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1. CDK9 inhibition as an effective therapy for small cell lung cancer

Author

Valdez Capuccino, L., Kleitke, T., Szokol, B., Svajda, L., Martin, F., Bonechi, F., Krekó, M., Azami, S., Montinaro, A., Wang, Y., Nikolov, V., Kaiser, L., Bonasera, D., Saggau, J., Scholz, T., Schmitt, A., Beleggia, F., Reinhardt, H. C., George, J., Liccardi, G., Walczak, H., Tóvári, J., Brägelmann, J., Montero, J., Sos, M. L., Őrfi, L., and Peltzer, N.

Published
2024
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2. P04.04 Single cell transcriptomics reveals cancer associated fibroblasts enable modeling of tumor associated macrophage like phenotypes and treatment responses in primary colorectal cancer organoid cultures

Author

Kabiljo, J, primary, Theophil, A, additional, Homola, J, additional, Renner, A, additional, Karall, J, additional, Hartman, N, additional, Stang, S, additional, Tran, L, additional, Laengle, J, additional, Kulu, A, additional, Chen, A, additional, Fabits, M, additional, Atanasova, V, additional, Walczak, H, additional, Herndler-Brandstetter, D, additional, Egger, G, additional, Dolznig, H, additional, Kusienicka, A, additional, Farlik, M, additional, and Bergmann, M, additional

Published
2024
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3. Oncogenic KRAS sensitizes premalignant, but not malignant cells, to Noxa-dependent apoptosis through the activation of the MEK/ERK pathway.

Author

Ashworth, Alan, Conti, A, Majorini, MT, Elliott, R, Lord, CJ, Cancelliere, C, Bardelli, A, Seneci, P, Walczak, H, and Delia, D

Abstract

KRAS is mutated in about 20-25% of all human cancers and especially in pancreatic, lung and colorectal tumors. Oncogenic KRAS stimulates several pro-survival pathways, but it also triggers the trans-activation of pro-apoptotic genes. In our work, we show t

Published
2015

4. Laparoscopic ischemic conditioning of the stomach prior to esophagectomy induces gastric neo-angiogenesis

Author

Schiffmann, L.M., primary, de Groot, E., additional, Albert, M.C., additional, Quaas, A., additional, Pinto dos Santos, D., additional, Babic, B., additional, Fuchs, H.F., additional, Walczak, H., additional, Chon, S.-H., additional, Ruurda, J.P., additional, Kashkar, H., additional, Bruns, C.J., additional, Schröder, W., additional, and van Hillegersberg, R., additional

Published
2023
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5. Laparoscopic ischemic conditioning of the stomach prior to esophagectomy induces gastric neo-angiogenesis

Author

Cancer, MS CGO, MCS-team, Schiffmann, L. M., de Groot, E., Albert, M. C., Quaas, A., Pinto dos Santos, D., Babic, B., Fuchs, H. F., Walczak, H., Chon, S. H., Ruurda, J. P., Kashkar, H., Bruns, C. J., Schröder, W., van Hillegersberg, R., Cancer, MS CGO, MCS-team, Schiffmann, L. M., de Groot, E., Albert, M. C., Quaas, A., Pinto dos Santos, D., Babic, B., Fuchs, H. F., Walczak, H., Chon, S. H., Ruurda, J. P., Kashkar, H., Bruns, C. J., Schröder, W., and van Hillegersberg, R.

Published
2023

7. P09.18 TNF induction in essential for oncolytic influenza A virus induced cancer regression and tumor associated macrophage repolarization

Author

Homola, J, primary, Kabiljo, J, additional, Theophil, A, additional, Hartman, N, additional, Kovacs, I, additional, Karall, J, additional, Lechner, KE, additional, Klicka, C, additional, Laengle, J, additional, Fabits, M, additional, Atanasova, VS, additional, Dome, B, additional, Dolznig, H, additional, Egger, G, additional, Walczak, H, additional, and Bergamnn, M, additional

Published
2022
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10. TNF INDUCTION IN ESSENTIAL FOR ONCOLYTIC INFLUENZA A VIRUS INDUCED CANCER REGRESSION AND TUMOR ASSOCIATED MACROPHAGE REPOLARIZATION

Author

Homola, J., Kabiljo, J., Theophil, A., Hartman, N., Kovacs, I., Karall, J., Lechner, K. E., Klicka, C., Laengle, J., Fabits, M., Atanasova, V. S., Dome, B., Dolznig, H., Egger, G., Walczak, H., Bergamnn, M., Homola, J., Kabiljo, J., Theophil, A., Hartman, N., Kovacs, I., Karall, J., Lechner, K. E., Klicka, C., Laengle, J., Fabits, M., Atanasova, V. S., Dome, B., Dolznig, H., Egger, G., Walczak, H., and Bergamnn, M.

Published
2022

15. Contributors

Author

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
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16. Correction to: Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4 (Cell Death & Differentiation, (2008), 15, 4, (762-772), 10.1038/sj.cdd.4402305)

Author

Todaro M., Lombardo Y., Francipane M. G., Alea M. P., Cammareri P., Iovino F., Di Stefano A. B., Di Bernardo C., Agrusa A., Condorelli G., Walczak H., Stassi G., Todaro M., Lombardo Y., Francipane M.G., Alea M.P., Cammareri P., Iovino F., Di Stefano A.B., Di Bernardo C., Agrusa A., Condorelli G., Walczak H., and Stassi G.

Subjects
IL-4, apoptosis resistance
Abstract

We have only now noticed that in Fig. 3a, the immunohistochemical analysis of IL-4Rα on paraffin-embedded sections from breast is incorrect: IL-4 from breast was duplicated and used for the IL-4Rα staining. The correct Fig. 3a is given below.

Published
2019

27. An ex situ study of the adsorption of calcium phosphate from solution onto TiO2(110) and Al2O3(0001)

Author

Murphy, M, Walczak, M S, Hussain, H, Acres, M J, Muryn, C A, Thomas, A G, Silikas, N, Lindsay, R, and M. Murphy, M.S. Walczak, H. Hussain, M.J. Acres, C.A. Muryn, A.G. Thomas, N. Silikas, R. Lindsay

Subjects
Induction period, Inorganic chemistry, Nucleation, chemistry.chemical_element, 02 engineering and technology, Calcium, 010402 general chemistry, 01 natural sciences, Low Miller index single crystal surface, Adsorption, X-ray photoelectron spectroscopy, Materials Chemistry, Chemical preparation, Aqueous solution, Metal oxide, Chemistry, Atomic force microscopy, Surfaces and Interfaces, 021001 nanoscience & nanotechnology, Condensed Matter Physics, 0104 chemical sciences, Surfaces, Coatings and Films, Deposition surface composition, Film growth, 0210 nano-technology
Abstract

Ex situ atomic force microscopy and x-ray photoelectron spectroscopy are employed to characterise the adsorption of calcium phosphate from an aqueous solution of CaCl2.H2O and KH2PO4 onto rutile-TiO2(110) and α-Al2O3(0001). Prior to immersion, the substrates underwent wet chemical preparation to produce well-defined surfaces. Calcium phosphate adsorption is observed on both rutile-TiO2(110) and α-Al2O3(0001), with atomic force microscopy images indicating island-type growth. In contrast to other studies on less well-defined TiO2 and Al2O3 substrates, the induction period for calcium phosphate nucleation appears to be comparable on these two surfaces. - An ex situ study of the adsorption of calcium phosphate from solution onto TiO2(110) and Al2O3(0001)

Published
2016

29. T1 Loss of BAP1 function leads to TRAIL sensitivity in mesothelioma

Author

Kumar, N, primary, Kolluri, KK, additional, Alifrangis, C, additional, Ishii, Y, additional, Price, S, additional, Michaut, M, additional, Williams, S, additional, Barthorpe, S, additional, Lightfoot, H, additional, Busacca, S, additional, Sharkey, A, additional, Yuan, Z, additional, Sage, EK, additional, Vallath, S, additional, Le Quesne, J, additional, Tice, DA, additional, Alrifai, D, additional, von Karstedt, S, additional, Montinaro, A, additional, Guppy, N, additional, Waller, DA, additional, Nakas, A, additional, Good, R, additional, Holmes, A, additional, Walczak, H, additional, Fennell, DA, additional, Garnett, M, additional, Iorio, F, additional, Wessels, L, additional, McDermott, U, additional, and Janes, SM, additional

Published
2018
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30. LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L

Author

Taraborrelli, L, Peltzer, N, Montinaro, A, Kupka, S, Rieser, E, Hartwig, T, Sarr, A, Darding, M, Draber, P, Haas, TL, Akarca, A, Marafioti, T, Pasparakis, M, Bertin, J, Gough, PJ, Bouillet, P, Strasser, A, Leverkus, M, Silke, J, Walczak, H, Taraborrelli, L, Peltzer, N, Montinaro, A, Kupka, S, Rieser, E, Hartwig, T, Sarr, A, Darding, M, Draber, P, Haas, TL, Akarca, A, Marafioti, T, Pasparakis, M, Bertin, J, Gough, PJ, Bouillet, P, Strasser, A, Leverkus, M, Silke, J, and Walczak, H

Abstract

The linear ubiquitin chain assembly complex (LUBAC), composed of HOIP, HOIL-1 and SHARPIN, is required for optimal TNF-mediated gene activation and to prevent cell death induced by TNF. Here, we demonstrate that keratinocyte-specific deletion of HOIP or HOIL-1 (E-KO) results in severe dermatitis causing postnatal lethality. We provide genetic and pharmacological evidence that the postnatal lethal dermatitis in HoipE-KO and Hoil-1E-KO mice is caused by TNFR1-induced, caspase-8-mediated apoptosis that occurs independently of the kinase activity of RIPK1. In the absence of TNFR1, however, dermatitis develops in adulthood, triggered by RIPK1-kinase-activity-dependent apoptosis and necroptosis. Strikingly, TRAIL or CD95L can redundantly induce this disease-causing cell death, as combined loss of their respective receptors is required to prevent TNFR1-independent dermatitis. These findings may have implications for the treatment of patients with mutations that perturb linear ubiquitination and potentially also for patients with inflammation-associated disorders that are refractory to inhibition of TNF alone.

Published
2018

31. LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis

Author

Peltzer, N, Darding, M, Montinaro, A, Draber, P, Draberova, H, Kupka, S, Rieser, E, Fisher, A, Hutchinson, C, Taraborrelli, L, Hartwig, T, Lafont, E, Haas, TL, Shimizu, Y, Boiers, C, Sarr, A, Rickard, J, Alvarez-Diaz, S, Ashworth, MT, Beal, A, Enver, T, Bertin, J, Kaiser, W, Strasser, A, Silke, J, Bouillet, P, Walczak, H, Peltzer, N, Darding, M, Montinaro, A, Draber, P, Draberova, H, Kupka, S, Rieser, E, Fisher, A, Hutchinson, C, Taraborrelli, L, Hartwig, T, Lafont, E, Haas, TL, Shimizu, Y, Boiers, C, Sarr, A, Rickard, J, Alvarez-Diaz, S, Ashworth, MT, Beal, A, Enver, T, Bertin, J, Kaiser, W, Strasser, A, Silke, J, Bouillet, P, and Walczak, H

Abstract

The linear ubiquitin chain assembly complex (LUBAC) is required for optimal gene activation and prevention of cell death upon activation of immune receptors, including TNFR1 1 . Deficiency in the LUBAC components SHARPIN or HOIP in mice results in severe inflammation in adulthood or embryonic lethality, respectively, owing to deregulation of TNFR1-mediated cell death2-8. In humans, deficiency in the third LUBAC component HOIL-1 causes autoimmunity and inflammatory disease, similar to HOIP deficiency, whereas HOIL-1 deficiency in mice was reported to cause no overt phenotype9-11. Here we show, by creating HOIL-1-deficient mice, that HOIL-1 is as essential for LUBAC function as HOIP, albeit for different reasons: whereas HOIP is the catalytically active component of LUBAC, HOIL-1 is required for LUBAC assembly, stability and optimal retention in the TNFR1 signalling complex, thereby preventing aberrant cell death. Both HOIL-1 and HOIP prevent embryonic lethality at mid-gestation by interfering with aberrant TNFR1-mediated endothelial cell death, which only partially depends on RIPK1 kinase activity. Co-deletion of caspase-8 with RIPK3 or MLKL prevents cell death in Hoil-1-/- (also known as Rbck1-/-) embryos, yet only the combined loss of caspase-8 with MLKL results in viable HOIL-1-deficient mice. Notably, triple-knockout Ripk3-/-Casp8-/-Hoil-1-/- embryos die at late gestation owing to haematopoietic defects that are rescued by co-deletion of RIPK1 but not MLKL. Collectively, these results demonstrate that both HOIP and HOIL-1 are essential LUBAC components and are required for embryogenesis by preventing aberrant cell death. Furthermore, they reveal that when LUBAC and caspase-8 are absent, RIPK3 prevents RIPK1 from inducing embryonic lethality by causing defects in fetal haematopoiesis.

Published
2018

32. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Author

Galluzzi, L, Vitale, I, Aaronson, SA, Abrams, JM, Adam, D, Agostinis, P, Alnemri, ES, Altucci, L, Amelio, I, Andrews, DW, Annicchiarico-Petruzzelli, M, Antonov, AV, Arama, E, Baehrecke, EH, Barlev, NA, Bazan, NG, Bernassola, F, Bertrand, MJM, Bianchi, K, Blagosklonny, MV, Blomgren, K, Borner, C, Boya, P, Brenner, C, Campanella, M, Candi, E, Carmona-Gutierrez, D, Cecconi, F, Chan, FK-M, Chandel, NS, Cheng, EH, Chipuk, JE, Cidlowski, JA, Ciechanover, A, Cohen, GM, Conrad, M, Cubillos-Ruiz, JR, Czabotar, PE, D'Angiolella, V, Dawson, TM, Dawson, VL, De laurenzi, V, De Maria, R, Debatin, K-M, DeBerardinis, RJ, Deshmukh, M, Di Daniele, N, Di Virgilio, F, Dixit, VM, Dixon, SJ, Duckett, CS, Dynlacht, BD, El-Deiry, WS, Elrod, JW, Fimia, GM, Fulda, S, Garcia-Saez, AJ, Garg, AD, Garrido, C, Gavathiotis, E, Golstein, P, Gottlieb, E, Green, DR, Greene, LA, Gronemeyer, H, Gross, A, Hajnoczky, G, Hardwick, JM, Harris, IS, Hengartner, MO, Hetz, C, Ichijo, H, Jaattela, M, Joseph, B, Jost, PJ, Juin, PP, Kaiser, WJ, Karin, M, Kaufmann, T, Kepp, O, Kimchi, A, Kitsis, RN, Klionsky, DJ, Knight, RA, Kumar, S, Lee, SW, Lemasters, JJ, Levine, B, Linkermann, A, Lipton, SA, Lockshin, RA, Lopez-Otin, C, Lowe, SW, Luedde, T, Lugli, E, MacFarlane, M, Madeo, F, Malewicz, M, Malorni, W, Manic, G, Marine, J-C, Martin, SJ, Martinou, J-C, Medema, JP, Mehlen, P, Meier, P, Melino, S, Miao, EA, Molkentin, JD, Moll, UM, Munoz-Pinedo, C, Nagata, S, Nunez, G, Oberst, A, Oren, M, Overholtzer, M, Pagano, M, Panaretakis, T, Pasparakis, M, Penninger, JM, Pereira, DM, Pervaiz, S, Peter, ME, Piacentini, M, Pinton, P, Prehn, JHM, Puthalakath, H, Rabinovich, GA, Rehm, M, Rizzuto, R, Rodrigues, CMP, Rubinsztein, DC, Rudel, T, Ryan, KM, Sayan, E, Scorrano, L, Shao, F, Shi, Y, Silke, J, Simon, H-U, Sistigu, A, Stockwell, BR, Strasser, A, Szabadkai, G, Tait, SWG, Tang, D, Tavernarakis, N, Thorburn, A, Tsujimoto, Y, Turk, B, Vanden Berghe, T, Vandenabeele, P, Heiden, MGV, Villunger, A, Virgin, HW, Vousden, KH, Vucic, D, Wagner, EF, Walczak, H, Wallach, D, Wang, Y, Wells, JA, Wood, W, Yuan, J, Zakeri, Z, Zhivotovsky, B, Zitvogel, L, Melino, G, Kroemer, G, Galluzzi, L, Vitale, I, Aaronson, SA, Abrams, JM, Adam, D, Agostinis, P, Alnemri, ES, Altucci, L, Amelio, I, Andrews, DW, Annicchiarico-Petruzzelli, M, Antonov, AV, Arama, E, Baehrecke, EH, Barlev, NA, Bazan, NG, Bernassola, F, Bertrand, MJM, Bianchi, K, Blagosklonny, MV, Blomgren, K, Borner, C, Boya, P, Brenner, C, Campanella, M, Candi, E, Carmona-Gutierrez, D, Cecconi, F, Chan, FK-M, Chandel, NS, Cheng, EH, Chipuk, JE, Cidlowski, JA, Ciechanover, A, Cohen, GM, Conrad, M, Cubillos-Ruiz, JR, Czabotar, PE, D'Angiolella, V, Dawson, TM, Dawson, VL, De laurenzi, V, De Maria, R, Debatin, K-M, DeBerardinis, RJ, Deshmukh, M, Di Daniele, N, Di Virgilio, F, Dixit, VM, Dixon, SJ, Duckett, CS, Dynlacht, BD, El-Deiry, WS, Elrod, JW, Fimia, GM, Fulda, S, Garcia-Saez, AJ, Garg, AD, Garrido, C, Gavathiotis, E, Golstein, P, Gottlieb, E, Green, DR, Greene, LA, Gronemeyer, H, Gross, A, Hajnoczky, G, Hardwick, JM, Harris, IS, Hengartner, MO, Hetz, C, Ichijo, H, Jaattela, M, Joseph, B, Jost, PJ, Juin, PP, Kaiser, WJ, Karin, M, Kaufmann, T, Kepp, O, Kimchi, A, Kitsis, RN, Klionsky, DJ, Knight, RA, Kumar, S, Lee, SW, Lemasters, JJ, Levine, B, Linkermann, A, Lipton, SA, Lockshin, RA, Lopez-Otin, C, Lowe, SW, Luedde, T, Lugli, E, MacFarlane, M, Madeo, F, Malewicz, M, Malorni, W, Manic, G, Marine, J-C, Martin, SJ, Martinou, J-C, Medema, JP, Mehlen, P, Meier, P, Melino, S, Miao, EA, Molkentin, JD, Moll, UM, Munoz-Pinedo, C, Nagata, S, Nunez, G, Oberst, A, Oren, M, Overholtzer, M, Pagano, M, Panaretakis, T, Pasparakis, M, Penninger, JM, Pereira, DM, Pervaiz, S, Peter, ME, Piacentini, M, Pinton, P, Prehn, JHM, Puthalakath, H, Rabinovich, GA, Rehm, M, Rizzuto, R, Rodrigues, CMP, Rubinsztein, DC, Rudel, T, Ryan, KM, Sayan, E, Scorrano, L, Shao, F, Shi, Y, Silke, J, Simon, H-U, Sistigu, A, Stockwell, BR, Strasser, A, Szabadkai, G, Tait, SWG, Tang, D, Tavernarakis, N, Thorburn, A, Tsujimoto, Y, Turk, B, Vanden Berghe, T, Vandenabeele, P, Heiden, MGV, Villunger, A, Virgin, HW, Vousden, KH, Vucic, D, Wagner, EF, Walczak, H, Wallach, D, Wang, Y, Wells, JA, Wood, W, Yuan, J, Zakeri, Z, Zhivotovsky, B, Zitvogel, L, Melino, G, and Kroemer, G

Abstract

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

Published
2018

33. TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis

Author

Singh, HD, Otano, I, Rombouts, K, Singh, KP, Peppa, D, Gill, US, Böttcher, K, Kennedy, PTF, Oben, J, Pinzani, M, Walczak, H, Fusai, G, Rosenberg, WMC, and Maini, MK

Subjects
Science, Antibodies, Monoclonal, Apoptosis, GPI-Linked Proteins, Article, Killer Cells, Natural, TNF-Related Apoptosis-Inducing Ligand, Receptors, TNF-Related Apoptosis-Inducing Ligand, Tumor Necrosis Factor Decoy Receptors, Liver, Hepatic Stellate Cells, Receptors, Tumor Necrosis Factor, Member 10c, Medicine, Humans, RNA Interference, RNA, Small Interfering, Cells, Cultured
Abstract

The TRAIL pathway can mediate apoptosis of hepatic stellate cells to promote the resolution of liver fibrosis. However, TRAIL has the capacity to bind to regulatory receptors in addition to death-inducing receptors; their differential roles in liver fibrosis have not been investigated. Here we have dissected the contribution of regulatory TRAIL receptors to apoptosis resistance in primary human hepatic stellate cells (hHSC). hHSC isolated from healthy margins of liver resections from different donors expressed variable levels of TRAIL-R2/3/4 (but negligible TRAIL-R1) ex vivo and after activation. The apoptotic potential of TRAIL-R2 on hHSC was confirmed by lentiviral-mediated knockdown. A functional inhibitory role for TRAIL-R3/4 was revealed by shRNA knockdown and mAb blockade, showing that these regulatory receptors limit apoptosis of hHSC in response to both oligomerised TRAIL and NK cells. A close inverse ex vivo correlation between hHSC TRAIL-R4 expression and susceptibility to apoptosis underscored its central regulatory role. Our data provide the first demonstration of non-redundant functional roles for the regulatory TRAIL receptors (TRAIL-R3/4) in a physiological setting. The potential for these inhibitory TRAIL receptors to protect hHSC from apoptosis opens new avenues for prognostic and therapeutic approaches to the management of liver fibrosis.

Published
2017

34. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution

Author

Abbosh, C, Birkbak, NJ, Wilson, GA, Jamal-Hanjani, M, Constantin, T, Salari, R, Quesne, JL, Moore, DA, Veeriah, S, Rosenthal, R, Marafioti, T, Kirkizlar, E, Watkins, TBK, McGranahan, N, Ward, S, Martinson, L, Riley, J, Fraioli, F, Bakir, MA, GrÖnroos, E, Zambrana, F, Endozo, R, Bi, WL, Fennessy, FM, Sponer, N, Johnson, D, Laycock, J, Shafi, S, Czyzewska-Khan, J, Rowan, A, Chambers, T, Matthews, N, Turajlic, S, Hiley, C, Lee, SM, Forster, MD, Ahmad, T, Falzon, M, Borg, E, Lawrence, D, Hayward, M, Kolvekar, S, Panagiotopoulos, N, Janes, SM, Thakrar, R, Ahmed, A, Blackhall, F, Summers, Y, Hafez, D, Naik, A, Ganguly, A, Kareht, S, Shah, R, Joseph, L, Quinn, AM, Crosbie, P, Naidu, B, Middleton, G, Langman, G, Trotter, S, Nicolson, M, Remmen, H, Kerr, K, Chetty, M, Gomersall, L, Fennell, DA, Nakas, A, Rathinam, S, Anand, G, Khan, S, Russell, P, Ezhil, V, Ismail, B, Irvin-sellers, M, Prakash, V, Lester, JF, Kornaszewska, M, Attanoos, R, Adams, H, Davies, H, Oukrif, D, Akarca, AU, Hartley, JA, Lowe, HL, Lock, S, Iles, N, Bell, H, Ngai, Y, Elgar, G, Szallasi, Z, Schwarz, RF, Herrero, J, Stewart, A, Quezada, SA, Van Loo, P, Dive, C, Lin, CJ, Rabinowitz, M, Aerts, HJWL, Hackshaw, A, Shaw, JA, Zimmermann, BG, Swanton, C, Bosshard-Carter, L, Goh, G, Gorman, P, Murugaesu, N, Hynds, RE, Wilson, G, Horswell, S, Al Bakir, M, Mitter, R, Escudero, M, Xu, H, Goldman, J, Stone, RK, Denner, T, Biggs, J, Costa, M, Begum, S, Phillimore, B, Nye, E, Graca, S, Joshi, K, Furness, A, Aissa, AB, Wong, YNS, Georgiou, A, Quezada, S, Simeon, C, Hector, G, Smith, A, Aranda, M, Novelli, M, Forster, M, Papadatos-Pastos, D, Carnell, D, Mendes, R, George, J, Navani, N, Taylor, M, Choudhary, J, Califano, R, Taylor, P, Krysiak, P, Rammohan, K, Fontaine, E, Booton, R, Evison, M, Moss, S, Idries, F, Bishop, P, Chaturved, A, Marie Quinn, A, Doran, H, leek, A, Harrison, P, Moore, K, Waddington, R, Novasio, J, Rogan, J, Smith, E, Tugwood, J, Brady, G, Rothwell, DG, Chemi, F, Pierce, J, Gulati, S, Bellamy, M, Bancroft, H, Kerr, A, Kadiri, S, Webb, J, Djearaman, M, Fennell, D, Le Quesne, J, Moore, D, Thomas, A, Walter, H, Monteiro, W, Marshall, H, Nelson, L, Bennett, J, Primrose, L, Amadi, A, Palmer, S, Miller, J, Buchan, K, Lester, J, Edwards, A, Morgan, F, Verjee, A, MacKenzie, M, Wilcox, M, Smith, S, Gower, N, Ottensmeier, C, Chee, S, Johnson, B, Alzetani, A, Shaw, E, Lim, E, De Sousa, P, Tavares Barbosa, M, Bowman, A, Jordan, S, Rice, A, Raubenheimer, H, Proli, C, Elena Cufari, M, Ronquillo, JC, Kwayie, A, Bhayani, H, Hamilton, M, Bakar, Y, Mensah, N, Ambrose, L, Devaraj, A, Buderi, S, Finch, J, Azcarate, L, Chavan, H, Green, S, Mashinga, H, Nicholson, AG, Lau, K, Sheaff, M, Schmid, P, Conibear, J, Light, T, Horey, T, Danson, S, Bury, J, Edwards, J, Hill, J, Matthews, S, Kitsanta, Y, Suvarna, K, Fisher, P, Keerio, AD, Shackcloth, M, Gosney, J, Postmus, P, Feeney, S, Asante-Siaw, J, Constatin, T, Zimmermann, B, Dentro, S, Dessimoz, C, Shiu, K-K, Bridgewater, J, Hochauser, D, Beck, S, Parker, P, Walczak, H, Enver, T, Proctor, I, Sinclair, R, Lok, C-W, Mitchison, M, Trevisan, G, Lynch, M, Brandner, S, Gishen, F, Tookman, A, Stone, P, Sterling, C, Larkin, J, Attard, G, Eeles, R, Foster, C, Bova, S, Sottoriva, A, Chowdhury, S, Ashish, C, Spicer, J, Stares, M, Lynch, J, Caldas, C, Brenton, J, Fitzgerald, R, Jimenez-Linan, M, Provenzano, E, Cluroe, A, Stewart, G, Watts, C, Gilbertson, R, McDermott, U, Tavare, S, Maughan, T, Tomlinson, I, Campbell, P, McNeish, I, Biankin, A, Chambers, A, Fraser, S, Oien, K, Krebs, M, Marais, R, Carter, L, Nonaka, D, Dhomen, N, Shaw, J, Baijal, S, Tanchel, B, Collard, M, Cockcroft, P, Taylor, J, Colloby, P, Olisemeke, B, Wilson, R, Harrison, D, Loda, M, Flanagan, A, McKenzie, M, Lederman, J, Sharp, A, and Farrelly, L

Subjects
0301 basic medicine, Oncology, Lung Neoplasms, IMPACT, Biopsy, DNA Mutational Analysis, Drug resistance, Metastasis, 0302 clinical medicine, Limit of Detection, Carcinoma, Non-Small-Cell Lung, Medicine, Neoplasm Metastasis, Early Detection of Cancer, Multidisciplinary, medicine.diagnostic_test, Phylogenetic tree, DNA, Neoplasm, STATISTICS, 3. Good health, Tumor Burden, Multidisciplinary Sciences, Cell Tracking, PEACE consortium, 030220 oncology & carcinogenesis, Disease Progression, Science & Technology - Other Topics, medicine.medical_specialty, CARCINOMA, Tumour heterogeneity, General Science & Technology, Early detection, Evolution, Molecular, 03 medical and health sciences, Internal medicine, MD Multidisciplinary, Carcinoma, Humans, Cell Lineage, Lung cancer, Postoperative Care, Science & Technology, MUTATIONS, TRACERx consortium, business.industry, CIRCULATING TUMOR DNA, Reproducibility of Results, medicine.disease, R1, NEGATIVE BREAST-CANCER, Clone Cells, 030104 developmental biology, Drug Resistance, Neoplasm, UPTAKE RATIO, Immunology, FDG PET, Neoplasm Recurrence, Local, business, Multiplex Polymerase Chain Reaction
Abstract

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

Published
2017

35. Getting TRAIL back on track for cancer therapy

Author

Lemke, J, von Karstedt, S, Zinngrebe, J, and Walczak, H

Subjects
TNF-Related Apoptosis-Inducing Ligand, Neoplasms, Animals, Humans, Review
Abstract

Unlike other members of the TNF superfamily, the TNF-related apoptosis-inducing ligand (TRAIL, also known as Apo2L) possesses the unique capacity to induce apoptosis selectively in cancer cells in vitro and in vivo. This exciting discovery provided the basis for the development of TRAIL-receptor agonists (TRAs), which have demonstrated robust anticancer activity in a number of preclinical studies. Subsequently initiated clinical trials testing TRAs demonstrated, on the one hand, broad tolerability but revealed, on the other, that therapeutic benefit was rather limited. Several factors that are likely to account for TRAs' sobering clinical performance have since been identified. First, because of initial concerns over potential hepatotoxicity, TRAs with relatively weak agonistic activity were selected to enter clinical trials. Second, although TRAIL can induce apoptosis in several cancer cell lines, it has now emerged that many others, and importantly, most primary cancer cells are resistant to TRAIL monotherapy. Third, so far patients enrolled in TRA-employing clinical trials were not selected for likelihood of benefitting from a TRA-comprising therapy on the basis of a valid(ated) biomarker. This review summarizes and discusses the results achieved so far in TRA-employing clinical trials in the light of these three shortcomings. By integrating recent insight on apoptotic and non-apoptotic TRAIL signaling in cancer cells, we propose approaches to introduce novel, revised TRAIL-based therapeutic concepts into the cancer clinic. These include (i) the use of recently developed highly active TRAs, (ii) the addition of efficient, but cancer-cell-selective TRAIL-sensitizing agents to overcome TRAIL resistance and (iii) employing proteomic profiling to uncover resistance mechanisms. We envisage that this shall enable the design of effective TRA-comprising therapeutic concepts for individual cancer patients in the future.

Published
2014

39. Opposing role of tumor necrosis factor receptor 1 signaling in T cell-mediated hepatitis and bacterial infection in mice

Author

Wroblewski R, Armaka M, Kondylis V, Pasparakis M, Walczak H, Mittrücker HW, Schramm C, Lohse AW, Kollias G, and Ehlken H

Abstract

Death receptor (DR) ligands such as tumor necrosis factor (TNF) have been identified as fundamental mediators of liver damage both in mouse models and in humans. While the essential site of function of DR signaling is conceivably the hepatocyte, a systematic analysis is missing. Using mice with conditional gene ablation, we analyzed the tissue-specific function of DR signaling in T cell-dependent (concanavalin A) and independent (lipopolysaccharide/galactosamine) hepatitis and in models of bacterial infection (Listeria monocytogenes, lipopolysaccharide). We report that lipopolysaccharide/galactosamine-induced liver injury depends on hepatocyte-intrinsic TNF receptor 1 (p55, TNFR1). In contrast, we show that T cell-induced hepatitis was independent of TNFR1 signaling in hepatocytes, T cells, or endothelial cells. Moreover, T cell-induced hepatitis was independent of hepatocyte-intrinsic Fas-associated protein with death domain, TNF-related apoptosis-inducing ligand receptor, or Fas signaling. Instead, concanavalin A-induced hepatitis was completely prevented in mice with myeloid-derived cell (MDC)-specific deletion of TNFR1. Significantly, however, mice lacking TNFR1 in MDCs succumbed to listeria infection, although they displayed similar sensitivity toward endotoxin-induced septic shock when compared to control mice. These results suggest that TNFR1 signaling in MDCs is a critical mediator of both the detrimental and the protective functions of TNF in T cell-induced hepatitis and bacterial infection, respectively. CONCLUSION: The critical site of action of DRs is completely dependent on the nature of hepatitis; the data specify MDCs as the essential cell type of TNFR1 function in T cell-mediated hepatitis and in the response to listeria, thereby identifying the opposing role of MDC TNFR1 in autoimmunity and bacterial infection. (Hepatology 2016).

Published
2016

41. The linear ubiquitin chain assembly complex: a new function in thymic T cell differentiation and regulatory T cell homeostasis

Author

Teh, C, Lalaoui, N, Jain, R, Policheni, A, Heinlein, M, Alvarez-Diaz, S, Rieser, E, Deuser, S, Koay, H-F, Hu, Y, Kupresanin, F, O'Reilly, L, Godfrey, D, Smyth, G, Bouillet, P, Strasser, A, Walczak, H, Silke, J, Gray, D, Teh, C, Lalaoui, N, Jain, R, Policheni, A, Heinlein, M, Alvarez-Diaz, S, Rieser, E, Deuser, S, Koay, H-F, Hu, Y, Kupresanin, F, O'Reilly, L, Godfrey, D, Smyth, G, Bouillet, P, Strasser, A, Walczak, H, Silke, J, and Gray, D

Published
2016

42. Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis

Author

Teh, CE, Lalaoui, N, Jain, R, Policheni, AN, Heinlein, M, Alvarez-Diaz, S, Sheridan, JM, Rieser, E, Deuser, S, Darding, M, Koay, H-F, Hu, Y, Kupresanin, F, O'Reilly, LA, Godfrey, DI, Smyth, GK, Bouillet, P, Strasser, A, Walczak, H, Silke, J, Gray, DHD, Teh, CE, Lalaoui, N, Jain, R, Policheni, AN, Heinlein, M, Alvarez-Diaz, S, Sheridan, JM, Rieser, E, Deuser, S, Darding, M, Koay, H-F, Hu, Y, Kupresanin, F, O'Reilly, LA, Godfrey, DI, Smyth, GK, Bouillet, P, Strasser, A, Walczak, H, Silke, J, and Gray, DHD

Abstract

The linear ubiquitin chain assembly complex (LUBAC) is essential for innate immunity in mice and humans, yet its role in adaptive immunity is unclear. Here we show that the LUBAC components HOIP, HOIL-1 and SHARPIN have essential roles in late thymocyte differentiation, FOXP3+ regulatory T (Treg)-cell development and Treg cell homeostasis. LUBAC activity is not required to prevent TNF-induced apoptosis or necroptosis but is necessary for the transcriptional programme of the penultimate stage of thymocyte differentiation. Treg cell-specific ablation of HOIP causes severe Treg cell deficiency and lethal immune pathology, revealing an ongoing requirement of LUBAC activity for Treg cell homeostasis. These data reveal stage-specific requirements for LUBAC in coordinating the signals required for T-cell differentiation.

Published
2016

43. Linear ubiquitination prevents inflammation and regulates immune signalling

Author

Gerlach, B, Cordier, S M, Schmukle, A C, Emmerich, C H, Rieser, E, Haas, T L, Webb, A I, Rickard, J A, Anderton, H, Wong, W W L, Nachbur, U, Gangoda, L, Warnken, U, Purcell, A W, Silke, J, Walczak, H, University of Zurich, and Walczak, H

Subjects
1000 Multidisciplinary, 570 Life sciences, biology, 610 Medicine & health, 10263 Institute of Experimental Immunology
Published
2011

45. Apoptosis resistance in ethithelial tumors is mediated by tumor-cell-derived interleukin-4

Author

Todaro M, Lombardo Y, Francipane MG, Alea MP, Cammareri P, Iovino F, Di Stefano AB, Di Bernardo C, Agrusa A, Walczak H, Stassi G., CONDORELLI, GEROLAMA, Todaro, M, Lombardo, Y, Francipane, Mg, Alea, Mp, Cammareri, P, Iovino, F, Di Stefano, Ab, Di Bernardo, C, Agrusa, A, Condorelli, Gerolama, Walczak, H, and Stassi, G.

Subjects
apoptosis resistance cancer IL4
Abstract

We investigated the mechanisms involved in the resistance to cell death observed in epithelial cancers. Here, we identify that primary epithelial cancer cells from colon, breast and lung carcinomas express high levels of the antiapoptotic proteins PED, cFLIP, Bcl-xL and Bcl-2. These cancer cells produced interleukin-4 (IL-4), which amplified the expression levels of these antiapoptotic proteins and prevented cell death induced upon exposure to TRAIL or other drug agents. IL-4 blockade resulted in a significant decrease in the growth rate of epithelial cancer cells and sensitized them, both in vitro and in vivo, to apoptosis induction by TRAIL and chemotherapy via downregulation of the antiapoptotic factors PED, cFLIP, Bcl-xL and Bcl-2. Furthermore, we provide evidence that exogenous IL-4 was able to upregulate the expression levels of these antiapoptotic proteins and potently stabilized the growth of normal epithelial cells rendering them apoptosis resistant. In conclusion, IL-4 acts as an autocrine survival factor in epithelial cells. Our results indicate that inhibition of IL-4/IL-4R signaling may serve as a novel treatment for epithelial cancers.

Published
2008

46. Activation of KIT modulates the function of tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) in mast cells

Author

Foerster, A., Grotha, S. P., Seeger, J. M., Rabenhorst, A., Gehring, M., Raap, U., Letard, S., Dubreuil, P., Kashkar, H., Walczak, H., Roers, A., Hartmann, K., Foerster, A., Grotha, S. P., Seeger, J. M., Rabenhorst, A., Gehring, M., Raap, U., Letard, S., Dubreuil, P., Kashkar, H., Walczak, H., Roers, A., and Hartmann, K.

Abstract

BackgroundMastocytosis is characterized by the accumulation of mast cells (MCs) associated with activating mutations of KIT. Tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL-Rs) are preferentially expressed on neoplastic cells and induce the extrinsic apoptotic pathway. Recent studies reported on the expression of TRAIL-Rs and TRAIL-induced apoptosis in cultured human MCs, which depend on stem cell factor (SCF)-induced or constitutive KIT activation. Material and methodsWe sought to further define the impact of TRAIL-Rs on MCs in vivo and in vitro. Using Cre/loxP recombination, we generated mice with MC-specific and ubiquitous knockout of TRAIL-R. In these mice, anaphylaxis and numbers of MCs were investigated. We also explored the expression and function of TRAIL-Rs in cultured murine and human MCs upon activation of KIT. By conducting immunofluorescence staining, we analyzed the expression of TRAIL-Rs in MCs infiltrating the bone marrow of patients with mastocytosis. ResultsMC-specific deletion of TRAIL-R was associated with a slight, but significant increase in anaphylaxis. Numbers of MCs in MC-specific knockouts of TRAIL-R were comparable to controls. Whereas cultured IL-3-dependent murine MCs from wild-type mice were resistant to TRAIL-induced apoptosis, SCF-stimulated MCs underwent apoptosis in response to TRAIL. Interestingly, activating KIT mutations also promoted sensitivity to TRAIL-mediated apoptosis in human MCs. In line with these findings, MCs infiltrating the bone marrow of patients with mastocytosis expressed TRAIL-R1. ConclusionsActivation of KIT regulates the function of TRAIL-Rs in MCs. TRAIL-R1 may represent an attractive diagnostic and therapeutic target in diseases associated with KIT mutations, such as mastocytosis.

Published
2015

47. Essential versus accessory aspects of cell death: Recommendations of the NCCD 2015

Author

Galluzzi, L., Bravo-San Pedro, J. M., Vitale, Ilio, Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., Baehrecke, E. H., Bazan, N. G., Bertrand, M. J., Bianchi, K., Blagosklonny, M. V., Blomgren, K., Borner, C., Bredesen, D. E., Brenner, C., Campanella, M., Candi, E., Cecconi, F., Chan, F. K., Chandel, N. S., Cheng, E. H., Chipuk, J. E., Cidlowski, J. A., Ciechanover, A., Dawson, T. M., Dawson, V. L., De Laurenzi, V., De Maria Marchiano, Ruggero, Debatin, K. -M., Di Daniele, N., Dixit, V. M., Dynlacht, B. D., El-Deiry, W. S., Fimia, G. M., Flavell, R. A., Fulda, S., Garrido, C., Gougeon, M. -L., Green, D. R., Gronemeyer, H., Hajnoczky, G., Hardwick, J. M., Hengartner, M. O., Ichijo, H., Joseph, B., Jost, P. J., Kaufmann, T., Kepp, O., Klionsky, D. J., Knight, R. A., Kumar, S., Lemasters, J. J., Levine, B., Linkermann, A., Lipton, S. A., Lockshin, R. A., López-Otín, C., Lugli, E., Madeo, F., Malorni, W., Marine, J. -C., Martin, S. J., Martinou, J. -C., Medema, Jan Paul, Meier, P., Melino, S., Mizushima, N., Moll, U., Muñoz-Pinedo, C., Nuñez, G., Oberst, A., Panaretakis, T., Penninger, J. M., Peter, M. E., Piacentini, M., Calzavara Pinton, Piergiacomo, Prehn, J. H., Puthalakath, H., Rabinovich, G. A., Ravichandran, K. S., Rizzuto, R., Rodrigues, C. M., Rubinsztein, D. C., Rudel, T., Shi, Y., Simon, H. -U., Stockwell, B. R., Szabadkai, G., Tait, S. W., Tang, H. L., Tavernarakis, N., Tsujimoto, Y., Vanden Berghe, T., Vandenabeele, P., Villunger, A., Wagner, E. F., Walczak, H., White, E., Wood, W. G., Yuan, J., Zakeri, Z., Zhivotovsky, B., Melino, G., Kroemer, G., Vitale, I., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Medema, J. P., Calzavara Pinton, P., Galluzzi, L., Bravo-San Pedro, J. M., Vitale, Ilio, Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., Baehrecke, E. H., Bazan, N. G., Bertrand, M. J., Bianchi, K., Blagosklonny, M. V., Blomgren, K., Borner, C., Bredesen, D. E., Brenner, C., Campanella, M., Candi, E., Cecconi, F., Chan, F. K., Chandel, N. S., Cheng, E. H., Chipuk, J. E., Cidlowski, J. A., Ciechanover, A., Dawson, T. M., Dawson, V. L., De Laurenzi, V., De Maria Marchiano, Ruggero, Debatin, K. -M., Di Daniele, N., Dixit, V. M., Dynlacht, B. D., El-Deiry, W. S., Fimia, G. M., Flavell, R. A., Fulda, S., Garrido, C., Gougeon, M. -L., Green, D. R., Gronemeyer, H., Hajnoczky, G., Hardwick, J. M., Hengartner, M. O., Ichijo, H., Joseph, B., Jost, P. J., Kaufmann, T., Kepp, O., Klionsky, D. J., Knight, R. A., Kumar, S., Lemasters, J. J., Levine, B., Linkermann, A., Lipton, S. A., Lockshin, R. A., López-Otín, C., Lugli, E., Madeo, F., Malorni, W., Marine, J. -C., Martin, S. J., Martinou, J. -C., Medema, Jan Paul, Meier, P., Melino, S., Mizushima, N., Moll, U., Muñoz-Pinedo, C., Nuñez, G., Oberst, A., Panaretakis, T., Penninger, J. M., Peter, M. E., Piacentini, M., Calzavara Pinton, Piergiacomo, Prehn, J. H., Puthalakath, H., Rabinovich, G. A., Ravichandran, K. S., Rizzuto, R., Rodrigues, C. M., Rubinsztein, D. C., Rudel, T., Shi, Y., Simon, H. -U., Stockwell, B. R., Szabadkai, G., Tait, S. W., Tang, H. L., Tavernarakis, N., Tsujimoto, Y., Vanden Berghe, T., Vandenabeele, P., Villunger, A., Wagner, E. F., Walczak, H., White, E., Wood, W. G., Yuan, J., Zakeri, Z., Zhivotovsky, B., Melino, G., Kroemer, G., Vitale, I., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Medema, J. P., and Calzavara Pinton, P.

Abstract

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

Published
2015

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