Effects of fish oil supplementation on learning and behaviour of children from Australian Indigenous remote community schools : a randomised controlled trial

Omega-3 fatty acids are essential for brain function. We recruited 409 children aged 3–13 years (M=8.27, SD=2.17) for a randomised controlled trial supplementing with placebo or fish oil capsules (providing 750 mg docosahexaenoic plus eicosapentaenoic acids, and 60 mg gamma linolenic acid/school day) for 20 school weeks (Phase 1) followed by one-way crossover to fish oil (Phase 2). Children undertook assessments of reading, spelling and non-verbal cognitive development (Draw-A-Person) at baseline, 20 and 40 weeks. Teachers completed Conners Behaviour Rating Scales (CBRS). The treatment group showed improvements in Draw-A-Person compared with the placebo during Phase 1 (p=0.029), with strongest effects in Indigenous 7–12 year olds (p=0.008). The placebo group showed significant within-group improvements after switching to treatment (p<0.001). There was no treatment effect for reading or spelling, and CBRS data were unable to be analysed. These findings may be understood in the context that sustained school attendance and nutrition interact to produce school-related achievement.

Cytotoxicity Associated with Artemis Overexpression After Lentiviral Vector-Mediated Gene Transfer

Artemis is one of the newest proteins identified in V(D)J recombination. Deficiency of functional Artemis can result in severe combined immunodeficiency (SCID). In this article by Multhaup and colleagues, the authors conduct preclinical in vitro studies examining the safety and efficacy of lentiviral-mediated delivery of Artemis in Artemis-deficient mammalian cells

Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment

Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types

Extensive preclinical evaluation of lutetium-177-labeled PSMA-specific tracers for prostate cancer radionuclide therapy

Purpose: Various radiolabeled prostate-specific membrane antigen (PSMA)–targeting tracers are clinically applied for prostate cancer (PCa) imaging and targeted radionuclide therapy. The PSMA binding affinities, biodistribution, and DNA-damaging capacities of these radiotracers have not yet been compared in detail. A major concern of PSMA-targeting radiotracers is the toxicity in other PSMA-expressing organs, such as the salivary glands, thus demanding careful evaluation of the most optimal and safest radiotracer. In this extensive preclinical study, we evaluated the clinically applied PSMA-targeting small molecule inhibitors DOTA-PSMA-617 (PSMA-617) and DOTAGA-PSMA-I&T (PSMA-I&T) and the PSMA nanobody DOTA-JVZ-007 (JVZ-007) using PSMA-expressing cell lines, a unique set of PCa patient-derived xenografts (PDX) and healthy human tissues. Methods and results: In vitro displacement studies on PSMA-expressing cells and cryosections of a PSMA-positive PDX revealed high and specific binding affinity for all three tracers labeled with lutetium-177 with IC50 values in the nanomolar range. Interestingly, [177Lu]Lu-JVZ-007 could not be displaced by PSMA-617 or PSMA-I&T, suggesting that this tracer targets an alternative binding site. Autoradiography assays on cryosections of human salivary and renal tissues revealed [177Lu]Lu-PSMA-617 to have the lowest binding to these healthy organs compared with [177Lu]Lu-PSMA-I&T. In vivo biodistribution assays confirmed the in vitro results with comparable tumor uptake of [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T at all timepoints, resulting in induction of similar levels of DNA double-strand breaks in the tumors. However, [177Lu]Lu-PSMA-I&T demonstrated approximately 40× higher renal uptake at 4 and 8 h post injection resulting in an unfavorable tumor-to-kidney ratio. Conclusion: [177Lu]Lu-PSMA-617 has the most favorable biodistribution in mice as well as more favorable binding characteristics in vitro in PSMA-positive cells and human kidney and salivary gland specimens compared with [177Lu]Lu-PSMA-I&T and [177Lu]Lu-JVZ-007. Based on our preclinical evaluation, [177Lu]Lu-PSMA-617 is the best performing tracer to be taken further into clinical evaluation for PSMA-targeted radiotherapeutic development although with careful evaluation of the tracer binding to PSMA-expressing organs

Feasibility of Implementing Infant Home Visiting in a Central Australian Aboriginal Community

© 2018, The Author(s). The Australian Nurse-Family-Partnership Program, an adaption of the Olds’ Nurse-Family-Partnership (NFP), commenced in Alice Springs in 2009 (Central Australia FPP), aiming to improve the health and social outcomes of Aboriginal mothers and infants. This study explores the feasibility of NFP implementation in a remote Australian Aboriginal community. Feasibility was defined by programme uptake by eligible women, retention in the programme, actual vs. scheduled visits and extent of programme content delivery. Programme uptake was established from pregnancy data in the patient Clinical Information System and programme referrals to December 31, 2015. Rates of withdrawal, retention and content delivery were derived from FPP data and compared with published NFP data. Modified Poisson regression was used to identify client characteristics associated with retention beyond the child’s first birthday. There were 469 valid referrals (43% of eligible pregnancies) and 299 women with at least one completed home visit by December 31, 2015. Of these, 41% completed the programme to the child’s second birthday and 53% beyond the child’s first birthday. Dominant reasons for leaving were “moved out of service area” (35%) and “declined further participation” (35%). There was a statistically significant positive association for programme retention with later gestational age at referral (RR = 1.27, p value = 0.03). A high proportion (75%) of scheduled visits was achieved and high delivery of programme content (80%). Central Australia FPP is the first implementation of the NFP model in a remote Aboriginal community. This study found that it can be implemented successfully in this setting. Outcome evaluation is needed to test achievement of hypothesised benefits