Search Results (205)

Objectives: Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) commonly relies on somatostatin receptor subtype 2 (SSTR2) agonists such as DOTA-TOC/TATE, which may show limited efficacy due to high hepatic uptake and therapy resistance in some patients. SSTR2 antagonists have demonstrated superior tumor targeting. This study aimed to establish the production and quality control of the Actinium-225-labeled SSTR2 antagonist [²²⁵Ac]Ac-DOTA-LM3 and to report in-human clinical experience with targeted alpha therapy (TAT). Methods: [²²⁵Ac]Ac-DOTA-LM3 was produced by radiolabeling DOTA-LM3 with Actinium-225 under validated conditions. Radiochemical conversion, purity, yield, and stability were assessed using radio-TLC, fractionated radio-HPLC combined with gamma spectroscopy, and in vitro serum stability testing. Clinical feasibility and therapeutic response were evaluated in a patient with metastatic neuroendocrine pancreatic neoplasm refractory to prior ¹⁷⁷Lu-based PRRT. Results: Radiolabeling achieved reproducibly high radiochemical purity (>97%) and decay-corrected yields exceeding 80%. The radiopharmaceutical showed high in vitro stability with minimal release of free Actinium-225 over five days. Fractionated radio-HPLC enabled indirect purity assessment. In the reported patient, [²²⁵Ac]Ac-DOTA-LM3 therapy resulted in partial remission without clinically relevant hematologic, renal, or hepatic toxicity and was associated with marked clinical improvement. Conclusions: [²²⁵Ac]Ac-DOTA-LM3 can be produced with high purity and stability using clinically applicable procedures. In-human results suggest promising efficacy and safety, supporting further clinical investigation of Actinium-225-labeled SSTR2 antagonists for advanced NETs. Full article

Here we present a retrospective, integrative review of the approaches and discoveries of our “collaboratory”, a meta-laboratory comprising cross-disciplinary collaborations across laboratories at fourteen different universities and clinics in seven different countries with shared lead investigators. By tying together insights from four decades of research and discovery, applied across cell types, as well as different tissues, organ systems, and organisms, we have aimed to elucidate the interplay between organisms’ movement and the physiology of their tissues, organs, and organ systems’ resident cells. We highlight the potential of increasing imaging and computing power, as well as machine learning/artificial intelligence approaches, to delineate the Laws of Biology. Codifying these laws will provide a foundation for the future, to promote not only the discovery of underpinning mechanisms but also the sustainability of our natural resources, from our brains to our bones, which serve as veritable “hard drives”, physically rendering a lifetime of cellular experiences and millennia of evolution. Full article

The aggregation of tau protein is a central pathological event in Alzheimer’s disease, and this pathology is hypothesized to spread via a prion-like mechanism driven by tau “seeds”. While aggregated tau from Alzheimer’s disease brains is known to contain age-related d-isomerized aspartic acid (d-Asp) residues, it remains unknown how this modification affects the seeding activity that drives disease propagation. Here, we investigated the impact of site-specific d-isomerization within R2 and R3 tau repeat-domain peptides, which form the core of tau fibrils. We demonstrate that the stereochemical integrity of these peptides is critical for their seeding function. d-isomerization at Asp314 within the R3 peptide seed severely impaired its ability to template the fibrillization of full-length tau in vitro. This finding was validated in a cellular model, where R3 seeds containing d-Asp314 were significantly less potent at inducing the formation of phosphorylated tau aggregates compared to wild-type seeds. Our results establish that Asp d-isomerization within tau seeds acts as a potent attenuator of their pathological seeding activity, suggesting this spontaneous modification may intrinsically modulate the progression of Alzheimer’s disease. Full article

Background/Objectives: The ¹⁰³Pd/^103mRh in vivo generator represents a promising Auger electron-emitting system, in which both parent and daughter radionuclides emit predominantly Auger electrons with minimal accompanying radiation. This study investigates the release dynamics of daughter radionuclides from the ¹⁰³Pd/^103mRh in vivo generator and evaluates the underlying mechanisms governing bond rupture and daughter retention. Methods: Cyclotron irradiation of rhodium foils was performed in two separate batches, followed by radionuclide separation using conventional wet chemistry and a novel dry distillation technique. The purified ¹⁰³Pd radionuclide was used to radiolabel DOTA-TATE, phthalocyanine-TATE, and DOTA-TOC chelators. The resulting complexes were immobilized on Strata-X and Strata-C18 solid-phase extraction columns. Scheduled elution experiments were conducted to quantify the release of the ^103mRh daughter radionuclide. Results: The measured ^103mRh release rates were 9.8 ± 3.0% and 9.6 ± 2.7% from Strata-X columns with DOTA-TATE and phthalocyanine-TATE, respectively, and 10.5 ± 2.7% and 12.0 ± 0.5% from Strata-X and Strata-C18 columns, respectively, with DOTA-TOC. These values are significantly lower than the ~100% release predicted based on the reported Auger electron yield of 186%. One explanation for this difference could be potential inconsistencies in decay data that may require correction; this needs further investigation. The results further demonstrated that delocalized π-electrons, introduced via phthalocyanine-based chelation, did not mitigate daughter release. Conclusions: The low observed daughter nuclide release represents a favorable characteristic for the future clinical translation of the ¹⁰³Pd/^103mRh Auger emitter pair. The findings support the conclusion that Auger electron cascades, rather than nuclear recoil energy, dominate bond rupture processes. Full article

Emergency Departments (EDs) are high-pressure environments that place significant psychological and physiological stress on both patients and healthcare staff. Despite increasing awareness of stress-related impacts, proactive stress management interventions have limited uptake in healthcare. This proof-of-concept study will evaluate WeCare: a 6-week, wearable-integrated, self-guided program grounded in a “Learn–Track–Act” framework to support stress regulation, resilience, and wellbeing. The study will examine four key aspects of implementing the program: (1) feasibility, (2) acceptability and usability, (3) preliminary clinical effectiveness (self-report and physiological outcomes), and (4) preliminary economic impacts. Using a mixed-methods, multiple-baseline N-of-1 design, the program will be trialled with up to 32 participants across four ED-exposed groups: patients with non-severe or severe injuries, patients with acute medical presentations, and ED staff. The intervention includes digital psychoeducation, continuous biofeedback via a smart ring, personalised guidance, and evidence-based self-regulation strategies. Assessments will include standardised questionnaires combined with continuous physiological monitoring via a smartwatch, and interviews. Quantitative outcomes include heart rate variability, sleep patterns, perceived stress, wellbeing, healthcare use, and time off work. Qualitative interviews will explore user experience, usability, and perceived barriers. The findings will inform the refinement of the intervention and co-design of a larger-scale trial, contributing valuable evidence to support low-cost, wearable-enabled proactive mental healthcare in high-stress healthcare environments. Full article

Background: Poor mental health is a major contributor to absenteeism and turnover among nurses. Psychological flexibility may act as a protective factor for work-related well-being. This early-phase feasibility study explored the delivery of an online adaptation of Acceptance and Commitment Therapy (ACT) training for UK nursing professionals. Methods: A self-guided, 4-week online adaptation of an ACT training course was delivered via Moodle. Measures of professional quality of life, work engagement, and work-related psychological flexibility were collected at baseline and post-intervention (6 weeks). Feasibility outcomes included recruitment, retention, intervention adherence, and user engagement, assessed through platform usage statistics and user experience feedback. Results: A total of 43 participants enrolled in this single-group pre–post feasibility study. Recruitment targets were met, and completion of baseline measures was high. Engagement with course content was acceptable for an early-stage digital intervention. Among the well-being outcomes, work engagement showed the clearest indication of potential measure responsiveness. Retention was acceptable for the post-intervention survey but low for the usability survey and follow-up interview, limiting further exploration of engagement drivers. Conclusions: This study supports the feasibility of delivering online ACT training to nursing professionals. Key areas for refinement were identified, including closer integration with existing workplace communication and professional development systems, ongoing stakeholder involvement across study phases, and workplace-embedded engagement mechanisms to improve retention. Future research should further explore how workplace context influences intervention acceptability in larger feasibility trials. Full article

Introduction: Peptide Receptor Radionuclide Therapy (PRRT) with [¹⁷⁷Lu]Lu-DOTA-TATE is effective in treating advanced Neuroendocrine Tumors (NETs), yet predicting individual response in this treatment remains a challenge due to inter-lesion heterogeneity. There is a lack of standardized, effective methods for using multi-lesion radiomics to predict progression and Time to Progression (TTP) in PRRT-treated patients. This study evaluated how aggregating radiomic features from multiple PET-identified lesions can be used to predict disease progression (event [progression and death] vs. event-free) and TTP. Methods: Eighty-one NETs patients with multiple lesions underwent pre-treatment PET/CT imaging. Lesions were segmented and ranked by minimum Standard Uptake Value (SUV_min) (both descending and ascending), SUV_mean, SUV_max, and volume (descending). From each sorting, the top one, three, and five lesions were selected. For the selected lesions, radiomic features were extracted (using the Pyradiomics library) and lesion aggregation was performed using stacked vs. statistical methods. Eight classification models along with three feature selection methods were used to predict progression, and five survival models and three feature selection methods were used to predict TTP under a nested cross-validation framework. Results: The overall appraisal showed that sorting lesions based on SUV_min (descending) yields better classification performance in progression prediction. This is in addition to the fact that aggregating features extracted from all the lesions, as well as the top five lesions sorted by SUV_mean, lead to the highest overall performance in TTP prediction. The individual appraisal in progression prediction models trained on the single top lesion sorted by SUV_min (descending) showed the highest recall and specificity despite data imbalance. The best-performing model was the Logistic Regression (LR) classifier with Recursive Feature Elimination (RFE) (recall: 0.75, specificity: 0.77). In TTP prediction, the highest concordance index was obtained using a Random Survival Forest (RSF) trained on statistically aggregated features from the top five lesions ranked by SUV_mean, selected via Univariate C-Index (UCI) (C-index = 0.68). Across both tasks, features from the Gray Level Size Zone Matrix (GLSZM) family were consistently among the most predictive, highlighting the importance of spatial heterogeneity in treatment response. Conclusions: This study demonstrates that informed lesion selection and tailored aggregation strategies significantly impact the predictive performance of radiomics-based models for progression and TTP prediction in PRRT-treated NET patients. These approaches can potentially enhance model accuracy and better capture tumor heterogeneity, supporting more personalized and practical PRRT implementation. Full article

Pediatric neuroendocrine tumors (NETs) and neuroblastomas are rare malignancies with poor outcomes when metastatic. Limited treatment options are currently available for pediatric NETs. Recently, radioligand therapy (RLT) consisting of a radionuclide attached to a ligand, such as [¹⁷⁷Lu]Lu-DOTA-TATE, has been approved for the treatment of NETs in adolescents aged ≥12 years. Although long-term safety of RLT in adolescents and other pediatric patients needs to be further investigated, data from large adult studies and early pediatric studies suggest feasibility and low toxicity. Future research is needed to assess potential combinations of RLTs with conventional chemotherapy and radiation sensitizers in order to optimize the treatment for pediatric patients with NETs. This review highlights the current status and future directions for RLTs as theranostics for pediatric patients with NETs and neuroblastomas. Full article

Black LGBTQ+ adults face significant health disparities stemming from intersecting minority stressors. While community belongingness is often theorized as a protective factor, these communities can also be sites of exclusion, creating a complex dynamic. This study’s objective was to test whether community belongingness moderates the relationship between minority stress, operationalized as microaggressions, and subjective well-being in a national sample of Black LGBTQ+ adults. Data were taken from a national online survey of 345 Black LGBTQ+ adults conducted between November 2020 and January 2021. We used validated scales to measure experiences of microaggressions, subjective well-being, and community belongingness. A moderated multiple regression analysis was conducted using the PROCESS macro to test for an interaction effect, controlling for demographic covariates. Minority stress was significantly negatively associated with well-being (b = −0.11, p = 0.005), while community belongingness was positively associated with well-being (b = 0.43, p < 0.001). A significant interaction emerged (b = −0.01, p = 0.021). Simple slopes analysis revealed that the negative relationship between minority stress and well-being was strongest for individuals with high community belongingness (b = −0.18, p < 0.001) and was not significant for those with low belongingness, potentially indicating an exacerbating effect. Contrary to the buffering hypothesis, community belongingness paradoxically amplified the negative impact of minority stress on well-being. This paradox of belonging suggests that highly connected communities may become sites for trauma bonding, which can amplify distress. Public health efforts must focus not only on fostering connection but on building communities that are resourceful, inclusive, and capable of transforming shared experiences into collective empowerment. Full article

Individuals with rheumatoid arthritis (RA) face increased cardiovascular mortality due to heart failure (HF) complications. Post-translational modifications, such as citrullination (CIT) and malondialdehyde–acetaldehyde (MAA) adduction, are implicated in RA pathogenesis. However, their role in RA-associated HF is not well understood. This study examines the deposition of MAA and CIT in cardiac tissues of RA-HF patients and investigates how MAA and CIT adducts on fibrinogen (FIB-MAA-CIT) drive crosstalk between macrophages and endothelial cells in vitro. We demonstrated elevated MAA and CIT adducts, strong perivascular MAA-CIT co-localization, and increased perivascular collagen deposition in the myocardium of RA-HF patients compared to non-RA HF controls. Treating human coronary artery endothelial cells (HCAECs) with FIB-MAA-CIT induced upregulation of inflammatory markers including MCP-1, IL-6, ICAM-1, and VCAM-1 compared to unmodified FIB. This response was amplified when HCAECs were treated with cell culture media obtained from FIB-MAA-CIT-stimulated macrophages. FIB-MAA-CIT activation of macrophages engaged NF-κB and p38 signaling pathways and inhibition of these pathways reduced FIB-MAA-CIT-mediated macrophage cytokine secretion and subsequent HCAEC responses. In summary, our findings support a novel mechanism by which endogenously modified proteins drive macrophage–endothelial cell crosstalk, promoting myocardial inflammation. Targeting these post-translational modifications may present novel therapeutic strategies to mitigate HF in RA. Full article

Background: Despite remarkable progress in expanding access to childhood vaccines in the last two decades, global coverage with the third dose of the diphtheria–tetanus–pertussis-containing vaccine (DTP3) has recently plateaued, with many countries yet to meet the targets of the Immunization Agenda 2030 (IA2030). As countries cluster around the 80% coverage mark, further gains require targeted interventions for unreached populations. This analysis disaggregates children missing DTP3 into three groups—zero dose (ZD), missed DTP (MD), and drop-out (DO)—which, with DTP3, form four mutually exclusive groups, and examines which of these groups contributes most to coverage changes across countries. Methods: A total of 295 Demographic and Health Surveys from 1986 to 2023 were analyzed across 80 countries, comprising over 2.4 million children. Children were classified into mutually exclusive groups: DTP3, ZD, MD, and DO. We described trends over time and conducted decomposition analyses using a naïve approach and a structural model with isometric log-ratio transformations and causal mediation pathways. Results: Among the 2.4 million children across 80 countries, 63.8% had received DTP3, while 16.2% were DO, 8.8% were MD, and 11.2% were ZD. Countries showed important variations: some mainly reduced ZD, others reduced MD or DO, many achieved balanced progress, and a few experienced setbacks. The naïve model showed that coverage changes reflected different combinations of shifts across ZD, MD, and DO depending on context. The structural model indicated that DO had the strongest direct association with DTP3 coverage, followed by MD and ZD. Conclusions: This analysis highlights the differential contribution of intermediate groups to coverage variations over time. Understanding the association between coverage gains and shifts in ZD, MD, or DO can complement existing strategies to inform targeted planning and accelerate progress towards IA2030 equity goals. Full article

Brain tumor-related epilepsy (BTRE) is a common and debilitating symptom of central nervous system (CNS) tumors. The epileptogenic zone, defined as cortex responsible for seizure generation, is located at the peritumoral region for most tumors, and lower-grade intrinsic brain tumors have the highest seizure incidence. Surgery is often the most effective treatment for the reduction in seizures in BTRE. However, surgical decisions have historically often been made exclusively for oncologic reasons, with less emphasis on seizure control. Surgical approaches for all tumor types are reviewed, highlighting relevant risk factors. Adjunctive tools during surgery, such as intraoperative electrocorticography (ECoG), may help identify and remove surrounding brain areas which are epileptogenic. Minimally invasive surgery is also gaining traction, given its utility in treating seizures deep-seated tumors. This review explores epileptogenic brain tumors, surgery for BTRE, and emerging strategies to better achieve seizure control. Full article

Radioligand therapy (RLT) is a targeted treatment modality that combines a tumour-specific ligand with a therapeutic radionuclide. Once administered, the radiopharmaceutical binds selectively to cancer-associated targets, delivering cytotoxic radiation directly to tumour cells while sparing surrounding tissues. Two RLT agents, [¹⁷⁷Lu]Lu-DOTA-TATE (Lutathera^®) and [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto^®), have received regulatory approval for the treatment of advanced gastroenteropancreatic neuroendocrine tumours and metastatic castration-resistant prostate cancer, respectively. As of July 2025, more than 400 clinical trials are registered, exploring novel molecular targets such as FAP, CAIX, and GRPR, as well as alternative radionuclides and combination regimens in both solid and haematologic malignancies. In this review, we describe the design principles and mechanisms of action of RLT, summarise clinical evidence for approved and emerging radiopharmaceuticals, and discuss current global disparities in access and availability. Finally, we outline the main clinical challenges, including fixed dosing regimens, resistance, toxicity, and variability in patient selection and response assessment. Continued research to optimise radiopharmaceutical design, together with investment in infrastructure, workforce capacity, and international collaboration, will be essential to expand access and realise the full potential of RLT as a leading treatment strategy in modern oncology. Full article

Eosinophils are innate immune cells that infiltrate tissues in response to cell proliferation and necrosis, which occurs during normal injury repair, parasitic infections, allergies, and cancer. Their involvement in cancer is controversial particularly with regard to tumor-associated tissue eosinophilia (TATE) and a recently defined mechanism of extracellular trap cell death (ETosis), a particular type of eosinophil cell death that is distinct from both apoptosis and necrosis. This narrative review synthesizes the literature regarding the prognostic significance of TATE, focusing on eosinophil ETosis and the important role of transmission electron microscopy (TEM) in its detection and morphological characterization. The prognostic role of TATE is contradictory: in certain tumors, it is a favorable prognostic marker, while in others, it is unfavorable. However, recent research reveals that TATE is associated with a better prognosis in non-viral neoplasms, but it may correlate with a poor prognosis in virus-related neoplasms, such as human T-lymphotropic virus type 1 (HTLV-1)-associated lymphomas and HPV-positive carcinomas. Our ultrastructural investigations revealed distinct phases of eosinophil ETosis in gastric cancer, which were defined by chromatin decondensation, plasma membrane disruption, granule discharge, and development of extracellular traps. We observed synapse-like interactions between eosinophils, exhibiting ETosis or compound exocytosis, and tumor cells, which showed various degrees of cellular damage, ultimately leading to colloid-osmotic tumor cell death. TEM provides important insights into eosinophil-mediated cytotoxicity, requiring further investigation as potential immune effector mechanisms in non-viral tumors. TATE evaluation, together with the viral status of the neoplasia, may be useful to confirm its prognostic significance and consequently its therapeutic implication in specific cancers. Full article

Background: Cardiotoxicity remains a concern across cancer therapies. To date, there is a lack of extensive studies evaluating the potential impact of radioligand therapy (RLT) on myocardial injury in patients with neuroendocrine tumors (NETs), particularly in subgroups with increased susceptibility to such injury. This study aimed to assess the potential cardiotoxic effects and myocardial dysfunction associated with RLT using both [¹⁷⁷Lu]Lu-DOTA-TATE and tandem therapy with [¹⁷⁷Lu]Lu-DOTA-TATE/[⁹⁰Y]Y-DOTA-TATE in patients with NETs, including specific high-risk subgroups such as patients with pre-existing heart failure, carcinoid heart disease or those previously treated with chemotherapy, by monitoring serum concentration of troponin I, CK-MB, and NT-proBNP before and after RLT. Methods: We conducted a retrospective observational analysis of 60 consecutive NET patients who underwent 228 RLT courses. A comprehensive cardiac assessment, including a detailed medical history, was performed. Additionally, serum troponin I, CKMB and NT-proBNP concentrations were measured prior to treatment and 48 h post-therapy. Fifty-two patients received [¹⁷⁷Lu]Lu-DOTA-TATE monotherapy, while eight patients were treated with tandem therapy. Results: No increase in cardiotoxicity markers was observed in the overall study population following RLT administration (ΔTroponin −0.2 [−1.4–0.3]ng/L, p = 0.007; ∆CKMB 0.0 [−4.0–3.0]U/L, p = 0.90; ΔNT-proBNP 4.0 [−45.6–33.6]pg/mL) as well as in the subgroup receiving tandem therapy (ΔTroponin 0.7 [−1.7–013]ng/L, p = 0.68; ΔCKMB −0.5 [−10.7–3.0]U/L, p = 0.21; ΔNT-proBNP −21.6 [−44.1–16.7]pg/mL). Furthermore, none of the predefined patient subgroups exhibited signs of cardiotoxicity or evidence of myocardial dysfunction. Conclusions: RLT is a safe anticancer treatment option for patients with NETs in terms of cardiotoxicity and cardiac dysfunction, including those at higher risk of cardiovascular complications. Full article