Towards exploratory hypothesis testing and analysis

10.1109/ICDE.2011.5767907Proceedings - International Conference on Data Engineering745-75

Multiplexed genotyping of ABC transporter polymorphisms with the Bioplex suspension array

We have developed and validated a consolidated bead-based genotyping platform, the Bioplex suspension array for simultaneous detection of multiple single nucleotide polymorphisms (SNPs) of the ATP-binding cassette transporters. Genetic polymorphisms have been known to influence therapeutic response and risk of disease pathologies. Genetic screening for therapeutic and diagnostic applications thus holds great promise in clinical management. The allele-specific primer extension (ASPE) reaction was used to assay 22 multiplexed SNPs for eight subjects. Comparison of the microsphere-based ASPE assay results to sequencing results showed complete concordance in genotype assignments. The Bioplex suspension array thus proves to be a reliable, cost-effective and high-throughput technological platform for genotyping. It can be easily adapted to customized SNP panels for specific applications involving large-scale mutation screening of clinically relevant markers

The Role of Transport Mechanisms in Mycobacterium Tuberculosis Drug Resistance and Tolerance

In the fight against tuberculosis, cell wall permeation of chemotherapeutic agents remains a critical but largely unsolved question. Here we review the major mechanisms of small molecule penetration into and efflux from Mycobacterium tuberculosis and other mycobacteria, and outline how these mechanisms may contribute to the development of phenotypic drug tolerance and induction of drug resistance. M. tuberculosis is intrinsically recalcitrant to small molecule permeation thanks to its thick lipid-rich cell wall. Passive diffusion appears to account for only a fraction of total drug permeation. As in other bacterial species, influx of hydrophilic compounds is facilitated by water-filled open channels, or porins, spanning the cell wall. However, the diversity and density of M. tuberculosis porins appears lower than in enterobacteria. Besides, physiological adaptations brought about by unfavorable conditions are thought to reduce the efficacy of porins. While intracellular accumulation of selected drug classes supports the existence of hypothesized active drug influx transporters, efflux pumps contribute to the drug resistant phenotype through their natural abundance and diversity, as well as their highly inducible expression. Modulation of efflux transporter expression has been observed in phagocytosed, non-replicating persistent and multi-drug resistant bacilli. Altogether, M. tuberculosis has evolved both intrinsic properties and acquired mechanisms to increase its level of tolerance towards xenobiotic substances, by preventing or minimizing their entry. Understanding these adaptation mechanisms is critical to counteract the natural mechanisms of defense against toxic compounds and develop new classes of chemotherapeutic agents that positively exploit the influx and efflux pathways of mycobacteria

Simultaneous determination of raltegravir and raltegravir glucuronide in human plasma by liquid chromatography-tandem mass spectrometric method

10.1002/jms.1874Journal of Mass Spectrometry462202-208JMSP

Graphical representation of allelic ratio (A) Subject 34 and (B) Subject 12

<p><b>Copyright information:</b></p><p>Taken from "Multiplexed genotyping of ABC transporter polymorphisms with the Bioplex suspension array"</p><p></p><p>Biological Procedures Online 2007;9():27-42.</p><p>Published online Jan 2007</p><p>PMCID:PMC2211573.</p><p>Article © by the author(s). This paper is Open Access and is published in Biological Procedures Online under license from the author(s). Copying, printing, redistribution and storage permitted. Journal © 1997-2007 Biological Procedures Online.</p

Abstract A1: Impact of CYP2D6*10 and CYP3A5*3 Polymorphisms on the Pharmacokinetics of Tamoxifen in Asian Breast Cancer Patients

Tamoxifen (TAM) is a selective estrogen receptor modulator employed in the treatment of breast cancer. It is a prodrug with a complex metabolic pathway involving several phase I and II metabolic enzymes. TAM is metabolized by cytochrome P450 (CYP) enzymes to N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen (4OHT) and endoxifen (END) with 4OHT and END being the active metabolites of TAM. CYP2D6 and CYP3A4/5 comprises the major CYP isoforms mediating the metabolism of TAM although other CYP isoforms also play a role. Polymorphisms present in genes encoding these CYP enzymes may influence the metabolism and pharmacokinetics of TAM and its metabolites

SAHA and cisplatin sensitize gastric cancer cells to doxorubicin by induction of DNA damage, apoptosis and perturbation of AMPK-mTOR signalling

Chemotherapy remains the most prescribed anti-cancer therapy, despite patients suffering severe side effects and frequently developing chemoresistance. These complications can be partially overcome by combining different chemotherapeutic agents that target multiple biological pathways. However, selecting efficacious drug combinations remains challenging. We previously used fission yeast Schizosaccharomycespombe as a surrogate model to predict drug combinations, and showed that suberoylanilide hydroxamic acid (SAHA) and cisplatin can sensitise gastric adenocarcinoma cells toward the cytotoxic effects of doxorubicin. Yet, how this combination undermines cell viability is unknown. Here, we show that SAHA and doxorubicin markedly enhance the cleavage of two apoptosis markers, caspase 3 and poly-ADP ribose polymerase (PARP-1), and increase the phosphorylation of γH2AX, a marker of DNA damage. Further, we found a prominent reduction in Ser485 phosphorylation of AMP-dependent protein kinase (AMPK), and reductions in its target mTOR and downstream ribosomal protein S6 phosphorylation. We show that SAHA contributes most of the effect, as confirmed using another histone deacetylase inhibitor, trichostatin A. Overall, our results show that the combination of SAHA and doxorubicin can induce apoptosis in gastric adenocarcinoma in a synthetically lethal manner, and that fission yeast offers an efficient tool for identifying potent drug combinations against human cancer cells