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Item does not contain fulltext, Background:Previously we demonstrated that an mRNA signature reflecting cellular proliferation had strong prognostic value. As clinical applicability of signatures can be controversial, we sought to improve our marker's clinical utility by validating its biological relevance, reproducibility in independent data sets and applicability using an independent technique.Methods:To facilitate signature evaluation with quantitative PCR (qPCR) a novel computational procedure was used to reduce the number of signature genes without significant information loss. These genes were validated in different human cancer cell lines upon serum starvation and in a 168 xenografts panel. Analyses were then extended to breast cancer and non-small-cell lung cancer (NSCLC) patient cohorts.Results:Expression of the qPCR-based signature was dramatically decreased under starvation conditions and inversely correlated with tumour volume doubling time in xenografts. The signature validated in breast cancer (hazard ratio (HR)=1.63, P<0.001, n=1820) and NSCLC adenocarcinoma (HR=1.64, P<0.001, n=639) microarray data sets. Lastly, qPCR in a node-negative, non-adjuvantly treated breast cancer cohort (n=129) showed that patients assigned to the high-proliferation group had worse disease-free survival (HR=2.25, P<0.05).Conclusion:We have developed and validated a qPCR-based proliferation signature. This test might be used in the clinic to select (early-stage) patients for specific treatments that target proliferation.

Item does not contain fulltext, Hypoxia has been shown to be an important microenvironmental parameter influencing tumor progression and treatment efficacy. Patient guidance for hypoxia-targeted therapy requires evaluation of tumor oxygenation, preferably in a noninvasive manner. The aim of this study was to evaluate and validate the uptake of [(18)F]HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [(18)F]HX4 was found within rat rhabdomyosarcoma tumors that was significantly (P < 0.0001) higher compared with the surrounding tissues, with temporal increasing tumor-to-blood ratios reaching a plateau of 7.638 +/- 0.926 and optimal imaging properties 4 h after injection. [(18)F]HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [(18)F]HX4 tumor uptake was analyzed based on 16 regions within the tumor according to the different orthogonal planes at the largest diameter. Validation of heterogeneous [(18)F]HX4 tumor uptake was shown by a strong and significant relationship (r = 0.722; P < 0.0001) with the hypoxic fraction as calculated by the percentage pimonidazole-positive pixels. Furthermore, a causal relationship with tumor oxygenation was established, because combination treatment of nicotinamide and carbogen resulted in a 40% reduction (P < 0.001) in [(18)F]HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake (P < 0.05). [(18)F]HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.

Item does not contain fulltext, High aggression is often linked to lowered serotonin (5-HT) neurotransmission. Although this may hold for high aggression as a trait characteristic of an individual, serotonergic activity is probably increased during performance of aggressive behavior. To test this hypothesis, first, the 5-HT1A agonist alnespirone and gamma aminobutyric acid-A agonist muscimol were administered into the dorsal raphe nucleus. These treatments, which inhibit 5-HT neuronal activity, were shown to decrease performance of aggressive behavior. Second, after a resident-intruder test, the activation of 5-HT neurons (measured by c-fos expression) was increased in high-aggressive rats, compared with low-aggressive rats or control rats that were not subjected to a social confrontation. Results show that performance of aggressive behavior increases 5-HT neuronal activity and that preventing this activation inhibits expression of aggressive behavior.

Item does not contain fulltext, In humans and other primates low cerebrospinal fluid (CSF) levels of the major serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been correlated to high aggressiveness. This finding forms the basis of the 5-HT deficiency hypothesis of aggression. Surprisingly, this correlation has not been confirmed in rodents so far, while manipulation studies aimed to investigate the link between 5-HT and aggressive behaviour are mostly carried out in rodents. In this study the relation between aggression and CSF monoamine and metabolite concentrations was investigated in male Wildtype Groningen rats. In sharp contrast to the hypothesis and our expectation, a clear positive correlation was found between the individual level of trait-like aggressiveness and CSF concentrations of 5-HT, 5-HIAA, norepinephrine (NE), dopamine (DA), and 3,4-dihydroxyphenylacetic acid (DOPAC). Shortly after the acute display of aggressive behaviour (as a state-like phenomenon), decreased 5-HT levels and an increase in 5-HIAA/5-HT ratio and NE concentrations were found. Surprisingly, pharmacological challenges known to influence 5-HT transmission and aggressive behaviour did not affect CSF 5-HT and 5-HIAA concentrations, only the NE level was increased. Lesioning 5-HT terminals by 5,7-dihydroxytryptamine (5,7-DHT) administration caused a decrease in CSF 5-HT and 5-HIAA, but without affecting aggressive behaviour. The observed positive correlation between CSF 5-HIAA and trait aggressiveness makes it questionable whether a direct extrapolation of neurobiological mechanisms of aggression between species is justified. Interpretation of CSF metabolite levels in terms of activity of neural substrates requires a far more detailed knowledge of the dynamics and kinetics of a neurotransmitter after its release.