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Matthew has been awarded a Diabetes Research Wellness Foundation Non-Clinical Research Fellowship.
Detecting and quantifying clonal selection in somatic stem cells.
As DNA variants accumulate in somatic stem cells, become selected or evolve neutrally, they may ultimately alter tissue function. When, and how, selection occurs in homeostatic tissues is incompletely understood. Here, we introduce SCIFER, a scalable method that identifies selection in an individual tissue, with…
Clonal tracing with somatic epimutations reveals dynamics of blood ageing.
Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset underg…
Oncogene aberrations drive medulloblastoma progression, not initiation.
Despite recent advances in understanding disease biology, treatment of group 3/4 medulloblastoma remains a therapeutic challenge in paediatric neuro-oncology1. Bulk-omics approaches have identified considerable intertumoural heterogeneity in group 3/4 medulloblastoma, including the presence of clear…
Spatio-temporal transcriptomics of chromothriptic SHH-medulloblastoma identifies multiple genetic clones that resist treatment and drive relapse.
Paediatric medulloblastomas with chromothripsis are characterised by high genomic instability and are among the tumours with the worst prognosis. However, the molecular makeup and the determinants of the aggressiveness of chromothriptic medulloblastoma are not well understood. Here, we apply s…
Multi-omic and single-cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instability.
Chromothripsis is a frequent form of genome instability, whereby a presumably single catastrophic event generates extensive genomic rearrangements of one or multiple chromosome(s). However, little is known about the heterogeneity of chromothripsis across different clones from the same tumour, as well a…
Neuroblastoma arises in early fetal development and its evolutionary duration predicts outcome
AbstractNeuroblastoma, the most frequent solid tumor in infants, shows very diverse outcomes from spontaneous regression to fatal disease. When these different tumors originate and how they evolve are not known. Here we quantify the somatic evolution of neuroblastoma by deep whole-genome sequencin…
Carbon ion radiotherapy eradicates medulloblastomas with chromothripsis in an orthotopic Li-Fraumeni patient-derived mouse model
Abstract Background Medulloblastomas with chromothripsis developing in children with Li-Fraumeni Syndrome (germline TP53 mutations) are highly aggressive brain tumors with dismal prognosis. Conventional photon radiotherapy and DNA-damaging chemotherapy are not successful for these patients a…
Chromothripsis in Human Breast Cancer
AbstractChromothripsis is a form of genome instability by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosomes. Widely assumed to be an early event in tumor development, this phenomenon plays a prominent role in tumor onset. In this study,…
Frailty and frailty syndromes in persons with haemophilia: a review.
Advances in treatment for persons with haemophilia (PWH) have improved life expectancy, but PWH face new challenges, including frailty. Frailty is a health state of increased functional vulnerability. It is associated with ageing and is linked to adverse outcomes such as falls, hospitalisation and institutionalisation.…
Epigenetic programming defines haematopoietic stem cell fate restriction.
Haematopoietic stem cells (HSCs) are multipotent, but individual HSCs can show restricted lineage output in vivo. Currently, the molecular mechanisms and physiological role of HSC fate restriction remain unknown. Here we show that lymphoid fate is epigenetically but not transcriptionally primed in HSCs. In mul…
Sex differences based on the timing of invasive management among patients with non-ST-elevation acute coronary syndrome: an individual patient data meta-analysis.
AIMS: Studies investigating the timing of coronary angiography in non-ST-elevation acute coronary syndrome (NSTE-ACS) have not evaluated sex differences. This study aims to investigate the sex-related differences in outcomes of NSTE-ACS patients undergoing early or delayed invasive management. METHODS…
A feedback circuitry involving γ-actin, β-actin and nonmuscle myosin-2 A controls tight junction and apical cortex mechanics.
Cytoplasmic β- and γ-actin isoforms, along with non-muscle myosin 2 isoforms, are tightly regulated in epithelial cells and compose the actomyosin cytoskeleton at the apical junctional complex. However, their specific role in regulating the mechanics of the membrane cortex and the organization of junc…
PFKP silencing suppresses tumor growth via the AXL-MET axis.
PFKP (Phosphofructokinase, Platelet Type isoform), as an essential metabolic enzyme, contributes to the high glycolysis rates seen in cancers while its role in oncogenic pathways, especially from a non-metabolic aspect, is not fully understood. We found that PFKP was highly expressed in NSCLC and was related t…
Structural domain in the Titin N2B-us region binds to FHL2 in a force-activation dependent manner
AbstractTitin N2B unique sequence (N2B-us) is a 572 amino acid sequence that acts as an elastic spring to regulate muscle passive elasticity. It is thought to lack stable tertiary structures and is a force-bearing region that is regulated by mechanical stretching. In this study, the conformation of N2B-us and its inte…