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Veröffentlichungen in wissenschaftlichen Zeitschriften zählen in der akademischen Welt zu den primären Karrieretreibern. Wissenschaftler:innen in frühen Karrierephasen eignen sich die Kompetenzen für erfolgreiches Publizieren jedoch erst während oder nach der Promotion an. Hierzu zählen etwa Kenntnisse der publikationsbezogenen Standards guter wissenschaftlicher Praxis oder der konstruktive Umgang mit dem Peer Review Verfahren. Daraus ergibt sich ein überfachlicher und überinstitutioneller Unterstützungsbedarf, den die Working Paper Series gender thoughts basierend auf folgenden Prinzipien leistet: 1. Die Sichtbarkeit von Autor:innen in frühen Karrierephasen durch Veröffentlichung ihrer wissenschaftlichen Erkenntnisse (Open Access) 2. Unterstützende Begleitung der Autor:innen auf den unterschiedlichen Etappen eines Publikationsprozesses (Forschendes Lernen) 3. Verringerung von Publication Biases und Gaps durch gender- und ungleichheitssensible Perspektiven, {"references":["Haberstroh, S., & Petersen, M. (2020). Publikationsformate im Forschenden Lernen. In C. Wulf, S. Haberstroh, & M. Petersen (Eds.) Forschendes Lernen: Theorie, Empirie, Praxis (pp. 290-297). Springer VS.","Kühl, S. (2015). Die publikationsorientierte Vermittlung von Schreibkompetenzen: Zur Orientierung des studentischen Schreibens i n der Soziologie am wissenschaftlichen Veröffentlichungsprozess. Soziologie, 44(1), 56-77.","Rahn, F. J. (2021). Studentische Publikation als Übung. In O. M. Pawlak & F. J. Rahn (Eds.), Ein transdisziplinäres Panoptikum: Aktuelle Forschungsbeiträge aus dem wissenschaftlichen Nachwuchs der Universität Bielefeld (pp. 121-128). Springer VS.","Schwertel, T., & Schulz, A. (2020). Publizieren statt archivieren. Ehrenamtliche Förderung des sozialwissenschaftlichen Nachwuch ses. Exposé, 1(2) , 18-21.."]}

Einleitung: In der Behandlung von rezidivierenden hochmalignen Gliomen stellt Bevacizumab (BEV) eine Therapieoption dar. In Deutschland wird BEV als „Off-Label-Use“ Medikament eingesetzt und muss von den Krankenkassen genehmigt werden. Patienten und Methoden: Wir analysierten 61 Patienten mit rezidivierenden hochmalignen Gliomen im Zeitraum von 06/2008 bis 01/2014. Alle Patienten stellten einen Antrag auf eine Bevacizumab-Therapie bei Ihrer Krankenkasse (KK). 37 von 61 Patienten (60,7%) erhielten eine Zusage (BEV-Arm), 24 Patienten (39,3%) wurde eine Absage erteilt (Nicht-BEV-Arm). Wir untersuchten wie sich die Zu- oder Absage der KK auf das Gesamtüberleben (GÜ) und das progressionsfreie Überleben (PFÜ) der Patienten auswirkte. Der Überlebenszeitstartpunkt wurde definiert als Zeitpunkt des ersten BEV Antrags bei der KK. Zudem betrachteten wir die Zeitintervalle zwischen den Antrags- und Genehmigungs- bzw. Ablehnungsschreiben der Krankenkassen. Anschließend analysierten wir wie sich Allgemeinzustand, Alter, Histologie und Rezidiv-Anzahl auf die Überlebensraten der Patienten der beiden Studienarme auswirkten. Ergebnis: Das Gesamtüberleben der Kohorte lag im Median bei 7,0 Monaten. Die Untersuchung der BEV-Patienten im Vergleich zu den Nicht-BEV-Patienten ergab ein signifikant längeres Gesamtüberleben (median 10,3 vs. 4,2 Monate, log rank p=0,023). Der größere Nutzen einer BEV Therapie zeigte sich auch bei Betrachtung der einzelnen Rezidivstadien (1. Rezidivtherapie; BEV vs. Nicht-BEV; 12,5 vs. 10,2 Monate; p=0,578 und 2. Rezidivtherapie/ weitere Rezidive; BEV vs. Nicht-BEV; 9,9 vs. 2,6 Monate; p=0,010). Die Zeitspanne zwischen Antragstellung und Antragsgenehmigung betrug im Median 29 Tage. Bei der multivarianten Analyse des Gesamtüberlebens bleibt die Wirkung von BEV signifikant (HR= 0,49; p=0,035) hinsichtlich ECOG-Status, Alter, Histologie und Rezidiv-Anzahl. Schlussfolgerung: Die Ergebnisse unserer, durch die Zu- bzw. Absagen der Krankenkassen, „pseudo-randomisierten“ Studie zeigen hinsichtlich des Gesamtüberlebens einen Nutzen der BEV Therapie, vor allem bei stark vorbehandelten Patienten mit hochmalignen Gliomen. Purpose: Bevacizumab (BEV) is a therapeutic option in recurrent glioblastoma multiforme. In Germany BEV is used as an off-label drug, its application has to be approved by health insurance. Patients and Methods: 61 patients (between 06/2008 and 01/2014) with recurrent high-grade glioma had reimbursement requests for BEV sent to their health insurance. 37 patients out of 61 (60.7%) had their requests approved and therefore received Bevacizumab (BEV-arm) as part of their treatment. The remaining 24 (39.3%) patients received standard therapy without Bevacizumab (Non-BEV-arm). Survival endpoints were defined with reference to the first BEV request to the health insurance provider. Time intervals were analyzed between letters of application and letters of approval. Both cohorts were investigated with regard to ECOG status, age, WHO grade and recurrence-order and its influence on OS. Results: Median overall survival (OS) for the whole cohort was 7.0 months. OS was significantly better for BEV vs. Non-BEV patients (median, 10.3 vs. 4.2 months, log rank p=0.023). There was an increased BEV benefit in cases of higher-order recurrences (first order recurrence BEV vs. Non-BEV, 12.5 vs. 10.2 months, p=0.578) (second or higher order recurrence, 9.9 vs. 2.6 months, p=0.010). The median timespan between letters of application and letters of approval was 29 days. On multivariate analysis for overall survival the prognostic impact of Bevacizumab (HR=0.49, p=0.035) remained significant. Conclusion: Although not truly randomized our results suggest an influence of BEV on overall survival in a heavily pretreated patient population suffering from high-grade gliomas.

Introduction: Door-to-CT scan time (DCT) and door-to-needle time (DNT) are important process measures in acute ischemic stroke (AIS) patients undergoing intravenous thrombolysis (IVT). We examined the impact of a telemedical prenotification by emergency medical service (EMS) (called the “Stroke Angel” program) on DCT and DNT and IVT rate compared to standard of care. Patients and Methods: Two prospective observational studies including AIS patients admitted via EMS from 2011 to 2013 (cohort I; n = 496) and from January 1, 2015 to May 31, 2018 (cohort II; n = 349) were conducted. After cohort I, the 4-Item Stroke Scale and a digital thrombolysis protocol were added. Multivariable logistic and linear regression analysis was performed. Results: In cohort I, DCT was lower in the intervention group (13 vs. 26 min using standard of care; p < 0.001), but no significant difference in median DNT (35 vs. 39 min; p = 0.24) was observed. In cohort II, a reduction of DCT (8 vs. 15 min; p < 0.001) and DNT (25 vs. 29 min p = 0.003) was observed in the intervention group. Compared to standard of care, the likelihood of DCT ≤10 min or DNT ≤20 min in the intervention group was 2.7 (adjusted odds ratio [aOR] 2.7; 95% CI: 2.1–3.5) and 1.8 (aOR 1.8; 95% CI: 1.1–2.9), respectively. In cohort II, IVT rate was higher (aOR 1.4; 95% CI: 1.1–1.9) in the intervention group. Conclusion: Although the positive effects of Stroke Angel in AIS provided a rationale for implementation in routine care, larger studies of practice implementation will be needed. Using Stroke Angel in the prehospital management of AIS impacts on important process measures of IVT delivery.

ATP-binding cassette (ABC) transporters constitute an omnipresent superfamily of integral membrane proteins, which catalyze the translocation of a multitude of chemically diverse substrates across biological membranes. In humans, ABC transporters typically act as highly promiscuous exporters, responsible for many physiological processes, multi-drug resistance, and severe diseases, such as hypercholesterolemia, lipid trafficking disorders, and immune deficiency. In all ABC transporters, ATP-driven movements within two highly conserved nucleotide-binding domains (NBDs) are coupled to conformational changes of two transmembrane domains (TMDs), which provide a framework for substrate binding and release on the opposite side of the membrane and enable the transporter to cycle between inward-facing and outward-facing orientations. Several structures of ABC transporters determined either by X-ray crystallography or single-particle electron cryo-microscopy (cryo-EM) have been reported, mostly exhibiting a variation of the inward-facing state, which highlights their dynamic behavior. However, for a complete understanding of the conformational dynamics, further structural information on intermediates is needed – especially for heterodimeric ABC transporters, which are predominant in humans and for which only limited structural information is available. One prime example of such human heterodimeric ABC transport complexes is the transporter associated with antigen processing (TAP). TAP is a key player of the adaptive immune response, because it translocates proteasomal degradation products into the ER lumen for loading of MHC I molecules. Many functional aspects of TAP have been disclosed in recent years. However, structural information is lacking far behind and a major challenge in the field of medical relevant transporters. Recently, the heterodimeric ABC export system TmrAB (Thermus thermophilus multidrug resistance proteins A and B) was identified as an ortholog of TAP, by sharing structural homology with TAP and, intriguingly, being able to restore antigen presentation in human TAP-deficient cells. Thus, TmrAB is a biochemically well-characterized ABC exporter that can be regarded as a functional ortholog of TAP and serves as a model system for (heterodimeric) ABC export systems in general. Thus, to illuminate the molecular basis of substrate translocation by single-particle cryo-EM, one of the main objectives of this work was the generation of stabilizing chaperones (synthetic antibodies, nanobodies, cyclic peptides) to reduce the conformational heterogeneity of TAP and TmrAB. Selected antibodies were analyzed with respect to stable complex formation, conformational trapping, and the ability to serve as alignment tools for structural studies by single-particle cryo-EM. Both antibody types were shown to form sufficiently stable complexes to serve as a rigid body for EM analyses. However, all selected antibodies bound to the inward-facing state exclusively. Hence, for EM studies, various ligands were added to elucidate the full spectrum of conformational states during the catalytic cycle. For TAP, first attempts by negative-stain EM revealed a homogenous distribution of particles on the grid. Surprisingly, no transporter-like features were observed although various attempts were applied to increase the overall sample quality. For TmrAB, in contrast, the complete conformational space in a native-like lipid environment under turnover conditions was mapped. Cryo-EM analysis of TmrAB incubated with ATP-Mg2+ and substrate revealed two distinct inward-facing conformations (IFwide and IFnarrow) as well as two asymmetric conformations with dimerized NBDs, which were markedly different from all previously reported structures. Here, the catalytically active site was slightly wider and contained ADP, while ATP was still bound at the catalytically-inactive site within the NBDs, demonstrating an asymmetric post-hydrolysis state. Intriguingly for the inward-facing conformations, a weak additional density close to residues M139TmrB and W297TmrB was observed in the inward-facing conformation, which displayed a higher degree of cytosolic gate opening (IFwide) indicating the presence of substrate. To verify that this density corresponds to substrate, single alanine mutations of M139TmrB and W297TmrB were introduced, leading to a strong reduction in substrate binding and transport. Since substrate release requires the opening of the extracellular gate, the absence of an outward-facing open conformation indicated that the opening must be highly transient. In order to explore the outward-facing open conformation, a cryo-EM analysis of the catalytically-inactive TmrAE523QB mutant upon incubation with ATP-Mg2+ was performed. Remarkably, within the same dataset, two different outward-facing conformations (occluded and open) were resolved, both in an ATP-bound state, which indicated that binding of ATP is sufficient to drive the large-scale conformational transition from inward-facing to outward-facing open. To explore the effect of nucleotide hydrolysis, TmrAB was trapped by vanadate. Again, two populations were observed, representing the outward-facing open and outward-facing occluded conformation. Based on several structures of key intermediates, determined under turnover conditions or trapped in the pre-hydrolysis and hydrolysis transition state, for the first time the complete description of the ATP hydrolysis and translocation cycle of a heterodimeric ABC transport complex was elucidated in one single study. By mapping the conformational landscape during active turnover, aided by mutational and chemical modulation of kinetic rates, fundamental and so-far hidden steps of the substrate translocation cycle of asymmetric ABC transporters were resolved and a general template for (heterodimeric) ABC exporter-catalyzed substrate translocation was provided.