Fred Hutchinson Cancer Research Center

Abstract: Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

Abstract: A simple and efficient procedure was employed for the electrophoretic transfer of proteins from sodium dodecyl sulfate-polyacrylamide gels to sheets of pure, unmodified nitrocellulose. Immobilized proteins could then be radiographically visualized in situ by reaction with specific antibody and the subsequent binding of radioiodinated Staphylococcus protein A to the immune complexes. The detection of murine leukemia virus antigens in complex cellular lysates was used to demonstrate the efficacy of this technique.

Abstract: Summary Background In 2010, overweight and obesity were estimated to cause 3·4 million deaths, 3·9% of years of life lost, and 3·8% of disability-adjusted life-years (DALYs) worldwide. The rise in obesity has led to widespread calls for regular monitoring of changes in overweight and obesity prevalence in all populations. Comparable, up-to-date information about levels and trends is essential to quantify population health effects and to prompt decision makers to prioritise action. We estimate the global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013. Methods We systematically identified surveys, reports, and published studies (n=1769) that included data for height and weight, both through physical measurements and self-reports. We used mixed effects linear regression to correct for bias in self-reports. We obtained data for prevalence of obesity and overweight by age, sex, country, and year (n=19 244) with a spatiotemporal Gaussian process regression model to estimate prevalence with 95% uncertainty intervals (UIs). Findings Worldwide, the proportion of adults with a body-mass index (BMI) of 25 kg/m 2 or greater increased between 1980 and 2013 from 28·8% (95% UI 28·4–29·3) to 36·9% (36·3–37·4) in men, and from 29·8% (29·3–30·2) to 38·0% (37·5–38·5) in women. Prevalence has increased substantially in children and adolescents in developed countries; 23·8% (22·9–24·7) of boys and 22·6% (21·7–23·6) of girls were overweight or obese in 2013. The prevalence of overweight and obesity has also increased in children and adolescents in developing countries, from 8·1% (7·7–8·6) to 12·9% (12·3–13·5) in 2013 for boys and from 8·4% (8·1–8·8) to 13·4% (13·0–13·9) in girls. In adults, estimated prevalence of obesity exceeded 50% in men in Tonga and in women in Kuwait, Kiribati, Federated States of Micronesia, Libya, Qatar, Tonga, and Samoa. Since 2006, the increase in adult obesity in developed countries has slowed down. Interpretation Because of the established health risks and substantial increases in prevalence, obesity has become a major global health challenge. Not only is obesity increasing, but no national success stories have been reported in the past 33 years. Urgent global action and leadership is needed to help countries to more effectively intervene. Funding Bill & Melinda Gates Foundation.

Abstract: Improved approaches for the detection of common epithelial malignancies are urgently needed to reduce the worldwide morbidity and mortality caused by cancer. MicroRNAs (miRNAs) are small (≈22 nt) regulatory RNAs that are frequently dysregulated in cancer and have shown promise as tissue-based markers for cancer classification and prognostication. We show here that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity. miRNAs originating from human prostate cancer xenografts enter the circulation, are readily measured in plasma, and can robustly distinguish xenografted mice from controls. This concept extends to cancer in humans, where serum levels of miR-141 (a miRNA expressed in prostate cancer) can distinguish patients with prostate cancer from healthy controls. Our results establish the measurement of tumor-derived miRNAs in serum or plasma as an important approach for the blood-based detection of human cancer.

Abstract: Methods for alignment of protein sequences typically measure similarity by using a substitution matrix with scores for all possible exchanges of one amino acid with another. The most widely used matrices are based on the Dayhoff model of evolutionary rates. Using a different approach, we have derived substitution matrices from about 2000 blocks of aligned sequence segments characterizing more than 500 groups of related proteins. This led to marked improvements in alignments and in searches using queries from each of the groups.