BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome.

Histone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A monoubiquitylation (H2AK119ub1), which is enriched at Polycomb-repressed gene promoters but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we found that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive genome-wide accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 preferentially counteracts Ser5 phosphorylation on the C-terminal domain of RNA polymerase II at gene regulatory elements and causes reductions in transcription and transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes, which leads to their derepression, providing a potential molecular rationale for why the BAP1 ortholog in Drosophila has been characterized as a Polycomb group gene. Together, these observations reveal that the transcriptional potential of the genome can be modulated by regulating the levels of a pervasive histone modification.

PRC1 Catalytic Activity Is Central to Polycomb System Function.

The Polycomb repressive system is an essential chromatin-based regulator of gene expression. Despite being extensively studied, how the Polycomb system selects its target genes is poorly understood, and whether its histone-modifying activities are required for transcriptional repression remains controversial. Here, we directly test the requirement for PRC1 catalytic activity in Polycomb system function. To achieve this, we develop a conditional mutation system in embryonic stem cells that completely removes PRC1 catalytic activity. Using this system, we demonstrate that catalysis by PRC1 drives Polycomb chromatin domain formation and long-range chromatin interactions. Furthermore, we show that variant PRC1 complexes with DNA-binding activities occupy target sites independently of PRC1 catalytic activity, providing a putative mechanism for Polycomb target site selection. Finally, we discover that Polycomb-mediated gene repression requires PRC1 catalytic activity. Together these discoveries provide compelling evidence that PRC1 catalysis is central to Polycomb system function and gene regulation.

A Behavioral Syndrome Linking Boldness and Flexibility Facilitates Invasion Success in Sticklebacks.

AbstractFor a species to expand its range, it needs to be good at dispersing and also capable of exploiting resources and adapting to different environments. Therefore, behavioral and cognitive traits could play key roles in facilitating invasion success. Marine threespined sticklebacks (Gasterosteus aculeatus) have repeatedly colonized freshwater environments and rapidly adapted to them. Here, by comparing the behavior of hundreds of lab-reared sticklebacks from six different populations, we show that marine sticklebacks are bold, while sticklebacks that have become established in freshwater lakes are flexible. Moreover, boldness and flexibility are negatively correlated with one another at the individual, family, and population levels. These results support the hypothesis that boldness is favored in invaders during the initial dispersal stage, while flexibility is favored in recent immigrants during the establishment stage, and they suggest that the link between boldness and flexibility facilitates success during both the dispersal stage and the establishment stage. This study adds to the growing body of work showing the importance of behavioral correlations in facilitating colonization success in sticklebacks and other organisms.

Impact of solitary pulmonary nodule size on qualitative and quantitative assessment using 18F-fluorodeoxyglucose PET/CT: the SPUTNIK trial.

PURPOSE: To compare qualitative and semi-quantitative PET/CT criteria, and the impact of nodule size on the diagnosis of solitary pulmonary nodules in a prospective multicentre trial. METHODS: Patients with an SPN on CT ≥ 8 and ≤ 30 mm were recruited to the SPUTNIK trial at 16 sites accredited by the UK PET Core Lab. Qualitative assessment used a five-point ordinal PET-grade compared to the mediastinal blood pool, and a combined PET/CT grade using the CT features. Semi-quantitative measures included SUVmax of the nodule, and as an uptake ratio to the mediastinal blood pool (SURBLOOD) or liver (SURLIVER). The endpoints were diagnosis of lung cancer via biopsy/histology or completion of 2-year follow-up. Impact of nodule size was analysed by comparison between nodule size tertiles. RESULTS: Three hundred fifty-five participants completed PET/CT and 2-year follow-up, with 59% (209/355) malignant nodules. The AUCs of the three techniques were SUVmax 0.87 (95% CI 0.83;0.91); SURBLOOD 0.87 (95% CI 0.83; 0.91, p = 0.30 versus SUVmax); and SURLIVER 0.87 (95% CI 0.83; 0.91, p = 0.09 vs. SUVmax). The AUCs for all techniques remained stable across size tertiles (p > 0.1 for difference), although the optimal diagnostic threshold varied by size. For nodules < 12 mm, an SUVmax of 1.75 or visual uptake equal to the mediastinum yielded the highest accuracy. For nodules > 16 mm, an SUVmax ≥ 3.6 or visual PET uptake greater than the mediastinum was the most accurate. CONCLUSION: In this multicentre trial, SUVmax was the most accurate technique for the diagnosis of solitary pulmonary nodules. Diagnostic thresholds should be altered according to nodule size. TRIAL REGISTRATION: ISRCTN - ISRCTN30784948. ClinicalTrials.gov - NCT02013063.

Predictors of individual variation in reversal learning performance in three-spined sticklebacks.

Behavioral flexibility is a type of phenotypic plasticity that can influence how animals cope with environmental change and is often measured with a reversal learning paradigm. The goal of this study was to understand why individuals differ in behavioral flexibility, and whether individual differences in behavioral flexibility fit the predictions of coping styles theory. We tested whether individual variation in flexibility correlates with response to novelty (response to a novel object), boldness (emergence into a novel environment), and behavioral persistence (response to a barrier), and tested for trade-offs between how quickly individuals learn an initial discrimination and flexibility. We compare results when reversal learning performance is measured during an early step of reversal learning (e.g. the number of errors during the first reversal session) to when reversal learning performance is measured by time to criterion. Individuals that made fewer mistakes during an early step of reversal learning spent more time away from the novel object, were less bold, less persistent, and performed worse during initial discrimination learning. In contrast, time to criterion was not correlated with any of the behaviors measured. This result highlights the utility of dissecting the steps of reversal learning to better understand variation in behavioral flexibility. Altogether, this study suggests that individuals differ in flexibility because flexibility is a key ingredient to their overall integrated strategy for coping with environmental challenges.

CT-based texture analysis potentially provides prognostic information complementary to interim fdg-pet for patients with hodgkin's and aggressive non-hodgkin's lymphomas.

OBJECTIVES: The purpose of this study was to investigate the ability of computed tomography texture analysis (CTTA) to provide additional prognostic information in patients with Hodgkin's lymphoma (HL) and high-grade non-Hodgkin's lymphoma (NHL). METHODS: This retrospective, pilot-study approved by the IRB comprised 45 lymphoma patients undergoing routine 18F-FDG-PET-CT. Progression-free survival (PFS) was determined from clinical follow-up (mean-duration: 40 months; range: 10-62 months). Non-contrast-enhanced low-dose CT images were submitted to CTTA comprising image filtration to highlight features of different sizes followed by histogram-analysis using kurtosis. Prognostic value of CTTA was compared to PET FDG-uptake value, tumour-stage, tumour-bulk, lymphoma-type, treatment-regime, and interim FDG-PET (iPET) status using Kaplan-Meier analysis. Cox regression analysis determined the independence of significantly prognostic imaging and clinical features. RESULTS: A total of 27 patients had aggressive NHL and 18 had HL. Mean PFS was 48.5 months. There was no significant difference in pre-treatment CTTA between the lymphoma sub-types. Kaplan-Meier analysis found pre-treatment CTTA (medium feature scale, p=0.010) and iPET status (p<0.001) to be significant predictors of PFS. Cox analysis revealed that an interaction between pre-treatment CTTA and iPET status was the only independent predictor of PFS (HR: 25.5, 95% CI: 5.4-120, p<0.001). Specifically, pre-treatment CTTA risk stratified patients with negative iPET. CONCLUSION: CTTA can potentially provide prognostic information complementary to iPET for patients with HL and aggressive NHL. KEY POINTS: • CT texture-analysis (CTTA) provides prognostic information complementary to interim FDG-PET in Lymphoma. • Pre-treatment CTTA and interim PET status were significant predictors of progression-free survival. • Patients with negative interim PET could be further stratified by pre-treatment CTTA. • Provide precision surveillance where additional imaging reserved for patients at greatest recurrence-risk. • Assists in risk-adapted treatment strategy based on interim PET and CTTA.

Can CT measures of tumour heterogeneity stratify risk for nodal metastasis in patients with non-small cell lung cancer?

AIM: To undertake a preliminary assessment of the potential for computed tomography (CT) measurement of tumour heterogeneity to stratify risk of nodal metastasis in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Tumour heterogeneity in CT images from combined positron-emission tomography (PET)/CT examinations in 150 consecutive patients with NSCLC was assessed using CT texture analysis (CTTA). The short axis diameter of the largest mediastinal node was also measured. Forty-two patients without distant metastases subsequently had tumour nodal status confirmed at surgery (n=26) or endobronchial ultrasound (EBUS; n=16). CTTA parameters and largest nodal diameter were related to nodal status using the rank correlation and the risk ratio for each nodal stage (>N0, >N1, >N2) was compared between patients categorised as high and low risk by CTTA or nodal size. The most significant predictor of nodal status was related to overall survival using Kaplan-Meier analysis. RESULTS: N-stage was more significantly correlated with CTTA than nodal diameter (Rs = -0.39, p=0.011, Rs = -0.45, p=0.0025, Rs = -0.40, p=0.0091 for normalised standard deviation (SD), normalised entropy and kurtosis respectively; Rs = -0.39, p=0.042 for nodal diameter). The presence of two or more high-risk CTTA values was the greatest risk factor for mediastinal metastasis (risk ratio: 11.0, 95% confidence interval: 1.56-77.8, p=0.0014) and was associated with significantly poorer overall survival (p=0.016). CONCLUSION: CTTA in NSCLC is related to nodal status in patients without distant metastases and has the potential to inform selection of investigative strategies for the assessment of mediastinal malignancy.

Public-private partnerships in the response to HIV: experience from the resource industry in Papua New Guinea.

CONTEXT: Although Papua New Guinea (PNG) has made some progress in social development over the past 30 years, the country's Human Development Index has slowed in recent years, placing it below the regional average. In 2012, the estimated HIV prevalence for adults aged 15-49 years was 0.5% and an estimated 25,000 people were living with HIV. Although reduced from previous estimates, the country's HIV prevalence remains the highest in the South Pacific region. While the faith-based and non-governmental sectors have engaged in HIV interventions since the epidemic began, until recently the corporate sector has remained on the margins of the national response. In 2008, the country's largest oil and gas producer began partnering with national and provincial health authorities, development partners and global financing institutions to contribute to the national HIV strategy and implementation plan. This article provides an overview of public-private partnerships (PPPs) and their application to public health program management, and then describes the PPP that was developed in PNG. ISSUES: Innovative national and local PPPs have become a core component of healthcare strategy in many countries. PPPs have many forms and their use in low- and middle-income countries has progressively demonstrated increased service outputs and health outcomes beyond what the public sector alone could achieve. A PPP in PNG has resulted in an oil and gas producer engaging in the response to HIV, including managing the country's US$46 million HIV grant from the Global Fund to Fight AIDS, Tuberculosis and Malaria. LESSONS LEARNED: Given the increasing expectations of the international community in relation to corporate responsibility and sustainability, the role of the corporate sector in countries like PNG is critical. Combining philanthropic investment with business strategy, expertise and organisational resource can contribute to enhancing health system structures and capacity.

Conservation applications of niche modeling: Native and naturalized ferns may compete for limited Hawaiian dryland habitat.

Premise: Competition from naturalized species and habitat loss are common threats to native biodiversity and may act synergistically to increase competition for decreasing habitat availability. We use Hawaiian dryland ferns as a model for the interactions between land-use change and competition from naturalized species in determining habitat availability. Methods: We used fine-resolution climatic variables and carefully curated occurrence data from herbaria and community science repositories to estimate the distributions of Hawaiian dryland ferns. We quantified the degree to which naturalized ferns tend to occupy areas suitable for native species and mapped the remaining available habitat given land-use change. Results: Of all native species, Doryopteris angelica had the lowest percentage of occurrences of naturalized species in its suitable area while D. decora had the highest. However, all Doryopteris spp. had a higher percentage overlap, while Pellaea ternifolia had a lower percentage overlap, than expected by chance. Doryopteris decora and D. decipiens had the lowest proportions (<20%) of suitable area covering native habitat. Discussion: Areas characterized by shared environmental preferences of native and naturalized ferns may decrease due to human development and fallowed agricultural lands. Our study demonstrates the value of place-based application of a recently developed correlative ecological niche modeling approach for conservation risk assessment in a rapidly changing and urbanized island ecosystem.

Temperature effects on food supply and chick mortality in tree swallows (Tachycineta bicolor).

Tree swallow (Tachycineta bicolor) breeding success in Ithaca, NY, USA, over the past quarter century has shown generally healthy fledgling production punctuated by years of high nestling mortality. This study tested the potential effects that temperature may have on the food supply and breeding success of swallows. Data from 17 years of daily insect samples were used to relate flying insect abundances to daily maximum temperatures and to define "cold snaps" as strings of consecutive days when the maximum temperatures did not exceed critical temperatures. The distributions of cold snaps and chick mortality events were investigated both through detailed reconstructions of the fates and fate dates of individual chicks, focused on the three breeding seasons of lowest fledging success, and with less detailed brood-level analyses of a larger 11-year dataset including years of more moderate mortality. Mark-recapture analyses of daily brood survival rate (DSR) reveal very strong support for the effects of cold temperatures on brood survival rates, and all the top models agree on a critical temperature of 18.5 °C for insect flight activity in Ithaca. The individual-level analyses, focused on years of higher mortality, favored a 3-day cold snap definition as the most predictive of DSR effects, whereas the larger-scale brood-level analyses revealed 1- and 2-day cold snaps as having the most significant effects on DSR. Regardless, all analyses reveal that, in an age of generally warmer climates, the largest effect of weather on swallow fledgling production is from cold temperatures.

Region Capture Micro-C reveals coalescence of enhancers and promoters into nested microcompartments.

Although enhancers are central regulators of mammalian gene expression, the mechanisms underlying enhancer-promoter (E-P) interactions remain unclear. Chromosome conformation capture (3C) methods effectively capture large-scale three-dimensional (3D) genome structure but struggle to achieve the depth necessary to resolve fine-scale E-P interactions. Here, we develop Region Capture Micro-C (RCMC) by combining micrococcal nuclease (MNase)-based 3C with a tiling region-capture approach and generate the deepest 3D genome maps reported with only modest sequencing. By applying RCMC in mouse embryonic stem cells and reaching the genome-wide equivalent of ~317 billion unique contacts, RCMC reveals previously unresolvable patterns of highly nested and focal 3D interactions, which we term microcompartments. Microcompartments frequently connect enhancers and promoters, and although loss of loop extrusion and inhibition of transcription disrupts some microcompartments, most are largely unaffected. We therefore propose that many E-P interactions form through a compartmentalization mechanism, which may partially explain why acute cohesin depletion only modestly affects global gene expression.

Current status and guidelines for the assessment of tumour vascular support with dynamic contrast-enhanced computed tomography.

Dynamic contrast-enhanced computed tomography (DCE-CT) assesses the vascular support of tumours through analysis of temporal changes in attenuation in blood vessels and tissues during a rapid series of images acquired with intravenous administration of iodinated contrast material. Commercial software for DCE-CT analysis allows pixel-by-pixel calculation of a range of validated physiological parameters and depiction as parametric maps. Clinical studies support the use of DCE-CT parameters as surrogates for physiological and molecular processes underlying tumour angiogenesis. DCE-CT has been used to provide biomarkers of drug action in early phase trials for the treatment of a range of cancers. DCE-CT can be appended to current imaging assessments of tumour response with the benefits of wide availability and low cost. This paper sets out guidelines for the use of DCE-CT in assessing tumour vascular support that were developed using a Delphi process. Recommendations encompass CT system requirements and quality assurance, radiation dosimetry, patient preparation, administration of contrast material, CT acquisition parameters, terminology and units, data processing and reporting. DCE-CT has reached technical maturity for use in therapeutic trials in oncology. The development of these consensus guidelines may promote broader application of DCE-CT for the evaluation of tumour vascularity. Key Points • DCE-CT can robustly assess tumour vascular support • DCE-CT has reached technical maturity for use in therapeutic trials in oncology • This paper presents consensus guidelines for using DCE-CT in assessing tumour vascularity.

Tumour heterogeneity in oesophageal cancer assessed by CT texture analysis: preliminary evidence of an association with tumour metabolism, stage, and survival.

AIM: To undertake a pilot study assessing whether tumour heterogeneity evaluated using computed tomography texture analysis (CTTA) has the potential to provide a marker of tumour aggression and prognosis in oesophageal cancer. MATERIALS AND METHODS: In 21 patients, unenhanced CT images of the primary oesophageal lesion obtained using positron-emission tomography (PET)-CT examinations underwent CTTA. CTTA was carried out using a software algorithm that selectively filters and extracts textures at different anatomical scales between filter values 1.0 (fine detail) and 2.5 (coarse features) with quantification as entropy and uniformity (measures image heterogeneity). Texture parameters were correlated with average tumour 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) uptake [standardized uptake values (SUV(mean) and SUV(max))] and clinical staging as determined by endoscopic ultrasound (nodal involvement) and PET-CT (distant metastases). The relationship between tumour stage, FDG uptake, and texture with survival was assessed using Kaplan-Meier analysis. RESULTS: Tumour heterogeneity correlated with SUV(max) and SUV(mean). The closest correlations were found for SUV(mean) measured as uniformity and entropy with coarse filtration (r=-0.754, p<0.0001; and r=0.748, p=0.0001 respectively). Heterogeneity was also significantly greater in patients with clinical stage III or IV for filter values between 1.0 and 2.0 (maximum difference at filter value 1.5: entropy: p=0.027; uniformity p=0.032). The median (range) survival was 21 (4-34) months. Tumour heterogeneity assessed by CTTA (coarse uniformity) was an independent predictor of survival [odds ratio (OR)=4.45 (95% CI: 1.08, 18.37); p=0.039]. CONCLUSION: CTTA assessment of tumour heterogeneity has the potential to identify oesophageal cancers with adverse biological features and provide a prognostic indicator of survival.

Low NAD+ Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice.

Advanced paternal age has increasingly been recognized as a risk factor for male fertility and progeny health. While underlying causes are not well understood, aging is associated with a continuous decline of blood and tissue NAD+ levels, as well as a decline of testicular functions. The important basic question to what extent ageing-related NAD+ decline is functionally linked to decreased male fertility has been difficult to address due to the pleiotropic effects of aging, and the lack of a suitable animal model in which NAD+ levels can be lowered experimentally in chronologically young adult males. We therefore developed a transgenic mouse model of acquired niacin dependency (ANDY), in which NAD+ levels can be experimentally lowered using a niacin-deficient, chemically defined diet. Using ANDY mice, this report demonstrates for the first time that decreasing body-wide NAD+ levels in young adult mice, including in the testes, to levels that match or exceed the natural NAD+ decline observed in old mice, results in the disruption of spermatogenesis with small testis sizes and reduced sperm counts. ANDY mice are dependent on dietary vitamin B3 (niacin) for NAD+ synthesis, similar to humans. NAD+-deficiency the animals develop on a niacin-free diet is reversed by niacin supplementation. Providing niacin to NAD+-depleted ANDY mice fully rescued spermatogenesis and restored normal testis weight in the animals. The results suggest that NAD+ is important for proper spermatogenesis and that its declining levels during aging are functionally linked to declining spermatogenesis and male fertility. Functions of NAD+ in retinoic acid synthesis, which is an essential testicular signaling pathway regulating spermatogonial proliferation and differentiation, may offer a plausible mechanism for the hypospermatogenesis observed in NAD+-deficient mice.

Endogenous metabolism in endothelial and immune cells generates most of the tissue vitamin B3 (nicotinamide).

In mammals, nicotinamide (NAM) is the primary NAD precursor available in circulation, a signaling molecule, and a precursor for methyl-nicotinamide (M-NAM) synthesis. However, our knowledge about how the body regulates tissue NAM levels is still limited. Here we demonstrate that dietary vitamin B3 partially regulates plasma NAM and NAM-derived metabolites, but not their tissue levels. We found that NAD de novo synthesis from tryptophan contributes to plasma and tissue NAM, likely by providing substrates for NAD-degrading enzymes. We also demonstrate that tissue NAM is mainly generated by endogenous metabolism and that the NADase CD38 is the main enzyme that produces tissue NAM. Tissue-specific CD38-floxed mice revealed that CD38 activity on endothelial and immune cells is the major contributor to tissue steady-state levels of NAM in tissues like spleen and heart. Our findings uncover the presence of different pools of NAM in the body and a central role for CD38 in regulating tissue NAM levels.

Live-cell single particle tracking of PRC1 reveals a highly dynamic system with low target site occupancy.

Polycomb repressive complex 1 (PRC1) is an essential chromatin-based repressor of gene transcription. How PRC1 engages with chromatin to identify its target genes and achieve gene repression remains poorly defined, representing a major hurdle to our understanding of Polycomb system function. Here, we use genome engineering and single particle tracking to dissect how PRC1 binds to chromatin in live mouse embryonic stem cells. We observe that PRC1 is highly dynamic, with only a small fraction stably interacting with chromatin. By integrating subunit-specific dynamics, chromatin binding, and abundance measurements, we discover that PRC1 exhibits low occupancy at target sites. Furthermore, we employ perturbation approaches to uncover how specific components of PRC1 define its kinetics and chromatin binding. Together, these discoveries provide a quantitative understanding of chromatin binding by PRC1 in live cells, suggesting that chromatin modification, as opposed to PRC1 complex occupancy, is central to gene repression.

Molecular imaging with dynamic contrast-enhanced computed tomography.

Dynamic contrast-enhanced computed tomography (DCE-CT) is a quantitative technique that employs rapid sequences of CT images after bolus administration of intravenous contrast material to measure a range of physiological processes related to the microvasculature of tissues. By combining knowledge of the molecular processes underlying changes in vascular physiology with an understanding of the relationship between vascular physiology and CT contrast enhancement, DCE-CT can be redefined as a molecular imaging technique. Some DCE-CT derived parameters reflect tissue hypoxia and can, therefore, provide information about the cellular microenvironment. DCE-CT can also depict physiological processes, such as vasodilatation, that represent the physiological consequences of molecular responses to tissue hypoxia. To date the main applications have been in stroke and oncology. Unlike some other molecular imaging approaches, DCE-CT benefits from wide availability and ease of application along with the use of contrast materials and software packages that have achieved full regulatory approval. Hence, DCE-CT represents a molecular imaging technique that is applicable in clinical practice today.

A clinical index for disease activity in cats with chronic enteropathy.

BACKGROUND: There is a need for a clinically useful, quantitative index for measurement of disease activity in cats with chronic enteropathy (CE). OBJECTIVE: To develop a numerical activity index that is of practical value to clinicians treating CE in cats. ANIMALS: Eighty-two cats with CE. METHODS: Retrospective case review of 59 cats diagnosed with inflammatory bowel disease (IBD). Prospective validation study of 23 cats having either IBD or food-responsive enteropathy (FRE). Multivariate regression analysis was used to identify which combination of clinical and laboratory variables were best associated with intestinal inflammation of IBD. This combination of variables was expressed in a score that was used as an activity index for the prospective assessment of disease activity and of the effect of treatment in cats with IBD or FRE. RESULTS: The combination of gastrointestinal signs, endoscopic abnormalities, serum total protein, serum alanine transaminase/alkaline phosphatase activity, and serum phosphorous concentration had the best correlation with histopathologic inflammation and comprise the feline chronic enteropathy activity index (FCEAI). Positive treatment responses in cats with CE were accompanied by significant (P < .05) reductions in FCEAI scores after treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: The FCEAI is a simple numerical measure of inflammatory activity in cats with CE. The scoring index can be reliably used in the initial assessment of disease severity for both IBD and FRE and as a measure of clinical response to treatment for these disorders.

The clinical efficacy of PSMA PET/MRI in biochemically recurrent prostate cancer compared with standard of care imaging modalities and confirmatory histopathology: results of a single-centre, prospective clinical trial.

Prospective evidence for the clinical role and efficacy of prostate specific membrane antigen (PSMA) positron emission tomography (PET)/magnetic resonance imaging (MRI) combining MRI characterization and localization of lesions with PET avidity in comparison to conventional imaging is limited. In a prospective clinical trial, we aimed to evaluate the diagnostic yield and therapeutic impact of PSMA PET/MRI in men with biochemical recurrence (BCR) following curative therapy. A single-centre, prospective clinical trial at the Princess Alexandra Hospital recruited 30 patients with BCR. Patients underwent PSMA PET/MRI and concurrent conventional CT chest, abdomen, pelvis and whole-body bone scan. Biopsy was performed when safety possible for histological correlation of identified lesions. Clinical efficacy and impact of PSMA PET findings were evaluated. 30 patients with BCR were recruited (median PSA 0.69 ng/ml). PSMA avid lesions were present in 21 patients (70%). 23 patients were previously treated with definitive surgery, 6 patients received external beam radiotherapy and 1 patient had low dose rate brachytherapy. A total of 8 of 9 lesions biopsied were positive (88.9% histological correlation). PSMA PET/MRI detected local recurrence (p = 0.005) and pelvic lesions (p = 0.06) more accurately than conventional imaging. PSMA PET/MRI may be useful in staging men with biochemical recurrence, especially when PSA is low. Our data demonstrates a high detection rate, especially for locally recurrent disease, and highlights the role of this modality when PSA is low. This modality has the potential to significantly improve prostate cancer detection and may have implications for earlier salvage treatment, avoidance of futile local therapy and change patient management to lead to improved outcomes.