Modeling spheroid growth, PET tracer uptake, and treatment effects of the Hsp90 inhibitor NVP-AUY922.

For a PET agent to be successful as a biomarker in early clinical trials of new anticancer agents, some conditions need to be fulfilled: the selected tracer should show a response that is related to the antitumoral effects, the quantitative value of this response should be interpretable to the antitumoral action, and the timing of the PET scan should be optimized to action of the drug. These conditions are not necessarily known at the start of a drug-development program and need to be explored. We proposed a translational imaging activity in which experiments in spheroids and later in xenografts are coupled to modeling of growth inhibition and to the related changes in the kinetics of PET tracers and other biomarkers. In addition, we demonstrated how this information can be used for planning clinical trials. METHODS: The first part of this concept is illustrated in a spheroid model with BT474 breast cancer cells treated with the heat shock protein 90 (Hsp90) inhibitor NVP-AUY922. The growth-inhibitory effect after a pulse treatment with the drug was measured with digital image analysis to determine effects on volume with high accuracy. The growth-inhibitory effect was described mathematically by a combined E(max) and time course model fitted to the data. The model was then used to simulate a once-per-week treatment; in these experiments the uptake of the PET tracers (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was determined at different doses and different time points. RESULTS: A drug exposure of 2 h followed by washout of the drug from the culture medium generated growth inhibition that was maximal at the earliest time point of 1 d and decreased exponentially with time during 10-12 d. The uptake of (18)F-FDG per viable tumor volume was minimally affected by the treatment, whereas the (18)F-FLT uptake decreased in correlation with the growth inhibition. CONCLUSION: The study suggests a prolonged action of the Hsp90 inhibitor that supports a once-per-week schedule. (18)F-FLT is a suitable tracer for the monitoring of effect, and the (18)F-FLT PET study might be performed within 3 d after dosing.     

A systematic review of resident‐as‐teacher programmes

Context Residents in all disciplines serve as clinical teachers for medical students. Since the 1970s, there has been increasing evidence to demonstrate that residents wish to teach and that they respond positively to formal teacher training. Effective resident‐as‐teacher (RaT) programmes have resulted in improved resident teaching skills. Current evidence, however, is not clear about the specific features of an effective RaT programme. Objectives This study was performed in order to investigate the effectiveness of RaT programmes on resident teaching abilities and to identify the features that ensure success. Methods of assessment used to ascertain the effectiveness of RaT programmes are also explored. Methods The literature search covered the period between 1971 and 2008. Articles focusing on improving resident teaching skills were included. Each study was reviewed by two reviewers and data were collected using a standard abstraction summary sheet. Study outcomes were graded according to a modified Kirkpatrick's model of educational outcomes. Results Twenty‐nine studies met review inclusion criteria. Interventions included workshops, seminars, lectures and teaching retreats. Twenty‐six studies used a pre‐ and post‐intervention outcome comparison method. Subjective outcome measures included resident self‐evaluation of teaching skills or evaluation by medical students, peers and faculty members. Objective outcome measures included written tests, evaluation of teaching performance by independent raters and utilisation of objective structured teaching examinations. One study objectively measured learning outcomes at the level of medical students, utilising the results of an objective structured clinical examination. Overall resident satisfaction with RaT programmes was high. Participants reported positive changes in attitudes towards teaching. Participant knowledge of educational principles improved. Study methodologies allowed for significant risks of bias. Conclusions More rigorous study designs and the use of objective outcome measures are needed to ascertain the true effectiveness of RaT programmes. Future research should focus on determining the impact of RaT programmes on learning achievement at the level of medical students.     

Modern medicine

6.30 am. Woken by the alarm clock before the morning chorus.The roads are pretty clear on my way in, so for a change I manageto find a place in the main hospital car park, opposite theone reserved for the director of finance. 7.45 am. A working breakfast with the chief executive andmedical director. Apparently they want me to re-write the sectionabout my unit in the Trust's annual report. Bob, the CEO, commentsthat it is ‘too factual’. Sarah—once my registrar,now the MD—suggests that we should cut out a lot of thetext and replace it with nice photos: she knows a good agencythat     

Catabolism of newly synthesized decorin in vitro by human peritoneal mesothelial cells.

OBJECTIVE: Previous studies have shown that decorin and biglycan account for over 70% of the proteoglycans (PGs) synthesized by human peritoneal mesothelial cells (HPMCs). Since these PGs are involved in the control of cell growth, cell differentiation, and matrix assembly, we investigated their turnover in cultured HPMCs. METHODS: Confluent HPMCs were metabolically labeled with [35S]-sulfate and the labeled products isolated from the cell medium and the cell layer characterized by sensitivity to bacterial eliminases. Experiments were undertaken with exogenous labeled decorin, and its metabolic state was studied. RESULTS: In a 24-hour labeling period, 75% of the newly synthesized chondroitin sulfate/dermatan sulfate (CS/DS) PGs appeared in the culture medium, the majority of which (90%) was decorin. In the cell layer, protein-free glycosaminoglycan (GAG) chains accounted for 21% of the total CS/DS at 24 hours and exhibited constant specific activity at 12-16 hours. The latter material was turned over with a half-life of approximately 2.5 hours. Exogenous decorin underwent receptor-mediated endocytosis and subsequent intracellular degradation. Uptake but not degradation could be inhibited by heparin. CONCLUSIONS: HPMCs are distinguished by a rapid turnover of decorin. A characteristic metabolic feature is the existence of a large intracellular pool of protein-free DS-GAGs. Understanding the control of decorin turnover in HPMCs might lead to delineation of its potential role in both the physiology and pathophysiology of the membrane in PD patients.