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Hepatocellular carcinoma (HCC) is a genetically heterogeneous disease for which a dominant actionable molecular driver has not been identified. Patients with the stem cell–like EpCAM+AFP+ HCC subtype have poor prognosis. Here, we performed a genome-wide RNAi screen to identify genes with a synthetic lethal interaction with EpCAM as a potential therapeutic target for the EpCAM+AFP+ HCC subtype. We identified 26 candidate genes linked to EpCAM/Wnt/β-catenin signaling and HCC cell growth. We further characterized the top candidate PMPCB, which plays a role in mitochondrial protein processing, as a bona fide target for EpCAM+ HCC. PMPCB blockage suppressed EpCAM expression and Wnt/β-catenin signaling via mitochondria-related reactive oxygen species production and FOXO activities, resulting in apoptosis and tumor suppression. These results indicate that a synthetic lethality screen is a viable strategy to identify actionable drivers of HCC and identify PMPCB as a therapeutically vulnerable gene in EpCAM+ HCC subpopulations.Significance:This study identifies PMPCB as critical to mitochondrial homeostasis and a synthetic lethal candidate that selectively kills highly resistant EpCAM+ HCC tumors by inactivating the Wnt/β-catenin signaling pathway.

Supplementary figures as related to the manuscript. Data represent schematic RNAi screen workflow, additional survival analyses, and experiments performed in different hepatocellular carcinoma cell lines.

Directly targeting RAS is a desirable approach for treating RAS-mutated tumors because direct RAS inhibitors block all RAS effector pathways simultaneously. Recently, several groups have developed agents that directly target KRAS by covalently modifying KRASG12C. KRAS is commonly altered in adult malignancies such as lung, pancreatic, and colorectal adenocarcinoma, but is less commonly altered in pediatric cancer. However, rare pediatric tumors harboring K-, H-, or NRASG12C are observed. The efficacy of KRASG12C inhibitors in pediatric malignancies is currently unknown, and the ability of these drugs to modify H- and NRASG12C has been incompletely characterized. Here we show that the KRASG12C inhibitors AMG 510, MRTX849, and ARS-1620 slow the release of GDP from H-, N-, and KRASG12C in vitro. Using RASless MEFs, we show that the activity of AMG 510 is specific for H-, N- or KRASG12C, while MRTX849 has both G12C and RAS-independent effects on cell viability. The KRASG12C inhibitors decreased cell viability in KRAS-mutant cell lines derived from patients with the pediatric solid tumor neuroblastoma. MRTX849 was more potent than AMG 510 in neuroblastoma cell lines but was less efficacious and less G12C-specific. The KRASG12C inhibitors also decreased cell viability in an NRASG12C-mutant T-cell ALL cell line derived from an adolescent patient but only MTRX849 decreased cell viability in an HRASG12C-mutant rhabdomyosarcoma cell line. These results suggest that KRASG12C inhibitors may be a treatment option for pediatric patients with H-, N- or KRASG12C mutant solid tumors or leukemia. Future studies will be aimed at testing the efficacy of these inhibitors in xenograft models of pediatric cancer and identifying non-RAS targets of MRTX849. Citation Format: Hannah Price, Stacey Stauffer, Katie Powell, Andrew Baker, Andrew Perciaccante, Edjay Ralph Hernandez, Patience Odeniyide, Christine Pratilas, William Burgan, Lisa Jenkins, Kent L. Rossman, Marielle Yohe. Preclinical efficacy of KRASG12C inhibitors in models of pediatric cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B038.

Shortly after the formation of the NCI Ras Initiative, a H/N/KRAS-less mouse embryonic fibroblast (MEF) cell line panel was generated, validated, and shared internationally to aid the research community in its reinvigorated effort to apply new technical advancements to understanding the structure and function of Ras and to ultimately design inhibitors. While this panel has been beneficial to the Ras research community, an inherent variability due in part to the ploidy of the parental pool from which the panel was derived complicated comparisons between isolates and alleles. We have minimized this variation by utilizing a diploid clone derived from the DU1473 MEF; Hras-/-; Nras-/-; Kraslox/lox; RERTert/ert - parental cell line. A diploid cell population was sorted, cloned and clones were cultured continuously for up to 20 passages to identify those that retained a diploid signature. These clones were further screened for p53 mutations and mouse exome sequenced from which a final clone was selected to develop the improved cell line panel. The selected clone was treated with 4-hydroxytamoxifen (4-OHT) to activate the Cre-recombinase which excised a portion of the endogenous Kras located between two loxP sites effectively arresting cells in a senescent G1 state. Molecular verification of Kras removal was performed, and the cells were then transduced with a third generation VSV-G pseudotyped lentiviral vector which delivered different versions of the human Ras transgene as well as an antibiotic selection marker. This transduction restored the proliferative ability of the cells allowing for expansion and selection of the transduced pool. The pools were single cell cloned and subsequent clones underwent a systematic, rigorous quality control evaluation culminating with another round of exome sequencing before clones were selected to be part of the MEF 2.0 panel. Clones contained in this new panel were confirmed to be diploid, had fewer integrations than the initial panel, and performed similarly on proliferation assays as well as epidermal growth factor stimulation signaling assays. The new panel has successfully recapitulated the initial panel, but in a far more stable and reproducible cellular background. Instructions to obtain the cell line panel will be presented on the Ras Initiative website at www.cancer.gov and these cells are scheduled to become available to the Ras research community late in the spring of 2023. Citation Format: William E. Burgan, Nicole Fer, Katie Powell, Bingfang Xu, Mackenzie Meyer, Scott Eury, Abigail Neish, Daniel Soppet, Dominic Esposito, Frank McCormick, Dwight V. Nissley. An isogenic H/N/KRAS-less mouse embryonic fibroblast cell line panel derived from a size sorted diploid clonal parent [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A028.

The RAS family of GTPases (HRAS, KRAS4A, KRAS4B, NRAS) provide a formidable challenge to standard proteomic workflows. Linking key N-terminal mutations (e.g., G12C, G13D) with C-terminal post-translational modifications (PTMs) on a given RAS isoform by proteolytic digestion and peptide-based analysis is further complicated by their high sequence identity, low endogenous abundance, and labile PTMs. Conversely, top-down mass spectrometry (TDMS), which measures intact and modified protein forms (proteoforms), can precisely identify and confidently localize mutations and PTMs within each RAS isoform sequence. Moreover, by combining immunoprecipitation with TDMS (IP-TDMS), endogenous RAS proteoforms can be isolated to near-homogeneity from malignant cell lines, detected at high signal-to-noise ratios via selected ion monitoring, and targeted for optimized MS2-based characterization to provide molecular detail simply unachievable by other proteomic methods. The NCI RAS Initiative has developed an optimized RAS proteoform assay incorporating IP-TDMS analysis on an Orbitrap Fusion Lumos mass spectrometer. We initially employed recombinant versions of each RAS isoform to determine the optimal targeted MS2 fragmentation (tMS2) parameters for sequence characterization and localization of endogenous PTMs. We next isolated FLAG-tagged KRAS4B -WT, -G12D, and -G12C expression constructs from HeLa cells to refine our liquid chromatography and tMS2 parameters while targeting stoichiometrically abundant KRAS4B proteoforms within each population. We then isolated FLAG-tagged HRAS-, KRAS4A-, KRAS4B-, and NRAS-G12V proteins from HeLa or Panc1 cells for further refinement of isoform-specific tMS2 parameters with emphasis on capturing unusual or labile PTMs (e.g. palmitoylation). This allowed us to visualize and directly compare the most abundant RAS isoform-specific proteoform populations within these cellular contexts. Complementary peptide-based analyses were performed on all samples to validate RAS isoform-specific PTM landscapes and facilitate detection of their respective endogenous versions. Finally, we applied our optimized IP-TDMS workflow to a panel of well-characterized malignant and RAS mutant cell lines with the goal of expanding our knowledge of the endogenous RAS proteoform landscape. In doing so, we identified a wealth of novel HRAS, KRAS4A, KRAS4B, and NRAS proteoforms bearing stoichiometrically abundant PTMs differing markedly from the established literature. We also performed direct comparisons between isoform- and mutation-specific RAS proteoforms, revealing clear indications of context dependence. These initial results further underscore the potential for top-down proteomics to broaden our understanding of RAS-dependent signaling within a range of cancer contexts. They also reveal that extensive investigations remain to be performed to elucidate the roles of RAS PTMs and proteoforms in normal and oncogenic signaling. Citation Format: Caroline J. DeHart, Robert A. D'Ippolito, Kanika Sharma, Nicole Fer, Brian Smith, Mackenzie Meyer, Scott Eury, Abigail Neish, Katie Powell, Vanessa Wall, William Burgan, Dominic Esposito, Anna E. Maciag, Frank McCormick, Dwight V. Nissley. Expanded RAS proteoform landscape in malignant cell lines revealed by top-down mass spectrometry [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A016.

Summary This article—third in a series of three—uses theoretical frameworks described in Part 1, and empirical markers reported in Part 2, to present evidence on how power dynamics shifted during the early years of a major English community empowerment initiative. We demonstrate how the capabilities disadvantaged communities require to exercise collective control over decisions/actions impacting on their lives and health (conceptualized as emancipatory power) and the exercise of power over these communities (conceptualized as limiting power) were shaped by the characteristics of participatory spaces created by and/or associated with this initiative. Two main types of participatory spaces were identified: governance and sense-making. Though all forms of emancipatory power emerged in all spaces, some were more evident in particular spaces. In governance spaces, the development and enactment of ‘power to’ emerged as residents made formal decisions on action, allocated resources and managed accountability. Capabilities for alliance building—power with—were more likely to emerge in these spaces, as was residents’ resistance to the exercise of institutional power over them. In contrast, in sense-making spaces residents met informally and ‘made sense’ of local issues and their ability to influence these. These processes led to the development of power within capabilities and power to resist stigmatizing forms of productive power. The findings highlight the importance of designing community initiatives that: nurture diverse participatory spaces; attend to connectivity between spaces; and identify and act on existing power dynamics undermining capabilities for collective control in disadvantaged communities.

Asset-based approaches to health promotion have become increasingly popular as a way to tackle health inequalities by empowering people in more disadvantaged communities to use local resources and increase control over health and its determinants. However, questions remain about how they work in practice. This article presents the findings from a systematic scoping review of the empirical literature on asset-based approaches in communities. The aim was to identify the key elements of asset-based approaches, and how they are operationalised in interventions aimed at promoting health and reducing inequalities in local communities. Four databases were searched (Medline, PsycINFO, CINAHL, ASSIA) and papers were included if they described interventions explicitly adopting an asset-based approach but excluded if limited to asset identification. Thirty articles were included in the review. Data were extracted on the type of assets that the intervention built upon, how assets were mobilised, the expected outcomes and evaluation methods. A framework is presented that synthesises the key characteristics of asset-based interventions to promote health in communities. Three main approaches to mobilising assets were identified in the literature: (A) connecting assets, (B) raising awareness of assets and (C) enabling assets to thrive. It is argued that asset-based approaches to health promotion take a wide variety of forms, making it difficult to anticipate outcomes and to evaluate interventions. The framework presented here can be used to better understand the processes through which asset-based approaches work in practice to promote health and reduce inequalities.

Hepatocellular carcinoma (HCC) is a genetically heterogeneous disease for which a dominant actionable molecular driver has not been identified. Patients with the stem cell–like EpCAM+AFP+ HCC subtype have poor prognosis. Here, we performed a genome-wide RNAi screen to identify genes with a synthetic lethal interaction with EpCAM as a potential therapeutic target for the EpCAM+AFP+ HCC subtype. We identified 26 candidate genes linked to EpCAM/Wnt/β-catenin signaling and HCC cell growth. We further characterized the top candidate PMPCB, which plays a role in mitochondrial protein processing, as a bona fide target for EpCAM+ HCC. PMPCB blockage suppressed EpCAM expression and Wnt/β-catenin signaling via mitochondria-related reactive oxygen species production and FOXO activities, resulting in apoptosis and tumor suppression. These results indicate that a synthetic lethality screen is a viable strategy to identify actionable drivers of HCC and identify PMPCB as a therapeutically vulnerable gene in EpCAM+ HCC subpopulations. Significance: This study identifies PMPCB as critical to mitochondrial homeostasis and a synthetic lethal candidate that selectively kills highly resistant EpCAM+ HCC tumors by inactivating the Wnt/β-catenin signaling pathway.

The substantial literature on interactions between places/spaces and well-being/health often differentiate between physical and social aspects of geographical location. This paper sidesteps this dualism, instead considering places as sociomaterial assemblages of human and non-human materialities. It uses this posthuman and ‘new materialist’ perspective to explore how place-assemblages affect human capacities, in terms of both health and social dis/advantage. Based on secondary analysis of interview data on human/place interactions, it analyses the physical, sociocultural, psychological and emotional effects of place-assemblages, assessing how these produce opportunities for, and constraints upon human bodies. It than assesses how these emergent capacities affect both social dis/advantage and well-being. This analysis of how place-assemblages contribute positively or negatively to health and dis/advantage offers possibilities for further research and for social and public health policy.

In the health field, there is great interest in the role empowerment might play in reducing social inequalities in health. Empowerment is understood here as the processes of developing capabilities that individuals and/or communities need to exercise control over decisions and actions impacting on their lives and health. There is a fundamental problem, however, in identifying and measuring capabilities for collective control that emerge at the level of the collective, with much of the existing literature focusing on individual measures even where community-level processes are concerned. Collective measures need to capture the dynamics of interactions within and between groups, not simply aggregate individual-level measures. This article, Part 2 in a three-part series, takes up the challenge of identifying qualitative markers of capabilities for collective control. We applied the emancipatory power framework (EPF) reported in Part 1 of the series, to qualitative data generated during a longitudinal evaluation of a major English area-based empowerment initiative, the Big Local (BL). We identified empirical ‘markers’ of shifts towards greater collective control pertaining to each of the ‘power’ dimensions in the EPF—‘power within’, ‘power with’ and ‘power to’—and markers of communities exercising ‘power over’ other institutions/community members. These markers can usefully be applied in the evaluation planning and evaluation of empowerment initiatives. Part 3 in the series uses these markers and a second analytical framework developed during our evaluation of BL to explore how power dynamics unfold in participatory spaces in BL neighbourhoods.

Background Systems thinking has emerged as a promising approach to addressing complex public health issues. For children, the focus of the approach has been on single outcomes e.g. obesity, rather than addressing the broad range of inequalities in health outcomes. We report on an approach to developing a system-oriented perspective on the determinants of inequalities in child health and wellbeing in English local authorities. Methods Qualitative group concept mapping workshops (a 'soft' system science approach) were held in two contrasting English local authorities with a range of stakeholders: professionals (N = 35); children and young people (N = 33) and carers (N = 5). Initial area maps were refined using data from qualitative interviews with professionals (N = 16) and resulting maps reviewed and validated by expert stakeholders in each area (N = 9; N = 35). Commonalities between two area-specific system maps (and removal of locality-specific factors) were used to develop a map that could be applied in any English local area. Two rounds of online consultation (N = 21; N = 8) and qualitative interviews (N = 12) with experts in public health, local governance and systems science refined the final system map displaying the determinants of child health inequalities, and give insight into its potential utilisation. Results The process created a map of over 150 factors influencing inequalities in health outcomes for children aged 0-25 years at the local area level. The system map has six domains; physical environment, governance, economic, social, service, and personal. Conclusions To our knowledge this is the first study taking a systems approach to addressing inequalities across all aspects of child health. Group concept mapping can support systems thinking at the local level. The resulting system map illustrates the complexity of factors influencing child health inequalities and is a useful tool for strategy development, action prioritisation and systems evaluation planning. Key messages Group concept mapping can be successfully applied to facilitate a systems approach to child health inequalities at the local area level. Mapping the local child health system highlights complex relationships between physical, social, personal, service, governance and economic factors which influence inequalities and health outcomes.

Background Many health outcomes for children and young people in England, UK remain poor compared to international peers, with persistent inequalities across the country. Our study sought to understand, from the perspectives of local stakeholders, the key factors affecting the development and implementation of policy to improve child health and reduce inequalities. Methods We carried out a detailed case study in an English local authority area. Our fieldwork comprised: documentary review of local policies, observation of key strategic and operational meetings and semi-structured interviews with local stakeholders. We followed Jessop's (2016) approach in using specific policy areas and policies (mental health, obesity and the early years) as 'entry points' to understand the local context. Results First, and most importantly, there was an overriding consensus that local action to reduce inequalities in child health is hampered by a persistent unequal distribution of the social determinants of health. Second, local stakeholders highlighted the damaging impact of austerity measures and poverty in the UK, which, they argued, had impacted most upon the most vulnerable. Third, while national policies often provided a framework and incentive for local action, there was an emphasis on the importance of local knowledge and place-based approaches, developed through close work with communities. Conclusions Our study highlights the need for progressive policies to begin to reduce the uneven distribution of the social determinants of health to enable local stakeholders to make progress in tackling inequalities in child health. It emphasises the futility of funding national policies to improve child health and reduce inequalities in the context of greatly reduced budgets for local authorities. National policy should also facilitate the mobilisation of context specific knowledge, produced in conjunction with community members. Key messages Our work evidences the pressing need to address structural inequalities and adequately resource and facilitate work to reduce inequalities at a local level. National policy should facilitate the mobilisation of context specific knowledge, produced in conjunction with community members.

Background In recent years, asset-based approaches (ABAs) to promote health have increasingly been adopted as a strategy to reduce health inequalities between neighbourhoods. However, evidence of impact is still limited due to their complexity. This research aimed to explore what changes ABAs generate, studying two asset-based initiatives that train local lay people to become peer health promoters, implemented in two different settings (Spain and UK). Methods A five months ethnography was conducted in each setting between March 2018 and March 2019. Data were collected through 127 hours of observations and interviews with 44 participants (learners, community workers and health professionals). Thematic analysis was performed to explore the impacts of the interventions and their interactions with local contexts. Results Preliminary findings indicate that learners' self-confidence, knowledge and skills for addressing local health determinants increased in both settings. However, contextual factors played an important role in supporting or hindering wider impacts in the communities where the initiatives were implemented. Opportunities for working together across sectors and being supported by local institutions were key elements supporting learners to transfer the acquired confidence, skills and knowledge to other settings beyond the time and space of the initiatives. These learners reported volunteering more in their communities, developing new activities, or transferring skills in their workplace to change practice and attitudes. Conclusions This study found that ABAs initiatives implemented in communities have the potential to support reduction of inequalities through increasing people's skills, knowledge and self-confidence. However, it is key to work intersectorally to create enabling environments where these acquired capacities can be mobilised, as the context can support or hinder wider changes to occur. Key messages Asset-based interventions to promote health increase people knowledge, skills and self-confidence, but it is key to consider how contextual factors can favour or hinder the potential for wider impacts. Community structures and institutional support for joint working influence mobilisation of learners’ acquired confidence, skills and knowledge beyond the formal spaces of asset-based interventions.

Fetal growth restriction (FGR) is the most common pregnancy complication in developed countries. Pregnancies affected by FGR, frequently concur with complications and high risk of neonatal morbidity and mortality. To date, no approved treatment is available for pregnant women affected with FGR. The objective of this study was to investigate the contribution of galectin-3 (gal-3), a β-galactoside binding protein involved in pregnancy, placental function and fetal growth. We demonstrated that lack of gal-3 during mouse pregnancy leads to placental dysfunction and drives FGR in the absence of a maternal preeclampsia syndrome. Analysis of gal-3 deficient dams revealed placental inflammation and malperfusion, as well as uterine natural killer cell infiltration with aberrant activation. Our results also show that FGR is associated with a failure to increase maternal circulating gal-3 levels during the second and third trimester in human pregnancies. Placentas from human pregnancies affected by FGR displayed lower gal-3 expression, which correlated with placental dysfunction. These data highlight the importance of gal-3 in the promotion of proper placental function, as its absence leads to placental disease and subsequent FGR.

Objective\ud This study examined the role of migration and acculturation in the diet of Ghanaian migrants in Europe by (1) comparing food intake of Ghanaian migrants in Europe with that of Ghanaians living in Ghana and (2) assessing the association between acculturation and food intake.\ud \ud Design\ud Data from the cross-sectional multicenter study Research on Obesity and Diabetes among African Migrants were used. Food intake was assessed using a Ghana-specific food propensity questionnaire (134 items and 14 food groups); foods were grouped based on a model of dietary change proposed by Koctürk-Runefors.\ud \ud Setting\ud Ghana, London, Amsterdam, and Berlin.\ud \ud Participants\ud A total of 4,534 Ghanaian adults living in Ghana and Europe, with complete dietary data. Of these, 1,773 Ghanaian migrants had complete acculturation data.\ud \ud Main Outcome Measure\ud Food intake (the weighted intake frequency per week of food categories).\ud \ud Analysis\ud Linear regression.\ud \ud Results\ud Food intake differed between Ghanaians living in Ghana and Europe. Among Ghanaian migrants in Europe, there were inconsistent and small associations between acculturation and food intake, except for ethnic identity, which was consistently associated with intake only of traditional staples.\ud \ud Conclusions and Implications\ud Findings indicate that migration is associated with dietary changes that cannot be fully explained by ethnic, cultural, and social acculturation. The study provides limited support to the differential changes in diet suggested by the Koctürk-Runefors’ model of dietary change.

The RAS proteins are GTP-dependent switches that regulate signaling pathways and are frequently mutated in cancer. RAS proteins concentrate in the plasma membrane via lipid-tethers and hypervariable region side-chain interactions in distinct nano-domains. However, little is known about RAS membrane dynamics and the details of RAS activation of downstream signaling. Here, we characterize RAS in live human and mouse cells using single-molecule-tracking methods and estimate RAS mobility parameters. KRAS4b exhibits confined mobility with three diffusive states distinct from the other RAS isoforms (KRAS4a, NRAS, and HRAS); and although most of the amino acid differences between RAS isoforms lie within the hypervariable region, the additional confinement of KRAS4b is largely determined by the protein’s globular domain. To understand the altered mobility of an oncogenic KRAS4b, we used complementary experimental and molecular dynamics simulation approaches to reveal a detailed mechanism.

This study explores the ways in which social networks might shape accounts about food practices. Drawing on insights from the work of Christakis and Fowler () whose claims about the linkages between obesity and social networks have been the subject of vigorous debate in the sociological literature, we present qualitative data from a study of women's' accounts of social networks and food practices, conducted in Nottingham, England. We tentatively suggest that whilst social networks in their broadest sense, might shape what was perceived to be normal and acceptable in relation to food practices (and provide everyday discursive resources which normalise practice), the relationship between the two is more complex than the linear relationship proposed by Christakis and Fowler. Here, we introduce the idea of assumed shared food narratives (ASFNs), which, we propose, sheds light on motive talk about food practices, and which also provide practical and discursive resources to actors seeking to protect and defend against 'untoward' behaviour, in the context of public health messages around food and eating. We suggest that understanding ASFNs and the ways in which they are embedded in social networks represents a novel way of understanding food and eating practices from a sociological perspective.

A growing body of research attests to the impact of welfare regimes on health and health equity. However, the mechanisms that link different kinds of welfare entitlement to health outcomes are less well understood. This study analysed the accounts of 29 older adults in England to delineate how the form of entitlement to welfare and other resources (specifically, whether this was understood as a universal entitlement or as targeted to those in need) impacts on the determinants of health. Mechanisms directly affecting access to material resources (through deterring uptake of benefits) have been well documented, but those that operate through psychosocial and more structural pathways less so, in part because they are more challenging to identify. Entitlement that was understood collectively, or as arising from financial or other contributions to a social body, had positive impacts on wellbeing beyond material gains, including facilitating access to important health determinants: social contact, recognition and integration. Entitlement understood as targeted in terms of individualised concepts of need or vulnerability deterred access to material resources, but also fostered debate about legitimacy, thus contributing to negative impacts on individual wellbeing and the public health through the erosion of social integration. This has important implications for both policy and evaluation. Calls to target welfare benefits at those in most need emphasise direct material pathways to health impact. We suggest a model for considering policy change and evaluation which also takes into account how psychosocial and structural pathways are affected by the nature of entitlement.

This is the author’s version of the article published in Critical Public Health The article has been peer-reviewed, but does not include the publisher’s layout, page numbers and proof-corrections. Citation for the published paper: Powell, K., Thurston, M. & Bloyce, D. (2017). Theorising lifestyle drift in health promotion: explaining community and voluntary sector engagement practices in disadvantaged areas. Critical Public Health, 27(5), 554-565. doi: http://dx.doi.org10.1080/09581596.2017.1356909 The past two decades have seen an increasing role for the UK community and voluntary sector (CVS) in health promotion in disadvantaged areas, largely based on assumptions on the part of funders that CVS providers are better able to engage ‘hard-to-reach’ population groups in services than statutory providers. However, there is limited empirical research exploring CVS provider practices in this field. Using ethnographic data, this paper examines the experiences of a network of CVS providers seeking to engage residents in health-promoting community services in a disadvantaged region in the North of England. The paper shows how CVS providers engaged in apparently contradictory practices, fluctuating between an empathically informed response to complex resident circumstances and (in the context of meeting externally set targets) behavioural lifestyle approaches to health promotion. Drawing on concepts from figurational sociology, the paper explains how lifestyle drift occurs in health promotion as a result of the complex web of relations (with funders, commissioners and residents) in which CVS providers are embedded. Despite the fact that research has revealed the impact of targets on the work of the CVS before, this paper demonstrates more specifically the way in which monitoring processes within CVS contracts can draw providers into the neoliberal lifestyle discourse so prevalent in health promotion.

BACKGROUND: Previous studies have identified a process of dietary acculturation when migrant groups adopt the food patterns of the host country. AIM: The aim of this study was to explore the influence of migration on dietary practices and the process of dietary acculturation amongst Ghanaians living in the UK. \ud \ud SUBJECT AND METHODS: A qualitative study of adults aged ≥ 25yrs (n = 31) of Ghanaian ancestry living in Greater Manchester using face to face interviews. Participants varied in socioeconomic status, gender and migration status. Interviews were transcribed verbatim and analysed thematically. \ud \ud RESULTS: Three distinct dietary practice typologies were discernible that differed in terms of typical meal formats, meal contexts, structure and patterning of meals, food preparation and purchasing behaviours: i. continuity practices; ii. flexible practices; and iii. changed practices. The identified practices were shaped by interrelating factors that fell into four main clusters: social and cultural environment; accessibility of foods; migration context; and food beliefs/perceptions. \ud \ud CONCLUSION: Participants retained, to a varying degree, some aspects of Ghanaian dietary practices whilst adopting key features of UK food culture. This study demonstrates the complexity of dietary change, indicating that it is not a linear process and it is dependent on several factors.

There is a need for greater conceptual clarity in place-based initiatives that seek to give residents of disadvantaged neighbourhoods more control over action to address the social determinants of health inequalities at a local level. In this article, we address this issue as it relates to the concepts of participation and inclusion. We draw on qualitative data generated during the first phase of the Communities in Control Study, a longitudinal multisite independent evaluation of the impact of Big Local on the social determinants of health and health inequalities. Big Local is a resident-led area improvement initiative in England, funded by the UK Big Lottery Fund. Initiatives focused on community empowerment are increasingly prominent in public health policy and practice globally. Approaches emphasise the promotion of greater control over decisions and action among individuals, groups, and communities, particularly those living in disadvantaged circumstances. However, when it comes to participation and inclusion in taking action and making decisions, the field is characterised by conceptual confusion. This risks undermining the impact of these initiatives. While participation and inclusion are necessary conditions for empowerment and collective control, they are not necessarily sufficient. Sufficiency requires attention to the breadth of participation (i.e., to inclusion) and to the depth of participation (i.e., the extent to which it is experienced as empowering and ultimately enables the exercise of collective control over decisions and actions). In observing how different Big Local resident-led partnerships across England are tackling the day-to-day challenges of engaging with their communities, we reveal the potential for policy and practice of reframing, and therefore clarifying (to highlight the different roles they have) the concepts of participation and inclusion in terms of depth and breadth.

In the UK, ethnic minority groups tend to have higher levels of poverty than the white British population and therefore may be at high risk of food insecurity. Ghanaians, living in Ghana or as migrants are thought to have a high level of social support in their communities, but the role of this resource in relation to food security is unknown. We explored participants' perceptions of social and economic factors influencing food security among Ghanaian migrants in Greater Manchester. Participants aged ≥25 years (n = 31) of Ghanaian ancestry living in Greater Manchester were interviewed using a semi-structured interview guide developed by the researchers. Participants varied in socioeconomic status (SES), gender and migration status. Interviews were transcribed verbatim and analysed thematically using a framework approach. Participants offered similar accounts of the social and economic factors influencing food security. Accounts were based on participants' perceptions and/or personal experiences of food insecurity within the community. Participants indicated that they and their fellow Ghanaians can "manage" even when they described quite challenging food access environments. This has negative implications on their food choices in the UK. Participants reported food insecure households may be reluctant to make use of food banks for fear of "gossip" and "pride". Paradoxically, this reluctance does not extend to close network. Many participants described the church and other social groups as a trusted base in which people operate; support given through these channels is more acceptable than through the "official context". Government assisted food banks could partner with the social groups within this community given that these are more trusted. Keywords: food insecurity; food choice; social networks; Ghanaians; healthy eating; migrants.

Children and young people in the UK have worse health outcomes than in many similar western countries and child health inequalities are persistent and increasing. Systems thinking has emerged as a promising approach to addressing complex public health issues. We report on a systems approach to mapping the determinants of child health inequalities at the local level in England for young people aged 0–25, and describe the resulting map. Qualitative group concept mapping workshops were held in two contrasting English local authorities with a range of stakeholders: professionals (N = 35); children and young people (N = 33) and carers (N = 5). Initial area maps were developed, and augmented using data from qualitative interviews with professionals (N = 16). The resulting local maps were reviewed and validated by expert stakeholders in each area (N = 9; N = 35). Commonalities between two area-specific system maps (and removal of locality-specific factors) were used to develop a map that could be applied in any English local area. Two rounds of online survey (N = 21; N = 8) experts in public health, local governance and systems science refined the final system map displaying the determinants of child health inequalities. The process created a map of over 150 factors influencing inequalities in health outcomes for children aged 0–25 years at the local area level. The system map has six domains; physical environment, governance, economic, social, service, and personal. To our knowledge this is the first study taking a systems approach to addressing inequalities across all aspects of child health. The study shows how group concept mapping can support systems thinking at the local level. The resulting system map illustrates the complexity of factors influencing child health inequalities, and it may be a useful tool in demonstrating to stakeholders the importance of policies that tackle the systemic drivers of child health inequalities beyond those traditionally associated with public health.

Pancreatic ductal adenocarcinoma (PDAC) is a recalcitrant and lethal disease with an overall 5-year survival rate of less than 8%. The abundance and heterogeneity of cancer-associated fibroblasts (CAFs) in a highly desmoplastic tumor microenvironment are unique features of PDAC. Therapeutic strategies aimed at indiscriminately eliminating CAFs have failed in clinical trials. The opposing tumor-restraining or tumor-promoting role of distinct CAFs subpopulations of has emerged as a new paradigm in PDAC basic and translational research. Understanding how the composition of these distinct CAF subpopulations is affected by and interferes with current treatments is a key question to solve in order to obtain more effective and durable clinical responses. Genetic studies in K-Ras-driven genetically engineered mouse models (GEMMs) indicate that α-smooth muscle actin-expressing (SMA+) CAFs have a predominant tumor-restraining role. Here, we studied global loss of pro-fibrotic non-coding regulatory microRNA-21 (miR-21) in PDAC GEMMs. We generated mouse strains carrying wild type or knockout alleles of Mir-21 in a well-characterized K-Ras-driven, p53-deleted PDAC model (LSL-KrasG12D; p53lox/+;Pdx1-Cre, KPC). Even though miR-21 expression was upregulated in cancer cells and cancer-associated fibroblasts in KPC tumors, global loss of miR-21 activity did not inhibit tumor growth. Strikingly, loss of miR-21 accelerated tumor initiation via mucinous cystic neoplastic lesions and progression to locally advanced invasive carcinoma from which animals precipitously succumbed at an early age. We uncovered a cell-autonomous requirement of miR-21 activity for induction of tumor-restraining SMA+ CAFs, whose absence led to a profound remodeling of the stroma and massive infiltrate of tumor-promoting immune cells. Low miR-21 expression negatively correlated with a fibroblast gene expression signature and positively with an immune cell gene expression signature in TCGA PDAC data set (n = 156) mirroring findings in GEMMs. In vitro and in vivo isograft experiments showed that miR-21 activity was dispensable for cancer cell growth, but required for complete execution of TGF-β-mediated programs. Our results suggest that modulation of miR-21 activity may provide a novel therapeutic opportunity to affect the composition of CAF subpopulations. We will present our genetic and pharmacological approaches to modulate stromal activity of miR-21 in established disease in order to enhance current chemotherapy and/or immunotherapy treatments. Citation Format: Josh Schipper, Brooke Jackson, Ian Beddows, Elizabeth Kenyon, Katie Powell, Neil Robertson, Galen Hostetter, Matti Kiupel, Anna Moore, Jose Conejo-Garcia, Lorenzo sempere. Tumor-suppressive stromal activity of pro-fibrogenic microRNA-21 in initiation and progression of K-Ras-driven mouse models of pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5719.

Hepatocellular carcinoma (HCC) is a genetically heterogeneous disease for which a dominant actionable molecular driver has not been identified. Patients with the stem cell-like EpCAM(+)AFP(+) HCC subtype have poor prognosis. Here we performed a genome-wide RNAi screen to identify genes with a synthetic lethal interaction with EpCAM as a potential therapeutic target for the EpCAM(+)AFP(+) HCC subtype. We identified 26 candidate genes linked to EpCAM/Wnt/β-catenin signaling and HCC cell growth. We further characterized the top candidate PMPCB, which plays a role in mitochondrial protein processing, as a bona fide target for EpCAM(+) HCC. PMPCB blockage suppressed EpCAM expression and Wnt/β-catenin signaling via mitochondria-related ROS production and FOXO activities, resulting in apoptosis and tumor suppression. These results indicate that a synthetic lethality screen is a viable strategy to identify actionable drivers of HCC and identify PMPCB as a therapeutically vulnerable gene in EpCAM(+) HCC subpopulations.

Summary: KRAS can bind numerous effector proteins, which activate different downstream signaling events. The best known are RAF, phosphatidylinositide (PI)-3′ kinase, and RalGDS families, but many additional direct and indirect effectors have been reported. We have assessed how these effectors contribute to several major phenotypes in a quantitative way, using an arrayed combinatorial siRNA screen in which we knocked down 41 KRAS effectors nodes in 92 cell lines. We show that every cell line has a unique combination of effector dependencies, but in spite of this heterogeneity, we were able to identify two major subtypes of KRAS mutant cancers of the lung, pancreas, and large intestine, which reflect different KRAS effector engagement and opportunities for therapeutic intervention.

Social participation following acquired disability is an important focus of rehabilitation for all members of the interdisciplinary rehabilitation team. Evidence demonstrates that social participation leads to increased life satisfaction and quality of life [1, 2]. However, “the presence of disability has been found to lead to participation that is less diverse, is located more in the home, involves fewer social relationships, and includes less active recreation” [3]. When individuals with disabilities return to their homes and communities, they often encounter psychological and physical barriers that limit their social participation. Historically the problems of people with disabilities were perceived to be more social and psychological rather than physical; however, later research examining all potential barriers found physical, medical, and political barriers to be more difficult [4]. This chapter outlines these barriers, highlights assessments to help identify or measure the barriers, provides interventions to overcome them, and expected outcomes of these interventions.

Background Europe has a growing population of ethnic minority groups whose dietary behaviours are potentially of public health concern. To promote healthier diets, the factors driving dietary behaviours need to be understood. This review mapped the broad range of factors influencing dietary behaviour among ethnic minority groups living in Europe, in order to identify research gaps in the literature to guide future research. Methods A systematic mapping review was conducted (protocol registered with PROSPERO 2014: CRD42014013549). Nine databases were searched for quantitative and qualitative primary research published between 1999 and 2014. Ethnic minority groups were defined as immigrants/populations of immigrant background from low and middle income countries, population groups from former Eastern Bloc countries and minority indigenous populations. In synthesizing the findings, all factors were sorted and structured into emerging clusters according to how they were seen to relate to each other. Results Thirty-seven of 2965 studies met the inclusion criteria (n = 18 quantitative; n = 19 qualitative). Most studies were conducted in Northern Europe and were limited to specific European countries, and focused on a selected number of ethnic minority groups, predominantly among populations of South Asian origin. The 63 factors influencing dietary behaviour that emerged were sorted into seven clusters: social and cultural environment (16 factors), food beliefs and perceptions (11 factors), psychosocial (9 factors), social and material resources (5 factors), accessibility of food (10 factors), migration context (7 factors), and the body (5 factors). Conclusion This review identified a broad range of factors and clusters influencing dietary behaviour among ethnic minority groups. Gaps in the literature identified a need for researchers to explore the underlying mechanisms that shape dietary behaviours, which can be gleaned from more holistic, systems-based studies exploring relationships between factors and clusters. The dominance of studies exploring ‘differences’ between ethnic minority groups and the majority population in terms of the socio-cultural environment and food beliefs suggests a need for research exploring ‘similarities’. The evidence from this review will feed into developing a framework for the study of factors influencing dietary behaviours in ethnic minority groups in Europe.

Background Although it is increasingly acknowledged that social networks are important to our understanding ofoverweight and obesity, there is limited understanding about the processes by which such networks shapetheir progression. This paper reports the findings of a scoping review of the literature that sought to identify the key processes through which social networks are understood to influence the development of overweight and obesity. Methods A scoping review was conducted. Forty five papers were included in the final review, the findings of which were synthesised to provide an overview of the main processes through which networks have been understood to influence the development of overweight and obesity. Results Included papers addressed a wide range of research questions framed around six types of networks: a paired network (one’s spouse or intimate partner); friends and family (including work colleagues and people within social clubs); ephemeral networks in shared public spaces (such as fellow shoppers in a supermarket or diners in a restaurant); people living within the same geographical region; peers (including co-workers, fellow students, fellow participants in a weight loss programme); and cultural groups (often related toethnicity). As individuals are embedded in many of these different types of social networks at any one time, the pathways of influence from social networks to the development of patterns of overweight and obesity are likely to be complex and interrelated. Included papers addressed a diverse set of issues: body weight trends over time; body size norms or preferences; weight loss and management; physical activity patterns; and dietary patterns. Discussion Three inter-related processes were identified: social contagion (whereby the network in which people are embedded influences their weight or weight influencing behaviours), social capital (whereby sense of belonging and social support influence weight or weight influencing behaviours), and social selection (whereby a person’s network might develop according to his or her weight). Conclusions The findings have important implications for understanding about methods to target the spread of obesity, indicating that much greater attention needs to be paid to the social context in which people make decisions about their weight and weight influencing behaviours. Electronic supplementary material The online version of this article (doi:10.1186/s12889-015-2314-0) contains supplementary material, which is available to authorized users.

In many welfare states, 'austerity' policies have ignited debates about the fairness and cost-effectiveness of universal welfare benefits, with benefits received by older citizens a particular topic of concern. Empirical studies suggest that conditionality generates problems of access and uptake but, to date, there has been little research on how different conditions of entitlement are understood by older citizens. This study drew on interviews with 29 older citizens from three areas of England to explore how eligibility for and uptake of different kinds of welfare benefits were understood. In interviews, current entitlement was understood in relation to a generational habitus, in which 'our generation' was framed as sharing cohort experiences, and moral orientations to self-reliance, hard work and struggle. Entitlement to some welfare benefits was taken for granted as a reward owed by the state to its citizens for hard-earned lives. State transfers such as pensions, free travel and fuel subsidies were congruent with a nationalised generational habitus, and fostered recognition, self-worth and the sense of a generation as a collective. In contrast, transfers contingent on economic or need-based conditionality were more explicitly framed as 'benefits', and negatively associated with vulnerability and moral contestation. Uptake was therefore often incompatible with their generational habitus. Calls for introducing further conditionality to benefits for older adults are often based on claims that this will increase fairness and equality. Our analysis suggests, however, that introducing conditionality has the potential to promote inequality and foster differentiation and division, within the older population and between generations.

In this paper an approach for motion capture of dressed people is presented. A cloth draping method is incorporated in a silhouette based motion capture system. This leads to a simultaneous estimation of pose, joint angles, cloth draping parameters and wind forces. An error functional is formalized to minimize the involved parameters simultaneously. This allows for reconstruction of the underlying kinematic structure, even though it is covered with fabrics. Finally, a quantitative error analysis is performed. Pose results are compared with results obtained from a commercially available marker based tracking system. The deviations have a magnitude of three degrees which indicates a reasonably stable approach.

This is the author's version before it was sent to the publisher. Therefore, it may differ slightly from the published version. For the published version, please go to: http://hea.sagepub.com/content/early/2014/03/28/1363459314524802.refs.html Area-based initiatives (ABIs) have formed an important part of public policy towards more socio-economically deprived areas in many countries. Co-ordinating service provision within and across sectors has been a common feature of these initiatives. Despite sustained policy interest in ABIs, little empirical work has explored relations between ABI providers and partnership development within this context remains under-theorised. This paper addresses both of these gaps by exploring partnerships as a social and developmental process, drawing on concepts from figurational sociology to explain how provider relations develop within an ABI. Qualitative methods were used to explore, prospectively, the development of an ABI targeted at a town in the north west of England. A central finding was that, although effective delivery of ABIs is premised on a high level of coordination between service providers, the pattern of interdependencies between providers limits the frequency and effectiveness of cooperation. In particular, the interdependency of ABI providers with others in their organisation (what is termed here ‘organisational pull’) constrained the ways in which they worked with providers outside of their own organisations. ‘Local’ status, which could be earned over time, enabled some providers to exert greater control over the way in which provider relations developed during the course of the initiative. These findings demonstrate how historically constituted social networks, within which all providers are embedded, shape partnership development. The theoretical insight developed here suggests a need for more realistic expectations among policy makers about how and to what extent provider partnerships can be managed.

The number of older adults living in Europe is expected to grow rapidly over the next 15 years, raising a number of new public health challenges. Inequalities in health are evident within all European countries, the most prominent of which relate to socio-economic differences. In the current European context of economic difficulties and austerity, fundamental aspects of welfare provision through the state have been challenged. In the UK, there have been calls to reconsider the viability and fairness of …

The RAS Initiative at the Frederick National Laboratory has generated an isogenic mouse embryonic fibroblast (MEFs) cell line panel containing single transgene alleles using the RAS-less MEF system developed by Matthias Drosten and Mariano Barbacid (CNIO). These MEFs are H, N and K-RAS null, growth is dependent on exogenous RAS or MAPK pathway activation. The panel includes: KRAS 4A WT, KRAS 4B WT, KRAS 4B G12C, G12D, G12V, G13D, Q61L, Q61R, HRAS WT, NRAS WT or BRAF V600E. The workflow to generate the lines requires cre-lox removal of endogenous KRAS and the cells arrest in the G1 phase of the cycle. Proliferation is resumed through the delivery of the transgene to the cells using lentiviral transduction. Clonal cell lines are derived from the initial pools and are thoroughly characterized including confirmation of endogenous KRAS gene removal, identification of the transgene insertion site(s), calculation of proliferation rates and doubling times, analysis of signaling pathways, response to tool compounds and exome sequenced to exclude lines with mutations in onco-relevant genes. This panel is a unique resource that can be used to ask allele and isoform specific questions (gene expression profiles, GTP-loading, etc.) and screen for RAS inhibitors as well as determine novel compound specificity. This panel is available to the academic RAS research community. Citation Format: Nicole Fer, Brian Smith, Leslie Garvey, William Burgan, Katie Powell, Kanika Sharma, Andrew Waters, Xiaolin Wu, Dan Soppet, Robert Stephens, Dwight Nissley, Matthew Holderfield, Rachel K. Bagni. Uncovering oncogenic KRAS allele specific phenotypes using an isogenic MEF cell line system. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1131.