190 results on '"Politi, K"'
Search Results
2. DOK2 inhibits EGFR-mutated lung adenocarcinoma
- Author
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Taylor, Barry, Berger, AH, Chen, M, Morotti, A, Janas, JA, Niki, M, Bronson, RT, Taylor, BS, Ladanyi, M, Van, L, and Politi, K
- Abstract
Somatic mutations in the EGFR proto-oncogene occur in ∼15% of human lung adenocarcinomas and the importance of EGFR mutations for the initiation and maintenance of lung cancer is well established from mouse models and cancer therapy trials in human lung ca
- Published
- 2013
3. EP08.02-125 Tumor Suppressor Gene Alterations Identified at Disease Progression Impact Outcomes in Patients with EGFR-mutant Lung Cancer
- Author
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Stockhammer, P., primary, Grant, M., additional, Wurtz, A., additional, Foggetti, G., additional, Chung, S., additional, Li, F., additional, Gettinger, S., additional, Politi, K., additional, and Goldberg, S., additional
- Published
- 2022
- Full Text
- View/download PDF
4. Evaluation of Methods of Pre-Vaccination Screening for Markers of Hepatitis B Infection
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Papaevangelou, G., Roumeliotou-Karayannis, A., Tassopoulos, N., Richardson, S. C., Stathopoulou, P., Papadoyannakis, N., Tsantoulis, N., Politi, K., and Tassiopoulou, A.
- Published
- 1985
5. EP.07C.10 Real-World Outcomes of Patients Treated with Neoadjuvant Immunotherapy for Resectable Non-Small Cell Lung Cancer
- Author
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Ermer, T., Kim, S.Y., Goldberg, S., Zolfaghari, E.J., Blasberg, J.D., Boffa, D.J., Herbst, R., Politi, K., Schalper, K., Dacic, S., and Woodard, G.A.
- Published
- 2024
- Full Text
- View/download PDF
6. Contributors
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Abbasi, S., primary, Adolphi, N.L., additional, Aikawa, E., additional, Akbar, H., additional, Akilesh, S., additional, Aladjem, M.I., additional, Allocca, M., additional, Alpini, G., additional, Alroy, J., additional, Altman, B.J., additional, Andujar, P., additional, Antonello, Z.A., additional, Antsiferova, M., additional, Apica, B.S., additional, Ariel, I., additional, Aronow, B.J., additional, Ashley, J.W., additional, Badell, I.R., additional, Bagg, A., additional, Bajaj, M., additional, Banerjee, S., additional, Barbieri, J.S., additional, Bardes, E.E., additional, Barisoni, L., additional, Barletta, J.A., additional, Baskin, D.G., additional, Bastarrachea, R.A., additional, Bayat, A., additional, Bayrak-Toydemir, P., additional, Beck, A.H., additional, Beebe, D.C., additional, Beltran, H., additional, Benichou, G., additional, Bergman, M., additional, Bernard, S.A., additional, Bernardi, P., additional, Best, D.H., additional, Blair, H.C., additional, Bonaldo, P., additional, Bondy, J., additional, Bosman, F.T., additional, Bouma, B.E., additional, Brandi, M.L., additional, Bresler, S.C., additional, Brewer, M.T., additional, Britto, C.J., additional, Brock, J.E., additional, Brosens, L.A.A., additional, Budge, H., additional, Burd, E.M., additional, Burness, M.L., additional, Bushnell, T., additional, Byrd, J., additional, Calderone, A., additional, Campbell, M.J., additional, Cao, D., additional, Capell, W., additional, Cardigan, R., additional, Carey, P.M., additional, Carneiro, F., additional, Carp, S.A., additional, Carter, A.M., additional, Cascio, M.J., additional, Castellani, R.J., additional, Castellanos, J., additional, Caviglia, J.M., additional, Cecconi, F., additional, Chamarthy, S., additional, Chamma, E., additional, Chang, A., additional, Chang, A.Y., additional, Chang, N.C., additional, Chapman, D.G., additional, Charles, A.K., additional, Chen, D., additional, Chen, D.F., additional, Chen, P., additional, Cheng, J., additional, Chernock, R.D., additional, Cheruvu, S., additional, Chiang, J., additional, Childs, G.V., additional, Cho, Y.-B., additional, Choi, A.M.K., additional, Choi, J.K., additional, Cipriani, N.A., additional, Cleary, J.O.S.H., additional, Clementi, E., additional, Clines, G.A., additional, Cohen, M.L., additional, Coleman, W.B., additional, Coletta, D.K., additional, Collie, A.M.B., additional, Cooling, L., additional, Coron, E., additional, Côté, D., additional, Coussens, L.M., additional, Crielaard, B.J., additional, Cron, R.Q., additional, Crum, C.P., additional, Cruz, N.M., additional, Dairkee, S.H., additional, Daly, C.A., additional, Dang, C.V., additional, Danila, M.I., additional, Daradich, A., additional, Darnell, C.M., additional, Dartt, D.A., additional, Das, A., additional, D’Asta, F., additional, DeFronzo, R., additional, De Hertogh, G., additional, Dela Cruz, C.S., additional, de la Cruz-Merino, L., additional, De Palma, C., additional, Demetris, A.J., additional, DeMorrow, S., additional, Denechaud, P.-D., additional, Di Carli, M.F., additional, DiCarlo, E.F., additional, Dikic, I., additional, Dimberg, A., additional, Dowell, M.L., additional, Doyle, L.A., additional, Drachenberg, C.B., additional, Driskell, E., additional, Duda, D.G., additional, Duker, J., additional, Dyck, J.R.B., additional, Ecker, C., additional, Elifritz, J.M., additional, Elsheikh, T.M., additional, Ensari, A., additional, Ernst, L.M., additional, Esch, K.J., additional, Fajas-Coll, L., additional, Fang, Q., additional, Farhat, N.A., additional, Farshid, G., additional, Faye-Petersen, O.M., additional, Fehlings, M.G., additional, Fend, F., additional, Feng, X., additional, Fernandes, H., additional, Fernandez-Checa, J.C., additional, Ferreira, B.P., additional, Fidler, I.J., additional, Finn, J.A., additional, Fischer, A., additional, Fishbein, M.C., additional, Fleit, H.B., additional, Flomenbaum, M., additional, Folkins, A., additional, Francis, H., additional, Frank, K.M., additional, Frevert, C.W., additional, Frias, A.E., additional, Friedman, J.R., additional, Fukumura, D., additional, Furie, M.B., additional, Gaffo, A.L., additional, Galateau-Sallé, F., additional, Gallegos-Cabriales, E.C., additional, Gandhi, C.R., additional, Gannon, M., additional, García-Moliner, M.L., additional, Gardner, J.M., additional, Gasper, C.A., additional, Gaulard, P., additional, Gaut, J.P., additional, Gavia-García, G., additional, Gerrard, C., additional, Ghosh, A.P., additional, Giersch, A.B.S, additional, Gilbert, S.R., additional, Gill, J.R., additional, Giusti, F., additional, Glorioso, J.M., additional, González-Torres, M.C., additional, Goolsby, C.L., additional, Gora, M.J., additional, Gordon, I.O., additional, Gotlieb, A.I., additional, Gouw, A.M., additional, Goyal, A., additional, Grégoire, M., additional, Graham, B.B., additional, Granger, D.N., additional, Greene, A.K., additional, Greenlee, J.J., additional, Griffiths, R., additional, Guimarães, A.R., additional, Gulati, M., additional, Gullet, A., additional, Gupta, S., additional, Haider, N.B., additional, Halushka, M.K., additional, Hambuch, T.M., additional, Hamza, S.M., additional, Han, Y., additional, Hansen, W.P., additional, Hard, R., additional, Harris, B.T., additional, Harris, J.E., additional, Hartnett, M.E., additional, Hasserjian, R.P., additional, Hatch, G.M., additional, Hefti, M.M., additional, Heller, D.S., additional, Hemminger, J.A., additional, Hendrickson, J.E., additional, Henley, K.D., additional, Herzog, E., additional, Hess, J.R., additional, Hill, C.E., additional, Hipp, J., additional, Hobbs, R., additional, Höller, D., additional, Hodges, R.R., additional, Homer, R.J., additional, Horowitz, N., additional, Hsi, E.D., additional, Hsieh, A.L., additional, Hunt, J.M., additional, Hure, S., additional, Husain, A.N., additional, Hussey, S., additional, Hutcheson, J.D., additional, Hutson, R.M., additional, Illescas-Vacas, A., additional, Irvin, C.G., additional, Jaffer, F.A., additional, Jäger, R., additional, Jain, R.K., additional, Jain, S., additional, James, J., additional, Jansen, M., additional, Jarzembowski, J.A., additional, Jaurand, M.-C., additional, Jean, D., additional, Jegga, A.G., additional, Jellinger, K.A., additional, Jen, K.-Y., additional, Jo, V.Y., additional, Johnson, B., additional, Jones, R.L., additional, Kalfa, T.A., additional, Kamionek, M., additional, Kang, D., additional, Kantari, C., additional, Kantor, P.F., additional, Kanzaki, G., additional, Karns, R., additional, Katzman, P.J., additional, Kawai, T., additional, Kelley, T.W., additional, Kent, J.W., additional, Kerr, E.H., additional, Kew, R.R., additional, Khalighi, M., additional, Khanh Vu, T.H., additional, Khong, T.Y., additional, Kim, B.S., additional, Kim, J., additional, Klein, M.J., additional, Knechtle, S.J., additional, Konkle, B.A., additional, Kowalewska, J., additional, Kricka, L.J., additional, Krishnan, B., additional, Kumar, A., additional, Kumar, S., additional, Kvietys, P., additional, Kwong, R.Y., additional, Lafont, E., additional, Laga, A.C., additional, Lagarrigue, S., additional, Lakin, A., additional, Laszik, Z.G., additional, Lauwers, G.Y., additional, Laver, N.V., additional, Lawlor, M.W., additional, Lederer, J.A., additional, Lee, R.E., additional, Lee, W.M., additional, LeGallo, R., additional, Leich, E., additional, Lemmens, B., additional, Le Pimpec-Barthes, F., additional, Leval, L., additional, Levy, B.D., additional, Lewis, J.S., additional, Lewis, T.L., additional, Leyva-Illades, D., additional, Li, L., additional, Li, Y.-P., additional, Lianidou, E.S., additional, Liao, L., additional, Liapis, H., additional, Lin, J.B., additional, Lin, A.-L., additional, Lindsay, M.E., additional, Liu, E., additional, Longacre, T., additional, Lopez-Alvarenga, J.C., additional, Lopez-Mejía, I., additional, Lozanski, G., additional, Lucia, M.S., additional, Luk, E., additional, Lutty, G.A., additional, Maclellan, R.A., additional, Madabhushi, A., additional, Mahindra, A., additional, Malek, E., additional, Mammucari, C., additional, Mani, H., additional, Mao, S.A., additional, Marboe, C.C., additional, Marí, M., additional, Marini, F., additional, Markou, A., additional, Marshall, A.H., additional, Martin, S.J., additional, Marzioni, M., additional, Masli, S., additional, Matsukuma, K.E., additional, Matulonis, U.A., additional, Mayfield, J., additional, McCoy, J.P., additional, McDougle, C.J., additional, McGinnis, M.R., additional, McGuire, A., additional, McKinstry, K.K., additional, McManus, B.M., additional, Means, A.L., additional, Meny, G.M., additional, Merchant, N., additional, Meserve, E.E.K, additional, Mess, A.M., additional, Minervini, M.I., additional, Mitchell, R.N., additional, Monaco, S.E., additional, Monga, S.P., additional, Monica Way, H.-Y., additional, Montecucco, C., additional, Montone, K.T., additional, Morgan, E.A., additional, Morgan, T.K., additional, Morrissey, K., additional, Mortensen, R.M., additional, Moser, S.A., additional, Mosquera, J.M., additional, Mossman, B.T., additional, Motta, A.C.F., additional, Mullins, E., additional, Murphy, G.F., additional, Murray, L., additional, Mysorekar, I.U., additional, Nadel, B., additional, Nadon, A.S., additional, Nagathihalli, N., additional, Nájera-Medina, O., additional, Nalesnik, M.A., additional, Nast, C.C., additional, Natkunam, Y., additional, Nault, J.C., additional, Nava-González, E.J., additional, Nayar, R., additional, Nerenz, R.D., additional, Neumann, H., additional, Ni, H., additional, Nolte, K.B., additional, Norton, L., additional, Nowak, J., additional, Nucera, C., additional, Nyberg, S.L., additional, Oakes, S.A., additional, Offerhaus, G.J.A., additional, Ojha, S., additional, Okabe, H., additional, Oliveira, A.M., additional, Osborn, E.A., additional, O'Tierney-Ginn, P., additional, Ott, G., additional, Ozcan, A., additional, Padera, R.F., additional, Pagano, M.B., additional, Page, E.K., additional, Paintal, A.S., additional, Pairon, J.-C., additional, Papadimitriou, J.C., additional, Park, H.-J., additional, Park, J.Y., additional, Parsons, L.N., additional, Patra, D., additional, Peclovits, A., additional, Peeters, P.M., additional, Perkins, T.N., additional, Perry, G., additional, Perumbeti, A., additional, Petersen, C.A., additional, Petrache, I., additional, Petroff, M.G., additional, Pettus, J.R., additional, Picken, M.M., additional, Pierson, C.R., additional, Pittman, M.E., additional, Pogoriler, J., additional, Politi, K., additional, Pollack, S.M., additional, Quintanilla-Martínez, L., additional, Rai, M.F., additional, Ramkissoon, S., additional, Randhawa, P.S., additional, Rangel, J.R., additional, Rasola, A., additional, Reeves, B., additional, Reheman, A., additional, Remick, D.G., additional, Reynaert, N.L., additional, Richmond, J.M., additional, Rivella, S., additional, Rivenbark, A.G., additional, Rizzuto, R., additional, Roberts, K.A., additional, Robin, D.A., additional, Robinson, L.J., additional, Rockey, D.C., additional, Rosenwald, A., additional, Rossetto, O., additional, Roth, K.A., additional, Roy-Chowdhury, J., additional, Roy-Chowdhury, N., additional, Rubin, M.A., additional, Rudnicki, M.A., additional, Russell, D.S., additional, Ryter, S.W., additional, Saban, D.R., additional, Sacher, R.A., additional, Sacks, D.B., additional, Sagaert, X., additional, Sagdeo, A., additional, Sahay, B., additional, Sahin, A., additional, Samali, A., additional, Sampson, B., additional, Sánchez-Escribano, R., additional, Sandri, M., additional, Sanyal, A., additional, Sasatomi, E., additional, Sauer, V., additional, Scherpereel, A., additional, Schmidt, E.P., additional, Schwabe, R.F., additional, Scorrano, L., additional, Scott, M.G., additional, Scull, J.C., additional, Seidman, M.A., additional, Seki, A., additional, Sellati, T.J., additional, Serban, K., additional, Serhan, C.N., additional, Seshan, S.V., additional, Seth, A., additional, Seykora, J.T., additional, Sharma, N., additional, Shi, C., additional, Shi, S.-R., additional, Shimada, M., additional, Shimizu, A., additional, Singer, D.B., additional, Sitko, K., additional, Smallwood, R.F., additional, Smiraglia, D.J., additional, Smith, B.R., additional, Smola, H., additional, Soubeyrand, M., additional, Stahl, W.L., additional, Stajić, M., additional, Stanworth, S.J., additional, Stathatos, N., additional, Stemler, K.M., additional, Stevens, T.M., additional, Stine, Z.E., additional, Stoll, M.L., additional, Strati, A., additional, Strutt, T.M., additional, Sund, M., additional, Sung, M.M., additional, Symonds, M.E., additional, Tabar, S., additional, Takahashi, N., additional, Talmadge, J.E., additional, Tang, V., additional, Tangrea, M., additional, Tarango, C., additional, Tario, J.D., additional, Taylor, C.R., additional, Taylor, R., additional, Tearney, G.J., additional, Tefera, K., additional, Thomas, S., additional, Thornburg, K.L., additional, Tirado, C.A., additional, Tobian, A.A.R., additional, Tomaszewski, J.E., additional, Tormey, C.A., additional, Torres, R., additional, Tran, M.-H., additional, Tredget, E.E., additional, Treister, N.S., additional, Trotter, J., additional, Troyer, D., additional, Truong, L., additional, Tubbs, R.R., additional, Turakhia, S., additional, Unglert, C.I., additional, Utheim, T., additional, Vahabzadeh, A., additional, van Bokhoven, A., additional, Vanden Berghe, T., additional, Vandenabeele, P., additional, van der Klei, I.J., additional, Vanguri, V.K., additional, Van Noorden, C.J.F, additional, Van Poznak, C., additional, Vassallo, R.R., additional, Vawda, R., additional, Vieth, M., additional, Visscher, D.W., additional, Volk, S.W., additional, Vyas, G.N., additional, Waggoner, S.N., additional, Walczak, H., additional, Walker, D.H., additional, Wallace, P.K., additional, Wanat, K.A., additional, Wang, J., additional, Wang, Y., additional, Wang, Y.X., additional, Warger, W.C., additional, Wei, S., additional, Weinman, S.A., additional, Wenig, B.M., additional, Wentz, S.C., additional, Werner, S., additional, Wertheim, G., additional, Whitley, E.M., additional, Wooderchak-Donahue, W., additional, Woods, K., additional, Wouters, E.F.M., additional, Wu, Y., additional, Xing, W., additional, Yachimski, P., additional, Yan, P., additional, Yang, J., additional, Yang, L., additional, Yoshizawa, S., additional, Yuan, J., additional, Yun, S.-H., additional, Yvon, A., additional, Zhang, H., additional, Zhang, P., additional, Zhao, Z., additional, Zhu, G., additional, Zhu, R., additional, Zordoky, B.N., additional, Zou, J., additional, Zuccato, J.A., additional, and Zucman-Rossi, J., additional
- Published
- 2014
- Full Text
- View/download PDF
7. Thoracic Neoplasia: Carcinoma
- Author
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Politi, K., primary, Dela Cruz, C.S., additional, and Homer, R., additional
- Published
- 2014
- Full Text
- View/download PDF
8. IA31 Genetic Contributors to Tumor Progression and Drug Resistance in EGFR Mutant Lung Cancer
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Politi, K., primary
- Published
- 2020
- Full Text
- View/download PDF
9. B32 Drug Sensitivity and Allele Specificity of First-Line Osimertinib Resistance EGFR Mutations
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Starrett, J.H., primary, Guernet, A., additional, Cuomo, M.E., additional, Poels, K., additional, van Alderwerelt van Rosenburgh, I.K., additional, Nagelberg, A., additional, Farnsworth, D., additional, Price, K., additional, Khan, H., additional, Ashtekar, K.D., additional, Gaefele, M., additional, Ayeni, D., additional, Stewart, T.F., additional, Kuhlmann, A., additional, Kaech, S.M., additional, Unni, A.M., additional, Homer, R., additional, Lockwood, W.W., additional, Michor, F., additional, Goldberg, S.B., additional, Lemmon, M.A., additional, Smith, P., additional, Cross, D., additional, and Politi, K., additional
- Published
- 2020
- Full Text
- View/download PDF
10. Evaluation of a risk score for interhospital transport of critically ill patients
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Markakis, C, Dalezios, M, Chatzicostas, C, Chalkiadaki, A, Politi, K, and Agouridakis, P J
- Published
- 2006
11. Deconstructing tumor heterogeneity : The stromal perspective
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Vickman, R. E., Faget, D. V., Beachy, P., Beebe, D., Bhowmick, N. A., Cukierman, E., Deng, W. -M, Granneman, J. G., Hildesheim, J., Kalluri, R., Lau, K. S., Lengyel, E., Lundeberg, Joakim, Moscat, J., Nelson, P. S., Pietras, K., Politi, K., Puré, E., Scherz-Shouval, R., Sherman, M. H., Tuveson, D., Weeraratna, A. T., White, R. M., Wong, M. H., Woodhouse, E. C., Zheng, Y., Hayward, S. W., Stewart, S. A., Vickman, R. E., Faget, D. V., Beachy, P., Beebe, D., Bhowmick, N. A., Cukierman, E., Deng, W. -M, Granneman, J. G., Hildesheim, J., Kalluri, R., Lau, K. S., Lengyel, E., Lundeberg, Joakim, Moscat, J., Nelson, P. S., Pietras, K., Politi, K., Puré, E., Scherz-Shouval, R., Sherman, M. H., Tuveson, D., Weeraratna, A. T., White, R. M., Wong, M. H., Woodhouse, E. C., Zheng, Y., Hayward, S. W., and Stewart, S. A.
- Abstract
Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive versus suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field. Copyright, QC 20210330
- Published
- 2020
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- View/download PDF
12. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial
- Author
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Vaccaro, O, Masulli, M, Nicolucci, A, Bonora, E, Del Prato, S, Maggioni, A, Rivellese, A, Squatrito, S, Giorda, C, Sesti, G, Mocarelli, P, Lucisano, G, Sacco, M, Signorini, S, Cappellini, F, Perriello, G, Babini, A, Lapolla, A, Gregori, G, Giordano, C, Corsi, L, Buzzetti, R, Clemente, G, Di Cianni, G, Iannarelli, R, Cordera, R, La Macchia, O, Zamboni, C, Scaranna, C, Boemi, M, Iovine, C, Lauro, D, Leotta, S, Dall'Aglio, E, Cannarsa, E, Tonutti, L, Pugliese, G, Bossi, A, Anichini, R, Dotta, F, Di Benedetto, A, Citro, G, Antenucci, D, Ricci, L, Giorgino, F, Santini, C, Gnasso, A, De Cosmo, S, Zavaroni, D, Vedovato, M, Consoli, A, Calabrese, M, di Bartolo, P, Fornengo, P, Riccardi, G, D'Angelo, F, Giansanti, R, Tanase, L, Lanari, L, Testa, I, Pancani, F, Ranchelli, A, Vagheggi, P, Scatona, A, Fontana, L, Laviola, L, Tarantino, L, Ippolito, C, Gigantelli, V, Manicone, M, Conte, E, Trevisan, R, Rota, R, Dodesini, A, Reggiani, G, Montesi, L, Mazzella, N, Forlani, G, Caselli, C, Di Luzio, R, Mazzotti, A, Aiello, A, Barrea, A, Musto, A, D'Amico, F, Sinagra, T, Longhitano, S, Trowpea, V, Sparti, M, Italia, S, Lisi, E, Grasso, G, Pezzino, V, Insalaco, F, Carallo, C, Scicchitano, C, De Franceschi, M, Calbucci, G, Ripani, R, Cuneo, G, Corsi, S, Romeo, F, Lesina, A, Comoglio, M, Bonetto, C, Robusto, A, Nada, E, Asprino, V, Cetraro, R, Impieri, M, Lucchese, G, Donnarumma, G, Tizio, B, Lenza, L, Paraggio, P, Tomasi, F, Dozio, N, Scalambra, E, Mannucci, E, Lamanna, C, Cignarelli, M, Macchia, O, Fariello, S, Sorrentino, M, Franzetti, I, Radin, R, Annunziata, F, Bonabello, L, Durante, A, Dolcino, M, Gallo, F, Mazzucchelli, C, Aleo, A, Melga, P, Briatore, L, Maggi, D, Storace, D, Cecoli, F, D'Ugo, E, Pupillo, M, Baldassarre, M, Salvati, F, Minnucci, A, De Luca, A, Zugaro, A, Santarelli, L, Bosco, A, Petrella, V, La Verghetta, G, D'Andrea, S, Giuliani, A, Polidoro, W, Sperandio, A, Sciarretta, F, Pezzella, A, Carlone, A, Potenziani, S, Venditti, C, Foffi, C, Carbone, S, Cipolloni, L, Moretti, C, Leto, G, Serra, R, Petrachi, F, Romano, I, Lacaria, E, Russo, L, Goretti, C, Sannino, C, Dolci, M, Bruselli, L, Mori, M, Baccetti, F, Del Freo, M, Cucinotta, D, Giunta, L, Ruffo, M, Cannizzaro, D, Pintaudi, B, Perrone, G, Pata, P, Ragonese, F, Lettina, G, Mancuso, T, Coppolino, A, Piatti, P, Monti, L, Stuccillo, M, Lucotti, P, Setola, M, Crippa, G, Loi, C, Oldani, M, Bottalico, M, Pellegata, B, Bonomo, M, Menicatti, L, Resi, V, Bertuzzi, F, Disoteo, E, Pizzi, G, Annuzzi, G, Capaldo, B, Nappo, R, Auciello, S, Turco, A, Costagliola, L, Corte, G, Vallefuoco, P, Nappi, F, Vitale, M, Cocozza, S, Ciano, O, Massimino, E, Garofalo, N, Avogaro, A, Guarneri, G, Fedele, D, Sartore, G, Chilelli, N, Burlina, S, Bonsembiante, B, Galluzzo, A, Torregrossa, V, Mancastroppa, G, Arsenio, L, Cioni, F, Caronna, S, Papi, M, Santeusanio, F, Calagreti, G, Timi, A, Tantucci, A, Marino, C, Ginestra, F, Di Biagio, R, Taraborelli, M, Miccoli, R, Bianchi, C, Garofolo, M, Politi, K, Penno, G, Livraga, S, Calzoni, F, Corsini, E, Tedeschi, A, Gagliano, M, Ippolito, G, Salutini, E, Cervellino, F, Natale, M, Salvatore, V, Zampino, A, Sinisi, R, Arcangeli, A, Zogheri, A, Guizzotti, S, Longo, R, Pellicano, F, Scolozzi, P, Termine, S, Luberto, A, Ballardini, G, Trojani, C, Mazzuca, P, Bruglia, M, Ciamei, M, Genghini, S, Zannoni, C, Rangel, G, Salvi, L, Zappaterreno, A, Cordone, S, Simonelli, P, Meggiorini, M, Frasheri, A, Di Pippo, C, Maglio, C, Mazzitelli, G, Rinaldi, M, Galli, A, Romano, M, D'Angelo, P, Suraci, C, Bacci, S, Palena, A, Genovese, S, Mancino, M, Rondinelli, M, Capone, F, Calabretto, E, Bulgheroni, M, Bucciarelli, L, Ceccarelli, E, Fondelli, C, Santacroce, C, Guarino, E, Nigi, L, Lalli, C, Di Vizia, G, Scarponi, M, Montani, V, Di Bernardino, P, Romagni, P, Dolcetti, K, Forte, E, Tamburo, L, Perin, P, Prinzis, T, Gruden, G, Bruno, G, Zucco, C, Perotta, M, Marena, S, Monsignore, S, Panero, F, Ponzi, F, Carpinteri, R, Casagrande, M, Coletti, M, Balini, A, Filopanti, M, Madaschi, S, Pulcina, A, Grimaldi, F, Venturini, G, Agus, S, Pagnutti, S, Guidotti, F, Cavarape, A, Cigolini, M, Pichiri, I, Brangani, C, Fainelli, G, Tomasetto, E, Zoppini, G, Galletti, A, Perrone, D, Capra, C, Bianchini, F, Ceseri, M, Di Nardo, B, Sasso, E, Bartolomei, B, Suliman, I, Fabbri, G, Romano, G, Maturo, N, Nunziata, G, Capobianco, G, De Simone, G, Villa, V, Rota, G, Pentangelo, C, Carbonara, O, Caiazzo, G, Cutolo, M, Sorrentino, T, Mastrilli, V, Amelia, U, Masi, S, Corigliano, G, Gaeta, I, Armentano, V, Calatola, P, Capuano, G, Angiulli, B, Auletta, P, Petraroli, E, Iodice, C, Agrusta, M, Vaccaro O., Masulli M., Nicolucci A., Bonora E., Del Prato S., Maggioni A. P., Rivellese A. A., Squatrito S., Giorda C. B., Sesti G., Mocarelli P., Lucisano G., Sacco M., Signorini S., Cappellini F., Perriello G., Babini A. C., Lapolla A., Gregori G., Giordano C., Corsi L., Buzzetti R., Clemente G., Di Cianni G., Iannarelli R., Cordera R., La Macchia O., Zamboni C., Scaranna C., Boemi M., Iovine C., Lauro D., Leotta S., Dall'Aglio E., Cannarsa E., Tonutti L., Pugliese G., Bossi A. C., Anichini R., Dotta F., Di Benedetto A., Citro G., Antenucci D., Ricci L., Giorgino F., Santini C., Gnasso A., De Cosmo S., Zavaroni D., Vedovato M., Consoli A., Calabrese M., di Bartolo P., Fornengo P., Riccardi G., D'Angelo F., Giansanti R., Tanase L., Lanari L., Testa I., Pancani F., Ranchelli A., Vagheggi P., Scatona A., Fontana L., Laviola L., Tarantino L., Ippolito C., Gigantelli V., Manicone M., Conte E., Trevisan R., Rota R., Dodesini A. R., Reggiani G. M., Montesi L., Mazzella N., Forlani G., Caselli C., Di Luzio R., Mazzotti A., Aiello A., Barrea A., Musto A., D'Amico F., Sinagra T., Longhitano S., Trowpea V., Sparti M., Italia S., Lisi E., Grasso G., Pezzino V., Insalaco F., Carallo C., Scicchitano C., De Franceschi M. S., Calbucci G., Ripani R., Cuneo G., Corsi S., Romeo F., Lesina A., Comoglio M., Bonetto C., Robusto A., Nada E., Asprino V., Cetraro R., Impieri M., Lucchese G., Donnarumma G., Tizio B., Lenza L., Paraggio P., Tomasi F., Dozio N., Scalambra E., Mannucci E., Lamanna C., Cignarelli M., Macchia O. L., Fariello S., Sorrentino M. R., Franzetti I., Radin R., Annunziata F., Bonabello L. A., Durante A., Dolcino M., Gallo F., Mazzucchelli C., Aleo A., Melga P., Briatore L., Maggi D., Storace D., Cecoli F., D'Ugo E., Pupillo M., Baldassarre M. P. A., Salvati F., Minnucci A., De Luca A., Zugaro A., Santarelli L., Bosco A., Petrella V., La Verghetta G. G., D'Andrea S., Giuliani A. E., Polidoro W. L., Sperandio A., Sciarretta F., Pezzella A., Carlone A., Potenziani S., Venditti C., Foffi C., Carbone S., Cipolloni L., Moretti C., Leto G., Serra R., Petrachi F., Romano I., Lacaria E., Russo L., Goretti C., Sannino C., Dolci M., Bruselli L., Mori M. L., Baccetti F., Del Freo M., Cucinotta D., Giunta L., Ruffo M. C., Cannizzaro D., Pintaudi B., Perrone G., Pata P., Ragonese F., Lettina G., Mancuso T., Coppolino A., Piatti P. M., Monti L., Stuccillo M., Lucotti P., Setola M., Crippa G. V., Loi C., Oldani M., Bottalico M. L., Pellegata B., Bonomo M., Menicatti L. S. M., Resi V., Bertuzzi F., Disoteo E. O., Pizzi G., Annuzzi G., Capaldo B., Nappo R., Auciello S. M., Turco A. A., Costagliola L., Corte G. D., Vallefuoco P., Nappi F., Vitale M., Cocozza S., Ciano O., Massimino E., Garofalo N., Avogaro A., Guarneri G., Fedele D., Sartore G., Chilelli N. C., Burlina S., Bonsembiante B., Galluzzo A., Torregrossa V., Mancastroppa G., Arsenio L., Cioni F., Caronna S., Papi M., Santeusanio F., Calagreti G., Timi A., Tantucci A., Marino C., Ginestra F., Di Biagio R., Taraborelli M., Miccoli R., Bianchi C., Garofolo M., Politi K. S., Penno G., Livraga S., Calzoni F., Mancastroppa G. L. F., Corsini E., Tedeschi A., Gagliano M. S., Ippolito G., Salutini E., Cervellino F., Natale M., Salvatore V., Zampino A., Sinisi R., Arcangeli A., Zogheri A., Guizzotti S., Longo R., Pellicano F., Scolozzi P., Termine S., Luberto A., Ballardini G., Trojani C., Mazzuca P., Bruglia M., Ciamei M., Genghini S., Zannoni C., Rangel G., Salvi L., Zappaterreno A., Cordone S., Simonelli P., Meggiorini M., Frasheri A., Di Pippo C., Maglio C., Mazzitelli G., Rinaldi M. E., Galli A., Romano M., D'Angelo P., Suraci C., Bacci S., Palena A. P., Genovese S., Mancino M., Rondinelli M., Capone F., Calabretto E., Bulgheroni M., Bucciarelli L., Ceccarelli E., Fondelli C., Santacroce C., Guarino E., Nigi L., Lalli C., Di Vizia G., Scarponi M., Montani V., Di Bernardino P., Romagni P., Dolcetti K., Forte E., Tamburo L., Perin P. C., Prinzis T., Gruden G., Bruno G., Zucco C., Perotta M., Marena S., Monsignore S., Panero F., Ponzi F., Carpinteri R., Casagrande M. L., Coletti M. F., Balini A., Filopanti M., Madaschi S., Pulcina A., Grimaldi F., Venturini G., Agus S., Pagnutti S., Guidotti F., Cavarape A., Cigolini M., Pichiri I., Brangani C., Fainelli G., Tomasetto E., Zoppini G., Galletti A., Perrone D., Capra C., Bianchini F., Ceseri M., Di Nardo B., Sasso E., Bartolomei B., Suliman I., Fabbri G., Romano G., Maturo N., Nunziata G., Capobianco G., De Simone G., Villa V., Rota G., Pentangelo C., Carbonara O., Caiazzo G., Cutolo M., Sorrentino T., Mastrilli V., Amelia U., Masi S., Corigliano G., Gaeta I., Armentano V., Calatola P., Capuano G., Angiulli B., Auletta P., Petraroli E., Iodice C. E., Agrusta M., Vaccaro, O, Masulli, M, Nicolucci, A, Bonora, E, Del Prato, S, Maggioni, A, Rivellese, A, Squatrito, S, Giorda, C, Sesti, G, Mocarelli, P, Lucisano, G, Sacco, M, Signorini, S, Cappellini, F, Perriello, G, Babini, A, Lapolla, A, Gregori, G, Giordano, C, Corsi, L, Buzzetti, R, Clemente, G, Di Cianni, G, Iannarelli, R, Cordera, R, La Macchia, O, Zamboni, C, Scaranna, C, Boemi, M, Iovine, C, Lauro, D, Leotta, S, Dall'Aglio, E, Cannarsa, E, Tonutti, L, Pugliese, G, Bossi, A, Anichini, R, Dotta, F, Di Benedetto, A, Citro, G, Antenucci, D, Ricci, L, Giorgino, F, Santini, C, Gnasso, A, De Cosmo, S, Zavaroni, D, Vedovato, M, Consoli, A, Calabrese, M, di Bartolo, P, Fornengo, P, Riccardi, G, D'Angelo, F, Giansanti, R, Tanase, L, Lanari, L, Testa, I, Pancani, F, Ranchelli, A, Vagheggi, P, Scatona, A, Fontana, L, Laviola, L, Tarantino, L, Ippolito, C, Gigantelli, V, Manicone, M, Conte, E, Trevisan, R, Rota, R, Dodesini, A, Reggiani, G, Montesi, L, Mazzella, N, Forlani, G, Caselli, C, Di Luzio, R, Mazzotti, A, Aiello, A, Barrea, A, Musto, A, D'Amico, F, Sinagra, T, Longhitano, S, Trowpea, V, Sparti, M, Italia, S, Lisi, E, Grasso, G, Pezzino, V, Insalaco, F, Carallo, C, Scicchitano, C, De Franceschi, M, Calbucci, G, Ripani, R, Cuneo, G, Corsi, S, Romeo, F, Lesina, A, Comoglio, M, Bonetto, C, Robusto, A, Nada, E, Asprino, V, Cetraro, R, Impieri, M, Lucchese, G, Donnarumma, G, Tizio, B, Lenza, L, Paraggio, P, Tomasi, F, Dozio, N, Scalambra, E, Mannucci, E, Lamanna, C, Cignarelli, M, Macchia, O, Fariello, S, Sorrentino, M, Franzetti, I, Radin, R, Annunziata, F, Bonabello, L, Durante, A, Dolcino, M, Gallo, F, Mazzucchelli, C, Aleo, A, Melga, P, Briatore, L, Maggi, D, Storace, D, Cecoli, F, D'Ugo, E, Pupillo, M, Baldassarre, M, Salvati, F, Minnucci, A, De Luca, A, Zugaro, A, Santarelli, L, Bosco, A, Petrella, V, La Verghetta, G, D'Andrea, S, Giuliani, A, Polidoro, W, Sperandio, A, Sciarretta, F, Pezzella, A, Carlone, A, Potenziani, S, Venditti, C, Foffi, C, Carbone, S, Cipolloni, L, Moretti, C, Leto, G, Serra, R, Petrachi, F, Romano, I, Lacaria, E, Russo, L, Goretti, C, Sannino, C, Dolci, M, Bruselli, L, Mori, M, Baccetti, F, Del Freo, M, Cucinotta, D, Giunta, L, Ruffo, M, Cannizzaro, D, Pintaudi, B, Perrone, G, Pata, P, Ragonese, F, Lettina, G, Mancuso, T, Coppolino, A, Piatti, P, Monti, L, Stuccillo, M, Lucotti, P, Setola, M, Crippa, G, Loi, C, Oldani, M, Bottalico, M, Pellegata, B, Bonomo, M, Menicatti, L, Resi, V, Bertuzzi, F, Disoteo, E, Pizzi, G, Annuzzi, G, Capaldo, B, Nappo, R, Auciello, S, Turco, A, Costagliola, L, Corte, G, Vallefuoco, P, Nappi, F, Vitale, M, Cocozza, S, Ciano, O, Massimino, E, Garofalo, N, Avogaro, A, Guarneri, G, Fedele, D, Sartore, G, Chilelli, N, Burlina, S, Bonsembiante, B, Galluzzo, A, Torregrossa, V, Mancastroppa, G, Arsenio, L, Cioni, F, Caronna, S, Papi, M, Santeusanio, F, Calagreti, G, Timi, A, Tantucci, A, Marino, C, Ginestra, F, Di Biagio, R, Taraborelli, M, Miccoli, R, Bianchi, C, Garofolo, M, Politi, K, Penno, G, Livraga, S, Calzoni, F, Corsini, E, Tedeschi, A, Gagliano, M, Ippolito, G, Salutini, E, Cervellino, F, Natale, M, Salvatore, V, Zampino, A, Sinisi, R, Arcangeli, A, Zogheri, A, Guizzotti, S, Longo, R, Pellicano, F, Scolozzi, P, Termine, S, Luberto, A, Ballardini, G, Trojani, C, Mazzuca, P, Bruglia, M, Ciamei, M, Genghini, S, Zannoni, C, Rangel, G, Salvi, L, Zappaterreno, A, Cordone, S, Simonelli, P, Meggiorini, M, Frasheri, A, Di Pippo, C, Maglio, C, Mazzitelli, G, Rinaldi, M, Galli, A, Romano, M, D'Angelo, P, Suraci, C, Bacci, S, Palena, A, Genovese, S, Mancino, M, Rondinelli, M, Capone, F, Calabretto, E, Bulgheroni, M, Bucciarelli, L, Ceccarelli, E, Fondelli, C, Santacroce, C, Guarino, E, Nigi, L, Lalli, C, Di Vizia, G, Scarponi, M, Montani, V, Di Bernardino, P, Romagni, P, Dolcetti, K, Forte, E, Tamburo, L, Perin, P, Prinzis, T, Gruden, G, Bruno, G, Zucco, C, Perotta, M, Marena, S, Monsignore, S, Panero, F, Ponzi, F, Carpinteri, R, Casagrande, M, Coletti, M, Balini, A, Filopanti, M, Madaschi, S, Pulcina, A, Grimaldi, F, Venturini, G, Agus, S, Pagnutti, S, Guidotti, F, Cavarape, A, Cigolini, M, Pichiri, I, Brangani, C, Fainelli, G, Tomasetto, E, Zoppini, G, Galletti, A, Perrone, D, Capra, C, Bianchini, F, Ceseri, M, Di Nardo, B, Sasso, E, Bartolomei, B, Suliman, I, Fabbri, G, Romano, G, Maturo, N, Nunziata, G, Capobianco, G, De Simone, G, Villa, V, Rota, G, Pentangelo, C, Carbonara, O, Caiazzo, G, Cutolo, M, Sorrentino, T, Mastrilli, V, Amelia, U, Masi, S, Corigliano, G, Gaeta, I, Armentano, V, Calatola, P, Capuano, G, Angiulli, B, Auletta, P, Petraroli, E, Iodice, C, Agrusta, M, Vaccaro O., Masulli M., Nicolucci A., Bonora E., Del Prato S., Maggioni A. P., Rivellese A. A., Squatrito S., Giorda C. B., Sesti G., Mocarelli P., Lucisano G., Sacco M., Signorini S., Cappellini F., Perriello G., Babini A. C., Lapolla A., Gregori G., Giordano C., Corsi L., Buzzetti R., Clemente G., Di Cianni G., Iannarelli R., Cordera R., La Macchia O., Zamboni C., Scaranna C., Boemi M., Iovine C., Lauro D., Leotta S., Dall'Aglio E., Cannarsa E., Tonutti L., Pugliese G., Bossi A. C., Anichini R., Dotta F., Di Benedetto A., Citro G., Antenucci D., Ricci L., Giorgino F., Santini C., Gnasso A., De Cosmo S., Zavaroni D., Vedovato M., Consoli A., Calabrese M., di Bartolo P., Fornengo P., Riccardi G., D'Angelo F., Giansanti R., Tanase L., Lanari L., Testa I., Pancani F., Ranchelli A., Vagheggi P., Scatona A., Fontana L., Laviola L., Tarantino L., Ippolito C., Gigantelli V., Manicone M., Conte E., Trevisan R., Rota R., Dodesini A. R., Reggiani G. M., Montesi L., Mazzella N., Forlani G., Caselli C., Di Luzio R., Mazzotti A., Aiello A., Barrea A., Musto A., D'Amico F., Sinagra T., Longhitano S., Trowpea V., Sparti M., Italia S., Lisi E., Grasso G., Pezzino V., Insalaco F., Carallo C., Scicchitano C., De Franceschi M. S., Calbucci G., Ripani R., Cuneo G., Corsi S., Romeo F., Lesina A., Comoglio M., Bonetto C., Robusto A., Nada E., Asprino V., Cetraro R., Impieri M., Lucchese G., Donnarumma G., Tizio B., Lenza L., Paraggio P., Tomasi F., Dozio N., Scalambra E., Mannucci E., Lamanna C., Cignarelli M., Macchia O. L., Fariello S., Sorrentino M. R., Franzetti I., Radin R., Annunziata F., Bonabello L. A., Durante A., Dolcino M., Gallo F., Mazzucchelli C., Aleo A., Melga P., Briatore L., Maggi D., Storace D., Cecoli F., D'Ugo E., Pupillo M., Baldassarre M. P. A., Salvati F., Minnucci A., De Luca A., Zugaro A., Santarelli L., Bosco A., Petrella V., La Verghetta G. G., D'Andrea S., Giuliani A. E., Polidoro W. L., Sperandio A., Sciarretta F., Pezzella A., Carlone A., Potenziani S., Venditti C., Foffi C., Carbone S., Cipolloni L., Moretti C., Leto G., Serra R., Petrachi F., Romano I., Lacaria E., Russo L., Goretti C., Sannino C., Dolci M., Bruselli L., Mori M. L., Baccetti F., Del Freo M., Cucinotta D., Giunta L., Ruffo M. C., Cannizzaro D., Pintaudi B., Perrone G., Pata P., Ragonese F., Lettina G., Mancuso T., Coppolino A., Piatti P. M., Monti L., Stuccillo M., Lucotti P., Setola M., Crippa G. V., Loi C., Oldani M., Bottalico M. L., Pellegata B., Bonomo M., Menicatti L. S. M., Resi V., Bertuzzi F., Disoteo E. O., Pizzi G., Annuzzi G., Capaldo B., Nappo R., Auciello S. M., Turco A. A., Costagliola L., Corte G. D., Vallefuoco P., Nappi F., Vitale M., Cocozza S., Ciano O., Massimino E., Garofalo N., Avogaro A., Guarneri G., Fedele D., Sartore G., Chilelli N. C., Burlina S., Bonsembiante B., Galluzzo A., Torregrossa V., Mancastroppa G., Arsenio L., Cioni F., Caronna S., Papi M., Santeusanio F., Calagreti G., Timi A., Tantucci A., Marino C., Ginestra F., Di Biagio R., Taraborelli M., Miccoli R., Bianchi C., Garofolo M., Politi K. S., Penno G., Livraga S., Calzoni F., Mancastroppa G. L. F., Corsini E., Tedeschi A., Gagliano M. S., Ippolito G., Salutini E., Cervellino F., Natale M., Salvatore V., Zampino A., Sinisi R., Arcangeli A., Zogheri A., Guizzotti S., Longo R., Pellicano F., Scolozzi P., Termine S., Luberto A., Ballardini G., Trojani C., Mazzuca P., Bruglia M., Ciamei M., Genghini S., Zannoni C., Rangel G., Salvi L., Zappaterreno A., Cordone S., Simonelli P., Meggiorini M., Frasheri A., Di Pippo C., Maglio C., Mazzitelli G., Rinaldi M. E., Galli A., Romano M., D'Angelo P., Suraci C., Bacci S., Palena A. P., Genovese S., Mancino M., Rondinelli M., Capone F., Calabretto E., Bulgheroni M., Bucciarelli L., Ceccarelli E., Fondelli C., Santacroce C., Guarino E., Nigi L., Lalli C., Di Vizia G., Scarponi M., Montani V., Di Bernardino P., Romagni P., Dolcetti K., Forte E., Tamburo L., Perin P. C., Prinzis T., Gruden G., Bruno G., Zucco C., Perotta M., Marena S., Monsignore S., Panero F., Ponzi F., Carpinteri R., Casagrande M. L., Coletti M. F., Balini A., Filopanti M., Madaschi S., Pulcina A., Grimaldi F., Venturini G., Agus S., Pagnutti S., Guidotti F., Cavarape A., Cigolini M., Pichiri I., Brangani C., Fainelli G., Tomasetto E., Zoppini G., Galletti A., Perrone D., Capra C., Bianchini F., Ceseri M., Di Nardo B., Sasso E., Bartolomei B., Suliman I., Fabbri G., Romano G., Maturo N., Nunziata G., Capobianco G., De Simone G., Villa V., Rota G., Pentangelo C., Carbonara O., Caiazzo G., Cutolo M., Sorrentino T., Mastrilli V., Amelia U., Masi S., Corigliano G., Gaeta I., Armentano V., Calatola P., Capuano G., Angiulli B., Auletta P., Petraroli E., Iodice C. E., and Agrusta M.
- Abstract
Background The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. Methods TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50–75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2–3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15–45 mg) or a sulfonylurea (5–15 mg glibenclamide, 2–6 mg glimepiride, or 30–120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. Findings Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 p
- Published
- 2017
13. Correction to: Toward a comprehensive view of cancer immune responsiveness: A synopsis from the SITC workshop (Journal for ImmunoTherapy of Cancer (2020) 7 (131) DOI: 10.1186/s40425-019-0602-4)
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Bedognetti, D., Ceccarelli, M., Galluzzi, L., Lu, R., Palucka, K., Samayoa, J., Spranger, S., Warren, S., Wong, K. -K., Ziv, E., Chowell, D., Coussens, L. M., De Carvalho, D. D., Denardo, D. G., Galon, J., Kaufman, H. L., Kirchhoff, T., Lotze, M. T., Luke, J. J., Minn, A. J., Politi, K., Shultz, L. D., Simon, R., Thorsson, V., Weidhaas, J. B., Ascierto, M. L., Ascierto, P. A., Barnes, J. M., Barsan, V., Bommareddy, P. K., Bot, A., Church, S. E., Ciliberto, G., De Maria, A., Draganov, D., W. S., Ho, Mcgee, H. M., Monette, A., Murphy, J. F., Nistico, P., Park, W., Patel, M., Quigley, M., Radvanyi, L., Raftopoulos, H., Rudqvist, N. -P., Snyder, A., Sweis, R. F., Valpione, S., Zappasodi, R., Butterfield, L. H., Disis, M. L., Fox, B. A., Cesano, A., and Marincola, F. M.
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- 2019
14. ES11.04 Mechanisms for Resistance to TKI and ICI
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Politi, K., primary
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- 2019
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15. OA10.04 Afatinib With or Without Cetuximab for EGFR-Mutant Non-Small Cell Lung Cancer: Safety and Efficacy Results from SWOG S1403
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Goldberg, S., primary, Redman, M., additional, Lilenbaum, R., additional, Politi, K., additional, Stinchcombe, T., additional, Horn, L., additional, Chen, E., additional, Mashru, S., additional, Gettinger, S., additional, Melnick, M.A., additional, Miao, J., additional, Moon, J., additional, Kelly, K., additional, and Gandara, D., additional
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- 2018
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16. A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers
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Gettinger, S. N., primary, Choi, J., additional, Mani, N., additional, Sanmamed, M. F., additional, Datar, I., additional, Sowell, Ryan, additional, Du, Victor Y., additional, Kaftan, E., additional, Goldberg, S., additional, Dong, W., additional, Zelterman, D., additional, Politi, K., additional, Kavathas, P., additional, Kaech, S., additional, Yu, X., additional, Zhao, H., additional, Schlessinger, J., additional, Lifton, R., additional, Rimm, D. L., additional, Chen, L., additional, Herbst, R. S., additional, and Schalper, K. A., additional
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- 2018
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17. P3.03-007 LCMC2: Expanded Profiling of Lung Adenocarcinomas Identifies ROS1 and RET Rearrangements and TP53 Mutations as a Negative Prognostic Factor
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Kris, M., primary, Aisner, D., additional, Sholl, L., additional, Berry, L., additional, Rossi, M., additional, Chen, H., additional, Fujimoto, J., additional, Moreira, A., additional, Ramalingam, S., additional, Villaruz, L., additional, Otterson, G., additional, Haura, E., additional, Politi, K., additional, Glisson, B., additional, Cetnar, J., additional, Garon, E., additional, Schiller, J., additional, Waqar, S., additional, Sequist, L., additional, Brahmer, J., additional, Shyr, Y., additional, Kugler, K., additional, Wistuba, I., additional, Johnson, B., additional, Minna, J., additional, Bunn, P., additional, and Kwiatkowski, D., additional
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- 2017
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18. OA 12.01 The Preclinical and Clinical Activity of Poziotinib, a Potent, Selective Inhibitor of EGFR Exon 20 Mutant NSCLC
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Elamin, Y., primary, Robichaux, J., additional, Lam, V., additional, Tsao, A., additional, Lu, C., additional, Blumenschein, G., additional, Kurie, J., additional, Brahmer, J., additional, Li, S., additional, Chen, T., additional, Estrada-Bernal, A., additional, Truini, A., additional, Nilsson, M., additional, Le, A., additional, Tan, Z., additional, Zhang, S., additional, Doebele, R., additional, Politi, K., additional, Yang, Z., additional, Liu, S., additional, Wong, K., additional, and Heymach, J., additional
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- 2017
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19. P3.01-046 Longitudinal Analysis of Plasma CtDNA in EGFR-Mutant NSCLC: SWOG S1403 Trial of Afatinib with or Without Cetuximab
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Mack, P., primary, Miao, J., additional, Banks, K., additional, Burich, R., additional, Politi, K., additional, Raymond, V., additional, Dix, D., additional, Lanman, R., additional, Moon, J., additional, Melnick, M.A., additional, Truini, A., additional, Redman, M., additional, Goldberg, S., additional, Gandara, D.R., additional, and Kelly, K., additional
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- 2017
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20. Assessing response to immunotherapy in patients with non-small cell lung cancer using circulating tumor DNA
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Goldberg, S.B., primary, Narayan, A., additional, Kole, A.J., additional, Decker, R.H., additional, Teysir, J., additional, Carriero, N.J., additional, Lee, A., additional, Nemati, R., additional, Nath, S.K., additional, Mane, S.M., additional, Deng, Y., additional, Sukumar, N., additional, Zelterman, D., additional, Boffa, D.J., additional, Politi, K., additional, Gettinger, S.N., additional, Wilson, L.D., additional, Herbst, R.S., additional, and Patel, A.A., additional
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- 2017
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21. 1341P - Assessing response to immunotherapy in patients with non-small cell lung cancer using circulating tumor DNA
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Goldberg, S.B., Narayan, A., Kole, A.J., Decker, R.H., Teysir, J., Carriero, N.J., Lee, A., Nemati, R., Nath, S.K., Mane, S.M., Deng, Y., Sukumar, N., Zelterman, D., Boffa, D.J., Politi, K., Gettinger, S.N., Wilson, L.D., Herbst, R.S., and Patel, A.A.
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- 2017
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22. Expression of p21waf1/Cip1 in stromal fibroblasts of primary breast tumors
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Trimis, G., primary, Chatzistamou, I., additional, Politi, K., additional, Kiaris, H., additional, and Papavassiliou, A. G., additional
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- 2008
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23. P1555 Human herpes virus 6 infection in children in Northern Greece
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Sidira, P., primary, Mitka, S., additional, Karabaxoglou, D., additional, Politi, K., additional, Kansouzidou, A., additional, and Papa, A., additional
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- 2007
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24. Oncogenes Come of Age
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VARMUS, H., primary, PAO, W., additional, POLITI, K., additional, PODSYPANINA, K., additional, and DU, Y.-C.N., additional
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- 2005
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25. Retinoic acid down-regulation of fibronectin and retinoic acid receptor alpha proteins in NIH-3T3 cells. Blocks of this response by ras transformation.
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Scita, G, Darwiche, N, Greenwald, E, Rosenberg, M, Politi, K, and De Luca, L M
- Abstract
All-trans-retinoic acid (RA) markedly reduced the level of intracellular fibronectin (FN) in a time- and concentration-dependent fashion in NIH-3T3 cells, but not in NIH-3T3 cells transformed by an activated Ha-ras oncogene. Pulse/chase experiments indicated that RA affects FN biosynthesis rather than its turnover rate. Steady state levels of FN transcripts did not change after treatment of the cells with RA for various times or concentrations, suggesting that RA acts at the translational level. Similar effects were observed in other fibroblasts. In NIH-3T3 cells, RA had distinct effects on different receptors; it down-modulated retinoic acid receptor (RAR) a protein and transcript levels, it up-regulated RAR beta transcripts, and it had no effect on RAR gamma. Transformation of NIH-3T3 cells with an activated Ha-ras oncogene down-modulated RAR expression and abolished responsiveness to RA. We identified the retinoid signal transduction pathways responsible for the effects of RA on FN and RAR alpha proteins by the use of the retinoid X receptor-selective compound, SR11237, by stable over-expression of a truncated form of the RAR alpha gene, RAR alpha 403 with strong RAR dominant negative activity, and by overexpression of RAR alpha. We conclude that: 1) RA-dependent FN down-modulation is mediated by RARs, 2) retinoid X receptors mediate the observed reduction of RAR alpha by RA, and 3) the block of RA responsiveness in Ha-ras cells cannot be overcome by overexpression of RAR alpha. These studies have defined fibronectin and RAR alpha as targets of RA in fibroblast cells and have shown that oncogenic transformation renders the cells resistant to RA action.
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- 1996
26. DEFECTIVE PHAGOCYTIC AND BACTERICIDAL FUNCTION OF POLYMORPHONUCLEAR LEUKOCYTES IN PATIENTS WITH BETA-THALASSEMIA MAJOR
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SKOUTELIS, AT LIANOU, E PAPAVASSILIOU, T KARAMEROU, A and POLITI, K BASSARIS, HP
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- 1984
27. Defective phagocytic and bactericidal function of polymorphonuclear leucocytes in patients with β-thalassaemia major
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Skoutelis, A.Th., primary, Lianou, E., additional, Papavassiliou, Th., additional, Karamerou, A., additional, Politi, K., additional, and Bassaris, H.P., additional
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- 1984
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28. Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer.
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Robles-Oteíza C, Hastings K, Choi J, Sirois I, Ravi A, Expósito F, de Miguel F, Knight JR, López-Giráldez F, Choi H, Socci ND, Merghoub T, Awad M, Getz G, Gainor J, Hellmann MD, Caron É, Kaech SM, and Politi K
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- Animals, Mice, Humans, Mice, Knockout, MutS Homolog 2 Protein metabolism, MutS Homolog 2 Protein genetics, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor metabolism, Cell Line, Tumor, B7-H1 Antigen metabolism, Mice, Inbred C57BL, Hypoxia, CTLA-4 Antigen metabolism, CTLA-4 Antigen antagonists & inhibitors, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Lung Neoplasms genetics, Lung Neoplasms immunology, Drug Resistance, Neoplasm genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung genetics
- Abstract
Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and ∼50% of patients whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers of AR, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed AR to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNγ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia-activated pro-drug delayed AR to ICIs in murine Msh2 KO tumors. Thus, this work provides a rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition., (© 2024 Robles-Oteíza et al.)
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- 2025
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29. OST Catalytic Subunit Redundancy Enables Therapeutic Targeting of N-Glycosylation.
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Baro M, Lee H, Kelley V, Lou R, Phoomak C, Politi K, Zeiss CJ, Van Zandt M, and Contessa JN
- Abstract
Protein asparagine (N)-glycosylation, which promotes folding and trafficking of cell surface receptors such as the EGFR, has not been considered a viable target in oncology due to the essential and non-redundant enzymatic activities required for glycan synthesis and transfer. In mammals an exception to this rule is the presence of the oligosaccharyltransferase (OST) catalytic subunit paralogs, STT3A and STT3B. Here we delineate the chemical biology of OST inhibitors and develop an approach for limited inhibition of N-glycosylation optimized for downstream effects on EGFR. Small molecules with enhanced pharmacokinetic properties and preferences for STT3A or STT3B were synthesized, characterized in vitro , and advanced to in vivo testing. The lead from this series, NGI-189, causes tumor regression or growth delay of patient derived and TKI resistant EGFR-mutant lung cancer xenografts without toxicity. Together these results suggest that bioavailable OST inhibitors can be developed as therapeutic agents for oncology., Competing Interests: CONFLICT OF INTEREST J.C. and M.V. are listed as inventors on a patent application for the analogs reported in this manuscript.
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- 2024
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30. Utility of Electroencephalograms for Enhancing Clinical Care and Rehabilitation of Children with Acquired Brain Injury.
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Politi K, Weiss PL, Givony K, and Zion Golumbic E
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- Humans, Child, Child, Preschool, Electroencephalography methods, Brain Injuries rehabilitation, Brain Injuries physiopathology
- Abstract
The objective of this literature review was to present evidence from recent studies and applications focused on employing electroencephalogram (EEG) monitoring and methodological approaches during the rehabilitation of children with acquired brain injuries and their related effects. We describe acquired brain injury (ABI) as one of the most common reasons for cognitive and motor disabilities in children that significantly impact their safety, independence, and overall quality of life. These disabilities manifest as dysfunctions in cognition, gait, balance, upper-limb coordination, and hand dexterity. Rehabilitation treatment aims to restore and optimize these impaired functions to help children regain autonomy and enhance their quality of life. Recent advancements in monitoring technologies such as EEG measurements are increasingly playing a role in clinical diagnosis and management. A significant advantage of incorporating EEG technology in pediatric rehabilitation is its ability to provide continuous and objective quantitative monitoring of a child's neurological status. This allows for the real-time assessment of improvement or deterioration in brain function, including, but not limited to, a significant impact on motor function. EEG monitoring enables healthcare providers to tailor and adjust interventions-both pharmacological and rehabilitative-based on the child's current neurological status.
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- 2024
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31. Chitinase 3-like-1 (CHI3L1) in the pathogenesis of epidermal growth factor receptor mutant non-small cell lung cancer.
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Kamle S, Ma B, Schor G, Bailey M, Pham B, Cho I, Khan H, Azzoli C, Hofstetter M, Sadanaga T, Herbst R, Politi K, Lee CG, and Elias JA
- Abstract
Non-small cell lung cancer (NSCLC) accounts for 85 % of all lung cancers. In NSCLC, 10-20 % of Caucasian patients and 30-50 % of Asian patients have tumors with activating mutations in the Epidermal Growth Factor Receptor (EGFR). A high percentage of these patients exhibit favorable responses to treatment with tyrosine kinase inhibitors (TKI). Unfortunately, a majority of these patients develop therapeutic resistance with progression free survival lasting 9-18 months. The mechanisms that underlie the tumorigenic effects of EGFR and the ability of NSCLC to develop resistance to TKI therapies, however, are poorly understood. Here we demonstrate that CHI3L1 is produced by EGFR activation of normal epithelial cells, transformed epithelial cells with wild type EGFR and cells with cancer-associated, activating EGFR mutations. We also demonstrate that CHI3L1 auto-induces itself and feeds back to stimulate EGFR and its ligands via a STAT3-dependent mechanism(s). Highly specific antibodies against CHI3L1 (anti-CHI3L1/FRG) and TKI, individually and in combination, abrogated the effects of EGFR activation on CHI3L1 and the ability of CHI3L1 to stimulate the EGFR axis. Anti-CHI3L1 also interacted with osimertinib to reverse TKI therapeutic resistance and induce tumor cell death and inhibit pulmonary metastasis while stimulating tumor suppressor genes including KEAP1. CHI3L1 is a downstream target of EGFR that feeds back to stimulate and activate the EGFR axis. Anti-CHI3L1 is an exciting potential therapeutic for EGFR mutant NSCLC, alone and in combination with osimertinib or other TKIs., Competing Interests: Declaration of competing interest JAE is a cofounder of Elkurt Therapeutics and is a founder of and stockholder of, and serves on the Board of Directors for Ocean Biomedical, Inc., which develops inhibitors of 18 glycosyl hydrolases as therapeutics. CGL, BM and SK serve as consultants for Ocean Biomedical. Inc. JAE, CGL and SK have composition of matter and use patents relating to antibodies against CHI3L1. The other Brown University authors have declared that no conflict of interest exists. KP reports grants and consulting fees from AstraZeneca; grants from Roche/Genentech, D2G Oncology and Boehringer Ingelheim; and consulting fees from Jannssen; and a patent for EGFR(T790M) mutation testing issued, licensed, and with royalties paid from Molecular Diagnostics/Memorial Sloan Kettering Cancer Center., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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32. Author Correction: Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.
- Author
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Robichaux JP, Elamin YY, Tan Z, Carter BW, Zhang S, Liu S, Li S, Chen T, Poteete A, Estrada-Bernal A, Le AT, Truini A, Nilsson MB, Sun H, Roarty E, Goldberg SB, Brahmer JR, Altan M, Lu C, Papadimitrakopoulou V, Politi K, Doebele RC, Wong KK, and Heymach JV
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- 2024
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33. Xanthogranulomatous Pyelonephritis: A pooled quantitative analysis of published cases.
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Parrill AM, Tsiyer A, Fogel J, Gala D, Politi K, Patel H, Bhatt H, Alvarez-Betancourt A, Smith A, Kim Z, Cadet B, Nalesnik J, and Mahoney J
- Subjects
- Adult, Female, Humans, Male, Nephrectomy adverse effects, Nephrectomy statistics & numerical data, Nephrotomy adverse effects, Nephrotomy statistics & numerical data, Pyelonephritis, Xanthogranulomatous complications, Pyelonephritis, Xanthogranulomatous diagnosis, Pyelonephritis, Xanthogranulomatous mortality, Pyelonephritis, Xanthogranulomatous surgery
- Abstract
Xanthogranulomatous Pyelonephritis (XGP) is a serious and rare inflammatory disease of unknown etiology. This systematic review analyzes XGP cases. We performed a literature search for "Pyelonephritis, Xanthogranulomatous." The primary composite outcome was recovery with post-surgery complications, partial recovery, death, or chronic kidney disease. The secondary outcome was any presentation or treatment complication. Predictor variables consisted of demographics, history, symptoms, and diagnosis/management. Among the 251 patients, the mean age was 36.1 years, and 57.4% were female. The most common symptom and finding were fever (55.0%) and renal stones (53.8%), respectively. There were 15.5% with the composite outcome. There were 51.0% with any presentation or treatment complication. Multivariate logistic regression analysis for the composite outcome showed that kidney of both/horseshoe (OR:3.86, 95% CI:1.01, 14.73, p = 0.048), dialysis required (OR:8.64, 95% CI:2.27, 32.94, p = 0.002), and operative treatment of nephrostomy or nephrostomy followed by nephrectomy (OR:4.57, 95% CI:1.58, 13.17, p = 0.01) were each significantly associated with increased odds. Fever (OR:3.04, 95% CI:1.63, 5.67, p <0.001) and renal stones (OR:2.55, 95% CI:1.35, 4.81, p = 0.004) were each significantly associated with increased odds for any presentation/treatment complication. In conclusion, XGP patients with involvement of both or horseshoe kidneys, dialysis requirements, or treatment of nephrostomy or nephrostomy followed by nephrectomy may require aggressive treatment to mitigate poor patient outcomes.
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- 2024
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34. Overexpression of Malat1 drives metastasis through inflammatory reprogramming of the tumor microenvironment.
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Martinez-Terroba E, Plasek-Hegde LM, Chiotakakos I, Li V, de Miguel FJ, Robles-Oteiza C, Tyagi A, Politi K, Zamudio JR, and Dimitrova N
- Subjects
- Animals, Mice, Humans, Cell Line, Tumor, Gene Expression Regulation, Neoplastic immunology, Inflammation immunology, Inflammation genetics, Macrophages immunology, RNA, Long Noncoding genetics, Tumor Microenvironment immunology, Lung Neoplasms immunology, Lung Neoplasms genetics, Lung Neoplasms pathology, Lung Neoplasms secondary, Adenocarcinoma of Lung immunology, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung pathology, Chemokine CCL2 genetics, Neoplasm Metastasis
- Abstract
Expression of the long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 ( MALAT1 ) correlates with tumor progression and metastasis in many tumor types. However, the impact and mechanism of action by which MALAT1 promotes metastatic disease remain elusive. Here, we used CRISPR activation (CRISPRa) to overexpress MALAT1/Malat1 in patient-derived lung adenocarcinoma (LUAD) cell lines and in the autochthonous K-ras/p53 LUAD mouse model. Malat1 overexpression was sufficient to promote the progression of LUAD to metastatic disease in mice. Overexpression of MALAT1/Malat1 enhanced cell mobility and promoted the recruitment of protumorigenic macrophages to the tumor microenvironment through paracrine secretion of CCL2/Ccl2. Ccl2 up-regulation was the result of increased global chromatin accessibility upon Malat1 overexpression. Macrophage depletion and Ccl2 blockade counteracted the effects of Malat1 overexpression. These data demonstrate that a single lncRNA can drive LUAD metastasis through reprogramming of the tumor microenvironment.
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- 2024
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35. The Evolution of Mouse Models of Cancer: Past, Present, and Future.
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Abate-Shen C and Politi K
- Abstract
In the nearly 50 years since the original models of cancer first hit the stage, mouse models have become a major contributor to virtually all aspects of cancer research, and these have evolved well beyond simple transgenic or xenograft models to encompass a wide range of more complex models. As the sophistication of mouse models has increased, an explosion of new technologies has expanded the potential to both further develop and apply these models to address major challenges in cancer research. In the current era, cancer modeling has expanded to include nongermline genetically engineered mouse models (GEMMs), patient-derived models, organoids, and adaptations of the models better suited for cancer immunology research. New technologies that have transformed the field include the application of CRISPR-Cas9-mediated genome editing, in vivo imaging, and single-cell analysis to cancer modeling. Here, we provide a historical perspective on the evolution of mouse models of cancer, focusing on how far we have come in a relatively short time and how new technologies will shape the future development of mouse models of cancer., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)
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- 2024
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36. ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts.
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Hu B, Wiesehöfer M, de Miguel FJ, Liu Z, Chan LH, Choi J, Melnick MA, Arnal Estape A, Walther Z, Zhao D, Lopez-Giraldez F, Wurtz A, Cai G, Fan R, Gettinger S, Xiao A, Yan Q, Homer R, Nguyen DX, and Politi K
- Subjects
- Humans, ErbB Receptors genetics, Drug Resistance, Neoplasm genetics, Neoplasm Recurrence, Local drug therapy, Aniline Compounds pharmacology, Aniline Compounds therapeutic use, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Mutation, Basic Helix-Loop-Helix Transcription Factors genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Acrylamides, Indoles, Pyrimidines
- Abstract
The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKI). However, most of these responses are partial, with drug-tolerant residual disease remaining even at the time of maximal response. This residual disease can ultimately lead to relapses, which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived xenograft (PDX) models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the third-generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally distinct from bulk pretreatment tumor. Single-cell transcriptional profiling provided evidence of cells matching the profiles of drug-tolerant cells present in the pretreatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, ASCL1 conferred drug tolerance by initiating an epithelial-to-mesenchymal gene-expression program in permissive cellular contexts. This study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment, and why specific phenotypes are observed only in certain tumors., Significance: Analysis of residual disease following tyrosine kinase inhibitor treatment identified heterogeneous and context-specific mechanisms of drug tolerance in lung cancer that could lead to the development of strategies to forestall drug resistance. See related commentary by Rumde and Burns, p. 1188., (©2024 American Association for Cancer Research.)
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- 2024
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37. Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma.
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Kim IK, Diamond MS, Yuan S, Kemp SB, Kahn BM, Li Q, Lin JH, Li J, Norgard RJ, Thomas SK, Merolle M, Katsuda T, Tobias JW, Baslan T, Politi K, Vonderheide RH, and Stanger BZ
- Subjects
- Humans, Cell Line, Tumor, Neoplasm Recurrence, Local, Immunotherapy, Epithelial-Mesenchymal Transition genetics, Tumor Microenvironment, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal therapy, Carcinoma, Pancreatic Ductal metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms therapy, Pancreatic Neoplasms metabolism
- Abstract
Acquired resistance to immunotherapy remains a critical yet incompletely understood biological mechanism. Here, using a mouse model of pancreatic ductal adenocarcinoma (PDAC) to study tumor relapse following immunotherapy-induced responses, we find that resistance is reproducibly associated with an epithelial-to-mesenchymal transition (EMT), with EMT-transcription factors ZEB1 and SNAIL functioning as master genetic and epigenetic regulators of this effect. Acquired resistance in this model is not due to immunosuppression in the tumor immune microenvironment, disruptions in the antigen presentation machinery, or altered expression of immune checkpoints. Rather, resistance is due to a tumor cell-intrinsic defect in T-cell killing. Molecularly, EMT leads to the epigenetic and transcriptional silencing of interferon regulatory factor 6 (Irf6), rendering tumor cells less sensitive to the pro-apoptotic effects of TNF-α. These findings indicate that acquired resistance to immunotherapy may be mediated by programs distinct from those governing primary resistance, including plasticity programs that render tumor cells impervious to T-cell killing., (© 2024. The Author(s).)
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- 2024
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38. Co-Occurring Alterations in Multiple Tumor Suppressor Genes Are Associated With Worse Outcomes in Patients With EGFR-Mutant Lung Cancer.
- Author
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Stockhammer P, Grant M, Wurtz A, Foggetti G, Expósito F, Gu J, Zhao H, Choi J, Chung S, Li F, Walther Z, Dietz J, Duffield E, Gettinger S, Politi K, and Goldberg SB
- Subjects
- Humans, Protein Kinase Inhibitors therapeutic use, ErbB Receptors, Genes, Tumor Suppressor, Mutation, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Acrylamides, Aniline Compounds, Indoles, Pyrimidines
- Abstract
Introduction: Patients with metastatic EGFR-mutant NSCLC inevitably have disease progression while on tyrosine kinase inhibitor (TKI) therapy. Co-occurring tumor suppressor gene (TSG) alterations have been associated with poor outcomes, however, detailed analyses of their impact on patient outcomes are limited., Methods: Patients with EGFR-mutant NSCLC treated with EGFR TKIs who had tumor genomic profiling were included. Alterations in TP53 and five additional TSGs (RB1, NF1, ARID1A, BRCA1, and PTEN) were used to stratify the cohort into the following three subgroups: patients with tumors harboring a TP53 mutation plus a mutation in at least one additional TSG (TP53
mut /TSGmut ), those having a TP53 mutation without additional TSG mutations (TP53mut /TSGwt ), and those with TP53wt . Patient characteristics and clinical outcomes were assessed in two independent cohorts., Results: A total of 101 patients from the Yale Cancer Center and 182 patients from the American Association for Cancer Research Project GENIE database were included. In the Yale cohort, TP53 mutations were identified in 65 cases (64%), of which 23 were TP53mut /TSGmut and 42 were TP53mut /TSGwt . Although the presence of a TP53 mutation was associated with worse outcomes, the additional TSG alteration in TP53mut tumors identified a subset of patients associated with particularly aggressive disease and inferior clinical outcome in both the Yale and the GENIE cohorts. Specifically, in the Yale cohort for patients receiving first-line TKIs, those with TP53mut /TSGmut tumors had shorter progression-free survival (PFS) and overall survival (OS) than TP53mut /TSGwt (PFS: hazard ratio [HR] = 2.03, confidence interval [CI]: 1.12-3.69, p < 0.01, OS: HR = 1.58, CI: 0.82-3.04, p = 0.12) or TP53wt cases (PFS: HR 2.4, CI: 1.28-4.47, p < 0.001, OS: HR = 2.54, CI: 1.21-5.34, p < 0.005). Inferior outcomes in patients with TP53mut /TSGmut tumors were also found in those receiving osimertinib as second-line therapy. Similar findings were seen in patients in the GENIE cohort., Conclusions: Patients with TP53mut /TSGmut tumors represent a patient subgroup characterized by an aggressive disease phenotype and inferior outcomes on EGFR TKIs. This information is important for understanding the biological underpinnings of differential outcomes with TKI treatment and has implications for identifying patients who may benefit from additional therapeutic interventions beyond osimertinib monotherapy., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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39. EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth.
- Author
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Kuhlmann-Hogan A, Cordes T, Xu Z, Kuna RS, Traina KA, Robles-Oteíza C, Ayeni D, Kwong EM, Levy S, Globig AM, Nobari MM, Cheng GZ, Leibel SL, Homer RJ, Shaw RJ, Metallo CM, Politi K, and Kaech SM
- Abstract
The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation, which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy-resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth., Significance: Alternate strategies harnessing anticancer innate immunity are required for lung cancers with poor response rates to T cell-based immunotherapies. This study identifies a targetable, mutually supportive, metabolic relationship between macrophages and transformed epithelium, which is exploited by tumors to obtain metabolic and immunologic support to sustain proliferation and oncogenic signaling., (©2024 American Association for Cancer Research.)
- Published
- 2024
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40. The New NCI Precision Medicine Trials.
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Harris LN, Blanke CD, Erba HP, Ford JM, Gray RJ, LeBlanc ML, Hu-Lieskovan S, Litzow MR, Luger SM, Meric-Bernstam F, O'Dwyer PJ, Othus MKD, Politi K, Shepherd LE, Allegra CJ, Chen HX, Ivy SP, Korde LA, Little RF, McShane LM, Moscow JA, Patton DR, Thurin M, Yee LM, and Doroshow JH
- Subjects
- Humans, Precision Medicine methods, Medical Oncology methods, Neoplasms drug therapy, Neoplasms genetics, Neoplasms, Second Primary
- Abstract
Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First-generation trials like NCI-MATCH (Molecular Analysis for Therapy Choice) have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single-agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target. As such, newer approaches employing combinations of targeted therapy, or targeted therapy with standard therapies, need to be considered. The NCI has recently embarked on three second-generation precision medicine trials to address this need: ComboMATCH, iMATCH, and myeloMATCH. The design of these trials and necessary infrastructure are discussed in the following perspective., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
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41. Oncogenic context shapes the fitness landscape of tumor suppression.
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Blair LM, Juan JM, Sebastian L, Tran VB, Nie W, Wall GD, Gerceker M, Lai IK, Apilado EA, Grenot G, Amar D, Foggetti G, Do Carmo M, Ugur Z, Deng D, Chenchik A, Paz Zafra M, Dow LE, Politi K, MacQuitty JJ, Petrov DA, Winslow MM, Rosen MJ, and Winters IP
- Subjects
- Mice, Humans, Animals, Oncogenes genetics, Carcinogenesis genetics, Cell Transformation, Neoplastic genetics, Mutation, Proto-Oncogene Proteins p21(ras) genetics, Lung Neoplasms genetics, Lung Neoplasms pathology
- Abstract
Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged-the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context-and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors., (© 2023. Springer Nature Limited.)
- Published
- 2023
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42. Effect of Dietary Supplementation with a Mixture of Natural Antioxidants on Milk Yield, Composition, Oxidation Stability and Udder Health in Dairy Ewes.
- Author
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Karageorgou A, Tsafou M, Goliomytis M, Hager-Theodorides A, Politi K, and Simitzis P
- Abstract
Due to the limitations in the use of antibiotic agents, researchers are constantly seeking natural bioactive compounds that could benefit udder health status but also milk quality characteristics in dairy animals. The aim of the current study was therefore to examine the effects of a standardized mixture of plant bioactive components (MPBC) originated from thyme, anise and olive on milk yield, composition, oxidative stability and somatic cell count in dairy ewes. Thirty-six ewes approximately 75 days after parturition were randomly allocated into three experimental treatments, which were provided with three diets: control (C); without the addition of the mixture, B1; supplemented with MPBC at 0.05% and B2; supplemented with rumen protected MPBC at 0.025%. The duration of the experiment was 11 weeks, and milk production was weekly recorded, while individual milk samples for the determination of composition, oxidative stability, somatic cell count (SCC), pH and electric conductivity were collected. Every two weeks, macrophage, lymphocyte, and polymorphonuclear leukocyte counts were also determined in individual milk samples. It was observed that milk yield was the greatest in the B2 group, with significant differences within the seventh and ninth week ( p < 0.05), whereas no significant differences were found for milk composition, with the exception of the seventh week, when protein, lactose and non-fat solid levels were lower in MPBC groups ( p < 0.05). Oxidative stability was improved in the groups that received the MPBC, with significant differences at the third, seventh, tenth and eleventh week ( p < 0.05). SCC was also significantly lower at the second, eighth and ninth week in B2 compared to the other groups ( p < 0.05), while no significant effects on the macrophage, lymphocyte, and polymorphonuclear leukocyte counts were observed. In conclusion, the MPBC addition had a positive effect on sheep milk yield, oxidative stability and somatic cell count, without any negative effect on its composition.
- Published
- 2023
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43. PTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of Regulatory T Cells.
- Author
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Exposito F, Redrado M, Houry M, Hastings K, Molero-Abraham M, Lozano T, Solorzano JL, Sanz-Ortega J, Adradas V, Amat R, Redin E, Leon S, Legarra N, Garcia J, Serrano D, Valencia K, Robles-Oteiza C, Foggetti G, Otegui N, Felip E, Lasarte JJ, Paz-Ares L, Zugazagoitia J, Politi K, Montuenga L, and Calvo A
- Subjects
- Animals, Humans, Mice, B7-H1 Antigen metabolism, Immunotherapy methods, Phosphatidylinositol 3-Kinases metabolism, Tumor Microenvironment, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell metabolism, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms metabolism, PTEN Phosphohydrolase genetics, PTEN Phosphohydrolase metabolism, T-Lymphocytes, Regulatory, Drug Resistance, Neoplasm genetics
- Abstract
Immunotherapy resistance in non-small cell lung cancer (NSCLC) may be mediated by an immunosuppressive microenvironment, which can be shaped by the mutational landscape of the tumor. Here, we observed genetic alterations in the PTEN/PI3K/AKT/mTOR pathway and/or loss of PTEN expression in >25% of patients with NSCLC, with higher frequency in lung squamous carcinomas (LUSC). Patients with PTEN-low tumors had higher levels of PD-L1 and PD-L2 and showed worse progression-free survival when treated with immunotherapy. Development of a Pten-null LUSC mouse model revealed that tumors with PTEN loss were refractory to antiprogrammed cell death protein 1 (anti-PD-1), highly metastatic and fibrotic, and secreted TGFβ/CXCL10 to promote conversion of CD4+ lymphocytes into regulatory T cells (Treg). Human and mouse PTEN-low tumors were enriched in Tregs and expressed higher levels of immunosuppressive genes. Importantly, treatment of mice bearing Pten-null tumors with TLR agonists and anti-TGFβ antibody aimed to alter this immunosuppressive microenvironment and led to tumor rejection and immunologic memory in 100% of mice. These results demonstrate that lack of PTEN causes immunotherapy resistance in LUSCs by establishing an immunosuppressive tumor microenvironment that can be reversed therapeutically., Significance: PTEN loss leads to the development of an immunosuppressive microenvironment in lung cancer that confers resistance to anti-PD-1 therapy, which can be overcome by targeting PTEN loss-mediated immunosuppression., (©2023 American Association for Cancer Research.)
- Published
- 2023
- Full Text
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44. Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment.
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Chiorazzi M, Martinek J, Krasnick B, Zheng Y, Robbins KJ, Qu R, Kaufmann G, Skidmore Z, Juric M, Henze LA, Brösecke F, Adonyi A, Zhao J, Shan L, Sefik E, Mudd J, Bi Y, Goedegebuure SP, Griffith M, Griffith O, Oyedeji A, Fertuzinhos S, Garcia-Milian R, Boffa D, Detterbeck F, Dhanasopon A, Blasberg J, Judson B, Gettinger S, Politi K, Kluger Y, Palucka K, Fields RC, and Flavell RA
- Subjects
- Humans, Animals, Mice, Tumor Microenvironment, Medical Oncology, Disease Models, Animal, Vascular Endothelial Growth Factor A, Neoplasms
- Abstract
Background: Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors., Method: With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient's hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual's TME. We used this system to prospectively study tumor-immune interactions in patients with solid tumor., Results: Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent vascular endothelial growth factor A (VEGFA) signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth., Conclusions: Humanization of the interleukin 6 locus in MISTRG6 mice enhances HSPC engraftment, making it feasible to model tumor-immune interactions in an autologous manner from a bedside bone marrow aspirate. The TME from these autologous tumors display hallmarks of the human TME including innate and adaptive immune activation and provide a platform for preclinical drug testing., Competing Interests: Competing interests: HHMI lab heads have previously granted a non-exclusive CC BY 4.0 license to the public and a sublicensable license to HHMI in their research articles. Pursuant to those licenses, the author-accepted manuscript of this article can be made freely available under a CC BY 4.0 license immediately upon publication. RF is an advisor to GlaxoSmithKline, EvolveImmune, and Ventus Therapeutics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2023
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45. Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations.
- Author
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Grant MJ, Aredo JV, Starrett JH, Stockhammer P, van Alderwerelt van Rosenburgh IK, Wurtz A, Piper-Valillo AJ, Piotrowska Z, Falcon C, Yu HA, Aggarwal C, Scholes D, Patil T, Nguyen C, Phadke M, Li FY, Neal J, Lemmon MA, Walther Z, Politi K, and Goldberg SB
- Subjects
- Humans, ErbB Receptors genetics, Retrospective Studies, Mutation, Protein Kinase Inhibitors therapeutic use, Aniline Compounds therapeutic use, Sequence Deletion, Exons, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology
- Abstract
Purpose: The uncommon EGFR exon 19 deletion (ex19del), L747_A750>P, demonstrates reduced sensitivity to osimertinib compared with the common ex19del, E746_A750del in preclinical models. The clinical efficacy of osimertinib in patients with non-small cell lung cancer harboring L747_A750>P and other uncommon ex19dels is not known., Experimental Design: The AACR GENIE database was interrogated to characterize the frequency of individual ex19dels relative to other variants, and a multicenter retrospective cohort was used to compare clinical outcomes for patients with tumors harboring E746_A750del, L747_A750>P, and other uncommon ex19dels who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (≥2L)., Results: ex19dels comprised 45% of EGFR mutations, with 72 distinct variants ranging in frequency from 28.1% (E746_A750del) to 0.03%, with L747_A750>P representing 1.8% of the EGFR mutant cohort. In our multi-institutional cohort (N = 200), E746_A750del was associated with significantly prolonged progression-free survival (PFS) with 1L osimertinib versus L747_A750>P [median 21.3 months (95% confidence interval, 17.0-31.7) vs. 11.7 months (10.8-29.4); adjusted HR 0.52 (0.28-0.98); P = 0.043]. Osimertinib efficacy in patients with other uncommon ex19dels varied on the basis of the specific mutation present., Conclusions: The ex19del L747_A750>P is associated with inferior PFS compared with the common E746_A750del mutation in patients treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR ex19del subtypes could alter management of these patients in the future., (©2023 American Association for Cancer Research.)
- Published
- 2023
- Full Text
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46. Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy.
- Author
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Kim IK, Diamond M, Yuan S, Kemp S, Li Q, Lin J, Li J, Norgard R, Thomas S, Merolle M, Katsuda T, Tobias J, Politi K, Vonderheide R, and Stanger B
- Abstract
Acquired resistance to immune checkpoint immunotherapy remains a critical yet incompletely understood biological mechanism. Here, using a mouse model of pancreatic ductal adenocarcinoma (PDAC) to study tumor relapse following immunotherapy-induced responses, we found that tumors underwent an epithelial-to-mesenchymal transition (EMT) that resulted in reduced sensitivity to T cell-mediated killing. EMT-transcription factors (EMT-TFs) ZEB1 and SNAIL function as master genetic and epigenetic regulators of this tumor-intrinsic effect. Acquired resistance was not due to immunosuppression in the tumor immune microenvironment, disruptions in the antigen presentation machinery, or altered expression of immune checkpoints. Rather, EMT was associated with epigenetic and transcriptional silencing of interferon regulatory factor 6 (Irf6), which renders tumor cells less sensitive to the pro-apoptotic effects of TNF-α. These findings show how resistance to immunotherapy in PDAC can be acquired through plasticity programs that render tumor cells impervious to T cell killing., Competing Interests: Competing interests Dr. Stanger receives research funding from Boehringer-Ingelheim and previously served as a consultant to iTeos Therapeutics. Dr. Vonderheide reports receiving consulting fees from BMS, is an inventor on a licensed patents relating to cancer cellular immunotherapy and cancer vaccines and receives royalties from Children’s Hospital Boston for a licensed research-only monoclonal antibody.
- Published
- 2023
- Full Text
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47. An intrinsic purine metabolite AICAR blocks lung tumour growth by targeting oncoprotein mucin 1.
- Author
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Aftab F, Rodriguez-Fuguet A, Silva L, Kobayashi IS, Sun J, Politi K, Levantini E, Zhang W, Kobayashi SS, and Zhang WC
- Subjects
- Mice, Animals, Mucin-1 genetics, Mucin-1 metabolism, Lung metabolism, Mice, Transgenic, Oncogene Proteins, Purines, Cell Line, Tumor, ErbB Receptors genetics, ErbB Receptors metabolism, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
Background: Lung cancer cells overexpress mucin 1 (MUC1) and active subunit MUC1-CT. Although a peptide blocks MUC1 signalling, metabolites targeting MUC1 are not well studied. AICAR is a purine biosynthesis intermediate., Methods: Cell viability and apoptosis were measured in AICAR-treated EGFR-mutant and wild-type lung cells. AICAR-binding proteins were evaluated by in silico and thermal stability assays. Protein-protein interactions were visualised by dual-immunofluorescence staining and proximity ligation assay. AICAR-induced whole transcriptomic profile was determined by RNA sequencing. EGFR-TL transgenic mice-derived lung tissues were analysed for MUC1 expression. Organoids and tumours from patients and transgenic mice were treated with AICAR alone or in combination with JAK and EGFR inhibitors to evaluate treatment effects., Results: AICAR reduced EGFR-mutant tumour cell growth by inducing DNA damage and apoptosis. MUC1 was one of the leading AICAR-binding and degrading proteins. AICAR negatively regulated JAK signalling and JAK1-MUC1-CT interaction. Activated EGFR upregulated MUC1-CT expression in EGFR-TL-induced lung tumour tissues. AICAR reduced EGFR-mutant cell line-derived tumour formation in vivo. Co-treating patient and transgenic mouse lung-tissue-derived tumour organoids with AICAR and JAK1 and EGFR inhibitors reduced their growth., Conclusions: AICAR represses the MUC1 activity in EGFR-mutant lung cancer, disrupting protein-protein interactions between MUC1-CT and JAK1 and EGFR., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
48. EGFR + lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth.
- Author
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Kuhlmann-Hogan A, Cordes T, Xu Z, Traina KA, Robles-Oteíza C, Ayeni D, Kwong EM, Levy SR, Nobari M, Cheng GZ, Shaw R, Leibel SL, Metallo CM, Politi K, and Kaech SM
- Abstract
The limited efficacy of currently approved immunotherapies in EGFR-mutant lung adenocarcinoma (LUAD) underscores the need to better understand mechanisms governing local immunosuppression. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophages (TA-AM) to proliferate and support tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases T cell effector functions. These results reveal new therapeutic combinations for immunotherapy resistant EGFR-mutant LUADs and demonstrate how such cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.
- Published
- 2023
- Full Text
- View/download PDF
49. Challenges and opportunities for modeling aging and cancer.
- Author
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Anczuków O, Airhart S, Chuang JH, Coussens LM, Kuchel GA, Korstanje R, Li S, Lucido AL, McAllister SS, Politi K, Polyak K, Ratliff T, Ren G, Trowbridge JJ, Ucar D, and Palucka K
- Subjects
- Animals, Mice, Disease Models, Animal, Risk Factors, Aging, Neoplasms genetics
- Abstract
Age is among the main risk factors for cancer, and any cancer study in adults is faced with an aging tissue and organism. Yet, pre-clinical studies are carried out using young mice and are not able to address the impact of aging and associated comorbidities on disease biology and treatment outcomes. Here, we discuss the limitations of current mouse cancer models and suggest strategies for developing novel models to address these major gaps in knowledge and experimental approaches., Competing Interests: Declaration of interests K. Polyak serves on the scientific advisory boards of Novartis, Vividion Therapeutics, Ideya Biosciences, and Scorpion Therapeutics; holds equity options in Scorpion Therapeutics; has received honorarium from Astra-Zeneca, New Equilibrium Biosciences, and Roche in the past 12 months; and receives sponsored research funding from Novartis. K. Politi is coinventor on a patent for EGFRT790M mutation testing issued, licensed, and with royalties paid from Molecular Diagnostics/Memorial Sloan Kettering Cancer Center. She reports research funding to her institution from AstraZeneca, Roche/Genentech, Boehringer Ingelheim, and D2G Oncology, and consulting for AstraZeneca and Jannssen. K. Palucka is a cofounder of Guardian Bio and holds equity and receives research support from Guardian Bio. She is a member of the scientific advisory board and holds equity from Cue Biopharma. She received research support from Merck in the past. O.A. has received research support from Sanofi and Pacbio in the past. J.J.T. receives patent royalties from Fate Therapeutics. She has also received research support from H3 Biomedicine, Inc. L.M.C. reports consulting services for Cell Signaling Technologies, AbbVie, the Susan G. Komen Foundation, and Shasqi; has received reagent and/or research support from Cell Signaling Technologies, Syndax Pharmaceuticals, ZelBio, Inc., Hibercell, Inc., Acerta Pharma, Prospect Creek Foundation, the Susan G. Komen Foundation, and National Foundation for Cancer Research; and has participated in advisory boards for Syndax Pharmaceuticals, Carisma Therapeutics, Inc., CytomX Therapeutics, Inc., Kineta, Inc., Hibercell, Inc., Cell Signaling Technologies, Alkermes, Inc., Genenta Sciences, Pio Therapeutics, Pty., Ltd., PDX Pharmaceuticals, Inc., NextCure, Guardian Bio, the AstraZeneca Partner of Choice Network, the Lustgarten Foundation, and the NIH/NCI-Frederick National Laboratory Advisory Committee., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
50. Overexpressed Malat1 Drives Metastasis through Inflammatory Reprogramming of Lung Adenocarcinoma Microenvironment.
- Author
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Mart Nez-Terroba E, de Miguel FJ, Li V, Robles-Oteiza C, Politi K, Zamudio JR, and Dimitrova N
- Abstract
Metastasis is the main cause of cancer deaths but the molecular events leading to metastatic dissemination remain incompletely understood. Despite reports linking aberrant expression of long noncoding RNAs (lncRNAs) with increased metastatic incidence , in vivo evidence establishing driver roles for lncRNAs in metastatic progression is lacking. Here, we report that overexpression of the metastasis-associated lncRNA Malat1 (metastasis-associated lung adenocarcinoma transcript 1) in the autochthonous K-ras/p53 mouse model of lung adenocarcinoma (LUAD) is sufficient to drive cancer progression and metastatic dissemination. We show that increased expression of endogenous Malat1 RNA cooperates with p53 loss to promote widespread LUAD progression to a poorly differentiated, invasive, and metastatic disease. Mechanistically, we observe that Malat1 overexpression leads to the inappropriate transcription and paracrine secretion of the inflammatory cytokine, Ccl2, to augment the mobility of tumor and stromal cells in vitro and to trigger inflammatory responses in the tumor microenvironment in vivo . Notably, Ccl2 blockade fully reverses cellular and organismal phenotypes of Malat1 overexpression. We propose that Malat1 overexpression in advanced tumors activates Ccl2 signaling to reprogram the tumor microenvironment to an inflammatory and pro-metastatic state.
- Published
- 2023
- Full Text
- View/download PDF
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