5,206 research outputs found
A Systems-Level Analysis of Total-Body PET Data Reveals Complex Skeletal Metabolism Networks in vivo
No full textBone is now regarded to be a key regulator of a number of metabolic processes, in
addition to the regulation of mineral metabolism. However, our understanding of complex
bone metabolic interactions at a systems level remains rudimentary. In vitro molecular
biology and bioinformatics approaches have frequently been used to understand the
mechanistic changes underlying disease at the cell level, however, these approaches
lack the capability to interrogate dynamic multi-bone metabolic interactions in vivo. Here
we present a novel and integrative approach to understand complex bone metabolic
interactions in vivo using total-body positron emission tomography (PET) network
analysis of murine 18F-FDG scans, as a biomarker of glucose metabolism in bones.
In this report we show that different bones within the skeleton have a unique glucose
metabolism and form a complex metabolic network, which could not be identified
using single tissue simplistic PET standard uptake values analysis. The application
of our approach could reveal new physiological and pathological tissue interactions
beyond skeletal metabolism, due to PET radiotracers diversity and the advent of clinical
total-body PET systems.
Karla J. Suchacki, Carlos J. Alcaide-Corral, Samah Nimale, Mark G. Macaskill,
Roland H. Stimson, Colin Farquharson, Tom C. Freeman and Adriana A. S. Tavare
Quantification of Macrophage-Driven Inflammation During Myocardial Infarction with 18F-LW223, a Novel TSPO Radiotracer with Binding Independent of the rs6971 Human Polymorphism
No full textMyocardial infarction (MI) is one of the leading causes of death
worldwide, and inflammation is central to tissue response and patient
outcomes. The 18-kDa translocator protein (TSPO) has been used in
PET as an inflammatory biomarker. The aims of this study were to
screen novel, fluorinated, TSPO radiotracers for susceptibility to the
rs6971 genetic polymorphism using in vitro competition binding assays
in human brain and heart; assess whether the in vivo characteristics
of our lead radiotracer, 18F-LW223, are suitable for clinical
translation; and validate whether 18F-LW223 can detect macrophage-
driven inflammation in a rat MI model. Methods: Fifty-one
human brain and 29 human heart tissue samples were screened
for the rs6971 polymorphism. Competition binding assays were conducted
with 3H-PK11195 and the following ligands: PK11195, PBR28,
and our novel compounds (AB5186 and LW223). Na¨ıve rats and mice
were used for in vivo PET kinetic studies, radiometabolite studies, and
dosimetry experiments. Rats underwent permanent coronary artery
ligation and were scanned using PET/CT with an invasive input function
at 7 d after MI. For quantification of PET signal in the hypoperfused
myocardium, K1 (rate constant for transfer from arterial plasma
to tissues) was used as a surrogate marker of perfusion to correct the
binding potential for impaired radiotracer transfer from plasma to
tissue (BPTC). Results: LW223 binding to TSPO was not susceptible
to the rs6971 genetic polymorphism in human brain and heart samples.
In rodents, 18F-LW223 displayed a specific uptake consistent
with TSPO expression, a slow metabolism in blood (69% of parent at
120 min), a high plasma free fraction of 38.5%, and a suitable dosimetry
profile (effective dose of 20.5–24.5 μSv/MBq). 18F-LW223 BPTC
was significantly higher in the MI cohort within the infarct territory of
the anterior wall relative to the anterior wall of na¨ıve animals (32.7 ±
5.0 vs. 10.0 ± 2.4 cm3/mL/min, P # 0.001). Ex vivo immunofluorescent
staining for TSPO and CD68 (macrophage marker) resulted in
the same pattern seen with in vivo BPTC analysis. Conclusion: 18FLW223
is not susceptible to the rs6971 genetic polymorphism in in
vitro assays, has favorable in vivo characteristics, and is able to accurately
map macrophage-driven inflammation after MI.
Mark G. MacAskill, Agne Stadulyte, Lewis Williams, Timaeus E.F. Morgan, Nikki L. Sloan, Carlos J. Alcaide-
Corral, Tashfeen Walton, Catriona Wimberley, Chris-Anne McKenzie, Nick Spath, William Mungall,
Ralph BouHaidar, Marc R. Dweck, Gillian A. Gray, David E. Newby, Christophe Lucatelli, Andrew Sutherland,
Sally L. Pimlott, and Adriana A.S. Tavare
A Systems-Level Analysis of Total-Body PET Data Reveals Complex Skeletal Metabolism Networks in vivo
No full textBone is now regarded to be a key regulator of a number of metabolic processes, in addition to the regulation of mineral metabolism. However, our understanding of complex bone metabolic interactions at a systems level remains rudimentary. In vitro molecular biology and bioinformatics approaches have frequently been used to understand the mechanistic changes underlying disease at the cell level, however, these approaches lack the capability to interrogate dynamic multi-bone metabolic interactions in vivo. Here we present a novel and integrative approach to understand complex bone metabolic interactions in vivo using total-body positron emission tomography (PET) network analysis of murine 18F-FDG scans, as a biomarker of glucose metabolism in bones. In this report we show that different bones within the skeleton have a unique glucose metabolism and form a complex metabolic network, which could not be identified using single tissue simplistic PET standard uptake values analysis. The application of our approach could reveal new physiological and pathological tissue interactions beyond skeletal metabolism, due to PET radiotracers diversity and the advent of clinical total-body PET systems. Karla J. Suchacki, Carlos J. Alcaide-Corral, Samah Nimale, Mark G. Macaskill, Roland H. Stimson, Colin Farquharson, Tom C. Freeman and Adriana A. S. TavaresSuchacki, Karla; Alcaide-Corral, Carlos Jose. (2021). A Systems-Level Analysis of Total-Body PET Data Reveals Complex Skeletal Metabolism Networks in vivo, [dataset]. University of Edinburgh. Centre for Cardiovascular Science. https://doi.org/10.7488/ds/3161
sj-pdf-1-jcb-10.1177_0271678X231205661 - Supplemental material for [<sup>18</sup>F]LW223 has low non-displaceable binding in murine brain, enabling high sensitivity TSPO PET imaging
No full textSupplemental material, sj-pdf-1-jcb-10.1177_0271678X231205661 for [18F]LW223 has low non-displaceable binding in murine brain, enabling high sensitivity TSPO PET imaging by Agne Knyzeliene, Mark G MacAskill, Carlos J Alcaide-Corral, Timaeus EF Morgan, Martyn C Henry, Christophe Lucatelli, Sally L Pimlott, Andrew Sutherland and Adriana AS Tavares in Journal of Cerebral Blood Flow & Metabolism</p
Sexually dimorphic murine brain uptake of the 18 kDa translocator protein PET radiotracer [18F]LW223
No full textThe 18 kDa translocator protein is a well-known biomarker of neuroinflammation, but also plays a role in homeostasis. PET with
18 kDa translocator protein radiotracers [11C]PBR28 in humans and [18F]GE180 in mice has demonstrated sex-dependent uptake patterns in the healthy brain, suggesting sex-dependent 18 kDa translocator protein expression, although humans and mice had differing results. This study aimed to assess whether the 18 kDa translocator protein PET radiotracer [18F]LW223 exhibited sexually dimorphic uptake in healthy murine brain and peripheral organs. Male and female C57Bl6/J mice (13.6 ± 5.4 weeks, 26.8 ± 5.4 g, mean ± SD) underwent 2 h PET scanning post-administration of [18F]LW223 (6.7 ± 3.6 MBq). Volume of interest and parametric analyses were performed using standard uptake values (90–120 min). Statistical differences were assessed by unpaired t-test or two-way ANOVA with Šidak’s test (alpha = 0.05). The uptake of [18F]LW223 was significantly higher across multiple regions of the male mouse brain, with the most pronounced difference detected in hypothalamus (P < 0.0001). Males also exhibited significantly higher [18F]LW223 uptake in the heart when compared to females (P = 0.0107). Data support previous findings on sexually dimorphic 18 kDa translocator protein radiotracer uptake patterns in mice and highlight the need to conduct sex-controlled comparisons in 18 kDa translocator protein PET imaging studies.File descriptions are included in a Readme.txt file
[18F]LW223 has low non-displaceable binding in murine brain, enabling high sensitivity TSPO PET imaging
No full textNeuroinflammation is associated with a number of brain diseases, making it a common feature of cerebral pathology.
Among the best-known biomarkers for neuroinflammation in Positron Emission Tomography (PET) research is the
18 kDa translocator protein (TSPO). This study aims to investigate the binding kinetics of a novel TSPO PETradiotracer,
[18F]LW223, in mice and specifically assess its volume of non-displaceable binding (VND) in brain as well as investigate the
use of simplified analysis approaches for quantification of [18F]LW223 PET data. Adult male mice were injected with [18F]
LW223 and varying concentrations of LW223 (0.003–0.55 mg/kg) to estimate VND of [18F]LW223. Dynamic PET imaging
with arterial input function studies and radiometabolite studies were conducted. Simplified quantification methods,
standard uptake values (SUV) and apparent volume of distribution (VTapp), were investigated. [18F]LW223 had low
VND in the brain (<10% of total binding) and low radiometabolism ( 15–20%). The 2-tissue compartment model
provided the best fit for [18F]LW223 PET data, although its correlation with SUV90–120min or VTapp allowed for [18F]
LW223 brain PET data quantification in healthy animals while using simpler experimental and analytical approaches. [18F]
LW223 has the required properties to become a successful TSPO PET radiotracer.File descriptions are included in a Readme.txt fil
Recensiones [Revista de Historia Económica Año IV Primavera-Verano 1986 n. 2 pp. 425-456]
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Trophic structure of oribatid mite communities from six different oak forests (Quercus robur)
No full textThe degree of trophic plasticity in soil animals is intensely debated. We used stable isotope ratios (N-15/N-14, C-13/C-12) of oribatid mite species from six oak (Quercus robur) forests to investigate (1) if trophic niches vary between forests and (2) the range of trophic levels spanned by oribatid mites. Using litter as baseline stable isotope signatures of most oribatid mite species differed between forests. Therefore, the stable isotope signatures were re-calibrated using stable isotope values of Platynothrus peltifer as primary decomposer species occurring in each of the six forests. Re-calibrated values of nine species (Cerachipteria jugata, Damaeus clavipes, Neotrichoppia variabilis, Oppia denticulata, Hermaniella dolosa, Steganacarus magnus, Ceratozetes peritus, Nanhermannia nana, Xenillus tegeocranus, Eremaeus cordiformis) differed significantly between forests indicating trophic plasticity in most of the studied oribatid mite species. Overall, calibrated stable isotope ratios spanned over 8.7 delta units for N-15 and 5.9 delta units for C-13 indicating that in forest ecosystems oribatid mite species span about three trophic levels. (C) 2015 Elsevier Ltd. All rights reserved.Basque Country (UPV-EHU); Basque Government [IE07-205
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