Model free approach to kinetic analysis of real-time hyperpolarized 13C magnetic resonance spectroscopy data.
Real-time detection of the rates of metabolic flux, or exchange rates of endogenous enzymatic reactions, is now feasible in biological systems using Dynamic Nuclear Polarization Magnetic Resonance. Derivation of reaction rate kinetics from this technique typically requires multi-compartmental modeli...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3762840?pdf=render |
| _version_ | 1818136605617029120 |
|---|---|
| author | Deborah K Hill Matthew R Orton Erika Mariotti Jessica K R Boult Rafal Panek Maysam Jafar Harold G Parkes Yann Jamin Maria Falck Miniotis Nada M S Al-Saffar Mounia Beloueche-Babari Simon P Robinson Martin O Leach Yuen-Li Chung Thomas R Eykyn |
| author_facet | Deborah K Hill Matthew R Orton Erika Mariotti Jessica K R Boult Rafal Panek Maysam Jafar Harold G Parkes Yann Jamin Maria Falck Miniotis Nada M S Al-Saffar Mounia Beloueche-Babari Simon P Robinson Martin O Leach Yuen-Li Chung Thomas R Eykyn |
| author_sort | Deborah K Hill |
| collection | DOAJ |
| description | Real-time detection of the rates of metabolic flux, or exchange rates of endogenous enzymatic reactions, is now feasible in biological systems using Dynamic Nuclear Polarization Magnetic Resonance. Derivation of reaction rate kinetics from this technique typically requires multi-compartmental modeling of dynamic data, and results are therefore model-dependent and prone to misinterpretation. We present a model-free formulism based on the ratio of total areas under the curve (AUC) of the injected and product metabolite, for example pyruvate and lactate. A theoretical framework to support this novel analysis approach is described, and demonstrates that the AUC ratio is proportional to the forward rate constant k. We show that the model-free approach strongly correlates with k for whole cell in vitro experiments across a range of cancer cell lines, and detects response in cells treated with the pan-class I PI3K inhibitor GDC-0941 with comparable or greater sensitivity. The same result is seen in vivo with tumor xenograft-bearing mice, in control tumors and following drug treatment with dichloroacetate. An important finding is that the area under the curve is independent of both the input function and of any other metabolic pathways arising from the injected metabolite. This model-free approach provides a robust and clinically relevant alternative to kinetic model-based rate measurements in the clinical translation of hyperpolarized (13)C metabolic imaging in humans, where measurement of the input function can be problematic. |
| first_indexed | 2024-12-11T09:43:04Z |
| format | Article |
| id | doaj.art-206e54d42db24a00bdc11c1c47e6760f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T09:43:04Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-206e54d42db24a00bdc11c1c47e6760f2022-12-22T01:12:37ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0189e7199610.1371/journal.pone.0071996Model free approach to kinetic analysis of real-time hyperpolarized 13C magnetic resonance spectroscopy data.Deborah K HillMatthew R OrtonErika MariottiJessica K R BoultRafal PanekMaysam JafarHarold G ParkesYann JaminMaria Falck MiniotisNada M S Al-SaffarMounia Beloueche-BabariSimon P RobinsonMartin O LeachYuen-Li ChungThomas R EykynReal-time detection of the rates of metabolic flux, or exchange rates of endogenous enzymatic reactions, is now feasible in biological systems using Dynamic Nuclear Polarization Magnetic Resonance. Derivation of reaction rate kinetics from this technique typically requires multi-compartmental modeling of dynamic data, and results are therefore model-dependent and prone to misinterpretation. We present a model-free formulism based on the ratio of total areas under the curve (AUC) of the injected and product metabolite, for example pyruvate and lactate. A theoretical framework to support this novel analysis approach is described, and demonstrates that the AUC ratio is proportional to the forward rate constant k. We show that the model-free approach strongly correlates with k for whole cell in vitro experiments across a range of cancer cell lines, and detects response in cells treated with the pan-class I PI3K inhibitor GDC-0941 with comparable or greater sensitivity. The same result is seen in vivo with tumor xenograft-bearing mice, in control tumors and following drug treatment with dichloroacetate. An important finding is that the area under the curve is independent of both the input function and of any other metabolic pathways arising from the injected metabolite. This model-free approach provides a robust and clinically relevant alternative to kinetic model-based rate measurements in the clinical translation of hyperpolarized (13)C metabolic imaging in humans, where measurement of the input function can be problematic.http://europepmc.org/articles/PMC3762840?pdf=render |
| spellingShingle | Deborah K Hill Matthew R Orton Erika Mariotti Jessica K R Boult Rafal Panek Maysam Jafar Harold G Parkes Yann Jamin Maria Falck Miniotis Nada M S Al-Saffar Mounia Beloueche-Babari Simon P Robinson Martin O Leach Yuen-Li Chung Thomas R Eykyn Model free approach to kinetic analysis of real-time hyperpolarized 13C magnetic resonance spectroscopy data. PLoS ONE |
| title | Model free approach to kinetic analysis of real-time hyperpolarized 13C magnetic resonance spectroscopy data. |
| title_full | Model free approach to kinetic analysis of real-time hyperpolarized 13C magnetic resonance spectroscopy data. |
| title_fullStr | Model free approach to kinetic analysis of real-time hyperpolarized 13C magnetic resonance spectroscopy data. |
| title_full_unstemmed | Model free approach to kinetic analysis of real-time hyperpolarized 13C magnetic resonance spectroscopy data. |
| title_short | Model free approach to kinetic analysis of real-time hyperpolarized 13C magnetic resonance spectroscopy data. |
| title_sort | model free approach to kinetic analysis of real time hyperpolarized 13c magnetic resonance spectroscopy data |
| url | http://europepmc.org/articles/PMC3762840?pdf=render |
| work_keys_str_mv | AT deborahkhill modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT matthewrorton modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT erikamariotti modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT jessicakrboult modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT rafalpanek modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT maysamjafar modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT haroldgparkes modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT yannjamin modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT mariafalckminiotis modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT nadamsalsaffar modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT mouniabelouechebabari modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT simonprobinson modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT martinoleach modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT yuenlichung modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata AT thomasreykyn modelfreeapproachtokineticanalysisofrealtimehyperpolarized13cmagneticresonancespectroscopydata |