Search

Objective: The UK Soft Drinks Industry Levy (SDIL) (announced in March 2016; implemented in April 2018) aims to incentivise reformulation of soft drinks to reduce added sugar levels. The SDIL has been applauded as a policy success, and it has survived calls from parliamentarians for it to be repealed. We aimed to explore parliamentary reaction to the SDIL following its announcement until two years post-implementation in order to understand how health policy can become established and resilient to opposition., Design: Searches of Hansard for parliamentary debate transcripts that discussed the SDIL retrieved 186 transcripts, with 160 included after screening. Five stages of Applied Thematic Analysis were conducted: familiarisation and creation of initial codebooks; independent second coding; codebook finalisation through team consensus; final coding of the dataset to the complete codebook; and theme finalisation through team consensus., Setting: The United Kingdom Parliament., Participants: N/A., Results: Between the announcement (16/03/2016) - royal assent (26/04/2017), two themes were identified 1: SDIL welcomed cross-party 2: SDIL a good start but not enough. Between royal assent - implementation (5/04/2018), one theme was identified 3: The SDIL worked - what next? The final theme identified from implementation until 16/03/2020 was 4: Moving on from the SDIL ., Conclusions: After the announcement, the SDIL had cross-party support and was recognised to have encouraged reformulation prior to implementation. Lessons for governments indicate that the combination of cross-party support and a policy's documented success in achieving its aim can help cement the resilience of it to opposition and threats of repeal.

The Healthy New Town programme in England set out to 'put health into place' by supporting the design and construction of healthy places to live, including by creating safe environments for active travel. To explore the impact of this approach, this study examined how children and their families experienced school journeys in two contrasting Healthy New Towns in England, one an affluent new town in the early stages of construction and the other more economically deprived and established. We undertook photo-elicitation and go-along interviews with 24 children aged 7-12 years and semi-structured interviews with 17 caregivers. We found that experiences of care were important for children's school travel. In the 'deprived' town, opportunities for children to care and to be cared for were enjoyed, facilitated by routes with limited traffic, pockets of 'nature', and possibilities to encounter meaningful others. For families living in a town under construction, the need to negotiate unfinished travel infrastructure, and a sense of being 'in limbo', was experienced as an absence of care by planners and developers. Interventions to promote children's active travel should consider the role of care-full planning in facilitating walking and cycling journeys., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Despite limited genetic and histologic heterogeneity, Ewing sarcoma (EwS) tumor cells are transcriptionally heterogeneous and display varying degrees of mesenchymal lineage specification in vitro. In this study, we investigated if and how transcriptional heterogeneity of EwS cells contributes to heterogeneity of tumor phenotypes in vivo., Experimental Design: Single-cell proteogenomic-sequencing of EwS cell lines was performed and integrated with patient tumor transcriptomic data. Cell subpopulations were isolated by FACS for assessment of gene expression and phenotype. Digital spatial profiling and human whole transcriptome analysis interrogated transcriptomic heterogeneity in EwS xenografts. Tumor cell subpopulations and matrix protein deposition were evaluated in xenografts and patient tumors using multiplex immunofluorescence staining., Results: We identified CD73 as a biomarker of highly mesenchymal EwS cell subpopulations in tumor models and patient biopsies. CD73+ tumor cells displayed distinct transcriptional and phenotypic properties, including selective upregulation of genes that are repressed by EWS::FLI1, and increased migratory potential. CD73+ cells were distinguished in vitro and in vivo by increased expression of matrisomal genes and abundant deposition of extracellular matrix (ECM) proteins. In epithelial-derived malignancies, ECM is largely deposited by cancer-associated fibroblasts (CAF), and we thus labeled CD73+ EwS cells, CAF-like tumor cells. Marked heterogeneity of CD73+ EwS cell frequency and distribution was detected in tumors in situ, and CAF-like tumor cells and associated ECM were observed in peri-necrotic regions and invasive foci., Conclusions: EwS tumor cells can adopt CAF-like properties, and these distinct cell subpopulations contribute to tumor heterogeneity by remodeling the tumor microenvironment. See related commentary by Kuo and Amatruda, p. 5002., (©2023 American Association for Cancer Research.)

Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent β-catenin-activating mutations. Here, we demonstrated that ACC differentiation is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes, and the epigenome. On chromatin, β-catenin bound master adrenal transcription factor SF1 and hijacked the adrenocortical super-enhancer landscape to maintain differentiation in CIMP-high ACC; off chromatin, β-catenin bound histone methyltransferase EZH2. SF1/β-catenin and EZH2/β-catenin complexes present in normal adrenals persisted through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC expelled SF1/β-catenin from chromatin and favored EZH2/β-catenin assembly, erasing differentiation and restraining cancer growth in vitro and in vivo. These studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities., Significance: Oncogenic β-catenin can use tissue-specific partners to regulate cellular differentiation programs that can be reversed by epigenetic therapies, identifying epigenetic control of differentiation as a viable target for β-catenin-driven cancers., (©2023 American Association for Cancer Research.)

Background: The COVID-19 pandemic accelerated the interest in implementing mobile health (mHealth) in population-based health studies, but evidence is lacking on engagement and adherence in studies. We conducted a fully remote study for ≥6 months tracking COVID-19 digital biomarkers and symptoms using a smartphone app nested within an existing cohort of adults., Objective: We aimed to investigate participant characteristics associated with initial and sustained engagement in digital biomarker collection from a bespoke smartphone app and if engagement changed over time or because of COVID-19 factors and explore participants' reasons for consenting to the smartphone substudy and experiences related to initial and continued engagement., Methods: Participants in the Fenland COVID-19 study were invited to the app substudy from August 2020 to October 2020 until study closure (April 30, 2021). Participants were asked to complete digital biomarker modules (oxygen saturation, body temperature, and resting heart rate [RHR]) and possible COVID-19 symptoms in the app 3 times per week. Participants manually entered the measurements, except RHR that was measured using the smartphone camera. Engagement was categorized by median weekly frequency of completing the 3 digital biomarker modules (categories: 0, 1-2, and ≥3 times per week). Sociodemographic and health characteristics of those who did or did not consent to the substudy and by engagement category were explored. Semistructured interviews were conducted with 35 participants who were purposively sampled by sex, age, educational attainment, and engagement category, and data were analyzed thematically; 63% (22/35) of the participants consented to the app substudy, and 37% (13/35) of the participants did not consent., Results: A total of 62.61% (2524/4031) of Fenland COVID-19 study participants consented to the app substudy. Of those, 90.21% (2277/2524) completed the app onboarding process. Median time in the app substudy was 34.5 weeks (IQR 34-37) with no change in engagement from 0 to 3 months or 3 to 6 months. Completion rates (≥1 per week) across the study between digital biomarkers were similar (RHR: 56,517/77,664, 72.77%; temperature: 56,742/77,664, 73.06%; oxygen saturation: 57,088/77,664, 73.51%). Older age groups and lower managerial and intermediate occupations were associated with higher engagement, whereas working, being a current smoker, being overweight or obese, and high perceived stress were associated with lower engagement. Continued engagement was facilitated through routine and personal motivation, and poor engagement was caused by user error and app or equipment malfunctions preventing data input. From these results, we developed key recommendations to improve engagement in population-based mHealth studies., Conclusions: This mixed methods study demonstrated both high initial and sustained engagement in a large mHealth COVID-19 study over a ≥6-month period. Being nested in a known cohort study enabled the identification of participant characteristics and factors associated with engagement to inform future applications in population-based health research., (©Kirsten L Rennie, Emma R Lawlor, Arrash Yassaee, Adam Booth, Kate Westgate, Stephen J Sharp, Carina S B Tyrrell, Mert Aral, Nicholas J Wareham. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 13.01.2023.)

Accumulating evidence shows that despite clonal origins tumors eventually become complex communities comprised of phenotypically distinct cell subpopulations. This heterogeneity arises from both tumor cell intrinsic programs and signals from spatially and temporally dynamic microenvironments. While pediatric cancers usually lack the mutational burden of adult cancers, they still exhibit high levels of cellular heterogeneity that are largely mediated by epigenetic mechanisms. Ewing sarcomas are aggressive bone and soft tissue malignancies with peak incidence in adolescence and the prognosis for patients with relapsed and metastatic disease is dismal. Ewing sarcomas are driven by a single pathognomonic fusion between a FET protein and an ETS family transcription factor, the most common of which is EWS::FLI1. Despite sharing a single driver mutation, Ewing sarcoma cells demonstrate a high degree of transcriptional heterogeneity both between and within tumors. Recent studies have identified differential fusion protein activity as a key source of this heterogeneity which leads to profoundly different cellular phenotypes. Paradoxically, increased invasive and metastatic potential is associated with lower EWS::FLI1 activity. Here, we review what is currently understood about EWS::FLI1 activity, the cell autonomous and tumor microenvironmental factors that regulate it, and the downstream consequences of these activity states on tumor progression. We specifically highlight how transcription factor regulation, signaling pathway modulation, and the extracellular matrix intersect to create a complex network of tumor cell phenotypes. We propose that elucidation of the mechanisms by which these essential elements interact will enable the development of novel therapeutic approaches that are designed to target this complexity and ultimately improve patient outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Apfelbaum, Wrenn and Lawlor.)

Purpose: Propagation of Ewing sarcoma requires precise regulation of EWS::FLI1 transcriptional activity. Determining the mechanisms of fusion regulation will advance our understanding of tumor progression. Here we investigated whether HOXD13, a developmental transcription factor that promotes Ewing sarcoma metastatic phenotypes, influences EWS::FLI1 transcriptional activity., Experimental Design: Existing tumor and cell line datasets were used to define EWS::FLI1 binding sites and transcriptional targets. Chromatin immunoprecipitation and CRISPR interference were employed to identify enhancers. CUT&RUN and RNA sequencing defined binding sites and transcriptional targets of HOXD13. Transcriptional states were investigated using bulk and single-cell transcriptomic data from cell lines, patient-derived xenografts, and patient tumors. Mesenchymal phenotypes were assessed by gene set enrichment, flow cytometry, and migration assays., Results: We found that EWS::FLI1 creates a de novo GGAA microsatellite enhancer in a developmentally conserved regulatory region of the HOXD locus. Knockdown of HOXD13 led to widespread changes in expression of developmental gene programs and EWS::FLI1 targets. HOXD13 binding was enriched at established EWS::FLI1 binding sites where it influenced expression of EWS::FLI1-activated genes. More strikingly, HOXD13 bound and activated EWS::FLI1-repressed genes, leading to adoption of mesenchymal and migratory cell states that are normally suppressed by the fusion. Single-cell analysis confirmed that direct transcriptional antagonism between HOXD13-mediated gene activation and EWS::FLI1-dependent gene repression defines the state of Ewing sarcoma cells along a mesenchymal axis., Conclusions: Ewing sarcoma tumors are comprised of tumor cells that exist along a mesenchymal transcriptional continuum. The identity of cells along this continuum is, in large part, determined by the competing activities of EWS::FLI1 and HOXD13. See related commentary by Weiss and Bailey, p. 4360., (©2022 American Association for Cancer Research.)

Primary bone sarcomas, including osteosarcoma (OS) and Ewing sarcoma (ES), are aggressive tumors with peak incidence in childhood and adolescence. The intense standard treatment for these patients consists of combined surgery and/or radiation and maximal doses of chemotherapy; a regimen that has not seen improvement in decades. Like other tumor types, ES and OS are characterized by dysregulated cellular metabolism and a rewiring of metabolic pathways to support the biosynthetic demands of malignant growth. Not only are cancer cells characterized by Warburg metabolism, or aerobic glycolysis, but emerging work has revealed a dependence on amino acid metabolism. Aside from incorporation into proteins, amino acids serve critical functions in redox balance, energy homeostasis, and epigenetic maintenance. In this review, we summarize current studies describing the amino acid metabolic requirements of primary bone sarcomas, focusing on OS and ES, and compare these dependencies in the normal bone and malignant tumor contexts. We also examine insights that can be gleaned from other cancers to better understand differential metabolic susceptibilities between primary and metastatic tumor microenvironments. Lastly, we discuss potential metabolic vulnerabilities that may be exploited therapeutically and provide better-targeted treatments to improve the current standard of care., Competing Interests: CL has received consulting fees from Astellas Pharmaceuticals, Odyssey Therapeutics, and T-Knife Therapeutics, and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiménez, Lawlor and Lyssiotis.)

The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled the study of multiple molecular biomarkers in EwS. Preliminary evidence requiring validation supports copy number changes, and loss of function mutations in tumor suppressor genes as biomarkers of outcome in EwS. Initial studies of circulating tumor DNA demonstrated that diagnostic ctDNA burden and ctDNA clearance during induction are also associated with outcome. In addition, fusion partner should be a pre-requisite for enrollment on EwS clinical trials, and the fusion type and structure require further study to determine prognostic impact. These emerging biomarkers represent a new horizon in our understanding of disease risk and will enable future efforts to develop risk-adapted treatment., (© 2022. The Author(s).)

The eighth Paediatric Strategy Forum focused on multi-targeted kinase inhibitors (mTKIs) in osteosarcoma and Ewing sarcoma. The development of curative, innovative products in these tumours is a high priority and addresses unmet needs in children, adolescents and adults. Despite clinical and investigational use of mTKIs, efficacy in patients with bone tumours has not been definitively demonstrated. Randomised studies, currently being planned or in progress, in front-line and relapse settings will inform the further development of this class of product. It is crucial that these are rapidly initiated to generate robust data to support international collaborative efforts. The experience to date has generally indicated that the safety profile of mTKIs as monotherapy, and in combination with chemotherapy or other targeted therapy, is consistent with that of adults and that toxicity is manageable. Increasing understanding of relevant predictive biomarkers and tumour biology is absolutely critical to further develop this class of products. Biospecimen samples for correlative studies and biomarker development should be shared, and a joint academic-industry consortium created. This would result in an integrated collection of serial tumour tissues and a systematic retrospective and prospective analyses of these samples to ensure robust assessment of biologic effect of mTKIs. To support access for children to benefit from these novel therapies, clinical trials should be designed with sufficient scientific rationale to support regulatory and payer requirements. To achieve this, early dialogue between academia, industry, regulators, and patient advocates is essential. Evaluating feasibility of combination strategies and then undertaking a randomised trial in the same protocol accelerates drug development. Where possible, clinical trials and development should include children, adolescents, and adults less than 40 years. To respond to emerging science, in approximately 12 months, a multi-stakeholder group will meet and review available data to determine future directions and priorities., Competing Interests: Conflcits of interest statement The authors declare the following financial interests/ personal relationships which may be considered as potential competing interests: FB is an employee and stockholder of Ipsen Pharma. JC is an employee of Bayer Healthcare Pharmaceuticals. MC has served as an advisor for Astra-Zeneca, Bayer, BMS, Pfizer, and Servier. SGD has received consulting fees from Amgen, Bayer, and Loxo Oncology and has received travel reimbursement from Roche and Salarius. EG is an employee of Oncoheroes Biosciences. AH is an employee of Blueprint Medicines. KJ has received consulting fees from Bayer and Ipsen and honoraria fromTakeda and Foundation Medicine. JK is an employee of Allarity Therapeutics. SK is an employee of HUTCHMED International Corporation. CO is an employee of Eisai GmbH. ADJP has consulted for Lilly, Norgine and Developmental Therapeutics Consortium Limited and been an advisor for Amgen. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This paper uses meta-ethnography to synthesise qualitative and ethnographic studies of children's (aged 5-13) experiences of socio-material environments on their school journey. Most of the 21 papers (18 studies) identified from the systematic search were from high-income countries and used self-report qualitative methods. Our synthesis shows children can feel vulnerable, but also negotiate journeys and manage risks, enjoy shared and solitary mobility, and explore their material environments. School journeys offer children a place to learn and develop agency within their socio-material environments. Attending to these wider benefits of school journeys, alongside supporting children to develop active modes attuned to the risks associated with these journeys, could improve the reach and impact of active school travel initiatives., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it has poor pharmacokinetic properties, and unfavorable bioavailability has hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4 + monocytic myeloid-derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long-term survival, with ∼60% of GBM tumor-bearing mice remaining tumor free after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability.

Introduction: The cost-effectiveness and long-term health impact of behavioural weight management programmes depends on post-treatment weight-loss maintenance. Growing evidence suggests that interventions using acceptance and commitment therapy (ACT) could improve long-term weight management. We developed an ACT-based, guided self-help intervention to support adults who have recently completed a behavioural weight loss programme. This study will assess the feasibility and acceptability of this type of intervention and findings will inform the development of a full-scale trial., Methods and Analysis: This is a pragmatic, randomised, single-blind, parallel group, two-arm, feasibility study with an embedded process evaluation. We will recruit and randomise 60 adults who have recently completed a behavioural weight loss programme to the ACT-based intervention or standard care, using a computer-generated sequence with 2:1 allocation stratified by diabetes status and sex. Baseline and 6-month measurements will be completed using online questionnaires. Qualitative interviews will be conducted with a subsample of participants and coaches about their experiences at 3 (mid-intervention) and 6 (postintervention) months. Feasibility and acceptability of the intervention, and a full-scale trial will be assessed using a number of outcomes, including adherence to, and engagement with the intervention, recruitment and retention rates, proportion of missing data for each outcome measure, participants' experiences of the intervention and study, and coaches' experiences of delivering intervention support. Quantitative and qualitative findings will be integrated and summarised to contribute to the interpretation of the main feasibility evaluation findings. Value of information methods will be used to estimate the decision uncertainty associated with the intervention's cost-effectiveness and determine the value of a definitive trial., Ethics and Dissemination: Ethical approval was received from Cambridge South Research Ethics Committee on 15/03/2021 (21/EE/0024). This protocol (V.2) was approved on 19 April 2021. Findings will be published in peer-reviewed scientific journals and communicated to other stakeholders as appropriate., Trial Registration Number: ISRCTN12685964., Competing Interests: Competing interests: ALA is principal investigator on another publicly funded trial where JW provided the intervention at no cost but has received no personal fees. SG reports grants from Medical Research Council, personal fees from Eli Lilly and personal fees from Janssen, outside this programme of research. AH reports personal fees from Slimming World and the College of Contemporary Health, outside this programme of research. CH reports informal unpaid advice to Thriva., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Aims/hypothesis: Weight loss is often recommended in the treatment of type 2 diabetes. While evidence has shown that large weight loss may lead to diabetes remission and improvement in cardiovascular risk factors, long-term impacts are unclear. We performed a systematic review of studies of weight loss and other weight changes and incidence of CVD among people with type 2 diabetes., Methods: Observational studies of behavioural (non-surgical and non-pharmaceutical) weight changes and CVD events among adults with type 2 diabetes, and trials of behavioural interventions targeting weight loss, were identified through searches of MEDLINE, EMBASE, Web of Science, CINAHL, and The Cochrane Library (CENTRAL) until 9 July 2019. Included studies reported change in weight and CVD and/or mortality outcomes among adults with type 2 diabetes. We performed a narrative synthesis of observational studies and meta-analysis of trial data., Results: Of 13,227 identified articles, 17 (14 observational studies, three trials) met inclusion criteria. Weight gain (vs no change) was associated with higher hazard of CVD events (HRs [95% CIs] ranged from 1.13 [1.00, 1.29] to 1.63 [1.11, 2.39]) and all-cause mortality (HRs [95% CIs] ranged from 1.26 [1.12, 1.41] to 1.57 [1.33, 1.85]). Unintentional weight loss (vs no change) was associated with higher risks of all-cause mortality, but associations with intentional weight loss were unclear. Behavioural interventions targeting weight loss showed no effect on CVD events (pooled HR [95% CI] 0.95 [0.71, 1.27]; I 2  = 50.1%). Risk of bias was moderate in most studies and was high in three studies, due to potential uncontrolled confounding and method of weight assessment., Conclusions/interpretation: Weight gain is associated with increased risks of CVD and mortality, although there is a lack of data supporting behavioural weight-loss interventions for CVD prevention among adults with type 2 diabetes. Long-term follow-up of behavioural intervention studies is needed to understand effects on CVD and mortality and to inform policy concerning weight management advice and support for people with diabetes. PROSPERO registration CRD42019127304., (© 2021. The Author(s).)

Background: The EWSR1/FLI1 gene fusion is the most common rearrangement leading to cell transformation in Ewing sarcoma (ES). Previous studies have indicated that expression at the cellular level is heterogeneous, and that levels of expression may oscillate, conferring different cellular characteristics. In ES the role of EWSR1/FLI1 in regulating subpopulation dynamics is currently unknown., Methods: We used siRNA to transiently suppress EWSR1/FLI1 expression and followed population dynamics using both single cell expression profiling, CyTOF and functional assays to define characteristics of exponentially growing ES cells and of ES cells in which EWSR1/FLI1 had been downregulated. Novel transcriptional states with distinct features were assigned using random forest feature selection in combination with machine learning. Cells isolated from ES xenografts in immune-deficient mice were interrogated to determine whether characteristics of specific subpopulations of cells in vitro could be identified. Stem-like characteristics were assessed by primary and secondary spheroid formation in vitro, and invasion/motility was determined for each identified subpopulation. Autophagy was determined by expression profiling, cell sorting and immunohistochemical staining., Results: We defined a workflow to study EWSR1/FLI1 driven transcriptional states and phenotypes. We tracked EWSR1/FLI1 dependent proliferative activity over time to discover sources of intra-tumoral diversity. Single-cell RNA profiling was used to compare expression profiles in exponentially growing populations (si-Control) or in two dormant populations (D1, D2) in which EWSR1/FLI1 had been suppressed. Three distinct transcriptional states were uncovered contributing to ES intra-heterogeneity. Our predictive model identified ~1% cells in a dormant-like state and ~ 2-4% cells with stem-like and neural stem-like features in an exponentially proliferating ES cell line and in ES xenografts. Following EWSR1/FLI1 knockdown, cells re-entering the proliferative cycle exhibited greater stem-like properties, whereas for those cells remaining quiescent, FAM134B-dependent dormancy may provide a survival mechanism., Conclusions: We show that time-dependent changes induced by suppression of oncogenic EWSR1/FLI1 expression induces dormancy, with different subpopulation dynamics. Cells re-entering the proliferative cycle show enhanced stem-like characteristics, whereas those remaining dormant for prolonged periods appear to survive through autophagy. Cells with these characteristics identified in exponentially growing cell populations and in tumor xenografts may confer drug resistance and could potentially contribute to metastasis., (© 2021. Springer Nature Switzerland AG.)

Background: The long-term impact and cost-effectiveness of weight management programs depend on posttreatment weight maintenance. There is growing evidence that interventions based on third-wave cognitive behavioral therapy, particularly acceptance and commitment therapy (ACT), could improve long-term weight management; however, these interventions are typically delivered face-to-face by psychologists, which limits the scalability of these types of intervention., Objective: The aim of this study is to use an evidence-, theory-, and person-based approach to develop an ACT-based intervention for weight loss maintenance that uses digital technology and nonspecialist guidance to minimize the resources needed for delivery at scale., Methods: Intervention development was guided by the Medical Research Council framework for the development of complex interventions in health care, Intervention Mapping Protocol, and a person-based approach for enhancing the acceptability and feasibility of interventions. Work was conducted in two phases: phase 1 consisted of collating and analyzing existing and new primary evidence and phase 2 consisted of theoretical modeling and intervention development. Phase 1 included a synthesis of existing evidence on weight loss maintenance from previous research, a systematic review and network meta-analysis of third-wave cognitive behavioral therapy interventions for weight management, a qualitative interview study of experiences of weight loss maintenance, and the modeling of a justifiable cost for a weight loss maintenance program. Phase 2 included the iterative development of guiding principles, a logic model, and the intervention design and content. Target user and stakeholder panels were established to inform each phase of development, and user testing of successive iterations of the prototype intervention was conducted., Results: This process resulted in a guided self-help ACT-based intervention called SWiM (Supporting Weight Management). SWiM is a 4-month program consisting of weekly web-based sessions for 13 consecutive weeks followed by a 4-week break for participants to reflect and practice their new skills and a final session at week 18. Each session consists of psychoeducational content, reflective exercises, and behavioral experiments. SWiM includes specific sessions on key determinants of weight loss maintenance, including developing skills to manage high-risk situations for lapses, creating new helpful habits, breaking old unhelpful habits, and learning to manage interpersonal relationships and their impact on weight management. A trained, nonspecialist coach provides guidance for the participants through the program with 4 scheduled 30-minute telephone calls and 3 further optional calls., Conclusions: This comprehensive approach facilitated the development of an intervention that is based on scientific theory and evidence for supporting people with weight loss maintenance and is grounded in the experiences of the target users and the context in which it is intended to be delivered. The intervention will be refined based on the findings of a planned pilot randomized controlled trial., (©Rebecca Richards, Rebecca A Jones, Fiona Whittle, Carly A Hughes, Andrew J Hill, Emma R Lawlor, Jennifer Bostock, Sarah Bates, Penny R Breeze, Alan Brennan, Chloe V Thomas, Marie Stubbings, Jennifer Woolston, Simon J Griffin, Amy L Ahern. Originally published in JMIR Formative Research (https://formative.jmir.org), 07.01.2022.)