Effects of degradable Mg-Ca alloys on dendritic cell function

Degradable magnesium alloys are new materials for implants used in orthopedic and trauma surgery. The aim of this study was to investigate the influence of degradable magnesium alloys on the function of dendritic cells (DC) as these cells represent the major antigen presenting cells of the body. MgP (pure magnesium), MgCa 0.6 (0.6% calcium), MgCa 0.8 (0.8% calcium), MgCa 1.0 (1% calcium), and MgCa 1.2 (1.2% calcium) alloys were degraded in cell culture medium. In parallel, murine bone marrow-derived DC were incubated with increasing concentrations (0.1-10 mmol/L) of magnesium chloride and calcium chloride, respectively. Incubation of DC with degradation media over 6 days had no influence on cell viability and only marginal influence on DC migration. Also, the production of TNFα and expression of CD86 was not enhanced by incubation with degraded magnesium alloys. The mixed leukocyte reaction revealed that there was also no increase of the T-cell proliferation in comparison to untreated controls. However, there was a trend toward macrophage development at the expense of DC expansion and an enhanced DC migration was induced by incubation with higher magnesium concentrations. Particularly the latter should be verified in in vivo experiments. © The Author(s), 2010

A Limited Role for the Cell Cycle Regulator Cyclin A1 in Murine Leukemogenesis

The quest for novel therapeutic targets in acute myeloid leukemia (AML) is still ongoing. One of such targets, cyclin A1, was shown to be overexpressed in AML including AML stem cells. However, the function of cyclin A1 in AML is largely unknown, and the data on its impact on patients´ survival remain controversial. Therefore, we developed a transgenic mouse model of stem cell-directed inducible cyclin A1 overexpression and crossed these mice with PML-RARα-knockin mice, which develop an AML M3-like phenotype. To observe the effects of cyclin A1 loss-of-function, we also crossed PML-RARα-knockin mice to cyclin A1-knockout mice. Neither overexpression nor loss of cyclin A1 significantly altered leukemogenesis in PML-RARα-knockin mice. These findings imply that upregulation of cyclin A1 is not essential for leukemogenesis. Our data suggest that cyclin A1 does not represent a suitable target for AML therapy

Maintenance of Leukemia-Initiating Cells Is Regulated by the CDK Inhibitor Inca1

Functional differences between healthy progenitor and cancer initiating cells may provide unique opportunities for targeted therapy approaches. Hematopoietic stem cells are tightly controlled by a network of CDK inhibitors that govern proliferation and prevent stem cell exhaustion. Loss of Inca1 led to an increased number of short-term hematopoietic stem cells in older mice, but Inca1 seems largely dispensable for normal hematopoiesis. On the other hand, Inca1-deficiency enhanced cell cycling upon cytotoxic stress and accelerated bone marrow exhaustion. Moreover, AML1-ETO9a-induced proliferation was not sustained in Inca1-deficient cells in vivo. As a consequence, leukemia induction and leukemia maintenance were severely impaired in Inca1−/− bone marrow cells. The re-initiation of leukemia was also significantly inhibited in absence of Inca1−/− in MLL—AF9- and c-myc/BCL2-positive leukemia mouse models. These findings indicate distinct functional properties of Inca1 in normal hematopoietic cells compared to leukemia initiating cells. Such functional differences might be used to design specific therapy approaches in leukemia

Proteinase-Activated Receptor 1 (PAR1) Regulates Leukemic Stem Cell Functions

External signals that are mediated by specific receptors determine stem cell fate. The thrombin receptor PAR1 plays an important role in haemostasis, thrombosis and vascular biology, but also in tumor biology and angiogenesis. Its expression and function in hematopoietic stem cells is largely unknown. Here, we analyzed expression and function of PAR1 in primary hematopoietic cells and their leukemic counterparts. AML patients' blast cells expressed much lower levels of PAR1 mRNA and protein than CD34+ progenitor cells. Constitutive Par1-deficiency in adult mice did not affect engraftment or stem cell potential of hematopoietic cells. To model an AML with Par1-deficiency, we retrovirally introduced the oncogene MLL-AF9 in wild type and Par1−/− hematopoietic progenitor cells. Par1-deficiency did not alter initial leukemia development. However, the loss of Par1 enhanced leukemic stem cell function in vitro and in vivo. Re-expression of PAR1 in Par1−/− leukemic stem cells delayed leukemogenesis in vivo. These data indicate that Par1 contributes to leukemic stem cell maintenance

Polarization Correlations of 1S0 Proton Pairs as Tests of Bell and Wigner Inequalities

In an experiment designed to overcome the loophole of observer dependent reality and satisfying the counterfactuality condition, we measured polarization correlations of 1S0 proton pairs produced in 12C(d,2He) and 1H(d,He) reactions in one setting. The results of these measurements are used to test the Bell and Wigner inequalties against the predictions of quantum mechanics.Comment: 8 pages, 4 figure

Language evolution and information theory

The use of Nowak's model to study the language evolution and to settle a conjecture by Nowak was discussed. These models explained the ways by which natural selection can lead to the gradual emergence of human language. It was shown that the Nowak's conjecture is true for a class of spaces defined by a certain condition on the distance function. A connection between Nowak's model and standard information-theoretic models was indicated

Tourette syndrome as a motor disorder revisited – Evidence from action coding

Because tics are the defining clinical feature of Tourette syndrome, it is conceptualized predominantly as a motor disorder. There is some evidence though suggesting that the neural basis of Tourette syndrome is related to perception–action processing and binding between perception and action. However, binding processes have not been examined in the motor domain in these patients. If it is particularly perception–action binding but not binding processes within the motor system, this would further corroborate that Tourette syndrome it is not predominantly, or solely, a motor disorder. Here, we studied N = 22 Tourette patients and N = 24 healthy controls using an established action coding paradigm derived from the Theory of Event Coding framework and concomitant EEG-recording addressing binding between a planned but postponed, and an interleaved immediate reaction with different levels of overlap of action elements. Behavioral performance during interleaved action coding was normal in Tourette syndrome. Response locked lateralized readiness potentials reflecting processes related to motor execution were larger in Tourette syndrome, but only in simple conditions. However, pre-motor processes including response preparation and configuration reflected by stimulus-locked lateralized readiness potentials were normal. This was supported by a Bayesian data analysis providing evidence for the null hypothesis. The finding that processes integrating different action-related elements prior to motor execution are normal in Tourette syndrome suggests that Tourette it is not solely a motor disorder. Considering other recent evidence, the data show that changes in “binding” in Tourette syndrome are specific for perception–action integration but not for action coding

Commissioning and validation of a novel commercial TPS for ocular proton therapy

Abstract Background Until today, the majority of ocular proton treatments worldwide were planned with the EYEPLAN treatment planning system TPS . Recently, the commercial, computed tomography CT based TPS for ocular proton therapy RayOcular was released, which follows the general concepts of model based treatment planning approach in conjunction with a pencil beam type dose algorithm PBA . Purpose To validate RayOcular with respect to two main features accurate geometrical representation of the eye model and accuracy of its dose calculation algorithm in combination with an Ion Beam Applications IBA eye treatment delivery system. Methods Different 3D printed eye ball phantoms were fabricated to test the geometrical representation of the corresponding CT based model, both in orthogonal 2D images for X ray image overlay and in fundus view overlaid with a funduscopy. For the latter, the phantom was equipped with a lens matching refraction of the human eye. Funduscopy was acquired in a Zeiss Claus 500 camera. Tantalum clips and fiducials attached to the phantoms were localized in the TPS model, and residual deviations to the actual position in X ray images for various orientations of the phantom were determined, after the nominal eye orientation was corrected in RayOcular to obtain a best overall fit. In the fundus view, deviations between known and displayed distances were measured. Dose calculation accuracy of the PBA on a 0.2 mm grid was investigated by comparing between measured lateral and depth dose profiles in water for various combinations of range, modulation, and field size. Ultimately, the modeling of dose distributions behind wedges was tested. A 1D gamma test was applied, and the lateral and distal penumbra were further compared. Results Average residuals between model clips and visible clips fiducials in orthogonal X ray images were within 0.3 mm, including different orientations of the phantom. The differences between measured distances on the registered funduscopy image in the RayOcular fundus view and the known ground truth were within 1 mm up to 10.5 mm distance from the posterior pole. No clear benefit projection of either polar mode or camera mode could be identified, the latter mimicking camera properties. Measured dose distributions were reproduced with gamma test pass rates of gt;95 with 2 0.3 mm for depth and lateral profiles in the middle of spread out Bragg peaks. Distal falloff and lateral penumbra were within 0.2 mm for fields without a wedge. For shallow depths, the agreement was worse, reaching pass rates down to 80 with 5 0.3 mm when comparing lateral profiles in air. This is caused by low energy protons from a scatter source in the IBA system not modeled by RayOcular. Dose distributions modified by wedges were reproduced, matching the wedge induced broadening of the lateral penumbra to within 0.4 mm for the investigated cases and showing the excess dose within the field due to wedge scatter. Conclusion RayOcular was validated for its use with an IBA single scattering delivery nozzle. Geometric modeling of the eye and representation of 2D projections fulfill clinical requirements. The PBA dose calculation reproduces measured distributions and allows explicit handling of wedges, overcoming approximations of simpler dose calculation algorithms used in other systems. Keywords RayOcular; proton therapy; uveal melanom

Sphingosine 1-phosphate modulates antigen capture by murine langerhans cells via the S1P2 receptor subtype

Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P2 receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P2 not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions