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Developing CAR T cells for acute myeloid leukemia (AML) has been hampered by a paucity of targets that are expressed on AML blasts and not on hematopoietic progenitor cells (HPCs). Here we demonstrate that GRP78 is expressed on the cell surface of primary AML blasts but not HPCs. To target GRP78, we generate T cell expressing a GRP78-specific peptide-based CAR, which show evidence of minimal fratricide post activation/transduction and antigen-dependent T cell differentiation. GRP78-CAR T cells recognize and kill GRP78-positive AML cells without toxicity to HPCs. In vivo, GRP78-CAR T cells have significant anti-AML activity. To prevent antigen-dependent T cell differentiation, we block CAR signaling and GRP78 cell surface expression post activation by using dasatinib during GRP78-CAR T cell manufacturing. This significantly improves their effector function in vitro and in vivo. Thus, targeting cell surface GRP78-positive AML with CAR T cells is feasible, and warrants further active exploration. There is an unmet need to discover suitable targets for CAR-T therapy in patients with acute myeloid leukemia (AML). Here the authors show that GRP78, a key regulator of the unfolded protein response, is highly expressed on the surface of primary AML blasts, but not on normal lymphocytes and hematopoietic progenitor cells, and that GRP78-CAR T have anti-AML activity in preclinical models.

In recent years, there has been an emphasis on harnessing the immune system for therapeutic interventions. Adoptive cell therapies (ACT) have emerged as an effective option for B-cell derived hematological malignancies. Despite remarkable successes with ACT, immune dysregulation and the leukemia microenvironment can critically alter clinical responses. Therefore, preclinical modeling can contribute to the advancement of ACT for leukemias. Human xenografts, the current mainstay of ACT in vivo models, cannot evaluate the impact of the immunosuppressive leukemia microenvironment on adoptively transferred cells. Syngeneic mouse models utilize murine tumor models and implant them into immunocompetent mice. This provides an alternative model, reducing the need for complicated breeding strategies while maintaining a matched immune system, stromal compartment, and leukemia burden. Syngeneic models that evaluate ACT have analyzed the complexity of cytotoxic T lymphocytes, T cell receptor transgenics, and chimeric antigen receptors. This review examines the immunosuppressive features of the leukemia microenvironment, discusses how preclinical modeling helps predict ACT associated toxicities and dysfunction, and explores publications that have employed syngeneic modeling in ACT studies for the improvement of therapy for leukemias.

Background Evidence suggests that dietary intake of UK children is suboptimal. As schools provide an ideal natural environment for public health interventions, effective and sustainable methods of improving food knowledge and dietary habits in this population must be identified. Project Daire aimed to improve children’s health-related quality of life, wellbeing, food knowledge and dietary habits via two multi-component interventions. Methods Daire was a randomised-controlled, factorial design trial evaluating two interventions across four arms. Primary schools in Northern Ireland were randomised to one of four 6-month intervention arms: i) ‘Nourish’, ii) ‘Engage’, iii) ‘Nourish’ and ‘Engage’ and iv) Control (Delayed). ‘Nourish’ was an intervention aiming to alter the whole-school food environment, provide food-related experiences and exposure to locally produced foods. ‘Engage’ was an age-appropriate, cross-curricular educational intervention on food, agriculture, nutrition science and related careers. Primary outcomes were emotional and behavioural wellbeing and health-related quality of life. A number of secondary outcomes, including dietary intake, cooking competence and food-related knowledge, were also measured. Results Fifteen schools from areas of varying socio-economic status participated in the randomised trial. A total of 903 ( n  = 445 aged 6–7 years and n  = 458 aged 10–11 years) primary school pupils took part. Total Difficulties Score improved in all pupils (6–7 and 10–11 year old pupils) who received the ‘Nourish’ intervention compared with those that did not (adjusted difference in mean = − 0.82; 95% CI -1.46, − 0.17; P  < 0.02). No statistically significant difference in Health-Related Quality of Life was observed. The ‘Nourish’ intervention also produced some changes in school-based dietary behaviour, which were most apparent in the 10–11 year old pupils. The ‘Nourish’ intervention also produced improvements in understanding of food labels (adjusted difference in mean = 0.15; 95% CI 0.05, 0.25; P  < 0.01) and knowledge of vegetables in season (adjusted difference in mean = 0.29; 95% CI 0.01,0.56; P  = 0.04) whilst an increased willingness to try new foods and improved perceived cooking competence was also observed. Conclusions Improvements in childhood emotional and behavioural wellbeing, dietary intake, knowledge about food, cooking skills and willingness to try new foods were associated with the ‘Nourish’ whole-school food environment intervention. Exploration of the sustainability and long-term effectiveness of such whole-school food interventions should be conducted. Trial registration National Institute of Health (NIH) U.S. National Library of Medicine Clinical Trials.gov (ID: NCT04277312 ).

Background This study explored the effects of Project Daire, a school-based food intervention, on secondary dietary outcomes Diet Diversity Score (DDS) and Diet Quality Score (DQS), among 6–7 and 10-11-year-old children. Methods A randomised-controlled, factorial design trial was conducted in 15 Northern Ireland primary schools across four intervention arms: Nourish, Engage, Nourish and Engage, and Control (Delayed). Nourish modified the school food environment and increased exposure to local foods, while Engage delivered educational activities on nutrition, food, and agriculture. Food consumption data were collected at baseline and at up to a 6-month follow-up. DDS and DQS (at home, at school and/or total) were determined based on the UK Eatwell Guide. Results A total of 445 children aged 6–7 and 458 aged 10–11 completed the trial. Among the 10-11-year-olds who received the Nourish intervention, significant increases were observed in the school DDS (adjusted mean difference = 2.79, 95% CI: 1.44–4.14; p  < 0.001) and total DDS (adjusted mean difference = 1.55, 95% CI: 0.65–2.44; p  = 0.001) compared to their counterparts who did not receive it. No such changes were observed in the DDS of 6-7-year-olds in the Nourish group, nor in either age group receiving the Engage intervention. The DQS of both age groups remained unchanged across all intervention groups. Conclusions The Nourish intervention was associated with improved dietary diversity among older children through modifications to the whole-school environment. However, the absence of measurable effects on diet quality highlights the need for future iterations of Project Daire to incorporate additional strategies. These should include targeted approaches to improve diet quality, foster active parental engagement, utilize validated dietary assessment tools, and ensure sustained implementation. Trial registration ClinicalTrials.gov Identifier: NCT04277312.

The school food environment (SFE) is an ideal setting for encouraging healthy dietary behaviour. We aimed to develop an instrument to assess whole-SFE, test the instrument in the school setting and demonstrate its use to make food environment recommendations. SFE literature and UK school food guidance were searched to inform instrument items. The instrument consisted of (i) an observation proforma capturing canteen areas systems, food presentation and monitoring of food intake and (ii) a questionnaire assessing food policies, provision and activities. The instrument was tested in schools and used to develop SFE recommendations. Descriptive analyses enabled narrative discussion. Primary schools. An observation was undertaken at schools in urban and rural geographical regions of Northern Ireland of varying socio-economic status ( 18). School senior management completed the questionnaire with input from school caterers ( 16). The instrument captured desired detail and potential instrument modifications were identified. SFE varied. Differences existed between food policies and how policies were implemented and monitored. At many schools, there was scope to enhance physical eating environments ( 12, 67 %) and food presentation ( 15, 83 %); emphasise healthy eating through food activities ( 7, 78 %) and increase parental engagement in school food ( 9, 56 %). The developed instrument can measure whole-SFE in primary schools and also enabled identification of recommendations to enhance SFE. Further assessment and adaptation of the instrument are required to enable future use as a research tool or for self-assessment use by schools.

Background Project DAIRE was a randomised-controlled, factorial design trial which aimed to improve children’s health-related quality of life, wellbeing, food knowledge and dietary habits via two multi-component interventions: Nourish and Engage. Nourish was an intervention aiming to alter the school food environment, provide food-based experiences and expose pupils to locally produced foods. Engage was an age-appropriate cross-curricular food education intervention incorporating food, agriculture, nutrition science and related careers. The purpose of this study was to conduct a process evaluation to evaluate DAIRE implementation, mechanisms of impact (MOI) and context to elucidate trial results, and inform scalable implementation of the DAIRE approach for successful future rollout. Methods The Medical Research Council’s (MRC) framework for process evaluation was followed. Formal (questionnaires designed for process evaluation) and informal (researcher records and communications) methods were used to collect quantitative and qualitative data during the DAIRE trial in relation to process evaluation. Quantitative data were analysed using descriptive statistics and qualitative data via thematic analysis to identify key themes. Results Fifteen schools and 983 pupils ( n  = 495 6–7 year olds/Year 3 and n  = 488 10–11 year olds/Year 7) were recruited for the 6-month DAIRE intervention; a 100% retention rate was observed at the school level and the interventions had a high level of pupil and teacher acceptability. Nourish schools delivered a higher mean dose of intervention elements (61.4%) than Engage (50%) schools but, overall, mixed implementation of both interventions occurred. DAIRE produced change through four key MOI: social learning, experimental learning, interactive engaging content and real-life connections. Lack of time was the main contextual barrier to implementation and lack of financial cost to schools indicated as a potential facilitator. Conclusions This process evaluation helped to identify important findings related to implementation, MOI and context. The most effective elements of the interventions which should be maintained include provision of interactive and engaging intervention elements at no financial cost to the school. Findings also identified suggestions for improvement including provision of increased teacher training, support and planning time, content reduction to facilitate easy integration, and implementation across the full academic year. A sustainable funding and resourcing mechanism is required for successful future roll-out across the UK and beyond. Trial registrations The original trial referenced in this process evaluation is registered as follows: National Institute of Health (NIH) U.S. National Library of Medicine Clinical Trials.gov (ID: NCT04277312; retrospectively registered 11th February 2020).

Background Learning cooking skills during childhood and adolescence is associated with positive dietary outcomes in adulthood as well as being tracked from adolescence to adulthood. In addition studies have found that perceived competence to be a greater motivator to perform a behaviour than actual competence. However, a lack of validated tools that effectively measure behavioural and dietary changes including cooking confidence in children is a limitation. Therefore, this research aimed to develop and validate age-appropriate perceived cooking competence measures for younger and older primary school aged children. Methods Two measures of perceived Coo king C ompetence ( CooC11 and CooC7 ) for older (8–12 years) and younger (6–7 years) children were developed from a critical evaluation of publically available recommendations and expert consultation. The cooking skills within the measures were illustrated by a graphic designer in consultation with a chef and reviewed in an iterative manner by the research team. The measures were piloted for clarity, ease of use and initial face validity. Multiple studies were used for both CooC11 and CooC7 to establish psychometric properties of the measures, temporal stability, internal consistency reliability, construct validity, as well as responsiveness to change for CooC11 . Analysis included Exploratory Factor Analysis, Confirmatory Factor Analysis, Intraclass Correlation Coefficients, Pearson’s Correlations, ANOVAs and Cronbach’s Alphas. Results Both measures had high levels of face validity and received positive user feedback. Two factors were shown in both measures with the measures showing excellent temporal stability (ICC > 0.9) and good internal consistency (Cronbach’s Alphas > 0.7). Both measures showed initial discriminant validity, with significant differences ( P < 0.001) between those who reported assisting their parents with dinner preparation and those who did not. Additionally, CooC11 was significantly correlated with an adult cooking measure and had a significant responsiveness to change ( P < 0.01). Conclusions The CooC11 and CooC7 are the first validated age-appropriate measures for assessing children’s perceived Coo king C ompetence for ages 8–12 and 6–7 years respectively. They can be used to evaluate the efficacy of children’s cooking intervention studies or school nutrition education programmes.

Background Mediterranean diet (MD) interventions are demonstrated to significantly reduce cardiovascular disease (CVD) risk but are typically resource intensive and delivered by health professionals. There is considerable interest to develop interventions that target sustained dietary behaviour change and that are feasible to scale-up for wider public health benefit. The aim of this paper is to describe the process used to develop a peer support intervention to encourage dietary behaviour change towards a MD in non-Mediterranean adults at high CVD risk. Methods The Medical Research Council (MRC) and Behaviour Change Wheel (BCW) frameworks and the COM-B (Capability, Opportunity, Motivation, Behaviour) theoretical model were used to guide the intervention development process. We used a combination of evidence synthesis and qualitative research with the target population, health professionals, and community health personnel to develop the intervention over three main stages: (1) we identified the evidence base and selected dietary behaviours that needed to change, (2) we developed a theoretical basis for how the intervention might encourage behaviour change towards a MD and selected intervention functions that could drive the desired MD behaviour change, and (3) we defined the intervention content and modelled outcomes. Results A theory-based, culturally tailored, peer support intervention was developed to specifically target behaviour change towards a MD in the target population. The intervention was a group-based program delivered by trained peer volunteers over 12-months, and incorporated strategies to enhance social support, self-efficacy, problem-solving, knowledge, and attitudes to address identified barriers to adopting a MD from the COM-B analysis. Conclusions The MRC and BCW frameworks provided a systematic and complementary process for development of a theory-based peer support intervention to encourage dietary behaviour change towards a MD in non-Mediterranean adults at high CVD risk. The next step is to evaluate feasibility, acceptability, and diet behaviour change outcomes in response to the peer support intervention (change towards a MD and nutrient biomarkers) using a randomized controlled trial design.

Background The number of women entering pregnancy with overweight or obesity is increasing. This can increase the risk for excessive gestational weight gain (GWG) which is associated with health complications for mother and baby. There are limited evidence-based interventions within antenatal care settings to encourage healthy eating and physical activity behaviours and support women with managing GWG. Methods A previous habit-based intervention ‘Ten Top Tips for a Healthy Weight’ (10TT) was adapted and made suitable for pregnancy in line with the Medical Research Council’s (MRC) complex intervention development guidelines. It involved three key activities: (1) identifying the evidence base; (2) identifying appropriate theory; and, (3) modelling processes. A core element was integrating lived experience via personal and public involvement (PPI). Results The original 10TTs were adapted with PPI in line with current advice on nutrition and physical activity in pregnancy. New intervention materials were devised, including a leaflet and a logbook and app for self-monitoring to be delivered alongside a brief 1:1 conversation. Behaviour change techniques (BCTs) included in the new materials were coded using a number of behavioural taxonomies. An E-learning resource was created to help standardise the approach to delivery of the intervention and avoid stigmatising conversations. Conclusion Following MRC guidance for the development of complex interventions alongside significant PPI allowed for the adaption of 10TT habit-based weight management intervention into the ‘Healthy Habits in Pregnancy and Beyond’ (HHIPBe) intervention. The feasibility and acceptability of implementing this intervention in the antenatal setting will be explored in a feasibility randomised controlled trial. Trial Registration This study was registered on Clinical Trials as ‘Healthy Habits in Pregnancy and Beyond (HHIPBe)’ ClinicalTrials.gov Identifier: NCT04336878. The study was registered on 07/04/2020.