Samira M. Kazan

The University of Sheffield, Sheffield, England, United Kingdom

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Publications (4)11.72 Total impact

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    ABSTRACT: To estimate the rate constant for pyruvate to lactate conversion in tumours in response to a hypoxic challenge, using hyperpolarised (13)C1-pyruvate and magnetic resonance spectroscopy. Hypoxic inspired gas was used to manipulate rat P22 fibrosarcoma oxygen tension (pO2), confirmed by luminescence decay of oxygen-sensitive probes. Hyperpolarised (13)C1-pyruvate was injected into the femoral vein of anaesthetised rats and slice-localised (13)C magnetic resonance (MR) spectra acquired. Spectral integral versus time curves for pyruvate and lactate were fitted to a precursor-product model to estimate the rate constant for tumour conversion of pyruvate to lactate (kpl). Mean arterial blood pressure (MABP) and oxygen tension (ArtpO2) were monitored. Pyruvate and lactate concentrations were measured in freeze-clamped tumours. MABP, ArtpO2 and tumour pO2 decreased significantly during hypoxia. kpl increased significantly (p<0.01) from 0.029±0.002s(-1) to 0.049±0.006s(-1) (mean±SEM) when animals breathing air were switched to hypoxic conditions, whereas pyruvate and lactate concentrations were minimally affected by hypoxia. Both ArtpO2 and MABP influenced the estimate of kpl, with a strong negative correlation between kpl and the product of ArtpO2 and MABP under hypoxia. The rate constant for pyruvate to lactate conversion, kpl, responds significantly to a rapid reduction in tumour oxygenation. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
    Radiotherapy and Oncology 03/2015; 11. DOI:10.1016/j.radonc.2015.03.011 · 4.86 Impact Factor
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    ABSTRACT: Mathematical models are required to estimate kinetic parameters of [1-(13) C] pyruvate-lactate interconversion from magnetic resonance spectroscopy data. One- or two-way exchange models utilizing a hypothetical approximation to the true arterial input function (AIF), (e.g. an ideal 'box-car' function) have been used previously. We present a method for direct measurement of the AIF in the rat. The hyperpolarized [1-(13) C] pyruvate signal was measured in arterial blood as it was continuously withdrawn through a small chamber. The measured signal was corrected for T(1) relaxation of pyruvate, RF pulses and dispersion of blood in the chamber to allow for the estimation of the direct AIF. Using direct AIF, rather than the commonly used box-car AIF, provided realistic estimates of the rate constant of conversion of pyruvate to lactate, k(pl) , the rate constant of conversion of lactate to pyruvate k(lp) , the clearance rate constant of pyruvate from blood to tissue, K(ip) , and the relaxation rate of lactate T(1la) . Since no lactate signal was present in blood, it was possible to use a simple precursor-product relationship, with the tumor tissue pyruvate time-course as the input for the lactate time-course. This provided a robust estimate of k(pl) , similar to that obtained using a directly measured AIF. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 10/2013; 70(4). DOI:10.1002/mrm.24546 · 3.40 Impact Factor
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    ABSTRACT: Over recent years hyperpolarization by dissolution dynamic nuclear polarization has become an established technique for studying metabolism in vivo in animal models. Temporal signal plots obtained from the injected metabolite and daughter products, e.g. pyruvate and lactate, can be fitted to compartmental models to estimate kinetic rate constants. Modelling and physiological parameter estimation can be made more robust by consistent and reproducible injections through automation. An injection system previously developed by us was limited in the injectable volume to between 0.6 and 2.4 ml and injection was delayed due to a required syringe filling step. An improved MR-compatible injector system has been developed that measures the pH of injected substrate, uses flow control to reduce dead volume within the injection cannula and can be operated over a larger volume range. The delay time to injection has been minimised by removing the syringe filling step by use of a peristaltic pump. For 100 ul to 10.000 ml, the volume range typically used for mice to rabbits, the average delivered volume was 97.8% of the demand volume. The standard deviation of delivered volumes was & ul for 100 ul and 200 ul for 10.000 ml demand volumes (mean S.D. was 9 ul in this range). In three repeat injections through a fixed 0.96 mm O.D tube the coefficient of variation for the area under the curve was 2%. For in vivo injections of hyperpolarized pyruvate in tumor-bearing rats, signal was first detected in the input femoral vein cannula at 3-4 s post injection trigger signal and at 9-12 s in tumor tissue. The pH of the injected pyruvate was 7.1± 0.3 (mean ± S.D., n=10). For small injection volumes, e.g. less than 100 ul, the internal diameter of the tubing contained within the peristaltic pump could be reduced to improve accuracy. Larger injection volumes are limited only by the size of the receiving vessel connected to the pump.
    Journal of Magnetic Resonance 01/2013; 239. DOI:10.1016/j.jmr.2013.10.024 · 2.32 Impact Factor
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    ABSTRACT: A major application of dynamic nuclear polarization has been in the study of the conversion of hyperpolarized 13C1-pyruvate to lactate in various disease models. In a typical experimental protocol, hyperpolarized pyruvate is converted from solid to liquid state with superheated fluid and collected in a receiving vessel. The hyperpolarized solution is then rapidly transferred by hand from the polarizer to the imaging magnet, where it is manually injected through an intravenous cannula into the test subject by an experienced operator. Such a procedure leads to inconsistencies in timing, injection rate and volume, all of which can influence the time resolved signal as the pyruvate is metabolized. We have developed a fully magnetic-resonance-compatible withdraw/infuse syringe pump made entirely of plastic so that it can be operated within the bore of an unshielded 7 T (310 mm) magnet. The injector can be programed for variable injection volumes and rates to permit the rapid and reproducible injection of hyperpolarized material without human intervention. The injector was designed for use with 1 ml or 3 ml syringes with a maximum delivery volume of 2.4 ml. The standard deviation of delivered volume from the desired volume was found to be 0.7 % across a volume range of 0.6–2.4 ml.
    Applied Magnetic Resonance 07/2012; 43(1-2). DOI:10.1007/s00723-012-0333-x · 1.15 Impact Factor