Src and ADAM-17-Mediated Shedding of Transforming Growth Factor-alpha Is a Mechanism of Acute Resistance to TRAIL

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L) has emerged as a promising anticancer agent. However, resistance to TRAIL is likely to be a major problem, and sensitization of cancer cells to TRAIL may therefore be an important anticancer strategy. In this study, we examined the effect of the epidermal growth factor receptor (EGFR)tyrosine kinase inhibitor (TKI) gefitinib and a human epidermal receptor 2 (HER2)-TKI (M578440) on the sensitivity of human colorectal cancer (CRC) cell lines to recombinant human TRAIL (rhTRAIL). A synergistic interaction between rhTRAIL and gefitinib and rhTRAIL and M578440 was observed in both rhTRAIL-sensitive and resistant CRC cells. This synergy correlated with an increase in EGFR and HER2 activation after rhTRAIL treatment. Furthermore, treatment of CRC cells with rhTRAIL resulted in activation of the Src family kinases (SFK). Importantly, we found that rhTRAIL treatment induced shedding of transforming growth factor-alpha (TGF-alpha) that was dependent on SFK activity and the protease ADAM-17. Moreover, this shedding of TGF-alpha was critical for rhTRAIL-induced activation of EGFR. In support of this, SFK inhibitors and small interfering RNAs targeting ADAM-17 and TGF-alpha also sensitized CRC cells to rhTRAIL-mediated apoptosis. Taken together, our findings indicate that both rhTRAIL-sensitive and resistant CRC cells respond to rhTRAIL treatment by activating an EGFR/HER2-mediated survival response and that these cells can be sensitized to rhTRAIL using EGFR/HER2-targeted therapies. Furthermore, this acute response to rhTRAIL is regulated by SFK-mediated and ADAM-17-mediated shedding of TGF-alpha, such that targeting SFKs or inhibiting ADAM-17, in combination with rhTRAIL, may enhance the response of CRC tumors to rhTRAIL. [Cancer Res 2008;68(20):8312-21]

Towards Educational Inclusion in a Transforming Society: Some Lessons from Community Relations and Special Needs Education in Northern Ireland

This paper takes an original approach to an important aspect of educational research and its role in transforming societies, namely that of educational inclusion. It brings together what some might consider two rather strange bedfellows i.e. community relations and special needs education. It also draws upon new tools for theorising educational inclusion, which give a central role to the discursive nature of human conduct and which take a view of human behaviour as socially embedded and meaningful.

Organisational Self-Evaluation and Teacher Education for Community Relations in a Transforming Society?

During 2004, the School of Education at the University of Ulster embarked on an innovative three-year project designed to embed community relations objectives within initial teacher education. With the advent of more peaceful times in Northern Ireland, this was a precipitous time for initial teacher educators to review the preparation given to beginner teachers for teaching in an increasingly pluralist society emerging from conflict. The present paper reports on one very specific and time-limited element of the broader project. That is, development work designed to investigate the possibilities of using processes of self-review and evaluation as a lever for improvements in initial teacher education for community relations. Following a brief contextualisation, the background to, and the development of, a set of materials designed to support rigorous and systematic self-review of all aspects of provision in a university-based initial teacher education department is described. The Community Relations Index for Initial Teacher Education (Cr-ITE) was envisaged as being of use to initial teacher education establishments in order to help teacher educators take responsibility for rigorous learning from their practice, whilst placing inclusive values at the centre of organisational development. The final section includes further critical reflection on the role of organisational self-review in transforming teacher education for inclusion in a society emerging from longstanding communal conflict.

Bone growth into a ceramic-filled defect around an implant - The response to transforming growth factor beta 1

Synthetic bone substitutes provide an alternative to autograft but do not give equivalent clinical results. Their performance may be enhanced by adding osteogenic growth factors. In this study, TGFbeta1 was absorbed on to a carrier of 0 tricalcium phosphate and Gelfoam(R) and used to fill a defect around a tibial implant in a rat model of revision arthoplasty.

Measuring the state of consciousness in a free-living diving sea turtle

We report on results from two types of data-logger attached to hawksbill turtles (Eretmochelys coriacea) in the breeding season at the Seychelles, Indian Ocean. Conventional time-depth recorders (TDRs) showed prolonged bouts of long dives to the seabed, consistent with benthic resting. This behaviour has been widely reported in sea turtles and appears to be a common feature for energy conservation. An Inter-Mandibular Angle Sensor (IMASEN) recorded mouth opening and buccal pumping by one turtle for 2.5 days. Buccal pumping occurred widely while the turtle was submerged, consistent with a function of olfactory sensory perception of the turtle's environment. However, buccal pumping stopped during the middle of long benthic dives consistent with the turtle entering a phase of sleep. It therefore appears that by recording buccal oscillations, it is possible to assess the state of consciousness of turtles allowing the eco-physiology of diving to be more fully explored. (C) 2007 Elsevier B.V. All rights reserved.

Connective tissue growth factor antagonizes transforming growth factor-beta 1/Smad signalling in renal mesangial cells

The critical involvement of TGF-beta 1 (transforming growth factor-beta 1) in DN (diabetic nephropathy) is well established. However, the role of CTGF (connective tissue growth factor) in regulating the complex interplay of TGF-beta 1 signalling networks is poorly understood. The purpose of the present study was to investigate co-operative signalling between CTGF and TGF-beta 1 and its physiological significance. CTGF was determined to bind directly to the T beta RIII (TGF-beta type III receptor) and antagonize TGF-beta 1-induced Smad phosphorylation and transcriptional responses via its N-terminal half. Furthermore, TGF-beta 1 binding to its receptor was inhibited by CTGF. A consequent shift towards non-canonical TGF-beta 1 signalling and expression of a unique profile of differentially regulated genes was observed in CTGF/TGF-beta 1-treated mesangial cells. Decreased levels of Smad2/3 phosphorylation were evident in STZ (streptozotocin)-induced diabetic mice, concomitant with increased levels of CTGF Knockdown of T beta RIII restored TGF-beta 1-mediated Smad signalling and cell contractility, suggesting that T beta RIII is key for CTGF-mediated regulation of TGF-beta 1. Comparison of gene expression profiles from CTGF/TGF-beta 1-treated mesangial cells and human renal biopsy material with histological diagnosis of DN revealed significant correlation among gene clusters. In summary, mesangial cell responses to TGF-beta 1 are regulated by cross-talk with CTGF, emphasizing the potential utility of targeting CTGF in DN.

‘Transforming justice’: challenges for restorative justice in an era of punishment-based corrections

Scholars of restorative justice have long debated its theoretical relationship with formal criminal justice. This analysis critically examines the range of sociostructural conditions in contemporary society that have halted the spread of restorative policies in practice and prevented them from realizing their transformative potential as an alternative system of justice. These factors are attributed largely to a punitive penal culture that is characterized by policy-making based on penal populism, the governance of risk and a managerialist criminal justice agenda; and the widespread co-optation of restorative programs by the state. This broad argument is explored in the context of two particular case studies – recent developments in youth justice and in sexual offending respectively in England and Wales and elsewhere. This examination ultimately highlights challenges for restorative justice in the current risk-driven penal climate and advocates a need to re-evaluate its relationship with formal state justice.