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Biomedical subjects

E Gray

Publications and source records attributed to E Gray.

At least 19 recordsLinked to original sources
PubMed2026

Longitudinal ctDNA tracking in early and recurrent breast cancer using an ultrasensitive structural variant-based assay: an extended analysis from the TRACER study.

BACKGROUND: Detection of circulating tumor DNA (ctDNA) following curative-intent therapy is prognostic of disease recurrence in early-stage breast cancer (EBC). An ultrasensitive structural variant (SV)-based ctDNA assay was evaluated previously in a 100-patient EBC cohort treated with neoadjuvant therapy, demonstrating high sensitivity, specificity, and a long lead-time to relapse. The stability of primary tumor-specific SVs at and after metastatic recurrence and their utility for longer-term ctDNA monitoring had not been established. PATIENTS AND METHODS: An updated retrospective analysis of ctDNA dynamics was conducted in an expanded cohort of 121 patients with EBC treated with neoadjuvant therapy. Plasma samples were collected at key clinical timepoints and serially in several patients who experienced metastatic recurrence. Clinical variables were abstracted from medical records. Associations between ctDNA detection, dynamics, and clinical outcomes were evaluated in the early-stage and metastatic settings. RESULTS: Thirty of 121 patients experienced clinical recurrence (28 distant, 2 local) over a median follow-up of 4.2 years (range 0.5-8.8; 25 ctDNA evaluable with adjuvant timepoints). All patients with detectable ctDNA in the adjuvant setting developed metastatic recurrence (22/22). Median lead time from ctDNA detection to metastatic recurrence was 346 days (range 0-1937). Among recurrent cases, 79% of primary tumor-specific SVs (n = 17 patients, tumor fraction ≥0.1%) remained detectable in plasma [range 7% (1/14 SV)-100% (15/15); median: 92%]. ctDNA dynamics in the recurrent metastatic setting demonstrated a strong relationship with radiographic outcomes in evaluable patients (n = 9). CONCLUSION: This SV-based digital PCR assay provided ultrasensitive ctDNA detection in an expanded EBC cohort, maintaining 100% positive predictive value for metastatic recurrence. In patients with recurrence, ctDNA dynamics were concordant with radiographic outcomes. Prospective studies evaluating the clinical utility of longitudinal ctDNA monitoring are warranted.

MRD↗
PubMed1999

Screening methods for thyroid hormone disruptors.

The U.S. Congress has passed legislation requiring the EPA to implement screening tests for identifying endocrine-disrupting chemicals. A series of workshops was sponsored by the EPA, the Chemical Manufacturers Association, and the World Wildlife Fund; one workshop focused on screens for chemicals that alter thyroid hormone function and homeostasis. Participants at this meeting identified and examined methods to detect alterations in thyroid hormone synthesis, transport, and catabolism. In addition, some methods to detect chemicals that bind to the thyroid hormone receptors acting as either agonists or antagonists were also identified. Screening methods used in mammals as well as other vertebrate classes were examined. There was a general consensus that all known chemicals which interfere with thyroid hormone function and homeostasis act by either inhibiting synthesis, altering serum transport proteins, or by increasing catabolism of thyroid hormones. There are no direct data to support the assertion that certain environmental chemicals bind and activate the thyroid hormone receptors; further research is indicated. In light of this, screening methods should reflect known mechanisms of action. Most methods examined, albeit useful for mechanistic studies, were thought to be too specific and therefore would not be applicable for broad-based screening. Determination of serum thyroid hormone concentrations following chemical exposure in rodents was thought to be a reasonable initial screen. Concurrent histologic evaluation of the thyroid would strengthen this screen. Similar methods in teleosts may be useful as screens, but would require indicators of tissue production of thyroid hormones. The use of tadpole metamorphosis as a screen may also be useful; however, this method requires validation and standardization prior to use as a broad-based screen.

Animals↗
PubMed1999

A collaborative study to establish the 2nd International Standard for Antithrombin Concentrate.

Eighteen laboratories participated in a collaborative study to calibrate a replacement for the 1st International Standard for Antithrombin. Concentrate (88/548). Excellent agreement between laboratories, as indicated by mean % gcv of 3.3 and 5.9 for functional and antigenic assays, was observed when the candidate concentrate (96/520) was assayed against the 1st International Standard for Antithrombin, Concentrate (88/548). The functional potency was found to be 7.9% (p<0.05) lower than the antigenic potency. Based on the results and with the agreement of the participants of this study and the authorisation of the Expert Committee on Biological Standardisation of the World Health Organisation, the antithrombin concentrate, coded 96/520, has been established as the 2nd International Standard for Antithrombin, Concentrate, with labelled potencies for both functional (4.7 IU/ampoule) and antigenic (5.1 IU/ampoule) activities.

Antithrombins↗
PubMed1998

Structural determination of lipid-bound human blood coagulation factor IX.

Human coagulation factor IX (FIX) is a serine protease which binds to a negatively charged phospholipid surface in the presence of Ca ions (Ca2+). FIX two-dimensional (2-D) crystals were obtained by the lipid layer crystallisation technique under near physiological conditions. The 2-D projection map of the protein was calculated to a resolution of 3 nm using electron crystallographic analysis. The structural organisation of membrane-bound FIX is discussed and compared with the known X-ray crystallographic data.

Binding Sites↗
PubMed1998

UKCCSG's germ cell tumour (GCT) studies: improving outcome for children with malignant extracranial non-gonadal tumours--carboplatin, etoposide, and bleomycin are effective and less toxic than previous regimens. United Kingdom Children's Cancer Study Group.

BACKGROUND: We report the efficacy and late effects of carboplatin, etoposide, and bleomycin (JEB) for extracranial non-gonadal tumours (GCII, 1989-95) compared with the 5 previous regimens (GCI, 1979-1988) consisting of 3 vincristine, actinomycin, and cyclophosphamide (VAC) and 2 platinum-based protocols. METHODS AND RESULTS: Median follow-up for 52 patients in the GCI study and 46 in GCII was 105 and 48 months, respectively. For GCI, 5- and 10-year actuarial survival was 63% (95% Confidence interval 50 to 75%) or 72% (57 to 83%) if 6 cases given low-dose VAC were excluded. For GCII, 5-year survival was significantly greater at 95% (83 to 99%), p = 0.01. Event-free survival was 46% at 5 years for GCI (33 to 59%) or 52% excluding the low-dose VAC cases (38 to 66%), while for GCII it was 87% (74 to 94%), p = 0.002. Five-year event-free survival of 21 children given cisplatin, etoposide, and bleomycin (BEP) in GCI was 57% (37 to 76%) compared with 87% (74 to 94%) for 46 given JEB in GCII, P = 0.02. Late effects in 30 evaluable survivors of GCI and 43 GCII included renal impairment in 6 in GCI and 0 in GCII and deafness in 11 and 4, respectively. Among 17 survivors of sacrococcygeal tumours treated in GCI, 4 have neuropathic bladder/bowel and another shortening of a leg. In GCII, 4 of 26 have neuropathic bladder/bowel with lower limb weakness in one. CONCLUSIONS: We found JEB to be more effective and less toxic than our previous regimens. Some survivors of sacrococcygeal tumours have neurological late effects.

Adolescent↗
PubMed1998

Confirmation of FWT1 as a Wilms' tumour susceptibility gene and phenotypic characteristics of Wilms' tumour attributable to FWT1.

A susceptibility gene for Wilms' tumour (WT), designated FWT1, was previously mapped to chromosome 17q12-q21 by linkage analysis of a single family. We now confirm the existence of this gene by analysis of additional cases in the original family (3-point LOD score=5.69), and by detecting strong evidence of linkage to this region in an unrelated pedigree with seven cases of WT (3-point LOD score=2.56). Analysis of 11 smaller WT families confirms that there is genetic heterogeneity in familial WT, as three families exhibit strong evidence against linkage to FWT1. One of these was subsequently found to have a predisposing WT1 mutation. However, the other two families show evidence against both FWT1 and WT1, suggesting that at least one further familial WT gene exists. Analysis of the phenotype of 16 WT cases from the families linked to FWT1 demonstrates that they present at a significantly older age and a significantly later stage than both sporadic WT and the six cases from two families unlinked to either FWT1 or WT1. The results confirm the role of FWT1 in susceptibility to WT, provide strong evidence for genetic heterogeneity in familial WT and suggest there are phenotypic differences between familial WT due to FWT1, familial WT due to other genes and non-familial WT.

Chromosomes, Human, Pair 17↗
PubMed1998

Tachycardia alone fails to change the myocardial pharmacokinetics and dynamics of lidocaine, thiopental, and verapamil after intravenous bolus administration in sheep.

Previous reports have suggested that tachycardia alone can increase the rate of myocardial uptake of some drugs. As part of a systematic study of the determinants of the myocardial uptake and effects of drugs in critical illness, the effect of tachycardia induced by intracardiac pacing on the myocardial disposition and effects of lidocaine, verapamil, and thiopental were studied in chronically instrumented sheep. For each drug, seven sheep received either 100 mg of lidocaine, 10 mg of verapamil, or 750 mg of thiopental over 2 min in unpaced and paced (140 beats/min) states on separate occasions and in random order. Arterial and coronary sinus (effluent from the heart) blood samples were taken at regular intervals for 30 min, and the maximum rate of change of left ventricular pressure (LV dP/dtmax) was measured as an index of myocardial contractility. There were no differences between unpaced and paced studies in the time courses of arterial and coronary sinus concentrations, or the time-courses of myocardial contractility and blood flow, after bolus iv injections of these drugs. Tachycardia alone does not appear to influence the myocardial kinetics or dynamics of lipophilic drugs that can rapidly diffuse into the heart.

Animals↗
PubMed1998

Antithrombotic activity of a fucosylated chondroitin sulphate from echinoderm: sulphated fucose branches on the polysaccharide account for its antithrombotic action.

The antithrombotic activity of a fucosylated, chondroitin-sulphate-like polysaccharide extracted from the body wall of sea cucumber, and of chemically modified derivatives of the same polysaccharide, have been assessed using a stasis thrombosis model in rabbits. Intravenous administration of the native polysaccharide reduced thrombosis in a dose-dependent manner and, at a dose of 1.5 mg/kg (60 IU/kg) body weight, completely prevented thrombosis after 10 min stasis. Removal of the sulphated fucose branches of the polysaccharide abolished antithrombotic effectiveness. After intravenous injection of an antithrombotic dose of radioactively labelled polysaccharide, a correlation was observed between removal of radioactivity from the plasma and decrease in ex vivo APTT values, demonstrating that antithrombotic effectiveness depends on the level of circulating polysaccharide rather than on an indirect effect of the polysaccharide on the vascular endothelium. Reduction of the glucuronic acid carboxyl groups in the polysaccharide did not affect its in vitro and in vivo activities. Both partial defucosylation and desulphation of the polysaccharide abolished all its anticoagulant or antithrombotic action.

Animals↗
PubMed1998

Pathologists dislike sound? Evaluation of a computerised training microscope.

AIM: To evaluate the use of multimedia enhancements, using a computerised microscope, in the training of microscope skills. METHODS: The HOME microscope provides facilities to highlight features of interest in conjunction with either text display or aural presentation. A pilot study was carried out with 10 individuals, eight of whom were at different stages of pathology training. A tutorial was implemented employing sound or text, and each individual tested each version. Both the subjective impressions of users and objective measurement of their patterns of use were recorded. RESULTS: Although both versions improved learning, users took longer to work through the aural than the text version; 90% of users preferred the text only version, including all eight individuals involved in pathology training. CONCLUSIONS: Pathologists appear to prefer visual rather than aural input when using teaching systems such as the HOME microscope and sound does not give added value to the training experience.

Attitude of Health Personnel↗
PubMed1997

Does expert psychological testimony inform or influence juror decision making? A social cognitive analysis.

The authors examined whether expert testimony serves an educational or a persuasive function. Participants watched a simulated sexual abuse trial in which the child witness had been prepared for her testimony (i.e., she was calm, composed, and confident) or unprepared (i.e., emotional, confused, and uncertain). The trial contained different levels of expert testimony: none, standard (i.e., a summary of the research), repetitive (i.e., standard testimony plus a 2nd summary of the research), or concrete (i.e., standard testimony plus a hypothetical scenario linking the research to the case facts) testimony. Repetitive testimony bolstered the child's testimony, whereas concrete and standard testimony did not. Concrete testimony sensitized jurors to behavioral correlates of sexual victimization; standard and repetitive testimony desensitized jurors to these correlates. Implications for the use of procedural innovations in sexual abuse trials are discussed.

Adolescent↗
PubMed1997

Molecular characterization of hpuAB, the haemoglobin-haptoglobin-utilization operon of Neisseria meningitidis.

We previously identified HpuB, an 85 kDa Fe-repressible protein required for utilization of Fe from, and binding to, haemoglobin and the haemoglobin-haptoglobin complex. The gene for hpuB was cloned from Neisseria meningitidis strain DNM2 and the predicted amino acid sequence indicates that HpuB is an outer membrane receptor belonging to the TonB family of high-affinity transport proteins. A second open reading frame, predicted to encode a 34.8 kDa lipoprotein, was discovered 5' to hpuB, and was designated hpuA. HpuA was identified in a total-membrane-protein preparation by construction of a mutant lacking HpuA. Acylation of HpuA was confirmed by [3H]-palmitic acid labelling of meningococci. Consensus promoter sequences were not apparent 5' to hpuB. The hpuA insertion mutation exerted a polar effect, abolishing expression of hpuB, suggesting that hpuA and hpuB are co-transcribed. The 3.5 kb polycistronic hpuAB mRNA was identified and shown to be transcriptionally repressed by iron. The transcriptional start site was identified 33 nucleotides 5' to the hpuA translational start site, appropriately positioned around consensus promoter and ferric uptake regulator (Fur)-box sequences. The structure of this operon suggests that HpuA-HpuB is a two-component receptor analogous to the bipartite transferrin receptor TbpB-TbpA.

Amino Acid Sequence↗
PubMed1997

Molecular weight measurements of low molecular weight heparins by gel permeation chromatography.

The molecular weight profiles of low molecular weight heparin samples have been measured by high-performance gel permeation chromatography using as calibrant the heparinase-degraded material (90/686) now established as the 1st International Reference Preparation (IRP) Low Molecular Weight Heparin for Molecular Weight Calibration Use of the calibrant as a broad molecular weight standard is described and a calibration table provided based on data collected over several years in one laboratory. In order to confirm the assignment of degree of polymerisation to resolved oligosaccharide peaks in the calibrant, molecular weights of oligosaccharides fractionated from the 1st IRP were independently determined by fast atom bombardment mass spectrometry (FAB MS). The molecular weight distributions of commercial low molecular weight heparins have been characterized. Measurements of molecular weight parameters of heparin molecular weight standards from several sources provide comparisons between the molecular weight scales of this and other studies.

Calibration↗
PubMed1996

Prostatic adenocarcinoma labelled with a monoclonal antibody and polyclonal serum: a quantitative assessment.

OBJECTIVE: To investigate the detection of tissue prostate-specific antigen (PSA) using a monoclonal antibody or polyclonal serum in patients with localized prostate cancer. PATIENTS AND METHODS: Fifteen samples of prostatic tissue from patients with localized prostate cancer were assessed for PSA using monoclonal antibodies and polyclonal serum. The intensity and area of chromogen precipitation in several microscopic fields was determined using image analysis. RESULTS: There were significant differences in the intensity and distribution of PSA labelling in the tumour between the methods; polyclonal serum was more sensitive in detecting PSA in tissue sections. Notably, there was a focal "possible clonal' pattern of negative labelling with the monoclonal antibody, which contrasted with the positivity of the polyclonal marker. CONCLUSIONS: The loss of PSA expression in some poorly differentiated cancers may represent the loss of specific epitopes rather than loss of the entire protein.

Adenocarcinoma↗
PubMed1996

Inhibition of thrombin generation by heparin and LMW heparins: a comparison of chromogenic and clotting methods.

Inhibition of thrombin generation by heparin and low-molecular-weight (LMW) heparins is an important parameter which relates to their anticoagulant actions in vivo. Previous studies in our laboratory used a clotting assay for assessment of thrombin generation but other published studies have used a chromogenic method. We have therefore measured the inhibition of thrombin generation by unfractionated heparin (UFH) and LMW heparins by a modified chromogenic method using microtitre plates and compared the results with the clotting method. The degree of inhibition of thrombin generation when calculated from both peak thrombin concentrations and areas under the curve in the chromogenic assay was the same. When the activities of each heparin were expressed as EC80, i.e. concentrations required for 80% inhibition of thrombin generation, the EC80 were higher in the chromogenic assay than in the clotting system. However when the potencies of the LMW heparins were expressed as percentages of that of the UFH standard by parallel line analysis, the differences between clotting and chromogenic assay results were small and not statistically significant (P > 0.05). This study demonstrates the feasibility of measuring inhibition of thrombin generation by a modified chromogenic method using microtitre plates, and shows that the results with this method are similar to those obtained with the clotting method.

Anticoagulants↗
PubMed1996

Inhibition of tissue factor and cytokine release.

The effect of inhibitors of cytokine release and plasma coagulation on lipopolysaccharide (LPS)-induced tissue factor and interleukin-6 (IL-6) was investigated. Dexamethasone, an inhibitor of cytokine production, inhibited LPS-induced tissue factor and IL-6 release by mononuclear cells (MNC), but enhanced IL-1beta-evoked tissue factor activity. Clinical antithrombin (AT) concentrates inhibited, in a dose-dependent manner, tissue factor and IL-6 production by MNC and human umbilical vein endothelial cells (HUVEC). The three AT preparations tested, when compared using the same antithrombin unit, had different potencies. Activated protein C (APC) augmented LPS stimulation of HUVEC and further increased the production of tissue factor and IL-6. The same effect was not observed with MNC; LPS-induced tissue factor and IL-6 release were unaffected by APC. Truncated tissue factor pathway inhibitor (TFPI1-161) inhibited LPS-induced MNC tissue factor and IL-6 production, but was unable to prevent LPS stimulatory activity on HUVEC. These data suggest a complex interaction between the coagulation pathway and the cytokine network.

Blood Coagulation↗
PubMed1996

The systemic and cerebral kinetics of thiopental in sheep: enantiomeric analysis.

Thiopental is used as a racemate (rac-thiopental). Enantiomeric pharmacokinetic differences could therefore influence the onset and duration of anesthesia of rac-thiopental. We studied the systemic and cerebral kinetics of R(+)- and S(-)-thiopental in five adult ewes after a 2-min intravenous infusion of 500 mg rac-thiopental sodium. Systemic kinetic values were determined from the time course of concentrations in arterial plasma; cerebral kinetic values were deduced from the time course of the concentration differences between arterial and superior sagittal sinus blood plasma. Enantiomeric differences were found in both sites, with the (R:S) ratio of thiopental enantiomer blood concentrations initially being > or = 1 then decreasing to < 1 after approximately 60 min. This is consistent with the finding of the mean total body clearance of R(+)-thiopental being 17% (SD 12%) greater than that of S(-)-thiopental (P = .04). Sagittal sinus plasma concentrations of both enantiomers followed closely behind those in arterial plasma and this is consistent with facile bidirectional exchange of thiopental between plasma and brain. No significant differences were found between enantiomers in the rates of brain influx or efflux. Onset and regression of anesthesia occurred while the enantiomer blood concentrations were similar. Hence published pharmacokinetic-pharmacodynamic models of the onset of thiopental effects probably are not significantly compromised by neglecting the enantiomeric duality of thiopental, but models based on its elimination kinetics could be compromised if enantiomeric differences are neglected.

Anesthetics, Intravenous↗
PubMed1996

Collaborative study on assays of activated FIX (FIXa). On behalf of the factor VIII and factor IX subcommittee of the ISTH. International Society on Thrombosis and Haemostasis.

A collaborative study has been organised by NIBSC to examine the performance of FIXa assays between laboratories, and to investigate the need for a standard. Ampoules of 3 materials, one monocomponent concentrate (coded C) and 2 different preparations of purified human FIXa (one proposed reference preparation, coded A and a test material coded B), have been assayed in 11 laboratories for FIXa using either the NIBSC method or a local method, with local standards (if available, coded D) to determine their potencies. The data showed high between assay variability; with the exception of one laboratory, most of the between assay variation expressed as %geometric coefficients of variation (gcv) were over 15%. The interlaboratory gcv when preparation B was assayed against the local standard was over 1700%, suggesting that most of the local standards are poorly calibrated. The %gcv was improved to 80% when reference A was used as the standard. These data clearly show that an international reference standard for FIXa would help to standardise FIXa preparations and would also improve in house assays for FIXa. However, an accelerated degradation study has shown that reference A is not suitable as a long term standard and another material with suitable stabilizers has to be established as an international standard for FIXa.

Factor IX↗