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Malvern, PA, United States

O'Shannessy D.J.,Morphotek Inc. | Somers E.B.,Morphotek Inc. | Palmer L.M.,Morphotek Inc. | Thiel R.P.,Thiel Statistical Consultants | And 3 more authors.
Journal of Ovarian Research

Background: Evaluate and compare the utility of serum folate receptor alpha (FRA) and megakaryocyte potentiating factor (MPF) determinations relative to serum CA125, mesothelin (MSLN) and HE4 for the diagnosis of epithelial ovarian cancer (EOC). Methods. Electrochemiluminescent assays were developed for FRA, MSLN and MPF and used to assess the levels of these biomarkers in 258 serum samples from ovarian cancer patients. Commercial assays for CA125 and HE4 were run on a subset of 176 of these samples representing the serous histology. Data was analyzed by histotype, stage and grade of disease. A comparison of the levels of the FRA, MSLN and MPF biomarkers in serum, plasma and urine was also performed in a subset of 57 patients. Results: Serum and plasma levels of FRA, MSLN and MPF were shown to be highly correlated between the two matrices. Correlations between all pairs of markers in 318 serum samples were calculated and demonstrated the highest correlation between HE4 and MPF, and the lowest between FRA and MPF. Serum levels of all markers showed a dependence on both stage and grade of disease. A multi-marker logistic regression model was developed resulting in an AUC=0.91 for diagnosis of serous ovarian cancer, a significant improvement over the AUC for any of the individual markers, including CA125 (AUC=0.84). Conclusions: FRA has significant potential as a biomarker for ovarian cancer, both as a stand-alone marker and in combination with other known markers for EOC. The lack of correlation between the various markers analyzed in the present study suggests that a panel of markers can aid in the detection and/or monitoring of this disease. © 2013 O'Shannessy et al.; licensee BioMed Central Ltd. Source

Dalvie D.,Pfizer | Xiang C.,Pfizer | Xiang C.,Celgene | Kang P.,Pfizer | And 3 more authors.

1. Aldehyde oxidase (AO) is a cytosolic enzyme that contributes to the Phase I metabolism of xenobiotics in human and preclinical species. 2. Current studies explored in vitro metabolism of zoniporide in various animal species and humans using S9 fractions. The animal species included commonly used pharmacology and toxicology models and domestic animals such as the cat, cow or bull, pig and horse. 3. In addition, gender and strain differences in some species were also explored. 4. All animals except the dog and cat converted zoniporide to 2-oxozoniporide (M1). 5. Michael-Menten kinetic studies were conducted in species that turned over zoniporide to M1. 6. Marked differences in KM, Vmax and Clint were observed in the oxidation of zoniporide. 7. Although the KM and Vmax of zoniporide oxidation in male and female human S9 was similar, some gender difference was observed in animals especially, in Vmax. 8. The domestic animals also showed marked species differences in the AO activity and affinity toward zoniporide. © 2013 Informa UK, Ltd. Source

Huang M.-Q.,Janssen Pharmaceutical | Lin Z.,Frontage Laboratories Inc. | Weng N.,Janssen Pharmaceutical

High-resolution MS (HRMS) in conjunction with LC (LC-HRMS) has become available to many laboratories in the pharmaceutical industry. Due to its enhanced, though sometime perceived, specificity using the high-resolution power and its capability of simultaneous quantitation and structural elucidation using the post-acquisition data mining feature, utilization of LC-HRMS for bioanalysis could lead to potential rapid and reliable method development as well as sample analysis, thus generating both cost and resource savings. Here, we would like to share our perspectives about several current and future applications of LC-HRMS in bioanalysis. We will also discuss the factors influencing the quality of method establishment and potential pitfalls that need to be considered for the utilization of LC-HRMS in the field of regulated bioanalysis. We believe when utilized appropriately, LC-HRMS will play a significant role in the future landscape of quantitative bioanalysis. © 2013 Future Science Ltd. Source

Wang Z.,University of Tennessee Health Science Center | Wang Z.,Frontage Laboratories Inc. | Chen J.,University of Tennessee Health Science Center | Wang J.,University of Tennessee Health Science Center | And 7 more authors.
Pharmaceutical Research

Purpose: To evaluate abilities of 2-aryl-4-benzoyl-imidazoles (ABI) to overcome multidrug resistance (MDR), define their cellular target, and assess in vivo antimelanoma efficacy. Methods: MDR cell lines that overexpressed P-glycoprotein, MDR-associated proteins, and breast cancer resistance protein were used to evaluate ABI ability to overcome MDR. Cell cycle analysis, molecular modeling, and microtubule imaging were used to define ABI cellular target. SHO mice bearing A375 human melanoma xenograft were used to evaluate ABI in vivo antitumor activity. B16-F10/C57BL mouse melanoma lung metastasis model was used to test ABI efficacy to inhibit tumor lung metastasis. Results: ABIs showed similar potency to MDR cells compared to matching parent cells. ABIs were identified to target tubulin on the colchicine binding site. After 31 days of treatment, ABI-288 dosed at 25 mg/kg inhibited melanoma tumor growth by 69%; dacarbazine at 60 mg/kg inhibited growth by 52%. ABI-274 dosed at 25 mg/kg showed better lung metastasis inhibition than dacarbazine at 60 mg/kg. Conclusions: This new class of antimitotic compounds can overcome several clinically important drug resistant mechanisms in vitro and are effective in inhibiting melanoma lung metastasis in vivo, supporting their further development. © 2012 Springer Science+Business Media, LLC. Source

Xue Y.-J.,Celgene | Gao H.,Vertex Pharmaceuticals | Ji Q.C.,Bristol Myers Squibb | Lam Z.,QPS LLC | And 5 more authors.

Distribution of drugs into tissues is an important determinant of the overall PK and PD profile. Thus, bioanalysis of drugs and their metabolites in tissues can play an important role in understanding the pharmacological and toxicological properties of new drug candidates. Unlike liquid matrices, bioanalysis in tissues offers unique challenges such as proper tissue sampling, appropriate tissue sample preparation, efficient extraction of the analytes from the tissue homogenates, and demonstration of stability and recovery of analytes in intact tissues. This article provides a systematic review of tissue sample analysis for small molecules using LC-MS/MS. The authors provide rationale for tissue sample analysis, and discuss strategies for method development, method qualification or validation, and sample analysis. Unique aspects of method development and qualification/validation are highlighted based on authors' direct experiences and literature summary. Analysis using intact tissue samples such as MALDI imaging is also briefly discussed. © 2012 Future Science Ltd. Source

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