TY - THES A1 - Götze, Michael Jan Werner T1 - Aktuelle Fragen der strafrechtlichen Providerhaftung insbesondere zur Haftung des Access-Providers T1 - Current issues of the criminal liability of internet service providers, in particular the liability of the access provider N2 - Dieses Werk widmet sich der Frage der strafrechtlichen Haftung von Internetprovidern und geht schwerpunktmäßig auf die spezielle Haftung des Access-Providers ein. N2 - The work deals with the question of criminal liability of internet service providers and deals in its essence with the peculiarities of the criminal liability of access providers KW - Access provider KW - Deep-Paket-Inspection KW - Content provider; Online-Dienst; Internetdienst KW - Internet der Dinge KW - Telemediengesetz KW - Service provider KW - Provider Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-156386 ER - TY - JOUR A1 - Werner, Rudolf A1 - Schmid, Jan-Stefan A1 - Higuchi, Takahiro A1 - Javadi, Mehrbod S. A1 - Rowe, Steven P. A1 - Märkl, Bruno A1 - Aulmann, Christoph A1 - Fassnacht, Martin A1 - Kroiß, Matthias A1 - Reiners, Christoph A1 - Buck, Andreas A1 - Kreissl, Michael A1 - Lapa, Constantin T1 - Predictive value of \(^{18}\)F-FDG PET in patients with advanced medullary thyroid carcinoma treated with vandetanib JF - Journal of Nuclear Medicine N2 - Introduction: Therapeutic options in advanced medullary thyroid carcinoma (MTC) have markedly improved since the introduction of tyrosine kinase inhibitors (TKI). We aimed to assess the role of metabolic imaging using 2-deoxy-2-(\(^{18}\)F)fluoro-D-glucose (\(^{18}\)F-FDG) positron emission tomography/computed tomography (PET/CT) shortly before and 3 months after initiation of TKI treatment. Methods: Eighteen patients with advanced and progressive MTC scheduled for vandetanib treatment underwent baseline \(^{18}\)F-FDG PET/CT prior to and 3 months after TKI treatment initiation. During follow-up, CT scans were performed every 3 months and analyzed according to Response Evaluation Criteria In Solid Tumors (RECIST). The predictive value for estimating progression-free (PFS) and overall survival (OS) was examined by investigating \(^{18}\)F-FDG mean/maximum standardized uptake values (SUVmean/max) of the metabolically most active lesion as well as by analyzing clinical parameters (tumor marker doubling times {calcitonin, carcinoembryonic antigen (CEA)}, prior therapies, RET (rearranged during transfection) mutational status, and disease type). Results: Within a median follow-up of 5.2 years, 9 patients experienced disease progression after a median time interval of 2.1y whereas the remainder had ongoing disease control (n=5 partial response and n=4 stable disease). Eight of the 9 patients with progressive disease died from MTC after a median of 3.5y after TKI initiation. Pre-therapeutic SUVmean >4.0 predicted a significantly shorter PFS (PFS: 1.9y vs. 5.2y; p=0.04). Furthermore, sustained high 18F-FDG uptake at 3 months with a SUVmean>2.8 tended to portend an unfavorable prognosis with a PFS of 1.9y (vs. 3.5y; p=0.3). Prolonged CEA doubling times were significantly correlated with longer PFS (r=0.7) and OS (r=0.76, p<0.01, respectively). None of the other clinical parameters had prognostic significance. Conclusions: Pre-therapeutic \(^{18}\)F-FDG PET/CT holds prognostic information in patients with advanced MTC scheduled for treatment with the TKI vandetanib. Low tumor metabolism of SUVmean < 4.0 prior to treatment predicts longer progression-free survival. KW - positron emission tomography KW - Medullärer Schilddrüsenkrebs KW - Positronen-Emissions-Tomografie KW - medullary thyroid carcinoma KW - tyrosine kinase inhibitor KW - vandetanib KW - 2- deoxy-2-(18F)fluoro-D-glucose KW - 18F-FDG Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161256 SN - 0161-5505 N1 - This research was originally published in JNM. Rudolf A. Werner, Jan-Stefan Schmid, Takahiro Higuchi, Mehrbod S. Javadi, Steven P. Rowe, Bruno Märkl, Christoph Aulmann, Martin Fassnacht, Matthias Kroiss, Christoph Reiners, Andreas K. Buck, Michael C. Kreissl, Constantin Lapa. Predictive value of 18F-FDG PET in patients with advanced medullary thyroid carcinoma treated with vandetanib. J Nucl Med. May 1, 2018;vol. 59 no. 5: 756-761. © SNMMI. ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Weich, Alexander A1 - Higuchi, Takahiro A1 - Schmid, Jan S. A1 - Schirbel, Andreas A1 - Lassmann, Michael A1 - Wild, Vanessa A1 - Rudelius, Martina A1 - Kudlich, Theodor A1 - Herrmann, Ken A1 - Scheurlen, Michael A1 - Buck, Andreas K. A1 - Kropf, Saskia A1 - Wester, Hans-Jürgen A1 - Lapa, Constantin T1 - Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach JF - Theranostics N2 - C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [\(^{68}\)Ga]Pentixafor in comparison to \(^{68}\)Ga-DOTA-D-Phe-Tyr3-octreotide ([\(^{68}\)Ga]DOTATOC) and \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [\(^{68}\)Ga]DOTATOC, [\(^{18}\)F]FDG, and [\(^{68}\)Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [\(^{68}\)Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [\(^{18}\)F]FDG revealed sites of disease in 10/12 and [\(^{68}\)Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [\(^{68}\)Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [\(^{68}\)Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors. KW - SSTR KW - peptide receptor radionuclide therapy KW - neuroendocrine tumor KW - [\(^{68}\)Ga]Pentixafor KW - CXCR4 KW - chemokine receptor KW - PET/CT KW - DOTATOC KW - PRRT KW - Positronen-Emissions-Tomografie Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158008 VL - 7 IS - 6 ER - TY - THES A1 - Werner, Jan T1 - Numerical Simulations of Heavy Fermion Systems: From He-3 Bilayers to Topological Kondo Insulators T1 - Numerische Simulationen von Schwer-Fermionen-Systemen: Von He-3-Doppellagen zu Topologischen Kondo Isolatoren N2 - Even though heavy fermion systems have been studied for a long time, a strong interest in heavy fermions persists to this day. While the basic principles of local moment formation, Kondo effect and formation of composite quasiparticles leading to a Fermi liquid, are under- stood, there remain many interesting open questions. A number of issues arise due to the interplay of heavy fermion physics with other phenomena like magnetism and superconduc- tivity. In this regard, experimental and theoretical investigations of He-3 can provide valuable insights. He-3 represents a unique realization of a quantum liquid. The fermionic nature of He-3 atoms, in conjunction with the absence of long-range Coulomb repulsion, makes this material an ideal model system to study Fermi liquid behavior. Bulk He-3 has been investigated for quite some time. More recently, it became possible to prepare and study layered He-3 systems, in particular single layers and bilayers. The pos- sibility of tuning various physical properties of the system by changing the density of He-3 and using different substrate materials makes layers of He-3 an ideal quantum simulator for investigating two-dimensional Fermi liquid phenomenology. In particular, bilayers of He-3 have recently been found to exhibit heavy fermion behavior. As a function of temperature, a crossover from an incoherent state with decoupled layers to a coherent Fermi liquid of composite quasiparticles was observed. This behavior has its roots in the hybridization of the two layers. The first is almost completely filled and subject to strong correlation effects, while the second layer is only partially filled and weakly correlated. The quasiparticles are formed due to the Kondo screening of localized moments in the first layer by the second-layer delocalized fermions, which takes place at a characteristic temperature scale, the coherence scale Tcoh. Tcoh can be tuned by changing the He-3 density. In particular, at a certain critical filling, the coherence scale is expected to vanish, corresponding to a divergence of the quasiparticle effective mass, and a breakdown of the Kondo effect at a quantum critical point. Beyond the critical point, the layers are decoupled. The first layer is a local moment magnet, while the second layer is an itinerant overlayer. However, already at a filling smaller than the critical value, preempting the critical point, the onset of a finite sample magnetization was observed. The character of this intervening phase remained unclear. Motivated by these experimental observations, in this thesis the results of model calcula- tions based on an extended Periodic Anderson Model are presented. The three particle ring exchange, which is the dominant magnetic exchange process in layered He-3, is included in the model. It leads to an effective ferromagnetic interaction between spins on neighboring sites. In addition, the model incorporates the constraint of no double occupancy by taking the limit of large local Coulomb repulsion. By means of Cellular DMFT, the model is investigated for a range of values of the chemical potential µ and inverse temperature β = 1/T . The method is a cluster extension to the Dy- namical Mean-Field Theory (DMFT), and allows to systematically include non-local correla- tions beyond the DMFT. The auxiliary cluster model is solved by a hybridization expansion CTQMC cluster solver, which provides unbiased, numerically exact results for the Green’s function and other observables of interest. As a first step, the onset of Fermi liquid coherence is studied. At low enough temperature, the self-energy is found to exhibit a linear dependence on Matsubara frequency. Meanwhile, the spin susceptibility crossed over from a Curie-Weiss law to a Pauli law. Both observations serve as fingerprints of the Fermi liquid state. The heavy fermion state appears at a characteristic coherence scale Tcoh. This scale depends strongly on the density. While it is rather high for small filling, for larger filling Tcoh is increas- ingly suppressed. This involves a decreasing quasiparticle residue Z ∼ Tcoh and an enhanced mass renormalization m∗/m ∼ Tcoh−1. Extrapolation leads to a critical filling, where the co- herence scale is expected to vanish at a quantum critical point. At the same time, the effective mass diverges. This corresponds to a breakdown of the Kondo effect, which is responsible for the formation of quasiparticles, due to a vanishing of the effective hybridization between the layers. Taking only single-site DMFT results into account, the above scenario seems plausible. However, paramagnetic DMFT neglects the ring exchange interaction completely. In or- der to improve on this, Cellular DMFT simulations are conducted for small clusters of size Nc = 2 and 3. The results paint a different physical picture. The ring exchange, by favor- ing a ferromagnetic alignment of spins, competes with the Kondo screening. As a result, strong short-range ferromagnetic fluctuations appear at larger values of µ. By lowering the temperature, these fluctuations are enhanced at first. However, for T < Tcoh they are increas- ingly suppressed, which is consistent with Fermi liquid coherence. However, beyond a certain threshold value of µ, fluctuations persist to the lowest temperatures. At the same time, while not apparent in the DMFT results, the total occupation n increases quite strongly in a very narrow range around the same value of µ. The evolution of n with µ is always continuous, but hints at a discontinuity in the limit Nc → ∞. This first-order transition breaks the Kondo effect. Beyond the transition, a ferromagnetic state in the first layer is established, and the second layer becomes a decoupled overlayer. These observations provide a quite appealing interpretation of the experimental results. As a function of chemical potential, the Kondo breakdown quantum critical point is preempted by a first-order transition, where the layers decouple and the first layer turns into a ferromagnet. In the experimental situation, where the filling can be tuned directly, the discontinuous transition is mirrored by a phase separation, which interpolates between the Fermi liquid ground state at lower filling and the magnetic state at higher filling. This is precisely the range of the intervening phase found in the experiments, which is characterized by an onset of a finite sample magnetization. Besides the interplay of heavy fermion physics and magnetic exchange, recently the spin- orbit coupling, which is present in many heavy fermion materials, attracted a lot of interest. In the presence of time-reversal symmetry, due to spin-orbit coupling, there is the possibility of a topological ground state. It was recently conjectured that the energy scale of spin-orbit coupling can become dom- inant in heavy fermion materials, since the coherence scale and quasiparticle bandwidth are rather small. This can lead to a heavy fermion ground state with a nontrivial band topology; that is, a topological Kondo insulator (TKI). While being subject to strong correlation effects, this state must be adiabatically connected to a non-interacting, topological state. The idea of the topological ground state realized in prototypical Kondo insulators, in par- ticular SmB6, promises to shed light on some of the peculiarities of these materials, like a residual conductivity at the lowest temperatures, which have remained unresolved so far. In this work, a simple two-band model for two-dimensional topological Kondo insulators is devised, which is based on a single Kramer’s doublet coupled to a single conduction band. The model is investigated in the presence of a Hubbard interaction as a function of interaction strength U and inverse temperature β. The bulk properties of the model are obtained by DMFT, with a hybridization expansion CTQMC impurity solver. The DMFT approximation of a local self-energy leads to a very simple way of computing the topological invariant. The results show that with increasing U the system can be driven through a topological phase transition. Interestingly, the transition is between distinct topological insulating states, namely the Γ-phase and M-phase. This appearance of different topological phases is possible due to the symmetry of the underlying square lattice. By adiabatically connecting both in- teracting states with the respective non-interacting state, it is shown that the transition indeed drives the system from the Γ-phase to the M-phase. A different behavior can be observed by pushing the bare position of the Kramer’s doublet to higher binding energies. In this case, the non-interacting starting point has a trivial band topology. By switching on the interaction, the system can be tuned through a quantum phase transition, with a closing of the band gap. Upon reopening of the band gap, the system is in the Γ-phase, i. e. a topological insulator. By increasing the interaction strength further, the system moves into a strongly correlated regime. In fact, close to the expected transition to the M phase, the mass renormalization becomes quite substantial. While absent in the para- magnetic DMFT simulations conducted, it is conceivable that instead of a topological phase transition, the system undergoes a time-reversal symmetry breaking, magnetic transition. The regime of strong correlations is studied in more detail as a function of temperature, both in the bulk and with open boundary conditions. A quantity which proved very useful is the bulk topological invariant Ns, which can be generalized to finite interaction strength and temperature. In particular, it can be used to define a temperature scale T ∗ for the onset of the topological state. Rescaling the results for Ns, a nice data collapse of the results for different values of U, from the local moment regime to strongly mixed valence, is obtained. This hints at T ∗ being a universal low energy scale in topological Kondo insulators. Indeed, by comparing T ∗ with the coherence scale extracted from the self-energy mass renormalization, it is found that both scales are equivalent up to a constant prefactor. Hence, the scale T ∗ obtained from the temperature dependence of topological properties, can be used as an independent measure for Fermi liquid coherence. This is particularly useful in the experimentally relevant mixed valence regime, where charge fluctuations cannot be neglected. Here, a separation of the energy scales related to spin and charge fluctuations is not possible. The importance of charge fluctuations becomes evident in the extent of spectral weight transfer as the temperature is lowered. For mixed valence, while the hybridization gap emerges, a substantial amount of spectral weight is shifted from the vicinity of the Fermi level to the lower Hubbard band. In contrast, this effect is strongly suppressed in the local moment regime. In addition to the bulk properties, the spectral function for open boundaries is studied as a function of temperature, both in the local moment and mixed valence regime. This allows an investigation of the emergence of topological edge states with temperature. The method used here is the site-dependent DMFT, which is a generalization of the conventional DMFT to inhomogeneous systems. The hybridization expansion CTQMC algorithm is used as impurity solver. By comparison with the bulk results for the topological quantity Ns, it is found that the temperature scale for the appearance of the topological edge states is T ∗, both in the mixed valence and local moment regime. N2 - Obwohl Heavy-Fermion-Systemen bereits seit vielen Jahrzehnten intensiv untersucht werden, ist auch heute ein großes Interesse an Heavy Fermions vorhanden. Obwohl die grundlegenden Konzepte wie die Ausbildung lokaler Momente, der Kondo-Effekt und die zur Entstehung einer Fermi-Flüssigkeit führenden, koha¨renten Quasiteilchen gut verstanden sind, gibt es weiterhin viele offene Fragestellungen. Diese ergeben sich u.a. aus dem Zusammenspiel von Heavy Fermions mit anderen Phänomenen wie Magnetismus und Supraleitung. In dieser Hinsicht können Untersuchungen an He-3 sehr wertvolle Einsichten liefern. Das liegt darin begründet, dass He-3 eine einzigartige Realisierung einer Quanten-Flu¨ssigkeit darstellt. Da He-3-Atome Fermionen sind, und da die langreichweitige Coulomb-Abstoßung keine Rolle spielt, ist dieses Material in idealer Weise dazu geeignet, um Fermi-Flüssigkeiten zu studieren. In drei Dimensionen wird He-3 bereits seit La¨ngerem untersucht. Vor Kurzem gelang es dann auch, Schichtsysteme aus He-3 zu erzeugen und zu untersuchen. Damit ergibt sich die Möglichkeit, die Phänomenologie zweidimensionaler Fermi-Flu¨ssigkeiten detailliert zu unter- suchen. He-3-Schichtsysteme stellen einen idealen Quanten-Simulator für diese Systeme dar, da sich durch Variation der He-3-Konzentration und durch die Wahl verschiedener Substrat- materialien unterschiedliche Eigenschaften der Fermi-Flüssigkeit gezielt einstellen lassen. So wurde in He-3-Doppellagen ein Heavy-Fermion-Verhalten nachgewiesen. In Abha¨ngig- keit der Temperatur wurde ein kontinuierlicher Übergang von einem inkohärenten Zustand mit entkoppelten Lagen zu einer koha¨renten Fermi-Flüssigkeit aus Quasiteilchen mit gemischtem Charakter beobachtet. Dieses Verhalten hat seinen Ursprung in der Hybridisierung der beiden Lagen. Die erste Lage ist beinahe vollständig gefüllt und von starken Korrelationseffekten beeinflusst, wa¨hrend die zweite Lage nur teilgefüllt ist und Korrelationen eine geringe Rolle spielen. Die Quasiteilchen entstehen bei der Kondo-Abschirmung der lokalisierten Momente der ersten Lage durch die delokalisierten Fermionen der zweiten Lage, die bei einer charakteristischen Temperatur-Skala, der Kohärenz-Skala Tcoh stattfindet. Durch das Verändern der Dichte von He-3-Atomen lässt sich Tcoh variieren. Dabei zeigte sich, dass bei einer kritischen Dichte ein Verschwinden der Kohärenzskala zu erwarten ist. Dies korrespondiert mit einer Divergenz der effektiven Masse der Quasiteilchen, und einem Zusammenbrechen des Kondo-Effekts an einem quantenkritischen Punkt. Jenseits dieses kritischen Punktes sind die Lagen vollständig entkoppelt. Die erste Lage ist ein Magnet von lokalen Momenten, während die zweite Lage einen itineranten Overlayer darstellt. Allerdings wurde bereits bei einer Dichte, die kleiner ist als der kritische Wert, die Herausbildung einer endlichen Magnetisierung der Probe beobachtet. Der Charakter dieser Zwischenphase, die dem kritischen Punkt voraus geht, blieb allerdings ungeklärt. In dieser Arbeit werden Resultate von Modellrechnungen eines erweiterten Periodischen Anderson Modell vorgestellt, die von den experimentellen Beobachtungen motiviert wur- den. Dabei ist der Ringaustausch dreier Teilchen, also der dominante magnetische Aus- tauschmechanismus in Schichtsystemen aus He-3, im Modell explizit enthalten. Dieser fu¨hrt zu einer effektiv ferromagnetischen Wechselwirkung zwischen Spins auf benachbarten Gitterplätzen. Zudem berücksichtigt das Modell die Bedingung, dass keine Doppelbesetzung von Gitterplätzen auftritt, indem der Grenzfall einer sehr großen lokalen Coulomb-Abstoßung angenommen wird. Mit Hilfe der Cellular DMFT wird das Modell als Funktion der Parameter chemisches Potential µ und inverse Temperature β = 1/T untersucht. Diese Methode stellt eine Cluster- Erweiterung der Dynamical Mean-Field Theory (DMFT) dar, und erlaubt es, auf systemati- sche Weise nichtlokale Korrelationen zu berücksichtigen, die über die DMFT-Approximation hinaus gehen. Für die Lösung der in jedem Iterationsschritt auftretenden Cluster-Modelle wird ein CTQMC-Cluster-Lo¨ser eingesetzt, der auf der Hybridisierungentwicklung basiert. Dieser liefert unverzehrte, numerisch exakte Ergebnisse für die Greensche Funktion und andere Observablen. In einem ersten Schritt wird die Entstehung der kohärenten Fermi-Flüssigkeitsphase unter- sucht. Bei ausreichend tiefer Temperatur zeigt die Selbst-Energie in Matsubara-Frequenzen eine lineare Frequenzabhängigkeit. Gleichzeitig findet in der Spin-Suszeptibilität ein Über- gang von einem Verhalten nach Curie-Weiss-Gesetz zu einem Pauli-Verhalten statt. Beide Beobachtungen sind eindeutige Hinweise auf einen Fermi-Flüssigkeitszustand. Heavy Fermions bilden sich unterhalb der Kohärenz-Skala Tcoh aus. Diese hängt stark von der He-3-Dichte ab. Tcoh ist bei kleiner Füllung recht hoch, wird bei größerer Fu¨llung allerdings zunehmend unterdrückt. Dies bedingt ein abnehmendes Quasiteilchen-Gewicht Z ∼ Tcoh und eine zunehmende Massenrenormierung m∗/m ∼ Tcoh−1. Durch Extrapolation erhält man einen quantenkritischen Punkt, an dem die Kohärenzskala verschwindet. Gleichzeitig divergiert hier die effektive Masse. Dies entspricht dem Zusammenbrechen des Kondo- Effekts, der für die Entstehung der Quasiteilchen verantwortlich ist, da die effektive Hybri- disierung zwischen den Lagen verschwindet. Berücksichtigt man nur Ergebnisse von paramagnetischer DMFT, so erscheint das obige Szenario plausibel. Allerdings wird in diesem Fall der Ringaustausch komplett vernachlässigt. Um diese Situation zu verbessern, werden Simulationen mit Hilfe von Cellular DMFT an kleinen Clustern der Gro¨ßen Nc = 2 and 3 durchgeführt. Die Ergebnisse zeichnen ein anderes physikalisches Bild. Der Ringaustausch konkurriert mit der Kondoabschirmung der lokalen Momente, da er eine ferromagnetische Ausrichtung der Spins bevorzugt. Daraus resultieren auf kurzen Längenskalen für steigendes µ starke ferromagnetische Fluktuationen. Mit sinkender Temperatur werden diese zunächst verstärkt, dann für T < Tcoh allerdings zunehmend unterdrückt. Dies ist konsistent mit einer kohärenten Fermi-Flüssigkeit. Bei Überschreiten eines gewissen Schwellwertes für µ bestehen die starken Fluktuationen bis zu den tiefsten Temperaturen, die in der Simulation erreicht wurden. Gleichzeitig, zeigt sich ein starker Anstieg der Gesamtbesetzung n in einem engen Fenster um denselben Schwellwert von µ. Dieses Verhalten fehlt in den DMFT-Resultaten vollständig. Die Entwicklung von n mit µ ist stets kontinuierlich, weist allerdings auf eine Diskontinuität im Grenzfall Nc → ∞ hin. Dieser Ü bergang erster Ordnung lässt den Kondo-Effekt abrupt zusammenbrechen. Jenseits des Übergangs ist in der ersten Lage ein ferromagnetischer Zustand ausgebildet, während die zweite Lage ein davon entkoppelter Overlayer wird. ... KW - Fermionensystem KW - Heavy Fermion Systems KW - Starke Kopplung KW - Fermi-Flüssigkeit KW - Topologischer Isolator KW - Stark korrelierte Fermionen KW - topologische Isolatoren Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112039 ER - TY - JOUR A1 - Holzapfel, Boris Michael A1 - Chhaya, Mohit Prashant A1 - Melchels, Ferry Petrus Wilhelmus A1 - Holzapfel, Nina Pauline A1 - Prodinger, Peter Michael A1 - von Eisenhart-Rothe, Rüdiger A1 - Griensven, Martijn van A1 - Schantz, Jan-Thorsten A1 - Rudert, Maximilian A1 - Hutmacher, Dietmar Werner T1 - Can Bone Tissue Engineering Contribute to Therapy Concepts after Resection of Musculoskeletal Sarcoma? JF - Sarcoma N2 - Resection of musculoskeletal sarcoma can result in large bone defects where regeneration is needed in a quantity far beyond the normal potential of self-healing. In many cases, these defects exhibit a limited intrinsic regenerative potential due to an adjuvant therapeutic regimen, seroma, or infection. Therefore, reconstruction of these defects is still one of the most demanding procedures in orthopaedic surgery. The constraints of common treatment strategies have triggered a need for new therapeutic concepts to design and engineer unparalleled structural and functioning bone grafts. To satisfy the need for long-term repair and good clinical outcome, a paradigm shift is needed from methods to replace tissues with inert medical devices to more biological approaches that focus on the repair and reconstruction of tissue structure and function. It is within this context that the field of bone tissue engineering can offer solutions to be implemented into surgical therapy concepts after resection of bone and soft tissue sarcoma. In this paper we will discuss the implementation of tissue engineering concepts into the clinical field of orthopaedic oncology. KW - musculoskeletal sarcoma Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132465 VL - 2013 IS - Article ID 153640 ER - TY - JOUR A1 - Jeanclos, Elisabeth A1 - Schlötzer, Jan A1 - Hadamek, Kerstin A1 - Yuan-Chen, Natalia A1 - Alwahsh, Mohammad A1 - Hollmann, Robert A1 - Fratz, Stefanie A1 - Yesilyurt-Gerhards, Dilan A1 - Frankenbach, Tina A1 - Engelmann, Daria A1 - Keller, Angelika A1 - Kaestner, Alexandra A1 - Schmitz, Werner A1 - Neuenschwander, Martin A1 - Hergenröder, Roland A1 - Sotriffer, Christoph A1 - von Kries, Jens Peter A1 - Schindelin, Hermann A1 - Gohla, Antje T1 - Glycolytic flux control by drugging phosphoglycolate phosphatase JF - Nature Communications N2 - Targeting the intrinsic metabolism of immune or tumor cells is a therapeutic strategy in autoimmunity, chronic inflammation or cancer. Metabolite repair enzymes may represent an alternative target class for selective metabolic inhibition, but pharmacological tools to test this concept are needed. Here, we demonstrate that phosphoglycolate phosphatase (PGP), a prototypical metabolite repair enzyme in glycolysis, is a pharmacologically actionable target. Using a combination of small molecule screening, protein crystallography, molecular dynamics simulations and NMR metabolomics, we discover and analyze a compound (CP1) that inhibits PGP with high selectivity and submicromolar potency. CP1 locks the phosphatase in a catalytically inactive conformation, dampens glycolytic flux, and phenocopies effects of cellular PGP-deficiency. This study provides key insights into effective and precise PGP targeting, at the same time validating an allosteric approach to control glycolysis that could advance discoveries of innovative therapeutic candidates. KW - phosphoglycolate phosphatase KW - glycolytic flux control KW - intrinsic metabolism Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300928 VL - 13 IS - 1 ER - TY - JOUR A1 - Harter, Philipp A1 - Hauke, Jan A1 - Heitz, Florian A1 - Reuss, Alexander A1 - Kommoss, Stefan A1 - Marmé, Frederik A1 - Heimbach, André A1 - Prieske, Katharina A1 - Richters, Lisa A1 - Burges, Alexander A1 - Neidhardt, Guido A1 - de Gregorio, Nikolaus A1 - El-Balat, Ahmed A1 - Hilpert, Felix A1 - Meier, Werner A1 - Kimmig, Rainer A1 - Kast, Karin A1 - Sehouli, Jalid A1 - Baumann, Klaus A1 - Jackisch, Christian A1 - Park-Simon, Tjoung-Won A1 - Hanker, Lars A1 - Kröber, Sandra A1 - Pfisterer, Jacobus A1 - Gevensleben, Heidrun A1 - Schnelzer, Andreas A1 - Dietrich, Dimo A1 - Neunhöffer, Tanja A1 - Krockenberger, Mathias A1 - Brucker, Sara Y. A1 - Nürnberg, Peter A1 - Thiele, Holger A1 - Altmüller, Janine A1 - Lamla, Josefin A1 - Elser, Gabriele A1 - du Bois, Andreas A1 - Hahnen, Eric A1 - Schmutzler, Rita T1 - Prevalence of deleterious germline variants in risk genes including \(BRCA1/2\) in consecutive ovarian cancer patients (AGO-TR-1) JF - PLoS ONE N2 - Background Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in \(BRCA1/2\) in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Methods Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (\(ATM\), \(BRCA1\), \(BRCA2\), \(CDH1\), \(CHEK2\), \(MLH1\), \(MSH2\), \(MSH6\), \(NBN\), \(PMS2\), \(PTEN\), \(PALB2\), \(RAD51C\), \(RAD51D\), \(STK11\), \(TP53\)) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. Results In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the \(BRCA1\) (15.5%), \(BRCA2\) (5.5%), \(RAD51C\) (2.5%) and \(PALB2\) (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in \(BRCA1/2\) (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients \(\geq\)60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for \(BRCA1/2\) would miss in our series more than 5% of the patients with a deleterious variant in established risk genes. Conclusions 26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to \(BRCA1/2\) seems to be not sufficient. KW - medicine KW - Genetic causes of cancer KW - ovarian cancer KW - cancer risk factors KW - histology KW - cancer detection and diagnosis KW - breast cancer KW - genetic testing KW - human genetics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173553 VL - 12 IS - 10 ER - TY - JOUR A1 - Wu, Hao A1 - Zhao, Xiufeng A1 - Hochrein, Sophia M. A1 - Eckstein, Miriam A1 - Gubert, Gabriela F. A1 - Knöpper, Konrad A1 - Mansilla, Ana Maria A1 - Öner, Arman A1 - Doucet-Ladevèze, Remi A1 - Schmitz, Werner A1 - Ghesquière, Bart A1 - Theurich, Sebastian A1 - Dudek, Jan A1 - Gasteiger, Georg A1 - Zernecke, Alma A1 - Kobold, Sebastian A1 - Kastenmüller, Wolfgang A1 - Vaeth, Martin T1 - Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming JF - Nature Communications N2 - T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy. KW - cytotoxic T cells KW - infection KW - lymphocyte differentiation KW - translational research Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358052 VL - 14 ER - TY - JOUR A1 - Schoffer, Olaf A1 - Schülein, Stefanie A1 - Arand, Gerlinde A1 - Arnholdt, Hans A1 - Baaske, Dieter A1 - Bargou, Ralf C. A1 - Becker, Nikolaus A1 - Beckmann, Matthias W. A1 - Bodack, Yves A1 - Böhme, Beatrix A1 - Bozkurt, Tayfun A1 - Breitsprecher, Regine A1 - Buchali, Andre A1 - Burger, Elke A1 - Burger, Ulrike A1 - Dommisch, Klaus A1 - Elsner, Gudrun A1 - Fernschild, Karin A1 - Flintzer, Ulrike A1 - Funke, Uwe A1 - Gerken, Michael A1 - Göbel, Hubert A1 - Grobe, Norbert A1 - Gumpp, Vera A1 - Heinzerling, Lucie A1 - Kempfer, Lana Raffaela A1 - Kiani, Alexander A1 - Klinkhammer-Schalke, Monika A1 - Klöcking, Sabine A1 - Kreibich, Ute A1 - Knabner, Katrin A1 - Kuhn, Peter A1 - Lutze, Stine A1 - Mäder, Uwe A1 - Maisel, Tanja A1 - Maschke, Jan A1 - Middeke, Martin A1 - Neubauer, Andreas A1 - Niedostatek, Antje A1 - Opazo-Saez, Anabelle A1 - Peters, Christoph A1 - Schell, Beatrice A1 - Schenkirsch, Gerhard A1 - Schmalenberg, Harald A1 - Schmidt, Peter A1 - Schneider, Constanze A1 - Schubotz, Birgit A1 - Seide, Anika A1 - Strecker, Paul A1 - Taubenheim, Sabine A1 - Wackes, Matthias A1 - Weiß, Steffen A1 - Welke, Claudia A1 - Werner, Carmen A1 - Wittekind, Christian A1 - Wulff, Jörg A1 - Zettl, Heike A1 - Klug, Stefanie J. T1 - Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011 JF - BMC Cancer N2 - Background Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients. Methods Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival. Results The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97–0.97), sex (OR 1.18, 95% CI 1.11–1.25), date of diagnosis (OR 1.05, 95% CI 1.04–1.06), ‘diagnosis during screening’ (OR 3.24, 95% CI 2.50–4.19) and place of residence (OR 1.23, 95% CI 1.16–1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8–83.9%). Conclusions No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008. " KW - Malignant melanoma KW - TNM staging KW - Survival analysis KW - Skin cancer screening KW - Stage distribution Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164544 VL - 16 IS - 936 ER - TY - JOUR A1 - Fröhlich, Matthias A1 - Serfling, Sebastian A1 - Higuchi, Takahiro A1 - Pomper, Martin G. A1 - Rowe, Steven P. A1 - Schmalzing, Marc A1 - Tony, Hans-Peter A1 - Gernert, Michael A1 - Strunz, Patrick-Pascal A1 - Portegys, Jan A1 - Schwaneck, Eva-Christina A1 - Gadeholt, Ottar A1 - Weich, Alexander A1 - Buck, Andreas K. A1 - Bley, Thorsten A. A1 - Guggenberger, Konstanze V. A1 - Werner, Rudolf A. T1 - Whole-Body [\(^{18}\)F]FDG PET/CT Can Alter Diagnosis in Patients with Suspected Rheumatic Disease JF - Diagnostics N2 - The 2-deoxy-d-[\(^{18}\)F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely utilized to assess the vascular and articular inflammatory burden of patients with a suspected diagnosis of rheumatic disease. We aimed to elucidate the impact of [\(^{18}\)F]FDG PET/CT on change in initially suspected diagnosis in patients at the time of the scan. Thirty-four patients, who had undergone [\(^{18}\)F]FDG PET/CT, were enrolled and the initially suspected diagnosis prior to [18F]FDG PET/CT was compared to the final diagnosis. In addition, a semi-quantitative analysis including vessel wall-to-liver (VLR) and joint-to-liver (JLR) ratios was also conducted. Prior to [\(^{18}\)F]FDG PET/CT, 22/34 (64.7%) of patients did not have an established diagnosis, whereas in 7/34 (20.6%), polymyalgia rheumatica (PMR) was suspected, and in 5/34 (14.7%), giant cell arteritis (GCA) was suspected by the referring rheumatologists. After [\(^{18}\)F]FDG PET/CT, the diagnosis was GCA in 19/34 (55.9%), combined GCA and PMR (GCA + PMR) in 9/34 (26.5%) and PMR in the remaining 6/34 (17.6%). As such, [\(^{18}\)F]FDG PET/CT altered suspected diagnosis in 28/34 (82.4%), including in all unclear cases. VLR of patients whose final diagnosis was GCA tended to be significantly higher when compared to VLR in PMR (GCA, 1.01 ± 0.08 (95%CI, 0.95–1.1) vs. PMR, 0.92 ± 0.1 (95%CI, 0.85–0.99), p = 0.07), but not when compared to PMR + GCA (1.04 ± 0.14 (95%CI, 0.95–1.13), p = 1). JLR of individuals finally diagnosed with PMR (0.94 ± 0.16, (95%CI, 0.83–1.06)), however, was significantly increased relative to JLR in GCA (0.58 ± 0.04 (95%CI, 0.55–0.61)) and GCA + PMR (0.64 ± 0.09 (95%CI, 0.57–0.71); p < 0.0001, respectively). In individuals with a suspected diagnosis of rheumatic disease, an inflammatory-directed [\(^{18}\)F]FDG PET/CT can alter diagnosis in the majority of the cases, particularly in subjects who were referred because of diagnostic uncertainty. Semi-quantitative assessment may be helpful in establishing a final diagnosis of PMR, supporting the notion that a quantitative whole-body read-out may be useful in unclear cases. KW - giant cell arteritis KW - GCA KW - [18F]FDG PET/CT KW - vasculature KW - inflammation KW - polymyalgia rheumatica KW - PMR KW - vasculitis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250227 SN - 2075-4418 VL - 11 IS - 11 ER -