Endoglin and TGF-β signaling in glioblastoma

Microvascular proliferation is a key feature of glioblastoma and neovascularization has been implicated in tumor progression. Glioblastomas use pro-angiogenic factors such as vascular endothelial growth factor (VEGF) for new blood vessel formation. Yet, anti-VEGF therapy does not prolong overall survival so that alternative angiogenic pathways may need to be explored as drug targets. Both glioma cells and glioma-associated endothelial cells produce TGF-β superfamily ligands which bind TGF-β receptors (TGF-βR). The TGF-βR type III endoglin (CD105), is a marker of proliferating endothelium that has already been studied as a potential therapeutic target. We studied endoglin expression in glioblastoma tissue and in glioma-associated endothelial cells in a cohort of 52 newly diagnosed and 10 recurrent glioblastoma patients by immunohistochemistry and by ex vivo single-cell gene expression profiling of 6 tumors. Endoglin protein levels were similar in tumor stroma and endothelium and correlated within tumors. Similarly, endoglin mRNA determined by ex vivo single-cell gene expression profiling was expressed in both compartments. There was positive correlation between endoglin and proteins of TGF-β superfamily signaling. No prognostic role of endoglin expression in either compartment was identified. Endoglin gene silencing in T98G glioma cells and in human cerebral microvascular endothelial cells (hCMEC) did not affect constitutive or exogenous TGF-β superfamily ligand-dependent signaling, except for a minor facilitation of pSmad1/5 signaling in hCMEC. These observations challenge the notion that endoglin might become a promising therapeutic target in glioblastoma

Acute ischemia of the extremities

Die akute Extremitätenischämie ist der häufigste gefäßchirurgische Notfall und bedarf je nach Schweregrad der akuten bis subakuten Versorgung, um den Extremitätenerhalt sicherzustellen. Dieser Artikel bietet eine Übersicht zu Definition, Pathophysiologie und Versorgungslage sowie zur Vielzahl an offen-chirurgischen und endovaskulären Versorgungsmöglichkeiten. Insbesondere die Anzahl an voroperierten Patienten und damit komplexerer Verschlusspathologien nimmt stetig zu. Damit steigt die Bedeutung moderner endovaskulärer Therapien (z. B. Katheterlyse oder perkutane Thrombektomie) sowie der Zu- und Abstromverbesserung mittels Ballonangioplastie oder Stents im Rahmen von Hybrideingriffen. Eine abschließende Bewertung der Verfahren aus wissenschaftlicher Sicht ist aufgrund der aktuellen Datenlage oft nicht möglich, aber dringend nötig. Bis dahin bleibt die Entscheidung über die geeignetste Therapie oft der Erfahrung und den technischen Möglichkeiten des Behandlers vorbehalten

Controlling the physics and chemistry of binary and ternary praseodymium and cerium oxide systems

Rare earth praseodymium and cerium oxides have attracted intense research interest in the last fewdecades, due to their intriguing chemical and physical characteristics. An understanding of the correlationbetween structure and properties, in particular the surface chemistry, is urgently required for their applicationin microelectronics, catalysis, optics and other fields. Such an understanding is, however, hampered by thecomplexity of rare earth oxide materials and experimental methods for their characterisation. Here, we reportrecent progress in studying high-quality, single crystalline, praseodymium and cerium oxide films as well asternary alloys grown on Si(111) substrates. Using these well-defined systems and based on a systematic multi-technique surface science approach, the correspondingphysical and chemical properties, such as the surfacestructure, the surface morphology, the bulk–surface interaction and the oxygen storage/release capability, areexplored in detail. We show that specifically the crystalline structure and the oxygen stoichiometry of theoxide thin films can be well controlled by the film preparation method. This work leads to a comprehensiveunderstanding of the properties of rare earth oxides and highlights the applications of these versatile materials.Furthermore, methanol adsorption studies are performed on binary and ternary rare earth oxide thinfilms, demonstrating the feasibility of employing such systems for model catalytic studies. Specifically forceria systems, we find considerable stability against normal environmental conditions so that they canbe considered as a ‘‘materials bridge’’ between surface science models and real catalysts

Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy

Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes.The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor(IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP

Myelin is dependent on the Charcot-Marie-Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells

Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot-Marie-Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4-Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4-Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies