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Inhibitoren der Apoptose (IAP, inhibitor of apoptosis) Proteine spielen eine wichtige Rolle in Bezug auf Zelltodregulation und es ist anzunehmen, dass eine Dysregulation dieser Proteine zu einer Tumorentwicklung und Tumorprogression beiträgt. Erhöhte Expressionslevel von IAP Proteinen verhindern die Aktivierbarkeit des Zelltodprogrammes von Tumorzellen und eine Reihe von Studien konnte bereits erhöhte IAP Level in Tumorzelllinien sowie in primären Tumorproben nachweisen. Des Weiteren korrelieren erhöhte Expressionslevel von IAPs in Tumoren mit Behandlungsresistenzen und schlechten Prognosen für die Patienten.
Das diffuse großzellige B-Zell Lymphom (DLBCL, diffuse large B-cell lymphoma) zählt zu den häufigsten Subtypen der Non-Hodgkin Lymphome (NHL) mit 40 % aller neu diagnostizierten NHL Fälle. DLBCL ist eine sehr heterogene Erkrankung die in drei verschiedene Gruppen klassifiziert wurde: aktivierter B-Zell Typ (ABC, activated B-cell), Keimzentrum B-Zell Typ (GCB, germinal center B-Cell) und Mediastinaler großzelliger B-Zell Typ (PMBL, primary mediastinal B-cell lymphoma). Erhöhte Expressionslevel von zellulärem IAP1 (cIAP, cellular IAP) und cIAP2 wurden ebenfalls in primären Tumorproben von DLBCL Patienten nachgewiesen. Smac mimetics wurden entwickelt, um IAPs zu antagonisieren und stellen damit eine Behandlungsstrategie für DLBCL Patienten dar, denn ca. 40 % aller DLBCL Patienten entwickeln ein Rezidiv oder erreichen gar keine Remission unter Standardtherapie. Jedoch ist der Effekt von Smac mimetics in einer Einzelbehandlung limitiert, weswegen Kombinationstherapien mit Smac mimetics eine vielversprechende Strategie für ihren klinischen Einsatz darstellen. Aus diesem Grund haben wir in dieser Arbeit den Effekt von Smac mimetic in Kombination mit Proteasom-Inhibitoren analysiert und einen speziellen Fokus auf den molekularen Mechanismus des ausgelösten Zelltodsignalweges gelegt.
Die Kombination verschiedener Konzentrationen des Smac mimetics BV6 mit dem Proteasom-Inhibitor carfilzomib (CFZ) löst in allen drei getesteten DLBCL Subtypen (ABC, GCB und PMBL) Zelltod aus. Die Kalkulation des Kombinationsindexes (CI, combination index) sowie des Bliss Scores, zwei quantitative Parameter zur Bestimmung eines Synergismus, zeigen, dass fast alle getesteten Kombinationen einen Synergismus aufweisen. Dies verdeutlicht, dass eine Co-Behandlung von BV6 und CFZ eine wirksame Kombination ist um Zelltod in DLBCL Zelllinien auszulösen. Außerdem zeigt eine Kombination von BV6 mit anderen Proteasom-Inhibitoren wie ixazomib (IXA) oder oprozomib (OPR), ebenfalls eine synergistische Reduktion der Zellviabilität. Diese Ergebnisse deuten darauf hin, dass der detektierte Effekt nicht auf eine Substanz limitiert ist, sondern, dass ein genereller Effekt von Smac mimetic und Proteasom-Inhibitoren vorliegt, um Zellviabilität in DLBCL zu reduzieren. BV6 und CFZ induzieren einen apoptotischen Zelltod, da sie die Spaltung und Aktivierung von Initiator- und Effektorcaspasen (Caspasen-3, -7, -8 und -9) initiieren und sich der induzierte Zelltod mit Hilfe des Caspasen-Inhibitors zVAD.fmk verhindern lässt. Die Behandlung mit BV6 und CFZ führt zu einer Akkumulation von NIK, ein Protein welches zur Aktivierung des non-kanonischen NF-kB Signalweges benötigt wird. Weitere Untersuchungen zeigen jedoch, dass NIK nicht an der Zelltodinduktion beteiligt ist, da eine siRNA-basierte Herunterregulierung des NIK Proteins keinen Einfluss auf die Zelltodinduktion nimmt. Ebenfalls ist der Zelltod unabhängig von dem TNFa Signalweg, da weder eine Behandlung mit dem TNFa Inhibitor Enbrel den Zelltod verringern kann noch eine zusätzliche Gabe von TNFa den Zelltod erhöht. Weitere mechanistische Studien zeigen eine kritische Rolle der mitochondrialen Apoptose für den BV6/CFZ-vermittelten Zelltod. Unter Behandlung mit BV6/CFZ wurde eine Aktivierung von BAX und BAK nachgewiesen, welche beide mit verantwortlich für die Porenbildung in der mitochondrialen Membran sind. Eine Herunterregulation dieser beiden Proteine mittels siRNA reduziert signifikant den durch BV6/CFZ-induzierten Zelltod auf ein Minimum. Gleichzeitig löst eine Co-Behandlung mit BV6/CFZ einen Verlust des mitochondrialen Membranpotentials (LOMMP, loss of mitochondrial membrane potential) aus. In Übereinstimmung mit den vorherigen Experimenten, zeigen wir eine Akkumulation von mitochondrialen reaktiven Sauerstoffspezies (ROS; reactive oxygen species), sowie einen generellen Anstieg des allgemeinen ROS Levels. Eine Behandlung mit BV6/CFZ zeigt eine deutliche Akkumulation des pro-apoptotischen Proteins NOXA. Um dessen funktionelle Relevanz zu überprüfen, wurde die Proteinmenge von NOXA mittels siRNA stark reduziert. Eine Behandlung mit der Kombination aus BV6 und CFZ zeigt daraufhin eine signifikant reduzierte Zelltodinduktion, was die funktionelle Relevanz von NOXA für den BV6/CFZ-vermittelten Zelltod unterstreicht. Immunopräzipitationsstudien zeigen, dass in RIVA und U2932 Zellen NOXA konstitutiv an seinen anti-apoptotischen Bindungspartner MCL-1 gebunden ist, was die Zellen bereits darauf vorbereitet Apoptose zu durchlaufen. Dieses sogenannte „primen“ für Apoptose wird durch die Behandlung mit BV6 und CFZ weiter verstärkt, da es die Bindung zwischen NOXA und MCL-1 weiter erhöht. Dadurch wird die Balance zwischen pro- und anti-apoptotischen Proteinen zu Gunsten der pro-apoptotischen Proteine verschoben und die Induktion von Apoptose begünstigt.
Insgesamt zeigen die Ergebnisse, dass DLBCL Zelllinien sensitiv auf eine Behandlung mit Smac mimetic und Proteasom-Inhibitor reagieren und damit eine mögliche neue Behandlungsstrategie für diese heterogene Tumorerkrankung darstellt.
Neutron total cross sections are an important source of experimental data in the evaluation of neutron-induced cross sections. The sum of all neutron-induced reaction cross sections can be determined with a precision of a few per cent in a relative measurement. The neutron spectrum of the photoneutron source nELBE extends in the fast region from about 100 keV to 10 MeV and has favourable conditions for transmission measurements due to the low instantaneous flux of neutrons and low gamma-flash background. Several materials of interest (in part included in the CIELO evaluation or on the HPRL of OECD/NEA) have been investigated: 197Au [1, 2], natFe [2], natW [2], 238U, natPt, 4He, natO, natNe, natXe. For gaseous targets high pressure gas cells with flat end-caps have been built that hold up to 200 bar pressure. The experimental setup will be presented including results from several transmission experiments and the data analysis leading to the total cross sections will be discussed.
An accurate measurement of the 140Ce(n,γ) energy-dependent cross-section was performed at the n_TOF facility at CERN. This cross-section is of great importance because it represents a bottleneck for the s-process nucleosynthesis and determines to a large extent the cerium abundance in stars. The measurement was motivated by the significant difference between the cerium abundance measured in globular clusters and the value predicted by theoretical stellar models. This discrepancy can be ascribed to an overestimation of the 140Ce capture cross-section due to a lack of accurate nuclear data. For this measurement, we used a sample of cerium oxide enriched in 140Ce to 99.4%. The experimental apparatus consisted of four deuterated benzene liquid scintillator detectors, which allowed us to overcome the difficulties present in the previous measurements, thanks to their very low neutron sensitivity. The accurate analysis of the p-wave resonances and the calculation of their average parameters are fundamental to improve the evaluation of the 140Ce Maxwellian-averaged cross-section.
Neutron capture on 241Am plays an important role in the nuclear energy production and also provides valuable information for the improvement of nuclear models and the statistical interpretation of the nuclear properties. A new experiment to measure the 241Am(n, γ) cross section in the thermal region and the first few resonances below 10 eV has been carried out at EAR2 of the n_TOF facility at CERN. Three neutron-insensitive C6D6 detectors have been used to measure the neutron-capture gamma cascade as a function of the neutron time of flight, and then deduce the neutron capture yield. Preliminary results will be presented and compared with previously obtained results at the same facility in EAR1. In EAR1 the gamma-ray background at thermal energies was about 90% of the signal while in EAR2 is up to a 25 factor much more favorable signal to noise ratio. We also extended the low energy limit down to subthermal energies. This measurement will allow a comparison with neutron capture measurements conducted at reactors and using a different experimental technique.
Although the 12C(n,p)12B and 12C(n,d)11B reactions are of interest in several fields of basic and applied Nuclear Physics the present knowledge of these two cross-sections is far from being accurate and reliable, with both evaluations and data showing sizable discrepancies. As part of the challenging n_TOF program on (n,cp) nuclear reactions study, the energy differential cross-sections of the 12C(n,p)12B and 12C(n,d)11 B reactions have been measured at CERN from the reaction thresholds up to 30 MeV neutron energy. Both measurements have been recently performed at the long flight-path (185 m) experimental area of the n_TOF facility at CERN using a pure (99.95%) rigid graphite target and two silicon telescopes. In this paper an overview of the experiment is presented together with a few preliminary results.
Background: The photon strength functions (PSFs) and nuclear level density (NLD) are key ingredients for calculation of the photon interaction with nuclei, in particular the reaction cross sections. These cross sections are important especially in nuclear astrophysics and in the development of advanced nuclear technologies.
Purpose: The role of the scissors mode in the M1 PSF of (well-deformed) actinides was investigated by several experimental techniques. The analyses of different experiments result in significant differences, especially on the strength of the mode. The shape of the low-energy tail of the giant electric dipole resonance is uncertain as well. In particular, some works proposed a presence of the E1 pygmy resonance just above 7 MeV. Because of these inconsistencies additional information on PSFs in this region is of great interest.
Methods: The γ-ray spectra from neutron-capture reactions on the 234U, 236 U, and 238 U nuclei have been measured with the total absorption calorimeter of the n_TOF facility at CERN. The background-corrected sum-energy and multi-step-cascade spectra were extracted for several isolated s-wave resonances up to about 140 eV.
Results: The experimental spectra were compared to statistical model predictions coming from a large selection of models of photon strength functions and nuclear level density. No combination of PSF and NLD models from literature is able to globally describe our spectra. After extensive search we were able to find model combinations with modified generalized Lorentzian (MGLO) E1 PSF, which match the experimental spectra as well as the total radiative widths.
Conclusions: The constant temperature energy dependence is favored for a NLD. The tail of giant electric dipole resonance is well described by the MGLO model of the E1 PSF with no hint of pygmy resonance. The M1 PSF must contain a very strong, relatively wide, and likely double-resonance scissors mode. The mode is responsible for about a half of the total radiative width of neutron resonances and significantly affects the radiative cross section.
73Ge(n, γ ) cross sections were measured at the neutron time-of-flight facility n_TOF at CERN up to neutron energies of 300 keV, providing for the first time experimental data above 8 keV. Results indicate that the stellar cross section at kT = 30 keV is 1.5 to 1.7 times higher than most theoretical predictions. The new cross sections result in a substantial decrease of 73Ge produced in stars, which would explain the low isotopic abundance of 73Ge in the solar system.
The 14N(n,p)14C reaction is of interest in neutron capture therapy, where nitrogen-related dose is the main component due to low-energy neutrons, and in astrophysics, where 14N acts as a neutron poison in the s-process. Several discrepancies remain between the existing data obtained in partial energy ranges: thermal energy, keV region and resonance region. Purpose: Measuring the 14N(n,p)14C cross section from thermal to the resonance region in a single measurement for the first time, including characterization of the first resonances, and providing calculations of Maxwellian averaged cross sections (MACS). Method: Time-of-flight technique. Experimental Area 2 (EAR-2) of the neutron time-of-flight (n_TOF) facility at CERN. 10B(n,α)7Li and 235U(n,f) reactions as references. Two detection systems running simultaneously, one on-beam and another off-beam. Description of the resonances with the R-matrix code sammy. Results: The cross section has been measured from sub-thermal energy to 800 keV resolving the two first resonances (at 492.7 and 644 keV). A thermal cross-section (1.809±0.045 b) lower than the two most recent measurements by slightly more than one standard deviation, but in line with the ENDF/B-VIII.0 and JEFF-3.3 evaluations has been obtained. A 1/v energy dependence of the cross section has been confirmed up to tens of keV neutron energy. The low energy tail of the first resonance at 492.7 keV is lower than suggested by evaluated values, while the overall resonance strength agrees with evaluations. Conclusions: Our measurement has allowed to determine the 14N(n,p) cross-section over a wide energy range for the first time. We have obtained cross-sections with high accuracy (2.5 %) from sub-thermal energy to 800 keV and used these data to calculate the MACS for kT = 5 to kT = 100 keV.
The neutron capture cross section of 154Gd was measured from 1 eV to 300 keV in the experimental area located 185 m from the CERN n_TOF neutron spallation source, using a metallic sample of gadolinium, enriched to 67% in 154Gd. The capture measurement, performed with four C6D6 scintillation detectors, has been complemented by a transmission measurement performed at the GELINA time-of-flight facility (JRC-Geel), thus minimising the uncertainty related to sample composition. An accurate Maxwellian averaged capture cross section (MACS) was deduced over the temperature range of interest for s process nucleosynthesis modelling. We report a value of 880(50) mb for the MACS at kT = 30 keV, significantly lower compared to values available in literature. The new adopted 154Gd(n,γ) cross section reduces the discrepancy between observed and calculated solar s-only isotopic abundances predicted by s-process nucleosynthesis models.