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Chun Xu,1,2,* Annika Verena Goß,1,* Carmen Dorneburg,1 Klaus-Michael Debatin,1 Jiwu Wei,2 Christian Beltinger1 1Department of Pediatrics and Adolescent Medicine, Section of Experimental Pediatric Oncology, University Medical Center Ulm, Ulm, Germany; 2Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, China *These authors contributed equally to this work Background: Attenuated oncolytic measles virus (OMV) is a promising antitumor agent in early-phase clinical trials. However, pre-existing immunity against measles might be a hurdle for OMV therapy. Methods: OMV was inactivated with short-wavelength ultraviolet light (UV-C). Loss of replication and oncolytic activity of UV-inactivated OMV were confirmed by tissue culture infective dose 50 (TCID50) assay using Vero cells and by flow cytometry using Jurkat cells. An enzyme-linked immunosorbent assay was performed to verify that UV-inactivated OMV remained antigenic. Different doses of UV-inactivated OMV were pre-cultured in media supplemented with measles immune serum. The mixture was transferred to Jurkat cells and active OMV was added. Active OMV-induced death of Jurkat cells was monitored by flow cytometry. Results: UV-inactivation abrogates OMV replication while maintaining its antigenicity. UV-inactivated OMV sequesters pre-existing anti-MV antibodies in Jurkat cell culture, thereby protecting active OMV from neutralization and preserving oncolytic activity. Conclusion: We prove the principle that a non-replicating OMV can serve as a “decoy” for neutralizing anti-MV antibodies, thereby allowing antitumor activity of OMV. Keywords: acute lymphoblastic leukemia, oncolytic measles virus, anti-measles antibodies, decoy for anti-measles antibodies

© 2018 American Association for Cancer Research. Purpose: To investigate whether lactate dehydrogenase A (LDHA), an important component of the LDH tetramer crucial for aerobic glycolysis, is associated with patient outcome and constitutes a therapeutic target in neuroblastoma (NB). Experimental Design: Expression of LDHA mRNA and protein was determined in 709 and 110 NB patient samples, respectively, and correlated with survival and risk factors. LDHA and LDHB were depleted in human NB cell lines by CRISPR/Cas9 and shRNA, respectively, and aerobic glycolysis, clonogenicity, and tumorigenicity were determined. Expression of LDHA in relation to MYCN was measured in NB cell lines and in the TH-MYCN NB mouse model. Results: Expression of LDHA, both on the mRNA and the protein level, was significantly and independently associated with decreased patient survival. Predominant cytoplasmic localization of LDHA protein was associated with poor outcome. Amplification and expression of MYCN did not correlate with expression of LDHA in NB cell lines or TH-MYCN mice, respectively. Knockout of LDHA inhibited clonogenicity, tumorigenicity, and tumor growth without abolishing LDH activity or significantly decreasing aerobic glycolysis. Concomitant depletion of LDHA and the isoform LDHB ablated clonogenicity while not abrogating LDH activity or decreasing aerobic glycolysis. The isoform LDHC was not expressed. Conclusions: High expression of LDHA is independently associated with outcome of NB, and NB cells can be inhibited by depletion of LDHA or LDHB. This inhibition appears to be unrelated to LDH activity and aerobic glycolysis. Thus, investigations of inhibitory mechanisms beyond attenuation of aerobic glycolysis are warranted, both in NB and normal cells.

Objective: The continuously poor prognosis of patients with glioblastoma urges the discovery of more effective therapeutics. Repurposing of already existing drugs involves the clinical application of old agents with previously not known or not utilized anti-cancer activity and represents a strategy [for full text, please go to the a.m. URL], 66. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

Objective: We have previously reported that combined inhibition of the epidermal growth factor receptor by erlotinib and of RAC1 by NSC23766 yielded a synergistic antiproliferative effect on established and primary glioblastoma cells. The current study aimed at identifying the cellular and molecular[for full text, please go to the a.m. URL], 64. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

Etwa 80% aller Patienten mit ALL können geheilt werden, jedoch erleidet etwa jeder fünfte ein Rezidiv der Erkrankung. Dies ist, insbesondere bei frühem Auftreten, mit einer schlechteren Prognose verbunden. Die Behandlung pädiatrischer ALL Patienten erfolgt adaptiert an das individuelle[for full text, please go to the a.m. URL], Süddeutsche Tage der Kinder- und Jugendmedizin; 61. Jahrestagung der Süddeutschen Gesellschaft für Kinder- und Jugendmedizin und der Süddeutschen Gesellschaft für Kinderchirurgie und dem Berufsverband für Kinder- und Jugendärzte – Landesverband Bayern

BACKGROUND: Apoptosis is known to be a crucial process involved in embryogenesis, development and homeostasis of the immune system. Impaired apoptosis causes dysfunction of lymphocyte homeostasis, growth advantage of tumor cells as well as resistance to current treatment protocols. To investigate the role of the apoptosis adaptor molecules TRADD and FADD in the development of hematological diseases, patient samples were screened for mutations in these genes. PROCEDURE: Genomic DNA from 51 children suffering from B-lineage-ALL (n = 17), T-lineage-ALL (n = 24), ALPS Type Ia (n = 3) and ALPS Type III (n = 7) were analyzed. Genomic DNA from 50 unrelated donors without hematological diseases served as controls. Identified mutations were cloned and their influence on cell viability and NFkappaB activation was analyzed by flow cytometry and luciferase assay, respectively. RESULTS: In the FADD gene no genetic alteration could be detected. However, three novel missense mutations in the TRADD gene could be detected. They are located within a region of TRADD known to exert mainly anti-apoptotic effects for example through the activation of the NFkappaB pathway. Functional analysis of cells overexpressing mutant TRADD cDNA demonstrated a reduced NFkappaB activity and consequently increased cell death compared to wild-type TRADD. CONCLUSION: Mutations in the TRADD gene may contribute to the development of different hematological diseases. The identified mutations demonstrate a putative impact on TRADD signaling and cell survival but may not mainly explain the pathology of the diseases investigated.

[english] High numbers of students, a drop in funding, and the lack of quality in higher education teaching, when compared internationally, have led to a change in the university landscape over recent years. But medicine itself has changed, too. Under the influence of science and research, new developments in specific fields of medicine are continually arising. This change demands the development of new learning concepts for the improvement of quality in higher education. During medical training, it should be taken into account that a large part of medical activity is affected by experiences gained in clinical practice. With the inclusion of these aspects in the development of new learning concepts, the students will profit from continuous medical training. This teaching is promoted by the Federal State of Baden-Württemberg with the establishment of Centres for Competence. The location Ulm has recognised the development and curricular inclusion of e-learning as a central task. Considerable infrastructure and technology development has taken place. The methods of e-learning are now already integrated into medical training in a variety of ways. A few years ago, the Faculty of Medicine at the University of Ulm began to pursue the concept initially of analysing teaching at various points, then giving it a new base, and continually evaluating and improving quality. [german] Hohe Studentenzahlen, ein Rückgang der finanziellen Mittel und die, im internationalen Vergleich, mangelnde Qualität der Hochschullehre haben die Hochschullandschaft in den vergangenen Jahren entscheidend verändert. Aber auch die Medizin selbst verändert sich. Unter dem Einfluss von Naturwissenschaft und Forschung entstehen kontinuierlich neue Entwicklungen in den medizinischen Fachgebieten. Dieser Wandel erfordert die Entwicklung neuer Lehrkonzepte zur Verbesserung der Qualität in der Hochschulausbildung. Es sollte während der ärztlichen Ausbildung auch berücksichtigt werden, dass ein wesentlicher Teil ärztlichen Handelns durch Erfahrungen, aus der klinischen Praxis, geprägt wird. Unter Einbezug dieser Aspekte bei der Entwicklung neuer Lehrkonzepte, profitiert der Student von einer kontinuierlichen medizinischen Ausbildung. Diese Lehre fördert das Land Baden-Württemberg mit der Einrichtung der Kompetenzzentren. Der Standort Ulm hat die Entwicklung und curriculare Einbindung von E-Learning als zentrale Aufgabe erkannt. Es wurden wesentliche Infrastruktur- und Technologie-entwicklungen betrieben. Deren Methoden des E-Learning sind bereits jetzt in vielfältiger Weise in die medizinische Ausbildung integriert. Die medizinische Fakultät der Universität Ulm hat vor einigen Jahren begonnen das Konzept zu verfolgen, die Lehre an verschiedenen Stellen zunächst einmal zu analysieren, dann auf eine neue Basis zu stellen, Qualität zu evaluieren und kontinuierlich zu verbessern.

Minimal requirements and their rationale for the diagnosis and the response to treatment in childhood acute lymphoblastic leukemia (ALL) were defined in the recently instituted "BFM-Family"-Group, in which the German, Austrian, Dutch, Italian, Belgian, French and Hungarian childhood leukemia study groups cooperate. ALL is defined as greater-than-or-equal-to 25% lymphoblasts in the bone marrow; for confirmation of the diagnosis and classification the criteria of the French-American-British (FAB) criteria are retained. For determination of the extent of the disease at diagnosis or relapse the criteria by the Rome Workshop [1986] are recommended: An obligatory panel of monoclonal antibodies for immunophenotyping was defined, as well as criteria for precursor B-ALL and T-ALL. Cytogenetic studies may support the diagnosis and subtyping, and are essential to identify certain patients with a high risk of treatment failure (f.i. t(9;22), t(4;11)). The role of molecular genetics for the diagnosis and the characterization of leukemia and the value of its clinical application needs further elucidation. Relapse was defined as recurrence of evident leukemia in the blood, bone marrow (greater-than-or-equal-to 25% lymphoblasts) or at any other site (to be confirmed by histological examination). Bone marrow involvement combined with extramedullary relapse was defined as greater-than-or-equal-to 5% lymphoblasts in the bone marrow.