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92 results on '"Niesen, J."'

1. Localized Patterns in Periodically Forced Systems: II. Patterns with Non-Zero Wavenumber

Author

Alnahdi, A. S., Niesen, J., and Rucklidge, A. M.

Subjects
Nonlinear Sciences - Pattern Formation and Solitons, Mathematics - Dynamical Systems, 35B36 (Primary) 35B32, 35Q35 (Secondary)
Abstract

In pattern-forming systems, localized patterns are readily found when stable patterns exist at the same parameter values as the stable unpatterned state. Oscillons are spatially localized, time-periodic structures, which have been found experimentally in systems that are driven by a time-periodic force, for example, in the Faraday wave experiment. This paper examines the existence of oscillatory localized states in a PDE model with single frequency time dependent forcing, introduced in [A. M. Rucklidge and M. Silber, SIAM J. Appl. Math., 8 (2009), pp. 298-347, arXiv:0805.0878] as a phenomenological model of the Faraday wave experiment. We choose parameters so that patterns set in with non-zero wavenumber (in contrast to [A. S. Alnahdi, J. Niesen and A. M. Rucklidge, SIAM J. Appl. Dyn. Syst., 13 (2014), pp. 1311-1327, arXiv:1312.2773]). In the limit of weak damping, weak detuning, weak forcing, small group velocity, and small amplitude, we reduce the model PDE to the coupled forced complex Ginzburg-Landau equations. We find localized solutions and snaking behaviour in the coupled forced complex Ginzburg-Landau equations and relate these to oscillons that we find in the model PDE. Close to onset, the agreement is excellent. The periodic forcing for the PDE and the explicit derivation of the amplitude equations make our work relevant to the experimentally observed oscillons., Comment: 24 pages. v2: Several clarifications and other corrections as suggested by referees

Published
2017
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4. Localized patterns in periodically forced systems

Author

Alnahdi, A S, Niesen, J, Rucklidge, A M, and Wagenknecht, T

Subjects
Mathematics - Dynamical Systems, Nonlinear Sciences - Pattern Formation and Solitons
Abstract

Spatially localized, time-periodic structures are common in pattern-forming systems, appearing in fluid mechanics, chemical reactions, and granular media. We examine the existence of oscillatory localized states in a PDE model with single frequency time dependent forcing, introduced in [20] as phenomenological model of the Faraday wave experiment. In this study, we reduce the PDE model to the forced complex Ginzburg-Landau equation in the limit of weak forcing and weak damping. This allows us to use the known localized solutions found in [7]. We reduce the forced complex Ginzburg-Landau equation to the Allen-Cahn equation near onset, obtaining an asymptotically exact expression for localized solutions. We also extend this analysis to the strong forcing case recovering Allen-Cahn equation directly without the intermediate step. We find excellent agreement between numerical localized solutions of the PDE, localized solutions of the forced complex Ginzburg-Landau equation, and the Allen-Cahn equation. This is the first time that a PDE with time dependent forcing has been reduced to the Allen-Cahn equation, and its localized oscillatory solutions quantitatively studied. This paper is dedicated to the memory of Thomas Wagenknecht.

Published
2013
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6. The basic helix-loop-helix transcription factor TCF4 impacts brain architecture as well as neuronal morphology and differentiation

Author

Schoof, M. (Melanie), Hellwig, M. (Malte), Harrison, L. (Luke), Holdhof, D. (Dörthe), Lauffer, M.C. (Marlen C.), Niesen, J. (Judith), Virdi, S. (Sanamjeet), Indenbirken, D. (Daniela), Schüller, U. (Ulrich), Schoof, M. (Melanie), Hellwig, M. (Malte), Harrison, L. (Luke), Holdhof, D. (Dörthe), Lauffer, M.C. (Marlen C.), Niesen, J. (Judith), Virdi, S. (Sanamjeet), Indenbirken, D. (Daniela), and Schüller, U. (Ulrich)

Abstract

Germline mutations in the basic helix-loop-helix transcription factor 4 (TCF4) cause the Pitt–Hopkins syndrome (PTHS), a developmental disorder with severe intellectual disability. Here, we report findings from a new mouse model with a central nervous system-specific truncation of Tcf4 leading to severe phenotypic abnormalities. Furthermore, it allows the study of a complete TCF4 knockout in adult mice, circumventing early postnatal lethality of previously published mouse models. Our data suggest that a TCF4 truncation results in an impaired hippocampal architecture affecting both the dentate gyrus as well as the cornu ammonis. In the cerebral cortex, loss of TCF4 generates a severe differentiation delay of neural precursors. Furthermore, neuronal morphology was critically affected with shortened apical dendrites and significantly increased branching of dendrites. Our data provide novel information about the role of Tcf4 in brain development and may help to understand the mechanisms leading to intellectual deficits observed in patients suffering from PTHS.

Published
2020
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7. Solving the Vlasov–Maxwell equations using Hamiltonian splitting

Author

Li, Y, He, Y, Sun, Y, Niesen, J, Qin, H, and Liu, J

Subjects
Mathematics::Symplectic Geometry
Abstract

In this paper, the numerical discretizations based on Hamiltonian splitting for solving the Vlasov–Maxwell system are constructed. We reformulate the Vlasov–Maxwell system in Morrison–Marsden–Weinstein Poisson bracket form. Then the Hamiltonian of this system is split into five parts, with which five corresponding Hamiltonian subsystems are obtained. The splitting method in time is derived by composing the solutions to these five subsystems. Combining the splitting method in time with the Fourier spectral method and finite volume method in space gives the full numerical discretizations which possess good conservation for the conserved quantities including energy, momentum, charge, etc. In numerical experiments, we simulate the Landau damping, Weibel instability and Bernstein wave to verify the numerical algorithms.

Published
2019

9. Efficient targeting of CD13 on cancer cells by the immunotoxin scFv13-ETA ' and the bispecific scFv [13xds16]

Author

Grieger, E., Gresch, G., Niesen, J., Woitok, M., Barth, S., Fischer, R., Fendel, R., Stein, C., and Publica

Abstract

Treatment of cancer using standard chemotherapy still offers a poor prognosis combined with severe side effects. Novel antibody-based therapies have been shown to overcome low efficiency and lack of selectivity by targeting cancer-associated antigens, such as aminopeptidase CD13. We isolated a high-affinity CD13-specific single-chain fragment variable (scFv13) from a phage display library of V-genes from mice immunized with soluble antigen. An immunotoxin comprising the scFv13 and a truncated version of the exotoxin A of Pseudomonas aeruginosa (ETA', scFv13-ETA') and a bispecific scFv targeting CD13 and CD16 simultaneously (bsscFv[13xds16]) was generated and investigated for their therapeutic potential. Both fusion proteins bound specifically to target cells with high affinity. Furthermore, scFv13-ETA' inhibited the proliferation of human cancer cell lines efficiently at low concentrations (IC50 values of 408 pM-7 nM) and induced apoptosis (40-85% of target cells). The bsscFv triggered dose-dependent antibody-dependent cell-mediated cytotoxicity, resulting in the lysis of up to 23.9% A2058 cells, 18.0% MDA-MB-468 cells and 19.1% HL-60 cells. The provided data demonstrate potent therapeutic activity of the scFv13-ETA' and the bsscFv[13xds16]. The CD13-specific scFv is therefore suitable for the direct and specific delivery of both cytotoxic agents and effector cells to cancer-derived cells, making it ideal for further therapeutic evaluation.

Published
2017

13. A novel fully-human cytolytic fusion protein based on granzyme B shows in vitro cytotoxicity and ex vivo binding to solid tumors overexpressing the epidermal growth factor receptor

Author

Niesen, J., Hehmann-Titt, G., Woitok, M., Fendel, R., Barth, S., Fischer, R., Stein, C., and Publica

Abstract

Human cytolytic fusion proteins (hCFPs) offer a promising immunotherapeutic approach for the treatment of solid tumors, avoiding the immunogenicity and undesirable side-effects caused by immunotoxins derived from plants or bacteria. The well-characterized human serine protease granzyme B has already been used as a therapeutic pro-apoptotic effector domain. We therefore developed a novel recombinant hCFP (GbR201K-scFv1711) consisting of an epidermal growth factor receptor-specific human antibody fragment and a granzyme B point mutant (R201K) that is insensitive to serpin B9 (PI9), a natural inhibitor of wild-type granzyme B that is often expressed in solid tumors. We found that GbR201K-scFv1711 selectively bound to epidermoid cancer and rhabdomyosarcoma cells and was rapidly internalized by them. Nanomolar concentrations of GbR201K-scFv1711 achieved the specific killing of epidermoid cancer cells by inducing apoptosis, and similar effects were observed in rhabdomyosarcoma cells when GbR201K-scFv1711 was combined with the endosomolytic substance chloroquine. The novel hCFP was stable in serum and bound to human rhabdomyosarcoma tissue ex vivo. These data confirm that GbR201K-scFv1711 is a promising therapeutic candidate suitable for further clinical investigation.

Published
2016

14. Novel EGFR-specific immunotoxins based on panitumumab and cetuximab show in vitro and ex vivo activity against different tumor entities

Author

Niesen, J., Stein, C., Brehm, H., Hehmann-Titt, G., Fendel, R., Melmer, G., Fischer, R., Barth, S., and Publica

Abstract

Purpose: The epidermal growth factor receptor (EGFR) is overexpressed in many solid tumors. EGFR-specific monoclonal antibodies (mAbs), such as cetuximab and panitumumab, have been approved for the treatment of colorectal and head and neck cancer. To increase tissue penetration, we constructed single-chain fragment variable (scFv) antibodies derived from these mAbs and evaluated their potential for targeted cancer therapy. The resulting scFv-based EGFR-specific immunotoxins (ITs) combine target specificity of the full-size mAb with the cell-killing activity of a toxic effector domain, a truncated version of Pseudomonas exotoxin A (ETA). Methods: The ITs and corresponding imaging probes were tested in vitro against four solid tumor entities (rhabdomyosarcoma, breast, prostate and pancreatic cancer). Specific binding and internalization of the ITs scFv2112-ETA (from cetuximab) and scFv1711-ETA (from panitumumab) were demonstrated by flow cytometry and for the scFv-SNAP-ta g imaging probes by live cell imaging. Cytotoxic potential of the ITs was analyzed in cell viability and apoptosis assays. Binding of the ITs was proofed ex vivo on rhabdomyosarcoma, prostate and breast cancer formalin-fixed paraffin-embedded biopsies. Results: Both novel ITs showed significant pro-apoptotic and anti-proliferative effects toward the target cells, achieving IC50 values of 4 pM (high EGFR expression) to 460 pM (moderate EGFR expression). Additionally, rapid internalization and specific in vitro and ex vivo binding on patient tissue were confirmed. Conclusions: These data demonstrate the potent therapeutic activity of two novel EGFR-specific ETA-based ITs. Both molecules are promising candidates for further development toward clinical use in the treatment of various solid tumors to supplement the existing therapeutic regimes.

Published
2015

15. The Fc-alpha receptor is a new target antigen for immunotherapy of myeloid leukemia

Author

Mladenov, R., Hristodorov, D., Cremer, C., Hein, L., Kreutzer, F., Stroisch, T., Niesen, J., Brehm, H., Blume, T., Brummendorf, T.H., Jost, E., Thepen, T., Fischer, R., Stockmeyer, B., Barth, S., Stein, C., and Publica

Abstract

Antibody-based immunotherapy of leukemia requires the targeting of specific antigens on the surface of blasts. The Fc gamma receptor (CD64) has been investigated in detail, and CD64-targeting immunotherapy has shown promising efficacy in the targeted ablation of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML) and chronic myeloid leukemia cells (CML). Here we investigate for the first time the potential of Fc alpha RI (CD89) as a new target antigen expressed by different myeloid leukemic cell populations. For specific targeting and killing, we generated a recombinant fusion protein comprising an anti-human CD89 single-chain Fragment variable and the well-characterized truncated version of the potent Pseudomonas aeruginosa exotoxin A (ETA'). Our novel therapeutic approach achieved in vitro EC50 values in range 0.2-3 nM depending on the applied stimuli, that is, interferon gamma or tumor necrosis factor alpha. We also observed a dose-dependent apoptosis-mediated cytotoxicity, which resulted in the elimination of up to 90% of the target cells within 72 hr. These findings were also confirmed ex vivo using leukemic primary cells from peripheral blood samples of three previously untreated patients. We conclude that CD89-specific targeting of leukemia cell lines can be achieved in vitro and that the efficient elimination of leukemic primary cells supports the potential of CD89-ETA' as a potent, novel immunotherapeutic agent.

Published
2015

16. Targeted killing of rhabdomyosarcoma cells by a MAP-based human cytolytic fusion protein

Author

Brehm, H., Hristodorov, D., Pardo, A., Mladenov, R., Niesen, J., Fischer, R., Tur, M.K., Barth, S., and Publica

Abstract

The treatment of rhabdomyosarcoma (RMS) is challenging, and the prognosis remains especially poor for high-grade RMS with metastasis. The conventional treatment of RMS is based on multi-agent chemotherapy combined with resection and radiotherapy, which are often marked by low success rate. Alternative therapeutic options include the combination of standard treatments with immunotherapy. We generated a microtubule-associated protein (MAP)-based fully human cytolytic fusion protein (hCFP) targeting the fetal acetylcholine receptor, which is expressed on RMS cells. We were able to express and purify functional scFv35-MAP from Escherichia coli cells. Moreover, we found that scFv35-MAP is rapidly internalized by target cells after binding its receptor, and exhibits specific cytotoxicity toward FL-OH1 and RD cells in vitro. We also confirmed that scFv35-MAP induces apoptosis in FL-OH1 and RD cells. The in vivo potential of scFv35-MAP will need to be considered in further studies.

Published
2015

17. Search for new color-octet vector particle decaying to t(t)over-bar in p(p)over-bar collisions at root s=1.96 TeV RID G-1087-2011 RID E-4473-2011

Author

Aaltonen, T, Adelman, J, Gonzalez, Ba, Amerio, S, Amidei, D, Anastassov, A, Annovi, A, Antos, J, Apollinari, G, Apresyan, A, Arisawa, T, Artikov, A, Asaadi, J, Ashmanskas, W, Attal, A, Aurisano, A, Azfar, F, Badgett, W, Barbaro Galtieri, A, Barnes, Ve, Barnett, Ba, Barria, P, Bartos, P, Bauer, G, Beauchemin, Ph, Bedeschi, F, Beecher, D, Behari, S, Bellettini, G, Bellinger, J, Benjamin, D, Beretvas, A, Bhatti, A, Binkley, M, Bisello, D, Bizjak, I, Blair, Re, Blocker, C, Blumenfeld, B, Bocci, A, Bodek, A, Boisvert, V, Bortoletto, D, Boudreau, J, Boveia, A, Brau, B, Bridgeman, A, Brigliadori, L, Bromberg, C, Brubaker, E, Budagov, J, Budd, Hs, Buddy, S, Burkett, K, Busetto, G, Bussey, P, Buzatu, A, Byrum, Kl, Cabrera, S, Calancha, C, Camarda, S, Campanelli, M, Campbell, M, Canelli, F, Canepa, A, Carls, B, Carlsmith, D, Carosi, R, Carrillo, S, Carron, S, Casal, B, Casarsa, M, Castro, A, Catastini, P, Cauz, D, Cavaliere, V, Cavalli Sforza, M, Cerri, A, Cerrito, L, Chang, Sh, Chen, Yc, Chertok, M, Chiarelli, G, Chlachidze, G, Chlebana, F, Cho, K, Chokheli, D, Chou, Jp, Chung, K, Chung, Wh, Chung, Ys, Chwalek, T, Ciobanu, Ci, Ciocci, Ma, Clark, A, Clark, D, Compostella, G, Convery, Me, Conway, J, Corbo, M, Cordelli, M, Cox, Ca, Cox, Dj, Crescioli, F, Almenar, Cc, Cuevas, J, Culbertson, R, Cully, Jc, Dagenhart, D, Datta, M, Davies, T, de Barbaro, P, de Cecco, S, Deisher, A, de Lorenzo, G, Dell'Orso, Mauro, Deluca, C, Demortier, L, Deng, J, Deninno, M, D'Errico, M, Di Canto, A, di Giovanni GP, Di Ruzza, B, Dittmann, Jr, D'Onofrio, M, Donati, Simone, Dong, P, Dorigo, T, Dube, S, Ebina, K, Elagin, A, Erbacher, R, Errede, D, Errede, S, Ershaidat, N, Eusebi, R, Fang, Hc, Farrington, S, Fedorko, Wt, Feild, Rg, Feindt, M, Fernandez, Jp, Ferrazza, C, Field, R, Flanagan, G, Forrest, R, Frank, M, Franklin, M, Freeman, Jc, Furic, I, Gallinaro, M, Galyardt, J, Garberson, F, Garcia, Je, Garfinkel, Af, Garosi, P, Gerberich, H, Gerdes, D, Gessler, A, Giagu, S, Giakoumopoulou, V, Giannetti, P, Gibson, K, Gimmell, Jl, Ginsburg, Cm, Giokaris, N, Giordani, M, Giromini, P, Giunta, M, Giurgiu, G, Glagolev, V, Glenzinski, D, Gold, M, Goldschmidt, N, Golossanov, A, Gomez, G, Gomez Ceballos, G, Goncharov, M, Gonzalez, O, Gorelov, I, Goshaw, At, Goulianos, K, Gresele, A, Grinstein, S, Grosso Pilcher, C, Group, Rc, Grundler, U, da Costa JG, Gunay Unalan, Z, Haber, C, Hahn, Sr, Halkiadakis, E, Han, By, Han, Jy, Happacher, E, Nara, K, Hare, D, Hare, M, Harr, Rf, Hartz, M, Hatakeyama, K, Hays, C, Heck, M, Heinrich, J, Herndon, M, Heuser, J, Hewamanage, S, Hidas, D, Hill, Cs, Hirschbuehl, D, Hocker, A, Hou, S, Houlden, M, Hsu, Sc, Hughes, Re, Hurwitz, M, Husemann, U, Hussein, M, Huston, J, Incandela, J, Introzzi, G, Iori, M, Ivanov, A, James, E, Jang, D, Jayatilaka, B, Jeon, Ej, Jha, Mk, Jindariani, S, Johnson, W, Jones, M, Joo, Kk, Jun, Sy, June, Je, Junk, Tr, Kamon, T, Kar, D, Karchin, Pe, Kato, Y, Kephart, R, Ketchum, W, Keung, J, Khotilovich, V, Kilminster, B, Kim, Dh, Kim, Hs, Kim, Hw, Kim, Je, Kim, Mj, Kim, Sb, Kim, Sh, Kim, Yk, Kimura, N, Kirsch, L, Klimenko, S, Kondo, K, Kong, Dj, Konigsberg, J, Korytov, A, Kotwal, Av, Kreps, M, Kroll, J, Krop, D, Krumnack, N, Kruse, M, Krutelyov, V, Kuhr, T, Kulkarni, Np, Kurata, M, Kwang, S, Laasanen, At, Lami, S, Lammel, S, Lancaster, M, Lander, Rl, Lannon, K, Lath, A, Latino, G, Lazzizzera, I, Lecompte, T, Lee, E, Lee, Hs, Lee, Js, Lee, Sw, Leone, S, Lewis, Jd, Lin, Cj, Linacre, J, Lindgren, M, Lipeles, E, Lister, A, Litvintsev, Do, Liu, C, Liu, T, Lockyer, Ns, Loginov, A, Lovas, L, Lucchesi, D, Lueck, J, Lujan, P, Lukens, P, Lungu, G, Lys, J, Lysak, R, Macqueen, D, Madrak, R, Maeshima, K, Makhoul, K, Maksimovic, P, Malde, S, Malik, S, Manca, G, Manousakis Katsikakis, A, Margaroli, F, Marino, C, Marino, Cp, Martin, A, Martin, V, Martinez, M, Martinez Ballarin, R, Mastrandrea, P, Mathis, M, Mattson, Me, Mazzanti, P, Mcfarland, Ks, Mclntyre, P, Mcnuty, R, Mehta, A, Mehtala, P, Menzione, A, Mesropian, C, Miao, T, Mietlicki, D, Miladinovic, N, Miller, R, Mills, C, Milnik, M, Mitra, A, Mitselmakher, G, Miyake, H, Moed, S, Moggi, N, Mondragon, Mn, Moon, Cs, Moore, R, Morello, Mj, Morlock, J, Fernandez, Pm, Mulmenstadt, J, Mukherjee, A, Muller, T, Murat, P, Mussini, M, Nachtman, J, Nagai, Y, Naganoma, J, Nakamura, K, Nakano, I, Napier, A, Nett, J, Neu, C, Neubauer, Ms, Neubauer, S, Niesen, J, Nodulman, L, Norman, M, Norniella, O, Nurse, E, Oakes, L, Oh, Sh, Oh, Yd, Oksuzian, I, Okusawa, T, Orava, R, Osterberg, K, Griso, Sp, Pagliarone, C, Palencia, E, Papadimitriou, V, Papaikonomou, A, Paramanov, Aa, Parks, B, Pashapour, S, Patrick, J, Pauletta, G, Paulini, M, Paus, C, Peiffer, T, Pellett, De, Penzo, A, Phillips, Tj, Piacentino, G, Pianori, E, Pinera, L, Pitts, K, Plager, C, Pondrom, L, Potamianos, K, Poukhov, O, Prokoshin, F, Pronko, A, Ptohos, F, Pueschel, E, Punzi, Giovanni, Pursley, J, Rademacker, Tj, Rahaman, A, Ramakrishnan, V, Ranjan, N, Redondo, I, Renton, R, Renz, M, Rescigno, M, Richter, S, Rimondi, F, Ristori, L, Robson, A, Rodrigo, T, Rodriguez, T, Rogers, E, Rolli, S, Roser, R, Rossi, M, Rossin, R, Roy, P, Ruiz, A, Russ, J, Rusu, V, Rutherford, B, Saarikko, H, Safonov, A, Sakumoto, Wk, Santi, L, Sartori, L, Sato, K, Savoy Navarro, A, Schlabach, R, Schmidt, A, Schmidt, Ee, Schmidt, Ma, Schmidt, Mp, Schmitt, M, Schwarz, T, Scodellaro, L, Scribano, A, Scuri, F, Sedov, A, Seidel, S, Seiya, Y, Semenov, A, Sexton Kennedy, L, Sforza, F, Sfyrla, A, Shalhout, Sz, Shears, T, Shepard, Pf, Shimojima, M, Shiraishi, S, Shochet, M, Shon, Y, Shreyber, I, Simonenko, A, Sinervo, P, Sisakyan, A, Slaughter, Aj, Slaunwhite, J, Sliwa, K, Smith, Jr, Snider, Fd, Snihur, R, Soha, A, Somalwar, S, Sorin, V, Squillacioti, P, Stanitzki, M, Denis, Rs, Stelzer, B, Stelzer Chilton, O, Stentz, D, Strologas, J, Strycker, Gl, Suh, Js, Sukhanov, A, Suslov, I, Taffard, A, Takashima, R, Takeuchi, Y, Tanaka, R, Tang, J, Tecchio, M, Teng, Pk, Thom, J, Thome, J, Thompson, Ga, Thomson, E, Tipton, P, Ttito Guzman, P, Tkaczyk, S, Toback, D, Tokar, S, Tollefson, K, Tomura, T, Tonelli, D, Torre, S, Torretta, D, Totaro, P, Tourneur, S, Trovato, M, Tsai, Sy, Tu, Y, Turini, N, Ukegawa, F, Uozumi, S, van Remortel, N, Varganov, A, Vataga, E, Vazquez, F, Velev, G, Vellidis, C, Vidal, M, Vila, I, Vilar, R, Vogel, M, Volobouev, I, Volpi, G, Wagner, P, Wagner, Rg, Wagner, Rl, Wagner, W, Wagner Kuhr, J, Wakisaka, T, Wallny, R, Wang, Sm, Warburton, A, Waters, D, Weinberger, M, Weinelt, J, Wester, Wc, Whitehouse, B, Whiteson, D, Wicklund, Ab, Wicklund, E, Wilbur, S, Williams, G, Williams, Hh, Wilson, P, Winer, Bl, Wittich, P, Wolbers, S, Wolfe, C, Wolfe, H, Wright, T, Wu, X, Wurthwein, F, Yagil, A, Yamamoto, K, Yamaoka, J, Yang, Uk, Yang, Yc, Yao, Wm, Yeh, Gp, Yi, K, Yoh, J, Yorita, K, Yoshida, T, Yu, Gb, Yu, I, Yu, Ss, Yun, Jc, Zanetti, A, Zeng, Y, Zhang, X, Zheng, Y, Zucchelli Sng, X, Zucchelli Slli, S., Aaltonen, T, Adelman, J, Gonzalez, Ba, Amerio, S, Amidei, D, Anastassov, A, Annovi, A, Antos, J, Apollinari, G, Apresyan, A, Arisawa, T, Artikov, A, Asaadi, J, Ashmanskas, W, Attal, A, Aurisano, A, Azfar, F, Badgett, W, Barbaro Galtieri, A, Barnes, Ve, Barnett, Ba, Barria, P, Bartos, P, Bauer, G, Beauchemin, Ph, Bedeschi, F, Beecher, D, Behari, S, Bellettini, G, Bellinger, J, Benjamin, D, Beretvas, A, Bhatti, A, Binkley, M, Bisello, D, Bizjak, I, Blair, Re, Blocker, C, Blumenfeld, B, Bocci, A, Bodek, A, Boisvert, V, Bortoletto, D, Boudreau, J, Boveia, A, Brau, B, Bridgeman, A, Brigliadori, L, Bromberg, C, Brubaker, E, Budagov, J, Budd, H, Buddy, S, Burkett, K, Busetto, G, Bussey, P, Buzatu, A, Byrum, Kl, Cabrera, S, Calancha, C, Camarda, S, Campanelli, M, Campbell, M, Canelli, F, Canepa, A, Carls, B, Carlsmith, D, Carosi, R, Carrillo, S, Carron, S, Casal, B, Casarsa, M, Castro, A, Catastini, P, Cauz, D, Cavaliere, V, Cavalli Sforza, M, Cerri, A, Cerrito, L, Chang, Sh, Chen, Yc, Chertok, M, Chiarelli, G, Chlachidze, G, Chlebana, F, Cho, K, Chokheli, D, Chou, Jp, Chung, K, Chung, Wh, Chung, Y, Chwalek, T, Ciobanu, Ci, Ciocci, Ma, Clark, A, Clark, D, Compostella, G, Convery, Me, Conway, J, Corbo, M, Cordelli, M, Cox, Ca, Cox, Dj, Crescioli, F, Almenar, Cc, Cuevas, J, Culbertson, R, Cully, Jc, Dagenhart, D, Datta, M, Davies, T, de Barbaro, P, de Cecco, S, Deisher, A, de Lorenzo, G, Dell'Orso, M, Deluca, C, Demortier, L, Deng, J, Deninno, M, D'Errico, M, Di Canto, A, di Giovanni, Gp, Di Ruzza, B, Dittmann, Jr, D'Onofrio, M, Donati, S, Dong, P, Dorigo, T, Dube, S, Ebina, K, Elagin, A, Erbacher, R, Errede, D, Errede, S, Ershaidat, N, Eusebi, R, Fang, Hc, Farrington, S, Fedorko, Wt, Feild, Rg, Feindt, M, Fernandez, Jp, Ferrazza, C, Field, R, Flanagan, G, Forrest, R, Frank, M, Franklin, M, Freeman, Jc, Furic, I, Gallinaro, M, Galyardt, J, Garberson, F, Garcia, Je, Garfinkel, Af, Garosi, P, Gerberich, H, Gerdes, D, Gessler, A, Giagu, S, Giakoumopoulou, V, Giannetti, P, Gibson, K, Gimmell, Jl, Ginsburg, Cm, Giokaris, N, Giordani, M, Giromini, P, Giunta, M, Giurgiu, G, Glagolev, V, Glenzinski, D, Gold, M, Goldschmidt, N, Golossanov, A, Gomez, G, Gomez Ceballos, G, Goncharov, M, Gonzalez, O, Gorelov, I, Goshaw, At, Goulianos, K, Gresele, A, Grinstein, S, Grosso Pilcher, C, Group, Rc, Grundler, U, da Costa, Jg, Gunay Unalan, Z, Haber, C, Hahn, Sr, Halkiadakis, E, Han, By, Han, Jy, Happacher, E, Nara, K, Hare, D, Hare, M, Harr, Rf, Hartz, M, Hatakeyama, K, Hays, C, Heck, M, Heinrich, J, Herndon, M, Heuser, J, Hewamanage, S, Hidas, D, Hill, C, Hirschbuehl, D, Hocker, A, Hou, S, Houlden, M, Hsu, Sc, Hughes, Re, Hurwitz, M, Husemann, U, Hussein, M, Huston, J, Incandela, J, Introzzi, G, Iori, M, Ivanov, A, James, E, Jang, D, Jayatilaka, B, Jeon, Ej, Jha, Mk, Jindariani, S, Johnson, W, Jones, M, Joo, Kk, Jun, Sy, June, Je, Junk, Tr, Kamon, T, Kar, D, Karchin, Pe, Kato, Y, Kephart, R, Ketchum, W, Keung, J, Khotilovich, V, Kilminster, B, Kim, Dh, Kim, H, Kim, Hw, Kim, Je, Kim, Mj, Kim, Sb, Kim, Sh, Kim, Yk, Kimura, N, Kirsch, L, Klimenko, S, Kondo, K, Kong, Dj, Konigsberg, J, Korytov, A, Kotwal, Av, Kreps, M, Kroll, J, Krop, D, Krumnack, N, Kruse, M, Krutelyov, V, Kuhr, T, Kulkarni, Np, Kurata, M, Kwang, S, Laasanen, At, Lami, S, Lammel, S, Lancaster, M, Lander, Rl, Lannon, K, Lath, A, Latino, G, Lazzizzera, I, Lecompte, T, Lee, E, Lee, H, Lee, J, Lee, Sw, Leone, S, Lewis, Jd, Lin, Cj, Linacre, J, Lindgren, M, Lipeles, E, Lister, A, Litvintsev, Do, Liu, C, Liu, T, Lockyer, N, Loginov, A, Lovas, L, Lucchesi, D, Lueck, J, Lujan, P, Lukens, P, Lungu, G, Lys, J, Lysak, R, Macqueen, D, Madrak, R, Maeshima, K, Makhoul, K, Maksimovic, P, Malde, S, Malik, S, Manca, G, Manousakis Katsikakis, A, Margaroli, F, Marino, C, Marino, Cp, Martin, A, Martin, V, Martinez, M, Martinez Ballarin, R, Mastrandrea, P, Mathis, M, Mattson, Me, Mazzanti, P, Mcfarland, K, Mclntyre, P, Mcnuty, R, Mehta, A, Mehtala, P, Menzione, A, Mesropian, C, Miao, T, Mietlicki, D, Miladinovic, N, Miller, R, Mills, C, Milnik, M, Mitra, A, Mitselmakher, G, Miyake, H, Moed, S, Moggi, N, Mondragon, Mn, Moon, C, Moore, R, Morello, MICHAEL JOSEPH, Morlock, J, Fernandez, Pm, Mulmenstadt, J, Mukherjee, A, Muller, T, Murat, P, Mussini, M, Nachtman, J, Nagai, Y, Naganoma, J, Nakamura, K, Nakano, I, Napier, A, Nett, J, Neu, C, Neubauer, M, Neubauer, S, Niesen, J, Nodulman, L, Norman, M, Norniella, O, Nurse, E, Oakes, L, Oh, Sh, Oh, Yd, Oksuzian, I, Okusawa, T, Orava, R, Osterberg, K, Griso, Sp, Pagliarone, C, Palencia, E, Papadimitriou, V, Papaikonomou, A, Paramanov, Aa, Parks, B, Pashapour, S, Patrick, J, Pauletta, G, Paulini, M, Paus, C, Peiffer, T, Pellett, De, Penzo, A, Phillips, Tj, Piacentino, G, Pianori, E, Pinera, L, Pitts, K, Plager, C, Pondrom, L, Potamianos, K, Poukhov, O, Prokoshin, F, Pronko, A, Ptohos, F, Pueschel, E, Punzi, G, Pursley, J, Rademacker, Tj, Rahaman, A, Ramakrishnan, V, Ranjan, N, Redondo, I, Renton, R, Renz, M, Rescigno, M, Richter, S, Rimondi, F, Ristori, L, Robson, A, Rodrigo, T, Rodriguez, T, Rogers, E, Rolli, S, Roser, R, Rossi, M, Rossin, R, Roy, P, Ruiz, A, Russ, J, Rusu, V, Rutherford, B, Saarikko, H, Safonov, A, Sakumoto, Wk, Santi, L, Sartori, L, Sato, K, Savoy Navarro, A, Schlabach, R, Schmidt, A, Schmidt, Ee, Schmidt, Ma, Schmidt, Mp, Schmitt, M, Schwarz, T, Scodellaro, L, Scribano, A, Scuri, F, Sedov, A, Seidel, S, Seiya, Y, Semenov, A, Sexton Kennedy, L, Sforza, F, Sfyrla, A, Shalhout, Sz, Shears, T, Shepard, Pf, Shimojima, M, Shiraishi, S, Shochet, M, Shon, Y, Shreyber, I, Simonenko, A, Sinervo, P, Sisakyan, A, Slaughter, Aj, Slaunwhite, J, Sliwa, K, Smith, Jr, Snider, Fd, Snihur, R, Soha, A, Somalwar, S, Sorin, V, Squillacioti, P, Stanitzki, M, Denis, R, Stelzer, B, Stelzer Chilton, O, Stentz, D, Strologas, J, Strycker, Gl, Suh, J, Sukhanov, A, Suslov, I, Taffard, A, Takashima, R, Takeuchi, Y, Tanaka, R, Tang, J, Tecchio, M, Teng, Pk, Thom, J, Thome, J, Thompson, Ga, Thomson, E, Tipton, P, Ttito Guzman, P, Tkaczyk, S, Toback, D, Tokar, S, Tollefson, K, Tomura, T, Tonelli, D, Torre, S, Torretta, D, Totaro, P, Tourneur, S, Trovato, M, Tsai, Sy, Tu, Y, Turini, N, Ukegawa, F, Uozumi, S, van Remortel, N, Varganov, A, Vataga, E, Vazquez, F, Velev, G, Vellidis, C, Vidal, M, Vila, I, Vilar, R, Vogel, M, Volobouev, I, Volpi, G, Wagner, P, Wagner, Rg, Wagner, Rl, Wagner, W, Wagner Kuhr, J, Wakisaka, T, Wallny, R, Wang, Sm, Warburton, A, Waters, D, Weinberger, M, Weinelt, J, Wester, Wc, Whitehouse, B, Whiteson, D, Wicklund, Ab, Wicklund, E, Wilbur, S, Williams, G, Williams, Hh, Wilson, P, Winer, Bl, Wittich, P, Wolbers, S, Wolfe, C, Wolfe, H, Wright, T, Wu, X, Wurthwein, F, Yagil, A, Yamamoto, K, Yamaoka, J, Yang, Uk, Yang, Yc, Yao, Wm, Yeh, Gp, Yi, K, Yoh, J, Yorita, K, Yoshida, T, Yu, Gb, Yu, I, Yu, S, Yun, Jc, Zanetti, A, Zeng, Y, Zhang, X, Zheng, Y, and Zucchelli, S.

Subjects
High Energy Physics::Lattice, Nuclear Theory, High Energy Physics::Phenomenology, High Energy Physics::Experiment
Abstract

We present the result of a search for a massive color-octet vector particle, (e.g. a massive gluon) decaying to a pair of top quarks in proton-antiproton collisions with a center-of-mass energy of 1.96 TeV. This search is based on 1.9 fb(-1) of data collected using the CDF detector during Run II of the Tevatron at Fermilab. We study t (t) over bar events in the lepton + jets channel with at least one b-tagged jet. A massive gluon is characterized by its mass, decay width, and the strength of its coupling to quarks. These parameters are determined according to the observed invariant mass distribution of top quark pairs. We set limits on the massive gluon coupling strength for masses between 400 and 800 GeV/c(2) and width-to-mass ratios between 0.05 and 0.50. The coupling strength of the hypothetical massive gluon to quarks is consistent with zero within the explored parameter space. (C) 2010 Elsevier B.V. All rights reserved.

Published
2010

18. In vitro effects and ex vivo binding of an EGFR-specific immunotoxin on rhabdomyosarcoma cells

Author

Niesen, J., Brehm, H., Stein, C., Berges, N., Pardo, A., Fischer, R., Haaf, A. ten, Gattenlöhner, S., Tur, M.K., Barth, S., and Publica

Abstract

PURPOSE: Rhabdomyosarcoma (RMS) is a rare and aggressive soft tissue sarcoma with limited treatment options and a high failure rate during standard therapy. New therapeutic strategies based on targeted immunotherapy are therefore much in demand. The epidermal growth factor receptor (EGFR) has all the characteristics of an ideal target. It is overexpressed in up to 80 % of embryonal RMS and up to 50 % of alveolar RMS tumors. We therefore tested the activity of the EGFR-specific recombinant immunotoxin (IT) 425(scFv)-ETA' against EGFR(+) RMS cells in vitro and ex vivo. METHODS: We tested the specific binding and internalization behavior of 425(scFv)-ETA' in RMS cell lines in vitro by flow cytometry, compared to the corresponding imaging probe 425(scFv)-SNAP monitored by live cell imaging. The cytotoxic activity of 425(scFv)-ETA' was tested using cell viability and apoptosis assays. Specific binding of the IT was confirmed on formalin-fixed paraffin-embedded tissue samples from two RMS patients. RESULTS: We confirmed the specific binding of 425(scFv)-ETA' to RMS cells in vitro and ex vivo. Both the IT and the corresponding imaging probe were rapidly internalized. The IT killed EGFR(+) RMS cells in a dose-dependent manner, while showing no effect against control cells. It showed specific apoptotic activity against one selected RMS cell line. CONCLUSIONS: This is the first study showing the promising therapeutic potential of a recombinant, EGFR-targeting, ETA'-based IT on RMS cells. We confirmed the selective killing with IC50 values of up to 50 pM, and immunohistochemical staining confirmed the specific ex vivo binding to primary RMS material.

Published
2014

19. Rapid optical imaging of EGF receptor expression with a single-chain antibody SNAP-tag fusion protein

Author

Kampmeier, F., Niesen, J., Koers, A., Ribbert, M., Brecht, A., Fischer, R., Kießling, F., Barth, S., Thepen, T., and Publica

Abstract

The epidermal growth factor receptor (EGFR) is overexpressed in several types of cancer and its inhibition can effectively inhibit tumour progression. The purpose of this study was to design an EGFR-specific imaging probe that combines efficient tumour targeting with rapid systemic clearance to facilitate non-invasive assessment of EGFR expression. Genetic fusion of a single-chain antibody fragment with the SNAP-tag produced a 48-kDa antibody derivative that can be covalently and site-specifically labelled with substrates containing 0 (6)-benzylguanine. The EGFR-specific single-chain variable fragment (scFv) fusion protein 425(scFv)SNAP was labelled with the near infrared (NIR) dye BG-747, and its accumulation, specificity and kinetics were monitored using NIR fluorescence imaging in a subcutaneous pancreatic carcinoma xenograft model. The 425(scFv)SNAP fusion protein accumulates rapidly and specifically at the tumour site. Its small size allows efficient renal clearance and a high tumour to background ratio (TBR) of 33.2 +/- 6.3 (n = 4) 10 h after injection. Binding of the labelled antibody was efficiently competed with a 20-fold excess of unlabelled probe, resulting in an average TBR of 6 +/- 1.35 (n = 4), which is similar to that obtained with a non-tumour-specific probe (5.44 +/- 1.92, n = 4). When compared with a full-length antibody against EGFR (cetuximab), 425(scFv)SNAP-747 showed significantly higher TBRs and complete clearance 72 h post-injection. The 425(scFv)SNAP fusion protein combines rapid and specific targeting of EGFR-positive tumours with a versatile and robust labelling technique that facilitates the attachment of fluorophores for use in optical imaging. The same approach could be used to couple a chelating agent for use in nuclear imaging.

Published
2010

20. Search for new color-octet vector particle decaying to t(t)over-bar in p(p)over-bar collisions at root s=1.96 TeV

Author

Aaltonen, T., Adelman, J., Gonzalez, B. A., Amerio, S., Amidei, D., Anastassov, A., Annovi, A., Antos, J., Apollinari, G., Apresyan, A., Arisawa, T., Artikov, A., Asaadi, J., Ashmanskas, W., Attal, A., Aurisano, A., Azfar, F., Badgett, W., Barbaro Galtieri, A., Barnes, V. E., Barnett, B. A., Barria, P., Bartos, P., Bauer, G., Beauchemin, P. H., Bedeschi, F., Beecher, D., Behari, S., Bellettini, G., Bellinger, J., Benjamin, D., Beretvas, A., Bhatti, A., Binkley, M., Bisello, D., Bizjak, I., Blair, R. E., Blocker, C., Blumenfeld, B., Bocci, A., Bodek, A., Boisvert, V., Bortoletto, D., Boudreau, J., Boveia, A., Brau, B., Bridgeman, A., Brigliadori, L., Bromberg, C., Brubaker, E., Budagov, J., Budd, H. S., Buddy, S., Burkett, K., Busetto, G., Bussey, P., Buzatu, A., Byrum, K. L., Cabrera, S., Calancha, C., Camarda, S., Campanelli, M., Campbell, M., Canelli, F., Canepa, A., Carls, B., Carlsmith, D., Carosi, R., Carrillo, S., Carron, S., Casal, B., Casarsa, M., Castro, A., Catastini, P., Cauz, D., Cavaliere, V., Cavalli Sforza, M., Cerri, A., Cerrito, L., Chang, S. H., Chen, Y. C., Chertok, M., Chiarelli, G., Chlachidze, G., Chlebana, F., Cho, K., Chokheli, D., Chou, J. P., Chung, K., Chung, W. H., Chung, Y. S., Chwalek, T., Ciobanu, C. I., Ciocci, MARIA AGNESE, Clark, A., Clark, D., Compostella, G., Convery, M. E., Conway, J., Corbo, M., Cordelli, M., Cox, C. A., Cox, D. J., Crescioli, F., Almenar, C. C., Cuevas, J., Culbertson, R., Cully, J. C., Dagenhart, D., Datta, M., Davies, T., Barbaro, P. d., Cecco, S. d., Deisher, A., Lorenzo, G. d., Dell'Orso, M., Deluca, C., Demortier, L., Deng, J., Deninno, M., D'Errico, M., Canto, A. D., G. P., Di, Ruzza, B. D., Dittmann, J. R., D'Onofrio, M., Donati, S., Dong, P., Dorigo, T., Dube, S., Ebina, K., Elagin, A., Erbacher, R., Errede, D., Errede, S., Ershaidat, N., Eusebi, R., Fang, H. C., Farrington, S., Fedorko, W. T., Feild, R. G., Feindt, M., Fernandez, J. P., Ferrazza, C., Field, R., Flanagan, G., Forrest, R., Frank, M., Franklin, M., Freeman, J. C., Furic, I., Gallinaro, M., Galyardt, J., Garberson, F., Garcia, J. E., Garfinkel, A. F., Garosi, P., Gerberich, H., Gerdes, D., Gessler, A., Giagu, S., Giakoumopoulou, V., Giannetti, P., Gibson, K., Gimmell, J. L., Ginsburg, C. M., Giokaris, N., Giordani, M., Giromini, P., Giunta, M., Giurgiu, G., Glagolev, V., Glenzinski, D., Gold, M., Goldschmidt, N., Golossanov, A., Gomez, G., Gomez Ceballos, G., Goncharov, M., Gonzalez, O., Gorelov, I., Goshaw, A. T., Goulianos, K., Gresele, A., Grinstein, S., Grosso Pilcher, C., Group, R. C., Grundler, U., J. G., Da, Gunay Unalan, Z., Haber, C., Hahn, S. R., Halkiadakis, E., Han, B. Y., Han, J. Y., Happacher, E., Nara, K., Hare, D., Hare, M., Harr, R. F., Hartz, M., Hatakeyama, K., Hays, C., Heck, M., Heinrich, J., Herndon, M., Heuser, J., Hewamanage, S., Hidas, D., Hill, C. S., Hirschbuehl, D., Hocker, A., Hou, S., Houlden, M., Hsu, S. C., Hughes, R. E., Hurwitz, M., Husemann, U., Hussein, M., Huston, J., Incandela, J., Introzzi, G., Iori, M., Ivanov, A., James, E., Jang, D., Jayatilaka, B., Jeon, E. J., Jha, M. K., Jindariani, S., Johnson, W., Jones, M., Joo, K. K., Jun, S. Y., June, J. E., Junk, T. R., Kamon, T., Kar, D., Karchin, P. E., Kato, Y., Kephart, R., Ketchum, W., Keung, J., Khotilovich, V., Kilminster, B., Kim, D. H., Kim, H. S., Kim, H. W., Kim, J. E., Kim, M. J., Kim, S. B., Kim, S. H., Kim, Y. K., Kimura, N., Kirsch, L., Klimenko, S., Kondo, K., Kong, D. J., Konigsberg, J., Korytov, A., Kotwal, A. V., Kreps, M., Kroll, J., Krop, D., Krumnack, N., Kruse, M., Krutelyov, V., Kuhr, T., Kulkarni, N. P., Kurata, M., Kwang, S., Laasanen, A. T., Lami, S., Lammel, S., Lancaster, M., Lander, R. L., Lannon, K., Lath, A., Latino, G., Lazzizzera, I., Lecompte, T., Lee, E., Lee, H. S., Lee, J. S., Lee, S. W., Leone, S., Lewis, J. D., Lin, C. J., Linacre, J., Lindgren, M., Lipeles, E., Lister, A., Litvintsev, D. O., Liu, C., Liu, T., Lockyer, N. S., Loginov, A., Lovas, L., Lucchesi, D., Lueck, J., Lujan, P., Lukens, P., Lungu, G., Lys, J., Lysak, R., Macqueen, D., Madrak, R., Maeshima, K., Makhoul, K., Maksimovic, P., Malde, S., Malik, S., Manca, G., Manousakis Katsikakis, A., Margaroli, F., Marino, C., Marino, C. P., Martin, A., Martin, V., Martinez, M., Martinez Ballarin, R., Mastrandrea, P., Mathis, M., Mattson, M. E., Mazzanti, P., Mcfarland, K. S., Mclntyre, P., Mcnuty, R., Mehta, A., Mehtala, P., Menzione, A., Mesropian, C., Miao, T., Mietlicki, D., Miladinovic, N., Miller, R., Mills, C., Milnik, M., Mitra, A., Mitselmakher, G., Miyake, H., Moed, S., Moggi, N., Mondragon, M. N., Moon, C. S., Moore, R., Morello, M. J., Morlock, J., Fernandez, P. M., Mulmenstadt, J., Mukherjee, A., Muller, T., Murat, P., Mussini, M., Nachtman, J., Nagai, Y., Naganoma, J., Nakamura, K., Nakano, I., Napier, A., Nett, J., Neu, C., Neubauer, M. S., Neubauer, S., Niesen, J., Nodulman, L., Norman, M., Norniella, O., Nurse, E., Oakes, L., S. H., Oh, Y. D., Oh, Oksuzian, I., Okusawa, T., Orava, R., Osterberg, K., Griso, S. P., Pagliarone, C., Palencia, E., Papadimitriou, V., Papaikonomou, A., Paramanov, A. A., Parks, B., Pashapour, S., Patrick, J., Pauletta, G., Paulini, M., Paus, C., Peiffer, T., Pellett, D. E., Penzo, A., Phillips, T. J., Piacentino, G., Pianori, E., Pinera, L., Pitts, K., Plager, C., Pondrom, L., Potamianos, K., Poukhov, O., Prokoshin, F., Pronko, A., Ptohos, F., Pueschel, E., Punzi, G., Pursley, J., Rademacker, T. J., Rahaman, A., Ramakrishnan, V., Ranjan, N., Redondo, I., Renton, R., Renz, M., Rescigno, M., Richter, S., Rimondi, F., Ristori, L., Robson, A., Rodrigo, T., Rodriguez, T., Rogers, E., Rolli, S., Roser, R., Rossi, M., Rossin, R., Roy, P., Ruiz, A., Russ, J., Rusu, V., Rutherford, B., Saarikko, H., Safonov, A., Sakumoto, W. K., Santi, L., Sartori, L., Sato, K., Savoy Navarro, A., Schlabach, R., Schmidt, A., Schmidt, E. E., Schmidt, M. A., Schmidt, M. P., Schmitt, M., Schwarz, T., Scodellaro, L., Scribano, A., Scuri, F., Sedov, A., Seidel, S., Seiya, Y., Semenov, A., Sexton Kennedy, L., Sforza, F., Sfyrla, A., Shalhout, S. Z., Shears, T., Shepard, P. F., Shimojima, M., Shiraishi, S., Shochet, M., Shon, Y., Shreyber, I., Simonenko, A., Sinervo, P., Sisakyan, A., Slaughter, A. J., Slaunwhite, J., Sliwa, K., Smith, J. R., Snider, F. D., Snihur, R., Soha, A., Somalwar, S., Sorin, V., Squillacioti, P., Stanitzki, M., Denis, R. S., Stelzer, B., Stelzer Chilton, O., Stentz, D., Strologas, J., Strycker, G. L., Suh, J. S., Sukhanov, A., Suslov, I., Taffard, A., Takashima, R., Takeuchi, Y., Tanaka, R., Tang, J., Tecchio, M., Teng, P. K., Thom, J., Thome, J., Thompson, G. A., Thomson, E., Tipton, P., Ttito Guzman, P., Tkaczyk, S., Toback, D., Tokar, S., Tollefson, K., Tomura, T., Tonelli, D., Torre, S., Torretta, D., Totaro, P., Tourneur, S., Trovato, M., Tsai, S. Y., Tu, Y., Turini, N., Ukegawa, F., Uozumi, S., Remortel, N. v., Varganov, A., Vataga, E., Vazquez, F., Velev, G., Vellidis, C., Vidal, M., Vila, I., Vilar, R., Vogel, M., Volobouev, I., Volpi, G., Wagner, P., Wagner, R. G., Wagner, R. L., Wagner, W., Wagner Kuhr, J., Wakisaka, T., Wallny, R., Wang, S. M., Warburton, A., Waters, D., Weinberger, M., Weinelt, J., Wester, W. C., Whitehouse, B., Whiteson, D., Wicklund, A. B., Wicklund, E., Wilbur, S., Williams, G., Williams, H. H., Wilson, P., Winer, B. L., Wittich, P., Wolbers, S., Wolfe, C., Wolfe, H., Wright, T., Wu, X., Wurthwein, F., Yagil, A., Yamamoto, K., Yamaoka, J., Yang, U. K., Yang, Y. C., Yao, W. M., Yeh, G. P., Yi, K., Yoh, J., Yorita, K., Yoshida, T., G. B., Yu, Yu, I., S. S., Yu, Yun, J. C., Zanetti, A., Zeng, Y., Zhang, X., Zheng, Y., and Zucchelli, S.

Subjects
PHYSICS, massive gluon, top quark
Published
2010

28. Brief an [Franz Reiter]

Author

Niesen, J.

Abstract

von J. Niesen, Deutsch, Verzeichnung=Description=Inventaire Februar 2013 Rekatalogisierung nach Findbuch zum Nachlass, Original und Briefkatalog

Published
1832
Full Text
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29. The efficient elimination of solid tumor cells by EGFR-specific and HER2-specific scFv-SNAP fusion proteins conjugated to benzylguanine-modified auristatin F

Author

Woitok M, Klose D, Niesen J, Richter W, Abbas M, Stein C, Fendel R, Bialon M, Püttmann C, Fischer R, Stefan Barth, Kolberg K, and Publica

Abstract

Antibody-drug conjugates (ADCs) combine the potency of cytotoxic drugs with the specificity of monoclonal antibodies (mAbs). Most ADCs are currently generated by the nonspecific conjugation of drugâlinker reagents to certain amino acid residues in mAbs, resulting in a heterogeneous product. To overcome this limitation and prepare ADCs with a defined stoichiometry, we use SNAP-tag technology as an alternative conjugation strategy. This allows the site-specific conjugation of O(6)-benzylguanine (BG)-modified small molecules to SNAP-tag fusion proteins. To demonstrate the suitability of this system for the preparation of novel recombinant ADCs, here we conjugated SNAP-tagged single chain antibody fragments (scFvs) to a BG-modified version of auristatin F (AURIF). We used two scFv-SNAP fusion proteins targeting members of the epidermal growth factor receptor (EGFR) family that are frequently overexpressed in breast cancer.

30. SNAP-tag technology: a useful tool to determine affinity constants and other functional parameters of novel antibody fragments

Author

Niesen J, Sack M, Seidel M, Fendel R, Stefan Barth, Fischer R, Stein C, and Publica

Abstract

Antibody derivatives, such as the single chain fragment variable (scFv), can be developed as diagnostic and therapeutic tools in cancer research, especially in the form of fusion proteins. Such derivatives are easier to produce and modify than monoclonal antibodies (mAbs) and achieve better tissue/tumor penetration. The genetic modification of scFvs is also much more straightforward than the challenging chemical modification of mAbs. Therefore, we constructed two scFvs derived from the approved monoclonal antibodies cetuximab (scFv2112) and panitumumab (scFv1711), both of which are specific for the epidermal growth factor receptor (EGFR), a well-characterized solid tumor antigen. Both scFvs were genetically fused to the SNAP-tag, an engineered version of the human DNA repair enzyme O6-alkylguanine DNA alkyltransferase that allows the covalent coupling of benzylguanine (BG)-modified substrates such as fluorescent dyes.

41. hGFAP -mediated GLI2 overexpression leads to early death and severe cerebellar malformations with rare tumor formation.

Author

Niesen J, Hermans-Borgmeyer I, Krüger C, Schoof M, Modemann F, and Schüller U

Abstract

The zinc-finger transcription factor GLI2 is frequently amplified in childhood medulloblastoma of the Sonic-hedgehog type (SHH-MB), with or without amplification of NMYC or deletion of TP53 . Despite the aggressive tumor behavior, tumorigenesis is not well understood, and adequate mouse models are lacking. Therefore, we generated mice with a GLI2 overexpression under control of the hGFAP -promoter. These mice died within 150 days. The majority only survived until postnatal day 40. They displayed severe cerebellar hypoplasia, cortical malformations, but no brain tumors, except for one out of 23 animals with an undifferentiated hindbrain lesion. Additional loss of p53 did not result in cerebellar tumors, but partially rescued the cerebellar phenotype induced by GLI2 overexpression. Similarly, the combination of GLI2 and NMYC was neither sufficient for the development of SHH-MB. We therefore assume that the development of childhood SHH-MB in mice is either occurring in cellular origins outside the hGFAP -positive lineage or needs additional genetic drivers., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Published
2023
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42. DIMEimmune: Robust estimation of infiltrating lymphocytes in CNS tumors from DNA methylation profiles.

Author

Safaei S, Mohme M, Niesen J, Schüller U, and Bockmayr M

Subjects
DNA Methylation genetics, Humans, Lymphocytes, Tumor-Infiltrating, Tumor Microenvironment genetics, Brain Neoplasms genetics, Central Nervous System Neoplasms genetics, Glioma genetics
Abstract

The interaction of CNS tumors with infiltrating lymphocytes plays an important role in their initiation and progression and might be related to therapeutic responses. Gene expression-based methods have been successfully used to characterize the tumor microenvironment. However, methylation data are now increasingly used for molecular diagnostics and there are currently only few methods to infer information about the microenvironment from this data type. Using an approach based on differential methylation and principal component analysis, we developed DIMEimmune (Differential Methylation Analysis for Immune Cell Estimation) to estimate CD4 + and CD8 + T cell abundance as well as tumor-infiltrating lymphocytes (TILs) scores from bulk methylation data. Well-established approaches based on gene expression data and immunohistochemistry-based lymphocyte counts were used as benchmarks. The comparison of DIMEimmune to the previously published MethylCIBERSORT and MeTIL algorithms showed an improved correlation with both gene expression-based and immunohistological results across different brain tumor types. Further, we applied our method to large datasets of glioma, medulloblastoma, atypical teratoid/rhabdoid tumors (ATRTs) and ependymoma. High-grade gliomas showed higher scores of tumor-infiltrating lymphocytes than lower-grade gliomas. There were overall only few tumor-infiltrating lymphocytes in medulloblastoma subgroups. ATRTs were highly infiltrated by lymphocytes, most prominently in the MYC subgroup. DIMEimmune-based estimates of TILs were a significant prognostic factor in the overall cohort of gliomas and medulloblastomas, but not within methylation-based diagnostic subgroups. To conclude, DIMEimmune allows for robust estimates of TIL abundance and might contribute to establishing them as a prognostic or predictive factor in future studies of CNS tumors., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Published
2021
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43. Using the SNAP-Tag technology to easily measure and demonstrate apoptotic changes in cancer and blood cells with different dyes.

Author

Woitok M, Grieger E, Akinrinmade OA, Bethke S, Pham AT, Stein C, Fendel R, Fischer R, Barth S, and Niesen J

Subjects
Affinity Labels chemistry, Annexin A5 chemistry, Annexin A5 metabolism, Blood Cells metabolism, Cell Line, Tumor, Flow Cytometry methods, Humans, Neoplasms metabolism, Proteins chemistry, Proteins metabolism, Technology, Apoptosis physiology, Fluorescent Dyes chemistry, Staining and Labeling methods
Abstract

In vitro and ex vivo development of novel therapeutic agents requires reliable and accurate analyses of the cell conditions they were preclinical tested for, such as apoptosis. The detection of apoptotic cells by annexin V (AV) coupled to fluorophores has often shown limitations in the choice of the dye due to interference with other fluorescent-labeled cell markers. The SNAP-tag technology is an easy, rapid and versatile method for functionalization of proteins and was therefore used for labeling AV with various fluorophores. We generated the fusion protein AV-SNAP and analyzed its capacity for the specific display of apoptotic cells in various assays with therapeutic agents. AV-SNAP showed an efficient coupling reaction with five different fluorescent dyes. Two selected fluorophores were tested with suspension, adherent and peripheral blood cells, treated by heat-shock or apoptosis-inducing therapeutic agents. Flow cytometry analysis of apoptotic cells revealed a strong visualization using AV-SNAP coupled to these two fluorophores exemplary, which was comparable to a commercial AV-Assay-kit. The combination of the apoptosis-specific binding protein AV with the SNAP-tag provides a novel solid method to facilitate protein labeling using several, easy to change, fluorescent dyes at once. It avoids high costs and allows an ordinary exchange of dyes and easier use of other fluorescent-labeled cell markers, which is of high interest for the preclinical testing of therapeutic agents in e.g. cancer research., Competing Interests: The authors have declared that no competing interests exist.

Published
2020
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44. The basic helix-loop-helix transcription factor TCF4 impacts brain architecture as well as neuronal morphology and differentiation.

Author

Schoof M, Hellwig M, Harrison L, Holdhof D, Lauffer MC, Niesen J, Virdi S, Indenbirken D, and Schüller U

Subjects
Animals, Facies, Hippocampus, Humans, Mice, Neurons, Hyperventilation, Intellectual Disability genetics, Transcription Factor 4 genetics
Abstract

Germline mutations in the basic helix-loop-helix transcription factor 4 (TCF4) cause the Pitt-Hopkins syndrome (PTHS), a developmental disorder with severe intellectual disability. Here, we report findings from a new mouse model with a central nervous system-specific truncation of Tcf4 leading to severe phenotypic abnormalities. Furthermore, it allows the study of a complete TCF4 knockout in adult mice, circumventing early postnatal lethality of previously published mouse models. Our data suggest that a TCF4 truncation results in an impaired hippocampal architecture affecting both the dentate gyrus as well as the cornu ammonis. In the cerebral cortex, loss of TCF4 generates a severe differentiation delay of neural precursors. Furthermore, neuronal morphology was critically affected with shortened apical dendrites and significantly increased branching of dendrites. Our data provide novel information about the role of Tcf4 in brain development and may help to understand the mechanisms leading to intellectual deficits observed in patients suffering from PTHS., (© 2020 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Published
2020
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45. Pik3ca mutations significantly enhance the growth of SHH medulloblastoma and lead to metastatic tumour growth in a novel mouse model.

Author

Niesen J, Ohli J, Sedlacik J, Dührsen L, Hellwig M, Spohn M, Holsten T, and Schüller U

Subjects
Animals, Cerebellar Neoplasms pathology, Disease Models, Animal, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, Humans, Medulloblastoma pathology, Mice, Transgenic, Neoplasms, Experimental diagnostic imaging, Neoplasms, Experimental genetics, Neoplasms, Experimental mortality, Patched-1 Receptor genetics, Smoothened Receptor genetics, Spinal Cord Neoplasms secondary, Survival Rate, Whole Genome Sequencing, Cerebellar Neoplasms genetics, Class I Phosphatidylinositol 3-Kinases genetics, Medulloblastoma genetics, Mutation
Abstract

Medulloblastoma (MB) is the most frequent malignant brain tumour in children with a poor outcome. Divided into four molecular subgroups, MB of the Sonic hedgehog (SHH) subgroup accounts for approximately 25% of the cases and is driven by mutations within components of the SHH pathway, such as its receptors PTCH1 or SMO. A fraction of these cases additionally harbour PIK3CA mutations, the relevance of which is so far unknown. To unravel the role of Pik3ca mutations alone or in combination with a constitutively activated SHH signalling pathway, transgenic mice were used. These mice show mutated variants within Smo, Ptch1 or Pik3ca genes in cerebellar granule neuron precursors, which represent the cellular origin of SHH MB. Our results show that Pik3ca mutations alone are insufficient to cause developmental alterations or to initiate MB. However, they significantly accelerate the growth of Shh MB, induce tumour spread throughout the cerebrospinal fluid, and result in lower survival rates of mice with a double Pik3caH1047R/SmoM2 or Pik3caH1047R/Ptch1 mutation. Therefore, PIK3CA mutations in SHH MB may represent a therapeutic target for first and second line combination treatments., Competing Interests: Declaration of competing interest The authors disclose no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Published
2020
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46. Screening and Prophylactic Amiodarone Reduces Post-Operative Atrial Fibrillation in At-Risk Patients.

Author

Pong T, Cyr K, Niesen J, Aparicio-Valenzuela J, Carlton C, Fischbein MP, Woo YJ, Boyd JH, and Lee AM

Subjects
Aged, Atrial Fibrillation etiology, Humans, Mass Screening, Middle Aged, Postoperative Complications etiology, Amiodarone therapeutic use, Anti-Arrhythmia Agents therapeutic use, Atrial Fibrillation prevention & control, Cardiac Surgical Procedures adverse effects, Postoperative Complications prevention & control
Published
2020
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47. hGFAP-Positive Stem Cells Depend on Brg1 for Proper Formation of Cerebral and Cerebellar Structures.

Author

Holdhof D, Schoof M, Hellwig M, Holdhof NH, Niesen J, and Schüller U

Subjects
Animals, Cerebellum pathology, Cerebral Cortex pathology, Female, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein metabolism, Hippocampus growth & development, Hippocampus physiology, Humans, Lateral Ventricles growth & development, Lateral Ventricles pathology, Male, Mice, Transgenic, Neural Stem Cells pathology, Neurons pathology, Neurons physiology, Cerebellum growth & development, Cerebral Cortex growth & development, DNA Helicases physiology, Neural Stem Cells physiology, Nuclear Proteins physiology, Transcription Factors physiology
Abstract

Brahma-related gene 1 (Brg1) is one of the two mutually exclusive catalytic subunits of the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. Several roles of Brg1 have been described including acting as a tumor suppressor but also functioning in neural stem cell (NSC) maintenance, neural crest development, or differentiation of oligodendrocytes and Schwann cells. Here, we generated human glial fibrillary acidic protein (hGFAP)-cre::Brg1fl/fl mice to analyze the function of Brg1 in multipotential NSCs during late stages of neural development. hGFAP-cre::Brg1fl/fl mice died approximately 2 weeks after birth. Macroscopic examination revealed a severe hydrocephalus and a decreased brain weight caused by the loss of Brg1. The cerebellum of hGFAP-cre::Brg1fl/fl mice displayed disorganized cortical layers as well as a massive hypoplasia due to a dramatically reduced number of granule neurons. The cerebrum presented with less proliferative and more apoptotic precursor cells in the subventricular zone (SVZ). Furthermore, the cerebral cortex stood out with significantly thinned upper layers and with impressive dendrite pathology. Finally, the hippocampus was severely underdeveloped with only a sparse number of detectable neurons. We conclude that NSCs depend on Brg1 to give rise to major essential brain structures including the cerebellum, the cerebral cortex, and the hippocampus., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Published
2020
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48. The transcriptional coactivator and histone acetyltransferase CBP regulates neural precursor cell development and migration.

Author

Schoof M, Launspach M, Holdhof D, Nguyen L, Engel V, Filser S, Peters F, Immenschuh J, Hellwig M, Niesen J, Mall V, Ertl-Wagner B, Hagel C, Spohn M, Lutz B, Sedlacik J, Indenbirken D, Merk DJ, and Schüller U

Subjects
Animals, CREB-Binding Protein genetics, Child, Preschool, Female, Humans, Infant, Male, Mice, Mice, Knockout, Mice, Transgenic, Retrospective Studies, Rubinstein-Taybi Syndrome diagnostic imaging, Rubinstein-Taybi Syndrome genetics, CREB-Binding Protein deficiency, Cell Movement physiology, Neural Stem Cells metabolism, Rubinstein-Taybi Syndrome metabolism, Transcriptional Activation physiology
Abstract

CREB (cyclic AMP response element binding protein) binding protein (CBP, CREBBP) is a ubiquitously expressed transcription coactivator with intrinsic histone acetyltransferase (KAT) activity. Germline mutations within the CBP gene are known to cause Rubinstein-Taybi syndrome (RSTS), a developmental disorder characterized by intellectual disability, specific facial features and physical anomalies. Here, we investigate mechanisms of CBP function during brain development in order to elucidate morphological and functional mechanisms underlying the development of RSTS. Due to the embryonic lethality of conventional CBP knockout mice, we employed a tissue specific knockout mouse model (hGFAP-cre::CBP Fl/Fl , mutant mouse) to achieve a homozygous deletion of CBP in neural precursor cells of the central nervous system.Our findings suggest that CBP plays a central role in brain size regulation, correct neural cell differentiation and neural precursor cell migration. We provide evidence that CBP is both important for stem cell viability within the ventricular germinal zone during embryonic development and for unhindered establishment of adult neurogenesis. Prominent histological findings in adult animals include a significantly smaller hippocampus with fewer neural stem cells. In the subventricular zone, we observe large cell aggregations at the beginning of the rostral migratory stream due to a migration deficit caused by impaired attraction from the CBP-deficient olfactory bulb. The cerebral cortex of mutant mice is characterized by a shorter dendrite length, a diminished spine number, and a relatively decreased number of mature spines as well as a reduced number of synapses.In conclusion, we provide evidence that CBP is important for neurogenesis, shaping neuronal morphology, neural connectivity and that it is involved in neuronal cell migration. These findings may help to understand the molecular basis of intellectual disability in RSTS patients and may be employed to establish treatment options to improve patients' quality of life.

Published
2019
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49. TCF4 (E2-2) harbors tumor suppressive functions in SHH medulloblastoma.

Author

Hellwig M, Lauffer MC, Bockmayr M, Spohn M, Merk DJ, Harrison L, Ahlfeld J, Kitowski A, Neumann JE, Ohli J, Holdhof D, Niesen J, Schoof M, Kool M, Kraus C, Zweier C, Holmberg D, and Schüller U

Subjects
Animals, Apoptosis genetics, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation genetics, Facies, Hedgehog Proteins metabolism, Humans, Hyperventilation genetics, Hyperventilation metabolism, Hyperventilation pathology, Intellectual Disability genetics, Intellectual Disability metabolism, Intellectual Disability pathology, Medulloblastoma metabolism, Medulloblastoma pathology, Mice, Mice, Knockout, Transcription Factor 4 metabolism, Hedgehog Proteins genetics, Medulloblastoma genetics, Mutation, Transcription Factor 4 genetics
Abstract

The TCF4 gene encodes for the basic helix-loop-helix transcription factor 4 (TCF4), which plays an important role in the development of the central nervous system (CNS). Haploinsufficiency of TCF4 was found to cause Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder. Recently, the screening of a large cohort of medulloblastoma (MB), a highly aggressive embryonal brain tumor, revealed almost 20% of adult patients with MB of the Sonic hedgehog (SHH) subtype carrying somatic TCF4 mutations. Interestingly, many of these mutations have previously been detected as germline mutations in patients with PTHS. We show here that overexpression of wild-type TCF4 in vitro significantly suppresses cell proliferation in MB cells, whereas mutant TCF4 proteins do not to the same extent. Furthermore, RNA sequencing revealed significant upregulation of multiple well-known tumor suppressors upon expression of wild-type TCF4. In vivo, a prenatal knockout of Tcf4 in mice caused a significant increase in apoptosis accompanied by a decreased proliferation and failed migration of cerebellar granule neuron precursor cells (CGNP), which are thought to be the cells of origin for SHH MB. In contrast, postnatal in vitro and in vivo knockouts of Tcf4 with and without an additional constitutive activation of the SHH pathway led to significantly increased proliferation of CGNP or MB cells. Finally, publicly available data from human MB show that relatively low expression levels of TCF4 significantly correlate with a worse clinical outcome. These results not only point to time-specific roles of Tcf4 during cerebellar development but also suggest a functional linkage between TCF4 mutations and the formation of SHH MB, proposing that TCF4 acts as a tumor suppressor during postnatal stages of cerebellar development.

Published
2019
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50. Determination of the instantaneous geostrophic flow within the three-dimensional magnetostrophic regime.

Author

Hardy CM, Livermore PW, Niesen J, Luo J, and Li K

Abstract

In his seminal work, Taylor (1963 Proc. R. Soc. Lond. A 274 , 274-283. (doi:10.1098/rspa.1963.0130).) argued that the geophysically relevant limit for dynamo action within the outer core is one of negligibly small inertia and viscosity in the magnetohydrodynamic equations. Within this limit, he showed the existence of a necessary condition, now well known as Taylor's constraint, which requires that the cylindrically averaged Lorentz torque must everywhere vanish; magnetic fields that satisfy this condition are termed Taylor states. Taylor further showed that the requirement of this constraint being continuously satisfied through time prescribes the evolution of the geostrophic flow, the cylindrically averaged azimuthal flow. We show that Taylor's original prescription for the geostrophic flow, as satisfying a given second-order ordinary differential equation, is only valid for a small subset of Taylor states. An incomplete treatment of the boundary conditions renders his equation generally incorrect. Here, by taking proper account of the boundaries, we describe a generalization of Taylor's method that enables correct evaluation of the instantaneous geostrophic flow for any three-dimensional Taylor state. We present the first full-sphere examples of geostrophic flows driven by non-axisymmetric Taylor states. Although in axisymmetry the geostrophic flow admits a mild logarithmic singularity on the rotation axis, in the fully three-dimensional case we show that this is absent and indeed the geostrophic flow appears to be everywhere regular., Competing Interests: We declare we have no competing interests.

Published
2018
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