Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Molecular basis of Yersinia enterocolitica temperature-dependent resistance to antimicrobial peptides

[eng] Antimicrobial peptides (APs) belong to the arsenal of weapons of the innate immune system against infections. In the case of Gram-negative bacteria, APs interact with the anionic lipid A moiety of the lipopolysaccharide (LPS). In yersiniae most virulence factors are temperature regulated. Studies from our laboratory demonstrated that Yersinia enterocolitica is more susceptible to polymyxin B, a model AP, when grown at 37°C than at 22°C (J. A. Bengoechea, R. Díaz, and I. Moriyón, Infect. Immun. 64:4891-4899, 1996), and here we have extended this observation to other APs, not structurally related to polymyxin B. Mechanistically, we demonstrate that the lipid A modifications with aminoarabinose and palmitate are downregulated at 37°C and that they contribute to AP resistance together with the LPS O-polysaccharide. Bacterial loads of lipid A mutants in Peyer's patches, liver, and spleen of orogastrically infected mice were lower than those of the wild-type strain at 3 and 7 days postinfection. PhoPQ and PmrAB two-component systems govern the expression of the loci required to modify lipid A with aminoarabinose and palmitate, and their expressions are also temperature regulated. Our findings support the notion that the temperature-dependent regulation of loci controlling lipid A modifications could be explained by H-NS-dependent negative regulation alleviated by RovA. In turn, our data also demonstrate that PhoPQ and PmrAB regulate positively the expression of rovA, the effect of PhoPQ being more important. However, rovA expression reached wild-type levels in the phoPQ pmrAB mutant background, hence indicating the existence of an unknown regulatory network controlling rovA expression in this background

Review and “Vote Count” Analysis of OTL-Effect Studies

In the fourth chapter an overview is given of 51 primary studies, conducted during the last twenty years. Schematic summary descriptions are put together in a large summary table. Although quantitative meta-analysis of these studies was beyond the scope of this review study, some basic summary tables were produced to provide an overall orientation on how OTL had been researched and what can be concluded about its effectiveness. It is concluded that the vote count measure of OTL, (i.e. the percentage of effect sizes that were statistically significant and positive) established in this study, and which was 44 %, is of comparable size to other effectiveness enhancing conditions like achievement orientation, learning time and parental involvement, but dramatically higher than vote count measures for variables like cooperation and educational leadership. What should be considered is that vote counting is a rather crude procedure and that comparison of quantitative effect sizes is more informative

Continuous ventricular cerebrospinal fluid drainage with intracranial pressure monitoring for management of posttraumatic diffuse brain swelling

BACKGROUND: Ventricular drainage has played an important role in the management of traumatic brain-injured patients. The aim of the present study was describe outcomes in a series of 57 patients with diffuse brain swelling underwent to intracranial pressure (ICP) monitoring. METHOD: Fifty-eight patients with diffuse posttraumatic brain swelling, were evaluated prospectively. The Glasgow Coma Scale (GCS) scores of patients varied from 4 to 12. Patients groups divided according to GCS and age. Patient neurological assessment was classified as favorable, unfavorable, and death. RESULTS: Mechanisms of injury were vehicle accidents in 72.4% and falls in 15.6%. 54% of patients had GCS scores between 6 and 8. There were no statistical differences, regarding outcome, between groups separated by age. In the adults group (n=47), 44.7% evolved favorably. CONCLUSION: Our results indicate a poor prognosis in patients with brain swelling. We believe that continuous ventricular CSF drainage with ICP monitoring is a simple method as an adjunct in the management of these patients