Relapse of acute myeloid leukemia after allogeneic stem cell transplantation: immune escape mechanisms and current implications for therapy

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the expansion of immature myeloid cells in the bone marrow (BM) and peripheral blood (PB) resulting in failure of normal hematopoiesis and life-threating cytopenia. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an established therapy with curative potential. Nevertheless, post-transplant relapse is common and associated with poor prognosis, representing the major cause of death after allo-HCT. The occurrence of relapse after initially successful allo-HCT indicates that the donor immune system is first able to control the leukemia, which at a later stage develops evasion strategies to escape from immune surveillance. In this review we first provide a comprehensive overview of current knowledge regarding immune escape in AML after allo-HCT, including dysregulated HLA, alterations in immune checkpoints and changes leading to an immunosuppressive tumor microenvironment. In the second part, we draw the line from bench to bedside and elucidate to what extend immune escape mechanisms of relapsed AML are yet exploited in treatment strategies. Finally, we give an outlook how new emerging technologies could help to improve the therapy for these patients, and elucidate potential new treatment options

Genetic interaction screen for severe neurodevelopmental disorders reveals a functional link between Ube3a and Mef2 in Drosophila melanogaster

Neurodevelopmental disorders (NDDs) are clinically and genetically extremely heterogeneous with shared phenotypes often associated with genes from the same networks. Mutations in TCF4, MEF2C, UBE3A, ZEB2 or ATRX cause phenotypically overlapping, syndromic forms of NDDs with severe intellectual disability, epilepsy and microcephaly. To characterize potential functional links between these genes/proteins, we screened for genetic interactions in Drosophila melanogaster. We induced ubiquitous or tissue specific knockdown or overexpression of each single orthologous gene (Da, Mef2, Ube3a, Zfh1, XNP) and in pairwise combinations. Subsequently, we assessed parameters such as lethality, wing and eye morphology, neuromuscular junction morphology, bang sensitivity and climbing behaviour in comparison between single and pairwise dosage manipulations. We found most stringent evidence for genetic interaction between Ube3a and Mef2 as simultaneous dosage manipulation in different tissues including glia, wing and eye resulted in multiple phenotype modifications. We subsequently found evidence for physical interaction between UBE3A and MEF2C also in human cells. Systematic pairwise assessment of the Drosophila orthologues of five genes implicated in clinically overlapping, severe NDDs and subsequent confirmation in a human cell line revealed interactions between UBE3A/Ube3a and MEF2C/Mef2, thus contributing to the characterization of the underlying molecular commonalities

Mechanisms of surface charge modification of carbonates in aqueous electrolyte solutions

The influence of different types of salts (NaCl, CaCl 2 , MgCl 2 , NaHCO 3 , and Na 2 SO 4 ) on the surface characteristics of unconditioned calcite and dolomite particles, and conditioned with stearic acid, was investigated. This study used zeta potential measurements to gain fundamental understanding of physico-chemical mechanisms involved in surface charge modification of carbonate minerals in the presence of diluted salt solutions. By increasing the salt concentration of divalent cationic salt solution (CaCl 2 and MgCl 2 ), the zeta potential of calcite particles was altered, resulting in charge reversal from negative to positive, while dolomite particles maintained positive zeta potential. This is due to the adsorption of potential-determining cations (Ca 2+ and Mg 2+ ), and consequent changes in the structure of the diffuse layer, predominantly driven by coulombic interactions. On the other hand, chemical adsorption of potential-determining anions (HCO −3 and SO 2−4 ) maintained the negative zeta potential of carbonate surfaces and increased its magnitude up to 10 mM, before decreasing at higher salt concentrations. Physisorption of stearic acid molecules on the calcite and dolomite surfaces changed the zeta potential to more negative values in all solutions. It is argued that divalent cations (Ca 2+ and Mg 2+ ) would result in positive and neutral complexes with stearic acid molecules, which may result in strongly bound stearic acid films, whereas ions resulting in negative mineral surface charges (SO 2−4 and HCO −3 ) will cause stearic acid films to be loosely bound to the carbonate mineral surfaces. The suggested mechanism for surface charge modification of carbonates, in the presence of different ions, is changes in both distribution of ions in the diffuse layer and its structure as a result of ion adsorption to the crystal lattice by having a positive contribution to the disjoining pressures when changing electrolyte concentration. This work extends the current knowledge base for dynamic water injection design by determining the effect of salt concentration on surface electrostatics

Raman spectroscopy as a tool to determine the thermal maturity of organic matter : application to sedimentary, metamorphic and structural geology

Raman spectrometry is a rapid, non-destructive alternative to conventional tools employed to assess the thermal alteration of organic matter (OM). Raman may be used to determine vitrinite reflectance equivalent OM maturity values for petroleum exploration, to provide temperature data for metamorphic studies, and to determine the maximum temperatures reached in fault zones. To achieve the wider utilisation of Raman, the spectrum processing method, and the positions and nomenclature of Raman bands and parameters, all need to be standardized. We assess the most widely used Raman parameters as well as the best analytical practices that have been proposed. Raman band separation and G-band full-width at half-maximum are the best parameters to estimate the maturity for rocks following diagenesis–metagenesis. For metamorphic studies, the ratios of band areas after performing deconvolution are generally used. Further work is needed on the second-order region, as well as assessing the potential of using integrated areas on the whole spectrum, to increase the calibrated temperature range of Raman parameters. Applying Raman spectroscopy on faults has potential to be able to infer both temperature and deformation processes. We propose a unified terminology for OM Raman bands and parameters that should be adopted in the future. The popular method of fitting several functions to a spectrum is generally unnecessary, as Raman parameters determined from an un-deconvoluted spectrum can track the maturity of OM. To progress the Raman application as a geothermometer a standardized approach must be developed and tested by means of an interlaboratory calibration exercise using reference materials

Floating New Orleans

Die folgende Arbeit befasst sich mit der Planung einer temporär schwimmenden Stadt am Beispiel des Lower Ninth Wards, New Orleans. Aufgrund der regelmäßigen Überschwemmungen seit der Gründung der Stadt sowie der Veränderung des Klimas bietet diese Arbeit einen Lösungsvorschlag, der das Wasser als Hauptelement in das Konzept einbindet. Das Ergebnis ist eine städtebauliche Struktur, die sich im Falle einer Überschwemmung zu einem Inselverbund zusammenfügt. Integriert ist die Struktur in ein neugestaltetes Viertel, das durch eine neue Uferzone sowie ein Straßensystem, das auf dem Prinzip der Neighborhood Units besteht, aufgewertet wird. Lebensmittellager und Gemeinschaftshäuser stellen eine Versorgung im Notfall sicher. Im zweiten Teil werden die ortstypischen Shotgun Houses dem neuen Konzept angepasst und um einen flexiblen Innenraum erweitert. Dabei entstehen zwei Typen des weiterentwickelten Shotgun Houses das Hofhaus und das OFF Haus. Beide Formen beschäftigen sich mit der flexiblen Nutzung des Innenraums, unterscheiden sich jedoch in der Betrachtung und Einbindung des Außenraums. Die Veranda wird in dieser Arbeit sowohl im Städtebau als auch im Wohnbau als wichtiges soziales und verbindendes Element hervorgehoben. Grundlegendes Ziel der Arbeit ist es, ein universal anwendbares Konzept zu entwickeln, das auch weltweit in überschwemmungsgefährdeten Gebieten eine Verbesserung der Wohnqualität ermöglicht.This thesis will explore the design of a temporarily floating city in the Lower Ninth Ward in New Orleans. Due to regular flooding since the founding of the city, as well as the effects of climate change, this thesis will propose a solution which includes water as a central component. The result is an urban structure that merges to form a network in the event of a flood. The structure is embedded in a redesigned area which includes a new riverside and an improved infrastructure based on the planning concept of the neighbourhood unit. Community spaces and food storage facilities has been developed in order to ensure the adequate supply of basic commodities in times of need. The concept of flexibility has been brought to this structure by adapting the typical shotgun house into two styles: the courtyard house and the OFF house. The flexible use of interior space is offered by both styles but the exterior space of each style differs. The porch is an important socially connective component of these houses, which strengthens not only the urban but equally the housing concept. The concept of this floating city can be applied globally in flood risk areas around the world and is an answer as to how architecture should deal with water.30

Reinigungsversuche an milchdurchstroemten Rohren auf der Basis der zeitabhaengigen Rueckstandsakkumulation

Untersucht wurde das Reinigungsverhalten von CrNi-Stahl, Acrylglas undPolypropylen hinsichtlich der Fett-, Eiweiss- und Kalziumakkumulation beim Einsatz eines chlorhaltigen sowie eines hochalkalischen chlorfreien Reinigungsmittels. Die Ergebnisse machten deutlich, dass bei richtiger Reinigerwahl sowohl an Chromnickel-Stahl als auch an denderzeit eingesetzten Kunststoffen ein vergleichbarer Reinigungserfolg erwartet werden kannSIGLEAvailable from: Technische Univ. Muenchen (Germany, F.R.). Universitaetsbibliothek / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Bildung einer sächsischen Steuergemeinschaft? Der Einfluss der Steuerverfassung auf die Konstruktion eines einheitlichen Staatsvolks

Im Fokus der Studie steht die Kursächsische Landstadt Leipzig. Anhand dieses Beispiels wird eine der Komponenten der klassischen Definition des modernen Staates untersucht: die des rechtlich homogenen Staatsvolkes und dessen Konstituierung durch die, der Steuerverfassung zugrunde liegenden, territorialen Ordnungsvorstellungen. Durch die Untersuchung von Maßnahmen der zentralen landesherrlichen Akkumulation von Wissen über lokale Begebenheiten, Prozessen des „otherings“ und vor allem von Aushandlungsprozessen zwischen Landesherren und Ständen auf und um den Landtag, die schließlich in den 1710er Jahren die bis ins 19.Jahrhundert maßgebliche Steuerverfassung hervorbrachten, wird die wichtige Rolle der Zwischengewalten für Territorialisierungsprozesse gezeigt und so ein Baustein zur Analyse des übergeordneten Prozesses der(sächsischen) Staatsbildung geliefert