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1.
Am J Hum Genet ; 110(5): 722-740, 2023 05 04.
Article in English | MEDLINE | ID: mdl-37060905

ABSTRACT

Coronary artery disease (CAD) is a pandemic disease where up to half of the risk is explained by genetic factors. Advanced insights into the genetic basis of CAD require deeper understanding of the contributions of different cell types, molecular pathways, and genes to disease heritability. Here, we investigate the biological diversity of atherosclerosis-associated cell states and interrogate their contribution to the genetic risk of CAD by using single-cell and bulk RNA sequencing (RNA-seq) of mouse and human lesions. We identified 12 disease-associated cell states that we characterized further by gene set functional profiling, ligand-receptor prediction, and transcription factor inference. Importantly, Vcam1+ smooth muscle cell state genes contributed most to SNP-based heritability of CAD. In line with this, genetic variants near smooth muscle cell state genes and regulatory elements explained the largest fraction of CAD-risk variance between individuals. Using this information for variant prioritization, we derived a hybrid polygenic risk score (PRS) that demonstrated improved performance over a classical PRS. Our results provide insights into the biological mechanisms associated with CAD risk, which could make a promising contribution to precision medicine and tailored therapeutic interventions in the future.


Subject(s)
Atherosclerosis , Coronary Artery Disease , Humans , Atherosclerosis/genetics , Coronary Artery Disease/genetics , Coronary Artery Disease/pathology , Risk Factors , Gene Expression Regulation , Genetic Predisposition to Disease , Genome-Wide Association Study/methods , Polymorphism, Single Nucleotide/genetics
2.
Eur J Nucl Med Mol Imaging ; 51(9): 2597-2613, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38676736

ABSTRACT

PURPOSE: Patients with fever and inflammation of unknown origin (FUO/IUO) are clinically challenging due to variable clinical presentations with nonspecific symptoms and many differential diagnoses. Positron emission tomography/computed tomography (PET/CT) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is increasingly used in FUO and IUO, but the optimal diagnostic strategy remains controversial. This consensus document aims to assist clinicians and nuclear medicine specialists in the appropriate use of [18F]FDG-PET/CT in FUO and IUO based on current evidence. METHODS: A working group created by the EANM infection and inflammation committee performed a systematic literature search based on PICOs with "patients with FUO/IUO" as population, "[18F]FDG-PET/CT" as intervention, and several outcomes including pre-scan characteristics, scan protocol, diagnostic yield, impact on management, prognosis, and cost-effectiveness. RESULTS: We included 68 articles published from 2001 to 2023: 9 systematic reviews, 49 original papers on general adult populations, and 10 original papers on specific populations. All papers were analysed and included in the evidence-based recommendations. CONCLUSION: FUO and IUO remains a clinical challenge and [18F]FDG PET/CT has a definite role in the diagnostic pathway with an overall diagnostic yield or helpfulness in 50-60% of patients. A positive scan is often contributory by directly guiding treatment or subsequent diagnostic procedure. However, a negative scan may be equally important by excluding focal disease and predicting a favorable prognosis. Similar results are obtained in specific populations such as ICU-patients, children and HIV-patients.


Subject(s)
Fever of Unknown Origin , Fluorodeoxyglucose F18 , Inflammation , Positron Emission Tomography Computed Tomography , Positron Emission Tomography Computed Tomography/standards , Humans , Inflammation/diagnostic imaging , Fever of Unknown Origin/diagnostic imaging , Consensus , Nuclear Medicine , Radiopharmaceuticals
3.
Eur J Nucl Med Mol Imaging ; 51(8): 2216-2228, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38532026

ABSTRACT

PURPOSE: Aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated mannosylated dextran derivative (Al[18F]F-NOTA-D10CM) is a new tracer for PET imaging. We report here on in vitro and in vivo validation of the tracer's ability to target the macrophage mannose receptor CD206. METHODS: First, the uptake of intravenously (i.v.) administered Al[18F]F-NOTA-D10CM was compared between wild-type (WT) and CD206-/- knockout (KO) mice. C57BL/6N mice were injected with complete Freund's adjuvant (CFA) in the left hind leg and the uptake of Al[18F]F-NOTA-D10CM after i.v. or intradermal (i.d.) injection was studied at 5 and 14 days after CFA induction of inflammation. Healthy C57BL/6N mice were studied as controls. Mice underwent PET/CT on consecutive days with [18F]FDG, i.v. Al[18F]F-NOTA-D10CM, and i.d. Al[18F]F-NOTA-D10CM. After the last imaging, Al[18F]F-NOTA-D10CM was i.v. injected for an ex vivo biodistribution study and autoradiography of inflamed tissues. Blood plasma samples were analyzed using high-performance liquid chromatography. To evaluate the specificity of Al[18F]F-NOTA-D10CM binding, an in vitro competitive displacement study was performed on inflamed tissue sections using autoradiography. CD206 expression was assessed by immunohistochemical staining. RESULTS: Compared with WT mice, the uptake of Al[18F]F-NOTA-D10CM was significantly lower in several CD206-/- KO mice tissues, including liver (SUV 8.21 ± 2.51 vs. 1.06 ± 0.16, P < 0.001) and bone marrow (SUV 1.63 ± 0.37 vs. 0.22 ± 0.05, P < 0.0001). The uptake of i.v. injected Al[18F]F-NOTA-D10CM was significantly higher in inflamed ankle joint (SUV 0.48 ± 0.13 vs. 0.18 ± 0.05, P < 0.0001) and inflamed foot pad skin (SUV 0.41 ± 0.10 vs. 0.04 ± 0.01, P < 0.0001) than in the corresponding tissues in healthy mice. The i.d.-injected Al[18F]F-NOTA-D10CM revealed differences between CFA-induced lymph node activation and lymph nodes in healthy mice. Ex vivo γ-counting, autoradiography, and immunohistochemistry supported the results, and a decrease of ~ 80% in the binding of Al[18F]F-NOTA-D10CM in the displacement study with excess NOTA-D10CM confirmed that tracer binding was specific. At 60 min after i.v. injection, an average 96.70% of plasma radioactivity was derived from intact Al[18F]F-NOTA-D10CM, indicating good in vivo stability. The uptake of Al[18F]F-NOTA-D10CM into inflamed tissues was positively associated with the area percentage of CD206-positive staining. CONCLUSION: The uptake of mannosylated dextran derivative Al[18F]F-NOTA-D10CM correlated with CD206 expression and the tracer appears promising for inflammation imaging.


Subject(s)
Dextrans , Fluorine Radioisotopes , Lectins, C-Type , Mannose Receptor , Mannose-Binding Lectins , Receptors, Cell Surface , Animals , Mice , Lectins, C-Type/metabolism , Receptors, Cell Surface/metabolism , Mannose-Binding Lectins/metabolism , Tissue Distribution , Dextrans/chemistry , Mannose/chemistry , Positron Emission Tomography Computed Tomography , Mice, Inbred C57BL , Macrophages/metabolism , Isotope Labeling , Heterocyclic Compounds, 1-Ring
4.
Mol Pharm ; 21(8): 4147-4156, 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-39008899

ABSTRACT

Fatty acid binding protein 3 (FABP3) is expressed both in tumor cells and in the tumor vasculature, making it a potential target for medical imaging and therapy. In this study, we aimed to radiolabel a CooP peptide with a free amino and thiol group, and evaluate the radiolabeled product [18F]FNA-N-CooP for imaging FABP3 expression in breast cancer brain metastases by positron emission tomography. [18F]FNA-N-CooP was prepared by highly chemoselective N-acylation and characterized using different chemical approaches. We validated its binding to the target using in vitro tissue section autoradiography and performed stability tests in vitro and in vivo. [18F]FNA-N-CooP was successfully synthesized in 16.8% decay-corrected radiochemical yield with high radiochemical purity (98.5%). It exhibited heterogeneous binding on brain metastasis tissue sections from a patient with breast cancer, with foci of radioactivity binding corresponding to FABP3 positivity. Furthermore, the tracer binding was reduced by 55% in the presence of nonradioactive FNA-N-CooP a blocker, indicating specific tracer binding and that FABP3 is a viable target for [18F]FNA-N-CooP. Favorably, the tracer did not bind to necrotic tumor tissue. However, [18F]FNA-N-CooP displayed limited stability both in vitro in mouse plasma or human serum and in vivo in mouse, therefore further studies are needed to improve the stability [18F]FNA-N-CooP to be used for in vivo applications.


Subject(s)
Brain Neoplasms , Breast Neoplasms , Fatty Acid Binding Protein 3 , Fluorine Radioisotopes , Positron-Emission Tomography , Radiopharmaceuticals , Animals , Humans , Female , Mice , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Positron-Emission Tomography/methods , Fatty Acid Binding Protein 3/metabolism , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Fluorine Radioisotopes/chemistry , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/chemistry , Cell Line, Tumor , Peptides/chemistry , Tissue Distribution , Sulfhydryl Compounds/chemistry , Mice, Nude
5.
Eur J Nucl Med Mol Imaging ; 50(2): 266-274, 2023 01.
Article in English | MEDLINE | ID: mdl-36166079

ABSTRACT

PURPOSE: Photoperiod determines the metabolic activity of brown adipose tissue (BAT) and affects the food intake and body mass of mammals. Sympathetic innervation of the BAT controls thermogenesis and facilitates physiological adaption to seasonal changes, but the exact mechanism remains elusive. Previous studies have shown that central opioid signaling regulates BAT thermogenesis, and that the expression of the brain mu-opioid receptor (MOR) varies seasonally. Therefore, it is important to know whether MOR expression in BAT shows seasonal variation. METHODS: We determined the effect of photoperiod on BAT MOR availability using [11C]carfentanil positron emission tomography (PET). Adult rats (n = 9) were repeatedly imaged under various photoperiods in order to simulate seasonal changes. RESULTS: Long photoperiod was associated with low MOR expression in BAT (ß = - 0.04, 95% confidence interval: - 0.07, - 0.01), but not in muscles. We confirmed the expression of MOR in BAT and muscle using immunofluorescence staining. CONCLUSION: Photoperiod affects MOR availability in BAT. Sympathetic innervation of BAT may influence thermogenesis via the peripheral MOR system. The present study supports the utility of [11C]carfentanil PET to study the peripheral MOR system.


Subject(s)
Adipose Tissue, Brown , Photoperiod , Receptors, Opioid, mu , Animals , Rats , Adipose Tissue, Brown/diagnostic imaging , Adipose Tissue, Brown/metabolism , Positron-Emission Tomography/methods , Thermogenesis , Receptors, Opioid, mu/metabolism
6.
Mol Pharm ; 20(10): 5043-5051, 2023 10 02.
Article in English | MEDLINE | ID: mdl-37531591

ABSTRACT

18F-Labeled [60]fullerene-based molecular spherical nucleic acids (MSNAs), consisting of a human epidermal growth factor receptor 2 (HER2) mRNA antisense oligonucleotide sequence with a native phosphodiester and phosphorothioate backbone, were synthesized, site-specifically labeled with a positron emitting fluorine-18 and intravenously administrated via tail vein to HER2 expressing HCC1954 tumor-bearing mice. The biodistribution of the MSNAs was monitored in vivo by positron emission tomography/computed tomography (PET/CT) imaging. MSNA with a native phosphodiester backbone (MSNA-PO) was prone to rapid nuclease-mediated degradation, whereas the corresponding phosphorothioate analogue (MSNA-PS) with improved enzymatic stability showed an interesting biodistribution profile in vivo. One hour after the injection, majority of the radioactivity was observed in spleen and liver but also in blood with an average tumor-to-muscle ratio of 2. The prolonged radioactivity in blood circulation may open possibilities to the targeted delivery of the MSNAs.


Subject(s)
Fullerenes , Neoplasms , Nucleic Acids , Mice , Humans , Animals , Positron Emission Tomography Computed Tomography/methods , Tissue Distribution , Positron-Emission Tomography/methods , Neoplasms/diagnostic imaging , Fluorine Radioisotopes , Cell Line, Tumor
7.
J Nucl Cardiol ; 30(6): 2760-2772, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37758963

ABSTRACT

BACKGROUND: Vascular adhesion protein-1 (VAP-1) is an adhesion molecule and primary amine oxidase, and Gallium-68-labeled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetra-acetic acid conjugated sialic acid-binding immunoglobulin-like lectin 9 motif containing peptide ([68Ga]Ga-DOTA-Siglec-9) is a positron emission tomography (PET) tracer targeting VAP-1. We evaluated the feasibility of PET imaging with [68Ga]Ga-DOTA-Siglec-9 for the detection of myocardial lesions in rats with autoimmune myocarditis. METHODS: Rats (n = 9) were immunized twice with porcine cardiac myosin in complete Freund's adjuvant. Control rats (n = 6) were injected with Freund's adjuvant alone. On day 21, in vivo PET/computed tomography (CT) imaging with [68Ga]Ga-DOTA-Siglec-9 was performed, followed by ex vivo autoradiography, histology, and immunohistochemistry of tissue sections. In addition, myocardial samples from three patients with cardiac sarcoidosis were studied. RESULTS: [68Ga]Ga-DOTA-Siglec-9 PET/CT images of immunized rats showed higher uptake in myocardial lesions than in myocardium outside lesions (SUVmean, 0.5 ± 0.1 vs 0.3 ± 0.1; P = .003) or control rats (SUVmean, 0.2 ± 0.03; P < .0001), which was confirmed by ex vivo autoradiography of tissue sections. Immunohistochemistry showed VAP-1-positive staining in lesions of rats with myocarditis and in patients with cardiac sarcoidosis. CONCLUSION: VAP-1-targeted [68Ga]Ga-DOTA-Siglec-9 PET is a potential novel technique for the detection of myocardial lesions.


Subject(s)
Myocarditis , Sarcoidosis , Humans , Rats , Animals , Swine , Positron Emission Tomography Computed Tomography , Gallium Radioisotopes/chemistry , Myocarditis/diagnostic imaging , Freund's Adjuvant , Tomography, X-Ray Computed , Positron-Emission Tomography/methods , Sialic Acid Binding Immunoglobulin-like Lectins/chemistry
8.
J Neurosci ; 41(6): 1265-1273, 2021 02 10.
Article in English | MEDLINE | ID: mdl-33361461

ABSTRACT

Seasonal rhythms influence mood and sociability. The brain µ-opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains elusive with no previously reported in vivo evidence. Here, we first conducted a cross-sectional study with previously acquired human [11C]carfentanil PET imaging data (132 male and 72 female healthy subjects) to test whether there is seasonal variation in MOR availability. We then investigated experimentally whether seasonal variation in daylength causally influences brain MOR availability in rats. Rats (six male and three female rats) underwent daylength cycle simulating seasonal changes; control animals (two male and one female rats) were kept under constant daylength. Animals were scanned repeatedly with [11C]carfentanil PET imaging. Seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability in humans. Brain regions sensitive to daylength spanned the socioemotional brain circuits, where MOR availability peaked during spring. In rats, MOR availabilities in the brain neocortex, thalamus, and striatum peaked at intermediate daylength. Varying daylength also affected the weight gain and stress hormone levels. We conclude that cerebral MOR availability in humans and rats shows significant seasonal variation, which is predominately associated with seasonal photoperiodic variation. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.SIGNIFICANCE STATEMENT Seasonal rhythms influence emotion and sociability. The central µ-opioid receptor (MOR) system modulates numerous seasonally varying socioemotional functions, but its seasonal variation remains elusive. Here we used positron emission tomography to show that MOR levels in both human and rat brains show daylength-dependent seasonal variation. The highest MOR availability was observed at intermediate daylengths. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.


Subject(s)
Brain/diagnostic imaging , Brain/metabolism , Positron-Emission Tomography/trends , Receptors, Opioid, mu/metabolism , Seasons , Adult , Animals , Cross-Sectional Studies , Female , Humans , Male , Rats , Rats, Sprague-Dawley , Young Adult
9.
Bioconjug Chem ; 33(7): 1393-1404, 2022 07 20.
Article in English | MEDLINE | ID: mdl-35709482

ABSTRACT

Radiolabeled peptides have emerged as highly specific agents for targeting receptors expressed in tumors for therapeutic and diagnostic purposes. Peptides developed for positron emission tomography (PET) are typically radiolabeled using prosthetic groups or bifunctional chelators for fast "kit-like" incorporation of the radionuclide into the structure. A novel [18F]alkylammoniomethyltrifluoroborate ([18F]AmBF3) tetrazine (Tz), [18F]AmBF3-Tz, was developed for the [18F]fluorination of trans-cyclooctene (TCO)-modified biomolecules using Tyr3-octreotides (TOCs) as model peptides. [18F]AmBF3-Tz (Am = 15.4 ± 9.2 GBq/µmol, n = 14) was evaluated in healthy mice by ex vivo biodistribution and PET/computed tomography (CT), where the radiolabel in the prosthetic group was found stable in vivo, indicated by the low bone uptake in tibia (0.4 ± 0.1% ID/g, t = 270 min). TCO-TOCs tailored with polyethylene glycol (PEG) linkers were radiolabeled with [18F]AmBF3-Tz, forming two new tracers, [18F]AmBF3-PEG4-TOC (Am = 2.8 ± 1.8 GBq/µmol, n = 3) and [18F]AmBF3-PEG7-TOC (Am of 6.0 ± 3.4 GBq/µmol, n = 13), which were evaluated by cell uptake studies and ex vivo biodistribution in subcutaneous AR42J rat pancreatic carcinoma tumor-bearing nude mice. The tracer demonstrating superior behavior ex vivo, the [18F]AmBF3-PEG7-TOC, was further evaluated with PET/CT, where the tracer provided clear tumor visualization (SUVbaseline = 1.01 ± 0.07, vs SUVblocked = 0.76 ± 0.04) at 25 min post injection. The novel AmBF3-Tz demonstrated that it offers potential as a prosthetic group for rapid radiolabeling of biomolecules in mild conditions using bioorthogonal chemistry.


Subject(s)
Heterocyclic Compounds , Octreotide , Animals , Cell Line, Tumor , Fluorine Radioisotopes/chemistry , Mice , Mice, Nude , Pancreatic Neoplasms , Polyethylene Glycols , Positron Emission Tomography Computed Tomography , Positron-Emission Tomography/methods , Radiopharmaceuticals/chemistry , Rats , Tissue Distribution , Pancreatic Neoplasms
10.
Am J Physiol Endocrinol Metab ; 320(5): E989-E998, 2021 05 01.
Article in English | MEDLINE | ID: mdl-33843281

ABSTRACT

Cardiovascular effects of glucagon-like peptide-1 receptor (GLP-1R) agonist therapies are potentially mediated by anti-inflammatory effects on atherosclerosis. Our study demonstrates that 68Ga-NODAGA-exendin-4, a radioligand specifically targeting GLP-1R, detects GLP-1R expression in inflamed atherosclerotic lesions in nondiabetic and diabetic hypercholesterolemic mice. Immunofluorescence staining suggests that GLP-1R is primarily localized in M2 macrophages in lesions. This study describes a new potential tool that may have translational relevance for studies of pharmacological modification of GLP-1R signaling in atherosclerosis.


Subject(s)
Atherosclerosis/metabolism , Diabetes Mellitus, Experimental/metabolism , Glucagon-Like Peptide-1 Receptor/metabolism , Acetates/pharmacokinetics , Animals , Apolipoproteins B/genetics , Apolipoproteins B/metabolism , Atherosclerosis/complications , Atherosclerosis/diagnosis , Atherosclerosis/genetics , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/diagnosis , Diabetes Mellitus, Experimental/genetics , Exenatide/pharmacokinetics , Female , Gallium Radioisotopes/pharmacokinetics , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/genetics , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Hypercholesterolemia/complications , Hypercholesterolemia/diagnosis , Hypercholesterolemia/genetics , Hypercholesterolemia/metabolism , Insulin-Like Growth Factor II/genetics , Insulin-Like Growth Factor II/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Positron-Emission Tomography/methods , Receptors, LDL/genetics , Receptors, LDL/metabolism
11.
J Neuroinflammation ; 18(1): 30, 2021 Jan 20.
Article in English | MEDLINE | ID: mdl-33472663

ABSTRACT

BACKGROUND: Activated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-ß (FR-ß), representing a promising target for the treatment of MS. Here, we both evaluated the efficacy of a novel folate-aminopterin construct (EC2319) in a rat focal model of multiple sclerosis (MS) and investigated the utility of 68Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate (68Ga-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-ß is expressed in the brain of patients with MS. METHODS: Focal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) was induced in 40 Lewis rats; 20 healthy Lewis rats were used as controls. Rats were divided into six groups according to the duration of disease (control, acute, or chronic) and intervention (vehicle versus EC2319). 68Ga-FOL analyses, histology, and immunofluorescence of the brain were performed to evaluate the efficacy of subcutaneously administered EC2319 on lesion development. Immunofluorescence was used to assess FR-ß expression in postmortem brain samples from 5 patients with MS and 5 healthy controls. RESULTS: Immunofluorescence and histological analyses revealed significant reductions in FR-ß expression (P < 0.05) and lesion size (P < 0.01), as well as improved inducible nitric oxide synthase/mannose receptor C type 1 ratios (P < 0.01) in macrophages and microglia during the chronic but not acute phase of fDTH-EAE in EC2319-treated rats. The uptake of IV-injected 68Ga-FOL in the brain was low and did not differ between the groups, but the in vitro binding of 68Ga-FOL was significantly lower in EC2319-treated rats (P < 0.01). FR-ß positivity was observed in chronically active lesions and in normal-appearing white matter in MS brain samples. CONCLUSIONS: EC2319 was well tolerated and attenuated inflammation and lesion development in a rat model of a chronic progressive form of MS. Human MS patients have FR-ß-positive cells in chronically active plaques, which suggests that these results may have translational relevance.


Subject(s)
Aminopterin/pharmacology , Encephalomyelitis, Autoimmune, Experimental/pathology , Folate Receptor 2/metabolism , Folic Acid Antagonists/pharmacology , Folic Acid/pharmacology , Animals , Humans , Multiple Sclerosis/metabolism , Rats , Rats, Inbred Lew
12.
Bioconjug Chem ; 32(6): 1130-1138, 2021 06 16.
Article in English | MEDLINE | ID: mdl-33998229

ABSTRACT

An azide-functionalized 12-armed Buckminster fullerene has been monosubstituted in organic media with a substoichiometric amount of cyclooctyne-modified oligonucleotides. Exposing the intermediate products then to the same reaction (i.e., strain-promoted alkyne-azide cycloaddition, SPAAC) with an excess of slightly different oligonucleotide constituents in an aqueous medium yields molecularly defined monofunctionalized spherical nucleic acids (SNAs). This procedure offers a controlled synthesis scheme in which one oligonucleotide arm can be functionalized with labels or other conjugate groups (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTA, and Alexa-488 demonstrated), whereas the rest of the 11 arms can be left unmodified or modified by other conjugate groups in order to decorate the SNAs' outer sphere. Extra attention has been paid to the homogeneity and authenticity of the C60-azide scaffold used for the assembly of full-armed SNAs.


Subject(s)
Fullerenes/chemistry , Nucleic Acids/chemistry , Alkynes/chemistry , Azides/chemistry , Catalysis , Click Chemistry , Copper/chemistry , Cycloaddition Reaction
13.
NMR Biomed ; 34(4): e4483, 2021 04.
Article in English | MEDLINE | ID: mdl-33543563

ABSTRACT

MRI is a common method of prostate cancer diagnosis. Several MRI-derived markers, including the apparent diffusion coefficient (ADC) based on diffusion-weighted imaging, have been shown to provide values for prostate cancer detection and characterization. The hypothesis of the study was that docetaxel chemotherapy response could be picked up earlier with rotating frame relaxation times TRAFF2 and TRAFF4 than with the continuous wave T1ρ , adiabatic T1ρ , adiabatic T2ρ , T1 , T2 or water ADC. Human PC3 prostate cancer cells expressing a red fluorescent protein were implanted in 21 male mice. Docetaxel chemotherapy was given once a week starting 1 week after cell implantation for 10 randomly selected mice, while the rest served as a control group (n = 11). The MRI consisted of relaxation along a fictitious field (RAFF) in the second (RAFF2) and fourth (RAFF4) rotating frames, T1 and T2 , continuous wave T1ρ , adiabatic T1ρ and adiabatic T2ρ relaxation time measurements and water ADC. MRI was conducted at 7 T, once a week up to 4 weeks from cell implantation. The tumor volume was monitored using T2 -weighted MRI and optical imaging. The histology was evaluated after the last imaging time point. Significantly reduced RAFFn, T1ρ, T2ρ and conventional relaxation times 4 weeks after tumor implantation were observed in the treated tumors compared with the controls. The clearest short- and long-term responses were obtained with T1 , while no clear improvement in response to treatment was detected with novel methods compared with conventional methods or with RAFFn compared with all others. The tumor volume decreased after a two-week time point for the treated group and increased significantly in the control group, which was supported by increasing red fluorescent light emission in the control tumors. Decreased relaxation times were associated with successful chemotherapy outcomes. The results indicate altered relaxation mechanisms compared with higher dose chemotherapies previously published.


Subject(s)
Docetaxel/therapeutic use , Magnetic Resonance Imaging/methods , Prostatic Neoplasms/drug therapy , Animals , Diffusion , Disease Models, Animal , Humans , Male , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Tumor Burden , Water
14.
J Nucl Cardiol ; 28(6): 2992-3003, 2021 12.
Article in English | MEDLINE | ID: mdl-32737839

ABSTRACT

BACKGROUND: The diagnosis of cardiac implantable electronic device (CIED) infection is challenging because of its variable presentations. We studied the value of 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in the detection of CIED infection. METHODS AND RESULTS: Thirty patients with suspected CIED infection underwent 18F-FDG-PET/CT. The control group was ten patients with asymptomatic CIED who underwent cancer-related 18F-FDG-PET/CT. 18F-FDG-PET/CT was evaluated visually, semiquantitatively as maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR). Final diagnosis of CIED infection was based on clinical and bacteriological data. 18F-FDG-PET/CT was visually positive in all 9 patients with recent (≤ 8 weeks) implantation of CIED, but only 4 had confirmed CIED infection. 18F-FDG-PET/CT was true positive in 9 out of 21 cases with remote implantation of CIED and false positive in 3 (14.3%) cases. 18F-FDG-PET/CT was also false positive in 3 (30%) cases of control group. The SUVmax of the pocket area was significantly higher in patients with CIED infection than in the control group (4.8 ± 2.4 vs 2.0 ± .8, P < .001). By using the cut-off value of TBR ≥ 1.8, sensitivity of 18F-FDG-PET/CT for the diagnosis of CIED infection in patients with remote implantation was 90% and specificity 73%, PPV 75%, and NPV 89%. CONCLUSIONS: 18F-FDG-PET/CT is a sensitive but nonspecific method in the diagnosis of CIED infection.


Subject(s)
Defibrillators, Implantable/adverse effects , Fluorodeoxyglucose F18 , Pacemaker, Artificial/adverse effects , Positron Emission Tomography Computed Tomography/methods , Prosthesis-Related Infections/diagnostic imaging , Prosthesis-Related Infections/etiology , Radiopharmaceuticals , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Prospective Studies
15.
J Nucl Cardiol ; 28(4): 1271-1280, 2021 08.
Article in English | MEDLINE | ID: mdl-31317328

ABSTRACT

BACKGROUND: Assessment of myocardial viability is often needed in patients with chest pain and reduced ejection fraction. We evaluated the performance of reduced resting MBF, perfusable tissue fraction (PTF), and perfusable tissue index (PTI) in the assessment of myocardial viability in a pig model of myocardial infarction (MI). METHODS AND RESULTS: Pigs underwent resting [15O]water PET perfusion study 12 weeks after surgical (n = 16) or 2 weeks after catheter-based (n = 4) occlusion of the proximal left anterior descending coronary artery. MBF, PTF, and PTI were compared with volume fraction of MI in matched segments as assessed by triphenyl tetrazolium chloride staining of LV slices. MBF and PTF were lower in infarcted than non-infarcted segments. Segmental analysis of MBF showed similar area under the curve (AUC) of 0.85, 0.86, and 0.90 with relative MBF, PTF, and PTI for the detection of viable myocardium defined as infarct volume fraction of < 75%. Cut-off values of relative MBF of ≥ 67% and PTF of ≥ 66% resulted in accuracies of 90% and 81%, respectively. CONCLUSIONS: Our results indicate that resting MBF, PTF, and PTI based on [15O]water PET perfusion imaging are useful for the assessment of myocardial viability.


Subject(s)
Myocardial Infarction/diagnostic imaging , Myocardial Infarction/pathology , Positron-Emission Tomography , Animals , Coronary Circulation , Disease Models, Animal , Myocardial Infarction/physiopathology , Oxygen Radioisotopes , Predictive Value of Tests , ROC Curve , Swine , Tissue Survival
16.
Mol Biol Rep ; 48(6): 5347-5353, 2021 Jun.
Article in English | MEDLINE | ID: mdl-34213709

ABSTRACT

Radiolabeled RGD peptides targeting expression of αvß3 integrin have been applied to in vivo imaging of angiogenesis. However, there is a need for more information on the quantitative relationships between RGD peptide uptake and the dynamics of angiogenesis. In this study, we sought to measure the binding of [68Ga]NODAGA-RGDyK to αvß3 integrin in a human cell-based three-dimensional (3D) in vitro model of angiogenesis, and to compare the level of binding with the amount of angiogenesis. Experiments were conducted using a human cell-based 3D model of angiogenesis consisting of co-culture of human adipose stem cells (hASCs) and of human umbilical vein endothelial cells (HUVECs). Angiogenesis was induced with four concentrations (25%, 50%, 75%, and 100%) of growth factor cocktail resulting in a gradual increase in the density of the tubule network. Cultures were incubated with [68Ga]NODAGA-RGDyK for 90 min at 37 °C, and binding of radioactivity was measured by gamma counting and digital autoradiography. The results revealed that tracer binding increased gradually with neovasculature density. In comparison with vessels induced with a growth factor concentration of 25%, the uptake of [68Ga]NODAGA-RGDyK was higher at concentrations of 75% and 100%, and correlated with the amount of neovasculature, as determined by visual evaluation of histological staining. Uptake of [68Ga]NODAGA-RGDyK closely reflected the amount of angiogenesis in an in vitro 3D model of angiogenesis. These results support further evaluation of RGD-based approaches for targeted imaging of angiogenesis.


Subject(s)
Acetates/pharmacokinetics , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Neovascularization, Physiologic/physiology , Oligopeptides/pharmacokinetics , Acetates/pharmacology , Angiogenesis Inducing Agents/pharmacology , Cell Culture Techniques, Three Dimensional/methods , Cell Line, Tumor , Endothelial Cells , Gallium Radioisotopes , Heterocyclic Compounds, 1-Ring/pharmacology , Humans , Integrin alphaVbeta3/metabolism , Isotope Labeling/methods , Models, Biological , Neovascularization, Physiologic/drug effects , Oligopeptides/pharmacology , Tissue Distribution
17.
Int J Mol Sci ; 22(17)2021 Sep 06.
Article in English | MEDLINE | ID: mdl-34502532

ABSTRACT

Brown adipose tissue (BAT) expresses uncoupling protein-1 (UCP1), which enables energy to be exerted towards needed thermogenesis. Beige adipocytes are precursor cells interspersed among white adipose tissue (WAT) that possess similar UCP1 activity and capacity for thermogenesis. The raccoon dog (Nyctereutes procyonoides) is a canid species that utilizes seasonal obesity to survive periods of food shortage in climate zones with cold winters. The potential to recruit a part of the abundant WAT storages as beige adipocytes for UCP1-dependent thermogenesis was investigated in vitro by treating raccoon dog adipocytes with different browning inducing factors. In vivo positron emission tomography/computed tomography (PET/CT) imaging with the glucose analog 18F-FDG showed that BAT was not detected in the adult raccoon dog during the winter season. In addition, UCP1 expression was not changed in response to chronic treatments with browning inducing factors in adipocyte cultures. Our results demonstrated that most likely the raccoon dog endures cold weather without the induction of BAT or recruitment of beige adipocytes for heat production. Its thick fur coat, insulating fat, and muscle shivering seem to provide the adequate heat needed for surviving the winter.


Subject(s)
Adaptation, Physiological/physiology , Adipose Tissue, Beige/metabolism , Adipose Tissue, Brown/metabolism , Raccoon Dogs/metabolism , Seasons , Adipocytes, Beige/metabolism , Adipocytes, Brown/metabolism , Adipose Tissue, Beige/diagnostic imaging , Adipose Tissue, Brown/diagnostic imaging , Adipose Tissue, White/diagnostic imaging , Adipose Tissue, White/metabolism , Animals , Cells, Cultured , Fluorodeoxyglucose F18/metabolism , Male , Positron Emission Tomography Computed Tomography , Thermogenesis , Uncoupling Protein 1/metabolism
18.
Am J Physiol Endocrinol Metab ; 319(3): E494-E508, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32691632

ABSTRACT

Hydroxysteroid 17ß dehydrogenase 12 (HSD17B12) is suggested to be involved in the elongation of very long chain fatty acids. Previously, we have shown a pivotal role for the enzyme during mouse development. In the present study we generated a conditional Hsd17b12 knockout (HSD17B12cKO) mouse model by breeding mice homozygous for a floxed Hsd17b12 allele with mice expressing the tamoxifen-inducible Cre recombinase at the ROSA26 locus. Gene inactivation was induced by administering tamoxifen to adult mice. The gene inactivation led to a 20% loss of body weight within 6 days, associated with drastic reduction in both white (83% males, 75% females) and brown (65% males, 60% females) fat, likely due to markedly reduced food and water intake. Furthermore, the knockout mice showed sickness behavior and signs of liver toxicity, specifically microvesicular hepatic steatosis and increased serum alanine aminotransferase (4.6-fold in males, 7.7-fold in females). The hepatic changes were more pronounced in females than males. Proinflammatory cytokines, such as interleukin-6 (IL-6), IL-17, and granulocyte colony-stimulating factor, were increased in the HSD17B12cKO mice indicating an inflammatory response. Serum lipidomics study showed an increase in the amount of dihydroceramides, despite the dramatic overall loss of lipids. In line with the proposed role for HSD17B12 in fatty acid elongation, we observed accumulation of ceramides, dihydroceramides, hexosylceramides, and lactosylceramides with shorter than 18-carbon fatty acid side chains in the serum. The results indicate that HSD17B12 is essential for proper lipid homeostasis and HSD17B12 deficiency rapidly results in fatal systemic inflammation and lipolysis in adult mice.


Subject(s)
17-Hydroxysteroid Dehydrogenases/physiology , Homeostasis/physiology , 17-Hydroxysteroid Dehydrogenases/genetics , Adipose Tissue, Brown/drug effects , Adipose Tissue, Brown/metabolism , Adipose Tissue, White/drug effects , Adipose Tissue, White/metabolism , Animals , Behavior, Animal , Body Weight/genetics , Cytokines/metabolism , Fatty Acids/metabolism , Feeding Behavior , Female , Homeostasis/genetics , Lipid Metabolism/genetics , Lipid Metabolism/physiology , Lipidomics , Liver Diseases/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Sex Characteristics , Tamoxifen/pharmacology
19.
J Nucl Cardiol ; 27(3): 891-898, 2020 06.
Article in English | MEDLINE | ID: mdl-31144229

ABSTRACT

BACKGROUND: Magnetic resonance imaging (MRI) with Gadolinium 1,4,7,10-tetraazacyclododecane-N',N″,N''',N″″-tetraacetic acid (Gd-DOTA) enables assessment of myocardial perfusion during first-pass of the contrast agent, while increased retention can signify areas of myocardial infarction (MI). We studied whether Gallium-68-labeled analog, 68Ga-DOTA, can be used to assess myocardial perfusion on positron emission tomography/computed tomography (PET/CT) in rats, comparing it with 11C-acetate. METHODS: Rats were studied with 11C-acetate and 68Ga-DOTA at 24 hours after permanent ligation of the left coronary artery or sham operation. One-tissue compartmental models were used to estimate myocardial perfusion in normal and infarcted myocardium. After the PET scan, hearts were sectioned for autoradiographic detection of 68Ga-DOTA distribution. RESULTS: 11C-acetate PET showed perfusion defects and histology showed myocardial necrosis in all animals after coronary ligation. Kinetic modeling of 68Ga-DOTA showed significantly higher k1 values in normal myocardium than in infarcted areas. There was a significant correlation (r = 0.82, P = 0.001) between k1 values obtained with 68Ga-DOTA and 11C-acetate. After 10 minutes of tracer distribution, the 68Ga-DOTA concentration was significantly higher in the infarcted than normal myocardium on PET imaging and autoradiography. CONCLUSIONS: Our results indicate that acute MI can be detected as reduced perfusion, as well as increased late retention of 68Ga-DOTA.


Subject(s)
Autoradiography/methods , Gallium Radioisotopes , Heart/diagnostic imaging , Heterocyclic Compounds, 1-Ring , Myocardial Perfusion Imaging/methods , Myocardium/pathology , Animals , Contrast Media , Cyclotrons , Disease Models, Animal , Kinetics , Male , Myocardial Infarction/diagnostic imaging , Positron Emission Tomography Computed Tomography/methods , Radiopharmaceuticals , Rats , Rats, Sprague-Dawley
20.
J Nucl Cardiol ; 27(6): 2386-2397, 2020 12.
Article in English | MEDLINE | ID: mdl-30547299

ABSTRACT

BACKGROUND: Activation of glucagon-like peptide-1 receptor (GLP-1R) signaling protects against cardiac dysfunction and remodeling after myocardial infarction (MI). The aim of the study was to evaluate 68Ga-NODAGA-exendin-4 positron emission tomography (PET) for assessment of GLP-1R expression after MI in rats. METHODS AND RESULTS: Rats were studied at 3 days, 1 and 12 weeks after permanent coronary ligation or a sham-operation. Rats were injected with 68Ga-NODAGA-exendin-4 and scanned with PET and contrast-enhanced computed tomography (CT) followed by digital autoradiography and histology of left ventricle tissue sections. 68Ga-NODAGA-exendin-4 PET/CT showed focally increased tracer uptake in the infarcted regions peaking at 3 days and continuing at 1 week after MI. Pre-treatment with an unlabeled exendin-4 peptide significantly reduced 68Ga-NODAGA-exendin-4 uptake. By autoradiography, 68Ga-NODAGA-exendin-4 uptake was 8.6-fold higher in the infarcted region and slightly increased also in the remote, non-infarcted myocardium at 1 week and 12 weeks post-MI compared with sham. Uptake of 68Ga-NODAGA-exendin-4 correlated with the amount of CD68-positive macrophages in the infarcted area and alpha-smooth muscle actin staining in the remote myocardium. CONCLUSIONS: 68Ga-NODAGA-exendin-4 PET detects up-regulation of cardiac GLP-1R expression during healing of MI in rats and may provide information on the activated repair mechanisms after ischemic myocardial injury.


Subject(s)
Acetates/chemistry , Exenatide/chemistry , Gallium Radioisotopes/chemistry , Glucagon-Like Peptide-1 Receptor/chemistry , Heterocyclic Compounds, 1-Ring/chemistry , Myocardial Infarction/diagnostic imaging , Positron Emission Tomography Computed Tomography/methods , Tomography/methods , Animals , Echocardiography , Gene Expression Profiling , Heart Ventricles/diagnostic imaging , Heart Ventricles/pathology , Kinetics , Macrophages/metabolism , Male , Rats , Rats, Sprague-Dawley , Signal Transduction
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