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Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.
Wird eine Klage auf Feststellung von Unfallfolgen rechtskräftig abgewiesen, steht diese Rechtskraft einem Anspruch auf Rücknahme des früheren, bestandskräftigen, Unfallfolgen verneinenden Bescheides nach § 44 SGB X entgegen. Denn es steht aufgrund der Rechtskraft der gerichtlichen Entscheidung fest, dass Unfallfolgen nicht vorliegen, der frühere Bescheid also rechtmäßig ist.
Qualität und Wirksamkeit – Gedanken zur qualitätsorientierten Steuerung in der Rehabilitation
(2018)
Der breite gesundheitspolitische Konsens, Qualitätsdaten stärker als Steuerungsinstrument zu nutzen, macht eine Beschäftigung mit der Wirksamkeit von gesundheitlichen Leistungen erforderlich. Der vorliegende Beitrag stellt einige Ansätze vor, Qualität als Wirksamkeit zu definieren, und unternimmt eine erste Übertragung auf den Bereich der medizinischen Rehabilitation. Er schlägt vor, die externe Qualitätssicherung um die Kategorie des Outcomes, verstanden als mittelfristige Wirksamkeit in Bezug auf die gesetzlichen Ziele, zu ergänzen. Relevant erscheint, dass die Qualitätsdaten auf den Ebenen der Leistungsempfänger (Wunsch- und Wahlrecht der Patienten), der Leistungsträger (Belegungs- und Vergütungssteuerung) und Leistungserbringer (internes Qualitätsmanagement) im Sinne einer effizienz- und effektivitätsorientierten Steuerung genutzt werden können.
Durch die Nutzung von Qualitätsindikatoren für die Zuweisungssteuerung gewinnt das interne QMS eine zentrale Bedeutung für die Zukunftssicherung der Einrichtungen. Vor diesem Hintergrund stellt sich für die Einrichtungen verstärkt die Frage, mit welchen internen QM-Maßnahmen die externen Qualitätskennzahlen der Rentenversicherung möglichst nachhaltig in der gewünschten Richtung beeinflusst werden können.
Die gemeinsame Betrachtung von drei Datenebenen (Katamnestische Patientenbefragung, Rehabilitations-Statistik-Datenbank (RSD), Qualitätskennzahlen der Kliniken des Qualitätsverbundes) konnte in der „Reha-QS-Outcome-Studie“ erstmals realisiert werden. Für die in diesem Beitrag näher betrachteten Ergebnisse der dritten Datenebene (Qualitätskennzahlen) und deren Zusammenhang mit den beiden anderen Datenebenen, stehen Daten von insgesamt 21 Kliniken zur Verfügung. Aufgrund der Gewichtung im Rahmen der Zuweisungssteuerung wird dabei der Schwerpunkt auf die Rehabilitandenzufriedenheit und den Reha-Erfolg gelegt. Auf der Basis der Daten des externen Qualitätssicherungsprogramms der DRV zeigt sich, dass die Verbundkliniken sowohl hinsichtlich der Rehabilitandenzufriedenheit als auch des Subjektiven Reha-Erfolgs im Durchschnitt besser abschneiden als die Referenzkliniken.
Raman-Microspectroscopy with subsequent chemometric evaluation was used for the rapid and non-destructive differentiation of seven important spoilage related microorganisms, namely Brochothrix thermosphacta DSM 20171, Pseudomonas fluorescens DSM 4358, Pseudomonas fluorescens DSM 50090, Micrococcus luteus, Escherichia coli HB101, Escherichia coli TOP10 and Bacillus thuringiensis israelensis DSM 5724. Therefore fast collected spectra directly from rapid surface blots without any pretreatments like purification or singulation steps were used. To estimate and classify the Raman-spectroscopic data at genera and strain level an adequate preprocessing together with a subsequent chemometric evaluation consisting of principal component analysis and discriminant analysis was used. Thereby, importance was attached to a balanced data set, as this makes the multivariate analysis of the data significantly more resilient and meaningful. The analysis showed that the differentiation of spoilage related microorganisms on genera and strain level was successful and the classification of independent test data showed only an error rate of 3.5%.
To save energy and reduce environmental impacts, new technologies towards a development of a sustainable ‘greener’ economy are needed. The main opportunity to improve sustainability by reducing emissions is within the transport sector. More than 90% of all goods worldwide are transported by ships. Particularly maritime ships using heavy fuel oil and marine gas oil play a major role. The total fuel consumption of shipping in 2016 was about 250 m t (domestic ca. 50 m t, international shipping ca. 200 m t). The vast portion of the energy consumption of a ship is the need to overcome the drag between ship hull and water—depending on the shape of the vessel and its size up to 90% of total fuel consumption. This means reducing drag helps to save fuel and reduces carbon emissions as well as pollution considerably. Different techniques for drag reduction are known, e.g. the micro-bubble technique or the bulbous bow. We investigated a novel bioinspired technique since 2002: the application of biomimetic surfaces with long-term stable air layers on ship hulls, serving as a slip agent. This technology is based on the Salvinia Effect, allowing a permanent stabilization of air layers under water. In this case study, we analysed the possible savings, which also could be combined with modified micro-bubble technologies.
Volatile organic compounds (VOCs) from alive Anoplophora glabripennis (ALB) imagoes, larvae and ovipositions were obtained by enrichment on adsorbents. They were analysed qualitatively by thermal desorption coupled with gas chromatography and a mass selective detector. All together 229 substances were identified: 34 from larvae, 19 from imago and 176 from oviposition. Ovipositions of two generations were analysed, both over an 8 week period with focus on aging and repeatability. (+)-α-Longipinene occurred in 100%, (+)-Cyclosativene and α-Cubebene in 99% of all oviposition measurements. 1R-α-Pinene occurred in 100% of all imago measurements. 2,4-Dimethyl-1-Heptene and (+)-Cyclosativene were detectable in all three ALB sample types.
We present the performance of the upGREAT heterodyne array receivers on the SOFIA telescope after several years of operations. This instrument is a multi-pixel high resolution (R≳10 7 R≳107) spectrometer for the Stratospheric Observatory for Far-Infrared Astronomy (SOFIA). The receivers use 7-pixel subarrays configured in a hexagonal layout around a central pixel. The low frequency array receiver (LFA) has 2×7 2×7 pixels (dual polarization), and presently covers the 1.83–2.07 THz frequency range, which allows to observe the [CII] and [OI] lines at 158 μ μm and 145 μ μm wavelengths. The high frequency array (HFA) covers the [OI] line at 63 μ μm and is equipped with one polarization at the moment (7 pixels, which can be upgraded in the near future with a second polarization array). The 4.7 THz array has successfully flown using two separate quantum-cascade laser local oscillators from two different groups. NASA completed the development, integration and testing of a dual-channel closed-cycle cryocooler system, with two independently operable He compressors, aboard SOFIA in early 2017 and since then, both arrays can be operated in parallel using a frequency separating dichroic mirror. This configuration is now the prime GREAT configuration and has been added to SOFIA’s instrument suite since observing cycle 6.
The application of Raman and infrared (IR) microspectroscopy is leading to hyperspectral data containing complementary information concerning the molecular composition of a sample. The classification of hyperspectral data from the individual spectroscopic approaches is already state-of-the-art in several fields of research. However, more complex structured samples and difficult measuring conditions might affect the accuracy of classification results negatively and could make a successful classification of the sample components challenging. This contribution presents a comprehensive comparison in supervised pixel classification of hyperspectral microscopic images, proving that a combined approach of Raman and IR microspectroscopy has a high potential to improve classification rates by a meaningful extension of the feature space. It shows that the complementary information in spatially co-registered hyperspectral images of polymer samples can be accessed using different feature extraction methods and, once fused on the feature-level, is in general more accurately classifiable in a pattern recognition task than the corresponding classification results for data derived from the individual spectroscopic approaches.
Polyurethane (PU) coatings were successfully produced using unmodified kraft lignin (KL) as an environmentally benign component in contents of up to 80 wt%. Lignin samples were precipitated from industrial black liquor in aqueous solution working at room temperature and different pH levels (pH 2 to pH 5). Lignins were characterized by UV-Vis, FTIR, pyrolysis-GC/MS, SEC and 31P-NMR. Results show a correlation between pH level, OH number and molecular weight Mw of isolated lignins. Lignin-based polyurethane coatings were prepared in an efficient one step synthesis dissolving lignin in THF and PEG425 in an ultrasonic bath followed by addition of 4,4-diphenylmethanediisocyanate (MDI) and triethylamine (TEA). Crosslinking was achieved under very mild conditions (1 hour at room temperature followed by 3 hours at 35 °C). The resulting coatings were characterized regarding their physical properties including ATR-IR, TGA, optical contact angle, light microscopy, REM-EDX and AFM data. Transparent homogeneous films of high flexibility resulted from lignins isolated at pH 4, possessing a temperature resistance up to 160 °C. Swelling tests revealed a resistance against water. Swelling in DMSO depends on index, pH of precipitation and catalyst utilization for PU preparation. According to AFM studies, surface roughness is between 10 and 28 nm.
Small Molecules Enhance Scaffold-Based Bone Grafts via Purinergic Receptor Signaling in Stem Cells
(2018)
The need for bone grafts is high, due to age-related diseases, such as tumor resections, but also accidents, risky sports, and military conflicts. The gold standard for bone grafting is the use of autografts from the iliac crest, but the limited amount of accessible material demands new sources of bone replacement. The use of mesenchymal stem cells or their descendant cells, namely osteoblast, the bone-building cells and endothelial cells for angiogenesis, combined with artificial scaffolds, is a new approach. Mesenchymal stem cells (MSCs) can be obtained from the patient themselves, or from donors, as they barely cause an immune response in the recipient. However, MSCs never fully differentiate in vitro which might lead to unwanted effects in vivo. Interestingly, purinergic receptors can positively influence the differentiation of both osteoblasts and endothelial cells, using specific artificial ligands. An overview is given on purinergic receptor signaling in the most-needed cell types involved in bone metabolism-namely osteoblasts, osteoclasts, and endothelial cells. Furthermore, different types of scaffolds and their production methods will be elucidated. Finally, recent patents on scaffold materials, as wells as purinergic receptor-influencing molecules which might impact bone grafting, are discussed.
Resveratrol (RSV) is a small compound first identified as an activator of sirtuin 1 (SIRT1), a key factor in mediating the effects of caloric restriction. Since then, RSV received great attention for its widespread beneficial effects on health and in connection to many diseases. RSV improves the metabolism and the mitochondrial function, and more recently it was shown to restore fatty acid β-oxidation (FAO) capacities in patient fibroblasts harboring mutations with residual enzyme activity. Many of RSV's beneficial effects are mediated by the transcriptional coactivator PGC-1α, a direct target of SIRT1 and a master regulator of the mitochondrial fatty acid oxidation. Despite numerous studies RSV's mechanism of action is still not completely elucidated. Our aim was to investigate the effects of RSV on gene regulation on a wide scale, possibly to detect novel genes whose up-regulation by RSV may be of interest with respect to disease treatment. We performed Next Generation Sequencing of RNA on normal fibroblasts treated with RSV. To investigate whether the effects of RSV are mediated through SIRT1 we expanded the analysis to include SIRT1-knockdown fibroblasts. We identified the aspartoacylase (ASPA) gene, mutated in Canavan disease, to be strongly up-regulated by RSV in several cell lines, including Canavan disease fibroblasts. We further link RSV to the up-regulation of other genes involved in myelination including the glial specific transcription factors POU3F1, POU3F2, and myelin basic protein (MBP). We also observe a strong up-regulation by RSV of the riboflavin transporter gene SLC52a1. Mutations in SLC52a1 cause transient multiple acyl-CoA dehydrogenase deficiency (MADD). Our analysis of alternative splicing identified novel metabolically important genes affected by RSV, among which is particularly interesting the α subunit of the stimulatory G protein (Gsα), which regulates the cellular levels of cAMP through adenylyl cyclase. We conclude that in fibroblasts RSV stimulates the PGC-1α and p53 pathways, and up-regulates genes affecting the glucose metabolism, mitochondrial β-oxidation, and mitochondrial biogenesis. We further confirm that RSV might be a relevant treatment in the correction of FAO deficiencies and we suggest that treatment in other metabolic disorders including Canavan disease and MADD might be also beneficial.
Die Bundeszentrale für gesundheitliche Aufklärung (BZgA) hat im Juni dieses Jahres ihren aktuellen Forschungsbericht zum Glücksspielverhalten und zur Glücksspielsucht in Deutschland mit Datum 15.2.2018 veröffentlicht: GLÜCKSSPIELVERHALTEN UND GLÜCKSSPIELSUCHT IN DEUTSCHLAND. Ergebnisse des Surveys 2017 und Trends. BZgA-Forschungsbericht / 15.2.2018.
The paper is about finding the global optimum for a wheel loader work cycle in a gravel application. This includes simulating the gravel and extracting the trajectories for the main actuators; propulsion, lift and tilt, during the work cycle. The optimal control method is dynamic programming and the optimum is calculated with regard to fuel efficiency [ton/l] but can be weighted towards productivity [ton/h].
Argentina substantially contributes to the global organic agriculture and food sector due to its large areas of organically managed agricultural land. However, most of the organic production is intended for export. Overall, food supply for the domestic organic market is hardly tapped. Based on this, we investigate the current importance of organic agriculture and food production as well as consumption attitudes and behavior within the country. The novelty of the study also lies in the observation, documentation and analysis of latest stakeholder‐driven developments towards organic agriculture and food. Furthermore, the publication allows the Argentinean organic market to be significantly more visible for the international audience.
