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Institute
Kinogeschichte
(2006)
Volker Eichelmanns Video Kurlichtspiele (Reminiszenz, 12. Dezember 1953) verknüpft zentrale Stationen der Film-, Videokunst- und Mediengeschichte im Hinblick auf ihre Wechselwirkungen mit individueller und kollektiver Geschichte beziehungsweise Erinnerung. Die Arbeit visualisiert und vertont Elemente des Zusammenspiels von Kinohistorie und persönlichem Gedächtnis. Erinnerungs- und Medienschichten werden miteinander überblendet und zusammen geschnitten. Eine wesentliche Rolle spielt dabei der Gegensatz von Immersion und Distanz zum Filmgeschehen. Eine reflektierende Haltung zur filmischen Narration wird in Kurlichtspiele durch die Integration und Ausstellung materieller Produktions- und Aufführungsbedingungen des Videos und anderer fotografischer und filmischer Techniken nahe gelegt.
Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer
(2022)
Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function of activated SUMOylation, which attenuated the immunogenicity of tumor cells. Activated SUMOylation allowed cancer cells to evade CD8+ T cell–mediated immunosurveillance by suppressing the MHC class I (MHC-I) antigen-processing and presentation machinery (APM). Loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, and the pharmacological inhibition of SUMOylation (SUMOi) resulted in reduced activity of the transcriptional repressor scaffold attachment factor B (SAFB) and induction of the MHC-I APM. Consequently, SUMOi enhanced the presentation of antigens and the susceptibility of tumor cells to CD8+ T cell–mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T cells and thereby drove a feed-forward loop amplifying the specific antitumor immune response. In summary, we showed that activated SUMOylation allowed tumor cells to evade antitumor immunosurveillance, and we have expanded the understanding of SUMOi as a rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.
Taking blood via venipuncture is part of the necessary surveillance before and after liver transplantation. The spectrum of response from children and their parents is variable, ranging from a short and limited aversion to paralyzing phobia. The aim of this retrospective, cross-sectional study was to determine the level of anxiety amongst children during venipuncture, to compare the anxiety reported by children and parents, and to identify the factors affecting the children’s and parents’ anxiety in order to develop therapeutic strategies. In total, 147 children (aged 0–17 years, 78 female) and their parents completed questionnaires. Statistical analysis was performed using qualitative and quantitative methods. Results showed that the majority of children reported anxiety and pain during venipuncture. Younger children had more anxiety (self-reported or assessed by parents). Children and parental reports of anxiety were highly correlated. However, the child’s anxiety was often reported as higher by parents than by the children themselves. The child’s general anxiety as well as the parents’ perceived stress from surgical interventions (but not the number of surgical interventions) prompted parental report of child anxiety. For children, the main stressors that correlated with anxiety and pain were factors during the blood collection itself (e.g., feeling the puncture, seeing the syringe). Parental anxiety was mainly related to circumstances before the blood collection (e.g., approaching the clinic, sitting in the waiting room). The main stressors mentioned by parents were the child’s discomfort and their inability to calm the child. Results indicate that the children’s fear of factors during the blood collection, along with the parents’ perceived stress and helplessness as well as their anticipatory anxiety are important starting points for facilitating the drawing of blood from children before and after liver transplantation, thereby supporting a better disease course in the future.
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
Introduction: For resectable soft tissue sarcoma (STS), radical surgery, usually combined with radiotherapy, is the mainstay of treatment and the only potentially curative modality. Since surgery is often complicated by large tumour size and extensive tumour vasculature, preoperative treatment strategies with the aim of devitalising the tumour are being explored. One option is treatment with antiangiogenic drugs. The multikinase inhibitor pazopanib, which possesses pronounced antiangiogenic effects, has shown activity in metastatic and unresectable STS, but has so far not been tested in the preoperative setting.
Methods and analysis: This open-label, multicentre phase II window-of-opportunity trial assesses pazopanib as preoperative treatment of resectable STS. Participants receive a 21-day course of pazopanib 800 mg daily during wait time for surgery. Major eligibility criteria are resectable, high-risk adult STS of any location, or metachronous solitary STS metastasis for which resection is planned, and adequate organ function and performance status. The trial uses an exact single-stage design. The primary end point is metabolic response rate (MRR), that is, the proportion of patients with >50% reduction of the mean standardised uptake value (SUVmean) in post-treatment compared to pre-treatment fluorodeoxyglucose positron emission tomography CT. The MRR below which the treatment is considered ineffective is 0.2. The MRR above which the treatment warrants further exploration is 0.4. With a type I error of 5% and a power of 80%, the sample size is 35 evaluable patients, with 12 or more responders as threshold. Main secondary end points are histopathological and MRI response, resectability, toxicity, recurrence-free and overall survival. In a translational substudy, endothelial progenitor cells and vascular epithelial growth factor receptor are analysed as potential prognostic and predictive markers.
Ethics and dissemination: Approval by the ethics committee II, University of Heidelberg, Germany (2012-019F-MA), German Federal Institute for Drugs and Medical Devices (61-3910-4038155) and German Federal Institute for Radiation Protection (Z5-22463/2-2012-007).
Trial registration number: NCT01543802, EudraCT: 2011-003745-18; Pre-results.
The outcome of high-risk soft tissue sarcoma (STS) is poor with radical surgery being the only potentially curative modality. Pazopanib is a multikinase inhibitor approved for the treatment of metastatic STS. Herein, in terms of the German Interdisciplinary Sarcoma Group (GISG-04/NOPASS) trial, we evaluate the potential role of kinetic analysis of fludeoxyglucose F-18 (18F-FDG) data derived from the application of dynamic positron emission tomography/computed tomography (PET/CT) in response assessment to pazopanib of STS patients scheduled for surgical resection. Sixteen STS patients treated with pazopanib as neoadjuvant therapy before surgery were enrolled in the analysis. All patients underwent dynamic PET/CT prior to and after pazopanib treatment. Data analysis consisted of visual (qualitative) analysis of the PET/CT scans, semi-quantitative evaluation based on standardized uptake value (SUV) calculations, and quantitative analysis of the dynamic 18F-FDG PET data, based on two-tissue compartment modeling. Resection specimens were histopathologically assessed and the percentage of regression grade was recorded in 14/16 patients. Time to tumor relapse/progression was also calculated. In the follow-up, 12/16 patients (75%) were alive without relapse, while four patients (25%) relapsed, among them one patient died. Median histopathological regression was 20% (mean 26%, range 5–70%). The studied population was dichotomized using a histopathological regression grade of 20% as cut-off. Based on this threshold, 10/14 patients (71%) showed partial remission (PR), while stable disease (SD) was seen in the rest 4 evaluable patients (29%). Semi-quantitative evaluation showed no statistically significant change in the widely used PET parameters, SUVaverage and SUVmax. On the other hand, 18F-FDG kinetic analysis revealed a significant decrease in the perfusion-related parameter K1, which reflects the carrier-mediated transport of 18F-FDG from plasma to tumor. This decrease can be considered as a marker in response to pazopanib in STS and could be due to the anti-angiogenic effect of the therapeutic agent.