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1.  Genome-wide discovery of genetic variants affecting tamoxifen sensitivity and their clinical and functional validation 
Annals of Oncology  2013;24(7):1867-1873.
Background
Beyond estrogen receptor (ER), there are no validated predictors for tamoxifen (TAM) efficacy and toxicity. We utilized a genome-wide cell-based model to comprehensively evaluate genetic variants for their contribution to cellular sensitivity to TAM.
Design
Our discovery model incorporates multidimensional datasets, including genome-wide genotype, gene expression, and endoxifen-induced cellular growth inhibition in the International HapMap lymphoblastoid cell lines (LCLs). Genome-wide findings were further evaluated in NCI60 cancer cell lines. Gene knock-down experiments were performed in four breast cancer cell lines. Genetic variants identified in the cell-based model were examined in 245 Caucasian breast cancer patients who underwent TAM treatment.
Results
We identified seven novel single-nucleotide polymorphisms (SNPs) associated with endoxifen sensitivity through the expression of 10 genes using the genome-wide integrative analysis. All 10 genes identified in LCLs were associated with TAM sensitivity in NCI60 cancer cell lines, including USP7. USP7 knock-down resulted in increasing resistance to TAM in four breast cancer cell lines tested, which is consistent with the finding in LCLs and in the NCI60 cells. Furthermore, we identified SNPs that were associated with TAM-induced toxicities in breast cancer patients, after adjusting for other clinical factors.
Conclusion
Our work demonstrates the utility of a cell-based model in genome-wide identification of pharmacogenomic markers.
doi:10.1093/annonc/mdt125
PMCID: PMC3690911  PMID: 23508821
gene expression; genome-wide association study; HapMap; SNP; tamoxifen
2.  Competition among memes in a world with limited attention 
Scientific Reports  2012;2:335.
The wide adoption of social media has increased the competition among ideas for our finite attention. We employ a parsimonious agent-based model to study whether such a competition may affect the popularity of different memes, the diversity of information we are exposed to, and the fading of our collective interests for specific topics. Agents share messages on a social network but can only pay attention to a portion of the information they receive. In the emerging dynamics of information diffusion, a few memes go viral while most do not. The predictions of our model are consistent with empirical data from Twitter, a popular microblogging platform. Surprisingly, we can explain the massive heterogeneity in the popularity and persistence of memes as deriving from a combination of the competition for our limited attention and the structure of the social network, without the need to assume different intrinsic values among ideas.
doi:10.1038/srep00335
PMCID: PMC3315179  PMID: 22461971
3.  Loss of Bacterial Diversity during Antibiotic Treatment of Intubated Patients Colonized with Pseudomonas aeruginosa▿  
Journal of Clinical Microbiology  2007;45(6):1954-1962.
Management of airway infections caused by Pseudomonas aeruginosa is a serious clinical challenge, but little is known about the microbial ecology of airway infections in intubated patients. We analyzed bacterial diversity in endotracheal aspirates obtained from intubated patients colonized by P. aeruginosa by using 16S rRNA clone libraries and microarrays (PhyloChip) to determine changes in bacterial community compositions during antibiotic treatment. Bacterial 16S rRNA genes were absent from aspirates obtained from patients briefly intubated for elective surgery but were detected by PCR in samples from all patients intubated for longer periods. Sequencing of 16S rRNA clone libraries demonstrated the presence of many orally, nasally, and gastrointestinally associated bacteria, including known pathogens, in the lungs of patients colonized with P. aeruginosa. PhyloChip analysis detected the same organisms and many additional bacterial groups present at low abundance that were not detected in clone libraries. For each patient, both culture-independent methods showed that bacterial diversity decreased following the administration of antibiotics, and communities became dominated by a pulmonary pathogen. P. aeruginosa became the dominant species in six of seven patients studied, despite treatment of five of these six with antibiotics to which it was sensitive in vitro. Our data demonstrate that the loss of bacterial diversity under antibiotic selection is highly associated with the development of pneumonia in ventilated patients colonized with P. aeruginosa. Interestingly, PhyloChip analysis demonstrated reciprocal changes in abundance between P. aeruginosa and the class Bacilli, suggesting that these groups may compete for a similar ecological niche and suggesting possible mechanisms through which the loss of microbial diversity may directly contribute to pathogen selection and persistence.
doi:10.1128/JCM.02187-06
PMCID: PMC1933106  PMID: 17409203
4.  P195-T Reproducible Label-Free Quantitative Analysis of Low-Abundance Plasma Proteins using 3D Protein/Peptide Analysis Coupled with Protein Expression Analysis Software 
Quantitative LC-MS/MS analyses of human plasma are predominantly challenged by the wide dynamic range of proteins and extensive biological sample variation, which make systematic detection and quantitation of low-abundant proteins for biomarker discovery quite difficult. In a proof-of-concept study, plasma samples were processed by alternative multi-dimensional workflows that first utilized immunodepletion of twenty abundant plasma proteins (ProteoPrep 20, Sigma). Multiple recombinant proteins were spiked into depleted plasma samples at varying levels to determine detection limits of subsequent SDS-PAGE + LC-MS/MS vs. LC-MS/MS only. After SDS-PAGE, entire lanes were cut into uniform slices, and each slice was digested with trypsin. Digests were subsequently analyzed by nanocapillary reverse-phase chromatography directly coupled to an ESI-LTQ-FT mass spectrometer (Thermo) operating in data-dependent mode. In addition, aliquots of each sample were either digested in solution or as single in-gel digests after brief electrophoresis in an SDS gel, to evaluate advantages and complications of multi-fraction vs. single-fraction LC-MS/MS analysis of a proteome. Resultant LC-MS/MS data were analyzed in a blinded fashion using the Elucidator protein expression data-analysis system. Using the PeakTeller algorithm and statistical analysis tools, we were able to effectively organize the data to distinguish controls from spiked samples and estimate the relative abundances of spiked-in proteins in different samples. Detection limits, protein coverage, and reproducibility of the alternative workflows were compared. This study demonstrates that reproducible relative quantitation can be achieved in complex mixtures such as plasma, using a combination of abundant protein depletion followed by different workflow approaches and data analysis using the Elucidator system.
PMCID: PMC2292043
5.  Interaction of hepatitis B surface antigen (Australia antigen) with membrane vesicles of Pseudomonas aeruginosa. 
Infection and Immunity  1975;12(1):180-186.
A lysogenic strain of Pseudomonas aeruginosa was cultured from the dialysis fluid of a patient on chronic hemodialysis treatment whose blood contained hepatitis B surface antigen (HB8Ag). When this bacterium was incubated for 4 to 7 days with serum containing HB8Ag or with purified HB8Ag, a loss of the HB8Ag-specific immunological reactivity was observed. Bacteriophages can be induced from the isolated P. aeruginosa with mitomycin C; the phages, after purification on CsCl gradients, also lyse P. aeruginosa strain 25102 (ATCC). Subsequent to gradient centrifugation of the lysate, a fraction was found with a density around 1.40 g/ml that inactivated HB8Ag after a 4-h incubation at 37 C as determined by counterelectrophoresis and hemagglutination inhibition. The activity was not found in appreciable amounts in other gradient fractions. The electron microscope shows that the active fraction contains envelope vesicles of 45 to 60 nm in diameter. In spite of their loss in HB8Ag activity, the HB8Ag particles (22nm) appeared morphologically intact. These findings suggest that an enzyme(s) is present in the vesicle fraction which inactivates antigenic determinants on HB8Ag particles. Thus, the presence of these bacteria in environments such as feces, dialysis tanks, and contaminated drinking water may prevent the detection of HB8Ag.
Images
PMCID: PMC415264  PMID: 49303

Results 1-5 (5)