Progress Report on Target Development

The present document is the D08 deliverable report of work package 1 (Target Development) from the MEGAPIE TEST project of the 5th European Framework Program. Deliverable D08 is the progress report on the activities performed within WP 1. The due date of this deliverable was the 5th month after the start of the EU project. This coincided with a technical status meeting of the MEGAPIE Initiative, that was held in March 2002 in Bologna (Italy). The content of the present document reflects the status of the MEGAPIE target development at that stage. It gives an overview of the Target Design, the related Design Support activities and the progress of the work done for the safety assessment and licensing of the target

Quantifying Sources of Variability in Infancy Research Using the Infant-Directed-Speech Preference

Psychological scientists have become increasingly concerned with issues related to methodology and replicability, and infancy researchers in particular face specific challenges related to replicability: For example, high-powered studies are difficult to conduct, testing conditions vary across labs, and different labs have access to different infant populations. Addressing these concerns, we report on a large-scale, multisite study aimed at (a) assessing the overall replicability of a single theoretically important phenomenon and (b) examining methodological, cultural, and developmental moderators. We focus on infants’ preference for infant-directed speech (IDS) over adult-directed speech (ADS). Stimuli of mothers speaking to their infants and to an adult in North American English were created using seminaturalistic laboratory-based audio recordings. Infants’ relative preference for IDS and ADS was assessed across 67 laboratories in North America, Europe, Australia, and Asia using the three common methods for measuring infants’ discrimination (head-turn preference, central fixation, and eye tracking). The overall meta-analytic effect size (Cohen’s d) was 0.35, 95% confidence interval = [0.29, 0.42], which was reliably above zero but smaller than the meta-analytic mean computed from previous literature (0.67). The IDS preference was significantly stronger in older children, in those children for whom the stimuli matched their native language and dialect, and in data from labs using the head-turn preference procedure. Together, these findings replicate the IDS preference but suggest that its magnitude is modulated by development, native-language experience, and testing procedure

Energy loss and impact of various stunning devices used for the slaughtering of water buffaloes.

Stock management of the Swiss water buffalo livestock results in the slaughtering of about 350 animals per year. As the stunning of water buffaloes still is an unresolved issue, we investigated the terminal ballistics of currently used perforating stunning devices. Cartridge fired captive bolt devices, handguns and a bullet casing gun were tested in a shooting steep by firing on bisected heads, forehead plates and soap blocks. Energy loss of captive bolts confirmed their inadequacy when used for heavy water buffaloes, notably adult males. As for the free projectiles, ballistics revealed that beyond the impact energy, bullet deformation has a strong impact on the outcome. Light 9mm Luger or .38 Spl bullets as well as large deformable .44 Rem. Magnum bullets should be avoided in favor of heavier .357 Magnum deformation ammunition. These data have been translated into the development of a new stunning device for water buffaloes meeting both animal welfare and occupational safety requirements

The double-stranded RNA-activated protein kinase mediates radiation resistance in mouse embryo fibroblasts through nuclear factor kappaB and Akt activation

PURPOSE: Activation of the double-stranded RNA-activated protein kinase (PKR) leads to the induction of various pathways including the down-regulation of translation through phosphorylation of the eukaryotic translation initiation factor 2alpha (eIF-2alpha). There have been no reports to date about the role of PKR in radiation sensitivity. EXPERIMENTAL DESIGN: A clonogenic survival assay was used to investigate the sensitivity of PKR mouse embryo fibroblasts (MEF) to radiation therapy. 2-Aminopurine (2-AP), a chemical inhibitor of PKR, was used to inhibit PKR activation. Nuclear factor-kappaB (NF-kappaB) activation was assessed by electrophoretic mobility shift assay (EMSA). Expression of PKR and downstream targets was examined by Western blot analysis and immunofluorescence. RESULTS: Ionizing radiation leads to dose- and time-dependent increases in PKR expression and function that contributes to increased cellular radiation resistance as shown by clonogenic survival and terminal nucleotidyl transferase-mediated nick end labeling (TUNEL) apoptosis assays. Specific inhibition of PKR with the chemical inhibitor 2-AP restores radiation sensitivity. Plasmid transfection of the PKR wild-type (wt) gene into PKR(-/-) MEFs leads to increased radiation resistance. The protective effect of PKR to radiation may be mediated in part through NF-kappaB and Akt because both NF-kappaB and Akt are activated after ionizing radiation in PKR+/+ but not PKR-/- cells. CONCLUSIONS: We suggest a novel role for PKR as a mediator of radiation resistance modulated in part through the protective effects of NF-kappaB and Akt activation. The modification of PKR activity may be a novel strategy in the future to overcome radiation resistance

LiSoR, a liquid metal loop for material investigation under irradiation

LiSoR is a liquid metal loop that will use PSI's 72 MeV Philips cyclotron to irradiate stressed steel specimens in contact with flowing lead-bismuth with 50µA proton beam. LiSoR is a joint effort of PSI and SUBATECH with the support from CNRS and the Institute of Physics from Riga. It has been initiated to explore whether or not liquid metal corrosion and liquid metal embrittlement are enhanced under irradiation in the presence of stress. Numerical simulations showed that the damage levels and gas production in thin specimens induced by 72 MeV protons are, within reasonable limits, comparable to those on the inside of the beam window of a spallation target at 600 MeV, while much less radioactivity is produced. The paper describes the basic features of the experiment, the technical concept of the liquid metal loop with a special emphasis on the test section exposed to the proton beam and some of the relevant safety aspects

OX40 expression enhances the prognostic significance of CD8 positive lymphocyte infiltration in colorectal cancer

BACKGROUND: OX40 is a TNF receptor family member expressed by activated T cells. Its triggering by OX40 ligand promotes lymphocyte survival and memory generation. Anti-OX40 agonistic monoclonal antibodies (mAb) are currently being tested in cancer immunotherapy. We explored the prognostic significance of tumor infiltration by OX40+ cells in a large colorectal cancer (CRC) collective. METHODS: OX40 gene expression was analyzed in 50 freshly excised CRC and corresponding healthy mucosa by qRT-PCR. A tissue microarray including 657 clinically annotated CRC specimens was stained with anti-OX40, -CD8 and -FOXP3 mAbs by standard immunohistochemistry. The CRC cohort was randomly split into training and validation sets. Correlations between CRC infiltration by OX40+ cells alone, or in combination with CD8+ or FOXP3+ cells, and clinical-pathological data and overall survival were comparatively evaluated. RESULTS: OX40 gene expression in CRC significantly correlated with FOXP3 and CD8 gene expression. High CRC infiltration by OX40+ cells was significantly associated with favorable prognosis in training and validation sets in univariate, but not multivariate, Cox regression analysis. CRC with OX40(high)/CD8(high) infiltration were characterized by significantly prolonged overall survival, as compared to tumors with OX40(low)/CD8(high), OX40(high)/CD8(low) or OX40(low)/CD8(low) infiltration in both uni- and multivariate analysis. In contrast, prognostic significance of OX40+ and FOXP3+ cell infiltration was not enhanced by a combined evaluation. Irrespective of TNM stage, CRC with OX40(high)/CD8(high) density infiltrates showed an overall survival similar to that of all stage I CRC included in the study. CONCLUSIONS: OX40(high)/CD8(high) density tumor infiltration represents an independent, favorable, prognostic marker in CRC with an overall survival similar to stage I cancers