Bruchmechanische Untersuchungen an einer Spanteckverbindung mit der Finite-Element-Methode

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Abschätzung der technischen und wirtschaftlichen Potentiale des Beitrags zur Energieversorgung und zur Minderung klimarelevanter Spurengase durch Kernenergie in der Bundesrepublik Deutschland : Studie A.4.2.a und A.4.2.b

In diesem Arbeitspaket A.4.2 werden die Möglichkeiten der Minderung von CO2-Emissionen durch den Einsatz der Kernenergie untersucht. Dabei werden sechs Einsatzbereiche betrachtet, in denen die Kernenergie eine CO2-Emissionsminderung durch Substitution fossiler Energieerzeugung bewirken kann. In Kapitel 2 werden mögliche CO2-Emissionsminderungen im Bereich der Stromerzeugung, in Kapitel 3 bei der Fern- bzw. Nahwärmeerzeugung diskutiert. In den Kapiteln 4 bis 7 werden die CO2-Minderungspotentiale durch die Nutzung der Kernenergie zur Veredelung fossiler Energieträger, zur Prozeßdampf- und Prozeßwärmeerzeugung, zur Wasserstofferzeugung über Elektrolyse und bei der tertiären Erdölförderung in der Bundesrepublik Deutschland untersucht

Sarcoma classification by DNA methylation profiling

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications

Beiträge zur Neutronenphysik des Kugelhaufenreaktors

The first chapter of this study involves problems an absorber rods calculations, the second chapter involves problems an the local dependence of the neutron spectrum. 1. The program-cycle KUP0MINOTAUR is decribed for the calculation of boundary conditions of absorber regions in diffusion regions. The application of the program considers first the reactivity of absorber rods of the AVR reactor at Jülich ; here, the threedimensional problems of the inserted absorber-rod Bank is transformed by the ring model into a two-dimensional one . Values were calculated for different burn-up conditions of the core, and they are in good accordance with the measured values . For some HTR cores is studied the mutual interdependence of control rods, the reactivity worth versus insertion depth, and the influenceof the rod diameter . For a global characterization of absorber rod Systems in HTR cores, the term "absorber surface density A" is proposed . The connection between A and shut-down reactivity $\rho$ is already available for some HTR reactors, and therefore can be used for the estimation of the required number of control rods for new core designs. 2. Description of a program-cycle for considering local variation in temperature and buckling by dividing the reactor core into an optional number of spectral zones . Investigation of the influence of local-dependent spectrum calculations by the example of the AVR reactor. lt is shown that the local dependence of the buckling is of little importance compared to that of temperature . The influence of spectral zones to the calculation of keff, of power density distribution, temperature distribution, and burn-up behavior is discussed . The program-cycle considered here permits also to calculate the temperature coefficient . Such a calculation has been performed for the primary core of the AVR ; the results Show good accordance with the measured values

Vorgespannte Guß-Druckbehälter (VGD) als berstsichere Druckbehälter für innovative Anwendungen in der Kerntechnik

Seit der Änderung des deutschen Atomgesetzes vom 28.07.1994 dürfen auch Ereignisse, "deren Eintritt durch die zu treffende Vorsorge gegen Schaden praktisch ausgeschlossen ist", d. h. Ereignisse, die unter die Kategorie Restrisiko fallen, ausserhalb der Anlage keine einschneidenden Schutzmassnahmen erforderlich machen. Das Restrisiko besteht bei einem konventionellen Reaktordruckbehälter in der sehr kleinen Wahr-scheinlichkeit dafür, dass er katastrophal versagt (Entstehen einer Grossen Bruchöffnung, Behalterbersten). Bei einem Vorgespannten Guss- Druckbehalter (VGD) sind das Entstehen einer grossen Bruchöffnung bzw. ein Behalterbersten aufgrund seiner konstruktiven Eigenschaften nicht möglich. Vor diesem Hintergrund wurde im Rahmen einer von verschiedenen Forschungsinstituten und Industriefirmen gegründeten "Arbeitsgemeinschaft Innovative Kerntechnik" (AGIK) auch die Möglichkeit eines Einsatzes dieses Behältertyps für Leichtwasserreaktoren untersucht. Darüber hinaus wurde überprüft, inwieweit der Einsatz des VGD die Realisierung eines Kernschmelze - Auffangsystems erleichtert. Die Ergebnisse sind im vorliegenden Bericht zusammengefasst. Für den VGD als innovatives, berstsicheres Behälterkonzept wurden die industriellen Entwicklungsarbeiten bei Siempelkamp sowie experimentelle und theoretische Sicherheitsuntersuchungen beim FZJ bereits vor vielen Jahren aufgegriffen. Ais Anwendung stand damals der HTR im Vordergrund. Im vorliegenden Bericht werden diese Entwicklung des VGD, sowie seine sicherheitstechnischen Eigenschaften ebenfalls zusammenfassend dargestellt

Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models

BACKGROUND The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms. METHODS We analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways. RESULTS In vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies. CONCLUSIONS Our study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC

Succession of transiently active tumor‐initiating cell clones in human pancreatic cancer xenografts

Abstract Although tumor‐initiating cell (TIC) self‐renewal has been postulated to be essential in progression and metastasis formation of human pancreatic adenocarcinoma (PDAC), clonal dynamics of TICs within PDAC tumors are yet unknown. Here, we show that long‐term progression of PDAC in serial xenotransplantation is driven by a succession of transiently active TICs producing tumor cells in temporally restricted bursts. Clonal tracking of individual, genetically marked TICs revealed that individual tumors are generated by distinct sets of TICs with very little overlap between subsequent xenograft generations. An unexpected functional and phenotypic plasticity of pancreatic TICs in vivo underlies the recruitment of inactive TIC clones in serial xenografts. The observed clonal succession of TIC activity in serial xenotransplantation is in stark contrast to the continuous activity of limited numbers of self‐renewing TICs within a fixed cellular hierarchy observed in other epithelial cancers and emphasizes the need to target TIC activation, rather than a fixed TIC population, in PDAC