Dr Karen Shaw

F-19-magnetic resonance imaging (MRI) is a promising technique that may allow us to measure the concentration of exogenous fluorinated imaging probes quantitatively in vivo. Here, we describe the synthesis and characterisation of a novel geminal bisphosphonate (F-19-BP) that contains chemically equivalent fluorine atoms that show a single and narrow F-19 resonance and a bisphosphonate group that may be used for labelling inorganic materials based in calcium phosphates and metal oxides. The potential of F-19-BP to provide contrast was analysed in vitro and in vivo using F-19-MRI. In vitro studies demonstrated the potential of F-19-BP as an MRI contrast agent in the millimolar concentration range with signal-to-noise ratios (SNR) comparable to previously reported fluorinated probes. The preliminary in vivo MRI study reported here allowed us to visualise the biodistribution of F-19-BP, showing uptake in the liver and in the bladder/urinary system areas. However, bone uptake was not observed. In addition,F-19-BP showed undesirable toxicity effects in mice that prevent further studies with this compound at the required concentrations for MRI contrast. This study highlights the importance of developing F-19-MRI probes with the highest signal intensity achievable. (C) 2016 The Authors. Published by Elsevier B.V.

We evaluated magnetic resonance imaging (MRI) voxel heterogeneity following trastuzumab and/or cisplatin in a HER2+ esophageal xenograft (OE19) as a potential response biomarker. OE19 xenografts treated with saline (controls), monotherapy, or combined cisplatin and trastuzumab underwent 9.4-T MRI. Tumor MRI parametric maps of T1 relaxation time (pre/post contrast), T2 relaxation time, T2* relaxation rate (R2*), and apparent diffusion coefficient obtained before (TIME0), after 24 hours (TIME1), and after 2 weeks of treatment (TIME2) were analyzed. Voxel histogram and fractal parameters (from the whole tumor, rim and center, and as a ratio of rim-to-center) were derived. Tumors were stained for immunohistochemical markers of hypoxia (CA-IX), angiogenesis (CD34), and proliferation (Ki-67). Combination therapy reduced xenograft growth rate (relative change, +0.58 +/- 0.43 versus controls, +4.1 +/- 1.0; P = 0.008). More spatially homogeneous voxel distribution between the rim to center was noted after treatment for combination therapy versus controls, respectively, for contrast-enhanced T1 relaxation time (90th percentile: ratio 1.00 versus 0.88, P = 0.009), T2 relaxation time (mean: 1.00 versus 0.92, P = 0.006; median: 0.98 versus 0.91, P = 0.006; 75th percentile: 1.02 versus 0.94, P = 0.007), and R2* (10th percentile: 0.99 versus 1.26, P = 0.003). We found that combination and trastuzumab monotherapy reduced MRI spatial heterogeneity and growth rate compared to the control or cisplatin groups, the former providing adjunctive tumor response information.

Sphingomyelin is the only sphingolipid occurring naturally in mammalian cells and can form up to 50% of the total phospholipid content of the myelin sheath which surrounds nerves. Having predominantly long, saturated acyl chains, it has a relatively high chain melting temperature and has been strongly associated with formation of lipid microdomains. Here, the lyotropic phase behaviour of sphingomyelin from three different natural sources (bovine brain, egg yolk and milk) in excess water is studied as a function of temperature and pressure by small- and wide-angle X-ray scattering, and solid state NMR. The different hydrocarbon chain length distributions of the three lipid extracts results in significant differences in their gel phase structure; both the bovine brain and egg yolk sphingomyelins can form a ripple gel phase but milk sphingomyelin forms an interdigitated gel phase due to the high degree of chain mismatch in its longer hydrocarbon chain components.

The subtle hypoxia underlying chronic cardiovascular disease is an attractive target for PET imaging, but the lead hypoxia imaging agents Cu-64-2,3-butanedione bis(N4-methylthiosemicarbazone) (ATSM) and F-18-fluoromisonidazole are trapped only at extreme levels of hypoxia and hence are insufficiently sensitive for this purpose. We have therefore sought an analog of Cu-64-ATSM better suited to identify compromised but salvageable myocardium, and we validated it using parallel biomarkers of cardiac energetics comparable to those observed in chronic cardiac ischemic syndromes. Methods: Rat hearts were perfused with aerobic buffer for 20 min, followed by a range of hypoxic buffers (using a computer-controlled gas mixer) for 45 min. Contractility was monitored by intraventricular balloon, energetics by P-31 nuclear MR spectroscopy, lactate and creatine kinase release spectrophotometrically, and hypoxia-inducible factor 1-alpha by Western blotting. Results: We identified a key hypoxia threshold at a 30% buffer O-2 saturation that induces a stable and potentially survivable functional and energetic compromise: left ventricular developed pressure was depressed by 20%, and cardiac phosphocreatine was depleted by 65.5% +/- 14% (P < 0.05 vs. control), but adenosine triphosphate levels were maintained. Lactate release was elevated (0.21 +/- 0.067 mmol/L/min vs. 0.056 +/- 0.01 mmol/L/min, P < 0.05) but not maximal (0.46 +/- 0.117 mmol/L/min), indicating residual oxidative metabolic capacity. Hypoxia-inducible factor 1-alpha was elevated but not maximal. At this key threshold, Cu-64-2,3-pentanedione bis(thiosemicarbazone) (CTS) selectively deposited significantly more Cu-64 than any other tracer we examined (61.8% +/- 9.6% injected dose vs. 29.4% +/- 9.5% for Cu-64-ATSM, P < 0.05). Conclusion: The hypoxic threshold that induced survivable metabolic and functional compromise was 30% O-2. At this threshold, only Cu-64-CTS delivered a hypoxic-to-normoxic contrast of 3: 1, and it therefore warrants in vivo evaluation for imaging chronic cardiac ischemic syndromes.