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

Permeability of human placenta and fetal membranes to thyrotropin-stimulating hormone in vitro

We determined the placental transfer of TSH in an in vitro model of dually perfused isolated lobule in 28 human term placentas by adding varying concentrations (5-60 mu IU mL(-1)) of TSH as a single bolus dose to the closed maternal circulation. Transmembrane transfer of TSH was also studied by adding 45 mu IU mL(-1) to the maternal or fetal compartment of a dual chamber of fetal membranes in culture. Passage of freely diffusible markers creatinine and antipyrine were also studied in this model. TSH concentration was measured by third generation chemiluminescence assay with a sensitivity of 10 mIU mL(-1). In the perfusion experiments, at physiologic concentrations the slow decline of TSH in the maternal circulation was associated with a small linear increase in fetal levels to 0.11 +/- 0.04% of initial dose at 2 h. The placental transfer rate was 0.08 mu IU min(-1). Increasing maternal concentrations of TSH were associated with proportional increases in transfer rate (y = 0.002x; R-2 = 0.99) and placental uptake (y = 0.01x; R-2 = 0.97). The placental permeability of TSH was 2.4 . 10(-4) mL min(-1) g(-1) and was proportional to its coefficients of diffusion in water and molecular size. The transmembrane transfer and permeability of TSH was comparable to those of the placenta. We conclude that TSH crosses the human term placenta and fetal membranes sparingly

Sidescan sonar imagery of widespread fossil and active cold seeps along the central Chilean continental margin

The central Chilean subduction zone between 35°S and 37°S was investigated in order to identify, document and possibly understand fluid flow and fluid venting within the forearc region. Several areas were mapped using multibeam bathymetry and backscatter, high-resolution sidescan sonar, chirp subbottom profiling and reflection seismic data. On a subsequent cruise ground-truthing observations were made using a video sled. In general, this dataset shows surprisingly little evidence of fluid venting along the mid-slope region, in contrast to other subduction zones such as Central America and New Zealand. There were abundant indications of active and predominantly fossil fluid venting along the upper slope between 36.5°S and 36.8°S at the seaward margin of an intraslope basin. Here, backscatter anomalies suggest widespread authigenic carbonate deposits, likely the result of methane-rich fluid expulsion. There is unpublished evidence that these fluids are of biogenic origin and generated within the slope sediments, similar to other accretionary margins but in contrast to the erosional margin off Central America, where fluids have geochemical signals indicating an origin from the subducting plate

BAG-1 interacts with the p50–p50 homodimeric NF-?B complex: implications for colorectal carcinogenesis

Understanding the mechanisms that promote aberrant tumour cell survival is critical for the determination of novel strategies to combat colorectal cancer (CRC). We have recently shown that the anti-apoptotic protein BAG-1, highly expressed in pre-malignant and CRC tissue, can potentiate cell survival through regulating NF-?B transcriptional activity. In this study, we identify a novel complex between BAG-1 and the p50–p50 NF-?B homodimers, implicating BAG-1 as a co-regulator of an atypical NF-?B pathway. Importantly, the BAG-1-p50 complex was detected at gene regulatory sequences including the epidermal growth factor receptor (EGFR) and COX-2 (PTGS2) genes. Suppression of BAG-1 expression using small interfering RNA was shown to increase EGFR and suppress COX-2 expression in CRC cells. Furthermore, mouse embryonic fibroblasts derived from the NF-?B1 (p105/p50) knock-out mouse were used to demonstrate that p50 expression was required for BAG-1 to suppress EGFR expression. This was shown to be functionally relevant as attenuation of BAG-1 expression increased ligand activated phosphorylation of EGFR in CRC cells. In summary, this paper identifies a novel role for BAG-1 in modulating gene expression through interaction with the p50–p50 NF-?B complexes. Data presented led us to propose that BAG-1 can act as a selective regulator of p50–p50 NF-?B responsive genes in colorectal tumour cells, potentially important for the promotion of cell survival in the context of the fluctuating tumour microenvironment. As BAG-1 expression is increased in the developing adenoma through to metastatic lesions, understanding the function of the BAG-1-p50 NF-?B complexes may aid in identifying strategies for both the prevention and treatment of CRC.<br/