Scale for the assessment and rating of ataxia (SARA): Übersetzung und kulturelle Anpassung an den deutschsprachigen Raum

BACKGROUND/OBJECTIVE: The scale for the assessment and rating of ataxia (SARA) is a feasible assessment for the classification and evaluation of therapeutic interventions. In order to provide access to the SARA in German, the aim of this work was to translate the SARA into German and to adapt it according to international guidelines for German-speaking countries. METHOD: The process involved six steps. The comprehensibility of the scale was assessed using interviews with potential users. RESULTS: A total of nine physiotherapists and six physicians working in various clinical settings were interviewed, seven of them worked in Germany and four each in Austria and Switzerland. The interviews led to a refined version of the translation. The comprehensibility testing revealed no country-specific differences. CONCLUSION: A German version of the SARA authorized by the co-author of the original publication, is now available. The results provide methodological insights into the translation process of observation-based standardized assessments

Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia

FMS-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene found in acute myeloid leukemia (AML) patients and its activating mutations have been proven to be a negative prognostic marker for clinical outcome. Pacritinib (SB1518) is a tyrosine kinase inhibitor (TKI) with equipotent activity against FLT3 (IC50=22 n) and Janus kinase 2 (JAK2, IC50=23 n). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3 K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Oral administration of pacritinib in murine models of FLT3-ITD-driven AML led to significant inhibition of primary tumor growth and lung metastasis. Upregulation of JAK2 in FLT3-TKI-resistant AML cells was identified as a potential mechanism of resistance to selective FLT3 inhibition. This resistance could be overcome by the combined FLT3 and JAK2 activities of pacritinib in this cellular model. Our findings provide a rationale for the clinical evaluation of pacritinib in AML including patients resistant to FLT3-TKI therapy

The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2V617F mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2V617F mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations

Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy

Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible. This implies that they are amenable to pharmacological interventions. Therefore, a lot of work in recent years has focussed on the development of small molecule enzyme inhibitors like DNA-methyltransferase inhibitors or inhibitors of histone-modifying enzymes. These may reverse misregulated epigenetic states and be implemented in the treatment of cancer or other diseases, e.g., neurological disorders. Today, several epigenetic drugs are already approved by the FDA and the EMEA for cancer treatment and around ten histone deacetylase (HDAC) inhibitors are in clinical development. This review will give an update on recent clinical trials of the HDAC inhibitors used systemically that were reported in 2009 and 2010 and will present an overview of different biomarkers to monitor the biological effects

Regulation of immune cell function and differentiation by the NKG2D receptor

NKG2D is one of the most intensively studied immune receptors of the past decade. Its unique binding and signaling properties, expression pattern, and functions have been attracting much interest within the field due to its potent antiviral and anti-tumor properties. As an activating receptor, NKG2D is expressed on cells of the innate and adaptive immune system. It recognizes stress-induced MHC class I-like ligands and acts as a molecular sensor for cells jeopardized by viral infections or DNA damage. Although the activating functions of NKG2D have been well documented, recent analysis of NKG2D-deficient mice suggests that this receptor may have a regulatory role during NK cell development. In this review, we will revisit known aspects of NKG2D functions and present new insights in the proposed influence of this molecule on hematopoietic differentiation

Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect

The histone deacetylase inhibitors (HDACi) have demonstrated anticancer efficacy across a range of malignancies, most impressively in the hematological cancers. It is uncertain whether this clinical efficacy is attributable predominantly to their ability to induce apoptosis and differentiation in the cancer cell, or to their ability to prime the cell to other pro-death stimuli such as those from the immune system. HDACi-induced apoptosis occurs through altered expression of genes encoding proteins in both intrinsic and extrinsic apoptotic pathways; through effects on the proteasome/aggresome systems; through the production of reactive oxygen species, possibly by directly inducing DNA damage; and through alterations in the tumor microenvironment. In addition HDACi increase the immunogenicity of tumor cells and modulate cytokine signaling and potentially T-cell polarization in ways that may contribute the anti-cancer effect in vivo. Here, we provide an overview of current thinking on the mechanisms of HDACi activity, with attention given to the hematological malignancies as well as scientific observations arising from the clinical trials. We also focus on the immune effects of these agents

Epigenetic modulators as therapeutic targets in prostate cancer

Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management.info:eu-repo/semantics/publishedVersio

Der Kronendübel : experimentelle Untersuchungen des Trag- und Verformungsvermögens eines alternativen Schubverbinders im Stahl-Beton Verbundbau

Zsfassung in engl. SpracheDas Ziel des Stahl-Beton Verbundbaues ist es, die positiven Eigenschaften von Stahlbeton und Stahl miteinander zu vereinen. Dazu ist es notwendig, in der Kontaktfuge zwischen Beton und Stahl mittels eines Schubverbinders eine kraftschlüssige Verbindung sicher zu stellen. Dies erfolgt beispielsweise durch den Kopfbolzendübel, dem heute weltweit gebräuchlichsten Verbundmittel.Aufgrund wirtschaftlicher und technischer Überlegungen kam es in der Forschung in den vergangenen Jahren wieder zu vermehrtem Bemühen, Alternativen zum Kopfbolzendübel zu finden. Am Institut für Tragkonstruktionen - Stahlbau laufen seit Herbst 2004 Forschungsprojekte zu dieser Thematik. Ziel ist die Entwicklung sogenannter Betondübelleisten. Deren Grundidee ist die Erzeugung eines Schubverbinders durch Aussparungen in Blechstreifen. Grundlage der Wirkungsweise dieser Schubverbinder ist die Bildung eines Betondübels in den mit Beton vergossenen Aussparungen des Bleches.Mittels experimenteller Untersuchung und numerischer Berechnung wurden zu diesem Zwecke unterschiedliche Geometrien untersucht. Aufgrund der Ergebnisse von zwei bereits durchgeführten Versuchsreihen mit unterschiedlichen Stahlzahngeometrien (Puzzledübel, Puzzledübel mit Aussparung und Kronendübel) konzentriert sich die weitere Forschung mit einer dritten Versuchsreihe speziell auf die geometrische Form des Kronendübels. Dieser wird mit fünf verschieden Stahlzahnvarianten und adaptierter Bewehrungsführung im Betonkörper ausführlich getestet.Im Unterschied zu den vorhergegangenen wird mit dieser Versuchsreihe auch eine neue den Anforderungen der Norm EN 1994-1-1:2004(D) [1] entsprechende Herstellungsform der Prüfkörper umgesetzt. Die Modifikation besteht im Detail darin, dass diese in horizontaler Lage und damit realitätsnäher betoniert werden. Um dies zu ermöglichen wurde ein teilbares und nach dem Erhärten des Betons wieder verschraubbares System gewählt. Diese Methode erwies sich als äußerst zielführend. Bei der Herstellung konnte bei minimiertem Zeitaufwand eine sehr gute Qualität der Prüfkörper erzeugt werden. Der Vorteil liegt also nicht nur in der praxisnahen Erzeugung sondern auch in der schnellen und qualitativ hochwertigen Versuchsabwicklung selbst.Die Versuchsdurchführung erfolgte ebenfalls nach den Vorgaben der Norm [1] und wurde mittels programmierbarer Simatic automatisiert durchgeführt. Dadurch ist im Nachhinein eine gute Vergleichbarkeit der Versuchsergebnisse sichergestellt.Die Auswertung der Versuche erfolgte in erster Linie bezüglich der Erfüllung der in der EN 1994-1-1:2004(D) [1] gestellten Anforderungen.Laut [1] müssen Schubverbinder im Stahl-Beton Verbundbau zwei Hauptkriterien erfüllen. Eines ist das Duktilitätskriterium, das Anforderungen bezüglich der Relativverschiebung zwischen Betonkörper und Stahlkörper stellt. Das zweite Kriterium legt Anforderungen bezüglich der Abhebung der Betonkörper vom Stahlträger fest. Alle fünf in dieser Versuchsreihe getesteten Schubverbinder des Typs Kronendübel konnten die laut [1] gestellten Forderungen problemlos erfüllen. Sie übertrafen sowohl bezüglich ihrer maximalen Traglast als auch bezüglich ihres duktilen Verhaltens im Nachbruchbereich die Erwartungen. Für einen späteren praktischen Einsatz des Kronendübels ist auch ein exaktes doch trotzdem einfach handzuhabendes Rechenmodell wichtig.Im Zuge der ersten beiden am Institut für Tragkonstruktionen - Stahlbau durchgeführten Versuchsreihen wurden unterschiedliche Tragmodelle speziell für den Kronendübel entwickelt. Der Vergleich der Ergebnisse aus der Tragmodellsberechnung mit den ausgewerteten Versuchsergebnissen der Serie 3 brachte sehr gute Ergebnisse. Voraussetzung ist, je nach Geometrie des Kronendübels das Tragmodell zu variieren. Der Neigungswinkel der Aussparungen des Kronendübels wäre z.B. ein gutes und einfaches Kriterium zur Auswahl des passenden Tragmodells.Zusammengefasst kann gesagt werden, dass der Kronendübel alle von der Norm gestellten Anforderungen erfüllte. Die sehr guten mechanischen Eigenschaften (hohe Anfangssteifigkeit, hohe Traglast, gute Duktilität) gepaart mit den guten Tragmodellen sind wichtige Faktoren für einen effizienten Praxiseinsatz. In Kombination mit den wirtschaftlichen Vorteilen bedingt durch günstige Produktion und Montage ist der Kronendübel eine ernst zu nehmende Alternative zum Kopfbolzendübel.Die ebenfalls in dieser Versuchsreihe untersuchte Dübelleiste der Form Kopfdübel konnte das Kriterium bezüglich Abhebung nicht erfüllen. Könnte jedoch mit etwas abgeänderter Geometrie bei einer neuerlichen Untersuchung auch alle Anforderungen der Norm erfüllen.The objective of reinforced concrete - steel composite construction is to combine the favourable characteristics of reinforced concrete and steel. It is therefore necessary to assure peak traction inside the contact joint in-between the concrete and steel by means of a shear connection. This for example takes place by use of the head bolt dowel, which is the most common device of interconnection worldwide.Due to economical and technical considerations research made efforts to find alternatives to the head bolt dowel in the preceding years. At the "Institut für Tragkonstruktionen -Stahlbau" research projects concerning this matter are in progress since fall 2004. The objective is the development of so called concrete dowel sheets. The basic idea is the generation of a shear connection via notches in sheet metal strips. The basis of the mode of action of these shear connections is the forming of a concrete dowel inside the concrete filled recesses of the sheet metal strips.For this purpose two different geometries were searched after by the bias of experimental verification and numerical calculation. Based on the results of two already accomplished test series with different steel tooth geometries (Puzzledübel, Puzzledübel with recess and crown dowel), further research with a third testing series puts focus especially on the geometric shape of the crown dowel. It is tested extensively with five different steel tooth modifications and adapted reinforcement inside the concrete body.In distinction from preceding testing series a new mould of the testing bodies according to the norm EN 1994-1-1:2004(D) [1] is implemented with this one as well. The specific modification consists in horizontal and therefore more realistic concrete placement. To enable this modification a separable system that stays rescrewable after the cure of the concrete had been chosen. This method turned out to be highly effective. At fabrication a very high quality of the testing bodies was produced under a minimized time exposure. Therefore the perk is not only to find in the practical production but also in the quick and high quality processing of the experiment.The processing of the experiment also followed the guidelines of the norm [1] and was accomplished automated by the use of programmable Simatic. Thus a good comparability of the test results in retrospect is guaranteed. The test evaluation attempted primarily to accomplish the requirements of the EN 1994-1-1:2004(D) [1]. According to [1] shear connections used in steel - concrete composite construction have to achieve two standards. One is the criterion of ductability which defines requirements concerning the relative displacement amongst the concrete body and the steel body. The second criterion determines requirements concerning the lifting of the concrete body off the steel joist. All five shear connections of the crown dowel type could accomplish the requirements set in [1] without any problems. They exceeded expectations concerning both their ultimate load and their ductile action at the new failure area.An accurate but easy to operate calculation model is indispensable for an eventual functional application of the crown dowel.Different beam models were developed especially for the crown dowel during the first two test series completed at the "Institut für Tragkonstruktionen - Stahlbau". The comparison of the results from the beam model calculation including the analysed data of the series 3 showed very good results. The precondition is to vary the beam model according to the geometry of the crown dowel. The angle of inclination of the recesses of the crown dowel would give an appropriate and simple criterion to choose a compatible beam model. As a final declaration it can be said that the crown dowel complied all requirements provided by the norm. The very positive mechanical characteristics (high initial rigidity, high ultimate load, good ductility) in addition with the good beam models are essential factors for an efficient practical approach. The combination of its economical advantages caused by low - cost production and assembling makes the crown dowel become a serious option to the head bolt dowel.The likewise analysed dowel sheet of the "Kopfdübel" type couldn't manage to comply the criterion referring with the lift off. It could though accomplish all the requirements set by the norm in a new examination with slightly modified geometry.16