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Biomedical subjects

Brendan Doyle

Publications and source records attributed to Brendan Doyle.

8 recordsLinked to original sources
PubMed2026

Prevalence of BRCA1/2 variants in an Ovarian Cancer Cohort: outcomes from a Nationwide Testing Program.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the management of BRCA1- and BRCA2-associated ovarian cancer (OC). In 2020, Ireland implemented a nationwide, oncology-led pathway for mainstreamed BRCA1/2 testing in patients with OC. This study evaluated the pathway and characterised the BRCA1/2 landscape in an Irish cohort of patients with OC. Samples collected between January 2020 and December 2023 were tested in two national molecular diagnostic laboratories. Single-molecule molecular inversion probe sequencing was used to detect single nucleotide variants, while multiplex ligation-dependent probe amplification assessed large genomic rearrangements. Variants were classified according to the American College of Medical Genetics and Genomics and Association for Clinical Genomic Science 2020 guidelines and CanVIG-UK specifications. In total, 535 patients were included, with a median age of 65.5 years (range, 27-89 years). Of these, 455/535 (85.0%) underwent germline BRCA1/2 (gBRCA) testing using peripheral blood, and 360/535 (67.2%) underwent tumour BRCA1/2 (tBRCA) testing, resulting in 292/535 (54.6%) patients having paired testing. Among gBRCA-tested patients, 10.3% (47/455) had a clinically actionable variant (CAV), while 2.1% (10/455) had a variant of uncertain significance. Of the 262 patients who underwent paired testing and had negative gBRCA results, 9.5% (25/262) had a somatic BRCA CAV. Recurrent germline BRCA CAVs were identified in regional clusters, including BRCA1 c.5266dup, BRCA1 c.1175_1214del, and BRCA2 c.4398_4402del. This nationwide real-world study demonstrates that mainstreamed germline and somatic BRCA1/2 testing is feasible in Ireland and reports the prevalence of BRCA CAVs in a cohort of patients with OC. Although the observed prevalence of germline BRCA CAVs was lower than anticipated, it is consistent with UK real-world data. The identification of recurrent, regionally clustered germline variants further enhances the characterisation of the Irish genomic landscape.

Journal Article↗
PubMed2007

Clinical trials in stem cell therapy: pitfalls and lessons for the future.

The first human trial of stem cell therapy for cardiovascular disease was performed 4 years ago. Since that time, almost a dozen studies have reported the early and late clinical effects of cell therapy in acute myocardial infarction and chronic ischemic cardiomyopathy. Initial nonrandomized trials universally showed slight improvement in the left ventricular ejection fraction. Later randomized, controlled trials, however, suggested a less significant effect. They showed either no difference between cell therapy and control treatment or a slight treatment benefit with cell therapy that is lost by 12 months' follow-up. These results have dampened the enthusiasm of some members of the scientific community for the continuation of clinical trials. Because early phase I trials should not be judged on issues other than safety, however, research is unlikely to be hindered. Indeed, the clinical studies reported so far have already taught us a lot about the biology of myocardial repair. Achieving clinical success will, however, probably require much more investment in basic and experimental research. Here, we address some of the current pitfalls in clinical cell therapy trials and lessons that should be learned as we face the challenges of the future.

Cardiomyopathies↗
PubMed2006

Targeting angiogenesis versus myogenesis with cardiac cell therapy.

Considerable hope has been vested in cell therapy strategies designed to augment the endogenous neovascularization response to obstructive coronary artery disease, and to replace cardiomyocyte loss caused by myocardial infarction. Conceptually, the relative importance of targeting angiogenesis versus myogenesis in this scheme will vary depending on the clinical context (the predominance of ischemia versus ventricular dysfunction and scarring). Although the evidence so far is encouraging, whether these processes can be effectively targeted in a selective fashion with cell therapy is still unclear. Intriguingly, data are now emerging suggesting that the beneficial effects of cardiac cell therapies in a variety of clinical settings may be accounted for by a greater interaction of angiogenesis, myocardial salvage and myogenesis than heretofore appreciated, and through mechanisms that may include both cellular and paracrine effects. Greater understanding of these mechanisms should accelerate the development of effective cell therapies for the growing number of patients with advanced, and in many cases 'no-option', cardiovascular disease. Possible clinical targets for angiogenic and myogenic cardiac cell therapy, the scientific rationale for this therapeutic approach and future directions in this field are discussed here.

Animals↗
PubMed2005

A new source of endothelial progenitor cells--vascular biology redefined?

The initial discovery of endothelial progenitor cells (EPCs) in tandem with emerging concepts in stem cell biology has generated enormous interest and excitement in fields as diverse as tissue engineering, regenerative medicine, and tumor and vascular biology. A recent paper by Ingram et al. identifies a complete hierarchy of EPCs in the vessel wall, providing a new framework for classification of cells supporting endopoiesis akin to that previously established for hematopoiesis. This could have fundamental implications for our understanding of the role of the endothelium and, more specifically, the role of EPC interfacing with the vessel wall in health and disease.

Blood Vessels↗
PubMed2005

Vascular progenitor cells: origin and mechanisms of mobilization, differentiation, integration, and vasculogenesis.

The recent discovery of progenitor cells in peripheral blood that can differentiate into endothelial or vascular smooth muscle cells has led to the re-evaluation of many traditionally held beliefs about vascular biology. Most notably, concepts of vascular regeneration and repair, previously considered limited to the proliferation of existing differentiated cells within vascular tissue, have been expanded to include the potential for postnatal vasculogenesis. These cells have since been identified in the bone marrow, heart, skeletal muscle, and other peripheral tissues, including the vasculature itself. The significance of these cells lies not only in developing our understanding of normal vascular biology, but also in the insights they may provide into vascular diseases such as atherosclerosis. In addition, a potential role in therapeutics has already been explored in early clinical trials in humans. The mechanisms underlying the mobilization, target tissue integration, differentiation, and the observed therapeutic benefits of these cells are now being elucidated. It is these mechanisms, and the current understanding of the lineage of these cells, that constitutes the focus of this review.

Animals↗
PubMed2004

Conservative management of ascending aortic dissection caused by percutaneous coronary intervention.

Despite notable refinements in percutaneous coronary intervention (PCI) techniques, these procedures are still associated with some morbidity and mortality. A case of elective coronary angioplasty is described that was complicated by coronary dissection and ST-elevation myocardial infarction. Subsequent efforts to recanalize the coronary artery resulted in a catheter-induced tear at the origin of the vessel, with proximal extension of the dissection to involve the ascending aorta. Literature relating to this complication (reviewed here) suggests that surgical management may be indicated under the circumstances we describe. However, a conservative approach was adopted in this instance with excellent long-term results.

Aortic Dissection↗
PubMedDate not supplied

Endothelial progenitor cells.

The identification of circulating endothelial progenitor cells (EPCs) has prompted an explosion of interest in postnatal vasculogenesis and the role of this mechanism in human health and disease. Previously considered restricted to the embryonic phase, the differentiation in situ of progenitor cells to vascular endothelium is now known to occur in the adult. A role for EPCs in the modulation of angiogenesis has also been recognized. These cells are enriched in the mononuclear cell fraction of peripheral blood but have also been isolated from bone marrow, the vessel wall, and a number of other organs and tissues. Accumulating data suggest an important vasculoprotective function for EPCs, although a maladaptive role underpinning a variety of angiogenesis-dependent diseases is also being investigated. Encouraging results observed with experimental and early human trials of EPC-based regenerative therapies have further underscored the significance of this recently discovered cell type. Notwithstanding the scope and pace of these developments, a number of challenges remain: the precise ontogeny and lineage of these cells is unknown, the true extent to which EPCs participate in neovascularization and vascular repair is still uncertain, and the efficacy of EPC-based regenerative therapies has yet to be proven in randomized controlled trials.

Cell Lineage↗