Radiosynthesis and analysis of (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid

Purpose: (S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid ([18F]FSPG) is an L-glutamate derivative used as a PET biomarker to assess intracellular redox status in vivo through targeting of the cystine/glutamate antiporter protein, xc− transporter. In this report, we describe a radiosynthesis of [18F]FSPG for use in PET studies that address specific challenges in relation to the radiotracer purity, molar activity, and quality control testing methods. Procedures: The radiosynthesis of [18F]FSPG was performed using a customised RNPlus Research automated radiosynthesis system (Synthra GmbH, Hamburg, Germany). [18F]FSPG was labelled in the 3-fluoropropylmoiety at the 4-position of the glutamic acid backbone with fluorine-18 via substitution of nucleophilic [18F]fluoride with a protected naphthylsulfonyloxy-propyl-L-glutamate derivative. Radiochemical purity of the final product was determined by radio HPLC using a new method of direct analysis using a Hypercarb C18 column. Results: The average radioactivity yield of [18F]FSPG was 4.2 GBq (range, 3.4–4.8 GBq) at the end of synthesis, starting from 16 GBq of [18F]fluoride at the end of bombardment (n = 10) in a synthesis time of 50 min. The average molar activity and radioactivity volumetric concentration at the end of synthesis were 66 GBq µmol−1 (range, 48–73 GBq µmol−1) and 343–400 MBq mL−1, respectively. Conclusion: Stability tests using a 4.6 GBq dose with a radioactivity volumetric concentration of 369 MBq mL−1 at the end of synthesis showed no observable radiolysis 3 h after production. The formulated product is of high radiochemical purity (> 95%) and higher molar activity compared to previous methods and is safe to inject into mice up to 3 h after production

A Near-Surface Microstructure Sensor System Used During TOGA COARE. Part I: Bow Measurements.

High-resolution probes mounted on the bow of the vessel at a 1.7-m depth in an undisturbed region ahead of the moving vessel were used for microstructure and turbulence measurements in the near-surface layer of the ocean during TOGA COARE. The probes measured temperature, conductivity, pressure, three-component fluctuation velocity, and two components of acceleration. Accumulation of large amounts of high-quality nearsurface data poses a difficult challenge, and deployment from the bow of a ship, such as is done with these sensors, requires rugged, well-calibrated, and low-noise sensors. The heaving motion of the ship that causes the sensors to break through the surface requires data processing algorithms unique to this application. Due to the presence of surface waves and the associated pitching of the vessel, the bow probes ‘‘scanned’’ the near-surface layer of the ocean. Combining the bow sensor’s signals with the ship’s thermosalinograph pumping water from 3-m depth resulted in the near-surface dataset with both fine temporal/spatial resolution and high absolute accuracy. Contour plots calculated using the bow signals reveal the spatial structure of the diurnal thermocline and rain-formed halocline. The localization in narrow frequency bands of the vibrations of the bow sensors allows calculation of dissipation rates. The characteristics of the sensors and the data processing algorithms related to the periodic surface penetration by the sensors are discussed in this paper

The Friendly Settlement of Human Rights Abuses in the Americas

We present a new method for estimation of seismic coda shape. It falls into the same class of methods as non-parametric shape reconstruction with the use of neural network techniques where data are split into a training and validation data sets. We particularly pursue the well-known problem of image reconstruction formulated in this case as shape isolation in the presence of a broadly defined noise. This combined approach is enabled by the intrinsic feature of seismogram which can be divided objectively into a pre-signal seismic noise with lack of the target shape, and the remainder that contains scattered waveforms compounding the coda shape. In short, we separately apply shape restoration procedure to pre-signal seismic noise and the event record, which provides successful delineation of the coda shape in the form of a smooth almost non-oscillating function of time. The new algorithm uses a recently developed generalization of classical computational-geometry tool of alpha-shape. The generalization essentially yields robust shape estimation by ignoring locally a number of points treated as extreme values, noise or non-relevant data. Our algorithm is conceptually simple and enables the desired or pre-determined level of shape detail, constrainable by an arbitrary data fit criteria. The proposed tool for coda shape delineation provides an alternative to moving averaging and/or other smoothing techniques frequently used for this purpose. The new algorithm is illustrated with an application to the problem of estimating the coda duration after a local event. The obtained relation coefficient between coda duration and epicentral distance is consistent with the earlier findings in the region of interest

Evolution and connectivity in the world-wide migration system of the mallard: Inferences from mitochondrial DNA

<p>Abstract</p> <p>Background</p> <p>Main waterfowl migration systems are well understood through ringing activities. However, in mallards (<it>Anas platyrhynchos</it>) ringing studies suggest deviations from general migratory trends and traditions in waterfowl. Furthermore, surprisingly little is known about the population genetic structure of mallards, and studying it may yield insight into the spread of diseases such as Avian Influenza, and in management and conservation of wetlands. The study of evolution of genetic diversity and subsequent partitioning thereof during the last glaciation adds to ongoing discussions on the general evolution of waterfowl populations and flyway evolution. Hypothesised mallard flyways are tested explicitly by analysing mitochondrial mallard DNA from the whole northern hemisphere.</p> <p>Results</p> <p>Phylogenetic analyses confirm two mitochondrial mallard clades. Genetic differentiation within Eurasia and North-America is low, on a continental scale, but large differences occur between these two land masses (<it>F</it>_ST= 0.51). Half the genetic variance lies within sampling locations, and a negligible portion between currently recognised waterfowl flyways, within Eurasia and North-America. Analysis of molecular variance (AMOVA) at continent scale, incorporating sampling localities as smallest units, also shows the absence of population structure on the flyway level. Finally, demographic modelling by coalescence simulation proposes a split between Eurasia and North-America 43,000 to 74,000 years ago and strong population growth (~100fold) since then and little migration (not statistically different from zero).</p> <p>Conclusions</p> <p>Based on this first complete assessment of the mallard's world-wide population genetic structure we confirm that no more than two mtDNA clades exist. Clade A is characteristic for Eurasia, and clade B for North-America although some representatives of clade A are also found in North-America. We explain this pattern by evaluating competing hypotheses and conclude that a complex mix of historical, recent and anthropogenic factors shaped the current mallard populations. We refute population classification based on flyways proposed by ornithologists and managers, because they seem to have little biological meaning. Our results have implications for wetland management and conservation, with special regard to the release of farmed mallards for hunting, as well as for the possible transmission of Avian Influenza by mallards due to migration.</p

High molar activity [18F]tetrafluoroborate synthesis for sodium iodide symporter imaging by PET

Background: Sodium iodide symporter (NIS) imaging by positron emission tomography (PET) is gaining traction in nuclear medicine, with an increasing number of human studies being published using fluorine-18 radiolabelled tetrafluoroborate ([18F]TFB). Clinical success of any radiotracer relies heavily on its accessibility, which in turn depends on the availability of robust radiolabelling procedures providing a radiotracer in large quantities and of high radiopharmaceutical quality. Results: Here we publish an improved radiolabelling method and quality control procedures for high molar activity [18F]TFB. The use of ammonium hydroxide for [18F]fluoride elution, commercially available boron trifluoride-methanol complex dissolved in acetonitrile as precursor and removal of unreacted [18F]fluoride on Florisil solid-phase extraction cartridges resulted in the reliable production of [18F]TFB on SYNTHRA and TRACERLAB FXFN automated synthesizers with radiochemical yields in excess of 30%, radiochemical purities in excess of 98% and molar activities in the range of 34–217 GBq/µmol at the end of synthesis. PET scanning of a mouse lung tumour model carrying a NIS reporter gene rendered images of high quality and improved sensitivity. Conclusions: A novel automated radiosynthesis procedure for [18F]tetrafluoroborate has been developed that provides the radiotracer with high molar activity, suitable for preclinical imaging of NIS reporter gene

18F-C2Am: a targeted imaging agent for detecting tumor cell death in vivo using positron emission tomography.

INTRODUCTION: Trialing novel cancer therapies in the clinic would benefit from imaging agents that can detect early evidence of treatment response. The timing, extent and distribution of cell death in tumors following treatment can give an indication of outcome. We describe here an 18F-labeled derivative of a phosphatidylserine-binding protein, the C2A domain of Synaptotagmin-I (C2Am), for imaging tumor cell death in vivo using PET. METHODS: A one-pot, two-step automated synthesis of N-(5-[18F]fluoropentyl)maleimide (60 min synthesis time, > 98% radiochemical purity) has been developed, which was used to label the single cysteine residue in C2Am within 30 min at room temperature. Binding of 18F-C2Am to apoptotic and necrotic tumor cells was assessed in vitro, and also in vivo, by dynamic PET and biodistribution measurements in mice bearing human tumor xenografts treated with a TRAILR2 agonist or with conventional chemotherapy. C2Am detection of tumor cell death was validated by correlation of probe binding with histological markers of cell death in tumor sections obtained immediately after imaging. RESULTS: 18F-C2Am showed a favorable biodistribution profile, with predominantly renal clearance and minimal retention in spleen, liver, small intestine, bone and kidney, at 2 h following probe administration. 18F-C2Am generated tumor-to-muscle (T/m) ratios of 6.1 ± 2.1 and 10.7 ± 2.4 within 2 h of probe administration in colorectal and breast tumor models, respectively, following treatment with the TRAILR2 agonist. The levels of cell death (CC3 positivity) following treatment were 12.9-58.8% and 11.3-79.7% in the breast and colorectal xenografts, respectively. Overall, a 20% increase in CC3 positivity generated a one unit increase in the post/pre-treatment tumor contrast. Significant correlations were found between tracer uptake post-treatment, at 2 h post-probe administration, and histological markers of cell death (CC3: Pearson R = 0.733, P = 0.0005; TUNEL: Pearson R = 0.532, P = 0.023). CONCLUSION: The rapid clearance of 18F-C2Am from the blood pool and low kidney retention allowed the spatial distribution of cell death in a tumor to be imaged during the course of therapy, providing a rapid assessment of tumor treatment response. 18F-C2Am has the potential to be used in the clinic to assess early treatment response in tumors

Correction to: The relationship between endogenous thymidine concentrations and [18F]FLT uptake in a range of preclinical tumour models.

Unfortunately, the original version of Figs. 4, 5 and 6b in the article [1] contained errors in the n numbers as indicated on the columns. Please note that column heights and error bars in the original figures and data in the ESM tables are correct and statistical tests are valid. These corrections do not affect any results or conclusions in this article

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution

Biological Earth observation with animal sensors

Space-based tracking technology using low-cost miniature tags is now delivering data on fine-scale animal movement at near-global scale. Linked with remotely sensed environmental data, this offers a biological lens on habitat integrity and connectivity for conservation and human health; a global network of animal sentinels of environmen-tal change