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

Effects of intensified forestry on the landscape-scale extinction risk of dead wood dependent species

In the future, a significant proportion of northern forests may become intensively managed through the planting of monospecific stands of native or introduced trees, and the use of multiple silvicultural treatments such as forest fertilization. Such an intensification of management in selected parts of the landscape is suggested by different zoning models, for example the Triad approach, which is under evaluation in some regions of North America. In this study, based on Fennoscandian conditions, we predicted landscape-scale extinction risks of five hypothetical model insect species dependent on fresh dead wood from Norway spruce (Picea abies), by simulating colonizations and local extinctions in forest stands. Intensified forestry applied to 50 % of the spruce stands led to strongly increased extinction risks of all species during the following 150 years. For one species – the sun-exposure specialist – there were strong effects already after 50 years. The negative effects of intensive plantation forestry could be compensated for by taking greater biodiversity conservation measures in other managed forests or by setting aside more forests. This is consistent with the Triad model, which is according to our analyses an effective way to decrease extinction risks, especially for the short-dispersing species and the species associated with closed forest. A zoning of forest land into intensive forestry, conventional forestry, and set asides may be better at combining increased timber production and maintenance of biodiversity in comparison to landscapes where all production forests are managed in the same way

Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype

Bathing suit ichthyosis (BSI) is a striking and unique clinical form of autosomal recessive congenital ichthyosis characterized by pronounced scaling on the bathing suit areas but sparing of the extremities and the central face. Here we report on a series of ten BSI patients. Our genetic, ultrastructural and biochemical investigations show that BSI is caused by transglutaminase-1 (TGase-1) deficiency. Altogether we identified 13 mutations in TGM1 - among them seven novel missense mutations and one novel nonsense mutation. Structural modelling for the Tyr276Asn mutation reveals that the residue is buried in the hydrophobic interior of the enzyme and that the hydroxyl side chain of Tyr276 is exposed to solvent in a cavity of the enzyme. Cryosections of healthy skin areas demonstrated an almost normal TGase activity, in contrast to the affected BSI skin, which only showed a cytoplasmic and clearly reduced TGase-1 activity. The distribution of TGase-1 substrates in the epidermis of affected skin corresponded to the situation in TGase-1 deficiency. Interestingly, the expression of TGase-3 and cathepsin D was reduced. Digital thermography validated a striking correlation between warmer body areas and presence of scaling in patients suggesting a decisive influence of the skin temperature. In situ TGase testing in skin of BSI patients demonstrated a marked decrease of enzyme activity when the temperature was increased from 25 degrees C to 37 degrees C. We conclude that BSI is caused by TGase-1 deficiency and suggest that it is a temperature sensitive phenotype