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

Nutritional Supplements for Age-Related Macular Degeneration

The Age-Related Eye Disease Study (AREDS) and The Age-Related Eye Disease Study 2, are the only large-scale, long-term, randomized controlled trials to demonstrate a role of nutritional supplements in reducing risk of progression to advanced forms of age-related macular degeneration (AMD). This review summarizes the study design, main results, and implications of these trials in the clinical care of nonexudative AMD patients. In addition, it discusses other recent prospective studies focusing on efficacy of nutritional supplementation for prevention or slowing progression of AMD as well as briefly discusses possible effect of genotypes on response to AREDS supplementation

Gene Delivery of a Mutant TGFβ3 Reduces Markers of Scar Tissue Formation After Cutaneous Wounding

The transforming growth factor-β (TGFβ) family plays a critical regulatory role in repair and coordination of remodeling after cutaneous wounding. TGFβ1-mediated chemotaxis promotes the recruitment of fibroblasts to the wound site and their resultant myofibroblastic transdifferentiation that is responsible for elastic fiber deposition and wound closure. TGFβ3 has been implicated in an antagonistic role regulating overt wound closure and promoting ordered dermal remodeling. We generated a mutant form of TGFβ3 (mutTGFβ3) by ablating its binding site for the latency-associated TGFβ binding protein (LTBP-1) in order to improve bioavailability and activity. The mutated cytokine is secreted as the stable latency-associated peptide (LAP)-associated form and is activated by normal intracellular and extracellular mechanisms including integrin-mediated activation but is not sequestered. We show localized intradermal transduction using a lentiviral vector expressing the mutTGFβ3 in a mouse skin wounding model reduced re-epithelialization density and fibroblast/myofibroblast transdifferentiation within the wound area, both indicative of reduced scar tissue formation