Abstract Purpose Multidrug resistance-associated proteins (MRPs) have a widespread tissue distribution. They play an important role in drug disposition and drug-drug interactions (DDIs) and have been associated with various diseases. PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) has been used to assess MRP1 function in the brain and lungs of mice. [11C]BMP crosses cellular membranes by passive diffusion followed by intracellular conjugation with glutathione and MRP1-mediated efflux of the radiolabelled glutathione-conjugate. In this study, we assessed the effect of the prototypical organic anion transporter inhibitor probenecid on the whole-body disposition of [11C]BMP to examine its suitability for measuring the function of MRP1 and possibly other MRP subtypes across multiple tissues. Methods Seven healthy volunteers (3 women, 4 men) underwent two dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [11C]BMP, without and with pre-treatment with a single oral dose of probenecid. Volumes of interest were outlined for several MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, skeletal muscle, kidneys, and liver). Tissue time-activity curves were corrected for the contribution of vascular radioactivity and the elimination rate constant (k E, h− 1) was calculated as a parameter for tissue MRP function. Results Radioactivity was primarily excreted into the urinary bladder and urinary clearance was significantly decreased after probenecid administration (− 50 ± 16%). Following probenecid administration, k E was significantly decreased in the kidneys (− 43 ± 20%), liver (− 18 ± 15%), myocardium (− 16 ± 12%), skeletal muscle (− 51 ± 34%), and retina (− 57 ± 29%, non-blood-corrected). Conclusion Our study highlights the great potential of LAFOV PET/CT to assess drug disposition and transporter-mediated DDIs in humans at a whole-body, multi-tissue level. Due to the slow elimination of [11C]BMP-derived radioactivity from the human brain, [11C]BMP appears unsuitable to measure cerebral MRP1 function in humans, but it may be used to assess the function of MRP1 and possibly other MRP subtypes in various peripheral tissues. Trial registration EudraCT 2021-006348-29. Registered 15 December 2021.

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Two extensions of the variational method with explicit energy functionals (EEFs) with respect to the spin-orbit force were performed. In this method, the energy per nucleon of nuclear matter is explicitly expressed as a functional of various two-body distribution functions, starting from realistic nuclear forces. The energy was then minimized by solving the Euler–Lagrange equation for the distribution functions derived from the EEF. In the first extension, an EEF of symmetric nuclear matter at zero temperature was constructed using the two-body central, tensor, and spin-orbit nuclear forces. The energy per nucleon calculated using the Argonne v8’ two-body nuclear potential was found to be lower than those calculated using other many-body methods, implying that the energy contribution caused by the spin-orbit correlation, whose relative orbital angular momentum operator acts on other correlations, is necessary. In a subsequent extension, the EEF of neutron matter at zero temperature, including the spin-orbit force, was extended to neutron matter at finite temperatures using the method by Schmidt and Pandharipande. The thermodynamic quantities of neutron matter calculated using the Argonne v8’ nuclear potential were found to be reasonable and self-consistent.

• Book : 8(1)
• Pub. Date : 2025
• Page : pp.11-11
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Using (2712±14)×106 ψ(2S) events collected with the BESIII detector at the BEPCII collider, we search for the decays ηc(2S)→ωω and ηc(2S)→ωϕ via the process ψ(2S)→γηc(2S). No statistically significant signals are observed. The upper limits of their product branching fractions at the 90% confidence level are determined to be B(ψ(2S)→γηc(2S),ηc(2S)→ωω)<1.04×10−6 and B(ψ(2S)→γηc(2S),ηc(2S)→ωϕ)<1.85×10−7, respectively. We also update the branching fractions of χcJ→ωω and χcJ→ωϕ via the ψ(2S)→γχcJ transition. Their branching fractions are determined to be B(χc0→ωω)=(10.66±0.11±0.57)×10−4, B(χc1→ωω)=(6.43±0.07±0.31)×10−4, B(χc2→ωω)=(8.75±0.08±0.42)×10−4, B(χc0→ωϕ)=(1.18±0.03±0.07)×10−4, B(χc1→ωϕ)=(2.04±0.15±0.11)×10−5, and B(χc2→ωϕ)=(9.58±1.07±0.76)×10−6, where the first uncertainties are statistical and the second are systematic. Published by the American Physical Society 2025

• Book : 111(3)
• Pub. Date : 2025
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Abstract Introduction The diagnosis of Growth Hormone Deficiency (GHD) during childhood has been the subject of much controversy over the last few years. Aiming to accurate medical treatment, there is a need for biomarker discovery. Objective To characterize the metabolic profile of GHD children, examine the effect of GH administration on the metabolic signature, and investigate the correlations between metabolites and IGF-1. Methods Nuclear Magnetic Resonance (NMR)-based untargeted and targeted metabolomic approach applied to study the metabolic profiles of children with GHD. Plasma, serum, and urine samples were collected from twenty-two children diagnosed with GHD and forty-eight age matched controls from the Pediatric Endocrinology Unit of the University Hospital of Patras. Experimental data were examined by both multivariate and univariate statistical analysis. Results The results of this pilot study revealed a different metabolic fingerprint of children with GHD in comparison to age-matched healthy individuals. However, the detected alterations in the metabolite patterns before and after GH treatment were subtle and of minor discriminative statistical power. Conclusions This study provides evidence that metabolome plays a pivotal role in GHD, but large-scale multicenter studies are warranted to validate the results.

• Book : 21(1)
• Pub. Date : 2025
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ABSTRACT We present a set of 11 two-temperature, radiative, general relativistic magnetohydrodynamic simulations of the black hole M87* in the magnetically arrested state, surveying different values of the black hole spin $a_*$. Our 3-D simulations self-consistently evolve the temperatures of separate electron and ion populations under the effects of adiabatic compression/expansion, viscous heating, Coulomb coupling, and synchrotron, bremsstrahlung, and inverse Compton radiation. We adopt a subgrid heating prescription from gyrokinetic simulations of plasma turbulence. Our simulations have accretion rates $\dot{M}=(0.5-1.5)\times 10^{-6}\dot{M}_{\rm Edd}$ and radiative efficiencies $\epsilon _{\rm rad}=$ 3–35 per cent. We compare our simulations to a fiducial set of otherwise identical single-fluid general relativistic magnetohydrodynamic (GRMHD) simulations and find no significant changes in the outflow efficiency or black hole spin-down parameter. Our simulations produce an effective adiabatic index for the two-temperature plasma of $\Gamma _{\rm gas}\approx 1.55$, larger than the $\Gamma _{\rm gas}=13/9$ value often adopted in single-fluid GRMHD simulations. We find moderate ion-to-electron temperature ratios in the 230 GHz emitting region of $R=T_{\rm i}/T_{\rm e}\,{\approx }\,5$. While total intensity 230 GHz images from our simulations are consistent with Event Horizon Telescope (EHT) results, our images have significantly more beam-scale linear polarization ($\langle |m|\rangle \approx 30~{{\rm per\ cent}}$) than is observed in EHT images of M87* ($\langle |m|\rangle \lt 10~{{\rm per\ cent}}$). We find a trend of the average linear polarization pitch angle $\angle \beta _2$ with black hole spin consistent with what is seen in single-fluid GRMHD simulations, and we provide a simple fitting function for $\angle \beta _2(a_*)$ motivated by the wind-up of magnetic field lines by black hole spin in the Blandford–Znajek mechanism.

• Book : 537(3)
• Pub. Date : 2025
• Page : pp.2496-2515
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AbstractBackgroundSpinocerebellar ataxia type 2 (SCA2) is a rare, inherited neurodegenerative disease characterized by progressive deterioration in both motor coordination and cognitive function. Atrophy of the cerebellum, brainstem, and spinal cord are core features of SCA2; however, the evolution and pattern of whole‐brain atrophy in SCA2 remain unclear.ObjectiveWe undertook a multisite, structural magnetic resonance imaging (MRI) study to comprehensively characterize the neurodegeneration profile of SCA2.MethodsVoxel‐based morphometry analyses of 110 participants with SCA2 and 128 controls were undertaken to assess groupwise differences in whole‐brain volume. Correlations with clinical severity and genotype, and cross‐sectional profiling of atrophy patterns at different disease stages, were also performed.ResultsAtrophy in SCA2 versus controls was greatest (Cohen's d >2.5) in the cerebellar white matter (WM), middle cerebellar peduncle, pons, and corticospinal tract. Very large effects (d >1.5) were also evident in the superior cerebellar, inferior cerebellar, and cerebral peduncles. In the cerebellar gray matter (GM), large effects (d >0.8) were observed in areas related to both motor coordination and cognitive tasks. Strong correlations (|r| > 0.4) between volume and disease severity largely mirrored these groupwise outcomes. Stratification by disease severity exhibited a degeneration pattern beginning in the cerebellar and pontine WM in preclinical subjects; spreading to the cerebellar GM and cerebro‐cerebellar/corticospinal WM tracts; and then finally involving the thalamus, striatum, and cortex in severe stages.ConclusionThe magnitude and pattern of brain atrophy evolve over the course of SCA2, with widespread, nonuniform involvement across the brainstem, cerebellar tracts, and cerebellar cortex; and late involvement of the cerebral cortex and striatum. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Abstract Fine-grained nuclear emulsion films have been developed as a tracking detector with nanometric spatial resolution to be used in direction-sensitive dark matter searches, thanks to novel readout technologies capable of exploiting this unprecedented resolution. Emulsion detectors are time insensitive. Therefore, a directional dark matter search with such detector requires the use of an equatorial telescope to absorb the Earth rotation effect. We have conducted for the first time a directional dark matter search in an unshielded location, at the sea level, by keeping an emulsion detector exposed for 39 days on an equatorial telescope mount. The observed angular distribution of the data collected during an exposure equivalent to 0.59 g days agrees with the background model and an exclusion plot was then derived in the dark matter mass and cross-section plane: cross-sections higher than 9.2 × 10-29 cm2 and 1.2 × 10-31 cm2 were excluded for a dark matter mass of 10 GeV/c 2 and 100 GeV/c 2, respectively. This is the first direction sensitive search for dark matter with a solid-state, particle tracking detector.

• Book : 2025(02)
• Pub. Date : 2025
• Page : pp.012-012
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Abstract Background JCOG1212 is a dose-finding and efficacy confirmatory study of concurrent superselective intra-arterial infusion of cisplatin and radiotherapy (RADPLAT) for locally advanced primary squamous cell carcinoma of the maxillary sinus (cT4a,bN0M0). In this study, we report the results of the final analysis of the efficacy confirmation phase for the T4a cohort with 5-year follow-up data to evaluate the late adverse events and long-term efficacy. Methods Based on the results of the dose-finding phase, the efficacy confirmation phase consisted of seven weekly intra-arterial infusions of cisplatin 100 mg/m2 combined with radiotherapy (70 Gy). The 5-year prognosis and late adverse events were evaluated. Results Between April 2014 and August 2018, 64 patients were included in the analysis (one ineligible patient was excluded); 31 patients were treated with three-dimensional conformal radiation therapy (3D-CRT) and 33 with intensity modulated radiation therapy (IMRT). The 5-year overall survival, event-free survival, and local event-free survival was 71.9, 54.7, and 57.5%, respectively. In terms of late adverse events, grade 3 or higher non-hematologic toxicity was observed in 42.9% of 63 patients (retinopathy: 12, cataract: 10, osteonecrosis of mandible: 4, etc.). Grade 3 and 4 cataracts of affected side appeared in 22.6% (7/31) of the 3D-CRT group compared to 3.1% (1/32) in the IMRT group. Twenty-one patients had died, with 15 from the primary disease, 5 from other causes, and 1 from treatment-related cause. Conclusion The prognosis of RADPLAT was favorable after 5-year follow-up with acceptable late adverse events and low proportion of treatment related death.

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