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1.  Preclinical Evaluation of the Novel Monoclonal Antibody H6-11 for Prostate Cancer Imaging 
Molecular pharmaceutics  2013;10(10):3655-3664.
The biological properties of the novel monoclonal antibody (mAb) H6-11 and its potential utility for oncological imaging studies were evaluated using in vitro and in vivo assays. Immunoreactivity of H6-11 to the human prostate cancer PC-3 cell line and solid tumor xenografts was initially demonstrated using immunofluorescence staining; the specificity of H6-11 for prostate cancer was further evaluated using a commercial array of human prostate cancer and normal tissue samples (n = 49) in which H6-11 detected 95% of prostate adenocarcinomas. The Kd value of 61.7 ± 30 nM was determined using 125I-labeled H6-11. Glycosylation analysis suggested the antigenic epitope of the glycan is an O-linked β-N-acetylglucoside (O-GlcNAc) group. Imaging studies of PC-3 tumor-bearing mice were performed using both optical imaging with NIR fluorescent dye-labeled H6-11 and microPET imaging with 89Zr-labeled H6-11. These in vivo studies revealed that the labeled probes accumulated in PC-3 tumors 48–72 h postinjection, although significant retention in liver was also observed. By 120 h postinjection, the tumors were still evident, although the liver showed significant clearance. These studies suggest that the mAb H6-11 may be a useful tool to detect prostate cancer in vitro and in vivo.
PMCID: PMC4031660  PMID: 23964702
prostate cancer; mAb; O-GlcNAc; positron emission tomography (PET); PC-3; glycosylation; tumor-associated carbohydrate antigens (TACA)
2.  Oxidatively Modified Proteins as Plasma Biomarkers in Breast Cancer 
Cancer biomarkers : section A of Disease markers  2013;13(3):10.3233/CBM-130349.
Post-translational protein modifications (PTMs) are increased in breast tumors.
We explored whether PTMs on proteins secreted by the breast could be detected in plasma and potentially used for the early detection of breast cancer.
We used a custom ELISA microarray platform to measure 4-hydroxynonenal (HNE), glutathione (GSH), nitrotyrosine and halotyrosine adducts in 27 secreted proteins, for a total of 108 candidate biomarkers. Two independent sets human plasma samples were measured, for a total of 160 samples. The results were analyzed for consistent cancer-associated changes across the two sample sets. Plasma samples for both cases and benign controls were collected at the time of tissue diagnosis after referral from a positive screen (such as mammography). The results from both studies were evaluated using ANOVA and t-tests or receiver operator curves (ROC).
Levels of GSH-modified ceruloplasmin and HNE-modified PDGF were significantly altered in plasma samples from cancer patients relative to benign controls. Healthy controls, which were only included in the first set of samples, were similar to the benign controls for both of these markers. A combination of three glutathionylated proteins had the best area under the ROC curve, with a value of 76%.
Specific PTMs in individual proteins may be useful for distinguishing between women with breast cancer and those with benign breast disease. These oxidative changes in plasma proteins may reflect redox changes in breast cancer. Additional studies on oxidative modifications in individual proteins are warranted.
PMCID: PMC3856946  PMID: 23912491
breast cancer; biomarkers; reactive oxygen species; protein adducts; hydroxynonenal; glutathione; plasma
3.  Synthesis and in vitro biological evaluation of pyrazole group-containing analogues for PDE10A† 
MedChemComm  2012;4(2):443-449.
Twenty eight new analogues were synthesized by optimizing the structure of MP-10 and their in vitro binding affinities towards PDE10A, PDE3A/B, and PDE4A/B were determined. Among these new analogues, 10a, 10b, 10d, 11a, 11b and 11d are very potent towards PDE10A and have IC50 values of 0.40 ± 0.02, 0.28 ± 0.06, 1.82 ± 0.25, 0.24 ± 0.05, 0.36 ± 0.03 and 1.78 ± 0.03 nM respectively; these six compounds displayed high selectivity for PDE10A versus PDE3A/3B/4A/4B. The promising compounds will be further validated in vivo to identify PDE10A imaging tracers.
PMCID: PMC3625062  PMID: 23585921
4.  Structure Determination and Functional Analysis of a Chromate Reductase from Gluconacetobacter hansenii 
PLoS ONE  2012;7(8):e42432.
Environmental protection through biological mechanisms that aid in the reductive immobilization of toxic metals (e.g., chromate and uranyl) has been identified to involve specific NADH-dependent flavoproteins that promote cell viability. To understand the enzyme mechanisms responsible for metal reduction, the enzyme kinetics of a putative chromate reductase from Gluconacetobacter hansenii (Gh-ChrR) was measured and the crystal structure of the protein determined at 2.25 Å resolution. Gh-ChrR catalyzes the NADH-dependent reduction of chromate, ferricyanide, and uranyl anions under aerobic conditions. Kinetic measurements indicate that NADH acts as a substrate inhibitor; catalysis requires chromate binding prior to NADH association. The crystal structure of Gh-ChrR shows the protein is a homotetramer with one bound flavin mononucleotide (FMN) per subunit. A bound anion is visualized proximal to the FMN at the interface between adjacent subunits within a cationic pocket, which is positioned at an optimal distance for hydride transfer. Site-directed substitutions of residues proposed to involve in both NADH and metal anion binding (N85A or R101A) result in 90–95% reductions in enzyme efficiencies for NADH-dependent chromate reduction. In comparison site-directed substitution of a residue (S118A) participating in the coordination of FMN in the active site results in only modest (50%) reductions in catalytic efficiencies, consistent with the presence of a multitude of side chains that position the FMN in the active site. The proposed proximity relationships between metal anion binding site and enzyme cofactors is discussed in terms of rational design principles for the use of enzymes in chromate and uranyl bioremediation.
PMCID: PMC3412864  PMID: 22879982
5.  Delivery of MicroRNA-10b with Polylysine Nanoparticles for Inhibition of Breast Cancer Cell Wound Healing 
Recent studies revealed that micro RNA-10b (mir-10b) is highly expressed in metastatic breast cancer cells and positively regulates breast cancer cell migration and invasion through inhibition of HOXD10 target synthesis. In this study we designed anti-mir-10b molecules and combined them with poly L-lysine (PLL) to test the delivery effectiveness. An RNA molecule sequence exactly matching the mature mir-10b minor antisense showed strong inhibition when mixed with PLL in a wound-healing assay with human breast cell line MDA-MB-231. The resulting PLL-RNA nanoparticles delivered the anti-microRNA molecules into cytoplasm of breast cancer cells in a concentration-dependent manner that displayed sustainable effectiveness.
PMCID: PMC3256732  PMID: 22259248
microRNA-10b; breast cancer metastasis; nanoparticles
6.  Smoking, COPD, and 3-Nitrotyrosine Levels of Plasma Proteins 
Environmental Health Perspectives  2011;119(9):1314-1320.
Background: Nitric oxide is a physiological regulator of endothelial function and hemodynamics. Oxidized products of nitric oxide can form nitrotyrosine, which is a marker of nitrative stress. Cigarette smoking decreases exhaled nitric oxide, and the underlying mechanism may be important in the cardiovascular toxicity of smoking. Even so, it is unclear if this effect results from decreased nitric oxide production or increased oxidative degradation of nitric oxide to reactive nitrating species. These two processes would be expected to have opposite effects on nitrotyrosine levels, a marker of nitrative stress.
Objective: In this study, we evaluated associations of cigarette smoking and chronic obstructive pulmonary disease (COPD) with nitrotyrosine modifications of specific plasma proteins to gain insight into the processes regulating nitrotyrosine formation.
Methods: A custom antibody microarray platform was developed to analyze the levels of 3-nitrotyrosine modifications on 24 proteins in plasma. In a cross-sectional study, plasma samples from 458 individuals were analyzed.
Results: Average nitrotyrosine levels in plasma proteins were consistently lower in smokers and former smokers than in never smokers but increased in smokers with COPD compared with smokers who had normal lung-function tests.
Conclusions: Smoking is associated with a broad decrease in 3-nitrotyrosine levels of plasma proteins, consistent with an inhibitory effect of cigarette smoke on endothelial nitric oxide production. In contrast, we observed higher nitrotyrosine levels in smokers with COPD than in smokers without COPD. This finding is consistent with increased nitration associated with inflammatory processes. This study provides insight into a mechanism through which smoking could induce endothelial dysfunction and increase the risk of cardiovascular disease.
PMCID: PMC3230408  PMID: 21652289
cigarette smoke; COPD; ELISA; eNOS; nitrotyrosine; posttranslational modification
7.  Protein Modifications as Potential Biomarkers in Breast Cancer 
Biomarker Insights  2009;4:191-200.
A variety of post-translational protein modifications (PTMs) are known to be altered as a result of cancer development. Thus, these PTMs are potentially useful biomarkers for breast cancer. Mass spectrometry, antibody microarrays and immunohistochemistry techniques have shown promise for identifying changes in PTMs. In this review, we summarize the current literature on PTMs identified in the plasma and tumor tissue of breast-cancer patients or in breast cell lines. We also discuss some of the analytical techniques currently being used to evaluate PTMs.
PMCID: PMC2805424  PMID: 20072669
PTMs; post-translational modifications; breast cancer; biomarkers

Results 1-7 (7)