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]

Measurement of the duration of X-ray lasing pumped by an optical laser pulse of picosecond duration

Measurements of the duration of X-ray lasing pumped with picosecond pulses from the VULCAN optical laser are obtained using a streak camera with 700 fs temporal resolution. Combined with a temporal smearing due to the spectrometer employed, we have measured X-ray laser pulse durations for Ni-like silver at 13.9 nm with a total time resolution of 1.1 ps. For Ni-like silver, the X-ray laser output has a steep rise followed by an approximately exponential temporal decay with measured full-width at half-maximum (FWHM) of 3.7 (+/-0.5) ps. For Ne-like nickel lasing at 23.1 nm, the measured duration of lasing is approximate to10.7 (+/-1) ps (FWHM). An estimate of the duration of the X-ray laser gain has been obtained by temporally resolving spectrally integrated continuum and resonance line emission. For Ni-like silver, this time of emission is approximate to22 (+/-2) ps (FWHM), while for Ne-like nickel we measure approximate to35 (+/-2) ps (FWHM). Assuming that these times of emission correspond to the gain duration, we show that a simple model consistently relates the gain durations to the measured durations of X-ray lasing. (C) 2002 Elsevier Science B.V. All rights reserved.

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.

Chemotherapy-Induced Activation of ADAM-17: A Novel Mechanism of Drug Resistance in Colorectal Cancer

Purpose: We have shown previously that exposure to anticancer drugs can trigger the activation of human epidermal receptor survival pathways in colorectal cancer (CRC). In this study, we examined the role of ADAMs (a disintegrin and metalloproteinases) and soluble growth factors in this acute drug resistance mechanism.

Experimental Design: In vitro and in vivo models of CRC were assessed. ADAM-17 activity was measured using a fluorometric assay. Ligand shedding was assessed by ELISA or Western blotting. Apoptosis was assessed by flow cytometry and Western blotting.

Results: Chemotherapy (5-fluorouracil) treatment resulted in acute increases in transforming growth factor-a, amphiregulin, and heregulin ligand shedding in vitro and in vivo that correlated with significantly increased ADAM-17 activity. Small interfering RNA–mediated silencing and pharmacologic inhibition confirmed that ADAM-17 was the principal ADAM involved in this prosurvival response. Furthermore, overexpression of ADAM-17 significantly decreased the effect of chemotherapy on tumor growth and apoptosis. Mechanistically, we found that ADAM-17 not only regulated phosphorylation of human epidermal receptors but also increased the activity of a number of other growth factor receptors, such as insulin-like growth factor-I receptor and vascular endothelial growth factor receptor.

Conclusions: Chemotherapy acutely activates ADAM-17, which results in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. Thus, pharmacologic inhibition of ADAM-17 in conjunction with chemotherapy may have therapeutic potential for the treatment of CRC.

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.