Comprehensive validation of published immunohistochemical prognostic biomarkers of prostate cancer -what has gone wrong? A blueprint for the way forward in biomarker studies.

BACKGROUND: Treatment planning of localised prostate cancer remains challenging. Besides conventional parameters, a wealth of prognostic biomarkers has been proposed so far. None of which, however, have successfully been implemented in a routine setting so far. The aim of our study was to systematically verify a set of published prognostic markers for prostate cancer. METHODS: Following an in-depth PubMed search, 28 markers were selected that have been proposed as multivariate prognostic markers for primary prostate cancer. Their prognostic validity was examined in a radical prostatectomy cohort of 238 patients with a median follow-up of 60 months and biochemical progression as endpoint of the analysis. Immunohistochemical evaluation was performed using previously published cut-off values, but allowing for optimisation if necessary. Univariate and multivariate Cox regression were used to determine the prognostic value of biomarkers included in this study. RESULTS: Despite the application of various cut-offs in the analysis, only four (14%) markers were verified as independently prognostic (AKT1, stromal AR, EZH2, and PSMA) for PSA relapse following radical prostatectomy. CONCLUSIONS: Apparently, many immunohistochemistry-based studies on prognostic markers seem to be over-optimistic. Codes of best practice, such as the REMARK guidelines, may facilitate the performance of conclusive and transparent future studies.

The Aedes aegypti genome: a comparative perspective.

The sequencing of the second mosquito genome, Aedes aegypti, in addition to Anopheles gambiae, is a major milestone that will drive molecular-level and genome-wide high-throughput studies of not only these but also other mosquito vectors of human pathogens. Here we overview the ancestry of the mosquito genes, list the major expansions of gene families that may relate to species adaptation processes, as exemplified by CYP9 cytochrome P450 genes, and discuss the conservation of chromosomal gene arrangements among the two mosquitoes and fruit fly. Many more invertebrate genomes are expected to be sequenced in the near future, including additional vectors of human pathogens (see http://www.vectorbase.org), and further comparative analyses will become increasingly refined and informative, hopefully improving our understanding of the genetic basis of phenotypical differences among these species, their vectorial capacity, and ultimately leading to the development of novel disease control strategies.

Sensitivity of the parietal cell to pentagastrin in health and duodenal ulcer disease: a reappraisal.

In view of the conflicting results on whether pentagastrin sensitivity is genuinely increased in duodenal ulcer (DU) patients, the pentagastrin-gastric acid relationship was restudied in 17 normal subjects and 15 DU patients. In a reproducibility study performed on nine healthy subjects the mean pentagastrin responses obtained on 2 different study days, using a step technique (range, 0.025-6.4 micrograms kg-1h-1), were congruent at each of the five measuring points. Analysis of variance revealed no significant overall differences. However, ED50 values showed a large within- and between-subject variation and failed to correlate significantly, this because a plateau response was not regularly obtained with the top dose. Consequently, ED50 values in normal subjects and DU patients showed a large scatter and were not significantly different, although the potency ratio calculated from the linear parts of the respective dose-response curves was significantly different (2.6; 95% confidence limits, 1.8-3.9). This study thus supplies further evidence that the parietal cell of DU patients has a higher sensitivity to pentagastrin and demonstrates that the reliability of individual ED50 estimations obtained in pentagastrin dose-response studied should not be overrated.