Imaging Somatostatin Subtype Receptor 2 (SST2) expressing macrophages by DOTA,Tyr3-octreotate (DOTATATE) has proven successful for plaque detection. DOTA-JR11 is a SST2 targeting ligand with a five ...times higher tumor uptake than DOTATATE, and holds promise to improve plaque imaging. The aim of this study was to evaluate the potential of DOTA-JR11 for plaque detection.
Atherosclerotic ApoE−/− mice (n = 22) fed an atherogenic diet were imaged by SPECT/CT two hours post injection of 111InIn-DOTA-JR11 (~ 200 pmol, ~ 50 MBq). In vivo plaque uptake of 111InIn-DOTA-JR11 was visible in all mice, with a target-to-background-ratio (TBR) of 2.23 ± 0.35. Post-mortem scans after thymectomy and ex vivo scans of the arteries after excision of the arteries confirmed plaque uptake of the radioligand with TBRs of 2.46 ± 0.52 and 3.43 ± 1.45 respectively. Oil red O lipid-staining and ex vivo autoradiography of excised arteries showed 111InIn-DOTA-JR11 uptake at plaque locations. Histological processing showed CD68 (macrophages) and SST2 expressing cells in plaques. SPECT/CT, in vitro autoradiography and immunohistochemistry performed on slices of a human carotid endarterectomy sample showed 111InIn-DOTA-JR11 uptake at plaque locations containing CD68 and SST2 expressing cells.
The results of this study indicate DOTA-JR11 as a promising ligand for visualization of atherosclerotic plaque inflammation.
Purpose
Atherosclerotic plaque development and progression signifies a complex inflammatory disease mediated by a multitude of proinflammatory leukocyte subsets. Using single photon emission computed ...tomography (SPECT) coupled with computed tomography (CT), this study tested a new dual-isotope acquisition protocol to assess each radiotracer’s capability to identify plaque phenotype and inflammation levels pertaining to leukocytes expressing leukocyte function-associated antigen-1 (LFA-1) and the leukocyte subset of proinflammatory macrophages expressing somatostatin receptor subtype-2 (SST
2
). Individual radiotracer uptake was quantified and the presence of corresponding immunohistological cell markers was assessed.
Methods
Human symptomatic carotid plaque segments were obtained from endarterectomy. Segments were incubated in dual-isotope radiotracers
111
InIn-DOTA-butylamino-NorBIRT (
111
InIn-Danbirt) and
99m
TcTc-N
0–1
4
,Asp
0
,Tyr
3
-octreotate (
99m
TcTc-Demotate 2) before scanning with SPECT/CT. Plaque phenotype was classified as pathological intimal thickening, fibrous cap atheroma or fibrocalcific using histology sections based on distinct morphological characteristics. Plaque segments were subsequently immuno-stained with LFA-1 and SST
2
and quantified in terms of positive area fraction and compared against the corresponding SPECT images.
Results
Focal uptake of co-localising dual-radiotracers identified the heterogeneous distribution of inflamed regions in the plaques which co-localised with positive immuno-stained regions of LFA-1 and SST
2
.
111
InIn-Danbirt and
99m
TcTc-Demotate 2 uptake demonstrated a significant positive correlation (
r
= 0.651;
p
= 0.001). Fibrous cap atheroma plaque phenotype correlated with the highest
111
InIn-Danbirt and
99m
TcTc-Demotate 2 uptake compared with fibrocalcific plaques and pathological intimal thickening phenotypes, in line with the immunohistological analyses.
Conclusion
A dual-isotope acquisition protocol permits the imaging of multiple leukocyte subsets and the pro-inflammatory macrophages simultaneously in atherosclerotic plaque tissue.
111
InIn-Danbirt may have added value for assessing the total inflammation levels in atherosclerotic plaques in addition to classifying plaque phenotype.
Purpose
Many radioligands have been developed for the visualization of atherosclerosis by targeting inflammation. However, interpretation of in vivo signals is often limited to plaque identification. ...We evaluated binding of some promising radioligands in an in vitro approach in atherosclerotic plaques with different phenotypes.
Methods
Tissue sections of carotid endarterectomy tissue were characterized as early plaque, fibro-calcific plaque, or phenotypically vulnerable plaque. In vitro binding assays for the radioligands
111
InIn-DOTATATE;
111
InIn-DOTA-JR11;
67
GaGa-Pentixafor;
111
InIn-DANBIRT; and
111
InIn-EC0800 were conducted, the expression of the radioligand targets was assessed via immunohistochemistry. Radioligand binding and expression of radioligand targets was investigated and compared.
Results
In sections characterized as vulnerable plaque, binding was highest for
111
InIn-EC0800; followed by
111
InIn-DANBIRT;
67
GaGa-Pentixafor;
111
InIn-DOTA-JR11; and
111
InIn-DOTATATE (0.064 ± 0.036; 0.052 ± 0.029; 0.011 ± 0.003; 0.0066 ± 0.0021; 0.00064 ± 0.00014 %Added activity/mm
2
, respectively). Binding of
111
InIn-DANBIRT and
111
InIn-EC0800 was highest across plaque phenotypes, binding of
111
InIn-DOTA-JR11 and
67
GaGa-Pentixafor differed most between plaque phenotypes. Binding of
111
InIn-DOTATATE was the lowest across plaque phenotypes. The areas positive for cells expressing the radioligand’s target differed between plaque phenotypes for all targets, with lowest percentage area of expression in early plaque sections and highest in phenotypically vulnerable plaque sections.
Conclusions
Radioligands targeting inflammatory cell markers showed different levels of binding in atherosclerotic plaques and among plaque phenotypes. Different radioligands might be used for plaque detection and discerning early from vulnerable plaque.
111
InIn-EC0800 and
111
InIn-DANBIRT appear most suitable for plaque detection, while
67
GaGa-Pentixafor and
111
InIn-DOTA-JR11 might be best suited for differentiation between plaque phenotypes.
This review addresses nuclear SPECT and PET imaging in small animals in relation to the atherosclerotic disease process, one of our research topics of interest. Imaging of atherosclerosis in small ...animal models is challenging, as it operates at the limits of current imaging possibilities regarding sensitivity, and spatial resolution. Several topics are discussed, including technical considerations that apply to image acquisition, reconstruction, and analysis. Moreover, molecules developed for or applied in these small animal nuclear imaging studies are listed, including target-directed molecules, useful for imaging organs or tissues that have elevated expression of the target compared to other tissues, and molecules that serve as substrates for metabolic processes. Differences between animal models and human pathophysiology that should be taken into account during translation from animal to patient as well as differences in tracer behavior in animal vs. man are also described. Finally, we give a future outlook on small animal radionuclide imaging in atherosclerosis, followed by recommendations. The challenges and solutions described might be applicable to other research fields of health and disease as well.
Imaging Somatostatin Subtype Receptor 2 (SST
) expressing macrophages by DOTA,Tyr
-octreotate (DOTATATE) has proven successful for plaque detection. DOTA-JR11 is a SST
targeting ligand with a five ...times higher tumor uptake than DOTATATE, and holds promise to improve plaque imaging. The aim of this study was to evaluate the potential of DOTA-JR11 for plaque detection.
Atherosclerotic ApoE
mice (n = 22) fed an atherogenic diet were imaged by SPECT/CT two hours post injection of
InIn-DOTA-JR11 (~ 200 pmol, ~ 50 MBq). In vivo plaque uptake of
InIn-DOTA-JR11 was visible in all mice, with a target-to-background-ratio (TBR) of 2.23 ± 0.35. Post-mortem scans after thymectomy and ex vivo scans of the arteries after excision of the arteries confirmed plaque uptake of the radioligand with TBRs of 2.46 ± 0.52 and 3.43 ± 1.45 respectively. Oil red O lipid-staining and ex vivo autoradiography of excised arteries showed
InIn-DOTA-JR11 uptake at plaque locations. Histological processing showed CD68 (macrophages) and SST
expressing cells in plaques. SPECT/CT, in vitro autoradiography and immunohistochemistry performed on slices of a human carotid endarterectomy sample showed
InIn-DOTA-JR11 uptake at plaque locations containing CD68 and SST
expressing cells.
The results of this study indicate DOTA-JR11 as a promising ligand for visualization of atherosclerotic plaque inflammation.
Urbanization is changing Earth’s ecosystems by altering the interactions and feedbacks between the fundamental ecological and evolutionary processes that maintain life. Humans in cities alter the ...eco-evolutionary play by simultaneously changing both the actors and the stage on which the eco-evolutionary play takes place. Urbanization modifies land surfaces, microclimates, habitat connectivity, ecological networks, food webs, species diversity, and species composition. These environmental changes can lead to changes in phenotypic, genetic, and cultural makeup of wild populations that have important consequences for ecosystem function and the essential services that nature provides to human society, such as nutrient cycling, pollination, seed dispersal, food production, and water and air purification. Understanding and monitoring urbanization-induced evolutionary changes is important to inform strategies to achieve sustainability. In the present article, we propose that understanding these dynamics requires rigorous characterization of urbanizing regions as rapidly evolving, tightly coupled human–natural systems. We explore how the emergent properties of urbanization affect eco-evolutionary dynamics across space and time. We identify five key urban drivers of change—habitat modification, connectivity, heterogeneity, novel disturbances, and biotic interactions—and highlight the direct consequences of urbanization-driven eco-evolutionary change for nature’s contributions to people. Then, we explore five emerging complexities—landscape complexity, urban discontinuities, socio-ecological heterogeneity, cross-scale interactions, legacies and time lags—that need to be tackled in future research. We propose that the evolving metacommunity concept provides a powerful framework to study urban eco-evolutionary dynamics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Socio‐eco‐evolutionary dynamics in cities Des Roches, Simone; Brans, Kristien I.; Lambert, Max R. ...
Evolutionary Applications,
January 2021, Letnik:
14, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Cities are uniquely complex systems regulated by interactions and feedbacks between nature and human society. Characteristics of human society—including culture, economics, technology and ...politics—underlie social patterns and activity, creating a heterogeneous environment that can influence and be influenced by both ecological and evolutionary processes. Increasing research on urban ecology and evolutionary biology has coincided with growing interest in eco‐evolutionary dynamics, which encompasses the interactions and reciprocal feedbacks between evolution and ecology. Research on both urban evolutionary biology and eco‐evolutionary dynamics frequently focuses on contemporary evolution of species that have potentially substantial ecological—and even social—significance. Still, little work fully integrates urban evolutionary biology and eco‐evolutionary dynamics, and rarely do researchers in either of these fields fully consider the role of human social patterns and processes. Because cities are fundamentally regulated by human activities, are inherently interconnected and are frequently undergoing social and economic transformation, they represent an opportunity for ecologists and evolutionary biologists to study urban “socio‐eco‐evolutionary dynamics.” Through this new framework, we encourage researchers of urban ecology and evolution to fully integrate human social drivers and feedbacks to increase understanding and conservation of ecosystems, their functions and their contributions to people within and outside cities.
The current study aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date, as well as aiming to ...determine the effect of AMD-associated genetic variants on metabolite levels and investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways.
Case-control association analysis of metabolomics data.
Five European cohorts consisting of 2267 AMD patients and 4266 control participants.
Metabolomics was performed using a high-throughput proton nuclear magnetic resonance metabolomics platform, which allows quantification of 146 metabolite measurements and 79 derivative values. Metabolome-AMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d-to-C3 ratio) were investigated using linear regression.
Metabolites associated with AMD.
We identified 60 metabolites that were associated significantly with AMD, including increased levels of large and extra-large high-density lipoprotein (HDL) subclasses and decreased levels of very low-density lipoprotein (VLDL), amino acids, and citrate. Of 52 AMD-associated genetic variants, 7 variants were associated significantly with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, and LIPC) with metabolites belonging to the large and extra-large HDL subclasses. Also, 57 of 60 metabolites were associated significantly with complement activation levels, independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation.
Lipoprotein levels were associated with AMD-associated genetic variants, whereas decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD.
Despite comprehensive research efforts over the last decades, the pathomechanisms of age-related macular degeneration (AMD) remain far from being understood. Large-scale genome wide association ...studies (GWAS) were able to provide a defined set of genetic aberrations which contribute to disease risk, with the strongest contributors mapping to distinct regions on chromosome 1 and 10. While the chromosome 1 locus comprises factors of the complement system with well-known functions, the role of the 10q26-locus in AMD-pathophysiology remains enigmatic. 10q26 harbors a cluster of three functional genes, namely PLEKHA1, ARMS2 and HTRA1, with most of the AMD-associated genetic variants mapping to the latter two genes. High linkage disequilibrium between ARMS2 and HTRA1 has kept association studies from reliably defining the risk-causing gene for long and only very recently the genetic risk region has been narrowed to ARMS2, suggesting that this is the true AMD gene at this locus. However, genetic associations alone do not suffice to prove causality and one or more of the 14 SNPs on this haplotype may be involved in long-range control of gene expression, leaving HTRA1 and PLEKHA1 still suspects in the pathogenic pathway. Both, ARMS2 and HTRA1 have been linked to extracellular matrix homeostasis, yet their exact molecular function as well as their role in AMD pathogenesis remains to be uncovered. The transcriptional regulation of the 10q26 locus adds an additional level of complexity, given, that gene-regulatory as well as epigenetic alterations may influence expression levels from 10q26 in diseased individuals. Here, we provide a comprehensive overview on the 10q26 locus and its three gene products on various levels of biological complexity and discuss current and future research strategies to shed light on one of the remaining enigmatic spots in the AMD landscape.
•variants in 10q26 are the strongest contributors to genetic AMD-risk.•The genetic risk region has recently been narrowed to ARMS2.•ARMS2 and HTRA1 are both interacting with extracellular matrix components, linking AMD pathology to ECM homeostasis.•Risk associated gene-regulatory and epigenetic alterations may influence expression levels from 10q26 in diseased individuals.•targeting 10q26 gene products remains risky due to lack of functional data.
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