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Biomedical subjects

K M Taylor

Publications and source records attributed to K M Taylor.

At least 19 recordsLinked to original sources
PubMed2006

Inhibition of complement activation by pexelizumab reduces death in patients undergoing combined aortic valve replacement and coronary artery bypass surgery.

OBJECTIVE: We sought to evaluate the effects of pexelizumab, a C5 complement inhibitor, on death and myocardial infarction in patients undergoing combined aortic valve replacement and coronary artery bypass grafting surgery. METHODS: The Pexelizumab for Reduction in Myocardial Infarction and Mortality in Coronary Artery Bypass Graft surgery trial, a phase III prospective, randomized, double-blind, placebo-controlled study, enrolled 3099 patients at 205 centers. The primary end point was the composite of death, myocardial infarction, or both at postoperative day 30 in patients undergoing coronary artery bypass grafting without valve surgery. Postoperative myocardial infarction was defined as a creatine kinase MB fraction value of 100 ng/mL or greater, Q-wave myocardial infarction with a creatine kinase MB fraction value of 70 ng/mL or greater, or new Q-wave evidence of myocardial infarction by postoperative day 30. Because patients undergoing coronary artery bypass grafting with a valve procedure were not included in the primary population, separate analysis of death and myocardial infarction was conducted in 218 patients undergoing combined aortic valve replacement and coronary artery bypass grafting surgery. RESULTS: Of the 353 patients randomized to any valve procedure, 106 (61%) underwent combined aortic valve replacement and coronary artery bypass grafting in the pexelizumab treatment group compared with 112 (63%) patients in the placebo group. Coronary artery bypass grafting was performed with 1 or more internal thoracic artery grafts in 139 (64%) patients and with 1 or more saphenous vein grafts in 179 (82%) patients. There were 4 (3.8%) deaths in the pexelizumab group versus 11 (9.9%) in the placebo group by postoperative day 30 and 6 (5.7%) deaths in the active group versus 16 (14.4%) in the placebo group by postoperative day 180 (P =.107 and P =.043, respectively, Fisher exact test). The incidence of myocardial infarction 30 days after surgical intervention was identical in the 2 groups, but the study was not designed to detect differences in this cohort of patients. CONCLUSIONS: Inhibition of complement activation by pexelizumab resulted in a decreased mortality at 180 days among 218 patients who underwent combined aortic valve replacement and coronary artery bypass grafting surgery. Additional studies are warranted to confirm this decrease in mortality with pexelizumab in combined aortic valve replacement and coronary artery bypass grafting procedures.

Aged↗
PubMed2006

Aprotinin and the protease-activated receptor 1 thrombin receptor: antithrombosis, inflammation, and stroke reduction.

Cardiopulmonary bypass, although remaining an indispensable asset in cardiac surgery, especially in more complex and repeat operations, is associated with significant thrombin generation in the bypass circuit, leading to the activation of platelets, the coagulation system, an inflammatory response, and perioperative stroke. Recent clinical studies and meta-analyses of clinical trials in coronary artery bypass grafting surgery have confirmed that aprotinin not only reduces transfusion requirements in cardiac surgery but also confers significant protection against platelet dysfunction, activation of the systemic inflammatory response, and perioperative stroke when administered at the full (or "Hammersmith") dose. This article reviews research from several independent groups to propose a novel mechanism through which the antithrombotic, anti-inflammatory, and neuroprotective mechanism might be mediated, via protection of the high-affinity thrombin receptor protease-activated receptor 1 (PAR1).

Animals↗
PubMed2005

Structure-function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14.

Here, we report the first investigation of a novel member of the LZT (LIV-1 subfamily of ZIP zinc Transporters) subfamily of zinc influx transporters. LZT subfamily sequences all contain a unique and highly conserved metalloprotease motif (HEXPHEXGD) in transmembrane domain V with both histidine residues essential for zinc transport by ZIP (Zrt-, Irt-like Proteins) transporters. We investigate here whether ZIP14 (SLC39A14), lacking the initial histidine in this motif, is still able to transport zinc. We demonstrate that this plasma membrane located glycosylated protein functions as a zinc influx transporter in a temperature-dependant manner.

Amino Acid Sequence↗
PubMed2005

Development of strategies for the use of anti-growth factor treatments.

Aberrant signalling through the epidermal growth factor receptor (EGFR) is associated with increased cancer cell proliferation, reduced apoptosis, invasion and angiogenesis. Over-expression of the EGFR is seen in a variety of tumours and is a rational target for antitumour strategies. Among the classes of agent targeting the EGFR are small-molecule inhibitors, which include gefitinib (IRESSA), which acts by preventing EGFR phosphorylation and downstream signal transduction. De novo and acquired resistance, however, have been reported to gefitinib and here we describe evidence which indicates that the type II receptor tyrosine kinases (RTKs) insulin-like growth factor-I receptor (IGF-IR) and/or insulin receptor (InsR) play important roles in the mediation of responses to gefitinib in the de novo- and acquired-resistance phenotypes in several cancer types. Moreover, combination strategies that additionally target the IGF-IR/InsR can enhance the antitumour effects of gefitinib.

Antineoplastic Agents↗
PubMed2004

Clinical inhibition of the seven-transmembrane thrombin receptor (PAR1) by intravenous aprotinin during cardiothoracic surgery.

BACKGROUND: Protease-activated receptor-1 (PAR1) is the principal thrombin receptor in the vasculature, and antagonists against this receptor are in preclinical trials. Aprotinin, already approved for clinical use to reduce transfusion requirements in cardiopulmonary bypass (CPB) surgery, has been shown to inhibit PAR1 activation in vitro. Here, we exploit CPB as a model for thrombin generation in humans to examine whether aprotinin can inhibit platelet PAR1 activation clinically. METHODS AND RESULTS: PAR1 expression and function on platelets was examined in coronary artery bypass grafting (CABG) patients randomized into 2 groups: (1) those receiving saline infusion during CPB (n=17) and (2) those receiving aprotinin (2x10(6) kallikrein inhibitor units [KIU] in pump prime, 2x10(6) KIU loading dose, followed by 0.5x10(6) KIU/h [n=13]). Platelets in the saline group showed loss of PAR1-specific function at 2 hours after CPB, but this was preserved in the aprotinin group (P<0.001). These effects were most likely targeted at PAR1 receptor cleavage, because (1) the level of thrombin generated during CPB did not vary significantly between groups, (2) expression of SPAN12, which detects only uncleaved PAR1 receptors, was preserved in the aprotinin but not the placebo group (P<0.05), and (3) supporting evidence in vitro showed reduced thrombin-induced PAR1 cleavage (P<0.001) and platelet aggregation (P<0.001) in the presence of aprotinin. CONCLUSIONS: This study demonstrates that platelet PAR1 activation by thrombin can be inhibited by aprotinin. Our results extend the clinical mechanism of action of aprotinin and provide the first proof of principle that PAR1 can be inhibited clinically. This has implications beyond cardiac surgery for the development of therapeutic PAR1 blockade.

Aprotinin↗
PubMed2004

Phenotypic and functional differences between human saphenous vein (HSVEC) and umbilical vein (HUVEC) endothelial cells.

The vascular endothelial cell (EC) plays an essential role in the pathogenesis of inflammation, transplant rejection and tumour metastasis. Most research on vascular ECs uses human umbilical vein endothelial cells (HUVECs). However, HUVECs are derived from immune-naive foetal tissue, and show significant functional differences from adult vascular endothelium. In this paper, we characterise an alternative model based on human saphenous vein ECs (HSVECs), describe their culture conditions and provide a detailed functional comparison with HUVECs. Compared with HUVECs, HSVECs show an increased sensitivity to ox-LDL and a reduced response to cytokines, as indicated by adhesion molecule expression as well as leukocyte adhesion and transmigration. With respect to their ability to present antigen, HSVECs have a higher level of HLA-DR, CD40 and ICOS-L following cytokine stimulation. In addition, HSVECs upregulate the costimulatory ligand CD80 (B7.1) following CD40 ligation, and support allogeneic T cell proliferation, while HUVECs fail to express CD80. Due to differential expression of adhesion molecules, poorly differentiated tumour cell lines also showed more adhesion to HSVECs than to HUVECs. These results indicate that HSVECs have advantages over HUVECs for studying adult vascular endothelial pathology in vitro.

Base Sequence↗
PubMed2004

Interferon-alpha-2b and oral cytarabine ocfosfate for newly diagnosed chronic myeloid leukaemia.

BACKGROUND: Treatment with interferon and subcutaneous cytarabine produces superior cytogenetic responses in chronic myeloid leukaemia (CML) than treatment with interferon alone, but at the expense of greater toxicity. Cytarabine ocfosfate (YNK01) is an oral precursor of cytarabine that may overcome some of the inconvenience and toxicities associated with subcutaneous cytarabine administration. PATIENTS AND METHODS: We studied the efficacy and tolerability of combination therapy with interferon-alpha-2b and YNK01 in patients with newly diagnosed, untreated CML. Forty patients were treated with interferon-alpha-2b (5 MU/m2/day) plus monthly courses of YNK01 (600 mg/day for 10 days) for 1 year. RESULTS: The 6-month complete haematological response rate was 63% and the 1-year major cytogenetic response rate was 30%, with 10% of cytogenetic responses being complete. With a median follow-up of 57 months, the estimated 5-year overall survival was 86% (95% confidence interval 70% to 94%). Treatment tolerability was poor, with toxicity leading to discontinuation of one or both drugs in 60% of cases. The median daily dose of interferon alpha-2b was 7.75 MU and the median dose of YNK01 was 600 mg/day for each 10-day treatment cycle. CONCLUSIONS: Interferon-alpha-2b and YNK01 produce cytogenetic responses comparable to those achieved with interferon-alpha-2b and parenteral cytarabine, although toxicity was excessive. Alternate dosing strategies may enhance the tolerability of YNK01.

Administration, Oral↗
PubMed2004

Comparison of outcomes after aortic valve replacement with a mechanical valve or a bioprosthesis using microsimulation.

BACKGROUND: Mechanical valves and bioprostheses are widely used for aortic valve replacement. Though previous randomised studies indicate that there is no important difference in outcome after implantation with either type of valve, knowledge of outcomes after aortic valve replacement is incomplete. OBJECTIVE: To predict age and sex specific outcomes of patients after aortic valve replacement with bileaflet mechanical valves and stented porcine bioprostheses, and to provide evidence based support for the choice of prosthesis. METHODS: Meta-analysis of published results of primary aortic valve replacement with bileaflet mechanical prostheses (nine reports, 4274 patients, and 25,726 patient-years) and stented porcine bioprostheses (13 reports, 9007 patients, and 54,151 patient-years) was used to estimate the annual risks of postoperative valve related events and their outcomes. These estimates were entered into a microsimulation model, which was employed to calculate age and sex specific outcomes after aortic valve replacement. RESULTS: Life expectancy (LE) and event-free life expectancy (EFLE) for a 65 year old man after implantation with a mechanical valve or a bioprosthesis were 10.4 and 10.7 years and 7.7 and 8.4 years, respectively. The lifetime risk of at least one valve related event for a mechanical valve was 48%, and for a bioprosthesis, 44%. For LE and EFLE, the age crossover point between the two valve types was 59 and 60 years, respectively. CONCLUSIONS: Meta-analysis based microsimulation provides insight into the long term outcome after aortic valve replacement and suggests that the currently recommended age threshold for implanting a bioprosthesis could be lowered further.

Aged↗
PubMed2004

Distinct yet complementary mechanisms of heparin and glycoprotein IIb/IIIa inhibitors on platelet activation and aggregation: implications for restenosis during percutaneous coronary intervention.

OBJECTIVE: To study the effect of unfractionated heparin (UFH) versus low molecular weight heparin (LMWH) in combination with glycoprotein (Gp) IIb/IIIa blockers on platelet activation and aggregation. METHODS: Washed platelets were stimulated with thrombin in the presence or absence of UFH (monoparin), LMWH (enoxaparin), and a Gp IIb/IIIa blocker (abciximab, eptifibatide, or tirofiban). RESULTS: Although Gp IIb/IIIa antagonists blocked the final common pathway of thrombin induced platelet aggregation, UFH and LMWH were better at blocking upstream platelet activation. UFH was significantly more effective than LMWH at inhibiting P selectin expression (p = 0.001) and platelet derived growth factor release from thrombin activated platelets (p = 0.012). CONCLUSIONS: UFH and LMWH exert complementary effects to Gp IIb/IIIa blockers by inhibiting afferent pathways of platelet activation. Coadministration of heparin with Gp IIb/IIIa blockers provides improved protection against persistent platelet activation, thereby improving outcome after percutaneous coronary intervention. Judging from these data, UFH may be more effective in this regard than LMWH, at least in vitro. The use of LMWH in preference to UFH during percutaneous coronary intervention, although initially attractive, may inadequately protect against platelet activation despite the presence of Gp IIb/IIIa blockers.

Abciximab↗
PubMed2003

Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery.

The recently described hemoglobin scavenger receptor CD163 mediates the endocytosis of hemoglobin:haptoglobin (Hb:Hp) complexes and thereby counters Hb-induced oxidative tissue damage after hemolysis. Although CD163 has been indirectly associated with antiinflammatory and atheroprotective activity, no ligand-receptor-effector pathway has yet been described for this receptor. To understand the significance of CD163 and more clearly define downstream pathways linked to inflammatory resolution, we studied the expression and function of CD163 in human monocytes/macrophages using both in vitro and in vivo models. Differentiation of human blood monocytes into macrophages either by in vitro culture or in resolving cantharidin-induced skin blisters led to an equivalent increase (>15x) in CD163 expression. Elevated CD163 levels were also noted on circulating monocytes in cardiac surgical patients during the resolution phase of the systemic inflammatory response to cardiopulmonary bypass surgery. In each case, binding of Hb:Hp to CD163-bearing cells elicited potent interleukin-10 secretion, and this was inhibited by the anti-CD163 antibody RM3/1. Release of interleukin-10, in turn, induced heme oxygenase-1 stress protein synthesis via an autocrine mechanism. Such induction of heme oxygenase-1 was observed in vivo 24 to 48 hours after the onset of cardiopulmonary bypass surgery. These results identify novel antiinflammatory and cytoprotective effector pathways in human monocytes/macrophages related to Hb scavenging and metabolism, which may have relevance in atheroprotection, wound healing, and patient recovery postoperatively.

Aged↗
PubMed2003

Antibody targeted gene transfer to endothelium.

BACKGROUND: One of the drawbacks of the currently available vectors for gene therapy is the lack of selectivity in gene delivery. We have therefore investigated a strategy to generate immunoliposomes to target non-viral vectors to cell surface receptors on endothelium. MATERIALS AND METHODS: We have developed a novel method of coupling antibodies (Abs) to liposomes complexed to DNA, using mild heat treatment to aggregate the immunoglobulin G (IgG). The interaction of plasmid DNA, liposomes and Abs was measured using a gel retardation assay and a resonant mirror biosensor. The size of the transfection complex was determined by light scattering, and the binding and internalization of the complex to cells was followed using flow cytometry. The transfection ability was tested on cell lines and primary cells in vitro and human corneal or vascular tissues ex vivo. RESULTS: The interaction of antibodies with liposomes is relatively stable (t(1/2) congruent with 45 min). The size of the liposome, Ab and DNA complex was found to be around 500 nm in 4% BSA. The addition of anti-transferrin receptor Abs increased the internalization of the liposome-DNA complex into cells. Abs against both transferrin receptor and E-selectin were shown to augment transfection efficiency of liposomes to cell expressing the appropriate antigens. They are also shown to be efficient in mediating gene delivery to corneal and vascular tissues ex vivo. CONCLUSIONS: We have shown that our novel vector is capable of in vitro and ex vivo gene delivery to cells and human tissues including cornea, artery and vein. In particular, an Ab against E-selectin was effective at selectively delivering genes to activated endothelial cells expressing the adhesion molecule. Such a strategy will have applications for targeting these tissues prior to transplantation or autologous grafting, and, in the longer term, may allow in vivo targeting of gene therapy to inflammatory sites.

Animals↗
PubMed2003

An evaluation of existing risk stratification models as a tool for comparison of surgical performances for coronary artery bypass grafting between institutions.

OBJECTIVE: Risk stratification systems are used in cardiac surgery to estimate mortality risk for individual patients and to compare surgical performance between institutions or surgeons. This study investigates the suitability of six existing risk stratification systems for these purposes. METHODS: Data on 5471 patients who underwent isolated coronary artery bypass grafting at two UK cardiac centres between 1993 and 1999 were extracted from a prospective computerised clinical data base. Of these patients, 184 (3.3%) died in hospital. In-hospital mortality risk scores were calculated for each patient using the Parsonnet score, the EuroSCORE, the ACC/AHA score and three UK Bayes models (old, new complex and new simple). The accuracy for predicting mortality at an institutional level was assessed by comparing total observed and predicted mortality. The accuracy of the risk scores for predicting mortality for a patient was assessed by the Hosmer-Lemeshow test. The receiver operating characteristic (ROC) curve was used to evaluate how well a system ranks the patient with respect to their risk of mortality and can be useful for patient management. RESULTS: Both EuroSCORE and the simple Bayes model were reasonably accurate at predicting overall mortality. However predictive accuracy at the patient level was poor for all systems, although EuroSCORE was accurate for low to medium risk patients. Discrimination was fair with the following ROC areas: Parsonnet 0.73, EuroSCORE 0.76, ACC/AHA system 0.76, old Bayes 0.77, complex Bayes 0.76, simple Bayes 0.76. CONCLUSIONS: This study suggests that two of the scores may be useful in comparing institutions. None of the risk scores provide accurate risk estimates for individual patients in the two hospitals studied although EuroSCORE may have some utility for certain patients. All six systems perform moderately at ranking the patients and so may be useful for patient management. More results are needed from other institutions to confirm that the EuroSCORE and the simple Bayes model are suitable for institutional risk-adjusted comparisons.

Bayes Theorem↗
PubMed2002

Differential expression of ribosomal L31, Zis, gas-5 and mitochondrial mRNAs following oxidant induction of proliferative vascular smooth muscle cell phenotypes.

Treatment of cultured vascular smooth muscle cells (vSMCs) with benzo(a)pyrene (BaP), a prooxidant present in the particulate phase of tobacco smoke, induces highly proliferative (i.e. atherogenic) phenotypes. Critical early target genes in vSMCs have been identified, but patterns of gene expression following repeated cycles of carcinogen treatment in vivo have yet to be evaluated. In the present study, male Sprague-Dawley rats (175-200 g) were given weekly injections of BaP (10 mg/kg) for 8 weeks to induce atherogenic phenotypes. At the end of this atherogenic regimen, vSMCs were established in serial culture and monitored for patterns of proliferative activity and gene expression. vSMCs isolated from BaP-treated animals (hence forth referred to as BaP cells) exhibited constitutively increased growth rates, and marked enhancement of proliferation in response to serum mitogens. Differential display polymerase chain reaction (DD-PCR) and Northern blot analyses revealed that mRNAs for ribosomal protein L31 and Zis genes were suppressed, while gas-5 and mitochondrial mRNAs were overexpressed in BaP cells relative to control mRNA populations. In situ hybridization experiments in vascular tissue confirmed these alterations in vivo. This is the first report linking expression of these genes to proliferative dysregulation during the course of experimentally-induced atherogenesis.

Animals↗
PubMed2001

TENB2, a proteoglycan identified in prostate cancer that is associated with disease progression and androgen independence.

TENB2 encodes a putative transmembrane proteoglycan, related to the EGF/heregulin family of growth factors and follistatin, which has been identified through the application of a differential display technique to a xenograft model of prostate cancer. Northern analysis and competitive PCR were used to demonstrate significantly increased TENB2 expression (p = 0.0003) on the acquisition of androgen independence in the model system. TENB2 is also overexpressed in clinical prostate carcinoma vs. its benign counterpart (p < 0.0001), with particular prominence in high-grade tumours, and shows a high degree of tissue specificity, being detected on a multitissue Northern array exclusively in brain and prostate material. Studies of recombinant protein expression demonstrate that TENB2 is a chondroitin sulphate proteoglycan. The presence of an EGF and 2 follistatin domains suggests a role in the regulation of growth factor signalling either as a ligand precursor, a membrane-bound receptor or as a binding protein for growth factors. These data are indicative of a significant role for TENB2 in the progression of poorly differentiated tumour types, with implications for prostate cancer detection, prognosis and therapy.

Amino Acid Sequence↗
PubMed2001

An assessment of jet and ultrasonic nebulisers for the delivery of lactate dehydrogenase solutions.

The aim of this study was to investigate the suitability of commercial jet and ultrasonic nebulisers for effective delivery of the model hydrophilic protein lactate dehydrogenase (LDH). Two jet nebulisers (Pari LC Plus and Pari LC Star) and two ultrasonic nebulisers (Sonix 2000 and Omron U1) were used to nebulise LDH solutions and the effects on protein activity and protein concentration determined. The size distribution of the aerosols produced, measured by laser diffraction analysis, temperature changes during nebulisation, the time to atomise a 5 ml dose volume and the mass output of the four nebulisers were compared. A twin impinger (TI) was used to collect the nebulised protein, which was assayed for total and active protein content. There was a large variation in the median size and size distribution of the aerosols produced by each of the nebulisers from LDH and Sørensen's modified phosphate buffer, and in the time taken to reach the sputtering phase of aerosolisation. During use, the concentration of LDH increased in the Omron U1 nebuliser, but did not change significantly in the others. The temperature of the protein solution decreased by approximately 8 degrees C during jet nebulisation but increased by 3 and 10 degrees C in the Omron U1 and Sonix 2000 nebulisers, respectively. Denaturation of LDH within the nebuliser reservoir, occurred in the order Sonix>Pari LC Plus>Pari LC Star>Omron U1, whilst the deposition of active and total protein within the stages and throat of the TI was a function of the particle size of the aerosols generated and the specific device used.

Aerosols↗