immunhistochemische und molekularbiologische Untersuchungsbefunde

Die Differentialdiagnose bösartiger, pleural lokalisierter Tumoren allein nach den histomorphologischen Befunden kann im Einzelfall auch für den erfahrenen Pathologen problematisch sein. Ein hochspezifischer und sensitiver Marker für die Diagnose bösartiger Pleuramesotheliome steht bislang nicht zur Verfügung. Im Rahmen der vorliegenden Arbeit wurde die Wertigkeit wichtiger, derzeit als potentiell relevant diskutierter Marker für die differentialdiagnostische Abgrenzung von Pleuramesotheliomen zu reaktiven Pleuraläsionen einerseits und sekundären bösartigen Pleuratumoren andererseits untersucht. Im einzelnen wurden immunhistochemische Untersuchungen zur Expression des Calcium-bindenden Proteins Calretinin und zur Akkumulation des Tumorsuppressorgenprodukts P53 sowie molekularpathologische Untersuchungen zum Nachweis einer SV 40-Infektion und zur Bestimmung von Veränderungen im Genom unter Einsatz der komparativen genomischen Hybridisierung an Gewebsproben von Pleuramesotheliomen, sekundären Pleuratumoren und reaktiven Pleuraläsionen durchgeführt. Die untersuchten Marker wiesen dabei in Bezug auf ihre Wertigkeit bei der Differentialdiagnose pleural lokalisierter Tumoren unterschiedliche, teilweise nur bedingt geeignete Sensitivitäten und Spezifitäten auf. Die Calretinin-Immunreaktion stellt für die Differentialdiagnose von primären und sekundären Pleuratumoren mit epitheloider Differenzierung einen sehr sensitiven und spezifischen Marker dar. Für keinen anderen, an einem größeren Kollektiv untersuchten Marker konnte eine vergleichbar hohe Sensitivität und Spezifität belegt werden. Für sarkomatoide Pleuramesotheliome erreicht Calretinin - bei hoher Spezifität für die Abgrenzung gegenüber Pleurasarkomatosen - aber eine niedrigere Sensitivität. Hier muss die Calretinin-Immunreaktion um ein Panel weiterer bewährter Antikörper ergänzt werden. Die Wertigkeit des immunhistochemischen Nachweises einer Akkumulation des P53-Tumorsuppressorgenprodukts muss bei der Abgrenzung zu reaktiven Pleuraläsionen und Pleurakarzinosen differenziert bewertet werden. Die Möglichkeit des Nachweises in Pleuramesotheliomen, pulmonalen Adenokarzinomen und in benignen Pleuraläsionen macht die P53-Akkumulation zu einem nur wenig geeigneten Marker. Im Einzelfall kann der Nachweis auf Grund des Reaktionsmusters aber einen ergänzenden Beitrag bei der Differentialdiagnose benigner und maligner Pleuraläsionen liefern. Der Nachweis von SV 40 TAg-Genfragmenten kann bei der Differentialdiagnose von Pleuramesotheliomen und Pleurakarzinosen bösartiger Lungentumoren im Einzelfall richtungsweisend sein. Für die Differentialdiagnose von reaktiven Pleuraläsionen und Pleuramesotheliomen erlangt der Nachweis keine diagnostische Bedeutung. Im Vergleich zu immunhistochemischen Untersuchungen mit einem Antikörperpanel besitzt der SV 40-Nachweis - bei vergleichbar guter Spezifität - eine deutlich geringere Sensitivität. Die mit der komparativen genomischen Hybridisierung (CGH) nachweisbaren chromosomalen Defekte sind für Mesotheliome wenig spezifisch. Die Methode ist auch nur bedingt sensitiv. Für die Differentialdiagnose pleural lokalisierter Tumoren stellt die CGH eine im Einzelfall wenig geeignete Methode dar. Auch für die Differentialdiagnose benigner und maligner pleuraler Prozesse ist die CGH nur bedingt geeignet. Zusammenfassend hat sich im Rahmen der vorliegenden Untersuchungen der immunhistochemische Nachweis der Calretinin-Expression als Marker mit höchster Sensisitivität und Spezifität erwiesen. Bei der pathologisch-anatomischen Begutachtung von Gewebsproben unter der Fragestellung eines Pleuramesothelioms sollte die Calretinin-Immunreaktion daher unbedingt durchgeführt werden. Letztendlich stellt für die Differentialdiagnose pleural lokalisierter Tumoren aber die Erfahrung des Untersuchers das entscheidende Kriterium bei der Auswahl geeigneter Zusatzuntersuchungen und bei der abschließenden diagnostischen Bewertung aller verfügbaren histomorphologischen, histochemischen, immunhistochemischen, staubanalytischen und letztendlich auch klinisch-radiologischen Befunde dar

Mobile Brenngaserzeugungssysteme mit Mitteldestillaten für Hochtemperatur-PEFC

This thesis discusses the development of a mobile fuel processing system for operating hightemperature polymer electrolyte fuel cells (HT-PEFCs) with reformate from middle distillates. Attention is focused on applications for on-board power supply. Using fuel cell systems to generate on-board power is an energy-efficient alternative to conventional on-board power generation via the engine or an auxiliary power unit with a diesel or kerosene engine. The fuel processing system serves to produce a hydrogen-rich gas from the fuel available on board. In the case of aircraft or trucks, these fuels are the middle distillates diesel or kerosene. Combining the reforming process with an HT-PEFC creates a simple system with high system efficiency. HT-PEFCs are particularly tolerant of carbon monoxide, which is always formed during thereforming of diesel or kerosene. The work described here focused on the analysis of system efficiency, the development of an appropriate start-up strategy, making the system more compact in order to increase the power density and the experimental validation of the (sub-)models. The methodology of this work was based on closely linking the results of stationary and dynamic models created using ASPEN Plus, Ansys Fluent and MATLAB/Simulink. Two variants of a new design were presented for the packaging. In this design, the reformer, the water-gas shift reactor and the reformate/cathode-air heat exchanger were combined in a cylindrical apparatus. The power density of the fuel processing system was increased from 118 W/l to 690 W/l. Various heating strategies were explored with the dynamic model. A suitable commercial diesel burner for these strategies was found and tested. The heating strategy was revised on the basis of the experimental findings, which made it possible to produce power within 720 s. The apparatuses in the different systems were tested in the experimental part of this study. The ATR 9.1 reformer enables the outlet temperatures to be set at the desired values of 460$^{\circ}$ for steam and 400$^{\circ}$C for reformate. This result is an important step on the way towards integrated steam generation in fuel cell systems. The experiments with the fuel processing system as a whole demonstrate the feasibility of the complex connection of reformer, watergasshift reactor and catalytic burner. Furthermore, this was the first time that electric power had been generated from middle distillates using a fuel cell system at the Institute of Energy and Climate Research

Quantum critical point in the spin glass-antiferromagnetism competition for fermionic Ising Models

The competition between spin glass ($SG$) and antiferromagnetic order ($AF$) is analyzed in two sublattice fermionic Ising models in the presence of a transverse $\Gamma$ and a parallel $H$ magnetic fields. The exchange interaction follows a Gaussian probability distribution with mean $-4J_0/N$ and standard deviation $J\sqrt{32/N}$, but only spins in different sublattices can interact. The problem is formulated in a path integral formalism, where the spin operators have been expressed as bilinear combinations of Grassmann fields. The results of two fermionic models are compared. In the first one, the diagonal $S^z$ operator has four states, where two eigenvalues vanish (4S model), which are suppressed by a restriction in the two states 2S model. The replica symmetry ansatz and the static approximation have been used to obtain the free energy. The results are showing in phase diagrams $T/J$ ($T$ is the temperature) {\it versus} $J_{0}/J$, $\Gamma/J$, and $H/J$. When $\Gamma$ is increased, $T_{f}$ (transition temperature to a nonergodic phase) reduces and the Neel temperature decreases towards a quantum critical point. The field $H$ always destroys $AF$; however, within a certain range, it favors the frustration. Therefore, the presence of both fields, $\Gamma$ and $H$, produces effects that are in competition. The critical temperatures are lower for the 4S model and it is less sensitive to the magnetic couplings than the 2S model.Comment: 15 pages, 6 figures, accepted in Physica

Fermionic van Hemmen Spin Glass Model with a Transverse Field

In the present work it is studied the fermionic van Hemmen model for the spin glass (SG) with a transverse magnetic field $\Gamma$. In this model, the spin operators are written as a bilinear combination of fermionic operators, which allows the analysis of the interplay between charge and spin fluctuations in the presence of a quantum spin flipping mechanism given by $\Gamma$. The problem is expressed in the fermionic path integral formalism. As results, magnetic phase diagrams of temperature versus the ferromagnetic interaction are obtained for several values of chemical potential $\mu$ and $\Gamma$. The $\Gamma$ field suppresses the magnetic orders. The increase of $\mu$ alters the average occupation per site that affects the magnetic phases. For instance, the SG and the mixed SG+ferromagnetic phases are also suppressed by $\mu$. In addition, $\mu$ can change the nature of the phase boundaries introducing a first order transition.Comment: 9 pages, 4 figures, accepted for publication in Phys. Lett.

Stability conditions for fermionic Ising spin-glass models in the presence of a transverse field

The stability of spin-glass (SG) phase is analyzed in detail for a fermionic Ising SG (FISG) model in the presence of a magnetic transverse field $\Gamma$. The fermionic path integral formalism, replica method and static approach have been used to obtain the thermodynamic potential within one step replica symmetry breaking ansatz. The replica symmetry (RS) results show that the SG phase is always unstable against the replicon. Moreover, the two other eigenvalues $\lambda_{\pm}$ of the Hessian matrix (related to the diagonal elements of the replica matrix) can indicate an additional instability to the SG phase, which enhances when $\Gamma$ is increased. Therefore, this result suggests that the study of the replicon can not be enough to guarantee the RS stability in the present quantum FISG model, especially near the quantum critical point. In particular, the FISG model allows changing the occupation number of sites, so one can get a first order transition when the chemical potential exceeds a certain value. In this region, the replicon and the $\lambda_{\pm}$ indicate instability problems for the SG solution close to all range of first order boundary.Comment: 15 pages, 4 figures, accepted in Physica

Development of an enzyme-linked immunosorbent assay for the detection of human calretinin in plasma and serum of mesothelioma patients

<p>Abstract</p> <p>Background</p> <p>Calretinin is one of the well-established immunohistochemical markers in the diagnostics of malignant mesothelioma (MM). Its utility as a diagnostic tool in human blood, however, is scarcely investigated. The aim of this study was to develop an enzyme-linked immunosorbent assay (ELISA) for human calretinin in blood and to assess its usefulness as a potential minimally invasive diagnostic marker for MM.</p> <p>Methods</p> <p>Initially, attempts were made to establish an assay using commercially available antibodies and to optimize it by including a biotin-streptavidin complex into the assay protocol. Subsequently, a novel ELISA based on polyclonal antibodies raised in rabbit immunized with human recombinant calretinin was developed. The assay performance in human serum and plasma (EDTA/heparin) and the influence of calcium concentrations on antibody recognition were studied. Stability of spiked-in calretinin in EDTA plasma under different storage conditions was also examined. In preliminary studies serum and plasma samples from 97 healthy volunteers, 35 asbestos-exposed workers, and 42 MM patients were analyzed.</p> <p>Results</p> <p>The mean detection range of the new ELISA was 0.12 to 8.97 ng/ml calretinin. The assay demonstrated markedly lower background and significantly higher sensitivity compared to the initially contrived assay that used commercial antibodies. Recovery rate experiments confirmed dependence of calretinin antibody recognition on calcium concentration. Calcium adjustment is necessary for calretinin measurement in EDTA plasma. Spiked-in calretinin revealed high stability in EDTA plasma when stored at room temperature, 4°C, or after repeated freeze/thaw cycles. Median calretinin values in healthy volunteers, asbestos workers, and MM patients were 0.20, 0.33, and 0.84 ng/ml, respectively (p < 0.0001 for healthy vs. MM, p = 0.0036 for healthy vs. asbestos-exposed, p < 0.0001 for asbestos-exposed vs. MM). Median values in patients with epithelioid and biphasic MM were similar. No influence of age, gender, smoking status, or type of medium (plasma/serum) on calretinin values was found.</p> <p>Conclusions</p> <p>The novel assay is highly sensitive and applicable to human serum and plasma. Calretinin appears to be a promising marker for the blood-based detection of MM and might complement other markers. However, further studies are required to prove its usefulness in the diagnosis of MM patients.</p

From proteomic analysis to potential therapeutic targets: functional profile of two lung cancer cell lines, A549 and SW900, widely studied in pre-clinical research

Lung cancer is a serious health problem and the leading cause of cancer death worldwide. The standard use of cell lines as in vitro pre-clinical models to study the molecular mechanisms that drive tumorigenesis and access drug sensitivity/effectiveness is of undisputable importance. Label-free mass spectrometry and bioinformatics were employed to study the proteomic profiles of two representative lung cancer cell lines and to unravel the specific biological processes. Adenocarcinoma A549 cells were enriched in proteins related to cellular respiration, ubiquitination, apoptosis and response to drug/hypoxia/oxidative stress. In turn, squamous carcinoma SW900 cells were enriched in proteins related to translation, apoptosis, response to inorganic/organic substances and cytoskeleton organization. Several proteins with differential expression were related to cancer transformation, tumor resistance, proliferation, migration, invasion and metastasis. Combined analysis of proteome and interactome data highlighted key proteins and suggested that adenocarcinoma might be more prone to PI3K/Akt/mTOR and topoisomerase IIα inhibitors, and squamous carcinoma to Ck2 inhibitors. Moreover, ILF3 overexpression in adenocarcinoma, and PCNA and NEDD8 in squamous carcinoma shows them as promising candidates for therapeutic purposes. This study highlights the functional proteomic differences of two main subtypes of lung cancer models and hints several targeted therapies that might assist in this type of cancer.publishe

Theorie der Verunreinigungsstreuung in zwischenvalenten Systemen

With many refs. and 10 figs.SIGLECopy held by FIZ Karlsruhe; available from UB/TIB Hannover / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman