"Wie kann ich dich unterstützen?". Chatbot-basierte Lernunterstützung für Studienanfänger:innen

Im Initiativprogramm BayernMINT fördert der Freistaat Bayern Maßnahmen zur Senkung der Studienabbruchquoten. An der Technischen Hochschule Nürnberg wird ein regelgeleiteter Chatbot als niedrigschwellige Kommunikationstechnologie zur Lernunterstützung konzipiert und implementiert. Auf Grundlage der Ergebnisse eines testpsychologisch fundierten Allgemeinen Studierfähigkeitstests unterstützt dieser Chatbot Studieninteressierte und vor allem Studienanfänger:innen individuell bei ihren Lernaktivitäten. Winkler und Söllner (2018) zeigen, dass der Einsatz von Chatbots einen signifikant positiven Einfluss auf den Lernerfolg verspricht. Nach erfolgreicher Pilotphase soll die Lehrinnovation in den Regelbetrieb an der Technischen Hochschule Nürnberg übernommen werden. Im aktuellen Chatbot werden KI-Technologien zum Verstehen natürlicher Sprache verwendet. Darüber hinaus bietet der Einsatz von KI weitere Potenziale für die Hochschulbildung, wie z.B. KI-basierte Analysen der Kompetenzen von Studieninteressierten als Grundlage für Empfehlungen für die Studiengangspassung. (DIPF/Orig.)With the BayernMINT program, the Free State of Bavaria supports measures to reduce dropout rates. As part of this project, a rule-based chatbot is being designed and implemented at the Nuremberg University of Applied Sciences as a low-threshold communication technology to support learning. Based on the results of a psychologically based general aptitude test, the chatbot is intended to provide support to individual prospective students and, in particular, first-term students in their learning activities. Winkler and Söllner (2018) show that the use of chatbots promises a significantly positive influence on learning success. After a successful pilot phase, the teaching innovation will be used in regular operation at the University of Applied Sciences, Nuremberg. In the current chatbot, AI technologies are used to understand natural language. In addition, the use of AI offers further potential for higher education, such as AI-based analyses of prospective studentsʼ competencies as a basis for recommendations for the choice of studies. (DIPF/Orig.

The Novel Somatostatin Receptor 2/Dopamine Type 2 Receptor Chimeric Compound BIM-23A758 Decreases the Viability of Human GOT1 Midgut Carcinoid Cells

The majority of neuroendocrine tumors (NETs) of thegastro-enteropancreatic system coexpress sornatostatin receptors (SSTRs)and dopamine type 2 receptors (D2R), thus providing a rationale for theuse of novel SSTR2/D2R chimeric compounds in NET disease. Here weinvestigate the antitumor potential of the SSTR2/D2R chimeric compoundsBIM-23A760 and BIM-23A758 in comparison to the selective SSTR2 agonistBIM-23023 and the selective D2R agonist BIM-53097 on human NET celllines of heterogeneous origin. While having only minor effects on humanpancreatic and bronchus carcinoid cells (BONI and NCI-H727), BIM-23A758induced significant antitumor effects in human midgut carcinoid cells(GOT1). These effects involved apoptosis induction as well as inhibitionof mitogen-activated protein kinase and Akt signaling. Consistent withtheir antitumor response to BIM-23A758, GOT1 cells showed relativelyhigh expression levels of SSTR2 and D2R mRNA. In particular, GOT1 cellshighly express the short transcript variant of D2R. In contrast toBIM-23A758, the SSTR2/D2R chimeric compound BIM-23A760 as well as theindividual SSTR2 and D2R agonistic compounds BIM-23023 and BIM-53097induced no or only minor antitumor responses in the examined NET celllines. Taken together, our findings suggest that the novel SSTR2/D2Rchimeric compound BIM-23A758 might be a promising substance for thetreatment of NETs highly expressing SSTR2 and D2R. In particular, asufficient expression of the short transcript variant of DR2 might playa pivotal role for effective treatment

The novel mTOR inhibitor RAD001 (Everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells

Background/Aim: Tumors exhibiting constitutively activated PI(3) K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3) K/Akt/mTOR signaling. Methods: BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation. Results: RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis. Conclusion: In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients. Copyright (c) 2007 S. Karger AG, Basel

PD-L1 and HIF-2α Upregulation in Head and Neck Paragangliomas after Embolization

Hypoxia activates pathways associated with tumor progression, metastatic spread, and alterations in the immune microenvironment leading to an immunosuppressive phenotype. In particular, the upregulation of PD-L1, a target for therapy with checkpoint inhibitors, is well-studied in several tumors. However, the relationship between hypoxia and PD-L1 regulation in pheochromocytomas and paragangliomas (PPGL), and especially in paragangliomas treated with embolization, is still largely unexplored. We investigated the expression of the hypoxia-marker HIF-2α and of PD-L1 in a PPGL-cohort with and without embolization as potential biomarkers that may predict the response to treatment with HIF-2α and checkpoint inhibitors. A total of 29 tumor samples from 25 patients who were operated at a single center were included and analyzed utilizing immunohistochemistry (IHC) for PD-L1 and HIF-2α. Embolization prior to surgery was performed in seven (24%) tumors. PD-L1 expression in tumor cells of head and neck paragangliomas (HNPGLs) receiving prior embolization (median PD-L1 positivity: 15%) was significantly higher as compared to PD-L1 expression in HNPGLs without prior embolization (median PD-L1 positivity: 0%) (p = 0.008). Consistently, significantly more HNPGLs with prior embolization were positive for HIF-2α (median nuclear HIF-2α positivity: 40%) as compared to HNPGLs without prior embolization (median nuclear HIF-2α positivity: 0%) (p = 0.016). Our results support the hypothesis that embolization with subsequent hypoxia leads to the upregulation of both PD-L1 and HIF-2α in HNPGLs, and could thus facilitate targeted treatment with HIF-2α and checkpoint inhibitors in the case of inoperable, locally advanced, or metastatic disease

Comparative analysis of the lambda-interferons IL-28A and IL-29 regarding their transcriptome and their antiviral properties against hepatitis C virus.

Specific differences in signaling and antiviral properties between the different Lambda-interferons, a novel group of interferons composed of IL-28A, IL-28B and IL-29, are currently unknown. This is the first study comparatively investigating the transcriptome and the antiviral properties of the Lambda-interferons IL-28A and IL-29. Expression studies were performed by microarray analysis, quantitative PCR (qPCR), reporter gene assays and immunoluminometric assays. Signaling was analyzed by Western blot. HCV replication was measured in Huh-7 cells expressing subgenomic HCV replicon. All hepatic cell lines investigated as well as primary hepatocytes expressed both IFN-λ receptor subunits IL-10R2 and IFN-λR1. Both, IL-28A and IL-29 activated STAT1 signaling. As revealed by microarray analysis, similar genes were induced by both cytokines in Huh-7 cells (IL-28A: 117 genes; IL-29: 111 genes), many of them playing a role in antiviral immunity. However, only IL-28A was able to significantly down-regulate gene expression (n = 272 down-regulated genes). Both cytokines significantly decreased HCV replication in Huh-7 cells. In comparison to liver biopsies of patients with non-viral liver disease, liver biopsies of patients with HCV showed significantly increased mRNA expression of IL-28A and IL-29. Moreover, IL-28A serum protein levels were elevated in HCV patients. In a murine model of viral hepatitis, IL-28 expression was significantly increased. IL-28A and IL-29 are up-regulated in HCV patients and are similarly effective in inducing antiviral genes and inhibiting HCV replication. In contrast to IL-29, IL-28A is a potent gene repressor. Both IFN-λs may have therapeutic potential in the treatment of chronic HCV

Metastatic Pheochromocytoma and Paraganglioma: Somatostatin Receptor 2 Expression, Genetics, and Therapeutic Responses

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. OBJECTIVE: Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. METHODS: Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical-pathological features of PPGLs. RESULTS: Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line "cold" somatostatin analogs 100% (n = 6, n = 3 SDHx). CONCLUSION: SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs

Potent antitumor activity of novel HSP90 inhibitors AUY922 and HSP990 in neuroendocrine carcinoid cells

The heat shock protein (HSP) 90 chaperone machine involved in numerous oncogenic signaling pathways is overexpressed in cancer cells and is currently being evaluated for anticancer therapy. Neuroendocrine tumors (NETs) of the gastroenteropancreatic (GEP) system comprise a heterogeneous group of tumors with increasing incidence and poor prognosis. Here we report antiproliferative effects of the HSP90 inhibitors AUY922 and HSP990 in neuroendocrine tumor cells. Treatment of human pancreatic BON1, bronchopulmonary NCI-H727 and midgut carcinoid GOT1 neuroendocrine tumor cells with increasing concentrations of AUY922 and HSP990 dose-dependently suppressed cell viability. Significant effects on neuroendocrine cell viability were observed with inhibitor concentrations as low as 5 nM. Inhibition of cell viability was associated with the induction of apoptosis as demonstrated by an increase in sub-G1 events and PARP cleavage. HSP90 inhibition was associated with decreased neuroendocrine ErbB and IGF-I receptor expression, decreased Erk and Akt phosphorylation and the induction of HSP70 expression. These findings provide evidence that targeted inhibition of upregulated HSP90 activity could be useful for the treatment of aggressive neuroendocrine tumors resistant to conventional therapy

Three Dimensional Models of Endocrine Organs and Target Tissues Regulated by the Endocrine System

Immortalized cell lines originating from tumors and cultured in monolayers in vitro display consistent behavior and response, and generate reproducible results across laboratories. However, for certain endpoints, these cell lines behave quite differently from the original solid tumors. Thereby, the homogeneity of immortalized cell lines and two-dimensionality of monolayer cultures deters from the development of new therapies and translatability of results to the more complex situation in vivo. Organoids originating from tissue biopsies and spheroids from cell lines mimic the heterogeneous and multidimensional characteristics of tumor cells in 3D structures in vitro. Thus, they have the advantage of recapitulating the more complex tissue architecture of solid tumors. In this review, we discuss recent efforts in basic and preclinical cancer research to establish methods to generate organoids/spheroids and living biobanks from endocrine tissues and target organs under endocrine control while striving to achieve solutions in personalized medicine