95 results on '"Frank Martiniuk"'
Search Results
2. Increasing Virulence in Leprosy Indicated by Global Mycobacterium spp.
- Author
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William Levis, Tina Rendini, and Frank Martiniuk
- Subjects
Mycobacterium lepromatosis ,leprae ,Lucio's phenomenon ,leprosy ,leprosy bonita ,autochthonous ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Published
- 2018
- Full Text
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3. Leprosy as Immune Reconstitution Inflammatory Syndrome in HIV-positive Persons
- Author
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Frank Martiniuk, Shaline D. Rao, Thomas H. Rea, Michael S. Glickman, Jerome Giovinazzo, William N. Rom, Aloys Cabrera, and William R. Levis
- Subjects
HAART ,Mycobacterium leprae ,subclinical ,HIV ,heat shock 65 ,hsp65 ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Published
- 2007
- Full Text
- View/download PDF
4. New insights into the genetic etiology of Alzheimer's disease and related dementias
- Author
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Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., Holmans, P. A., Boland, A., Damotte, V., van der Lee, S. J., Costa, M. R., Kuulasmaa, T., Yang, Q., de Rojas, I., Bis, J. C., Yaqub, A., Prokic, I., Chapuis, J., Ahmad, S., Giedraitis, V., Aarsland, D., Garcia-Gonzalez, P., Abdelnour, C., Alarcón-Martín, E., Alcolea, D., Alegret, M., Alvarez, I., Álvarez, V., Armstrong, N. J., Tsolaki, A., Antúnez, C., Appollonio, I., Arcaro, M., Archetti, S., Pastor, A. A., Arosio, B., Athanasiu, L., Bailly, H., Banaj, N., Baquero, M., Barral, S., Beiser, A., Pastor, A. B., Below, J. E., Benchek, P., Benussi, L., Berr, C., Besse, C., Bessi, V., Binetti, G., Bizarro, A., Blesa, R., Boada, M., Boerwinkle, E., Borroni, B., Boschi, S., Bossù, P., Bråthen, G., Bressler, J., Bresner, C., Brodaty, H., Brookes, K. J., Brusco, L. I., Buiza-Rueda, D., Bûrger, K., Burholt, V., Bush, W. S., Calero, M., Cantwell, L. B., Chene, G., Chung, J., Cuccaro, M. L., Carracedo, Á., Cecchetti, R., Cervera-Carles, L., Charbonnier, C., Chen, H. -H., Chillotti, C., Ciccone, S., Claassen, J. A. H. R., Clark, C., Conti, E., Corma-Gómez, A., Costantini, E., Custodero, C., Daian, D., Dalmasso, M. C., Daniele, A., Dardiotis, E., Dartigues, J. -F., de Deyn, P. P., de Paiva Lopes, K., de Witte, L. D., Debette, S., Deckert, J., del Ser, T., Denning, N., Destefano, A., Dichgans, M., Diehl-Schmid, J., Diez-Fairen, M., Rossi, P. D., Djurovic, S., Duron, E., Düzel, E., Dufouil, C., Eiriksdottir, G., Engelborghs, S., Escott-Price, V., Espinosa, A., Ewers, M., Faber, K. M., Fabrizio, T., Nielsen, S. F., Fardo, D. W., Farotti, L., Fenoglio, C., Fernández-Fuertes, M., Ferrari, R., Ferreira, C. B., Ferri, E., Fin, B., Fischer, P., Fladby, T., Fließbach, K., Fongang, B., Fornage, M., Fortea, J., Foroud, T. M., Fostinelli, S., Fox, N. C., Franco-Macías, E., Bullido, M. J., Frank-García, A., Froelich, L., Fulton-Howard, B., Galimberti, D., García-Alberca, J. M., García-González, P., Garcia-Madrona, S., Garcia-Ribas, G., Ghidoni, R., Giegling, I., Giorgio, G., Goate, A. M., Goldhardt, O., Gomez-Fonseca, D., González-Pérez, A., Graff, C., Grande, G., Green, E., Grimmer, T., Grünblatt, E., Grunin, M., Gudnason, V., Guetta-Baranes, T., Haapasalo, A., Hadjigeorgiou, G., Haines, J. L., Hamilton-Nelson, K. L., Hampel, H., Hanon, O., Hardy, J., Hartmann, A. M., Hausner, L., Harwood, J., Heilmann-Heimbach, S., Helisalmi, S., Heneka, M. T., Hernández, I., Herrmann, M. J., Hoffmann, P., Holmes, C., Holstege, H., Vilas, R. H., Hulsman, M., Humphrey, J., Biessels, G. J., Jian, X., Johansson, C., Jun, G. R., Kastumata, Y., Kauwe, J., Kehoe, P. G., Kilander, L., Ståhlbom, A. K., Kivipelto, M., Koivisto, A., Kornhuber, J., Kosmidis, M. H., Kukull, W. A., Kuksa, P. P., Kunkle, B. W., Kuzma, A. B., Lage, C., Laukka, E. J., Launer, L., Lauria, A., Lee, C. -Y., Lehtisalo, J., Lerch, O., Lleó, A., Longstreth, W., Lopez, O., de Munain, A. L., Love, S., Löwemark, M., Luckcuck, L., Lunetta, K. L., Ma, Y., Macías, J., Macleod, C. A., Maier, W., Mangialasche, F., Spallazzi, M., Marquié, M., Marshall, R., Martin, E. R., Montes, A. M., Rodríguez, C. M., Masullo, C., Mayeux, R., Mead, S., Mecocci, P., Medina, M., Meggy, A., Mehrabian, S., Mendoza, S., Menéndez-González, M., Mir, P., Moebus, S., Mol, M., Molina-Porcel, L., Montrreal, L., Morelli, L., Moreno, F., Morgan, K., Mosley, T., Nöthen, M. M., Muchnik, C., Mukherjee, S., Nacmias, B., Ngandu, T., Nicolas, G., Nordestgaard, B. G., Olaso, R., Orellana, A., Orsini, M., Ortega, G., Padovani, A., Paolo, C., Papenberg, G., Parnetti, L., Pasquier, F., Pastor, P., Peloso, G., Pérez-Cordón, A., Pérez-Tur, J., Pericard, P., Peters, O., Pijnenburg, Y. A. L., Pineda, J. A., Piñol-Ripoll, G., Pisanu, C., Polak, T., Popp, J., Posthuma, D., Priller, J., Puerta, R., Quenez, O., Quintela, I., Thomassen, J. Q., Rábano, A., Rainero, I., Rajabli, F., Ramakers, I., Real, L. M., Reinders, M. J. T., Reitz, C., Reyes-Dumeyer, D., Ridge, P., Riedel-Heller, S., Riederer, P., Roberto, N., Rodriguez-Rodriguez, E., Rongve, A., Allende, I. R., Rosende-Roca, M., Royo, J. L., Rubino, E., Rujescu, D., Sáez, M. E., Sakka, P., Saltvedt, I., Sanabria, Á., Sánchez-Arjona, M. B., Sanchez-Garcia, F., Juan, P. S., Sánchez-Valle, R., Sando, S. B., Sarnowski, C., Satizabal, C. L., Scamosci, M., Scarmeas, N., Scarpini, E., Scheltens, P., Scherbaum, N., Scherer, M., Schmid, M., Schneider, A., Schott, J. M., Selbæk, G., Seripa, D., Serrano, M., Sha, J., Shadrin, A. A., Skrobot, O., Slifer, S., Snijders, G. J. L., Soininen, H., Solfrizzi, V., Solomon, A., Song, Y. E., Sorbi, S., Sotolongo-Grau, O., Spalletta, G., Spottke, A., Squassina, A., Stordal, E., Tartan, J. P., Tárraga, L., Tesí, N., Thalamuthu, A., Thomas, T., Tosto, G., Traykov, L., Tremolizzo, L., Tybjærg-Hansen, A., Uitterlinden, A., Ullgren, A., Ulstein, I., Valero, S., Valladares, O., Broeckhoven, C. V., Vance, J., Vardarajan, B. N., van der Lugt, A., Dongen, J. V., van Rooij, J., van Swieten, J., Vandenberghe, R., Verhey, F., Vidal, J. -S., Vogelgsang, J., Vyhnalek, M., Wagner, M., Wallon, D., Wang, L. -S., Wang, R., Weinhold, L., Wiltfang, J., Windle, G., Woods, B., Yannakoulia, M., Zare, H., Zhao, Y., Zhang, X., Zhu, C., Zulaica, M., Laczo, J., Matoska, V., Serpente, M., Assogna, F., Piras, F., Ciullo, V., Shofany, J., Ferrarese, C., Andreoni, S., Sala, G., Zoia, C. P., Zompo, M. D., Benussi, A., Bastiani, P., Takalo, M., Natunen, T., Laatikainen, T., Tuomilehto, J., Antikainen, R., Strandberg, T., Lindström, J., Peltonen, M., Abraham, R., Al-Chalabi, A., Bass, N. J., Brayne, C., Brown, K. 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M., Pickering-Brown, S., Sussams, R., Warner, N., Bayer, A., Heuser, I., Drichel, D., Klopp, N., Mayhaus, M., Riemenschneider, M., Pinchler, S., Feulner, T., Gu, W., van den Bussche, H., Hüll, M., Frölich, L., Wichmann, H. -E., Jöckel, K. -H., O’Donovan, M., Owen, M., Bahrami, S., Bosnes, I., Selnes, P., Bergh, S., Palotie, A., Daly, M., Jacob, H., Matakidou, A., Runz, H., John, S., Plenge, R., Mccarthy, M., Hunkapiller, J., Ehm, M., Waterworth, D., Fox, C., Malarstig, A., Klinger, K., Call, K., Behrens, T., Loerch, P., Mäkelä, T., Kaprio, J., Virolainen, P., Pulkki, K., Kilpi, T., Perola, M., Partanen, J., Pitkäranta, A., Kaarteenaho, R., Vainio, S., Turpeinen, M., Serpi, R., Laitinen, T., Mäkelä, J., Kosma, V. -M., Kujala, U., Tuovila, O., Hendolin, M., Pakkanen, R., Waring, J., Riley-Gillis, B., Liu, J., Biswas, S., Diogo, D., Marshall, C., Hu, X., Gossel, M., Graham, R., Cummings, B., Ripatti, S., Schleutker, J., Arvas, M., Carpén, O., Hinttala, R., Kettunen, J., Mannermaa, A., Laukkanen, J., Julkunen, V., Remes, A., Kälviäinen, R., Peltola, J., Tienari, P., Rinne, J., Ziemann, A., Esmaeeli, S., Smaoui, N., Lehtonen, A., Eaton, S., Lahdenperä, S., van Adelsberg, J., Michon, J., Kerchner, G., Bowers, N., Teng, E., Eicher, J., Mehta, V., Gormley, P., Linden, K., Whelan, C., Xu, F., Pulford, D., Färkkilä, M., Pikkarainen, S., Jussila, A., Blomster, T., Kiviniemi, M., Voutilainen, M., Georgantas, B., Heap, G., Rahimov, F., Usiskin, K., Lu, T., Oh, D., Kalpala, K., Miller, M., Mccarthy, L., Eklund, K., Palomäki, A., Isomäki, P., Pirilä, L., Kaipiainen-Seppänen, O., Huhtakangas, J., Lertratanakul, A., Hochfeld, M., Bing, N., Gordillo, J. 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A., Ollila, T., Seitsonen, S., Uusitalo, H., Aaltonen, V., Uusitalo-Järvinen, H., Luodonpää, M., Hautala, N., Loomis, S., Strauss, E., Podgornaia, A., Hoffman, J., Tasanen, K., Huilaja, L., Hannula-Jouppi, K., Salmi, T., Peltonen, S., Koulu, L., Harvima, I., Wu, Y., Choy, D., Pussinen, P., Salminen, A., Salo, T., Rice, D., Nieminen, P., Palotie, U., Siponen, M., Suominen, L., Mäntylä, P., Gursoy, U., Anttonen, V., Sipilä, K., Davis, J. W., Quarless, D., Petrovski, S., Wigmore, E., Chen, C. -Y., Bronson, P., Tsai, E., Huang, Y., Maranville, J., Shaikho, E., Mohammed, E., Wadhawan, S., Kvikstad, E., Caliskan, M., Chang, D., Bhangale, T., Pendergrass, S., Holzinger, E., Chen, X., Hedman, Å., King, K. 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P., Brein, G., Awaisa, G., Shcherban, A., Donner, K., Loukola, A., Laiho, P., Sistonen, T., Kaiharju, E., Laukkanen, M., Järvensivu, E., Lähteenmäki, S., Männikkö, L., Wong, R., Mattsson, H., Hiekkalinna, T., Paajanen, T., Pärn, K., Gracia-Tabuenca, J., Abner, E., Adams, P. M., Aguirre, A., Albert, M. S., Albin, R. L., Allen, M., Alvarez, L., Apostolova, L. G., Arnold, S. E., Asthana, S., Atwood, C. S., Ayres, G., Baldwin, C. T., Barber, R. C., Barnes, L. L., Beach, T. G., Becker, J. T., Beecham, G. W., Beekly, D., Benitez, B. A., Bennett, D., Bertelson, J., Margaret, F. E., Bird, T. D., Blacker, D., Boeve, B. F., Bowen, J. D., Boxer, A., Brewer, J., Burke, J. R., Burns, J. M., Buxbaum, J. D., Cairns, N. J., Cao, C., Carlson, C. S., Carlsson, C. M., Carney, R. M., Carrasquillo, M. M., Chasse, S., Chesselet, M. -F., Chesi, A., Chin, N. A., Chui, H. C., Craft, S., Crane, P. K., Cribbs, D. H., Crocco, E. A., Cruchaga, C., Cullum, M., Darby, E., Davis, B., De Jager, P. L., Decarli, C., Detoledo, J., Dick, M., Dickson, D. W., Dombroski, B. A., Doody, R. S., Duara, R., Ertekin-Taner, N., Evans, D. A., Fairchild, T. J., Fallon, K. B., Farlow, M. R., Farrell, J. J., Fernandez-Hernandez, V., Ferris, S., Frosch, M. P., Galasko, D. R., Gamboa, A., Gearing, M., Geschwind, D. H., Ghetti, B., Gilbert, J. R., Grabowski, T. J., Graff-Radford, N. R., Grant, S. F. A., Green, R. C., Growdon, J. H., Hakonarson, H., Hall, J., Hamilton, R. L., Harari, O., Harrell, L. E., Haut, J., Head, E., Henderson, V. W., Hernandez, M., Hohman, T., Honig, L. S., Huebinger, R. M., Huentelman, M. J., Hulette, C. M., Hyman, B. T., Hynan, L. S., Ibanez, L., Jarvik, G. P., Jayadev, S., Jin, L. -W., Johnson, K., Johnson, L., Kamboh, M. I., Karydas, A. M., Katz, M. J., Kaye, J. A., Keene, C. D., Khaleeq, A., Kim, R., Knebl, J., Kowall, N. W., Kramer, J. H., Laferla, F. M., Lah, J. J., Larson, E. B., Lee, E. B., Lerner, A., Leung, Y. Y., Leverenz, J. B., Levey, A. I., Li, M., Lieberman, A. P., Lipton, R. B., Logue, M., Lyketsos, C. G., Malamon, J., Mains, D., Marson, D. C., Martiniuk, F., Mash, D. C., Masliah, E., Massman, P., Masurkar, A., Mccormick, W. C., Mccurry, S. M., Mcdavid, A. N., Mckee, A. C., Mesulam, M., Mez, J., Miller, B. L., Miller, C. A., Miller, J. W., Montine, T. J., Monuki, E. S., Morris, J. C., Myers, A. J., Nguyen, T., O’Bryant, S., Olichney, J. M., Ory, M., Palmer, R., Parisi, J. E., Paulson, H. L., Pavlik, V., Paydarfar, D., Perez, V., Peskind, E., Petersen, R. C., Phillips-Cremins, J. E., Pierce, A., Polk, M., Poon, W. W., Potter, H., Qu, L., Quiceno, M., Quinn, J. F., Raj, A., Raskind, M., Reiman, E. M., Reisberg, B., Reisch, J. S., Ringman, J. M., Roberson, E. D., Rodriguear, M., Rogaeva, E., Rosen, H. J., Rosenberg, R. N., Royall, D. R., Sager, M. A., Sano, M., Saykin, A. J., Schneider, J. A., Schneider, L. S., Seeley, W. W., Small, S., Smith, A. G., Smith, J. P., Sonnen, J. A., Spina, S., George-Hyslop, P. S., Stern, R. A., Stevens, A. B., Strittmatter, S. M., Sultzer, D., Swerdlow, R. H., Tanzi, R. E., Tilson, J. L., Trojanowski, J. Q., Troncoso, J. C., Tsuang, D. W., Van Deerlin, V. M., van Eldik, L. J., Vassar, R., Vinters, H. V., Vonsattel, J. -P., Weintraub, S., Welsh-Bohmer, K. A., Whitehead, P. L., Wijsman, E. M., Wilhelmsen, K. C., Williams, B., Williamson, J., Wilms, H., Wingo, T. S., Wisniewski, T., Woltjer, R. L., Woon, M., Wright, C. B., C. -K., Wu, Younkin, S. G., C. -E., Yu, Yu, L., Zhang, Y., Zhu, X., Adams, H., Akinyemi, R. O., Ali, M., Armstrong, N., Aparicio, H. J., Bahadori, M., Breteler, M., Chasman, D., Chauhan, G., Comic, H., Cox, S., Cupples, A. L., Davies, G., Decarli, C. S., Duperron, M. -G., Dupuis, J., Evans, T., Fan, F., Fitzpatrick, A., Fohner, A. E., Ganguli, M., Geerlings, M., Glatt, S. J., Gonzalez, H. M., Goss, M., Grabe, H., Habes, M., Heckbert, S. R., Hofer, E., Hong, E., Hughes, T., Kautz, T. F., Knol, M., Kremen, W., Lacaze, P., Lahti, J., Grand, Q. L., Litkowski, E., Li, S., Liu, X., Loitfelder, M., Manning, A., Maillard, P., Marioni, R., Mazoyer, B., van Lent, D. M., Mei, H., Mishra, A., Nyquist, P., O’Connell, J., Paus, T., Pausova, Z., Raikkonen-Talvitie, K., Riaz, M., Rich, S., Rotter, J., Romero, J., Roshchupkin, G., Saba, Y., Sargurupremraj, M., Schmidt, H., Schmidt, R., Shulman, J. M., Smith, J., Sekhar, H., Rajula, R., Shin, J., Simino, J., Sliz, E., Teumer, A., Thomas, A., Tin, A., Tucker-Drob, E., Vojinovic, D., Wang, Y., Weinstein, G., Williams, D., Wittfeld, K., Yanek, L., Yang, Y., Farrer, L. A., Psaty, B. M., Ghanbari, M., Raj, T., Sachdev, P., Mather, K., Jessen, F., Ikram, M. A., de Mendonça, A., Hort, J., Tsolaki, M., Pericak-Vance, M. A., Amouyel, P., Williams, J., Frikke-Schmidt, R., Clarimon, J., Deleuze, J. -F., Rossi, G., Seshadri, S., Andreassen, O. A., Ingelsson, M., Hiltunen, M., Sleegers, K., Schellenberg, G. D., van Duijn, C. M., Sims, R., van der Flier, W. M., Ruiz, A., Ramirez, A., Lambert J., -C, Jan, Laczo, Vaclav, Matoska, Maria, Serpente, Francesca, Assogna, Fabrizio, Piras, Federica, Piras, Valentina, Ciullo, Jacob, Shofany, Carlo, Ferrarese, Simona, Andreoni, Gessica, Sala, Chiara Paola Zoia, Maria Del Zompo, Benussi, Alberto, Patrizia, Bastiani, Mari, Takalo, Teemu, Natunen, Tiina, Laatikainen, Jaakko, Tuomilehto, Riitta, Antikainen, Timo, Strandberg, Jaana, Lindström, Markku, Peltonen, Richard, Abraham, Ammar, Al-Chalabi, Nicholas, J Bass, Carol, Brayne, Kristelle, S Brown, John, Collinge, David, Craig, Pangiotis, Deloukas, Nick, Fox, Amy, Gerrish, Michael, Gill, Rhian, Gwilliam, Denise, Harold, Paul, Hollingworth, Jarret, A Johnston, Lesley, Jones, Brian, Lawlor, Gill, Livingston, Simon, Lovestone, Michelle, Lupton, Aoibhinn, Lynch, David, Mann, Bernadette, Mcguinness, Andrew, Mcquillin, Michael, C O'Donovan, Michael, J Owen, Peter, Passmore, John, F Powell, Petra, Proitsi, Martin, Rossor, Christopher, E Shaw, A David Smith, Hugh, Gurling, Stephen, Todd, Catherine, Mummery, Nathalie, Ryan, Giordano, Lacidogna, Adarmes-Gómez, Ad, Ana, Mauleón, Ana, Pancho, Anna, Gailhajenet, Asunción, Lafuente, Macias-García, D, Elvira, Martín, Esther, Pelejà, Carrillo, F, Isabel Sastre Merlín, Garrote-Espina, L, Liliana, Vargas, Carrion-Claro, M, Marín, M, Labrador, Ma, Mar, Buendia, María Dolores Alonso, Marina, Guitart, Mariona, Moreno, Marta, Ibarria, Periñán, Mt, Nuria, Aguilera, Gómez-Garre, P, Pilar, Cañabate, Escuela, R, Pineda-Sánchez, R, Vigo-Ortega, R, Jesús, S, Silvia, Preckler, Silvia, Rodrigo-Herrero, Susana, Diego, Alessandro, Vacca, Fausto, Roveta, Nicola, Salvadori, Elena, Chipi, Henning, Boecker, Christoph, Laske, Robert, Perneczky, Costas, Anastasiou, Daniel, Janowitz, Rainer, Malik, Anna, Anastasiou, Kayenat, Parveen, Carmen, Lage, Sara, López-García, Anna, Antonell, Kalina Yonkova Mihova, Diyana, Belezhanska, Heike, Weber, Silvia, Kochen, Patricia, Solis, Nancy, Medel, Julieta, Lisso, Zulma, Sevillano, Daniel, G Politis, Valeria, Cores, Carolina, Cuesta, Cecilia, Ortiz, Juan Ignacio Bacha, Mario, Rios, Aldo, Saenz, Mariana Sanchez Abalos, Eduardo, Kohler, Dana Lis Palacio, Ignacio, Etchepareborda, Matias, Kohler, Gisela, Novack, Federico Ariel Prestia, Pablo, Galeano, Eduardo, M Castaño, Sandra, Germani, Carlos Reyes Toso, Matias, Rojo, Carlos, Ingino, Carlos, Mangone, David, C Rubinsztein, Stefan, Teipel, Nathalie, Fievet, Vincent, Deramerourt, Charlotte, Forsell, Håkan, Thonberg, Maria, Bjerke, Ellen De Roeck, María Teresa Martínez-Larrad, Natividad, Olivar, Amanda, Cano, Juan, Macias, Olalla, Maroñas, Raúl, Nuñez-Llaves, Clàudia, Olivé, Ester, Pelejá, Astrid, D Adarmes-Gómez, Guillermo, Amer-Ferrer, Martirio, Antequera, Juan Andrés Burguera, Fátima, Carrillo, Mario, Carrión-Claro, María José Casajeros, Marian Martinez de Pancorbo, Rocío, Escuela, Lorena, Garrote-Espina, Pilar, Gómez-Garre, Saray, Hevilla, Silvia, Jesús, Miguel Angel Labrador Espinosa, Agustina, Legaz, Daniel, Macias-García, Salvadora, Manzanares, Marta, Marín, Juan, Marín-Muñoz, Tamara, Marín, Begoña, Martínez, Victoriana, Martínez, Pablo Martínez-Lage Álvarez, Maite Mendioroz Iriarte, María Teresa Periñán-Tocino, Rocío, Pineda-Sánchez, Diego Real de Asúa, Silvia, Rodrigo, Isabel, Sastre, Maria Pilar Vicente, Rosario, Vigo-Ortega, Liliana, Vivancos, Jacques, Epelbaum, Didier, Hannequin, Dominique, Campion, Vincent, Deramecourt, Christophe, Tzourio, Alexis, Brice, Bruno, Dubois, Amy, Williams, Charlene, Thomas, Chloe, Davies, William, Nash, Kimberley, Dowzell, Atahualpa Castillo Morales, Mateus, Bernardo-Harrington, James, Turton, Jenny, Lord, Kristelle, Brown, Emma, Vardy, Elizabeth, Fisher, Jason, D Warren, Natalie, S Ryan, Rita, Guerreiro, James, Uphill, Nick, Bass, Reinhard, Heun, Heike, Kölsch, Britta, Schürmann, André, Lacour, Christine, Herold, Janet, A Johnston, John, Powell, Yogen, Patel, Angela, Hodges, Tim, Becker, Donald, Warden, Gordon, Wilcock, Robert, Clarke, Panagiotis, Deloukas, Yoav, Ben-Shlomo, Nigel, M Hooper, Stuart, Pickering-Brown, Rebecca, Sussams, Nick, Warner, Anthony, Bayer, Isabella, Heuser, Dmitriy, Drichel, Norman, Klopp, Manuel, Mayhaus, Matthias, Riemenschneider, Sabrina, Pinchler, Thomas, Feulner, Wei, Gu, Hendrik van den Bussche, Michael, Hüll, Lutz, Frölich, H-Erich, Wichmann, Karl-Heinz, Jöckel, Michael, O'Donovan, Michael, Owen, Shahram, Bahrami, Ingunn, Bosnes, Per, Selnes, Sverre, Bergh, Aarno, Palotie, Mark, Daly, Howard, Jacob, Athena, Matakidou, Heiko, Runz, Sally, John, Robert, Plenge, Mark, Mccarthy, Julie, Hunkapiller, Meg, Ehm, Dawn, Waterworth, Caroline, Fox, Anders, Malarstig, Kathy, Klinger, Kathy, Call, Tim, Behrens, Patrick, Loerch, Tomi, Mäkelä, Jaakko, Kaprio, Petri, Virolainen, Kari, Pulkki, Terhi, Kilpi, Markus, Perola, Jukka, Partanen, Anne, Pitkäranta, Riitta, Kaarteenaho, Seppo, Vainio, Miia, Turpeinen, Raisa, Serpi, Tarja, Laitinen, Johanna, Mäkelä, Veli-Matti, Kosma, Urho, Kujala, Outi, Tuovila, Minna, Hendolin, Raimo, Pakkanen, Jeff, Waring, Bridget, Riley-Gillis, Jimmy, Liu, Shameek, Biswas, Dorothee, Diogo, Catherine, Marshall, Xinli, Hu, Matthias, Gossel, Robert, Graham, Beryl, Cummings, Samuli, Ripatti, Johanna, Schleutker, Mikko, Arvas, Olli, Carpén, Reetta, Hinttala, Johannes, Kettunen, Arto, Mannermaa, Jari, Laukkanen, Valtteri, Julkunen, Anne, Remes, Reetta, Kälviäinen, Jukka, Peltola, Pentti, Tienari, Juha, Rinne, Adam, Ziemann, Jeffrey, Waring, Sahar, Esmaeeli, Nizar, Smaoui, Anne, Lehtonen, Susan, Eaton, Sanni, Lahdenperä, Janet van Adelsberg, John, Michon, Geoff, Kerchner, Natalie, Bowers, Edmond, Teng, John, Eicher, Vinay, Mehta, Padhraig, Gormley, Kari, Linden, Christopher, Whelan, Fanli, Xu, David, Pulford, Martti, Färkkilä, Sampsa, Pikkarainen, Airi, Jussila, Timo, Blomster, Mikko, Kiviniemi, Markku, Voutilainen, Bob, Georgantas, Graham, Heap, Fedik, Rahimov, Keith, Usiskin, Tim, Lu, Danny, Oh, Kirsi, Kalpala, Melissa, Miller, Linda, Mccarthy, Kari, Eklund, Antti, Palomäki, Pia, Isomäki, Laura, Pirilä, Oili, Kaipiainen-Seppänen, Johanna, Huhtakangas, Apinya, Lertratanakul, Marla, Hochfeld, Nan, Bing, Jorge Esparza Gordillo, Nina, Mars, Margit, Pelkonen, Paula, Kauppi, Hannu, Kankaanranta, Terttu, Harju, David, Close, Steven, Greenberg, Hubert, Chen, Betts, Jo, Soumitra, Ghosh, Veikko, Salomaa, Teemu, Niiranen, Markus, Juonala, Kaj, Metsärinne, Mika, Kähönen, Juhani, Junttila, Markku, Laakso, Jussi, Pihlajamäki, Juha, Sinisalo, Marja-Riitta, Taskinen, Tiinamaija, Tuomi, Ben, Challis, Andrew, Peterson, Audrey, Chu, Jaakko, Parkkinen, Anthony, Muslin, Heikki, Joensuu, Tuomo, Meretoja, Lauri, Aaltonen, Johanna, Mattson, Annika, Auranen, Peeter, Karihtala, Saila, Kauppila, Päivi, Auvinen, Klaus, Elenius, Relja, Popovic, Jennifer, Schutzman, Andrey, Loboda, Aparna, Chhibber, Heli, Lehtonen, Stefan, Mcdonough, Marika, Crohns, Diptee, Kulkarni, Kai, Kaarniranta, Joni, A Turunen, Terhi, Ollila, Sanna, Seitsonen, Hannu, Uusitalo, Vesa, Aaltonen, Hannele, Uusitalo-Järvinen, Marja, Luodonpää, Nina, Hautala, Stephanie, Loomis, Erich, Strauss, Hao, Chen, Anna, Podgornaia, Joshua, Hoffman, Kaisa, Tasanen, Laura, Huilaja, Katariina, Hannula-Jouppi, Teea, Salmi, Sirkku, Peltonen, Leena, Koulu, Ilkka, Harvima, Ying, Wu, David, Choy, Pirkko, Pussinen, Aino, Salminen, Tuula, Salo, David, Rice, Pekka, Nieminen, Ulla, Palotie, Maria, Siponen, Liisa, Suominen, Päivi, Mäntylä, Ulvi, Gursoy, Vuokko, Anttonen, Kirsi, Sipilä, Justin Wade Davis, Danjuma, Quarless, Slavé, Petrovski, Eleonor, Wigmore, Chia-Yen, Chen, Paola, Bronson, Ellen, Tsai, Yunfeng, Huang, Joseph, Maranville, Elmutaz, Shaikho, Elhaj, Mohammed, Samir, Wadhawan, Erika, Kvikstad, Minal, Caliskan, Diana, Chang, Tushar, Bhangale, Sarah, Pendergrass, Emily, Holzinger, Xing, Chen, Åsa, Hedman, Karen, S King, Clarence, Wang, Ethan, Xu, Franck, Auge, Clement, Chatelain, Deepak, Rajpal, Dongyu, Liu, Katherine, Call, Tai-He, Xia, Matt, Brauer, Mitja, Kurki, Juha, Karjalainen, Aki, Havulinna, Anu, Jalanko, Priit, Palta, Pietro Della Briotta Parolo, Wei, Zhou, Susanna, Lemmelä, Manuel, Rivas, Jarmo, Harju, Arto, Lehisto, Andrea, Ganna, Vincent, Llorens, Hannele, Laivuori, Sina, Rüeger, Mari, E Niemi, Taru, Tukiainen, Mary Pat Reeve, Henrike, Heyne, Kimmo, Palin, Javier, Garcia-Tabuenca, Harri, Siirtola, Tuomo, Kiiskinen, Jiwoo, Lee, Kristin, Tsuo, Amanda, Elliott, Kati, Kristiansson, Kati, Hyvärinen, Jarmo, Ritari, Miika, Koskinen, Katri, Pylkäs, Marita, Kalaoja, Minna, Karjalainen, Tuomo, Mantere, Eeva, Kangasniemi, Sami, Heikkinen, Eija, Laakkonen, Csilla, Sipeky, Samuel, Heron, Antti, Karlsson, Dhanaprakash, Jambulingam, Venkat Subramaniam Rathinakannan, Risto, Kajanne, Mervi, Aavikko, Manuel González Jiménez, Pietro Della Briotta Parola, Arto, Lehistö, Masahiro, Kanai, Mari, Kaunisto, Elina, Kilpeläinen, Timo, P Sipilä, Georg, Brein, Ghazal, Awaisa, Anastasia, Shcherban, Kati, Donner, Anu, Loukola, Päivi, Laiho, Tuuli, Sistonen, Essi, Kaiharju, Markku, Laukkanen, Elina, Järvensivu, Sini, Lähteenmäki, Lotta, Männikkö, Regis, Wong, Hannele, Mattsson, Tero, Hiekkalinna, Teemu, Paajanen, Kalle, Pärn, Javier, Gracia-Tabuenca, Erin, Abner, Perrie, M Adams, Alyssa, Aguirre, Marilyn, S Albert, Roger, L Albin, Mariet, Allen, Lisa, Alvarez, Liana, G Apostolova, Steven, E Arnold, Sanjay, Asthana, Craig, S Atwood, Gayle, Ayres, Clinton, T Baldwin, Robert, C Barber, Lisa, L Barnes, Sandra, Barral, Thomas, G Beach, James, T Becker, Gary, W Beecham, Duane, Beekly, Jennifer, E Below, Penelope, Benchek, Bruno, A Benitez, David, Bennett, John, Bertelson, Flanagan, E Margaret, Thomas, D Bird, Deborah, Blacker, Bradley, F Boeve, James, D Bowen, Adam, Boxer, James, Brewer, James, R Burke, Jeffrey, M Burns, Will, S Bush, Joseph, D Buxbaum, Nigel, J Cairns, Chuanhai, Cao, Christopher, S Carlson, Cynthia, M Carlsson, Regina, M Carney, Minerva, M Carrasquillo, Scott, Chasse, Marie-Francoise, Chesselet, Alessandra, Chesi, Nathaniel, A Chin, Helena, C Chui, Jaeyoon, Chung, Suzanne, Craft, Paul, K Crane, David, H Cribbs, Elizabeth, A Crocco, Carlos, Cruchaga, Michael, L Cuccaro, Munro, Cullum, Eveleen, Darby, Barbara, Davis, Philip, L De Jager, Charles, Decarli, John, Detoledo, Malcolm, Dick, Dennis, W Dickson, Beth, A Dombroski, Rachelle, S Doody, Ranjan, Duara, Nilüfer, Ertekin-Taner, Denis, A Evans, Thomas, J Fairchild, Kenneth, B Fallon, Martin, R Farlow, John, J Farrell, Victoria, Fernandez-Hernandez, Steven, Ferris, Matthew, P Frosch, Brian, Fulton-Howard, Douglas, R Galasko, Adriana, Gamboa, Marla, Gearing, Daniel, H Geschwind, Bernardino, Ghetti, John, R Gilbert, Thomas, J Grabowski, Neill, R Graff-Radford, Struan F, A Grant, Robert, C Green, John, H Growdon, Jonathan, L Haines, Hakon, Hakonarson, James, Hall, Ronald, L Hamilton, Oscar, Harari, Lindy, E Harrell, Jacob, Haut, Elizabeth, Head, Victor, W Henderson, Michelle, Hernandez, Timothy, Hohman, Lawrence, S Honig, Ryan, M Huebinger, Matthew, J Huentelman, Christine, M Hulette, Bradley, T Hyman, Linda, S Hynan, Laura, Ibanez, Gail, P Jarvik, Suman, Jayadev, Lee-Way, Jin, Kim, Johnson, Leigh, Johnson, M Ilyas Kamboh, Anna, M Karydas, Mindy, J Katz, Jeffrey, A Kaye, C Dirk Keene, Aisha, Khaleeq, Ronald, Kim, Janice, Knebl, Neil, W Kowall, Joel, H Kramer, Pavel, P Kuksa, Frank, M LaFerla, James, J Lah, Eric, B Larson, Chien-Yueh, Lee, Edward, B Lee, Alan, Lerner, Yuk Yee Leung, James, B Leverenz, Allan, I Levey, Mingyao, Li, Andrew, P Lieberman, Richard, B Lipton, Mark, Logue, Constantine, G Lyketsos, John, Malamon, Douglas, Mains, Daniel, C Marson, Frank, Martiniuk, Deborah, C Mash, Eliezer, Masliah, Paul, Massman, Arjun, Masurkar, Wayne, C McCormick, Susan, M McCurry, Andrew, N McDavid, Ann, C McKee, Marsel, Mesulam, Jesse, Mez, Bruce, L Miller, Carol, A Miller, Joshua, W Miller, Thomas, J Montine, Edwin, S Monuki, John, C Morris, Amanda, J Myers, Trung, Nguyen, Sid, O'Bryant, John, M Olichney, Marcia, Ory, Raymond, Palmer, Joseph, E Parisi, Henry, L Paulson, Valory, Pavlik, David, Paydarfar, Victoria, Perez, Elaine, Peskind, Ronald, C Petersen, Jennifer, E Phillips-Cremins, Aimee, Pierce, Marsha, Polk, Wayne, W Poon, Huntington, Potter, Liming, Qu, Mary, Quiceno, Joseph, F Quinn, Ashok, Raj, Murray, Raskind, Eric, M Reiman, Barry, Reisberg, Joan, S Reisch, John, M Ringman, Erik, D Roberson, Monica, Rodriguear, Ekaterina, Rogaeva, Howard, J Rosen, Roger, N Rosenberg, Donald, R Royall, Mark, A Sager, Mary, Sano, Andrew, J Saykin, Julie, A Schneider, Lon, S Schneider, William, W Seeley, Susan, H Slifer, Scott, Small, Amanda, G Smith, Janet, P Smith, Yeunjoo, E Song, Joshua, A Sonnen, Salvatore, Spina, Peter St George-Hyslop, Robert, A Stern, Alan, B Stevens, Stephen, M Strittmatter, David, Sultzer, Russell, H Swerdlow, Rudolph, E Tanzi, Jeffrey, L Tilson, John, Q Trojanowski, Juan, C Troncoso, Debby, W Tsuang, Otto, Valladares, Vivianna, M Van Deerlin, Linda, J van Eldik, Robert, Vassar, Harry, V Vinters, Jean-Paul, Vonsattel, Sandra, Weintraub, Kathleen, A Welsh-Bohmer, Patrice, L Whitehead, Ellen, M Wijsman, Kirk, C Wilhelmsen, Benjamin, Williams, Jennifer, Williamson, Henrik, Wilms, Thomas, S Wingo, Thomas, Wisniewski, Randall, L Woltjer, Martin, Woon, Clinton, B Wright, Chuang-Kuo, Wu, Steven, G Younkin, Chang-En, Yu, Lei, Yu, Yuanchao, Zhang, Zhao, Yi, Xiongwei, Zhu, Hieab, Adams, Rufus, O Akinyemi, Muhammad, Ali, Nicola, Armstrong, Hugo, J Aparicio, Maryam, Bahadori, Monique, Breteler, Daniel, Chasman, Ganesh, Chauhan, Hata, Comic, Simon, Cox, Adrienne, L Cupples, Gail, Davies, Charles, S DeCarli, Marie-Gabrielle, Duperron, Josée, Dupuis, Tavia, Evans, Frank, Fan, Annette, Fitzpatrick, Alison, E Fohner, Mary, Ganguli, Mirjam, Geerlings, Stephen, J Glatt, Hector, M Gonzalez, Monica, Goss, Hans, Grabe, Mohamad, Habes, Susan, R Heckbert, Edith, Hofer, Elliot, Hong, Timothy, Hughes, Tiffany, F Kautz, Maria, Knol, William, Kremen, Paul, Lacaze, Jari, Lahti, Quentin Le Grand, Elizabeth, Litkowski, Shuo, Li, Dan, Liu, Xuan, Liu, Marisa, Loitfelder, Alisa, Manning, Pauline, Maillard, Riccardo, Marioni, Bernard, Mazoyer, Debora Melo van Lent, Hao, Mei, Aniket, Mishra, Paul, Nyquist, Jeffrey, O'Connell, Yash, Patel, Tomas, Paus, Zdenka, Pausova, Katri, Raikkonen-Talvitie, Moeen, Riaz, Stephen, Rich, Jerome, Rotter, Jose, Romero, Gena, Roshchupkin, Yasaman, Saba, Murali, Sargurupremraj, Helena, Schmidt, Reinhold, Schmidt, Joshua, M Shulman, Jennifer, Smith, Hema, Sekhar, Reddy, Rajula, Jean, Shin, Jeannette, Simino, Eeva, Sliz, Alexander, Teumer, Alvin, Thomas, Adrienne, Tin, Elliot, Tucker-Drob, Dina, Vojinovic, Yanbing, Wang, Galit, Weinstein, Dylan, Williams, Katharina, Wittfeld, Lisa, Yanek, Yunju, Yang, Bellenguez, C, Küçükali, F, Jansen, I, Kleineidam, L, Moreno-Grau, S, Amin, N, Naj, A, Campos-Martin, R, Grenier-Boley, B, Andrade, V, Holmans, P, Boland, A, Damotte, V, van der Lee, S, Costa, M, Kuulasmaa, T, Yang, Q, de Rojas, I, Bis, J, Yaqub, A, Prokic, I, Chapuis, J, Ahmad, S, Giedraitis, V, Aarsland, D, Garcia-Gonzalez, P, Abdelnour, C, Alarcón-Martín, E, Alcolea, D, Alegret, M, Alvarez, I, Álvarez, V, Armstrong, N, Tsolaki, A, Antúnez, C, Appollonio, I, Arcaro, M, Archetti, S, Pastor, A, Arosio, B, Athanasiu, L, Bailly, H, Banaj, N, Baquero, M, Barral, S, Beiser, A, Below, J, Benchek, P, Benussi, L, Berr, C, Besse, C, Bessi, V, Binetti, G, Bizarro, A, Blesa, R, Boada, M, Boerwinkle, E, Borroni, B, Boschi, S, Bossù, P, Bråthen, G, Bressler, J, Bresner, C, Brodaty, H, Brookes, K, Brusco, L, Buiza-Rueda, D, Bûrger, K, Burholt, V, Bush, W, Calero, M, Cantwell, L, Chene, G, Chung, J, Cuccaro, M, Carracedo, Á, Cecchetti, R, Cervera-Carles, L, Charbonnier, C, Chen, H, Chillotti, C, Ciccone, S, Claassen, J, Clark, C, Conti, E, Corma-Gómez, A, Costantini, E, Custodero, C, Daian, D, Dalmasso, M, Daniele, A, Dardiotis, E, Dartigues, J, de Deyn, P, de Paiva Lopes, K, de Witte, L, Debette, S, Deckert, J, Del Ser, T, Denning, N, Destefano, A, Dichgans, M, Diehl-Schmid, J, Diez-Fairen, M, Rossi, P, Djurovic, S, Duron, E, Düzel, E, Dufouil, C, Eiriksdottir, G, Engelborghs, S, Escott-Price, V, Espinosa, A, Ewers, M, Faber, K, Fabrizio, T, Nielsen, S, Fardo, D, Farotti, L, Fenoglio, C, Fernández-Fuertes, M, Ferrari, R, Ferreira, C, Ferri, E, Fin, B, Fischer, P, Fladby, T, Fließbach, K, Fongang, B, Fornage, M, Fortea, J, Foroud, T, Fostinelli, S, Fox, N, Franco-Macías, E, Bullido, M, Frank-García, A, Froelich, L, Fulton-Howard, B, Galimberti, D, García-Alberca, J, García-González, P, Garcia-Madrona, S, Garcia-Ribas, G, Ghidoni, R, Giegling, I, Giorgio, G, Goate, A, Goldhardt, O, Gomez-Fonseca, D, González-Pérez, A, Graff, C, Grande, G, Green, E, Grimmer, T, Grünblatt, E, Grunin, M, Gudnason, V, Guetta-Baranes, T, Haapasalo, A, Hadjigeorgiou, G, Haines, J, Hamilton-Nelson, K, Hampel, H, Hanon, O, Hardy, J, Hartmann, A, Hausner, L, Harwood, J, Heilmann-Heimbach, S, Helisalmi, S, Heneka, M, Hernández, I, Herrmann, M, Hoffmann, P, Holmes, C, Holstege, H, Vilas, R, Hulsman, M, Humphrey, J, Biessels, G, Jian, X, Johansson, C, Jun, G, Kastumata, Y, Kauwe, J, Kehoe, P, Kilander, L, Ståhlbom, A, Kivipelto, M, Koivisto, A, Kornhuber, J, Kosmidis, M, Kukull, W, Kuksa, P, Kunkle, B, Kuzma, A, Lage, C, Laukka, E, Launer, L, Lauria, A, Lee, C, Lehtisalo, J, Lerch, O, Lleó, A, Longstreth, W, Lopez, O, de Munain, A, Love, S, Löwemark, M, Luckcuck, L, Lunetta, K, Ma, Y, Macías, J, Macleod, C, Maier, W, Mangialasche, F, Spallazzi, M, Marquié, M, Marshall, R, Martin, E, Montes, A, Rodríguez, C, Masullo, C, Mayeux, R, Mead, S, Mecocci, P, Medina, M, Meggy, A, Mehrabian, S, Mendoza, S, Menéndez-González, M, Mir, P, Moebus, S, Mol, M, Molina-Porcel, L, Montrreal, L, Morelli, L, Moreno, F, Morgan, K, Mosley, T, Nöthen, M, Muchnik, C, Mukherjee, S, Nacmias, B, Ngandu, T, Nicolas, G, Nordestgaard, B, Olaso, R, Orellana, A, Orsini, M, Ortega, G, Padovani, A, Paolo, C, Papenberg, G, Parnetti, L, Pasquier, F, Pastor, P, Peloso, G, Pérez-Cordón, A, Pérez-Tur, J, Pericard, P, Peters, O, Pijnenburg, Y, Pineda, J, Piñol-Ripoll, G, Pisanu, C, Polak, T, Popp, J, Posthuma, D, Priller, J, Puerta, R, Quenez, O, Quintela, I, Thomassen, J, Rábano, A, Rainero, I, Rajabli, F, Ramakers, I, Real, L, Reinders, M, Reitz, C, Reyes-Dumeyer, D, Ridge, P, Riedel-Heller, S, Riederer, P, Roberto, N, Rodriguez-Rodriguez, E, Rongve, A, Allende, I, Rosende-Roca, M, Royo, J, Rubino, E, Rujescu, D, Sáez, M, Sakka, P, Saltvedt, I, Sanabria, Á, Sánchez-Arjona, M, Sanchez-Garcia, F, Juan, P, Sánchez-Valle, R, Sando, S, Sarnowski, C, Satizabal, C, Scamosci, M, Scarmeas, N, Scarpini, E, Scheltens, P, Scherbaum, N, Scherer, M, Schmid, M, Schneider, A, Schott, J, Selbæk, G, Seripa, D, Serrano, M, Sha, J, Shadrin, A, Skrobot, O, Slifer, S, Snijders, G, Soininen, H, Solfrizzi, V, Solomon, A, Song, Y, Sorbi, S, Sotolongo-Grau, O, Spalletta, G, Spottke, A, Squassina, A, Stordal, E, Tartan, J, Tárraga, L, Tesí, N, Thalamuthu, A, Thomas, T, Tosto, G, Traykov, L, Tremolizzo, L, Tybjærg-Hansen, A, Uitterlinden, A, Ullgren, A, Ulstein, I, Valero, S, Valladares, O, Broeckhoven, C, Vance, J, Vardarajan, B, van der Lugt, A, Dongen, J, van Rooij, J, van Swieten, J, Vandenberghe, R, Verhey, F, Vidal, J, Vogelgsang, J, Vyhnalek, M, Wagner, M, Wallon, D, Wang, L, Wang, R, Weinhold, L, Wiltfang, J, Windle, G, Woods, B, Yannakoulia, M, Zare, H, Zhao, Y, Zhang, X, Zhu, C, Zulaica, M, Andreoni, S, Ferrarese, C, Sala, G, Zoia, C, Farrer, L, Psaty, B, Ghanbari, M, Raj, T, Sachdev, P, Mather, K, Jessen, F, Ikram, M, de Mendonça, A, Hort, J, Tsolaki, M, Pericak-Vance, M, Amouyel, P, Williams, J, Frikke-Schmidt, R, Clarimon, J, Deleuze, J, Rossi, G, Seshadri, S, Andreassen, O, Ingelsson, M, Hiltunen, M, Sleegers, K, Schellenberg, G, van Duijn, C, Sims, R, van der Flier, W, Ruiz, A, Ramirez, A, Lambert, J, VU University medical center, Amsterdam Neuroscience - Neurodegeneration, Neurology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, APH - Personalized Medicine, APH - Methodology, Bellenguez, Céline [0000-0002-1240-7874], Küçükali, Fahri [0000-0002-3835-9639], Amin, Najaf [0000-0002-8944-1771], Holmans, Peter A [0000-0003-0870-9412], van der Lee, Sven J [0000-0003-1606-8643], Costa, Marcos R [0000-0002-4928-2163], Kuulasmaa, Teemu [0000-0002-1795-7314], Yang, Qiong [0000-0002-3658-1375], de Rojas, Itziar [0000-0002-2148-381X], Bis, Joshua C [0000-0002-3409-1110], Yaqub, Amber [0000-0002-3579-8054], Prokic, Ivana [0000-0002-0370-1473], Chapuis, Julien [0000-0002-5802-2857], Ahmad, Shahzad [0000-0002-8658-3790], Giedraitis, Vilmantas [0000-0003-3423-2021], Garcia-Gonzalez, Pablo [0000-0003-0125-5403], Alcolea, Daniel [0000-0002-3819-3245], Alvarez, Ignacio [0000-0002-8537-3935], Tsolaki, Anthoula [0000-0002-5563-7776], Baquero, Miquel [0000-0002-6861-1831], Pastor, Ana Belén [0000-0001-9637-4688], Berr, Claudine [0000-0001-5254-7655], Bessi, Valentina [0000-0002-6176-3584], Boada, Mercè [0000-0003-2617-3009], Bossù, Paola [0000-0002-1432-0078], Bråthen, Geir [0000-0003-3224-7983], Bressler, Jan [0000-0001-6578-4772], Bresner, Catherine [0000-0003-2673-9762], Brodaty, Henry [0000-0001-9487-6617], Brookes, Keeley J [0000-0003-2427-2513], Burholt, Vanessa [0000-0002-6789-127X], Bush, William S [0000-0002-9729-6519], Calero, Miguel [0000-0001-5366-3324], Chung, Jaeyoon [0000-0002-6431-9454], Cervera-Carles, Laura [0000-0003-2286-200X], Costantini, Emanuele [0000-0002-1096-8221], Dalmasso, Maria Carolina [0000-0002-4901-9955], de Paiva Lopes, Katia [0000-0002-0240-0126], de Witte, Lot D [0000-0002-7235-9958], Debette, Stéphanie [0000-0001-8675-7968], Del Ser, Teodoro [0000-0001-9806-7083], Dichgans, Martin [0000-0002-0654-387X], Diehl-Schmid, Janine [0000-0002-7745-1382], Diez-Fairen, Mónica [0000-0003-1882-0309], Djurovic, Srdjan [0000-0002-8140-8061], Dufouil, Carole [0000-0003-2442-4476], Escott-Price, Valentina [0000-0003-1784-5483], Ewers, Michael [0000-0001-5231-1714], Fabrizio, Tagliavini [0000-0003-1039-7315], Fladby, Tormod [0000-0002-9984-9797], Fornage, Myriam [0000-0003-0677-8158], Fox, Nick C [0000-0002-6660-657X], Bullido, María J [0000-0002-6477-1117], Froelich, Lutz [0000-0003-1494-0813], Galimberti, Daniela [0000-0002-9284-5953], García-Alberca, Jose Maria [0000-0003-2951-6644], Goate, Alison M [0000-0002-0576-2472], González-Pérez, Antonio [0000-0001-9771-5982], Green, Emma [0000-0002-8687-5590], Grünblatt, Edna [0000-0001-8505-7265], Gudnason, Vilmundur [0000-0001-5696-0084], Haapasalo, Annakaisa [0000-0003-0959-2957], Harwood, Janet [0000-0002-3225-0069], Heilmann-Heimbach, Stefanie [0000-0003-1057-465X], Herrmann, Martin J [0000-0001-9970-2122], Holstege, Henne [0000-0002-7688-3087], Biessels, Geert Jan [0000-0001-6862-2496], Jian, Xueqiu [0000-0002-0313-6494], Johansson, Charlotte [0000-0002-5351-1950], Jun, Gyungah R [0000-0002-3230-8697], Kastumata, Yuriko [0000-0002-0188-8094], Kehoe, Patrick G [0000-0002-7542-1139], Kornhuber, Johannes [0000-0002-8096-3987], Kosmidis, Mary H [0000-0001-8790-1220], Lage, Carmen [0000-0003-1703-121X], Launer, Lenore [0000-0002-3238-7612], Lee, Chien-Yueh [0000-0002-4304-974X], Lleó, Alberto [0000-0002-2568-5478], Lopez, Oscar [0000-0002-8546-8256], de Munain, Adolfo Lopez [0000-0002-9509-4032], Lunetta, Kathryn L [0000-0002-9268-810X], Ma, Yiyi [0000-0002-3609-8877], MacLeod, Catherine A [0000-0002-9314-7380], Marquié, Marta [0000-0002-0660-0950], Montes, Angel Martín [0000-0002-1694-786X], Mead, Simon [0000-0002-4326-1468], Medina, Miguel [0000-0002-7016-5340], Menéndez-González, Manuel [0000-0002-5218-0774], Mol, Merel [0000-0003-2533-2530], Morgan, Kevin [0000-0002-8217-2396], Nöthen, Markus M [0000-0002-8770-2464], Muchnik, Carolina [0000-0002-1542-3706], Nacmias, Benedetta [0000-0001-9338-9040], Nicolas, Gael [0000-0001-9391-7800], Nordestgaard, Børge G [0000-0002-1954-7220], Pasquier, Florence [0000-0001-9880-9788], Pastor, Pau [0000-0002-7493-8777], Peloso, Gina [0000-0002-5355-8636], Pérez-Cordón, Alba [0000-0002-6028-0791], Pérez-Tur, Jordi [0000-0002-9111-1712], Pericard, Pierre [0000-0001-8167-6448], Pineda, Juan A [0000-0002-3751-0296], Pisanu, Claudia [0000-0002-9151-4319], Posthuma, Danielle [0000-0001-7582-2365], Puerta, Raquel [0000-0002-1191-5893], Quenez, Olivier [0000-0002-8273-8505], Thomassen, Jesper Qvist [0000-0003-3484-9531], Real, Luis M [0000-0003-4932-7429], Reinders, Marcel JT [0000-0002-1148-1562], Reitz, Christiane [0000-0001-8757-7889], Riedel-Heller, Steffi [0000-0003-4321-6090], Rodriguez-Rodriguez, Eloy [0000-0001-7742-677X], Rongve, Arvid [0000-0002-0476-4134], Sáez, María Eugenia [0000-0001-9299-2534], Saltvedt, Ingvild [0000-0002-7897-9808], Juan, Pascual Sánchez [0000-0002-6081-8037], Sarnowski, Chloé [0000-0002-6090-7099], Satizabal, Claudia L [0000-0002-1115-4430], Schott, Jonathan M [0000-0003-2059-024X], Selbæk, Geir [0000-0001-6511-8219], Shadrin, Alexey A [0000-0002-7467-250X], Soininen, Hilkka [0000-0002-2785-9937], Solfrizzi, Vincenzo [0000-0002-8524-0315], Song, Yeunjoo [0000-0002-7452-3731], Sotolongo-Grau, Oscar [0000-0002-9679-0670], Spalletta, Gianfranco [0000-0002-7432-4249], Squassina, Alessio [0000-0001-7415-7607], Stordal, Eystein [0000-0002-2443-7923], Tosto, Giuseppe [0000-0001-7075-8245], Uitterlinden, Andre [0000-0002-7276-3387], Valladares, Otto [0000-0001-8055-2187], Broeckhoven, Christine Van [0000-0003-0183-7665], Vidal, Jean-Sébastien [0000-0001-6770-0720], Vogelgsang, Jonathan [0000-0001-9326-8193], Wagner, Michael [0000-0003-2589-6440], Wallon, David [0000-0002-2634-7198], Wiltfang, Jens [0000-0003-1492-5330], Woods, Bob [0000-0002-6781-651X], Yannakoulia, Mary [0000-0003-2171-7337], Zare, Habil [0000-0001-5902-6238], Zhang, Xiaoling [0000-0001-8237-1857], Farrer, Lindsay A [0000-0001-5533-4225], Psaty, Bruce M [0000-0002-7278-2190], Ghanbari, Mohsen [0000-0002-9476-7143], Raj, Towfique [0000-0002-9355-5704], Sachdev, Perminder [0000-0002-9595-3220], Mather, Karen [0000-0003-4143-8941], Ikram, M Arfan [0000-0003-0372-8585], Tsolaki, Magda [0000-0002-2072-8010], Pericak-Vance, Margaret A [0000-0001-7283-8804], Amouyel, Philippe [0000-0001-9088-234X], Williams, Julie [0000-0002-4069-0259], Frikke-Schmidt, Ruth [0000-0003-4084-5027], Seshadri, Sudha [0000-0001-6135-2622], Andreassen, Ole A [0000-0002-4461-3568], Sleegers, Kristel [0000-0002-0283-2332], van Duijn, Cornelia M [0000-0002-2374-9204], Sims, Rebecca [0000-0002-3885-1199], van der Flier, Wiesje M [0000-0001-8766-6224], Ramirez, Alfredo [0000-0003-4991-763X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Complex Trait Genetics, Clinical sciences, Neuroprotection & Neuromodulation, Pathologic Biochemistry and Physiology, Clinical Biology, Epidemiology, Internal Medicine, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), UAM. Departamento de Biología Molecular, University of Helsinki, Department of Neurosciences, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Neurocenter, Neurologian yksikkö, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (France), European Commission, LabEx DISTALZ, Pérez-Tur, Jordi, University Children’s Hospital Basel (Suiza), INSERM (Francia), Lille Métropole Communauté Urbaine, Government of France (Francia), EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE, Holmans, Peter A. [0000-0003-0870-9412], van der Lee, Sven J. [0000-0003-1606-8643], Costa, Marcos R. [0000-0002-4928-2163], Bis, Joshua C. [0000-0002-3409-1110], Brookes, Keeley J. [0000-0003-2427-2513], Bush, William S. [0000-0002-9729-6519], de Witte, Lot D. [0000-0002-7235-9958], del Ser, Teodoro [0000-0001-9806-7083], Fox, Nick C. [0000-0002-6660-657X], Bullido, María J. [0000-0002-6477-1117], Goate, Alison M. [0000-0002-0576-2472], Herrmann, Martin J. [0000-0001-9970-2122], Jun, Gyungah R. [0000-0002-3230-8697], Kehoe, Patrick G. [0000-0002-7542-1139], Kosmidis, Mary H. [0000-0001-8790-1220], Lunetta, Kathryn L. [0000-0002-9268-810X], MacLeod, Catherine A. [0000-0002-9314-7380], Nöthen, Markus M. [0000-0002-8770-2464], Nordestgaard, Børge G. [0000-0002-1954-7220], Pineda, Juan A. [0000-0002-3751-0296], Real, Luis M. [0000-0003-4932-7429], Reinders, Marcel J. T. [0000-0002-1148-1562], Satizabal, Claudia L. [0000-0002-1115-4430], Schott, Jonathan M. [0000-0003-2059-024X], Shadrin, Alexey A. [0000-0002-7467-250X], Farrer, Lindsay A. [0000-0001-5533-4225], Psaty, Bruce M. [0000-0002-7278-2190], Ikram, M. Arfan [0000-0003-0372-8585], Pericak-Vance, Margaret A. [0000-0001-7283-8804], Andreassen, Ole A. [0000-0002-4461-3568], van Duijn, Cornelia M. [0000-0002-2374-9204], van der Flier, Wiesje M. [0000-0001-8766-6224], and Molecular Neuroscience and Ageing Research (MOLAR)
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tau Proteins/genetics ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,Neurologi ,MED/03 - GENETICA MEDICA ,45/43 ,Medizin ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,genetics [Alzheimer Disease] ,Genome-Wide Association Study ,Humans ,tau Proteins ,Alzheimer Disease ,Cognitive Dysfunction ,VARIANTS ,pathology [Alzheimer Disease] ,Tau Proteins ,Settore BIO/13 - Biologia Applicata ,Cognitive Dysfunction/psychology ,692/699/375/365/1283 ,IMPUTATION ,article ,1184 Genetics, developmental biology, physiology ,Biología y Biomedicina / Biología ,AMYLOID-BETA ,Settore MED/26 - NEUROLOGIA ,Neurology ,psychology [Cognitive Dysfunction] ,Medical Genetics ,Human ,Neuroscience(all) ,631/208/205/2138 ,All institutes and research themes of the Radboud University Medical Center ,SDG 3 - Good Health and Well-being ,ddc:570 ,Genetics ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,METAANALYSIS ,Medicinsk genetik ,MED/26 - NEUROLOGIA ,Alzheimer Disease/genetics ,neurology ,tau Protein ,NECROSIS-FACTOR-ALPHA ,RISK LOCI ,genetics [tau Proteins] ,PREDICTION MODELS ,Human medicine ,GENERATION ,RESPONSES - Abstract
25 páginas, 6 figuras, 2 tablas, Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not
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- 2022
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5. Supplementary Figure Legend from Topical TLR7 Agonist Imiquimod Can Induce Immune-Mediated Rejection of Skin Metastases in Patients with Breast Cancer
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Sandra Demaria, Derya Unutmaz, Nina Bhardwaj, Silvia C. Formenti, Judith D. Goldberg, Amy Tiersten, Yelena Novik, James Speyer, Deborah Axelrod, Nicholas Shuman, Tsivia Hochman, Leonard Liebes, Luis Chiriboga, Tze-Chiang Meng, Frank Martiniuk, Lina Kozhaya, and Sylvia Adams
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PDF file, 73K.
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- 2023
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6. Supplementary Table 1 from Topical TLR7 Agonist Imiquimod Can Induce Immune-Mediated Rejection of Skin Metastases in Patients with Breast Cancer
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Sandra Demaria, Derya Unutmaz, Nina Bhardwaj, Silvia C. Formenti, Judith D. Goldberg, Amy Tiersten, Yelena Novik, James Speyer, Deborah Axelrod, Nicholas Shuman, Tsivia Hochman, Leonard Liebes, Luis Chiriboga, Tze-Chiang Meng, Frank Martiniuk, Lina Kozhaya, and Sylvia Adams
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XLS file, 17K, Patient demographics, tumor characteristics, treatment, occurrence and severity of local and systemic adverse events and anti-tumor response per patient (n=10).
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- 2023
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7. Supplementary Figure 1 from Topical TLR7 Agonist Imiquimod Can Induce Immune-Mediated Rejection of Skin Metastases in Patients with Breast Cancer
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Sandra Demaria, Derya Unutmaz, Nina Bhardwaj, Silvia C. Formenti, Judith D. Goldberg, Amy Tiersten, Yelena Novik, James Speyer, Deborah Axelrod, Nicholas Shuman, Tsivia Hochman, Leonard Liebes, Luis Chiriboga, Tze-Chiang Meng, Frank Martiniuk, Lina Kozhaya, and Sylvia Adams
- Abstract
PDF file, 282K, A (non-responder 1): In situ TILs analysis by IHC in a patient with minimal T cell infiltrate before treatment (H&E stain and IHC for CD3, CD4, CD8 and FoxP3, 200x). B: (non-responder 2): In situ TILs analysis by IHC in a patient with moderate T cell infiltrate before imiquimod treatment. (H&E stain and IHC for CD3, CD4, CD8 and FoxP3, 200x).
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- 2023
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8. Association of Adenosine Deaminase (ADA) +22 G->A (rs73598374) Genotype in Latino Adult Obese
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Melissa Watt, Kyle Yocum, Fritz Francois, Alexander H. Wong, Gilbert Smolenski, Frank Martiniuk, Kahmun Lo, Kam-Meng Tchou-Wong, Angela Chen, Arthur Nadas, Ian Fagan, Chelsea O’Koren, Anna Barangan, and Esme Cribb
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medicine.medical_specialty ,Type 1 diabetes ,biology ,business.industry ,medicine.disease ,Adenosine ,Obesity ,Endocrinology ,Adenosine deaminase ,Internal medicine ,Genotype ,medicine ,biology.protein ,SNP ,Allele ,business ,Body mass index ,medicine.drug - Abstract
Obesity is a health burden that currently affects over 13% of the global adult population, consisting of over 650 million adults. Obesity is evaluated based on a body mass index (BMI) scale, which is calculated as weight in kilograms divided by the square of height in meters. Adults with a BMI greater than 30kg/m2 are considered to be obese while adults with a BMI greater than 40kg/m2 are considered morbidly obese. Adenosine deaminase (ADA) is a polymorphic enzyme that plays an important role in both immune functions and the regulation of intracellular and extracellular concentrations of adenosine. Three alleles of the ADA gene (ADA1, ADA2, ADA6) are associated with type 1 diabetes mellitus (DM1). ADA2/6 may increase susceptibility to DM1 in females. Given the evidence linking obesity with DM1, we wanted to determine whether a correlation exists between ADA2 allele and obesity. The ADA2 (+22 G->A, rs73598374) SNP changes the amino acid at position 8 from aspartic acid (Asp8)(D) to asparagine (Asn)(N). In this study, we present significant evidence of association between the ADA2 allele and obesity or BMIs greater than 25 in the Latino adult but not in the Caucasian population and therefore, may be a risk for obesity and its complications such as DM1.
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- 2021
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9. Preclinical studies for plant-based oral enzyme replacement therapy (Oral-ERT) in Pompe disease knockout mice with transgenic tobacco seeds expressing human GAA (tobrhGAA)
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Peter Meinke, Justin Martiniuk, David Reimer, Nancy Rossi, Ruby Gupta, Benedikt Schoser, Angelo Kambitsis, Adra Mack, Mariel Nigro, Sussan Saleh, John Arvanitopoulos, Leslie Sheppard Bird, Shoreh Miller, Elena Arvanitopoulos, Feng Wu, Gregory Voronin, Kam-Meng Tchou-Wong, and Frank Martiniuk
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Glycogen ,business.industry ,Transgene ,Genetic enhancement ,Enzyme replacement therapy ,Pharmacology ,medicine.disease ,chemistry.chemical_compound ,chemistry ,Oral administration ,Glycogen storage disease type II ,Knockout mouse ,medicine ,business ,Alglucosidase alfa ,medicine.drug - Abstract
Genetic deficiency of acid α-glucosidase (GAA) results in glycogen storage disease type II (GSDII) or Pompe disease (PD) encompassing at least four clinical subtypes of varying severity (infantile; childhood, juvenile and late onset). Our objective is to develop an innovative and affordable approach for enzyme replacement therapy (ERT) via oral administration (Oral-ERT) to maintain a sustained, therapeutic level of enzyme on a daily basis to improve efficacy of treatment and quality of life for people living with Pompe disease. A consensus at a 2019 US Acid Maltase Deficiency (AMDA) conference suggested that a multi-pronged approach including gene therapy, diet, exercise, etc. must be evaluated for a successful treatment of Pompe disease. Tobacco seeds contain the metabolic machinery that is more compatible with mammalian glycosylation-phosphorylation and processing. Previously, we have shown that a lysate from transgenic tobacco seeds expressing human GAA (tobrhGAA) was enzymatically active and can correct enzyme deficiency in cultured PD cells and in adult lymphocytes of Pompe patients and in vivo in disease-relevant tissues in GAA knockout (KO) mice when administered IP.We have extended these pre-clinical studies in PD knockout (KO) mice with ground tobrhGAA seeds that supports proof-of-concept for Oral-ERT for future clinical trials. Briefly in GAA KO mice, Oral-ERT with ground tobrhGAA seeds showed significant reversal of fore-limb and hind-limb muscle weakness, increased motor coordination/balance/strength and mobility, improved spontaneous learning, increased GAA baseline activity in tissues, reduced glycogen in tissues and negible serum titers to GAA. Pharmacokinetics showed maximum serum GAA concentration (Cs) at 8-10 hr and peak urine excretion at 10-12 hr. The tobrhGAA was taken up in PD fibroblast, lymphoid and myoblast cells. Enzyme kinetics compared favorably or superior to placental hGAA, plus alglucosidase alfa or other rhGAAs for Km, Vmax, pH optima, thermal heat stability and IC50 for inhibitors. The tobrhGAA in seeds was extremely stable stored for 15 years at room temperature. NGS-genome sequencing of the tobrhGAA and wild-type plants and RNA expression profiles was performed and will be posted on our website. Thus, Oral-ERT with ground tobrhGAA seeds is an innovative approach that overcomes some of the challenges of alglucosidase alfa-ERT and provides a more effective, safe and significantly less expensive treatment.
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- 2021
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10. Correspondence to: Phase 2a randomized clinical trial of dupilumab (anti‐IL‐4Rα) for alopecia areata patients
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Eamonn, Maher, Frank, Martiniuk, and William, Levis
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Alopecia Areata ,Immunology ,Humans ,Immunology and Allergy ,Antibodies, Monoclonal, Humanized ,Dermatitis, Atopic - Published
- 2022
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11. Crotamine as a vehicle for non-viral gene delivery for Pompe disease
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Peter Meinke, Adra Mack, Frank Martiniuk, Benedikt Schoser, Kam-Meng Tchou-Wong, Karpel R, Martiniuk J, and Feng Wu
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Chemistry ,Genetic enhancement ,Chinese hamster ovary cell ,Enzyme replacement therapy ,Gene delivery ,Molecular biology ,Defective virus ,law.invention ,law ,medicine ,Recombinant DNA ,Acid alpha-glucosidase ,Alglucosidase alfa ,medicine.drug - Abstract
Genetic deficiency of lysosomal acid alpha glucosidase or acid maltase (GAA) results in Pompe disease (PD), encompassing at least five clinical subtypes of varying severity. The current approved enzyme replacement therapy (ERT) for PD is via IV infusion every 2 weeks of a recombinant human GAA (rhGAA) secreted by Chinese hamster ovary (CHO) cells (alglucosidase alfa/Myozyme, Sanofi/Genzyme). Although alglucosidase alfa has proven to be efficient in rescuing cardiac abnormalities and extending the life span of the infantile form, the response in skeletal muscle is variable. ERT usually begins when the patients are symptomatic and secondary problems are already present which are compounded by low alglucosidase alfa uptake, transient nature (every 2 weeks with a rapid return to defect levels), variable glycogen reduction, autophagic accumulation, immune response and high cost. A consensus at a recent US Acid Maltase Deficiency (AMD) conference suggested that a multi-pronged approach including gene therapy, diet, exercise, etc. must be evaluated for a successful treatment of PD. Compared to replication defective viruses, non-viral gene transfer offers fewer safety concerns and, if recent studies are validated, has a wider range of cells. In order for gene therapy (GT) to succeed, the gene of interest must be delivered into the affected cell and expressed to overcome the inherited deficiency. Cell penetrating peptides (CPPs) enter eukaryotic cells through an energy-independent mechanism and efficiently carry biologically active and therapeutic molecules into cells and localize in the cytoplasm or nucleus. CPPs are usually covalently linked to the cargo, including peptides and DNA. Crotamine (Cro) from the South American rattlesnake-Crotalus durrissus terrificus venom, can bind electrostatically to plasmid DNA to deliver into cells, including muscle. We have assembled a bacterial expression vector for Cro and purified the recombinant Cro (rCro). Transient transfection in AMD fibroblasts and ex vivo in whole blood from an adult Pompe patient with rCro complexed with the pcDNA3 x hGAA cDNA demonstrated increased GAA activity. In GAA knockout (KO) mice receiving a single injection of rCro complexed to pcDNA3 x hGAA cDNA intraperitoneally (IP), we found increased GAA activity in tissues after 48 hr. After 8 treatments-IP over 55 days, we found increased vertical hang-time activity, reduced glycogen deposition, increased GAA activity/hGAA plasmid in tissues and minimal immune-reaction to rCro. A subsequent study of 5 administrations every 2 to 3 weeks showed reverse of the clinical phenotypes by running wheel activity, Rotarod, grip-strength meter, open field mobility and T-maze. Tissue culture experiments in PD fibroblast, lymphoid and skeletal muscle cell lines showed increased GAA activity after rCro transient gene delivery.
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- 2021
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12. In Vitro Clonal Priming Data Suggests Mechanism for Lower Initial Vaccine Dose Yielding Increased Immunity in Astra-Zeneca Vaccine Trial
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Alan Dattner, Frank Martiniuk, and William Levis
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General Medicine - Published
- 2021
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13. Leprosy as a model to understand cancer immunosurveillance and T cell anergy
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Tina Rendini, Frank Martiniuk, Andrew J. Park, and William R. Levis
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0301 basic medicine ,T-Lymphocytes ,T cell ,medicine.medical_treatment ,Immunology ,Tuberculoid leprosy ,Lymphocyte Activation ,Models, Biological ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Leprosy ,Neoplasms ,medicine ,Animals ,Humans ,Immunology and Allergy ,Mycobacterium leprae ,Immunity, Cellular ,Lepromatous leprosy ,biology ,Cell Biology ,medicine.disease ,biology.organism_classification ,Immunosurveillance ,030104 developmental biology ,medicine.anatomical_structure ,Immunoediting ,030220 oncology & carcinogenesis ,Nivolumab - Abstract
Leprosy is a disease caused by Mycobacterium leprae that presents on a spectrum of both clinical manifestations and T cell response. On one end of this spectrum, tuberculoid leprosy is a well-controlled disease, characterized by a cell-mediated immunity and immunosurveillance. On the opposite end of the spectrum, lepromatous leprosy is characterized by M. leprae proliferation and T cell anergy. Similar to progressive tumor cells, M. leprae escapes immunosurveillance in more severe forms of leprosy. The mechanisms by which M. leprae is able to evade the host immune response involve many, including the alterations of lipid droplets, microRNA, and Schwann cells, and involve the regulation of immune regulators, such as the negative checkpoint regulators CTLA-4, programmed death 1, and V-domain Ig suppressor of T cell activation—important targets in today’s cancer immunotherapies. The means by which tumor cells become able to escape immunosurveillance through negative checkpoint regulators are evidenced by the successes of treatments, such as nivolumab and ipilimumab. Many parallels can be drawn between the immune responses seen in leprosy and cancer. Therefore, the understanding of how M. leprae encourages immune escape during proliferative disease states has potential to add to our understanding of cancer immunotherapy.
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- 2016
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14. Increasing Virulence in Leprosy Indicated by Global Mycobacterium spp
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Tina Rendini, Frank Martiniuk, and William R Levis
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Letter ,Epidemiology ,Yersinia pestis ,Antitubercular Agents ,lcsh:Medicine ,Drug resistance ,medicine.disease_cause ,Global Health ,Communicable Diseases, Emerging ,Disease Outbreaks ,0302 clinical medicine ,fleas ,leptospirosis ,Public Health Surveillance ,Mycobacterium lepromatosis ,030212 general & internal medicine ,bacteria ,Mycobacterium leprae ,Lucio's phenomenon ,Singapore ,biology ,Virulence ,Zoonosis ,transmission ,lice ,Infectious Diseases ,Geography ,Democratic Republic of the Congo ,Leprosy ,pneumonic plague ,multidrug therapy ,Lucio’s phenomenon ,Microbiology (medical) ,China ,autochthonous ,030231 tropical medicine ,India ,leprae ,lcsh:Infectious and parasitic diseases ,Microbiology ,03 medical and health sciences ,Drug Resistance, Bacterial ,medicine ,Madagascar ,Humans ,lcsh:RC109-216 ,armadillo ,Letters to the Editor ,leprosy bonita ,M. leprae ,Plague ,Increasing Virulence in Leprosy Indicated by Global Mycobacterium spp ,lcsh:R ,zoonosis ,ectoparasite ,medicine.disease ,biology.organism_classification ,United States ,Africa ,Investigation of Pneumonic Plague, Madagascar ,Mycobacterium - Published
- 2017
15. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
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John Hardy, Nick C. Fox, Lena Lilius, Christine Van Broeckhoven, Mindy J. Katz, Carlos Cruchaga, Joshua W. Miller, Carol Brayne, Letizia Concari, Christopher Shaw, Minerva M. Carrasquillo, Richard Mayeux, Anne Boland, Charles DeCarli, Helena C. Chui, Laura B. Cantwell, Yoland Aladro Benito, Chuang Kuo Wu, Elaine R. Peskind, Andrew McDavid, M. Ilyas Kamboh, Amanda Smith, Pascual Sánchez-Juan, Jean-François Deleuze, Jayanadra J. Himali, Thomas H. Mosley, Thomas J. Montine, Chuanhai Cao, Andreas J. Forstner, Thomas G. Beach, Robert Barber, Miquel Aguilar, Liming Qu, Jerome I. Rotter, Matthew J. Huentelman, Christiane Reitz, Christopher J. O'Donnell, Steven G. Younkin, Bradley T. Hyman, Bruce L. Miller, Rachelle S. Doody, Eric B. Larson, Ronald L. Hamilton, Todd E. Golde, Steven E. Arnold, Melissa E. Garcia, Rachel Raybould, Lena Kilander, Mark A. Sager, Kevin Morgan, Kathryn L. Lunetta, William Perry, Joseph D. Buxbaum, Craig S. Atwood, Thomas D. Bird, Michael Conlon O'Donovan, Robert Olaso, Juan Fortea, Susanne Moebus, Lisa L. Barnes, Rachel Marshall, Huntington Potter, Mercè Boada, Shahzad Ahmad, Paolo Caffarra, Daniel C. Marson, Jonathan L. Haines, Perrie M. Adams, John M Olichney, Lars Lannfelt, Stefanie Heilmann-Heimbach, Markus M. Nöthen, Shubhabrata Mukherjee, John Malamon, Xue Wang, Christopher S. Carlson, Karen Ritchie, Roger N. Rosenberg, Paul K. Crane, Alexa S. Beiser, Céline Bellenguez, Robert C. Green, Maria Urbano, Petra Proitsi, John Powell, Elisa Majounie, Ammar Al-Chalabi, Hakon Hakonarson, Yogen Patel, Martin Scherer, Julie Williams, Richard B. Lipton, Vincent Dermecourt, Adam L. Boxer, Gerard D. Schellenberg, David G. Clark, Anita L. DeStefano, Joel H. Kramer, Victoria Alvarez, Nandini Badarinarayan, Oscar L. Lopez, Chris Corcoran, Ubaldo Bonuccelli, Donald R. Royall, James Bowen, Monica Diez Fairen, Tricia A. Thornton-Wells, Nilufer Ertekin-Taner, Florence Pasquier, Martin Ingelsson, Yi Zhao, John R. Gilbert, Valentina Escott-Price, Amanda B. Kuzma, Fabienne Garzia, Reinhard Heun, Otto Valladares, Andrew J. Saykin, Sara Ortega-Cubero, Liana G. Apostolova, Henry L. Paulson, John K Kauwe, Imelda Barber, Carolina Ceballos Diaz, Douglas Galasko, M. Arfan Ikram, Lluís Tárraga, Carlo Caltagirone, Joan S. Reisch, Wolfgang Maier, Bruno Vellas, Rebecca Sims, Angela Hodges, Matthew P. Frosch, Isabel Henández, Annakaisa Haapasalo, Thor Aspelund, Håkan Thonberg, Aimee Pierce, Roger L. Albin, Wayne W. Poon, Rebecca Sussams, Amy Braddel, Ranjan Duara, Albert V. Smith, Kirk C. Wilhelmsen, Gianfranco Spalletta, Simon Lovestone, Peter Passmore, Ana Frank-García, Cynthia M. Carlsson, Jade Chapman, Nathan D. Price, Philip L. De Jager, John M. Ringman, Seung Hoan Choi, Nicola Denning, Michael John Owen, Clinton T. Baldwin, Amalia C. Bruni, Denis A. Evans, Rudolph E. Tanzi, Dominique Campion, Laura Fratiglioni, Alberto Lleó, Per Hoffmann, Carole Dufouil, Charlotte Forsell, Alun Meggy, Charlene Thomas, Robert S. Stern, James B. Leverenz, Tatiana Foroud, William W. Seeley, James J. Lah, Brian A. Lawlor, Kenneth B. Fallon, Matthias Riemenschneider, Ryan M. Huebinger, Regina M. Carney, Clinton B. Wright, Didier Hannequin, Deborah Blacker, Anne Kinhult-Ståhlbom, Ekaterina Rogaeva, Andrew P. Lieberman, Bernardino Ghetti, Linda J. Van Eldik, Bernadette McGuinness, Thomas Fairchild, Margaret A. Pericak-Vance, Ashok Raj, Reinhold Schmidt, Ronald C. Petersen, Harald Hampel, María J. Bullido, Steven L. Carroll, Maria Candida Deniz Naranjo, Kathleen A. Welsh-Bohmer, Myriam Fornage, Joseph F. Quinn, Caroline Graff, Claudia L. Satizabal, Patrice L. Whitehead, David Wallon, Christopher Medway, Lindsay A. Farrer, Vilmundur Gudnason, Peter St George-Hyslop, Pau Pastor, Frank Jessen, Erin L. Abner, Johanna Jakobsdottir, Hieab H.H. Adams, Roberta Cecchetti, Walter A. Kukull, Thomas S. Wingo, Michelle K. Lupton, Valur Emilsson, Susan M. McCurry, Simon Mead, Hilkka Soininen, Sandra Weintraub, Amy Gerrish, Lindy E. Harrell, Lina Keller, Jean-Charles Lambert, Denise Harold, Stephen Todd, Wei Gu, Maura Gallo, Najaf Amin, Lenore J. Launer, Eleonora Sacchinelli, Mikko Hiltunen, Cécile Dulary, Eliecer Coto, Xueqiu Jian, Nathalie Fievet, Patrizia Mecocci, Sarah Taylor, Eric Boerwinkle, Maria Serpente, Ronald G. Munger, Ina Giegling, Carlo Masullo, Aoibhinn Lynch, Eliezer Masliah, Anne M. Koivisto, Chang En Yu, Qiong Yang, Benedetta Nacmias, Wayne C. McCormick, Kristelle Brown, Alessio Squassina, Deborah C. Mash, Brian W. Kunkle, Makrina Daniilidou, Alison Goate, David Carrell, Kara L. Hamilton-Nelson, Sandra Barral, Vincent Chouraki, Kristel Sleegers, Frank J. Wolters, Joseph E. Parisi, Iwona Kłoszewska, Ronald C. Kim, Sonia Moreno-Grau, Marina Arcaro, Carmen Muñoz Fernadez, Vernon S. Pankratz, Duane Beekly, Sabrina Pichler, Gislain Septier, Delphine Bacq, Amanda J. Myers, Adam C. Naj, Frank Martiniuk, Sudha Seshadri, Badri N. Vardarajan, Joshua A. Sonnen, M.-Marsel Mesulam, Howard J. Rosen, James T. Becker, Chiara Fenoglio, Ge Li, Alberto Pilotto, Mary Sano, Olivier Hanon, Honghuang Lin, Jean Paul G. Vonsattel, W. T. Longstreth, Daniela Galimberti, David C. Rubinsztein, RoseMarie Brundin, Vilmantas Giedraitis, Christine M. Hulette, Peter Holmans, Martin Dichgans, Maria Vronskaya, Céline Derbois, Michelangelo Mancuso, Constantine G. Lyketsos, Christophe Tzourio, Jacques Epelbaum, Raffaele Maletta, Mariet Allen, Hong-Dong Li, James R. Burke, Rik Vandenberghe, David G. Mann, Bruce M. Psaty, Lawrence S. Honig, Beth A. Dombroski, Erik D. Roberson, Cornelia M. van Duijn, Benjamin Grenier-Boley, Seppo Helisalmi, Jean-François Dartigues, Russell H. Swerdlow, Paola Bossù, Ashley R. Winslow, Elio Scarpini, Lesley Jones, Sebastien Engelborghs, John Q. Trojanowski, Jeffrey Kaye, Jenny Lord, Chiara Cupidi, Janet A. Johnston, Dan Rujescu, Feroze Golamaully, Anne Braae, Rafael Blesa, L. Adrienne Cupples, Dennis W. Dickson, Gail P. Jarvik, David W. Fardo, David H. Cribbs, Michael Gill, Jose Bras, Allan I. Levey, Jennifer Williamson, Rhodri Thomas, John C. Morris, Lei Yu, Debby W. Tsuang, Annette M. Hartmann, John H. Growdon, John Collinge, Claudine Berr, Fernando Rivadeneira, Oliver Peters, Albert Hofman, Frank M. LaFerla, Vivianna M. Van Deerlin, James Uphill, David A. Bennett, Onofre Combarros, Gudny Eiriksdottir, Jeremy D. Burgess, Melanie L. Dunstan, Elizabeth Crocco, Keeley J. Brookes, Robert R. Graham, Lon S. Schneider, Eden R. Martin, Matt Hill, Neill R. Graff-Radford, Joseph T. Hughes, Vincenzo Solfrizzi, Taniesha Morgan, Antonio Ciaramella, Bruno Dubois, Juan C. Troncoso, Paolo Bosco, Jordi Clarimón, Daniel H. Geschwind, Virginia Boccardi, Barry Reisberg, Timothy W. Behrens, Annette L. Fitzpatrick, Salvatore Spina, Alexis Brice, Eileen H. Bigio, Marla Gearing, Jeffrey M. Burns, Carol A. Miller, Marilyn S. Albert, Sven J. van der Lee, Sandro Sorbi, C. Dirk Keene, Daniel Levy, Antonio Daniele, Eric M. Reiman, Paramita Chakrabarty, Oscar Sotolongo-Grau, Helena Schmidt, Francesco Panza, Murray A. Raskind, Rita Guerreiro, Gyungah Jun, Anna Karydas, Markus Leber, Harry V. Vinters, Cory C. Funk, Charles C. White, Jill R. Murrell, Sid E. O'Bryant, Nigel J. Cairns, Josée Dupuis, Ann C. McKee, Julie A. Schneider, Megan L. Grove, Malcolm B. Dick, Bradley F. Boeve, Jennifer A. Brody, Sanjay Asthana, Agustín Ruiz, Stefan Herms, Yuning Chen, David Craig, Neil W. Kowall, Maria Donata Orfei, JoAnn T. Tschanz, Florentino Sanchez Garcia, Manuel Mayhaus, Alfredo Ramirez, James Turton, André G. Uitterlinden, Davide Seripa, Lee-Way Jin, Kelley Faber, Maria C. Norton, Shuo Li, Steven H. Ferris, Steffi G. Riedel-Heller, Joshua C. Bis, Li-San Wang, Johannes Kornhuber, Peter Paul De Deyn, Martin R. Farlow, Randall L. Woltjer, Gary W. Beecham, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Icelandic Heart Association [Kopavogur, Iceland] (IHA), John P. Hussman Institute for Human Genomics [Miami, FL, USA], University of Miami [Coral Gables], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Medicine, University of Washington [Seattle], Dr. John T. Macdonald Foundation [Miami, FL, USA] (Department of Human Genetics), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Genomics [Bonn, Germany] (Institute of Human Genetics), University of Bonn-Institute of Human Genetics [Bonn, Germany], Department of Molecular Genetics, Institut Català de Neurociències Aplicades [Barcelona, Spain], Well Advanced Solutions, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], The University of Texas Health Science Center at Houston (UTHealth), Columbia University [New York], University of Eastern Finland, Life & Brain Center - Department of Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), John P. Hussman Institute for Human Genomics, Neurobiologie de la Croissance et de la Senescence, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Emmy Noether Project (SFB 833), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Boston University [Boston] (BU), Department of Genomics, Institute for Systems Biology [Seattle, WA, USA], Universitätsklinikum Bonn (UKB), Centre of Excellence for Robotic Vision [Canberra], Australian Research Council [Canberra] (ARC), Neuroscience and Mental Health Research Institute [Cardiff, UK] (School of Medicine), Boston University School of Medicine (BUSM), Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, University of Pennsylvania [Philadelphia], Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Department of Epidemiology and Biostatistics, ERASMUS, Hospital Universitario Doctor Negrín [Las Palmas de Gran Canaria, Spain], Department of Neurodegenerative Diseases, University of Mississippi Medical Center (UMMC), Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Penn Neurodegeneration Genomics Center), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatics, GlaxoSmithKline, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], University of Nottingham, UK (UON), University of Texas Health Science Center, Department of Neurobiology, Caring Sciences and Society (NVS), University of Bari Aldo Moro (UNIBA), Ageing Group, Centre for Public Health, Queen's University [Belfast] (QUB), Mayo Clinic [Jacksonville], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Università degli Studi di Perugia (UNIPG), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), CHU Rouen, Normandie Université (NU), Universidad Autonoma de Madrid (UAM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Florida [Gainesville] (UF), University of Parma = Università degli studi di Parma [Parme, Italie], Center for Cognitive Disorders AUSL [Parma, Italy], School of Public Health [Boston], Uppsala University, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Xi'an Jiaotong University (Xjtu), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Institute of Gerontology and Geriatrics, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Geriatric Medicine and Metabolic Diseases, Departments of Nuclear Medicine, University Medical Centre Hamburg-Eppendorf [Hamburg, Germany], University of Texas Southwestern Medical Center [Dallas], University of Cologne, Laboratoire d'Etudes et de Recherche en Informatique d'Angers (LERIA), Université d'Angers (UA), Johns Hopkins University (JHU), Universität Leipzig [Leipzig], University of Iceland [Reykjavik], Metacohorts Consortium, Harvard School of Public Health, Catholic University of Rome, Medical University Graz, Baylor College of Medicine (BCM), Baylor University, University of North Texas Health Science Center [Fort Worth], Santa Lucia Foundation (IRCCS), Nextel S.A. [Bilbao], Massachusetts General Hospital [Boston], Department of Pathology and Laboratory Medicine and Indiana Alzheimer disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Joint Institute for the Study of the Atmosphere and Ocean (JISAO), Beijing University of Technology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Saul B. Korey Department of Neurology, Albert Einstein College of Medicine [New York]-Yeshiva University, Utah State University (USU), Fundació per la Recerca Biomèdica i Social Mútua Terrassa [Barcelona, Spain], Hospital Universitario Mutua de Terrassa, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Medical University of Łódź (MUL), University of Leicester, MRC Prion Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Fondazione Istituto di Ricerca e Cura Carattere Scientifico [Rome], Università degli Studi di Roma Tor Vergata [Roma], Saarland University Hospital, Universitat Autònoma de Barcelona (UAB), Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Universidade do Porto, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Experimental and Clinical Pharmacology, St. James Hospital and Trinity College [Dublin, Ireland], School of Medicine [Dublin], Trinity College Dublin, University of Sheffield [Sheffield], Lancaster University, University of Michigan [Ann Arbor], University of Michigan System, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University of Wisconsin-Madison, Rush Alzheimer Disease Center [Chicago, IL, États-Unis], Rush University Medical Center [Chicago], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), School of Engineering [Cardiff], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Northwestern University Feinberg School of Medicine, Mayo Clinic [Rochester], Swedish Medical Center [Seattle, WA, USA], University of California [San Francisco] (UCSF), University of California, Duke University [Durham], University of Kansas Medical Center [Lawrence], Laboratory of Molecular Neuropsychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Washington University in Saint Louis (WUSTL), University of South Florida [Tampa] (USF), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Medical University of South Carolina [Charleston] (MUSC), University of Southern California (USC), Los Alamos National Laboratory (LANL), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurology Department, University of California, Davis (UCDavis-Neuro), University of California [Davis] (UC Davis), University of California [Irvine] (UCI), Mount Sinai Medical Center, Indiana State University, University of Alabama at Birmingham [ Birmingham] (UAB), University of Kentucky, New York University [New York] (NYU), NYU System (NYU), Department of Medical and Molecular Genetics, Department of Epidemiology and biostatistics, VU University Medical Center [Amsterdam], Emory University [Atlanta, GA], Department of Neurology, University of California-University of California-David Geffen School of Medicine [Los Angeles], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Department of Medical Genetics, HMNC Brain Health, Alzheimer Disease Research Laboratory, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Laboratoire d'Informatique, Systèmes, Traitement de l'Information et de la Connaissance (LISTIC), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Department of Psychiatry, School of Medicine-Johns Hopkins University and Johns Hopkins Bayview Medical Center, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Department of neurosciences, University of California [San Diego] (UC San Diego), Department of Physics and Astronomy [Fort Worth], Texas Christian University (TCU), Department of Computer Science [University of California, Davis], Indiana University System, Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), Department of Laboratory Medicine and Pathology, Mayo Clinic, Institute for Memory Impairments and Neurological Disorders [Irvine], University of Colorado Anschutz [Aurora], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Keck School of Medicine [Los Angeles], Indiana University [South Bend], Massachusetts General Hospital, Novartis Institutes for Biomedical Research [Cambridge, MA, USA], Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, UCLA Medical Center-David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Institut de Génomique d'Evry (IG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Antwerp (UA), Institute Born-Bunge, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], University of Kuopio, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Laboratoire d'Analyse Génomique, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Inserm-U1167, Dpt Gériatrie [CHU Broca], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Epidemiology, University of Washington, School of Medicine [Los Angeles], Albert Einstein College of Medicine [New York], IdiPAZ - Instituto de Investigación La Paz [Madrid, Spain], Instituto de Física Teórica UAM/CSIC (IFT), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Department of Internal Medicine, University of Central Asturias [Oviedo, Spain], Human Genome Sequencing Center, Baylor College of Medicine, Baylor University-Baylor University, Department of Epidemiology, Erasmus Medical Centre, Translational Genomics Research Institute [Phoenix, AZ, USA], University of Arizona, Banner Alzheimer's Institute [Phoenix, AZ, États-Unis], University of Texas Health Science Center at San Antonio [San Antonio], Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department. of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico, Centre for Research in Neurodegenerative Diseases, VA Puget Sound Health Care System/GRECC [Seattle, WA, USA], University of Pisa - Università di Pisa, Pfizer Worldwide Research and Development [Cambridge, MA, USA], Università cattolica del Sacro Cuore [Piacenza e Cremona] (Unicatt), Texas Tech University Health Sciences Center, Texas Tech University [Lubbock] (TTU), Saarland University [Saarbrücken], University of Bonn, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Cambridge Institute for Medical Research (CIMR), Department of Molecular Neurosciences, Institute of Neurology, UCL, Institute of Psychiatry, Institute of psychiatry, University of British Columbia (UBC), the Clinical Neuroscience Research Group, University of Manchester [Manchester]-Greater Manchester Neurosciences Centre, Aristotle University of Thessaloniki, Memory and Dementia Centre, 3rd Department of Neurology, G. Pa, University of Barcelona, University of Southampton, Department of Psychiatry [Oxford] (POWIC), University of Oxford [Oxford]-The Warneford Hospital, School of Psychology [Cardiff University], Department of Medical Sciences, UCL, Institute of Neurology [London], Washington University School of Medicine, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), School of Medecine, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], School of Life Sciences, Department of Neuroscience, Mayo Clinic Jacksonville, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Clínica Universidad de Navarra [Pamplona], Neurodegenerative Brain Diseases Group, VIB, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Brigham Young University (BYU), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, The Gertrude H Sergivesky Center, Columbia University College of Physicians and Surgeons, Genetic Epidemiology Unit, Section of Clinical and Molecular Neurogenetics, Universität zu Lübeck [Lübeck], University of Pennsylvania - Department of Pathology & Laboratory Medecine, Framingham Heart Study [Framingham, MA, USA], ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), European Project: 29845,LSH-ACC-MENTOR, University of Pennsylvania-University of Pennsylvania, Universität Bonn = University of Bonn-Institute of Human Genetics [Bonn, Germany], Universität Leipzig-Universität Leipzig, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli Studi di Perugia = University of Perugia (UNIPG), Universidad Autónoma de Madrid (UAM), Università degli studi di Parma = University of Parma (UNIPR), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Universität Leipzig, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Yeshiva University- Albert Einstein College of Medicine [New York], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Università degli Studi di Milano = University of Milan (UNIMI), Saarland University Hospital (UKS), Università degli Studi di Firenze = University of Florence (UniFI), Universidade do Porto = University of Porto, University of California (UC)-University of California (UC), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Kansas Medical Center [Kansas City, KS, USA], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of California [Irvine] (UC Irvine), University of Kentucky (UK), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Department of Computer Science [Univ California Davis] (CS - UC Davis), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], Universität Bonn = University of Bonn, University of Oxford-The Warneford Hospital, Medical Research Council-Cardiff University, Universität zu Lübeck = University of Lübeck [Lübeck], Epidemiology, Neurology, Gastroenterology & Hepatology, Internal Medicine, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen, IRCCS 'Casa Sollievo della Sofferenza', Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (Ciberned), University of Florida [Gainesville], University of Parma, Troubles cognitifs dégénératifs et vasculaires (U1171), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-INSERM, Yeshiva University- Albert Einstein College of Medicine, Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université Polytechnique Hauts-de-France (UPHF)-Ecole Centrale de Lille-Université Polytechnique Hauts-de-France (UPHF)-Institut supérieur de l'électronique et du numérique (ISEN), Autonomous University of Barcelona (UAB), Università degli Studi di Firenze [Firenze], Universidade do Porto [Porto], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Washington University in St Louis, University of South Florida (USF), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, McGill University, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique, Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Albert Einstein College of Medicine, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Università Cattolica del S. Cuore - Catholic University of the Sacred Hearth, University of Florence (UNIFI), CIBER de Enfermedades Neurodegenerativas (CIBERNED), Universität zu Lübeck [Lübeck] - University of Lübeck [Lübeck], [ANR-10-IAIHU-06],« Investissements d'avenir » ,Agence nationale de la recherche (ANR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Department of Psychiatry, van der Lee, Sven J [0000-0003-1606-8643], Naj, Adam C [0000-0002-9621-2942], Badarinarayan, Nandini [0000-0002-6944-748X], Chouraki, Vincent [0000-0002-4698-1794], Graham, Robert R [0000-0001-7151-4277], Hoffmann, Per [0000-0002-6573-983X], Smith, Albert V [0000-0003-1942-5845], Satizabal, Claudia L [0000-0002-1115-4430], Brody, Jennifer A [0000-0001-8509-148X], Wolters, Frank J [0000-0003-2226-4050], Lupton, Michelle K [0000-0002-7274-7299], Lin, Honghuang [0000-0003-3043-3942], Adams, Hieab H [0000-0003-3687-2508], Giedraitis, Vilmantas [0000-0003-3423-2021], Pasquier, Florence [0000-0001-9880-9788], Chen, Yuning [0000-0002-7358-7055], Bossù, Paola [0000-0002-1432-0078], Ghetti, Bernardino [0000-0002-1842-8019], Yang, Qiong [0000-0002-3658-1375], Aspelund, Thor [0000-0002-7998-5433], Bullido, María J [0000-0002-6477-1117], Rivadeneira, Fernando [0000-0001-9435-9441], Rubinsztein, David C [0000-0001-5002-5263], Al-Chalabi, Ammar [0000-0002-4924-7712], Tsolaki, Magda [0000-0002-2072-8010], De Jager, Philip L [0000-0002-8057-2505], Dickson, Dennis W [0000-0001-7189-7917], Van Broeckhoven, Christine [0000-0003-0183-7665], Ikram, M Arfan [0000-0003-0372-8585], Amouyel, Philippe [0000-0001-9088-234X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Berr, Claudine, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, and Mentoring of LifeSciHealth-Multipliers in the Accession Candidate Countries - LSH-ACC-MENTOR - 29845 - OLD
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0301 basic medicine ,Linkage disequilibrium ,[SDV]Life Sciences [q-bio] ,Medizin ,Sequence Homology ,Genome-wide association study ,genetics [Alzheimer Disease] ,metabolism [Microglia] ,Linkage Disequilibrium ,0302 clinical medicine ,genetics [Protein Interaction Maps] ,genetics [Membrane Glycoproteins] ,Gene Frequency ,Immunologic ,genetics [Adaptor Proteins, Signal Transducing] ,Receptors ,genetics [Exome] ,Odds Ratio ,Innate ,genetics [Receptors, Immunologic] ,Exome ,Protein Interaction Maps ,genetics [Genetic Predisposition to Disease] ,Receptors, Immunologic ,ABI3 protein, human ,Genetics ,Adaptor Proteins, Signal Transducing ,Alzheimer Disease ,Amino Acid Sequence ,Case-Control Studies ,Gene Expression Profiling ,Genetic Predisposition to Disease ,Genotype ,Humans ,Immunity, Innate ,Membrane Glycoproteins ,Microglia ,Phospholipase C gamma ,Sequence Homology, Amino Acid ,Polymorphism, Single Nucleotide ,Adaptor Proteins ,Single Nucleotide ,3. Good health ,[SDV] Life Sciences [q-bio] ,Amino Acid ,Settore MED/26 - NEUROLOGIA ,genetics [Phospholipase C gamma] ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Alzheimer's disease ,Common disease-common variant ,Biology ,Article ,03 medical and health sciences ,ddc:570 ,medicine ,Journal Article ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Polymorphism ,Allele frequency ,TREM2 protein, human ,TREM2 ,Case-control study ,Signal Transducing ,Immunity ,medicine.disease ,R1 ,Minor allele frequency ,genetics [Immunity, Innate] ,030104 developmental biology ,Human medicine ,030217 neurology & neurosurgery - Abstract
International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
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- 2017
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16. The Effect of Intraoperative Infusion of Dexmedetomidine on the Quality of Recovery After Major Spinal Surgery
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Frank Martiniuk, Michael Urban, Richard Kline, Ramesh Babu, Sorosch Didehvar, Michael Haile, and Alex Bekker
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business.industry ,Convalescence ,media_common.quotation_subject ,Article ,law.invention ,Fentanyl ,Anesthesiology and Pain Medicine ,Randomized controlled trial ,law ,Anesthesia ,Clinical endpoint ,Medicine ,Surgery ,Neurology (clinical) ,Anesthesia Recovery Period ,Dexmedetomidine ,business ,Propofol ,Prospective cohort study ,medicine.drug ,media_common - Abstract
Background Surgery induces a variety of metabolic, endocrine, and immune changes collectively known as the "stress response," which may often lead to prolonged postoperative convalescence. Anesthetic management may modulate this physiological response, thus affecting the postoperative course. We hypothesized that the intraoperative administration of dexmedetomidine (DEX), a sympatholytic agent, would reduce the stress response and improve the quality of recovery in patients undergoing major surgery. Methods We conducted a prospective randomized double-blinded study of 54 patients undergoing multilevel spinal fusion. Anesthesia was maintained using either propofol/fentanyl/dexmedetomidine (PFD) or propofol/fentanyl/placebo-saline (PFS). The quality of recovery (a primary endpoint) was assessed using a 40-item quality of recovery questionnaire and a 9-question Fatigue Severity Scores. The tests were carried out preoperatively on postoperative days (POD) 1, 2, 3, and 30. Blood samples were collected at baseline, in the postanesthesia care unit, and at POD 1 and were analyzed for levels of cortisol, C-reactive proteins (CRP), and cytokines interleukin (IL)-1α, IL-1β, IL-1ra, IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-α. Data were analyzed using SPSS software (version 18) using a multivariate and mixed model approach to test for the effect of surgery and drug group. Pairwise comparisons were assessed by means of the t test or rank tests after correcting for multiple comparisons. Results The global 40-item quality of recovery questionnaire scores showed a significant effect of time (F(4,114)=22.63, P Conclusions DEX infusion during multilevel spinal fusions moderately improved the quality of recovery and possibly reduced fatigue in the early postoperative period. Moreover, it reduced plasma levels of cortisol and IL-10 in comparison with the control group. Our sample size was not sufficient to detect differences either in the incidence of complications or in clinically relevant outcomes.
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- 2013
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17. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis
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Marla Gearing, David G. Clark, Steven L. Carroll, Marianne Johnstone, Darwin L. Conwell, Gregory A. Cote, Sandra Weintraub, Matthew P. Frosch, Stuart Sherman, Badri N. Vardarajan, Joshua A. Sonnen, Lindy E. Harrell, Peter B. Cotton, Lisa L. Barnes, Lawrence S. Honig, Carol A. Miller, Adam Slivka, Michelle A. Anderson, Nadine M. Melhem, David A. Bennett, Joel H. Kramer, Jill P. Smith, Michele D. Lewis, Mary Ganguli, Jean Paul Vonsatte, Thomas J. Montine, Lee-Way Jin, Kenneth B. Fallon, Marilyn S. Albert, Eliezer Masliah, John H. Growdon, Barry Reisberg, Chuanhai Cao, Patricia L. Kramer, Douglas J. Hartman, Allan I. Levey, Jennifer Williamson, Vivianna M. Van Deerlin, Wayne W. Poon, Alison Goate, Vijay P. Singh, Bernie Devlin, Christiane Reitz, Ann C. McKee, Amanda Smith, Neill R. Graff-Radford, Walter A. Kukul, John Baillie, Andres Gelrud, Ranjan Duara, Thomas D. Bird, Clinton B. Wright, Deborah Blacker, Chiao-Feng Lin, Ge Li, Ronald C. Kim, Deborah C. Mash, Debby W. Tsuang, John P. Neoptolemos, Timothy B. Gardner, Kathryn L. Lunetta, Steven G. Younkin, Kara L. Hamilton-Nelson, Ronald L. Hamilton, F. Yesim Demirci, Eric M. Reiman, Charles DeCarli, John M Olichney, Richard Mayeux, Gregory A. Jicha, Michael R. O'Connell, Matt Tector, Eileen H. Bigio, Jonathan D. Glass, M. Ilyas Kamboh, Randall E. Brand, Christopher Lawrence, Steven E. Arnold, Jessica LaRusch, Elaine R. Peskind, David H. Cribbs, M.-Marsel Mesulam, Constantine G. Lyketsos, Michelle L. Kienholz, Frank M. LaFerla, Duane Beekly, Kelley Faber, Salvatore Spina, Gyungah Jun, Thiruvengadam Muniraj, Erik D. Roberson, Anna Karydas, Steven H. Ferris, Bruce L. Miller, Randall L. Woltjer, Li-San Wang, Lon S. Schneider, John C. Morris, John Q. Trojanowski, Jeffrey Kaye, Joseph E. Parisi, Nilufer Ertekin-Taner, Harry V. Vinters, Lidiya Orlichenko, Robert Barber, Chris E. Forsmark, Mary Sano, Bimaljit S. Sandhu, Peter A. Banks, Martin R. Farlow, Bradley T. Hyman, Joseph F. Quinn, Gary W. Beecham, James A. DiSario, Hakon Hakonarson, Daniel C. Marson, Adam C. Naj, Frank Martiniuk, Oscar L. Lopez, Mary E. Money, Julia Mayerle, William Greenhalf, Kathryn Roeder, Adam L. Boxer, Christine M. Hulette, Gerard D. Schellenberg, Georgios I. Papachristou, Douglas Galasko, James R. Burke, Donna B. Stolz, Murray A. Raskind, Peter Simon, Linda J. Van Eldik, Robert A. Hawes, Chang En Yu, Tatiana Foroud, Jonathan L. Haines, Stephen R. Wisniewski, William W. Seeley, Dhiraj Yadav, James J. Lah, C. Mel Wilcox, Sid Gilman, Liana G. Apostolova, Howard J. Rosen, Clinton T. Baldwin, Robert S. Stern, Narcis O. Zarnescu, Dennis W. Dickson, Margaret A. Pericak-Vance, Ashok Raj, Stephen T. Amann, Joseph D. Buxbaum, Ronald C. Petersen, Robert C. Green, David C. Whitcomb, Rudolph E. Tanzi, Lindsay A. Farrer, Helena C. Chui, Laura B. Cantwell, Wendy J. Mack, Samer Alkaade, Nigel J. Cairns, Thomas G. Beach, Frank Ulrich Weiss, Alyssa M. Krasinskas, Elizabeth Head, Nalini M. Guda, Julie A. Schneider, Malcolm B. Dick, Roger N. Rosenberg, Jill R. Murrel, Otto Valladares, Andrew J. Saykin, Huntington Potter, John R. Gilbert, Neil W. Kowall, Joseph Romagnuolo, Markus M. Lerch, Aimee Pierce, Roger L. Albin, John M. Ringman, James B. Leverenz, Carlos Cruchaga, Joshua W. Miller, Lei Yu, M. Michael Barmada, Lambertus Klei, Andrew P. Lieberman, Bernardino Ghetti, Robert Sutton, Kathleen A. Welsh-Bohmer, Juan C. Troncoso, Edward H. Koo, Elizabeth Crocco, Eden R. Martin, Daniel H. Geschwind, and Regina M. Carney
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Male ,Pancreatic disease ,Pancreatitis, Alcoholic ,Genome-wide association study ,Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Sex Factors ,Gene Frequency ,Genotype ,Genetics ,medicine ,PRSS2 ,Humans ,Genetic Predisposition to Disease ,Trypsin ,Allele ,Allele frequency ,Homozygote ,Genetic Variation ,medicine.disease ,3. Good health ,Hemizygote ,030220 oncology & carcinogenesis ,Immunology ,Claudins ,Mutation ,Trypsinogen ,Pancreatitis ,030211 gastroenterology & hepatology ,Female ,Genome-Wide Association Study - Abstract
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).
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- 2012
18. Expression of Sox10 and c-kit in Sinonasal Mucosal Melanomas Arising in the Chinese Population
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Robert Shibata, Shu Yi Wang, Frank Martiniuk, Herman Yee, Qian Yao, Beverly Y. Wang, Max Xiangtian Kong, and Hong Gang Liu
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Gene mutation ,Stain ,S100 protein ,Pathology and Forensic Medicine ,Asian People ,Biomarkers, Tumor ,medicine ,Humans ,Melanoma ,Aged ,Original Paper ,Mucous Membrane ,biology ,SOXE Transcription Factors ,CD117 ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Staining ,Proto-Oncogene Proteins c-kit ,Oncology ,Otorhinolaryngology ,Monoclonal ,biology.protein ,Female ,Paranasal Sinus Neoplasms - Abstract
Sinonasal mucosal melanomas (SNMM) of the head and neck regions are rare and aggressive malignancies. Although they can affect patients of any ethnicity, they are more numerous in Chinese patients. The diagnosis and treatment of these tumors can be challenging. Recent studies have reported that Sox10 is a sensitive melanocytic marker for cutaneous melanoma (Nonaka et al. in Am J Surg Pathol 32:1291–1298, 2008). In addition, a CD117 (c-kit) gene mutation has been identified in cutaneous melanomas, indicating that there may be potential therapeutic benefits of tyrosine kinase inhibitors, such as Imatinib. The purpose of this study was to detect and test the immunohistochemical expression of Sox10 and c-kit in mucosal melanomas (MM) arising in the nasal cavities of Chinese patients. Twenty eight patients with mucosal melanomas of the nasal cavity were treated in two major hospitals in China. All cases had been locally diagnosed as primary SNMM. We confirmed all diagnoses with positive immunohistochemical stains for S100 and HMB-45. Additionally, automated immunohistochemistry was performed using a goat polyclonal Sox10 antibody and a monoclonal c-kit antibody counterstained using a standard avidin–biotin complex method. Immunohistochemical positive expression of Sox10 was defined by nuclear stain; and positivity for c-kit resulted in a distinct membranous staining. The extent of nuclear positivity for Sox10 and membranous stain for c-kit was graded by 4 board certified pathologists as follows: 1+, 1–25 % of positive tumor cells; 2+, 25–50 %; 3+, 50–75 %; and 4+, ≥75 %. Sox10 nuclear expression was found in all cases (100 %), with 4+ staining in 26 out of 28 cases (92.8 %) and 3+ staining in two cases with (7.1 %). The overall positivity for S100 staining was 23 out of 28 (82.1 %), with 1+ staining in 10 cases, 2+ staining in 6 cases, 3+ staining in 7 cases, and no staining in 5 cases. The sensitivity and intensity of Sox10 immunohistochemistry were both higher than with S100 immunohistochemistry. Immunopositivity of membranous stain for c-kit (CD117) was seen in 24 out of 28 cases (85.7 %), including 6 tumors that were 4+, eight that were 3+, six that were 2+, and four that showed 1+ staining. Our results demonstrate that Sox10 is a sensitive marker for SNMM and it may possess diagnostic value in addition to that of S100 protein. The expression of c-kit in the majority of MMs suggests that it may be useful in the assessment of these tumors for potential treatment with tyrosine kinase inhibitors.
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- 2012
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19. TOMM40 poly-T Variants and Cerebrospinal Fluid Amyloid Beta Levels in the Elderly
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Frank Martiniuk, Henrik Zetterberg, Pankaj D. Mehta, Kaj Blennow, Nunzio Pomara, Davide Bruno, John J. Sidtis, and Jay Nierenberg
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Apolipoprotein E ,Linkage disequilibrium ,medicine.medical_specialty ,Neurology ,Amyloid beta ,Disease ,Biochemistry ,Article ,Cellular and Molecular Neuroscience ,Cerebrospinal fluid ,Internal medicine ,Mitochondrial Precursor Protein Import Complex Proteins ,Humans ,Medicine ,Neurochemistry ,Aged ,Genetics ,Amyloid beta-Peptides ,biology ,business.industry ,Membrane transport protein ,Membrane Transport Proteins ,General Medicine ,Endocrinology ,biology.protein ,business - Abstract
A variable poly-T polymorphism in the TOMM40 gene, which is in linkage disequilibrium with APOE, was recently implicated with increased risk and earlier onset age for late-onset Alzheimer's disease in APOE ε3 carriers. To elucidate potential neurobiological mechanisms underlying this association, we compared the effect of TOMM40 poly-T variants to the effect of APOE, an established LOAD-risk modulator, on cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau levels, in cognitively intact elderly subjects. APOE ε4 carriers showed significant reductions in Aβ 1-42 levels compared to non-ε4 carriers, but no differences were detected across TOMM40 variants. Neither Aβ 1-40 nor tau levels were affected by APOE or TOMM40.
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- 2011
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20. Common variants in MS4A4/MS4A6E, CD2uAP, CD33, and EPHA1 are associated with late-onset Alzheimer’s disease
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Bradley T. Hyman, Tatiana Foroud, James J. Lah, Roger N. Rosenberg, Philip L. De Jager, John M. Ringman, Thomas D. Bird, Ramon Diaz-Arrastia, Wayne W. Poon, Barry Reisberg, Juan C. Troncoso, Peter St George-Hyslop, Deborah Blacker, Ronald C. Kim, Adam L. Boxer, Gerard D. Schellenberg, Douglas Galasko, John Hardy, Erik D. Roberson, Minerva M. Carrasquillo, Richard Mayeux, Steven L. Carroll, Elaine R. Peskind, Walter A. Kukull, Marla Gearing, Lee-Way Jin, Paul K. Crane, James D. Bowen, Deborah C. Mash, Carol A. Miller, Eileen H. Bigio, Duane Beekly, Kenneth B. Fallon, Bruce L. Miller, Eliezer Masliah, Charles DeCarli, Gyungah Jun, Mary Ganguli, M. Ilyas Kamboh, Steven E. Arnold, Patricia L. Kramer, Gregory A. Jicha, David G. Clark, Lon S. Schneider, William G. Ellis, Anna Karydas, Alison Goate, Michael A. Slifer, Matthew P. Frosch, Steven G. Younkin, Steven T. DeKosky, F. Yesim Demirci, John Q. Trojanowski, Jeffrey Kaye, Sandra Weintraub, Jonathan D. Glass, Lindy E. Harrell, Adam C. Naj, Frank Martiniuk, Harry V. Vinters, Gail P. Jarvik, Ronald L. Hamilton, Ruchita Rajbhandary, Wayne C. McCormick, Neill R. Graff-Radford, Allan I. Levey, Jennifer Williamson, Daniel C. Marson, Andrew McDavid, John R. Gilbert, Thomas H. Beach, Christine M. Hulette, David A. Bennett, William P. Seeley, Christopher S. Carlson, Amanda J. Myers, Hakon Hakonarson, Debby W. Tsuang, Kathryn L. Lunetta, James R. Burke, Sid Gilman, John C. Morris, Bradley F. Boeve, Oscar L. Lopez, Nilufer Ertekin-Taner, Thomas J. Montine, Daniel P. Perl, Eric M. Reiman, Joseph F. Quinn, Susan M. McCurry, Paul Gallins, Murray A. Raskind, Badri N. Vardarajan, Joshua A. Sonnen, Robert S. Stern, Denis A. Evans, Lawrence S. Honig, Ekaterina Rogaeva, John H. Growdon, Michael L. Shelanski, Vivianna M. Van Deerlin, Joseph E. Parisi, Mary Sano, Dennis W. Dickson, Steven H. Ferris, Randall L. Woltjer, Li-San Wang, Jonathan L. Haines, Bruno Giordani, Martin R. Farlow, Jason J. Corneveaux, Gary W. Beecham, Clinton T. Baldwin, Ann C. McKee, Jean Paul Vonsattel, Julie A. Schneider, Malcolm B. Dick, Kelley Faber, John S. K. Kauwe, Neil W. Kowall, Wendy J. Mack, W Marsel Mesulam, Nigel J. Cairns, Nancy Johnson, Jacqueline L. Buros, Eric B. Larson, Ronald C. Petersen, Laura B. Cantwell, Margaret A. Pericak-Vance, Elizabeth Head, Petra Nowotny, Joseph D. Buxbaum, Andrew J. Saykin, Robert C. Green, Lindsay A. Farrer, Carlos Cruchaga, Joshua W. Miller, Matthew J. Huentelman, Rudolph E. Tanzi, Beth A. Dombroski, Andrew P. Lieberman, Daniel H. Geschwind, Robert W Barber, Jeffrey L. Cummings, Charles D. Smith, Bernardino Ghetti, Salvatore Spina, Regina M. Carney, Kathleen A. Welsh-Bohmer, Jason Karlawish, Edward H. Koo, Eden R. Martin, M. Michael Barmada, Carl W. Cotman, and Helena C. Chui
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Male ,Sialic Acid Binding Ig-like Lectin 3 ,Antigens, Differentiation, Myelomonocytic ,Late onset ,Joint analysis ,Biology ,Polymorphism, Single Nucleotide ,Article ,Cohort Studies ,03 medical and health sciences ,Disease susceptibility ,0302 clinical medicine ,Alzheimer Disease ,Antigens, CD ,Databases, Genetic ,Genetics ,Humans ,Genetic Predisposition to Disease ,Age of Onset ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Aged ,Aged, 80 and over ,0303 health sciences ,Receptor, EphA1 ,Genetic Variation ,Membrane Proteins ,Molecular biology ,3. Good health ,Cytoskeletal Proteins ,Multigene Family ,Female ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.
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- 2011
21. Collision Tumor of Primary Laryngeal Mucosal Melanoma and Invasive Squamous Cell Carcinoma with IL-17A and CD70 Gene Over-Expression
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Sasis Sirikanjanapong, Frank Martiniuk, Milan R. Amin, Hideko Kamino, Biana G. Lanson, and Beverly Y. Wang
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Male ,Larynx ,Pathology ,medicine.medical_specialty ,Case Report ,Vocal Cords ,Biology ,Pathology and Forensic Medicine ,RAR-related orphan receptor gamma ,Biomarkers, Tumor ,Carcinoma ,medicine ,Humans ,Neoplasm Invasiveness ,Laryngeal Neoplasms ,Melanoma ,CD70 ,Regulation of gene expression ,Mucous Membrane ,Reverse Transcriptase Polymerase Chain Reaction ,Interleukin-17 ,Mucosal melanoma ,FOXP3 ,Neoplasms, Second Primary ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,Otorhinolaryngology ,Carcinoma, Squamous Cell ,CD27 Ligand - Abstract
The most common primary malignancy of the larynx is the squamous cell carcinoma (SCC). The primary malignant melanoma is quite rare in this location. Less than 60 cases of laryngeal melanomas have been reported to date. To our knowledge, collision primary malignant melanoma and invasive squamous cell carcinoma in the vocal cords has not been reported. We report a 53-year-old male patient who was diagnosed with a collision tumor of laryngeal melanoma and invasive SCC. Multiple Th17 pathway related genes including CTLA-4, IL-17A-F, PLZF, FoxP3, RorγT, CD27, and CD70 were analyzed by reverse transcriptase-polymerase chain reaction (Rt–PCR) in this case. Both IL-17A and CD70 genes were detected in this case of collision tumor. The results may define useful biomarkers for early diagnosis of mucosal melanoma and open an immunotherapeutic field for clinical management with the potential benefit from the immunomodulators that enhance both genes.
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- 2010
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22. The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer's disease
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Lidia Glodzik-Sobanska, Raymond Zinkowski, Elizabeth Pirraglia, Miroslaw Brys, Lisa Mosconi, Susan De Santi, Pankaj D. Mehta, Mony J. de Leon, Kaj Blennow, Martin J. Sadowski, Domenico Praticò, Kenneth Rich, Frank Martiniuk, Remigiusz Switalski, and Leslie A. Saint Louis
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Adult ,Male ,Apolipoprotein E ,Senescence ,Aging ,medicine.medical_specialty ,Isoprostane ,Genotype ,Amyloid beta ,Apolipoprotein E4 ,DNA Mutational Analysis ,tau Proteins ,Biology ,Dinoprost ,Article ,chemistry.chemical_compound ,Apolipoproteins E ,Cerebrospinal fluid ,Gene Frequency ,Alzheimer Disease ,Internal medicine ,mental disorders ,medicine ,Humans ,Genetic Predisposition to Disease ,Phosphorylation ,Aged ,Aged, 80 and over ,Amyloid beta-Peptides ,Polymorphism, Genetic ,General Neuroscience ,Middle Aged ,medicine.disease ,Peptide Fragments ,Oxidative Stress ,Endocrinology ,chemistry ,biology.protein ,Female ,Neurology (clinical) ,Tauopathy ,Geriatrics and Gerontology ,Alzheimer's disease ,Biomarkers ,Developmental Biology - Abstract
While cerebrospinal fluid (CSF) biomarkers are of use in the prediction and diagnosis of Alzheimer’s disease our understanding of the background effects of age and the ApoE genotype is limited. Seventy-eight community-based normal volunteers (mean age 60 ± 10 years, range 36–86) were examined to determine the relationships between CSF measures of total tau (T-tau), hyperphosphorylated tau (P-tau 231), amyloid beta (Aβ42/Aβ40 ratio), and isoprostane (IP) with age and ApoE genotype. The results showed that age by ε4 genotype interactions were found for P-tau231 (β = 1.82; p < 0.05) and IP (β = 1.6; p < 0.05). T-tau CSF concentration increased with age. The increasing CSF concentrations of P-tau and IP in ε4 carriers suggest that early tauopathy and oxidative stress may be related to the increased risk for AD. The data also suggest that T-tau changes are more age dependent than Aβ changes. The evidence that P-tau231 and IP are the earliest markers for the neuronal damage related to AD awaits longitudinal study. © 2007 Elsevier Inc. All rights reserved.
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- 2009
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23. The role of the armadillo and sooty mangabey monkey in human leprosy
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William R. Levis, Heather K. Hamilton, Aloys Cabrera, Frank Martiniuk, and John Wolf
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Animal Experimentation ,Armadillos ,Simian Acquired Immunodeficiency Syndrome ,HIV Infections ,Dermatology ,medicine.disease_cause ,Cercocebus atys ,Acquired immunodeficiency syndrome (AIDS) ,Leprosy ,Zoonoses ,biology.animal ,medicine ,Animals ,Humans ,Animal testing ,biology ,Transmission (medicine) ,Monkey Diseases ,Zoonosis ,HIV ,Simian immunodeficiency virus ,medicine.disease ,biology.organism_classification ,Macaca mulatta ,Virology ,Mycobacterium leprae ,Armadillo ,Immunology ,Sooty mangabey ,Simian Immunodeficiency Virus - Abstract
Background The armadillo was the first animal model of leprosy. Its role in the transmission of leprosy remains controversial. The sooty mangabey model of leprosy led to the discovery that rhesus monkeys were more susceptible to leprosy when coinfected with simian immunodeficiency virus (SIV), but that leprosy may play a protective role against acquired immunodeficiency syndrome (AIDS) mortality. Recently, molecular methods have been developed for leprosy and may help resolve the role of zoonoses in leprosy. Observations The recent identification of a case of leprosy in a native-born American on the east coast of the USA and the identification of leprosy as an immunologic reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)-positive cases raise the question of what role zoonoses may play in leprosy. Conclusions Leprosy in armadillos and sooty mangabeys has been manipulated by human experimentation. In the case of the armadillo, further study, including molecular techniques, is required to elucidate the role of the armadillo as a zoonosis in human leprosy. Experimentation with the sooty mangabey led to the discovery of an interaction between SIV and leprosy in rhesus monkeys, and prompted the continued investigation of the relationship between HIV and leprosy.
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- 2008
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24. Apoptotic Gene Expression in Alzheimer's Disease Hippocampal Tissue
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Frank Martiniuk, Elizabeth Z. Bordayo, Michael L. Freedman, Farrah D. Sajan, William H. Frey, David L. Marcus, and Richard Hite
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Male ,Programmed cell death ,Gene Expression ,Apoptosis ,Biology ,Hippocampal formation ,Hippocampus ,03 medical and health sciences ,0302 clinical medicine ,Genes, jun ,Downregulation and upregulation ,Alzheimer Disease ,Gene expression ,Humans ,E2F1 ,Aged ,Aged, 80 and over ,030214 geriatrics ,General Neuroscience ,Genes, fos ,Middle Aged ,Up-Regulation ,Reverse transcription polymerase chain reaction ,Psychiatry and Mental health ,Clinical Psychology ,bcl-2 Homologous Antagonist-Killer Protein ,Cancer research ,Female ,Geriatrics and Gerontology ,Signal transduction ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Alzheimer's disease (AD) is the major cause of dementia, accounting for 50% to 70% of the late-onset patients, with 17 to 20 million affected. It is characterized by neurofibrillary tangles, neuronal loss, and amyloid plaques in tissues of the cortex, hippocampus, and amygdala. Apoptosis or programmed cell death appears in the progression of AD. In this study, we investigated the gene expression of 14 apoptotic genes ( E2F1, p21/WAF, ICE-LAP3, Fas Antigen, CPP-32, GADD153, ICE-β, c-Fos, c-Jun, Bax-α, Bcl-2, Bcl-(x)L, BAK, and p53) in 5 normal and 6 AD human hippocampal tissues, using reverse transcription-polymerase chain reaction. Our results show an upregulation of gene expression in AD patients for c-Fos and BAK. ICE-β, c-Jun, Bax-α, Bcl-x(L), p53, and GADD153 were found to be upregulated in some AD samples but were not detected or downregulated in other AD or normal samples. No gene expression was found for E2F1 , p21/WAF, ICE-LAP3, Fas Antigen, CPP32, or Bcl-2. These results indicate significant increases in c-Fos , c-Jun, and Bak; therefore, we suggest that these genes may be critical in the apoptotic cascades of AD.
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- 2007
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25. Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals
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Lee-Way Jin, Rudolph E. Tanzi, Lisa L. Barnes, Neill R. Graff-Radford, Joel H. Kramer, Tatiana Foroud, John R. Gilbert, Wayne W. Poon, Philip L. De Jager, Lei Yu, John M. Ringman, James J. Lah, Marla Gearing, David A. Bennett, Susan M. McCurry, Kenneth B. Fallon, Clinton B. Wright, Deborah Blacker, Bradley T. Hyman, Patricia L. Kramer, Joseph F. Quinn, Alison Goate, Gail P. Jarvik, Allan I. Levey, Jennifer Williamson, Mary Ganguli, Carlos Cruchaga, Julie A. Schneider, Amanda Smith, Eric M. Reiman, Lon S. Schneider, Steven H. Ferris, Richard Mayeux, Randall L. Woltjer, Li-San Wang, Goldie S. Byrd, Malcolm B. Dick, Towfique Raj, Steven L. Carroll, Carol A. Miller, Bradley F. Boeve, John S. K. Kauwe, Elaine R. Peskind, Hugh C. Hendrie, R. C. Kim, Jonathan D. Glass, Helena C. Chui, Guiqing Cai, Deborah C. Mash, Gyungah Jun, James Bowen, Marilyn S. Albert, Kathryn L. Lunetta, Huntington Potter, Walter A. Kukull, Paul K. Crane, Neil W. Kowall, Mark W. Logue, Lindsay A. Farrer, Jean Paul G. Vonsattel, Chang-En Yu, Thomas G. Beach, Gary W. Beecham, Erik D. Roberson, John M Olichney, Gerard D. Schellenberg, Harry V. Vinters, Chiao-Feng Lin, Bruce L. Miller, Duane Beekly, Daniel H. Geschwind, Murray A. Raskind, Kara L. Hamilton-Nelson, Jill R. Murrell, Linda J. Van Eldik, Wendy J. Mack, A. Karydas, Douglas Galasko, Barry Reisberg, Thomas O. Obisesan, Aimee Pierce, Andrew McDavid, Salvatore Spina, M.-Marsel Mesulam, Steven T. DeKosky, Andrew P. Lieberman, Ann C. McKee, Robert Barber, Nigel J. Cairns, Roger L. Albin, Bernardino Ghetti, Nilufer Ertekin-Taner, Kathleen A. Welsh-Bohmer, James B. Leverenz, M. Michael Barmada, F. Yesim Demirci, Hakon Hakonarson, Rodney C.P. Go, Oscar L. Lopez, Joseph D. Buxbaum, Adam C. Naj, Frank Martiniuk, Charles DeCarli, Otto Valladares, Andrew J. Saykin, Kelley Faber, Christine M. Hulette, John C. Morris, M. Ilyas Kamboh, Eliezer Masliah, Christine Sato, Steven E. Arnold, James R. Burke, Daniel C. Marson, Edward H. Koo, Ronald C. Petersen, David G. Clark, William W. Seeley, Robert C. Green, Constantine G. Lyketsos, Rosalyn Lang-Walker, John Q. Trojanowski, Jeffrey Kaye, Eileen H. Bigio, Laura B. Cantwell, Matthew P. Frosch, Jonathan L. Haines, Debby W. Tsuang, Juan C. Troncoso, Joshua W. Miller, Denis A. Evans, Kathleen S. Hall, Frank M. LaFerla, Joseph E. Parisi, Elizabeth Crocco, Mary Sano, Mahdi Ghani, Patrick Griffith, Margaret A. Pericak-Vance, Ashok Raj, Christopher S. Carlson, Jennifer J. Manly, Sid Gilman, Thomas J. Montine, Chuanhai Cao, A. Boxer, Ekaterina Rogaeva, Steven G. Younkin, Ronald L. Hamilton, Rong Cheng, Vahram Haroutunian, Peter St George-Hyslop, Liana G. Apostolova, M. Daniele Fallin, Clinton T. Baldwin, Ruchita Rajbhandary, Robert S. Stern, Sandra Weintraub, David H. Cribbs, Lindy E. Harrell, Wayne C. McCormick, Ge Li, Christiane Reitz, Eric B. Larson, Thomas D. Bird, Gregory A. Jicha, Regina M. Carney, Badri N. Vardarajan, Joshua A. Sonnen, Lawrence S. Honig, Joseph H. Lee, John H. Growdon, and Vivianna M. Van Deerlin
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Genetics ,Chicago ,Indiana ,business.industry ,Haplotype ,Homozygote ,Case-control study ,Single-nucleotide polymorphism ,Genome-wide association study ,Genes, Recessive ,Runs of Homozygosity ,Polymorphism, Single Nucleotide ,Article ,Black or African American ,Alzheimer Disease ,Case-Control Studies ,SNP ,Medicine ,Humans ,Neurology (clinical) ,business ,Imputation (genetics) ,SNP array ,Aged ,Genome-Wide Association Study - Abstract
Importance Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. Objective To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. Design, Setting, and Participants Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer’s Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. Main Outcomes and Measures The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. Results The African American cohort had a low degree of inbreeding ( F ~ 0.006). In the Alzheimer’s Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb ( P = .004) or greater than 3 Mb ( P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. Conclusions and Relevance To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.
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- 2015
26. Interleukin-10 Induces Inhibitory C/EBPβ through STAT-3 and Represses HIV-1 Transcription in Macrophages
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Satomi Hoshino, Frank Martiniuk, Yoshihiko Hoshino, Richard Pine, William N. Rom, Takeshi Kurata, David E. Levy, Naohiko Tanaka, Jeffrey A. Gold, and Michael D. Weiden
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STAT3 Transcription Factor ,Pulmonary and Respiratory Medicine ,Transcription, Genetic ,medicine.medical_treatment ,Clinical Biochemistry ,Repressor ,Biology ,Article ,Monocytes ,Mice ,medicine ,Animals ,Humans ,Molecular Biology ,Transcription factor ,Cells, Cultured ,Lipoarabinomannan ,CCAAT-Enhancer-Binding Protein-beta ,Macrophages ,Interleukin ,Cell Biology ,Molecular biology ,Interleukin-10 ,DNA-Binding Proteins ,Interleukin 10 ,Cytokine ,Gene Expression Regulation ,HIV-1 ,Trans-Activators ,Interferons ,biological phenomena, cell phenomena, and immunity ,Signal transduction ,hormones, hormone substitutes, and hormone antagonists - Abstract
Pulmonary tuberculosis (TB) has been characterized by inflammation with increased pro- or anti-inflammatory cytokines produced by macrophages. We have reported that IFN produces inhibitory C/EBPbeta and represses transcription of the HIV-1 LTR in macrophages. STAT-1 and type I IFN receptor knockout mice have macrophages that are defective in IFN signaling, yet LPS stimulation induces inhibitory C/EBPbeta, demonstrating that other cytokines can induce this repressor. LPS or Mycobacterium tuberculosis-derived lipoarabinomannan induce the anti-inflammatory cytokine interleukin (IL)-10, which represses the HIV-1 LTR in differentiated THP-1 macrophages by inducing inhibitory C/EBPbeta. In contrast, in undifferentiated THP-1 monocytes, IL-10 did not inhibit HIV-1 replication or induce C/EBPbeta. IL-10 signal transduction uses STAT-3, and macrophages from STAT-3-/- mice fail to produce inhibitory C/EBPbeta after LPS or IL-10 stimulation. Transfection of STAT-3 into THP-1 cells enhances C/EBPbeta promoter activity. THP-1 differentiation also increases STAT-3 protein, but not STAT-3 gene transcription, and induces a translational regulator, CUG-binding protein, that was essential for production of C/EBPbeta. Differentiation induced post-transcriptional regulation is required to produce inhibitory C/EBPbeta in response to IL-10. Only macrophages are able to repress HIV-1 LTR promoter activity and inhibit viral replication in response to IL-10 or type I IFN.
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- 2005
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27. Correction of Glycogen Storage Disease Type II by Enzyme Replacement with a Recombinant Human Acid Maltase Produced by Over-Expression in a CHO-DHFRneg Cell Line
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William N. Rom, Nina Raben, Paul H. Plotz, Eleni Arvanitopoulos, Alfred E. Slonim, Frank Martiniuk, Agnes Chen, and Vincent Donnabella
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congenital, hereditary, and neonatal diseases and abnormalities ,Gene Dosage ,Biophysics ,CHO Cells ,Motor Activity ,Biochemistry ,Monocytes ,law.invention ,Mice ,law ,Cricetinae ,Dihydrofolate reductase ,Glycogen storage disease type II ,medicine ,Animals ,Humans ,Lymphocytes ,RNA, Messenger ,Immunoelectrophoresis ,Molecular Biology ,Mice, Knockout ,Mannosephosphates ,biology ,Glycogen Storage Disease Type II ,Chinese hamster ovary cell ,nutritional and metabolic diseases ,alpha-Glucosidases ,Cell Biology ,Enzyme replacement therapy ,Fibroblasts ,medicine.disease ,Molecular biology ,Recombinant Proteins ,Enzyme assay ,Blotting, Southern ,Tetrahydrofolate Dehydrogenase ,Methotrexate ,Phenotype ,biology.protein ,Recombinant DNA ,Acid alpha-glucosidase ,Glucan 1,4-alpha-Glucosidase ,Maltase ,Gene Deletion - Abstract
Inherited genetic deficiency of lysosomal acid alpha glucosidase or acid maltase (GAA) results in the autosomal recessive glycogen storage disease type II (GSD II). To investigate whether we could generate a functional recombinant human GAA (rhGAA) for enzyme replacement therapy, we subcloned the cDNAs for human GAA and mouse dihydrofolate reductase (DHFR) into DHFRneg Chinese hamster ovary cells and established a stable cotransformant that expressed rhGAA. We cultured the recombinant cells in media with progressively increasing concentrations of methotrexate and found that human GAA enzyme activity increased to over 2,000 IU per gram protein. Importantly, the human GAA enzyme activity correlated to equivalent amounts of human GAA protein by rocketimmunoelectrophoresis. We confirmed that the human GAA enzyme activity corresponded to an amplification in human GAA mRNA by Northern analysis and human GAA cDNA copy number by Southern analysis. Exposing the rhGAA to human GSDII fibroblast cells or patient's lymphocytes or monocytes resulted in uptake of the rhGAA and reversal of the enzymatic defect. Mannose-6-phosphate in the media blocked uptake. GAA −/− mice were treated with the rhGAA at 1 mg/kg, which resulted in heterozygous levels of GAA in tissues, most notably skeletal muscle, heart and diaphragm after two infusions. More importantly, after multiple infusions, hind, and fore-limb muscle weakness was reversed. This rhGAA would be ideal for enzyme replacement therapy in GSD II.
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- 2000
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28. Leprosy as Immune Reconstitution Inflammatory Syndrome in HIV-positive Persons
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Thomas H. Rea, Michael S. Glickman, William R. Levis, Aloys Cabrera, Shaline D. Rao, Frank Martiniuk, Jerome Giovinazzo, and William N. Rom
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Microbiology (medical) ,medicine.medical_specialty ,HAART ,Epidemiology ,030231 tropical medicine ,hsp65 ,letter ,lcsh:Medicine ,Leprostatic agent ,Tuberculoid leprosy ,Dapsone ,heat shock 65 ,lcsh:Infectious and parasitic diseases ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Immune reconstitution inflammatory syndrome ,medicine ,lcsh:RC109-216 ,Letters to the Editor ,Mycobacterium leprae ,Lepromatous leprosy ,biology ,medicine.diagnostic_test ,business.industry ,lcsh:R ,HIV ,medicine.disease ,biology.organism_classification ,Dermatology ,3. Good health ,Infectious Diseases ,Skin biopsy ,Immunology ,RFLP ,Leprosy ,business ,subclinical ,leprosy ,medicine.drug - Abstract
To the Editor: More than 2 decades ago, when HIV was first detected, many investigators predicted the rise of leprosy secondary to opportunistic infection (1). Recently, the phenomenon of immune reconstitution inflammatory syndrome (IRIS), or leprosy reversal response, has received attention. IRIS often occurs secondary to initiating highly active antiretroviral therapy (HAART). The first indications of an interaction between HIV and Mycobacterium leprae occurred only recently, with the identification of IRIS after initiation of HAART in patients with HIV and previously undetected leprosy. A review by Pustianowski et al. discusses the paradox of HIV and leprosy with IRIS (2). In addition, Lawn et al. described the first case of IRIS after the onset of HAART in a patient who had tuberculoid leprosy that was never confirmed by molecular analysis (3). Multiple reports (4–7) unmasked subclinical Hansen disease (M. leprae infection) occurring with HAART or spontaneously (8). In case reports by Lu et al. (6) and Sharma et al. (7), leprosy was associated with erythema nodosum leprosum. Pereira et al. discovered that patients known to have HIV and leprosy, when treated with HAART manifested a type 1 reversal reaction, acute leprosy inflammatory episode (4), or IRIS. We describe the first, to our knowledge, 2 cases in the United States of HIV and leprosy infections in which IRIS has occurred after HAART initiation and which has been confirmed by molecular analysis. Three skin-biopsy samples, 2 from patient 1 and 1 from patient 2, were analyzed to confirm the presence of M. leprae. Patient 1 met the diagnostic criteria for leprosy according to biopsy result; patient 2’s case was compatible with such criteria. Each patient was treated for leprosy, and each responded favorably. The purpose of our case study was to confirm M. leprae DNA in skin samples. The skin specimens were paraffin-embedded slides. DNA was extracted by standard molecular biologic methods that used xylene. PCR amplified the M. leprae heat shock protein 65 gene (hsp65). After amplification, restriction fragment-length polymorphism (RFLP)–polyacrylamide gel electrophoresis (PAGE) was performed with HaeIII (6). Patient 1 was a 60-year-old Hispanic man who was first evaluated in Los Angeles, California, with skin lesions covering >50% of his body. He reported having erythematous scaly plaques that had been waxing and waning for several months. Several skin biopsy samples were taken, and an HIV test was conducted; results showed that he had lepromatous leprosy and was HIV positive. Biopsy specimens were both Fite stain positive for numerous acid-fast bacilli. Three months after HAART was initiated, repeat skin biopsy samples were taken from nodules that had recently developed on his right arm and torso. Histologic assessment showed Fite stain–positive granulomatous dermatitis with many foamy cells. He was treated for leprosy and is continuing HAART. Patient 2 was a 37-year-old West African black man from Burkina Faso who was evaluated in New York for gram-negative bacteremia. He was admitted and treated for disseminated salmonellosis and was found to be HIV positive. His T-lymphocyte count was 7/μL. He was promptly prescribed HAART and responded well to treatment: his T-cell count rose to 112/μL during 5 months and is currently >700/μL. Within 2 years of HAART initiation, multiple anesthetic, hypopigmented skin macules that failed to resolve over 6 months developed. These macules developed further into nodules. Punch biopsy results were consistent with granulomatous dermatitis. Fite stain was negative for acid-fast bacilli, but leprosy was diagnosed on the basis of anesthesia localized to his skin lesions. When the biopsy samples were taken, the patient was receiving dapsone in addition to HAART. Rifampin treatment was started subsequent to biopsies. PCR amplification for M. leprae hsp65 was positive for all 3 samples. Thus, mycobacterial DNA was present in both patients. The RFLP analysis results are shown in the Figure. The hsp65 RFLP pattern for patient 1 was identical to those described by Martiniuk et al. (9) and for the wild-type pattern for patient 2, as shown by Lu et al. (6), thus demonstrating the presence of M. leprae DNA in these samples. Figure Polyacrylamide gel electrophoresis–restriction fragment length polymorphism of PCR amplicons digested with HaeIII with standards. STDs, sexually transmitted diseases; Pat., patient; WT, wild type. Previous studies have highlighted the low rate of HIV and leprosy co-infection. For example in Ethiopia, Frommel et al. noted that, before HAART was available in resource-poor settings, increased HIV seropositivity did not alter the natural course of leprosy nor increase the number of patients with M. leprae (10). Nevertheless, positive reports of IRIS and leprosy after initiation of HAART have been reported from other nations (3–5). If this syndrome can be detected even in the mildly leprosy–endemic United States (8), an increase in similar cases in areas where HIV and leprosy occur in higher frequency can be anticipated.
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- 2007
29. Molecular skin research can impact systemic cancers
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William, Levis and Frank, Martiniuk
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Biomedical Research ,Skin Neoplasms ,Drug Design ,Neoplasms ,Humans ,Immunotherapy ,Molecular Targeted Therapy ,Periodicals as Topic - Published
- 2013
30. Production of a functional human acid maltase in tobacco seeds: biochemical analysis, uptake by human GSDII cells, and in vivo studies in GAA knockout mice
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Matteo Busconi, Serena Reggi, William N. Rom, Kam-Meng Tchou-Wong, Frank Martiniuk, and Corrado Fogher
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Bioengineering ,Biology ,Applied Microbiology and Biotechnology ,Biochemistry ,Article ,law.invention ,Mice ,law ,Complementary DNA ,Glycogen storage disease type II ,Tobacco ,medicine ,Animals ,Humans ,Recombinant human acid maltase ,Enzyme replacement ,Molecular Biology ,chemistry.chemical_classification ,Mice, Knockout ,Transgenic tobacco plants ,Mice, Inbred BALB C ,Glycogen Storage Disease Type II ,food and beverages ,Biological activity ,alpha-Glucosidases ,General Medicine ,Enzyme replacement therapy ,Pompe’s disease ,medicine.disease ,Plants, Genetically Modified ,Settore AGR/07 - GENETICA AGRARIA ,Enzyme ,chemistry ,Seeds ,Recombinant DNA ,Acid alpha-glucosidase ,Female ,Glucan 1,4-alpha-Glucosidase ,Maltase ,Biotechnology - Abstract
Genetic deficiency of acid alpha glucosidase (GAA) results in glycogen storage disease type II (GSDII) or Pompe's disease. To investigate whether we could generate a functional recombinant human GAA enzyme (tobrhGAA) in tobacco seeds for future enzyme replacement therapy, we subcloned the human GAA cDNA into the plant expression plasmid-pBI101 under the control of the soybean β-conglycinin seed-specific promoter and biochemically analyzed the tobrhGAA. Tobacco seeds contain the metabolic machinery that is more compatible with mammalian glycosylation-phosphorylation and processing. We found the tobrhGAA to be enzymatically active was readily taken up by GSDII fibroblasts and in white blood cells from whole blood to reverse the defect. The tobrhGAA corrected the enzyme defect in tissues at 7 days after a single dose following intraperitoneal (IP) administration in GAA knockout (GAA(-/-)) mice. Additionally, we could purify the tobrhGAA since it bound tightly to the matrix of Sephadex G100 and can be eluted by competition with maltose. These data demonstrate indirectly that the tobrhGAA is fully functional, predominantly proteolytically cleaved and contains the minimal phosphorylation and mannose-6-phosphate residues essential for biological activity.
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- 2013
31. Primary mucosal melanoma arising from the eustachian tube with CTLA-4, IL-17A, IL-17C, and IL-17E upregulation
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Beverly Y. Wang, Sasis Sirikanjanapong, William R. Levis, Mark D. DeLacure, Seth M. Lieberman, Calvin Wei, and Frank Martiniuk
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Male ,Pathology ,medicine.medical_specialty ,Eustachian tube ,medicine.medical_treatment ,Ear neoplasm ,Article ,Downregulation and upregulation ,medicine ,Humans ,CTLA-4 Antigen ,Melanoma ,Ear Neoplasms ,business.industry ,Eustachian Tube ,Interleukin-17 ,Mucosal melanoma ,FOXP3 ,Immunotherapy ,Middle Aged ,medicine.disease ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Otorhinolaryngology ,CTLA-4 ,business - Abstract
Primary malignant melanoma arising from the eustachian tube is extremely rare. We report the case of a 63-year-old white man who presented with a 1-month history of left-sided hearing loss and aural fullness. Flexible fiberoptic laryngoscopy detected a blue-purple mass that appeared to arise from the left lateral nasopharynx. Computed tomography demonstrated an enhancing mass arising from an orifice of the left eustachian tube. The tumor was debulked endoscopically and was confirmed to have originated in the left eustachian tube. Histologically, the tumor was made up of heavily pigmented pleomorphic spindle cells with frequent mitoses. The tumor cells were immunohistochemically positive for S-100 protein, HMB-45, Melan-A, and PNL-2. The final diagnosis was a mucosal malignant melanoma. We also performed a nested polymerase chain reaction assay for several genes of interest, including CTLA-4, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F, PLZF, Foxp3, RORγt, CD27, and CD70. These genes have been studied mainly in cutaneous melanomas, especially for the development of immunotherapy, but only very limited studies have been done on mucosal melanomas. Our investigation found upregulation of CTLA-4, IL-17A, IL-17C, and IL-17E. Based on our finding of CTLA-4 upregulation, it may be suggested that our patient might have had low antitumor immunity and that he might have benefited from CTLA-4 blockade. On the other hand, upregulation of IL-17A and IL-17E might reflect increased antitumor immunity, which could suggest that patients with a mucosal melanoma might benefit from immunomodulators associated with the effect of T17. These genes also have great potential to help melanoma patients obtain tailored treatment, and they can be used as biomarkers for predicting prognosis.
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- 2013
32. Assessment of the genetic variance of late-onset Alzheimer's disease
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Perry G. Ridge, Kaitlyn B. Hoyt, Kevin Boehme, Shubhabrata Mukherjee, Paul K. Crane, Jonathan L. Haines, Richard Mayeux, Lindsay A. Farrer, Margaret A. Pericak-Vance, Gerard D. Schellenberg, John S.K. Kauwe, Perrie M. Adams, Marilyn S. Albert, Roger L. Albin, Liana G. Apostolova, Steven E. Arnold, Sanjay Asthana, Craig S. Atwood, Clinton T. Baldwin, Robert C. Barber, Michael M. Barmada, Lisa L. Barnes, Sandra Barral, Thomas G. Beach, James T. Becker, Gary W. Beecham, Duane Beekly, David A. Bennett, Eileen H. Bigio, Thomas D. Bird, Deborah Blacker, Bradley F. Boeve, James D. Bowen, Adam Boxer, James R. Burke, Jeffrey M. Burns, Joseph D. Buxbaum, Nigel J. Cairns, Laura B. Cantwell, Chuanhai Cao, Chris S. Carlson, Cynthia M. Carlsson, Regina M. Carney, Minerva M. Carrasquillo, Steven L. Carroll, Helena C. Chui, David G. Clark, Jason Corneveaux, David H. Cribbs, Elizabeth A. Crocco, Carlos Cruchaga, Philip L. De Jager, Charles DeCarli, F. Yesim Demirci, Malcolm Dick, Dennis W. Dickson, Rachelle S. Doody, Ranjan Duara, Nilufer Ertekin-Taner, Denis A. Evans, Kelley M. Faber, Thomas J. Fairchild, Kenneth B. Fallon, David W. Fardo, Martin R. Farlow, Steven Ferris, Tatiana M. Foroud, Matthew P. Frosch, Douglas R. Galasko, Marla Gearing, Daniel H. Geschwind, Bernardino Ghetti, John R. Gilbert, Alison M. Goate, Neill R. Graff-Radford, Robert C. Green, John H. Growdon, Hakon Hakonarson, Ronald L. Hamilton, Kara L. Hamilton-Nelson, John Hardy, Lindy E. Harrell, Lawrence S. Honig, Ryan M. Huebinger, Matthew J. Huentelman, Christine M. Hulette, Bradley T. Hyman, Gail P. Jarvik, Gregory A. Jicha, Lee-Way Jin, Gyungah Jun, M. Ilyas Kamboh, Anna Karydas, Mindy J. Katz, Jeffrey A. Kaye, Ronald Kim, Neil W. Kowall, Joel H. Kramer, Walter A. Kukull, Brian W. Kunkle, Frank M. LaFerla, James J. Lah, Eric B. Larson, James B. Leverenz, Allan I. Levey, Ge Li, Andrew P. Lieberman, Chiao-Feng Lin, Richard B. Lipton, Oscar L. Lopez, Kathryn L. Lunetta, Constantine G. Lyketsos, Wendy J. Mack, Daniel C. Marson, Eden R. Martin, Frank Martiniuk, Deborah C. Mash, Eliezer Masliah, Wayne C. McCormick, Susan M. McCurry, Andrew N. McDavid, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, Thomas J. Montine, John C. Morris, Jill R. Murrell, Amanda J. Myers, Adam C. Naj, Sid O'Bryant, John M. Olichney, Vernon S. Pankratz, Joseph E. Parisi, Amanda Partch, Henry L. Paulson, William Perry, Elaine Peskind, Ronald C. Petersen, Aimee Pierce, Wayne W. Poon, Huntington Potter, Joseph F. Quinn, Ashok Raj, Murray Raskind, Eric M. Reiman, Barry Reisberg, Joan S. Reisch, Christiane Reitz, John M. Ringman, Erik D. Roberson, Ekaterina Rogaeva, Howard J. Rosen, Roger N. Rosenberg, Donald R. Royall, Mark A. Sager, Mary Sano, Andrew J. Saykin, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Amanda G. Smith, Joshua A. Sonnen, Salvatore Spina, Peter St George-Hyslop, Robert A. Stern, Russell H. Swerdlow, Rudolph E. Tanzi, Tricia A. Thornton-Wells, John Q. Trojanowski, Juan C. Troncoso, Debby W. Tsuang, Otto Valladares, Vivianna M. Van Deerlin, Linda J. Van Eldik, Badri N. Vardarajan, Harry V. Vinters, Jean Paul Vonsattel, Li-San Wang, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Jens R. Wendland, Kirk C. Wilhelmsen, Jennifer Williamson, Thomas S. Wingo, Ashley R. Winslow, Sarah Wishnek, Randall L. Woltjer, Clinton B. Wright, Chuang-Kuo Wu, Steven G. Younkin, Chang-En Yu, and Lei Yu
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0301 basic medicine ,Male ,Risk ,Aging ,Neuroscience(all) ,Clinical Neurology ,Datasets as Topic ,Genome-wide association study ,Single-nucleotide polymorphism ,Receptors, Cell Surface ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Amyloid beta-Protein Precursor ,0302 clinical medicine ,Alzheimer Disease ,Genetic variation ,medicine ,Genetics ,Humans ,Allele ,Receptors, Immunologic ,Genetic variance ,Aged ,Aged, 80 and over ,Membrane Glycoproteins ,TREM2 ,General Neuroscience ,Genetic disorder ,Genetic Variation ,Alzheimer's disease ,Explained variation ,medicine.disease ,Genetic architecture ,3. Good health ,Ageing ,030104 developmental biology ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Netrin Receptors ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Developmental Biology - Abstract
Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) estimate phenotypic variance explained by genetics; (2) calculate genetic variance explained by known AD single nucleotide polymorphisms (SNPs); and (3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions.
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- 2016
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33. Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer
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Tsivia Hochman, Sylvia Adams, Amy Tiersten, Nina Bhardwaj, James L. Speyer, Sandra Demaria, Leonard Liebes, Judith D. Goldberg, Nicholas Shuman, Silvia C. Formenti, Deborah Axelrod, Yelena Novik, Derya Unutmaz, Luis Chiriboga, Tze-Chiang Meng, Lina Kozhaya, and Frank Martiniuk
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Oncology ,Agonist ,Cancer Research ,Tumor microenvironment ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Imiquimod ,TLR7 ,medicine.disease ,Article ,Clinical trial ,Breast cancer ,Immune system ,Immunity ,Internal medicine ,Immunology ,Medicine ,business ,medicine.drug - Abstract
Purpose: Skin metastases of breast cancer remain a therapeutic challenge. Toll-like receptor 7 agonist imiquimod is an immune response modifier and can induce immune-mediated rejection of primary skin malignancies when topically applied. Here we tested the hypothesis that topical imiquimod stimulates local antitumor immunity and induces the regression of breast cancer skin metastases. Experimental Design: A prospective clinical trial was designed to evaluate the local tumor response rate of breast cancer skin metastases treated with topical imiquimod, applied 5 d/wk for 8 weeks. Safety and immunologic correlates were secondary objectives. Results: Ten patients were enrolled and completed the study. Imiquimod treatment was well tolerated, with only grade 1 to 2 transient local and systemic side effects consistent with imiquimod's immunomodulatory effects. Two patients achieved a partial response [20%; 95% confidence interval (CI), 3%–56%]. Responders showed histologic tumor regression with evidence of an immune-mediated response, showed by changes in the tumor lymphocytic infiltrate and locally produced cytokines. Conclusion: Topical imiquimod is a beneficial treatment modality for breast cancer metastatic to skin/chest wall and is well tolerated. Importantly, imiquimod can promote a proimmunogenic tumor microenvironment in breast cancer. Preclinical data generated by our group suggest superior results with a combination of imiquimod and ionizing radiation and we are currently testing in patients whether the combination can further improve antitumor immune and clinical responses. Clin Cancer Res; 18(24); 6748–57. ©2012 AACR.
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- 2012
34. Novel late-onset Alzheimer disease loci variants associate with brain gene expression
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Mariet, Allen, Fanggeng, Zou, High Seng, Chai, Curtis S, Younkin, Julia, Crook, V Shane, Pankratz, Minerva M, Carrasquillo, Christopher N, Rowley, Asha A, Nair, Sumit, Middha, Sooraj, Maharjan, Thuy, Nguyen, Li, Ma, Kimberly G, Malphrus, Ryan, Palusak, Sarah, Lincoln, Gina, Bisceglio, Constantin, Georgescu, Debra, Schultz, Fariborz, Rakhshan, Christopher P, Kolbert, Jin, Jen, Jonathan L, Haines, Richard, Mayeux, Margaret A, Pericak-Vance, Lindsay A, Farrer, Gerard D, Schellenberg, Ronald C, Petersen, Neill R, Graff-Radford, Dennis W, Dickson, Steven G, Younkin, Nilüfer, Ertekin-Taner, Liana G, Apostolova, Steven E, Arnold, Clinton T, Baldwin, Robert, Barber, Michael M, Barmada, Thomas, Beach, Gary W, Beecham, Duane, Beekly, David A, Bennett, Eileen H, Bigio, Thomas D, Bird, Deborah, Blacker, Bradley F, Boeve, James D, Bowen, Adam, Boxer, James R, Burke, Jacqueline, Buros, Joseph D, Buxbaum, Nigel J, Cairns, Laura B, Cantwell, Chuanhai, Cao, Chris S, Carlson, Regina M, Carney, Steven L, Carroll, Helena C, Chui, David G, Clark, Jason, Corneveaux, Carl W, Cotman, Paul K, Crane, Carlos, Cruchaga, Jeffrey L, Cummings, Philip L, De Jager, Charles, DeCarli, Steven T, DeKosky, F Yesim, Demirci, Ramon, Diaz-Arrastia, Malcolm, Dick, Beth A, Dombroski, Ranjan, Duara, William D, Ellis, Denis, Evans, Kelley M, Faber, Kenneth B, Fallon, Martin R, Farlow, Steven, Ferris, Tatiana M, Foroud, Matthew, Frosch, Douglas R, Galasko, Paul J, Gallins, Mary, Ganguli, Marla, Gearing, Daniel H, Geschwind, Bernardino, Ghetti, John R, Gilbert, Sid, Gilman, Bruno, Giordani, Jonathan D, Glass, Alison M, Goate, Robert C, Green, John H, Growdon, Hakon, Hakonarson, Ronald L, Hamilton, John, Hardy, Lindy E, Harrell, Elizabeth, Head, Lawrence S, Honig, Matthew J, Huentelman, Christine M, Hulette, Bradley T, Hyman, Gail P, Jarvik, Gregory A, Jicha, Lee-Way, Jin, Gyungah, Jun, M Ilyas, Kamboh, Jason, Karlawish, Anna, Karydas, John S K, Kauwe, Jeffrey A, Kaye, Nancy, Kennedy, Ronald, Kim, Edward H, Koo, Neil W, Kowall, Patricia, Kramer, Walter A, Kukull, James J, Lah, Eric B, Larson, Allan I, Levey, Andrew P, Lieberman, Oscar L, Lopez, Kathryn L, Lunetta, Wendy J, Mack, Daniel C, Marson, Eden R, Martin, Frank, Martiniuk, Deborah C, Mash, Eliezer, Masliah, Wayne C, McCormick, Susan M, McCurry, Andrew N, McDavid, Ann C, McKee, Marsel, Mesulam, Bruce L, Miller, Carol A, Miller, Joshua W, Miller, Thomas J, Montine, John C, Morris, Amanda J, Myers, Adam C, Naj, Petra, Nowotny, Joseph E, Parisi, Daniel P, Perl, Elaine, Peskind, Wayne W, Poon, Huntington, Potter, Joseph F, Quinn, Ashok, Raj, Ruchita A, Rajbhandary, Murray, Raskind, Eric M, Reiman, Barry, Reisberg, Christiane, Reitz, John M, Ringman, Erik D, Roberson, Ekaterina, Rogaeva, Roger N, Rosenberg, Mary, Sano, Andrew J, Saykin, Julie A, Schneider, Lon S, Schneider, William, Seeley, Michael L, Shelanski, Michael A, Slifer, Charles D, Smith, Joshua A, Sonnen, Salvatore, Spina, Peter, St George-Hyslop, Robert A, Stern, Rudolph E, Tanzi, John Q, Trojanowski, Juan C, Troncoso, Debby W, Tsuang, Vivianna M, Van Deerlin, Badri Narayan, Vardarajan, Harry V, Vinters, Jean Paul, Vonsattel, Li-San, Wang, Sandra, Weintraub, Kathleen A, Welsh-Bohmer, Jennifer, Williamson, and Randall L, Woltjer
- Subjects
Male ,Candidate gene ,Genotype ,Apolipoprotein E4 ,Gene Dosage ,Gene Expression ,Single-nucleotide polymorphism ,Genome-wide association study ,Locus (genetics) ,Biology ,Gene dosage ,Polymorphism, Single Nucleotide ,PICALM ,Alzheimer Disease ,Risk Factors ,Humans ,Genetic Predisposition to Disease ,Alleles ,Genetic association ,Aged ,Temporal cortex ,Genetics ,Brain Chemistry ,Temporal Lobe ,Linear Models ,RNA ,Female ,Neurology (clinical) ,Autopsy - Abstract
Objective: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression. Methods: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis -association with expression of 6 nearby LOAD candidate genes detectable in human brain ( ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM ) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis -associations. Results: CLU rs11136000 ( p = 7.81 × 10 −4 ) and MS4A4A rs2304933/rs2304935 ( p = 1.48 × 10 −4 –1.86 × 10 −4 ) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis -variants that significantly influence brain expression of CLU and ABCA7 ( p = 4.01 × 10 −5 –9.09 × 10 −9 ), some of which also associate with AD risk ( p = 2.64 × 10 −2 –6.25 × 10 −5 ). Conclusions: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.
- Published
- 2012
35. Mycobacterium lepromatosis: emerging strain or species?
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William R, Levis, Shali, Zhang, and Frank, Martiniuk
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Leprosy, Lepromatous ,Male ,Mycobacterium leprae ,Humans - Published
- 2012
36. Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases
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Jason Lee, Ranjan Duara, Michael A. Slifer, Kenneth B. Fallon, Thomas J. Montine, Beth A. Dombroski, Peter St George-Hyslop, Debby W. Tsuang, Patricia L. Kramer, Duane Beekly, Ronald C. Petersen, Carl W. Cotman, Helena C. Chui, Alison Goate, Michelle K. Lupton, Sid Gilman, Thomas G. Beach, A. Karydas, Andrew McDavid, Susan M. McCurry, William G. Ellis, Bradley T. Hyman, Badri N. Vardarajan, Joshua A. Sonnen, Neill R. Graff-Radford, Robert Barber, Elisavet Preza, Paul Gallins, Lawrence S. Honig, Adam C. Naj, Frank Martiniuk, Jacek Biernat, Christopher S. Carlson, Richard J. Caselli, Huntington Potter, Chris Zarow, Christine M. Hulette, Hakon Hakonarson, Oscar L. Lopez, Alexandra I. Soto-Ortolaza, Eric Klein, Margaret A. Pericak-Vance, Ashok Raj, Marla Gearing, Kathryn L. Lunetta, Adam L. Boxer, Gerard D. Schellenberg, John H. Growdon, Ramon Diaz-Arrastia, Wayne W. Poon, James R. Burke, Michael D. Geschwind, Douglas Galasko, Ruchita Rajbhandary, Eric M. Reiman, Gregory A. Jicha, Steven L. Carroll, Robert S. Stern, Vivianna M. Van Deerlin, Murray A. Raskind, Carol A. Miller, Ekaterina Rogaeva, Carlos Cruchaga, Joshua W. Miller, Matthew J. Huentelman, Joseph E. Parisi, Charles C. DeCarli, Eliezer Masliah, Didier Hannequin, Deborah Blacker, Michael L. Shelanski, Roger L. Albin, Mary Sano, Paul K. Crane, David G. Clark, Jean Paul G. Vonsattel, Mary Ganguli, John Hardy, John Powell, Charles DeCarli, Ronald C. Kim, Charles D. Smith, Jonathan D. Glass, M. Ilyas Kamboh, Steven E. Arnold, Gyungah Jun, Gail P. Jarvik, Anna Karydas, Suzee E. Lee, Carol F. Lippa, Allan I. Levey, Eckhard Mandelkow, Petra Nowotny, Dennis W. Dickson, Jennifer Williamson, John Q. Trojanowski, Isabelle Le Ber, Zbigniew K. Wszolek, Jeffrey Kaye, Eric B. Larson, Matthew P. Frosch, Harry V. Vinters, David A. Bennett, Joseph D. Buxbaum, Sandra Weintraub, Charles L. White, Lindy E. Harrell, Jonathan L. Haines, Minerva M. Carrasquillo, Robert O. Kenet, Lindsay A. Farrer, Robert C. Green, Wayne C. McCormick, Richard Mayeux, Denis A. Evans, Erik D. Roberson, Bruno Giordani, Liana G. Apostolova, Virginia M.-Y. Lee, Elizabeth Finger, Subashchandrabose Chinnathambi, Clinton T. Baldwin, Satish Kumar, Christiane Reitz, Steven H. Ferris, Randall L. Woltjer, Li-San Wang, Elaine R. Peskind, Thomas D. Bird, Eden R. Martin, Ryan J. Uitti, Martin R. Farlow, Amanda J. Myers, Jason J. Corneveaux, Gary W. Beecham, James D. Bowen, Juan C. Troncoso, Daniel H. Geschwind, Ann C. McKee, Roger N. Rosenberg, Bruce L. Miller, Daniel C. Marson, Jeffrey L. Cummings, Salvatore Spina, Regina M. Carney, Lee-Way Jin, Yvette Bordelon, Jean Paul Vonsattel, John R. Gilbert, Simon Lovestone, Kelley Faber, Mario F. Mendez, Laura B. Cantwell, Philip L. De Jager, John M. Ringman, Elizabeth Head, Wendy J. Mack, Giovanni Coppola, Nigel J. Cairns, Nilufer Ertekin-Taner, Nancy Johnson, Jacqueline L. Buros, Wallace W. Tourtellotte, Julie A. Schneider, Rosa Rademakers, Malcolm B. Dick, Ian R. A. Mackenzie, Andrew J. Saykin, Bradley F. Boeve, John S. K. Kauwe, Neil W. Kowall, Eva Maria Mandelkow, Andrew Kertesz, Lon S. Schneider, Joseph F. Quinn, F. Yesim Demirci, John C. Morris, Barry Reisberg, Andrew P. Lieberman, Bernardino Ghetti, Kathleen A. Welsh-Bohmer, Edward H. Koo, Alden Y. Huang, Walter A. Kukull, Alexis Brice, Eileen H. Bigio, M.-Marsel Mesulam, Steven T. DeKosky, Jorge L. Juncos, Neil Graff-Radford, M. Michael Barmada, Rudolph E. Tanzi, Owen A. Ross, Jason Karlawish, Tatiana Foroud, William W. Seeley, James J. Lah, Deborah C. Mash, Chuanhai Cao, Daniel P. Perl, A. Boxer, Matt Baker, Steven G. Younkin, Ronald L. Hamilton, Renee L. Sears, Jessica Lane, and Alzheimer's Dis Genetics Consortiu
- Subjects
Risk ,Genotype ,epidemiology [Alzheimer Disease] ,Tau protein ,epidemiology [Frontotemporal Dementia] ,Locus (genetics) ,genetics [Alzheimer Disease] ,MAPT protein, human ,tau Proteins ,Disease ,Progressive supranuclear palsy ,Alzheimer Disease ,ddc:570 ,Genetic variation ,Rare mutations ,mental disorders ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Gene ,Biology ,genetics [Frontotemporal Dementia] ,Genetics (clinical) ,Aged ,biology ,Association Studies Articles ,Genetic Variation ,General Medicine ,Middle Aged ,medicine.disease ,eye diseases ,nervous system diseases ,Chemistry ,genetics [tau Proteins] ,Haplotypes ,Clinical diagnosis ,Frontotemporal Dementia ,biology.protein ,Human medicine - Abstract
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
- Published
- 2012
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37. CD70 and Th17 are involved in human contact sensitivity
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David S, Lee, Nicholas, Gulati, Frank, Martiniuk, and William R, Levis
- Subjects
Reverse Transcriptase Polymerase Chain Reaction ,chemical and pharmacologic phenomena ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,Dermatitis, Contact ,Article ,Up-Regulation ,Killer Cells, Natural ,Mice ,Gene Expression Regulation ,Dermatitis, Allergic Contact ,Animals ,Humans ,Natural Killer T-Cells ,Th17 Cells ,CD27 Ligand - Abstract
CD70 (CD27L) has been shown to be preferentially expressed on Th1, but not Th2, CD4+ lymphocytes in murine contact sensitivity. The CD70-CD27 co-stimulatory pathway as well as the Th17 subset of lymphocytes have also been identified in human contact sensitivity reactions. The authors have previously reported increased expression of CD70 and the Th17-specific transcription factor retinoid orphan receptor gamma T in the elicitation phase of allergic contact dermatitis by reverse transcriptase-polymerase chain reaction. The manipulation of these pathways has potential for ameliorating autoimmune and inflammatory disorders such as allergic contact dermatitis, psoriasis, and rheumatoid arthritis. Also, upregulation of the CD70-CD27 and Th17 pathways has been associated with the remarkable ability of topical sensitizers to treat warts and skin cancers including melanoma. As natural killer and natural killer T cells are also involved in contact sensitivity, future studies investigating the function of these cells are necessary to elucidate the transition between innate and acquired immune responses in the context of the Th1/Th2/Th17 and regulatory T cell paradigm.
- Published
- 2011
38. TH17 is involved in the remarkable regression of metastatic malignant melanoma to topical diphencyprone
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Frank, Martiniuk, Diona L, Damian, John F, Thompson, Richard A, Scolyer, Kam-Meng, Tchou-Wong, and William R, Levis
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Cyclopropanes ,Male ,Scalp ,Skin Neoplasms ,Reverse Transcriptase Polymerase Chain Reaction ,Administration, Topical ,Interleukin-17 ,Kruppel-Like Transcription Factors ,Article ,Ointments ,Antigens, CD ,Humans ,Th17 Cells ,CTLA-4 Antigen ,Promyelocytic Leukemia Zinc Finger Protein ,Haptens ,Melanoma ,Aged - Abstract
The authors provide an update on a previously reported patient with in-transit metastatic melanoma of the scalp treated with topical diphencyprone (DPCP). Molecular studies implicate the thymus-derived TH17 lymphocyte subset in a remarkable immunotherapeutic regression. The authors performed RT-PCR of total RNA from paraffin-embedded tissue before and after treatment with DPCP. Before treatment with DPCP, the authors found elevated expression of IL 17C/D/E/F; after treatment there was no detectable expression. Conversely, increased expression of PLZF/CD27 and CTLA4 was seen after treatment with no expression before treatment. No expression of IL17A/B, CD7, RORgTand FoxP3 were before or after treatment. Conclusions are limited to only the time samples were obtained. Remarkable regression of an in-transit metastatic melanoma treated with the immunomodulatory agent DPCP showed gain and loss of gene expression of the TH17 pathway. Further study of this pathway from NK to NK-T to TH7 and TH1 cells both with and without accessory or dendritic cells will improve understanding of contact sensitizers as topical immunomodulators.
- Published
- 2010
39. The role of complement in dendritic cell (DC) control of T-cell subsets
- Author
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William R, Levis and Frank, Martiniuk
- Subjects
Male ,T-Lymphocyte Subsets ,Tissue Extracts ,Animals ,Humans ,Prostatic Neoplasms ,Complement System Proteins ,Dendritic Cells ,T-Lymphocytes, Helper-Inducer ,Cancer Vaccines - Abstract
This section of the Journal of Drugs in Dermatology (JDD) is dedicated to Dendreon's Provenge (Sipuleucel-T), the first therapeutic DC vaccine proven effective and approved by the United States (U.S.) Food and Drug Administration (FDA) for advanced cancer. This editorial will discuss three articles in this issue, their relationship to Provenge and the recent TH17-Treg subsets that are regulated by CD46.
- Published
- 2010
40. Correlation between Serum and Plasma Antibody Titers to Mycobacterial Antigens ▿
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Rafael Prados-Rosales, Frank Martiniuk, Jacqueline M. Achkar, Xian Yu, Michael Siev, and Arturo Casadevall
- Subjects
Microbiology (medical) ,Adult ,Male ,Serum ,Tuberculosis ,Clinical Biochemistry ,Immunology ,HIV Infections ,Biology ,Serology ,Mannans ,Plasma ,Bacterial Proteins ,medicine ,Immunology and Allergy ,Clinical Laboratory Immunology ,Humans ,Antigens, Bacterial ,Plasma samples ,Antibody titer ,Malate Synthase ,Mycobacterium tuberculosis ,Middle Aged ,medicine.disease ,Virology ,Antibodies, Bacterial ,Mycobacterium bovis ,Mycobacterial antigen ,Female ,Antibody detection - Abstract
The ability to utilize serum or plasma samples interchangeably is useful for tuberculosis (TB) serology. We demonstrate a strong correlation between antibody titers to several mycobacterial antigens in serum versus plasma from HIV-infected and non-HIV-infected TB and non-TB patients ( r = 0.99 to 0.89; P < 0.0001). Plasma and serum can be used interchangeably in the same antibody detection assays.
- Published
- 2010
41. Protective effects of anti-ricin A-chain antibodies delivered intracellularly against ricin-induced cytotoxicity
- Author
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Frank Martiniuk, Feng Wu, Sybille Muller, Seth H. Pincus, Shaoan Fan, Kam-Meng Tchou-Wong, and Heinz Kohler
- Subjects
endocrine system ,biology ,medicine.drug_class ,business.industry ,hemic and immune systems ,General Medicine ,Monoclonal antibody ,Molecular biology ,carbohydrates (lipids) ,chemistry.chemical_compound ,enzymes and coenzymes (carbohydrates) ,Ricin ,chemistry ,medicine ,biology.protein ,Fluorescence microscope ,Cell-penetrating peptide ,MTT assay ,lipids (amino acids, peptides, and proteins) ,Original Article ,Viability assay ,Antibody ,business ,Cytotoxicity - Abstract
AIM: To evaluate the ability of anti-ricin A-chain antibodies, delivered intracellularly, to protect against ricin-induced cytotoxicity in RAW264.7 cells. METHODS: Anti-deglycosylated ricin A-chain antibody and RAC18 anti-ricin A-chain monoclonal antibody were delivered intracellularly by encapsulating in liposomes or via conjugation with the cell-penetrating MTS-transport peptide. RAW264.7 cells were incubated with these antibodies either before or after ricin exposure. The changes in cytotoxicity were estimated by MTT assay. Co-localization of internalized antibody and ricin was evaluated by fluorescence microscopy. RESULTS: Internalized antibodies significantly increased cell viability either before or after ricin exposure compared to the unconjugated antibodies. Fluorescence microscopy confirmed the co-localization of internalized antibodies and ricin inside the cells. CONCLUSION: Intracellular delivery of antibodies to neutralize the ricin toxin after cellular uptake supports the potential use of cell-permeable antibodies for post-exposure treatment of ricin intoxication.
- Published
- 2010
42. Recombinant Human Acid α-Glucosidase Generated in Bacteria: Antigenic, but Enzymatically Inactive
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S. Tzall, Frank Martiniuk, and Agnes Chen
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Glycosylation ,Molecular Sequence Data ,Enzyme-Linked Immunosorbent Assay ,law.invention ,chemistry.chemical_compound ,Antigen ,law ,Complementary DNA ,Gene expression ,Genetics ,Humans ,Amino Acid Sequence ,Antigens ,Cloning, Molecular ,Molecular Biology ,chemistry.chemical_classification ,Expression vector ,Bacteria ,Base Sequence ,biology ,nutritional and metabolic diseases ,alpha-Glucosidases ,DNA ,Cell Biology ,General Medicine ,Molecular biology ,Recombinant Proteins ,Enzyme ,Biochemistry ,chemistry ,Polyclonal antibodies ,biology.protein ,Recombinant DNA ,Electrophoresis, Polyacrylamide Gel ,Plasmids - Abstract
Genetic deficiency of acid α-glucosidase (GAA) results in glycogen storage disease type II. To investigate whether we could generate a functional recombinant human GAA protein for future enzyme replacement therapy, we subcloned the GAA cDNA into the bacterial expression plasmid pMaI and analyzed the recombinant protein produced. This nonglycosylated recombinant human GAA was found to be antigenic by reacting with polyclonal rabbit antibody to human placental GAA using ELISA and Western techniques. However, the protein was not enzymatically active, suggesting that glycosylation may play a role in enzymatic function.
- Published
- 1992
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43. Hyperimmunoglobulin E syndrome with a novel STAT3 mutation
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Sarina B. Elmariah, Robert Anolik, Frank Martiniuk, Stephanie Lehrhoff, William R. Levis, and Henry J Votava
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Past medical history ,medicine.medical_specialty ,business.industry ,Dermatology ,General Medicine ,Gene mutation ,Acute Pharyngitis ,Staphylococcal infections ,medicine.disease ,Otitis ,medicine ,Eczematous dermatitis ,medicine.symptom ,Hyperimmunoglobulin E syndrome ,business ,Staphylococcal Skin Infections - Abstract
A 35-year-old man with severe eczematous dermatitis and recurrent staphylococcal skin infections, some of which required hospitalization, is presented. Other medical concerns include recurrent oral staphylococcal infections, otitis media, ocular herpes simplex virus keratitis, asthma, steroid-induced gastritis, steroid-induced cataracts, recurrent upper respiratory infections, and acute pharyngitis. Past medical history includes retained dentition of six primary teeth, two episodes of childhood pneumonia that required hospitalization, and three wrist and ankle fractures. Laboratory data showed an eosinophil count of 2,400 cells/ml; the highest IgE level was 17,028 IU/mL. Considering the clinical and laboratory findings, the diagnosis of hyperimmunoglobulin E syndrome was made. DNA sequencing showed a novel signal transducer and activator of transcription 3 (STAT3) gene mutation within intron 12, specifically adenine to cytosine, two base pairs upstream of exon 13.
- Published
- 2009
44. Developmental expression of glycogenolytic enzymes in rabbit tissues: possible relationship to fetal lung maturation
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Ward Coats, Brian Norkiewicz, Frank Martiniuk, Steven D. Hughes, Rene A. Frenkel, John M. Johnston, and Christopher B. Newgard
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Gene isoform ,medicine.medical_specialty ,Glycogenolysis ,Phosphorylases ,Molecular Sequence Data ,Biophysics ,Biology ,Biochemistry ,Isozyme ,Gene Expression Regulation, Enzymologic ,Embryonic and Fetal Development ,Mice ,chemistry.chemical_compound ,Glycogen phosphorylase ,Structural Biology ,Internal medicine ,Gene expression ,Genetics ,medicine ,Animals ,Lung ,Messenger RNA ,Fetus ,Base Sequence ,Glycogen ,Muscles ,Myocardium ,DNA ,Endocrinology ,Liver ,chemistry ,Organ Specificity ,Female ,Rabbits - Abstract
Glycogen can be degraded in mammalian tissues by one of three isozymes of glycogen phosphorylase, termed muscle (M), liver (L) and brain (B) after the tissues in which they are preferentially expressed in adult animals, or by members of the family of α-glucosidases. In the current study, we have examined the developmental expression of these enzymes and their respective mRNAs in rabbit tissues, with particular emphasis on the developing lung, a tissue in which glycogen serves as an important source of carbon for surfactant phospholipid biosynthesis. Native gel activity assays and RNA blot hybridization analysis revealed that the B isoform of glycogen phosphorylase predominates in fetal and adult lung tissues, accompanied by a low level of expression of the M isoform. Total B and M phosphorylase activities increased during fetal lung development, with a peak at day 28 of gestation, then decreased to the adult level at term. This peak in activity coincided with the peak period of glycogen degradation in developing lung. While the increase in M isozyme activity was correlated with an increase in the level of its mRNA, B isoform mRNA showed no significant alteration during development, suggesting that the increase in B isoform activity is determined by a posttranscriptional mechanism. Analysis of phosphorylase mRNA levels in developing liver, skeletal muscle, brain and heart revealed a diverse expression pattern. The L isozyme mRNA was predominant at all time points in liver, the M isozyme was predominant at all time points in muscle, the B isozyme was predominant at all time points in brain, and heart contained a mixture of B and M mRNA in roughly equal ratios at all time points. Thus, our studies of phosphorylase mRNA in the rabbit provide no evidence for general predominance of the B isozyme in fetal tissues, or for isozyme ‘switching’ from the B to the L or M forms during development, as has been suggested by others. In addition to the increase in phosphorylase activity, acid, but not neutral α-glucosidase activity was found to increase significantly during fetal lung development, again with a peak at day 28 of gestation. Interestingly, RNA blot hybridization analysis with a probe for lysosomal α-glucosidase revealed no change in the level of expression of its 4 kb transcript in developing lung. Instead, we observed induction of a structurally related mRNA of 7.4 kb that peaked at day 28 of gestation. Hybridization with a sucrase/isomaltase-specific oligonucleotide excluded the possibility that the 7.4 kb transcript encodes this protein. The identity of the large glucosidase-like transcript and its potential role in fetal lung glycogenolysis thus remains to be established.
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- 1991
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45. Identification of a Missense Mutation in an Adult-Onset Patient with Glycogenosis Type II Expressing Only One Allele
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Mark F. Mehler, M Bodkin, Nan Zhong, Kurt Hirschhorn, S. Tzall, Frank Martiniuk, and R. Hirschhorn
- Subjects
medicine.medical_specialty ,Transcription, Genetic ,Molecular Sequence Data ,Biology ,Polymerase Chain Reaction ,Cell Line ,chemistry.chemical_compound ,Internal medicine ,Glycogen storage disease type II ,Genetics ,medicine ,Humans ,Missense mutation ,Allele ,Codon ,Molecular Biology ,Gene ,Alleles ,Gene Library ,chemistry.chemical_classification ,Base Sequence ,Glycogen ,Glycogen Storage Disease Type II ,alpha-Glucosidases ,Cell Biology ,General Medicine ,Blotting, Northern ,medicine.disease ,Blotting, Southern ,Enzyme ,Endocrinology ,chemistry ,Mutagenesis ,Mutation ,Acid alpha-glucosidase ,Glucan 1,4-alpha-Glucosidase ,Maltase ,Polymorphism, Restriction Fragment Length - Abstract
The lysosomal enzyme acid alpha glucosidase (GAA) or acid maltase is deficient in glycogen storage disease type II. We sought to determine the molecular basis for the disease in an adult-onset patient, unusual for very low enzyme activity similar to that seen with the infantile-onset form and with a previously reported defect in phosphorylation. We constructed cDNA and genomic DNA libraries from the patient's cell line (GM 1935) and determined the nucleotide sequence of the coding region. There were three base-pair substitutions in one allele (C1935 to A; G2446 to A and C2780 to T), all predicting amino acid changes (Asp-645 to Glu; Val-816 to Ile and Thr-927 to Ile). To determine which of the three base-pair substitutions resulted in loss of enzyme activity, we next utilized primer-directed mutagenesis and transient gene expression in an SV40-immortalized GAA-deficient fibroblast cell line. Only the construct containing the G2446 to A mutation (Val-816 to Ile) lost GAA enzyme activity, while the other two substitutions (including the Thr-927 to Ile change that predicts a loss of a potential site for N-linked glycosylation and mannose phosphorylation) each resulted in enzyme activity equal to the control. Analysis of RFLPs in genomic DNA, as well as sequence analysis for the three base-pair alterations, indicated that the patient was a genetic compound. We next digested PCR-amplified cDNA (reverse-transcribed from RNA) with Aat II to detect the base-pair 1935 substitution and found that virtually all of the mRNA was derived from the allele with the three base-pair substitutions.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1991
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46. Identification of the promoter region and gene expression for human acid alpha glucosidase
- Author
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Frank Martiniuk and S. Tzall
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Restriction Mapping ,Biophysics ,Gene Expression ,Simian virus 40 ,Biology ,Biochemistry ,Cell Line ,Complementary DNA ,Gene expression ,medicine ,Humans ,Coding region ,Cloning, Molecular ,Promoter Regions, Genetic ,Fibroblast ,Molecular Biology ,Messenger RNA ,Expression vector ,Glycogen Storage Disease Type II ,nutritional and metabolic diseases ,alpha-Glucosidases ,DNA ,Cell Biology ,Transfection ,Cell Transformation, Viral ,Molecular biology ,Blotting, Southern ,medicine.anatomical_structure ,Acid alpha-glucosidase ,Glucan 1,4-alpha-Glucosidase - Abstract
Genetic deficiency of acid alpha glucosidase (GAA) results in glycogen storage disease type II. A cDNA containing the complete coding region was constructed and cloned into the expression vector pSV2 and was transiently transfected into an SV40 immortalized GAA deficient human fibroblast cell line which has undetectable levels of GAA enzyme activity and does not express GAA mRNA. Transfected cells had 4.9% of normal human fibroblast enzyme activity. Additionally a 5' 1.8 kb genomic fragment was ligated to the 5' end of the GAA cDNA construct and cloned into pUC19. Transient and stable transfection also resulted in expressed GAA enzyme activity in deficient fibroblast cells, indicating that the genomic fragment has GAA promoter function.
- Published
- 1991
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47. Expression of CD70 and the TH17 transcription factor RORgammaT in human contact dermatitis
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Frank, Martiniuk, David S, Lee, Anthony, Gaspari, Herman, Yee, Luis, Chiriboga, Maryann, Huie, Kam-Meng, Tchou-Wong, and William R, Levis
- Subjects
Electrophoresis, Agar Gel ,Receptors, Thyroid Hormone ,Tissue Fixation ,Receptors, Retinoic Acid ,Reverse Transcriptase Polymerase Chain Reaction ,T-Lymphocyte Subsets ,Humans ,Immunologic Factors ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,Dermatitis, Contact ,CD27 Ligand - Abstract
Contact sensitizers are a major cause of inflammatory skin disease and as topical immunomodulators also have the potential for treating cancer, viral diseases and certain autoimmune disorders. In the present study, the authors identify the upregulation of the TH17 lymphocyte subset transcription factor retinoid orphan receptor gamma T (RORgammaT) and the CD70 costimulatory pathway in human contact sensitivity (CS) using molecular techniques. Identification of this important new subset of T lymphocytes and a recognized costimulatory pathway offers potential for ameliorating CS and insight into antitumor and antiviral mechanism of haptens as topical immunomodulators.
- Published
- 2008
48. Protective effects of anti-ricin A-chain RNA aptamer against ricin toxicity
- Author
-
Martha L. Hale, Frank Martiniuk, Feng Wu, Andrew D. Ellington, Kam Meng Tchou-Wong, and Shaoan Fan
- Subjects
endocrine system ,Aptamer ,viruses ,Antidotes ,CHO Cells ,Ricin ,Biology ,Transfection ,chemistry.chemical_compound ,Cricetulus ,Genes, Reporter ,Cricetinae ,Protein biosynthesis ,Animals ,Luciferase ,Cytotoxicity ,Luciferases ,Cell Proliferation ,Protein Synthesis Inhibitors ,Dose-Response Relationship, Drug ,Chinese hamster ovary cell ,Gastroenterology ,RNA ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,Aptamers, Nucleotide ,Molecular biology ,carbohydrates (lipids) ,enzymes and coenzymes (carbohydrates) ,Kinetics ,Biochemistry ,chemistry ,Protein Biosynthesis ,Nucleic acid inhibitor ,Rapid Communication - Abstract
AIM: To investigate the therapeutic potential of an RNA ligand (aptamer) specific for the catalytic ricin A-chain (RTA), the protective effects of a 31-nucleotide RNA aptamer (31RA), which formed a high affinity complex with RTA, against ricin-induced toxicity in cell-based luciferase translation and cell cytotoxicity assays were evaluated. METHODS: To test the therapeutic potential of anti-RTA aptamers in Chinese hamster ovary (CHO) AA8 cells stably transfected with a tetracycline regulatable promoter, ricin ribotoxicity was measured using luciferase and ricin-induced cytotoxicity was ascertained by MTS cell proliferation assay with tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium]. RESULTS: Inhibition of protein synthesis by ricin in CHO AA8 cells resulted in diminished luciferase activity and treatment with polyclonal antibody against deglycosylated RTA (dgA) neutralized the inhibitory effects of ricin on luciferase activity and protected against ricin-induced cytotoxicity as measured by MTS assay. The 31RA anti-RTA aptamer inhibited the translation of luciferase mRNA in cell-free reticulocyte translation assay. 31RA aptamer also partially neutralized the inhibitory effects of ricin on luciferase activity and partially protected against ricin-induced cytotoxicity in CHO AA8 cells. CONCLUSION: We have shown that anti-RTA RNA aptamer can protect against ricin ribotoxicity in cell-based luciferase and cell cytotoxicity assays. Hence, RNA aptamer that inhibits RTA enzymatic activity represents a novel class of nucleic acid inhibitor that has the potential to be developed as a therapeutic agent for the treatment of ricin intoxication.
- Published
- 2008
49. Molecular origin of endemic leprosy in New York City
- Author
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Aloys Cabrera, Jo-Ann Latkowski, Thormika Keo, William N. Rom, Frank Martiniuk, and William R. Levis
- Subjects
Microbiology (medical) ,Gerontology ,DNA, Bacterial ,Male ,Endemic Diseases ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Indigenous ,Foreign born ,Leprosy ,Genotype ,Medicine ,Humans ,Mycobacterium leprae ,Skin ,biology ,business.industry ,biology.organism_classification ,medicine.disease ,Infectious Diseases ,New York City ,Immunocompetence ,business ,Demography - Abstract
We report an indigenous case of leprosy in New York City in an immunocompetent patient who was infected with a Mycobacterium leprae genotype that is consistent with an exogenous origin. Physicians in the eastern United States should be alerted that, although most patients who develop leprosy in the United States are foreign born, native-born Americans are also susceptible to the infection.
- Published
- 2008
50. Heat-shock proteins as drugs: potential applications in cancer, infections, and autoimmune and atopic diseases
- Author
-
Aton M, Holzer, Frank, Martiniuk, and William R, Levis
- Subjects
Treatment Outcome ,Papillomavirus Infections ,Humans ,Melanoma ,Heat-Shock Proteins ,Autoimmune Diseases ,Dermatitis, Atopic ,Skin - Abstract
Heat-shock proteins (HSPs) serve as both a valuable target as well as a potent tool in the therapy of melanoma and human papillomavirus infections. HSPs have been found to associate with key pathogenic antigens and, under different circumstances, activate or suppress both innate and adaptive immunity via several mechanisms. The dominant mechanism of HSP is as a chaperonin to upregulate antigens on antigen-presenting cell surfaces. While no HSP-based therapies are currently FDA approved, several are currently in phase III clinical trials. This study reviews the current literature on therapeutic studies of HSP and the significant role these proteins are likely to play in future therapeutic approaches to neoplasms, infections, and inflammatory diseases of the skin.
- Published
- 2007
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