Clinical Epigenetics

Biological ageing begins before birth, with early-life exposures shaping late-life health. These exposures drive health inequities early, yet specific exposures and the composition of the ageing exposome remain largely undefined. This gap may persist as the field lacks agnostic investigations accounting for non-linearity, interactions and subtle signals. We aimed to identify exposures predictive of epigenetic ageing accumulated during childhood and adolescence and explore the composition of the...

Study question: How is glycodelin, a glycoprotein secreted by reproductive tissues, causally related to reproductive diseases and traits? Summary answer: We present evidence for a causal role of sex hormones in determining glycodelin levels, but limited evidence that glycodelin subsequently causally impacts reproductive traits. What is known already: Glycodelin is expressed in female and male reproductive tissues and has four glycoforms (-A, -C, -F and -S), with the glycosylation pattern determi...

BackgroundColorectal carcinoma (CRC) remains a significant cause of cancer morbidity and mortality worldwide. Right- and left-sided tumours differ in clinical, morphological, and molecular features. Microsatellite instability-high (MSI-H) tumours, often right-sided, are associated with distinct histopathological characteristics and prognostic implications. In Sri Lanka, molecular MSI testing is currently unavailable, highlighting the need for alternative predictive approaches. ObjectivesGeneral...

Ambient air pollution has been associated with increased incidence of chronic disease and is estimated to contribute towards 4.2 million early deaths annually. Whilst the health impacts are well described, less is understood about the underlying biological mechanisms, particularly when considering the co-occurrence of multiple pollutants. Using an atmospheric chemistry transportation model (EMEP4UK), we generate pre-baseline sampling pollution exposure estimates for eight pollutants in Generatio...

OBJECTIVEUsing two cohorts and synthetic datasets, we estimated effects of prospectively reported alcohol use on memory outcomes across middle age. METHODSData were from National Longitudinal Study of Youth 1979 (NLSY79, n=7540, alcohol reports from ages 18-26), Health and Retirement Study (HRS age 50-56 at enrollment, n=13,090), and a synthetic cohort matching early life exposure information from 3,259 NLSY79 participants to later life memory information from 5,451 HRS participants. Covariate-...

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common and life-threatening complication of chimeric antigen receptor (CAR) T-cell therapy, with early detection being critical for timely intervention and improved outcomes. Cytokines such as interleukin-6 (IL-6) are key mediators of the inflammatory cascade underlying ICANS pathogenesis, but prospective clinical evidence for their predictive value is limited. Here we quantify IL-6 levels in a prospective cohort of 40 CAR-T pat...

Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part o...

Vaccination frequently elicits suboptimal immunogenicity in organ transplant recipients, particularly those on long-term immunosuppressive therapy, highlighting the need for improved understanding of immunosuppression mechanisms and optimized vaccination strategies. This study enrolled a cohort of 132 individuals and observed significantly lower antibody levels in kidney transplant recipients (KTRs) compared to non-transplant controls (non-KTRs). Antibody levels were inversely associated with bo...

BackgroundAnthracyclines are central to childhood cancer therapy but predispose patients to cardiotoxicity leading to long-term cardiovascular risk. Endothelial injury and impaired repair contribute to this, yet pediatric data remain limited. ObjectiveTo longitudinally assess endothelial injury and repair in childhood cancer patients treated with anthracyclines by quantifying circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs). MethodsIn a single-centre retrospective c...

Accurate classification of BRCA1 and BRCA2 variants is essential for cancer risk assessment and therapy selection, yet over one-third remain variants of uncertain significance (VUS). Here, using 120,660 real-world cancer genomic profiles with BRCA1 or BRCA2 variants from a >800,000-sample cohort, we develop machine learning models that predict pathogenicity using clinical and tumor-derived features, including a pan-cancer homologous recombination deficiency signature, co-mutated genes, zygosity,...

BackgroundNo randomized clinical trial comparing the most established new modalities of treatment for patients with localized prostate cancer has been published, and there is scarce comparative effectiveness research assessing Patient-Reported Outcome Measures (PROMs). Objectiveto compare the impact of active surveillance, robot-assisted radical prostatectomy (RARP), Intensity-modulated radiotherapy (IMRT), and real-time brachytherapy on patients, through PROMs, from pre-treatment to five years...

ObjectivesGrowth Mindset and Grit have been proposed as key psychological resources for resilience and adaptation, yet their manifestation and social distribution in later life remain underexplored. This study examines the structure, distribution, and correlates of Growth Mindset and Grit in older adulthood using proxy indicators in the English Longitudinal Study of Ageing (ELSA). MethodsProxy indicators reflecting learning behaviour, personality traits, affect, and beliefs were used to derive ...

BackgroundThe management of residual axillary disease after neoadjuvant therapy (NAT) remains controversial, as current recommendations often treat ypN1 breast cancer as a homogeneous entity despite potential prognostic heterogeneity. Evidence supporting uniform axillary surgical strategies across different levels of residual nodal burden is limited. We investigated whether survival associations related to axillary surgical evaluation differ according to residual nodal burden in ypN1 disease, us...

BackgroundPacked lunches are a common feature of early childhood food provision, yet evidence describing their nutritional composition in early years settings remains limited. Understanding the foods provided during this developmental period is important, given the potential influence of early dietary exposures on later health. AimTo characterise the composition, nutritional quality, cost, and dietary patterns of packed lunches brought from home in Early Childhood Education and Care settings, a...

Anti-{beta}2-glycoprotein I (anti-{beta}2GPI) antibodies are central to the pathogenesis of antiphospholipid syndrome (APS), an autoimmune disease characterized by a strong predisposition to venous thromboembolism (VTE). In this study, we conducted a multi-ancestry genome-wide association study (GWAS) of quantitative total anti-{beta}2GPI levels in 5,969 participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) and identified a genome-wide significant association at the APOH locu...

Acute kidney injury (AKI) and chronic kidney disease (CKD) are two interconnected clinical conditions, both defined by degree of functional impairment, but with heterogeneous clinical trajectories. Using new transcriptomic technologies, recent studies have described the cellular diversity in the healthy and injured kidney at the single cell level. Here, we used single nucleus transcriptomics to investigate the molecular diversity and commonalities in kidney biopsies from over 150 participants wi...

Tumour typing from whole-genome sequencing is increasingly accurate, yet molecular subtyping from somatic variants remains challenging because of tumour heterogeneity and inconsistent clinical annotations. Here, we present Mutation-Attention Dual-Task (MuAt2), a Transformer model that jointly classifies histological tumour types and subtypes directly from somatic single-nucleotide variants, indels and structural variants. MuAt2 leverages encoders pre-trained on 2,587 pan-cancer whole genomes, an...

Abstract Background: Enhanced Recovery After Surgery (ERAS) optimizes perioperative management for colorectal cancer (CRC), improving short-term outcomes, but its impact on long-term outcomes remains inconclusive, supporting the need for this meta-analysis. This study evaluates the effect of perioperative ERAS (therapy-focused) on 1-, 2-, 3-, and 5-year postoperative survival in patients with CRC. Methods: We conducted a systematic review and meta-analysis following a pre-registered protocol in ...

Clear cell renal cell carcinoma (ccRCC) is the leading cause of kidney cancer-related death, but how the tumor microenvironment shapes patient survival is not completely understood. Here, we describe the characterization of ccRCC tumor ecosystems from 498 patients using imaging mass cytometry with a focus on tumor, myeloid, and T cell landscapes. Data from more than 3 million single cells is analyzed using machine-learning to identify key ecosystem features that outperform basic clinical data fo...

Multi-cancer early detection (MCED) tests can detect several cancer types and stages. We previously developed a methylation and protein (MP V1) MCED classifier. In this study, we present a refined MP V2 classifier, developed by evaluating model architectures that improved performance in prospectively enrolled case-control cohorts under standard testing conditions. The newly developed MP V2 classifier was trained to be more generalizable and achieve increased early-stage sensitivity at a target s...