Formation of the pro-apoptotic death-inducing signaling complex (DISC) can be initiated in cancer cells via binding of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to its two pro-apoptotic receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2. Primary components of the DISC are trimerized TRAIL-R1/-R2, FADD, caspase 8 and caspase 10. The anti-apoptotic protein FLIP can also be recruited to the DISC to replace caspase 8 and form an inactive complex. Caspase 8/10 processing at the DISC triggers the caspase cascade, which eventually leads to apoptotic cell death. Besides TRAIL, TRAIL-R1- or TRAIL-R2-selective variants of TRAIL and agonistic antibodies have been designed. These ligands are of interest as anti-cancer agents since they selectively kill tumor cells. To increase tumor sensitivity to TRAIL death receptor-mediated apoptosis and to overcome drug resistance, TRAIL receptor ligands have already been combined with various therapies in preclinical models. In this review, we discuss factors influencing the initial steps of the TRAIL apoptosis signaling pathway, focusing on mechanisms modulating DISC assembly and caspase activation at the DISC. These insights will direct rational design of drug combinations with TRAIL receptor ligands to maximize DISC signaling. © 2009 Elsevier B.V. All rights reserved.
DOCUMENT
Diagnosing teachers are teachers who perceive diagnostic information about students’ learning process, interpret these aspects, decide how to respond, and act based on this diagnostic decision. During supervision meetings about the undergraduate thesis supervisors make in-the-moment decisions while interacting with their students. We regarded research supervision as a teaching process for the supervisor and a learning process for the student. We tried to grasp supervisors’ in-the-moment decisions and students’ perceptions of supervisors’ actions. Supervisor decisions and student perceptions were measured with video-stimulated recall interviews and coded using a content analysis approach. The results showed that the in-the-moment decisions our supervisors made had a strong focus on student learning. Supervisors often asked questions to empower students or to increase student understanding. These supervising strategies seemed to be adapted to students’ needs, as the latter had positive perceptions when their control increased or when they received stimuli to think for themselves.
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