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Lambda and Antilambda reconstruction in central Pb+Pb collisions using a time projection chamber
(1997)
Yates, Tim A. ; Afanasiev, Sergey V. ; Alber, Thomas ; Appelshäuser, Harald ; Bächler, Joachim ; Bailey, Stephen John ; Barnby, Lee Stuart ; Bartke, Jerzy ; Białkowska, Helena ; Blyth, Charles O. ; Bock, Rudolf ; Bormann, Christian ; Brady, Franklin Paul ; Brockmann, Robert ; Buncic, Nenad ; Bunčić, Predrag ; Caines, Helen Louise ; Cebra, Daniel A. ; Chan, P ; Cooper, Glenn E. ; Cramer, John G. ; Cramer, Pauline B. ; Csató, Péter ; Dietz, Oliver ; Dunn, Jason ; Eckardt, Volker ; Eckhardt, Frank ; Ferguson, M. I. ; Fischer, Hans Gerhard ; Flierl, Dominik Bernhard ; Fodor, Zoltán ; Foka, Panagiota ; Freund, Peter ; Friese, Volker ; Fuchs, M ; Gabler, Frank ; Gál, József ; Gaździcki, Marek ; Gładysz-Dziaduś, Ewa ; Grebieszkow, Jaroslaw ; Günther, Jörg ; Harris, John W. ; Hegyi, Sándor ; Henkel, Torsten ; Hill, L. A. ; Huang, Isaac ; Howe, Mark A. ; Hümmler, Holm Gero ; Igo, George J. ; Irmscher, Detlef ; Jacobs, Peter Martin ; Jones, Peter Graham ; Kadija, Krešo ; Kolesnikov, Vadim I. ; Kowalski, Marek ; Lasiuk, Brian ; Lévai, Péter ; Malakhov, Aleksandr I. ; Margetis, Spyridon ; Markert, Christina ; Melkumov, Georgy L. ; Mock, Andreas ; Molnár, József ; Nelson, John M. ; Odyniec, Grazyna Janina ; Pálla, Gabriella ; Panagiotou, Apostolos D. ; Petridis, Athanasios ; Piper, Andreas ; Porter, R. Jefferson ; Poskanzer, Arthur M. ; Poziombka, Stefan ; Prindle, Duncan J. ; Pühlhofer, Falk ; Rauch, Wolfgang Hans ; Reid, Jeffrey G. ; Renfordt, Rainer Arno Ernst ; Retyk, Waldemar ; Ritter, Hans Georg ; Röhrich, Dieter ; Roland, Christof ; Roland, Gunther ; Rudolph, Heinrich ; Rybicki, Andrzej ; Sakrejda, Iwona ; Sandoval, Andres ; Sann, Hans ; Semenov, Alexei Yu. ; Schäfer, Erich ; Schmischke, Dirk ; Schmitz, Norbert ; Schönfelder, Stefan ; Seyboth, Peter ; Seyerlein, Jürgen ; Siklér, Ferenc ; Skrzypczak, Ewa ; Squier, Gordon Thomas Anderson ; Stock, Reinhard ; Ströbele, Herbert ; Szentpétery, Imre ; Sziklai, János ; Toy, Milton Y. ; Trainor, Thomas A. ; Trentalange, Stephen ; Ullrich, Thomas ; Vassiliou, Maria ; Vesztergombi, György ; Vranić, Danilo ; Wang, Feipeng ; Weerasundara, Dhammika D. ; Wenig, Siegfried ; Whitten, Charles A. ; Wienold, Thomas ; Wood, Lindsay ; Zimányi, József ; Zhu, X Z ; Zybert, Ryszard
The large acceptance time projection chambers of the NA49 experiment are used to record the trajectory of charged particles from Pb + Pb collisions at 158 GeV per nucleon. Neutral strange hadrons have been reconstructed from their charged decay products. To obtain distributions of Λ, and Ks0 in discrete bins of rapidity, y, and transverse momentum, pT, calculations have been performed to determine the acceptance of the detector and the efficiency of the reconstruction software as a function of both variables. The lifetime distributions obtained give values of cτ = 7.8 ± 0.6 cm for Λ and cτ = 2.5 ± 0.3 cm for Ks0, consistent with data book values.
Voskens, Caroline J. ; Goldinger, Simone M. ; Loquai, Carmen ; Robert, Caroline ; Kähler, Katharina C. ; Berking, Carola ; Bergmann, Tanja Regina ; Bockmeyer, Clemens Luitpold ; Eigentler, Thomas Kurt ; Fluck, Michael ; Garbe, Claus ; Gutzmer, Ralf ; Grabbe, Stephan ; Hauschild, Axel ; Hein, Rüdiger ; Hundorfean, Gheorghe ; Justich, Armin ; Keller, Ullrich ; Klein, Christina ; Mateus, Christine ; Mohr, Peter ; Pätzold, Sylvie ; Satzger, Imke ; Schadendorf, Dirk ; Schlaeppi, Marc ; Schuler, Gerold ; Schuler-Thurner, Beatrice ; Trefzer, Uwe ; Ulrich, Jens ; Vaubel, Julia ; Moos, Roger von ; Weder, Patrik ; Wilhelm, Tabea ; Göppner, Daniela ; Dummer, Reinhard ; Heinzerling, Lucie
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
Natural Killer (NK) cells are involved in the host immune response against infections due to viral, bacterial and fungal pathogens, all of which are a significant cause of morbidity and mortality in immunocompromised patients. Since the recovery of the immune system has a major impact on the outcome of an infectious complication, there is major interest in strengthening the host response in immunocompromised patients, either by using cytokines or growth factors or by adoptive cellular therapies transfusing immune cells such as granulocytes or pathogen-specific T-cells. To date, relatively little is known about the potential of adoptively transferring NK cells in immunocompromised patients with infectious complications, although the anti-cancer property of NK cells is already being investigated in the clinical setting. This review will focus on the antimicrobial properties of NK cells and the current standing and future perspectives of generating and using NK cells as immunotherapy in patients with infectious complications, an approach which is promising and might have an important clinical impact in the future.
Odyniec, Grazyna Janina ; Afanasiev, Sergey V. ; Alber, Thomas ; Appelshäuser, Harald ; Bächler, Joachim ; Bailey, Stephen John ; Barnby, Lee Stuart ; Bartke, Jerzy ; Białkowska, Helena ; Blyth, Charles O. ; Bock, Rudolf ; Bormann, Christian ; Brady, Franklin Paul ; Brockmann, Robert ; Buncic, Nenad ; Bunčić, Predrag ; Caines, Helen Louise ; Cebra, Daniel A. ; Chan, P. ; Cooper, Glenn E. ; Cramer, John G. ; Cramer, Pauline B. ; Csató, Péter ; Dietz, Oliver ; Dunn, Jason ; Eckardt, Volker ; Eckhardt, Frank ; Ferguson, M. I. ; Fischer, Hans Gerhard ; Flierl, Dominik Bernhard ; Fodor, Zoltán ; Foka, Panagiota ; Freund, Peter ; Friese, Volker ; Fuchs, M. ; Gabler, Frank ; Gál, József ; Gaździcki, Marek ; Gładysz-Dziaduś, Ewa ; Grebieszkow, Jaroslaw ; Günther, Jörg ; Harris, John W. ; Hegyi, Sándor ; Henkel, Torsten ; Hill, L. A. ; Huang, Isaac ; Howe, Mark A. ; Hümmler, Holm Gero ; Igo, George J. ; Irmscher, Detlef ; Jacobs, Peter Martin ; Jones, Peter Graham ; Kadija, Krešo ; Kolesnikov, Vadim I. ; Konashenok, Anton ; Kowalski, Marek ; Lasiuk, Brian ; Lévai, Péter ; Malakhov, Aleksandr I. ; Margetis, Spyridon ; Markert, Christina ; Melkumov, Georgy L. ; Mock, Andreas ; Molnár, József ; Nelson, John M. ; Pálla, Gabriella ; Panagiotou, Apostolos D. ; Petridis, Athanasios ; Piper, Andreas ; Porter, R. Jefferson ; Poskanzer, Arthur M. ; Poziombka, Stefan ; Prindle, Duncan J. ; Pühlhofer, Falk ; Rauch, Wolfgang Hans ; Reid, Jeffrey G. ; Renfordt, Rainer Arno Ernst ; Retyk, Waldemar ; Ritter, Hans Georg ; Röhrich, Dieter ; Roland, Christof ; Roland, Gunther ; Rudolph, Heinrich ; Rybicki, Andrzej ; Sakrejda, Iwona ; Sandoval, Andres ; Sann, Hans ; Semenov, Alexei Yu. ; Schäfer, Erich ; Schmischke, Dirk ; Schmitz, Norbert ; Schönfelder, Stefan ; Seyboth, Peter ; Seyerlein, Jürgen ; Siklér, Ferenc ; Skrzypczak, Ewa ; Squier, Gordon Thomas Anderson ; Stock, Reinhard ; Ströbele, Herbert ; Szentpétery, Imre ; Sziklai, János ; Toy, Milton Y. ; Trainor, Thomas A. ; Trentalange, Stephen ; Ullrich, Thomas ; Vassiliou, Maria ; Vesztergombi, György ; Vranić, Danilo ; Wang, Feipeng ; Weerasundara, Dhammika D. ; Wenig, Siegfried ; Whitten, Charles A. ; Wienold, Thomas ; Wood, Lindsay ; Yates, Tim A. ; Zimányi, József ; Zhu, Xue-Zhou ; Zybert, Ryszard
Using the NA49 main TPC, the central production of hyperons has been measured in CERN SPS Pb - Pb collisions at 158 GeV c-1. The preliminary ratio, studied at 2.0 < y < 2.6 and 1 < pT < 3 GeV c-1, equals ~ (13 ± 4)% (systematic error only). It is compatible, within errors, with the previously obtained ratios for central S + S [1], S + W [2], and S + Au [3] collisions. The fit to the transverse momentum distribution resulted in an inverse slope parameter T of 297 MeV. At this level of statistics we do not see any noticeable enhancement of hyperon production with the increased volume (and, possibly, degree of equilibration) of the system from S + S to Pb + Pb. This result is unexpected and counterintuitive, and should be further investigated. If confirmed, it will have a significant impact on our understanding of mechanisms leading to the enhanced strangeness production in heavy-ion collisions.
Merker, Michael ; Wagner, Juliane ; Kreyenberg, Hermann ; Heim, Catrin Birgit ; Moser, Laura M. ; Wels, Winfried ; Bönig, Halvard-Björn ; Ullrich, Evelyn ; Klingebiel, Thomas ; Bader, Peter ; Rettinger, Eva
High-risk rhabdomyosarcoma (RMS) occurring in childhood to young adulthood is associated with a poor prognosis; especially children above the age of 10 with advanced stage alveolar RMS still succumb to the disease within a median of 2 years. The advent of chimeric antigen receptor (CAR)-engineered T cells marked significant progress in the treatment of refractory B cell malignancies, but experience for solid tumors has proven challenging. We speculate that this is at least in part due to the poor quality of the patient's own T cells and therefore propose using CAR-modified cytokine-induced killer (CIK) cells as effector cells. CIK cells are a heterogeneous population of polyclonal T cells that acquire phenotypic and cytotoxic properties of natural killer (NK) cells through the cultivation process, becoming so-called T-NK cells. CIK cells can be genetically modified to express CARs. They are minimally alloreactive and can therefore be acquired from haploidentical first-degree relatives. Here, we explored the potential of ERBB2-CAR-modified random-donor CIK cells as a treatment for RMS in xenotolerant mice bearing disseminated high-risk RMS tumors. In otherwise untreated mice, RMS tumors engrafted 13–35 days after intravenous tumor cell injection, as shown by in vivo bioluminescence imaging, immunohistochemistry, and polymerase chain reaction for human gDNA, and mice died shortly thereafter (median/range: 62/56–66 days, n = 5). Wild-type (WT) CIK cells given at an early stage delayed and eliminated RMS engraftment in 4 of 6 (67%) mice, while ERBB2-CAR CIK cells inhibited initial tumor load in 8 of 8 (100%) mice. WT CIK cells were detectable but not as active as CAR CIK cells at distant tumor sites. CIK cell therapies during advanced RMS delayed but did not inhibit tumor progression compared to untreated controls. ERBB2-CAR CIK cell therapy also supported innate immunity as evidenced by selective accumulation of NK and T-NK cell subpopulations in disseminated RMS tumors, which was not observed for WT CIK cells. Our data underscore the power of heterogenous immune cell populations (T, NK, and T-NK cells) to control solid tumors, which can be further enhanced with CARs, suggesting ERBB2-CAR CIK cells as a potential treatment for high-risk RMS.
Magdy Abdelwahab Abdelrahman, Niseem ; Adamczyk, Leszek ; Adkins, J. Kevin ; Agakishiev, Geydar ; Aggarwal, Madan Mohan ; Ahammed, Zubayer ; Alekseev, Igor G. ; Alford, J. ; Anson, Christopher Daniel ; Aparin, Alexey ; Arkhipkin, Dmitry A. ; Aschenauer, Elke Caroline ; Averichev, Georgy S. ; Banerjee, A. ; Beavis, Dana Richard ; Bellwied, Rene ; Bhasin, Anju ; Bhati, Ashok Kumar ; Bhattarai, P. ; Bielčík, Jaroslav ; Bielčíková, Jana ; Bland, Leslie C. ; Bordyuzhin, Igor G. ; Borowski, W. ; Bouchet, Jonathan ; Brandin, Andrei V. ; Brovko, Samantha G. ; Bültmann, Stephen L. ; Bunzarov, Ivan ; Burton, T.P. ; Butterworth, Joseph ; Caines, Helen Louise ; Calderón de la Barca Sánchez, Manuel ; Campbell, J.M. ; Cebra, Daniel A. ; Cendejas, R. ; Cervantes, M.C. ; Chaloupka, Petr ; Chang, Z. ; Chattopadhyay, S. ; Chen, H.F. ; Chen, J.H. ; Chen, L. ; Cheng, J. ; Cherney, Michael Gerard ; Chikanian, Alexei ; Christie, William ; Codrington, M.J.M. ; Contin, Giacomo ; Cramer, John G. ; Crawford, Henry J. ; Cui, X. ; Das, Supriya ; Davila Leyva, A. ; De Silva, L.C. ; Debbe, R.R. ; Dedovič, Tatiana G. ; Deng, J. ; Derevschikov, Anatoly A. ; Souza, Rafael Derradi de ; di Ruzza, Benedetto ; Didenko, Lidia ; Dilks, Christopher ; Ding, F. ; Djawotho, P. ; Dong, X. ; Drachenberg, James Lucus ; Draper, James E. ; Du, C.M. ; Dunkelberger, Lloyd Edward ; Dunlop, James C. ; Efimov, Leonid G. ; Engelage, Jon M. ; Engle, K.S. ; Eppley, Geary Wareham ; Eun, L. ; Evdokimov, Olga Y. ; Eyser, Kjeld Oleg ; Fatemi, Renee H. ; Fazio, Salvatore ; Fedorišin, Jan ; Filip, Peter ; Fisyak, Yuri V. ; Flores, C.E. ; Gagliardi, Carl A. ; Gangadharan, Dhevan Raja ; Garand, David ; Geurts, Frank ; Gibson, Adam ; Girard, M. ; Gliske, S. ; Greiner, Leo Clifford ; Grosnick, David P. ; Gunarathne, D.S. ; Guo, Y. ; Gupta, Anik ; Gupta, S. ; Guryn, Włodzimierz ; Haag, B. ; Hamed, Ahmed M. ; Han, L-X. ; Haque, R. ; Harris, John W. ; Heppelmann, Steven Francis ; Hirsch, Andrew S. ; Hoffmann, Gerald W. ; Hofman, D.J. ; Horvat, S. ; Huang, B. ; Huang, H.Z. ; Huang, X. ; Huck, Patrick ; Humanic, Thomas J. ; Igo, George J. ; Jacobs, William W. ; Jang, H. ; Judd, Eleanor G. ; Kabana, Sonia ; Kalinkin, Dmitry ; Kang, K. ; Kauder, Kolja ; Ke, Hongwei ; Keane, Declan ; Kechechyan, Armen ; Kesich, A. ; Khan, Z.H. ; Kikola, D.P. ; Kisel, Ivan ; Kisiel, Adam Ryszard ; Koetke, Donald D. ; Kollegger, Thorsten ; Konzer, J. ; Koralt, I. ; Kosarzewski, Leszek Krzysztof ; Kotchenda, L. ; Kraishan, A.F. ; Kravtsov, Peter ; Krueger, Keith William ; Kulakov, Igor ; Kumar, Lokesh ; Kycia, R.A. ; Lamont, Matthew A. C. ; Landgraf, Jeffery M. ; Landry, K.D. ; Lauret, Jerome ; Lebedev, Alexei ; Lednicky, Richard ; Lee, J.H. ; Li, C. ; Li, W. ; Li, Xiaomei ; Li, Xiaomei ; Li, Y. ; Li, Z.M. ; Lisa, Michael A. ; Liu, F. ; Ljubicic, Tonko A. ; Llope, William Joseph ; Lomnitz, Michael ; Longacre, Ronald S. ; Luo, X. ; Ma, G.L. ; Ma, Yu-Gang ; Mahapatra, D.P. ; Majka, Richard Daniel ; Margetis, Spyridon ; Markert, Christina ; Masui, H. ; Matis, Howard S. ; McDonald, Daniel ; McShane, Tom S. ; Minaev, Nikolai G. ; Mioduszewski, Saskia ; Mohanty, Bedangadas ; Mondal, Mriganka Mouli ; Morozov, Dmitry A. ; Mustafa, M.K. ; Nandi, Basanta Kumar ; Nasim, Md. ; Nayak, Tapan Kumar ; Nelson, John M. ; Nigmatkulov, Grigory A. ; Nogach, Larisa V. ; Noh, S.Y. ; Novak, J. ; Nurušev, Sandibek B. ; Odyniec, Grazyna Janina ; Ogawa, Akio ; Oh, Kunsu ; Ohlson, Alice ; Okorokov, Vitaly A. ; Oldag, E.W. ; Olvitt, D.L. ; Page, Brian S. ; Pan, Y.X. ; Pandit, Y. ; Panebratsev, Yuri ; Pawlak, Tomasz Jan ; Pawlik, Bogdan ; Pei, Hua ; Perkins, Chris ; Pile, P. ; Planinic, Mirko ; Pluta, Jan Marian ; Poljak, Nikola ; Poniatowska, K. ; Porter, Jeffrey Brent ; Poskanzer, Arthur M. ; Pruthi, Navneet Kumar ; Przybycien, Mariusz ; Putschke, Jörn H. ; Qiu, H. ; Quintero, Amilkar ; Ramachandran, Suvarna ; Raniwala, Rashmi ; Raniwala, Sudhir ; Ray, Robert L. ; Riley, C.K. ; Ritter, Hans Georg ; Roberts, Jabus B. ; Rogačevskij, Oleg V. ; Romero, Juan L. ; Ross, J.F. ; Roy, Ankhi ; Ruan, Lijuan ; Rusnak, Jan ; Rusnakova, Olga ; Sahoo, Nihar Ranjan ; Sahu, Pradip Kumar ; Sakrejda, Iwona ; Salur, Sevil ; Sandacz, Andrzej ; Sandweiss, Jack H. ; Sangaline, Evan ; Sarkar, Amal ; Schambach, Joachim ; Scharenberg, Rolf Paul ; Schmah, Alexander ; Schmidke, William B. ; Schmitz, Norbert ; Seger, Janet Elizabeth ; Seyboth, Peter ; Shah, N. ; Shahaliev, Ehtiram ; Shanmuganathan, Prashanth V. ; Shao, M. ; Sharma, B. ; Shen, W.Q. ; Shi, S.S. ; Shou, Q.Y. ; Sichtermann, Ernst P. ; Šimko, Miroslav ; Skoby, M.J. ; Smirnov, Dmitri V. ; Smirnov, Nikolai ; Solanki, D. ; Sorensen, Paul Richard ; Spinka, Harold. M. ; Srivastava, Brijesh Kumar ; Stanislaus, T. D. Shirvel ; Stevens, J.R. ; Stock, Reinhard ; Strichanov, Michail Nikolaevič ; Stringfellow, Blair ; Šumbera, Michal ; Sun, X. ; Sun, X.M. ; Sun, Y. ; Sun, Z. ; Surrow, Bernd ; Svirida, Dmitry N. ; Symons, Timothy James MacNeil ; Szelezniak, M.A. ; Takahashi, Jun ; Tang, Aihong ; Tang, Zebo ; Tarnowsky, Terence J. ; Thomas, James H. ; Timmins, Anthony Robert ; Tlusty, David ; Tokarev, Mikhail V. ; Trentalange, Stephen ; Tribble, Robert E. ; Tribedy, Prithwish ; Trzeciak, Barbara Antonina ; Tsai, Oleg D. ; Turnau, J. ; Ullrich, Thomas ; Underwood, David G. ; Van Buren, Gene ; Nieuwenhuizen, Gerrit J. van ; Vandenbroucke, Maxence ; Vanfossen, Joseph A. ; Varma, Raghava ; Vasconcelos, Geraldo M. S. ; Vasiliev, Alexander Nikolaevich ; Vértesi, Róbert ; Videbæk, Flemming ; Viyogi, Yogendra P. ; Vokal, Stanislav ; Vossen, A. ; Wada, M. ; Wang, F. ; Wang, G. ; Wang, H. ; Wang, J.S. ; Wang, X.L. ; Wang, Y. ; Wang, Y. ; Webb, Grant ; Webb, Jason C. ; Westfall, Gary D. ; Wieman, Howard ; Wissink, Scott W. ; Wu, Y.F. ; Xiao, Z. ; Xie, W. ; Xin, K. ; Xu, H. ; Xu, J. ; Xu, N. ; Xu, Q.H. ; Xu, Y. ; Xu, Z. ; Yan, W. ; Yang, C. ; Yang, Y. ; Yang, Y. ; Ye, Z. ; Yepes, Pablo P. ; Yi, L. ; Yip, K. ; Yoo, In-Kwon ; Yu, N. ; Zbroszczyk, Hanna Paulina ; Zha, W. ; Zhang, J.B. ; Zhang, J.L. ; Zhang, S. ; Zhang, X.P. ; Zhang, Y. ; Zhang, Z.P. ; Zhao, F. ; Zhao, J. ; Zhong, C. ; Zhu, X. ; Zhu, Y.H. ; Zoulkarneeva, Youlia ; Zyzak, Maksym
A data-driven method was applied to Au+Au collisions at √sNN = 200 GeV made with the STAR detector at RHIC to isolate pseudorapidity distance η-dependent and η-independent correlations by using two- and four-particle azimuthal cumulant measurements. We identified a η-independent component of the correlation, which is dominated by anisotropic flow and flow fluctuations. It was also found to be independent of η within the measured range of pseudorapidity |η| < 1. In 20–30% central Au+Au collisions, the relative flow fluctuation was found to be 34%±2%(stat.)±3%(sys.) for particles with transverse momentum pT less than 2 GeV/c. The η-dependent part, attributed to nonflow correlations, is found to be 5% ± 2%(sys.) relative to the flow of the measured second harmonic cumulant at |η| > 0.7.
Hünecke, Sabine ; Cappel, Claudia ; Esser, Ruth ; Pfirrmann, Verena ; Salzmann-Manrique, Emilia ; Betz, Sibille ; Keitl, Eileen ; Banisharif-Dehkordi, Julia ; Bakhtiar, Shahrzad ; Königs, Christoph ; Jarisch, Andrea ; Sörensen, Jan ; Ullrich, Evelyn ; Klingebiel, Thomas ; Bader, Peter ; Bremm, Melanie
Natural killer (NK) cells play an important role following allogeneic hematopoietic stem cell transplantation (HSCT) exerting graft-versus-leukemia/tumor effect and mediating pathogen-specific immunity. Although NK cells are the first donor-derived lymphocytes reconstituting post-HSCT, their distribution of CD56++CD16− (CD56bright), CD56++CD16+ (CD56intermediate=int), and CD56+CD16++ (CD56dim) NK cells is explicitly divergent from healthy adults, but to some extent comparable to the NK cell development in early childhood. The proportion of CD56bright/CD56int/CD56dim changed from 15/8/78% in early childhood to 6/4/90% in adults, respectively. Within this study, we first compared the NK cell reconstitution post-HSCT to reference values of NK cell subpopulations of healthy children. Afterward, we investigated the reconstitution of NK cell subpopulations post-HSCT in correlation to acute graft versus host disease (aGvHD) and chronic graft versus host disease (cGvHD) as well as to viral infections. Interestingly, after a HSCT follow-up phase of 12 months, the distribution of NK cell subpopulations largely matched the 50th percentile of the reference range for healthy individuals. Patients suffering from aGvHD and cGvHD showed a delayed reconstitution of NK cells. Remarkably, within the first 2 months post-HSCT, patients suffering from aGvHD had significantly lower levels of CD56bright NK cells compared to patients without viral infection or without graft versus host disease (GvHD). Therefore, the amount of CD56bright NK cells might serve as an early prognostic factor for GvHD development. Furthermore, a prolonged and elevated peak in CD56int NK cells seemed to be characteristic for the chronification of GvHD. In context of viral infection, a slightly lower CD56 and CD16 receptor expression followed by a considerable reduction in the absolute CD56dim NK cell numbers combined with reoccurrence of CD56int NK cells was observed. Our results suggest that a precise analysis of the reconstitution of NK cell subpopulations post-HSCT might indicate the occurrence of undesired events post-HSCT such as severe aGvHD.values
No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors
(2019)
Hopfner, Franziska ; Müller, Stefanie H. ; Steppat, Dagmar ; Miller, Joanna ; Schmidt, Nele ; Wandinger, Klaus-Peter ; Leypoldt, Frank ; Berg, Daniela ; Franke, Andre ; Lieb, Wolfgang ; Tittmann, Lukas ; Balzer-Geldsetzer, Monika ; Baudrexel, Simon ; Dodel, Richard ; Hilker-Roggendorf, Rüdiger ; Kalbe, Elke ; Kassubek, Jan ; Klockgether, Thomas ; Liepelt-Scarfone, Inga ; Mollenhauer, Brit ; Neuser, Petra ; Reetz, Kathrin ; Riedel, Oliver ; Schulte, Claudia ; Schulz, Jörg B. ; Spottke, Annika ; Storch, Alexander ; Trenkwalder, Claudia ; Wittchen, Hans-Ulrich ; Witt, Karsten ; Wüllner, Ullrich ; Deuschl, Günther ; Kuhlenbäumer, Gregor
Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.
Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.
Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.
Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.
Heinze, Annekathrin ; Grebe, Beatrice ; Bremm, Melanie ; Hünecke, Sabine ; Munir, Tasleem Ah. ; Graafen, Lea ; Früh, Jochen ; Merker, Michael ; Rettinger, Eva ; Sörensen, Jan ; Klingebiel, Thomas ; Bader, Peter ; Ullrich, Evelyn ; Cappel, Claudia
Neuroblastoma (NB) is the most common solid extracranial tumor in childhood. Despite therapeutic progress, prognosis in high-risk NB is poor and innovative therapies are urgently needed. Therefore, we addressed the potential cytotoxic capacity of interleukin (IL)-activated natural killer (NK) cells compared to cytokine-induced killer (CIK) cells for the treatment of NB. NK cells were isolated from peripheral blood mononuclear cells (PBMCs) by indirect CD56-enrichment or CD3/CD19-depletion and expanded with different cytokine combinations, such as IL-2, IL-15, and/or IL-21 under feeder-cell free conditions. CIK cells were generated from PBMCs by ex vivo stimulation with interferon-γ, IL-2, OKT-3, and IL-15. Comparative analysis of expansion rate, purity, phenotype and cytotoxicity was performed. CD56-enriched NK cells showed a median expansion rate of 4.3-fold with up to 99% NK cell content. The cell product after CD3/CD19-depletion consisted of a median 43.5% NK cells that expanded significantly faster reaching also 99% of NK cell purity. After 10–12 days of expansion, both NK cell preparations showed a significantly higher median cytotoxic capacity against NB cells relative to CIK cells. Remarkably, these NK cells were also capable of efficiently killing NB spheroidal 3D culture in long-term cytotoxicity assays. Further optimization using a novel NK cell culture medium and a prolonged culturing procedure after CD3/CD19-depletion for up to 15 days enhanced the expansion rate up to 24.4-fold by maintaining the cytotoxic potential. Addition of an IL-21 boost prior to harvesting significantly increased the cytotoxicity. The final cell product consisted for the major part of CD16−, NCR-expressing, poly-functional NK cells with regard to cytokine production, CD107a degranulation and antitumor capacity. In summary, our study revealed that NK cells have a significantly higher cytotoxic potential to combat NB than CIK cell products, especially following the synergistic use of IL-15 and IL-21 for NK cell activation. Therefore, the use of IL-15+IL-21 expanded NK cells generated from CD3/CD19-depleted apheresis products seems to be highly promising as an immunotherapy in combination with haploidentical stem cell transplantation (SCT) for high-risk NB patients.