Biology subjects

Buckland, M. E.

Publications and source records attributed to Buckland, M. E..

4 recordsLinked to original sources

bioRxiv2025

Spatially resolved transcriptomics reveals a unique disease signature and potential biomarkers for chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a poorly understood environmental tauopathy uniquely associated with repetitive head injury. It is clinically ambiguous, and at present can only be diagnosed post-mortem. There is a pressing need to understand CTE pathophysiology in order to identify targets for possible intervention and biomarkers for in-life diagnosis, however molecular characterisation of the disease is hampered by the stochastic distribution of CTE lesions. Here we have taken advantage of Visium spatial transcriptomics to map gene expression in discrete CTE lesions and matched normal tissue from the same individuals. In doing so we derived a common 21-gene "signature" of CTE lesions that highlights astrocytic activation, neuroinflammation, blood-brain barrier function, and extracellular matrix remodeling as key in situ features of CTE lesions. Almost all CTE signature genes were strongly expressed in astrocytes, and ontological and protein association analyses implicated extracellular matrix functions as drivers of the disease. These findings provide the first glimpse into the intricate molecular dynamics underlying CTE lesions in situ, and present 21 candidate molecules for the development of in-life CTE diagnostics.

neuroscience↗

bioRxiv2020

A comprehensive proteomic SWATH-MS workflow for profiling blood extracellular vesicles: a new avenue for glioma tumour surveillance

There is a real need for biomarkers that can indicate glioma disease burden and inform clinical management, particularly in the recurrent glioblastoma (GBM; grade IV glioma) setting where treatment-associated brain changes can confound current and expensive tumour surveillance methods. In this regard, extracellular vesicles (EVs; 30-1000 nm membranous particles) hold major promise as robust tumour biomarkers. GBM-EVs encapsulate molecules that reflect the identity and molecular state of their cell-of-origin and cross the blood-brain-barrier into the periphery where they are readily accessible. Despite the suitability of circulating-EVs for GBM biomarker discovery, sample complexity has hindered comprehensive quantitative proteomic studies. Here, sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) was used in conjunction with a targeted data extraction strategy to comprehensively profile circulating-EVs isolated from plasma. Plasma-EVs sourced from pre-operative glioma II-IV patients (n=41) and controls (n=11) were sequenced by SWATH-MS, and the identities and absolute quantities of the proteins were extracted by aligning the SWATH-MS data against a custom glioma spectral library comprised of 8662 high confidence protein species. Overall, 4054 plasma-EV proteins were quantified across the cohorts, and putative circulating-EV biomarker proteins identified (adjusted p-value<0.05) included previously reported GBM-EV proteins identified in vitro and in neurosurgical aspirates. Principle component analyses showed that plasma-EV protein profiles clustered according to glioma subtype and WHO-grade, and plasma-EV proteins reflected the extent of glioma aggression. Using SWATH-MS, we describe the most comprehensive proteomic plasma-EV profiles for glioma and highlight the promise of this approach as an accurate and sensitive tumour monitoring method. Objective blood-based measurements of glioma tumour activity will support the implementation of next-generation, patient-centred therapies and are ideal surrogate endpoints for recurrent progression that would allow clinical trial protocols to be more dynamic and adapt to the individual patient and their cancer.

pathology↗

bioRxiv2018

Epigenetic Profiling for the Molecular Classification of Metastatic Brain Tumors

Optimal treatment of brain metastases is often hindered by limitations in diagnostic capabilities. To meet these challenges, we generated genome-scale DNA methylomes of the three most frequent types of brain metastases: melanoma, breast, and lung cancers (n=96). Using supervised machine learning and integration of multiple DNA methylomes from normal, primary, and metastatic tumor specimens (n=1,860), we unraveled epigenetic signatures specific to each type of metastatic brain tumor and constructed a three-step DNA methylation-based classifier (BrainMETH) that categorizes brain metastases according to the tissue of origin and therapeutically-relevant subtypes. BrainMETH predictions were supported by routine histopathologic evaluation. We further characterized and validated the most predictive genomic regions in a large cohort of brain tumors (n=165) using quantitative methylation-specific PCR. Our study highlights the importance of brain tumor-defining epigenetic alterations, which can be utilized to further develop DNA methylation profiling as a critical tool in the histomolecular stratification of patients with brain metastases.

cancer biology↗

bioRxiv2016

Monozygotic twin pairs discordant for amyotrophic lateral sclerosis carry both common and unique epigenetic differences relevant to disease

Amyotrophic lateral sclerosis (ALS) is a devastating late-onset neurodegenerative disorder in which only a small proportion of patients carry an identifiable causative genetic lesion. Despite high heritability estimates, a genetic etiology for most sporadic ALS remains elusive. Here we report the epigenetic profiling of five monozygotic twin pairs discordant for ALS in whom previous genome sequencing excluded a genetic basis for their disease discordance. By studying cytosine methylation patterns in peripheral blood DNA we identified thousands of large between-twin differences at individual CpGs. While the specific sites of difference were largely idiosyncratic to a twin pair, a proportion (involving GABA signalling) were common to all affected individuals. In both instances the differences occurred within genes and pathways related to neurobiological function and dysfunction. Our findings reveal widespread changes in epigenetic marks in ALS patients, consistent with an epigenetic contribution to disease. These findings may be exploited to develop blood-based biomarkers of ALS and develop further insight into disease pathogenesis. We expect that our findings will provide a useful point of reference for further large scale studies of sporadic ALS.

neuroscience↗