SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia.

SIRT1 is an important regulator of cellular stress response and genomic integrity. Its role in tumorigenesis is controversial. Whereas sirtuin 1 (SIRT1) can act as a tumor suppressor in some solid tumors, increased expression has been demonstrated in many cancers, including hematologic malignancies. In chronic myeloid leukemia, SIRT1 promoted leukemia development, and targeting SIRT1 sensitized chronic myeloid leukemia progenitors to tyrosine kinase inhibitor treatment. In this study, we investigated the role of SIRT1 in acute myeloid leukemia (AML). We show that SIRT1 protein, but not RNA levels, is overexpressed in AML samples harboring activating mutations in signaling pathways. In FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)(+)-cells protein, expression of SIRT1 is regulated by FLT3 kinase activity. In addition, SIRT1 function is modulated via the ATM-DBC1-SIRT1 axis in a FLT3-ITD-dependent manner. In murine leukemia models driven by MLL-AF9 or AML1-ETO coexpressing FLT3-ITD, SIRT1 acts as a safeguard to counteract oncogene-induced stress, and leukemic blasts become dependent on SIRT1 activity. Pharmacologic targeting or RNAi-mediated knockdown of SIRT1 inhibited cell growth and sensitized AML cells to tyrosine kinase inhibitor treatment and chemotherapy. This effect was a result of the restoration of p53 activity. Our data suggest that targeting SIRT1 represents an attractive therapeutic strategy to overcome primary resistance in defined subsets of patients with AML.

[Quality assurance of faculty examinations: Optimization of examination management in the Heidelberg Curriculum Medicinale (HeiCuMed)]. / Qualitätssicherung fakultätsinterner Prüfungen ­ Optimierung des Prüfungsmanagements im Heidelberger Curriculum Medicinale (HeiCuMed).

INTRODUCTION: Examinations are a central element of the medical curriculum: they contribute significantly to the quality assurance of medical training and subsequent medical care. In order to meet the high expectations placed on examinations in terms of content, legal and organizational aspects, continuous quality assurance measures are necessary. The aim of this paper was to record and analyze the quality assurance measures implemented at the medical faculty of Heidelberg. METHODS: We investigated quality indicators that are relevant to medical examinations - adequate choice of examination formats, blueprint/validity, reliability and distribution of grades, feedback to students, consequences of examinations - within the faculty examinations in the decentrally organized Heidelberg Curriculum Medicinale (HeiCuMed). In addition, the organizational structures in examination management were examined. For this purpose, interviews were conducted with teaching staff, students and the technical examination administration. RESULTS: The surveys show that the quality indicators in HeiCuMed have already been met in many areas. Optimization work remains to be done concerning the criteria "adequate choice of examination formats", "feedback to students" as well as the documentation of the examination process and the definition of substitution regulations. DISCUSSION: Training courses, statistical analysis and accompanying research are essential for establishing additional innovative, practice-oriented examination formats. In order to improve feedback to students, formative assessments should be more intensively integrated into the curriculum. As a measure for structured quality-oriented examination management, it is also helpful to document the examination procedure and the staff assigned to it using templates. CONCLUSION: Especially with decentralized examination management, the internal coordination of individual departments is of great importance in order to guarantee the quality of examinations. Regular surveys of the parties involved can be of support by collecting best-practice examples and deliver the respective information in handouts encouraging interdisciplinary exchange.

Do it together! Conception and long-term results of the trans-institutional Master of Medical Education (MME) program in Germany.

Medical education has the responsibility to react to developments and changing demands in healthcare. This implies the need for experts in the area of medical education as well as nationally coordinated initiatives. An innovative model based on trans-institutional cooperation and nationwide consensus for establishing a master's degree course in Medical Education (MME) and long-term results are presented here to other countries and other programs, facing similar challenges. A MME program with the following goals was implemented at the Medical Faculty of Heidelberg University, Germany, in 2004: Qualification of leaders in medical faculties, professionalization and improvement of teaching quality, promotion of nationwide and international exchange, and stimulation of research in medical education. Since then, 15 cohorts with a total of 380 participants have started their studies, 179 participants have graduated and 90 publications resulted from the master's theses (as at November 2018). Evaluation and survey data revealed a very high degree of satisfaction among the participants and a lasting development to medical education experts. Our concept shows that the bundling of regional expertise into a clearly structured trans-institutional network can be a driving force for nationwide comprehensive changes, in order to address changing demands in healthcare systems and transfer it into medical education programs.

Individual and institutional influencing factors on completion rates in a medical education master's program in Germany.

Background: The increasing significance of didactic aspects in medical education has also led to the development of special postgraduate programs. Completion rates represent an important outcome criterion for these programs of study. Up to today, detailed studies on what factors influence these completion rates have been lacking. Methods: Within the framework of outcomes research, a semi-structured online survey of students was conducted in the Master of Medical Education Germany program. Of the 90 items, 21 referred to the master's thesis that is required for graduation. Results: 157 out of 246 (63.8%) of students from classes 1-10 of the program (study period 2004-2014) participated in the survey. 109 participants had submitted a master's thesis, whereas 45 participants had not completed their studies by submitting a master's thesis. Influencing factors of successful completion were, among other things, little difficulty in choosing the topic, retention of the originally chosen topic, general support by the program administration in the modules and ensuring timely feedback from the advisor, and the provision of temporal, staff and financial resources by the home faculty. The failure to turn in the project report and a lengthy interruption of master thesi's work could be identified as critical parameters. Conclusion: Taking into account these results can contribute to increasing completion rates in medical education graduate programs. Systematic outcomes research leads, moreover, to quality assurance. Such studies should be conducted in a standardized manner in the future, in order to facilitate comparisons between medical education programs.

STAT5 is crucial to maintain leukemic stem cells in acute myelogenous leukemias induced by MOZ-TIF2.

MOZ-TIF2 is a leukemogenic fusion oncoprotein that confers self-renewal capability to hematopoietic progenitor cells and induces acute myelogenous leukemia (AML) with long latency in bone marrow transplantation assays. Here, we report that FLT3-ITD transforms hematopoietic cells in cooperation with MOZ-TIF2 in vitro and in vivo. Coexpression of FLT3-ITD confers growth factor independent survival/proliferation, shortens disease latency, and results in an increase in the number of leukemic stem cells (LSC). We show that STAT5, a major effector of aberrant FLT3-ITD signal transduction, is both necessary and sufficient for this cooperative effect. In addition, STAT5 signaling is essential for MOZ-TIF2-induced leukemic transformation itself. Lack of STAT5 in fetal liver cells caused rapid differentiation and loss of replating capacity of MOZ-TIF2-transduced cells enriched for LSCs. Furthermore, mice serially transplanted with Stat5(-/-) MOZ-TIF2 leukemic cells develop AML with longer disease latency and finally incomplete penetrance when compared with mice transplanted with Stat5(+/+) MOZ-TIF2 leukemic cells. These data suggest that STAT5AB is required for the self-renewal of LSCs and represents a combined signaling node of FLT3-ITD and MOZ-TIF2 driven leukemogenesis. Therefore, targeting aberrantly activated STAT5 or rewired downstream signaling pathways may be a promising therapeutic option.