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103. Mass Spectrometry in High-Throughput Clinical Biomarker Assays: Multiple Reaction Monitoring

Author

Parker, Carol E., Domanski, Dominik, Percy, Andrew J., Chambers, Andrew G., Camenzind, Alexander G., Smith, Derek S., Borchers, Christoph H., Houk, Kendall N., Series editor, Hunter, Christopher A., Series editor, Krische, Michael J, Series editor, Lehn, Jean-Marie, Series editor, Ley, Steven V., Series editor, Olivucci, Massimo, Series editor, Thiem, Joachim, Series editor, Venturi, Margherita, Series editor, Wong, Chi-Huey, Series editor, Wong, Henry N.C., Series editor, L.S. Tang, Nelson, editor, and Poon, Terence, editor

Published
2014
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105. ePoster Vascular Discovery 2020 MDG.pdf

Author

De Giorgi, Marco, Jarrett, Kelsey, Burton, Jason, Doerfler, Alexandria, Hurley, Ayrea, Li, Ang, Hsu, Rachel, Furgurson, Mia N., Han, Jun, Borchers, Christoph H., and R. Lagor, William

Subjects
Cell metabolism
Abstract

Hmg-CoA Reductase (Hmgcr) catalyzes the conversion of Hmg-CoA to mevalonate, which is the rate-limiting step in the cholesterol biosynthetic pathway. Hmgcr is the target of statins, which are the front line therapy for hypercholesterolemia. In addition to cholesterol, Hmgcr activity is also required for the synthesis of non-sterol isoprenoids, such as heme A, dolichol, ubiquinone, farnesylated and geranylgeranylated proteins. The goal of this project is to investigate the effects of Hmgcr inhibition on non-sterol isoprenoids in the liver, in order to better understand the physiological regulation and function of the mevalonate pathway. We have generated new genetic models to acutely delete genes in the mevalonate pathway in the liver using viral delivery of Cre-recombinase (AAV-Cre) or CRISPR/Cas9 (AAV-CRISPR). The genetic deletion of Hmgcr by AAV-Cre resulted in extensive hepatocyte apoptosis and liver regeneration. We observed compensatory upregulation of genes in the mevalonate pathway, likely a response to sterol depletion. At the biochemical level, we observed decreased levels of sterol intermediates and cholesterol. In parallel, we also detected decreased production of the non-sterol isoprenoids, dolichol and ubiquinone. At the cellular level, Hmgcr null hepatocytes showed ER stress-induced apoptosis and impaired N-linked glycosylation. Given the important role for N-linked glycosylation in protein folding in the ER, we hypothesized that depletion of dolichol, a scaffold for synthesis of N-linked glycans, could be responsible for the hepatocyte ER stress. To test this, we used AAV-CRISPR to somatically disrupt Dehydrodolichyl diphosphate synthase subunit (Dhdds), a branch point enzyme required for the synthesis of dolichol. Dhdds null livers showed ER stress and impaired N-linked glycosylation, along with apoptosis and regeneration, partially mimicking the phenotype observed in Hmgcr null livers. Finally, the combined deletion of Hmgcr and Dhdds resulted in exacerbation of ER stress and liver damage. Taken together, our data show a critical role for mevalonate-derived dolichol in the liver, and suggest that dolichol depletion is at least partially responsible for ER stress and apoptosis upon potent Hmgcr inhibition.

Published
2023
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106. ATVB presentation 5-10-2019.pptx

Author

De Giorgi, Marco, Jarrett, Kelsey, Burton, Jason, Doerfler, Alexandria, Hurley, Ayrea, Li, Ang, Hsu, Rachel, Furgurson, Mia N., Han, Jun, Borchers, Christoph H., and R. Lagor, William

Subjects
Cell metabolism
Abstract

Hmg-CoA Reductase (Hmgcr) catalyzes the conversion of Hmg-CoA to mevalonate, which is the rate-limiting step in the cholesterol biosynthetic pathway. Hmgcr is the target of statins, which are the front line therapy for hypercholesterolemia. In addition to cholesterol, Hmgcr activity is also required for the synthesis of non-sterol isoprenoids, such as heme A, dolichol, ubiquinone, farnesylated and geranylgeranylated proteins. The goal of this project is to investigate the effects of Hmgcr inhibition on non-sterol isoprenoids in the liver, in order to better understand the physiological regulation and function of the mevalonate pathway. We have generated new genetic models to acutely delete genes in the mevalonate pathway in the liver using viral delivery of Cre-recombinase (AAV-Cre) or CRISPR/Cas9 (AAV-CRISPR). The genetic deletion of Hmgcr by AAV-Cre resulted in extensive hepatocyte apoptosis and liver regeneration. We observed compensatory upregulation of genes in the mevalonate pathway, likely a response to sterol depletion. At the biochemical level, we observed decreased levels of sterol intermediates and cholesterol. In parallel, we also detected decreased production of the non-sterol isoprenoids, dolichol and ubiquinone. At the cellular level, Hmgcr null hepatocytes showed expanded and swollen ER and upregulation of Chop, suggestive of ER stress. Given the important role for N-linked glycosylation in protein folding in the ER, we hypothesized that depletion of dolichol, a scaffold for synthesis of N-linked glycans, could be responsible for the hepatocyte ER stress. To test this, we used AAV-CRISPR to somatically disrupt Dehydrodolichyl diphosphate synthase subunit (Dhdds), a branch point enzyme required for the synthesis of dolichol. Dhdds null livers showed severe hepatocyte apoptosis and regeneration, along with significant induction of Chop, partially mimicking the phenotype observed in Hmgcr null livers. Taken together, our data show a critical role for mevalonate-derived dolichol in the liver, and suggest that dolichol depletion is at least partially responsible for ER-stress induced apoptosis upon potent Hmgcr inhibition.

Published
2023
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107. Standard Operating Procedures and Protocols for the Preparation and Analysis of Plasma Samples Using the iTRAQ Methodology

Author

Ohlund, Leanne B., Hardie, Darryl B., Elliott, Monica H., Camenzind, Alexander G., Smith, Derek S., Reid, Jennifer D., Cohen Freue, Gabriela V., Bergman, Axel P., Sasaki, Mayu, Robertson, Lisa, Balshaw, Robert F., Ng, Raymond T., Mui, Alice, McManus, Bruce M., Keown, Paul A., McMaster, W. Robert, Parker, Carol E., Borchers, Christoph H., Ivanov, Alexander R., editor, and Lazarev, Alexander V., editor

Published
2011
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108. Discovery-Based Proteomics Identify Skeletal Muscle Mitochondrial Alterations as an Early Metabolic Defect in a Mouse Model of β-Thalassemia

Author

Reboucas, Patricia, primary, Fillebeen, Carine, additional, Botta, Amy, additional, Cleverdon, Riley, additional, Steele, Alexandra P., additional, Richard, Vincent, additional, Zahedi, René P., additional, Borchers, Christoph H., additional, Burelle, Yan, additional, Hawke, Thomas J., additional, Pantopoulos, Kostas, additional, and Sweeney, Gary, additional

Published
2023
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109. The E3 Ubiquitin Ligase Nedd4L Acts as a Checkpoint Against Activation in Quiescent Muscle Stem Cells

Author

Blackburn, Darren M., primary, Sahinyan, Korin, additional, Hernandez-Corchado, Aldo, additional, Lazure, Felicia, additional, Richard, Vincent, additional, Raco, Laura, additional, Perron, Gabrielle, additional, Zahedi, René P., additional, Borchers, Christoph H., additional, Lepper, Christoph, additional, Kawabe, Hiroshi, additional, Jahani-Asl, Arezu, additional, Najafabadi, Hamed S., additional, and Soleimani, Vahab D., additional

Published
2023
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110. Inhibition of the MNK1/2–eIF4E Axis Augments Palbociclib-Mediated Antitumor Activity in Melanoma and Breast Cancer

Author

Prabhu, Sathyen A., primary, Moussa, Omar, additional, Gonçalves, Christophe, additional, LaPierre, Judith H., additional, Chou, Hsiang, additional, Huang, Fan, additional, Richard, Vincent R., additional, Ferruzo, Pault Y. M., additional, Guettler, Elizabeth M., additional, Soria-Bretones, Isabel, additional, Kirby, Laura, additional, Gagnon, Natascha, additional, Su, Jie, additional, Silvester, Jennifer, additional, Krisna, Sai Sakktee, additional, Rose, April A. N., additional, Sheppard, Karen E., additional, Cescon, David W., additional, Mallette, Frédérick A., additional, Zahedi, Rene P., additional, Borchers, Christoph H., additional, del Rincon, Sonia V., additional, and Miller, Wilson H., additional

Published
2022
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125. Exploring phlebotomy technique as a pre-analytical factor in proteomic analyses by mass spectrometry

Author

Penn, Andrew M., Lu, Linghong, Chambers, Andrew G., Balshaw, Robert F., Morrison, Jaclyn L., Votova, Kristine, Wood, Eileen, Smith, Derek S., Lesperance, Maria, del Zoppo, Gregory J., and Borchers, Christoph H.

Subjects
Technology application, Research, Blood tests -- Analysis -- Methods -- Technology application, Phlebotomy -- Research, Mass spectrometry -- Research -- Technology application, Blood -- Medical examination, Veins -- Puncture
Abstract

Introduction Blood is a desirable sample for biomarker development because its collection is routine in most general, acute, and urgent care health settings. Multiple reaction monitoring mass spectrometry (MRM-MS) combined [...], Multiple reaction monitoring mass spectrometry (MRM-MS) is an emerging technology for blood biomarker verification and validation; however, the results may be influenced by pre-analytical factors. This exploratory study was designed to determine if differences in phlebotomy techniques would significantly affect the abundance of plasma proteins in an upcoming biomarker development study. Blood was drawn from 10 healthy participants using four techniques: (1) a 20-gauge IV with vacutainer, (2) a 21-gauge direct vacutainer, (3) an 18-gauge butterfly with vacutainer, and (4) an 18-gauge butterfly with syringe draw. The abundances of a panel of 122 proteins (117 proteins, plus 5 matrix metalloproteinase (MMP) proteins) were targeted by LC/MRM-MS. In addition, complete blood count (CBC) data were also compared across the four techniques. Phlebotomy technique significantly affected 2 of the 11 CBC parameters (red blood cell count, p = 0.010; hemoglobin concentration, p = 0.035) and only 12 of the targeted 117 proteins (p < 0.05). Of the five MMP proteins, only MMP7 was detectable and its concentration was not significantly affected by different techniques. Overall, most proteins in this exploratory study were not significantly influenced by phlebotomy technique; however, a larger study with additional patients will be required for confirmation. Key words: mass spectrometry, biomarkers, proteomics, plasma, multiple reaction monitoring. La spectrometrie de masse en mode MRM (<>; MRM-MS) est une technologie emergente pour la mesure et la validation de biomarqueurs sanguins, cependant ses resultats peuvent etre affectes par plusieurs facteurs pre-analytiques. Cette etude exploratoire a ete concue pour determiner si des differences dans les techniques de phlebotomie avaient un effet significatif sur l'abondance des proteines plasmatiques en vue d'un travail futur visant le developpement d'un biomarqueur. Du sang a ete preleve chez 10 participants en sante au moyen de quatre techniques : (1) IV 20 gauges sous vide (<>), (2) 21 gauges sous vide direct, (3) aiguille papillon 18 gauges sous vide, et (4) aiguille papillon a 18 gauges avec seringue. L'abondance de 122 proteines (117 proteines et 5 metalloproteinases matricielles (MMP)) a ete mesuree par LC/MRM-MS. En plus, les donnees issues de l'analyse de la formule sanguine complete (CBC) ont ete comparees pour les quatre techniques de prelevement. La technique de phlebotomie a affecte significativement deux des 11 parametres de la formule sanguine (nombre de globules rouges, p = 0,010; concentration de l'hemoglobine, p = 0,035) et seulement 12 des 117 proteines ciblees (p < 0,05). Des cinq MMR, seule MMP7 s'est averee detectable mais sa concentration n'etait pas affectee par la technique de prelevement sanguin. Globalement, la plupart des proteines examinees dans cette etude preliminaire n'etaient pas affectees par la technique de phlebotomie; cependant, une etude de plus grande ampleur comportant plus de patients sera necessaire pour en confirmer les resultats. [Traduit par la Redaction] Mots-cles: spectrometrie de masse, biomarqueurs, proteomique, plasma sanguin, <> (MRM).

Published
2015
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135. Immuno-multiple reaction monitoring (iMRM) for quantitation of PD-L1 and PD-1-signaling proteins in non-small cell lung carcinoma (NSCLC).

Author

Lacasse, Vincent, primary, Richard, Vincent, additional, Wang, Hangjun, additional, Mitsa, Georgia, additional, Poetz, Olivier, additional, Papadakis, Andreas I, additional, Elchebly, Mounib, additional, Cohen, Victor, additional, Agulnik, Jason S., additional, Batist, Gerald, additional, Zahedi, Rene P., additional, Borchers, Christoph H., additional, and Spatz, Alan, additional

Published
2022
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137. The Human Proteome Project: Current State and Future Direction

Author

Legrain, Pierre, Aebersold, Ruedi, Archakov, Alexander, Bairoch, Amos, Bala, Kumar, Beretta, Laura, Bergeron, John, Borchers, Christoph H., Corthals, Garry L., Costello, Catherine E., Deutsch, Eric W., Domon, Bruno, Hancock, William, He, Fuchu, Hochstrasser, Denis, Marko-Varga, György, Salekdeh, Ghasem Hosseini, Sechi, Salvatore, Snyder, Michael, Srivastava, Sudhir, Uhlén, Mathias, Wu, Cathy H., Yamamoto, Tadashi, Paik, Young-Ki, and Omenn, Gilbert S.

Published
2011
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141. Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation

Author

Zhang, Anni M.Y., primary, Xia, Yi Han, additional, Lin, Jeffrey S.H., additional, Chu, Ken H., additional, Wang, Wei Chuan K., additional, Ruiter, Titine J.J., additional, Yang, Jenny C.C., additional, Chen, Nan, additional, Chhuor, Justin, additional, Patil, Shilpa, additional, Cen, Haoning Howard, additional, Rideout, Elizabeth J., additional, Richard, Vincent R., additional, Schaeffer, David F., additional, Zahedi, Rene P., additional, Borchers, Christoph H., additional, Johnson, James D., additional, and Kopp, Janel L., additional

Published
2022
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142. A Non-Hazardous Deparaffinization Protocol Enables Quantitative Proteomics of Core Needle Biopsy-Sized Formalin-Fixed and Paraffin-Embedded (FFPE) Tissue Specimens

Author

Mitsa, Georgia, primary, Guo, Qianyu, additional, Goncalves, Christophe, additional, Preston, Samuel E. J., additional, Lacasse, Vincent, additional, Aguilar-Mahecha, Adriana, additional, Benlimame, Naciba, additional, Basik, Mark, additional, Spatz, Alan, additional, Batist, Gerald, additional, Miller, Wilson H., additional, del Rincon, Sonia V., additional, Zahedi, René P., additional, and Borchers, Christoph H., additional

Published
2022
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148. Evaluation of a 'plug and play' nanoflow liquid chromatography system for MS-based proteomic characterization of clinical FFPE specimens.

Author

Mitsa, Georgia, Richard, Vincent R., Majedi, Yasamin, Lafleur, Josiane, Aguilar-Mahecha, Adriana, Basik, Mark, and Borchers, Christoph H.

Abstract

Proteomic analysis of formalin-fixed paraffin-embedded (FFPE) tumor tissue specimens has gained interest in the last 5 years due to technological advances and improved sample collection, as well as biobanking for clinical trials. The real-world implementation of clinical proteomics to these specimens, however, is hampered by tedious sample preparation steps and long instrument acquisition times. To advance the translation of quantitative proteomics into the clinic, we are comparing the performance of the leading commercial nanoflow liquid chromatography (nLC) system (based on literature reviews), the Easy-nLC 1200 (Thermo Fisher Scientific, Waltham, MA, U.S.A.), to the Evosep One HPLC (Evosep Biosystems, Odense, Denmark). We measured FFPE-tissue digests from 21 biological replicates with a similar gradient on both of the LC systems while keeping the on-column amount (1 µg total protein) and the single-shot data-dependent acquisition-based MS/MS method constant. Overall, the Evosep One facilitates robust and sensitive high-throughput sample acquisition, making it suitable for clinical MS. We found the Evosep One to be a useful platform for positioning mass spectrometry-based proteomics in the clinical setting. The clinical application of nLC/MS will inform clinical decision-making in oncology and other diseases. [ABSTRACT FROM AUTHOR]

Published
2023
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