Search Results (208)

Diagnosis and endoradiotherapy using copper radioisotopes—defined as Theranostics or, more specifically, CopperNostics—have the potential to play a prominent role in modern precision medicine, as demonstrated by the FDA approval of [⁶⁴Cu]Cu-DOTA-TATE (Detectnet). In this review we highlight current developments in the production, radiochemical purification, quality control, availability, logistics, and regulatory hurdles of the most relevant copper radioisotopes, ⁶⁰Cu, ⁶¹Cu, ⁶²Cu, ⁶⁴Cu, and ⁶⁷Cu, for nuclear medicine. Radiopharmaceuticals based on their application in registered clinical trials, either as molecular imaging agents, companion diagnostics or therapeutic agents, are also presented addressing unmet medical needs. Full article

Influenza A virus remains a major global health threat, causing annual epidemics and occasional pandemics. Programmed cell death, including apoptosis, pyroptosis, and necroptosis, with emerging evidence for ferroptosis, plays a dual role in influenza pathogenesis, both limiting viral replication and contributing to immunopathology. Most mechanistic insights have been derived from murine genetic models, which have been invaluable for establishing causal roles of these pathways. However, murine models and cancer-derived cell lines differ significantly from human physiology. This review systematically compares influenza-induced programmed cell death across human-relevant platforms, including primary cells, immortalized non-cancerous lines, co-cultures, organoids, and precision-cut lung slices. The increasing complexity of these models reveals distinct aspects of pathway activation, bystander effects, cell-type vulnerability, and spatial dynamics. We highlight critical divergences between model systems, identify gaps in comparative analyses across viral strains and experimental platforms, and outline future directions leveraging advanced model systems, multi-omics, and functional genomics to enhance translational relevance and guide the development of host-directed therapies. Full article

Background/Objectives: Prostate cancer is the most commonly diagnosed cancer in men and a leading cause of cancer-related mortality, highlighting the need for delivery systems capable of efficiently transporting both chemotherapeutic drugs and therapeutic genes to tumor cells. Generation-3 diaminobutyric polypropylenimine (DAB) dendrimers display low toxicity, high drug loading capacity and efficient gene delivery, and can be engineered as camptothecin-bearing PEGylated carriers complexed with plasmid DNA. The aim of this study was to compare microfluidic processing with conventional hand mixing for the preparation of camptothecin-bearing PEGylated DAB dendriplexes and to evaluate the impact of formulation methods and microfluidic parameters on their physicochemical properties, cellular uptake and gene expression in prostate cancer cells. Methods: Camptothecin-bearing PEGylated DAB dendrimers were synthesized and complexed with plasmid DNA to form dendriplexes. Formulations were prepared either by microfluidics, using different total flow rates and aqueous: organic flow rate ratios, or by conventional hand mixing. The resulting dendriplexes were characterized for DNA condensation, particle size, polydispersity index and zeta potential. Morphology was assessed by transmission electron microscopy. Cellular uptake of fluorescein-labelled DNA and β-galactosidase reporter gene expression were evaluated in PC3-Luc and DU145 prostate cancer cells. Results: Both microfluidic and hand-mixed methods produced stable, nanosized, positively charged dendriplexes with efficient and sustained DNA condensation (more than 99% over 24 h). Microfluidic processing, particularly at an aqueous: organic flow rate ratio of 3:1, yielded dendriplexes with hydrodynamic diameters and zeta potentials comparable to or slightly improved over hand-mixed formulations. These microfluidic conditions significantly enhanced cellular uptake in both PC3-Luc and DU145 cells. In PC3-Luc cells, this translated into β-galactosidase expression levels comparable to hand-mixed dendriplexes and higher than naked DNA, whereas in DU145 cells, transfection efficiencies remained modest for all formulations despite increased uptake. Conclusions: Microfluidic processing enables the reproducible and scalable preparation of camptothecin-bearing PEGylated DAB dendriplexes with tunable physicochemical properties. Under selected conditions, in vitro cellular uptake and gene expression were comparable to conventional hand mixing, supporting microfluidics as a robust alternative platform for the manufacture of dendrimer-based systems for combined chemo–gene delivery in prostate cancer. Full article

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