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The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients.
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Caquexia/tratamento farmacológico , Neoplasias/patologia , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/administração & dosagem , Atrofia/tratamento farmacológico , Caquexia/patologia , Morte Celular , Neoplasias do Colo/tratamento farmacológico , Citocina TWEAK , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Desenvolvimento Muscular , Neoplasias/metabolismo , Receptores do Fator de Necrose Tumoral/química , Receptores do Fator de Necrose Tumoral/metabolismo , Alinhamento de Sequência , Transdução de Sinais , Receptor de TWEAK , Fatores de Necrose Tumoral/metabolismoRESUMO
Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1-4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass6-8. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.
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Proteína Forkhead Box O1 , Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Células-Tronco , Linfócitos T , Humanos , Camundongos , Linhagem Celular Tumoral , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Mitocôndrias/metabolismo , Fenótipo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/citologia , Microambiente Tumoral/imunologia , Células-Tronco/citologia , Células-Tronco/imunologia , Células-Tronco/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapiaRESUMO
[This corrects the article DOI: 10.1371/journal.ppat.0030119.].
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Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states1-6. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.
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Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/imunologia , Proteínas de Grupo de Alta Mobilidade/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/deficiência , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Homeodomínio/genética , Humanos , Memória Imunológica , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Neoplasias/patologia , Fenótipo , Receptores de Antígenos de Linfócitos T/imunologia , Transcrição GênicaRESUMO
This paper is the first of a Series on theranostics that summarises the current landscape of the radiopharmaceutical sciences as they pertain to oncology. In this Series paper, we describe exciting developments in radiochemistry and the production of radionuclides, the development and translation of theranostics, and the application of artificial intelligence to our field. These developments are catalysing growth in the use of radiopharmaceuticals to the benefit of patients worldwide. We also highlight some of the key issues to be addressed in the coming years to realise the full potential of radiopharmaceuticals to treat cancer.
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Neoplasias , Compostos Radiofarmacêuticos , Humanos , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias/terapia , Neoplasias/radioterapia , Oncologia , Inteligência ArtificialRESUMO
Theranostics has become a major area of innovation and progress in cancer care over the last decade. In view of the introduction of approved therapeutics in neuroendocrine tumours and prostate cancer in the last 10 years, the ability to provide access to these treatments has emerged as a key factor in ensuring global benefits from this cancer therapy approach. In this Series paper we explore the issues that affect access to and availability of theranostic radiopharmaceuticals, including supply and regulatory issues that might affect the availability of theranostic treatments for patients with cancer.
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Compostos Radiofarmacêuticos , Nanomedicina Teranóstica , Humanos , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias/terapia , Medicina de PrecisãoRESUMO
Although the promise of radionuclides for the diagnosis and treatment of disease was recognised soon after the discovery of radioactivity in the late 19th century, the systematic use of radionuclides in medicine only gradually increased over the subsequent hundred years. The past two decades, however, has seen a remarkable surge in the clinical application of diagnostic and therapeutic radiopharmaceuticals, particularly in oncology. This development is an exciting time for the use of theranostics in oncology, but the rapid growth of this area of nuclear medicine has created challenges as well. In particular, the infrastructure for the manufacturing and distribution of radiopharmaceuticals remains in development, and regulatory bodies are still optimising guidelines for this new class of drug. One issue of paramount importance for achieving equitable access to theranostics is building a sufficiently trained workforce in high-income, middle-income, and low-income countries. Here, we discuss the key challenges and opportunities that face the field as it seeks to build its workforce for the 21st century.
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Oncologia , Medicina Nuclear , Compostos Radiofarmacêuticos , Humanos , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/provisão & distribuição , Medicina Nuclear/educação , Medicina Nuclear/tendências , Neoplasias/radioterapia , Neoplasias/terapia , Mão de Obra em Saúde/tendênciasRESUMO
Response Assessment in Neuro-Oncology (RANO) response criteria have been established and were updated in 2023 for MRI-based response evaluation of diffuse gliomas in clinical trials. In addition, PET-based imaging with amino acid tracers is increasingly considered for disease monitoring in both clinical practice and clinical trials. So far, a standardised framework defining timepoints for baseline and follow-up investigations and response evaluation criteria for PET imaging of diffuse gliomas has not been established. Therefore, in this Policy Review, we propose a set of criteria for response assessment based on amino acid PET imaging in clinical trials enrolling participants with diffuse gliomas as defined in the 2021 WHO classification of tumours of the central nervous system. These proposed PET RANO criteria provide a conceptual framework that facilitates the structured implementation of PET imaging into clinical research and, ultimately, clinical routine. To this end, the PET RANO 1.0 criteria are intended to encourage specific investigations of amino acid PET imaging of gliomas.
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Glioma , Neurologia , Humanos , Glioma/diagnóstico por imagem , Glioma/terapia , Aminoácidos , Medicina Interna , Tomografia por Emissão de Pósitrons , Fatores de TranscriçãoRESUMO
BACKGROUND: The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [177Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [68Ga]Ga-PSMA-11 and 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) PET-CT. METHODS: TheraP was an open-label, randomised phase 2 trial at 11 centres in Australia. Eligible participants had metastatic castration-resistant prostate cancer progressing after docetaxel, and PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG that showed prostate-specific membrane antigen (PSMA)-positive disease and no sites of metastatic disease with discordant 2-[18F]FDG-positive and PSMA-negative findings. Participants were randomly assigned (1:1) to treatment with [177Lu]Lu-PSMA-617 (every 6 weeks for a maximum of six cycles; starting at 8·5 GBq, decreasing by 0.5 GBq to 6·0 GBq for the sixth cycle) versus cabazitaxel (20 mg/m2 every 3 weeks, maximum of ten cycles). Overall survival was analysed by intention-to-treat and summarised as restricted mean survival time (RMST) to account for non-proportional hazards, with a 36-month restriction time corresponding to median follow-up. This trial is registered with ClinicalTrials.gov, NCT03392428, and is complete. FINDINGS: 291 men were registered from Feb 6, 2018, to Sept 3, 2019; after study imaging, 200 were eligible and randomly assigned to treatment with [177Lu]Lu-PSMA-617 (n=99) or cabazitaxel (n=101). After completing study treatment, 20 (20%) participants assigned to cabazitaxel and 32 (32%) assigned to [177Lu]Lu-PSMA-617 were subsequently treated with the alternative regimen. After a median follow-up of 35·7 months (IQR 31·1 to 39·2), 77 (78%) participants had died in the [177Lu]Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to [177Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (RMST 19·1 months [95% CI 16·9 to 21·4] vs 19·6 months [17·4 to 21·8]; difference -0·5 months [95% CI -3·7 to 2·7]; p=0·77). No additional safety signals were identified with the longer follow-up in this analysis. 80 (27%) of 291 men who were registered after initial eligibility screening were excluded after [68Ga]Ga-PSMA-11 and 2-[18F]FDG PET. In the 61 of these men with follow-up available, RMST was 11·0 months (95% CI 9·0 to 13·1). INTERPRETATION: These results support the use of [177Lu]Lu-PSMA-617 as an alternative to cabazitaxel for PSMA-positive metastatic castration-resistant prostate cancer progressing after docetaxel. We did not find evidence that overall survival differed between the randomised groups. Median overall survival was shorter for men who were excluded because of low PSMA expression or 2-[18F]FDG-discordant disease. FUNDING: Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, It's a Bloke Thing, CAN4CANCER, and The Distinguished Gentleman's Ride.
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Radioisótopos de Gálio , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Resultado do Tratamento , Docetaxel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18 , Austrália , Antígeno Prostático EspecíficoRESUMO
PURPOSE: The study aims to assess the potential of referenceless methods of EPI ghost correction to accelerate the acquisition of in vivo diffusion tensor cardiovascular magnetic resonance (DT-CMR) data using both computational simulations and data from in vivo experiments. METHODS: Three referenceless EPI ghost correction methods were evaluated on mid-ventricular short axis DT-CMR spin echo and STEAM datasets from 20 healthy subjects at 3T. The reduced field of view excitation technique was used to automatically quantify the Nyquist ghosts, and DT-CMR images were fit to a linear ghost model for correction. RESULTS: Numerical simulation showed the singular value decomposition (SVD) method is the least sensitive to noise, followed by Ghost/Object method and entropy-based method. In vivo experiments showed significant ghost reduction for all correction methods, with referenceless methods outperforming navigator methods for both spin echo and STEAM sequences at b = 32, 150, 450, and 600 smm - 2 $$ {\mathrm{smm}}^{-2} $$ . It is worth noting that as the strength of the diffusion encoding increases, the performance gap between the referenceless method and the navigator-based method diminishes. CONCLUSION: Referenceless ghost correction effectively reduces Nyquist ghost in DT-CMR data, showing promise for enhancing the accuracy and efficiency of measurements in clinical practice without the need for any additional reference scans.
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Imagem Ecoplanar , Processamento de Imagem Assistida por Computador , Humanos , Imagem Ecoplanar/métodos , Processamento de Imagem Assistida por Computador/métodos , Razão Sinal-Ruído , Imagens de Fantasmas , Espectroscopia de Ressonância Magnética , Artefatos , Encéfalo , AlgoritmosRESUMO
BACKGROUND: Our study aims to explore the current utilisation of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in the diagnostic pathway of pyrexia of unknown origin (PUO) and associated cost of illness in a large tertiary teaching hospital in Australia. METHOD: 1257 febrile patients between June 2016 and September 2022 were retrospectively reviewed. There were 57 patients who met the inclusion criteria of "classical PUO", of which FDG-PET/CT was performed in 31 inpatients, 15 outpatients and 11 inpatients did not have an FDG-PET/CT scan. The patient demographics, clinical characteristics and inpatient cost were analysed, together with the diagnostic performance of FDG-PET/CT and impact on clinical management. RESULT: The mean age, length of stay and total cost of admission were higher for inpatients who received FDG-PET/CT versus those who did not. The median cost per patient-bed-day did not differ between the two groups. Inpatients who received earlier FDG-PET/CTs (≤ 7 days from admission) had shorter length of stays and lower total cost compared to those who received a later scan. A negative FDG-PET/CT scan, demonstrating no serious or life-threatening abnormalities resulted in subsequent discharge from hospital or outpatient clinic in 7/10 (70%) patients. There were 11/40 (28%) scans where ancillary abnormalities were identified, requiring further evaluation. CONCLUSION: FDG-PET/CT showed high diagnostic accuracy and significant impact on patient management in patients with PUO. FDG-PET/CT performed earlier in admission for PUO was associated with shorter length of stay and lower total cost.
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Febre de Causa Desconhecida , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Fluordesoxiglucose F18 , Estudos Retrospectivos , Febre de Causa Desconhecida/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Efeitos Psicossociais da Doença , Compostos RadiofarmacêuticosRESUMO
PURPOSE: To develop a nuclear medicine specific patient journey audit tool (PJAT) to survey and audit patient journeys in a nuclear medicine department such as staff interaction with patients, equipment, quality of imaging and laboratory procedures, patient protection, infection control and radiation safety, with a view to optimising patient care and providing a high-quality nuclear medicine service. METHODS: The PJAT was developed specifically for use in nuclear medicine practices. Thirty-two questions were formulated in the PJAT to test the department's compliance to the Australian National Safety and Quality Health Service Standards, namely clinical governance, partnering with consumers, preventing and controlling health care infection, medication safety, comprehensive care, communicating for safety, blood management and recognising and responding to acute deterioration. The PJAT was also designed to test our department's adherence to diagnostic reference levels (DRL). A total of 60 patient journey audits were completed for patients presenting for nuclear medicine, positron emission tomography and bone mineral density procedures during a consecutive 4-week period to audit the range of procedures performed. A further 120 audits were captured for common procedures in nuclear medicine and positron emission tomography during the same period. Thus, a total of 180 audits were completed. A subset of 12 patients who presented for blood labelling procedures were audited to solely assess the blood management standard. RESULTS: The audits demonstrated over 85% compliance for the Australian national health standards. One hundred percent compliance was noted for critical aspects such as correct patient identification for the correct procedure prior to radiopharmaceutical administration, adherence to prescribed dose limits and distribution of the report within 24 h of completion of the imaging procedure. CONCLUSION: This PJAT can be applied in nuclear medicine departments to enhance quality programmes and patient care. Austin Health has collaborated with the IAEA to formulate the IAEA PJAT, which is now available globally for nuclear medicine departments to survey patient journeys.
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Medicina Nuclear , Medicina Nuclear/normas , Humanos , Indicadores de Qualidade em Assistência à Saúde , Auditoria Médica , AustráliaRESUMO
PURPOSE: Cachexia is a complex syndrome characterized by unintentional weight loss, progressive muscle wasting and loss of appetite. Anti-Fn14 antibody (mAb 002) targets the TWEAK receptor (Fn14) in murine models of cancer cachexia and can extend the lifespan of mice by restoring the body weight of mice. Here, we investigated glucose metabolic changes in murine models of cachexia via [18F]FDG PET imaging, to explore whether Fn14 plays a role in the metabolic changes that occur during cancer cachexia. METHODS: [18F]FDG PET/MRI imaging was performed in cachexia-inducing tumour models versus models that do not induce cachexia. SUVaverage was calculated for all tumours via volume of interest (VOI) analysis of PET/MRI overlay images using PMOD software. RESULTS: [18F]FDG PET imaging demonstrated increased tumour and brain uptake in cachectic versus non-cachectic tumour-bearing mice. Therapy with mAb 002 was able to reduce [18F]FDG uptake in tumours (P < 0.05, n = 3). Fn14 KO tumours did not induce body weight loss and did not show an increase in [18F]FDG tumour and brain uptake over time. In non-cachectic mice bearing Fn14 KO tumours, [18F]FDG tumour uptake was significantly lower (P < 0.01) than in cachectic mice bearing Fn14 WT counterparts. As a by-product of glucose metabolism, l-lactate production was also increased in cachexia-inducing tumours expressing Fn14. CONCLUSION: Our results demonstrate that Fn14 receptor activation is linked to glucose metabolism of cachexia-inducing tumours.
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BACKGROUND: In the rapidly evolving field of nuclear medicine, the paramount importance of radiation protection, safety, and quality systems cannot be overstated. This document provides a comprehensive analysis of the intricate regulatory frameworks and guidelines, meticulously crafted and updated by national and international regulatory bodies to ensure the utmost safety and efficiency in the practice of nuclear medicine. METHODS: We explore the dynamic nature of these regulations, emphasizing their adaptability in accommodating technological advancements and the integration of nuclear medicine with other medical and scientific disciplines. RESULTS: Audits, both internal and external, are spotlighted for their pivotal role in assessing and ensuring compliance with established standards, promoting a culture of continuous improvement and excellence. We delve into the significant contributions of entities like the International Atomic Energy Agency (IAEA) and relevant professional societies in offering universally applicable guidelines that amalgamate the latest in scientific research, ethical considerations, and practical applicability. CONCLUSIONS: The document underscores the essence of international collaborations in pooling expertise, resources, and insights, fostering a global community of practice where knowledge and innovations are shared. Readers will gain an in-depth understanding of the practical applications, challenges, and opportunities presented by these regulatory frameworks and audit processes. The ultimate goal is to inspire and inform ongoing efforts to enhance safety, quality, and effectiveness in nuclear medicine globally.
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Medicina Nuclear , Proteção Radiológica , Medicina Nuclear/normas , Proteção Radiológica/normas , Humanos , Controle de Qualidade , SegurançaRESUMO
PURPOSE: ATG-101, a bispecific antibody that simultaneously targets the immune checkpoint PD-L1 and the costimulatory receptor 4-1BB, activates exhausted T cells upon PD-L1 crosslinking. Previous studies demonstrated promising anti-tumour efficacy of ATG-101 in preclinical models. Here, we labelled ATG-101 with 89Zr to confirm its tumour targeting effect and tissue biodistribution in a preclinical model. We also evaluated the use of immuno-PET to study tumour uptake of ATG-101 in vivo. METHODS: ATG-101, anti-PD-L1, and an isotype control were conjugated with p-SCN-Deferoxamine (Df). The Df-conjugated antibodies were radiolabelled with 89Zr, and their radiochemical purity, immunoreactivity, and serum stability were assessed. We conducted PET/MRI and biodistribution studies on [89Zr]Zr-Df-ATG-101 in BALB/c nude mice bearing PD-L1-expressing MDA-MB-231 breast cancer xenografts for up to 10 days after intravenous administration of [89Zr]Zr-labelled antibodies. The specificity of [89Zr]Zr-Df-ATG-101 was evaluated through a competition study with unlabelled ATG-101 and anti-PD-L1 antibodies. RESULTS: The Df-conjugation and [89Zr]Zr -radiolabelling did not affect the target binding of ATG-101. Biodistribution and imaging studies demonstrated biological similarity of [89Zr]Zr-Df-ATG-101 and [89Zr]Zr-Df-anti-PD-L1. Tumour uptake of [89Zr]Zr-Df-ATG-101 was clearly visualised using small-animal PET imaging up to 7 days post-injection. Competition studies confirmed the specificity of PD-L1 targeting in vivo. CONCLUSION: [89Zr]Zr-Df-ATG-101 in vivo distribution is dependent on PD-L1 expression in the MDA-MB-231 xenograft model. Immuno-PET with [89Zr]Zr-Df-ATG-101 provides real-time information about ATG-101 distribution and tumour uptake in vivo. Our data support the use of [89Zr]Zr-Df-ATG-101 to assess tumour and tissue uptake of ATG-101.
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BACKGROUND: CI-8993 is a fully human IgG1κ monoclonal antibody (mAb) that binds specifically to immune checkpoint molecule VISTA (V-domain Ig suppressor of T-cell activation). Phase I safety has been established in patients with advanced cancer (NCT02671955). To determine the pharmacokinetics and biodistribution of CI-8993 in patients, we aimed to develop 89Zr-labelled CI-8993 and validate PET imaging and quantitation in preclinical models prior to a planned human bioimaging trial. METHODS: CI-8993 and human isotype IgG1 control were conjugated to the metal ion chelator p-isothiocyanatobenzyl-desferrioxamine (Df). Quality of conjugates were assessed by SE-HPLC, SDS-PAGE, and FACS. After radiolabelling with zirconium-89 (89Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. [89Zr]Zr-Df-CI-8993 alone (1 mg/kg, 4.6 MBq) or in combination with 30 mg/kg unlabelled CI-8993, as well as isotype control [89Zr]Zr-Df-IgG1 (1 mg/kg, 4.6 MBq) were assessed in human VISTA knock-in female (C57BL/6 N-Vsirtm1.1(VSIR)Geno, huVISTA KI) or control C57BL/6 mice bearing syngeneic MB49 bladder cancer tumours; and in BALB/c nu/nu mice bearing pancreatic Capan-2 tumours. RESULTS: Stable constructs with an average chelator-to-antibody ratio of 1.81 were achieved. SDS-PAGE and SE-HPLC showed integrity of CI-8993 was maintained after conjugation; and ELISA indicated no impact of conjugation and radiolabelling on binding to human VISTA. PET imaging and biodistribution in MB49 tumour-bearing huVISTA KI female mice showed specific localisation of [89Zr]Zr-Df-CI-8993 to VISTA in spleen and tumour tissues expressing human VISTA. Specific tumour uptake was also demonstrated in Capan-2 xenografted BALB/c nu/nu mice. CONCLUSIONS: We radiolabelled and validated [89Zr]Zr-Df-CI-8993 for specific binding to huVISTA in vivo. Our results demonstrate that 89Zr-labelled CI-8993 is now suitable for targeting and imaging VISTA expression in human trials.
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PURPOSE: The recent development and approval of new diagnostic imaging and therapy approaches in the field of theranostics have revolutionised nuclear medicine practice. To ensure the provision of these new imaging and therapy approaches in a safe and high-quality manner, training of nuclear medicine physicians and qualified specialists is paramount. This is required for trainees who are learning theranostics practice, and for ensuring minimum standards for knowledge and competency in existing practising specialists. METHODS: To address the need for a training curriculum in theranostics that would be utilised at a global level, a Consultancy Meeting was held at the IAEA in May 2023, with participation by experts in radiopharmaceutical therapy and theranostics including representatives of major international organisations relevant to theranostics practice. RESULTS: Through extensive discussions and review of existing curriculum and guidelines, a harmonised training program for theranostics was developed, which aims to ensure safe and high quality theranostics practice in all countries. CONCLUSION: The guiding principles for theranostics training outlined in this paper have immediate relevance for the safe and effective practice of theranostics.
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Medicina Nuclear , Humanos , Medicina Nuclear/educação , Nanomedicina Teranóstica , CurrículoRESUMO
The paper describes an investigation of phase decomposition of apatite lattice doped with rare earth ions (cerium, samarium, and holmium) at temperatures ranging from 25-1200 °C. The rare-earth ion-doped apatite minerals were synthesized using the sol-gel method. In situ high-temperature powder X-ray diffraction (XRD) was used to observe the phase changes and the lattice parameters were analyzed to ascertain the crystallographic transformations. The expansion coefficient of the compounds was determined, and it was found that the c-axis was the most expandable due to relatively weak chemical bonds along the c-crystallographic axis. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to examine the decomposition properties of the materials. Due to rare earth ion doping, the produced materials had slightly variable decomposition behaviour. The cerium and samarium ions were present in multiple oxidation states (Ce3+, Ce4+, Sm3+, Sm2+), whereas only Ho3+ ions were observed. Rare earth ion substitution affects tri-calcium phosphate proportion during decomposition by regulating concentrations of vacancies. X-ray photoelectron spectroscopy (XPS) analysis indicated that cerium and samarium ion-doped apatite yielded only 25 % tricalcium phosphate during decomposition. This finding advances our understanding of apatite structures, with implications for various high-temperature processes like calcination, sintering, hydrothermal processing, and plasma spraying.
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BACKGROUND: In-vivo diffusion tensor cardiovascular magnetic resonance (DT-CMR) is an emerging technique for microstructural tissue characterization in the myocardium. Most studies are performed at 3T, where higher signal-to-noise ratio (SNR) should benefit this signal-starved method. However, a few studies have suggested that DT-CMR is possible at 1.5T, where echo planar imaging artifacts may be less severe and 1.5T hardware is more widely available. METHODS: We recruited 20 healthy volunteers and performed mid-ventricular short-axis DT-CMR at 1.5T and 3T. Acquisitions were performed at peak systole and end-diastole using both stimulated echo acquisition mode (STEAM) and motion-compensated spin-echo (MCSE) sequences at matched spatial resolutions. DT-CMR parameters were averaged over the left ventricle and compared between 1.5T and 3T sequences using both datasets with and without the blow reference data included. RESULTS: Eleven (1.5T) and 12 (3T) diastolic MCSE acquisitions were rejected as the helix angle (HA) demonstrated <50% normal appearance circumferentially or the acquisition was abandoned due to poor image quality; a maximum of one acquisition was rejected for other datasets. Subjective HA map quality was significantly better at 3T than 1.5T for STEAM (p < 0.05), but not for MCSE and other DT-CMR quality measures were consistent with improvements in STEAM at 3T over 1.5T. When blow data were excluded, no significant differences in mean diffusivity were observed between field strengths, but fractional anisotropy was significantly higher at 1.5T than 3T for STEAM systole (p < 0.05). Absolute second eigenvector orientation (E2A, sheetlet angle) was significantly higher at 1.5T than 3T for MCSE systole and STEAM diastole, but significantly lower for STEAM systole (all p < 0.05). Transmural HA distribution was less steep at 1.5T than 3T for STEAM diastole data (p < 0.05). SNR was higher at 3T than 1.5T for all acquisitions (p < 0.05). CONCLUSION: While 3T provides benefits in terms of SNR, both STEAM and MCSE can be performed at 1.5T. However, MCSE is unreliable in diastole at both field strengths and STEAM benefits from the improved SNR at 3T over 1.5T. Future clinical research studies may be able to leverage the wider availability of 1.5T CMR hardware where MCSE acquisitions are desirable.
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CD4+CD25+FOXP3+ regulatory T (Treg) cells control immunological tolerance. Treg cells are generated in the thymus (tTreg) or in the periphery. Their superior lineage fidelity makes tTregs the preferred cell type for adoptive cell therapy (ACT). How human tTreg cells develop is incompletely understood. By combining single-cell transcriptomics and flow cytometry, we in this study delineated three major Treg developmental stages in the human thymus. At the first stage, which we propose to name pre-Treg I, cells still express lineage-inappropriate genes and exhibit signs of TCR signaling, presumably reflecting recognition of self-antigen. The subsequent pre-Treg II stage is marked by the sharp appearance of transcription factor FOXO1 and features induction of KLF2 and CCR7, in apparent preparation for thymic exit. The pre-Treg II stage can further be refined based on the sequential acquisition of surface markers CD31 and GPA33. The expression of CD45RA, finally, completes the phenotype also found on mature recent thymic emigrant Treg cells. Remarkably, the thymus contains a substantial fraction of recirculating mature effector Treg cells, distinguishable by expression of inflammatory chemokine receptors and absence of CCR7. The developmental origin of these cells is unclear and warrants caution when using thymic tissue as a source of stable cells for ACT. We show that cells in the major developmental stages can be distinguished using the surface markers CD1a, CD27, CCR7, and CD39, allowing for their viable isolation. These insights help identify fully mature tTreg cells for ACT and can serve as a basis for further mechanistic studies into tTreg development.