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  • 1
    Language: English
    In: Molecular cancer, 2015-01-27, Vol.14 (1), p.13-13
    Description: Voltage-gated Na(+) channels (VGSCs) are heteromeric protein complexes containing pore-forming α subunits and smaller, non-pore-forming β subunits. VGSCs are classically expressed in electrically excitable cells, e.g. neurons. VGSCs are also expressed in tumour cells, including breast cancer (BCa) cells, where they enhance cellular migration and invasion. However, despite extensive work defining in detail the molecular mechanisms underlying the expression of VGSCs and their pro-invasive role in cancer cells, there has been a notable lack of clinically relevant in vivo data exploring their value as potential therapeutic targets. We have previously reported that the VGSC-blocking antiepileptic drug phenytoin inhibits the migration and invasion of metastatic MDA-MB-231 cells in vitro. The purpose of the present study was to establish whether VGSCs might be viable therapeutic targets by testing the effect of phenytoin on tumour growth and metastasis in vivo. We found that expression of Nav1.5, previously detected in MDA-MB-231 cells in vitro, was retained on cells in orthotopic xenografts. Treatment with phenytoin, at a dose equivalent to that used to treat epilepsy (60 mg/kg; daily), significantly reduced tumour growth, without affecting animal weight. Phenytoin also reduced cancer cell proliferation in vivo and invasion into surrounding mammary tissue. Finally, phenytoin significantly reduced metastasis to the liver, lungs and spleen. This is the first study showing that phenytoin reduces breast tumour growth and metastasis in vivo. We propose that pharmacologically targeting VGSCs, by repurposing antiepileptic or antiarrhythmic drugs, should be further studied as a potentially novel anti-cancer therapy.
    Subject(s): Animals ; Anticonvulsants - administration & dosage ; Anticonvulsants - pharmacology ; Antiepileptic ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Disease Models, Animal ; Female ; Growth ; Humans ; Liver ; Metastasis ; Mice ; Neoplasm Metastasis ; Neovascularization, Pathologic - drug therapy ; Neovascularization, Pathologic - metabolism ; Phenytoin ; Phenytoin - administration & dosage ; Phenytoin - pharmacology ; Short Communication ; Sodium Channel Blockers - administration & dosage ; Sodium Channel Blockers - pharmacology ; Sodium Channels - metabolism ; Tumor Burden - drug effects ; Voltage-gated Na+ channel ; Xenograft Model Antitumor Assays
    ISSN: 1476-4598
    E-ISSN: 1476-4598
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: Analytical chemistry (Washington), 2017-02-07, Vol.89 (3), p.1955-1964
    Description: In this study, a data-dependent, high-resolution tandem mass spectrometry (ddHRMS/MS) method capable of detecting all organophosphorus nerve agent (OPNA) adducts to human butyrylcholinesterase (BChE) was developed. After an exposure event, immunoprecipitation from blood with a BChE-specific antibody and digestion with pepsin produces a nine amino acid peptide containing the OPNA adduct. Signature product ions of this peptic BChE nonapeptide (FGES*AGAAS) offer a route to broadly screen for OPNA exposure. Taking this approach on an HRMS instrument identifies biomarkers, including unknowns, with high mass accuracy. Using a set of pooled human sera exposed to OPNAs as quality control (QC) materials, the developed method successfully identified precursor ions with 〈1 ppm and tied them to signature product ions with 〈5 ppm deviation from their chemical formulas. This high mass accuracy data from precursor and product ions, collected over 23 independent immunoprecipitation preparations, established method operating limits. QC data and experiments with 14 synthetic reference peptides indicated that reliable qualitative identification of biomarkers was possible for analytes 〉15 ng/mL. The developed method was applied to a convenience set of 96 unexposed serum samples and a blinded set of 80 samples treated with OPNAs. OPNA biomarkers were not observed in convenience set samples and no false positive or negative identifications were observed in blinded samples. All biomarkers in the blinded serum set 〉15 ng/mL were correctly identified. For the first time, this study reports a ddHRMS/MS method capable of complementing existing quantitative methodologies and suitable for identifying exposure to unknown organophosphorus agents.
    Subject(s): Accuracy ; Acetylcholinesterase ; Adducts ; Analytical chemistry ; Antibody Capture ; Biomarkers ; Biomarkers - blood ; Butyrylcholinesterase ; Butyrylcholinesterase - blood ; Butyrylcholinesterase - chemistry ; Butyrylcholinesterase - drug effects ; Cholinesterase ; Chromatography, High Pressure Liquid - methods ; Chromatography, High Pressure Liquid - standards ; Exposure ; False Negative Reactions ; False Positive Reactions ; High Resolution Mass Spectrometry ; Humans ; Immunoprecipitation ; Ions ; Mass spectrometry ; Nerve Agents ; Nerve Agents - standards ; Nerve Agents - toxicity ; Oligopeptides - blood ; Oligopeptides - chemistry ; Organophosphorus Compounds - standards ; Organophosphorus Compounds - toxicity ; Peptides ; Precursors ; Quality Control ; Reference Standards ; Signatures ; Tandem Mass Spectrometry - methods ; Tandem Mass Spectrometry - standards
    ISSN: 0003-2700
    E-ISSN: 1520-6882
    Source: Hellenic Academic Libraries Link
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  • 3
    Language: English
    In: Analytical and bioanalytical chemistry, 2021-01-28, Vol.413 (6), p.1765-1776
    Description: Chlorine is a toxic industrial chemical with a history of use as a chemical weapon. Chlorine is also produced, stored, and transported in bulk making it a high-priority pulmonary threat in the USA. Due to the high reactivity of chlorine, few biomarkers exist to identify exposure in clinical and environmental samples. Our laboratory evaluates acute chlorine exposure in clinical samples by measuring 3-chlorotyrosine (Cl-Tyr) and 3,5-dichlorotyrosine (Cl 2 -Tyr) using liquid chromatography tandem mass spectrometry (LC-MS/MS). Individuals can have elevated biomarker levels due to their environment and chronic health conditions, but levels are significantly lower in individuals exposed to chlorine. Historically these biomarkers have been evaluated in serum, plasma, blood, and bronchoalveolar lavage (BAL) fluid. We report the expansion into hair and lung tissue samples using our newly developed tissue homogenization protocol which fits seamlessly with our current chlorinated tyrosine quantitative assay. Furthermore, we have updated the chlorinated tyrosine assay to improve throughput and ruggedness and reduce sample volume requirements. The improved assay was used to measure chlorinated tyrosine levels in 198 mice exposed to either chlorine gas or air. From this animal study, we compared Cl-Tyr and Cl 2 -Tyr levels among three matrices (i.e., lung, hair, and blood) and found that hair had the most abundant chlorine exposure biomarkers. Furthermore, we captured the first timeline of each analyte in the lung, hair, and blood samples. In mice exposed to chlorine gas, both Cl-Tyr and Cl 2 -Tyr were present in blood and lung samples up to 24 h and up to 30 days in hair samples.
    Subject(s): 3,5-Dichlorotyrosine ; 3-Chlorotyrosine ; Alveoli ; Analytical Chemistry ; Animal tissues ; Assaying ; Biochemistry ; Biomarkers ; Blood ; Bronchus ; Characterization and Evaluation of Materials ; Chemical properties ; Chemical weapons ; Chemistry ; Chemistry and Materials Science ; Chlorination ; Chlorine ; Chlorine compounds ; Chlorine gas ; Evaluation ; Exposure ; Food Science ; general ; Hair ; Hair and lung tissue ; Health aspects ; In vivo mouse study ; Inhalation ; Laboratory Medicine ; LC-MS ; Liquid chromatography ; Lungs ; Mass spectrometry ; Mass spectroscopy ; Measurement ; Methods ; Monitoring/Environmental Analysis ; Research Paper ; Respiration ; Ruggedness ; Technology application ; Tyrosine
    ISSN: 1618-2642
    E-ISSN: 1618-2650
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: Analytical chemistry (Washington), 2013-11-19, Vol.85 (22), p.11106-11111
    Description: Hydrolysis of G- and V-series organophosphorus nerve agents (OPNAs) containing a phosphorus–methyl bond yields a methylphosphonic acid (MeP) product when adducted to human butyrylcholinesterase (BChE). The MeP adduct is considered a sign of “aging” and results in loss of the o-alkyl identifier specific to each nerve agent. After aging has occurred, common therapeutics such as oximes cannot reactivate the cholinesterase enzyme and relieve cholinergic inhibition. Until now, a direct, quantitative method for determination of the MeP adduct to BChE was unavailable. Aged adducts in serum samples were processed by immunomagnetic separation of BChE by antibody conjugated bead, isotope-dilution, pepsin digestion, followed by UHPLC separation and detection by conventional electrospray ionization–tandem mass spectrometry (ESI-MS/MS). Ions were detected in selected reaction monitoring (SRM) mode, and transition m/z 874.3 → 778.3 was used for quantitation. The analytical response ratio was linearly proportional to the serum concentration of MeP-adducted peptide (MeP-P) over the nominal concentration range of 2.0–250 ng/mL, with a coefficient of determination of R 2 ≥ 0.997. Intrarun accuracy, expressed as %Relative Error (%RE), was ≤13.5%, 16.3%, and 3.20% at 2.0, 16, and 250 ng/mL, respectively; the corresponding precision expressed as %RSD was ≤11.9%, 6.15%, and 3.39%. Interday %RSD was ≤7.13%, 5.69%, and 1.91%. Recovery of MeP-P from serum was ≥68% across the validated concentration range, and contributions from matrix effects were minimal. The method provides a direct, quantitative measurement of MeP-P found in clinical samples suspected of nerve agent exposure and subjected to such post-sampling stresses as elevated temperature and extended shipping.
    Subject(s): Adducts ; aging ; Analysis ; Beads ; Biochemistry ; Bonding agents ; butyrylcholinesterase ; Butyrylcholinesterase - metabolism ; Chemical Warfare Agents - analysis ; cholinesterase inhibitors ; Cholinesterases ; Chromatography, High Pressure Liquid - methods ; Enzymes ; Human ; Humans ; Hydrolysis ; Immunoglobulins ; Immunomagnetic Separation - methods ; Ionization ; Ions ; Mass spectrometry ; Methods ; methyl phosphonate ; methyl phosphonic acid ; Nerves ; Organic chemicals ; Organophosphonates - metabolism ; Organophosphorus Compounds - metabolism ; organophosphorus nerve agent ; Peptide Fragments - analysis ; Separation ; Serum - chemistry ; Serum - enzymology ; Serums ; Spectrometry, Mass, Electrospray Ionization - methods ; Tandem Mass Spectrometry - methods
    ISSN: 0003-2700
    E-ISSN: 1520-6882
    Source: Hellenic Academic Libraries Link
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  • 5
    Language: English
    In: Analytical and bioanalytical chemistry, 2014-03-07, Vol.406 (21), p.5187-5194
    Description: Organophosphorus nerve agent (OPNA) adducts to butyrylcholinesterase (BChE) can be used to confirm exposure in humans. A highly accurate method to detect G- and V-series OPNA adducts to BChE in 75 μL of filtered blood, serum, or plasma has been developed using immunomagnetic separation (IMS) coupled with liquid chromatography tandem mass spectrometry (LC-MS/MS). The reported IMS method captures 〉 88 % of the BChE in a specimen and corrects for matrix effects on peptide calibrators. The optimized method has been used to quantify baseline BChE levels (unadducted and OPNA-adducted) in a matched-set of serum, plasma, and whole blood (later processed in-house for plasma content) from 192 unexposed individuals to determine the interchangeability of the tested matrices. The results of these measurements demonstrate the ability to accurately measure BChE regardless of the format of the blood specimen received. Criteria for accepting or denying specimens were established through a series of sample stability and processing experiments. The results of these efforts are an optimized and rugged method that is transferrable to other laboratories and an increased understanding of the BChE biomarker in matrix.
    Subject(s): Adducts ; Analysis ; Analysis of Chemicals Relevant to the Chemical Weapons Convention ; Analytical Chemistry ; Antibodies, Monoclonal - chemistry ; Biochemistry ; Biological Assay ; Biomarkers ; Blood ; butyrylcholinesterase ; Butyrylcholinesterase - chemistry ; Calibration ; Characterization and Evaluation of Materials ; Chemical Warfare Agents - analysis ; Chemical Warfare Agents - chemistry ; Chemistry ; Chemistry and Materials Science ; cholinesterase inhibitors ; Cholinesterases ; Chromatography, Liquid ; Exposure ; Food Science ; general ; Health aspects ; Human ; Humans ; Immunomagnetic Separation ; In Vitro Techniques ; Laboratory Medicine ; Measurement ; Monitoring/Environmental Analysis ; Nerve gas ; Nerves ; Organophosphorus nerve agent ; Organothiophosphorus Compounds - blood ; Organothiophosphorus Compounds - chemistry ; protein adduct ; Research Paper ; Sarin - blood ; Sarin - chemistry ; Serums ; Tandem Mass Spectrometry ; Usage
    ISSN: 1618-2642
    E-ISSN: 1618-2650
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 6
    Language: English
    In: Journal of proteome research, 2016-10-07, Vol.15 (10), p.3550-3562
    Description: Diagnostic classification accuracy is critical in expression proteomics to ensure that as many true differences as possible are identified with acceptable false-positive rates. We present a comparison of the diagnostic accuracy of iTRAQ with three label-free methods, peak area, spectral counting, and emPAI, for relative quantification using a spiked proteome standard. We provide the first validation of emPAI for intersample relative quantification and find clear differences among the four quantification approaches that could be considered when designing an experiment. Spectral counting was observed to perform surprisingly well in all regards. Peak area performed best for smaller fold differences and was shown to be capable of discerning a 1.1-fold difference with acceptable specificity and sensitivity. The performance of iTRAQ was dramatically worse than the label-free methods with low abundance proteins. Using the iTRAQ data set for validation, we also demonstrate a novel iTRAQ analysis regime that avoids the use of ratios in significance testing and outperforms a common commercial alternative.
    Subject(s): Classification - methods ; Diagnostic Techniques and Procedures ; Humans ; Mass Spectrometry ; Proteomics - methods ; Proteomics - standards ; Reference Standards ; ROC Curve ; Staining and Labeling
    ISSN: 1535-3893
    E-ISSN: 1535-3907
    Source: Hellenic Academic Libraries Link
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  • 7
    Language: English
    In: Analytical chemistry (Washington), 2015-06-02, Vol.87 (11), p.5723-5729
    Description: Dried matrix spots are safer to handle and easier to store than wet blood products, but factors such as intraspot variability and unknown sample volumes have limited their appeal as a sampling format for quantitative analyses. In this work, we introduce a dried spot activity assay for quantifying butyrylcholinesterase (BChE) specific activity which is BChE activity normalized to the total protein content in a sample spot. The method was demonstrated with blood, serum, and plasma spotted on specimen collection devices (cards) which were extracted to measure total protein and BChE activity using a modified Ellman assay. Activity recovered from dried spots was ∼80% of the initial spotted activity for blood and 〉90% for plasma and serum. Measuring total protein in the sample and calculating specific activity substantially improved quantification and reduced intraspot variability. Analyte stability of nerve agent adducts was also evaluated, and the results obtained via BChE-specific activity measurements were confirmed by quantification of BChE adducts using a previously established LC-MS/MS method. The spotted samples were up to 10 times more resistant to degradation compared to unspotted control samples when measuring BChE inhibition by the nerve agents sarin and VX. Using this method, both BChE activity and adducts can be accurately measured from a dried sample spot. This use of a dried sample spot with normalization to total protein is robust, demonstrates decreased intraspot variability without the need to control for initial sample volume, and enhances analyte stability.
    Subject(s): Adducts ; Analytical chemistry ; Assaying ; Blood ; Butyrylcholinesterase - analysis ; Butyrylcholinesterase - metabolism ; Butyrylcholinesterase activity ; Chemical Warfare Agents - analysis ; Dried Blood Spot Testing - methods ; Dried blood spots ; Enzyme inhibition ; Enzyme kinetics ; Humans ; Mass spectrometry ; Nerve Agents - analysis ; Nerves ; Organophosphorus nerve agents ; Protein adducts ; Proteins ; Specimen Handling ; Spots ; Stability
    ISSN: 0003-2700
    E-ISSN: 1520-6882
    Source: Hellenic Academic Libraries Link
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  • 8
    Language: English
    In: Journal of proteome research, 2014-03-07, Vol.13 (3), p.1167-1176
    Description: We have developed a simple method for the release and isolation of glycoprotein N-glycans from whole-cell lysates using less than a million cells, for subsequent implementation with mass spectrometric analysis. Cellular protein extracts prepared using SDS solubilization were sequentially treated in a membrane filter device to ultimately release glycans enzymatically using PNGase F in the volatile buffer ammonium bicarbonate. The released glycans are recovered in the filtrate following centrifugation and typically permethylated prior to mass spectrometric analysis. We call our method “filter-aided N-glycan separation” and have successfully applied it to investigate N-glycan profiles of wild-type and mutant Chinese hamster ovary cells. This method is readily multiplexed and, because of the small numbers of cells needed, is compatible with the analysis of replicate samples to assess the true nature of glycan variability in tissue culture samples.
    Subject(s): Animals ; Carbohydrate Sequence ; Cell Extracts - chemistry ; Chemical Fractionation - methods ; CHO Cells ; Cricetulus ; cultured mammalian cells ; filter-aided sample preparation ; Filtration ; Glycoproteins - chemistry ; MALDI-MS ; Molecular Sequence Data ; N-glycans ; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase - chemistry ; permethylation ; Polysaccharides - chemistry ; Polysaccharides - isolation & purification ; SDS solubilization ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
    ISSN: 1535-3893
    E-ISSN: 1535-3907
    Source: Hellenic Academic Libraries Link
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  • 9
    Language: English
    In: Journal of agricultural and food chemistry, 2016-07-13, Vol.64 (27), p.5607-5613
    Description: Methylenecyclopropylglycine (MCPG) and hypoglycin A (HGA) are naturally occurring amino acids found in some soapberry fruits. Fatalities have been reported worldwide as a result of HGA ingestion, and exposure to MCPG has been implicated recently in the Asian outbreaks of hypoglycemic encephalopathy. In response to an outbreak linked to soapberry ingestion, the authors developed the first method to simultaneously quantify MCPG and HGA in soapberry fruits from 1 to 10 000 ppm of both toxins in dried fruit aril. Further, this is the first report of HGA in litchi, longan, and mamoncillo arils. This method is presented to specifically address the laboratory needs of public-health investigators in the hypoglycemic encephalitis outbreaks linked to soapberry fruit ingestion.
    Subject(s): Acer ; Aceraceae ; ackee ; Aesculus ; Chromatography, High Pressure Liquid - methods ; Cyclopropanes - analysis ; Cyclopropanes - toxicity ; cyclopropylamino acids ; Fruit - chemistry ; Fruit - toxicity ; Glycine - analogs & derivatives ; Glycine - analysis ; Glycine - toxicity ; hypoglycin A ; Hypoglycins - analysis ; Hypoglycins - toxicity ; Litchi ; lychee ; methylenecyclopropylalanine ; methylenecyclopropylglycine ; rambutan ; Sapindaceae ; Sapindaceae - chemistry ; Sapindaceae - toxicity ; soapberry ; Tandem Mass Spectrometry - methods
    ISSN: 0021-8561
    E-ISSN: 1520-5118
    Source: Hellenic Academic Libraries Link
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  • 10
    Language: English
    In: Chemical research in toxicology, 2015-09-21, Vol.28 (9), p.1753-1759
    Description: Ingestion of soapberry fruit toxins hypoglycin A and methylenecyclopropylglycine has been linked to public health challenges worldwide. In 1976, over 100 years after Jamaican vomiting sickness (JVS) was first reported, the cause of JVS was linked to the ingestion of the toxin hypoglycin A produced by ackee fruit. A structural analogue of hypoglycin A, methylenecyclopropylglycine (MCPG), was implicated as the cause of an acute encephalitis syndrome (AES). Much of the evidence linking hypoglycin A and MCPG to these diseases has been largely circumstantial due to the lack of an analytical method for specific metabolites. This study presents an analytical approach to identify and quantify specific urine metabolites for exposure to hypoglycin A and MCPG. The metabolites are excreted in urine as glycine adducts methylenecyclopropylacetyl-glycine (MCPA-Gly) and methylenecyclopropylformyl-glycine (MCPF-Gly). These metabolites were processed by isotope dilution, separated by reverse-phase liquid chromatography, and monitored by electrospray ionization tandem mass spectrometry. The analytical response ratio was linearly proportional to the concentration of MCPF-Gly and MCPA-Gly in urine from 0.10 to 20 μg/mL with a correlation coefficient of r 〉 0.99. The assay demonstrated accuracy ≥80% and precision ≤20% RSD across the calibration range. This method has been applied to assess exposure to hypoglycin A and MCPG as part of a larger public health initiative and was used to provide the first reported identification of MCPF-Gly and MCPA-Gly in human urine.
    Subject(s): Acer species ; Aceraceae ; ackee ; Aesculus ; Animals ; Cyclopropanes - toxicity ; cyclopropylamino acids ; Environmental Exposure ; Glycine - analogs & derivatives ; Glycine - toxicity ; Humans ; hypoglycin A ; Hypoglycins - toxicity ; Litchi ; lychee ; methylenecyclopropylalanine ; methylenecyclopropylglycine ; Rats ; Sapindaceae ; Sapindus - chemistry ; soapberry
    ISSN: 0893-228X
    E-ISSN: 1520-5010
    Source: Hellenic Academic Libraries Link
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