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Measurements of hyperpolarized 13C label exchange between injected [1‐13C]pyruvate and the endogenous tumor lactate pool can give an apparent first‐order rate constant for the exchange. The determination of the isotope flux, however, requires an estimate of the labeled pyruvate concentration in the tumor. This was achieved here by measurement of the tumor uptake of [1‐14C]pyruvate, which showed that <2% of the injected pyruvate reached the tumor site. Multiplication of this estimated labeled pyruvate concentration in the tumor with the apparent first‐order rate constant for hyperpolarized 13C label exchange gave an isotope flux that showed good agreement with a flux determined directly by the injection of non‐polarized [3‐13C]pyruvate, rapid excision of the tumor after 30 s and measurement of 13C‐labeled lactate concentrations in tumor extracts. The distribution of labeled lactate between intra‐ and extracellular compartments and the blood pool was investigated by imaging, by measurement of the labeled lactate concentration in blood and tumor, and by examination of the effects of a gadolinium contrast agent and a lactate transport inhibitor on the intensity of the hyperpolarized [1‐13C]lactate signal. These measurements showed that there was significant export of labeled lactate from the tumor, but that labeled lactate in the blood pool produced by the injection of hyperpolarized [1‐13C]pyruvate showed only relatively low levels of polarization. This study shows that measurements of hyperpolarized 13C label exchange between pyruvate and lactate in a murine tumor model can provide an estimate of the true isotope flux if the concentration of labeled pyruvate that reaches the tumor can be determined. [ABSTRACT FROM AUTHOR]

Meeting Summary The 24th annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK on Friday 6th November 2015. The meeting was attended by 77 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral presentations, short 'flash' presentations in association with particular posters and poster presentations. The scientific areas covered included isotopic synthesis, regulatory issues, applications of labelled compounds in imaging, isotopic separation and novel chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium was divided into a morning session chaired by Dr Rebekka Hueting (University of Oxford, UK) and afternoon sessions chaired by Dr Sofia Pascu (University of Bath, UK) and by Dr Alan Dowling (Syngenta, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK). [ABSTRACT FROM AUTHOR]

Glioma-derived cell-free DNA (cfDNA) is challenging to detect using liquid biopsy because quantities in body fluids are low. We determined the glioma-derived DNA fraction in cerebrospinal fluid (CSF), plasma, and urine samples from patients using sequencing of personalized capture panels guided by analysis of matched tumor biopsies. By sequencing cfDNA across thousands of mutations, identified individually in each patient's tumor, we detected tumor-derived DNA in the majority of CSF (7/8), plasma (10/12), and urine samples (10/16), with a median tumor fraction of 6.4 × 10 -3 , 3.1 × 10 -5 , and 4.7 × 10 -5 , respectively. We identified a shift in the size distribution of tumor-derived cfDNA fragments in these body fluids. We further analyzed cfDNA fragment sizes using whole-genome sequencing, in urine samples from 35 glioma patients, 27 individuals with non-malignant brain disorders, and 26 healthy individuals. cfDNA in urine of glioma patients was significantly more fragmented compared to urine from patients with non-malignant brain disorders (P = 1.7 × 10 -2 ) and healthy individuals (P = 5.2 × 10 -9 ). Machine learning models integrating fragment length could differentiate urine samples from glioma patients (AUC = 0.80-0.91) suggesting possibilities for truly non-invasive cancer detection., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

The aim of this brief review has been to illustrate the enormous power of molecular genetic techniques for testing out our, sometimes old, models of metabolic control. The technology allows us to ask some very simple but direct questions about the importance of specific enzymes in the control of flux. The answers, however, may not always be straightforward in that the absence of a change in pathway flux does not necessarily indicate that the enzyme is unimportant in flux control. Rather it would seem, from the relatively few studies that have been done, that the changes in the biological system which occur in response to a change in the concentration of a specific enzyme could tell us a lot about the role of that enzyme in metabolism and how it is controlled. I have restricted my discussion to studies in which relatively large numbers of cells have been modified genetically and subsequently characterized. This ignores a large and growing area in which micro-injection techniques are being used to introduce plasmid DNA or proteins into individual cells. The resultant phenotypes are then characterized at the single cell level using very sensitive optical techniques, such as fluorescence and bioluminescence. The reader is referred to a recent article for an example of this type of approach.