Free Tracer Research Articles

Whole-Body Multiparametric PET in Clinical Oncology: Current Status, Challenges, and Opportunities.

The interpretation of clinical oncologic PET studies has historically used static reconstructions based on SUVs. SUVs and SUV-based images have important limitations, including dependence on uptake times and reduced conspicuity of tracer-avid lesions in organs with high background uptake. The acquisition of dynamic PET images enables additional PET reconstructions via Patlak modeling, which assumes that a tracer is irreversibly trapped by tissues of interest. The resulting multiparametric PET images capture a tracer's net trapping rate (Ki) and apparent volume of distribution (VD), separating the contributions of bound and free tracer fractions to the PET signal captured in the SUV. Potential benefits of multiparametric PET include higher quantitative stability, superior lesion conspicuity, and greater accuracy for differentiating malignant and benign lesions. However, the imaging protocols necessary for multiparametric PET are inherently more complex and time-intensive, despite the recent introduction of automated or semiautomated scanner-based reconstruction packages. In this Review, we examine the current state of multiparametric PET in whole-body oncologic imaging. We summarize the Patlak methodology and relevant tracer kinetics, discuss clinical workflows and protocol considerations, and highlight clinical challenges and opportunities. We aim to help oncologic imagers make informed decisions about whether to implement multiparametric PET in their clinical practices.

Physically informed deep neural networks for metabolite-corrected plasma input function estimation in dynamic PET imaging

Introduction:We propose a novel approach for the non-invasive quantification of dynamic PET imaging data, focusing on the arterial input function (AIF) without the need for invasive arterial cannulation. Methods:Our method utilizes a combination of three-dimensional depth-wise separable convolutional layers and a physically informed deep neural network to incorporatea priori knowledge about the AIF’s functional form and shape, enabling precise predictions of the concentrations of [11C]PBR28 in whole blood and the free tracer in metabolite-corrected plasma. Results:We found a robust linear correlation between our model’s predicted AIF curves and those obtained through traditional, invasive measurements. We achieved an average cross-validated Pearson correlation of 0.86 for whole blood and 0.89 for parent plasma curves. Moreover, our method’s ability to estimate the volumes of distribution across several key brain regions – without significant differences between the use of predicted versus actual AIFs in a two-tissue compartmental model – successfully captures the intrinsic variability related to sex, the binding affinity of the translocator protein (18 kDa), and age. Conclusions:These results not only validate our method’s accuracy and reliability but also establish a foundation for a streamlined, non-invasive approach to dynamic PET data quantification. By offering a precise and less invasive alternative to traditional quantification methods, our technique holds significant promise for expanding the applicability of PET imaging across a wider range of tracers, thereby enhancing its utility in both clinical research and diagnostic settings.

Exact parameter identification in PET pharmacokinetic modeling using the irreversible two tissue compartment model * *This work was partly funded by the NIH Grants P41-EB017183 and R01-EB031199-02.

Objective. In quantitative dynamic positron emission tomography (PET), time series of images, reflecting the tissue response to the arterial tracer supply, are reconstructed. This response is described by kinetic parameters, which are commonly determined on basis of the tracer concentration in tissue and the arterial input function. In clinical routine the latter is estimated by arterial blood sampling and analysis, which is a challenging process and thus, attempted to be derived directly from reconstructed PET images. However, a mathematical analysis about the necessity of measurements of the common arterial whole blood activity concentration, and the concentration of free non-metabolized tracer in the arterial plasma, for a successful kinetic parameter identification does not exist. Here we aim to address this problem mathematically. Approach. We consider the identification problem in simultaneous pharmacokinetic modeling of multiple regions of interests of dynamic PET data using the irreversible two-tissue compartment model analytically. In addition to this consideration, the situation of noisy measurements is addressed using Tikhonov regularization. Furthermore, numerical simulations with a regularization approach are carried out to illustrate the analytical results in a synthetic application example.Main results. We provide mathematical proofs showing that, under reasonable assumptions, all metabolic tissue parameters can be uniquely identified without requiring additional blood samples to measure the arterial input function. A connection to noisy measurement data is made via a consistency result, showing that exact reconstruction of the ground-truth tissue parameters is stably maintained in the vanishing noise limit. Furthermore, our numerical experiments suggest that an approximate reconstruction of kinetic parameters according to our analytic results is also possible in practice for moderate noise levels. Significance. The analytical result, which holds in the idealized, noiseless scenario, suggests that for irreversible tracers, fully quantitative dynamic PET imaging is in principle possible without costly arterial blood sampling and metabolite analysis.

Enhanced Delivery of 5-Aminolevulinic Acid by Lecithin Invasomes in 3D Melanoma Cancer Model.

Photodynamic therapy (PDT) is a noninvasive therapeutic approach for the treatment of skin cancer and diseases. 5-Aminolevulinic acid is a prodrug clinically approved for PDT. Once internalized by cancer cells, it is rapidly metabolized to the photosensitizer protoporphyrin IX, which under the proper light irradiation, stimulates the deleterious reactive oxygen species (ROS) production and leads to cell death. The high hydrophilicity of 5-aminolevulinic acid limits its capability to cross the epidermis. Lipophilic derivatives of 5-aminolevulinic acid only partly improved skin penetration, thus making its incorporation into nanocarriers necessary. Here we have developed and characterized 5-aminolevulinic acid loaded invasomes made of egg lecithin, either 1,2-dilauroyl-sn-glycero-3-phosphocholine or 1,2-dioleoyl-sn-glycero-3-phosphocholine, and the terpene limonene. The obtained invasomes are highly thermostable and display a spherical morphology with an average size of 150 nm and an encapsulation efficiency of 80%; moreover, the ex vivo epidermis diffusion tests established that nanovesicles containing the terpene led to a much higher skin penetration (up to 80% in 3 h) compared to those without limonene and to the free fluorescent tracer (less than 50%). Finally, in vitro studies with 2D and 3D human cell models of melanoma proved the biocompatibility of invasomes, the enhanced intracellular transport of 5-aminolevulinic acid, its ability to generate ROS upon irradiation, and consequently, its antiproliferative effect. A simplified scaffold-based 3D skin model containing melanoma spheroids was also prepared. Considering the results obtained, we conclude that the lecithin invasomes loaded with 5-aminolevulinic acid have a good therapeutic potential and may represent an efficient tool that can be considered a valid alternative in the topical treatment of melanoma and other skin diseases.

Revealing the infiltration process and retention mechanisms of surface applied free DNA tracer through soil under flood irrigation

It has been recently demonstrated that free DNA tracers have the potential in tracing water flow and contaminant transport through the vadose zone. However, whether the free DNA tracer can be used in flood irrigation area to track water flow and solute/contaminant transport is still unclear. To reveal the infiltration process and retention mechanisms of surface applied free DNA tracer through soil under flood irrigation, we tested the fate and transport behavior of surface applied free DNA tracers through packed saturated sandy soil columns with a 10 cm water head mimicking flood irrigation. From the experimental breakthrough curves and by fitting a two-site kinetic sorption model (R2 = 0.83–0.91 and NSE = 0.79–0.89), adsorption/desorption rates could be obtained and tracer retention profiles could be simulated. Together these results revealed that 1) the adsorption of free DNA was dominantly to clay particles in the soil, which took up 1.96 % by volume, but took up >97.5 % by surface area and densely cover the surface of sand particles; and 2) at a pore water pH of 8.0, excluding the 4.9 % passing through and 3.1 % degradation amount, the main retention mechanisms in the experimental soil were ligand exchange (42.0 %), Van der Waals interactions (mainly hydrogen bonds), electrostatic forces and straining (together 44.7 %), and cation bridge (5.3 %). To our knowledge, this study is the first to quantify the contribution of each of the main retention mechanisms of free synthetic DNA tracers passing through soil. Our findings could facilitate the application of free DNA tracer to trace vadose zone water flow and solute/contaminant transport under flood irrigation and other infiltration conditions.

First-in-human study of a novel cell death tracer [99mTc]Tc-Duramycin: safety, biodistribution and radiation dosimetry in healthy volunteers

BackgroundImaging of cell death can provide an early indication of treatment response in cancer. [99mTc]Tc-Duramycin is a small-peptide SPECT tracer that recognizes both apoptotic and necrotic cells by binding to phosphatidylethanolamine present in the cell membrane. Preclinically, this tracer has shown to have favorable pharmacokinetics and selective tumor accumulation early after the onset of anticancer therapy. In this first-in-human study, we report the safety, biodistribution and internal radiation dosimetry of [99mTc]Tc-Duramycin in healthy human volunteers.ResultsSix healthy volunteers (3 males, 3 females) were injected intravenously with [99mTc]Tc-Duramycin (dose: 6 MBq/kg; 473 ± 36 MBq). [99mTc]Tc-Duramycin was well tolerated in all subjects, with no serious adverse events reported. Following injection, a 30-min dynamic planar imaging of the abdomen was performed, and whole-body (WB) planar scans were acquired at 1, 2, 3, 6 and 23 h post-injection (PI), with SPECT acquisitions after each WB scan and one low-dose CT after the first SPECT. In vivo 99mTc activities were determined from semi-quantitative analysis of the images, and time-activity curves were generated. Residence times were calculated from the dynamic and WB planar scans. The mean effective dose was 7.61 ± 0.75 µSv/MBq, with the kidneys receiving the highest absorbed dose (planar analysis: 43.82 ± 4.07 µGy/MBq, SPECT analysis: 19.72 ± 3.42 μGy/MBq), followed by liver and spleen. The median effective dose was 3.61 mSv (range, 2.85–4.14). The tracer cleared slowly from the blood (effective half-life of 2.0 ± 0.4 h) due to high plasma protein binding with < 5% free tracer 3 h PI. Excretion was almost exclusively renal.Conclusion[99mTc]Tc-Duramycin demonstrated acceptable dosimetry (< 5 mSv) and a favorable safety profile. Due to slow blood clearance, optimal target-to-background ratios are expected 5 h PI. These data support the further assessment of [99mTc]Tc-Duramycin for clinical treatment response evaluation.Trial registration: NCT05177640, Registered April 30, 2021, https://clinicaltrials.gov/study/NCT05177640.

Simulation of experimental synthetic DNA tracer transport through the vadose zone

Although multiple experimental studies have proven the use of free synthetic DNA as tracers in hydrological systems, their quantitative fate and transport, especially through the vadose zone, is still not well understood. Here we simulate the water flow and breakthrough of deuterium (D) and one free synthetic DNA tracer from a 10-day experiment conducted in a transient variably saturated 1m3 10° sloped lysimeter using the HYDRUS-2D software package. Recovery and breakthrough flux of D (97.78%) and the DNA tracer (1.05%) were captured well with the advection-dispersion equation (R2 = 0.949, NSE = 0.937) and the Schijven and Šimůnek two-site kinetic sorption model recommended for virus transport modeling (R2 = 0.824, NSE = 0.823), respectively. The degradation of the DNA tracer was very slow (estimated to be 10% in 10 days), because the “loamy sand” porous media in our lysimeter was freshly crushed basaltic tephra (i.e., crushed rocks) and the microbes and DNase that could potentially degrade DNA in regular soils were rare in our “loamy sand”. The timing of the concentration peaks and the HYDRUS-2D simulated temporal and spatial distribution of DNA in the lysimeter both revealed the role of the solid-water-air contact lines in mobilizing and carrying DNA tracer under the experimental variably saturated transient flow condition. The free DNA was nearly non-selectively transported through the porous media, and showed a slightly early breakthrough, possibly due to a slight effect of anion exclusion or size exclusion. Our results indicate that free DNA have the potential to trace vadose zone water flow and solute/contaminant transport, and to serve as surrogates to trace viral pathogen pollution in soil-water systems. To our knowledge, this study is the first to simulate transport mechanisms of free synthetic DNA tracers through real soil textured porous media under variably saturated transient flow condition.

Novel plasma protein binding analysis method for a PET tracer and its radiometabolites: A case study with [11C]SMW139 to explain the high uptake of radiometabolites in mouse brain

Radiometabolites of PET tracers interfere with imaging and need to be taken into account when modeling PET data. Various tracer and radiometabolite characteristics affect the uptake rate into tissue. In this study, we investigated two such factors, lipophilicity and protein-free fraction. A novel rapid method was developed using thin-layer chromatography with digital autoradiography (radioTLC) and ultrafiltration for analyzing the protein-free fractions of an exemplar PET tracer, [11C]SMW139 (fP, free parent tracer over all radioactivity), and its radiometabolites (fM, free radiometabolites over all radioactivity). Detailed understanding of the uptake of radiometabolites into extravascular cells requires analyzing fM, which has not previously been performed for PET tracers. Mice were injected with [11C]SMW139, and time-activity curves from plasma and brain coupled with the parent fraction and free fraction data were analyzed to demonstrate the true levels of protein-free and protein-bound [11C]SMW139 and its radiometabolites in plasma. The ultrafiltration method included separate membrane correction factors for the parent tracer and its radiometabolites for analysis of unbiased fP and fM. Metabolism of [11C]SMW139 was rapid, and after 45 min, the parent fraction was 0.33 in plasma and 0.28 in brain. Ultrafiltration membrane correction had a significant effect on the fP but not the fM. From 10–45 min, the fP decreased from 0.032 to 0.007, while fM remained between 0.52 and 0.35. The much higher fM in plasma could explain why the less lipophilic radiometabolites enter the brain efficiently. This detailed understanding of fP and fM from rodents can be used in translational studies to explain the behavior of the tracer in humans. Similar parent fraction and plasma protein binding methods can be used for human in vivo analysis.

Computational modeling of PET tracer distribution in solid tumors integrating microvasculature

BackgroundWe present computational modeling of positron emission tomography radiotracer uptake with consideration of blood flow and interstitial fluid flow, performing spatiotemporally-coupled modeling of uptake and integrating the microvasculature. In our mathematical modeling, the uptake of fluorodeoxyglucose F-18 (FDG) was simulated based on the Convection–Diffusion–Reaction equation given its high accuracy and reliability in modeling of transport phenomena. In the proposed model, blood flow and interstitial flow are solved simultaneously to calculate interstitial pressure and velocity distribution inside cancer and normal tissues. As a result, the spatiotemporal distribution of the FDG tracer is calculated based on velocity and pressure distributions in both kinds of tissues.ResultsInterstitial pressure has maximum value in the tumor region compared to surrounding tissue. In addition, interstitial fluid velocity is extremely low in the entire computational domain indicating that convection can be neglected without effecting results noticeably. Furthermore, our results illustrate that the total concentration of FDG in the tumor region is an order of magnitude larger than in surrounding normal tissue, due to lack of functional lymphatic drainage system and also highly-permeable microvessels in tumors. The magnitude of the free tracer and metabolized (phosphorylated) radiotracer concentrations followed very different trends over the entire time period, regardless of tissue type (tumor vs. normal).ConclusionOur spatiotemporally-coupled modeling provides helpful tools towards improved understanding and quantification of in vivo preclinical and clinical studies.

Validation of a combined image derived input function and venous sampling approach for the quantification of [18F]GE-179 PET binding in the brain

Blood-based kinetic analysis of PET data relies on an accurate estimate of the arterial plasma input function (PIF). An alternative to invasive measurements from arterial sampling is an image-derived input function (IDIF). However, an IDIF provides the whole blood radioactivity concentration, rather than the required free tracer radioactivity concentration in plasma. To estimate the tracer PIF, we corrected an IDIF from the carotid artery with estimates of plasma parent fraction (PF) and plasma-to-whole blood (PWB) ratio obtained from five venous samples. We compared the combined IDIF+venous approach to gold standard data from arterial sampling in 10 healthy volunteers undergoing [18F]GE-179 brain PET imaging of the NMDA receptor. Arterial and venous PF and PWB ratio estimates determined from 7 patients with traumatic brain injury (TBI) were also compared to assess the potential effect of medication. There was high agreement between areas under the curves of the estimates of PF (r = 0.99, p<0.001), PWB ratio (r = 0.93, p<0.001), and the PIF (r = 0.92, p<0.001) as well as total distribution volume (VT) in 11 regions across the brain (r = 0.95, p<0.001). IDIF+venous VT had a mean bias of −1.7% and a comparable regional coefficient of variation (arterial: 21.3 ± 2.5%, IDIF+venous: 21.5 ± 2.0%). Simplification of the IDIF+venous method to use only one venous sample provided less accurate VT estimates (mean bias 9.9%; r = 0.71, p<0.001). A version of the method that avoids the need for blood sampling by combining the IDIF with population-based PF and PWB ratio estimates systematically underestimated VT (mean bias −20.9%), and produced VT estimates with a poor correlation to those obtained using arterial data (r = 0.45, p<0.001). Arterial and venous blood data from 7 TBI patients showed high correlations for PF (r = 0.92, p = 0.003) and PWB ratio (r = 0.93, p = 0.003). In conclusion, the IDIF+venous method with five venous samples provides a viable alternative to arterial sampling for quantification of [18F]GE-179 VT.

Tailored optical propulsion forces for controlled transport of resonant gold nanoparticles and associated thermal convective fluid flows.

Noble metal nanoparticles illuminated at their plasmonic resonance wavelength turn into heat nanosources. This phenomenon has prompted the development of numerous applications in science and technology. Simultaneous optical manipulation of such resonant nanoparticles could certainly extend the functionality and potential applications of optothermal tools. In this article, we experimentally demonstrate optical transport of single and multiple resonant nanoparticles (colloidal gold spheres of radius 200 nm) directed by tailored transverse phase-gradient forces propelling them around a 2D optical trap. We show how the phase-gradient force can be designed to efficiently change the speed of the nanoparticles. We have found that multiple hot nanoparticles assemble in the form of a quasi-stable group whose motion around the laser trap is also controlled by such optical propulsion forces. This assembly experiences a significant increase in the local temperature, which creates an optothermal convective fluid flow dragging tracer particles into the assembly. Thus, the created assembly is a moving heat source controlled by the propulsion force, enabling indirect control of fluid flows as a micro-optofluidic tool. The existence of these flows, probably caused by the temperature-induced Marangoni effect at the liquid water/superheated water interface, is confirmed by tracking free tracer particles migrating towards the assembly. We propose a straightforward method to control the assembly size, and therefore its temperature, by using a nonuniform optical propelling force that induces the splitting or merging of the group of nanoparticles. We envision further development of microscale optofluidic tools based on these achievements.

Water tracking in surface water, groundwater and soils using free and alginate-chitosan encapsulated synthetic DNA tracers

Investigating contamination pathways and hydraulic connections in complex hydrological systems will benefit greatly from multi-tracer approaches. The use of non-toxic synthetic DNA tracers is promising, because unlimited numbers of tracers, each with a unique DNA identifier, could be used concurrently and detected at extremely low concentrations. This study aimed to develop multiple synthetic DNA tracers as free molecules and encapsulated within microparticles of biocompatible and biodegradable alginate and chitosan, and to validate their field utility in different systems. Experiments encompassing a wide range of conditions and flow rates (19cm/day-39km/day) were conducted in a stream, an alluvial gravel aquifer, a fine coastal sand aquifer, and in lysimeters containing undisturbed silt loam over gravels. The DNA tracers were identifiable in all field conditions investigated, and they were directly detectable in the stream at a distance of at least 1km. The DNA tracers showed promise at tracking fast-flowing water in the stream, gravel aquifer and permeable soils, but were unsatisfactory at tracking slow-moving groundwater in the fine sand aquifer. In the surface water experiments, the microencapsulated DNA tracers' concentrations and mass recoveries were 1-3 orders of magnitude greater than those of the free DNA tracers, because encapsulation protected them from environmental stressors and they were more negatively charged. The opposite was observed in the gravel aquifer, probably due to microparticle filtration by the aquifer media. Although these new DNA tracers showed promise in proof-of-concept field validations, further work is needed before they can be used for large-scale investigations.

3D Printing of Digitally Traced Neurons for Neuroanatomy Education

PurposeThree dimensional (3D) printing technology is being increasingly utilized in anatomy education, and its efficacy as a teaching tool is a growing area of education research. Most curriculum guides for 3D printing activities have students download pre‐designed digital anatomical 3D object files from websites (i.e. www.thingiverse.comor www.neuromorpho.org) rather than generate their own 3D models from original data. Recently a technique was published for tracing and 3D‐printing neurons, but it required expensive software, as well as extensive computer programing experience (McDougal and Shepard, 2015). The goal of our study was to develop a simple, intuitive, and inexpensive method to allow students to generate an original reconstructed neuron suitable for 3D‐printing, and to evaluate this method among targeted learners.MethodsNeurons from mouse brain and retina were labeled with fluorescent dye, fixed and imaged sequentially in 1 μm sections with a Zeiss LSM laser scanning microscope. The image stack was loaded into ImageJ, traced, and morphologically analyzed using the free ImageJ plugin Simple Neurite Tracer (SNT). Traced neurons were then exported as an object file into Blender, a free 3D graphics software program, edited, and printed with PLA, ABA, and gypsum powder material, in various sizes and color patterns. Based on this work, a “3D Printing Neurons Made Easy” instruction guide and 5‐part tutorial video was crafted; the raw neuron image stack was published in The Cell Image Library, a freely accessible online public repository that students can access from any computer and trace to create their own digital 3D model. The curriculum was piloted in a neuroanatomy laboratory session for high school students in a summer neuroscience outreach program. Students were given a pre‐ and post‐test on topics related to microscopy, neuroanatomy and image analysis, as well as an exit survey.ResultsOur “3D Printing Neurons Made Easy” curriculum guide enabled students to participate in an optional, self‐guided activity to learn principles in confocal microscopy, neuroanatomy, and image analysis. By using open source software (Image J and Blender) and a public repository, this self‐guided activity engages students in neuroanatomy research at a relatively low cost. 70% students attempted (31/44) and of the 31 students that attempted the project, 87% of the students successfully printed a 3D neuron. 97% of these students had a positive experience with the activity and 80% agreed that they would recommend the activity to their high school biology class. The curriculum is now being piloted among undergraduate and graduate anatomy students, and analysis is ongoing.ConclusionsWe have developed an easy method for students to reconstruct z‐stack images of neurons for 3D printing. These 3D models provide dramatic examples of the complex structure of neurons, and may help communicate complex 3‐dimensional concepts to students. The activity also allows students with no prior research experience to learn principles in microscopy and 3D image analysis in a way that is fun, engaging, and low cost. Our “3D Printing Neurons Made Easy” instructions guide and tutorial videos may be useful for crowd‐sourcing data collection, anatomy education, training students in anatomical research methods, or attracting students to careers in research.

A three-time-point method for assessing kinetic parameters of 64Cu-labeled Ramucirumab trapping in VEGFR-2 positive lung tumors

ObjectiveTo describe a three-time-point method for estimating kinetic parameters involved in 64Cu-labeled Ramucirumab (64Cu-NOTA-RamAb) trapping of VEGFR-2 positive lung tumors. Materials and methodsPositron emission tomography (microPET) data of tumor-bearing mice for 64Cu-NOTA-RamAb trapping in VEGFR-2 positive HCC4006 tumor were used, involving tissue activity measurements acquired at 3, 24 and 48 h post-injection, without and with administration of RamAb blocking dose. A kinetic model provided an analytical formula describing the tissue time-activity-curve, involving 64Cu-NOTA-RamAb uptake (Ki), release rate constant (kR) and fraction of free tracer in blood and interstitial volume (F). ResultsFitting analytical formula outcomes on mean microPET data yielded values of the kinetic parameters: Ki = 0.0314/0.0123 gram of blood per hour per gram of tissue, kR = 0.0387/0.0313 h−1 and F = 0.2075/0.2007 gram of blood per gram of tissue, without/with RamAb blocking dose, respectively (R = 0.99999 for the graph displaying microPET versus theoretical data; P < .01). ConclusionsThree independent kinetic parameters (Ki, kR and F) can be assessed from three data points acquired at early, mid and late imaging, i.e., at 3, 24 and 48 h post-injection, for further characterization of 64Cu-NOTA-RamAb trapping in VEGFR-2 positive lung tumors.

Metallicity Structure across the Galactic Disk: Radio Observations of H ii Regions

AbstractHii regions are the sites of massive star formation and are the archetypal tracers of spiral arms. Because of their short lifetimes (&amp;lt;10 Myr) their abundances provide a measure of the nuclear processing of many stellar generations. Here we review our ongoing efforts to explore the metallicity structure of the Galactic disk by observing radio recombination line (RRL) and thermal radio continuum emission toward Hii regions. The RRL-to-continuum ratio provides an accurate measure of the electron temperature which is used as a proxy for metallicity. Since collisionally excited lines from metals (e.g., O, C) are the main coolant in Hii regions, the thermal electron temperature is well correlated with metallicity (e.g., [O/H]). We determine Hii region distances from maser parallax measurements when possible; otherwise we use kinematic distances. Such radio diagnostics of Hii regions yield an extinction free tracer to map the metallicity distribution across the entire Galactic disk.

Abstract 12454: Vildagliptin Attenuates Cardiac Hypertrophy and Improves Ventricular Efficiency Through FGF21 Expression in Pressure-overloaded Mouse Heart

Introduction: Basic and clinical studies have shown that Dipeptidyl Peptidase-4 (DPP-4) inhibitor an anti-hyperglycemic agent, has cardioprotective effects through angiogenesis, anti-hypertrophy or anti-apoptosis effect. However, recent clinical trials in patients with diabetes raise a concern about DPP-4 inhibitor’s effect on heart failure. Based on the controversy, we performed precise analyses for cardiac energy metabolism and cardiac performance in hypertrophied heart induced by pressure-overload mouse model with or without diabetes. Methods and Results: Non-diabetic C57Bl6 mice (BL6) and type2 diabetic C57Bl6 mice produced by high fat diet (diet-induced obesity, DIO) were treated with or without a DPP-4 inhibitor, vildagliptin (VLD) after inducing pathological cardiac hypertrophy by transverse aortic constriction (TAC). After 3-week treatment, VLD attenuated cardiac hypertrophy and dysfunction compared with vehicle (Veh) treated animals in BL6. However these effects were not observed in DIO mice. Myocardial energy substrate assay using 12 C-FDG (glucose tracer) and 132 I-BMIPP (free fatty acid tracer) showed that not only glucose uptake but also free fatty acid uptake were increased with VLD treatment in TAC heart. Gene expression analysis showed that fibroblast growth factor (FGF) 21, a protein which has been shown to have a critical role in energy metabolism, was increased in heart with VLD treatment. In vitro experiments showed that VLD administration increased FGF21 expression dose-dependently in cultured human cardiac fibroblasts but not in neonatal cardiomyocytes, suggesting that fibroblast-mediated FGF21 expression may regulate energy metabolism in stressed heart. Conclusions: VLD has a beneficial effect on myocardial energy metabolism associating with an improvement of ventricular performance in hypertrophied heart, partially through upregulation of FGF21. However, these beneficial effects in heart may be attenuated under type2 diabetic condition.

Percutaneous Tumor Ablation: Cryoablation Facilitates Targeting of Free Epirubicin-Ethanol-Ioversol Solution Interstitially Coinjected in a Rabbit VX2 Tumor Model.

This acute study was aimed at exploring the ability of a cryoablative lesion to drive the distribution of a concomitant in situ injection of a free epirubicin-ethanol-ethiodol-methylene blue mixture. We report the feasibility and safety of this new percutaneous computed tomography-guided combinatorial ablative procedure on VX2 tumors. Eight New Zealand white rabbits bearing 16 tumors on both side of the back muscle were randomly selected and treated on the same day with the following procedures: (1) 8 concomitant cryoablation and interstitial chemotherapy and (2) 8 intratumor marginal chemotherapy. For the latter, an injection needle was positioned at the inner distal margin of a first selected tumor side, where the chemotherapy was delivered during 5 serial sequences. For the concomitant therapy, a single cryoneedle maintained the ice front at the tumor margin, where a needle delivered the drug dose during 5 freeze-injection-thaw sequences. Enhanced computed tomography scans on days 3, 7, and 10 assessed the tumor contours and the tracer localization. Two rabbits were killed on days 0, 3, 7, and 10 for gross and histopathological analyses. During the concomitant therapy, ioversol was distributed at the tumor and iceball margins along with the methylene blue. Enhanced computed tomography on days 3, 7, and 10 showed a focal enlarging defect of the tumor marginal enhancing rim. The rim coincided with focal necrosis at histopathology. During the intratumor chemotherapy procedure, computed tomography showed that the tracers distributed mostly over the tumor mass. No marginal necrosis was detected at histopathology. On day 10, the tumor size for the intratumor chemotherapy group was twice that of the concomitant therapy group. No adverse events were observed. In this VX2 tumor model, our image-guided concomitant therapy is feasible and may enhance the effectiveness of a free epirubicin tracer mixture at the tumor margin.

First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430.

This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand (18)F-PF-05270430. The primary goals were to determine the appropriate tracer kinetic model to quantify brain uptake and to examine the within-subject test-retest variability. In advance of human studies, radiation dosimetry was determined in nonhuman primates. Six healthy male subjects participated in a test-retest protocol with dynamic scans and metabolite-corrected input functions. Nine brain regions of interest were studied, including the striatum, white matter, neocortical regions, and cerebellum. Multiple modeling methods were applied to calculate volume of distribution (VT) and binding potentials relative to the nondisplaceable tracer in tissue (BPND), concentration of tracer in plasma (BPP), and free tracer in tissue (BPF). The cerebellum was selected as a reference region to calculate binding potentials. The dosimetry study provided an effective dose of less than 0.30 mSv/MBq, with the gallbladder as the critical organ; the human target dose was 185 MBq. There were no adverse events or clinically detectable pharmacologic effects reported. Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were well fit by multilinear analysis-1, and a 70-min scan duration was sufficient to quantify VT and the binding potentials. BPND, with mean values ranging from 0.3 to 0.8, showed the best intrasubject and intersubject variability and reliability. Test-retest variability in the whole brain (excluding the cerebellum) of VT, BPND, and BPP were 8%, 16%, and 17%, respectively. (18)F-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values.

Effect of tanniniferous food from Bauhinia pulchella on pasture contamination with gastrointestinal nematodes from goats

BackgroundTannin-rich plants have been examined as an alternative for controlling the gastrointestinal nematodes in ruminants. In vivo assays typically examine the anthelmintic activity in female fecundity and/or the adult worm burden, without considering other life-cycle stages or the impact on pasture contamination. The aim of the present study was to evaluate the anthelmintic activity of tanniniferous food from Bauhinia pulchella in goats and the potential impact on pasture contamination with the infective larval stage of gastrointestinal nematodes.FindingsSixteen cross breed Boer goats that were naturally infected with gastrointestinal nematodes were fed tanniniferous concentrate from the leaves of B. pulchella and compared to a separate paddock of control animals without condensed tannin supplementation. A range of parasite characteristics were monitored throughout the 63 days of experimentation, including faecal egg count (FEC), egg hatching and relative numbers of hatched helminth larvae on herbage. Worm free tracer animals were used to assess the infective larval stage load of the contaminated pasture. The tanniniferous food did not reduce the combined FEC values, but egg hatching was significantly affected (p < 0.05). The pasture grazed by goats fed with tanniniferous food from B. pulchella showed reduced contamination through infective larval stages. Tracer goats maintained in paddocks grazed with animals fed with tanniniferous food had lower numbers of Trichostrongylus colubriformis than did those in the control group (86 % reduction).ConclusionsCondensed tannin from B. pulchella showed anthelmintic activity, affected egg viability and reduced pasture contamination, which led to the reduced infection of the animals by T. colubriformis.

First-in-human PET quantification study of cerebral α4β2* nicotinic acetylcholine receptors using the novel specific radioligand (−)-[18F]Flubatine

α4β2* nicotinic receptors (α4β2* nAChRs) could provide a biomarker in neuropsychiatric disorders (e.g., Alzheimer's and Parkinson's diseases, depressive disorders, and nicotine addiction). However, there is a lack of α4β2* nAChR specific PET radioligands with kinetics fast enough to enable quantification of nAChR within a reasonable time frame. Following on from promising preclinical results, the aim of the present study was to evaluate for the first time in humans the novel PET radioligand (−)-[18F]Flubatine, formerly known as (−)-[18F]NCFHEB, as a tool for α4β2* nAChR imaging and in vivo quantification.Dynamic PET emission recordings lasting 270min were acquired on an ECAT EXACT HR+ scanner in 12 healthy male non-smoking subjects (71.0±5.0years) following the intravenous injection of 353.7±9.4MBq of (−)-[18F]Flubatine. Individual magnetic resonance imaging (MRI) was performed for co-registration. PET frames were motion-corrected, before the kinetics in 29 brain regions were characterized using 1- and 2-tissue compartment models (1TCM, 2TCM). Given the low amounts of metabolite present in plasma, we tested arterial input functions with and without metabolite corrections. In addition, pixel-based graphical analysis (Logan plot) was used. The model's goodness of fit, with and without metabolite correction was assessed by Akaike's information criterion. Model parameters of interest were the total distribution volume VT (mL/cm3), and the binding potential BPND relative to the corpus callosum, which served as a reference region.The tracer proved to have high stability in vivo, with 90% of the plasma radioactivity remaining as untransformed parent compound at 90min, fast brain kinetics with rapid uptake and equilibration between free and receptor-bound tracer. Adequate fits of brain TACs were obtained with the 1TCM. VT could be reliably estimated within 90min for all regions investigated, and within 30min for low-binding regions such as the cerebral cortex.The rank order of VT by region corresponded well with the known distribution of α4β2* receptors (VT [thalamus] 27.4±3.8, VT [putamen] 12.7±0.9, VT [frontal cortex] 10.0±0.8, and VT [corpus callosum] 6.3±0.8). The BPND, which is a parameter of α4β2* nAChR availability, was 3.41±0.79 for the thalamus, 1.04±0.25 for the putamen and 0.61±0.23 for the frontal cortex, indicating high specific tracer binding. Use of the arterial input function without metabolite correction resulted in a 10% underestimation in VT, and was without important biasing effects on BPND.Altogether, kinetics and imaging properties of (−)-[18F]Flubatine appear favorable and suggest that (−)-[18F]Flubatine is a very suitable and clinically applicable PET tracer for in vivo imaging of α4β2* nAChRs in neuropsychiatric disorders.