Single-cell spatial multiomics reveals tumor microenvironment vulnerabilities in cancer resistance to immunotherapy.

Heterogeneous resistance to immunotherapy remains a major challenge in cancer treatment, often leading to disease progression and death. Using CITE-seq and matched 40-plex PhenoCycler tissue imaging, we performed longitudinal multimodal single-cell analysis of tumors from metastatic melanoma patients with innate resistance, acquired resistance, or response to immunotherapy. We established the multimodal integration toolkit to align transcriptomic features, cellular epitopes, and spatial information to provide deeper insights into the tumors. With longitudinal analysis, we identified an "immune-striving" tumor microenvironment marked by peri-tumor lymphoid aggregates and low infiltration of T cells in the tumor and the emergence of MITF+SPARCL1+ and CENPF+ melanoma subclones after therapy. The enrichment of B cell-associated signatures in the molecular composition of lymphoid aggregates was associated with better survival. These findings provide further insights into the establishment of microenvironmental cell interactions and molecular composition of spatial structures that could inform therapeutic intervention.

Health and lifestyle advisors in support of primary care: An evaluation of an innovative pilot service in a region of high health inequality.

INTRODUCTION: A health and lifestyle advisor service embedded within primary care was piloted in Kingston-upon-Hull from January 2021. We aimed to evaluate the first two years of service delivery by identifying patient demographics referred to the service, reason for referral, determine uptake and retention rates, and monitor individual lifestyle-related risk factor changes following discharge. METHODS: Anonymised data were extracted from the SystmOne database for all patients referred to the service between January 2021 and January 2023. RESULTS: In the initial two years of the service, 705 unique patients were referred at a mean rate of ∼29 per month. Each unique patient received a median (robust median absolute deviation; [MAD]) of 3 (Steel N, et al 2018) planned consultations prior to discharge over this period. The majority of referrals were for symptom management and health promotion purposes (95%). Of those referred, 69% attended their appointments, and 14% did not attend. The majority of referrals were white British (55%), however, the service did receive a substantial number of referrals from minority ethnic groups, with only 67% of referrals speaking English as their main language. Eighteen distinct languages were spoken. Most referrals were classified as class I obese (59.4%). Across initial and final appointments, median (robust MAD) systolic blood pressure was 130 (15) mmHg and 130 (15) mmHg, and median (robust MAD) waist circumference was 103.0 (13.3) cm and 101.0 (13.3) cm. CONCLUSION: The evaluation highlighted the demand for this service embedded within primary care settings in Kingston-upon-Hull. Service engagement was evident, and a large proportion of those who engaged were from minority ethnic groups. A high proportion of referrals presented with obesity and/or hypertension which requires further investigation.

Proxies of Trustworthiness: A Novel Framework to Support the Performance of Trust in Human Health Research.

Without trust there is no credible human health research (HHR). This article accepts this truism and addresses a crucial question that arises: how can trust continually be promoted in an ever-changing and uncertain HHR environment? The article analyses long-standing mechanisms that are designed to elicit trust-such as consent, anonymization, and transparency-and argues that these are best understood as trust represented by proxies of trustworthiness, i.e., regulatory attempts to convey the trustworthiness of the HHR system and/or its actors. Often, such proxies are assumed to operate as markers that trust exists or, at least, has not been lost. But, since trust can neither be "built" nor "secured," this is a precarious assumption. Worryingly, there is no existing theoretical account of how to understand and evaluate these proxies of trustworthiness as part of a trusted HHR ecosystem. To remedy this, the paper argues for a radical reimagining of trust and trustworthiness as performative acts that ought to be understood in relation to each other and by reference to the common values at stake. It is shown that proxies of trustworthiness are the operational tools used to perform trustworthiness. It advocates for a values-based approach to understanding the relationship between trust and trustworthiness. This establishes a strong basis for an evaluative framework for proxies of trustworthiness, i.e., to determine how to perform trustworthiness well. Five common proxies in HHR are scrutinized from a values perspective. The contribution is to provide a far-reaching normative and practical framework by which existing and future proxies of trustworthiness can be identified, assessed, maintained, or replaced in rapidly changing HHR regulatory ecosystems where trust itself is crucial to the success of the entire HHR enterprise.

Detailed DNA methylation characterisation of phyllodes tumours identifies a signature of malignancy and distinguishes phyllodes from metaplastic breast carcinoma.

Phyllodes tumours (PTs) are rare fibroepithelial lesions of the breast that are classified as benign, borderline, or malignant. As little is known about the molecular underpinnings of PTs, current diagnosis relies on histological examination. However, accurate classification is often difficult, particularly for distinguishing borderline from malignant PTs. Furthermore, PTs can be misdiagnosed as other tumour types with shared histological features, such as fibroadenoma and metaplastic breast cancers. As DNA methylation is a recognised hallmark of many cancers, we hypothesised that DNA methylation could provide novel biomarkers for diagnosis and tumour stratification in PTs, whilst also allowing insight into the molecular aetiology of this otherwise understudied tumour. We generated whole-genome methylation data using the Illumina EPIC microarray in a novel PT cohort (n = 33) and curated methylation microarray data from published datasets including PTs and other potentially histopathologically similar tumours (total n = 817 samples). Analyses revealed that PTs have a unique methylome compared to normal breast tissue and to potentially histopathologically similar tumours (metaplastic breast cancer, fibroadenoma and sarcomas), with PT-specific methylation changes enriched in gene sets involved in KRAS signalling and epithelial-mesenchymal transition. Next, we identified 53 differentially methylated regions (DMRs) (false discovery rate < 0.05) that specifically delineated malignant from non-malignant PTs. The top DMR in both discovery and validation cohorts was hypermethylation at the HSD17B8 CpG island promoter. Matched PT single-cell expression data showed that HSD17B8 had minimal expression in fibroblast (putative tumour) cells. Finally, we created a methylation classifier to distinguish PTs from metaplastic breast cancer samples, where we revealed a likely misdiagnosis for two TCGA metaplastic breast cancer samples. In conclusion, DNA methylation alterations are associated with PT histopathology and hold the potential to improve our understanding of PT molecular aetiology, diagnostics, and risk stratification. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Living in food insecurity: A qualitative study exploring parents' food parenting practices and their perceptions of the impact of food insecurity on their children's eating.

Food insecurity in rich countries is a growing problem with far reaching consequences but how it impacts parents, particularly their food parenting practices, is under researched. Food parenting practices play a critical role in the development of children's eating and may be a mechanism in the link between food insecurity and children's health outcomes; this study aims to illuminate their potential role. Twenty-one parents participated in a qualitative interview study. Their household food security was very low (18/21) or low (3/21). Reflexive Thematic Analysis generated three themes. Challenges of food insecurity: parents shielded children from hunger by eating less themselves, relying on free school meals and turning to family and food banks when in crisis. They perceived a conflict between giving children food of high nutritional quality and its cost. Practical impact of food insecurity: although motivated to provide children with healthy food, finances meant parents struggled to achieve this goal. Parents used a range of food parenting practices but their use of some that are known to be effective may have been compromised by their food insecurity. Emotional impact of food insecurity: parents described feelings of failure, despair, helplessness and shame. Food insecurity adversely effects both children and parents, and non-stigmatising services that mitigate its impact and facilitate children's exposure to food parenting practices known to be effective are needed.