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Purpose Treatment of late-stage prostate cancer by targeted radiotherapeutics such as 131 I-MIP-1095 and 177 Lu-PSMA-617 has shown encouraging early results. Lu-177 is preferred to I-131 in clinical settings, but targeted radioligand therapy (RLT) with 177 Lu-PSMA-617 has not reached its full potential due to insufficient dose delivery to the tumor. We recently developed a dual-targeting radioiodinated ligand, RPS-027, that targets PSMA and uses albumin binding to enable good tumor uptake and significantly reduced kidney uptake in a preclinical model. Further development of this ligand is limited by the inability to independently modify PSMA and albumin binding and the requirement of I-131 for therapeutic application. We therefore sought to devise a new class of trifunctional ligands for RLT with (1) a high-affinity PSMA-binding domain, (2) an albumin-binding group (ABG), and (3) a chelator for radiometals such as 68 Ga 3+ , 177 Lu 3+ and 225 Ac 3+ . Methods Ligands incorporating a triazolylphenylurea-containing PSMA-targeting group, an N ε -(2-(4-iodophenyl)acetyl)lysine ABG and the bifunctional chelator p -SCN-Bn-DOTA linked by a PEG-containing polymer containing 0,3,4,6,8 or 12 repeats were prepared. PSMA affinity was determined in LNCaP cells and uptake and tissue distribution was studied in mice bearing LNCaP tumor xenografts and compared to 177 Lu-PSMA-617. Imaging studies were performed up to 24 h post-injection (p.i.) using 66 Ga 3+ and biodistribution studies at 4 h, 24 h and 96 h p.i. with 177 Lu 3+ . Results PSMA affinity was high (IC 50  = 1–10 nM) and inversely proportional to the linker length. Tumor uptake correlated with binding affinity and was significantly greater than for 177 Lu-PSMA-617 over 96 h. The highest uptake was achieved with 177 Lu-RPS-063 (30.0 ± 6.9 %ID/g; 4 h p.i.). Kidney uptake was generally high, with the exception of the lowest affinity ligand 177 Lu-RPS-067. Each of the compounds showed slower blood clearance than 177 Lu-PSMA-617, with clearance proportional to linker length. Conclusions The high tumor uptake achieved with these trifunctional ligands predicts larger (up to 4×) doses delivered to the tumor than can be achieved with 177 Lu-PSMA-617. Although PSMA-mediated kidney uptake was also observed, the exceptional area under the curve (AUC) in the tumor warrants further investigation of these novel ligands as candidates for RLT.

Purpose Current clinical imaging of PSMA-positive prostate cancer by positron emission tomography (PET) mainly features 68 Ga-labeled tracers, notably [ 68 Ga]Ga-PSMA-HBED-CC. The longer half-life of fluorine-18 offers significant advantages over Ga-68, clinically and logistically. We aimed to develop high-affinity PSMA inhibitors labeled with fluorine-18 as alternative tracers for prostate cancer. Methods Six triazolylphenyl ureas and their alkyne precursors were synthesized from the Glu-urea-Lys PSMA binding moiety. PSMA affinity was determined in a competitive binding assay using LNCaP cells. The [ 18 F]triazoles were isolated following a Cu(I)-catalyzed click reaction between the alkynes and [ 18 F]fluoroethylazide. The 18 F-labeled compounds were evaluated in nude mice bearing LNCaP tumors and compared to [ 68 Ga]Ga-PSMA-HBED-CC and [ 18 F]DCFPyL. Biodistribution studies of the two tracers with the highest imaged-derived tumor uptake and highest PSMA affinity were undertaken at 1 h, 2 h and 4 h post-injection (p.i.), and co-administration of PMPA was used to determine whether uptake was PSMA-specific. Results F-18-labeled triazolylphenyl ureas were prepared with a decay-corrected RCY of 20–40 %, >98 % radiochemical and chemical purity, and specific activity of up to 391 GBq/μmol. PSMA binding (IC 50 ) ranged from 3–36 nM. The position of the triazole influenced tumor uptake (3 > 4 > 2), and direct conjugation of the triazole with the phenylurea moiety was preferred to insertion of a spacer group. Image-derived tumor uptake ranged from 6–14 %ID/g at 2 h p.i., the time of maximum tumor uptake; uptake of [ 68 Ga]Ga-PSMA-HBED-CC and [ 18 F]DCFPyL was 5–6 %ID/g at 1–3 h p.i., the time of maximum tumor uptake. Biodistribution studies of the two most promising compounds gave maximum tumor uptakes of 10.9 ± 1.0 % and 14.3 ± 2.5 %ID/g, respectively, as compared to 6.27 ± 1.44 %ID/g for [ 68 Ga]Ga-PSMA-HBED-CC. Conclusions Six [ 18 F]triazolylphenyl ureas were prepared in good radiochemical yield. Compounds showed PSMA-specific uptake in LNCaP tumors as high as 14 % ID/g, more than a 2-fold increase over [ 68 Ga]Ga-PSMA-HBED-CC. The facile and high-yielding radiosynthesis of these 18 F-labeled triazoles as well as their promising in vitro and in vivo characteristics make them worthy of clinical development for PET imaging of prostate cancer.

Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [68Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of 68Ga. We screened a library of >200 fluorine-containing structural derivatives of AMD-3465 to identify promising candidates for in vivo imaging of CXCR4 expression by positron emission tomography (PET). Compounds containing fluoroethyltriazoles consistently achieved higher docking scores. Six of these higher scoring compounds were radiolabeled by click chemistry and evaluated in PC3-CXCR4 cells and BALB/c mice bearing bilateral PC3-WT and PC3-CXCR4 xenograft tumors. The apparent CXCR4 affinity of the ligands was relatively low, but tumor uptake was CXCR4-specific. The tumor uptake of [18F]RPS-534 (7.2 ± 0.3 %ID/g) and [18F]RPS-547 (3.1 ± 0.5 %ID/g) at 1 h p.i. was highest, leading to high tumor-to-blood, tumor-to-muscle, and tumor-to-lung ratios. Total cell-associated activity better predicted in vivo tumor uptake than did the docking score or apparent CXCR4 affinity. By this metric, and on the basis of their high yielding radiosynthesis, high tumor uptake, and good contrast to background, [18F]RPS-547, and especially [18F]RPS-534, are promising 18F-labeled candidates for imaging CXCR4 expression.

In 2007 the Department of Education introduced the standards-based Advanced Certificate in Education: School Management and Leadership. The standardisation of leadership and management development in South African schools has been uncritically accepted by most academics and professionals. The purpose of this article is to problematise the standardisation of leadership and management development, using the critiques of the Interstate School Leadership Licensure Consortium standards of the United States as the basis of analysis. This article indicates the following areas of concern: the lack of clarity regarding the empirical basis of the unit standards; the incorporation of certain non-empirical ideals into the programme; the generic instead of contextualised approaches to leadership and management development; the use of a generic programme for school principals, deputy principals, and heads of department in spite of their differentiated roles; and the lack of a single, generally accepted policy document containing an exposition of the role of school principals that could form the basis of leadership and management development. This emphasises the need for the unit standards to be subjected to regular scrutiny and revision to address areas of concern and to ensure relevance thereof in the face of current developments and empirical research findings.

Cancer cells require lipids to fulfill energetic, proliferative, and signaling requirements. Even though these cells can take up exogenous fatty acids, the majority exhibit a dependency on de novo fatty acid synthesis. Fatty acid synthase (FASN) is the rate-limiting enzyme in this process. Expression and activity of FASN is elevated in multiple cancers, where it correlates with disease progression and poor prognosis. These observations have sparked interest in developing methods of detecting FASN expression in vivo. One promising approach is the imaging of radiolabeled molecular probes targeting FASN by positron emission tomography (PET). However, although [11C]acetate uptake by prostate cancer cells correlates with FASN expression, no FASN-specific PET probes currently exist. Our aim was to synthesize and evaluate a series of small molecule triazolones based on GSK2194069, an FASN inhibitor with IC50 = 7.7 ± 4.1 nM, for PET imaging of FASN expression. These triazolones were labeled with carbon-11 in good yield and excellent radiochemical purity, and binding to FASN-positive LNCaP cells was significantly higher than FASN-negative PC3 cells. Despite these promising characteristics, however, these molecules exhibited poor in vivo pharmacokinetics and were predominantly retained in lymph nodes and the hepatobiliary system. Future studies will seek to identify structural modifications that improve tumor targeting while maintaining the excretion profile of these first-generation 11C-methyltriazolones.

Emerging interest in extending the plasma half-life of small molecule radioligands warrants a consideration of the appropriate radionuclide for PET imaging at longer time points (>8 h). Among candidate positron-emitting radionuclides, 66Ga (t1/2 = 9.5 h, β+ = 57%) has suitable nuclear and chemical properties for the labeling and PET imaging of radioligands of this profile. We investigated the value of 66Ga to preclinical screening and the evaluation of albumin-binding PSMA-targeting small molecules. 66Ga was produced by irradiation of a natZn target. 66Ga3+ ions were separated from Zn2+ ions by an optimized UTEVA anion exchange column that retained 99.99987% of Zn2+ ions and allowed 90.2 ± 2.8% recovery of 66Ga3+. Three ligands were radiolabeled in 46.4 ± 20.5%; radiochemical yield and >90% radiochemical purity. Molar activity was 632 ± 380 MBq/µmol. Uptake in the tumor and kidneys at 1, 3, 6, and 24 h p.i. was determined by µPET/CT imaging and more completely predicted the distribution kinetics than uptake of the [68Ga]Ga-labeled ligands did. Although there are multiple challenges to the use of 66Ga for clinical PET imaging, it can be a valuable research tool for ligand screening and preclinical imaging beyond 24 h.

The current study describes how a community-partnered participatory research (CPPR) model was used to enhance hair cortisol research engagement among low-income adults of diverse ethnicities and sexual and gender identities. Participants' reported motivations and concerns surrounding providing a hair sample are also described. Participants from a larger longitudinal study were invited to provide a hair sample and/or complete acceptability interviews. Results indicated that 71% of all persons (N=133) contacted participated in the current study, of whom 82% provided hair samples. Several themes emerged from the interviews indicating that participants were motivated to provide a hair sample due to internal and external factors; however, concerns about mistrust of research remained. Thus, collecting biospecimens in research with underserved groups requires careful consideration of benefits and risks to the individual and their communities. Our results provide guidelines for engaging low-income racially/ethnically and sexually diverse community members in biospecimen research to understand stress-health relationships.

IntroductionDepression is the leading cause of adult disability and common among sexual and gender minority (SGM) adults. The current study builds on findings showing the effectiveness of depression quality improvement (QI) and delivery of cognitive behavioural therapy (CBT) skills provided by community health workers in reducing depression. Depression QI approaches across healthcare and social/community services in safety-net settings have shown improvements in mental wellness, mental health quality of life and depression over 12 months. Further, a randomised study showed improved depression among low-income racial/ethnic minorities enrolled in a CBT-informed resiliency class (Building Resilience and Increasing Community Hope (B-RICH)). The current protocol describes a comparativeness effectiveness study to evaluate whether predominantly low-income, SGM racial/ethnic minority adults randomised to a CBT-informed resiliency class have improvements in depressive symptoms over and above community-engaged QI resources and training only.Methods and analysisThe study approached three clusters of four to five programs serving predominantly SGM and racial/ethnic minority communities in the USA: two clusters in Los Angeles, California, and one in New Orleans, Louisiana. Clusters are comprised of one primary care, one mental health and two to three community agencies (eg, faith-based, social services/support, advocacy). All programs received depression QI training. The current study employed a community-partnered participatory research model to adapt the CBT-informed resiliency class, B-RICH+, to SGM communities. Study participants were screened and recruited in person from participating programs, and will complete baseline, 6- and 12-month survey follow-ups. Participants were depressed adults (8-item Patient Health Questionnaire ≥10; ≥18 years of age) who provided contact information. Enrolled participants were individually randomised to B-RICH+ or depression QI alone. Primary outcomes are depressive symptoms; secondary outcomes are mental health quality of life, mental wellness and physical health quality of life. Data collection for this study is ongoing.Ethics and disseminationThe current study was approved by the UCLA Institutional Review Board. Study findings will be disseminated through scientific publications and community conferences.Trial registration number https://clinicaltrials.gov/ct2/show/NCT02986126

The Resilience Against Depression Disparities (RADD), a community partnered, randomized comparative effectiveness study, aimed to address mental health in Lesbian, Gay, Bisexual, Transgender, and Queer/Questioning (LGBTQ) racial/ethnic populations in New Orleans and Los Angeles. To describe engagement methods, lessons learned, and recommendations in engaging LGBTQ individuals and agencies throughout the RADD study. RADD used a community partnered participatory research framework to engage LGBTQ community members and agencies. Observational and quantitative data were collected to describe engagement activities and study adaptations from October 2016 to May 2019. Our partnered approach resulted in multiple study adaptations. The principles of cultural humility, coleadership, and addressing health determinants were important to successful engagement with LGBTQ community members and study participants. We recommend maintaining cultural humility as the tenant of all research activities. This project's engagement plan demonstrates that community-academic partnerships can be forged to create and modify existing study models for LGBTQ communities.

In 2007 the Department of Education introduced the standards-based Advanced Certificate in Education: School Management and Leadership. The standardisation of leadership and management development in South African schools has been uncritically accepted by most academics and professionals. The purpose of this article is to problematise the standardisation of leadership and management development, using the critiques of the Interstate School Leadership Licensure Consortium standards of the United States as the basis of analysis. This article indicates the following areas of concern: the lack of clarity regarding the empirical basis of the unit standards; the incorporation of certain non-empirical ideals into the programme; the generic instead of contextualised approaches to leadership and management development; the use of a generic programme for school principals, deputy principals, and heads of department in spite of their differentiated roles; and the lack of a single, generally accepted policy document containing an exposition of the role of school principals that could form the basis of leadership and management development. This emphasises the need for the unit standards to be subjected to regular scrutiny and revision to address areas of concern and to ensure relevance thereof in the face of current developments and empirical research findings.