The effect of age on the acquisition and selection of cancer driver mutations in sun-exposed normal skin

BACKGROUND: The accumulation of somatic mutations contributes to ageing and cancer. Sunlight is the principal aetiological factor associated with skin cancer development. However, genetic and phenotypic factors also contribute to skin cancer risk. This study aimed at exploring the role of photoaging, as well as other well-known epidemiological risk factors, in the accumulation of somatic mutations in cancer-free human epidermis. MATERIAL AND METHODS: We deeply sequenced 46 genes in normal skin biopsies from 127 healthy donors, from which phenotypic data (including age, pigmentation-related genotype and phenotype) and sun exposure habits were collected. We determined the somatic mutational burden, mutational signatures, clonal selection and frequency of driver mutations in all samples. RESULTS: Our results reveal an exponential accumulation of UV-related somatic mutations with age, matching skin cancer incidence. The increase of mutational burden is in turn modified by an individual's skin phototype. Somatic mutations preferentially accumulated in cutaneous squamous cell carcinoma (cSCC) cancer genes and clonally expanded with age, with distinct mutational processes underpinning different age groups. Our results suggest loss of fidelity in transcription-coupled repair later in life. CONCLUSION: Our findings reveal that aging is not only associated with an exponential increase in the number of somatic mutations accumulated in normal epidermis, but also with selection and expansion of cancer-associated mutations. Aged, sun-exposed normal skin is thus an extended mosaic of multiple clones with driver mutations, poised for the acquisition of transforming events

With and beyond the state -- co-production as a route to political influence, power and transformation for grassroots organizations

This paper reviews the use of co-production – with state and citizensworking together – as a grassroots strategy to secure political infl uence and accessresources and services. To date, the literature on social movements has concentratedon more explicitly political strategies used by such movements to contest forpower and infl uence. Co-production, when considered, is viewed as a strategy usedby citizens and the state to extend access to basic services with relatively littleconsideration given to its wider political ramifi cations. However, co-productionis used increasingly by grassroots organizations and federations as part of anexplicit political strategy. This paper examines the use of co-productive strategiesby citizen groups and social movement organizations to enable individualmembers and their associations to secure effective relations with state institutionsthat address both immediate basic needs and enable them to negotiate for greaterbenefits.ESRC-DFI

The impact of mental health recovery narratives on recipients experiencing mental health problems: Qualitative analysis and change model.

BACKGROUND: Mental health recovery narratives are stories of recovery from mental health problems. Narratives may impact in helpful and harmful ways on those who receive them. The objective of this paper is to develop a change model identifying the range of possible impacts and how they occur. METHOD: Semi-structured interviews were conducted with adults with experience of mental health problems and recovery (n = 77). Participants were asked to share a mental health recovery narrative and to describe the impact of other people's recovery narratives on their own recovery. A change model was generated through iterative thematic analysis of transcripts. RESULTS: Change is initiated when a recipient develops a connection to a narrator or to the events descripted in their narrative. Change is mediated by the recipient recognising experiences shared with the narrator, noticing the achievements or difficulties of the narrator, learning how recovery happens, or experiencing emotional release. Helpful outcomes of receiving recovery narratives are connectedness, validation, hope, empowerment, appreciation, reference shift and stigma reduction. Harmful outcomes are a sense of inadequacy, disconnection, pessimism and burden. Impact is positively moderated by the perceived authenticity of the narrative, and can be reduced if the recipient is experiencing a crisis. CONCLUSIONS: Interventions that incorporate the use of recovery narratives, such as peer support, anti-stigma campaigns and bibliotherapy, can use the change model to maximise benefit and minimise harms from narratives. Interventions should incorporate a diverse range of narratives available through different mediums to enable a range of recipients to connect with and benefit from this material. Service providers using recovery narratives should preserve authenticity so as to maximise impact, for example by avoiding excessive editing

DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer

BACKGROUND: The APOBEC3 family of cytidine deaminases mutate the cancer genome in a range of cancer types. Although many studies have documented the downstream effects of APOBEC3 activity through next-generation sequencing, less is known about their upstream regulation. In this study, we sought to identify a molecular basis for APOBEC3 expression and activation. RESULTS: HER2 amplification and PTEN loss promote DNA replication stress and APOBEC3B activity in vitro and correlate with APOBEC3 mutagenesis in vivo. HER2-enriched breast carcinomas display evidence of elevated levels of replication stress-associated DNA damage in vivo. Chemical and cytotoxic induction of replication stress, through aphidicolin, gemcitabine, camptothecin or hydroxyurea exposure, activates transcription of APOBEC3B via an ATR/Chk1-dependent pathway in vitro. APOBEC3B activation can be attenuated through repression of oncogenic signalling, small molecule inhibition of receptor tyrosine kinase signalling and alleviation of replication stress through nucleoside supplementation. CONCLUSION: These data link oncogene, loss of tumour suppressor gene and drug-induced replication stress with APOBEC3B activity, providing new insights into how cytidine deaminase-induced mutagenesis might be activated in tumourigenesis and limited therapeutically

Mental Health Recovery Narratives and Their Impact on Recipients: Systematic Review and Narrative Synthesis.

OBJECTIVE: Mental health recovery narratives are often shared in peer support work and antistigma campaigns. Internet technology provides access to an almost unlimited number of narratives, and yet little is known about how they affect recipients. The aim of this study was to develop a conceptual framework characterizing the impact of recovery narratives on recipients. METHOD: A systematic review of evidence about the impact of mental health recovery narratives was conducted. Searches used electronic databases ( n = 9), reference tracking, hand-searching of selected journals ( n = 2), grey literature searching, and expert consultation ( n = 7). A conceptual framework was generated through a thematic analysis of included articles, augmented by consultation with a Lived Experience Advisory Panel. RESULTS: In total, 8137 articles were screened. Five articles were included. Forms of impact were connectedness, understanding of recovery, reduction in stigma, validation of personal experience, affective responses, and behavioural responses. Impact was moderated by characteristics of the recipient, context, and narrative. Increases in eating disorder behaviours were identified as a harmful response specific to recipients with eating disorders. CONCLUSIONS: Mental health recovery narratives can promote recovery. Recovery narratives might be useful for clients with limited access to peers and in online interventions targeted at reducing social isolation in rural or remote locations, but support is needed for the processing of the strong emotions that can arise. Caution is needed for use with specific clinical populations. Protocol registration: Prospero-CRD42018090923

Spatio-temporal patterns of pre-eclampsia and eclampsia in relation to drinking water salinity at the district level in Bangladesh from 2016 to 2018

This analysis examines whether salinity in drinking water is associated with pre-eclampsia and eclampsia (PE/E), a leading cause of maternal morbidity and mortality. Bangladesh’s national health information system data were extracted at the district level (n = 64) to assess PE/E rates, and these were overlaid with three environmental measures approximating drinking water salinity, remotely sensed low-elevation coastal zone (LECZ), monthly rainfall data, and electrical conductivity of groundwater (i.e., water salinity). Results from a negative binomial fixed effects model suggest PE/E rates are higher with less rainfall (dry season), lower population density, and that district level rates of PE/E increase with higher groundwater salinity and in the high risk LECZ category closest to the coast. Results suggest that drinking water salinity may be associated with PE/E and that using national health surveillance data can improve understanding of this association. This approach can potentially be leveraged in the future to inform targeted interventions to high risk regions and times

Cell Dispersal Influences Tumor Heterogeneity and Introduces a Bias in NGS Data Interpretation

Short and long distance cell dispersal can have a marked effect on tumor structure, high cellular motility could lead to faster cell mixing and lower observable intratumor heterogeneity. Here we evaluated a model for cell mixing that investigates how short-range dispersal and cell turnover will account for mutational proportions. We show that cancer cells can penetrate neighboring and distinct areas in a matter of days. In next generation sequencing runs, higher proportions of a given cell line generated frequencies with higher precision, while mixtures with lower amounts of each cell line had lower precision manifesting in higher standard deviations. When multiple cell lines were co-cultured, cellular movement altered observed mutation frequency by up to 18.5%. We propose that some of the shared mutations detected at low allele frequencies represent highly motile clones that appear in multiple regions of a tumor owing to dispersion throughout the tumor. In brief, cell movement will lead to a significant technical (sampling) bias when using next generation sequencing to determine clonal composition. A possible solution to this drawback would be to radically decrease detection thresholds and increase coverage in NGS analyses. © 2017 The Author(s)

A clonal expression biomarker associates with lung cancer mortality

An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage1. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types2,3,4,5,6. Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types

Post-traumatic growth in mental health recovery: qualitative study of narratives.

OBJECTIVES: Post-traumatic growth, defined as positive psychological change experienced as a result of the struggle with challenging life circumstances, is under-researched in people with mental health problems. The aim of this study was to develop a conceptual framework for post-traumatic growth in the context of recovery for people with psychosis and other severe mental health problems. DESIGN: Qualitative thematic analysis of cross-sectional semi-structured interviews about personal experiences of mental health recovery. SETTING: England. PARTICIPANTS: Participants were adults aged over 18 and: (1) living with psychosis and not using mental health services (n=21); (2) using mental health services and from black and minority ethnic communities (n=21); (3) underserved, operationalised as lesbian, gay, bisexual and transgender community or complex needs or rural community (n=19); or (4) employed in peer roles using their lived experience with others (n=16). The 77 participants comprised 42 (55%) female and 44 (57%) white British. RESULTS: Components of post-traumatic growth were present in 64 (83%) of recovery narratives. Six superordinate categories were identified, consistent with a view that post-traumatic growth involves learning about oneself (self-discovery) leading to a new sense of who one is (sense of self) and appreciation of life (life perspective). Observable positively valued changes comprise a greater focus on self-management (well-being) and more importance being attached to relationships (relationships) and spiritual or religious engagement (spirituality). Categories are non-ordered and individuals may start from any point in this process. CONCLUSIONS: Post-traumatic growth is often part of mental health recovery. Changes are compatible with research about growth following trauma, but with more emphasis on self-discovery, integration of illness-related experiences and active self-management of well-being. Trauma-related growth may be a preferable term for participants who identify as having experienced trauma. Trauma-informed mental healthcare could use the six identified categories as a basis for new approaches to supporting recovery. TRIAL REGISTRATION NUMBER: ISRCTN11152837

Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity