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Autologous stem cell transplantation is routinely used in the management of several hematological diseases, solid tumors, and immune disorders. Peripheral blood stem cell (PBSC) collection performed by apheresis is the preferred source of stem cells. In this study, the potential impact of mobilization regimens on the performance of the Spectra Optia® continuous mononuclear cell collection system was evaluated. We performed a retrospective data analysis for patients undergoing autologous PBSC collection at the Medical University Vienna, Vienna General Hospital between September 2016 and June 2018. Collections were divided into two main groups according to the mobilization regimen received: without (210 collections) or with (99 collections) plerixafor. Assessed variables included product characteristics and collection efficiency (CE). Overall, product characteristics were similar between the groups. Median CD34+ CE2 was 50.1% versus 53.0%, and CE1 was 66.9% versus 69.9% following mobilization without and with plerixafor, respectively; the difference was not statistically significant. Simple linear regression showed a very weak positive correlation between the mobilization method and CE1 or CE2 (mobilization with plerixafor increased CE2 by 4.106%). In conclusion, the Spectra Optia® apheresis system led to high CE and a good quality of PBSC products when mobilization regimens with or without plerixafor were used.

Immune checkpoint control is one of several mechanisms that negatively influence the immune system and contribute to the development and progression of cancer. To enhance anti-tumor immune responses in patients with advanced solid tumors, we employ a novel autologous cancer cell therapy, APN401, which allows transient and highly specific silencing of Casitas B-lineage lymphoma-b (Cbl-b) in patients’ peripheral mononuclear cells (PBMCs). Cbl-b is an E3 ubiquitin protein ligase that plays a central role in both innate and adaptive immune responses. Here we present two patients with advanced, metastatic solid tumors: one patient diagnosed with appendix carcinoma, and one patient diagnosed with head and neck squamous cell carcinoma (HNSCC). Both showed stable disease (SD) during treatment with APN401. In an open-label, multicenter Phase Ib trial, two increasing dose levels of APN401 were evaluated in patients with advanced solid tumors. Using invIOs’s closed cell-processing platform - Enhancement Platform for immune Cells (EPiC) - patients’ PBMCs were purified from leukapheresis products and subsequently transfected with a small interfering ribonucleic acid (siRNA) to specifically block Cbl-b expression. The entire manufacturing process required less than six hours, and the drug product could be reinfused on the same day. The trial evaluated safety and clinical outcomes, as well as the activity and potency of the drug product. Additionally, various biomarkers were analyzed in patients’ peripheral blood, which was collected prior to each treatment cycle. Two patients, one with appendix carcinoma and one with HNSCC, showed stable disease after repeated APN401 treatments at the lowest and/or intermediate dose levels. Subsequent drug product analyses revealed increased IL-2 levels and elevated CD8/CD4 ratios, suggesting potential cytotoxic efficacy. In stimulation assays with HLA class I-restricted viral or tumor antigens, increased IFN-γ levels were detected and served as surrogate markers for improved immunity and tumor reactivity. 10X genomics and TCR clonotyping revealed clonal expansion of T cell subsets throughout the course of the treatment. Taken together, these initial results indicate that APN401, a novel personalized cancer cell therapy based on targeted silencing of Cbl-b in PBMCs, may be a safe and effective immunotherapy for solid tumors. This cell therapy will be further evaluated as a monotherapy along with potential combinations in clinical trials in various solid tumors. Ethics approval: The clinical trial was approved by the Medical University of Vienna institution’s independent Ethics Committee, approval number 1778/2020. Citation Format: Mario Kuttke, Alexander Dohnal, Andreas Tanzmann, Beate Pribitzer, Felix Batrina, Stefan Bunka, Sophia Spagl, Manuela Branka, Sarah Bischof, Kathrin Thell, Maria Urban, Hannes Muehleisen, Bernhard Peball, Bianca Gapp, Angela Halfmann, Markus Raderer, Gerald Prager, Thorsten Fuereder, Romana Gugenberger, Nina Worel. Case report: APN401, a novel cancer therapy using Cbl-b silenced autologous PBMCs, induced stable disease in two patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB187.

Gamma-irradiation of blood products is mandatory to avoid graft versus host disease in patients with immunosuppressed clinical conditions. Pathogen inactivation techniques were implemented to optimize safe blood component supply. The INTERCEPT treatment uses amotosalen together with UVA irradiation. The functional and molecular implications of these essential treatments have not yet been systematically assessed. The irradiation-induced inactivation of nucleic acids may actually be accompanied with modifications of chemically reactive polyunsaturated fatty acids, known to be important mediators of platelet functions. Thus, here we investigated eicosanoids and related fatty acids released upon treatment and during platelet storage for 7 days, complemented by the analysis of functional and metabolic consequences of these treatments. In contrast to gamma-irradiation, here we demonstrate that UVA treatment attenuated the formation of ALOX12-products such as 12-HETE and 12-HEPE but induced the formation of trans-arachidonic acids in addition to 11-HETE and HpODEs. Metabolic and functional issues like glucose consumption, lactate formation, platelet aggregation and clot firmness hardly differed between the two treatment groups. In vitro synthesis of trans-arachidonic acids (trans-AA) out of arachidonic acid in the presence of β-mercaptoethanol suggested that thiol radicals formed by UVA treatment are responsible for the INTERCEPT-specific effects observed in platelet concentrates. It is plausible to assume that trans-AA and other UVA-induced molecules may have specific biological effects on the recipients, which need to be addressed in future studies.Key pointsA previously unrecognized radical mechanisms for the generation of trans-fatty acids by UVA was identifiedIrradiation with UVA was found to immediately affect the generation of polyunsaturated fatty acid oxidation products

The global restrictions used to control the COVID-19 pandemic have caused an increase in malnutrition and hunger. Building resilient food systems will therefore be an absolute priority for the United Nations. Critics say the planned UN Food Systems Summit (FSS) under the influence of the agricultural lobby will hardly pay attention to local food markets and agroecology as the fundament for crisis-proof food systems. The agroindustrial system, with its enormous dependencies on global supply chains, has shown how fast farmers lose income in times of crisis and food insecurity.

Background: Therapies involving adoptive transfer of chimeric antigen receptor-modified T-cells (CARTs) targeting CD19-expressing B-cells have shown remarkable efficacy in patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). We hypothesized, that a higher fraction of more differentiated, senescent and exhausted T-cells affects negatively ex vivo T-cell expansion in the manufacturing phase of CARTs and the in vivo function of CARTs after infusion. Of note, naïve CD4+ T-cells were shown to uniformly express the co-stimulatory receptors CD27 and CD28, while repeated cycles of activation led to their progressive loss (van Leewen et al, J. Immunol, 2004), accompanied by telomere erosion and replicative senescence (van Baarle et al., Immunol. Lett. 2005; Effros RB et al., Dev Comp Immunol 1997). CD28 expression on T-cells within the tumor environment was shown to be a decisive factor for the efficacy of anti-PD-1 therapy (Kamphorst RO et al, Science 2017). We have therefore analyzed the CD27 and CD28 expression status of CD3+ T-cells from the peripheral blood and apheresis products of adult r/r DLBCL patients at the day of leukapheresis. Methods: Peripheral blood and apheresis samples of 22 consecutive r/r DLBCL patients scheduled for CART therapy were analyzed by flow cytometry to assess their CD27 and CD28 expression status on CD3+ T-cells. Samples were stained with fluorochrome conjugated antibodies (anti-CD3 PerCP, anti-CD27 FITC, CD28 PE, anti-CD4 FITC, BioLegend) and analyzed using a FACScalibur flow cytometer supported by CELLQUEST software (Becton Dickinson, BD, Palo Alto, CA). Results: To rule out an apheresis-related bias within cell populations we analyzed peripheral blood and apheresis samples for each patient. No differences in the distribution of CD27-, CD28-, CD27-/CD28- or CD27+/CD28+ T-cells between peripheral blood and apheresis product were detected. Mean CD3+ cell count in blood samples before apheresis was 624±399/µl (range, 75-1853cells/µL) with only about 25% of the patients presenting with CD3+ cell counts within the normal range (690-3320/µL) and 70% of the patients showed an inverse CD4/CD8 ratio (1.0) CD4/CD8 ratio (Figure 1c) in responding patients. Furthermore, we did not observe significant differences in CD27-and CD28- expression in samples derived from patients who died prior to receiving CART therapy (n=6) when compared to patients responding or progressing after CART therapy. Three patients have not been infused yet. Conclusion: We demonstrate in this small patient cohort that individuals with a lower percentage of more differentiated, senescent or exhausted T-cells are more likely to respond to CART therapy. Our observation underscores the importance of T-cells with normal replicative capacity in the apheresis material for consecutive CART production to achive therapeutic success. Further analysis is needed to determine the effect of cytotoxic pretreatment on the fraction of immunosenescent/exhausted T-cells. However, to confirm our findings additional investigations including the T-cell status of manufactured cells are warranted. Disclosures Worel: Sanofi Genzyme, Malinckrodt Therakos: Speakers Bureau; Sanofi Genzyme, Malinckrodt Therakos: Research Funding; Jazz, Sanofi, Celgene, Novartis, Malinckrodt Therakos: Honoraria. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria. Hopfinger:Celgene, Gilead, GlaxoSmithKline, Janssen, Novartis, Roche, Takeda,: Honoraria; Gilead: Research Funding.

Das kirchliche Hilfswerk Brot fur die Welt – Evangelischer Entwicklungsdienst ist in Zusammenhang mit seinem ethischen und religiosen Impetus, dem armen Teil der Weltbevolkerung zu Gerechtigkeit zu verhelfen, schon seit uber zehn Jahren mit den komplexen und gravierenden Folgen des globalen Huhnerfleisch-Konsums konfrontiert. Als Entwicklungshilfeorganisation betrachtet Brot fur die Welt das Thema vor allem aus Sicht der Armen und Marginalisierten in den Entwicklungslandern. Nicht zuletzt waren es Partnerorganisationen aus Kamerun, die das Thema auf die Agenda der Lobby- und Advocacy-Arbeit von Brot fur die Welt gesetzt haben. Somit beginnt die Thematik des Konsums von Huhnerfleisch am Ende der Produktionskette, denn es sind die Reste der europaischen Produktion, die auf die Markte Afrikas drangen und dort fur schwere Verwerfungen sorgen.

The demand for blood components is constantly increasing, while the exclusion criteria for donors are strengthened in order to reach maximal safety for donors and patients. To counterbalance reduced availability of volunteers, multicomponent collections (MCC) is an attractive approach to produce more than one component during a single apheresis procedure from one donor, such as packed red blood cells (PRBCs) and platelet concentrates (PCs). Further, the exposures of patients to a limited number of donors reduces the possibility of alloimmunization and transfusion-related diseases. We measured the quality of PRBCs and PCs obtained by MCC, using the MCS+ device with the LDPRBC program, Revision B, and compared them with the quality of manually collected PRBCs and PCs collected with the Revision C2 of the MCS+. We found higher pH levels and lower hemolysis assessed by means of fHb and K+ in the supernatant of PRBCs over the whole storage period of 42 days in MCC-derived PRBCs. The functional metabolism assessed by intracellular ATP was higher in PRBCs collected by MCC than in manually collected units. Furthermore, PCs obtained during MCC showed an increase in p-selectin expression on day 5 of storage compared to PCs collected with the Revision C2 of the MCS+. The p-selectin expression on MCC platelets was within the range of p-selectin expression found in PCs obtained by other apheresis devices. These results indicate less storage lesion in MCC-derived PRBCs compared to manually collected units and no compromise in the quality of MCC PCs obtained in the same apheresis procedure. J. Clin. Apheresis 18:21–25, 2003. © 2003 Wiley-Liss, Inc.

Kommunen finanzieren einen beträchtlichen Teil ihrer Ausgaben durch vertikale Zuweisungen. Die Dissertation geht der Frage nach, welche Wechselwirkungen zwischen Zuweisungen und dem politischen Wettbewerb bestehen. So können Zuweisungen vom Zuweisungsgeber instrumentalisiert werden, um die Wiederwahlaussichten zu erhöhen. Vor diesem Hintergrund wird eine empirische Untersuchung für die westdeutschen Flächenländer durchgeführt, in der überprüft wird, ob ein politischer Zyklus in der Zuweisungsvergabe zu beobachten ist. Darüber hinaus geht es in der Dissertation um die Frage, ob Zuweisungen den politischen Wettbewerb stabilisieren können. Den Ausgangspunkt bildet die These, dass Wähler Politiker nicht vollständig kontrollieren können und deswegen ein Prinzipal-Agenten-Problem auftritt, wobei Unsicherheit beim Wähler beispielsweise über Arbeitseinsatz, Kompetenz oder Aufrichtigkeit eines Politikers bestehen kann. Allerdings haben Wähler die Möglichkeit, Politikergebnisse in unterschiedlichen Gebietskörperschaften miteinander zu vergleichen, um das politisches Agenturproblem abzumildern. Dies ist die Grundidee der Theorie des Yardstick-Wettbewerbs. Nach einer kritischen Diskussion dieses Ansatzes innerhalb der Föderalismustheorie, werden in der Untersuchung die wichtigsten theoretischen Modelle des Yardstick-Wettbewerbs erörtert und empirische Untersuchungen vorgestellt. Im Anschluss daran wird ein Modell des Yardstick-Wettbewerbs entwickelt, in dem Politiker eine Innovation einführen, was mit einem besonders hohen Maß an Unsicherheit für die Wähler verbunden ist. In diesem Modellrahmen werden schließlich horizontale Zuweisungen eingeführt und deren Auswirkungen auf die Wählerwohlfahrt untersucht., Municipalities finance a substantial part of their expenditures by vertical grants. This thesis deals with the interaction between political competition and grants. Grantors may use grants to maximize their re-election prospects. The thesis contains an empirical study of the area states in West-Germany that tests the hypothesis of a political cycle in the allocation of grants. Another research question adressed in the thesis is, whether grants can stabilize the political competition. Starting point is the assumption that voters cannot control entirely their politicians and therefore a principal-agent problem arises. There might exist uncertainty on the part of the voters concerning a politician s effort, competency or corruptibility. The possibility of comparing the performances of different politicians across jurisdictions may be used by voters to alleviate the political agency problem. This is the basic idea of yardstick-competition. After a critical discussion of this approach within the theory of federalism, the most important theoretical models are introduced and empiricial findings presented. In a next step a model of yardstick-competition is developed, in which a politician introduces an innovation, that causes a high degree of uncertainty for voters. In this framework horizontal grants are introduced and their effect on voter welfare is analyzed.

Up to present the fact that the protagonist of the Rosmersholm-tragedy had become a victim of sexual abuse by her own father, has entirely been neglected nor been subject of any scientific research on Ibsen's works. The tabou constantly avoiding implications conscerning sexual abuse, and, in addition to that, Freud's interpretation of the tragedy, which favors (sic !) the daughter's sexual desire towards her father instead of the father's one towards his own daughter, might have been the underlying reason for this scientific negligence. The essay is a revised version of a basic chapter of the author's thesis critically debating psychoanalytic samples of research on and about the works of Gottfried Keller.

Nyní je na místě pohovořit o důvodech, které mě vedly k volbě období raného novověku respektive 16. a 17. století. Důvody se vlastně nabízejí samy. Most byl založen v polovině 14. století a tudíž starší období nepřichází v úvahu. 15. století není v pramenech, které jsem měl k dispozici, zastoupeno v dostatečném rozsahu. K období zhruba mezi lety 1500 a 1700 naopak existuje ideální množství dokumentů, pro potřeby této práce, které se dá prostudovat. Navíc je to epocha, která byla nazvána nazval zlatou dobou měst českých, připadala mi tedy nejvhodnější. Powered by TCPDF (www.tcpdf.org)

Mismatches between donor and recipient for human platelet antigens (HPA) may affect the success of transplantation due to: (a) serving as minor histocompa-tibility antigens and therefore render recipients at risk for graft-versus-host disease (GvHD), (b) inhibition of thrombopoiesis due to platelet antibodies. We therefore evaluated the occurrence of GvHD and need of platelet support by prospective analysis of donor–recipient pairs (n=53) for HPA-1, -2, -3, and -5 allotypes and screening for platelet antibodies prior to transplantation and in weekly intervals until day 100 after transplantation. Neither the incidence of GvHD nor the onset of thrombopoiesis, nor the CCI after platelet transfusions, nor the frequency of platelet transfusions was affected by HPA mismatches. Settings of homozygous donors vs heterozygous recipients or homozygous recipients vs heterozygous donors were not associated with any adverse effects on the outcome of the transplantation. Thus, the HPA-match does not affect the success of transplantation.