50 results on '"McComb M"'
Search Results
2. A Proteomic Approach to the Study of Systemic Amyloidoses
- Author
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Perlman, D, primary, Prokaeva, T, additional, Lavatelli, F, additional, Seldin, D, additional, Merlini, G, additional, McComb, M, additional, Skinner, M, additional, Costello, C, additional, Bellotti, V, additional, Spencer, B, additional, Théberge, R, additional, and Connors, L, additional
- Published
- 2007
- Full Text
- View/download PDF
3. Detection and Characterization of Immunoglobulin Light Chain Post-Translational Modifications Using Lc/Ms-Ms/Ms
- Author
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Prokaeva, T, primary, Seldin, D, additional, McComb, M, additional, Jiang, Y, additional, Skinner, M, additional, Costello, C, additional, Théberge, R, additional, and Connors, L, additional
- Published
- 2007
- Full Text
- View/download PDF
4. Clinical Diagnosis of Familial Transthyretin Amyloidosis by Automated Data Acquisition and Processing with Quadrupole Orthogonal Time-of-Flight Mass Spectrometry
- Author
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Prokaeva, T, primary, Costello, C, additional, Théberge, R, additional, Connors, L, additional, Lim, A, additional, McComb, M, additional, and Skinner, M, additional
- Published
- 2004
- Full Text
- View/download PDF
5. Qualitative analysis of complex mixtures of VOCs using the inside needle capillary adsorption trap
- Author
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Shojania, S, McComb, M E, Oleschuk, R D, Perreault, H, Gesser, H D, and Chow, A
- Published
- 1999
6. Scholarly publishing depends on peer reviewers
- Author
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Fernandez-Llimos, F, Berti, AD, Yeung, D, Yusuff, KB, El Zowalaty, ME, Adane, ED, Al-Aqeel, S, Al-Jumaili, AA, Alili-Idrizi, E, Andelkovic, M, Aranha, A, Arief, M, Arkaravichien, W, Armoiry, X, Attarabeen, OF, Ayoub, N, Bajorek, BV, Beninger, P, Billups, SJ, Bowen, JF, Bouwmeester, C, Campbell, P, Chan, V, Connor, SE, Danziger, LH, Dawood, OT, Dunnenberger, M, Elrouby, S, Fakih, S, Abu Farha, RK, Figueiredo, IV, Foroutan, N, Forsythe, LE, Frail, CK, Friesner, D, Funk, K, Gaither, C, Gallimore, CE, Gan, V, Garcia, BH, Gaskins, JL, Gastelurrutia, MA, Gatwood, J, Genord, CK, Gilliam, E, Goodbar, NH, Gossell-Williams, M, Grundy, Q, Guénette, L, Hadi, MA, Hallit, S, Hammond, DA, Hawasli, RS, Herdeiro, MT, Hermansyah, A, Hincapie, AL, Hoehns, JD, Hossain, LN, Hudspeth, B, Ibrahim, MIBM, Islahudin, F, Jacobsen, R, Jones, M, Kälvemark Sporrong, S, Kantelhardt, P, Katangwe, T, Katoue, MG, King, SR, Kinnear, M, Kouladjian O’Donnell, L, Kovacevic, SV, Krass, I, Kraus, SK, Lakic, D, Larson, D, LeMay, K, Loh, BC, Lowres, N, Luetsch, K, Lunghi, C, Lyra, DP, Ma, CS, MacDonald, EA, Mancuso, MA, Mazhar, F, McCarthy, L, McComb, M, McFarland, MS, Mehralian, G, Merks, P, Modun, D, Mohammed, MA, Motulsky, A, Mukattash, TL, Nabhani-Gebara, S, Najafi, S, Ni, W, Nitadpakorn, S, Ogbo, PU, and Palaian, S
- Subjects
Pharmacology & Pharmacy - Abstract
© 2018, Grupo de Investigacion en Atencion Farmaceutica. All rights reserved. The peer-review crisis is posing a risk to the scholarly peer-reviewed journal system. Journals have to ask many potential peer reviewers to obtain a minimum acceptable number of peers accepting reviewing a manuscript. Several solutions have been suggested to overcome this shortage. From reimbursing for the job, to eliminating pre-publication reviews, one cannot predict which is more dangerous for the future of scholarly publishing. And, why not acknowledging their contribution to the final version of the article published? PubMed created two categories of contributors: authors [AU] and collaborators [IR]. Why not a third category for the peer-reviewer?.
- Published
- 2018
7. Scholarly publishing depends on peer reviewers
- Author
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Fernandez-Llimos F., Berti A.D., Yeung D., Yusuff K.B., El Zowalaty M.E., Adane E.D., Al-Aqeel S., Al-Jumaili A.A., Alili-Idrizi E., Andelkovic M., Aranha A., Arief M., Arkaravichien W., Armoiry X., Attarabeen O.F., Ayoub N., Bajorek B.V., Beninger P., Billups S.J., Bowen J.F., Bouwmeester C., Campbell P., Chan V., Connor S.E., Danziger L.H., Dawood O.T., Dunnenberger M., Elrouby S., Fakih S., Abu Farha R.K., Figueiredo I.V., Foroutan N., Forsythe L.E., Frail C.K., Friesner D., Funk K., Gaither C., Gallimore C.E., Gan V., Garcia B.H., Gaskins J.L., Gastelurrutia M.A., Gatwood J., Genord C.K., Gilliam E., Goodbar N.H., Gossell-Williams M., Grundy Q., Guenette L., Hadi M.A., Hallit S., Hammond D.A., Hawasli R.S., Herdeiro M.T., Hermansyah A., Hincapie A.L., Hoehns J.D., Hossain L.N., Hudspeth B., Ibrahim M.I.B.M., Islahudin F., Jacobsen R., Jones M., Kälvemark Sporrong S., Kantelhardt P., Katangwe T., Katoue M.G., King S.R., Kinnear M., Kouladjian O'Donnell L., Kovacevic S.V., Krass I., Kraus S.K., Lakic D., Larson D., LeMay K., Loh B.C., Lowres N., Luetsch K., Lunghi C., Lyra D.P., Jr., Ma C.S., MacDonald E.A., Mancuso M.A., Mazhar F., McCarthy L., McComb M., McFarland M.S., Mehralian G., Merks P., Modun D., Mohammed M.A., Motulsky A., Mukattash T.L., Nabhani-Gebara S., Najafi S., Ni W., Nitadpakorn S., Ogbo P.U., Palaian S., Patel R.J., Payne M.H., Peaslee A.K., Pereira L.R., Perry T.D., Phan Y., Plage S., Prybylski J.P., Quffa L.H., Raka L., Ramos-Esquivel A., Ramsbottom H., Rayes I.K., Rodriguez J.V., Rosenthal M., Sadowski C.A., Sage A., Salgado T.M., Saw P.S., Schafer K.M., Schutte T., Shafie A.A., Shah R.M., Sharma A., Shehnaz S.I., Shiyanbola O.O., Siitonen P., Skinner I., Snyder M.E., Stewart D., Strang A., Stranges P.M., Sultana K., Surbhi S., Suzen H.S., Swieczkowski D., Tasaka C.L., Taylor A.M., Theberge C.R., Travlos D.V., Turner J.R., Vandenberk B., Wettergreen S.A., White C.M., Wietholter J.P., Wirth F., Young A., Zembles T., Pharmacy Practice 2017 peer reviewers, Fernandez-Llimos F., Berti A.D., Yeung D., Yusuff K.B., El Zowalaty M.E., Adane E.D., Al-Aqeel S., Al-Jumaili A.A., Alili-Idrizi E., Andelkovic M., Aranha A., Arief M., Arkaravichien W., Armoiry X., Attarabeen O.F., Ayoub N., Bajorek B.V., Beninger P., Billups S.J., Bowen J.F., Bouwmeester C., Campbell P., Chan V., Connor S.E., Danziger L.H., Dawood O.T., Dunnenberger M., Elrouby S., Fakih S., Abu Farha R.K., Figueiredo I.V., Foroutan N., Forsythe L.E., Frail C.K., Friesner D., Funk K., Gaither C., Gallimore C.E., Gan V., Garcia B.H., Gaskins J.L., Gastelurrutia M.A., Gatwood J., Genord C.K., Gilliam E., Goodbar N.H., Gossell-Williams M., Grundy Q., Guenette L., Hadi M.A., Hallit S., Hammond D.A., Hawasli R.S., Herdeiro M.T., Hermansyah A., Hincapie A.L., Hoehns J.D., Hossain L.N., Hudspeth B., Ibrahim M.I.B.M., Islahudin F., Jacobsen R., Jones M., Kalvemark Sporrong S., Kantelhardt P., Katangwe T., Katoue M.G., King S.R., Kinnear M., Kouladjian O'Donnell L., Kovacevic S.V., Krass I., Kraus S.K., Lakic D., Larson D., LeMay K., Loh B.C., Lowres N., Luetsch K., Lunghi C., Lyra D.P., Ma C.S., MacDonald E.A., Mancuso M.A., Mazhar F., McCarthy L., McComb M., McFarland M.S., Mehralian G., Merks P., Modun D., Mohammed M.A., Motulsky A., Mukattash T.L., Nabhani-Gebara S., Najafi S., Ni W., Nitadpakorn S., Ogbo P.U., Palaian S., Patel R.J., Payne M.H., Peaslee A.K., Pereira L.R., Perry T.D., Phan Y., Plage S., Prybylski J.P., Quffa L.H., Raka L., Ramos-Esquivel A., Ramsbottom H., Rayes I.K., Rodriguez J.V., Rosenthal M., Sadowski C.A., Sage A., Salgado T.M., Saw P.S., Schafer K.M., Schutte T., Shafie A.A., Shah R.M., Sharma A., Shehnaz S.I., Shiyanbola O.O., Siitonen P., Skinner I., Snyder M.E., Stewart D., Strang A., Stranges P.M., Sultana K., Surbhi S., Suzen H.S., Swieczkowski D., Tasaka C.L., Taylor A.M., Theberge C.R., Travlos D.V., Turner J.R., Vandenberk B., Wettergreen S.A., White C.M., Wietholter J.P., Wirth F., Young A., Zembles T., and Internal medicine
- Subjects
lcsh:RS1-441 ,Pharmaceutical Science ,Economic shortage ,Pharmacy ,030226 pharmacology & pharmacy ,lcsh:Pharmacy and materia medica ,03 medical and health sciences ,0302 clinical medicine ,Periodicals as topic ,Open access publishing ,Political science ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Original Research ,Final version ,business.industry ,Research ,mesh:Periodicals as Topic ,lcsh:RM1-950 ,mesh:Open Access Publishing ,Public relations ,lcsh:Therapeutics. Pharmacology ,Ask price ,Publishing ,030221 ophthalmology & optometry ,business - Abstract
The peer-review crisis is posing a risk to the scholarly peer-reviewed journal system. Journals have to ask many potential peer reviewers to obtain a minimum acceptable number of peers accepting reviewing a manuscript. Several solutions have been suggested to overcome this shortage. From reimbursing for the job, to eliminating pre-publication reviews, one cannot predict which is more dangerous for the future of scholarly publishing. And, why not acknowledging their contribution to the final version of the article published? PubMed created two categories of contributors: authors [AU] and collaborators [IR]. Why not a third category for the peer-reviewer? published
- Published
- 2018
8. Recognizing the Need for Civic Engagement.
- Author
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McComb, M. Toni
- Subjects
COMMUNITY involvement ,EMPATHY ,HUMAN services - Published
- 2023
9. Patterns of Tissue-Specific Glycosaminoglycan Expression Revealed by Tandem Mass Spectrometry and Statistical Methods
- Author
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Naimy, H., Staples, G.O., Mccomb, M., Costello, C.E., Zaia, J., and Leymarie, N.
- Subjects
Poster Session Abstracts - Abstract
RP-15
- Published
- 2010
10. Perceptual Organization Influences Memory, Search, and Aesthetic Judgment
- Author
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Schloss, K. B., primary and McComb, M., additional
- Published
- 2013
- Full Text
- View/download PDF
11. On-membrane digestion of ?-casein for determination of phosphorylation sites by matrix-assisted laser desorption/ionization quadrupole/time-of-flight mass spectrometry
- Author
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Lee, C. H., primary, McComb, M. E., additional, Bromirski, M., additional, Jilkine, A., additional, Ens, W., additional, Standing, K. G., additional, and Perreault, H., additional
- Published
- 2001
- Full Text
- View/download PDF
12. Geology and resource potential of a proposed national marine park, Lancaster Sound, Northwest Territories
- Author
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Smith, D R, primary, Gowan, R J, additional, and McComb, M, additional
- Published
- 1989
- Full Text
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13. Analysis of trace metals in water by in-situ sample pre-concentration combined with wavelength dispersive X-ray fluorescence spectroscopy and inductively coupled plasma-optical emission spectroscopy
- Author
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McComb, M, primary
- Published
- 1999
- Full Text
- View/download PDF
14. Microextraction of volatile organic compounds using the inside needle capillary adsorption trap (INCAT) device
- Author
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McComb, M, primary
- Published
- 1997
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- View/download PDF
15. Preparation of polyacryloamidoxime chelating cloth for the extraction of heavy metals from water
- Author
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McComb, M. E., primary and Gesser, H.D., additional
- Published
- 1997
- Full Text
- View/download PDF
16. Expression of stress proteins in porcine tissues: developmental changes and effect of immunological challenge.
- Author
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McComb, M A, primary and Spurlock, M E, additional
- Published
- 1997
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17. On-membrane digestion of β-casein for determination of phosphorylation sites by matrix-assisted laser desorption/ionization quadrupole/time-of-flight mass spectrometry.
- Author
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Lee, C. H., McComb, M. E., Bromirski, M., Jilkine, A., Ens, W., Standing, K. G., and Perreault, H.
- Published
- 2001
- Full Text
- View/download PDF
18. Isotope-Coded Affinity Tag (ICAT) Approach to Redox Proteomics: Identification and Quantitation of Oxidant-Sensitive Cysteine Thiols in Complex Protein Mixtures
- Author
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Sethuraman, M., McComb, M. E., Huang, H., Huang, S., Heibeck, T., Costello, C. E., and Cohen, R. A.
- Abstract
An approach is described for the simultaneous identification and quantitation of oxidant-sensitive cysteine thiols in a complex protein mixture using a thiol-specific, acid-cleavable isotope-coded affinity tag (ICAT) reagent (Applied Biosystems, USA). The approach is based on the fact that only free cysteine thiols are susceptible to labeling by the iodoacetamide-based ICAT, and that mass spectrometry can be used to quantitate the relative labeling of free thiols. Applying this approach, we have identified cysteine thiols of proteins in a rabbit heart membrane fraction that are sensitive to a high concentration of hydrogen peroxide. Previously known and some novel proteins with oxidant-sensitive cysteines were identified. Of the many protein thiols labeled by the ICAT, only relatively few were oxidized more than 50% despite the high concentration of oxidant used, indicating that oxidant-sensitive thiols are relatively rare, and denoting their specificity and potential functional relevance. Keywords: oxidation • cysteine • thiol • iodoacetamide • isotope coded affinity tag (ICAT) • proteomics • post-translational modification
- Published
- 2004
19. Characterization of plasma proteins adsorbed onto biomaterials by MALDI-TOFMS
- Author
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Oleschuk, R. D., McComb, M. E., Chow, A., Ens, W., Standing, K. G., Perreault, H., Marois, Y., and King, M.
- Published
- 2000
- Full Text
- View/download PDF
20. Sensitive high-resolution analysis of biological molecules by capillary zone electrophoresis coupled with reflecting time-of-flight mass spectrometry
- Author
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McComb, M. E., Krutchinsky, A. N., Ens, W., Standing, K. G., and Perreault, H.
- Published
- 1998
- Full Text
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21. Passive monitoring of trace metals in water by in situ sample preconcentration via chelation on a textile based solid sorbent
- Author
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McComb, M. E. and Gesser, H. D.
- Published
- 1997
- Full Text
- View/download PDF
22. PANAMA-enabled high-sensitivity dual nanoflow LC-MS metabolomics and proteomics analysis.
- Author
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Lin W, Mousavi F, Blum BC, Heckendorf CF, Lawton M, Lampl N, Hekman R, Guo H, McComb M, and Emili A
- Subjects
- Chromatography, Liquid, Humans, Animals, Nanotechnology methods, Liquid Chromatography-Mass Spectrometry, Proteomics methods, Metabolomics methods, Tandem Mass Spectrometry methods
- Abstract
High-sensitivity nanoflow liquid chromatography (nLC) is seldom employed in untargeted metabolomics because current sample preparation techniques are inefficient at preventing nanocapillary column performance degradation. Here, we describe an nLC-based tandem mass spectrometry workflow that enables seamless joint analysis and integration of metabolomics (including lipidomics) and proteomics from the same samples without instrument duplication. This workflow is based on a robust solid-phase micro-extraction step for routine sample cleanup and bioactive molecule enrichment. Our method, termed proteomic and nanoflow metabolomic analysis (PANAMA), improves compound resolution and detection sensitivity without compromising the depth of coverage as compared with existing widely used analytical procedures. Notably, PANAMA can be applied to a broad array of specimens, including biofluids, cell lines, and tissue samples. It generates high-quality, information-rich metabolite-protein datasets while bypassing the need for specialized instrumentation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
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23. A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer.
- Author
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Dorff T, Horvath LG, Autio K, Bernard-Tessier A, Rettig MB, Machiels JP, Bilen MA, Lolkema MP, Adra N, Rottey S, Greil R, Matsubara N, Tan DSW, Wong A, Uemura H, Lemech C, Meran J, Yu Y, Minocha M, McComb M, Penny HL, Gupta V, Hu X, Jurida G, Kouros-Mehr H, Janát-Amsbury MM, Eggert T, and Tran B
- Subjects
- Male, Humans, Prostate-Specific Antigen, Half-Life, Treatment Outcome, Androgen Receptor Antagonists therapeutic use, T-Lymphocytes metabolism, Prostatic Neoplasms, Castration-Resistant pathology, Antineoplastic Agents therapeutic use
- Abstract
Purpose: Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed., Results: In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0-4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0-5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion., Conclusions: Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity., (©2024 American Association for Cancer Research.)
- Published
- 2024
- Full Text
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24. A Commentary on Fasting of Nonclinical Research Animals.
- Author
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Gauvin DV, McComb M, and Farero R
- Subjects
- Humans, Animals, Animals, Laboratory, Animal Welfare, Fasting, Animal Care Committees, Animal Experimentation
- Abstract
This commentary discusses the implementation of fasting in nonclinical animal experimental subjects. The short-term removal of food from cages of experimental animals is in all respects innocuous. The term "stress" is ill-defined and the statutes and regulations governing animal research laboratories that exert their authority in the performance of their operations do so without substantive grounds to base compliance. The legislative and administrative history of the implementation of the Animal Welfare Act (AWA) has evolved into the development of laboratory management strategies that focus on the reduction of the biological cost of stress to the animals and the determination of when subclinical stress (eustress) becomes distress. Animal welfare is based on the tenet that in laboratories conducting animal research in compliance with Good Laboratory Practices (Title 21 USC, Chapter 13,§58), it is the study protocol and the study director that establish procedures and processes that are approved by each Institutional Animal Care and Use Committee to ensure the humane care and use of animals in research, teaching, and testing and to ensure compliance with guidelines and regulations. This approval process establishes the justification of eustress in the environment that do not rise to the threshold of distress under the AWA., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2024
- Full Text
- View/download PDF
25. Corrigendum: Integrated metabolomics and proteomics reveal biomarkers associated with hemodialysis in end-stage kidney disease.
- Author
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Lin W, Mousavi F, Blum BC, Heckendorf CF, Moore J, Lampl N, McComb M, Kotelnikov S, Yin W, Rabhi N, Layne MD, Kozakov D, Chitalia VC, and Emili A
- Abstract
[This corrects the article DOI: 10.3389/fphar.2023.1243505.]., (Copyright © 2024 Lin, Mousavi, Blum, Heckendorf, Moore, Lampl, McComb, Kotelnikov, Yin, Rabhi, Layne, Kozakov, Chitalia and Emili.)
- Published
- 2024
- Full Text
- View/download PDF
26. Integrated metabolomics and proteomics reveal biomarkers associated with hemodialysis in end-stage kidney disease.
- Author
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Lin W, Mousavi F, Blum BC, Heckendorf CF, Moore J, Lampl N, McComb M, Kotelnikov S, Yin W, Rabhi N, Layne MD, Kozakov D, Chitalia VC, and Emili A
- Abstract
Background: We hypothesize that the poor survival outcomes of end-stage kidney disease (ESKD) patients undergoing hemodialysis are associated with a low filtering efficiency and selectivity. The current gold standard criteria using single or several markers show an inability to predict or disclose the treatment effect and disease progression accurately. Methods: We performed an integrated mass spectrometry-based metabolomic and proteomic workflow capable of detecting and quantifying circulating small molecules and proteins in the serum of ESKD patients. Markers linked to cardiovascular disease (CVD) were validated on human induced pluripotent stem cell (iPSC)-derived cardiomyocytes. Results: We identified dozens of elevated molecules in the serum of patients compared with healthy controls. Surprisingly, many metabolites, including lipids, remained at an elevated blood concentration despite dialysis. These molecules and their associated physical interaction networks are correlated with clinical complications in chronic kidney disease. This study confirmed two uremic toxins associated with CVD, a major risk for patients with ESKD. Conclusion: The retained molecules and metabolite-protein interaction network address a knowledge gap of candidate uremic toxins associated with clinical complications in patients undergoing dialysis, providing mechanistic insights and potential drug discovery strategies for ESKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lin, Mousavi, Blum, Heckendorf, Moore, Lampl, McComb, Kotelnikov, Yin, Rabhi, Layne, Kozakov, Chitalia and Emili.)
- Published
- 2023
- Full Text
- View/download PDF
27. Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy.
- Author
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Penny HL, Hainline K, Theoharis N, Wu B, Brandl C, Webhofer C, McComb M, Wittemer-Rump S, Koca G, Stienen S, Bargou RC, Hummel HD, Loidl W, Grüllich C, Eggert T, Tran B, and Mytych DT
- Subjects
- Male, Humans, Root Cause Analysis, Prostate-Specific Antigen metabolism, Antibodies metabolism, Antigens, Surface metabolism, T-Lymphocytes, Prostate, Biological Products
- Abstract
Introduction: In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics., Methods: Here we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration., Results: Treatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm., Discussion: These mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics., Competing Interests: All authors, except for NT, SW-R, GK, RB, H-DH, WL, CG, and BT, were/are employees of Amgen during the time this study and associated analyses were being conducted. SW-R and GK are employees of Bayer AG. Author WL was employed by Ordensklinikum Linz GmbH. RB is a patent holder for blinatumomab, from which he receives royalty payments, and has consulted for and received honoraria from Amgen, Cellex and Gemoab. H-DH has received travel, accommodations or other expenses from Johnson & Johnson, Boehringer Ingelheim, Amgen Inc. and Bristol Myers Squibb. WL has received honoraria from Accord and Novartis. BT has received a grant, consulting fees, and honoraria from Amgen Inc. NT was an employee of Labcorp Translational Biomarker Solutions at the time of this study and has no conflicts to disclose. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Bayer and Amgen. The funders were involved in the study design, collection, analysis, interpretation of results, the writing of this article and the decision to submit it for publication., (Copyright © 2023 Penny, Hainline, Theoharis, Wu, Brandl, Webhofer, McComb, Wittemer-Rump, Koca, Stienen, Bargou, Hummel, Loidl, Grüllich, Eggert, Tran and Mytych.)
- Published
- 2023
- Full Text
- View/download PDF
28. Distortion Product Otoacoustic Emission Test is Not the Test to Use in Nonclinical Safety Assessment.
- Author
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Gauvin DV, McComb M, Tapp R, Yoder J, and Zimmermann ZJ
- Subjects
- Animals, Evoked Potentials, Auditory, Brain Stem physiology, Otoacoustic Emissions, Spontaneous physiology, Ototoxicity
- Abstract
Ototoxicity and ocular toxicity screening are but two examples of specialty product lines that are often employed as Tier II or III nonclinical safety/hazard screening assessments. Compared to the regulatory guidelines that govern over standard toxicology or neurotoxicology programs, there is a paucity of regulatory strategies to address these specialized product lines. With respect to ototoxicity testing, we argue for the inclusion of the "least burdensome principles" adopted by the US FDA in providing the most pragmatic, efficient, and directed identification of potential harm to auditory function in the nonclinical safety arena. We argue for the exclusive use of the auditory brainstem response and the exclusion of the distortion product otoacoustic emissions (DPOAEs) in these Tiered II safety assessment programs. The inclusion of both are a burden on operational staff and, due to the extended episodes of anesthesia required to conduct both assays, this strategy poses a health and welfare concern for the selected animal species to be used. The DPOAE does not provide any sufficiently valid or reliable data above and beyond the gold standard ABR data, followed by complete oto-histopathology and cytocochleogram combination designs.
- Published
- 2022
- Full Text
- View/download PDF
29. Machine learning in pharmacometrics: Opportunities and challenges.
- Author
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McComb M, Bies R, and Ramanathan M
- Subjects
- Algorithms, Big Data, Humans, Pharmaceutical Preparations, Artificial Intelligence, Machine Learning
- Abstract
The explosive growth in medical devices, imaging and diagnostics, computing, and communication and information technologies in drug development and healthcare has created an ever-expanding data landscape that the pharmacometrics (PMX) research community must now traverse. The tools of machine learning (ML) have emerged as a powerful computational approach in other data-rich disciplines but its effective utilization in the pharmaceutical sciences and PMX modelling is in its infancy. ML-based methods can complement PMX modelling by enabling the information in diverse sources of big data, e.g. population-based public databases and disease-specific clinical registries, to be harnessed because they are capable of efficiently identifying salient variables associated with outcomes and delineating their interdependencies. ML algorithms are computationally efficient, have strong predictive capabilities and can enable learning in the big data setting. ML algorithms can be viewed as providing a computational bridge from big data to complement PMX modelling. This review provides an overview of the strengths and weaknesses of ML approaches vis-à-vis population methods, assesses current research into ML applications in the pharmaceutical sciences and provides perspective for potential opportunities and strategies for the successful integration and utilization of ML in PMX., (© 2021 British Pharmacological Society.)
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- 2022
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30. Machine learning-guided, big data-enabled, biomarker-based systems pharmacology: modeling the stochasticity of natural history and disease progression.
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McComb M, Blair RH, Lysy M, and Ramanathan M
- Subjects
- Bayes Theorem, Biomarkers, Disease Progression, Humans, Machine Learning, Models, Biological, Nutrition Surveys, Big Data, Network Pharmacology
- Abstract
The incidence of systemic and metabolic co-morbidities increases with aging. The purpose was to investigate a novel paradigm for modeling the orchestrated changes in many disease-related biomarkers that occur during aging. A hybrid strategy that integrates machine learning and stochastic modeling was evaluated for modeling the long-term dynamics of biomarker systems. Bayesian networks (BN) were used to identify quantitative systems pharmacology (QSP)-like models for the inter-dependencies for three disease-related datasets of metabolic (MB), metabolic with leptin (MB-L), and cardiovascular (CVB) biomarkers from the NHANES database. Biomarker dynamics were modeled using discrete stochastic vector autoregression (VAR) equations. BN were used to derive the topological order and connectivity of a data driven QSP model structure for inter-dependence of biomarkers across the lifespan. The strength and directionality of the connections in the QSP models were evaluated using bootstrapping. VAR models based on QSP model structures from BN were assessed for modeling biomarker system dynamics. BN-restricted VAR models of order 1 were identified as parsimonious and effective for characterizing biomarker system dynamics in the MB, MB-L and CVB datasets. Simulation of annual and triennial data for each biomarker provided good fits and predictions of the training and test datasets, respectively. The novel strategy harnesses machine learning to construct QSP model structures for inter-dependence of biomarkers. Stochastic modeling with the QSP models was effective for predicting the age-varying dynamics of disease-relevant biomarkers over the lifespan., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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31. The cholesterol autoxidation products, 7-ketocholesterol and 7β-hydroxycholesterol are associated with serum neurofilaments in multiple sclerosis.
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McComb M, Browne RW, Bhattacharya S, Bodziak ML, Jakimovski D, Weinstock-Guttman B, Kuhle J, Zivadinov R, and Ramanathan M
- Subjects
- Humans, Hydroxycholesterols, Intermediate Filaments, Ketocholesterols, Longitudinal Studies, Multiple Sclerosis
- Abstract
Background: Serum neurofilament light chain (sNfL) is an established marker of neuroaxonal injury in multiple sclerosis (MS)., Objectives: To investigate if oxysterols produced from non-enzymatic and enzymatic cholesterol oxidation are differentially associated with sNfL measurements in MS., Methods: This longitudinal study included 62 relapsing-remitting (RR-MS) and 36 progressive MS (PMS) patients with baseline and 5-year follow-up measures of serum levels of 6 oxysterols, sNfL and lipids. The oxysterols, 24-hydroxycholesterol (24HC), 25HC, 27HC, 7αHC, 7βHC and 7-ketocholesterol (7KC), were measured using liquid chromatography-mass spectrometry. sNfL was measured using single molecular array assay. Serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were obtained from a lipid profile., Results: The enzymatically produced oxysterols 24HC, 25HC, 27HC and 7αHC were not associated with sNfL. However, baseline levels of reactive oxygen species (ROS) produced oxysterols, 7KC (p = 0.032) and 7βHC (p = 0.0025), were positively associated with sNfL levels at follow-up. Follow-up 7KC (p = 0.038) levels were also associated with follow-up sNfL levels. The associations of 7KC or 7βHC with sNfL remained significant after adjusting for LDL-C or HDL-C., Conclusions: 7KC and 7βHC, produced by ROS-mediated cholesterol oxidation are associated with neuroaxonal injury as assessed by sNfL in MS., (Copyright © 2021. Published by Elsevier B.V.)
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- 2021
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32. Neurofilament levels are associated with blood-brain barrier integrity, lymphocyte extravasation, and risk factors following the first demyelinating event in multiple sclerosis.
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Uher T, McComb M, Galkin S, Srpova B, Oechtering J, Barro C, Tyblova M, Bergsland N, Krasensky J, Dwyer M, Havrdova EK, Posova H, Vaneckova M, Zivadinov R, Horakova D, Kuhle J, and Ramanathan M
- Subjects
- Adult, Biomarkers, Female, Humans, Intermediate Filaments, Lymphocytes, Male, Neurofilament Proteins, Risk Factors, Young Adult, Blood-Brain Barrier, Multiple Sclerosis
- Abstract
Background: Increased blood brain barrier (BBB) permeability, CNS inflammation and neuroaxonal damage are pathological hallmarks in early multiple sclerosis (MS)., Objective: To investigate the associations of neurofilament light chain (NfL) levels with measures of BBB integrity and central nervous system (CNS) inflammation in MS during the first demyelinating event., Methods: Blood and cerebrospinal fluid (CSF) were obtained from 142 MS (McDonald 2017) treatment-naive patients from the SET study (63% female; age: 29.7 ± 7.9 years) following the disease onset. NfL, albumin, immunoglobulin G (IgG), and immunoglobulin M (IgM) levels were measured in CSF and blood samples. Albumin quotient was computed as a marker of BBB integrity. Immune cell subset counts in CSF were measured using flow cytometry. MS risk factors, such as Human leukocyte antigen DRB1 locus gene ( HLA DRB1 )*1501, anti-Epstein-Barr virus (EBV) antibodies, and 25-hydroxy vitamin D
3 , were also measured., Results: Higher serum NfL (sNfL) levels were associated with higher albumin quotient ( p < 0.001), CSF CD80+ ( p = 0.012), and CD80+ CD19+ ( p = 0.015) cell frequency. sNfL levels were also associated with contrast-enhancing and T2 lesions on brain magnetic resonance imaging (MRI; all p ⩽ 0.001). Albumin quotient was not associated with any of the MS risk factors assessed. sNfL levels were associated with anti-EBV viral capsid antigen (VCA) IgG levels ( p = 0.0026)., Conclusion: sNfL levels during the first demyelinating event of MS are associated with greater impairment of BBB integrity, immune cell extravasation, and brain lesion activity on MRI.- Published
- 2021
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33. Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2.
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Hekman RM, Hume AJ, Goel RK, Abo KM, Huang J, Blum BC, Werder RB, Suder EL, Paul I, Phanse S, Youssef A, Alysandratos KD, Padhorny D, Ojha S, Mora-Martin A, Kretov D, Ash PEA, Verma M, Zhao J, Patten JJ, Villacorta-Martin C, Bolzan D, Perea-Resa C, Bullitt E, Hinds A, Tilston-Lunel A, Varelas X, Farhangmehr S, Braunschweig U, Kwan JH, McComb M, Basu A, Saeed M, Perissi V, Burks EJ, Layne MD, Connor JH, Davey R, Cheng JX, Wolozin BL, Blencowe BJ, Wuchty S, Lyons SM, Kozakov D, Cifuentes D, Blower M, Kotton DN, Wilson AA, Mühlberger E, and Emili A
- Published
- 2021
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34. Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2.
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Hekman RM, Hume AJ, Goel RK, Abo KM, Huang J, Blum BC, Werder RB, Suder EL, Paul I, Phanse S, Youssef A, Alysandratos KD, Padhorny D, Ojha S, Mora-Martin A, Kretov D, Ash PEA, Verma M, Zhao J, Patten JJ, Villacorta-Martin C, Bolzan D, Perea-Resa C, Bullitt E, Hinds A, Tilston-Lunel A, Varelas X, Farhangmehr S, Braunschweig U, Kwan JH, McComb M, Basu A, Saeed M, Perissi V, Burks EJ, Layne MD, Connor JH, Davey R, Cheng JX, Wolozin BL, Blencowe BJ, Wuchty S, Lyons SM, Kozakov D, Cifuentes D, Blower M, Kotton DN, Wilson AA, Mühlberger E, and Emili A
- Subjects
- Alveolar Epithelial Cells pathology, Alveolar Epithelial Cells virology, Animals, Antiviral Agents, COVID-19 genetics, COVID-19 pathology, Chlorocebus aethiops, Cytopathogenic Effect, Viral, Cytoskeleton, Drug Evaluation, Preclinical, Humans, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells pathology, Induced Pluripotent Stem Cells virology, Phosphoproteins genetics, Protein Transport, Proteome genetics, SARS-CoV-2 genetics, Signal Transduction, Vero Cells, COVID-19 Drug Treatment, Alveolar Epithelial Cells metabolism, COVID-19 metabolism, Phosphoproteins metabolism, Proteome metabolism, SARS-CoV-2 metabolism
- Abstract
Human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative pathogen of the COVID-19 pandemic, exerts a massive health and socioeconomic crisis. The virus infects alveolar epithelial type 2 cells (AT2s), leading to lung injury and impaired gas exchange, but the mechanisms driving infection and pathology are unclear. We performed a quantitative phosphoproteomic survey of induced pluripotent stem cell-derived AT2s (iAT2s) infected with SARS-CoV-2 at air-liquid interface (ALI). Time course analysis revealed rapid remodeling of diverse host systems, including signaling, RNA processing, translation, metabolism, nuclear integrity, protein trafficking, and cytoskeletal-microtubule organization, leading to cell cycle arrest, genotoxic stress, and innate immunity. Comparison to analogous data from transformed cell lines revealed respiratory-specific processes hijacked by SARS-CoV-2, highlighting potential novel therapeutic avenues that were validated by a high hit rate in a targeted small molecule screen in our iAT2 ALI system., Competing Interests: Declaration of Interests B.L.W. declares a position as CSO of Aquinnah Pharmaceuticals. A.E. and D.N.K. declare industry funding from Johnson & Johnson, Merck, and Novartis., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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35. Neuroprotective associations of apolipoproteins A-I and A-II with neurofilament levels in early multiple sclerosis.
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McComb M, Krikheli M, Uher T, Browne RW, Srpova B, Oechtering J, Maceski AM, Tyblova M, Jakimovski D, Ramasamy DP, Bergsland N, Krasensky J, Noskova L, Fialova L, Weinstock-Guttman B, Havrdova EK, Vaneckova M, Zivadinov R, Horakova D, Kuhle J, and Ramanathan M
- Subjects
- Adult, Female, Humans, Longitudinal Studies, Male, Multiple Sclerosis pathology, Neuroprotective Agents blood, Neuroprotective Agents cerebrospinal fluid, Prognosis, Prospective Studies, Apolipoprotein A-I blood, Apolipoprotein A-II blood, Multiple Sclerosis blood, Multiple Sclerosis cerebrospinal fluid, Neurofilament Proteins cerebrospinal fluid
- Abstract
Background: The role of cholesterol homeostasis in neuroaxonal injury in multiple sclerosis is not known., Objective: The objective of the study is to investigate the associations of cerebrospinal fluid (CSF) and serum neurofilament light chain levels (CSF-NfL and sNfL, respectively), which are biomarkers of neuroaxonal injury, with cholesterol biomarkers at the clinical onset of multiple sclerosis., Methods: sNfL, serum cholesterol profile (total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), serum apolipoprotein (Apo) levels (ApoA-I, ApoA-II, ApoB, and ApoE), and albumin quotient were obtained for 133 patients (63% female, age: 29.9 ± 8.0 years) during the first demyelinating event. CSF-NfL was available for 103 (77%) patients., Results: CSF-NfL and sNfL were negatively associated with serum ApoA-II (P = .005, P < .001) and positively associated with albumin quotient (P < .001, P < .0001). In addition, higher CSF-NfL was associated with lower serum ApoA-I (P = .009) levels and higher sNfL was associated with lower high-density lipoprotein cholesterol (P = .010). In stepwise regression, age (P = .045), serum ApoA-II (P = .022), and albumin quotient (P < .001) were associated with CSF-NfL; albumin quotient (P = .002) and ApoA-II (P = .001) were associated with sNfL. Path analysis identified parallel pathways from ApoA-II (P = .009) and albumin quotient (P < .001) to the sNfL outcome that were mediated by CSF-NfL (P < .001). The associations of CSF-NfL with ApoA-I (P = .014) and ApoA-II (P = .015) and sNfL with ApoA-II (P < .001) remained significant after adjusting for number of contrast-enhancing lesions and T2 lesion volume., Conclusion: Lower serum ApoA-II and ApoA-I levels are associated with greater neuroaxonal injury as measured by CSF-NfL., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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36. Generalized Pharmacometric Modeling, a Novel Paradigm for Integrating Machine Learning Algorithms: A Case Study of Metabolomic Biomarkers.
- Author
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McComb M and Ramanathan M
- Subjects
- Bayes Theorem, Big Data, Biomarkers metabolism, Cholesterol metabolism, Humans, Nutrition Surveys, Pharmaceutical Preparations administration & dosage, Pharmaceutical Preparations metabolism, Algorithms, Machine Learning, Metabolomics methods, Models, Biological
- Abstract
There is an unmet need for identifying innovative machine learning (ML) strategies to improve drug treatment regimens and therapeutic outcomes. We investigate Generalized Pharmacometric Modeling (GPM), a novel paradigm that integrates ML algorithms with pharmacokinetic and pharmacodynamic structural models, population covariate modeling, and "big data," and enables identification of patient-specific factors contributing to drug disposition. We hypothesize that GPM will enhance forecasting of drug outcomes in diverse populations. We assessed random forest regression in conjunction with Bayesian networks as the ML methods within GPM and used the National Health and Nutrition Examination Survey population-based study database. GPM was utilized to identify subject-specific factors associated with cholesterol dynamics. Our results demonstrate the utility of GPM to enhance pharmacometrics modeling and its potential for modeling drug outcomes in diverse populations., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2020
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37. RuvbL1 and RuvbL2 enhance aggresome formation and disaggregate amyloid fibrils.
- Author
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Zaarur N, Xu X, Lestienne P, Meriin AB, McComb M, Costello CE, Newnam GP, Ganti R, Romanova NV, Shanmugasundaram M, Silva ST, Bandeiras TM, Matias PM, Lobachev KS, Lednev IK, Chernoff YO, and Sherman MY
- Subjects
- ATPases Associated with Diverse Cellular Activities, Amyloid genetics, Carrier Proteins genetics, DNA Helicases genetics, HEK293 Cells, HeLa Cells, Heat-Shock Proteins genetics, Heat-Shock Proteins metabolism, Humans, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Organelles genetics, Organelles pathology, Amyloid metabolism, Carrier Proteins metabolism, DNA Helicases metabolism, Organelles metabolism
- Abstract
The aggresome is an organelle that recruits aggregated proteins for storage and degradation. We performed an siRNA screen for proteins involved in aggresome formation and identified novel mammalian AAA+ protein disaggregases RuvbL1 and RuvbL2. Depletion of RuvbL1 or RuvbL2 suppressed aggresome formation and caused buildup of multiple cytoplasmic aggregates. Similarly, downregulation of RuvbL orthologs in yeast suppressed the formation of an aggresome-like body and enhanced the aggregate toxicity. In contrast, their overproduction enhanced the resistance to proteotoxic stress independently of chaperone Hsp104. Mammalian RuvbL associated with the aggresome, and the aggresome substrate synphilin-1 interacted directly with the RuvbL1 barrel-like structure near the opening of the central channel. Importantly, polypeptides with unfolded structures and amyloid fibrils stimulated the ATPase activity of RuvbL. Finally, disassembly of protein aggregates was promoted by RuvbL. These data indicate that RuvbL complexes serve as chaperones in protein disaggregation., (© 2015 The Authors.)
- Published
- 2015
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38. Abuse liability assessment of hydrocodone under current draft regulatory guidelines.
- Author
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Gauvin DV, McComb M, Code R, Dalton JA, and Baird TJ
- Subjects
- Analgesics, Opioid administration & dosage, Analgesics, Opioid pharmacology, Animals, Discrimination, Psychological, Guidelines as Topic, Hydrocodone pharmacology, Male, Morphine administration & dosage, Morphine pharmacology, Oxycodone administration & dosage, Oxycodone pharmacology, Rats, Rats, Sprague-Dawley, Hydrocodone administration & dosage, Opioid-Related Disorders physiopathology, Self Administration, Substance Withdrawal Syndrome physiopathology
- Abstract
Introduction: The abuse liability of hydrocodone was assessed in male Sprague-Dawley rats under the European Medicines Agency, the International Commission on Harmonisation, and the U.S. Food & Drug Administration draft guidelines for the non-clinical investigation of the dependence potential of medicinal products., Methods: Self-administration, drug discrimination, and repeat-dose two week dependence liability studies were conducted to compare hydrocodone to the prototypical opiates, morphine and oxycodone., Results: Hydrocodone was self-administered, produced an opiate-like subjective discriminative generalization profile and produced a significant discontinuation syndrome following abrupt treatment cessation that was quantitatively and qualitatively similar to morphine and/or oxycodone., Conclusion: Hydrocodone has abuse liability more similar to Schedule II opiates than other Schedule III compounds currently controlled under the U.S. Controlled Substance Act., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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39. Interlaboratory study on differential analysis of protein glycosylation by mass spectrometry: the ABRF glycoprotein research multi-institutional study 2012.
- Author
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Leymarie N, Griffin PJ, Jonscher K, Kolarich D, Orlando R, McComb M, Zaia J, Aguilan J, Alley WR, Altmann F, Ball LE, Basumallick L, Bazemore-Walker CR, Behnken H, Blank MA, Brown KJ, Bunz SC, Cairo CW, Cipollo JF, Daneshfar R, Desaire H, Drake RR, Go EP, Goldman R, Gruber C, Halim A, Hathout Y, Hensbergen PJ, Horn DM, Hurum D, Jabs W, Larson G, Ly M, Mann BF, Marx K, Mechref Y, Meyer B, Möginger U, Neusüβ C, Nilsson J, Novotny MV, Nyalwidhe JO, Packer NH, Pompach P, Reiz B, Resemann A, Rohrer JS, Ruthenbeck A, Sanda M, Schulz JM, Schweiger-Hufnagel U, Sihlbom C, Song E, Staples GO, Suckau D, Tang H, Thaysen-Andersen M, Viner RI, An Y, Valmu L, Wada Y, Watson M, Windwarder M, Whittal R, Wuhrer M, Zhu Y, and Zou C
- Subjects
- Chromatography, Liquid, Glycosylation, Humans, Laboratories, Mass Spectrometry methods, Proteomics methods, Reproducibility of Results, Glycoproteins metabolism, Kallikreins metabolism, Polysaccharides metabolism, Prostate-Specific Antigen metabolism
- Abstract
One of the principal goals of glycoprotein research is to correlate glycan structure and function. Such correlation is necessary in order for one to understand the mechanisms whereby glycoprotein structure elaborates the functions of myriad proteins. The accurate comparison of glycoforms and quantification of glycosites are essential steps in this direction. Mass spectrometry has emerged as a powerful analytical technique in the field of glycoprotein characterization. Its sensitivity, high dynamic range, and mass accuracy provide both quantitative and sequence/structural information. As part of the 2012 ABRF Glycoprotein Research Group study, we explored the use of mass spectrometry and ancillary methodologies to characterize the glycoforms of two sources of human prostate specific antigen (PSA). PSA is used as a tumor marker for prostate cancer, with increasing blood levels used to distinguish between normal and cancer states. The glycans on PSA are believed to be biantennary N-linked, and it has been observed that prostate cancer tissues and cell lines contain more antennae than their benign counterparts. Thus, the ability to quantify differences in glycosylation associated with cancer has the potential to positively impact the use of PSA as a biomarker. We studied standard peptide-based proteomics/glycomics methodologies, including LC-MS/MS for peptide/glycopeptide sequencing and label-free approaches for differential quantification. We performed an interlaboratory study to determine the ability of different laboratories to correctly characterize the differences between glycoforms from two different sources using mass spectrometry methods. We used clustering analysis and ancillary statistical data treatment on the data sets submitted by participating laboratories to obtain a consensus of the glycoforms and abundances. The results demonstrate the relative strengths and weaknesses of top-down glycoproteomics, bottom-up glycoproteomics, and glycomics methods.
- Published
- 2013
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40. An AC electrokinetics facilitated biosensor cassette for rapid pathogen identification.
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Ouyang M, Mohan R, Lu Y, Liu T, Mach KE, Sin ML, McComb M, Joshi J, Gau V, Wong PK, and Liao JC
- Subjects
- Bacteria genetics, DNA, Bacterial analysis, DNA, Bacterial chemistry, Electrochemistry, Humans, Nucleic Acid Hybridization, Oligonucleotide Probes chemistry, Point-of-Care Systems, Thermometry, Time Factors, Urine microbiology, Bacteria isolation & purification, Biosensing Techniques methods
- Abstract
To develop a portable point-of-care system based on biosensors for common infectious diseases such as urinary tract infection, the sensing process needs to be implemented within an enclosed fluidic system. On chip sample preparation of clinical samples remains a significant obstacle to achieving robust sensor performance. Herein AC electrokinetics is applied in an electrochemical biosensor cassette to enhance molecular convection and hybridization efficiency through electrokinetics induced fluid motion and Joule heating induced temperature elevation. Using E. coli as an exemplary pathogen, we determined the optimal electrokinetic parameters for detecting bacterial 16S rRNA in the biosensor cassette based on the current output, signal-to-noise ratio, and limit of detection. In addition, a panel of six probe sets targeting common uropathogenic bacteria was demonstrated. The optimized parameters were also validated using patient-derived clinical urine samples. The effectiveness of electrokinetics for on chip sample preparation will facilitate the implementation of point-of-care diagnosis of urinary tract infection in the future.
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- 2013
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41. Human Proteinpedia enables sharing of human protein data.
- Author
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Mathivanan S, Ahmed M, Ahn NG, Alexandre H, Amanchy R, Andrews PC, Bader JS, Balgley BM, Bantscheff M, Bennett KL, Björling E, Blagoev B, Bose R, Brahmachari SK, Burlingame AS, Bustelo XR, Cagney G, Cantin GT, Cardasis HL, Celis JE, Chaerkady R, Chu F, Cole PA, Costello CE, Cotter RJ, Crockett D, DeLany JP, De Marzo AM, DeSouza LV, Deutsch EW, Dransfield E, Drewes G, Droit A, Dunn MJ, Elenitoba-Johnson K, Ewing RM, Van Eyk J, Faca V, Falkner J, Fang X, Fenselau C, Figeys D, Gagné P, Gelfi C, Gevaert K, Gimble JM, Gnad F, Goel R, Gromov P, Hanash SM, Hancock WS, Harsha HC, Hart G, Hays F, He F, Hebbar P, Helsens K, Hermeking H, Hide W, Hjernø K, Hochstrasser DF, Hofmann O, Horn DM, Hruban RH, Ibarrola N, James P, Jensen ON, Jensen PH, Jung P, Kandasamy K, Kheterpal I, Kikuno RF, Korf U, Körner R, Kuster B, Kwon MS, Lee HJ, Lee YJ, Lefevre M, Lehvaslaiho M, Lescuyer P, Levander F, Lim MS, Löbke C, Loo JA, Mann M, Martens L, Martinez-Heredia J, McComb M, McRedmond J, Mehrle A, Menon R, Miller CA, Mischak H, Mohan SS, Mohmood R, Molina H, Moran MF, Morgan JD, Moritz R, Morzel M, Muddiman DC, Nalli A, Navarro JD, Neubert TA, Ohara O, Oliva R, Omenn GS, Oyama M, Paik YK, Pennington K, Pepperkok R, Periaswamy B, Petricoin EF, Poirier GG, Prasad TS, Purvine SO, Rahiman BA, Ramachandran P, Ramachandra YL, Rice RH, Rick J, Ronnholm RH, Salonen J, Sanchez JC, Sayd T, Seshi B, Shankari K, Sheng SJ, Shetty V, Shivakumar K, Simpson RJ, Sirdeshmukh R, Siu KW, Smith JC, Smith RD, States DJ, Sugano S, Sullivan M, Superti-Furga G, Takatalo M, Thongboonkerd V, Trinidad JC, Uhlen M, Vandekerckhove J, Vasilescu J, Veenstra TD, Vidal-Taboada JM, Vihinen M, Wait R, Wang X, Wiemann S, Wu B, Xu T, Yates JR, Zhong J, Zhou M, Zhu Y, Zurbig P, and Pandey A
- Subjects
- Internationality, Magnetic Resonance Spectroscopy methods, Peptide Mapping methods, Proteome classification, Proteomics methods, Software, User-Computer Interface, Database Management Systems, Databases, Protein, Gene Expression Profiling methods, Information Storage and Retrieval methods, Internet, Proteome chemistry, Proteome metabolism
- Published
- 2008
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42. Is the "virtual school nurse" for your community?
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L'Heureux RA, Jackson M, and McComb M
- Subjects
- Humans, Needs Assessment organization & administration, Nursing Evaluation Research, School Nursing education, Program Evaluation methods, School Nursing organization & administration, Telemedicine organization & administration
- Published
- 2002
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43. The effects of oral conscious sedation on future behavior and anxiety in pediatric dental patients.
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McComb M, Koenigsberg SR, Broder HL, and Houpt M
- Subjects
- Anesthesia, Dental psychology, Case-Control Studies, Child Behavior, Child, Preschool, Female, Follow-Up Studies, Humans, Male, Manifest Anxiety Scale, Statistics, Nonparametric, Surveys and Questionnaires, Anesthesia, Dental methods, Conscious Sedation psychology, Dental Anxiety prevention & control, Dental Care for Children methods
- Abstract
Purpose: This study investigated the relationship between oral conscious sedation and subsequent behavior in the dental setting., Methods: The sample consisted of 38 children between the ages of 39 to 71 months (mean=50 months) who had been treated with oral sedation 2 to 34 months(mean=13 months) previously, and a control group of 38 children, matched by age (mean=51 months) and gender, who had received dental treatment without conscious sedation or general anesthesia one week to 3 years previously. Subjects were matched by age and gender. All children received a standard recall examination and a prophylaxis, during which behavior and anxiety were measured. Independent variables included age at the time of sedation, present age, gender, time elapsed since sedation, effectiveness of sedation, parental scores on Corah's Dental Anxiety Scale and parent's answers to a questionnaire. The dependent variables were child behavior (rated with the 4-point Frankl scale) and self-reported anxiety ratings., Results: Both groups had mean behavior ratings of positive or very positive (experimental group mean=3.13; control group mean=3.34). There were no statistically significant differences between the groups and there was little correlation of independent and dependent variables., Conclusions: There is no relationship between oral conscious sedation and the future behavior of children in the dental setting.
- Published
- 2002
44. On-membrane digestion of beta-casein for determination of phosphorylation sites by matrix-assisted laser desorption/ionization quadrupole/time-of-flight mass spectrometry.
- Author
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Lee CH, McComb ME, Bromirski M, Jilkine A, Ens W, Standing KG, and Perreault H
- Subjects
- Phosphates analysis, Phosphorylation, Polyurethanes, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization methods, Caseins analysis, Membranes, Artificial, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization instrumentation
- Abstract
This article discusses the features of a newly developed matrix-assisted laser desorption/ionization quadrupole/time-of-flight (MALDI-QqTOF) mass spectrometer that is useful in the analysis of phosphorylated peptides. Aliquots of beta-casein, a commonly used phosphorylated protein standard, were digested with trypsin directly on a non-porous polyurethane membrane used as sample support in MALDI-QqTOF mass spectrometry (MS) experiments. Although a complete peptide map was obtained, it was difficult to obtain sequence information for some of the tryptic fragments, in particular T1-2, which bears four phosphate groups and is thus difficult to ionize in positive mode. This article focuses on the sequencing of this particular fragment by comparing MS/MS spectra obtained using different precursor ions. These precursors associated with T1-2 were [M + H](+), [M + H](2+), and [M + H - nH(3)PO(4)](+) ions. Typically, phosphorylated ions showed facile unimolecular losses of phosphoric acid moieties, and produced limited backbone fragmentation. The abundance of [M + H](2+) ions of T1-2 in the full mass spectrum was low relative to that of [M + H](+). [M + H - 4H(3)PO(4)](+) ions as MS/MS precursors underwent backbone fragmentations, with phosphoserine residues transformed into dehydroalanines or serines. Unusual b + 18 u fragments were observed, although only for segments with previously phosphorylated serines. These partly interfered with c-ions, and were noticeable due to overlapping isotopic envelopes. It was possible to establish the sequence of phosphorylated tryptic fragment T1-2 and the location of phosphate groups using the mass of dehydroalanine residues (69 Da) and b + 18 u fragments as markers. All MS and MS/MS spectra obtained with fully phosphorylated beta-casein were compared with spectra acquired with dephosphorylated beta-casein obtained commercially. These comparisons helped assess the spectral differences caused by the presence of phosphate groups. Also, they highlighted the potential usefulness of conducting dephosphorylation directly on the probe prior to MALDI analysis in future studies., (Copyright 2001 John Wiley & Sons, Ltd.)
- Published
- 2001
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45. Secondary structure and oligomerization of the E. coli glycerol facilitator.
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Manley DM, McComb ME, Perreault H, Donald LJ, Duckworth HW, and O'Neil JD
- Subjects
- Bacterial Outer Membrane Proteins genetics, Bacterial Outer Membrane Proteins isolation & purification, Biological Transport, Cell Membrane metabolism, Circular Dichroism, Cross-Linking Reagents chemistry, Detergents, Electrophoresis, Polyacrylamide Gel, Escherichia coli genetics, Molecular Weight, Protein Structure, Secondary, Recombinant Proteins biosynthesis, Recombinant Proteins chemistry, Recombinant Proteins isolation & purification, Recombinant Proteins metabolism, Solubility, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Succinimides chemistry, Aquaporins, Bacterial Outer Membrane Proteins chemistry, Bacterial Outer Membrane Proteins metabolism, Escherichia coli metabolism, Escherichia coli Proteins, Glycerol metabolism
- Abstract
The Major Intrinsic Proteins are found throughout the bacterial, plant, and animal kingdoms and are responsible for the rapid transport of water and other small, polar solutes across membranes. The superfamily includes the aquaporins, the aquaglyceroporins, and the glycerol facilitators. We have overexpressed and purified the Escherichia coli inner membrane glycerol facilitator. Approximately 7.5 mg of 95% pure protein is obtained from 1 L of Escherichia coli cells using immobilized metal affinity chromatography. Well-resolved matrix-assisted laser desorption ionization mass spectra were obtained by solubilization of the protein in octyl-beta-D-glucopyranoside (M(r) = 33 650.3; error approximately 0.4%). The recombinant glycerol facilitator is inserted into the bacterial inner membrane, is functional, and is inhibited by HgCl(2). Polyacrylamide gel electrophoresis suggests that the facilitator is predominantly monomeric when solubilized with dodecyl-beta-D-maltoside, octyl-beta-D-glucopyranoside, and sodium dodecyl sulfate, but that it self-associates, forming soluble oligomers when urea is used during extraction. Similar oligomeric species are demonstrated to exist in the bacterial membrane by chemical cross-linking experiments. Circular dichroism analysis shows that the protein is predominantly alpha-helical. Helix content is significantly higher in protein prepared in the absence of urea (42-55%) than in its presence (32%). A possible role for the facilitator oligomers in interactions with, and regulation of, the glycerol kinase is discussed.
- Published
- 2000
- Full Text
- View/download PDF
46. Design of a sheathless capillary eletrophoresis-mass spectrometry probe for operation with a Z-spray ionization source.
- Author
-
McComb ME and Perreault H
- Subjects
- Myoglobin analysis, Electrophoresis, Capillary methods, Mass Spectrometry methods, Proteins analysis
- Abstract
The construction of a sheathless interface for capillary electrophoresis-electrospray ionization mass spectrometry (CE-ESI-MS), for operation with a Z-Spray source on a Micromass Quattro-LC triple quadrupole mass spectrometer is described. Designing the interface involved machining a probe compatible with the setup already in place on the mass spectrometer, i.e., MegaFlow-Z ESI. The probe was made of Lexan with the same dimensions as the ESI probe supplied with the instrument. The electrical connection at the electrospray end of the CE capillary was made possible by gold-coating (sheathless CE-ESI-MS). The probe design as well as the electrical and power supply requirements are described in detail. Experiments were performed using this interface, and CE separations of mixtures containing pmole and sub-pmole amounts of peptides were monitored by on-line MS. For a standard peptide mixture (10(-4) M), separation efficiency was typically characterized by N > 10(4) theoretical plates with S/N > 400. Using the same experimental setup, it was also possible to conduct on-line CE-ESI-tandem MS (MS/MS) experiments on the same peptide mixture, and to determine the sequence of the peptides. MS/MS scan functions for different precursor ions were used either alternately or sequentially and the results from both methods were compared. The possibility of peptide mass mapping was explored, and CE-ESI-MS results were obtained for the digestion products of equine myoglobin. Separation efficiencies and S/N values were similar to those obtained for standard peptides. A complete map of the digestion products was obtained.
- Published
- 2000
- Full Text
- View/download PDF
47. The active and passive sampling of benzene, toluene, ethyl benzene and xylenes compounds using the inside needle capillary adsorption trap device.
- Author
-
Shojania S, Oleschuk RD, McComb ME, Gesser HD, and Chow A
- Abstract
A new and simple method of solventless extraction of volatile organic compounds (VOCs) from air is presented. The sampling device has an adsorbing carbon coating on the interior surface of a hollow needle, and is called the inside needle capillary adsorption trap (INCAT). This paper describes a study of the reproducibility in the preparation and sampling of the INCAT device. In addition, this paper examines the effects of sample volume in active sampling and exposure time in passive sampling on the analyte adsorption. Analysis was achieved by sampling the air from an environmental chamber doped with benzene, toluene, ethyl benzene and xylenes (BTEX) compounds. Initial rates of adsorption were found to vary among the different compounds, but ranged from 0.0099 to 0.016 nmol h(-1) for passive sampling and from 2.2 to 10 nmol h(-1) for active sampling. Analysis was done by thermal desorption of the adsorbed compounds directly into a gas chromatograph injection port. Quantification of the analysis was done by comparison to actively sampled activated carbon solid phase extraction (SPE) measurements.
- Published
- 1999
- Full Text
- View/download PDF
48. Characterization of hemoglobin variants by MALDI-TOF MS using a polyurethane membrane as the sample support.
- Author
-
McComb ME, Oleschuk RD, Chow A, Ens W, Standing KG, Perreault H, and Smith M
- Subjects
- Genetic Variation, Hemoglobins genetics, Hemoglobins, Abnormal analysis, Humans, Membranes, Artificial, Trypsin, Hemoglobins analysis, Polyurethanes, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization methods
- Abstract
A new method for the sampling and off-site analysis of hemoglobin variants by mass spectrometry is reported. This technique uses a nonporous polyurethane membrane as the collection device and transportation medium of a blood sample for analysis. The same membrane is then used as the MALDI-TOF MS sample support for mass spectrometric analysis. Minimal invasive sample collection is afforded by collecting less than 1 microL of blood using a common lancet device. MALDI-TOF MS is performed directly on the membrane, after washing off the interfering plasma components, followed by the addition of matrix. This reduces the time of analysis and prevents sample loss. Enzymatic digestion can be performed directly on the membrane, using in this case trypsin, allowing for further characterization of the sample. The method is much less invasive compared to drawing blood with a syringe. The sample may be transported to the laboratory by regular mail, and thus the method can serve remote locations. We demonstrate the procedure by characterizing the Hb Shepherds Bush hemoglobin variant, b74-(E18)Gly-->Asp.
- Published
- 1998
- Full Text
- View/download PDF
49. Use of a non-porous polyurethane membrane as a sample support for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of peptides and proteins.
- Author
-
McComb ME, Oleschuk RD, Manley DM, Donald L, Chow A, O'Neil JD, Ens W, Standing KG, and Perreault H
- Subjects
- Citrate (si)-Synthase chemistry, Endopeptidases, Hydrolysis, Indicators and Reagents, Membranes, Artificial, Microscopy, Electron, Scanning, Polyurethanes, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Peptides analysis, Proteins analysis
- Abstract
Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) of proteins and peptides was performed on samples deposited onto non-porous ether-type polyurethane (PU) membranes. Spectra obtained using PU membranes showed that mass resolution and accuracy were equivalent to values observed using a metal target, and superior to those obtained using poly(vinylidene difluoride) (PVDF) membranes. A small apparent increase in the mass of proteins and also loss of resolution were observed at very high laser irradiance due to charging, but were not observed under normal conditions. Analysis of NaCl-doped standards demonstrated that PU membranes yielded better results than a metallic target for salt-containing solutions. Relatively strong hydrophobic interactions between the proteins and peptides and the PU membrane allowed the incorporation of a washing step. This step allowed for the removal of salts and buffer components and thus provided an increase in resolution and mass accuracy. Digestion of citrate synthase (a protein of molecular weight 47,886) with trypsin was performed directly on the surface of the membrane for variable periods of time, and characteristic peptide fragments were observed by MALDI-TOFMS. Delayed extraction was used to increase the resolution and to permit more accurate mass assignments for those fragments. The use of PU membranes for MALDI-TOFMS analysis of proteins with higher molecular weights is also demonstrated.
- Published
- 1997
- Full Text
- View/download PDF
50. Coordinate nursing care with auxiliary workers.
- Author
-
McCOMB MH
- Subjects
- Humans, Hospitals, Nursing
- Published
- 1950
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