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

Análise do tratamento da tuberculose pulmonar em idosos de um hospital universitário do Rio de Janeiro, RJ, Brasil Analysis of the treatment of pulmonary tuberculosis in elderly patients at a university hospital in Rio de Janeiro, Brazil

OBJETIVOS: Descrever os aspectos clínicos e terapêuticos da tuberculose pulmonar e comparar os efeitos adversos e resultados do tratamento entre idosos e não idosos. MÉTODOS: Foi realizado um estudo caso-controle com 117 indivíduos idosos (acima de 60 anos) e 464 não idosos (15-49 anos) portadores de tuberculose pulmonar atendidos no Instituto de Doenças do Tórax da Universidade Federal do Rio de Janeiro no período de 1980 a 1996. RESULTADOS: No grupo de idosos, houve associação entre diabetes mellitus (OR = 3,98; IC95% = 2,07-7,65; p = 0,001), doenças pulmonares (OR = 7,24; IC95% = 3,64-14,46; p = 0,001) e cardiovasculares (OR = 5,86; IC95% = 2.88-11.95; p = 0,001). O tabagismo (OR = 2,07; IC95% = 1,26-3,42; p = 0,002) e o etilismo (OR = 1,63; IC95% = 1,01-2,68; p = 0,041) também foram mais freqüentes neste grupo. O tratamento levou a freqüentes reações adversas nos idosos (OR = 1,62; IC95% = 1,04-2,54; p = 0,024), principalmente de origem gastrintestinal (OR = 1,64; IC95% = 1,01-2,77; p = 0,047), e sua eficácia foi menor neste grupo: apenas 51% de cura e 24% de óbitos. O abandono do tratamento foi elevado nos dois grupos, em torno de 23%. CONCLUSÕES: As reações adversas e o resultado do tratamento foram piores nos idosos, com maior freqüência de complicações e letalidade, devido a uma maior toxicidade farmacológica e a uma maior prevalência de doenças associadas neste grupo etário.<br>OBJECTIVE: To describe the clinical and therapeutic aspects of pulmonary tuberculosis and compare the adverse effects of the treatment and its outcome in elderly and nonelderly patients. METHODS: This was a case-control study of 117 elderly individuals (over the age of 60 years) and 464 nonelderly individuals (aged 15-49 years). All subjects presented pulmonary tuberculosis that had been diagnosed and treated at the Thoracic Diseases Institute of the Federal University of Rio de Janeiro between 1980 and 1996. RESULTS: In the elderly group, pulmonary tuberculosis was found to be correlated with diabetes (OR = 3.98; 95% CI = 2.07-7.65; p = 0.001), lung disease (OR = 7.24; 95% CI = 3.64-14.46; p = 0.001) and heart disease (OR = 5.86; 95% CI = 2.88-11.95; p = 0.001). Smoking (OR = 2.07; 95% CI = 1.26-3.42; p = 0.002) and alcohol abuse (OR = 1.63; 95% CI = 1.01-2.68; p = 0.041) were also more common in the elderly group. In the elderly group, the treatment more frequently resulted in adverse reactions (OR = 1.62; 95% CI = 1.04-2.54; p = 0.024), especially gastrointestinal reactions (OR = 1.64; 95% CI = 1.01-2.77; p = 0.047), and treatment efficacy was lower: cure rate, 51%; mortality rate, 24%. Treatment adherence was low (approximately 77%) in both groups. CONCLUSIONS: In the elderly group, adverse reactions were more common, treatment outcomes were less favorable, there was a greater frequency of clinical complications and deaths related to drug toxicity, and the prevalence of concomitant diseases was higher