Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance

Staged carotid and coronary surgery for concomitant carotid and coronary artery disease

OBJECTIVE: To demonstrate that staged, consecutive, carotid endarterectomy (CEA) and coronary artery bypass grafting (CABG) are safe, perhaps preferable, alternative for the treatment of patients with severe carotid and coronary artery disease. METHODS: During an 8-year period ending December 1999, 77 (2.1%) of 3633 consecutive patients who were referred for isolated coronary surgery were found to have significant carotid disease and underwent CEA, and subsequently, CABG. The mean age was 65.2 +/- 5.9 years and 66 (85.7%) were males. The majority (84.4%) had triple vessel and 19.4% had left main disease. Carotid disease was unilateral in 71 patients (92.2%) and bilateral in six (7.8%), and 57 (74.0%) were neurologically asymptomatic. Only obstructions >70% were considered for endarterectomy. RESULTS: Eighty-three isolated CEAs were performed with direct clamping of the artery (mean 20.1 +/- 5.9 min) in all but one. There were no deaths. There were two strokes (2.4%) and three (3.6%) myocardial infarctions (MI). The mean admission time was 6.0 +/- 3.5 days. The staging interval was 32.4 days. During coronary surgery, a mean of 2.9 coronary grafts/patient was performed and all but one patient received at least one IMA graft. One patient (1.3%) died. There were two cases (2.6%) of MI and three patients (3.9%) had a stroke. Hence, the overall rates of perioperative mortality, MI and stroke were 1.3, 6.3 and 6.3%, respectively. The mean admission time was 8.3 +/- 6.0 days. CONCLUSIONS: Staging of carotid and coronary operations resulted in low global perioperative mortality and morbidity rates in these high-risk patients and is a good alternative therapeutic option

Bootstrap confidence intervals for industrial recurrent event data

Industrial recurrent event data where an event of interest can be observed more than once in a single sample unit are presented in several areas, such as engineering, manufacturing and industrial reliability. Such type of data provide information about the number of events, time to their occurrence and also their costs. Nelson (1995) presents a methodology to obtain asymptotic confidence intervals for the cost and the number of cumulative recurrent events. Although this is a standard procedure, it can not perform well in some situations, in particular when the sample size available is small. In this context, computer-intensive methods such as bootstrap can be used to construct confidence intervals. In this paper, we propose a technique based on the bootstrap method to have interval estimates for the cost and the number of cumulative events. One of the advantages of the proposed methodology is the possibility for its application in several areas and its easy computational implementation. In addition, it can be a better alternative than asymptotic-based methods to calculate confidence intervals, according to some Monte Carlo simulations. An example from the engineering area illustrates the methodology

Advantages of Monodisperse and Chemically Robust “SpheriCal” Polyester Dendrimers as a “Universal” MS Calibrant

The utilization of dendrimer calibrants as an alternative to peptides and proteins for high mass calibration is explored. These synthetic macromolecules exhibited a number of attractive advantages, including exceptional shelf-lives, broad compatibility with a wide range of matrices and solvents, and evenly spaced calibration masses across the mass range examined, 700-30,000 u. The exceptional purity of these dendrimers and the technical simplicity of this calibration platform validate their broad relevance for high molecular weight mass spectrometry.</p