Towards gene therapy for EBV-associated posttransplant lymphoma with genetically modified EBV-specific cytotoxic T cells

Epstein-Barr virus (EBV)-associated posttransplant lymphoma (PTLD) is a major cause of morbidity/mortality after hematopoietic stem cell (SCT) or solid organ (SOT) transplant. Adoptive immunotherapy with EBV-specific cytotoxic lymphocytes (CTLs), although effective in SCT, is less successful after SOT where lifelong immunosuppression therapy is necessary. We have genetically engineered EBV-CTLs to render them resistant to calcineurin (CN) inhibitor FK506 through retroviral transfer of a calcineurin A mutant (CNA12). Here we examined whether or not FK506-resistant EBV-CTLs control EBV-driven tumor progression in the presence of immunosuppression in a xenogeneic mouse model. NOD/SCID/IL2rγnull mice bearing human B-cell lymphoma were injected with autologous CTLs transduced with either CNA12 or eGFP in the presence/absence of FK506. Adoptive transfer of autologous CNA12-CTLs induced dramatic lymphoma regression despite the presence of FK506, whereas eGFP-CTLs did not. CNA12-CTLs persisted longer, homed to the tumor, and expanded more than eGFP-CTLs in mice treated with FK506. Mice receiving CNA12-CTLs and treated with FK506 survived significantly longer than control-treated animals. Our results demonstrate that CNA12-CTL induce regression of EBV-associated tumors in vivo despite ongoing immunosuppression. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy

Overexpression of piRNA pathway genes in epithelial ovarian cancer

The importance of the Piwi-interacting RNA (piRNA) pathway for germ cell maintenance, genome integrity, DNA methylation and retrotransposon control raises possible roles of this pathway in cancer. Indeed aberrant expression of human PIWI orthologs and Maelstrom has been observed in various cancers. In this study we explored the expression and function of piRNA pathway genes in human ovarian cancer, based on our recent work, which showed widespread expression of piRNA pathway genes in the mammalian. Our work shows that PIWIL1 and MAEL expression is significantly increased in malignant EOC (n = 25) compared to benign tumor tissues (n = 19) and normal ovarian tissue (n = 8). The expression of PIWIL3 is lower in malignant and benign tissues when compared to normal ovary. Sequencing of PIWIL1 transcript revealed that in many tumors deletion of exon 17 leads to the introduction of a premature stop codon in the PIWI domain, likely due to a splicing error. In situ hybridization on tumor sections revealed that L1, PIWIL1, 2 and MAEL are specifically expressed in epithelial cells (cancerous cells) of EOC. Furthermore, PIWIL2 and MAEL are co-expressed in the stromal cells adjacent to tumor cells. Since PIWIL1 and MAEL are up regulated in malignant EOC and expressed in the epithelial cells, we investigated if these two genes affect invasiveness of ovarian cancer cell lines that do not normally express these genes. PIWIL1 and MAEL were transiently over expressed in the ovarian cancer cell line SKOV3, followed by real-time measurements of cell invasiveness. Surprisingly both PIWIL1 and MAEL over expression decreased the invasiveness of SKOV3 cells. Our findings support a growing body of evidence that shows that genes in this pathway are upregulated in cancer. In ovarian cancer we show for the first time that Piwil1 transcript may often be abnormal result in non functional product. In contrast to what has been observed in other cell types, we found that PIWIL1 and MAEL have a repressive effect on cell invasiveness.Shu Ly Lim, Carmela Ricciardelli, Martin K. Oehler, Izza M. D. De Arao Tan, Darryl Russell, Frank Grützne

The morphologies and masses of extremely red galaxies in the Groth Strip survey

We present a new cataloge of EROs from the Groth strip and study the relation between their morphology and mass. We find 102 EROs (F814W-K=>4, K<=21.0), over a survey area of 155 arcmin^2. The photometric data include U,B,F606W,F814W,J,K bands. Morphologies are based on a by eye classification and we distinguish between 3 basic classes: compact objects, targets with a disc and/or a bulge component and irregular or merger candidates. The majority of our targets has either a very compact morphology (33+-6%), or show more or less distinct disc components (41+-6%). 14+-4% are merger or irregulars and 7 objects could not be classified. We also study the dependence of structural parameters on morphological appearance. EROs that are either compact or show a distinct bulge component have smaller median effective radii (1.22+-0.14 kpc and 3.31+-0.53 kpc) than disc dominated (5.50+-0.51 kpc) or possible irregular galaxies or merger candidates (4.92+-0.14 kpc). The Sersic index changes from 2.30+-0.34 and 3.24+-0.55, to 1.03+-0.24 and 1.54+-0.40 respectively. Most the EROs in our sample have redshifts between z=1 and z=2; however, compact EROs in our sample are found at redshifts as low as z=0.4 and as high as z=2.8; the latter qualify as well as DRGs. Disc-like EROs are also found up to z=2.8; however those with a bulge-disc structure are only seen at z<1.5. For each of these EROs we determined the stellar mass and mean population age by fitting synthetic Bruzual (2007) spectra to the SED. Mass estimates were obtained by assuming an exponentially declining star formation rate. Total stellar masses are in the range 9.1<log(M/M_sun)<11.6. We cannot detect significant differences between the stellar mass distribution of the morphological classes. EROs with masses of log(M/M_sun)>11.0 dominantly show compact morphologies, but also include a significant number of sources with a disc morphology.Comment: 21 pages, 17 figures, accepted for publication in MNRA

Promoting fit bodies, healthy eating and physical activity among Indigenous Australian men: a study protocol

Background: Overall the physical health of Indigenous men is among the worst in Australia. Research has indicated that modifiable lifestyle factors, such as poor nutrition and physical inactivity, appear to contribute strongly to these poor health conditions. To effectively develop and implement strategies to improve the health of Australia&rsquo;s Indigenous peoples, a greater understanding is needed of how Indigenous men perceive health, and how they view and care for their bodies. Further, a more systematic understanding of how sociocultural factors affect their health attitudes and behaviours is needed. This article presents the study protocol of a communitybased investigation into the factors surrounding the health and body image of Indigenous Australian men.Methods and design: The study will be conducted in a collaborative manner with Indigenous Australian men using a participatory action research framework. Men will be recruited from three locations around Australia (metropolitan, regional, and rural) and interviewed to understand their experiences and perspectives on a number of issues related to health and health behaviour. The information that is collected will be analysed using modified grounded theory and thematic analysis. The results will then be used to develop and implement community events in each location to provide feedback on the findings to the community, promote health enhancing strategies, and determine future action and collaboration.Discussion: This study will explore both risk and protective factors that affect the health of Indigenous Australian men. This knowledge will be disseminated to the wider Indigenous community and can be used to inform future health promotion strategies. The expected outcome of this study is therefore an increased understanding of health and health change in Indigenous Australian men, the development of strategies that promote healthy eating and positive patterns of physical activity and, in the longer term, more effective and culturally-appropriate interventions to improve health.<br /

Why do dogs (Canis familiaris) select the empty container in an observational learning task?

Many argue that dogs show unique susceptibility to human communicative signals that make them suitable for being engaged in complex co-operation with humans. It has also been revealed that socially provided information is particularly effective in influencing the behaviour of dogs even when the human’s action demonstration conveys inefficient or mistaken solution of task. It is unclear, however, how the communicative nature of the demonstration context and the presence of the human demonstrator affect the dogs’ object-choice behaviour in observational learning situations. In order to unfold the effects of these factors, 76 adult pet dogs could observe a communicative or a non-communicative demonstration in which the human retrieved a tennis ball from under an opaque container while manipulating another distant and obviously empty (transparent) one. Subjects were then allowed to choose either in the presence of the demonstrator or after she left the room. Results showed a significant main effect of the demonstration context (presence or absence of the human’s communicative signals), and we also found some evidence for the response-modifying effect of the presence of the human demonstrator during the dogs’ choice. That is, dogs predominantly chose the baited container, but if the demonstration context was communicative and the human was present during the dogs’ choice, subjects’ tendency to select the baited container has been reduced. In agreement with the studies showing sensitivity to human’s communicative signals in dogs, these findings point to a special form of social influence in observational learning situations when it comes to learning about causally opaque and less efficient (compared to what comes natural to the dog) action demonstrations