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]

Development of a monoclonal antibody binding okadaic acid and dinophysistoxins-1, -2 in proportion to their toxicity equivalence factors

Okadaic acid (OA) and structurally related toxins dinophysistoxin-1 (DTX-1), and DTX-2, are lipophilic marine biotoxins. The current reference method for the analysis of these toxins is the mouse bioassay (MBA). This method is under increasing criticism both from an ethical point of view and because of its limited sensitivity and specificity. Alternative replacement methods must be rapid, robust, cost effective, specific and sensitive. Although published immuno-based detection techniques have good sensitivities, they are restricted in their use because of their inability to: (i) detect all of the OA toxins that contribute to contamination; and (ii) factor in the relative toxicities of each contaminant. Monoclonal antibodies (MAbs) were produced to OA and an automated biosensor screening assay developed and compared with ELISA techniques. The screening assay was designed to increase the probability of identifying a MAb capable of detecting all OA toxins. The result was the generation of a unique MAb which not only cross-reacted with both DTX-1 and DTX-2 but had a cross-reactivity profile in buffer that reflected exactly the intrinsic toxic potency of the OA group of toxins. Preliminary matrix studies reflected these results. This antibody is an excellent candidate for the development of a range of functional immunochemical-based detection assays for this group of toxins.

The Paradox of art criticism: Jacques Derrida in front of the Greco, Henri Michaux before René Magritte

This paper analyzes the rethinking of art criticism during French post-structuralism and deconstruction in the second half of the XX century. From Michel Foucault to Gilles Deleuze, from Jacques Derrida to Jean-Claude Lebensztejn, the article develops several conceptions and functions of art criticism by means of paradox, paying special attention to Henri Michaux’s essay on René Magritte En rêvant à partir de peintures énigmatiques [Dreams like Enigmatic Paintings].

Accounting and business students' approaches to learning: A longitudinal study

This study reports the results of an investigation into the learning approaches of undergraduate accounting and business students from three universities in Ireland who were exposed to a learning environment, namely the case study method, which aimed to encourage a deep approach to learning. In order to assess the effectiveness of the intervention, the ASSIST research instrument was used to investigate changes in students’ approaches to learning over time. Consistent with previous research, this study considers whether gender is related to students’ approaches to learning over time and if there are differences between students majoring in accounting or business in their approaches to learning. The results of the study indicate that the case study intervention was successful in some respects. However, contrary to expectations, an overall statistically significant increase in students’ surface approach to learning was found. Additionally, it is reported that changes in students’ approaches to learning over time are not associated with gender or degree program. The results of this study offer insights to accounting educators developing educational interventions to encourage deep approaches to learning.

Accounting Undergraduates’ Perceptions of Cooperative Learning as a Model for Enhancing their Interpersonal and Communication Skills to Interface Successfully with Professional Accountancy Education and Training

To interface effectively with professional accountancy training, accounting educationalists should ensure that they turn out graduates who possess the interpersonal and communication skills required of today's accountant. Attainment of these skills is promoted by group work. However, little empirical evidence exists to help academics make an informed choice about which form of group learning enhances interpersonal and communication skills. This paper addresses this deficiency by comparing perceptions of skills enhancement between accounting students who experienced traditional or simple group learning and those who undertook cooperative learning. The findings reveal that the cooperative learning cohort perceived their learning experience to be significantly more effective at enhancing interpersonal and communication skills than that of the simple group learning cohort. This study provides evidence that cooperative learning is a more effective model for delivering interpersonal and communication skills than simple group learning, thereby creating a more successful interface between academic accounting and professional accountancy training.

Missing the targets and being misunderstood: Child phonology and interactive problems

Effects of vowel variation on interaction are considered, with particular relevance to their role in conversational breakdown. The effect of speaker knowledge and experience is noted as a variable in developmental progress which must inform profiling decisions, and the need for appropriate taxonomies of speech varieties is emphasized as a precursor to clinical and educational assessments. It is noted, too, that a shared sociolinguistic background between speaker and listener does not always resolve difficulties arising from non-target realizations, casting some doubt on ideas that assessors always possess a guaranteed sense of phonological variability and its effects. Hence, an informed understanding of phonological variation, rather than merely awareness that such variation exists, is advocated.

Verteporfin Photodynamic Therapy Cohort Study Report 2: Clinical Measures of Vision and Health-Related Quality of Life

Purpose: To quantify decreases in health-related quality of life (HRQoL) for given deterioration in clinical measures of vision; to describe the shape of these relationships; and to test whether the gradients of these relationships change with duration of visual loss.

Community Cohesion and Social Inclusion: Unravelling a Complex Relationship

In a global context of an emphasis on identity politics and a ‘cultural turn’ in social analysis, deep concern has been expressed about multiethnic Britain becoming a broken society with many ‘sleepwalking’ into segregation and separatism. Given the close correspondence between areas of acute ethnic segregation and those of multiple deprivation, intercommunal tensions have included disputes about the equitable allocation of scarce urban resources across ethnicity. This creates the possibility that urban programmes may inadvertently accentuate intercommunal tension and confound efforts to synchronise cohesion and inclusion agendas. Following recent debates about the implications of increased diversity, influenced by arguments that multiculturalism has encouraged ‘parallel lives’, an emergent policy framework emphasises more proactive integration to promote ‘common belonging’. Criticism of this agenda includes its confusion between community and social cohesion, and its disproportionate focus on cultural aspects such as identity formation and recognition, relative to structural issues of income and class. In exploring this contested terrain in Britain, the article suggests that the longer-term debate about segregation, deprivation and community differentials in Northern Ireland can offer useful insight for Britain’s policy discourse.

Baudelaire, Daumier and the Art of Memory

This article reassesses the importance of the Baudelaire's criticism of the art of Daumier in relation to his theorization of memory. It argues that more than Guys, Daumier may represent for the poet the quintessential 'peintre de la vie moderne'.

The Impact of Ethical Orientation and Gender on Final Year Undergraduate Auditing Students’ Ethical Judgments

This study considers the possibility of auditing students’ ethical judgment being affected by two factors, namely ethical orientation and gender. While tests revealed that more idealistic students judged some unethical situations more strictly than less idealistic students, overall no significant relationship was found between ethical orientation and ethical judgment. The study also reported no significant relationship between gender and ethical judgment. Furthermore, males were as likely as females to be classified as high idealists. Overall, the findings from the current study inform auditing educators that discriminating among students on the basis of ethical orientation and gender may not assist in stimulating students’ discussion and resolution of ethical dilemmas.