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Abstract Background Despite the development of positron emission tomography (PET), single photon emission computed tomography (SPECT) still accounts for around 80% of all examinations performed in nuclear medicine departments. The search for new radiotracers or chelating agents for Technetium-99m is therefore still ongoing. O-TRENSOX and O-TRENOX two synthetic siderophores would be good candidates for this purpose as they are hexadentate ligands based on the very versatile and efficient 8-hydroxyquinoline chelating subunit. First, the radiolabeling of O-TRENOX and O-TRENSOX with 99mTc was investigated. Different parameters such as the quantity of chelating agent, type of reducing agent, pH and temperature of the reaction mixture were adjusted in order to find the best radiolabeling conditions. Then an assessment of the partition coefficient by measuring the distribution of each radiosynthesized complex between octanol and phosphate-buffered saline was realized. The complex’s charge was evaluated on three different celluloses (neutral, negatively charged P81 and positively charged DE81), and finally in vivo studies with biodistribution and SPECT imaging of [99mTc]Tc-O-TRENOX and [99mTc]Tc-O-TRENSOX were performed. Results The radiolabeling studies showed a rapid and efficient complexation of 99mTc with both chelating agents. Using tin pyrophosphate as the reducing agent and a minimum of 100 nmol of ligand, we obtained the [99mTc]Tc-O-TRENOX complex with a radiochemical purity of more than 98% and the [99mTc]Tc-O-TRENSOX complex with one above 97% at room temperature within 5 min. [99mTc]Tc-O-TRENOX complex was lipophilic and neutral, leading to a hepatobiliary elimination in mice. On the contrary, the [99mTc]Tc-O-TRENSOX complex was found to be hydrophilic and negatively charged. This was confirmed by a predominantly renal elimination in mice. Conclusions These encouraging results allow us to consider the O-TRENOX/99mTc and O-TRENSOX/99mTc complexes as serious candidates for SPECT imaging chelators. This study should be continued by conjugating these tris-oxine ligands to peptides or antibodies and comparing them with the other bifunctional agents used with Tc.

Here, the authors present a noninvasive tool to detect liver inflammation using nuclear imaging, as an alternative to biopsy. The prove the diagnostic power of this tool to detect liver inflammation in preclinical models of chronic liver disease.

Context Linum is the largest genus of the Linaceae family; the species of this genus are known to have anticancer activity.Objective In this study, ethyl acetate extracts of L. numidicum Murb. (EAELN) and L. trigynum L. (EAELT) were examined, for the first time, for their anticancer capacity. The secondary metabolites compositions were analysed by LC-HRMS/MS.Materials and methods The antiproliferative effect of EAELN and EAELT (0–10.000 μg/mL) against PC3 and MDA-MB-231 cell lines were evaluated by the MTT assay after 72 h of treatment. Flow cytometer analysis of apoptosis (Annexin V-FITC/PI) and cell cycle (PI/RNase) was also performed after treatment with EAELN and EAELT at 250, 500, and 1000 μg/mL, for 24 h.Results EAELN had the highest antiproliferative activity against PC3 (IC50 133.2 ± 5.73 μg/mL) and MDA-MB-231 (IC50 156.9 ± 2.83 μg/mL) lines, EAELN had also shown better apoptotic activity with 19 ± 2.47% (250 μg/mL), 87.5 ± 0.21% (500 μg/mL), and 92 ± 0.07% (1000 μg/mL), respectively, causing cell cycle arrest of PC3 cells in G2/M phase, whereas arrest in G0/G1 and G2/M phases was observed after treatment with EAELT. LC-HRMS/MS profiling of the extracts revealed the presence of known compounds that might be responsible for the observed anticancer activity such as chicoric acid, vicenin-2, vitexin and podophyllotoxin-β-d-glucoside.Discussion and conclusions We have shown, for the first time, that EAELN and EAELT exert anticancer activity through cell cycle arrest and induction of apoptosis. EAELN can be considered as a source to treat cancer. Further studies will be required to evaluate the effect of the active compounds, once identified, on other cancer cell lines.

ObjectivesThis study sought to develop an integrative positron emission tomography (PET) with magnetic resonance imaging (MRI) procedure for accurate atherosclerotic plaque phenotyping, facilitated by clinically approved and nanobody radiotracers.BackgroundNoninvasive characterization of atherosclerosis remains a challenge in clinical practice. The limitations of current diagnostic methods demonstrate that, in addition to atherosclerotic plaque morphology and composition, disease activity needs to be evaluated.MethodsWe screened 3 nanobody radiotracers targeted to different biomarkers of atherosclerosis progression, namely vascular cell adhesion molecule (VCAM)-1, lectin-like oxidized low-density lipoprotein receptor (LOX)-1, and macrophage mannose receptor (MMR). The nanobodies, initially radiolabeled with copper-64 (64Cu), were extensively evaluated in Apoe-/- mice and atherosclerotic rabbits using a combination of in vivo PET/MRI readouts and ex vivo radioactivity counting, autoradiography, and histological analyses.ResultsThe 3 nanobody radiotracers accumulated in atherosclerotic plaques and displayed short circulation times due to fast renal clearance. The MMR nanobody was selected for labeling with gallium-68 (68Ga), a short-lived radioisotope with high clinical relevance, and used in an ensuing atherosclerosis progression PET/MRI study. Macrophage burden was longitudinally studied by 68Ga-MMR-PET, plaque burden by T2-weighted MRI, and neovascularization by dynamic contrast-enhanced (DCE) MRI. Additionally, inflammation and microcalcifications were evaluated by fluorine-18 (18F)-labeled fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF) PET, respectively. We observed an increase in all the aforementioned measures as disease progressed, and the imaging signatures correlated with histopathological features.ConclusionsWe have evaluated nanobody-based radiotracers in rabbits and developed an integrative PET/MRI protocol that allows noninvasive assessment of different processes relevant to atherosclerosis progression. This approach allows the multiparametric study of atherosclerosis and can aid in early stage anti-atherosclerosis drug trials.

Atherosclerotic plaque rupture or erosion remain the primary mechanism responsible for myocardial infarction and the major challenge of cardiovascular researchers is to develop non-invasive methods of accurate risk prediction to identify vulnerable plaques before the event occurs. Multimodal imaging, by CT-TEP or CT-SPECT, provides both morphological and activity information about the plaque and cumulates the advantages of anatomic and molecular imaging to identify vulnerability features among coronary plaques. However, the rate of acute coronary syndromes remains low and the mechanisms leading to adverse events are clearly more complex than initially assumed. Indeed, recent studies suggest that the detection of a state of vulnerability in a patient is more important than the detection of individual sites of vulnerability as a target of focal treatment. Despite this evolution of concepts, multimodal imaging offers a strong potential to assess patient's vulnerability. Here we review the current state of multimodal imaging to identify vulnerable patients, and then focus on emerging imaging techniques and precision medicine.

In this study, the total phenolic and flavonoid contents (TPC and TFC), secondary metabolite composition (LC-HRMS/MS analyses) and antioxidant potential (DPPH, ABTS, GOR, CUPRAC, and phenanthroline assays) of Linum trigynum L. (LT) extracts were determined. Our results showed for the first time that the extracts (PE, CHCl3, AcOEt, and n-BuOH) of LT exert antioxidant activity. The AcOEt and n-BuOH extracts were the most antioxidant compared to the standards, and had a higher amount of TPC (323.51 ± 0.62; 229.98 ± 6.80 µg GAE/mL) and TFC (183.75 ± 1.17 and 157.50 ± 1.77 µg QE/mL), resectively. The high antioxidant properties of these extracts may be due to their major compounds (phenolic compounds) detected by LC-HRMS/MS analyses including flavonoids (40 compounds) and phenolic acids and derivatives (18 and 19 compounds, respectively). AcOEt and n-BuOH extracts of LT can be used as an excellent source of antioxidant phytochemicals to prevent or treat various diseases. [ABSTRACT FROM AUTHOR]

Coronary physiological assessment is now widely used to assess epicardial coronary lesions in cath lab. Based on clinical evidence, fractional flow reserve (FFR) is the gold standard method to select whether epicardial coronary lesions need revascularization. While additional epicardial indexes, such as instantaneous wave-free ratio (iFR), are also used for revascularization decision-making, several indexes are now also available to explore the coronary microcirculation. Therefore, coronary physiological assessment now allows to explore the entire coronary tree and offer the potential of precision medicine for patients affected by coronary artery disease (CAD). This paper will provide review of the epicardial and microvascular indexes available for the assessment of coronary physiology. More specifically, the already demonstrated contributions of these indexes in the management of CAD and the role they could play in precision medicine will be reviewed with special emphasis on chronic coronary syndrome.

Humoral rejection is the most common cause of solid organ transplant failure. Here, we evaluated a cohort of 49 patients who were successfully grafted with allogenic islets and determined that the appearance of donor-specific anti- HLA antibodies (DSAs) did not accelerate the rate of islet graft attrition, suggesting resistance to humoral rejection. Murine DSAs bound to allogeneic targets expressed by islet cells and induced their destruction in vitro; however, passive transfer of the same DSAs did not affect islet graft survival in murine models. Live imaging revealed that DSAs were sequestrated in the circulation of the recipients and failed to reach the endocrine cells of grafted islets. We used murine heart transplantation models to confirm that endothelial cells were the only accessible targets for DSAs, which induced the development of typical microvascular lesions in allogeneic transplants. In contrast, the vasculature of DSA-exposed allogeneic islet grafts was devoid of lesions because sprouting of recipient capillaries reestablished blood flow in grafted islets. Thus, we conclude that endothelial chimerism combined with vascular sequestration of DSAs protects islet grafts from humoral rejection. The reduced immunoglobulin concentrations in the interstitial tissue, confirmed in patients, may have important implications for biotherapies such as vaccines and monoclonal antibodies., Introduction Type 1 diabetes is one of the most prevalent chronic diseases of childhood. Epidemiologic studies have estimated that approximately 70,000 new cases are diagnosed every year and that the [...]

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all pancreatic tumors, is a highly devastating disease with poor prognosis and rising incidence. The lack of available specific diagnostics tests and the limited treatment opportunities contribute to this pejorative issue. Over the last 10 years, a growing interest pointing towards mesothelin (MSLN) as a promising PDAC-associated antigen has emerged. The limited expression of MSLN in normal tissues (peritoneum, pleura and pericardium) and its overexpression in 80 to 90% of PDAC make it an attractive candidate for therapeutic management of PDAC patients. Moreover, its role in malignant progression related to its involvement in tumor cell proliferation and resistance to chemotherapy has highlighted the relevance of its targeting. Hence, several clinical trials are investigating anti-MSLN efficacy in PDAC. In this review, we provide a general overview of the different roles sustained by MSLN during PDAC progression. Finally, we also summarize the different MSLN-targeted therapies that are currently tested in the clinic.

Since atherosclerotic plaques are small and sparse, their non-invasive detection via PET imaging requires both highly specific radiotracers as well as imaging systems with high sensitivity and resolution. This study aimed to assess the targeting and biodistribution of a novel fluorine-18 anti-VCAM-1 Nanobody (Nb), and to investigate whether sub-millimetre resolution PET imaging could improve detectability of plaques in mice. The anti-VCAM-1 Nb functionalised with the novel restrained complexing agent (RESCA) chelator was labelled with [18F]AlF with a high radiochemical yield (>75%) and radiochemical purity (>99%). Subsequently, [18F]AlF(RESCA)-cAbVCAM1-5 was injected in ApoE−/− mice, or co-injected with excess of unlabelled Nb (control group). Mice were imaged sequentially using a cross-over design on two different commercially available PET/CT systems and finally sacrificed for ex vivo analysis. Both the PET/CT images and ex vivo data showed specific uptake of [18F]AlF(RESCA)-cAbVCAM1-5 in atherosclerotic lesions. Non-specific bone uptake was also noticeable, most probably due to in vivo defluorination. Image analysis yielded higher target-to-heart and target-to-brain ratios with the β-CUBE (MOLECUBES) PET scanner, demonstrating that preclinical detection of atherosclerotic lesions could be improved using the latest PET technology.

Maurocalcine (MCa) is the first natural cell penetrating peptide to be discovered in animal venom. In addition to the fact that it represents a potent vector for the cell penetration of structurally diverse therapeutic compounds, MCa also displays several distinguishing features that make it a potential peptide of choice for clinical and biotechnological applications. The aim of the present study was to gain new information about the properties of MCa in vivo in order to delineate the future potential applications of this vector. For this purpose, two analogues of this peptide with (Tyr-MCa) and without (Lin-Tyr-MCa) disulfide bridges were synthesized, radiolabeled with 125I, and their in vitro stabilities were first evaluated in mouse blood. The results indicated that 125I-Tyr-MCa was stable in vitro and that the disulfide bridges conferred a competitive advantage for the stability of peptide. Following in vivo injection in mice, 125I-Tyr-MCa targeted peripheral organs with interesting quantitative differences and the main route of peptide elimination was renal.