, F., O'Hara, M., Okeefe, L., Bradley, C., Eastgate-Jackson, C., Filipe, H., Martin, D., Maharajh, A., Garcia, S. M., Pakou, G., De Neef, M., Dent, K., Horsley, E., Akhtar, M. N., Pearson, S., Potoczna, D., Spencer, S., Clapham, M., Harper, R., Poultney, U., Rice, P., Mutch, R., Armstrong, L., Bates, H., Dooks, E., Farquhar, F., Hairsine, B., Packham, S., Bi, R., Scholefield, B., Ashton, L., George, L., Twiss, S., Wright, D., Chablani, M., Kirkby, A., Netherton, K., Davies, K., O'Brien, L., Omar, Z., Otahal, I., Perkins, E., Lewis, T., Sutherland, I., Burns, K., Chandler, B., Elliott, K., Mallinson, J., Turnbull, A., Gondo, P., Hadebe, B., Kayani, A., Masunda, B., Anderson, T., Hawcutt, D., O'Malley, L., Rad, L., Rogers, N., Saunderson, P., Allison, K. S., Afolabi, D., Whitbread, J., Jones, D., Dore, R., Halkes, M., Mercer, P., Thornton, L., Dawson, J., Garrioch, S., Tolson, M., Aldridge, J., Kapoor, R., Loader, D., Castle, K., Humphreys, S., Tampsett, R., Mackintosh, K., Ayers, A., Harrison, W., North, J., Allibone, S., Genetu, R., Kasipandian, V., Patel, A., Mac, A., Murphy, A., Mahjoob, P., Nazari, R., Worsley, L., Fagan, A., Bemand, T., Black, E., Rosa, A. D., Howle, R., Jhanji, S., Baikady, R. R., Tatham, K. C., Thomas, B., Bell, D., Boyle, R., Douglas, K., Glass, L., Lee, E., Lennon, L., Rattray, A., Taylor, Anita, Hughes, R. 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D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Bandini, M, Caldarelli, G, Piacentini, P, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Pancrazzi, A, Lorubbio, M, D'Arminio Monforte, A, Miraglia, F, Girardis, M, Venturelli, S, Cossarizza, A, Antinori, A, Vergori, A, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Scotton, P, Andretta, F, Panese, S, Scaggiante, R, Gatti, F, Parisi, S, Baratti, S, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Squeo, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Martinelli, E, Mancarella, S, Tavecchia, L, Crotti, L, Gabbi, C, Rizzi, M, Maggiolo, F, Ripamonti, D, Bachetti, T, La Rovere, M, Sarzi-Braga, S, Bussotti, M, Ceri, S, Pinoli, P, Raimondi, F, Biscarini, F, Stella, A, Zguro, K, Capitani, K, Suardi, C, Dei, S, Parati, G, Ravaglia, S, Artuso, R, Botta, G, Di Domenico, P, Rancan, I, Perrella, A, Bianchi, F, Romani, D, Bergomi, P, Catena, E, Colombo, R, Tanfoni, M, Vincenti, A, Ferri, C, Grassi, D, Pessina, G, Tumbarello, M, Di Pietro, M, Sabrina, R, Luchi, S, Barbieri, C, Acquilini, D, Andreucci, E, Segala, F, Tiseo, G, Falcone, M, Lista, M, Poscente, M, De Vivo, O, Petrocelli, P, Guarnaccia, A, Baroni, S, Smith, A, Boughton, A, Li, K, Lefaive, J, Annis, A, Chittoor, G, Josyula, N, Leader, J, Carey, D, Gass, M, Cantor, M, Yadav, A, van Heel, D, Hunt, K, Mason, D, Huang, Q, Finer, S, Trivedi, B, Griffiths, C, Martin, H, Wright, J, Trembath, R, Soranzo, N, Zhao, J, Butterworth, A, Danesh, J, Di Angelantonio, E, Franke, L, Boezen, M, Deelen, P, Claringbould, A, Lopera, E, Warmerdam, R, Vonk, J, van Blokland, I, Lanting, P, Ori, A, Zollner, S, Wang, J, Beck, A, Peloso, G, Ho, Y, Sun, Y, Huffman, J, O'Donnell, C, Cho, K, Tsao, P, Gaziano, J, Nivard, M, de Geus, E, Bartels, M, Jan Hottenga, J, Weiss, S, Karlson, E, Smoller, J, Green, R, Feng, Y, Murphy, S, Meigs, J, Woolley, A, Perez, E, Li, B, Verma, S, Lucas, A, Bradford, Y, Zeberg, H, Frithiof, R, Hultstrom, M, Lipcsey, M, Tardif, N, Rooyackers, O, Grip, J, Maricic, T, Karczewski, K, Atkinson, E, Tsuo, K, Baya, N, Turley, P, Gupta, R, Callier, S, Walters, R, Palmer, D, Sarma, G, Cheng, N, Lu, W, Bryant, S, Churchhouse, C, Cusick, C, Goldstein, J, King, D, Seed, C, Finucane, H, Martin, A, Satterstrom, F, Wilson, D, Armstrong, J, Rudkin, J, Band, G, Earle, S, Lin, S, Arning, N, Crook, D, Wyllie, D, O'Connell, A, Spencer, C, Koelling, N, Caulfield, M, Scott, R, Moutsianas, L, Pasko, D, Ball, C, Hong, E, Rand, K, Girshick, A, Guturu, H, Baltzell, A, Roberts, G, Park, D, Coignet, M, Mccurdy, S, Knight, S, Partha, R, Rhead, B, Zhang, M, Berkowitz, N, Gaddis, M, Noto, K, Ruiz, L, Pavlovic, M, Sloofman, L, Charney, A, Beckmann, N, Schadt, E, Jordan, D, Thompson, R, Gettler, K, Abul-Husn, N, Ascolillo, S, Buxbaum, J, Chaudhary, K, Cho, J, Itan, Y, Kenny, E, Belbin, G, Sealfon, S, Sebra, R, Salib, I, Collins, B, Levy, T, Britvan, B, Keller, K, Tang, L, Peruggia, M, Hiester, L, Niblo, K, Aksentijevich, A, Labkowsky, A, Karp, A, Zlatopolsky, M, Preuss, M, Loos, R, Nadkarni, G, Do, R, Hoggart, C, Choi, S, Underwood, S, O'Reilly, P, Huckins, L, Zyndorf, M, Daly, M, Neale, B, Ganna, A, Fawkes, A, Murphy, L, Rowan, K, Ponting, C, Vitart, V, Yang, J, Bretherick, A, Hendry, S, Law, A, Baillie, J, Kousathanas, Athanasios [0000-0001-6265-6521], Pairo-Castineira, Erola [0000-0002-2423-3090], Rawlik, Konrad [0000-0002-0010-370X], Walker, Susan [0000-0002-5016-6426], Malinauskas, Tomas [0000-0002-4847-5529], Wu, Yang [0000-0002-0128-7280], Shen, Xia [0000-0003-4390-1979], Elliott, Katherine S [0000-0002-8125-797X], Keating, Sean [0000-0001-8552-5604], Wang, Bo [0000-0002-1580-797X], Klaric, Lucija [0000-0003-3105-8929], Parkinson, Nick [0000-0001-6336-5654], Nichol, Alistair [0000-0002-4689-1238], Semple, Malcolm G [0000-0001-9700-0418], Salehi, Shahla [0000-0002-5058-7706], Knight, Julian [0000-0002-0377-5536], Elgar, Greg [0000-0001-7323-1596], Patch, Christine [0000-0002-4191-0663], Baras, Aris [0000-0002-6830-3396], Abecasis, Goncalo R [0000-0003-1509-1825], Ferreira, Manuel AR [0000-0001-9059-1825], Rader, Daniel J [0000-0002-9245-9876], Ritchie, Marylyn D [0000-0002-1208-1720], Shankar-Hari, Manu [0000-0002-5338-2538], Summers, Charlotte [0000-0002-7269-2873], Hinds, Charles [0000-0001-5094-8324], McAuley, Danny [0000-0002-3283-1947], Montgomery, Hugh [0000-0001-8797-5019], Elliott, Paul [0000-0002-7511-5684], Tenesa, Albert [0000-0003-4884-4475], Murphy, Lee [0000-0001-6467-7449], Rowan, Kathy [0000-0001-8217-5602], Ponting, Chris P [0000-0003-0202-7816], Vitart, Veronique [0000-0002-4991-3797], Wilson, James F [0000-0001-5751-9178], Yang, Jian [0000-0003-2001-2474], Bretherick, Andrew D [0000-0001-9258-3140], Hendry, Sara Clohisey [0000-0001-7489-9846], Moutsianas, Loukas [0000-0001-5453-345X], Law, Andy [0000-0003-1868-2364], Caulfield, Mark J [0000-0001-9295-3594], Baillie, J Kenneth [0000-0001-5258-793X], Apollo - University of Cambridge Repository, National Institute for Health Research, UKRI MRC COVID-19 Rapid Response Call, UK Research and Innovation, Internal Medicine, Epidemiology, Center of Experimental and Molecular Medicine, AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), APH - Methodology, APH - Mental Health, Biological Psychology, AMS - Ageing & Vitality, AMS - Sports, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Department of Health & Social Care (UK), Medical Research Council (UK), Roslin Institute, Pérez-Tur, Jordi, Institute for Molecular Medicine Finland, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Faculty Common Matters (Faculty of Social Sciences), Data Science Genetic Epidemiology Lab, CAMM - Research Program for Clinical and Molecular Metabolism, investigators, GenOMICC, investigators, 23andMe, and Initiative, COVID-19 Human Genetics
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Genome-wide association studies ,PATHWAY ,Fucosyltransferase ,Lectins ,Receptors ,Genetics research ,TOOL ,Phospholipid Transfer Proteins ,Genome ,Multidisciplinary ,C-Type ,ATP-Binding Cassette Transporters ,Cell Adhesion Molecules ,Critical Care ,E-Selectin ,Factor VIII ,Fucosyltransferases ,Genome-Wide Association Study ,Humans ,Interleukin-10 Receptor beta Subunit ,Lectins, C-Type ,Mucin-1 ,Nerve Tissue Proteins ,Receptors, Cell Surface ,Repressor Proteins ,SARS-CoV-2 ,COVID-19 ,Critical Illness ,Genome, Human ,Host-Pathogen Interactions ,Whole Genome Sequencing ,1184 Genetics, developmental biology, physiology ,ASSOCIATION ,GenOMICC investigators ,COVID-19/genetics ,Host-Pathogen Interactions/genetics ,Multidisciplinary Sciences ,Host-Pathogen Interaction ,Cell Surface ,Science & Technology - Other Topics ,Infectious diseases ,Critical Illne ,Human ,Respiratory distress syndrome ,General Science & Technology ,ATP-Binding Cassette Transporter ,DENDRITIC CELLS ,23andMe investigators ,Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA ,Phospholipid Transfer Protein ,SDG 3 - Good Health and Well-being ,LINKAGE ,Science & Technology ,SARS-CoV-2/pathogenicity ,Repressor Protein ,SIGNAL ,ONTOLOGY ,COVID-19 Human Genetics Initiative ,Critical Illness/mortality ,Cell Adhesion Molecule ,Nerve Tissue Protein ,Genome, Human/genetics - Abstract
34 páginas, 3 figuras, 1 tabla., Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease., GenOMICC was funded by the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council (MRC), UKRI, Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (J.K.B., 223164/Z/21/Z) a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_ PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. WGS was performed by Illumina Article at Illumina Laboratory Services and was overseen by Genomics England. We would like to thank all at Genomics England who have contributed to the sequencing, clinical and genomic data analysis. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref. MC_PC_20029). A.D.B. would like to acknowledge funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z) and the Edinburgh Clinical Academic Track (ECAT) programme. We thank the research participants and employees of 23andMe for making this work possible. Genomics England and the 100,000 Genomes Project were funded by the National Institute for Health Research, the Wellcome Trust, the MRC, Cancer Research UK, the DHSC and NHS England. We are grateful for the support from S. Hill and the team in NHS England and the 13 Genomic Medicine Centres that delivered the 100,000 Genomes Project, which provided most of the control genome sequences for this study. We thank the participants in the 100,000 Genomes Project, who made this study possible, and the Genomics England Participant Panel for their strategic advice, involvement and engagement. We acknowledge NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre, who provided life-course longitudinal clinical data on the participants. This work forms part of the portfolio of research of the National Institute for Health Research Barts Biomedical Research Centre. Mark Caulfield is an NIHR Senior Investigator. This study owes a great deal to the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. Additional replication was conducted using the UK Biobank Resource (project 26041). The Penn Medicine BioBank is funded by a gift from the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health under CTSA award number UL1TR001878; and the Perelman School of Medicine at the University of Pennsylvania. We thank the AncestryDNA customers who voluntarily contributed information in the COVID-19 survey. HRS (dbGaP accession: phs000428.v1.p1): HRS was supported by the National Institute on Aging (NIA U01AG009740). The genotyping was funded separately by the National Institute on Aging (RC2 AG036495, RC4 AG039029). Genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the Genetics Coordinating Center at the University of Washington. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 22 August 2021 (GTEx Analysis Release v.8 (dbGaP Accession phs000424.v8.p2). We thank the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available at https://www.covid19hg.org/acknowledgements. The views expressed are those of the authors and not necessarily those of the DHSC, NHS, Department for International Development (DID), NIHR, MRC, Wellcome Trust or Public Health England.
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- 2022
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5. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues
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D'Antonio, M., Nguyen, J. P., Arthur, T. D., Matsui, H., D'Antonio-Chronowska, A., Frazer, K. A., Neale, B. M., Daly, M., Ganna, A., Stevens, C., Pathak, G. A., Andrews, S. J., Kanai, M., Cordioli, M., Karjalainen, J., Polimanti, R., Pirinen, M., Harerimana, N., Veerapen, K., Wolford, B., Nguyen, H., Solomonson, M., Liao, R. G., Chwialkowska, K., Trankiem, A., Balaconis, M. K., Hayward, C., Richmond, A., Campbell, A., Morris, M., Fawns-Ritchie, C., Glessner, J. T., Shaw, D. M., Chang, X., Polikowski, H., Lauren, P. E., Chen, H. -H., Wanying, Z., Hakonarson, H., Porteous, D. J., Below, J., North, K., Mccormick, J. B., Timmers, P. R. H. J., Wilson, J. F., Tenesa, A., D'Mellow, K., Kerr, S. M., Niemi, M. E. K., Nkambul, L., von Hohenstaufen, K. A., Sobh, A., Eltoukhy, M. M., Yassen, A. M., Hegazy, M. A. F., Okasha, K., Eid, M. A., Moahmed, H. S., Shahin, D., El-Sherbiny, Y. M., Elhadidy, T. A., Abd Elghafar, M. S., El-Jawhari, J. J., Mohamed, A. A. S., Elnagdy, M. 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R., Chavan, S., Laisk, T., Lall, K., Lepamets, M., Magi, R., Esko, T., Reimann, E., Milani, L., Alavere, H., Metsalu, K., Puusepp, M., Metspalu, A., Naaber, P., Laane, E., Pesukova, J., Peterson, P., Kisand, K., Tabri, J., Allos, R., Hensen, K., Starkopf, J., Ringmets, I., Tamm, A., Kallaste, A., Bochud, P. -Y., Rivolta, C., Bibert, S., Quinodoz, M., Kamdar, D., Boillat, N., Nussle, S. G., Albrich, W., Suh, N., Neofytos, D., Erard, V., Voide, C., de Cid, R., Galvan-Femenia, I., Blay, N., Carreras, A., Cortes, B., Farre, X., Sumoy, L., Moreno, V., Mercader, J. M., Guindo-Martinez, M., Torrents, D., Kogevinas, M., Garcia-Aymerich, J., Castano-Vinyals, G., Dobano, C., Renieri, A., Mari, F., Fallerini, C., Daga, S., Benetti, E., Baldassarri, M., Fava, F., Frullanti, E., Valentino, F., Doddato, G., Giliberti, A., Tita, R., Amitrano, S., Bruttini, M., Croci, S., Meloni, I., Mencarelli, M. A., Rizzo, C. L., Pinto, A. M., Beligni, G., Tommasi, A., Di Sarno, L., Palmieri, M., Carriero, M. 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G., Girardis, M., Venturelli, S., Cossarizza, A., Antinori, A., Vergori, A., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Paciosi, F., Scotton, P. G., Andretta, F., Panese, S., Scaggiante, R., Gatti, F., Parisi, S. G., Baratti, S., Della Monica, M., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Fiorentino, G., Carella, M., Castori, M., Merla, G., Squeo, G. M., Aucella, F., Raggi, P., Marciano, C., Perna, R., Bassetti, M., Di Biagio, A., Sanguinetti, Maurizio, Masucci, Luca, Valente, S., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Coviello, D. A., Mussini, C., Martinelli, E., Mancarella, S., Tavecchia, L., Crotti, L., Gabbi, C., Rizzi, M., Maggiolo, F., Ripamonti, D., Bachetti, T., La Rovere, M. 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F., Romani, D., Bergomi, P., Catena, E., Colombo, R., Tanfoni, M., Vincenti, A., Ferri, C., Grassi, D., Pessina, G., Tumbarello, M., Di Pietro, M., Sabrina, R., Luchi, S., Barbieri, C., Acquilini, D., Andreucci, E., Segala, F. V., Tiseo, G., Falcone, M., Lista, M., Poscente, M., De Vivo, O., Petrocelli, P., Guarnaccia, A., Baroni, S., Smith, A. V., Boughton, A. P., Li, K. W., Lefaive, J., Annis, A., Justice, A. E., Mirshahi, T., Chittoor, G., Josyula, N. S., Kosmicki, J. A., Ferreira, M. A. R., Leader, J. B., Carey, D. J., Gass, M. C., Horowitz, J. E., Cantor, M. N., Yadav, A., Baras, A., Abecasis, G. R., van Heel, D. A., Hunt, K. A., Mason, D., Huang, Q. Q., Finer, S., Trivedi, B., Griffiths, C. J., Martin, H. C., Wright, J., Trembath, R. C., Soranzo, N., Zhao, J. H., Butterworth, A. S., Danesh, J., Di Angelantonio, E., Boezen, L. F. M., Deelen, P., Claringbould, A., Lopera, E., Warmerdam, R., Vonk, J. M., van Blokland, I., Lanting, P., Ori, A. P. S., Zollner, B. W. S., Wang, J., Beck, A., Peloso, G., Ho, Y. -L., Sun, Y. V., Huffman, J. E., O'Donnell, C. J., Cho, K., Tsao, P., Michael Gaziano, J., Nivard, M. M. G., de Geus, E. E. J. C., Bartels, M., Hottenga, J. J., Weiss, S. T., Karlson, E. W., Smoller, J. W., Green, R. C., Feng, Y. -C. A., Mercader, J., Murphy, S. N., Meigs, J. B., Woolley, A. E., Perez, E. F., Rader, D., Verma, A., Ritchie, M. D., Li, B., Verma, S. S., Lucas, A., Bradford, Y., Zeberg, H., Frithiof, R., Hultstrom, M., Lipcsey, M., Tardif, N., Rooyackers, O., Grip, J., Maricic, T., Karczewski, K. J., Atkinson, E. G., Tsuo, K., Baya, N., Turley, P., Gupta, R., Callier, S., Walters, R. K., Palmer, D. S., Sarma, G., Cheng, N., Lu, W., Bryant, S., Churchhouse, C., Cusick, C., Goldstein, J. I., King, D., Seed, C., Finucane, H., Martin, A. R., Kyle Satterstrom, F., Wilson, D. J., Armstrong, J., Rudkin, J. K., Band, G., Earle, S. G., Lin, S. -K., Arning, N., Crook, D. W., Wyllie, D. H., O'Connell, A. M., Spencer, C. C. A., Koelling, N., Field, M. J., Scott, R. H., Fowler, T., Moutsianas, L., Kousathanas, A., Pasko, D., Walker, S., Rendon, A., Stuckey, A., Odhams, C. A., Rhodes, D., Chan, G., Arumugam, P., Ball, C. A., Hong, E. L., Rand, K., Girshick, A., Guturu, H., Baltzell, A. H., Roberts, G., Park, D., Coignet, M., Mccurdy, S., Knight, S., Partha, R., Rhead, B., Zhang, M., Berkowitz, N., Gaddis, M., Noto, K., Ruiz, L., Pavlovic, M., Sloofman, L. G., Charney, A. W., Beckmann, N. D., Schadt, E. E., Jordan, D. M., Thompson, R. C., Gettler, K., Abul-Husn, N. S., Ascolillo, S., Buxbaum, J. D., Chaudhary, K., Cho, J. H., Itan, Y., Kenny, E. E., Belbin, G. M., Sealfon, S. C., Sebra, R. P., Salib, I., Collins, B. L., Levy, T., Brit-Van, B., Keller, K., Tang, L., Peruggia, M., Hiester, L. L., Niblo, K., Aksentijevich, A., Labkowsky, A., Karp, A., Zlatopolsky, M., Preuss, M., Loos, R. J. F., Nadkarni, G. N., Do, R., Hoggart, C., Choi, S., Underwood, S. J., O'Reilly, P., Huckins, L. M., Zyndorf, M., Sanguinetti M. (ORCID:0000-0002-9780-7059), and Masucci L. (ORCID:0000-0002-8358-6726)
- Abstract
Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types.
- Published
- 2021
6. OS10.1 Genomic landscape of pituitary adenomas
- Author
-
Bi, W. L., primary, Greenwald, N. F., additional, Abedalthagafi, M., additional, Horowitz, P., additional, Laws, E. R., additional, Beroukhim, R., additional, and Dunn, I. F., additional
- Published
- 2017
- Full Text
- View/download PDF
7. OS08.3 Genomic landscape of meningiomas
- Author
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Bi, W. L., primary, Greenwald, N. F., additional, Abedalthagafi, M., additional, Agarwalla, P., additional, Horowitz, P., additional, Santagata, S., additional, Al-Mefty, O., additional, Beroukhim, R., additional, and Dunn, I. F., additional
- Published
- 2017
- Full Text
- View/download PDF
8. SU-D-207B-02: Early Grade Classification in Meningioma Patients Combining Radiomics and Semantics Data
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Coroller, T, primary, Bi, W, additional, Abedalthagafi, M, additional, Aizer, A, additional, Wu, W, additional, Greenwald, N, additional, Beroukhim, R, additional, Al-Mefty, O, additional, Santagata, S, additional, Dunn, I, additional, Alexander, B, additional, Huang, R, additional, and Aerts, H, additional
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- 2016
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9. A Prognostic Molecular Scoring System to Guide the Adjuvant Management of Patients With Gross Totally Resected Atypical Meningioma
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Aizer, A.A., primary, Abedalthagafi, M., additional, Bi, L., additional, Horvath, M.C., additional, Ligon, A.H., additional, Arvold, N.D., additional, Dunn, I.F., additional, Santagata, S., additional, and Alexander, B., additional
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- 2015
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10. Adjuvant radiation therapy, local recurrence, and the need for salvage therapy in atypical meningioma
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Aizer, A. A., primary, Arvold, N. D., additional, Catalano, P., additional, Claus, E. B., additional, Golby, A. J., additional, Johnson, M. D., additional, Al-Mefty, O., additional, Wen, P. Y., additional, Reardon, D. A., additional, Lee, E. Q., additional, Nayak, L., additional, Rinne, M. L., additional, Beroukhim, R., additional, Weiss, S. E., additional, Ramkissoon, S. H., additional, Abedalthagafi, M., additional, Santagata, S., additional, Dunn, I. F., additional, and Alexander, B. M., additional
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- 2014
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11. Gastrointestinal stromal tumour originating from the hepatic falciform ligament
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Abedalthagafi, M., primary
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- 2012
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12. Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage gliomas
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Cryan, J. B., Haidar, S., Ramkissoon, L. A., Bi, W. L., David Knoff, Schultz, N., Abedalthagafi, M., Brown, L., Wen, P. Y., Reardon, D. A., Dunn, I. F., Folkerth, R. D., Santagata, S., Lindeman, N. I., Ligon, A. H., Beroukhim, R., Hornick, J. L., Alexander, B. M., Ligon, K. L., and Ramkissoon, S. H.
13. Radiation-induced glioma following CyberKnife® treatment of metastatic renal cell carcinoma: a case report
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Abedalthagafi Malak and Bakhshwin Ahmed
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Medicine - Abstract
Abstract Introduction Post-stereotactic radiation-induced neoplasms, although relatively rare, have raised the question of benefit regarding CyberKnife® treatments versus the risk of a secondary malignancy. The incidence of such neoplasms arising in the nervous system is thought to be low, given the paucity of case reports regarding such secondary lesions. Case presentation Here we describe a case of a 43-year-old Middle Eastern woman with primary clear cell renal cell carcinoma and a metastatic focus to the left brain parenchyma who presented with focal neurologic deficits. Following post-surgical stereotactic radiation in the region of the brain metastasis, the patient developed a secondary high-grade astrocytoma nearly 5 years after the initial treatment. Conclusion Although the benefit of CyberKnife® radiotherapy treatments continues to outweigh the relatively low risk of a radiation-induced secondary malignancy, knowledge of such risks and a review of the literature are warranted.
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- 2012
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14. CyberKnife radiosurgery for inoperable stage IA non-small cell lung cancer: 18F-fluorodeoxyglucose positron emission tomography/computed tomography serial tumor response assessment
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Chang Thomas, Gutierrez Constanza J, Yousefi Shadi, Suy Simeng, DeBrito Pedro, Abedalthagafi Malak, Yu Xia, Collins Sean P, Oermann Eric K, Vahdat Saloomeh, Banovac Filip, Anderson Eric D, Esposito Giuseppe, and Collins Brian T
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Objective To report serial 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) tumor response following CyberKnife radiosurgery for stage IA non-small cell lung cancer (NSCLC). Methods Patients with biopsy-proven inoperable stage IA NSCLC were enrolled into this IRB-approved study. Targeting was based on 3-5 gold fiducial markers implanted in or near tumors. Gross tumor volumes (GTVs) were contoured using lung windows; margins were expanded by 5 mm to establish the planning treatment volumes (PTVs). Doses ranged from 42-60 Gy in 3 equal fractions. 18F-FDG PET/CT was performed prior to and at 3-6-month, 9-15 months and 18-24 months following treatment. The tumor maximum standardized uptake value (SUVmax) was recorded for each time point. Results Twenty patients with an average maximum tumor diameter of 2.2 cm were treated over a 3-year period. A mean dose of 51 Gy was delivered to the PTV in 3 to 11 days (mean, 7 days). The 30-Gy isodose contour extended an average of 2 cm from the GTV. At a median follow-up of 43 months, the 2-year Kaplan-Meier overall survival estimate was 90% and the local control estimate was 95%. Mean tumor SUVmax before treatment was 6.2 (range, 2.0 to 10.7). During early follow-up the mean tumor SUVmax remained at 2.3 (range, 1.0 to 5.7), despite transient elevations in individual tumor SUVmax levels attributed to peritumoral radiation-induced pneumonitis visible on CT imaging. At 18-24 months the mean tumor SUVmax for controlled tumors was 2.0, with a narrow range of values (range, 1.5 to 2.8). A single local failure was confirmed at 24 months in a patient with an elevated tumor SUVmax of 8.4. Conclusion Local control and survival following CyberKnife radiosurgery for stage IA NSCLC is exceptional. Early transient increases in tumor SUVmax are likely related to radiation-induced pneumonitis. Tumor SUVmaxvalues return to background levels at 18-24 months, enhancing 18F-FDG PET/CT detection of local failure. The value of 18F-FDG PET/CT imaging for surveillance following lung SBRT deserves further study.
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- 2010
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15. Expression of Programmed Cell Death-L1 (PD-L1) Protein and Mismatch Repair Mutations in Orbital Tumours-a Pilot Study
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Mohammad A AlSemari, Diego Strianese, Leen Abu Safieh, Hailah Al Hussain, Malak Abedalthagafi, Deepak P. Edward, Alsemari, M. A., Strianese, D., Abu Safieh, L., Al Hussain, H., Abedalthagafi, M., and Edward, D. P.
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Mismatch repair (MMR) ,orbital tumour ,Brain Neoplasms ,Programmed Cell Death 1 Receptor ,lacrimal gland tumour ,Apoptosis ,Pilot Projects ,General Medicine ,DNA Mismatch Repair ,B7-H1 Antigen ,DNA-Binding Proteins ,Programmed cell death ligand 1 (PD-L1) protein ,Ophthalmology ,Neoplastic Syndromes, Hereditary ,Mutation ,Rhabdomyosarcoma ,Biomarkers, Tumor ,Humans ,Orbital Neoplasms ,Apoptosis Regulatory Proteins ,Colorectal Neoplasms - Abstract
Purpose Programmed cell death protein 1 (PD-1) and DNA mismatch repair (MMR) deficiency play an important role in tumour progression and response to treatment. Both markers have been studied in some ocular tumours but little is known about these markers in orbital tumours. This pilot study reports on PD-L1 expression and MMR mutations using next generation sequencing (NGS) in specific orbital tumours. Methods We reviewed surgical specimens from patients with rhabdomyosarcoma, adenoid cystic carcinoma (ACC), pleomorphic adenoma (PA) and biopsy negative tissue from orbital tumours used as a control. immunohistochemistry (IHC) was performed on Formalin fixed paraffin embedded tissue using a PD-L1 antibody. DNA was extracted for targeted gene panel NGS of the MMR genes PMS2, MLH1, MSH6 and MSH2. Results The study included 17 orbital specimens. Scattered membrane PD-L1 staining was noted in 3/6 rhabdomyosarcoma specimens without an accompanying lymphocytic infiltrate. PD-L1 immunostaining was absent in 3/3 ACC, and 5/6 PA specimens. PD-L1 immunostaining was not detected in 2/2 control specimens. 4/17 samples shared the same pathogenic mutation in the MLH1 gene, including 3/6 rhabdomyosarcoma and 1/3 ACC samples. 1/6 PA samples had a mutation in MSH6. Conclusions Our study demonstrated scattered, non-quantifiable or absent PD-L1 staining in a limited sample of orbital tumours suggesting that PD-1/PD-L1 inhibitor therapy may not be useful in treatment of malignant orbital tumours (rhabdomyosarcoma and ACC) when refractory to conventional therapy. Our pilot study suggest that PD-L1/MMR axis might not play a major role in the pathogenesis of primary orbital tumour.
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- 2021
16. The clinico-pathologic profile of primary and recurrent orbital/periorbital plexiform neurofibromas (OPPN)
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Mohammad A. Alabduljabbar, Deepak P. Edward, Diego Strianese, Rajiv Khandekar, Hind M. Alkatan, Azza Maktabi, Malak Abedalthagafi, Osama Al-Sheikh, Hailah Al-Hussain, Alabduljabbar, M., Strianese, D., Al-Sheikh, O., Alkatan, H. M., Al-Hussain, H., Maktabi, A. M. Y., Khandekar, R., Abedalthagafi, M., and Edward, D. P.
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Male ,Macroglial Cells ,Pathology ,Proliferation index ,Medical Conditions ,Diffuse Pattern ,Retrospective Studie ,Animal Cells ,Medicine and Health Sciences ,Neurofibroma ,Child ,Connective Tissue Cells ,Staining ,Multidisciplinary ,biology ,Cell Staining ,Middle Aged ,Prognosis ,Oncology ,Connective Tissue ,Genetic Diseases ,Child, Preschool ,Immunohistochemistry ,Medicine ,Female ,Anatomy ,Cellular Types ,Human ,Research Article ,Adult ,medicine.medical_specialty ,Histology ,Adolescent ,Prognosi ,Science ,Saudi Arabia ,Surgical and Invasive Medical Procedures ,Glial Cells ,Research and Analysis Methods ,Young Adult ,Malignant Tumors ,Plexiform neurofibroma ,medicine ,Humans ,Neurofibromatosis ,Retrospective Studies ,Neurofibroma, Plexiform ,Clinical Genetics ,CD117 ,business.industry ,Autosomal Dominant Diseases ,Cancers and Neoplasms ,Biology and Life Sciences ,Cell Biology ,Fibroblasts ,medicine.disease ,Biological Tissue ,Specimen Preparation and Treatment ,biology.protein ,Schwann Cells ,Neurofibromatosis Type 1 ,Neoplasm Recurrence, Local ,business - Abstract
To evaluate and compare the clinical and histopathological profile of primary and recurrent orbital-periorbital plexiform neurofibromas (OPPN) in patients with neurofibromatosis type 1. We retrospectively evaluated 43 primary or recurrent neurofibroma (NF) specimens from 26 patients (2002 to 2018) at the King Khaled Eye Specialist Hospital, Saudi Arabia. Demographics, clinical presentation, and surgical intervention data were collected. Histopathological specimens were studied with hematoxylin-eosin, Alcian blue, and immunohistochemical markers; S-100, CD44, CD117, smooth muscle actin (SMA), neurofilament, and Ki-67. Of the 43 NFs specimens, 20 were primary and 23 recurrent tumors. For primary NF, the ratio of plexiform to the diffuse type was 13:7, however in recurrent tumors was 3:8 after the first recurrence, and 1:5 after multiple recurrences. Of the 17 patients with primary tumors that had paired recurrent tumors, 12/17 (70.6%) primary NFs were plexiform and 5/17 (29.4%) were diffuse. However, when tumors recurred, 13/17 tumors (76.5%) were diffuse and only 4/17 tumors (23.5%) had a plexiform pattern. The odds of a tumor having a diffuse pattern in recurrent NF was significantly higher than the plexiform pattern [OR = 7.8 (95% confidence interval 1.69:36.1) P = 0.008]. Primary plexiform NFs underwent an excision at a significantly younger age than the diffuse type. Recurrent NFs had significantly higher CD44, CD117, and neurofilament labeling (P = 0.02, P = 0.01 and P.001 respectively) but had significantly decreased Alcian blue, and S-100 labeling (P = 0.03, and P = 0.02 respectively) compared to primary tumors. SMA and Ki-67 proliferation index were not different between primary and recurrent NFs (P = 0.86, and P = 0.3 respectively). There appears to be a high risk for primary plexiform NFs to develop a diffuse histologic pattern when they recur. Immunohistochemical staining suggests a role of mast cells (CD117) and expression of infiltration makers (CD44) in the transformation of plexiform tumors to the diffuse phenotype.
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- 2021
17. Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas
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Brian M. Alexander, Malak Abedalthagafi, Patrick Y. Wen, Arie Perry, Matthew Meyerson, Aaron R. Thorner, Sandro Santagata, Scott L. Carter, Naema Nayyar, Parker H. Merrill, Fred G. Barker, Priscilla K. Brastianos, William T. Curry, Azra H. Ligon, Paul Van Hummelen, Daniel P. Cahill, Ryan Brewster, Ossama Al-Mefty, David A. Reardon, Pankaj K. Agarwalla, Corey M. Gill, Wenya Linda Bi, Caterina Giannini, Rameen Beroukhim, Tracy T. Batchelor, David N. Louis, Ian F. Dunn, Keith L. Ligon, Ganesh M. Shankar, Rachael A. Vaubel, Shankar G.M., Abedalthagafi M., Vaubel R.A., Merrill P.H., Nayyar N., Gill C.M., Brewster R., Bi W.L., Agarwalla P.K., Thorner A.R., Reardon D.A., Al-Mefty O., Wen P.Y., Alexander B.M., Van Hummelen P., Batchelor T.T., Ligon K.L., Ligon A.H., Meyerson M., Dunn I.F., Beroukhim R., Louis D.N., Perry A., Carter S.L., Giannini C., Curry W.T., Cahill D.P., Barker F.G., Brastianos P.K., and Santagata S.
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Oncology ,Cancer Research ,Germline ,0302 clinical medicine ,Meningeal Neoplasms ,2.1 Biological and endogenous factors ,Family history ,Aetiology ,Meningeal Neoplasm ,Exome sequencing ,Cancer ,BAP1 ,030220 oncology & carcinogenesis ,Basic and Translational Investigations ,rhabdoid meningioma ,Disease Progression ,Immunohistochemistry ,Survival Analysi ,Meningioma ,Ubiquitin Thiolesterase ,Human ,medicine.medical_specialty ,Tumor suppressor gene ,Oncology and Carcinogenesis ,03 medical and health sciences ,Breast cancer ,Rare Diseases ,Clinical Research ,Internal medicine ,otorhinolaryngologic diseases ,medicine ,Genetics ,Humans ,Oncology & Carcinogenesis ,neoplasms ,Rhabdoid Tumor ,Germ-Line Mutation ,Tumor Suppressor Protein ,business.industry ,Tumor Suppressor Proteins ,rhabdoid meningiomas ,Neurosciences ,medicine.disease ,Survival Analysis ,nervous system diseases ,Good Health and Well Being ,Mutation ,Neurology (clinical) ,Neoplasm Grading ,business ,exome sequencing ,030217 neurology & neurosurgery - Abstract
Background. Patients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making. Methods. To define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas. Results. The tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome. Conclusion. We define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.
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- 2017
18. A case of myxopapillary ependymoma with predominant giant cell morphology: A rare entity with comprehensive genomic profiling and review of literature.
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Morales-Vargas B, Saad H, Refai D, Schniederjan M, Abdullaev Z, Aldape K, and Abedalthagafi M
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- Humans, Male, Adult, Giant Cells pathology, Ependymoma pathology, Ependymoma genetics, Spinal Cord Neoplasms pathology, Spinal Cord Neoplasms genetics
- Abstract
In the evolving landscape of ependymoma classification, which integrates histological, molecular, and anatomical context, we detail a rare case divergent from the usual histopathological spectrum. We present the case of a 37-year-old man with symptomatic spinal cord compression at the L3-L4 level. Neuroradiological evaluation revealed an intradural, encapsulated mass. Histologically, the tumor displayed atypical features: bizarre pleomorphic giant cells, intranuclear inclusions, mitotic activity, and a profusion of eosinophilic cytoplasm with hyalinized vessels, deviating from the characteristic perivascular pseudorosettes or myxopapillary patterns. Immunohistochemical staining bolstered this divergence, marking the tumor cells positive for glial fibrillary acidic protein and epithelial membrane antigen with a characteristic ring-like pattern, and CD99 but negative for Olig-2. These markers, alongside methylation profiling, facilitated its classification as a myxopapillary ependymoma (MPE), despite the atypical histologic features. This profile underscores the necessity of a multifaceted diagnostic process, especially when histological presentation is uncommon, confirming the critical role of immunohistochemistry and molecular diagnostics in classifying morphologically ambiguous ependymomas and exemplifying the histological diversity within MPEs., (© 2024 Japanese Society of Neuropathology.)
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- 2025
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19. Progress in personalized immunotherapy for patients with brain metastasis.
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Patel L, Kolundzic N, and Abedalthagafi M
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Brain metastasis leads to poor outcomes and CNS injury, significantly reducing quality of life and survival rates. Advances in understanding the tumor immune microenvironment have revealed the promise of immunotherapies, which, alongside surgery, chemotherapy, and radiation, offer improved survival for some patients. However, resistance to immunotherapy remains a critical challenge. This review explores the immune landscape of brain metastases, current therapies, clinical trials, and the need for personalized, biomarker-driven approaches to optimize outcomes., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)
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- 2025
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20. Patterns of population structure and genetic variation within the Saudi Arabian population.
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Malomane DK, Williams MP, Huber CD, Mangul S, Abedalthagafi M, and Chiang CWK
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The Arabian Peninsula is considered the initial site of historic human migration out of Africa. The modern-day indigenous Arabians are believed to be the descendants who remained from the ancient split of the migrants into Eurasia. Here, we investigated how the population history and cultural practices such as endogamy have shaped the genetic variation of the Saudi Arabians. We genotyped 3,352 individuals and identified twelve genetic sub-clusters that corresponded to the geographical distribution of different tribal regions, differentiated by distinct components of ancestry based on comparisons to modern and ancient DNA references. These sub-clusters also showed variation across ranges of the genome covered in runs of homozygosity, as well as differences in population size changes over time. Using 25,488,981 variants found in whole genome sequencing data (WGS) from 302 individuals, we found that the Saudi tend to show proportionally more deleterious alleles than neutral alleles when compared to Africans/African Americans from gnomAD (e.g. a 13% increase of deleterious alleles annotated by AlphaMissense between 0.5 - 5% frequency in Saudi, compared to 7% decrease of the benign alleles; P < 0.001). Saudi sub-clusters with greater inbreeding and lower effective population sizes showed greater enrichment of deleterious alleles as well. Additionally, we found that approximately 10% of the variants discovered in our WGS data are not observed in gnomAD; these variants are also enriched with deleterious annotations. To accelerate studying the population-enriched deleterious alleles and their health consequences in this population, we made available the allele frequency estimates of 25,488,981 variants discovered in our samples. Taken together, our results suggest that Saudi's population history impacts its pattern of genetic variation with potential consequences to the population health. It further highlights the need to sequence diverse and unique populations so to provide a foundation on which to interpret medical- and pharmaco- genomic findings from these populations., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.
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- 2025
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21. CffDNA screening for Niemann-pick disease, type C1: a case series.
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Lau SA, Fawaz RI, Rigobello R, Bawazeer S, Alajaji NM, Faqeih E, Li Y, Feng Y, Xia F, Eng CM, and Abedalthagafi M
- Abstract
Cell-free fetal DNA (cffDNA) screening is a valuable tool in clinical practice for detecting chromosomal abnormalities and autosomal dominant (AD) conditions. This study introduces a novel proof-of-concept assay designed for autosomal recessive (AR) cffDNA screening, focusing on cases involving the NPC1 gene. We aim to illustrate the significant benefits of AR cffDNA screening in managing high-risk pregnancies, specifically where biallelic pathogenic variants in NPC1 cause Niemann-Pick disease, type C1 (NPC), a disorder marked by progressive neurodegeneration. Three participants for this study were recruited and gave consent to a hospital in Saudi Arabia. These participants were either carriers of NPC or had a first- or second-degree relative affected by the disorder. No specific criteria were set for the age of the participants. All were between 15 and 18 weeks of gestation. Using amplicon-based next-generation sequencing (NGS), we analyzed the zygosity and variants in cffDNA extracted from maternal peripheral blood. After amplicon NGS, analysis was completed by a custom data analysis pipeline that included in-house-built data processing scripts and commonly used software packages. Importantly, the results were not disclosed to the patients. Our findings showed that in all three cases, AR cffDNA screening results were consistent with standard invasive diagnostic testing. This screening method offers several advantages: it provides critical information to families earlier in the pregnancy compared to invasive diagnostic tests, and it helps to alleviate parental anxiety. Moreover, this non-invasive method can determine pregnancy status in the first trimester for known familial variants. Future research may extend this approach to screen for known disease-causing variants in common AR conditions., Competing Interests: MA was a founder of Shomool, a company specializing in cffDNA screening for AR conditions. SL, RF, RR, YL, and YF were employed by Baylor Genetics. FX and CE were employed by Baylor College of Medicine and provide services for Baylor Genetics through a professional services agreement. One of Baylor Genetics’ many product offerings is PreSeek, a cffDNA screening for 30 genes associated with clinically significant and life-limiting AD conditions. The remaining 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 © 2024 Lau, Fawaz, Rigobello, Bawazeer, Alajaji, Faqeih, Li, Feng, Xia, Eng and Abedalthagafi.)
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- 2024
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22. Analytical code sharing practices in biomedical research.
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Sharma NK, Ayyala R, Deshpande D, Patel Y, Munteanu V, Ciorba D, Bostan V, Fiscutean A, Vahed M, Sarkar A, Guo R, Moore A, Darci-Maher N, Nogoy N, Abedalthagafi M, and Mangul S
- Abstract
Data-driven computational analysis is becoming increasingly important in biomedical research, as the amount of data being generated continues to grow. However, the lack of practices of sharing research outputs, such as data, source code and methods, affects transparency and reproducibility of studies, which are critical to the advancement of science. Many published studies are not reproducible due to insufficient documentation, code, and data being shared. We conducted a comprehensive analysis of 453 manuscripts published between 2016-2021 and found that 50.1% of them fail to share the analytical code. Even among those that did disclose their code, a vast majority failed to offer additional research outputs, such as data. Furthermore, only one in ten articles organized their code in a structured and reproducible manner. We discovered a significant association between the presence of code availability statements and increased code availability. Additionally, a greater proportion of studies conducting secondary analyses were inclined to share their code compared to those conducting primary analyses. In light of our findings, we propose raising awareness of code sharing practices and taking immediate steps to enhance code availability to improve reproducibility in biomedical research. By increasing transparency and reproducibility, we can promote scientific rigor, encourage collaboration, and accelerate scientific discoveries. We must prioritize open science practices, including sharing code, data, and other research products, to ensure that biomedical research can be replicated and built upon by others in the scientific community., Competing Interests: Nicole Nogoy is an Executive Editor for GigaScience Press., (© 2024 Sharma et al.)
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- 2024
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23. Extracavitary primary effusion lymphoma presenting as a solitary brain mass.
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Javadi T, Morales B, Olson JJ, Kothari S, Zhang L, and Abedalthagafi M
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- Humans, Male, Middle Aged, Lymphoma, Primary Effusion pathology, Lymphoma, Primary Effusion diagnosis, Brain Neoplasms pathology, Brain Neoplasms diagnostic imaging, Brain Neoplasms diagnosis
- Abstract
Primary effusion lymphoma (PEL) is an uncommon B-cell lymphoma associated with human herpesvirus 8 and comprises 3-4% of all HIV-related lymphomas. It traditionally presents as a pleural, pericardial, and/or peritoneal effusion, though it can occasionally manifest as an extracavitary or solid mass in the absence of an effusion. The extracavitary or solid variant of primary effusion lymphoma has been reported in the skin, gastrointestinal tract, lung, and lymph nodes. However, very few cases have been reported in the central nervous system. We describe a case of extracavitary or solid variant of primary effusion lymphoma presenting as a brain mass in an HIV-positive man, highlighting the clinicopathologic and immunophenotypic findings of a rare entity.
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- 2024
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24. Artificial intelligence in neuro-oncology: advances and challenges in brain tumor diagnosis, prognosis, and precision treatment.
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Khalighi S, Reddy K, Midya A, Pandav KB, Madabhushi A, and Abedalthagafi M
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This review delves into the most recent advancements in applying artificial intelligence (AI) within neuro-oncology, specifically emphasizing work on gliomas, a class of brain tumors that represent a significant global health issue. AI has brought transformative innovations to brain tumor management, utilizing imaging, histopathological, and genomic tools for efficient detection, categorization, outcome prediction, and treatment planning. Assessing its influence across all facets of malignant brain tumor management- diagnosis, prognosis, and therapy- AI models outperform human evaluations in terms of accuracy and specificity. Their ability to discern molecular aspects from imaging may reduce reliance on invasive diagnostics and may accelerate the time to molecular diagnoses. The review covers AI techniques, from classical machine learning to deep learning, highlighting current applications and challenges. Promising directions for future research include multimodal data integration, generative AI, large medical language models, precise tumor delineation and characterization, and addressing racial and gender disparities. Adaptive personalized treatment strategies are also emphasized for optimizing clinical outcomes. Ethical, legal, and social implications are discussed, advocating for transparency and fairness in AI integration for neuro-oncology and providing a holistic understanding of its transformative impact on patient care., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2024
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25. Non-invasive prenatal testing: a revolutionary journey in prenatal testing.
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Abedalthagafi M, Bawazeer S, Fawaz RI, Heritage AM, Alajaji NM, and Faqeih E
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Non-invasive prenatal testing (NIPT) is a pioneering technique that has consistently advanced the field of prenatal testing to detect genetic abnormalities and conditions with the aim of decreasing the incidence and prevalence of inherited conditions. NIPT remains a method of choice for common autosomal aneuploidies, mostly trisomy 21, and several monogenic disorders. The advancements in gene sequencing techniques have expanded the panel of conditions where NIPT could be offered. However, basic research on the impact of several genetic conditions lags behind the methods of detection of these sequence aberrations, and the impact of the expansion of NIPT should be carefully considered based on its utility. With interest from commercial diagnostics and a lack of regulatory oversight, there remains a need for careful validation of the predictive values of different tests offered. NIPT comes with many challenges, including ethical and economic issues. The scientific evidence, technical feasibility, and clinical benefit of NIPT need to be carefully investigated before new tests and developments are translated into clinical practice. Moreover, the implementation of panel expansion of NIPT should accompany expert genetic counseling pre- and post-testing., Competing Interests: MA is a founder of Shomool, which specializes in NIPT for ARD. RF and AM are employed by Baylor Genetics. The remaining 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 © 2023 Abedalthagafi, Bawazeer, Fawaz, Heritage, Alajaji and Faqeih.)
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- 2023
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26. Ameloblastic Fibrosarcoma of the Jaw: Case Report, Genetic Profiling, and Literature Review.
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Barakeh D, Alsolami A, and Abedalthagafi M
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Ameloblastic fibrosarcoma (AFS) is considered a malignant progression resulting from dysplastic changes in an ameloblastic fibroma (AF). Both tumors are extremely rare, with only a few cases reported in the scientific literature. Notably, BRAF mutations have been identified in ameloblastomas, suggesting a connection between ameloblastic morphology and BRAF mutations, as AF is believed to be the precursor neoplasm leading to AFS. In this study, we present a case of AFS in a 25-year-old male. The tumor tissue underwent molecular analysis, specifically next-generation sequencing (NGS) using the Oncomine Comprehensive Assay v3 System. The analysis revealed pathogenic mutations in TP53 and RB genes, as well as copy number gains in NTRK1, MDM4, and BRAF. Additionally, we provide a summary of the literature's findings from the analysis of 107 previously reported AFS cases. Our findings suggest the existence of a molecularly distinct subtype, emphasizing the importance of comprehensive molecular testing for these patients., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)
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- 2023
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27. Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system.
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Alhattab DM, Isaioglou I, Alshehri S, Khan ZN, Susapto HH, Li Y, Marghani Y, Alghuneim AA, Díaz-Rúa R, Abdelrahman S, Al-Bihani S, Ahmed F, Felimban RI, Alkhatabi H, Alserihi R, Abedalthagafi M, AlFadel A, Awidi A, Chaudhary AG, Merzaban J, and Hauser CAE
- Abstract
Background: Acute myeloid leukemia (AML) is a hematological malignancy that remains a therapeutic challenge due to the high incidence of disease relapse. To better understand resistance mechanisms and identify novel therapies, robust preclinical models mimicking the bone marrow (BM) microenvironment are needed. This study aimed to achieve an automated fabrication process of a three-dimensional (3D) AML disease model that recapitulates the 3D spatial structure of the BM microenvironment and applies to drug screening and investigational studies., Methods: To build this model, we investigated a unique class of tetramer peptides with an innate ability to self-assemble into stable hydrogel. An automated robotic bioprinting process was established to fabricate a 3D BM (niche-like) multicellular AML disease model comprised of leukemia cells and the BM's stromal and endothelial cellular fractions. In addition, monoculture and dual-culture models were also fabricated. Leukemia cell compatibility, functionalities (in vitro and in vivo), and drug assessment studies using our model were performed. In addition, RNAseq and gene expression analysis using TaqMan arrays were also performed on 3D cultured stromal cells and primary leukemia cells., Results: The selected peptide hydrogel formed a highly porous network of nanofibers with mechanical properties similar to the BM extracellular matrix. The robotic bioprinter and the novel quadruple coaxial nozzle enabled the automated fabrication of a 3D BM niche-like AML disease model with controlled deposition of multiple cell types into the model. This model supported the viability and growth of primary leukemic, endothelial, and stromal cells and recapitulated cell-cell and cell-ECM interactions. In addition, AML cells in our model possessed quiescent characteristics with improved chemoresistance attributes, resembling more the native conditions as indicated by our in vivo results. Moreover, the whole transcriptome data demonstrated the effect of 3D culture on enhancing BM niche cell characteristics. We identified molecular pathways upregulated in AML cells in our 3D model that might contribute to AML drug resistance and disease relapse., Conclusions: Our results demonstrate the importance of developing 3D biomimicry models that closely recapitulate the in vivo conditions to gain deeper insights into drug resistance mechanisms and novel therapy development. These models can also improve personalized medicine by testing patient-specific treatments., (© 2023. The Author(s).)
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- 2023
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28. The Genomic Landscape of Colorectal Cancer in the Saudi Arabian Population Using a Comprehensive Genomic Panel.
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Alsolme E, Alqahtani S, Fageeh M, Barakeh D, Sharma NK, Mangul S, Robinson HA, Fathaddin A, Hauser CAE, and Abedalthagafi M
- Abstract
Purpose: Next-generation sequencing (NGS) technology detects specific mutations that can provide treatment opportunities for colorectal cancer (CRC) patients., Patients and Methods: We analyzed the mutation frequencies of common actionable genes and their association with clinicopathological characteristics and oncologic outcomes using targeted NGS in 107 Saudi Arabian patients without a family history of CRC., Results: Approximately 98% of patients had genetic alterations. Frequent mutations were observed in BRCA2 (79%), CHEK1 (78%), ATM (76%), PMS2 (76%), ATR (74%), and MYCL (73%). The APC gene was not included in the panel. Statistical analysis using the Cox proportional hazards model revealed an unusual positive association between poorly differentiated tumors and survival rates ( p = 0.025). Although no significant univariate associations between specific mutations or overall mutation rate and overall survival were found, our preliminary analysis of the molecular markers for CRC in a predominantly Arab population can provide insights into the molecular pathways that play a significant role in the underlying disease progression., Conclusions: These results may help optimize personalized therapy when drugs specific to a patient's mutation profile have already been developed.
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- 2023
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29. Author Correction: GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.
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Pairo-Castineira E, Rawlik K, Bretherick AD, Qi T, Wu Y, Nassiri I, McConkey GA, Zechner M, Klaric L, Griffiths F, Oosthuyzen W, Kousathanas A, Richmond A, Millar J, Russell CD, Malinauskas T, Thwaites R, Morrice K, Keating S, Maslove D, Nichol A, Semple MG, Knight J, Shankar-Hari M, Summers C, Hinds C, Horby P, Ling L, McAuley D, Montgomery H, Openshaw PJM, Begg C, Walsh T, Tenesa A, Flores C, Riancho JA, Rojas-Martinez A, Lapunzina P, Yang J, Ponting CP, Wilson JF, Vitart V, Abedalthagafi M, Luchessi AD, Parra EJ, Cruz R, Carracedo A, Fawkes A, Murphy L, Rowan K, Pereira AC, Law A, Fairfax B, Hendry SC, and Baillie JK
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- 2023
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30. Investigating the prevalence of pathogenic variants in Saudi Arabian patients with familial cancer using a multigene next generation sequencing panel.
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AlHarbi M, Mobark NA, AlJabarat WAR, ElBardis H, AlSolme E, Hamdan AB, AlFakeeh AH, AlMushawah F, AlHarthi F, AlSharm AA, Balbaid AAO, AlJohani N, Zhou AY, Robinson HA, Alqahtani SA, and Abedalthagafi M
- Subjects
- Humans, Saudi Arabia, High-Throughput Nucleotide Sequencing, Prevalence, Genetic Predisposition to Disease, Colorectal Neoplasms, Nasopharyngeal Neoplasms
- Abstract
Family history is an important factor in determining hereditary cancer risk for many cancer types. The emergence of next-generation sequencing (NGS) has expedited the discovery of many hereditary cancer susceptibility genes and the development of rapid, affordable testing kits. Here, a 30-gene targeted NGS panel for hereditary cancer risk assessment was tested and validated in a Saudi Arabian population. A total of 310 subjects were screened, including 57 non-cancer patients, 110 index patients with cancer and 143 of the cancer patients' family members, 16 of which also had cancer. Of the 310 subjects, 119 (38.4%) were carriers of pathogenic or likely pathogenic variants (PVs) affecting one or more of the following genes: TP53, ATM, CHEK2, CDH1, CDKN2A, BRCA1, BRCA2, PALB2, BRIP1, RAD51D, APC, MLH1, MSH2, MSH6, PMS2, PTEN, NBN/NBS1 and MUTYH . Among 126 patients and relatives with a history of cancer, 49 (38.9%) were carriers of PVs or likely PVs. Two variants in particular were significantly associated with the occurrence of a specific cancer in this population (APC c.3920T>A - colorectal cancer/Lynch syndrome ( p = 0.026); TP53 c.868C>T; - multiple colon polyposis ( p = 0.048)). Diverse variants in BRCA2, the majority of which have not previously been reported as pathogenic, were found at higher frequency in those with a history of cancer than in the general patient population. There was a higher background prevalence of genetic variants linked to familial cancers in this cohort than expected based on prevalence in other populations.
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- 2023
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31. GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.
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Pairo-Castineira E, Rawlik K, Bretherick AD, Qi T, Wu Y, Nassiri I, McConkey GA, Zechner M, Klaric L, Griffiths F, Oosthuyzen W, Kousathanas A, Richmond A, Millar J, Russell CD, Malinauskas T, Thwaites R, Morrice K, Keating S, Maslove D, Nichol A, Semple MG, Knight J, Shankar-Hari M, Summers C, Hinds C, Horby P, Ling L, McAuley D, Montgomery H, Openshaw PJM, Begg C, Walsh T, Tenesa A, Flores C, Riancho JA, Rojas-Martinez A, Lapunzina P, Yang J, Ponting CP, Wilson JF, Vitart V, Abedalthagafi M, Luchessi AD, Parra EJ, Cruz R, Carracedo A, Fawkes A, Murphy L, Rowan K, Pereira AC, Law A, Fairfax B, Hendry SC, and Baillie JK
- Subjects
- Humans, Genotype, Genotyping Techniques, Monocytes metabolism, Phenotype, rab GTP-Binding Proteins genetics, Transcriptome, Whole Genome Sequencing, COVID-19 genetics, Critical Illness, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Genome-Wide Association Study
- Abstract
Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown
1 to be highly efficient for discovery of genetic associations2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A)., (© 2023. The Author(s).)- Published
- 2023
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32. Clinicopathologic and genomic characterizations of brain metastases using a comprehensive genomic panel.
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Barakeh DH, Alsolme E, Alqubaishi F, Almutairi A, Alhabeeb L, Al Abdulmohsen S, Almohsen SS, Alayed D, AlAnazi SR, AlZahrani M, Binowayn AM, AlOtaibi SS, Alkhureeb FA, Al Shakweer W, Al-Hindi H, Alassiri A, Robinson HA, and Abedalthagafi M
- Abstract
Central nervous system (CNS) metastasis is the most common brain tumor type in adults. Compared to their primary tumors, these metastases undergo a variety of genetic changes to be able to survive and thrive in the complex tissue microenvironment of the brain. In clinical settings, the majority of traditional chemotherapies have shown limited efficacy against CNS metastases. However, the discovery of potential driver mutations, and the development of drugs specifically targeting affected signaling pathways, could change the treatment landscape of CNS metastasis. Genetic studies of brain tumors have so far focused mainly on common cancers in western populations. In this study, we performed Next Generation Sequencing (NGS) on 50 pairs of primary tumors, including but not limited to colorectal, breast, renal and thyroid tumors, along with their brain metastatic tumor tissue counterparts, from three different local tertiary centers in Saudi Arabia. We identified potentially clinically relevant mutations in brain metastases that were not detected in corresponding primary tumors, including mutations in the PI3K, CDK, and MAPK pathways. These data highlight the differences between primary cancers and brain metastases and the importance of acquiring and analyzing brain metastatic samples for further clinical management., 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 Barakeh, Alsolme, Alqubaishi, Almutairi, Alhabeeb, Al Abdulmohsen, Almohsen, Alayed, AlAnazi, AlZahrani, Binowayn, AlOtaibi, Alkhureeb, Al Shakweer, Al-Hindi, Alassiri, Robinson and Abedalthagafi.)
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- 2022
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33. Editorial: Women in science: Genetics.
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de Vasconcellos JF, Abedalthagafi M, Calo S, Dajani R, Dlamini Z, Hidalgo B, Le Goff C, and Vasanthakumar A
- Abstract
Competing Interests: Author AV was employed by the company AbbVie. The remaining 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.
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- 2022
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34. Commentary: Von Hippel-Lindau disease: A clinical and scientific review.
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Abedalthagafi M
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- Humans, von Hippel-Lindau Disease diagnosis, von Hippel-Lindau Disease genetics
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- 2022
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35. Expression of Programmed Cell Death-L1 (PD-L1) Protein and Mismatch Repair Mutations in Orbital Tumours-a Pilot Study.
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AlSemari MA, Strianese D, Abu Safieh L, Al Hussain H, Abedalthagafi M, and Edward DP
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- Apoptosis, Apoptosis Regulatory Proteins genetics, B7-H1 Antigen genetics, B7-H1 Antigen metabolism, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Brain Neoplasms, Colorectal Neoplasms, DNA Mismatch Repair genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Humans, Mutation, Neoplastic Syndromes, Hereditary, Pilot Projects, Programmed Cell Death 1 Receptor genetics, Orbital Neoplasms genetics, Rhabdomyosarcoma genetics
- Abstract
Purpose: Programmed cell death protein 1 (PD-1) and DNA mismatch repair (MMR) deficiency play an important role in tumour progression and response to treatment.Both markers have been studied in some ocular tumours but little is known about these markers in orbital tumours. This pilot study reports on PD-L1 expression and MMR mutations using next generation sequencing (NGS) in specific orbital tumours., Methods: We reviewed surgical specimens from patients with rhabdomyosarcoma, adenoid cystic carcinoma (ACC), pleomorphic adenoma (PA) and biopsy negative tissue from orbital tumours used as a control. immunohistochemistry (IHC) was performed on Formalin fixed paraffin embedded tissue using a PD-L1 antibody. DNA was extracted for targeted gene panel NGS of the MMR genes PMS2 , MLH1 , MSH6 and MSH2 ., Results: The study included 17 orbital specimens. Scattered membrane PD-L1 staining was noted in 3/6 rhabdomyosarcoma specimens without an accompanying lymphocytic infiltrate. PD-L1 immunostaining was absent in 3/3 ACC, and 5/6 PA specimens. PD-L1 immunostaining was not detected in 2/2 control specimens. 4/17 samples shared the same pathogenic mutation in the MLH1 gene, including 3/6 rhabdomyosarcoma and 1/3 ACC samples. 1/6 PA samples had a mutation in MSH6 ., Conclusions: Our study demonstrated scattered, non-quantifiable or absent PD-L1 staining in a limited sample of orbital tumours suggesting that PD-1/PD-L1 inhibitor therapy may not be useful in treatment of malignant orbital tumours (rhabdomyosarcoma and ACC) when refractory to conventional therapy. Our pilot study suggest that PD-L1/MMR axis might not play a major role in the pathogenesis of primary orbital tumour.
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- 2022
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36. Periocular Pigmented Basal Cell Carcinomas: Clinicopathologic Features and Mutational Profile.
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Hassanin F, Al Hussain H, Maktabi A, Adly N, Alsuabeyl M, Abedalthagafi M, Edward DP, and Strianese D
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- Female, Humans, Male, Mutation, Skin pathology, Carcinoma, Basal Cell genetics, Carcinoma, Basal Cell pathology, Eyelid Neoplasms genetics, Eyelid Neoplasms pathology, Skin Neoplasms genetics, Skin Neoplasms pathology
- Abstract
Purpose: Pigmented basal cell carcinomas (PBCC) is an uncommon variant of basal cell carcinoma of the periocular region with limited information in the literature. We highlight the clinicopathological profile and somatic mutations in periocular PBCC., Methods: The clinicopathological features and somatic mutations in patients with periocular PBCC were examined and compared with periocular non-PBCC reported in the literature. Next-generation sequencing panel analysis for the excised tumors identified somatic mutations., Results: In a total of 31 patients, PBCC was common in females (54%; p = 0.03); as a unilateral lower eyelid (n = 22; 71%), solitary mass (n = 30; 98%). Pathologic subtypes were variable. Most were nodular or mixed variants (n = 23; 74%). During the follow up (2.5-4.5 years), 1 patient (3.5%) had a recurrence. The clinical and pathologic features of PBCC were similar to those reported in nonperiocular locations. Somatic mutations detected in 25/31 tumors. Variants in 50/161 genes in the panel were noted. PTCH1 (14/31), TERT (12/31), and SMO (7/31) variants were common. Fifteen patients had novel drivers, including POLE, FANCD2, and CREBBP. SMO mutations were significantly more common in females (7/7), lower eyelid (5/7), and TERT mutations were more common in nodular subtype (10/12)., Conclusions: In this large cohort of a relatively uncommon variant of BCC, the clinicopathological features and tumor behavior of PBCC was similar to periocular non-PBCC. The somatic mutation spectrum of PBCC resembles that reported in nonperiocular cutaneous BCC with novel drivers identified. We identified several potential actionable mutations that could be targeted with molecular therapy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)
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- 2022
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37. A molecularly integrated grade for meningioma.
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Driver J, Hoffman SE, Tavakol S, Woodward E, Maury EA, Bhave V, Greenwald NF, Nassiri F, Aldape K, Zadeh G, Choudhury A, Vasudevan HN, Magill ST, Raleigh DR, Abedalthagafi M, Aizer AA, Alexander BM, Ligon KL, Reardon DA, Wen PY, Al-Mefty O, Ligon AH, Dubuc AM, Beroukhim R, Claus EB, Dunn IF, Santagata S, and Bi WL
- Subjects
- Adult, Cohort Studies, Humans, Neoplasm Grading, Neoplasm Recurrence, Local genetics, Prognosis, Retrospective Studies, World Health Organization, Meningeal Neoplasms pathology, Meningioma pathology
- Abstract
Background: Meningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management., Methods: We evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms., Results: We developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score., Conclusion: We propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
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- 2022
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38. Index case identification and outcomes of cascade testing in high-risk breast and colorectal cancer predisposition genes.
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Abedalthagafi M
- Subjects
- Female, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Humans, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Colorectal Neoplasms diagnosis, Colorectal Neoplasms genetics
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- 2022
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39. The Saudi Critical Care Society practice guidelines on the management of COVID-19 in the ICU: Therapy section.
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Alhazzani W, Alshahrani M, Alshamsi F, Aljuhani O, Eljaaly K, Hashim S, Alqahtani R, Alsaleh D, Al Duhailib Z, Algethamy H, Al-Musawi T, Alshammari T, Alqarni A, Khoujah D, Tashkandi W, Dahhan T, Almutairi N, Alserehi HA, Al-Yahya M, Al-Judaibi B, Arabi YM, Abualenain J, Alotaibi JM, Al Bshabshe A, Alharbi R, Al-Hameed F, Elhazmi A, Almaghrabi RS, Almaghlouth F, Abedalthagafi M, Al Khathlan N, Al-Suwaidan FA, Bunyan RF, Baw B, Alghamdi G, Al Hazmi M, Mandourah Y, Assiri A, Enani M, Alawi M, Aljindan R, Aljabbary A, Alrbiaan A, Algurashi F, Alsaawi A, Alenazi TH, Alsultan MA, Alqahtani SA, Memish Z, Al-Tawfiq JA, and Al-Jedai A
- Subjects
- Critical Care, Humans, Intensive Care Units, SARS-CoV-2, Saudi Arabia, COVID-19
- Abstract
Background: The rapid increase in coronavirus disease 2019 (COVID-19) cases during the subsequent waves in Saudi Arabia and other countries prompted the Saudi Critical Care Society (SCCS) to put together a panel of experts to issue evidence-based recommendations for the management of COVID-19 in the intensive care unit (ICU)., Methods: The SCCS COVID-19 panel included 51 experts with expertise in critical care, respirology, infectious disease, epidemiology, emergency medicine, clinical pharmacy, nursing, respiratory therapy, methodology, and health policy. All members completed an electronic conflict of interest disclosure form. The panel addressed 9 questions that are related to the therapy of COVID-19 in the ICU. We identified relevant systematic reviews and clinical trials, then used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach as well as the evidence-to-decision framework (EtD) to assess the quality of evidence and generate recommendations., Results: The SCCS COVID-19 panel issued 12 recommendations on pharmacotherapeutic interventions (immunomodulators, antiviral agents, and anticoagulants) for severe and critical COVID-19, of which 3 were strong recommendations and 9 were weak recommendations., Conclusion: The SCCS COVID-19 panel used the GRADE approach to formulate recommendations on therapy for COVID-19 in the ICU. The EtD framework allows adaptation of these recommendations in different contexts. The SCCS guideline committee will update recommendations as new evidence becomes available., (Copyright © 2021. Published by Elsevier Ltd.)
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- 2022
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40. The History and Challenges of Women in Genetics: A Focus on Non-Western Women.
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Elbardisy H and Abedalthagafi M
- Abstract
"Women in much of the world lack support for fundamental functions of a human life." This truthful portrait was pointed out by Martha Nussbaum in her book " Introduction: Feminism & International Development." Throughout history, gender inequality has been persistent in many aspects of life, including health and empowerment. Unfortunately, this inequality has not been excluded from the field of science. Perpetual assumption that women's absence or restriction to secondary roles in various disciplines is an acceptable law of nature misrepresents women's contribution to science and maintains hurdles for participation in the future. According to a recent UNESCO's report, women make up only 30% of researchers worldwide. But despite all the obstacles, women made major contributions with discoveries that shaped the progress in many scientific fields. In the field of genetics, Rosalind Franklin is an example of unwittingly compromised women's scientific achievements. Franklin was an expert in X-ray crystallography; her data, especially the "photo 51," was critical to James Watson and Francis Crick along with their own data to publish the discovery of the double helix DNA structure in 1953. Her contribution was acknowledged posthumously in Watson's memoir in 1968. Barbara McClintock was a 20th century American cytogeneticist who remains up to date the only woman receiving an unshared Nobel prize in Physiology or Medicine. McClintock dedicated her work to cytogenetics and discovered the phenomenon of mobile genes. Her research was initially subjected to skepticism in the 1950s. It was not until the late 1960s that the community realized the significance of McClintock's discovery. The history of science is occupied with a myriad of similar tales of such inspiring women that, after tremendous struggles, thrived and achieved breakthroughs in their respective fields. It is prominent our limited knowledge of women's experience and struggle in science in non-western world. Addressing the stories of this outstanding minority is critical to expand the understanding of the gender disparity factors embedded in diverse cultures. In this article, we attempt to put the spotlight on some fascinating non-western women and their significant contributions to the field of genetics., 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 Elbardisy and Abedalthagafi.)
- Published
- 2021
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41. The clinico-pathologic profile of primary and recurrent orbital/periorbital plexiform neurofibromas (OPPN).
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Alabduljabbar M, Strianese D, Al-Sheikh O, Alkatan HM, Al-Hussain H, Maktabi AMY, Khandekar R, Abedalthagafi M, and Edward DP
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local epidemiology, Neurofibroma, Plexiform epidemiology, Prognosis, Retrospective Studies, Saudi Arabia epidemiology, Young Adult, Neoplasm Recurrence, Local pathology, Neurofibroma, Plexiform pathology
- Abstract
To evaluate and compare the clinical and histopathological profile of primary and recurrent orbital-periorbital plexiform neurofibromas (OPPN) in patients with neurofibromatosis type 1. We retrospectively evaluated 43 primary or recurrent neurofibroma (NF) specimens from 26 patients (2002 to 2018) at the King Khaled Eye Specialist Hospital, Saudi Arabia. Demographics, clinical presentation, and surgical intervention data were collected. Histopathological specimens were studied with hematoxylin-eosin, Alcian blue, and immunohistochemical markers; S-100, CD44, CD117, smooth muscle actin (SMA), neurofilament, and Ki-67. Of the 43 NFs specimens, 20 were primary and 23 recurrent tumors. For primary NF, the ratio of plexiform to the diffuse type was 13:7, however in recurrent tumors was 3:8 after the first recurrence, and 1:5 after multiple recurrences. Of the 17 patients with primary tumors that had paired recurrent tumors, 12/17 (70.6%) primary NFs were plexiform and 5/17 (29.4%) were diffuse. However, when tumors recurred, 13/17 tumors (76.5%) were diffuse and only 4/17 tumors (23.5%) had a plexiform pattern. The odds of a tumor having a diffuse pattern in recurrent NF was significantly higher than the plexiform pattern [OR = 7.8 (95% confidence interval 1.69:36.1) P = 0.008]. Primary plexiform NFs underwent an excision at a significantly younger age than the diffuse type. Recurrent NFs had significantly higher CD44, CD117, and neurofilament labeling (P = 0.02, P = 0.01 and P<0.001 respectively) but had significantly decreased Alcian blue, and S-100 labeling (P = 0.03, and P = 0.02 respectively) compared to primary tumors. SMA and Ki-67 proliferation index were not different between primary and recurrent NFs (P = 0.86, and P = 0.3 respectively). There appears to be a high risk for primary plexiform NFs to develop a diffuse histologic pattern when they recur. Immunohistochemical staining suggests a role of mast cells (CD117) and expression of infiltration makers (CD44) in the transformation of plexiform tumors to the diffuse phenotype., Competing Interests: The authors have declared that no competing interests exist.
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- 2021
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42. Fabrication of a Lateral Flow Assay for Rapid In-Field Detection of COVID-19 Antibodies Using Additive Manufacturing Printing Technologies.
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Alrashoudi AA, Albalawi HI, Aldoukhi AH, Moretti M, Bilalis P, Abedalthagafi M, and Hauser CAE
- Abstract
The development of lateral flow immunoassay (LFIA) using three-dimensional (3D) printing and bioprinting technologies can enhance and accelerate the optimization process of the fabrication. Therefore, the main goal of this study is to investigate methods to speed up the developing process of a LFIA as a tool for community screening. To achieve this goal, an in-house developed robotic arm and microfluidic pumps were used to print the proteins during the development of the test. 3D printing technologies were used to design and print the housing unit for the testing strip. The proposed design was made by taking into consideration the environmental impact of this disposable medical device., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2021 Alrashoudi, et al.)
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- 2021
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43. Editorial: Genomics and Epigenomics of Cancer Immunotherapy: Challenges and Clinical Implications.
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Abedalthagafi M
- Abstract
Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2021
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44. Immune profiling of pituitary tumors reveals variations in immune infiltration and checkpoint molecule expression.
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Mei Y, Bi WL, Agolia J, Hu C, Giantini Larsen AM, Meredith DM, Al Abdulmohsen S, Bale T, Dunn GP, Abedalthagafi M, and Dunn IF
- Subjects
- Humans, Immunohistochemistry, MutS Proteins, Neoplasm Recurrence, Local, Tumor Microenvironment, B7-H1 Antigen, Pituitary Neoplasms genetics
- Abstract
Purpose: Pituitary tumors are the second most common primary brain tumors. Functional tumors demonstrate increased PD-L1 expression, but expression of other checkpoint regulators has not been characterized. We sought to characterize the immune microenvironment of human pituitary tumors to identify new treatment opportunities., Methods: 72 pituitary tumors were evaluated for expression of the immune regulatory markers programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), V-domain Ig suppressor of T cell activation (VISTA), lymphocyte activation gene 3 (LAG3) and tumor necrosis factor receptor superfamily member 4 (OX40) by immunohistochemistry (IHC). Lymphocyte infiltration, macrophage infiltration, and angiogenesis were analyzed using IHC. Expression of pituitary tumor initiating cell marker CD15 and mismatch repair proteins MutS protein homolog 2 (MSH2) and MutS protein homolog 6 (MSH6) was also assessed., Results: Pituitary tumors were infiltrated by macrophages and T cells, and they expressed varying levels of PD-L1, PD-L2, VISTA, LAG3, and OX40. Functional tumors and tumors with high expression of tumor stem cell markers had higher immune cell infiltration and greater expression of immunosuppressive checkpoint regulators. Increased PD-L1 and LAG3 and reduced VISTA were observed in primary tumors compared to recurrent tumors., Conclusion: Immune cell infiltration and checkpoint regulator expression vary depending on functional status and presence of pituitary tumor initiating cells. Functional tumors may have a particularly immunosuppressive microenvironment. Further studies of immune checkpoint blockade of pituitary tumors, particularly functional tumors, are warranted, though combination therapy may be required.
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- 2021
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45. Epigenomics and immunotherapeutic advances in pediatric brain tumors.
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Abedalthagafi M, Mobark N, Al-Rashed M, and AlHarbi M
- Abstract
Brain tumors are the leading cause of childhood cancer-related deaths. Similar to adult brain tumors, pediatric brain tumors are classified based on histopathological evaluations. However, pediatric brain tumors are often histologically inconsistent with adult brain tumors. Recent research findings from molecular genetic analyses have revealed molecular and genetic changes in pediatric tumors that are necessary for appropriate classification to avoid misdiagnosis, the development of treatment modalities, and the clinical management of tumors. As many of the molecular-based therapies developed from clinical trials on adults are not always effective against pediatric brain tumors, recent advances have improved our understanding of the molecular profiles of pediatric brain tumors and have led to novel epigenetic and immunotherapeutic treatment approaches currently being evaluated in clinical trials. In this review, we focus on primary malignant brain tumors in children and genetic, epigenetic, and molecular characteristics that differentiate them from brain tumors in adults. The comparison of pediatric and adult brain tumors highlights the need for treatments designed specifically for pediatric brain tumors. We also discuss the advancements in novel molecularly targeted drugs and how they are being integrated with standard therapy to improve the classification and outcomes of pediatric brain tumors in the future.
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- 2021
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46. Landscape of somatic mutations in breast cancer: new opportunities for targeted therapies in Saudi Arabian patients.
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Barakeh DH, Aljelaify R, Bashawri Y, Almutairi A, Alqubaishi F, Alnamnakani M, Almubarak L, Al Naeem A, Almushawah F, Alrashed M, and Abedalthagafi M
- Abstract
Breast cancer (BCa) ranks first in incidence rate among cancers in Arab females. The association between genetic polymorphisms in tumor suppressor genes and the risk of BCa has been studied in many ethnic populations with conflicting conclusions while Arab females and Saudi Arabian studies are still lacking. We screened a cohort of Saudi BCa patients by NGS using a bespoke gene panel to clarify the genetic landscape of this population, correlating and assessing genetic findings with clinical outcomes. We identified a total of 263 mutations spanning 51 genes, including several frequently mutated. Among the genes analyzed, the highest mutation rates were found in PIK3CA (12.9%), BRCA2 (11.7%), BRCA1 (10.2%), TP53 (6.0%), MSH2 (3.8%), PMS2 (3.8%), BARD1 (3.8%), MLH1 (3.4%), CDH1 (3.0%), RAD50 (3.0%), MSH6 (3.0%), NF1 (2.6%), in addition to others. We identified multiple common recurrent variants and previously reported mutations. We also identified 46 novel variants in 22 genes that were predicted to have a pathogenic effect. Survival analysis according to the four most common mutations (BRCA1, BRCA2, TP53, and PIK3CA) showed reduced survival in BRCA1 and BRCA2-mutant patients compared to total patients. Moreover, BRCA2 was demonstrated as an independent predictor of reduced survival using independent Cox proportional hazard models. We reveal the landscape of the mutations associated with BCa in Saudi women, highlighting the importance of routine genetic sequencing in implementation of precision therapies in KSA., Competing Interests: CONFLICTS OF INTEREST The authors have no competing interests or other interests that might be perceived to influence the results and discussion reported in this paper., (Copyright: © 2021 Barakeh et al.)
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- 2021
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47. Immunophenotype of Vestibular Schwannomas.
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Bi WL, Gupta S, Mei Y, Abdulmohsen SA, Giantini Larsen A, Unadkat P, Ramkissoon S, Abedalthagafi M, and Dunn IF
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- Biomarkers, Tumor, Humans, Macrophages, Neoplasm Recurrence, Local, Tumor Burden, Tumor Microenvironment, Neuroma, Acoustic diagnostic imaging
- Abstract
Background: Vestibular schwannomas exhibit a uniquely variable natural history of growth, stability, or even spontaneous regression. We hypothesized that a transitory population of immune cells, or immunomodulation of tumors cells, may influence the growth pattern of schwannomas. We therefore sought to characterize the impact of the immune microenvironment on schwannoma behavior., Methods: Forty-eight vestibular schwannomas with preoperative magnetic resonance imaging and 11 with serial imaging were evaluated for presence of immune infiltrates (including the pan-leukocyte marker Cluster of Differentiation (CD)45, CD4 and CD8 T-cell, and CD68 and CD163 macrophages) as well as expression of immunomodulatory regulators (Programmed Death Ligand 1 (PD-L1), Programmed Death Ligand 2 (PD-L2), LAG-3, TIM-3, V-domain Ig Suppressor of T cell Activation). Maximal diameter, volume, and recurrence were annotated., Results: Vestibular schwannomas were characterized by diverse signatures of tumor infiltrating leukocytes and immunomodulatory markers. The median tumor volume was 4.7 cm (Interquartile Range (IQR) 1.0-13.0) and maximum diameter was 2.3 cm (IQR 1.5-3.2). Among tumors with serial imaging, the median volumetric growth was 0.04 cm/mo (IQR 0.01-0.18). Tumor volume and maximum diameter demonstrated strong concordance (R = 0.90; p < 0.001). Vestibular schwannoma volume was positively associated with CD4, CD68, and CD163, but not CD8, immune infiltration (all p < 0.05). Tumor growth was positively associated with CD163 and PD-L1 (both p < 0.05). Further, CD163 modified this effect: the relationship between PD-L1 and growth strengthened with increasing CD163 infiltration (R = 0.81, p = 0.007). No other immune cell types modified this relationship. These associations were inconsistently observed for maximum diameter and linear growth., Conclusion: Vestibular schwannomas demonstrate variable expression of immune regulatory markers as well as immune infiltrates. Tumor size is associated with immune infiltrates and tumor growth is associated with PD-L1, especially in the presence of M2-subtype macrophages. Volumetric measures may associate with the biological signature more accurately than linear parameters. Future exploration of the role of immune modulation in select schwannomas will further enhance our understanding of the biology of these tumors and suggest potential therapeutic avenues for control of tumor growth.
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- 2020
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48. Genomic Profiling of Circulating Tumor DNA From Cerebrospinal Fluid to Guide Clinical Decision Making for Patients With Primary and Metastatic Brain Tumors.
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Ramkissoon LA, Pegram W, Haberberger J, Danziger N, Lesser G, Strowd R, Dahiya S, Cummings TJ, Bi WL, Abedalthagafi M, Sathyan P, McGregor K, Reddy P, Severson E, Williams E, Lin D, Edgerly C, Huang RSP, Hemmerich A, Creeden J, Brown C, Venstrom J, Hegde P, Ross JS, Alexander BM, Elvin J, and Ramkissoon SH
- Abstract
Despite advances in systemic therapies for solid tumors, the development of brain metastases remains a significant contributor to overall cancer mortality and requires improved methods for diagnosing and treating these lesions. Similarly, the prognosis for malignant primary brain tumors remains poor with little improvement in overall survival over the last several decades. In both primary and metastatic central nervous system (CNS) tumors, the challenge from a clinical perspective centers on detecting CNS dissemination early and understanding how CNS lesions differ from the primary tumor, in order to determine potential treatment strategies. Acquiring tissue from CNS tumors has historically been accomplished through invasive neurosurgical procedures, which restricts the number of patients to those who can safely undergo a surgical procedure, and for which such interventions will add meaningful value to the care of the patient. In this review we discuss the potential of analyzing cell free DNA shed from tumor cells that is contained within the cerebrospinal fluid (CSF) as a sensitive and minimally invasive method to detect and characterize primary and metastatic tumors in the CNS., (Copyright © 2020 Ramkissoon, Pegram, Haberberger, Danziger, Lesser, Strowd, Dahiya, Cummings, Bi, Abedalthagafi, Sathyan, McGregor, Reddy, Severson, Williams, Lin, Edgerly, Huang, Hemmerich, Creeden, Brown, Venstrom, Hegde, Ross, Alexander, Elvin and Ramkissoon.)
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- 2020
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49. iSCAN: An RT-LAMP-coupled CRISPR-Cas12 module for rapid, sensitive detection of SARS-CoV-2.
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Ali Z, Aman R, Mahas A, Rao GS, Tehseen M, Marsic T, Salunke R, Subudhi AK, Hala SM, Hamdan SM, Pain A, Alofi FS, Alsomali A, Hashem AM, Khogeer A, Almontashiri NAM, Abedalthagafi M, Hassan N, and Mahfouz MM
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- COVID-19, COVID-19 Testing, Clinical Laboratory Techniques instrumentation, Colorimetry instrumentation, Coronavirus Infections virology, Endodeoxyribonucleases chemistry, Humans, Molecular Diagnostic Techniques instrumentation, Nucleic Acid Amplification Techniques instrumentation, Pandemics, Pneumonia, Viral virology, Point-of-Care Systems, Rheology, SARS-CoV-2, Sensitivity and Specificity, Betacoronavirus genetics, CRISPR-Cas Systems, Clinical Laboratory Techniques methods, Colorimetry methods, Coronavirus Infections diagnosis, Molecular Diagnostic Techniques methods, Nucleic Acid Amplification Techniques methods, Pneumonia, Viral diagnosis
- Abstract
The COVID-19 pandemic caused by SARS-CoV-2 affects all aspects of human life. Detection platforms that are efficient, rapid, accurate, specific, sensitive, and user friendly are urgently needed to manage and control the spread of SARS-CoV-2. RT-qPCR based methods are the gold standard for SARS-CoV-2 detection. However, these methods require trained personnel, sophisticated infrastructure, and a long turnaround time, thereby limiting their usefulness. Reverse transcription-loop-mediated isothermal amplification (RT-LAMP), a one-step nucleic acid amplification method conducted at a single temperature, has been used for colorimetric virus detection. CRISPR-Cas12 and CRISPR-Cas13 systems, which possess collateral activity against ssDNA and RNA, respectively, have also been harnessed for virus detection. Here, we built an efficient, rapid, specific, sensitive, user-friendly SARS-CoV-2 detection module that combines the robust virus amplification of RT-LAMP with the specific detection ability of SARS-CoV-2 by CRISPR-Cas12. Furthermore, we combined the RT-LAMP-CRISPR-Cas12 module with lateral flow cells to enable highly efficient point-of-care SARS-CoV-2 detection. Our iSCAN SARS-CoV-2 detection module, which exhibits the critical features of a robust molecular diagnostic device, should facilitate the effective management and control of COVID-19., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2020
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50. Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy.
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Del Caño-Ochoa F, Ng BG, Abedalthagafi M, Almannai M, Cohn RD, Costain G, Elpeleg O, Houlden H, Karimiani EG, Liu P, Manzini MC, Maroofian R, Muriello M, Al-Otaibi A, Patel H, Shimon E, Sutton VR, Toosi MB, Wolfe LA, Rosenfeld JA, Freeze HH, and Ramón-Maiques S
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- Cell Line, Dihydroorotase, Humans, Uridine, Aspartate Carbamoyltransferase, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)
- Abstract
Purpose: Pathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the nonspecific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy., Methods: Using CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype., Results: We identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype., Conclusions: We designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD-deficient individuals who could benefit from uridine therapy.
- Published
- 2020
- Full Text
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