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Find video protocols related to scientific articles indexed in Pubmed.
Longitudinal PET-MRI reveals ?-amyloid deposition and rCBF dynamics and connects vascular amyloidosis to quantitative loss of perfusion.
Nat. Med.
PUBLISHED: 07-10-2014
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The dynamics of ?-amyloid deposition and related second-order physiological effects, such as regional cerebral blood flow (rCBF), are key factors for a deeper understanding of Alzheimer's disease (AD). We present longitudinal in vivo data on the dynamics of ?-amyloid deposition and the decline of rCBF in two different amyloid precursor protein (APP) transgenic mouse models of AD. Using a multiparametric positron emission tomography and magnetic resonance imaging approach, we demonstrate that in the presence of cerebral ?-amyloid angiopathy (CAA), ?-amyloid deposition is accompanied by a decline of rCBF. Loss of perfusion correlates with the growth of ?-amyloid plaque burden but is not related to the number of CAA-induced microhemorrhages. However, in a mouse model of parenchymal ?-amyloidosis and negligible CAA, rCBF is unchanged. Because synaptically driven spontaneous network activity is similar in both transgenic mouse strains, we conclude that the disease-related decline of rCBF is caused by CAA.
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PET/MR imaging and optical imaging of metastatic rhabdomyosarcoma in mice.
J. Nucl. Med.
PUBLISHED: 06-24-2014
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The combination of PET and MR imaging synergizes molecular and morphologic information, allowing better diagnosis in cancer patients. The diagnosis of tumor recurrence in rhabdomyosarcoma is extremely challenging and could be improved with PET/MR imaging. The aim of this study was to validate PET/MR imaging in a disseminated rhabdomyosarcoma mouse model.
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Checkpoint kinase Chk2 controls renal Cyp27b1 expression, calcitriol formation, and calcium-phosphate metabolism.
Pflugers Arch.
PUBLISHED: 06-06-2014
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Checkpoint kinase 2 (Chk2) is the main effector kinase of ataxia telangiectasia mutated (ATM) and responsible for cell cycle regulation. ATM signaling has been shown to upregulate interferon-regulating factor-1 (IRF-1), a transcription factor also expressed in the kidney. Calcitriol (1,25 (OH)2D3), a major regulator of mineral metabolism, is generated by 25-hydroxyvitamin D 1?-hydroxylase in the kidney. Since 25-hydroxyvitamin D 1?-hydroxylase expression is enhanced by IRF-1, the present study explored the role of Chk2 for calcitriol formation and mineral metabolism. Chk2-deficient mice (chk2 (-/-)) were compared to wild-type mice (chk2 (+/+)). Transcript levels of renal 25-hydroxyvitamin D 1?-hydroxylase, Chk2, and IRF-1 were determined by RT-PCR; Klotho expression by Western blotting; bone density by ?CT analysis; serum or plasma 1,25 (OH)2D3, PTH, and C-terminal FGF23 concentrations by immunoassays; and serum, fecal, and urinary calcium and phosphate concentrations by photometry. The renal expression of IRF-1 and 25-hydroxyvitamin D 1?-hydroxylase as well as serum 1,25 (OH)2D3 and FGF23 levels were significantly lower in chk2 (-/-) mice compared to chk2 (+/+) mice. Plasma PTH was not different between the genotypes. Renal calcium and phosphate excretion were significantly higher in chk2 (-/-) mice than in chk2 (+/+) mice despite hypophosphatemia and normocalcemia. Bone density was not different between the genotypes. We conclude that Chk2 regulates renal 25-hydroxyvitamin D 1?-hydroxylase expression thereby impacting on calcium and phosphate metabolism.
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Preclinical and Translational PET/MR Imaging.
J. Nucl. Med.
PUBLISHED: 05-15-2014
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Combined PET and MR imaging (PET/MR imaging) has progressed tremendously in recent years. The focus of current research has shifted from technologic challenges to the application of this new multimodal imaging technology in the areas of oncology, cardiology, neurology, and infectious diseases. This article reviews studies in preclinical and clinical translation. The common theme of these initial results is the complementary nature of combined PET/MR imaging that often provides additional insights into biologic systems that were not clearly feasible with just one modality alone. However, in vivo findings require ex vivo validation. Combined PET/MR imaging also triggers a multitude of new developments in image analysis that are aimed at merging and using multimodal information that ranges from better tumor characterization to analysis of metabolic brain networks. The combination of connectomics information that maps brain networks derived from multiparametric MR data with metabolic information from PET can even lead to the formation of a new research field that we would call cometomics that would map functional and metabolic brain networks. These new methodologic developments also call for more multidisciplinarity in the field of molecular imaging, in which close interaction and training among clinicians and a variety of scientists is needed.
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Principles of PET/MR Imaging.
J. Nucl. Med.
PUBLISHED: 05-12-2014
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Hybrid PET/MR systems have rapidly progressed from the prototype stage to systems that are increasingly being used in the clinics. This review provides an overview of developments in hybrid PET/MR systems and summarizes the current state of the art in PET/MR instrumentation, correction techniques, and data analysis. The strong magnetic field requires considerable changes in the manner by which PET images are acquired and has led, among others, to the development of new PET detectors, such as silicon photomultipliers. During more than a decade of active PET/MR development, several system designs have been described. The technical background of combined PET/MR systems is explained and related challenges are discussed. The necessity for PET attenuation correction required new methods based on MR data. Therefore, an overview of recent developments in this field is provided. Furthermore, MR-based motion correction techniques for PET are discussed, as integrated PET/MR systems provide a platform for measuring motion with high temporal resolution without additional instrumentation. The MR component in PET/MR systems can provide functional information about disease processes or brain function alongside anatomic images. Against this background, we point out new opportunities for data analysis in this new field of multimodal molecular imaging.
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Up-regulation of hepatic alpha-2-HS-glycoprotein transcription by testosterone via androgen receptor activation.
Cell. Physiol. Biochem.
PUBLISHED: 05-05-2014
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Fetuin-A (alpha-2-HS-glycoprotein, AHSG), a liver borne plasma protein, contributes to the prevention of soft tissue calcification, modulates inflammation, reduces insulin sensitivity and fosters weight gain following high fat diet or ageing. In polycystic ovary syndrome, fetuin-A levels correlate with free androgen levels, an observation pointing to androgen sensitivity of fetuin-A expression. The present study thus explored whether the expression of hepatic fetuin-A is modified by testosterone.
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A data driven method for estimation of B(avail) and appK(D) using a single injection protocol with [¹¹C]raclopride in the mouse.
Neuroimage
PUBLISHED: 04-09-2014
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The partial saturation approach (PSA) is a simple, single injection experimental protocol that will estimate both B(avail) and appK(D) without the use of blood sampling. This makes it ideal for use in longitudinal studies of neurodegenerative diseases in the rodent. The aim of this study was to increase the range and applicability of the PSA by developing a data driven strategy for determining reliable regional estimates of receptor density (B(avail)) and in vivo affinity (1/appK(D)), and validate the strategy using a simulation model.
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Simulation-based optimisation of the PET data processing for partial saturation approach protocols.
Neuroimage
PUBLISHED: 03-27-2014
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Positron emission tomography (PET) with [(11)C]Raclopride is an important tool for studying dopamine D2 receptor expression in vivo. [(11)C]Raclopride PET binding experiments conducted using the Partial Saturation Approach (PSA) allow the estimation of receptor density (B(avail)) and the in vivo affinity appK(D). The PSA is a simple, single injection, single scan experimental protocol that does not require blood sampling, making it ideal for use in longitudinal studies. In this work, we generated a complete Monte Carlo simulated PET study involving two groups of scans, in between which a biological phenomenon was inferred (a 30% decrease of B(avail)), and used it in order to design an optimal data processing chain for the parameter estimation from PSA data. The impact of spatial smoothing, noise removal and image resolution recovery technique on the statistical detection was investigated in depth. We found that image resolution recovery using iterative deconvolution of the image with the system point spread function associated with temporal data denoising greatly improves the accuracy and the statistical reliability of detecting the imposed phenomenon. Before optimisation, the inferred B(avail) variation between the two groups was underestimated by 42% and detected in 66% of cases, while a false decrease of appK(D) by 13% was detected in more than 11% of cases. After optimisation, the calculated B(avail) variation was underestimated by only 3.7% and detected in 89% of cases, while a false slight increase of appK(D) by 3.7% was detected in only 2% of cases. We found during this investigation that it was essential to adjust a factor that accounts for difference in magnitude between the non-displaceable ligand concentrations measured in the target and in the reference regions, for different data processing pathways as this ratio was affected by different image resolutions.
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Combined PET/MR: Where are we now? Summary report of the second international workshop on PET/MR imaging April 8-12, 2013, Tubingen, Germany.
Mol Imaging Biol
PUBLISHED: 03-27-2014
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This workshop was held a year after the initial positron emission tomography/magnetic resonance (PET/MR) workshop in Tübingen, which was recently reported in this journal. The discussions at the 2013 workshop, however, differed substantially from those of the initial workshop, attesting to the progress of combined PET/MR as an innovative imaging modality. Discussions were focused on the search for truly novel, unique clinical and research applications as well as technical issues such as reliable and accurate approaches for attenuation and scatter correction of PET emission data. The workshop provided hands-on experience with PET and MR imaging. In addition, structured and moderated open discussion sessions, including six dialogue boards and two roundtable discussions, provided input from current and future PET/MR imaging users. This summary provides a snapshot of the current achievements and challenges for PET/MR.
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Evaluation of positron emission tomographic tracers for imaging of papillomavirus-induced tumors in rabbits.
Mol Imaging
PUBLISHED: 03-14-2014
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In this study, simultaneous positron emission tomography (PET)/magnetic resonance (MR) imaging was employed to evaluate the feasibility of the PET tracers 2-deoxy-2-18F-fluoro-d-glucose (18F-FDG), 11C-choline, and 18F-fluorothymidine (18F-FLT) to detect papillomavirus-induced tumors in an established rabbit model system. The combined PET/MR allowed the analysis of tracer uptake of the tumors using the morphologic information acquired by MR. New Zealand White rabbits were infected with cottontail rabbit papillomavirus genomes and were imaged for up to 10 months with a simultaneous PET/MR system during the course of infection. The uptake characteristics of the PET tracers 11C-choline and 18F-FLT of tumors and reference tissues were examined relative to the clinical standard, 18F-FDG. Tracer biodistribution of various organs was measured by gamma-counting after the last PET scan and compared to the in vivo PET/MR 18F-FDG uptake. Increased tracer uptake was found 2 months postinfection in primary tumors with 18F-FDG and 11C-choline, whereas 18F-FLT failed to detect the tumors at all measured time points. Our data show that the PET tracer 18F-FDG is superior for imaging papillomavirus-induced tumors in rabbits compared to 11C-choline and 18F-FLT. However, 11C-choline imaging, which has previously been applied to detect various tumor entities in patients, appears to be an alternative to 18F-FDG.
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Pharmacokinetics and PET imaging properties of two recombinant anti-PSMA antibody fragments in comparison to their parental antibody.
Prostate
PUBLISHED: 01-31-2014
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Radioimmunoimaging with disease-specific tracers can be advantageous compared to that with nonspecific tracers for the imaging of glucose metabolism and cell proliferation. Monoclonal antibodies (mAbs) or their fragments are excellent tools for immuno-positron emission tomography (PET). In this study, PSMA-specific mAb 3/F11 and its recombinant fragments were compared for the imaging of prostate cancer in xenografts.
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Apical constriction: location and dimensions in molars-a micro-computed tomography study.
J Endod
PUBLISHED: 01-17-2014
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The existence of the apical constriction has been repeatedly questioned. The aim of the present study was to validate the existence of the apical constriction and determine its location and dimensions in molars by using substantial micro-computed tomography analysis.
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In vivo tracking of Th1 cells by PET reveals quantitative and temporal distribution and specific homing in lymphatic tissue.
J. Nucl. Med.
PUBLISHED: 01-16-2014
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Although T cells can be labeled for noninvasive in vivo imaging, little is known about the impact of such labeling on T-cell function, and most imaging methods do not provide holistic information about trafficking kinetics, homing sites, or quantification.
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Radioimmunoimaging of liver metastases with PET using a 64Cu-labeled CEA antibody in transgenic mice.
PLoS ONE
PUBLISHED: 01-01-2014
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Colorectal cancer is one of the most common forms of cancer, and the development of novel tools for detection and efficient treatment of metastases is needed. One promising approach is the use of radiolabeled antibodies for positron emission tomography (PET) imaging and radioimmunotherapy. Since carcinoembryonic antigen (CEA) is an important target in colorectal cancer, the CEA-specific M5A antibody has been extensively studied in subcutaneous xenograft models; however, the M5A antibody has not yet been tested in advanced models of liver metastases. The aim of this study was to investigate the (64)Cu-DOTA-labeled M5A antibody using PET in mice bearing CEA-positive liver metastases.
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Preclinical evaluation of a novel c-Met inhibitor in a gastric cancer xenograft model using small animal PET.
Mol Imaging Biol
PUBLISHED: 11-20-2013
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Here, we describe the efficacy of the novel small molecule c-Met inhibitor BAY 853474 in reducing tumor growth in the Hs746T gastric cancer xenograft model and tested the suitability of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) versus 3-deoxy-3-18F-fluorothymidine ([(18)F]FLT) for response monitoring in a gastric cancer xenograft mouse model using small animal PET.
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Feasibility of sequential PET/MRI using a state-of-the-art small animal PET and a 1 T benchtop MRI.
Mol Imaging Biol
PUBLISHED: 11-20-2013
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Combined PET/MRI studies receive increasing attention, as their combination allows deeper insight into disease progression. We evaluated a novel 1 T benchtop MRI scanner (1T-MRI) for its use in sequential PET/MRI studies.
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Non-invasive monitoring of pancreatic tumor progression in the RIP1-Tag2 mouse by magnetic resonance imaging.
Mol Imaging Biol
PUBLISHED: 11-20-2013
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Assessing information on tumor progression in the RIP1-Tag2 mouse in vivo is a great challenge because the tumors form spontaneously throughout the pancreas and are difficult to detect with current imaging modalities. In this study, we focused on non-invasive magnetic resonance imaging, providing information on tumor growth.
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Assessment of rodent brain activity using combined [(15)O]H2O-PET and BOLD-fMRI.
Neuroimage
PUBLISHED: 10-01-2013
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The study of brain activation in small animals is of high interest for neurological research. In this study, we proposed a protocol to monitor brain activation in rats following whisker stimulation using the short half-life PET tracer [(15)O]H2O as a marker for cerebral blood flow. This technique enables the study of baseline and activation conditions in fast succession within the same scanning session. Furthermore, we compared the results obtained from PET imaging with additional BOLD-fMRI data acquired in the same animals within the same anesthetic session in immediate succession. Although the maximum relative signal changes during brain activity observed with PET were substantially higher compared to the BOLD-fMRI results, statistical analyses showed that the number of activated voxels in PET was lower compared to the fMRI measurements. Furthermore, there was a difference in the activation centers in both the shape and location between PET and fMRI. The discrepancy in the number of activated voxels could be attributed to a lower overall contrast-to-noise ratio of the PET images compared to BOLD-fMRI, whereas the difference in the spatial location indicates a more fundamental process, involving the different physiological origins of the PET and BOLD-fMRI response. This study clearly demonstrates that [(15)O]H2O-PET activation studies may be performed in small laboratory animals, and shows the complimentary nature of studying brain activation using [(15)O]H2O-PET and fMRI.
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MR-Based PET attenuation correction for PET/MR imaging.
Semin Nucl Med
PUBLISHED: 09-17-2013
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Recent progress has allowed hybrid positron emission tomography/magnetic resonance (PET/MR) systems to make the transition from research prototypes to systems with full potential for clinical imaging. Options for directly measuring the attenuation maps, as is possible with PET/computed tomography or PET transmission scans, are not included in PET/MR scanners. New methods to compute attenuation maps from MR data have therefore been developed.
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MR-based attenuation correction methods for improved PET quantification in lesions within bone and susceptibility artifact regions.
J. Nucl. Med.
PUBLISHED: 09-05-2013
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Hybrid PET/MR systems have recently entered clinical practice. Thus, the accuracy of MR-based attenuation correction in simultaneously acquired data can now be investigated. We assessed the accuracy of 4 methods of MR-based attenuation correction in lesions within soft tissue, bone, and MR susceptibility artifacts: 2 segmentation-based methods (SEG1, provided by the manufacturer, and SEG2, a method with atlas-based susceptibility artifact correction); an atlas- and pattern recognition-based method (AT&PR), which also used artifact correction; and a new method combining AT&PR and SEG2 (SEG2wBONE).
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SOX2 expression associates with stem cell state in human ovarian carcinoma.
Cancer Res.
PUBLISHED: 07-18-2013
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The SRY-related HMG-box family of transcription factors member SOX2 regulates stemness and pluripotency in embryonic stem cells and plays important roles during early embryogenesis. More recently, SOX2 expression was documented in several tumor types including ovarian carcinoma, suggesting an involvement of SOX2 in regulation of cancer stem cells (CSC). Intriguingly, however, studies exploring the predictive value of SOX2 protein expression with respect to histopathologic and clinical parameters report contradictory results in individual tumors, indicating that SOX2 may play tumor-specific roles. In this report, we analyze the functional relevance of SOX2 expression in human ovarian carcinoma. We report that in human serous ovarian carcinoma (SOC) cells, SOX2 expression increases the expression of CSC markers, the potential to form tumor spheres, and the in vivo tumor-initiating capacity, while leaving cellular proliferation unaltered. Moreover, SOX2-expressing cells display enhanced apoptosis resistance in response to conventional chemotherapies and TRAIL. Hence, our data show that SOX2 associates with stem cell state in ovarian carcinoma and induction of SOX2 imposes CSC properties on SOC cells. We propose the existence of SOX2-expressing ovarian CSCs as a mechanism of tumor aggressiveness and therapy resistance in human SOC.
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Impact of anesthetics on 3-[18F]fluoro-3-deoxythymidine ([18F]FLT) uptake in animal models of cancer and inflammation.
Mol Imaging
PUBLISHED: 06-14-2013
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The aim of this study was to evaluate the impact of different anesthetics on 3-[18F]fluoro-3-deoxythymidine ([18F]FLT) uptake in carcinomas and arthritic ankles. To determine the amount of [18F]FLT uptake in subcutaneous CT26 colon carcinomas or arthritic ankles, spontaneously room air/medical air-breathing mice were anesthetized with isoflurane, a combination of medetomidine/midazolam, or ketamine/xylazine. Mice were kept conscious or anesthetized during [18F]FLT uptake before the 10-minute static positron emission tomographic (PET) investigations. [18F]FLT uptake in CT26 colon carcinomas and arthritic ankles was calculated by drawing regions of interest. We detected a significantly reduced (4.4 ± 0.9 %ID/cm3) [18F]FLT uptake in the carcinomas of ketamine/xylazine-anesthetized mice compared to the [18F]FLT-uptake in carcinomas of medetomidine/midazolam- (7.0 ± 1.5 %ID/cm3) or isoflurane-anesthetized mice (6.4 ± 1.5 %ID/cm3), whereas no significant differences were observed in arthritic ankles regardless of whether mice were anesthetized or conscious during tracer uptake. The time-activity curves of carcinomas and arthritic ankles yielded diverse [18F]FLT accumulation related to the used anesthetics. [18F]FLT uptake dynamics are different in arthritic ankles and carcinoma, and the magnitude and pharmacokinetics of [18F]FLT uptake are sensitive to anesthetics. Thus, for preclinical in vivo [18F]FLT PET studies in experimental tumor or inflammation models, we recommend the use of isoflurane anesthesia as it yields a stable tracer uptake and is easy to handle.
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A novel transgenic rat model for spinocerebellar ataxia type 17 recapitulates neuropathological changes and supplies in vivo imaging biomarkers.
J. Neurosci.
PUBLISHED: 05-24-2013
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Spinocerebellar ataxia 17 (SCA17) is an autosomal-dominant, late-onset neurodegenerative disorder caused by an expanded polyglutamine (polyQ) repeat in the TATA-box-binding protein (TBP). To further investigate this devastating disease, we sought to create a first transgenic rat model for SCA17 that carries a full human cDNA fragment of the TBP gene with 64 CAA/CAG repeats (TBPQ64). In line with previous observations in mouse models for SCA17, TBPQ64 rats show a severe neurological phenotype including ataxia, impairment of postural reflexes, and hyperactivity in early stages followed by reduced activity, loss of body weight, and early death. Neuropathologically, the severe phenotype of SCA17 rats was associated with neuronal loss, particularly in the cerebellum. Degeneration of Purkinje, basket, and stellate cells, changes in the morphology of the dendrites, nuclear TBP-positive immunoreactivity, and axonal torpedos were readily found by light and electron microscopy. While some of these changes are well recapitulated in existing mouse models for SCA17, we provide evidence that some crucial characteristics of SCA17 are better mirrored in TBPQ64 rats. Thus, this SCA17 model represents a valuable tool to pursue experimentation and therapeutic approaches that may be difficult or impossible to perform with SCA17 transgenic mice. We show for the first time positron emission tomography (PET) and diffusion tensor imaging (DTI) data of a SCA animal model that replicate recent PET studies in human SCA17 patients. Our results also confirm that DTI are potentially useful correlates of neuropathological changes in TBPQ64 rats and raise hope that DTI imaging could provide a biomarker for SCA17 patients.
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Summary report of the First International Workshop on PET/MR imaging, March 19-23, 2012, Tübingen, Germany.
Mol Imaging Biol
PUBLISHED: 03-22-2013
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We report from the First International Workshop on positron emission tomography/magnetic resonance imaging (PET/MRI) that was organized by the University of Tübingen in March 2012. Approximately 100 imaging experts in MRI, PET and PET/computed tomography (CT), among them early adopters of pre-clinical and clinical PET/MRI technology, gathered from March 19 to 24, 2012 in Tübingen, Germany. The objective of the workshop was to provide a forum for sharing first-hand methodological and clinical know-how and to assess the potential of combined PET/MRI in various applications from pre-clinical research to scientific as well as clinical applications in humans. The workshop was comprised of pro-active sessions including tutorials, specific discussion panels and grand rounds. Pre-selected experts moderated the sessions, and feedback from the subsequent discussions is presented here to a greater readership. Naturally, the summaries provided herein are subjective descriptions of the hopes and challenges of PET/MR imaging as seen by the workshop attendees at a very early point in time of adopting PET/MRI technology and, as such, represent only a snapshot of current approaches.
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Imaging findings and therapy response monitoring in chronic sclerodermatous graft-versus-host disease: preliminary data of a simultaneous PET/MRI approach.
Clin Nucl Med
PUBLISHED: 03-05-2013
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Our objective was a multifunctional imaging approach of chronic sclerodermatous graft-versus-host disease (ScGVHD) and its course during therapy using PET/MRI.
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Selective poisoning of Ctnnb1-mutated hepatoma cells in mouse liver tumors by a single application of acetaminophen.
Arch. Toxicol.
PUBLISHED: 02-25-2013
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Mouse liver tumors that harbor activating mutations in Ctnnb1, encoding ?-catenin, express high levels of various cytochromes P450 (CYP), including CYP2E1 and CYP1A2. Acetaminophen (AAP) is metabolized in hepatocytes by these CYPs to the reactive intermediate N-acetyl-p-benzoquinone-imine, which is toxic to hepatocytes at high doses where depletion of glutathione occurs. We have induced liver tumors in mice by treatment with the liver carcinogen N-nitrosodiethylamine followed by chronic treatment with the tumor promoter phenobarbital. Under this protocol, ~80 % of tumors display Ctnnb1 mutations and express high levels of various CYP isoforms. Tumor-bearing animals were given a single intraperitoneal injection of 300 mg/kg body weight AAP, which was well tolerated by the animals. This dose, however, eradicated essentially all larger Ctnnb1-mutated, CYP-positive liver tumors, killing >90 % of hepatoma cells: at 2 days after AAP, large necrotic areas filled with cell debris were observed in tumors. These were infiltrated in the following days by immune cells starting from the outer parts of the damaged areas slowly closing the "wounds" left from the poisoned tumor cells. During this period, there was increased proliferation of normal hepatocytes, but some residual tumor cells were also proliferating. Our results show that a selective poisoning of Ctnnb1-mutated liver tumors by administration of AAP is possible in this experimental system. Application of an adapted protocol could be envisaged for neo-adjuvant treatment of human hepatoblastoma which are frequently mutated in CTNNB1 and often show high expression of CYP2E1.
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A progressive dopaminergic phenotype associated with neurotoxic conversion of ?-synuclein in BAC-transgenic rats.
Brain
PUBLISHED: 02-16-2013
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Conversion of soluble ?-synuclein into insoluble and fibrillar inclusions is a hallmark of Parkinsons disease and other synucleinopathies. Accumulating evidence points towards a relationship between its generation at nerve terminals and structural synaptic pathology. Little is known about the pathogenic impact of ?-synuclein conversion and deposition at nigrostriatal dopaminergic synapses in transgenic mice, mainly owing to expression limitations of the ?-synuclein construct. Here, we explore whether both the rat as a model and expression of the bacterial artificial chromosome construct consisting of human full-length wild-type ?-synuclein could exert dopaminergic neuropathological effects. We found that the human promoter induced a pan-neuronal expression, matching the rodent ?-synuclein expression pattern, however, with prominent C-terminally truncated fragments. Ageing promoted conversion of both full-length and C-terminally truncated ?-synuclein species into insolube and proteinase K-resistant fibres, with strongest accumulation in the striatum, resembling biochemical changes seen in human Parkinsons disease. Transgenic rats develop early changes in novelty-seeking, avoidance and smell before the progressive motor deficit. Importantly, the observed pathological changes were associated with severe loss of the dopaminergic integrity, thus resembling more closely the human pathology.
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Simultaneous PET-MRI reveals brain function in activated and resting state on metabolic, hemodynamic and multiple temporal scales.
Nat. Med.
PUBLISHED: 01-28-2013
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Combined positron emission tomography (PET) and magnetic resonance imaging (MRI) is a new tool to study functional processes in the brain. Here we study brain function in response to a barrel-field stimulus simultaneously using PET, which traces changes in glucose metabolism on a slow time scale, and functional MRI (fMRI), which assesses fast vascular and oxygenation changes during activation. We found spatial and quantitative discrepancies between the PET and the fMRI activation data. The functional connectivity of the rat brain was assessed by both modalities: the fMRI approach determined a total of nine known neural networks, whereas the PET method identified seven glucose metabolism-related networks. These results demonstrate the feasibility of combined PET-MRI for the simultaneous study of the brain at activation and rest, revealing comprehensive and complementary information to further decode brain function and brain networks.
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Multimodal elucidation of choline metabolism in a murine glioma model using magnetic resonance spectroscopy and 11C-choline positron emission tomography.
Cancer Res.
PUBLISHED: 01-23-2013
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The metabolites, transporters, and enzymes involved in choline metabolism are regarded as biomarkers for disease progression in a variety of cancers, but their in vivo detection is not ideal. Both magnetic resonance spectroscopy [MRS using chemical shift imaging (CSI) total choline (tCho)] and C-choline positron emission tomography (PET) can probe this pathway, but they have not been compared side by side. In this study, we used the spontaneous murine astrocytoma model SMA560 injected intracranially into syngeneic VM/Dk mice, analyzing animals at various postimplantation time points using dynamic microPET imaging and CSI MRS. We observed an increase in tumor volume and C-choline uptake between days 5 and 18. Similarly, tCho levels decreased at days 5 to 18. We found a negative correlation between the tCho and PET results in the tumor and a positive correlation between the tCho tumor-to-brain ratio and choline uptake in the tumor. PCR results confirmed expected increases in expression levels for most of the transporters and enzymes. Using MRS quantification, a good agreement was found between CSI and C-choline PET data, whereas a negative correlation occurred when CSI was not referenced. Thus, C-choline PET and MRS methods seemed to be complementary in strengths. While advancing tumor proliferation caused an increasing C-choline uptake, gliosis and inflammation potentially accounted for a high peritumoral tCho signal in CSI, as supported by histology and secondary ion mass spectrometry imaging. Our findings provide definitive evidence of the use of MRS, CSI, and PET for imaging tumors in vivo.
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Assessment of PET tracer uptake in hormone-independent and hormone-dependent xenograft prostate cancer mouse models.
J. Nucl. Med.
PUBLISHED: 08-22-2011
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The pharmacokinetics of (18)F-fluorodeoxythymidine (FLT), (18)F-FDG, (11)C-choline, and (18)F-fluoroethylcholine (FEC) in 2 hormone-independent (PC-3, DU145) and 2 hormone-dependent (CWR22, PAC120) prostate cancer xenograft mouse models were evaluated by PET and compared by immunohistochemistry. Further investigation was performed to determine whether PET can detect early changes in tumor metabolism after androgen ablation therapy through surgical castration.
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Significant impact of different oxygen breathing conditions on noninvasive in vivo tumor-hypoxia imaging using [¹?F]-fluoro-azomycinarabino-furanoside ([¹?F]FAZA).
Radiat Oncol
PUBLISHED: 08-16-2011
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[18F]FAZA is a PET biomarker with great potential for imaging tumor hypoxia. Aim of our study was to compare [18F]FAZA uptake in mice with subcutaneous exogenous CT26 colon carcinomas and endogenous polyoma middle-T (PyV-mT) mammary carcinomas and to analyze the influence of different breathing protocols in CT26 colon carcinomas as well as the reversibility or irreversibility of [18F]FAZA uptake.
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MRI-based attenuation correction for whole-body PET/MRI: quantitative evaluation of segmentation- and atlas-based methods.
J. Nucl. Med.
PUBLISHED: 08-09-2011
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PET/MRI is an emerging dual-modality imaging technology that requires new approaches to PET attenuation correction (AC). We assessed 2 algorithms for whole-body MRI-based AC (MRAC): a basic MR image segmentation algorithm and a method based on atlas registration and pattern recognition (AT&PR).
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In vivo quantification of dopamine transporters in mice with unilateral 6-OHDA lesions using [11C]methylphenidate and PET.
Neuroimage
PUBLISHED: 06-26-2011
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Quantification of the binding of [11C]methylphenidate to the dopamine transporter (DAT) using positron emission tomography (PET) is often used to evaluate the integrity of dopaminergic neurons in the striatal regions of the brain. Over the past decade, many genetically engineered mouse models of human disease have been developed and have become particularly useful for the study of disease onset and progression over time. Quantitative imaging of small structures such as the mouse brain is especially challenging. Thus, the aims of this study were (1) to evaluate the accuracy of quantifying DAT binding using in vivo PET and (2) to examine the impact of different methodologies.
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Noninvasive nuclear imaging enables the in vivo quantification of striatal dopamine receptor expression and raclopride affinity in mice.
J. Nucl. Med.
PUBLISHED: 06-16-2011
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The increasing use of genetically engineered mice as animal models of human disease in biomedical research, latest advances in imaging technologies, and development of novel, highly specific radiolabeled biomarkers provide great potential to study receptor expression and gene function in vivo in mice. (11)C-raclopride is a widely used PET tracer to measure striatal D(2) receptor binding and was used to test the feasibility of the multiple-ligand-concentration receptor assay for D(2) receptor quantification.
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Ex vivoimaging of injured arteries in rabbits using fluorescence-labelled glycoprotein VI-Fc.
Platelets
PUBLISHED: 06-14-2011
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Vascular lesion formation and collagen presentation are key events leading to the development of vulnerable plaques. Glycoprotein VI (GPVI) significantly contributes to plaque-associated collagen binding and thrombus formation. The aim of this study was to image endothelial injury using fluorescence-labelled GPVI-Fc (Fc, fragment crystallized), a soluble form of GPVI that was generated by cloning and fusing GPVI to an Fc-domain, in an ex-vivo rabbit model. This study serves as a proof-of-principle study to demonstrate that GPVI-Fc is a useful tool for detecting endothelial damage. The carotid and femoral arteries and the aorta abdominalis were isolated from rabbits and perfused with phosphate buffered saline (PBS) to remove all blood, and a catheter was placed into the vessels in situ. Endothelial damage was achieved by pulling an inflated balloon approximately 1 inch through the vessels, while control vessels were not balloon-treated. After balloon deflation, the catheter was removed. Fluorescence-labelled GPVI-Fc (50?µg/mL) was injected into the injured and control intact vessels, and the opened vessels were sealed by clamps. After incubation, the vessels were rinsed with PBS, and optical imaging was performed to measure GPVI-Fc binding to injured endothelium. The optical data corresponding to the mean detected optical signal of the regions of interest were corrected by subtracting the mean data of the background fluorescence (arbitrary units). After denudation, fluorescence was enhanced in injured femoral and carotid arteries when compared to intact femoral (41.1?±?17.5 vs. 14.6?±?6.5; P?=?0.021) and carotid (30.2?±?7.6 vs. 7.9?±?3.9; P?=?0.005) arteries. This preclinical GPVI-Fc-based vascular lesion imaging approach may be the first step towards a method that allows identification of vascular lesions in vivo.
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Increased apical enlargement contributes to excessive dentin removal in curved root canals: a stepwise microcomputed tomography study.
J Endod
PUBLISHED: 05-28-2011
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To determine whether increased apical enlargement would result in a complete preparation of curved canals and to progressively assess shaping quality using multiple microcomputed tomography (MCT) scans.
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PKB/SGK-resistant GSK3 enhances phosphaturia and calciuria.
J. Am. Soc. Nephrol.
PUBLISHED: 04-14-2011
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Insulin and IGF1-dependent signaling activates protein kinase B and serum and glucocorticoid inducible kinase (PKB/SGK), which together phosphorylate and inactivate glycogen synthase kinase GSK3. Because insulin and IGF1 increase renal tubular calcium and phosphorus reabsorption, we examined GSK3 regulation of phosphate transporter activity and determined whether PKB/SGK inactivates GSK3 to enhance renal phosphate and calcium transport. Overexpression of GSK3 and the phosphate transporter NaPi-IIa in Xenopus oocytes decreased electrogenic phosphate transport compared with NaPi-IIa-expressing oocytes. PKB/SGK serine phosphorylation sites in GSK3 were mutated to alanine to create gsk3(KI) mice resistant to PKB/SGK inactivation. Compared with wildtype animals, gsk3(KI) animals exhibited greater urinary phosphate and calcium clearances with higher excretion rates and lower plasma concentrations. Isolated brush border membranes from gsk3(KI) mice showed less sodium-dependent phosphate transport and Na-phosphate co-transporter expression. Parathyroid hormone, 1,25-OH vitamin D levels, and bone mineral density were decreased in gsk3(KI) mice, suggesting a global dysregulation of bone mineral metabolism. Taken together, PKB/SGK phosphorylation of GSK3 increases phosphate transporter activity and reduces renal calcium and phosphate loss.
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Decreased bone density and increased phosphaturia in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase 3.
Kidney Int.
PUBLISHED: 03-30-2011
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Insulin and growth factors activate the phosphatidylinositide-3-kinase pathway, leading to stimulation of several kinases including serum- and glucocorticoid-inducible kinase isoform SGK3, a transport regulating kinase. Here, we explored the contribution of SGK3 to the regulation of renal tubular phosphate transport. Coexpression of SGK3 and sodium-phosphate cotransporter IIa significantly enhanced the phosphate-induced current in Xenopus oocytes. In sgk3 knockout and wild-type mice on a standard diet, fluid intake, glomerular filtration and urine flow rates, and urinary calcium ion excretion were similar. However, fractional urinary phosphate excretion was slightly but significantly larger in the knockout than in wild-type mice. Plasma calcium ion, phosphate concentration, and plasma parathyroid hormone levels were not significantly different between the two genotypes, but plasma calcitriol and fibroblast growth factor 23 concentrations were significantly lower in the knockout than in wild-type mice. Moreover, bone density was significantly lower in the knockouts than in wild-type mice. Histological analysis of the femur did not show any differences in cortical bone but there was slightly less prominent trabecular bone in sgk3 knockout mice. Thus, SGK3 has a subtle but significant role in the regulation of renal tubular phosphate transport and bone density.
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Imaging of injured and atherosclerotic arteries in mice using fluorescence-labeled glycoprotein VI-Fc.
Eur J Radiol
PUBLISHED: 03-15-2011
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To assess endothelial injury and repair using fluorescence-labeled glycoprotein VI (GPVI)-Fc in a murine model.
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[68Ga]NODAGA-RGD for imaging ?v?3 integrin expression.
Eur. J. Nucl. Med. Mol. Imaging
PUBLISHED: 02-11-2011
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A molecular target involved in the angiogenic process is the ?(v)?(3) integrin. It has been demonstrated in preclinical as well as in clinical studies that radiolabelled RGD peptides and positron emission tomography (PET) allow noninvasive monitoring of ?(v)?(3) expression. Here we introduce a (68)Ga-labelled NOTA-conjugated RGD peptide ([(68)Ga]NODAGA-RGD) and compare its imaging properties with [(68)Ga]DOTA-RGD using small animal PET.
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The effect of patient positioning aids on PET quantification in PET/MR imaging.
Eur. J. Nucl. Med. Mol. Imaging
PUBLISHED: 02-10-2011
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Clinical PET/MR requires the use of patient positioning aids to immobilize and support patients for the duration of the combined examination. Ancillary immobilization devices contribute to overall attenuation of the PET signal, but are not detected with conventional MR sequences and, hence, are ignored in standard MR-based attenuation correction (MR-AC). We report on the quantitative effect of not accounting for the attenuation of patient positioning aids in combined PET/MR imaging.
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Simultaneous 68Ga-DOTATOC-PET/MRI for IMRT treatment planning for meningioma: first experience.
Int. J. Radiat. Oncol. Biol. Phys.
PUBLISHED: 02-06-2011
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To evaluate intensity-modulated radiotherapy (IMRT) treatment planning based on simultaneous positron-emission tomography and magnetic resonance imaging (PET/MRI) of meningioma.
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Feasibility of simultaneous PET/MR imaging in the head and upper neck area.
Eur Radiol
PUBLISHED: 01-20-2011
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The aim of this pilot study was to test and demonstrate the feasibility of simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) of the head and upper neck area using a new hybrid PET/MRI system.
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A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons.
Hum. Mol. Genet.
PUBLISHED: 08-31-2010
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The molecular motor dynein and its associated regulatory subunit dynactin have been implicated in several neurodegenerative conditions of the basal ganglia, such as Huntingtons disease (HD) and Perry syndrome, an atypical Parkinson-like disease. This pathogenic role has been largely postulated from the existence of mutations in the dynactin subunit p150(Glued). However, dynactin is also able to act independently of dynein, and there is currently no direct evidence linking dynein to basal ganglia degeneration. To provide such evidence, we used here a mouse strain carrying a point mutation in the dynein heavy chain gene that impairs retrograde axonal transport. These mice exhibited motor and behavioural abnormalities including hindlimb clasping, early muscle weakness, incoordination and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signalling, decreased dopamine D1 and D2 receptor binding in positron emission tomography SCAN and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. Altogether, these findings provide a direct genetic evidence for the requirement of dynein for the morphology and function of striatal neurons. Our study supports a role for dynein dysfunction in the pathogenesis of neurodegenerative disorders of the basal ganglia, such as Perry syndrome and HD.
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High-resolution animal PET imaging of prostate cancer xenografts with three different 64Cu-labeled antibodies against native cell-adherent PSMA.
Prostate
PUBLISHED: 08-06-2010
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The prostate specific membrane antigen (PSMA) is expressed by virtually all prostate cancers and represents an ideal target for diagnostic and therapeutic strategies. This article compares the in vivo behavior and tumor uptake of three different radiolabeled anti-PSMA monoclonal antibodies (mAbs) and corresponding F(ab)(2) and Fab fragments thereof.
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Isochronous assessment of cardiac metabolism and function in mice using hybrid PET/MRI.
J. Nucl. Med.
PUBLISHED: 07-21-2010
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Recently, integrated small-animal PET/MRI prototypes that provide isochronous and coregistered datasets of morphology and function through the simultaneous acquisition of PET and MRI data have been developed. However, the need for MRI compatibility can constrain the technical design of the PET components and may lead to a lower sensitivity and lower spatial and temporal resolutions. The aim of this study was to evaluate the suitability of a prototype preclinical PET/MRI system for the simultaneous assessment of cardiac metabolism and function in mice. A stand-alone high-resolution small-animal PET scanner using the same evaluation protocols was used as a reference.
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Hybrid PET/MRI of intracranial masses: initial experiences and comparison to PET/CT.
J. Nucl. Med.
PUBLISHED: 07-21-2010
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Simultaneous PET and MRI using new hybrid PET/MRI systems promises optimal spatial and temporal coregistration of structural, functional, and molecular image data. In a pilot study of 10 patients with intracranial masses, the feasibility of tumor assessment using a PET/MRI system comprising lutetium oxyorthosilicate scintillators coupled to avalanche photodiodes was evaluated, and quantification accuracy was compared with conventional PET/CT datasets.
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Phosphoglycerate kinase 1 promoting tumor progression and metastasis in gastric cancer - detected in a tumor mouse model using positron emission tomography/magnetic resonance imaging.
Cell. Physiol. Biochem.
PUBLISHED: 07-05-2010
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Tumor dissemination is frequent in gastric cancer and implies a poor prognosis. Cure is only achievable provided an accurate staging is performed at primary diagnosis. In previous studies we were able to show a relevant impact of increased phosphoglycerate kinase 1 expression (PGK1; a glycolytic enzyme) on invasive properties of gastric cancer in-vivo and in-vitro. Thus the aim of the present study was to evaluate the effect of enhanced PGK1 expression in gastric cancer employing magnetic resonance (MR)-imaging combined with positron emission tomography (PET), a recently emerging new high resolution imaging technique in a mouse model.
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Combined PET/MRI: one step further in multimodality imaging.
Trends Mol Med
PUBLISHED: 06-25-2010
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Given the need for sophisticated in vivo detection techniques to better characterize the cellular and subcellular processes in animals and humans, molecular imaging has become an important discipline. Techniques in molecular imaging have developed from stand alone modalities to multimodality methods. Among these, the combination of positron emission tomography (PET) and computed tomography (CT) is a successful imaging method and has become an important tool in clinical practice. Technological approaches that combine magnetic resonance imaging (MRI) with diffuse optical tomography (DOT), fluorescence tomography (FT) and PET have now been introduced. PET/MRI and the resulting combination of molecular, morphological and functional information will pave the way for a better understanding of physiological and disease mechanisms in preclinical and clinical settings.
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Diffusion tensor imaging in a human PET/MR hybrid system.
Invest Radiol
PUBLISHED: 03-31-2010
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The aim of this study was to test and demonstrate the feasibility of diffusion tensor imaging (DTI) with a hybrid positron emission tomography (PET)/magnetic resonance imaging system for simultaneous PET and magnetic resonance (MR) data acquisition.
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Effects of in vitro exposure of Echinococcus multilocularis metacestodes to cytostatic drugs on in vivo growth and proliferation of the parasite.
Parasitol. Res.
PUBLISHED: 03-22-2010
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The cytostatic drugs Vincristine (VCR), Navelbine (NAV), and Methotrexate (MTX) were evaluated for their growth inhibitory potential against metacestodes of Echinococcus multilocularis (Em) by in vitro and in vivo assays. In vitro cultures of E. multilocularis were exposed to IC 90, IC 80, and IC 5 concentrations of VCR, NAV, or MTX for 1 week, then parasite tissue cultures were kept for 1 week without drug exposure in vitro, and thereafter, metacestode tissues were injected intra-peritoneally into Meriones unguiculatus. Metacestode growth was monitored for several months post-infection (p.i.) by body weight control, magnetic resonance imaging (MRI), and autopsy at 5 months p.i. Weight monitoring of infected M. unguiculatus did not provide conclusive evidence for Em-metacestode growth, while MRI could detect growing Em-metacestode in the MTX-treated group at 8 weeks (p.i.), whereas metacestodes exposed to VCR and NAV were at 17 weeks (p.i.) detectable. MRI disclosed progressive and massive growth of Em-metacestode in the VCR- and MTX-exposed groups, while the NAV-pretreated Em-metacestodes volume did not exceed 4 cm(3). At autopsy, Em-metacestodes of less than 4 cm(3) were found in infected M. unguiculatus, which was not detected by MRI. In summary, the cytostatic drugs Methotrexate, Navelbine, and Vincristine--as applied in the present work--did not show parasitocidal or clear parasitostatic effects on metacestodes of E. multilocularis. While parasite growth in vivo was inhibited in NAV- and VCR-pretreated Em-metacestodes, MTX pretreatment seemed to enhance parasite proliferation. Magnetic resonance imaging appears suitable to monitor in vivo the effects of drugs on growth progression and regression only of larger Em-metacestode tissues.
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Evaluation of Geiger-mode APDs for PET block detector designs.
Phys Med Biol
PUBLISHED: 03-05-2010
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This paper presents an evaluation of two types of Geiger-mode avalanche photodiodes (G-APDs) for their potential to be used in a positron emission tomography (PET) detector. While the MPPC G-APD had only 3600 cells, the solid state photomultiplier (SSPM)-type G-APD had 8100 cells. In a single-channel G-APD/LSO setup, the energy resolution (DeltaEpsilon/Epsilon) of the SSPM at 511 keV was 25%, while the (DeltaEpsilon/Epsilon) of the MPPC was 13.5% (FWHM). No influences were observed while the detectors were inside a 7 T magnetic resonance (MR) scanner. A time resolution of 2.7 ns (FWHM) was measured for the LSO/SSPM and 0.9 ns for the LSO/MPPC detector setup. Although the linearity was superior for the SSPM in the single detector readout, the inferior energy and time resolution excluded them to be used for the block detector readout. All 12 x 12 LSO crystals of the block could be resolved in a crystal map using a 3 x 3 MPPC G-APD array. The time resolution of the block detector was 950 ps. While the energy spectra for the MPPC-based single-channel setup were nonlinear, they reached linearity better than 5% in the block detector. A high number of G-APD cells provide a linear signal in a single-channel detector setup, but not necessarily a good timing or (DeltaEpsilon/Epsilon) due to a larger inactive surface resulting in lower photon detection efficiency. G-APDs with a low number of cells provide a good timing and (DeltaEpsilon/Epsilon) and linear signals in block detector designs, where the scintillation light is shared over many G-APDs.
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PET/MRI: paving the way for the next generation of clinical multimodality imaging applications.
J. Nucl. Med.
PUBLISHED: 02-11-2010
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Multimodality imaging and, more specifically, the combination of PET and CT has matured into an important diagnostic tool. During the same period, concepts for PET scanners integrated into an MR tomograph have emerged. The excellent soft-tissue contrast of MRI and the multifunctional imaging options it offers, such as spectroscopy, functional MRI, and arterial spin labeling, complement the molecular information of PET. The development of a fully integrated PET/MRI system is technologically challenging. It requires not only significant modifications of the PET detector to make it compact and insensitive to magnetic fields but also a major redesign of the MRI hardware.
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Direct crosstalk between mast cell-TNF and TNFR1-expressing endothelia mediates local tissue inflammation.
Blood
PUBLISHED: 06-22-2009
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Signaling through tumor necrosis factor receptor 1 (TNFR1) controls bacterial infections and the induction of inflammatory Th1 cell-mediated autoimmune diseases. By dissecting Th1 cell-mediated delayed-type hypersensitivity responses (DTHRs) into single steps, we localized a central defect to the missing TNFR1 expression by endothelial cells (ECs). Adoptive transfer and mast cell knockin experiments into Kit(W)/Kit(W-v), TNF(-/-), and TNFR1(-/-) mice showed that the signaling defect exclusively affects mast cell-EC interactions but not T cells or antigen-presenting cells. As a consequence, TNFR1(-/-) mice had strongly reduced mRNA and protein expression of P-selectin, E-selectin, ICAM-1, and VCAM-1 during DTHR elicitation. In consequence, intravital fluorescence microscopy revealed up to 80% reduction of leukocyte rolling and firm adhesion in TNFR1(-/-) mice. As substitution of TNF(-/-) mice with TNF-producing mast cells fully restored DTHR in these mice, signaling of mast cell-derived TNF through TNFR1-expressing ECs is essential for the recruitment of leukocytes into sites of inflammation.
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Towards quantitative PET/MRI: a review of MR-based attenuation correction techniques.
Eur. J. Nucl. Med. Mol. Imaging
PUBLISHED: 05-27-2009
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Positron emission tomography (PET) is a fully quantitative technology for imaging metabolic pathways and dynamic processes in vivo. Attenuation correction of raw PET data is a prerequisite for quantification and is typically based on separate transmission measurements. In PET/CT attenuation correction, however, is performed routinely based on the available CT transmission data.
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New perspectives on bone marrow contrast agents and molecular imaging.
Semin Musculoskelet Radiol
PUBLISHED: 05-19-2009
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Magnetic resonance (MR) imaging of bone marrow provides a noninvasive diagnosis of the vascularity, cell quantity, and composition of the normal and pathological bone marrow. This article reviews new and evolving techniques for bone marrow MR imaging with a special focus on translational and clinical applications. Evaluations of bone marrow perfusion with standard small molecular contrast agents and, more recently, with macromolecular contrast agents are currently being applied for therapy monitoring. Cell-specific contrast agents are expected to improve the sensitivity and specificity of bone marrow MR imaging. Novel cellular and molecular imaging techniques for the depiction of cell metabolism and specific biochemical pathways are discussed. Cell tracking techniques may allow specific diagnoses of inflammatory processes as well as monitoring of novel therapies based on stem cells. Future developments of fusion imaging techniques and bifunctional contrast agents are directed to combine comprehensive information about bone marrow structure and function with targeted and image-guided therapies.
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An integrated MR/PET system: prospective applications.
Abdom Imaging
PUBLISHED: 03-27-2009
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Radiology is strongly depending on medical imaging technology and consequently directing technological progress. A novel technology can only be established, however, if improved diagnostic accuracy influence on therapeutic management and/or overall reduced cost can be evidenced. It has been demonstrated recently that Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) can technologically be integrated into one single hybrid system. Some scientific arguments on the benefits are obvious, e.g., that simultaneous imaging of morphological and functional information will improve tissue characterization. However, crossfire of questions still remains: what unmet radiological needs are addressed by the novel system? What level of hardware integration is reasonable, or would software-based image co-registration be sufficient? Will MR/PET achieve higher diagnostic accuracy compared to separate imaging? What is the added value compared to other hybrid imaging modalities like PET/CT? And finally, is the system economically reasonable and has the potential to reduce overall costs for therapy planning and monitoring? This article tries to highlight some perspectives of applying an integrated MR/PET system for simultaneous morphologic and functional imaging.
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PET imaging of prostate cancer xenografts with a highly specific antibody against the prostate-specific membrane antigen.
J. Nucl. Med.
PUBLISHED: 03-16-2009
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Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, is highly expressed by virtually all prostate cancers and is currently the focus of several diagnostic and therapeutic strategies. We have previously reported on the generation of several monoclonal antibodies (mAb) and antibody fragments that recognize and bind with high affinity to the extracellular domain of cell-adherent PSMA. This article reports the in vivo behavior and tumor uptake of the radiolabeled anti-PSMA mAb 3/A12 and its potential as a tracer for PET.
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Pre-clinical PET/MR: technological advances and new perspectives in biomedical research.
Eur. J. Nucl. Med. Mol. Imaging
PUBLISHED: 02-06-2009
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Combined PET/MRI allows for multi-parametric imaging and reveals one or more functional processes simultaneously along with high-resolution morphology. Especially in small-animal research, where high soft tissue contrast is required, and the scan time as well as radiation dose are critical factors, the combination of PET and MRI would be beneficial compared with PET/CT.
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Enhanced FGF23 serum concentrations and phosphaturia in gene targeted mice expressing WNK-resistant SPAK.
Kidney Blood Press. Res.
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The WNK-dependent STE20/SPS1-related proline/alanine-rich kinase (SPAK) regulates the renal thiazide sensitive NaCl cotransporter (NCC) and the renal furosemide sensitive Na+, K+, 2Cl- cotransporter (NKCC2) and thus participates in the regulation of renal salt excretion, extracellular fluid volume and blood pressure. Inhibition of NCC leads to anticalciuria. Moreover, NCC is also expressed in osteoblasts where it is implicated in the regulation of bone mineralization. Osteoblasts further influence mineral metabolism by releasing the phosphaturic hormone FGF23. The present study explored, whether SPAK participates in the regulation of calcium-phosphate homeostasis.
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In vivo imaging of cell proliferation enables the detection of the extent of experimental rheumatoid arthritis by 3-deoxy-3-18f-fluorothymidine and small-animal PET.
J. Nucl. Med.
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The aim of this work was to study the feasibility of measuring cell proliferation noninvasively in vivo during different stages of experimental arthritis using the PET proliferation tracer 3-deoxy-3-(18)F-fluorothymidine ((18)F-FLT).
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Simultaneous PET/MR imaging of the brain: feasibility of cerebral blood flow measurements with FAIR-TrueFISP arterial spin labeling MRI.
Acta Radiol
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Hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) with simultaneous data acquisition promises a comprehensive evaluation of cerebral pathophysiology on a molecular, anatomical, and functional level. Considering the necessary changes to the MR scanner design the feasibility of arterial spin labeling (ASL) is unclear.
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A novel BACHD transgenic rat exhibits characteristic neuropathological features of Huntington disease.
J. Neurosci.
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Huntington disease (HD) is an inherited progressive neurodegenerative disorder, characterized by motor, cognitive, and psychiatric deficits as well as neurodegeneration and brain atrophy beginning in the striatum and the cortex and extending to other subcortical brain regions. The genetic cause is an expansion of the CAG repeat stretch in the HTT gene encoding huntingtin protein (htt). Here, we generated an HD transgenic rat model using a human bacterial artificial chromosome (BAC), which contains the full-length HTT genomic sequence with 97 CAG/CAA repeats and all regulatory elements. BACHD transgenic rats display a robust, early onset and progressive HD-like phenotype including motor deficits and anxiety-related symptoms. In contrast to BAC and yeast artificial chromosome HD mouse models that express full-length mutant huntingtin, BACHD rats do not exhibit an increased body weight. Neuropathologically, the distribution of neuropil aggregates and nuclear accumulation of N-terminal mutant huntingtin in BACHD rats is similar to the observations in human HD brains. Aggregates occur more frequently in the cortex than in the striatum and neuropil aggregates appear earlier than mutant htt accumulation in the nucleus. Furthermore, we found an imbalance in the striatal striosome and matrix compartments in early stages of the disease. In addition, reduced dopamine receptor binding was detectable by in vivo imaging. Our data demonstrate that this transgenic BACHD rat line may be a valuable model for further understanding the disease mechanisms and for preclinical pharmacological studies.
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Imaging DA release in a rat model of L-DOPA-induced dyskinesias: a longitudinal in vivo PET investigation of the antidyskinetic effect of MDMA.
Neuroimage
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In the context of Parkinsons disease, motor symptoms result from the degeneration of nigrostriatal neurons. Dopamine (DA) replacement using l-3,4-dihydroxyphenylalanine (L-DOPA) has been the treatment of choice in the early stages of the disease. However, with disease progression, patients suffer from motor complications, which have been suggested to arise from DA released from serotonergic terminals according to the false neurotransmitter hypothesis. The synthetic amphetamine derivative (±) 3,4-methylenedioxymethamphetamine (MDMA) has been shown to significantly inhibit dyskinesia in humans and in animal models of PD. In this study, we examined the effect of MDMA on L-DOPA-induced DA release by using [(11)C]raclopride kinetic modeling to assess alterations in DA neurotransmission in a rat model of L-DOPA-induced dyskinesia (LID) in a longitudinal in vivo PET study. Rats were submitted to 6-OHDA lesions, and the lesions were confirmed to be sufficiently severe based on the performance during stepping tests and [(11)C]methylphenidate PET scans. The rats underwent two [(11)C]raclopride PET sessions before (baseline) and after two weeks of chronic L-DOPA treatment (priming). L-DOPA priming led to strong abnormal involuntary movements (AIMs). In group 1, L-DOPA priming reduced L-DOPA-induced DA release in the lesioned striatum with no effect on the healthy side, while the concomitant administration of L-DOPA and MDMA (group 2) increased the DA levels in the lesioned and healthy striatum. In addition, behavioral analysis, which was performed two weeks after the second PET session, confirmed the antidyskinetic effect of MDMA. Our data show that L-DOPA-induced DA release is attenuated in the Parkinsonian striatum after chronic L-DOPA pretreatment and that the antidyskinetic mechanism of MDMA does not depend primarily on dopaminergic neurotransmission.
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Quantification accuracy and partial volume effect in dependence of the attenuation correction of a state-of-the-art small animal PET scanner.
Phys Med Biol
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Quantification accuracy and partial volume effect (PVE) of the Siemens Inveon PET scanner were evaluated. The influence of transmission source activities (40 and 160 MBq) on the quantification accuracy and the PVE were determined. Dynamic range, object size and PVE for different sphere sizes, contrast ratios and positions in the field of view (FOV) were evaluated. The acquired data were reconstructed using different algorithms and correction methods. The activity level of the transmission source and the total emission activity in the FOV strongly influenced the attenuation maps. Reconstruction algorithms, correction methods, object size and location within the FOV had a strong influence on the PVE in all configurations. All evaluated parameters potentially influence the quantification accuracy. Hence, all protocols should be kept constant during a study to allow a comparison between different scans.
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6-Hydroxydopamine leads to T2 hyperintensity, decreased claudin-3 immunoreactivity and altered aquaporin 4 expression in the striatum.
Behav. Brain Res.
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The neurotoxin 6-hydroxydopamine (6-OHDA) is frequently used in animal models to mimic Parkinsons disease. Imaging studies describe hyperintense signalling in regions close to the site of the 6-OHDA injection in T2-weighted (T2w) magnetic resonance imaging (MRI). The nature of this hyperintense signal remains elusive and still is matter of discussion. Here we demonstrate hyperintense signalling in T2w MRI and decreased apparent diffusion coefficient (ADC) values following intraventricular injection of 6-OHDA. Moreover, we show decreased GFAP immunoreactivity in brain regions corresponding to the region revealing the hyperintense signalling, probably indicating a loss of astrocytes due to a toxic effect of 6-OHDA. In the striatum, where no hyperintense signalling in MRI was observed following intraventricular 6-OHDA injection, immunohistochemical and molecular analyses revealed an altered expression of the water channel aquaporin 4 and the emergence of vasogenic edema, indicated by an increased perivascular space. Moreover, a significant decrease of claudin-3 immunoreactivity was observed, implying alterations in the blood brain barrier. These findings indicate that intraventricular injection of 6-OHDA results (1) in effects close to the ventricles that can be detected as hyperintense signalling in T2w MRI accompanied by reduced ADC values and (2) in effects on brain regions not adjacent to the ventricles, where a disturbance of water homeostasis occurs. We clearly demonstrate that 6-OHDA leads to brain edema that in turn may affect the overall results of experiments (e.g. behavioral alterations). Therefore, when using 6-OHDA in Parkinsons models effects that are not mediated by degeneration of catecholaminergic neurons have to be considered.
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Oxygen breathing affects 3-deoxy-3-18F-fluorothymidine uptake in mouse models of arthritis and cancer.
J. Nucl. Med.
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Noninvasive in vivo imaging of biologic processes using PET is an important tool in preclinical studies. We observed significant differences in 3-deoxy-3-(18)F-fluorothymidine ((18)F-FLT) uptake in arthritic ankles and carcinomas between dynamic and static PET measurements when mice breathed oxygen. Thus, we suspected that air or oxygen breathing and the anesthesia protocol might influence (18)F-FLT tracer uptake.
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Generation of a novel rodent model for DYT1 dystonia.
Neurobiol. Dis.
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A mutation in the coding region of the Tor1A gene, resulting in a deletion of a glutamic acid residue in the torsinA protein (?ETorA), is the major cause of the inherited autosomal-dominant early onset torsion dystonia (DYT1). The pathophysiological consequences of this amino acid loss are still not understood. Currently available animal models for DYT1 dystonia provided important insights into the disease; however, they differ with respect to key features of torsinA associated pathology. We developed transgenic rat models harboring the full length human mutant and wildtype Tor1A gene. A complex phenotyping approach including classical behavioral tests, electrophysiology and neuropathology revealed a progressive neurological phenotype in ?ETorA expressing rats. Furthermore, we were able to replicate key pathological features of torsinA associated pathology in a second species, such as nuclear envelope pathology, behavioral abnormalities and plasticity changes. We therefore suggest that this rat model represents an appropriate new model suitable to further investigate the pathophysiology of ?ETorA and to test for therapeutic approaches.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.