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Introduction: Ultra Carbonaceous Antarctic MicroMeteorites (UCAMMs) are sub-millimeter extraterrestrial particles with high abundance of organic matter and low abundance of minerals (C/Si ? 10 - 103), identified independently in the French and Japanese micrometeorite collections [1-6]. The organic matter in UCAMMs present high N/C ratios ranging from 0.02 to 0.2 [2, 7] and can present extreme D/H ratio. The characteristics of UCAMMs suggest that they were formed by irradiation by Galactic Cosmic Rays (GCRs) of nitrogen-rich ice mantles at the surface of small icy bodies [4, 8]. We investigated the isotopic signature of light elements in the organic matter of UCAMMs to study their links with organic matter from carbonaceous chondrites and interplanetary dust particles (IDPs). We present here a summary of our recent results, including sample analyses and ice irradiation experiments that aim at synthesizing analogs of the organic matter in UCAMMs. NanoSIMS analyses of UCAMMs: the H, C and N isotopic compositions of the 4 UCAMMs DC06-05-94 (DC94), DC06-07-18 (DC18), DC06-14-309 (DC309) and DC06-04-43 (DC43) were analyzed by nanoscale secondary ion mass spectrometry (NanoSIMS) at the Carnegie Earth and Planets Laboratory, the Museum National d'Histoire Naturelle and the Institut Curie [9]. The 4 UCAMMs do not exhibit similar isotopic compositions, with δD bulk values ranging from 1000‰ to 9000‰, δ13C from -90‰ to 30‰ and δ15N from -120‰ to 270‰. Each UCAMM is characterized by isotopic heterogeneities, typically at scales of a few μm [9]. Ice irradiation experiments: We performed ice irradiation experiments during 3 sessions in 2019, 2020 and 2021 at GANIL (Caen, France) [10], using the IGLIAS experimental setup connected to the IRRSUD ion beam (0.5-1 MeV/u). We formed 10μm - thick ice films by gas condensation on IR-transparent windows cooled down to 10K [8, 11]. The ice films consisted in one layer of isotopically labeled ice (with D, 15N and/or 13C-rich ice) between 2 layers of isotopically unlabeled ice (14N2-12CH4 or 14NH3-12CH4), forming an ice sandwich. The labeled layer accounted for 1% to 4% of the total thickness. Ice sandwiches were subsequently irradiated by heavy ions and slowly warmed up to the room temperature to obtain refractory organic residues. The residues, exhibiting an IR signature comparable to that of the organic matter in UCAMMs [8], were subsequently analyzed by NanoSIMS at the Institut Curie, to map the H, C and N isotopic heterogeneities. This study shows that the ion-processing of ice sandwiches made of N2-CH4 form an organic refractory residue that keeps the large isotopic heterogeneities of the initial ice sandwich, while that of NH3-CH4 ice sandwiches appears less favorable to the formation of isotopic heterogeneities. Extreme isotopic heterogeneities at low scale were observed in organic residues, indicating that local preservation of the initial ice sandwich composition can occur, maybe related to sporadic events during the annealing of the ice films. Results and discussion: These irradiation experiments demonstrate the possibility to form large micron-scale isotopic heterogeneities in organic residues from multilayer, isotopically heterogeneous, ice precursors. The organic matter of UCAMMs can thus have formed by irradiation by GCRs of isotopically heterogeneous ice mantles. Numerical models of the evolution of the early solar system predict the existence of gaseous reservoirs isotopically fractionated in H, C and N at different locations in the protoplanetary disk [12, 13]. The parent body/bodies of UCAMMs may have inherited from these fractionated reservoirs, condensed on its/their surface under the form of ice mantles. The diversity of isotopic signatures from one UCAMM to another also suggest that UCAMMs do not have anomalies inherited from one single parent gaseous reservoir. Further investigations on the correlation of elemental and isotopic ratios in the organic matter of UCAMMs will bring new insights to better constrain the characteristics of the parent reservoirs of UCAMMs. Acknowledgments: This work was funded by contract ANR-18-CE31-0011, CNES (MIAMI2), DIM-ACAV+ (C3E), CNRS-INSU/IN2P3 (PNP). The work at CONCORDIA Station (Projet#1120) was supported by IPEV and PNRA. [ABSTRACT FROM AUTHOR]

Background: Telehomecare monitoring (TM) in patients with cancer is a complex intervention. Research shows variations in the benefits and challenges TM brings to equitable access to care, the therapeutic relationship, self-management, and practice transformation. Further investigation into these variations factors will improve implementation processes and produce effective outcomes., Objective: This study aims to concurrently analyze implementation and evaluate the effectiveness of TM for patients receiving anticancer oral therapy. The objectives are to (1) contextualize how and why TM is implemented according to (a) site characteristics, (b) team characteristics, and (c) characteristics of patients receiving anticancer oral therapy; (2) assess TM effectiveness for recording electronic patient-reported outcome measures (ePROMs) and patient-reported experience measures (ePREMs) according to the site, implementation process, and patient characteristics; (3) describe the acceptability and feasibility of TM from the perspectives of the people directly or indirectly involved and provide evidence-based actionable guidance in anticipation of provincewide implementation., Methods: This type II hybrid effectiveness-implementation study uses a concurrent mixed methods design. Evaluability assessment is integrated into an emerging practice in 3 participating sites to enable the evaluation of implementation strategies on TM clinical outcomes. Quantitative data for ePROMs and ePREMs will be collected using validated oncology questionnaire. Descriptive statistics and repeated measures using multiple linear mixed models and generalized estimating equations analyses will be undertaken alongside interpretive descriptive coding of qualitative data. Qualitative data will be gathered from key informants guided by the RE-AIM (reach, efficacy, adoption, implementation, maintenance) framework and its extension, PRISM (practical robust implementation and sustainability model). The concurrent approach allows results at multiple stages of this study to be integrated iteratively. The methodological choice aims to provide real-world data that are rigorous, rapidly usable in practice, and transferable to other settings., Results: Questionnaires were pretested and the technological platform was codeveloped with members of the cancer care team and patients. Preparatory work was carried out to configure the TM platform and activate coordinating mechanisms between members of the cancer care team, patients, information technology experts, and the research team. A steering committee with 3 working groups was established to oversee the technological, clinical, and evaluation aspects of this study. Recruitment of patients for ePROMs started in February 2024, and data collection is expected to continue until March 2025. Interviews with members of the cancer care team began in November 2024. Full analysis should be completed by September 2025., Conclusions: This study will clarify how, why, for whom, and under what conditions TM can complement current care models. Our evaluability assessment will help to address implementation complexities and better understand intervention-to-practice operationalization so that implementation might be adapted to contextual factors without potentially harmful or inequitable impacts on patients., International Registered Report Identifier (irrid): DERR1-10.2196/63099., (©Dominique Tremblay, Thomas Joly-Mischlich, Annick Dufour, Marie-Claude Battista, Djamal Berbiche, José Côté, Marco Décelles, Catherine Forget, Brigitte Guérin, Manon Larivière, Frédéric Lemay, Manon Lemonde, Éric Maillet, Nathalie Moreau, Michel Pavic, Sara Soldera, Catherine Wilhelmy. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 20.01.2025.)

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease characterized by motor neuron loss in the motor cortex, brain stem, and spinal cord. Mutations in the superoxide dismutase 1 (SOD1) gene, resulting in misfolding of its protein product, are a common cause of ALS. Currently, there is no approved ALS diagnostic tool. Here, we present the development of a PET radiotracer, [ 89 Zr]Zr-desferoxamine (DFO)-α-miSOD1, targeting selectively misfolded SOD1 (misSOD1). Methods: DFO-α-miSOD1 was prepared by conjugating α-miSOD1 antibody with DFO and labeled with 89 Zr. A longitudinal imaging study was performed to identify the optimal mouse age and time after administration of [ 89 Zr]Zr-DFO-α-miSOD1 for the detection of misSOD1 aggregation in transgenic mice overexpressing misSOD1 and in wild-type mice. Subsets of mice were either coinjected with an excess of α-miSOD1 or imaged with deglycosylated [ 89 Zr]Zr-DFO-α-miSOD1 to assess target specificity. The internal radiation dose for [ 89 Zr]Zr-DFO-α-miSOD1 was estimated by extrapolating data from mouse biodistribution experiments. Results: Imaging with [ 89 Zr]Zr-DFO-α-miSOD1 was optimal in 136-d-old transgenic mice on day 10 after administration. Significant accumulation of [ 89 Zr]Zr-DFO-α-miSOD1 was detected in the spinal cord and cartilage of ALS transgenic mice compared with the wild-type mice ( P = 0.01). The radiotracer accumulation is selective and blockable with an excess of α-miSOD1. Deglycosylated [ 89 Zr]Zr-DFO-α-miSOD1 results in high-contrast detection of misSOD1 but is prone to aggregation. The dosimetry for [ 89 Zr]Zr-DFO-α-miSOD1 is comparable to that for other 89 Zr-based tracers currently used in humans. Conclusion: This work thus establishes that [ 89 Zr]Zr-DFO-α-miSOD1 PET can detect misSOD1 in transgenic mice, paving the way for application in early diagnosis of ALS and therapeutic monitoring., (© 2025 by the Society of Nuclear Medicine and Molecular Imaging.)

Intrapatient intermetastatic heterogeneity (IIH) has been demonstrated in metastatic castration-resistant prostate cancer (mCRPC) patients and is of the utmost importance for radiopharmaceutical therapy (RPT) eligibility. This study was designed to determine the prevalence of IIH and RPT eligibility in mCRPC patients through a triple-tracer PET imaging strategy. Methods: This was a multisite prospective observational study in which mCRPC patients underwent both 18 F-FDG and 68 Ga-prostate-specific membrane antigen (PSMA)-617 PET/CT scans. A third scan with 68 Ga-DOTATATE, a potential biomarker of neuroendocrine differentiation, was performed if an 18 F-FDG-positive/ 68 Ga-PSMA-negative lesion was found. Per-tracer lesion positivity was defined as having an uptake at least 50% above that of the liver. IIH prevalence was defined as the percentage of participants having at least 2 lesions with discordant features on multitracer PET. Results: IIH was observed in 81 patients (82.7%), and at least 1 18 F-FDG-positive/ 68 Ga-PSMA-negative lesion was found in 45 patients (45.9%). Of the 37 participants who also underwent 68 Ga-DOTATATE PET/CT, 6 (16.2%) had at least 1 68 Ga-DOTATATE-positive lesion. In total, 12 different combinations of lesion imaging phenotypes were observed. On the basis of our prespecified criteria, 52 (53.1%) participants were determined to be eligible for PSMA RPT, but none for DOTATATE RPT. Patients with IIH had a significantly shorter median overall survival than patients without IIH (9.5 mo vs. not reached; log-rank P = 0.03; hazard ratio, 2.7; 95% CI, 1.1-6.8). Conclusion: Most mCRPC patients showed IIH, which was associated with shorter overall survival. On the basis of a triple-tracer PET approach, multiple phenotypic combinations were found. Correlation of these imaging phenotypes with genomics and treatment response will be relevant for precision medicine., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Aim: Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off-target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a β 3 -adrenergic receptor (β 3 -AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a β 1 -AR antagonist could suppress these unwanted effects and increase the stimulation of the β 3 -AR and β 2 -AR in BAT., Methods: We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the β 1 -AR antagonist bisoprolol (10 mg). Dynamic [ 11 C]-acetate and 2-deoxy-2-[ 18 F]fluoro-d-glucose PET/CT scans were performed sequentially after oral administration of mirabegron ± bisoprolol., Results: Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 ± 0.46 vs. 1.79 ± 0.91 min -1 , p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [ 18 F]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 ± 10 vs. 16 ± 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron-induced increase in systolic blood pressure and heart rate., Conclusion: The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis., (© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Background: The present study explored the acceptability of psilocybin-assisted group therapy from the perspective of patients with cancer and depression who participated in a clinical trial assessing the safety and efficacy of this novel intervention., Methods: Guided by the conceptual framework of acceptability, the authors conducted semi-structured interviews with participants of the psilocybin trial. Data were analyzed using template and thematic analyses., Results: Participants' (n = 28) perspectives on the acceptability of the group and simultaneous sessions was generally positive, both in terms of safety and efficacy: first, the groups contributed to increase participants' sense of safety and preparedness as they were engaging in the therapy; and second, the groups fostered a sense of connection and of belonging, which served to enrich and deepen the meaning of participants' experience, ultimately opening a dimension of self-transcendence and compassion. Other subthemes related to factors influencing the acceptability of the group approach included: 1) the importance of the therapeutic framework, 2) the complementary value of individual sessions, 3) disruptive factors related to the group and/or simultaneous setting, and 4) opportunities and challenges related to group size and how to structure interactions., Conclusions: This study enhances understanding of what promotes acceptability of the psilocybin-assisted therapy group model for the treatment of MDD in cancer patients., Plain Language Summary: We conducted exit interviews with participants of a phase 2 trial of psilocybin-assisted therapy (PAT) conducted in a community cancer center, to assess the acceptability of a novel psilocybin delivery model combining simultaneous individual therapy and group sessions. Our findings support the acceptability of this intervention and suggest that in addition to being feasible, it might also enhance participants' perceived safety and efficacy compared to uniquely individual or group delivery models of PAT. Our analysis highlights critical factors conditioning acceptability and suggests new ways PAT may be scaled and integrated into cancer care., (© 2023 American Cancer Society.)

Photolysis of DNA attached to gold nanoparticles (AuNPs) with ultraviolet (UV) photons induces DNA damage. The release of nucleobases (Cyt, Gua, Ade, and Thy) from DNA was the major reaction (99%) with an approximately equal release of pyrimidines and purines. This reaction contributes to the formation of abasic sites in DNA. In addition, liquid chromatography-mass spectrometry/MS (LC-MS/MS) analysis revealed the formation of reduction products of pyrimidines (5,6-dihydrothymidine and 5,6-dihydro-2'-deoxyuridine) and eight 2',3'- and 2',5'-dideoxynucleosides. In contrast, there was no evidence of the formation of 5-hydroxymethyluracil and 8-oxo-7,8-dihydroguanine, which are common oxidation products of thymine and guanine, respectively. Using appropriate filters, the main photochemical reactions were found to involve photoelectrons ejected from AuNPs by UV photons. The contribution of "hot" conduction band electrons with energies below the photoemission threshold was minor. The mechanism for the release of free nucleobases by photoelectrons is proposed to take place by the initial formation of transient molecular anions of the nucleobases, followed by dissociative electron attachment at the C1'-N glycosidic bond connecting the nucleobase to the sugar-phosphate backbone. This mechanism is consistent with the reactivity of secondary electrons ejected by X-ray irradiation of AuNPs attached to DNA, as well as the reactions of various nucleic acid derivatives irradiated with monoenergetic very-low-energy electrons (∼2 eV). These studies should help us to understand the chemistry of nanoparticles that are exposed to UV light and that are used as scaffolds and catalysts in molecular biology, curative agents in photodynamic therapy, and components of sunscreens and cosmetics.

Purpose: Modern high-amplitude gradient systems can be limited by the International Electrotechnical Commission 60601-2-33 cardiac stimulation (CS) limit, which was set in a conservative manner based on electrode experiments and E-field simulations in uniform ellipsoidal body models. Here, we show that coupled electromagnetic-electrophysiological modeling in detailed body and heart models can predict CS thresholds, suggesting that such modeling might lead to more detailed threshold estimates in humans. Specifically, we compare measured and predicted CS thresholds in eight pigs., Methods: We created individualized porcine body models using MRI (Dixon for the whole body, CINE for the heart) that replicate the anatomy and posture of the animals used in our previous experimental CS study. We model the electric fields induced along cardiac Purkinje and ventricular muscle fibers and predict the electrophysiological response of these fibers, yielding CS threshold predictions in absolute units for each animal. Additionally, we assess the total modeling uncertainty through a variability analysis of the 25 main model parameters., Results: Predicted and experimental CS thresholds agree within 19% on average (normalized RMS error), which is smaller than the 27% modeling uncertainty. No significant difference was found between the modeling predictions and experiments (p < 0.05, paired t-test)., Conclusion: Predicted thresholds matched the experimental data within the modeling uncertainty, supporting the model validity. We believe that our modeling approach can be applied to study CS thresholds in humans for various gradient coils, body shapes/postures, and waveforms, which is difficult to do experimentally., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Peripheral nerve stimulation (PNS) limits the image encoding performance of both body gradient coils and the latest generation of head gradients. We analyze a variety of head gradient design aspects using a detailed PNS model to guide the design process of a new high-performance asymmetric head gradient to raise PNS thresholds and maximize the usable image-encoding performance., Methods: A novel three-layer coil design underwent PNS optimization involving PNS predictions of a series of candidate designs. The PNS-informed design process sought to maximize the usable parameter space of a coil with <10% nonlinearity in a 22 cm region of linearity, a relatively large inner diameter (44 cm), maximum gradient amplitude of 200 mT/m, and a high slew rate of 900 T/m/s. PNS modeling allowed identification and iterative adjustment of coil features with beneficial impact on PNS such as the number of winding layers, shoulder accommodation strategy, and level of asymmetry. PNS predictions for the final design were compared to measured thresholds in a constructed prototype., Results: The final head gradient achieved up to 2-fold higher PNS thresholds than the initial design without PNS optimization and compared to existing head gradients with similar design characteristics. The inclusion of a third intermediate winding layer provided the additional degrees of freedom necessary to improve PNS thresholds without significant sacrifices to the other design metrics., Conclusion: Augmenting the design phase of a new high-performance head gradient coil by PNS modeling dramatically improved the usable image-encoding performance by raising PNS thresholds., (© 2023 International Society for Magnetic Resonance in Medicine.)

Transient soluble oligomers of amyloid-β (Aβ) are considered among the most toxic species in Alzheimer's disease (AD). Soluble Aβ oligomers accumulate early prior to insoluble plaque formation and cognitive impairment. The cyclic d,l-α-peptide CP-2 ( 1 ) self-assembles into nanotubes and demonstrates promising anti-amyloidogenic activity likely by a mechanism involving engagement of soluble oligomers. Systematic replacement of the residues in peptide 1 with aza-amino acid counterparts was performed to explore the effects of hydrogen bonding on propensity to mitigate Aβ aggregation and toxicity. Certain azapeptides exhibited improved ability to engage, alter the secondary structure, and inhibit aggregation of Aβ. Moreover, certain azapeptides disassembled preformed Aβ fibrils and protected cells from Aβ-mediated toxicity. Substitution of the l-norleucine 3 and d-serine 6 residues in peptide 1 with aza-norleucine and aza-homoserine provided, respectively, nontoxic [azaNle 3 ]- 1 ( 4 ) and [azaHse 6 ]- 1 ( 7 ), that significantly abated symptoms in a transgenic Caenorhabditis elegans AD model by decreasing Aβ oligomer levels.

Chemoradiation therapy (CRT), which combines a chemotherapeutic drug with ionizing radiation (IR), is the most common cancer treatment. At the molecular level, the binding of Pt-drugs to DNA sensitizes cancer cells to IR, mostly by increasing the damage induced by secondary low-energy (0-20 eV) electrons (LEEs). We investigate such enhancements by binding terpyridine-platinum (Tpy-Pt) to supercoiled plasmid DNA. Fifteen nanometer thick films of Tpy-Pt-DNA complexes in a molar ratio of 5 : 1 were irradiated with monoenergetic electrons of 5 and 10 eV, which principally attach to the DNA bases to form transient anions (TAs) decaying into a multitude of bond-breaking channels. At both energies, the effective yields of crosslinks (CLs), base damage (BD) related CLs, single and double strand breaks (SSBs and DSBs), non-DSB-cluster lesions, loss of supercoiled configuration and base lesions are 6.5 ± 1.5, 8.8± 3.0, 88 ± 11, 5.3 ± 1.3, 9.6 ± 2.2, 106 ± 17, 189 ± 31 × 10 -15 per electron per molecule, and 11.9 ± 2.6, 19.9 ± 4.4, 128 ± 18, 7.7 ± 3.0, 13.4 ± 3.9, 144 ± 19, 229 ± 42 × 10 -15 per electron per molecule, respectively. DNA damage increased 1.2-4.2-fold due to Tpy-Pt, the highest being for BD-related CLs. These enhancements are slightly higher than those obtained by the conventional Pt-drugs cisplatin, carboplatin and oxaliplatin, apart from BD-related CLs, which are about 3 times higher. Enhancements are related to the strong perturbation of the DNA helix by Tpy-Pt, its high dipole moment and its favorable binding to guanine (G), all of which increase bond-breaking via TA formation. In CRT, Tpy-Pt could considerably enhance crosslinking within genomic DNA and between DNA and other components of the nucleus, causing roadblocks to replication and transcription, particularly within telomeres, where it binds preferentially within G-quadruplexes.

Cyclotron production of 68 Ga is a promising approach to supply 68 Ga radiopharmaceuticals. To validate this capability, an integrated solution for a robust synthesis of 68 Ga-DOTATATE prepared from cyclotron-produced 68 Ga was achieved. A retrospective comparison analysis was performed on patients who underwent PET/CT imaging after injection of DOTATATE labeled with 68 Ga produced by a cyclotron or eluted from a generator to demonstrate the clinical safety and diagnostic efficacy of the radiopharmaceutical as a routine standard-of-care diagnostic tool in the clinic. Methods: An enriched pressed 68 Zn target was irradiated by a cyclotron with a proton beam set at 12.7 MeV for 100 min. The fully automated process uses an in-vault dissolution system in which a liquid distribution system transfers the dissolved target to a dedicated hot cell for the purification of 68 GaCl 3 and radiolabeling of DOTATATE using a cassette-based automated module. Quality control tests were performed on the resulting tracer solution. The internal radiation dose for 68 Ga-DOTATATE was based on extrapolation from rat biodistribution experiments. A retrospective comparison analysis was performed on patients who underwent PET/CT imaging after injection of DOTATATE labeled with cyclotron- or generator-produced 68 Ga. Results: The synthesis of 68 Ga-DOTATATE (20.7 ± 1.3 GBq) with high apparent molar activity (518 ± 32 GBq/μmol at the end of synthesis) was completed in 65 min, and the radiopharmaceutical met the requirements specified in the European Pharmacopoeia monograph on 68 Ga-chloride (accelerator-produced) solution for radiolabeling. 68 Ga-DOTATATE was stable for at least 5 h after formulation. The dosimetry calculated with OLINDA for cyclotron- and generator-produced 68 Ga-DOTATATE was roughly equivalent. The SUV mean or SUV max of tumoral lesions with cyclotron-produced 68 Ga-DOTATATE was equivalent to that with generator-produced 68 Ga. Among physiologic uptake levels, a significant difference was found in kidneys, spleen, and stomach wall, with lower values in cyclotron-produced 68 Ga-DOTATATE in all cases. Conclusion: Integrated cyclotron production achieves reliable high yields of clinical-grade 68 Ga-DOTATATE. The clinical safety and imaging efficacy of cyclotron-produced 68 Ga-DOTATATE in humans provide supporting evidence for its use in routine clinical practice., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: We have previously shown that copper-64 ( 64 Cu)-DOTHA 2 -PSMA can be used for positron emission tomography (PET) imaging of prostate cancer. Owing to the long-lasting, high tumoral uptake of 64 Cu-DOTHA 2 -PSMA, the objective of the current study was to evaluate the therapeutic potential of 64 Cu-DOTHA 2 -PSMA in vivo ., Methods: LNCaP tumor-bearing NOD- Rag1 null IL2rg null (NRG) mice were treated with an intraveinous single-dose of 64 Cu-DOTHA 2 -PSMA at maximal tolerated injected activity, nat Cu-DOTHA 2 -PSMA at equimolar amount (control) or lutetium-177 ( 177 Lu)-PSMA-617 at 120 MBq to assess their impact on survival. Weight, well-being and tumor size were followed until mice reached 62 days post-injection or ethical limits. Toxicity was assessed through weight, red blood cells (RBCs) counts, pathology and dosimetry calculations., Results: Survival was longer with 64 Cu-DOTHA 2 -PSMA than with nat Cu-DOTHA 2 -PSMA ( p < 0.001). Likewise, survival was also longer when compared to 177 Lu-PSMA-617, although it did not reach statistical significance ( p = 0.09). RBCs counts remained within normal range for the 64 Cu-DOTHA 2 -PSMA group. 64 Cu-DOTHA 2 -PSMA treated mice showed non-pathological fibrosis and no other signs of radiation injury. Human extrapolation of dosimetry yielded an effective dose of 3.14 × 10 -2 mSv/MBq, with highest organs doses to gastrointestinal tract and liver., Discussion: Collectively, our data showed that 64 Cu-DOTHA 2 -PSMA-directed radioligand therapy was effective for the treatment of LNCaP tumor-bearing NRG mice with acceptable toxicity and dosimetry. The main potential challenge is the hepatic and gastrointestinal irradiation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Milot, Bélissant-Benesty, Dumulon-Perreault, Ait-Mohand, Geha, Richard, Rousseau and Guérin.)

Transient soluble oligomers of amyloid-β (Aβ) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer's disease (AD). Synthetic cyclic D,L-α-peptides (e.g., 1 ) self-assemble into cross β-sheet nanotubes, react with early Aβ species (1-3 mers), and inhibit Aβ aggregation and toxicity in stoichiometric concentrations, in vitro. Employing a semicarbazide as an aza-glycine residue with an extra hydrogen-bond donor to tune nanotube assembly and amyloid engagement, [azaGly 6 ]- 1 inhibited Aβ aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly 6 ]- 1 and Aβ42 residues F19 and F20, which are pivotal for early dimerization and aggregation. In an AD mouse model, brain positron emission tomography (PET) imaging using stable 64 Cu-labeled (aza)peptide tracers gave unprecedented early amyloid detection in 44-d presymptomatic animals. No tracer accumulation was detected in the cortex and hippocampus of 44-d-old 5xFAD mice; instead, intense PET signal was observed in the thalamus, from where Aβ oligomers may spread to other brain parts with disease progression. Compared with standard 11 C-labeled Pittsburgh compound-B ( 11 C-PIB), which binds specifically fibrillar Aβ plaques, 64 Cu-labeled (aza)peptide gave superior contrast and uptake in young mouse brain correlating with Aβ oligomer levels. Effectively crossing the blood-brain barrier (BBB), peptide 1 and [azaGly 6 ]- 1 reduced Aβ oligomer levels, prolonged lifespan of AD transgenic Caenorhabditis elegans , and abated memory and behavioral deficits in nematode and murine AD models. Cyclic (aza)peptides offer novel promise for early AD diagnosis and therapy.

Purpose: Powerful MRI gradient systems can surpass the International Electrotechnical Commission (IEC) 60601-2-33 limit for cardiac stimulation (CS), which was determined by simple electromagnetic simulations and electrode stimulation experiments. Only a few canine studies measured magnetically induced CS thresholds in vivo and extrapolating them to human safety limits can be challenging., Methods: We measured cardiac magnetostimulation thresholds in 10 healthy, anesthetized pigs using capacitors discharged into a flat spiral coil to produce damped sinusoidal waveforms with effective stimulus duration t s,eff  = 0.45 ms. Electrocardiography (ECG), blood pressure, and peripheral oximetry signals were recorded to determine threshold coil currents yielding cardiac capture. Dixon and CINE MR volumes from each animal were segmented to generate porcine-specific electromagnetic models to calculate dB/dt and E-field values in the porcine heart at threshold. For comparison, we also simulated maximum dB/dt and E-field values created by three MRI gradient systems in the heart of a human body model., Results: The average dB/dt threshold estimated in the porcine heart was 1.66 ± 0.23 kT/s, which is 11-fold greater than the IEC dB/dt limit at t s,eff  = 0.45 ms, and 31-fold greater than the maximum value created by the investigated MRI gradients in the human heart. The average E-field threshold estimated in the porcine heart was 92.9 ± 13.5 V/m, which is 6-fold greater than the IEC E-field limit at t s,eff  = 0.45 ms and 37-fold greater than the maximum gradient-induced E-field in the human heart., Conclusion: This first measurement of cardiac magnetostimulation thresholds in pigs indicates that the IEC cardiac safety limit is conservative for the investigated stimulus duration (t s,eff  = 0.45 ms)., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

To overcome resistance to chemotherapy for colorectal cancer, we propose to validate in vivo a novel terpyridine-platinum (TP) compound radiolabeled with the radio-theranostic isotope 64 Cu. In vivo stability, biodistribution, PET imaging, tumor growth delay, toxicity and dosimetry of [ 64 Cu]NOTA-C3-TP were determined. The current experimental studies show that [ 64 Cu]NOTA-C3-TP is stable in vivo , rapidly eliminated by the kidneys and has a promising tumor uptake ranging from 1.8 ± 0.4 to 3.0 ± 0.2 %ID/g over 48 h. [ 64 Cu]NOTA-C3-TP retarded tumor growth by up to 6 ± 2.0 days and improved survival relative to vehicle and non-radioactive [ Nat Cu]NOTA-C3-TP over 17 days of tumor growth observation. This effect was obtained with only 0.4 nmol i.v . injection of [ 64 Cu]NOTA-C3-TP, which delivers 3.4 ± 0.3 Gy tumoral absorbed dose. No evidence of toxicity, by weight loss or mortality was revealed. These findings confirm the high potential of [ 64 Cu]NOTA-TP as a novel radio-theranostic agent., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Khosravifarsani, Ait-Mohand, Paquette, Sanche and Guérin.)

Diets rich in added sugars are associated with metabolic diseases, and studies have shown a link between these pathologies and changes in the microbiome. Given the reported associations in animal models between the microbiome and brown adipose tissue (BAT) function, and the alterations in the microbiome induced by high-glucose or high-fructose diets, we investigated the potential causal link between high-glucose or -fructose diets and BAT dysfunction in humans. Primary outcomes are changes in BAT cold-induced thermogenesis and the fecal microbiome (clinicaltrials.gov, NCT03188835). We show that BAT glucose uptake, but not thermogenesis, is impaired by a high-fructose but not high-glucose diet, in the absence of changes in the gastrointestinal microbiome. We conclude that decreased BAT glucose metabolism occurs earlier than other pathophysiological abnormalities during fructose overconsumption in humans. This is a potential confounding factor for studies relying on 18 F-FDG to assess BAT thermogenesis., Competing Interests: Declaration of interests A.C.C. received research funding by Eli Lilly (2019–2021) and NovoNordisk (2021–ongoing) and consultation fees by HLS Therapeutics, Janssen Inc., Novartis Pharmaceuticals Canada Inc., and Novo Nordisk Canada Inc. K.M.M. is an advisory board member for NovoNordisk., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To determine the prevalence of intra-patient inter-metastatic heterogeneity based on positron emission tomography (PET)/computed tomography (CT) in patients with metastatic castration-resistant prostate cancer (mCRPC) and to determine the prevalence of neuroendocrine disease in these patients and their eligibility for radioligand therapies (RLTs)., Patients and Methods: This multicentre observational prospective clinical study will include 100 patients with mCRPC from five Canadian academic centres. Patients with radiological or biochemical progression and harbouring at least three metastases by conventional imaging will be accrued. Intra-patient inter-metastatic heterogeneity will be determined with triple-tracer imaging using fluorine-18 fluorodeoxyglucose ( 18 F-FDG), gallium-68-( 68 Ga)-prostate-specific membrane antigen (PSMA)-617 and 68 Ga-DOTATATE, which are a glucose analogue, a PSMA receptor ligand and a somatostatin receptor ligand, respectively. The 68 Ga-PSMA-617 and 18 F-FDG PET/CT scans will be performed first. If at least one PSMA-negative/FDG-positive lesion is observed, an additional PET/CT scan with 68 Ga-DOTATATE will be performed. The tracer uptake of individual lesions will be assessed for each PET tracer and patients with lesions presenting discordant uptake profiles will be considered as having inter-metastatic heterogeneous disease and may be offered a biopsy., Expected Results: The proposed triple-tracer approach will allow whole-body mCRPC characterisation, investigating the inter-metastatic heterogeneity in order to better understand the phenotypic plasticity of prostate cancer, including the neuroendocrine transdifferentiation that occurs during mCRPC progression. Based on 68 Ga-PSMA-617 or 68 Ga-DOTATATE PET positivity, the potential eligibility of patients for PSMA and DOTATATE-based RLT will be assessed. Non-invasive whole-body determination of mCRPC heterogeneity and transdifferentiation is highly innovative and might establish the basis for new therapeutic strategies. Comparison of molecular imaging findings with biopsies will also link metastasis biology to radiomic features., Conclusion: This study will add novel, biologically relevant dimensions to molecular imaging: the non-invasive detection of inter-metastatic heterogeneity and transdifferentiation to neuroendocrine prostate cancer by using a multi-tracer PET/CT strategy to further personalise the care of patients with mCRPC., (© 2021 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Excessive lean tissue uptake of fatty acids (FAs) is important in the development of insulin resistance and may be caused by impaired dietary FA (DFA) storage and/or increased nonesterified FA (NEFA) flux from adipose tissue intracellular lipolysis. Cardiac and hepatic total postprandial FA uptake of NEFA+DFA has, however, never been reported in prediabetes with overweight. In this study, 20 individuals with impaired glucose tolerance (IGT) and 19 participants with normal glucose tolerance (NGT) and normal fasting glucose underwent postprandial studies with whole-body positron emission tomography/computed tomography (PET/CT) with oral [18F]fluoro-thia-heptadecanoic acid and dynamic PET/CT with intravenous [11C]palmitate. Hepatic (97 [range 36-215] mmol/6 h vs. 68 [23-132] mmol/6 h, P = 0.03) but not cardiac (11 [range 4-24] mmol/6 h vs. 8 [3-20] mmol/6 h, P = 0.09) uptake of most sources of postprandial FA (NEFA + DFA uptake) integrated over 6 h was higher in IGT versus NGT. DFA accounted for lower fractions of total cardiac (21% [5-47] vs. 25% [9-39], P = 0.08) and hepatic (19% [6-52] vs. 28% [14-50], P = 0.04) uptake in IGT versus NGT. Increased adipose tissue DFA trapping predicted lower hepatic DFA uptake and was associated with higher total cardiac FA uptake. Hence, enhanced adipose tissue DFA trapping in the face of increased postprandial NEFA flux is insufficient to fully curb increased postprandial lean organ FA uptake in prediabetes with overweight (ClinicalTrials.gov; NCT02808182)., (© 2022 by the American Diabetes Association.)

Prostate cancer imaging and late-stage management can be improved with prostate-specific membrane antigen (PSMA)-targeting radiotracers. We developed a PSMA positron emission tomography (PET) radiotracer, DOTHA2-PSMA radiolabeled with 64Cu (T1/2: 12.7 h), to leverage its large imaging time window. This preclinical study aimed to evaluate the biological and imaging properties of 64Cu-DOTHA2-PSMA. Its stability was assessed in plasma ex vivo and in mice. Cellular behavior was studied for up to 48 h in LNCaP cells. Biodistribution studies were performed in balb/c mice for up to 48 h. Dynamic (1 h) and static (4 h and 24 h) PET imaging was completed in LNCaP tumor-bearing mice. 64Cu-DOTHA2-PSMA was stable ex vivo in plasma and reached cellular internalization up to 34.1 ± 4.9% injected activity (IA)/106 cells at 48 h post-injection (p.i.). Biodistribution results showed significantly lower uptake in kidneys than 68Ga-PSMA-617, our reference PET tracer (p < 0.001), but higher liver uptake at 2 h p.i. (p < 0.001). PET images showed 64Cu-DOTHA2-PSMA’s highest tumoral uptake at 4 h p.i., with a significant difference between blocked and non-blocked groups from the time of injection to 24 h p.i. The high stability and tumor uptake with a long tumor imaging time window of 64Cu-DOTHA2-PSMA potentially contribute to the prostate cancer theranostic approach and its local recurrence detection.

This article reports the preliminary results of a phase II clinical trial investigating the use of the estrogen receptor (ER)-targeting PET tracer 4-fluoro-11β-methoxy-16α- 18 F-fluoroestradiol ( 18 F-4FMFES) and 18 F-FDG PET in endometrial cancers. In parallel, noninvasive interventions were attempted to slow progression of 18 F-4FMFES metabolites in the intestines to reduce abdominal background uptake. Methods: In an ongoing study, 25 patients who received prior pathologic confirmation of an ER-positive endometrial cancer or endometrial intraepithelial neoplasia agreed to participate in the ongoing clinical trial. Patients were scheduled for 18 F-FDG and 18 F-4FMFES PET/CT imaging in random order and within 2 wk. Patients were administered either 4 mg of loperamide orally before 18 F-4FMFES tracer injection or repeated intravenous injection of 20 mg of hyoscine N -butylbromide during 18 F-4FMFES PET/CT. Regions of interest covering the whole abdomen and excluding the liver, bladder, and uterus were drawn for the 18 F-4FMFES PET images, and an SUV threshold of more than 4 was applied. The volume of the resulting region was compared between the different interventions to estimate the extent of the intestinal background uptake. Results: Repeated injection of hyoscine N -butylbromide substantially reduced the intestinal background volume, whereas loperamide had a significant but moderate effect. 18 F-4FMFES tumor SUV max ranged from 3.0 to 14.4 (9.4 ± 3.2), whereas 18 F-FDG SUV max ranged from 0 to 22.0 (7.5 ± 5.1). Tumor-to-background ratio was significantly higher for 18 F-4FMFES (16.4 ± 5.4) than for 18 F-FDG (7.4 ± 4.6). Significant differences were observed between grade 1 and higher-grade tumors concerning 18 F-4FMFES uptake and contrast, 18 F-FDG uptake, and the 18 F-FDG/ 18 F-4FMFES uptake ratio. Conclusion: It is possible to improve 18 F-4FMFES abdominal background using hyoscine N -butylbromide. Both 18 F-FDG and 18 F-4FMFES PET are suitable for detection of ER-positive endometrial cancers, although 18 F-4FMFES yielded a better tumor contrast than did 18 F-FDG., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Assessment of the radiation dose delivered to a tumor and different organs is a major issue when using radiolabelled compounds for diagnostic imaging or endoradiotherapy. The present article reports on a study to correlate the mean 18 F-fluorodeoxyglucose ( 18 F-FDG) activity in different tissues measured in a mouse model by positron emission tomography (PET) imaging, with the dose assessed in vitro by Fricke dosimetry., Methods: The dose-response relationship of the Fricke dosimeter and PET data was determined at different times after adding 18 F-FDG (0-80 MBq) to a Fricke solution (1 mM ferrous ammonium sulfate in 0.4 M sulfuric acid). The total dose was assessed at 24 h (~13 half-lives of 18 F-FDG). The number of coincident events produced in 3 mL of Fricke solution or 3 mL of deionized water that contained 60 MBq of 18 F-FDG was measured using the Triumph/LabPET8 TM preclinical PET/CT scanner. The total activity concentration measured by PET was correlated with the calculated dose from the Fricke dosimeter, at any exposure activity of 18 F-FDG., Results: The radiation dose measured with the Fricke dosimeter increased rapidly during the first 4 h after adding 18 F-FDG and then gradually reached a plateau. Presence of non-radioactive-FDG did not alter the Fricke dosimetry. The characteristic responses of the dosimeter and PET imaging clearly exhibit linearity with injected activity of 18 F-FDG. The dose (Gy) to time-integrated activity (MBq.h) relationship was measured, yielding a conversion factor of 0.064 ± 0.06 Gy/MBq.h in the present mouse model. This correlation provides an efficient alternative method to measure, three-dimensionally, the total and regional dose absorbed from 18 F-radiotracers., Conclusions: The Fricke dosimeter can be used to calibrate a PET scanner, thus enabling the determination of dose from the measured radioactivity emitted by 18 F-FDG in tissues. The method should be applicable to radiotracers with other positron-emitting radionuclides., Competing Interests: RL is a founder and Chief Scientific Officer of IR&T Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tippayamontri, Betancourt-Santander, Guérin, Lecomte, Paquette and Sanche.)