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This study investigates practices of sharing the experience of stroke on Instagram through use of the hashtag #strokesurvivor. The hashtag brings together people from different cultural backgrounds and professions and those who experience different kinds of healthcare and varying degrees of physical or cognitive impairment. Through a digital ethnography of #strokesurvivor, the conjunctive experiences and communicative practices of the community are reconstructed. Instagram enables specific forms of sociality and sharing, like long-term visual storytelling and influencer dynamics. Adapting to a transformed body and identity is perceived and practiced as a conjunctive experience and a struggle. A strong orientation towards a “normal life” is a recurring theme. Mourning and perseverance are put forward as two modes of coping with and adapting to a transforming body and self.

Der gewaltsame Tod von George Floyd Ende Mai 2020 löste eine globale Protestbewegung aus: Ausgehend von den USA fanden weltweit zahlreiche Kundgebungen, Demonstrationen und Mahnwachen statt, mit denen gegen Rassismus und Polizeigewalt Stellung bezogen wurde. Dieser Protest war und ist Gegenstand unterschiedlicher visueller Repräsentationen und medialer Formen, die einen wichtigen Anteil an den Bedeutungsproduktionen rund um die Protesthandlungen haben. Auf Basis einer Bildtypenanalyse der (Bild-)Berichterstattung über die Proteste in deutschsprachigen Tageszeitungen sowie der Darstellungsformen auf Instagram im Kontext von Demonstrationen im deutschsprachigen Raum setzt sich der Beitrag mit visuellen Konstruktionen von Protest auseinander und diskutiert deren Bedeutung vor dem Hintergrund gesellschaftlicher, medialer und politischer Kontexte. Es zeigen sich jeweils unterschiedlich dominierende Bildtypen: So sind in der Medienberichterstattung Bilder von Demonstrierenden als Masse vorherrschend, die die einzelnen Teilnehmer:innen nicht wahrnehmbar machen. Auf Instagram finden sich vor allem Innen-Perspektiven der Demonstrationen durch individuelle (Selbst-)Inszenierungen der Demonstrierenden. Deutlich wird zudem, dass die journalistischen Bilder die Proteste insbesondere im Hinblick auf spannungsreiche Konfliktsituationen im US-Kontext mit hohem Nachrichtenwert zeigen, während auf Instagram die Vergemeinschaftung über Gruppenbilder und damit die Inszenierung und Mobilisierung der Teilnehmenden in den Vordergrund rückt. The violent death of George Floyd at the end of May 2020 triggered a global protest movement: Starting in the US, numerous rallies, demonstrations, and vigils took place around the world, taking a stand against racism and police violence. This protest was and is subject to different visual representations and mediated expressions, which have an important share in the production of meaning around the protest actions. Based on a picture type analysis of the (image) coverage of the protests in Austrian, German and Swiss newspapers as well as on visual expressions on Instagram in the context of demonstrations in German-speaking cities, the article deals with visual constructions of protest and discusses their meaning against the background of social, media, and political contexts. Different dominant image types emerge in each case: In media coverage, for example, images of demonstrators as a mass are predominant, which make the individual participants imperceptible. On Instagram, there are mainly internal perspectives of the demonstrations through individual self-dramatizations of the demonstrators. It also becomes clear that journalistic images show protests with a high news value, especially with regard to tense conflict situations in the US context, while on Instagram the communalization via group images and thus the staging and mobilization of the participants comes to the fore.

Building on previous online-ethnographic fieldwork on the #strokesurvivor-community on Instagram, this contribution dives deeper into practices of echo-locating (Markham 2020) the vulnerable self on Instagram. This paper aims to reconstruct practices of adapting to a new body, identity and self through communicating on Instagram from a symbolic-interactionist perspective. I build on Goffman’s concept of stigma, Charmaz’ studies on adapting to illness and impairment and use the lens of Markham’s (2020) concept of echo-locating the self through online connection, Based on close readings and interpretations of postings, including pictures, captions and comments, as well as interviews with active community members, two critical antipodes of sense- and self-making in the #strokesurvivor-community emerged: First, mourning the loss of the familiar body, self, and identity and related identity goals. Users seek permission to mourn and also validation for their grief through their postings and comments. Second, and probably oppositional, perseverance, or in its extreme form, toxic positivity - this concept refers to a (more or less forced) attitude of optimism while ignoring valid reasons to actually not be positive, a mindset that seems to be embedded in a “contemporary cult of happiness” (Wright 2014) and cruel optimism (Berlant 2010). In the #strokesurvivor-community, a positive mindset and belief in the possibility of regaining physical and mental functions is a recurring theme and strong imperative. The contribution focuses on the reconstruction of patterns and practices of mourning and perseverance and their relevance to the echo-location of the vulnerable self.

Orientador: Eduardo Roberto Junqueira Guimarães Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Estudos da Linguagem Resumo: Inicia-se o estudo com o objetivo de levantar hipóteses sobre o estatuto gramatical do morfema aliás. Em seguida consideram-se basicamente os trabalhos do lingüista Oswald Ducrot. Apresenta-se a abordagem sobre o aliás (Ducrot e outros: 1980b). Questões levantadas nesta primeira abordagem aparecem reinterpretadas a partir da Teoria Polifõnica da Enunciação (Ducrot, 1987), aqui apresentada. Fala-se sobre estudos da Polifonia no Brasil e há uma análise de uma seqüência textual, principalmente com base em Guimarães (1987). Mais adiante caracteriza-se o aliás em relação à Polifonia e Argumentação. Compara-se o aliás com na verdade, de fato, com efeito, além disso, até mesmo. Conclui-se que o aliás apresenta polifonia e seu funcionamento enunciativo aponta, inclusive, para a textualidade. O estudo, ao contrário do que se previa, considera que se o aliás é polifônico e tem a ver com a textualidade, então na seqüência X aliás Y não interessa muito dizer em que classe gramatical essa expressão se encaixa Abstract: Not informed. Mestrado Mestre em Linguística

Nosso objetivo é explicar a mobilidade do sentido de negra numa postagem do presidente da Fundação Cultural Palmares (FCP). Analisamos o agenciamento enunciativo (GUIMARÃES, 2002; 2018) e as redes enunciativas (DIAS, 2018). Por esta relação teórica, observamos que o funcionamento dos lugares enunciativos nos mostra diferentes movimentos na enunciação. Estes por sua vez se explicam no memorável e se ancoram nos referenciais históricos das redes enunciativas, aliados às enunciações estudadas. Vimos que ao significar negra, o referencial histórico ao qual se vincula o que é ser negro para o partido em questão é apagado para desmoralizá-lo e, por consequência, desmoraliza o movimento negro, produzindo uma enunciação com um efeito de cinismo.

O presente artigo tem o objetivo de analisar enunciados em livros didáticos sobre as expressões migração, ditadura militar e conquistadores. Com base na Semântica do Acontecimento (2009; 2017; 2018), as análises dessas expressões apresentam uma descrição da cena enunciativa, tratando a questão da alusão no agenciamento enunciativo e de como a argumentação e a argumentatividade são construídas no acontecimento do livro didático. Temos como corpus três capítulos de três livros didáticos (dois de história e um de geografia) com selos do Programa Nacional do Livro e do Material Didático (PNLD). Constatamos a mobilização dos lugares de enunciação para sustentar as argumentações nos livros.

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In den vorangehenden Kapiteln wurden die relevanten theoretischen Konzepte Praktiken (2.1), Bilder (2.2) und Medien (2.3) im Detail diskutiert. Wie bereits in der Einleitung skizziert, konvergieren diese drei Dimensionen im Forschungsgegenstand der vorliegenden Arbeit, den digitalen, fotografischen Bildpraktiken: Diese werden als Praktiken der Kommunikation in und mit digitalen (fotografischen) Bildern gefasst, die innerhalb bestimmter medialer Bedingungen der Hardware Smartphone und diverser Software-Applikationen stattfinden. Das method(olog)ische Vorgehen wurde entlang der theoretischen Perspektiven entwickelt und systematisiert.

Neste artigo, estudo como a cidade se significa pelo digital, analisando enunciados e ícones que se formulam pelo digital. Preocupo-me com a materialidade específica da ideologia no discurso digital no modo de interpretação do sujeito. Trabalho com a noção de forma material de Orlandi (1996) para analisar a relação entre a Língua Portuguesa e a Língua Inglesa. Apoio-me nos estudos de Dias (2018) e na noção de Textualidade de Guimarães (2018). Retomo o conceito de Link conforme Schreiber da Silva, Stalhauer (2016). Trabalho com a visão de memória de Dias, (2018).

This research investigates how the practices of sharing pictures with specific audiences on social media may be related to aesthetics and affordances. Based on fieldwork (interviews, picture analysis and digital ethnography) with a group of female teenagers in Vienna, Austria, how they visually curate their accounts is mapped and reconstructed. Regarding content and aesthetics, different kinds of pictures are shared using different apps. Snapchat, for example, (for this specific group at the time of the investigation) is the preferred medium for live communication with very close friends using fast, pixelated, “ugly” pictures, while Instagram serves to share polished, conventional, “beautiful” pictures with broader audiences. Based on this case study, three conceptual arguments can be made. First, visual communication is practised in relation to specific social settings or audiences. Social media is part of these practices, and users navigate differences between platforms to manage identities and relationships. Second, the analysis of practices embedded in specific software, therefore, has to be contextualised and related to the structures of these environments. Software co-constructs processes of editing, distribution, sharing and affirmation, and its affordances have to be related to the ways in which users exploit them. Third, as visual communication becomes an intrinsic part of online communication, the exploration of how distinctions between audiences and affordances play out stylistically appears to be of particular interest, which entails calibrated aesthetics; however, this visual layer is seldom investigated closely.

Background: Conventional CAR-T cells targeting CD123 in rrAML have achieved objective responses, but led to long-lasting myelosuppression due to expression of CD123 on progenitor cells. UniCAR-T-CD123 is a rapidly switchable two-component CAR-T therapy. An inert universal CAR-T cell (UniCAR-T) is combined with a CD123-specific soluble targeting module with a short half-life (TM123). By administering or withholding the continuous infusion of TM123, the UniCAR-T-cell can be rapidly switched on and off. Within the ongoing Phase IA study in rrAML, we investigated the expansion kinetics of UniCAR-T cells during TM123 administration in peripheral blood and bone marrow as well as cytokine profiles of treated patients. Methods: Prior to administration of autologous UniCAR-T cells, patients received a standard Flu/Cy lymphodepletion regimen at day -5 to -3. TM123 was administered as continuous infusion over 24 days starting at day 0. At day 1 a single dose of UniCAR-T cells was given. Dosing started with 1 x 108 UniCAR-T cells and 0.5 mg TM123 per day in patient 1. Patient 2 received the same TM123 dose and a UniCAR-T dose of 2.5 x 108 cells. Patient 3 received the same cell dose as patient 2 but a higher TM123 dose (1 mg/day). Pharmacokinetic of UniCAR-T and TM123 was determined from peripheral blood and bone marrow by droplet digital PCR and TM123-specific ELISA, respectively. Cytokine levels were measured by microfluidic immunoassay. Results: All 3 patients treated so far achieved an objective response, with one showing a PR and two a CRi. Treatment proved to be tolerable, no DLTs were observed to date and adverse events were mild. Grade 1 CRS (fever) was observed in 2 patients but subsided within 48 h after use of antipyretics. Myelosuppression was observed starting after lymphodepletion, which immediately recovered after TM123 withdrawal on day 24 in all patients, providing evidence for the rapid off-switch of UniCAR-T cells post TM123 administration. UniCAR-T cells expanded in all patients in peripheral blood and bone marrow comparable to data reported for conventional CD123 CAR-T products, and were so far detectable for up to 6 months after administration. Expansion kinetics were TM123-dependent. Patients showed periods of transient increase of IL-6, IFN-γ and TNF-α levels preceding peak expansion and decreasing after termination of TM123 administration. One patient showed additional coinciding momentary elevation of GM-CSF and IL-2. Conclusions: The initial clinical and translational results of UniCAR-T-CD123 represent, to our understanding, a first time evidence for a well-tolerated and effective rapidly switchable CAR-T product. Even though the number of patients treated so far is limited, the data obtained provide clinical proof-of-concept for the opportunity to abrogate side effects by withdrawal of TM123. Enrollment into the Phase IA study is ongoing. Citation Format: Armin Ehninger, Julia Riewaldt, Cordula Gründer, Kristin Franke, Maria Schreiber, Martin Wermke, Sabrina Kraus, Carla Kreissig, Jan Koedam, Michael Pehl, Gerhard Ehninger, Marc Cartellieri. Expansion kinetics and cytokine profiles of UniCAR-T-CD123, a rapidly switchable two-component CAR-T therapy, in patients with relapsed/refractory AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1506.

We examine how compensation policies of audit firms are associated with audit quality. Specifically, we investigate the effects of the ratio of variable to fixed compensation and the size of the basis for profit sharing (i.e., whether partners share profits in a small or in a large profit pool). For our analyses, we use detailed mandatory disclosure of the compensation policies in German audit firms. We document that compensation policies vary considerably across audit firms. We find that profit sharing in a small profit pool and high variable compensation are two characteristics of auditor compensation associated with lower audit quality. We also find some evidence suggesting that audit quality may be most at risk in cases in which partners rely more heavily on variable compensation to divide a relatively small profit pool. In additional analyses, we find that these associations are more pronounced in medium‐sized audit firms. We argue that this finding may result from these firms being too large for audit partners to directly monitor each other effectively, yet simultaneously too small to have sophisticated centralized monitoring systems in place. Finally, we find that integrating partner‐specific, nonprofit‐related performance metrics into the compensation structure mitigates the adverse effects of small profit pools and high variable compensation. Les politiques de remuneration des cabinets d’audit sont‐elles liees a la qualite de l’audit? Les auteurs s'interrogent sur la nature du lien entre les politiques de remuneration des cabinets d'audit et la qualite de l'audit. Ils s'interessent plus precisement a l'incidence de la proportion de la remuneration variable par rapport a la remuneration fixe et de la taille de la masse beneficiaire (modeste ou importante) servant de base a la participation aux benefices. Ils utilisent dans leurs analyses l'information detaillee que les cabinets d'audit allemands sont tenus de fournir quant a leurs politiques de remuneration. Les donnees recueillies confirment que les politiques de remuneration varient considerablement selon les cabinets d'audit. Les auteurs constatent que la participation a une masse beneficiaire modeste et une proportion elevee de remuneration variable sont deux caracteristiques de la remuneration des auditeurs qui sont associees a une qualite inferieure de l'audit. Ils relevent egalement des donnees qui tendent a demontrer que la qualite de l'audit peut etre exposee a un maximum de risque dans les cas ou les associes s'appuient davantage sur la remuneration variable pour le partage d'une masse beneficiaire relativement modeste. Des analyses supplementaires revelent que ces liens sont plus marques dans les cabinets d'audit de taille moyenne. Selon les auteurs, cette observation pourrait etre attribuable au fait que la taille de ces cabinets est trop importante pour que les associes d'audit puissent se livrer directement a une surveillance reciproque efficace, mais neanmoins trop modeste pour qu'ils se dotent de systemes de surveillance centralises perfectionnes. Enfin, les auteurs constatent que l'integration de parametres de rendement non lies aux benefices propres aux associes dans la structure de remuneration attenue les repercussions negatives des masses beneficiaires modestes et de la proportion elevee de remuneration variable.

Zusammenfassung Bildpraktiken auf Social Media Plattformen konnen als eine komplexe Verzahnung ikonischer, textbasierter und anderer Artikulationen charakterisiert werden. Die Analyse vielschichtiger Prozesse der bildlichen und diskursiven Bedeutungskonstitution stellt die qualitative Sozialforschung vor methodologische und methodische Herausforderungen, die in diesem Beitrag diskutiert werden. Ziel ist es, einen theoretisch gerahmten und empirisch fundierten Vorschlag zu liefern, wie ein sensibler Umgang mit Ikonizitat und Medialitat im Kontext von Bildpraktiken in Social Media im Paradigma der rekonstruktiven Sozialforschung konzipiert werden kann. Schlagworte: Bildpraktiken, digitale Fotografie, Social Media, Instagram, Dokumentarische Methode, Bildinterpretation, Adoleszenz ----- Abstract Pictorial practices on Social Media can be characterised as complex entanglements of visual, textual and other articulations. The analysis of multi-layered processes of pictorial and discursive constitutions of meaning poses methodical and methodological challenges to qualitative social research, which are discussed in this article. Our main objective is to propose a sensitive framework, which is theoretically and empirically grounded, to be able to connect iconicity and mediality in pictorial practices on social media within the paradigm of reconstructive social research. Keywords: Pictorial Practices, Digital Photography, Social Media, Instagram, Documentary Method, Picture Interpretation, Adolescence ----- Bibliographie: Pohn-Lauggas, Maria: „Verdammt schon“. Methodologische und methodische Herausforderungen der Rekonstruktion von Bildpraktiken auf Instagram, ZQF, 1+2-2016, S. 81-106. https://doi.org/10.3224/zqf.v17i1-2.25544

CAR-T cell therapy holds great promise for treating a wide range of malignancies. Nevertheless, the CAR-T approach faces multiple challenges, including lack of suitable targets, insufficient tumor penetration and a microenvironment hostile to CAR-T cells. Here we provide pre-clinical evidence for using a low-molecular-weight, chemically synthesized compound to re-target CAR-T cells against solid tumors in conjunction with the CD28 co-stimulatory domain to address several of these challenges. PSMA is a validated target for treatment of advanced and metastatic prostate cancer (PCa), but also broadly expressed on tumor neo-vasculature beyond PCa. PSMA is also known to be expressed on a number of normal tissues, albeit to a much lower extent, which necessitates additional safety mechanisms for CAR-T therapy. Therefore, a rapidly switchable universal CAR-T platform (UniCAR) was developed. In this system, antigen-specificity is provided by soluble adaptors termed targeting modules (TM), which redirect T-cells engineered to express a universal CAR in an antigen-specific manner against tumors. The TM explored in the present study incorporates a clinically well-characterized radiotracer peptide motif binding to the enzymatic groove of PSMA. The small-sized TM has favorable pharmacokinetic and pharmacodynamics properties (short half-life of < 30 min; rapid internalization in < 1h), which allows a fast silencing and excellent controllability of UniCAR-T reactivity (< 4 h). Furthermore, the small molecule TM efficiently penetrates and rapidly accumulates within solid tumors as clinically demonstrated by related radiotracers. Results from our pre-clinical in vivo model demonstrate potent recruitment of UniCAR-T into tumor tissue by the TM and an efficient anti-tumor response. Of note, it was recently shown that the chosen PCa model suppresses CAR-T response by secreting high levels of transforming growth factor beta (TGF-β), creating an immunosuppressive milieu. We could overcome immunosuppression utilizing CD28 compared to 4-1-BB in the intracellular signaling domain of the UniCAR. Administered CD28/zeta UniCAR efficiently suppressed tumor growth in our in vivo model and could be re-activated by consecutive cycles of TM administration even after several weeks. In contrast to CARs with fixed binding moieties, which continuously signal and thereby induce T- cell exhaustion, the discontinuous activation of UniCAR keeps a balanced mix of T-effector and T-memory cells. In summary, our rapidly switchable universal CAR-T platform in combination with a low-molecular-weight TM allows to target less differentially expressed solid tumor antigens. Furthermore, incorporation of the CD28 costimulatory domain overcomes the immunosuppressive tumor microenvironment while discontinuous activation of UniCAR-T prevents exhaustion. Citation Format: Marc Cartellieri, Simon Loff, Johannes Spehr, Mridula Swayampakula, Julia Riewaldt, Cordula Gründer, Maria Schreiber, Michael Bachmann, Anja Feldmann, Michael Pehl, Gerhard Ehninger, Armin Ehninger. Using a PSMA-specific low-molecular-weight compound for prostate cancer treatment with rapidly switchable universal CAR-T cells: Overcoming the challenges of cellular immunotherapies in solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2176.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 or BCMA is tremendously effective in treating hematological malignancies. However, the application of CAR-T beyond certain B-cell malignancies such as ALL, MM, lymphoma and CLL remains challenging due to the lack of tumor-specific antigens and the limited ability to control acute and potential long term CAR-T reactivity in patients. Therefore, a rapidly switchable universal CAR-T platform (UniCAR) was developed. In this system, antigen-specificity is provided by soluble adaptors of short pharmacokinetic half-life, termed targeting modules (TM), which redirect T-cells engineered to express a universal CAR against tumors, allowing for excellent controllability of CAR-T reactivity while maintaining the high anti-tumor activity of CAR-T cells. Here we present results from late stage pre-clinical characterization of UniCAR-T targeting CD123 (UniCAR-T-CD123) for treatment of acute leukemia. Pre-clinical characterization confirmed specificity and safety of the approach. UniCAR-T proofed to be per se inert and safe in clinically relevant in vivo toxicity models. Activation of UniCAR-T occurs solely in the presence of the CD123-specific TM (TM123) and upon cross-linkage to CD123 expressing leukemic cells. Specific lysis of leukemic target cell lines and primary patient material is induced in a dose-dependent manner at pico-molar TM123 concentrations. Notably, induction of cytokine release occurs at higher TM doses than on-set of target cell lysis, opening a therapeutic window for clinical application. In vivo efficacy of UniCAR-T re-directed against CD123 was proven in CDX and PDX mouse models. Interestingly, anti-leukemic responses of switch-controllable UniCAR-T were demonstrated to be comparable to conventional CD123-specific CAR-T in vitro at comparable doses. In contrast to conventional CD123 CAR-T, CD123-specific toxicity of TM-activated UniCAR-T towards hematopoietic progenitors was reversible and could be abrogated by withdrawal of TM, allowing for normal development of human hematopoiesis in a xenograft model. In summary, in vitro and in vivo evidence suggests that UniCAR-T-CD123 could provide strong efficacy against CD123 expressing hematological malignancies while providing excellent control and ensuring recovery of normal hematopoiesis post treatment. A phase IA dose-finding study is ongoing. Citation Format: Simon Loff, Jan-Erik Meyer, Johannes Spehr, Julia Riewaldt, Cordula Gründer, Maria Schreiber, Michael Bachmann, Michael Pehl, Gerhard Ehninger, Armin Ehninger, Marc Cartellieri. More than a bridging therapy: Targeting CD123 with rapidly switchable universal CAR-T cells for treatment of acute leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4232.

Despite remarkable therapeutic success using chimeric antigen receptor modified T-cells (CAR-T) in hematologic malignancies, targeting solid tumors still remains challenging, given their heterogeneity and immunosuppressive milieu, including the expression of inhibitory immune checkpoints such as PD-1/PD-L1. Preclinical models demonstrate that combining CAR-T therapy with checkpoint inhibitors targeting the PD-1/PD-L1 axis could be a promising strategy to enhance anti-cancer activity of CAR-T in solid tumors and on-going phase I trials are clinically evaluating this strategy. However, primary and acquired resistance to checkpoint blockade is frequently observed limiting its broad applicability and efficacy. In addition, lack of specificity results in frequent occurrence of immune-related adverse events affecting several organs. Alternatively, expression of PD-L1 by solid tumor cells could be an attractive target for CAR-T therapy, especially in order to prevent or reverse tumor re-growth and relapse after successful initial tumor cell lysis. The development of a rapidly switchable universal CAR-T platform (UniCAR) with enhanced safety features allowed us to explore the possibility to directly attack PD-L1 expressing solid tumor cells. An inherent key feature of the UniCAR-T platform is a rapid and reversible turn off mechanism (less than 4 hours) determined by the short pharmacokinetic half-life of soluble targeting modules (TMs) and fast internalization of cell-bound TMs. TMs provide the antigen-specificity for UniCAR gene-modified T-cells (UniCAR-T) and consist of an antigen-binding moiety, e.g. an scFv, linked to a small peptide motif recognized by the UniCAR. For redirecting UniCAR-T against the PD-1/PD-L1 axis, a PD-L1 specific TM (TM-PD-L1) was developed and its functionality confirmed in binding assays to human and murine PD-L1 using surface plasmon resonance as well as in cell-based cytotoxicity assays. Half maximal killing efficacy (EC50) mediated by TM-PD-L1 redirected UniCAR-T was in the low picomolar range. As PD-L1 is also expressed on healthy tissue, toxicity studies were performed in a humanized mouse model with human UniCAR-T. Humanized mice treated with TM-PD-L1 twice a day for ten consecutive days did not reveal any signs of toxicity. In a prostate cancer (PCa) xenograft model efficient suppression of tumor growth could be demonstrated by administration of TM-PD-L1. Our data are the first to demonstrate safety and feasibility of active targeting of PD-L1 expressed by solid tumors with CAR-T and that this approach is capable of inducing a significant anti-tumor response. Citation Format: Josephine Dietrich, Simon Loff, Johannes Spehr, Julia Riewaldt, Cordula Gründer, Maria Schreiber, Michael Bachmann, Gerhard Ehninger, Michael Pehl, Marc Cartellieri, Armin Ehninger. Rapidly switchable universal CAR-T cells with improved safety profile allow for active targeting of PD-L1 expressing solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2209.

Checkpoint kinases sense replicative stress to prevent DNA damage. Here we show that the histone deacetylases HDAC1/HDAC2 sustain the phosphorylation of the checkpoint kinases ATM, CHK1 and CHK2, activity of the cell cycle gatekeeper kinases WEE1 and CDK1, and induction of the tumour suppressor p53 in response to stalled DNA replication. Consequently, HDAC inhibition upon replicative stress promotes mitotic catastrophe. Mechanistically, HDAC1 and HDAC2 suppress the expression of PPP2R3A/PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2 (PP2A). Genetic elimination of PR130 reveals that PR130 promotes dephosphorylation of ATM by PP2A. Moreover, the ablation of PR130 slows G1/S phase transition and increases the levels of phosphorylated CHK1, replication protein A foci and DNA damage upon replicative stress. Accordingly, stressed PR130 null cells are very susceptible to HDAC inhibition, which abrogates the S phase checkpoint, induces apoptosis and reduces the homologous recombination protein RAD51. Thus, PR130 controls cell fate decisions upon replicative stress., Checkpoint kinases control cell cycle progression via the regulation of many key regulators. Here the authors demonstrate how HDAC1 and HDAC2 modulate checkpoint kinase signalling via the suppression of PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2.

CD4+ regulatory T (Treg) cells expressing the transcription factor fork head box P3 (Foxp3) prevent catastrophic autoimmunity and maintain immune homeostasis throughout life, and are being increasingly implicated in non-immune functions, such as the control of metabolic and regenerative processes in mice and humans. Early studies have attributed a major role of the thymus and intrathymic Foxp3+ Treg lineage commitment (referred to as ‘tTreg’ cells) in the establishment and maintenance of the mature Foxp3+ Treg cell pool residing in peripheral lymphoid tissue. In addition, numerous experimental modalities have been shown to instruct Foxp3+ Treg cell commitment in peripheral, initially naive CD4+Foxp3- T cells, which includes the induction of a Foxp3+ Treg cell phenotype and suppressor function by TGF-β in vitro (‘iTreg’ cells) and by sub-immunogenic T cell receptor stimulation in vivo (‘pTreg’ cells). This led to the hypothesis that, under physiological conditions, the induction of pTreg cells may also contribute to the peripheral Foxp3+ Treg cell compartment in the steady state of nonmanipulated, immunocompetent mice. However, until recently, studies on developmental Foxp3+ Treg cell heterogeneity have been hampered by the lack of suitable markers to discriminate naturally induced tTreg and pTreg cells. Here, we provide an overview of recently proposed approaches to track such developmental sub-lineages, with a particular emphasis on Helios, Neuropilin-1, and Foxp3RFP/GFP mice, in which Foxp3RFP+ tTreg and pTreg cells are stably marked by differential GFP expression.

Ranking systems and comparisons of quality and performance indicators will be of increasing relevance for complex "high-risk" procedures such as esophageal cancer surgery. The identification of evidence-based standards relevant for key performance indicators in esophageal surgery is essential for establishing monitoring systems and furthermore a requirement to enhance treatment quality. In the course of this review, we analyze the key performance indicators case volume, radicality of resection, and postoperative morbidity and mortality, leading to continuous quality improvement. Ranking systems established on this basis will gain increased relevance in highly complex procedures within the national and international comparison and furthermore improve the treatment of patients with esophageal carcinoma.