Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor–like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100–1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors

Towards Commercial Production of Sponge Medicines

Sponges can provide potential drugs against many major world-wide occurring diseases. Despite the high potential of sponge derived drugs no sustainable production method has been developed. Thus far it is not fully understood why, when, where and how these metabolites are produced in sponges. For the near future sea-based sponge culture seems to be the best production method. However, for controlled production in a defined system it is better to develop in vitro production methods, like in vitro sponge culture or even better sponge cell culture, culture methods for symbionts or the transfer of production routes into another host. We still have insufficient information about the background of metabolite production in sponges. Before production methods are developed we should first focus on factors that can induce metabolite production. This could be done in the natural habitat by studying the relation between stress factors (such as predation) and the production of bioactive metabolites. The location of production within the sponge should be identified in order to choose between sponge cell culture and symbiont culture. Alternatively the biosynthetic pathways could be introduced into hosts that can be cultured. For this the biosynthetic pathway of metabolite production should be unraveled, as well as the genes involved. This review discusses the current state of sponge metabolite production and the steps that need to be taken to develop commercial production techniques. The different possible production techniques are also discussed

The neutron and its role in cosmology and particle physics

Experiments with cold and ultracold neutrons have reached a level of precision such that problems far beyond the scale of the present Standard Model of particle physics become accessible to experimental investigation. Due to the close links between particle physics and cosmology, these studies also permit a deep look into the very first instances of our universe. First addressed in this article, both in theory and experiment, is the problem of baryogenesis ... The question how baryogenesis could have happened is open to experimental tests, and it turns out that this problem can be curbed by the very stringent limits on an electric dipole moment of the neutron, a quantity that also has deep implications for particle physics. Then we discuss the recent spectacular observation of neutron quantization in the earth's gravitational field and of resonance transitions between such gravitational energy states. These measurements, together with new evaluations of neutron scattering data, set new constraints on deviations from Newton's gravitational law at the picometer scale. Such deviations are predicted in modern theories with extra-dimensions that propose unification of the Planck scale with the scale of the Standard Model ... Another main topic is the weak-interaction parameters in various fields of physics and astrophysics that must all be derived from measured neutron decay data. Up to now, about 10 different neutron decay observables have been measured, much more than needed in the electroweak Standard Model. This allows various precise tests for new physics beyond the Standard Model, competing with or surpassing similar tests at high-energy. The review ends with a discussion of neutron and nuclear data required in the synthesis of the elements during the "first three minutes" and later on in stellar nucleosynthesis.Comment: 91 pages, 30 figures, accepted by Reviews of Modern Physic

Beiträge zur Bronzezeit

Layoutgetreues Digitalisat der Ausg.: Marburg, 1987 Standort: Universität Marburg, Fachgebiet Vor- u. Frühgeschichte (411) Signatur: gelb Sc 520, 21 Bemerkungen: Enth. u.a.: Ein mittelbronzezeitliches Hügelgrab in der Gemarkung Stausebach bei Kirchhain / Hanne Nitschke ; Frank-O. Däcke ; Dirk Vorlauf. Eine Bronzetasse von Typ Kirkendrup - Jenisovice aus Mittelhessen / Wolfgang Ebe

Performance Analysis of the Integrated V2527-Engine Fan at Ground Operation

The paper focuses on the holistic assessment of the integrated fan stage of DLRs Advanced Technology Research Aircraft ATRA, an Airbus A320 equipped with two IAE-V2527 engines. For the entire engine and all its components, a cycle model was established in order to derive realistic operating conditions for all components. The model was validated against experimental data taken by the Electronic Engine Control (EEC) at the aircrafts last shop visit at Lufthansa Technik. Furthermore the engines nacelle and major fan components including its disk, casing, Outlet Guide Vanes (OGV) and Booster-Inlet Guide Vanes (IGV) etc. were optically scanned and transferred to surfaced based CAD models in a reverse engineering approach to obtain the geometry in a most accurate manner. This allowed for dedicated CFD studies of the fan itself and by including the nacelle its interaction with ground induced inlet distortions at realistic engine operating conditions as being derived from the cycle analysis. A mechanical model of the hollow, honeycomb structured fan blade was set up based on the information from computer tomography (CT) scans of one blade and corresponding experimental determination of the blades Eigen-Frequencies. This model allowed for the cold-to-hot transformation of the fan blade geometry under running conditions. The updated CFD results in terms of stage performance with the realistic deformed geometry will then be used to update the cycle model in an iterative manner. Furthermore, a parametric study characterizing the fan inlet flow at the nacelle entry at varying boundary conditions (e.g. cross flows, different fan mass flow rates etc.) was carried out, allowing to quantify the nacelle induced inlet distortions potentially influencing the fan performance

Isoflurane preconditions myocardium against infarction via release of free radicals

BACKGROUND: Isoflurane exerts cardioprotective effects that mimic the ischemic preconditioning phenomenon. Generation of free radicals is implicated in ischemic preconditioning. The authors investigated whether isoflurane-induced preconditioning may involve release of free radicals. METHODS: Sixty-one alpha-chloralose-anesthetized rabbits were instrumented for measurement of left ventricular (LV) pressure (tip-manometer), cardiac output (ultrasonic flowprobe), and myocardial infarct size (triphenyltetrazolium staining). All rabbits were subjected to 30 min of occlusion of a major coronary artery and 2 h of subsequent reperfusion. Rabbits of all six groups underwent a treatment period consisting of either no intervention for 35 min (control group, n = 11) or 15 min of isoflurane inhalation (1 minimum alveolar concentration end-tidal concentration) followed by a 10-min washout period (isoflurane group, n = 12). Four additional groups received the radical scavenger N-(2-mercaptoproprionyl)glycine (MPG; 1 mg. kg-1.min-1) or Mn(III)tetrakis(4-benzoic acid)porphyrine chloride (MnTBAP; 100 microg.kg-1.min-1) during the treatment period with (isoflurane + MPG; n = 11; isoflurane + MnTBAP, n = 9) or without isoflurane inhalation (MPG, n = 11; MnTBAP, n = 7). RESULTS: Hemodynamic baseline values were not significantly different between groups (LV pressure, 97 +/- 17 mmHg [mean +/- SD]; cardiac output, 228 +/- 61 ml/min). During coronary artery occlusion, LV pressure was reduced to 91 +/- 17% of baseline and cardiac output to 94 +/- 21%. After 2 h of reperfusion, recovery of LV pressure and cardiac output was not significantly different between groups (LV pressure, 83 +/- 20%; cardiac output, 86 +/- 23% of baseline). Infarct size was reduced from 49 +/- 17% of the area at risk in controls to 29 +/- 19% in the isoflurane group (P = 0.04). MPG and MnTBAP themselves had no effect on infarct size (MPG, 50 +/- 14%; MnTBAP, 56 +/- 15%), but both abolished the preconditioning effect of isoflurane (isoflurane + MPG, 50 +/- 24%, P = 0.02; isoflurane + MnTBAP, 55 +/- 10%, P = 0.001). CONCLUSION: Isoflurane-induced preconditioning depends on the release of free radical

Influence of the interleukin-converting enzyme inhibitor HMR-3480 on myocardial stunning in pigs in vivo

BACKGROUND: The proinflammatory cytokine interleukin-1 beta is converted into its active form by interleukin-1 beta-converting enzyme (ICE). Circulating cytokines may promote myocardial dysfunction (stunning) after ischemia. OBJECTIVE: To investigate whether ICE inhibition by HMR-3840 improves myocardial stunning in vivo. METHODS: Anesthetized (isoflurane and fentanyl) pigs were used for measurement of left ventricular (LV) pressure, cardiac output and blood flow in the left anterior descending coronary artery (LAD) and left circumflex coronary artery. Regional myocardial function was assessed by sonomicrometry as systolic wall thickening and mean systolic thickening velocity in the anteroapical and posterobasal walls. The animals were subjected to 10 min of LAD occlusion followed by 4 h of reperfusion. The ICE inhibitor (flow-adjusted to achieve coronary plasma concentrations of 10 mug/mL) (ISCH, n=7) or the vehicle (CON, n=7) was infused via a side branch into the LAD during ischemia, or during ischemia and the first 60 min of reperfusion (REP, n=6). RESULTS: Occlusion of the LAD resulted in systolic outward movement (bulging) of the anteroapical wall during ischemia in all groups. Infusion of the ICE inhibitor had no effect on functional recovery when given during ischemia or when given during reperfusion (at the end of reperfusion in the anteroapical wall, values for systolic wall thickening were: CON 17.3+/-7.3%, ISCH 23.2+/-9.8% and REP 19.3+/-6.1%; and values for mean systolic thickening velocity were: CON 4.3+/-1.1 mm/s, ISCH 6.1+/-3.9 mm/s and REP 5.2+/-1.7 mm/s; all P values not significant for CON versus ISCH or REP). LAD blood flow was not affected by HMR-3840 (23.4+/-5.2 mL/min versus 24.3+/-8.1 mL/min; P not significant). Global myocardial function (LV pressure, maximum rate of LV pressure increase and cardiac output) was not different between controls and treatment groups during reperfusion. CONCLUSION: ICE inhibition by HMR-3480 had no effect on myocardial stunning in pigs in viv

Aerodynamic Performance Characteristics of the Installe V2527 Fan at Ground Operation

This paper describes the aerodynamic assessment of the V2500 fan stage during ground operation at maximum fan rotational speed. In order to analyze the ground effect and resulting vortex ingestion into the fan, full annulus uRANS computations of the fan including the nacelle and the ground were performed. The numerical results were used prior to the tests at DLRs research aircraft ATRA to support planning the experimental setup in terms of measurement plane location and seeding introduction. In return, the obtained PIV measurement results were used to verify the numerical data. In particular, the formation of the ground vortex, although its location being highly unstable in the experiments, was observed in both, numerical and experimental results in a very similar fashion and its characteristics could be studied in detail. The numerical results furthermore allowed for a detailed assessment of the interaction between this incoming vortical distortion and the fan blades. Apart from high-fidelity uRANS computations, the fan performance over the entire speed range or fight regime respectively was evaluated by single passage and steady state RANS simulations. Appropriate boundary conditions were derived from a thermodynamic cycle model of the entire engine which was validated with available data from engine acceptance tests. The CFD results in terms of performance characteristics were then introduced again into the cycle model to update and further improve the cycle model

The direct myocardial effects of xenon in the dog heart in vivo

Xenon has minimal hemodynamic side effects, but no data are available on its direct myocardial effects in vivo. We examined myocardial function during the global and regional administration of xenon in the dog heart. Anesthetized (midazolam/piritramide) dogs (n = 8) were instrumented for measurement of left ventricular pressure, cardiac output, and blood flow in the left anterior descending coronary artery (LAD) and circumflex coronary artery. Regional myocardial function was assessed by sonomicrometry in the antero-apical and the postero-basal wall. Hemodynamics were recorded during baseline conditions and during inhalation of 50% or 70% xenon, respectively. Subsequently, a bypass containing a membrane oxygenator was installed from the carotid artery to the LAD, allowing xenon administration only to the LAD-dependent myocardium. No changes in myocardial function were observed during inhalation of xenon. The regional administration of 50% xenon had no significant effect on regional myocardial function (systolic wall thickening and mean velocity of systolic wall thickening). Seventy percent xenon reduced systolic wall thickening by 7.2% +/- 4.0% and mean velocity of systolic wall thickening by 8.2% +/- 4.0% in the LAD-perfused area (P < 0.05). There were no changes of global hemodynamics, coronary blood flow, and regional myocardial function in the circumflex coronary artery-dependent myocardium. Xenon produces a small but consistent direct negative inotropic effect in vivo. IMPLICATIONS: Regional administration of xenon direct to the left anterior descending-perfused myocardium resulted in a small but consistent negative inotropic effect of the noble gas in the dog heart in viv

Blockade of anaesthetic-induced preconditioning in the hyperglycaemic myocardium - The regulation of different mitogen-activated protein kinases

Preconditioning by volatile anaesthetics is blocked by hyperglycaemia. The regulation of mitogen-activated protein kinases during this effect has yet not been investigated. For infarct size measurements, anaesthetized rats were subjected to 25 min coronary artery occlusion followed by 120 min reperfusion. Control animals were not further treated. One group was preconditioned by two 5-min periods of desflurane inhalation (desflurane preconditioning, Des-preconditioning, 1 MAC), each followed by 10-min washout. Four groups received glucose 50% in order to achieve blood glucose concentrations between 22.2 and 33.3 mM/l. Glucose infusion started 40 min before ischaemia (early hyperglycaemia, EH) and stopped with the onset of artery occlusion with (EH+Des-preconditioning) or without (EH) preconditioning. The other two groups received glucose during ischaemia (late hyperglycaemia, LH), again with (LH+Des-preconditioning) or without ((LH) preconditioning. Additional hearts were excised for Western blot of mitogen-activated protein kinases. Infarct size was reduced from 51.7 +/- 9.0% in controls to 28.8 +/- 11.8% after Des-preconditioning (P <0.01 vs Con). Hyperglycaemia alone did not affect infarct size (EH, 51.5 +/- 9.0%, LH, 44.3 +/- 16.9%), but EH as well as LH blocked Des-preconditioning (49.1 +/- 12.3%, P <0.01, 48.1 +/- 17.6%, P <0.05 vs Des-preconditioning). All three mitogen-activated protein kinases showed a similar time course pattern of phosphorylation in the Despreconditioning, EH and EH+Des-preconditioning group. Despite the lack of cardioprotection, mitogen-activated protein kinases are activated in hyperglycaemic myocardium. Therefore, it can be assumed that the hyperglycaemic induced blockade of Des-preconditioning is situated downstream or in parallel of these mitogen-activated protein kinases or involves different signal transduction pathways. (C) 2008 Elsevier B.V. All rights reserve