A detailed simulation study on radionuclide dispersion under spent fuel road transportation conditions: Effects of vessel type and coniferous vegetation growth.

Vegetation barriers are an important environmental characteristic of spent fuel road transportation accidents. Spent fuel vessels may be affected by force majeure factors during transportation, which leads to damage to spent fuel assemblies and containers and can cause radionuclides to gradually release from assemblies to vessels to the external environment. In this work, considering the growth periods of coniferous vegetation barriers and vessel type, a radionuclide dispersion model based on computational fluid dynamics (CFD) was established by adding a decay term and a pressure loss term. The simulations showed that, first, compared to the small (Type-II) vessel, the effects of fluid flow around the large vessel (Type-I) have a more significant impact on radionuclide dispersion. The backflow around the Type-I vessel causes leaked radionuclides to disperse towards the vessel, and the larger the vessel is, the more significant the rise of the leaked radionuclide plume tail will be due to the increased negative pressure gradient area. Moreover, the area contaminated exceeding the maximum allowable concentration by radioactivity for the Type-I vessel is reduced gradually with the growth of coniferous vegetation barriers due to the weakening of the backflow effect by growing vegetation. Second, compared to vegetation barriers of 15 years and 23 years, the horizontal distance exceeding the maximum allowable concentration of the leaked 131I dispersion from Type II vessels near vegetation barriers for 12 years is the longest. The older the vegetation barrier is, the shorter the horizontal dispersion range, and the shape of radionuclide dispersion gradually transforms from flat to semicircular with vegetation barrier growth, but this could cause a greater radioactive accumulation effect near the leakage point, and the maximum concentration of leaked 131I reached 0.54 kBq·m-3 for leaked radionuclides from the Type II vessel under vegetation barriers of 23 years. In addition, improvement suggestions based on the proposed method are presented, which will enable the Standards Institutes to apply the research methodologies described herein across various scenarios. ENVIRONMENTAL IMPLICATION: Compared to nonradioative pollutants, radioactive pollutants are intercepted by vegetation barriers and then migrate to the soil through leaves, stems, and roots, which can contaminate the surrounding environment. Considering the effects of vessel type and coniferous vegetation growth, a radionuclide dispersion model based on CFD was established. Suggestions for decontaminating radioactive pollution areas have been proposed based on the simulation results of hypothetical scenarios. The scenario applicability improvements based on the proposed model could assist relevant Standards Institutes to making improving measures.

Exploring the top 30 drugs associated with drug-induced constipation based on the FDA adverse event reporting system.

Objective: This project aims to identify the top 30 drugs most commonly associated with constipation and their signal values within the FDA Adverse Event Reporting System database. Methods: We extracted adverse drug events (ADEs) related to constipation from the FAERS database spanning from January 1, 2004, to September 30, 2023. We compiled the 30 most frequently reported drugs based on the frequency of constipation events. We employed signal detection methodologies to ascertain whether these drugs elicited significant signals, including reporting odds ratio, proportional reporting ratio, multi-item gamma Poisson shrinker, and information component given by the Bayesian confidence propagation neural network. Furthermore, we conducted a time-to-onset (TTO) analysis for drugs generating significant signals using the medians, quartiles, and the Weibull shape parameter test. Results: We extracted a total of 50, 659, 288 ADEs, among which 169,897 (0.34%) were related to constipation. We selected and ranked the top 30 drugs. The drug with the highest ranking was lenalidomide (7,730 cases, 4.55%), with the most prevalent drug class being antineoplastic and immunomodulating agents. Signal detection was performed for the 30 drugs, with constipation risk signals identified for 26 of them. Among the 26 drugs, 22 exhibited constipation signals consistent with those listed on the FDA-approved drug labels. However, four drugs (orlistat, nintedanib, palbociclib, and dimethyl fumarate) presented an unexpected risk of constipation. Ranked by signal values, sevelamer carbonate emerged as the drug with the strongest risk signal [reporting odds ratio (95% CI): 115.51 (110.14, 121.15); PRR (χ2): 83.78 (191,709.73); EBGM (EB05): 82.63 (79.4); IC (IC025): 6.37 (4.70)]. A TTO analysis was conducted for the 26 drugs that generated risk signals, revealing that all drugs exhibited an early failure type. The median TTO for orlistat was 3 days, the shortest of all the drugs, while the median TTO for clozapine was 1,065 days, the longest of all the drugs. Conclusion: Our study provides a list of drugs potentially associated with drug-induced constipation (DIC). This could potentially inform clinicians about some alternative medications to consider when managing secondary causes of constipation or caring for patients prone to DIC, thereby reducing the incidence and mortality associated with DIC.

Comparative study of [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1p as novel PD-L1 targeting PET probes for tumor imaging.

PD-L1 is expressed in many tumors but rarely in normal tissues, therefore, it can be a target of PET imaging. In this work, we developed new peptide-based PET probes [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1p with yields of 20-25 % and 40-55 %, respectively. [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1p were synthesized within 30 min with high molar activities. [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1p showed good stability in vivo and in vitro. In vitro cell studies showed [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1p target PD-L1 specifically, with high uptake of 61.52 ± 4.39 and 19.29 ± 2.17 %ID/1 million cells in B16F10 cells at 60 min, respectively. Biodistribution results showed that both [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1p had lower liver accumulation. In vivo PET imaging results showed that [18F]AlF-PAI-PDL1p had a high tumor uptake of 4.23 ± 0.81 %ID/g at 2 h and increased uptake of 6.60 ± 1.01 %ID/g at 12 h. [68Ga]Ga-PAI-PDL1p also showed high tumor uptake of 2.30 ± 0.20 %ID/g at 2 h and slightly increased uptake of 3.80 ± 0.26 %ID/g at 6 h. In conclusion, [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1 seemed to be potential tracers for PET imaging of PD-L1 expression.

Cerebral [18F]AIF-FAPI-42-Based PET Imaging of Fibroblast Activation Protein for Non-invasive Quantification of Fibrosis After Ischemic Stroke.

The development of fibrosis after injury to the brain or spinal cord limits the regeneration of the central nervous system in adult mammals. However, the extent of fibrosis in the injured brain has not been systematically investigated in mammals in vivo. This study aimed to assess whether [18F]AlF-FAPI-42-based cerebral positron emission tomography (PET) can be utilized to assess the extent of fibrosis in ischemic regions of the brain in vivo. Sprague-Dawley rats underwent permanent occlusion of the right middle cerebral artery (MCAO). On days 3, 7, 14, and 21 after MCAO, the uptake of [18F]AlF-FAPI-42 in the ischemic region of the brain in the MCAO groups surpassed that in the control group (day 0). The specific expression of fibroblast activation protein-α (FAP) in ischemic regions of the brain was also confirmed in immunohistofluorescence experiments in vitro. [18F]AlF-FAPI-42 intensity correlated with the density of collagen deposition in the ischemic hemisphere (p < 0.001). [18F]AlF-FAPI-42 PET/CT imaging demonstrated a specific uptake of radioactivity in the infarcted area in an ischemic stroke patient. PET imaging by using [18F]AlF-FAPI-42 offers a promising non-invasive method for monitoring the progression of cerebral fibrosis caused by ischemic stroke and may facilitate the clinical management of stroke patients. Trial registration: chictr.org.cn ChiCTR2200059004. Registered April 22, 2022.

Synthesis and preclinical evaluation of a novel PET/fluorescence dual-modality probe targeting fibroblast activation protein.

Early diagnosis and precise surgical intervention are crucial for cancer patients. We aimed to develop a novel positron emission tomography (PET)/fluorescence dual-modality probe for preoperative diagnosis, intraoperative guidance, and postoperative monitoring of fibroblast activation protein (FAP)-positive tumors. FAPI-FAM was synthesized and labeled with gallium-68. [68Ga]Ga-FAPI-FAM showed favorable in vivo and in vitro characteristics, specific binding affinity, and excellent tumor accumulation in FAP-positive cells and mice xenografts. Excellent tumor-to-background contrast was found owing to high tumor uptake, prolonged retention, and rapid renal clearance of [68Ga]Ga-FAPI-FAM. Moreover, a specific fluorescence signal was detected in FAP-positive tumors during ex vivo fluorescence imaging, demonstrating the feasibility of whole-body tumor detection and intraoperative tumor delineation.

Synthesis and preclinical evaluation of novel 18F-labeled fibroblast activation protein tracers for positron emission tomography imaging of cancer-associated fibroblasts.

Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts in more than 90% of epithelial tumors. Several radiotracers targeting FAPs have been used in clinical settings in recent years. However, the number of 18F-labeled FAP tracers is still limited. Herein, we aimed to develop 18F-labeled FAP tracers with optimized pharmacokinetics. Labeling precursors (NOTA-DD-FAPI and NOTA-PD-FAPI) were synthesized and labeled with fluorine-18. The precursors NOTA-DD-FAPI (IC50 = 0.21 ± 0.06 nM) and NOTA -PD-FAPI (IC50 = 0.13 ± 0.07 nM) showed a higher affinity for FAP compared to NOTA-FAPI-42 (IC50 = 0.66 ± 0.19 nM). Novel 18F-labeled FAP tracers showed a specific uptake, high internalized fraction, and low cellular efflux in vitro. Compared to the clinically used tracer [18F]AlF-FAPI-42, both the novel 18F-labeled FAP tracers, and especially the [18F]AlF-PD-FAPI tracer with a higher tumor-to-background ratio demonstrated rapid renal excretion and higher tumor uptake during preclinical evaluation, resulting in images with higher contrast. Thus, [18F]AlF-PD-FAPI shows promise for use as a FAP-targeting tracer for clinical translation.

177Lu-Labeled Bivalent Ligands of Prostate-Specific Membrane Antigen for Endoradiotherapy of Prostate Cancer.

Recently, we developed a bivalent prostate-specific membrane antigen (PSMA) radioligand ([18F]AlF-Bi-PSMA), which showed higher tumor uptake and retention in PSMA-positive mouse models than the clinically used radioligands, [68Ga]Ga-PSMA-11 and [18F]PSMA-1007. Here, we developed two 177Lu-labeled bivalent PSMA ligands with (DOTA-Alb-Bi-PSMA) or without an albumin-binding motif (DOTA-Bi-PSMA) to enhance radiotherapeutic efficacy with minimal toxicity. The results demonstrated that both 177Lu-labeled bivalent radioligands showed good stability, high binding affinity, and PSMA-targeting specificity in vitro. Compared with [177Lu]Lu-PSMA-617, both [177Lu]Lu-Bi-PSMA and [177Lu]Lu-Alb-Bi-PSMA showed a higher area under the curve (AUC) of tumor accumulation and superior therapeutic efficacy. However, [177Lu]Lu-Alb-Bi-PSMA exhibited a dose-dependent increase in acute damage to kidneys. In terms of the radionuclide therapy efficacy and side effects, [177Lu]Lu-Bi-PSMA exhibited well-balanced action with high tumor-to-organs AUC ratios, resulting in remarkable therapeutic efficacy and negligible side effects. These promising results warrant further investigations to achieve the clinical translation of [177Lu]Lu-Bi-PSMA.