Dermot Cox

Dermot Cox
Royal College of Surgeons in Ireland | RCSI · Department of Molecular and Cellular Therapeutics

PhD

About

111
Publications
29,171
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5,699
Citations
Citations since 2016
6 Research Items
2087 Citations
2016201720182019202020212022050100150200250300350
2016201720182019202020212022050100150200250300350
2016201720182019202020212022050100150200250300350
2016201720182019202020212022050100150200250300350

Publications

Publications (111)
Article
Full-text available
Background The prevalence of ex vivo ‘high on-treatment platelet reactivity (HTPR)’ and its relationship with recurrent vascular events/outcomes in patients with ischaemic cerebrovascular disease (CVD) is unclear.MethodsA systematic review and meta-analysis was performed in accordance with the PRISMA statement. MEDLINE, EMBASE and Cochrane Library...
Article
Introduction Cerebral micro-embolic signals (MES) predict risk of stroke in carotid stenosis patients. However, MES-negative ‘recently symptomatic patients’ also have a higher stroke risk than ‘asymptomatic patients’. Differences in platelet activation status may contribute to this disparity in risk. Methods This prospective, observational study as...
Article
Introduction: The mechanisms responsible for the disparity in stroke risk between asymptomatic and symptomatic carotid stenosis are not fully understood. Profiles of ‘reticulated platelets’ and red cell reticulocytes in carotid stenosis patients are poorly understood. Methods: This prospective, multi-centre, observational analytical study compared...
Article
Introduction: Cerebral microembolic signals (MES) predict increased stroke risk in carotid stenosis however micro-emboli negative symptomatic patients also demonstrate increased risk compared to asymptomatic patients. Enhanced platelet activation may contribute to this risk disparity. Methods: We performed a prospective, observational analytical st...
Article
Full-text available
Gram-negative Escherichia coli cause diseases such as sepsis and hemolytic uremic syndrome in which thrombotic disorders can be found. Direct platelet-bacterium interactions might contribute to some of these conditions; however, mechanisms of human platelet activation by E. coli leading to thrombus formation are poorly understood. While the IgG rec...
Article
While the interactions between Gram-positive bacteria and platelets have been well characterized, there is a paucity of data on the interaction between other pathogens and platelets. However, thrombocytopenia is a common feature with many infections especially viral hemorrhagic fever. The little available data on these interactions indicate a simil...
Article
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Objectives The potential of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) surface modified with octa-arginine (R8) for central nervous system (CNS) delivery was investigated.MethodsPLGA NPs containing coumarin-6 or loperamide were surface modified using R8 and characterised for size, zeta potential, drug loading and release. We examined...
Article
The integrin αIIbβ3 on resting platelets can bind to immobilised fibrinogen resulting in platelet spreading and activation but requires activation to bind to soluble fibrinogen. αIIbβ3 is known to interact with the general integrin-recognition motif RGD (arginine-glycine-aspartate) as well as the fibrinogen-specific γ-chain dodecapeptide; however,...
Article
Due to their role in processes central to cancer and autoimmune disease I-domain integrins are an attractive drug target. Both antibodies and small molecule antagonists have been discovered and tested in the clinic. Much of the effort has focused on αLβ2 antagonists. Maybe the most successful was the monoclonal antibody efalizumab, which was approv...
Article
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Viral hemorrhagic fevers (VHF) are acute zoonotic diseases that, early on, seem to cause platelet destruction or dysfunction. Here we present the four major ways viruses affect platelet development and function and new evidence of molecular factors that are preferentially induced by the more pathogenic members of the families Flaviviridae, Bunyavir...
Article
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Bacterial adhesion to platelets is mediated via a range of strain-specific bacterial surface proteins that bind to a variety of platelet receptors. It is unclear how these interactions lead to platelet activation. We demonstrate a critical role for the immune receptor FcγRIIA, αIIbβ3, and Src and Syk tyrosine kinases in platelet activation by Staph...
Article
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Infective endocarditis is a life threatening disease caused by a bacterial infection of the endocardial surfaces of the heart. The oral pathogen, Streptococcus gordonii is amongst the most common pathogens isolated from infective endocarditis patients. Previously we identified a novel cell wall protein expressed on S. gordonii called platelet adher...
Article
Full-text available
Hemorrhagic Fever Viruses Viral hemorrhagic fevers (VHF) are a group of illnesses that are characterized by a loss of homeostasis leading to increased bleeding and shock. VHFs are caused by enveloped RNA viruses from four different families: Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae [1]. The bleeding signs of VHF are more frequently...
Conference Paper
Drug delivery to the central nervous system (CNS) remains a challenge due to the difficulty in facilitating drug transport across the blood-brain barrier (BBB). Various types of nanoparticle (NPs) have been investigated and shown to enhance drug delivery and targeting to various cells and tissues including the CNS [1]. The aim of this study was to...
Article
Infective endocarditis (IE) is characterized by thrombus formation on a cardiac valve. The oral bacterium, Streptococcus oralis, is recognized for its ability to colonize damaged heart valves and is frequently isolated from patients with IE. Platelet interaction with S. oralis leads to the development of a thrombotic vegetation on heart valves, whi...
Article
Background: The prevalence of ex vivo high on-treatment platelet reactivity (HTPR) to commonly prescribed antiplatelet regimens after transient ischemic attack (TIA) or ischemic stroke is uncertain. Methods: Platelet function inhibition was simultaneously assessed with modified light transmission aggregometry (VerifyNow; Accumetrics Inc, San Die...
Chapter
Full-text available
Endocarditis is an inflammation of the lining of the heart and valves. It can be due to a noninfectious cause (Asopa et al., 2007) but when the inflammation is associated with an infection, usually bacterial, it is known as infective endocarditis (IE) and is characterized by the development of a large septic thrombus on one of the cardiac valves (B...
Article
The synthetic feasibility of any compound library used for virtual screening is critical to the drug discovery process. TIN, a recursive acronym for 'TIN Is Not commercial', is a virtual combinatorial database enumeration of diversity-orientated multicomponent syntheses (MCR). Using a 'one-pot' synthetic technique, 12 unique small molecule scaffold...
Article
It has become clear that platelets are not simply cell fragments that plug the leak in a damaged blood vessel; they are, in fact, also key components in the innate immune system, which is supported by the presence of Toll-like receptors (TLRs) on platelets. As the cells that respond first to a site of injury, they are well placed to direct the immu...
Article
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While deployment of intracoronary stents has been shown to reduce restenosis, stenting can also damage the endothe-lial monolayer lining the vessel wall, leading to possible in-stent thrombosis. Local drug delivery from stent surfaces represents a means of delivering therapeutic doses of drug directly to the target site. The aim of this study was t...
Article
There is a growing awareness of the role of oral pathogens in cardiovascular disease. Chronic oral disease such as periodontitis, leads to inflammation and bleeding of the gums. This bleeding provides a viable portal of entry for the bacteria to the circulation. Once in the circulation oral bacteria can interact with circulating platelets. Their ab...
Article
Full-text available
To better understand the mechanism of platelet recruitment and activation by Streptococcus gordonii. The oral bacterium Streptococcus gordonii, is amongst the most common pathogens isolated from infective endocarditis patients, and has the property of being able to activate platelets, leading to thrombotic complications. The mechanism of platelet r...
Article
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The integrins are a large family of cell adhesion molecules that are essential for the regulation of cell growth and function. The identification of key roles for integrins in a diverse range of diseases, including cancer, infection, thrombosis and autoimmune disorders, has revealed their substantial potential as therapeutic targets. However, so fa...
Article
Sepsis is the most common manifestation of invasive pneumococcal disease and is characterized by a severe systemic inflammatory state that leads to circulatory compromise or end organ malperfusion or dysfunction. Patients suffering from sepsis often display low platelet counts characterized by thrombocytopenia as a result of platelet activation. To...
Data
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While the ability of cell wall components of bacteria to interact with platelets has been well established there is also evidence that bacterial toxins have the potential to activate platelets. In particular pore-forming toxins such as pneu-molysin, streptolysins and a-toxin can activate platelets probably in a manner similar to the calcium ionopho...
Article
Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G-protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41-amino-acid deletion) of the human G-protein beta3 (Gbeta3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery di...
Article
Malaria is a major cause of morbidity and mortality in the developing world and cerebral malaria is responsible for the majority of malaria-associated deaths. There is a strong association between thrombocytopenia and outcome in malaria, suggesting a role for platelets in the pathogenesis of malaria. This thrombocytopenia is likely due to platelet...
Article
Full-text available
Many bacteria are capable of interacting with platelets and inducing platelet aggregation. This interaction may be a direct interaction between a bacterial surface protein and a platelet receptor or may be an indirect interaction where plasma proteins bind to the bacterial surface and subsequently bind to a platelet receptor. However, these interac...
Article
Full-text available
The concept of an infectious agent playing a role in cardiovascular disease is slowly gaining attention. Among several pathogens identified, the oral bacterium Streptococcus gordonii has been implicated as a plausible agent. Platelet adhesion and subsequent aggregation are critical events in the pathogenesis and dissemination of the infective proce...
Article
Full-text available
In recent times the concept of infectious agents playing a role in cardiovascular disease has attracted much attention. Chronic oral disease such as periodontitis, provides a plausible route for entry of bacteria to the circulation. Upon entry to the circulation, the oral bacteria interact with platelets. It has been proposed that their ability to...
Article
Staphylococcus epidermidis is a commensal of the human skin that has been implicated in infective endocarditis and infections involving implanted medical devices. S. epidermidis induces platelet aggregation by an unknown mechanism. The fibrinogen-binding protein serine-aspartate repeat protein G (SdrG) is present in 67-91% of clinical strains. To d...
Article
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Obstructive sleep apnoea (OSA) is a complex condition associated with a number of cardiovascular sequelae including hypertension (both systemic and pulmonary), congestive heart failure, arrhythmias, myocardial infarction and stroke [1-6]. However, the recent American Heart Association/American College of Cardiology scientific statement on sleep apn...
Article
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Epidemiological and clinical studies provide compelling support for a causal relationship between Helicobacter pylori infection and endothelial dysfunction, leading to vascular diseases. However, clear biochemical evidence for this association is limited. In the present study, we have conducted a comprehensive investigation of endothelial injury in...
Article
Both platelets and neutrophils play major roles in the pathology of ischaemic heart disease. Platelets are involved in the development of an occlusive thrombus, while neutrophils are implicated in the oxidative damage of reperfusion injury. In both cases, integrins play key roles in these pathological processes: in the case of platelets, the fibrin...
Article
Staphylococcus aureus is the most frequent causative organism of infective endocarditis (IE) and is characterized by thrombus formation on a cardiac valve that can embolize to a distant site. Previously, we showed that S. aureus clumping factor A (ClfA) and fibronectin-binding protein A (FnBPA) can stimulate rapid platelet aggregation. In this stud...
Article
Full-text available
Streptococcus gordonii colonization of damaged heart surfaces in infective endocarditis is dependent upon the recognition of host receptors by specific bacterial surface proteins. However, despite several attempts to identify the mechanisms involved in this interaction, the nature of the bacterial proteins required remains poorly understood. This s...
Article
Full-text available
Staphylococcus aureus can stimulate activation and aggregation of platelets, which are thought to be factors in the development of infective endocarditis. Previous studies have identified clumping factor A (ClfA) and fibronectin binding proteins A and B (FnBPA and FnBPB) as potent platelet aggregators. These proteins are able to stimulate rapid pla...
Article
Full-text available
Helicobacter pylori is the major causative agent in peptic ulcer disease and is strongly implicated in the development of gastric cancer. It has also been linked, less strongly, to cardiovascular disease. The mechanisms by which certain strains of H pylori induce platelet aggregation through interactions with platelet glycoprotein Ib have been prev...
Article
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The term aspirin resistance has been used increasingly in clinical studies. The aim of this Review is to analyze the origin of this term, to discuss the biochemical, functional and clinical correlates of the phenomenon and to offer a conceptual framework to redefine the major determinants of variability between individuals in response to aspirin. A...
Article
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Solid-phase peptide synthesis is the archetypal example of combinatorial chemistry. Advances in amino acid synthesis allow unprecedented structural diversity using automated synthesis. In this chapter we briefly introduce the history and advances in peptide synthesis and include strategies for peptidomimetic development. We highlight examples of th...
Article
Full-text available
Solid-phase peptide synthesis is the archetypal example of combinatorial chemistry. Advances in amino acid synthesis allow unprecedented structural diversity using automated synthesis. In this chapter we briefly introduce the history and advances in peptide synthesis and include strategies for peptidomimetic development. We highlight examples of th...
Article
Protein A (Spa) is a surface-associated protein of Staphylococcus aureus best known for its ability to bind to the Fc region of IgG. Spa also binds strongly to the Fab region of the immunoglobulins bearing V(H)3 heavy chains and to von Willebrand factor (vWF). Previous studies have suggested that the protein A-vWF interaction is important in S. aur...
Article
Infective endocarditis (IE) is characterized by thrombus formation on a cardiac valve that can embolize to a distant site. Staphylococcus aureus is the most frequent causative organism of IE. Previously we showed that fibrinogen binding to the S. aureus surface protein Clumping Factor A (ClfA) plays an essential role in mediating platelet aggregati...
Article
C-reactive protein (CRP) is a well established marker for inflammation, and a good predictor of coronary heart disease. It is also known to interact with the platelet FcγRIIa and to enhance the inhibition of platelet aggregation by aspirin by an unknown mechanism. CRP has also recently been demonstrated to compete for PAC-1 binding in collagen stim...
Article
Aspirin resistance may be relatively common and associated with adverse outcome. Meta-analysis has clearly shown that 75 mg plain aspirin is the lowest effective dose; however, it is not known whether the recent increased use of enteric-coated aspirin could account for aspirin resistance. This study was designed to determine whether enteric-coated...
Article
Full-text available
In recent years, the frequency of serious cardiovascular infections such as endocarditis has increased, particularly in association with nosocomially acquired antibiotic-resistant pathogens. Growing evidence suggests a crucial role for the interaction of bacteria with human platelets in the pathogenesis of cardiovascular infections. Here, we review...
Article
The serine-rich repeat glycoprotein Hsa in Streptococcus gordonii Challis mediates bacterial cell interactions with fetuin, glycocalicin, fibronectin and human platelets. Different strains of S. gordonii vary markedly in their adhesion levels to sialylated proteins, while other mitis group streptococci have distinct patterns of recognition of sialy...
Article
Staphylococcus aureus is a leading cause of infective endocarditis (IE). Platelet activation promoted by S. aureus resulting in aggregation and thrombus formation is an important step in the pathogenesis of IE. Here, we report that the fibrinogen/fibronectin-binding proteins FnBPA and FnBPB are major platelet-activating factors on the surface of S....
Article
A neural network (NN) pharmacodynamic model was developed that correlates the inhibition of ex vivo platelet aggregation by orbofiban, an oral glycoprotein IIb/IIIa antagonist, with the administered dose and patient characteristics. Data were obtained from a Phase-II dose-finding study of orbofiban in patients presenting with acute coronary syndrom...
Article
We investigated whether use of low-dose enteric-coated (EC) aspirin for secondary prevention of cardiovascular events has sufficient bioavailability to achieve complete platelet cyclooxygenase (COX) inhibition in all individuals. Aspirin reduces cardiovascular morbidity and mortality in patients with pre-existing vascular disease; however, there is...
Article
Aspirin (acetylsalicylic acid) irreversibly inhibits platelet cyclooxygenase (COX)-1, the enzyme that converts arachidonic acid (AA) to the potent platelet agonist thromboxane (TX) A2. Despite clear benefit from aspirin in patients with cardiovascular disease (CAD), evidence of heterogeneity in the way individuals respond has given rise to the conc...
Article
Full-text available
Streptococcus gordonii colonizes multiple sites within the human oral cavity. This colonization depends upon the initial interactions of streptococcal adhesins with host receptors. The adhesins that bind salivary agglutinin glycoprotein (gp340) and human cell surface receptors include the antigen I/II (AgI/II) family polypeptides SspA and SspB and...
Article
Staphylococcus aureus is an important cause of infective endocarditis (IE) in patients without a history of prior heart valve damage. The ability to stimulate the activation of resting platelets and their subsequent aggregation is regarded as an important virulence factor of bacteria that cause IE. Clumping factor A is the dominant surface protein...
Article
Sleep-disordered breathing is associated with chronic intermittent asphyxia and with a variety of cardiovascular abnormalities. Cardiovascular morbidity and mortality are linked to altered platelet function, and platelet function is affected in sleep-disordered breathing. As there is evidence that chronic continuous hypoxia may alter platelet numbe...
Article
Streptococcus sanguis is the most common oral bacterium causing infective endocarditis and its ability to adhere to platelets, leading to their activation and aggregation, is thought to be an important virulent factor. Previous work has shown that S. sanguis can bind directly to platelet glycoprotein (GP) Ib but the nature of the adhesin was unknow...
Article
Background/AimsThe purpose of this study was to develop a neural network (NN) pharmacodynamic (PD) model that correlates the inhibition of ex vivo platelet aggregation by orbofiban, an oral GPIIb/IIIa antagonist, with the administered dose and patient characteristics.Methods Data were obtained from a Phase-II dose-finding study in patients presenti...
Chapter
Full-text available
Platelets play an essential role in hemostasis and thrombosis (1). A defect in platelet function can result in platelets that are unresponsive or hypersensitive. Characterization of a defect is an important first step in the treatment of the disorder. Although defects usually present as bleeding or bruising, the existence of a defect is not always...
Article
S. epidermidis is normally present on the surface of the skin, however in a hospital setting, it is responsible for many infections involving implanted medical devices resulting in potentially fatal complications such as infective endocarditis and septicemia. S. epidermidis has previously been shown to induce platelet aggregation (Ohshima et al. Mi...
Article
We examined the contribution of cyclooxygenase (COX)-1 and -2 to the generation of prostacyclin, thromboxane (Tx) A(2), and 8-epi prostaglandin (PG) F(2alpha) during percutaneous transluminal coronary angioplasty (PTCA). Both TxA(2) and 8-epi PGF(2alpha) activate platelets and are mitogenic, whereas prostacyclin is a platelet inhibitor, and therefo...
Article
Full-text available
Cigarette smoking results in abnormalities of platelets and endothelium with platelet dysfunction implicated in vascular complications. Healthy endothelium plays a pivotal role in regulating hemostasis via the inhibition of platelet activation and aggregation. Thus, we examined if platelet dysfunction correlated with serum vWF levels-a circulating...
Article
The fibrinogen receptor on platelets is glycoprotein (GP) IIb/IIIa, also known as αIIbβ3. This receptor can bind to immobilized fibrinogen in its resting state. Binding to soluble fibrinogen, however, requires activation of the receptor. This can occur due to inside-out signaling in response to a platelet agonist such as ADP, or directly by agents...