Evidence for Kidney Rejection After Combined Bone Marrow and Renal Transplantation Despite Ongoing Whole‐Blood Chimerism in Rhesus Macaques

Although there is evidence linking hematopoietic chimerism induction and solid organ transplant tolerance, the mechanistic requirements for chimerism‐induced tolerance are not clearly elucidated. To address this, we used an MHC‐defined primate model to determine the impact of impermanent, T cell‐poor, mixed‐chimerism on renal allograft survival. We compared two cohorts: one receiving a bone marrow and renal transplant (“BMT/renal”) and one receiving only a renal transplant. Both cohorts received maintenance immunosuppression with CD28/CD40‐directed costimulation blockade and sirolimus. As previously demonstrated, this transplant strategy consistently induced compartmentalized donor chimerism, (significant whole‐blood chimerism, lacking T cell chimerism). This chimerism was not sufficient to prolong renal allograft acceptance: the BMT/renal mean survival time (MST, 76 days) was not significantly different than the renal transplant alone MST (85 days, p = 0.46), with histopathology documenting T cell mediated rejection. Flow cytometric analysis revealed significant enrichment for CD28–/CD95+ CD4+ and CD8+ Tem cells in the rejected kidney, suggesting a link between CD28‐negative Tem and costimulation blockade‐resistant rejection. These results suggest that in some settings, transient T cell‐poor chimerism is not sufficient to induce tolerance to a concurrently placed renal allograft and that the presence of this chimerism per se is not an independent biomarker to identify tolerance.     

Protein kinases as targets for anticancer agents: from inhibitors to useful drugs

Many components of mitogenic signaling pathways in normal and neoplastic cells have been identified, including the large family of protein kinases, which function as components of signal transduction pathways, playing a central role in diverse biological processes, such as control of cell growth, metabolism, differentiation, and apoptosis. The development of selective protein kinase inhibitors that can block or modulate diseases caused by abnormalities in these signaling pathways is widely considered a promising approach for drug development. Because of their deregulation in human cancers, protein kinases, such as Bcr-Abl, those in the epidermal growth factor-receptor (HER) family, the cell cycle regulating kinases such as the cyclin-dependent kinases, as well as the vascular endothelial growth factor-receptor kinases involved in the neo-vascularization of tumors, are among the protein kinases considered as prime targets for the development of selective inhibitors. These drug-discovery efforts have generated inhibitors and low-molecular weight therapeutics directed against the ATP-binding site of various protein kinases that are in various stages of development (up to Phase II/III clinical trials). Three examples of inhibitors of protein kinases are reviewed, including low-molecular weight compounds targeting the cell cycle kinases; a potent and selective inhibitor of the HER1/HER2 receptor tyrosine kinase, the pyrollopyrimidine PKI166; and the 2-phenyl-aminopyrimidine STI571 (Glivec(R), Gleevec) a targeted drug therapy directed toward Bcr-Abl, the key player in chronic leukemia (CML). Some members of the HER family of receptor tyrosine kinases, in particular HER1 and HER2, have been found to be overexpressed in a variety of human tumors, suggesting that inhibition of HER signaling would be a viable antiproliferative strategy. The pyrrolo-pyrimidine PKI166 was developed as an HER1/HER2 inhibitor with potent in vitro antiproliferative and in vivo antitumor activity. Based upon its clear association with disease, the Bcr-Abl tyrosine kinase in CML represents the ideal target to validate the clinical utility of protein kinase inhibitors as therapeutic agents. In a preclinical model, STI571 (Glivec(R), Gleevec) showed potent in vitro and in vivo antitumor activity that was selective for Abl, c-Kit, and the platelet-derived growth factor-receptor. Phase I/II studies demonstrated that STI571 is well tolerated, and that it showed promising hematological and cytogenetic responses in CML and clinical responses in the c-Kit-driven gastrointestinal tumors.     

Enhancing the management of deteriorating patients with Australian on line e‐simulation software: Acceptability,transferability, and impact in Hong Kong

International concerns relating to healthcare professionals’ failure to rescue deteriorating patients exist. Web‐based training programs have been developed and evaluated in Western settings but further testing is required before application in non‐Western countries, as traditional modalities of learning may differ between cultures. We trialed an Australian English language online simulation program for the management of deteriorating patients, Feedback Incorporating Review and Simulation Techniques to Act on Clinical Trends (FIRST²ACTWeb), to test cultural acceptability, transferability, and educational impact. The study was designed as a quasi‐experimental evaluation of the FIRST²ACTWeb program with final year nursing students from a Bachelor of Nursing program at the University of Hong Kong. Participants completed pre‐course and post‐course tests, three interactive scenarios, and program evaluations. The program was positively evaluated, with significant improvements in knowledge, skills, self‐rating of performance, confidence, and competence. Outcomes were comparable to earlier evaluations with Australian students, demonstrating that an interactive simulation‐based program of patient deterioration management has cultural and language acceptability and transferability across communities with significant educational impact.     

Clinical trial transparency update: an assessment of the disclosure of results of company-sponsored trials associated with new medicines approved in Europe in 2012

Background:

The objective of this study was to assess the timely disclosure of results of company-sponsored clinical trials related to all new medicines approved by the European Medicines Agency (EMA) during 2012. This is an extension of the previously reported study of trials related to all new medicines approved in Europe in 2009, 2010 and 2011, which found that over three-quarters of all these trials were disclosed within 12 months and almost 90% were disclosed by the end of the study.

Methods:

The methodology used was exactly as previously reported. Various publicly available information sources were searched for both clinical trial registration and disclosure of results. All completed company-sponsored trials related to each new medicine approved for marketing by the EMA in 2012, carried out in patients and recorded on a clinical trials registry and/or included in an EMA European Public Assessment Report (EPAR), were included. Information sources were searched between 1 May and 31 July 2014.

Outcome measures and results:

The main outcome measure was the proportion of trials for which results had been disclosed on a registry or in the scientific literature either within 12 months of the later of either first regulatory approval or trial completion, or by 31 July 2014 (end of survey). Of the completed trials associated with 23 new medicines licensed to 17 different companies in 2012, results of 90% (307/340) had been disclosed within 12 months, and results of 92% (312/340) had been disclosed by 31 July 2014.

Conclusions:

The disclosure rate within 12 months of 90% suggests the industry is now achieving disclosure in a timely manner more consistently than before. The overall disclosure rate at study end of 92% indicates that the improvement in transparency amongst company-sponsored trials has been maintained in the trials associated with new medicines approved in 2012.     

The Hierarchical Clustering of Clinical Psychology Practicum Competencies: A Multisite Study of Supervisor Ratings

Competency evaluation rating forms are widely used to assess a range of global and specific psychology practitioner competencies during and at the end of clinical placements. Surprisingly, there is little research examining the dimensional structure or the hierarchical clustering of items on these ratings. The current, multisite study examined supervisor ratings of clinical psychology trainees (N = 204) on the Clinical Psychology Practicum Competencies Rating Scale (CΨPRS). Based on the proximity criterion chosen, hierarchical clustering yielded either nine clusters or four super clusters: Good Practitioner Attributes and Conduct, Scientist Practitioner and Professional Management, Assessment and Intervention, and Psychological Testing. The study also tracked the developmental trajectory of competency attainment. CΨPRS ratings differentiated groups between early but not between later stages of training. Measurement issues and implications for training and practice are discussed.