Matthias Lehmann

Comprehensive molecular characterization of multifocal glioblastoma proves its monoclonal origin and reveals novel insights into clonal evolution and heterogeneity of glioblastomas

Abstract Background. The evolution of primary glioblastoma (GBM) is poorly understood. Multifocal GBM (ie, multiple synchronous lesions in one patient) could elucidate GBM development. Methods. We present the first comprehensive study of 12 GBM foci from 6 patients using array-CGH, spectral karyotyping, gene expression arrays, and next-generation sequencing. Results. Multifocal GBMs genetically resemble primary GBMs. Comparing foci from the same patient proved their monoclonal origin. All tumors harbored alterations in the 3 GBM core pathways: RTK/PI3K, p53, and RB regulatory pathways with aberrations of EGFR and CDKN2A/B in all (100%) patients. This unexpected high frequency reflects a distinct genetic signature of multifocal GBMs and might account for their highly malignant and invasive phenotype. Surprisingly, the types of mutations in these genes/pathways were different in tumor foci from the same patients. For example, we found distinct mutations/aberrations in PTEN, TP53, EGFR, and CDKN2A/B, which therefore must have occurred independently and late during tumor development. We also identified chromothripsis as a late event and in tumors with wild-type TP53. Only 2 events were found to be early in all patients: single copy loss of PTEN and TERT promoter point mutations. Conclusions. Multifocal GBMs develop through parallel genetic evolution. The high frequency of alterations in 3 main pathways suggests that these are essential steps in GBM evolution; however, their late occurrence indicates that they are not founder events but rather subclonal drivers. This might account for the marked genetic heterogeneity seen in primary GBM and therefore has important implications for GBM therapy.

Design approach for component-based automation systems using exact cover

Networked systems consisting of many different components are gaining more and more importance in humans living environment (e.g. communication, entertainment, building automation). The design process for such systems is also harder because of the growing complexity and the inhomogeneity of sub-systems realizing different functions. This results in a multi-criteria high-complex combinatorial device selection problem. In this paper a general domain-independent model for Component-based Automation Systems is introduced. To help solving the mentioned selection problem, it is transformed into an Exact Cover Problem. Thus, it is possible to use efficient algorithms like Knuths Dancing Links for solving the selection problem.

Architecture for self-organizing, co-operative and robust Building Automation Systems

This paper provides an overview of the architecture for self-organizing, co-operative and robust Building Automation Systems (BAS) proposed by the EC funded FP7 SCUBA1 project. We describe the current situation in monitoring and control systems and outline the typical stakeholders involved in the case of building automation systems. We derive seven typical use cases which will be demonstrated and evaluated on pilot sites. From these use cases the project designed an architecture relying on six main modules that realize the design, commissioning and operation of self-organizing, co-operative, robust BAS.

Complexity reduction for automated design problems of building automation systems

Modern large buildings like office buildings include a great number of building automation systems like heating, cooling or lighting. To compose them, the design process should be automated, because no system designer have an overall knowledge about all the different available systems on the market. An important problem is the complexity of the optimization of the device selection: many different systems should be integrated, the costs and the number of integrated devices should be minimized, etc. Well-known population-based algorithms are suited to such complex multi-criterial optimization processes. But the most important drawback of these algorithms is their disadvantageous time performance by a high number of available devices or by many criteria. This paper gives a solution to handle this problem by restricting the device domain to provide a good scalability of the device selection.

Sensors, models and platform for ambient control

The future of ambient intelligence (AmI) brings new challenges in designing adequate control systems able to handle a diversity of sensors, and actuators. The paper analyzes on the example of a personalized climate control the classification of sensor, actuator and control approaches and derives a system architecture for an AmI-based control system.

A systematic engineering tool chain approach for self-organizing building automation systems

There is a strong push towards smart buildings that aim to achieve comfort, safety and energy efficiency, through building automation systems (BAS) that incorporate multiple subsystems such as heating and air-conditioning, lighting, access control etc. The design, commissioning and operation of BAS is already challenging when handling an individual subsystem; however when introducing co-operation between systems the complexity increases dramatically. Balancing the contradictory requirements of comfort, safety and energy efficiency and coping with the dynamics of constantly changing environmental conditions, usage patterns, user needs etc. is a demanding task. This paper outlines an approach to the systematic engineering of cooperating, adaptive building automation systems, which aims to formalize the engineering approach in the form of an integrated tool chain that supports the building stakeholders to produce site-specific robust and reliable building automation.

Monitoring service choreographies

The document describes an approach for monitoring automated choreographed business processes. Process choreographies are characterized by a chain of single processes. The progress state of the whole process chain and each of its components is regarded as an important information to gather. This paper depicts a general method for monitoring process choreographies. The described approach is based on unified process instance log structure. A system architecture to enable monitoring in a decentralized network is introduced as well. It uses common web service technologies to log execution data and to supervise the process chains. It therefore can be integrated into any business process execution environment. The application of the described method for online and offline monitoring is examined for feasibility and discussed in detail.

Towards a comprehensive life cycle approach of building automation systems

The communication between different partners to handle the different tasks during the life cycle of buildings is far from being perfect. Fragmented engineering, lack of data consistency, insufficient system documentation or sensitivity for data sharing are only a few of many problems in this field that have not been efficiently handled through researches as well as in practice. This paper focuses on a deeper analysis of these problems mainly in the planning and engineering phases (they are the basis for all other phases) from both technical and economical point of view. An approach to handle these problems will be presented and thoroughly discussed.

Vorausschau in frühen Planungsphasen der Gebäudeautomation

Zusammenfassung Die Planung der Gebäudeautomation (GA) wird durch zahlreiche Brüche in fachlicher (Gewerketrennung) und zeitlicher Hinsicht (Planungsphasen) behindert. Eine integrale Herangehensweise kann nur durch Stärkung der frühen Planungsphasen erreicht werden. Dafür wird eine wissensbasierte Methoden- und Toolunterstützung vorgestellt, die nur wenig Mehraufwand kostet.

Abstract LB-308: Effects of the IDH1 R132H mutation on redox status and metabolism are cell type dependent but independent from D-2-hydroxyglutarate accumulation

IDH1 R132H mutations are considered to play a key role in the development of low grade gliomas and therefrom derived secondary glioblastomas (GBM). Wild type IDH1 converts isocitrate to α-ketoglutarate (a-KG) while reducing NADP+. IDH1R132H has a neomorphic enzymatic function using a-KG to generate high amounts of the oncometabolite D-2-hydroxyglutarate (D-2-HG). While the effects of D-2-HG have been subject to intense research, D-2-HG independent effects of IDH1R132H on energy homeostasis and redox status are not well studied. Here we demonstrate that IDH1R132H transduction but not D-2-HG alone leads to significantly decreased Krebs cycle metabolite concentrations and proliferation in U87 and the primary GBM cell line HT7606 as well as in immortalized astrocytes SVGp12. Furthermore, IDH1R132H mutation, but not D-2-HG treatment, resulted in a significant drop in NADPH levels in tumor cells (U87 and HT7606), whereas immortalized astrocytes retained normal NADPH levels. Since NAPDH levels can be restored via the reaction of the NAD-kinase, we analyzed NAD levels and enzymes involved in NAD-synthesis in our cell lines. Indeed we found a significant drop of NAD levels and in the activity of the NAD-dependent enzyme sirtuin in IDH1R132H mutant U87 and HT7606 but not in NADPH stable SVGp12-IDH1R132H. Interestingly, there were marked differences in expression of NAD-synthesis enzymes between the different cell-lines. In particular, NAMPT-levels were much higher in U87 and HT7606 then in astrocytes (SVGp12) and significantly decreased in U87-IDH1R132H and HT7606-IDH1R132H. Importantly, we also found decreased levels of NAMPT in primary tumor tissues and patient derived glioma cell lines with IDH1 R132H compared to wild type gliomas. Altogether our results for the first time show that the IDH1 mutation directly affects energy homeostasis and redox status in a cell-type dependent manner. We hypothesize that this leads to a drop in NADPH and NAD-levels during malignant progression, resulting in a disadvantage for proliferating tumor cells. This is in line with the favorable prognosis and good response to chemo- and radiation therapy clinically observed in IDH-mutated gliomas. Our findings suggest that the impaired metabolism in IDH1-mutant tumors might be a promising target for future therapies. Citation Format: Evelin Schrock, Julia Biedermann, Khalil Abou-El-Ardat, Matthias Lehmann, Marina Conde, Mirko Peitzsch, Susan Richter, Ralf Wiedemuth, Matthias Meinhardt, William P. J. Leenders, Christel Herold-Mende, Graeme Eisenhofer, Simone P. Niclou, Leoni Kunz-Schughart, Achim Temme, Barbara Klink. Effects of the IDH1 R132H mutation on redox status and metabolism are cell type dependent but independent from D-2-hydroxyglutarate accumulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-308.